TW202448484A - Mapt-modulating compositions and methods of use thereof - Google Patents

Abstract

Aspects of the disclosure provide compounds, compositions, and methods for modulating the expression or activity of microtubule associated protein tau (MAPT). In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of MAPT mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of MAPT protein in a cell or animal.

Description

Translated fromChinese

MAPT調節組合物及其使用方法MAPT modulating compositions and methods of use thereof

本揭示案提供用於調節微管相關蛋白tau (MAPT)之表現或活性之化合物、組合物及方法。在某些實施例中，該等化合物、組合物及方法可用於降低細胞或動物中MAPT mRNA之表現。在某些實施例中，該等化合物、組合物及方法可用於減少細胞或動物中MAPT蛋白之量。The present disclosure provides compounds, compositions and methods for regulating the expression or activity of microtubule-associated protein tau (MAPT). In certain embodiments, the compounds, compositions and methods can be used to reduce the expression of MAPT mRNA in cells or animals. In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of MAPT protein in cells or animals.

在某些實施例中，動物患有CNS相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為神經退化性疾病，包括tau蛋白病變、阿茲海默氏病(Alzheimer’s disease)、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群(Dravet’s Syndrome)。本文所提供之某些化合物、組合物及方法係關於減少動物的CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，本文所提供之化合物及組合物係強效且可耐受的，且抑制MAPT表現，該等化合物及組合物可用於治療、預防、改善CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或減緩其進展。In some embodiments, the animal suffers from a CNS-related disease, disorder or condition. In some embodiments, the disease, disorder or condition is a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy or Dravet's Syndrome. Certain compounds, compositions and methods provided herein relate to reducing CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof in animals, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compounds and compositions provided herein are potent and tolerable, and inhibit MAPT expression, and can be used to treat, prevent, improve CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or slow down their progression.

在某些實施例中，該等化合物及組合物包含一或多種有效增加效能之特徵。在某些實施例中，該等化合物及組合物包含一或多種有效增加耐受性之特徵。在某些實施例中，化合物及組合物包含一或多種有效使化合物或組合物靶向細胞或組織之特徵。在某些實施例中，該等化合物及組合物相較於已公開揭示之化合物更強效、作用持續時間更長或治療價值更大。In some embodiments, the compounds and compositions comprise one or more features effective to increase potency. In some embodiments, the compounds and compositions comprise one or more features effective to increase tolerance. In some embodiments, the compounds and compositions comprise one or more features effective to target the compound or composition to cells or tissues. In some embodiments, the compounds and compositions are more potent, have a longer duration of action, or have greater therapeutic value than disclosed compounds.

相關申請案之交叉引用Cross-references to related applications

本申請案根據35 U.S.C. § 119(e)主張2023年4月20日提出申請之美國臨時申請案第63/460,874號；2023年8月16日提出申請之美國臨時申請案第63/520,070號；及2024年1月9日提出申請之美國臨時申請案第63/619,022號之優先權權益。每一先前申請案之揭示內容視為本申請案之揭示內容之一部分，且係以全文引用的方式併入本申請案之揭示內容中。This application claims the benefit of priority pursuant to 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/460,874, filed on April 20, 2023; U.S. Provisional Application No. 63/520,070, filed on August 16, 2023; and U.S. Provisional Application No. 63/619,022, filed on January 9, 2024. The disclosure of each prior application is deemed part of and incorporated by reference in its entirety into the disclosure of this application.

應理解，前述發明內容及以下實施方式均僅為例示性及解釋性的，而不限制所主張之實施例。本文所用之章節標題僅用於組織目的，而不應解釋為限制所描述之標的物。It should be understood that the foregoing invention content and the following embodiments are only exemplary and explanatory, and do not limit the claimed embodiments. The section headings used herein are only used for organizational purposes and should not be interpreted as limiting the subject matter described.

截至本申請案之申請日期，本申請案中引用之所有文件或文件部分，包括(但不限於)專利、專利申請案、文章、書籍、論文及GenBank、NCBI及其他序列參考記錄就本文所論述之文件部分以及全文在此係以引用方式明確地併入。As of the filing date of this application, all documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, theses, and GenBank, NCBI and other sequence reference records are expressly incorporated by reference for the part or portions of the documents discussed herein and in their entirety.

應理解，即使在上下文中與經修飾之化合物一起顯示，但本文所含之每一SEQ ID NO中所示之序列獨立於對糖部分、核苷間鍵聯或核鹼基之任何修飾。因此，由SEQ ID NO定義之化合物可獨立地包含對糖部分、核苷間鍵聯或核鹼基之一或多種修飾。由化合物編號或Ref ID NO提及之寡聚化合物指示核鹼基序列、化學修飾及模體之組合。It should be understood that the sequence shown in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, the internucleoside linkage, or the nucleobase, even if shown in context with a modified compound. Thus, the compound defined by the SEQ ID NO may independently comprise one or more modifications to the sugar moiety, the internucleoside linkage, or the nucleobase. The oligomeric compounds referred to by the compound number or Ref ID NO indicate a combination of nucleobase sequences, chemical modifications, and motifs.

在本文中，除非另有明確說明，否則單數之使用包括複數。舉例而言，冠詞「一種/個(a及an)」在本文中用於指該冠詞之一個或一個以上(亦即指至少一個)文法受詞。舉例而言，「要素」意指一個要素或一個以上要素，例如複數個要素。除非另有說明，否則如本文所用，使用「或」意指「及/或」。此外，術語「包括(including)」以及諸如「包括(includes及included)」等其他形式之使用不為限制性的，且可與片語「包括(但不限於)」互換使用。定義As used herein, the use of the singular includes the plural unless expressly stated otherwise. For example, the articles "a" and "an" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element, for example, a plurality of elements. As used herein, the use of "or" means "and/or" unless otherwise stated. In addition, the use of the term "including" and other forms such as "includes and included" is not limiting and can be used interchangeably with the phrase "including, but not limited to."Definitions

除非另有指示，否則以下術語具有以下含義：Unless otherwise indicated, the following terms have the following meanings:

「微管相關蛋白Tau」可與術語「MAPT」互換使用，其係指MAPT之任何核酸或蛋白質。MAPT之例示性核苷酸及胺基酸序列可參見例如GenBank登錄號NM_001377265.1 (以SEQ ID NO: 1併入本文中)，及NT_010783.14之核苷酸2624000至2761000 (以SEQ ID NO: 2併入本文中)。MAPT序列之其他實例可經由可公開獲得之資料庫容易地獲得，例如GenBank、UniProt及OMIM。關於MAPT之進一步資訊可參見例如www.ncbi.nlm.nih.gov/gene/?term=MAPT。如本文所用，MAPT亦指MAPT基因之變化形式，包括SNP資料庫中所提供之變異體。已鑑別出MAPT基因內之多種序列變化形式，且可參見例如NCBI dbSNP及UniProt (例如，參見www.ncbi.nlm.nih.gov/snp/?term=MAPT)。「MAPT mRNA」意指編碼MAPT蛋白之mRNA。MAPT可以大寫或小寫字母來提及。"Microtubule-associated protein Tau" can be used interchangeably with the term "MAPT", which refers to any nucleic acid or protein of MAPT. Exemplary nucleotide and amino acid sequences of MAPT can be found, for example, in GenBank accession number NM_001377265.1 (incorporated herein with SEQ ID NO: 1), and nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein with SEQ ID NO: 2). Other examples of MAPT sequences can be easily obtained through publicly available databases, such as GenBank, UniProt, and OMIM. For further information about MAPT, see, for example, www.ncbi.nlm.nih.gov/gene/?term=MAPT. As used herein, MAPT also refers to variant forms of the MAPT gene, including variants provided in the SNP database. A variety of sequence variations within the MAPT gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov/snp/?term=MAPT). "MAPT mRNA" means mRNA encoding the MAPT protein. MAPT can be referred to in uppercase or lowercase letters.

「MAPT特異性抑制劑」係指能夠在分子層面上特異性地抑制MAPT RNA及/或MAPT蛋白表現或活性之任何劑。舉例而言，MAPT特異性抑制劑包括能夠抑制MAPT RNA及/或MAPT蛋白之表現之核酸(包括寡核苷酸化合物)、肽、抗體、小分子及其他劑。"MAPT specific inhibitor" refers to any agent that can specifically inhibit the expression or activity of MAPT RNA and/or MAPT protein at the molecular level. For example, MAPT specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules and other agents that can inhibit the expression of MAPT RNA and/or MAPT protein.

「2’-O-甲氧基乙基」或「2’-MOE」意指2’-O(CH₂)₂-OCH₃修飾。2’-O-甲氧基乙基修飾之糖係用2’-O(CH₂)₂-OCH₃代替核糖基環之2’-OH基團之經修飾糖。"2'-O-methoxyethyl" or "2'-MOE" means a 2'-O(CH₂ )₂ -OCH₃ modification. A 2'-O-methoxyethyl modified sugar is a sugar modified in which the 2'-OH group of the ribosyl ring is replaced with 2'-O(CH₂ )₂ -OCH₃ .

「5’起始位點」意指靶核酸或區域之與反義寡核苷酸之最3’核苷對齊之核苷酸。"5' start site" refers to the nucleotide of the target nucleic acid or region that is aligned with the 3'-most nucleoside of the antisense oligonucleotide.

「3’終止位點」意指與反義寡核苷酸之最5’核苷對齊之靶核酸或區域之核苷酸。"3' stop site" refers to the nucleotide of the target nucleic acid or region to which the 5'-most nucleoside of the antisense oligonucleotide is aligned.

「約」意指在一值之±10%內。舉例而言，若陳述「化合物達成約70%之MAPT抑制」，則其暗示MAPT水準受抑制之範圍為60%至80%。當約出現在一系列數值或範圍之前時，應理解，「約」可修飾該系列或範圍內之每一數值。"About" means within ±10% of a value. For example, if it is stated that "the compound achieves about 70% inhibition of MAPT", it implies that the range of inhibition of MAPT levels is 60% to 80%. When about appears before a series of values or ranges, it should be understood that "about" can modify each value in the series or range.

「投與(administer或administering)」係指將本文所提供之化合物或組合物引入至個體以實現其預期功能之途徑。可使用之實例投與途徑包括(但不限於)鞘內(IT)投與、腦室內(ICV)投與、非經腸投與，諸如皮下投與、靜脈內投與、肌內投與、動脈內投與、腹膜內投與或顱內投與，例如鞘內或腦室內投與。"Administer" or "administering" refers to a route by which a compound or composition provided herein is introduced into a subject to achieve its intended function. Example routes of administration that may be used include, but are not limited to, intrathecal (IT), intracerebroventricular (ICV), parenteral administration, such as subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial, such as intrathecal or intracerebroventricular.

「改善」係指改進或減輕相關疾病、病症或疾患之至少一種指標、徵象或症狀。在某些實施例中，改善包括延遲或減緩疾患或疾病之一或多種指標之進展或嚴重程度。指標之進展或嚴重程度可藉由主觀或客觀量度來確定，其為熟習此項技術者所已知。"Improvement" refers to the improvement or alleviation of at least one indicator, sign or symptom of the relevant disease, disorder or condition. In certain embodiments, improvement includes delaying or slowing the progression or severity of one or more indicators of the disease or condition. The progression or severity of the indicators can be determined by subjective or objective measurement, which is known to those skilled in the art.

「動物」係指人類或非人類動物，包括(但不限於)小鼠、大鼠、兔、狗、貓、豬及非人類靈長類動物，包括(但不限於)猴及黑猩猩。“Animal” means human or non-human animals, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including but not limited to monkeys and chimpanzees.

「反義寡核苷酸」或「反義股」意指包括與靶核酸(例如MAPT RNA或其區域)互補之區域的寡核苷酸。"Antisense oligonucleotide" or "antisense strand" means an oligonucleotide that includes a region complementary to a target nucleic acid (eg, MAPT RNA or a region thereof).

就寡核苷酸而言，「互補性」意指當兩個核鹼基序列以相反方向對齊時，此寡核苷酸或其一或多個區域之核鹼基序列與另一寡核苷酸或核酸或其一或多個區域之核鹼基序列互補。除非另有指定，否則如本文所闡述之互補核鹼基限於以下各對：腺嘌呤(A)與胸腺嘧啶(T)、腺嘌呤(A)與尿嘧啶(U)，及胞嘧啶(C)與鳥嘌呤(G)。互補寡核苷酸及/或核酸不需要在每一核苷處具有核鹼基互補性，且可包括一或多個核鹼基失配。相比之下，就寡核苷酸而言，「完全互補」或「100%互補」意指此等寡核苷酸在每一核苷處具有核鹼基匹配，而無任何核鹼基失配。With respect to oligonucleotides, "complementarity" means that the nucleobase sequence of one oligonucleotide or one or more regions thereof is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposite directions. Unless otherwise specified, complementary nucleobases as described herein are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G). Complementary oligonucleotides and/or nucleic acids do not need to have nucleobase complementarity at every nucleoside and may include one or more nucleobase mismatches. In contrast, "fully complementary" or "100% complementary" with respect to oligonucleotides means that such oligonucleotides have nucleobase matches at every nucleoside, without any nucleobase mismatches.

「組合物」或「醫藥組合物」意指適於投與給個體之物質混合物。舉例而言，組合物可包含一或多種化合物或其鹽及無菌水溶液。"Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or their salts and a sterile aqueous solution.

「共投與」意指以任何方式投與兩種或更多種化合物，其中兩者之藥理學效應在患者體內同時顯現。共投與不要求兩種化合物以單一醫藥組合物、以相同劑型、按相同投與途徑或同時投與。兩種化合物之效應不需要同時顯現。該等效應僅需要在一段時間內重疊，而無需同延。共投與包括同時或依序投與一或多種化合物。"Co-administration" means the administration of two or more compounds in any manner where the pharmacological effects of both compounds are manifested in the patient at the same time. Co-administration does not require that the two compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of the two compounds do not need to manifest at the same time. The effects need only overlap over a period of time, not be coextensive. Co-administration includes the administration of one or more compounds simultaneously or sequentially.

「結合基團」意指連接至寡核苷酸之原子團。結合基團視情況經由結合連接體連接至寡核苷酸。結合基團可例如改變併有該結合基團之化合物之分佈、靶向或半衰期。結合基團包括脂質(或親脂性部分)、配位體及其他靶向部分。"Binding group" means a group of atoms that is linked to an oligonucleotide. A binding group is optionally linked to an oligonucleotide via a binding linker. A binding group can, for example, alter the distribution, targeting, or half-life of a compound incorporating the binding group. Binding groups include lipids (or lipophilic moieties), ligands, and other targeting moieties.

「結合連接體」意指包含至少一個將連接部分連結至寡核苷酸之鍵的原子團。"Binding linker" means a group of atoms comprising at least one bond that links a linking moiety to an oligonucleotide.

就寡核苷酸而言，「一致性」意指此寡核苷酸或其一或多個區域之核鹼基序列與另一寡核苷酸或核酸或其一或多個區域之核鹼基序列匹配。寡核苷酸與另一寡核苷酸或核酸之一致性不要求每一核鹼基均匹配，且可包括一或多個不同的核鹼基。相比之下，就寡核苷酸而言，「完全一致」或「100%一致性」意指此等寡核苷酸在其長度上之每一相對位置具有與另一寡核苷酸或核酸相同之核鹼基。In the case of oligonucleotides, "identity" means that the base sequence of the oligonucleotide or one or more regions thereof matches the base sequence of another oligonucleotide or nucleic acid or one or more regions thereof. The identity of an oligonucleotide to another oligonucleotide or nucleic acid does not require that every base match, and may include one or more different bases. In contrast, in the case of oligonucleotides, "complete identity" or "100% identity" means that these oligonucleotides have the same base as another oligonucleotide or nucleic acid at every relative position along their length.

「個體」意指選擇進行治療或療法之人類或非人類動物。“Individual” means a human or non-human animal selected for treatment or therapy.

就靶核酸或蛋白質而言，「抑制表現或活性」意指相對於未經處理或對照樣品中之表現或活性，降低或阻斷此靶標之表現或活性，且不一定指示完全消除表現或活性。With respect to a target nucleic acid or protein, "inhibiting expression or activity" means reducing or blocking the expression or activity of this target relative to the expression or activity in an untreated or control sample, and does not necessarily indicate complete elimination of expression or activity.

如本文所用，術語「核苷間鍵聯」係寡核苷酸中毗鄰核苷之間的共價鍵聯。如本文所用，「經修飾之核苷間鍵聯」意指除磷酸二酯核苷間鍵聯以外之任何核苷間鍵聯。「硫代磷酸酯核苷間鍵聯」係經修飾之核苷間鍵聯，其中磷酸二酯核苷間鍵聯之一個非橋接氧原子經硫原子置換。As used herein, the term "internucleoside linkage" is a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, "modified internucleoside linkage" means any internucleoside linkage other than a phosphodiester internucleoside linkage. A "phosphorothioate internucleoside linkage" is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester internucleoside linkage is replaced by a sulfur atom.

具有手性中心之代表性核苷間鍵聯包括(但不限於)烷基膦酸酯及硫代磷酸酯。如下文進一步闡述，可將包含具有手性中心之核苷間鍵聯的經修飾之寡核苷酸製備成包含立體隨機核苷間鍵聯的經修飾之寡核苷酸群體，或製備成包含呈特定立體化學構形之硫代磷酸酯鍵聯的經修飾之寡核苷酸群體。除非另有指示，否則本文所闡述之經修飾之寡核苷酸的手性核苷間鍵聯可為立構隨機的或呈特定立體化學構形。Representative internucleoside linkages with chiral centers include, but are not limited to, alkylphosphonates and phosphorothioates. As further described below, modified oligonucleotides comprising internucleoside linkages with chiral centers can be prepared as a population of modified oligonucleotides comprising stereorandom internucleoside linkages, or as a population of modified oligonucleotides comprising phosphorothioate linkages in a specific stereochemical configuration. Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereorandom or in a specific stereochemical configuration.

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

術語「同位素變異體」係指在構成治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)之一或多個原子處含有非天然比例之同位素的此一治療劑。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、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，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、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)。The term "isotopic variant" refers to a therapeutic agent (eg, a compound and/or modified oligonucleotide disclosed herein) that contains unnatural proportions of isotopes at one or more atoms that constitute such an agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (^2H ), tritium (^3H ), carbon-11 (^11C ), carbon-12 (^12C ), carbon-13 (^13C ), carbon-14 (^14C ), nitrogen-13 (^13N ), nitrogen-14 (^14N ), nitrogen-15 (^15N ), oxygen-14 (^14O ), oxygen-¹⁵ (^15O ), oxygen-16 (16O), oxygen-17 (^17O ), oxygen-¹⁸ (18O), fluorine-17 (^17F ), fluorine-18 (^18F ), phosphorus-31 (^31P ), phosphorus-32 (^{32P), phosphorus-33 (33P)} , 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, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (^2H ), tritium (^3H ), carbon-11 (^11C ), carbon-12 (^12C ), carbon-13 (^13C ), carbon-14 (^14C ), nitrogen-13 (^13N ), nitrogen-14 (^14N ), nitrogen-15 (^15N ), oxygen-14 (^14O ), oxygen-¹⁵ (^15O ), oxygen-16 (16O), oxygen-17 (^17O ), oxygen-¹⁸ (18O), fluorine-17 (^17F ), fluorine-18 (^18F ), phosphorus-31 (^31P ), phosphorus-32 (^{32P), phosphorus-33 (33P)} , 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).

將理解，在治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)中，根據熟習此項技術者之判斷，在可行之情形下，任何氫可為例如²H，或任何碳可為例如¹³C，或任何氮可為例如¹⁵N，或任何氧可為例如¹⁸O。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之氘(D)。It will be understood that in a therapeutic agent (e.g., a compound and/or modified oligonucleotide disclosed herein), where applicable, any hydrogen may be, for example,² H, or any carbon may be, for example,¹³ C, or any nitrogen may be, for example,¹⁵ N, or any oxygen may be, for example,¹⁸ O, according to the judgment of one skilled in the art. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

「脂質」或「親脂性部分」係指脂肪族、環狀(諸如脂環族)或多環(諸如多脂環族)化合物，諸如類固醇(例如固醇)或直鏈或具支鏈脂肪族烴。術語脂質包括膽固醇、視黃酸、膽酸、金剛烷乙酸、1-芘丁酸、二氫睪固酮、1,3-雙-O(十六烷基)甘油、香葉草基氧己醇(geranyloxyhexyanol)、十六烷基甘油、冰片、薄荷醇、1,3-丙二醇、十七烷基、棕櫚酸、肉豆蔻酸、O3-(油醯基)石膽酸、O3-(油醯基)膽烯酸、布洛芬(ibuprofen)、萘普生(naproxen)、二甲氧基三苯甲基或吩噁嗪。術語脂質包括飽和或不飽和C₄-C₃₀烴鏈(例如C₄-C₃₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₅-C₂₀烴鏈(例如直鏈C₅-C₂₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₄-C₂₀烴鏈(例如直鏈C₁₄-C₂₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₆-C₁₈烴鏈(例如直鏈C₆-C₁₈烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₆烴鏈(例如直鏈C₁₆烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₇烴鏈(例如直鏈C₁₇烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₈烴鏈(例如直鏈C₁₈烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₂₂烴鏈(例如直鏈C₂₂烷基或烯基)。"Lipid" or "lipophilic moiety" refers to an aliphatic, cyclic (eg, alicyclic) or polycyclic (eg, polyalicyclic) compound, such as a steroid (eg, sterol) or a straight or branched chain aliphatic hydrocarbon. The term lipid includes cholesterol, retinoic acid, bile acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O (hexadecyl) glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propylene glycol, heptadecyl, palmitic acid, myristic acid, O3-(oleyl) cholecalciferol, O3-(oleyl) cholecalciferol, ibuprofen, naproxen, dimethoxytrityl or phenoxazine. The term lipid includes saturated or unsaturated C₄ -C₃₀ alkyl chains (e.g., C₄ -C₃₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain (e.g., a straight chain C₅ -C₂₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain (e.g., a straight chain C₁₄ -C₂₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₆ -C₁₈ hydrocarbon chain (e.g., a straight chain C₆ -C₁₈ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₁₆ hydrocarbon chain (e.g., a straight chain C₁₆ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C17 hydrocarbon chain (e.g., a straight chain C17 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C18 hydrocarbon chain (e.g., a straight chain_C18 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C22 hydrocarbon chain (e.g._, a straight chain_C22 alkyl or alkenyl).

「失配」或「非互補」意指當將第一寡核苷酸/核酸與第二寡核苷酸/核酸以反平行定向對齊時，第一寡核苷酸或核酸之核鹼基不與第二寡核苷酸或核酸之相應核鹼基互補。舉例而言，核鹼基、包括(但不限於)通用核鹼基、肌苷及次黃嘌呤，能夠與至少一個核鹼基雜交，但仍與其所雜交之核鹼基失配或不互補。作為另一實例，當將第一與第二寡核苷酸以反平行定向對齊時，第一寡核苷酸/核酸中不能與第二寡核苷酸/核酸之相應核鹼基雜交之核鹼基為失配或非互補核鹼基。"Mismatched" or "non-complementary" means that a nucleobase of the first oligonucleotide or nucleic acid is not complementary to the corresponding nucleobase of the second oligonucleotide or nucleic acid when the first oligonucleotide/nucleic acid is aligned in an antiparallel orientation with the second oligonucleotide/nucleic acid. For example, nucleobases, including but not limited to the universal nucleobases, inosine and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with the nucleobase to which it hybridizes. As another example, a nucleobase in the first oligonucleotide/nucleic acid that is unable to hybridize with the corresponding nucleobase of the second oligonucleotide/nucleic acid when the first and second oligonucleotides are aligned in an antiparallel orientation is a mismatched or non-complementary nucleobase.

「經修飾之寡核苷酸」意指其中至少一個糖、核鹼基或核苷間鍵聯經修飾之寡核苷酸。"Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage has been modified.

「調節」係指改變或調整細胞、組織、器官或生物體中之特徵。舉例而言，調節MAPT RNA可意指增加或減少細胞、組織、器官或生物體中MAPT RNA及/或MAPT蛋白之水準。「調節劑」引起細胞、組織、器官或生物體中之變化。舉例而言，MAPT化合物可為減少細胞、組織、器官或生物體中MAPT RNA及/或MAPT蛋白之量的調節劑。"Regulate" means to change or adjust a characteristic in a cell, tissue, organ, or organism. For example, regulating MAPT RNA may mean increasing or decreasing the level of MAPT RNA and/or MAPT protein in a cell, tissue, organ, or organism. "Regulator" causes a change in a cell, tissue, organ, or organism. For example, a MAPT compound may be a regulator that decreases the amount of MAPT RNA and/or MAPT protein in a cell, tissue, organ, or organism.

「模體」意指寡核苷酸中未經修飾及經修飾之糖部分、核鹼基及/或核苷間鍵聯之模式。"Motif" refers to the pattern of unmodified and modified sugar moieties, nucleobases and/or internucleoside linkages in an oligonucleotide.

「核酸」係指由單體核苷酸構成之分子。核酸包括(但不限於)核糖核酸(RNA)、去氧核糖核酸(DNA)、單股核酸及雙股核酸。"Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include (but are not limited to) ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid and double-stranded nucleic acid.

「核鹼基」意指能夠與另一核酸之鹼基配對之雜環部分。如本文所用，「天然核鹼基」為腺嘌呤(A)、胸腺嘧啶(T)、胞嘧啶(C)、尿嘧啶(U)及鳥嘌呤(G)。「經修飾之核鹼基」係經化學修飾之天然核鹼基。「通用鹼基」或「通用核鹼基」係除天然核鹼基及經修飾之核鹼基以外且能夠與任何核鹼基配對之核鹼基。"Nucleobase" means a heterocyclic moiety that is capable of pairing with a base of another nucleic acid. As used herein, "natural nucleobases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nucleobases" are natural nucleobases that have been chemically modified. "Universal base" or "universal nucleobase" is a nucleobase other than natural nucleobases and modified nucleobases that is capable of pairing with any nucleobase.

「核鹼基序列」意指核酸或寡核苷酸中鄰接核鹼基之順序，該順序與任何糖或核苷間鍵聯無關。"Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

「核苷」意指包含核鹼基及糖部分之化合物。核鹼基及糖部分各自獨立地未經修飾或經修飾。「經修飾之核苷」意指包含經修飾之核鹼基及/或經修飾之糖部分的核苷。經修飾之核苷包括缺少核鹼基之無鹼基核苷。"Nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides lacking a nucleobase.

「寡聚化合物」意指包含一或多種寡核苷酸及視情況一或多種額外特徵(諸如結合基團或末端基團)之化合物。寡聚化合物之實例包括單股及雙股化合物，諸如寡核苷酸、反義寡核苷酸、干擾RNA化合物(RNAi化合物)、靶向微小RNA之寡核苷酸、基於佔位之化合物(例如mRNA加工或轉譯阻斷化合物及剪接化合物)。RNAi化合物包括雙股化合物(例如短干擾RNA (siRNA)及雙股RNA (dsRNA))及單股化合物(例如單股siRNA (ssRNA)、單股RNAi (ssRNAi)、短髮夾RNA (shRNA)及微小RNA模擬物)，其至少部分地經由RNA誘導之沈默複合物(RISC)路徑起作用，從而經由稱為RNA干擾(RNAi)之過程導致靶核酸之序列特異性降解及/或螯合。術語「RNAi化合物」意欲等同於用於描述能夠介導序列特異性RNA干擾之核酸化合物之其他術語，例如干擾RNA (iRNA)、iRNA劑、RNAi劑、短干擾寡核苷酸、短干擾核酸、短干擾經修飾寡核苷酸、經化學修飾之siRNA等。另外，術語「RNAi」意欲等同於用於描述序列特異性RNA干擾之其他術語。"Oligomeric compound" means a compound comprising one or more oligonucleotides and, optionally, one or more additional features, such as binding groups or terminal groups. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides targeting microRNAs, occupancy-based compounds such as mRNA processing or translation blocking compounds and splicing compounds. RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least in part through the RNA-induced silencing complex (RISC) pathway, thereby causing sequence-specific degradation and/or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, etc. Additionally, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

「寡聚雙鏈體」意指由兩種具有互補核鹼基序列之寡聚化合物形成的雙鏈體。寡聚雙鏈體之每一寡聚化合物可稱為「雙鏈體化之寡聚化合物」。寡聚雙鏈體之每一寡聚化合物之寡核苷酸可包括非互補懸垂核苷。在一些實施例中，術語「雙鏈體化之寡聚化合物」及「經修飾之寡核苷酸」可互換使用。在其他實施例中，術語「寡聚雙鏈體」與「化合物」可互換使用。"Oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of the oligomeric duplex may be referred to as a "duplexed oligomeric compound". The oligonucleotides of each oligomeric compound of the oligomeric duplex may include non-complementary pendant nucleosides. In some embodiments, the terms "duplexed oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

「寡核苷酸」意指連接核苷之聚合物，每一核苷可彼此獨立地經修飾或未經修飾。"Oligonucleotide" refers to a polymer of linked nucleosides, each of which may be independently modified or unmodified.

「非經腸投與」意指經由注射或輸注投與。非經腸投與包括皮下投與、靜脈內投與、肌內投與、動脈內投與、腹膜內投與或顱內投與，例如鞘內或腦室內投與。"Parenteral administration" means administration by injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, such as intrathecal or intraventricular administration.

「醫藥學上可接受之載劑或稀釋劑」意指適用於投與給個體之任何物質。在某些實施例中，醫藥學上可接受之載劑或稀釋劑有助於將化合物投與給個體並由個體吸收，且可包括在本揭示案之組合物中，而不會對患者產生顯著不良毒性效應。醫藥學上可接受之賦形劑之非限制性實例包括水、NaCl、生理鹽水溶液及諸如此類。舉例而言，醫藥學上可接受之載劑可為無菌水溶液，諸如PBS或注射用水。熟習此項技術者將認識到，其他醫藥賦形劑可用於本揭示案中。"Pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent facilitates administration of the compound to an individual and absorption by the individual and may be included in the compositions of the present disclosure without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solutions, and the like. For example, a pharmaceutically acceptable carrier may be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients may be used in the present disclosure.

「醫藥學上可接受之鹽」意指或係指化合物(諸如寡聚化合物或寡核苷酸)之生理學及醫藥學上可接受之鹽，亦即保留母體化合物之期望生物活性且不會產生不期望之毒性效應之鹽。"Pharmaceutically acceptable salt" means or refers to a physiologically and pharmaceutically acceptable salt of a compound (such as an oligomeric compound or oligonucleotide), that is, a salt that retains the desired biological activity of the parent compound and does not produce undesired toxicological effects.

在本文中可互換使用之「原肌凝蛋白受體激酶B」或「TrkB」意指腦源性神經營養因子(BDNF)蛋白受體，其由NTRK2基因編碼。TrkB亦稱為酪胺酸受體激酶B、BDNF/NT-3生長因子受體及2型神經營養酪胺酸激酶受體。"Tropomyosin receptor kinase B" or "TrkB" used interchangeably herein refers to the brain-derived neurotrophic factor (BDNF) protein receptor, which is encoded by the NTRK2 gene. TrkB is also known as tyrosine receptor kinase B, BDNF/NT-3 growth factor receptor, and neurotrophic tyrosine kinase receptor type 2.

如本文所用，醫藥學上可接受之鹽係保留本文所提供化合物之生物性質且無毒或不會在其他方面為醫藥用途不期望之任何鹽。本文所揭示治療劑之醫藥學上可接受之鹽包括利用相對無毒酸或鹼製備之鹽，此取決於在本文所闡述化合物或經修飾之寡核苷酸上所發現之特定取代基。As used herein, a pharmaceutically acceptable salt is any salt that retains the biological properties of the compounds provided herein and is not toxic or otherwise undesirable for pharmaceutical uses. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared using relatively nontoxic acids or bases, depending on the particular substituents found on the compounds or modified oligonucleotides described herein.

當本揭示案之化合物含有相對酸性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望鹼接觸來獲得鹼加成鹽。When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base either neat or in a suitable inert solvent.

當本揭示案之化合物含有相對鹼性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望酸接觸來獲得酸加成鹽。When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid either neat or in a suitable inert solvent.

因此，本揭示案之化合物可以鹽形式存在，諸如與醫藥學上可接受之酸的鹽。此等鹽可源自此項技術中所熟知之多種有機及無機相對離子。此等鹽包括(但不限於)：(1)與有機或無機酸形成之酸加成鹽，該等有機或無機酸諸如為鹽酸、氫溴酸、硫酸、硝酸、磷酸、胺基磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、己酸、環戊基丙酸、羥乙酸、戊二酸、丙酮酸、乳酸、丙二酸、琥珀酸、山梨酸、抗壞血酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、苦味酸、肉桂酸、扁桃酸、酞酸、月桂酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦酸、樟腦磺酸、4-甲基雙環[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡萄糖酸、苯甲酸、麩胺酸、羥基萘酸、柳酸、硬脂酸、環己基胺基磺酸、奎尼酸、黏康酸及類似酸；或(2)當存在於母體化合物中之酸性質子(a)經金屬離子(例如鹼金屬離子、鹼土離子或鋁離子)或鹼金屬或鹼土金屬氫氧化物(諸如氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、氫氧化鋁、氫氧化鋰、氫氧化鋅及氫氧化鋇)、氨置換或(b)與有機鹼(諸如脂肪族、脂環族或芳香族有機胺，諸如氨、甲胺、二甲胺、二乙胺、甲吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、離胺酸、精胺酸、鳥胺酸、膽鹼、N,N'-二苯甲基乙二胺、氯普魯卡因(chloroprocaine)、二乙醇胺、普魯卡因、N-苯甲基苯乙胺、N-甲基葡萄糖胺六氫吡嗪、參(羥甲基)-胺基甲烷、四甲基氫氧化銨及諸如此類)配位時形成之鹽(例如，參見Berge等人，「Pharmaceutical Salts」, Journal of Pharmaceutical Science, 1977, 66, 1-19)。Thus, the compounds of the present disclosure may exist in the form of salts, such as salts with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminosulfonic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, hydroxyacetic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, apple acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid; , cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamine, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid , quinic acid, muconic acid and similar acids; or (2) when the acidic proton present in the parent compound is replaced (a) by a metal ion (e.g., an alkali metal ion, an alkali earth ion or an aluminum ion) or an alkali metal or alkali earth metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide), ammonia or (b) by an organic base (e.g., an aliphatic, alicyclic or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picolinyl Salts formed when the amine is coordinated with ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine hexahydropyrazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

醫藥學上可接受之鹽進一步包括(僅舉例而言而不限於)鈉、鉀、鈣、鎂、銨、四烷基銨及諸如此類，及(當化合物含有鹼性官能基時)無毒有機或無機酸之鹽，諸如氫鹵化物(例如鹽酸鹽及氫溴酸鹽)、硫酸鹽、磷酸鹽、胺基磺酸鹽、硝酸鹽、乙酸鹽、三氟乙酸鹽、三氯乙酸鹽、丙酸鹽、己酸鹽、環戊基丙酸鹽、羥乙酸鹽、戊二酸鹽、丙酮酸鹽、乳酸鹽、丙二酸鹽、琥珀酸鹽、山梨酸鹽、抗壞血酸鹽、蘋果酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、檸檬酸鹽、苯甲酸鹽、3-(4-羥基苯甲醯基)苯甲酸鹽、苦味酸鹽、肉桂酸鹽、扁桃酸鹽、酞酸鹽、月桂酸鹽、甲磺酸鹽(methanesulfonate、mesylate)、乙磺酸鹽、1,2-乙二磺酸鹽、2-羥基乙磺酸鹽、苯磺酸鹽(benzenesulfonate、besylate)、4-氯苯磺酸鹽、2-萘磺酸鹽、4-甲苯磺酸鹽、樟腦酸鹽、樟腦磺酸鹽、4-甲基雙環[2.2.2]-辛-2-烯-1-甲酸鹽、葡庚糖酸鹽、3-苯基丙酸鹽、三甲基乙酸鹽、第三丁基乙酸鹽、月桂基硫酸鹽、葡萄糖酸鹽、苯甲酸鹽、麩胺酸鹽、羥基萘酸鹽、柳酸鹽、硬脂酸鹽、環己基胺基磺酸鹽、奎尼酸鹽、黏康酸鹽及諸如此類。在一些實施例中，本文所揭示之化合物及經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽或鉀鹽。在一些實施例中，本文所揭示之化合物及經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽。Pharmaceutically acceptable salts further include, by way of example and not limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and (when the compound contains a basic functional group) salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetic acid. Salt, propionate, caproate, cyclopentylpropionate, hydroxyacetate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, apple acid salt, maleate, fumarate, tartaric acid salt, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate , laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, Camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamine, hydroxynaphthoate, salicylate, stearate, cyclohexylaminesulfonate, quinate, muconate, and the like. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt or a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt.

化合物之中性形式較佳藉由使鹽與鹼或酸接觸且以習用方式分離母體化合物來再生。化合物之母體形式可在某些物理性質(諸如於極性溶劑中之溶解性)方面與各種鹽形式不同。在實施例中，本揭示案之化合物含有容許將該等化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基二者。化合物之中性形式可藉由使鹽與鹼或酸接觸且以習用方式分離母體化合物來再生。化合物之母體形式在某些物理性質(諸如於極性溶劑中之溶解性)方面與各種鹽形式不同，但除非明確指示，否則出於本揭示案之目的，本文所揭示之鹽等效於化合物之母體形式。The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, the compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless expressly indicated, the salts disclosed herein are equivalent to the parent forms of the compound for purposes of the present disclosure.

「醫藥劑」意指在投與給個體時提供治療益處之化合物。"Pharmaceutical agent" means a compound that provides a therapeutic benefit when administered to a subject.

「硫代磷酸酯鍵聯」意指經修飾之磷酸酯鍵聯，其中一個非橋接氧原子經硫原子置換。"Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

「部分」意指核酸中確定數量之鄰接(亦即連接)核鹼基。在某些實施例中，部分係靶核酸中確定數量之鄰接核鹼基。在某些實施例中，部分係寡核苷酸中確定數量之鄰接核鹼基。"Portion" means a defined number of adjacent (i.e., linked) nucleobases in a nucleic acid. In certain embodiments, a portion is a defined number of adjacent nucleobases in a target nucleic acid. In certain embodiments, a portion is a defined number of adjacent nucleobases in an oligonucleotide.

「預防」係指在一段時間內延遲或預先阻止疾病、病症或疾患之發作、發展或進展。"Prevention" means delaying or arresting for a period of time the onset, development or progression of a disease, symptom or condition.

「RNA干擾化合物」或「RNAi化合物」意指至少部分地經由RNA誘導之沈默複合物(RISC)路徑或Ago2、而不經由RNA酶H起作用，以調節靶核酸及/或由靶核酸編碼之蛋白質之化合物。RNAi化合物包括(但不限於)雙股siRNA、單股siRNA及微小RNA，包括微小RNA模擬物。"RNA interference compound" or "RNAi compound" means a compound that acts at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than through RNase H, to regulate a target nucleic acid and/or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimetics.

「有義寡核苷酸」或「有義股」意指雙股化合物之股，其包括與該化合物之反義股區域實質上互補之區域。"Sense oligonucleotide" or "sense strand" means a strand of a two-stranded compound that includes a region that is substantially complementary to the antisense strand of the compound.

就靶核酸或蛋白質而言，「特異性地抑制」意指降低或阻斷靶核酸或蛋白質之表現或活性，同時最小化或消除對非靶核酸或蛋白質之效應。With respect to a target nucleic acid or protein, "specifically inhibiting" means reducing or blocking the expression or activity of the target nucleic acid or protein while minimizing or eliminating the effects on non-target nucleic acids or proteins.

就寡核苷酸而言，「亞單元」意指如本文所提供之核苷酸、核苷、核鹼基或糖或者經修飾之核苷酸、核苷、核鹼基或糖。With respect to an oligonucleotide, "subunit" means a nucleotide, nucleoside, nucleobase or sugar, or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

「靶核酸」、「靶RNA」及「核酸靶標」均意指能夠由本文所闡述之化合物靶向之核酸。"Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

「靶區域」意指一或多種化合物靶向之靶核酸之一部分。"Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

「靶向部分」意指例如與不存在此一部分之化合物相比，對選定靶標(例如分子、細胞或細胞類型、區室(例如細胞或器官區室)、組織、器官或身體區域)提供增強親和力之結合基團。"Targeting moiety" means a binding group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type, compartment (e.g., a cellular or organ compartment), tissue, organ, or body region), e.g., compared to a compound without such moiety.

「末端基團」意指共價連接至寡核苷酸末端之化學基團或原子團。"Terminus group" refers to a chemical group or group of atoms covalently linked to the end of an oligonucleotide.

「治療有效量」或「有效量」意指化合物、醫藥劑或組合物為個體提供治療益處之量。「治療有效量」或「有效量」係相對於不存在化合物時，化合物足以實現所述目的之量(例如，達成投與該化合物之效應，治療、預防或改善疾病，或減少疾病或疾患之一或多種症狀)。「治療有效量」或「有效量」之實例為足以有助於治療、預防、改善或減少疾病之一或多種症狀之量。一或多種症狀之「減少」(及此片語之文法等效形式)意指降低該(等)症狀之嚴重程度或頻率，或消除該(等)症狀。藥物之「預防有效量」係當投與給個體時將具有預期預防效應之藥物量，例如預防或延遲損傷、疾病、病狀或疾患之發作(或復發)，或降低損傷、疾病、病狀或疾患或其症狀發作(或復發)之可能性。如本文所用，術語「治療有效量」係指治療劑足以為個體提供治療益處之量，諸如如上文所闡述治療、預防或改善疾病或病症或其症狀。舉例而言，對於給定參數，治療有效量將顯示出至少5%、10%、15%、20%、25%、40%、50%、60%、75%、80%、90%或至少100%之增加或減少。治療功效亦可表述為「倍」數增加或減小。舉例而言，治療有效量之效應可為對照的至少1.2倍、1.5倍、2倍、5倍或更高。"Therapeutically effective amount" or "effective amount" means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual. "Therapeutically effective amount" or "effective amount" is an amount of a compound sufficient to achieve the stated purpose (e.g., to achieve the effect of administration of the compound, to treat, prevent, or ameliorate a disease, or to reduce one or more symptoms of a disease or disorder) relative to the absence of the compound. Examples of "therapeutically effective amount" or "effective amount" are amounts sufficient to help treat, prevent, ameliorate, or reduce one or more symptoms of a disease. "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s), or eliminating the symptom(s). A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to an individual, will have the desired prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or a symptom thereof. As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing, or ameliorating a disease or disorder, or a symptom thereof, as described above. For example, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% for a given parameter. The therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, the effect of a therapeutically effective amount can be at least 1.2 times, 1.5 times, 2 times, 5 times or more of the control.

術語「治療(treating或treatment)」係指在療法或改善損傷、疾病、病狀或疾患方面之任何成功跡象，包括任何客觀或主觀參數，諸如減輕；緩解；減少症狀或使患者更能耐受損傷、病狀或疾患；減緩退化或衰退之速率；使退化終點較少地減弱；改進患者之身體或心理健康。症狀之治療或改善可基於客觀或主觀參數，包括身體檢查結果。術語「治療」及其詞形變化可包括預防損傷、病狀、疾患或疾病。在實施例中，治療為預防。在實施例中，治療不包括預防。The term "treating" or "treatment" refers to any sign of success in curing or ameliorating an injury, disease, ailment, or illness, including any objective or subjective parameter, such as amelioration; relief; reduction of symptoms or making the patient more tolerant of the injury, disease, or illness; slowing the rate of degeneration or decline; making the endpoint of degeneration less severe; improving the patient's physical or mental health. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including physical examination results. The term "treating" and its variations may include preventing an injury, disease, ailment, or illness. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention.

如本文所用(且如此項技術中所充分理解)，「治療(treating或treatment)」亦廣泛地包括針對個體疾患獲得有益或期望結果(包括臨床結果)之方法。有益或期望之臨床結果可包括(但不限於)緩和或改善一或多種症狀或疾患、減輕疾病程度、使疾病狀態穩定(亦即不惡化)、預防疾病傳播或擴散、延遲或減緩疾病進展、改善或減輕疾病狀態、減少疾病復發，以及緩解，無論為部分還是全部，且無論可偵測到還是偵測不到。換言之，如本文所用之「治療」包括疾病之任何治癒、改善或預防。治療可預防疾病發生；抑制疾病傳播；減輕疾病症狀；完全或部分消除疾病潛在原因；縮短疾病持續時間；或該等事項之組合。As used herein (and as is well understood in the art), "treating" or "treatment" also broadly includes methods for obtaining beneficial or desired results (including clinical results) for an individual disease. Beneficial or desired clinical results may include (but are not limited to) alleviation or improvement of one or more symptoms or diseases, reduction in the severity of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or reduction of the disease state, reduction of disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of disease. Treatment may prevent the disease from occurring; inhibit its spread; reduce the symptoms of the disease; completely or partially eliminate the underlying cause of the disease; shorten the duration of the disease; or a combination of these things.

如本文所用，「治療(treating及treatment)」包括預防性治療。治療方法包括向個體投與治療有效量之本文所闡述之化合物。投與步驟可由單次投與組成，或可包括一系列投與。治療期之長度取決於多種因素，諸如疾患之嚴重程度、患者年齡、化合物濃度、治療中所用組合物之活性或其組合。亦應瞭解，用於治療或預防之劑的有效劑量可在特定治療或預防方案之過程中增加或減少。在一些情況下，可能需要長期投與。舉例而言，將組合物以足以治療患者之量及持續時間向個體投與。「治療」係指向動物投與化合物或醫藥組合物，以實現動物疾病、病症或疾患之改變或改進。As used herein, "treating" and "treatment" include preventive treatment. The treatment method includes administering to an individual a therapeutically effective amount of a compound as described herein. The administration step may consist of a single administration, or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may increase or decrease during the course of a specific treatment or prevention regimen. In some cases, long-term administration may be required. For example, the composition is administered to an individual in an amount and for a duration sufficient to treat the patient. "Treatment" refers to the administration of a compound or pharmaceutical composition to an animal to effect a change or improvement in a disease, disorder or condition in the animal.

本揭示案之某些化合物具有不對稱碳原子(光學或手性中心)或雙鍵；鏡像異構物、外消旋物、非鏡像異構物、互變異構物、幾何異構物、就絕對立體化學而言可定義為(R)-或(S)-或對於胺基酸而言可定義為(D)-或(L)-之立體異構形式以及個別異構物涵蓋在本揭示案之範圍內。本揭示案之化合物不包括此項技術中已知之太不穩定而不能合成及/或分離之彼等化合物。本揭示案意欲包括呈外消旋及光學純形式之化合物。光學活性(R)-及(S)-或(D)-及(L)-異構物可使用手性合成子或手性試劑來製備，或使用習用技術來拆分。當本文所闡述之化合物含有烯烴鍵或其他幾何不對稱性中心時，且除非另有指定，否則預期該等化合物包括E及Z幾何異構物二者。Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; mirror isomers, racemates, non-mirror isomers, tautomers, geometric isomers, stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry or as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds that are too unstable to be synthesized and/or separated as known in the art. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is contemplated that the compounds include both E and Z geometric isomers.

如本文所用，術語「異構物」係指具有相同數量及種類之原子且由此具有相同之分子量，但關於原子之結構排列或構形有所不同之化合物。As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

如本文所用，術語「互變異構物」係指兩種或更多種結構異構物中之一者，該等結構異構物以平衡狀態存在且易於自一種異構形式轉化成另一種異構形式。As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another.

熟習此項技術者將明瞭，本揭示案之某些化合物可以互變異構形式存在，該等化合物之所有此等互變異構形式均在本揭示案之範圍內。It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric isomeric forms and that all such tautomeric forms of the compounds are within the scope of the present disclosure.

除非另有說明，否則本文所繪示之結構亦意欲包括該結構之所有立體化學形式(亦即，每一不對稱中心之R及S構形)。因此，本發明化合物之單一立體化學異構物以及鏡像異構及非鏡像異構混合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as mirror and non-mirror isomeric mixtures of the compounds of the invention are within the scope of the present disclosure.

如本文所用，「手性富集群體」意指複數個具有相同分子式之分子，其中群體內在特定手性中心處含有特定立體化學構形之分子的數目或百分比大於在該特定手性中心為立體隨機的情況下群體內在相同特定手性中心處預期含有相同特定立體化學構形之分子的數目或百分比。在每一分子內具有多個手性中心之分子的手性富集群體可含有一或多個立體隨機手性中心。在某些實施例中，分子為經修飾之寡核苷酸。在某些實施例中，分子為包含經修飾之寡核苷酸之化合物。As used herein, "chirally enriched population" means a plurality of molecules having the same molecular formula, wherein the number or percentage of molecules within the population containing a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules within the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In some embodiments, the molecule is a modified oligonucleotide. In some embodiments, the molecule is a compound comprising a modified oligonucleotide.

除非另有說明，否則本文所繪示之結構亦意欲包括不同之處僅在於存在一或多個同位素富集原子之化合物。舉例而言，除用氘或氚置換氫或用¹³C或¹⁴C富集碳置換碳外具有本發明結構之化合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with^a13Cor14C enriched carbon are within the scope of this disclosure.

如本文所用，「立體隨機手性中心」在具有相同分子式之分子群體背景下意指具有隨機立體化學構形之手性中心。舉例而言，在包含立體隨機手性中心之分子群體中，具有立體隨機手性中心(S)構形之分子的數目可與具有立體隨機手性中心(R)構形之分子的數目相同，但不一定相同。當手性中心之立體化學構形係並非為控制立體化學構形而設計之合成方法的結果時，可將其視為隨機的。在某些實施例中，立體隨機手性中心為立體隨機硫代磷酸酯核苷間鍵聯。某些實施例As used herein, "stereo-random chiral center" in the context of a population of molecules having the same molecular formula means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereo-random chiral center, the number of molecules with a stereo-random chiral center (S) configuration may be the same as the number of molecules with a stereo-random chiral center (R) configuration, but is not necessarily the same. The stereochemical configuration of a chiral center can be considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereo-random chiral center is a stereo-random phosphorothioate internucleoside linkage.Certain Embodiments

在某些態樣中，本揭示案係關於抑制MAPT之方法、化合物及組合物。在某些實施例中，MAPT特異性地受到抑制。在某些實施例中，MAPT特異性地降解。在某些實施例中，MAPT表現受到抑制。在某些實施例中，MAPT轉譯受到抑制。在某些實施例中，MAPT活性受到抑制。在某些實施例中，相對於未經處理或對照樣品中之表現、轉譯或活性，MAPT表現、轉譯或活性降低至少10%。舉例而言，在某些實施例中，相對於未經處理或對照樣品中之表現、轉譯或活性，MAPT表現、轉譯或活性降低至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、10%-50%、25%-50%、25%-75%、50%-75%、50%-99%或75%-99%。在某些實施例中，如藉由任何適宜分析所量測，MAPT表現、轉譯或活性降低，該適宜分析包括(但不限於)免疫分析、基於雜交之分析或基於測序之分析(例如RNA-Seq)。In certain aspects, the disclosure relates to methods, compounds and compositions for inhibiting MAPT. In certain embodiments, MAPT is specifically inhibited. In certain embodiments, MAPT is specifically degraded. In certain embodiments, MAPT expression is inhibited. In certain embodiments, MAPT translation is inhibited. In certain embodiments, MAPT activity is inhibited. In certain embodiments, MAPT expression, translation or activity is reduced by at least 10% relative to expression, translation or activity in untreated or control samples. For example, in some embodiments, MAPT expression, translation or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10%-50%, 25%-50%, 25%-75%, 50%-75%, 50%-99% or 75%-99% relative to expression, translation or activity in untreated or control samples. In some embodiments, MAPT expression, translation or activity is reduced as measured by any suitable assay, including but not limited to immunoassays, hybridization-based assays or sequencing-based assays (e.g., RNA-Seq).

在某些態樣中，本揭示案係關於靶向MAPT核酸之化合物。在某些實施例中，MAPT核酸具有GenBank登錄號NM_001377265.1 (以SEQ ID NO: 1併入本文中)，及NT_010783.14之核苷酸2624000至2761000 (以SEQ ID NO: 2併入本文中)中所示之序列。In some aspects, the disclosure is about the compound of targeting MAPT nucleic acid. In some embodiments, MAPT nucleic acid has GenBank accession number NM_001377265.1 (incorporated herein with SEQ ID NO: 1), and the sequence shown in nucleotide 2624000 to 2761000 of NT_010783.14 (incorporated herein with SEQ ID NO: 2).

在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物係單股的。在某些實施例中，化合物係雙股的。In some embodiments, the compound is an oligomeric compound. In some embodiments, the compound is single-stranded. In some embodiments, the compound is double-stranded.

某些實施例提供包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)之化合物，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。Certain embodiments provide compounds comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.

某些實施例提供包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)之化合物，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。Certain embodiments provide compounds comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.

某些實施例提供包含經修飾之寡核苷酸之化合物，該經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者組成之群的核鹼基序列。Certain embodiments provide compounds comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.

在某些實施例中，經修飾之寡核苷酸與SEQ ID NO: 1或2至少80%、至少85%、至少90%或至少95%互補。在某些實施例中，經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，化合物係雙股的。In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 2. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double-stranded.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含表2及表3中所提供之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of the nucleobase sequences provided in Tables 2 and 3; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising: a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其包含5'-膦酸酯修飾，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及第二經修飾之寡核苷酸，其包含一或多種本文所闡述之配位體(例如，一或多種原肌凝蛋白受體B (TrkB)配位體、一或多種1型大麻素受體(CB₁)配位體或一或多種α₄β_1/7整聯蛋白配位體)。在某些實施例中，第一經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。Certain embodiments provide compounds comprising: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands as described herein (e.g., one or more tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (_CB1 ) ligands, or one or more_α4β1/7 integrin ligands). In certain embodiments, the first modified oligonucleotide comprises a 5'-terminal nucleoside containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification.

在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206.

在某些實施例中，任一前述化合物之經修飾之寡核苷酸或第一經修飾之寡核苷酸在其長度上與SEQ ID NO: 1或2具有至少80%、至少85%、至少90%或至少95%之互補性或一致性。在某些實施例中，經修飾之寡核苷酸或第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域具有至少1個、至少2個、至少3個失配。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為14至30個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為14至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為19至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為21至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸與第二經修飾之寡核苷酸完全互補。In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the foregoing compounds has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in its length. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a region of SEQ ID NO: 1 or 2. In certain embodiments, the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 30 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 23 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 19 to 23 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

在某些實施例中，任一前述化合物之經修飾之寡核苷酸或第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，任一前述化合物之第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。在某些實施例中，硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯位於第一或第二經修飾之寡核苷酸之3’末端或位於第一經修飾之寡核苷酸之5’末端。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。在某些實施例中，經修飾之糖包含2’-F修飾。在某些實施例中，經修飾之糖包含2’-OMe修飾。在某些實施例中，第一經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖或其組合組成之群的修飾。在某些實施例中，經修飾之糖包含選自由2’-MOE、2’-F及2’-OMe或其組合組成之群的修飾。在某些實施例中，第一經修飾之寡核苷酸包含不超過十個2’-F糖修飾。在某些實施例中，第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。In certain embodiments, a modified oligonucleotide or a first modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, a second modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is located at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars. In certain embodiments, the modified sugar comprises a 2'-F modification. In certain embodiments, the modified sugar comprises a 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars or a combination thereof. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

在某些實施例中，任一前述實施例之化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種配位體。在某些實施例中，靶向部分包含一或多種選自一或多種原肌凝蛋白受體B (TrkB)配位體、一或多種1型大麻素受體(CB₁)配位體及一或多種α₄β_1/7整聯蛋白配位體之配位體。在某些實施例中，靶向部分包含一或多種TrkB配位體。在某些實施例中，靶向部分包含一或多種CB₁配位體。在某些實施例中，靶向部分包含一或多種α₄β_1/7整聯蛋白配位體。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多種TrkB配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，該一或多種CB₁配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。In certain embodiments, the compound of any of the foregoing embodiments comprises a binding group. In certain embodiments, the binding group is linked to the 5' end of the modified oligonucleotide. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more ligands selected from one or more tropomyosin receptor B (TrkB) ligands, one or more type 1 cannabinoid receptor (CB₁ ) ligands, and one or more α₄ β_1/7 integrin ligands. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the targeting moiety comprises one or more CB₁ ligands. In certain embodiments, the targeting moiety comprises one or more α₄ β_1/7 integrin ligands. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In some embodiments, the one or more TrkB ligands are attached to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide. In some embodiments, the one or more CB₁ ligands are attached to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide. In some embodiments, the one or more α₄ β_1/7 integrin ligands are attached to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(I)或為其鹽、溶劑合物或水合物：式(I)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³及L⁴係如本文所闡述； R²為氫、-OR⁷、-SR⁸或-NR⁹R¹⁰； R³為氫、-OR¹¹、-SR¹²或-NR¹³R¹⁴； R⁴為氫、-OR¹⁵、-SR¹⁶或-NR¹⁷R¹⁸； R⁵為氫、-OR¹⁹、-SR²⁰或-NR²¹R²²； R⁶為氫、-OH、視情況經取代之-O-烷基、視情況經取代之-OAc、-NH₂、視情況經取代之-NHAc、-SH或=O； R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基、視情況經取代之雜芳基； Y為CH₂、NH、S或O；且 Z為視情況經取代之芳基或視情況經取代之雜芳基。In certain embodiments, the TrkB ligand of the modified oligonucleotide has formula (I) or is a salt, solvate or hydrate thereof: Formula (I), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ and L⁴ are as described herein; R² is hydrogen, -OR⁷ , -SR⁸ or -NR⁹ R¹⁰ ; R³ is hydrogen, -OR¹¹ , -SR¹² or -NR¹³ R¹⁴ ; R⁴ is hydrogen, -OR¹⁵ , -SR¹⁶ or -NR¹⁷ R¹⁸ ; R⁵ is hydrogen, -OR¹⁹ , -SR²⁰ or -NR²¹ R²² ; R⁶ is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH₂ , optionally substituted -NHAc, -SH or =O; R⁷ , R⁸ , R⁹ , R^R10 ,^R11 ,^R12 ,^R13 ,^R14 ,^R15 ,^R16 ,^R17 ,^R18 ,^R19 ,^R20 ,^R21 and^R22 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is_CH2 , NH, S or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

在某些實施例中，R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為烯基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為炔基。In certain embodiments, R⁷ , R⁸ , R⁹ , R¹⁰ , R¹¹ , R¹² , R¹³ , R¹⁴ , R¹⁵ , R¹⁶ , R¹⁷ , R¹⁸ , R¹⁹ , R²⁰ , R²¹ and R²² are each independently an unsaturated or partially unsaturated alkyl group which is optionally substituted. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkenyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkynyl group.

在某些實施例中，R²為OR⁷。在某些實施例中，R³為OR¹¹。在某些實施例中，R⁷及R¹¹各自獨立地為氫、視情況經取代之烷基或視情況經取代之烯基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為氫。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為烯基。在某些實施例中，R⁷為視情況經取代之烷基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烷基。在某些實施例中，R⁷為烯基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烯基。In certain embodiments, R² is OR⁷ . In certain embodiments, R³ is OR¹¹ . In certain embodiments, R⁷ and R¹¹ are each independently hydrogen, optionally substituted alkyl or optionally substituted alkenyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R 7 and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R 11 are each independently substituted alkyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently unsaturated or partially unsaturated alkyl, which may be substituted. In certain embodiments, one or both of R⁷ and R¹¹ are each independently alkenyl. In certain embodiments, R⁷ is optionally substituted alkyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkyl. In certain embodiments, R^{7 is alkenyl and R 11 is hydrogen. In certain embodiments, R 7is hydrogen and R 11isoptionally} substituted alkenyl.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(II-A)、式(II-B)、式(II-C)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³、L⁴及R¹係如本文所闡述。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (II-A), Formula (II-B), Formula (II-C), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ , L⁴ and R¹ are as described herein.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXVII)或為其鹽、溶劑合物或水合物：式(XXXXXVII)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R¹¹及R¹³各自獨立地不存在、為氫或視情況經取代之烷基； R¹²、R¹⁴及R¹⁵各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R¹⁶為氫、鹵素、-CN、-N₃、-SO_n16R^1A、-SO_v16NR^16BR^16C、-NHNR^16BR^16C、-ONR^16BR^16C、-NHC(O)NHNR^16BR^16C、-NHC(O)NR^16BR^16C、-N(O)_m16、-NR^16BR^16C、-C(O)R^16D、-C(O)OR^16D、-C(O)NR^16BR^16C、-OR^16A、-NR^16BSO₂R^16A、-NR^16BC(O)R^16D、-NR^16BC(O)OR^16D、-NR^16BOR^16D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基；In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXVII) or is a salt, solvate or hydrate thereof: Formula (XXXXXVII), wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; R¹¹ and R¹³ are each independently absent, hydrogen or an optionally substituted alkyl group; R¹² , R¹⁴ and R¹⁵ are each independently hydrogen, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group,^an optionally substituted aryl group or an optionally substituted heteroaryl group; R¹⁶ is^hydrogen ,^ahalogen ,_-CN , -N₃ ,_-SON16R1A , -SOv16NR16BR16C ,^-NHNR16BR16C ,^-ONR16BR16C , -NHC(O)NHNR^16B R^16C , -NHC(O)NR^16B R^16C , -N(O)_m16 , -NR^16B R^16C , -C(O)R^16D , -C(O)OR^16D , -C(O)NR^16B R^16C , -OR^16A , -NR^16B SO₂ R^16A , -NR^16B C(O)R^16D , -NR^16B C(O)OR^16D , -NR^16B OR^16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

及各自獨立地為單鍵或雙鍵，其中若為單鍵，則為雙鍵且R¹³不存在；且進一步其中若為單鍵，則為雙鍵且R¹¹不存在； R^16A、R^16B、R^16C、R^16D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基；或鍵結至同一氮原子之R^16B及R^16C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； z3為0、1、2、3、4或5； n16為0、1、2、3或4；且 v16及m16各自獨立地為1或2。and Each is independently a single key or a double key, where if is a single key, then is a double key and R¹³ does not exist; and further wherein if is a single key, then is a double bond and R¹¹ is absent; R^16A , R^16B , R^16C , R^16D are each independently hydrogen, halogen, -CF₃ , -CCl₃ , -CBr₃ , -CI₃ , -COOH, -CONH₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or the R^16B and R^16C substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, as appropriate; z3 is 0, 1, 2, 3, 4 or 5; n16 is 0, 1, 2, 3 or 4; and v16 and m16 are each independently 1 or 2.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXIX)或為其鹽、溶劑合物或水合物：式(XXXXXIX)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R¹⁷、R¹⁸及R¹⁹各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； z4為0、1或2；且 z5為0、1、2或3。In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXIX) or is a salt, solvate or hydrate thereof: Formula (XXXXXIX), wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; R¹⁷ , R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; z4 is 0, 1 or 2; and z5 is 0, 1, 2 or 3.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXX)或為其鹽、溶劑合物或水合物：式(XXXXXX)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R²⁰為氫、鹵素、-CN、-N₃、-SO_n20R^1A、-SO_v20NR^20BR^20C、-NHNR^20BR^20C、-ONR^20BR^20C、-NHC(O)NHNR^20BR^20C、-NHC(O)NR^20BR^20C、-N(O)_m20、-NR^20BR^20C、-C(O)R^20D、-C(O)OR^20D、-C(O)NR^20BR^20C、-OR^20A、-NR^20BSO₂R^20A、-NR^20BC(O)R^20D；-NR^20BC(O)OR^20D、-NR^20BOR^20D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²¹為氫、鹵素、-CN、-N₃、-SO_n21R^1A、-SO_v21NR^21BR^21C、-NHNR^21BR^21C、-ONR^21BR^21C、-NHC(O)NHNR^21BR^21C、-NHC(O)NR^21BR^21C、-N(O)_m21、-NR^21BR^21C、-C(O)R^21D、-C(O)OR^21D、-C(O)NR^21BR^21C、-OR^21A、-NR^21BSO₂R^21A、-NR^21BC(O)R^21D；-NR^21BC(O)OR^21D、-NR^21BOR^21D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²²及R²³各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²⁴為氫、鹵素、-CN、-N₃、-SO_n24R^24A、-SO_v24NR^24BR^24C、-NHNR^24BR^24C、-ONR^24BR^24C、-NHC(O)NHNR^24BR^24C、-NHC(O)NR^24BR^24C、-N(O)_m24、-NR^24BR^24C、-C(O)R^24D、-C(O)OR^24D、-C(O)NR^24BR^24C、-OR^24A、-NR^24BSO₂R^24A、-NR^24BC(O)R^24D；-NR^24BC(O)OR^24D、-NR^24BOR^24D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R^20A、R^20B、R^20C、R^20D、R^21A、R^21B、R^21C、R^21D、R^24A、R^24B、R^24C及R^24D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 鍵結至同一氮原子之R^20B、R^20C、R^21B、R^21C、R^24B、R^24C、R^24B及R₂^4C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； n21、n22、n24、z6及z8各自獨立地為0、1、2、3或4； v20、v21、v24、m20、m21及m24各自獨立地為1或2；且 z7為0、1或2。In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXX) or is a salt, solvate or hydrate thereof: Formula (XXXXXX), wherein:^L1 ,^L2 ,^L3 ,^L4 and^R1are as described herein;^R20 is^hydrogen , halogen, -CN,_-N3 ,_-SON20R1A ,^{-SOv20NR20BR20C} , -NHNR20BR20C, -ONR20BR20C,^{-NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C,}_-N^{(O)20,-NR20BR20C,}_-C (^O )^R20D , -C(O^)OR20D_, -C(O^{)NR20BR20C,-OR20A,-NR20BSO2R20A} , -NR^20B C(O)R^20D ; -NR^20B C(O)OR^20D , -NR^20B OR^20D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted^aryl or optionally substituted_heteroaryl ;^R21is hydrogen, halogen, -CN,^-N₃ ,_-SON21R1A , -SOv21NR21BR21C ,^-NHNR21BR21C ,^-ONR21BR21C ,^-NHC (^O )^NHNR21BR21C , -NHC(O^)NR21BR21C_R^{22andR​​​​​}_​^{​​​​​​​​R 23} is each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R²⁴ is hydrogen, halogen, -CN, -N₃ ,_-SON24R^24A , -SO_v24 NR^24B R^24C , -NHNR^24B R^24C , -ONR^24B R^24C , -NHC(O)NHNR^24B R^24C , -NHC(O)NR^24B R^24C , -N(O)_m24 , -NR^24B R^24C , -C(O)R^24D , -C(O)OR^24D , -C(O)NR^24B R^24C , -OR^24A , -NR^24B SO₂ R^24A , -NR^24B C(O)R^24D ; -NR^24B C(O)OR^24D , -NR^24B OR^24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R^20A , R^20B , R 20C , R^20D , R^21A , R^21B , R^21C , R^21D , R^24A ,^{RR 24B} , R^24C and R^24D are each independently hydrogen, halogen, -CF₃ , -CCl₃ , -CBr₃ , -CI₃ , -COOH, -CONH₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R^20B , R^20C , R^21B , R 21C^, R^24B , R^{24C, R 24Band} R^24C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl_; n21, n22, n24, z6 and z8 are each independently 0, 1, 2, 3 or 4; v20, v21, v24, m20, m21 and m24 are each independently 1 or 2; and z7 is 0, 1 or 2.

在某些實施例中，經修飾之寡核苷酸之CB₁配位體具有式(XXXXXXI)或為其鹽、溶劑合物或水合物：， 式(XXXXXXI) 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； X¹為NR¹⁰或CR¹¹R¹²； R¹⁰、R¹¹及R¹²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R¹⁹為氫、-SO_n19R^19A、-SO_v19NR^19BR^19C、-NHNR^19BR^19C、-ONR^19BR^19C、-NHC(O)NHNR^19BR^19C、-NHC(O)NR^19BR^19C、-NR^19BR^19C、-C(O)R^19D、-C(O)OR^19D、-C(O)NR^19BR^19C、-OR^19A、-NR^19BSO₂R^19A、-NR^19BC(O)R^19D、-NR^19BC(O)OR^19D、-NR^19BOR^19D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R^19A、R^19B、R^19C、R^19D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基；其中鍵結至同一氮原子之R^19B及R^19C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； n19為0、1、2、3或4；且 v19為1或2。In certain embodiments, the_CB1 ligand of the modified oligonucleotide has the formula (XXXXXXI) or is a salt, solvate or hydrate thereof: , Formula (XXXXXXI) wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; X¹ is NR¹⁰ or CR¹¹ R¹² ; R¹⁰ , R¹¹ and R¹² are each independently hydrogen, optionally substituted alkyl, optionally substituted^heteroalkyl , optionally substituted^cycloalkyl , optionally substituted^{heterocycloalkyl} , optionally substituted aryl or optionally substituted^heteroaryl ;^R19 is hydrogen,_-SON19R19A ,_{-SOv19NR19BR19C}^{,-NHNR19BR19C} ,^-ONR19BR19C , -NHC(O)^NHNR19BR19C , -NHC(O)NR^19B R^19C , -NR^19B R^19C , -C(O)R^19D , -C(O)OR^19D , -C(O)NR^19B R^19C , -OR^19A , -NR^19B SO₂ R^19A , -NR^19B C(O)R^19D , -NR^19B C(O)OR^19D , -NR^19B OR^19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R^19A , R^19B , R^19C , R^R19D is each independently hydrogen, halogen,_-CF3 ,_-CCl3 ,_-CBr3 ,_-CI3 , -COOH,_-CONH2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; wherein^R19B and^R19C substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl as appropriate; n19 is 0, 1, 2, 3 or 4; and v19 is 1 or 2.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、聚乙二醇(PEG)、視情況經取代之雜烷基或視情況經取代之雜芳基；且 R³及R⁴各自獨立地為H、鹵素、視情況經取代之烷基或視情況經取代之-O-烷基。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXII) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, polyethylene glycol (PEG), an optionally substituted heteroalkyl group or an optionally substituted heteroaryl group; and R³ and R⁴ are each independently H, a halogen, an optionally substituted alkyl group or an optionally substituted -O-alkyl group.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXIII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXIII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²、R³、R⁴及R⁵各自獨立地為H、鹵素、視情況經取代之烷基、視情況經取代之-O-烷基、環烷基，或不存在； R⁸為視情況經取代之C₁-C₅烷基、視情況經取代之C₁-C₅伸烷基-(C₃-C₆)-環烷基或視情況經取代之(C₁-C₄)-伸烷基-(C₁-C₄)-烷氧基；且 R⁶及R⁷各自獨立地為H、鹵素、烷基或視情況經取代之烷基、視情況經取代之雜烷基、、、、、或。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXIII) or is a salt, solvate or hydrate thereof: Formula (XXXXXXIII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² , R³ , R⁴ and R⁵ are each independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent; R⁸ is optionally substituted C₁ -C₅ alkyl, optionally substituted C₁ -C₅ alkylene-(C₃ -C₆ )-cycloalkyl or optionally substituted (C₁ -C₄ )-alkylene-(C₁ -C₄ )-alkoxy; and R⁶ and R⁷ are each independently H, halogen, alkyl or optionally substituted alkyl, optionally substituted heteroalkyl, , , , , or .

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXIV)或為其鹽、溶劑合物或水合物：. 式(XXXXXXIV) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、-CONHR⁴、-CH₂OR⁴、-(CH₂)₂OR⁴、-CH₂NHCOR⁴或-OR⁴； R³為H、視情況經取代之烷基或視情況經取代之環烷基； R⁴為H、聚乙二醇、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基或視情況經取代之雜芳基； R⁵為-OH或不存在；且 X為H、視情況經取代之CH₂、視情況經取代之NH或環烷基。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXIV) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXIV) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, -CONHR⁴ , -CH₂ OR⁴ , -(CH₂ )₂ OR⁴ , -CH₂ NHCOR⁴ or -OR⁴ ; R³ is H, optionally substituted alkyl or optionally substituted cycloalkyl; R⁴ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; R⁵ is -OH or absent; and X is H, optionally substituted CH₂ , optionally substituted NH or cycloalkyl.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXXXIII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXXXIII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、-CONHR³、-CH₂OR³、-(CH₂)₂OR³、-CH₂NHCOR³或-OR³； R³之每一實例獨立地為H、聚乙二醇、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基或視情況經取代之雜芳基；且 X為H或鹵素。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXXXIII) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXXXIII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, -CONHR³ , -CH₂ OR³ , -(CH₂ )₂ OR³ , -CH₂ NHCOR³ or -OR³ ; each instance of R³ is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; and X is H or a halogen.

在某些實施例中，L¹、L²、L³及L⁴各自獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體。In certain embodiments, L¹ , L² , L³ and L⁴ are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之雜芳基連接體。In certain embodiments, L¹ is an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之不飽和雜芳基、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L¹ is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L¹包含結構：。In certain embodiments,^L1 comprises the structure: .

在某些實施例中，L¹為視情況經取代之雜烷基連接體。在某些實施例中，視情況經取代之雜烷基連接體為視情況經取代之雜烷基或視情況經取代之C₁-C₁₀烷基鏈，其中一或多個碳原子經O、N或S置換。In certain embodiments, L¹ is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C₁ -C₁₀ alkyl chain in which one or more carbon atoms are replaced by O, N or S.

在某些實施例中，L¹包含結構：或。In certain embodiments,^L1 comprises the structure: or .

在某些實施例中，L¹包含結構：或-N(CH₃)-。In certain embodiments,^L1 comprises the structure: or -N(CH₃ )-.

在某些實施例中，L²為視情況經取代之PEG連接體。In certain embodiments,^L2 is an optionally substituted PEG linker.

在某些實施例中，PEG連接體之長度為五個PEG單元。在某些實施例中，PEG連接體之長度為四個PEG單元。在某些實施例中，PEG連接體之長度為三個PEG單元。In some embodiments, the length of the PEG conjugate is five PEG units. In some embodiments, the length of the PEG conjugate is four PEG units. In some embodiments, the length of the PEG conjugate is three PEG units.

在某些實施例中，L²為視情況經取代之烷基連接體。在某些實施例中，L²為視情況經取代之C_1-20烷基連接體。在某些實施例中，L²為視情況經取代之C₈烷基連接體。在某些實施例中，L³為視情況經取代之雜芳基連接體。In some embodiments,^L2 is an optionally substituted alkyl linker. In some embodiments,^L2 is an optionally substituted_C1-20 alkyl linker. In some embodiments,^L2 is an optionally substituted_C8 alkyl linker. In some embodiments,^L3 is an optionally substituted heteroaryl linker.

在某些實施例中，L³為視情況經取代之部分不飽和雜芳基連接體、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L³ is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L³包含結構：。In certain embodiments,^L3 comprises the structure: .

在某些實施例中，L⁴為視情況經取代之雜烷基連接體。在某些實施例中，雜烷基連接體經一或多個=O取代基取代。In certain embodiments,^L4 is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents.

在某些實施例中，雜烷基連接體包含兩個接合在一起形成視情況經取代之碳環基環之取代基。In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L¹-L²-L³-L⁴包含結構：、、、、、、、、、、、、、、、、、、， 或其鹽，其中X為O或S。In certain embodiments, L¹ -L² -L³ -L⁴ comprises the structure: , , , , , , , , , , , , , , , , , , , or a salt thereof, wherein X is O or S.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)、式(XII)、式(XIII)、式(XIV)、式(XV)、式(XVI)、式(XVII)、式(XVIII)、式(XIX)、式(XX)、BA-129 式(XXI)、BA-169 式(XXII)、BA-170：異構物混合物 式(XXIII)、BA-173 式(XXIV)、BA-183 式(XXV)、BA-201 式(XXVI)、BA-203 式(XXVII)、BA-196 式(XXIX)BA-197 式(XXX)BA-198 式(XXXI)BA-225 式(XXXIII)BA-246 式(XXXIV)式(XXXXXXV)式(XXXXXXVI)式(XXXXXXVII)式(XXXXXXIX)式(XXXXXXX)式(XXXXXXXI)式(XXXXXXXII)式(XXXXXXXIII)， 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), BA-129 (XXI), BA-169 (XXII), BA-170: isomer mixture formula (XXIII), BA-173 (XXIV), BA-183 (XXV), BA-201 type (XXVI), BA-203 type (XXVII), BA-196 Type (XXIX) BA-197 Type (XXX) BA-198 Type (XXXI) BA-225 Formula (XXXIII) BA-246 Type (XXXIV) Formula (XXXXXXV) Formula (XXXXXXVI) Formula (XXXXXXVII) Formula (XXXXXXIX) Formula (XXXXXXX) Formula (XXXXXXXI) Formula (XXXXXXXII) Formula (XXXXXXXIII), wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，經修飾之寡核苷酸之CB₁配位體係選自以下各式或其鹽、溶劑合物或水合物：式(XXXXXXXIV)式(XXXXXXXV)式(XXXXXXXVI)式(XXXXXXXVII)式(XXXXXXXVIII) 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the_CB1 ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (XXXXXXXIV) Formula (XXXXXXXV) Formula (XXXXXXXVI) Formula (XXXXXXXVII) Formula (XXXXXXXVIII) wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體係選自以下各式或其鹽、溶劑合物或水合物：式(XXXXXXXIX)式(XXXXXXXX)式(XXXXXXXXI)式(XXXXXXXXII)式(XXXXXXXXIV) 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (XXXXXXXIX) Formula (XXXXXXXX) Formula (XXXXXXXXI) Formula (XXXXXXXXII) Formula (XXXXXXXXIV) wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，任一前述實施例之化合物包含脂質。在某些實施例中，脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多種脂質。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the preceding embodiments comprises a lipid. In certain embodiments, the lipid is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more lipids. In certain embodiments, the one or more lipids are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，任一前述實施例之化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide. In certain embodiments, a modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups is linked to one or more internucleoside linkages of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₄ -C₃₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated_C18 hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated_C22 hydrocarbon chains.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is attached to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。In certain embodiments, the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any one of Formula XXXV-Formula XXXXXVI.

在某些實施例中，經修飾之寡核苷酸包含式(XXXV)，或其鹽、溶劑合物或水合物：式(XXXV)， 其中： Y為-C(=O)N(R^C)-或-N(R^C)C(=O)-； Q¹及Q³各自獨立地為-H、-OR⁴、配位體、連接體或脂質； Q²及Q⁴各自獨立地為鍵、、配位體、連接體或脂質； R^C獨立地為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基； 每一R⁹獨立地為經取代或未經取代之雜芳基； Z¹或Z²之每一實例獨立地為鍵、C₁-C₆伸烷基或C₂-C₆伸烯基；且 每一X獨立地為O或S； 或其鹽。In certain embodiments, the modified oligonucleotide comprises formula (XXXV), or a salt, solvate or hydrate thereof: Formula (XXXV), wherein: Y is -C(=O)N(^RC )- or -N(^RC )C(=O)-;^Q1 and^Q3 are each independently -H,^-OR4 , a ligand, a linker or a lipid;^Q2 and^Q4 are each independently a bond, , ligand, linker or lipid;^RC is independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(R6) or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ) or^-SR7 ;^R4 and^R5 are independently an oligonucleotide, or^R4 and^R5 are independently an^{oligonucleotide} .⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl; each R⁹ is independently substituted or unsubstituted heteroaryl; each instance of Z¹ or Z² is independently a bond, C₁ -C₆ alkylene, or C₂ -C₆ alkenylene; and each X is independently O or S; or a salt thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVI)，或其鹽、溶劑合物或水合物：式(XXXVI)， 其中： R^C為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVI), or a salt, solvate or hydrate thereof: Formula (XXXVI), wherein:^RC is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted^alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(^R6 ), or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ), or^-SR7 ;^R4 and^R5 are independently oligonucleotides, or^R4 and^R5 are joined together to form a single oligonucleotide; each R R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl ring; each R⁹ is independently substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVII)，或其鹽、溶劑合物或水合物：式(XXXVII)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVII), or a salt, solvate or hydrate thereof: Formula (XXXVII), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVIII)，或其鹽、溶劑合物或水合物：式(XXXVIII)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVIII), or a salt, solvate or hydrate thereof: Formula (XXXVIII), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXIX)，或其鹽、溶劑合物或水合物：式(XXXIX)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXIX), or a salt, solvate or hydrate thereof: Formula (XXXIX), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXX)，或其鹽、溶劑合物或水合物：式(XXXX)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXX), or a salt, solvate or hydrate thereof: Formula (XXXX), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXI)，或其鹽、溶劑合物或水合物：mUëmU式(XXXXI) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXI), or a salt, solvate or hydrate thereof:mUëmU Formula (XXXXI) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXII)，或其鹽、溶劑合物或水合物：mAëmA式(XXXXII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXII), or a salt, solvate or hydrate thereof:mAëmA Formula (XXXXII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIII)，或其鹽、溶劑合物或水合物：mAëmU式(XXXXIII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIII), or a salt, solvate or hydrate thereof:mAëmU Formula (XXXXIII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIV)，或其鹽、溶劑合物或水合物：mAëmG式(XXXXIV) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIV), or a salt, solvate or hydrate thereof:mAëmG Formula (XXXXIV) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXV)，或其鹽、溶劑合物或水合物：mAëmC式(XXXXV) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXV), or a salt, solvate or hydrate thereof:mAëmC Formula (XXXXV) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVI)，或其鹽、溶劑合物或水合物：mUëmA式(XXXXVI) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVI), or a salt, solvate or hydrate thereof:Formula (XXXXVI ) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVII)，或其鹽、溶劑合物或水合物：mUëmG式(XXXXVII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVII), or a salt, solvate or hydrate thereof:mUëmG Formula (XXXXVII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVIII)，或其鹽、溶劑合物或水合物：mUëfC式(XXXXVIII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVIII), or a salt, solvate or hydrate thereof:Formula (XXXXVIII)wherein : R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIX)，或其鹽、溶劑合物或水合物：fGëmU式(XXXXIX) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIX), or a salt, solvate or hydrate thereof:fGëmU Formula (XXXXIX) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXX)，或其鹽、溶劑合物或水合物：mGëfG式(XXXXX) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXX), or a salt, solvate or hydrate thereof:mGëfG formula (XXXXX) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXXI)，或其鹽、溶劑合物或水合物：mGëmC式(XXXXXI) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXXI), or a salt, solvate or hydrate thereof:mGëmC Formula (XXXXXI) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXXII)，或其鹽、溶劑合物或水合物：mCëmA式(XXXXXII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXXII), or a salt, solvate or hydrate thereof:mCëmA Formula (XXXXXII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含以下各式中之一者之核苷間鍵聯：式(XXXXXIII)、式(XXXXXIV)、式(XXXXXV)、式(XXXXXVI)。In certain embodiments, the modified oligonucleotide comprises an internucleoside linkage of one of the following formulas: Formula (XXXXXIII), Formula (XXXXXIV), Formula (XXXXXV), Formula (XXXXXVI).

在某些實施例中，任一前述實施例之化合物包含5'-膦酸酯修飾。舉例而言，在某些實施例中，經修飾之寡核苷酸包含一或多個在5'位具有膦酸酯修飾之糖。在某些實施例中，經修飾之寡核苷酸包含5'-膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷(例如5'末端)。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸為第一經修飾之寡核苷酸或反義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., the 5' end) containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其包含5'-膦酸酯修飾，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及第二經修飾之寡核苷酸，其包含一或多種配位體。Certain embodiments provide compounds comprising: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands.

在一些實施例中，第一經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷。在一些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在一些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在一些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。In some embodiments, the first modified oligonucleotide comprises a 5' terminal nucleoside containing a 5'-phosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種選自一或多種TrkB配位體、一或多種CB₁配位體及一或多種α4β1/7整聯蛋白配位體之配位體。在一些實施例中，該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α4β1/7整聯蛋白配位體連接至第二經修飾之寡核苷酸之5’端。在一些實施例中，該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α4β1/7整聯蛋白配位體連接至第二經修飾之寡核苷酸之3’端。在一些實施例中，該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α4β1/7整聯蛋白配位體連接至第二經修飾之寡核苷酸之5’端及3’端。在一些實施例中，該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者；該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者；且該一或多種α4β1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。In some embodiments, the second modified oligonucleotide comprises one or more ligands selected from one or more TrkB ligands, one or more CB₁ ligands, and one or more α4β1/7 integrin ligands. In some embodiments, the one or more TrkB ligands, the one or more CB₁ ligands, or the one or more α4β1/7 integrin ligands are linked to the 5' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands, the one or more CB₁ ligands, or the one or more α4β1/7 integrin ligands are linked to the 3' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands, the one or more CB₁ ligands, or the one or more α4β1/7 integrin ligands are linked to the 5' and 3' ends of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII, and Formula XXXXXXIX-XXXXXXIII; the one or more CB₁ ligands are selected from any one of Formula XXXXXXXI and Formula XXXXXXXIV-XXXXXXVIII; and the one or more α4β1/7 integrin ligands are selected from any one of Formula XXXXXXXII-XXXXXXIV and Formula XXXXXXXIX-XXXXXXXXXIV.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種TrkB配位體。在一些實施例中，該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者。在一些實施例中，該一或多種TrkB配位體係選自式XXIX-式XXXI及式XXXXXXV中之任一者。在一些實施例中，第二經修飾之寡核苷酸包含一種TrkB配位體。在一些實施例中，第二經修飾之寡核苷酸包含兩種TrkB配位體。在一些實施例中，第二經修飾之寡核苷酸包含至少兩種TrkB配位體。在一些實施例中，該至少兩種TrkB配位體係相同的。在一些實施例中，該至少兩種TrkB配位體係不同的。In some embodiments, the second modified oligonucleotide comprises one or more TrkB ligands. In some embodiments, the one or more TrkB ligands are selected from any one of Formula I-Formula XXXIV, Formula XXXXXVII, Formula XXXXXIX-Formula XXXXXX, Formula XXXXXXV-Formula XXXXXXVII and Formula XXXXXXIX-Formula XXXXXXXIII. In some embodiments, the one or more TrkB ligands are selected from any one of Formula XXIX-Formula XXXI and Formula XXXXXXV. In some embodiments, the second modified oligonucleotide comprises one TrkB ligand. In some embodiments, the second modified oligonucleotide comprises two TrkB ligands. In some embodiments, the second modified oligonucleotide comprises at least two TrkB ligands. In some embodiments, the at least two TrkB ligands are the same. In some embodiments, the at least two TrkB ligands are different.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種CB₁配位體。在一些實施例中，該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者。在一些實施例中，該一或多種CB₁配位體係選自式XXXXXXXIV-式XXXXXXXVI中之任一者。在一些實施例中，第二經修飾之寡核苷酸包含一種CB₁配位體。在一些實施例中，第二經修飾之寡核苷酸包含兩種CB₁配位體。在一些實施例中，第二經修飾之寡核苷酸包含至少兩種CB₁配位體。在一些實施例中，該至少兩種CB₁配位體係相同的。在一些實施例中，該至少兩種CB₁配位體係不同的。In some embodiments, the second modified oligonucleotide comprises one or more CB₁ ligands. In some embodiments, the one or more CB₁ ligands are selected from any one of formula XXXXXXXI and formula XXXXXXXIV-formula XXXXXXXVIII. In some embodiments, the one or more CB₁ ligands are selected from any one of formula XXXXXXXIV-formula XXXXXXXVI. In some embodiments, the second modified oligonucleotide comprises one CB₁ ligand. In some embodiments, the second modified oligonucleotide comprises two CB₁ ligands. In some embodiments, the second modified oligonucleotide comprises at least two CB₁ ligands. In some embodiments, the at least two CB₁ ligands are the same. In some embodiments, the at least two CB₁ ligands are different.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種α₄β_1/7整聯蛋白配位體。在一些實施例中，該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。在一些實施例中，該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXXXI、式XXXXXXXXII及式XXXXXXXXIV中之任一者。在一些實施例中，第二經修飾之寡核苷酸包含一種α₄β_1/7整聯蛋白配位體。在一些實施例中，第二經修飾之寡核苷酸包含兩種α₄β_1/7整聯蛋白配位體。在一些實施例中，第二經修飾之寡核苷酸包含至少兩種α₄β_1/7整聯蛋白配位體。在一些實施例中，該至少兩種α₄β_1/7整聯蛋白配位體係相同的。在一些實施例中，該至少兩種α₄β_1/7整聯蛋白配位體係不同的。In some embodiments, the second modified oligonucleotide comprises one or more α₄ β_1/7 integrin ligands. In some embodiments, the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXII-XXXXXXXIV and XXXXXXXIX-XXXXXXXIV. In some embodiments, the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXXI, Formula XXXXXXXXXII and Formula XXXXXXXXXIV. In some embodiments, the second modified oligonucleotide comprises one α₄ β_1/7 integrin ligand. In some embodiments, the second modified oligonucleotide comprises two α₄ β_1/7 integrin ligands. In some embodiments, the second modified oligonucleotide comprises at least two α₄ β_1/7 integrin ligands. In some embodiments, the at least two_α4β1/7 integrin ligands are the same. In some embodiments, the at least two_α4β1/7 integrin ligands are different.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種脂質。在一些實施例中，第二經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。In some embodiments, the second modified oligonucleotide comprises one or more lipids. In some embodiments, the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₄ -C₃₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain, or a saturated or unsaturated_C22 hydrocarbon chain.

在一些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至第二經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端5個位置內的核苷之間。In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to the internucleoside linkage of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., 5' end and/or 3' end) of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 3' end of the second modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the second modified oligonucleotide.

在一些實施例中，第二經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。在一些實施例中，第二經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。In some embodiments, the internucleoside bond of the second modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI. In some embodiments, the second modified oligonucleotide comprises any one of Formula XXXV-Formula XXXXXVI.

在一些實施例中，第一經修飾之寡核苷酸之長度為14至30個連接核苷。在一些實施例中，第二經修飾之寡核苷酸之長度為14至30個連接核苷，其具有與第一經修飾之寡核苷酸互補之區域。在一些實施例中，第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少14個鄰接核鹼基之核鹼基序列。在一些實施例中，第二經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之至少14個鄰接核鹼基之核鹼基序列。在一些實施例中，第一經修飾之寡核苷酸係選自表3中IA Ref ID NO中之任一者。在一些實施例中，第二經修飾之寡核苷酸係選自表3中IS Ref ID NO中之任一者。In some embodiments, the first modified oligonucleotide has a length of 14 to 30 linked nucleosides. In some embodiments, the second modified oligonucleotide has a length of 14 to 30 linked nucleosides having a region complementary to the first modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the second modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the first modified oligonucleotide is selected from any one of the IA Ref ID NOs in Table 3. In some embodiments, the second modified oligonucleotide is selected from any one of the IS Ref ID NOs in Table 3.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之Ref ID NO中之任一者組成之群；及長度為14至21個連接核苷之第二經修飾之寡核苷酸，其與該第一經修飾之寡核苷酸完全互補。Certain embodiments provide a compound comprising: a first modified oligonucleotide selected from the group consisting of any one of the Ref ID NOs listed in Table 3; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides that is completely complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之IA Ref ID NO中之任一者組成之群；及第二經修飾之寡核苷酸，其係選自由表3中所列示之IS Ref ID NO中之任一者組成之群。在某些實施例中，第二經修飾之寡核苷酸包含本文所提供之任一或多種TrkB配位體。在某些實施例中，TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，TrkB配位體係選自式XXIX-式XXXI及式XXXXXXV，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至TrkB配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至TrkB配位體。在某些實施例中，本文提供選自由表3中所列示之化合物中之任一者組成之群的化合物。Certain embodiments provide compounds comprising: a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3; and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more TrkB ligands provided herein. In certain embodiments, the TrkB ligand is selected from Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII, and Formula XXXXXXIX-XXXXXXIII, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the TrkB ligand is selected from Formula XXIX-XXXI and Formula XXXXXXV, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a phosphorothioate group. In certain embodiments, provided herein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之IA Ref ID NO中之任一者組成之群；及第二經修飾之寡核苷酸，其係選自由表3中所列示之IS Ref ID NO中之任一者組成之群。在某些實施例中，第二經修飾之寡核苷酸包含本文所提供之任一或多種CB₁配位體。在某些實施例中，CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，CB₁配位體係選自式XXXXXXXIV-式XXXXXXXVI，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至CB₁配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至CB₁配位體。在某些實施例中，本文提供選自由表3中所列示之化合物中之任一者組成之群的化合物。Certain embodiments provide compounds comprising: a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3; and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more CB₁ ligands provided herein. In certain embodiments, the CB_{1 ligand is selected from Formula XXXXXXXI and Formula XXXXXXXIV-Formula XXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the CB 1ligand} is selected from Formula XXXXXXXIV-Formula XXXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the CB₁ ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the CB₁ ligand via a phosphorothioate group. In certain embodiments, provided herein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之IA Ref ID NO中之任一者組成之群；及第二經修飾之寡核苷酸，其係選自由表3中所列示之IS Ref ID NO中之任一者組成之群。在某些實施例中，第二經修飾之寡核苷酸包含本文所提供之任一或多種α₄β_1/7整聯蛋白配位體。在某些實施例中，α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，α₄β_1/7整聯蛋白配位體係選自式XXXXXXXXI、式XXXXXXXXII及式XXXXXXXXIV，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至α₄β_1/7整聯蛋白配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至α₄β_1/7整聯蛋白配位體。在某些實施例中，本文提供選自由表3中所列示之化合物中之任一者組成之群的化合物。Certain embodiments provide compounds comprising: a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3; and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more α₄ β_1/7 integrin ligands provided herein. In certain embodiments, the α₄ β_1/7 integrin ligand is selected from Formula XXXXXXII-Formula XXXXXXXIV and Formula XXXXXXXIX-Formula XXXXXXXIV, or a salt, solvate or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the α₄ β_1/7 integrin ligand is selected from Formula XXXXXXXXI, Formula XXXXXXXXII and Formula XXXXXXXXIV, or a salt, solvate or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the α₄ β_1/7 integrin ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the α₄ β_1/7 integrin ligand via a phosphorothioate group. In certain embodiments, provided herein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

在某些實施例中，本文所提供之經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽或鉀鹽。在某些實施例中，本文所提供化合物之醫藥學上可接受之鹽為鈉鹽或鉀鹽。In certain embodiments, the pharmaceutically acceptable salt of the modified oligonucleotides provided herein is a sodium salt or a potassium salt. In certain embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a sodium salt or a potassium salt.

在某些實施例中，本文提供經修飾之寡核苷酸群體，其中經修飾之寡核苷酸之所有硫代磷酸酯核苷間鍵聯均為立體隨機的。在某些實施例中，本文提供化合物群體，其中經修飾之寡核苷酸之所有硫代磷酸酯核苷間鍵聯均為立體隨機的。In certain embodiments, provided herein are populations of modified oligonucleotides, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random. In certain embodiments, provided herein are populations of compounds, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random.

在某些實施例中，任一前述實施例之化合物係呈醫藥學上可接受之鹽形式。在某些實施例中，醫藥學上可接受之鹽為鈉鹽。在某些實施例中，醫藥學上可接受之鹽為鉀鹽。In some embodiments, the compound of any of the foregoing embodiments is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt.

某些實施例提供組合物，其包含如前述實施例中任一項之化合物以及醫藥學上可接受之載劑。Certain embodiments provide a composition comprising a compound as described in any of the preceding embodiments and a pharmaceutically acceptable carrier.

某些實施例提供包含任一前述實施例之化合物之組合物，其用於療法中。Certain embodiments provide a composition comprising a compound of any preceding embodiment for use in therapy.

某些實施例提供治療、預防或改善個體之與MAPT相關的疾病、病症或疾患之方法，其包括向該個體投與靶向MAPT之化合物，藉此治療、預防或改善該疾病。Certain embodiments provide methods for treating, preventing or ameliorating a disease, disorder or condition associated with MAPT in a subject, comprising administering to the subject a compound that targets MAPT, thereby treating, preventing or ameliorating the disease.

在某些實施例中，向個體投與任一前述實施例之化合物或組合物。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。In some embodiments, a compound or composition of any of the preceding embodiments is administered to a subject. In some embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.

在某些實施例中，投與化合物抑制或減少或改進CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。In certain embodiments, administration of the compound inhibits or reduces or ameliorates a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.

在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以治療有效量投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以足以遞送約1至100 mg/kg個體體重之劑量水準投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以約25 mg至約1,000 mg之固定劑量投與給個體。在某些實施例中，在一天內向個體投與一或多次化合物或組合物，直至該劑量水準或固定劑量。In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject in a therapeutically effective amount. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject at a dosage level sufficient to deliver about 1 to 100 mg/kg of the subject's body weight. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, a compound or composition is administered to a subject one or more times a day up to the dosage level or fixed dose.

在某些實施例中，每天、每週、每月、每季度或每年向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次(亦即每三個月一次)至約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次、約每六個月一次或約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject daily, weekly, monthly, quarterly, or annually. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject about once a quarter, about once every six months, or about once a year.

某些實施例提供抑制細胞中之MAPT表現之方法，其包括使該細胞與靶向MAPT之化合物接觸，藉此抑制該細胞中之MAPT表現。在某些實施例中，細胞在個體之肝臟中。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或處於患有此類疾病、病症或疾患或其症狀之風險下。Certain embodiments provide methods for inhibiting MAPT expression in a cell, comprising contacting the cell with a compound targeting MAPT, thereby inhibiting MAPT expression in the cell. In certain embodiments, the cell is in the liver of an individual. In certain embodiments, the individual suffers from a CNS-related disease, disorder or illness or its symptoms or a neurodegenerative disease or its symptoms, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or is at risk of suffering from such a disease, disorder or illness or its symptoms.

某些實施例提供減少或抑制個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害之方法，其包括向該個體投與靶向MAPT之化合物，藉此減少或抑制該個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物為靶向MAPT之化合物。在某些實施例中，化合物為前述化合物中之任一者。在某些實施例中，非經腸投與化合物或組合物。在某些實施例中，藉由鞘內(IT)投與來投與化合物或組合物。Certain embodiments provide methods of reducing or inhibiting a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof in a subject, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, comprising administering to the subject The invention relates to administering a compound targeting MAPT to a subject to reduce or inhibit a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof in the subject, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In some embodiments, the individual suffers from a CNS-related disease, disorder or illness or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or is at risk of such a disease, disorder or illness or its symptoms. In some embodiments, the compound is a compound targeting MAPT. In some embodiments, the compound is any one of the aforementioned compounds. In some embodiments, the compound or composition is administered parenterally. In some embodiments, the compound or composition is administered by intrathecal (IT) administration.

某些實施例提供靶向MAPT之化合物之用途，其用於治療、預防或改善與MAPT相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物為靶向MAPT之化合物。在某些實施例中，化合物為前述化合物中之任一者。Some embodiments provide the use of a compound targeting MAPT, which is used to treat, prevent or improve a disease, disorder or illness associated with MAPT. In some embodiments, the disease, disorder or illness is a CNS-related disease, disorder or illness or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In some embodiments, the compound is a compound targeting MAPT. In some embodiments, the compound is any one of the aforementioned compounds.

某些實施例提供靶向MAPT之化合物之用途，其用於製造用以治療、預防或改善與MAPT相關之疾病、病症或疾患的藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物為靶向MAPT之化合物。在某些實施例中，化合物為前述化合物中之任一者。Certain embodiments provide the use of a compound targeting MAPT, which is used to manufacture a medicament for treating, preventing or improving a disease, disorder or illness associated with MAPT. In certain embodiments, the disease, disorder or illness is a CNS-related disease, disorder or illness or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compound is a compound targeting MAPT. In certain embodiments, the compound is any one of the aforementioned compounds.

在某些實施例中，圖1-圖4、表A、表2及表3中所示之任一化合物可用於本揭示案之任何態樣中。在本揭示案之化合物、組合物、方法或用途之一些實施例中，化合物為圖1-圖4、表A、表2及表3中所示之任一化合物。In some embodiments, any compound shown in Figures 1-4, Table A, Table 2 and Table 3 can be used in any aspect of the present disclosure. In some embodiments of the compounds, compositions, methods or uses of the present disclosure, the compound is any compound shown in Figures 1-4, Table A, Table 2 and Table 3.

在某些實施例中，圖1-圖4中所示之任一化合物可用於本揭示案之任何態樣中。在本揭示案之化合物、組合物、方法或用途之一些實施例中，化合物為圖1-圖4中所示之任一化合物。In some embodiments, any of the compounds shown in Figures 1-4 can be used in any aspect of the present disclosure. In some embodiments of the compounds, compositions, methods or uses of the present disclosure, the compound is any of the compounds shown in Figures 1-4.

在某些實施例中，表2中之任一化合物可用於本揭示案之任何態樣中。在本揭示案之化合物、組合物、方法或用途之一些實施例中，化合物為表2中之任一化合物。In some embodiments, any of the compounds in Table 2 can be used in any aspect of the present disclosure. In some embodiments of the compounds, compositions, methods or uses of the present disclosure, the compound is any of the compounds in Table 2.

在某些實施例中，表3中之任一化合物可用於本揭示案之任何態樣中。在本揭示案之化合物、組合物、方法或用途之一些實施例中，化合物為表3中之任一化合物。In some embodiments, any of the compounds in Table 3 can be used in any aspect of the present disclosure. In some embodiments of the compounds, compositions, methods or uses of the present disclosure, the compound is any of the compounds in Table 3.

在某些實施例中，表A中之任一化合物可用於本揭示案之任何態樣中。在本揭示案之化合物、組合物、方法或用途之一些實施例中，化合物為表A中之任一化合物。在本揭示案之任一態樣之一些實施例中，化合物係選自表A中化合物1至285中之任一者。下文所示之表A為化合物1至285中之每一者提供以下：顯示股修飾(如表1中所定義)之反義(「A」)及有義(「S」)股核鹼基序列(SEQ ID NO)，且在有義股包含配位體之情形下，在有義股5’端(「5’-配位體」)及/或3’端(「3’-配位體」)處之配位體類型(例如如本文所闡述之TrkB配位體、CB₁配位體或α₄β_1/7整聯蛋白配位體)。在一些實施例中，5’-配位體及/或3’-配位體經由連接體連接至有義股。在一些實施例中，連接體包含聚乙二醇(PEG)。在一些實施例中，連接體包含長度為一個、兩個、三個、四個、五個、六個、七個或八個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為一個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為兩個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為三個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為四個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為五個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為六個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為七個PEG單元之PEG鏈。在某些實施例中，連接體包含長度為八個PEG單元之PEG鏈。在一些實施例中，連接體包含視情況經取代之雜芳基或視情況經取代之雜環基。在某些實施例中，連接體包含PEG及視情況經取代之雜芳基或視情況經取代之雜環基。表A. 例示性化合物名稱股5’-配位體經修飾之股(5’-3’)3’-配位體SEQ ID 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certain embodiments, any compound in Table A can be used in any aspect of the present disclosure. In some embodiments of the compounds, compositions, methods or uses of the present disclosure, the compound is any compound in Table A. In some embodiments of any aspect of the present disclosure, the compound is selected from any one of compounds 1 to 285 in Table A. Table A, shown below, provides the following for each of compounds 1 to 285: the antisense ("A") and sense ("S") strand base sequences (SEQ ID NOs) showing strand modifications (as defined in Table 1), and where the sense strand comprises a ligand, the type of ligand at the 5' end ("5'-ligand") and/or 3' end ("3'-ligand") of the sense strand (e.g., TrkB ligands, CB₁Ligand or α₄β_1/7Integrin ligands). In some embodiments, the 5'-ligand and/or the 3'-ligand are linked to the sense strand via a linker. In some embodiments, the linker comprises polyethylene glycol (PEG). In some embodiments, the linker comprises a PEG chain that is one, two, three, four, five, six, seven, or eight PEG units in length. In some embodiments, the linker comprises a PEG chain that is one PEG unit in length. In some embodiments, the linker comprises a PEG chain that is two PEG units in length. In some embodiments, the linker comprises a PEG chain that is three PEG units in length. In some embodiments, the linker comprises a PEG chain that is four PEG units in length. In some embodiments, the linker comprises a PEG chain that is five PEG units in length. In some embodiments, the linker comprises a PEG chain of six PEG units in length. In some embodiments, the linker comprises a PEG chain of seven PEG units in length. In some embodiments, the linker comprises a PEG chain of eight PEG units in length. In some embodiments, the linker comprises an optionally substituted heteroaryl or an optionally substituted heterocyclic group. In some embodiments, the linker comprises PEG and an optionally substituted heteroaryl or an optionally substituted heterocyclic group.Table A. Exemplary compoundsNameshare5'-ligandModified strands (5'-3')3'-ligandSEQ ID NO:1 A vU*fU*mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG.fA.mG.fC.mU*mU*mU 11S TkB mA*mG.mC.mU.mC.mG.fC.mA.fU.fG.fG.fU.mC.mA.mG.mU.mA.mA.mA.mA*mA*dQ 812 A vU*fU*mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fU.mU.fG.mG.fU.mU.fA.mG*mC*mC 12S TkB mC*mU.mA.mA.mC.mC.fA.mA.fU.fU.fC.fU.mC.mU.mU.mU.mG.mU.mA.mA*mA*dQ 823 A vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC 13S TkB mU*mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ 834 A vA*fG*mU.fC.mC.fU.mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fC.mU.fG.mG*mU*mU 14S TkB mC*mC.mA.mG.mU.mU.fC.mU.fC.fU.fU.fU.mG.mU.mA.mA.mG.mG.mA.mC*mU*dQ 845 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU 15S TkB mC*mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 856 A vA*fA*mC.fA.mU.fC.mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG*mC*mU 16S TkB mC*mU.mG.mA.mA.mC.fA.mU.fA.fU.fA.fC.mA.mU.mA.mG.mA.mU.mG.mU*mU*dQ 867 A vU*fC*mU.fA.mA.fA.mC.fC.mA.fU.mG.fA.mU.fU.mU.fU.mA.fG.mG.fC.mU*mG*mG 17S TkB mA*mG.mC.mC.mU.mA.fA.mA.fA.fU.fC.fA.mU.mG.mG.mU.mU.mU.mA.mG*mA*dQ 878 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18S TkB mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ 889 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19S TkB mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 8910 A vA*fU*mA.fG.mC.fA.mA.fA.mC.fA.mG.fG.mA.fU.mA.fC.mA.fG.mU.fC.mU*mC*mA 20S TkB mA*mG.mA.mC.mU.mG.fU.mA.fU.fC.fC.fU.mG.mU.mU.mU.mG.mC.mU.mA*mU*dQ 9011 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC twenty oneS TkB mA*mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 9112 A vA*fC*mU.fA.mU.fA.mU.fA.mG.fA.mC.fA.mU.fU.mC.fA.mC.fA.mG.fA.mC*mA*mG twenty twoS TkB mG*mU.mC.mU.mG.mU.fG.mA.fA.fU.fG.fU.mC.mU.mA.mU.mA.mU.mA.mG*mU*dQ 9213 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU twenty threeS TkB mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 9314 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 9415 A vU*fG*mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU.fU.mC*mC*mA 25S TkB mG*mA.mA.mG.mC.mG.fA.mU.fG.fA.fC.fA.mA.mA.mA.mA.mA.mG.mC.mC*mA*dQ 9516 A vU*fU*mG.fG.mC.fU.mU.fU.mU.fU.mU.fG.mU.fU.mA.fU.mC.fG.mC.fU.mU*mC*mC 26S TkB mA*mA.mG.mC.mG.mA.fU.mA.fA.fC.fA.fA.mA.mA.mA.mA.mG.mC.mC.mA*mA*dQ 9617 A vU*fU*mU.fG.mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU*mU*mC 27S TkB mA*mG.mC.mG.mA.mU.fG.mA.fC.fA.fA.fA.mA.mA.mA.mG.mC.mC.mA.mA*mA*dQ 9718 A vU*fU*mC.fA.mA.fC.mU.fG.mG.fU.mU.fU.mG.fU.mA.fG.mA.fC.mU.fA.mU*mU*mU 28S TkB mA*mU.mA.mG.mU.mC.fU.mA.fC.fA.fA.fA.mC.mC.mA.mG.mU.mU.mG.mA*mA*dQ 9819 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29S TkB mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ 9920 A vA*fU*mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC.fU.mG*mC*mU 30S TkB mC*mA.mG.mC.mU.mG.fA.mA.fC.fA.fU.fA.mU.mA.mC.mA.mU.mA.mG.mA*mU*dQ 100twenty one A vA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC*mU*mG 31S TkB mG*mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG*mU*dQ 101twenty two A vU*fA*mA.fG.mC.fA.mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC*mA*mA 32S TkB mG*mG.mA.mU.mU.mU.fG.mU.fC.fU.fG.fU.mU.mU.mA.mU.mG.mC.mU.mU*mA*dQ 102twenty three A vU*fA*mC.fA.mC.fU.mA.fU.mA.fU.mA.fG.mA.fU.mA.fU.mU.fC.mA.fC.mA*mG*mA 33S TkB mU*mG.mU.mG.mA.mA.fU.mA.fU.fC.fU.fA.mU.mA.mU.mA.mG.mU.mG.mU*mA*dQ 103twenty four A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 34S TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 10425 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 37S TkB mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 10726 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 38S TkB mC*mU.mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 10827 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mA 39S TkB mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 10928 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG 40S TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 11029 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU 41S TkB mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 11130 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU*mG*mA 42S TkB mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 11231 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 43S TkB mG*mC.mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ 11332 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC 44S TkB mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 11433 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU*mU*mG 45S TkB mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 11534 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU 46S TkB mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 11635 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA*mG*mC 47S TkB mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 11736 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU*fG*mC 48S TkB mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ 11837 A vU*fC*mU.fU.mU.fU.mA.fC.mU.fG.mA.fC.mC.fA.mU.fG.mC.fG.mA.fG.mC*mU*mU 49S TkB mG*mC.mU.mC.mG.mC.fA.mU.fG.fG.fU.fC.mA.mG.mU.mA.mA.mA.mA.mG*mA*dQ 11938 A vA*fA*mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU.fU.mG*mC*mA 50S TkB mG*mC.mA.mA.mA.mU.mA.fG.mU.fC.fU.fA.fC.mA.mA.mA.mC.mC.mA.mG.mU*mU*dQ 12039 A vU*fC*mA.fA.mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU*mU*mG 51S TkB mA*mA.mA.mU.mA.mG.mU.fC.mU.fA.fC.fA.fA.mA.mC.mC.mA.mG.mU.mU.mG*mA*dQ 12140 A vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC 52S TkB mC*mU.mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ 12241 A vU*fA*mA.fC.mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA*mG*mC 53S TkB mC*mU.mG.mA.mA.mC.mA.fU.mA.fU.fA.fC.fA.mU.mA.mG.mA.mU.mG.mU.mU*mA*dQ 12342 A vA*fA*mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU.fA.mC.fA.mA*mC*mU 54S TkB mG*mU.mU.mG.mU.mA.mG.fU.mU.fG.fG.fA.fU.mU.mU.mG.mU.mC.mU.mG.mU*mU*dQ 12443 A vU*fA*mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU*mA*mC 55S TkB mU*mA.mG.mU.mU.mG.mG.fA.mU.fU.fU.fG.fU.mC.mU.mG.mU.mU.mU.mA.mU*mA*dQ 12544 A vU*fC*mA.fU.mA.fA.mA.fC.mA.fG.mA.fC.mA.fA.mA.fU.mC.fC.mA.fA.mC*mU*mA 56S TkB mA*mG.mU.mU.mG.mG.mA.fU.mU.fU.fG.fU.fC.mU.mG.mU.mU.mU.mA.mU.mG*mA*dQ 12645 A vA*fA*mG.fC.mA.fU.mA.fA.mA.fC.mA.fG.mA.fU.mA.fA.mA.fU.mC.fC.mA*mA*mC 57S TkB mU*mU.mG.mG.mA.mU.mU.fU.mA.fU.fC.fU.fG.mU.mU.mU.mA.mU.mG.mC.mU*mU*dQ 12746 A vA*fC*mC.fU.mC.fU.mU.fU.mA.fC.mA.fA.mG.fU.mA.fU.mU.fU.mC.fA.mA*mG*mA 58S TkB mC*mU.mU.mG.mA.mA.mA.fU.mA.fC.fU.fU.fG.mU.mA.mA.mA.mG.mA.mG.mG*mU*dQ 12847 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC 59S TkB mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA*mA*dQ 12948 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60S TkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 13049 A vA*fU*mU.fC.mA.fU.mC.fC.mC.fA.mA.fU.mC.fU.mC.fU.mG.fC.mU.fG.mU*mG*mG 61S TkB mC*mA.mC.mA.mG.mC.mA.fG.mA.fG.fA.fU.fU.mG.mG.mG.mA.mU.mG.mA.mA*mU*dQ 13150 A vA*fU*mG.fG.mA.fG.mU.fU.mU.fG.mU.fG.mC.fA.mA.fG.mG.fU.mC.fA.mG*mC*mG 62S TkB mC*mU*mG.mA.mC.mC.fU.mU.fG.fC.fA.fC.mA.mA.mA.mC.mU.mC.mC.mA*mU*dQ 13251 A vU*fA*mU.fG.mG.fA.mG.fU.mU.fU.mG.fU.mG.fU.mA.fA.mG.fG.mU.fC.mA*mG*mC 63S TkB mC*mU.mG.mA.mC.mC.mU.fU.mA.fC.fA.fC.fA.mA.mA.mC.mU.mC.mC.mA.mU*mA*dQ 13352 A 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eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152182 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.mC 149183 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ TkB 149184 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 152185 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 152186 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 94187 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ 94188 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 152189 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C16 152190 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S C18*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 130191 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC*mA*dQ*t6.mC 152192 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC*mA*dQ*t6.mC TkB 152193 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ TkB 130194 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ TkB 130195 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 149196 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 130197 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ TkB 130198 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 164199 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mC*mU.mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 165200 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG 190S TkB mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 166201 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mA*mA*mG 191S TkB mU*mU.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 167202 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA 192S TkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 168203 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA 192S TkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 164204 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mG 194S TkB mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 166205 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mC*mA 195S TkB mU*mG.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 171206 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC 196S TkB mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 172207 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG 197S TkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 168208 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG 197S TkB mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 174209 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mG 199S TkB mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 174210 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fG.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 200S TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fC.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 176211 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152212 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C22 152213 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94214 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS c6*mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.mC 149215 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 168216 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 164217 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG 190S TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 94218 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ 94219 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC 59S TkB mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TkB 129220 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fU.mC*mU*mC 209S TkB mA*mG.mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TkB 201221 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mU*mU*mC 210S TkB mA*mA.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TkB 202222 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fU*mC 211S TkB mG*mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TkB 203223 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fC*mU 212S TkB mA*mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TkB 204224 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mC 177S TkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 154225 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mU*mC 213S TkB mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 205226 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC 214S TkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 154227 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA*mG*mU 215S TkB mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 205228 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA*fA*mG 216S TkB mC*mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 206229 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mU 217S TkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TkB 154230 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ TkB 164231 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188S TkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TkB 164232 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC 196S TkB mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TkB 172233 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TkB 94234 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mGëmC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TkB 94235 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94236 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 130237 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*c6 130238 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TkB 130239 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TkB 94240 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94241 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS α₄ β_1/7 integrin c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94242 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94243 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC CB1 149244 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS α₄ β_1/7 integrin c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC α₄ β_1/7 integrin 149245 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94246 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94247 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS c6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC TkB 149248 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC α₄ β_1/7 integrin 149249 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94250 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS c6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC TkB 149251 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94252 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS α₄ β_1/7 integrin c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94253 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152254 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S CB1 c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152255 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S α₄ β_1/7 integrin c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152256 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S α₄ β_1/7 integrin t6.mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC α₄ β_1/7 integrin 152257 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S CB1 c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC 152258 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94259 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94260 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94261 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94262 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94263 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94264 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94265 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG twenty fourS TkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 TkB 94266 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18S TkB c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 TkB 88267 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18S α₄ β_1/7 integrin c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 α₄ β_1/7 integrin 88268 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18S CB1 c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 CB1 88269 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19S TkB c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 TkB 89270 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19S α₄ β_1/7 integrin c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 α₄ β_1/7 integrin 89271 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19S CB1 c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 CB1 89272 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29S TkB c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 TkB 99273 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29S α₄ β_1/7 integrin c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 α₄ β_1/7 integrin 99274 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29S CB1 c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 CB1 99275 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66S TkB c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 TkB 136276 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66S α₄ β_1/7 integrin c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 α₄ β_1/7 integrin 136277 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66S CB1 c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 CB1 136278 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 130279 A fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 130280 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 130281 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 130282 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 130283 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145S TkB AC6*mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 130284 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60S TkB AC6*mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 150285 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60S TkB AC6*mG*mGëmC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 TkB 150Certain indications

在某些態樣中，本揭示案係關於藉由投與靶向MAPT之化合物而抑制MAPT表現之方法，其可用於治療、預防或改善個體之與MAPT相關之疾病。在某些實施例中，該化合物可為MAPT特異性抑制劑。在某些實施例中，該化合物可為靶向MAPT之反義寡核苷酸、寡聚化合物或寡核苷酸(例如圖1-圖4、表A、表2及表3中所示化合物中之任一者之化合物)。In some aspects, the present disclosure is about a method of inhibiting the expression of MAPT by administering a compound targeting MAPT, which can be used to treat, prevent or improve a disease associated with MAPT in an individual. In some embodiments, the compound can be a MAPT-specific inhibitor. In some embodiments, the compound can be an antisense oligonucleotide, an oligomeric compound or an oligonucleotide targeting MAPT (e.g., a compound of any one of the compounds shown in Figures 1-4, Table A, Table 2 and Table 3).

在某些態樣中，本揭示案係關於治療、預防或改善與MAPT相關之疾病、病症或疾患。在某些實施例中，本文所提供之方法可治療、可預防及/或可改善之與MAPT相關之疾病、病症或疾患包括CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。本文所提供之某些化合物係關於減少動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害之化合物及組合物。In some aspects, the disclosure is about treating, preventing or improving diseases, disorders or illnesses associated with MAPT. In some embodiments, the methods provided herein can treat, prevent and/or improve diseases, disorders or illnesses associated with MAPT, including CNS-related diseases, disorders or illnesses or symptoms thereof or neurodegenerative diseases or symptoms thereof, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. Certain compounds provided herein are compounds and compositions for reducing CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof in animals, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.

在某些實施例中，治療、預防或改善個體之與MAPT相關之疾病的方法包括向該個體投與包含MAPT特異性抑制劑之化合物，藉此治療、預防或改善該疾病。在某些實施例中，個體鑑別為患有與MAPT相關之疾病，或處於患有該疾病之風險下。在某些實施例中，疾病為CNS相關之疾病。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在某些實施例中，單股化合物之長度可為14至30個、14至23個、14至20個、16至20個或14至16個連接核苷。在某些實施例中，單股化合物之長度可為14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個連接核苷。在某些實施例中，如本文中別處所闡述，雙股化合物可包含兩個相同或不同長度之寡核苷酸。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，投與化合物改進、保持或預防動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。In certain embodiments, the method for treating, preventing or improving a disease associated with MAPT in an individual comprises administering to the individual a compound comprising a specific inhibitor of MAPT, thereby treating, preventing or improving the disease. In certain embodiments, the individual is identified as suffering from a disease associated with MAPT, or is at risk of suffering from the disease. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In certain embodiments, the length of a single-stranded compound may be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 linked nucleosides. In certain embodiments, the length of a single-stranded compound may be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleosides. In certain embodiments, as described elsewhere herein, a double-stranded compound may comprise two oligonucleotides of the same or different lengths. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to a subject parenterally. In certain embodiments, the compound is administered to a subject by intrathecal (IT) administration. In certain embodiments, administration of the compound ameliorates, maintains or prevents a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, in an animal, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.

在某些實施例中，治療、預防或改善動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害之方法包括向個體投與包含MAPT特異性抑制劑之化合物，藉此治療、預防或改善CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，投與化合物改進、保持或預防動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，個體鑑別為患有與MAPT相關之疾病，或處於患有該疾病之風險下。In certain embodiments, a method of treating, preventing or ameliorating a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof in an animal, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment comprises administering to the individual Compounds comprising a specific inhibitor of MAPT, thereby treating, preventing or ameliorating CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In some embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In some embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217, and ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide of 19 to 23 linked nucleosides in length. In certain embodiments, the administration of the compound improves, maintains or prevents a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof in an animal, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the individual is identified as having a disease associated with MAPT, or is at risk of having the disease.

在某些實施例中，抑制患有與MAPT相關之疾病或處於患有該疾病之風險下的個體中之MAPT表現之方法包括向該個體投與包含MAPT特異性抑制劑之化合物，藉此抑制該個體中之MAPT表現。在某些實施例中，投與化合物抑制肝臟中之MAPT表現。在某些實施例中，疾病為CNS相關之疾病。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，投與化合物改進、保持或預防CNS相關之疾病、病症或疾患或其症狀、神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。In certain embodiments, a method of inhibiting the expression of MAPT in an individual suffering from a disease associated with MAPT or at risk of suffering from the disease comprises administering to the individual a compound comprising a MAPT-specific inhibitor, thereby inhibiting the expression of MAPT in the individual. In certain embodiments, the administration of the compound inhibits the expression of MAPT in the liver. In certain embodiments, the disease is a CNS-related disease. In some embodiments, the individual suffers from a CNS-related disease, disorder or condition or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or is at risk of suffering from such a disease, disorder or condition or its symptoms. In some embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In some embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to a subject parenterally. In certain embodiments, the compound is administered to a subject by intrathecal (IT) administration. In certain embodiments, administration of the compound ameliorates, maintains or prevents a CNS-related disease, disorder or condition or symptoms thereof, a neurodegenerative disease or symptoms thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.

在某些實施例中，抑制細胞中之MAPT表現之方法包括使該細胞與包含MAPT特異性抑制劑之化合物接觸，藉此抑制該細胞中之MAPT表現。在某些實施例中，細胞為肝細胞。在某些實施例中，細胞在肝臟中。在某些實施例中，細胞在個體之肝臟中，該個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之任一核鹼基序列或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之序列組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。In some embodiments, the method of inhibiting MAPT expression in a cell comprises contacting the cell with a compound comprising a MAPT-specific inhibitor, thereby inhibiting MAPT expression in the cell. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is in the liver. In some embodiments, the cell is in the liver of an individual who suffers from a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or is at risk of suffering from such a disease, disorder or condition or symptoms thereof. In some embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In some embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217, or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of the sequence of at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases; and a second modified oligonucleotide (e.g., 14 to 30, such as 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217, or a sequence of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

在某些實施例中，減少或抑制患有與MAPT相關之疾病或處於患有該疾病之風險下的個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害之方法包括向該個體投與包含MAPT特異性抑制劑之化合物，藉此減少或抑制該個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206序列中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之序列之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，個體鑑別為患有與MAPT相關之疾病，或處於患有該疾病之風險下。In certain embodiments, the invention reduces or inhibits a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof in an individual suffering from or at risk of suffering from a disease related to MAPT, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. The method of treating a subject comprises administering to the subject a compound comprising a specific inhibitor of MAPT, thereby reducing or inhibiting a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof in the subject, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In some embodiments, the individual suffers from a CNS-related disease, disorder or condition or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment, or is at risk of suffering from such a disease, disorder or condition or its symptoms. In some embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In some embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206 sequences. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to a subject parenterally. In certain embodiments, the compound is administered to a subject by intrathecal (IT) administration. In certain embodiments, the individual is identified as having, or being at risk for, a disease associated with MAPT.

某些實施例係關於包含MAPT特異性抑制劑之化合物，其用於治療與MAPT相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。Some embodiments are about compounds comprising MAPT specific inhibitors, which are used to treat diseases, disorders or illnesses associated with MAPT. In some embodiments, the disease, disorder or illness is a CNS-related disease, disorder or illness or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In some embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In some embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to a subject parenterally. In certain embodiments, the compound is administered to a subject by intrathecal (IT) administration.

某些實施例係關於包含MAPT特異性抑制劑之化合物，其用於減少或抑制CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to compounds comprising a specific inhibitor of MAPT, which are used to reduce or inhibit CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide of 19 to 23 linked nucleosides in length.

某些實施例係關於包含MAPT特異性抑制劑之化合物之用途，其用於製造或製備用以治療與MAPT相關之疾病之藥劑。某些實施例係關於包含MAPT特異性抑制劑之化合物之用途，其用於製備用以治療與MAPT相關之疾病、病症或疾患之藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀。在某些實施例中，疾病、病症或疾患為神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to the use of a compound comprising a specific inhibitor of MAPT for the manufacture or preparation of a medicament for treating a disease associated with MAPT. Certain embodiments relate to the use of a compound comprising a specific inhibitor of MAPT for the preparation of a medicament for treating a disease, disorder or condition associated with MAPT. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide of 19 to 23 linked nucleosides in length.

某些實施例係關於包含MAPT特異性抑制劑之化合物之用途，其用於製造或製備用以減少或抑制個體之CNS相關之疾病、病症或疾患或其症狀的藥劑，該個體患有與MAPT相關之CNS相關之疾病、病症或疾患或其症狀，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，CNS相關之疾病、病症或疾患為神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。某些實施例係關於包含MAPT特異性抑制劑之化合物之用途，其用於製備用以治療與MAPT相關之疾病、病症或疾患之藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇、德拉韋氏症候群或認知損害。在某些實施例中，化合物包含靶向MAPT之反義寡核苷酸。在某些實施例中，化合物包含靶向MAPT之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to the use of compounds comprising specific inhibitors of MAPT for the manufacture or preparation of a medicament for reducing or inhibiting a CNS-related disease, disorder or condition or symptoms thereof in an individual suffering from, or at risk of suffering from, a CNS-related disease, disorder or condition or symptoms thereof that is associated with MAPT. In certain embodiments, the CNS-related disease, disorder or condition is a neurodegenerative disease or symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. Certain embodiments are related to the use of compounds comprising specific inhibitors of MAPT, which are used to prepare medicaments for treating diseases, disorders or diseases associated with MAPT. In certain embodiments, the disease, disorder or disease is a CNS-related disease, disorder or disease or its symptoms or a neurodegenerative disease or its symptoms, including tau pathology, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), and the modified oligonucleotide has a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217; and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence; and a second modified oligonucleotide (e.g., a length of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206; and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide of 19 to 23 linked nucleosides in length.

在任一前述方法或用途中，化合物可為寡聚化合物。在任一前述方法或用途中，化合物可為單股或雙股的。在任一前述方法或用途中，化合物可靶向MAPT。在某些實施例中，化合物包含經修飾之寡核苷酸或由其組成。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸。在某些實施例中，化合物包含第一經修飾之寡核苷酸及第二經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸之長度為8至80個連接核苷、長度為10至30個連接核苷、長度為14至30個連接核苷、長度為14至23個連接核苷或長度為19至23個連接核苷。在某些實施例中，經修飾之寡核苷酸在其長度上與SEQ ID NO: 1及3中所列舉之任一核鹼基序列至少80%、至少85%、至少90%、至少95%或100%互補。在某些實施例中，經修飾之寡核苷酸包含至少一個經修飾之核苷間鍵聯、至少一個經修飾之糖及/或至少一個經修飾之核鹼基。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯。在某些實施例中，經修飾之糖為雙環糖、2’-MOE、2’-F或2’-OMe。在某些實施例中，經修飾之核鹼基為5-甲基胞嘧啶。在任一前述實施例中，每一經修飾之寡核苷酸之長度獨立地為12至30個、14至30個、14至25個、14至24個、14至23個、16至23個、17至23個、18至23個、19至23個、19至22個或19至20個連接核苷。在某些實施例中，經修飾之寡核苷酸與SEQ ID NO: 1及2之區域具有至少1個、至少2個、至少3個失配。In any of the aforementioned methods or uses, the compound may be an oligomeric compound. In any of the aforementioned methods or uses, the compound may be single-stranded or double-stranded. In any of the aforementioned methods or uses, the compound may target MAPT. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the length of the modified oligonucleotide is 8 to 80 linked nucleosides, a length of 10 to 30 linked nucleosides, a length of 14 to 30 linked nucleosides, a length of 14 to 23 linked nucleosides, or a length of 19 to 23 linked nucleosides. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary in length to any of the nucleobase sequences listed in SEQ ID NOs: 1 and 3. In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In certain embodiments, the modified nucleobase is 5-methylcytosine. In any of the foregoing embodiments, the length of each modified oligonucleotide is independently 12-30, 14-30, 14-25, 14-24, 14-23, 16-23, 17-23, 18-23, 19-23, 19-22, or 19-20 linked nucleosides. In certain embodiments, the modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with regions of SEQ ID NOs: 1 and 2.

在任一前述方法或用途中，化合物包含第一及第二經修飾之寡核苷酸，其中在第一經修飾之寡核苷酸與第二經修飾之寡核苷酸之間存在互補區。在某些實施例中，第一寡核苷酸與第二寡核苷酸之間的互補區之長度為14至23個、19至23個或21至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸與第二經修飾之寡核苷酸完全互補。在某些實施例中，第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。在某些實施例中，經修飾之核苷間鍵聯位於第一或第二經修飾之寡核苷酸之3’末端或位於第一或第二經修飾之寡核苷酸之5’末端。在某些實施例中，第一或第二經修飾之寡核苷酸包含一或多個經修飾之糖。在某些實施例中，第一或第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。在某些實施例中，經修飾之糖包含選自由2’-MOE、2’-F及2’-OMe或其組合組成之群的修飾。在某些實施例中，第一或第二經修飾之寡核苷酸包含不超過十個2’-F糖修飾。在某些實施例中，第一或第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。In any of the foregoing methods or uses, the compound comprises a first and a second modified oligonucleotide, wherein there is a complementary region between the first modified oligonucleotide and the second modified oligonucleotide. In certain embodiments, the complementary region between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide and the second modified oligonucleotide are completely complementary. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the modified internucleoside linkage is located at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

在任一前述方法或用途中，在某些實施例中，化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，一個結合基團連接至經修飾之寡核苷酸之5’端，且一個結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種配位體。在某些實施例中，靶向部分包含一或多種TrkB配位體。在某些實施例中，該一或多種TrkB配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至TrkB配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至TrkB配位體。在某些實施例中，結合基團包含一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸包含一或多種配位體及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含一或多種TrkB配位體及一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之5’端。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之3’端。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物。在某些實施例中，該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸亦包含式XXXV-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。In any of the aforementioned methods or uses, in certain embodiments, the compound comprises a binding group. In certain embodiments, the binding group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the binding group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, one binding group is attached to the 5' end of the modified oligonucleotide, and one binding group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the one or more TrkB ligands are attached to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide. In certain embodiments, the TrkB ligand is selected from Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII and Formula XXXXXXIX-XXXXXXIII, or a salt, solvate or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a thiophosphate group. In certain embodiments, the binding group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide. In some embodiments, the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide. In some embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises any one of Formula XXXV-Formula XXXXXVI. In some embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In some embodiments, the modified oligonucleotide is a second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are linked to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are linked to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are linked to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups) are linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII, and Formula XXXXXXIX-XXXXXXIII, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide, and the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXIII-XXXXXVI, or a salt, solvent or hydrate thereof. In certain embodiments, the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII, and Formula XXXXXXIX-XXXXXXIII, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide, and the modified oligonucleotide also comprises any one of Formula XXXV-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide.

在任一前述方法或用途中，在某些實施例中，化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，一個結合基團連接至經修飾之寡核苷酸之5’端，且一個結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種配位體。在某些實施例中，靶向部分包含一或多種CB₁配位體。在某些實施例中，該一或多種CB₁配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至CB₁配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至CB₁配位體。在某些實施例中，結合基團包含一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸包含一或多種配位體及一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含一或多種CB₁配位體，及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種CB₁配位體連接至經修飾之寡核苷酸之5’端。在某些實施例中，該一或多種CB₁配位體連接至經修飾之寡核苷酸之3’端。在某些實施例中，該一或多種CB₁配位體連接至經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物。在某些實施例中，該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸亦包含式XXXV-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。In any of the aforementioned methods or uses, in certain embodiments, the compound comprises a binding group. In certain embodiments, the binding group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the binding group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, one binding group is attached to the 5' end of the modified oligonucleotide, and one binding group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more CB₁ ligands. In certain embodiments, the one or more CB₁ ligands are attached to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide. In certain embodiments, the CB₁ ligand is selected from Formula XXXXXXXI and Formula XXXXXXXIV-Formula XXXXXXXVIII, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the CB₁ ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the CB₁ ligand via a thiophosphate group. In certain embodiments, the binding group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide. In certain embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups) are linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXXXXIII-XXXXXVI, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any one of Formula XXXV-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more CB₁ ligands, and one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide. In certain embodiments, the one or more CB₁ ligands are linked to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more CB₁ ligands are linked to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more CB₁ ligands are linked to the 5' end and the 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more CB₁ ligands are selected from any one of Formula XXXXXXXI and Formula XXXXXXXIV-Formula XXXXXXXVIII, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide, and the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXXXXXXIII-Formula XXXXXXVI, or a salt, solvent or hydrate thereof. In certain embodiments, the one or more_CB1 ligands are selected from Formula XXXXXI and any one of Formula XXXXXXXIV-XXXXXXXVIII, or a salt, a solvate or a hydrate thereof, wherein R is a modified oligonucleotide, and the modified oligonucleotide also includes any one of Formula XXXV-XXXXVI, or a salt, a solvate or a hydrate thereof, wherein R is a modified oligonucleotide.

在任一前述方法或用途中，在某些實施例中，化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，一個結合基團連接至經修飾之寡核苷酸之5’端，且一個結合基團連接至經修飾之寡核苷酸之3’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種配位體。在某些實施例中，靶向部分包含一或多種α₄β_1/7整聯蛋白配位體。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至α₄β_1/7整聯蛋白配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至α₄β_1/7整聯蛋白配位體。在某些實施例中，結合基團包含一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸包含一或多種配位體及一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種脂質(例如一或多個經取代或未經取代之烷基或烯基)連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含一或多種α₄β_1/7整聯蛋白配位體及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體連接至經修飾之寡核苷酸之5’端。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體連接至經修飾之寡核苷酸之3’端。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體連接至經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物。在某些實施例中，該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸亦包含式XXXV-式XXXXXVI中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。In any of the aforementioned methods or uses, in certain embodiments, the compound comprises a binding group. In certain embodiments, the binding group is linked to the 5' end of the modified oligonucleotide. In certain embodiments, the binding group is linked to the 3' end of the modified oligonucleotide. In certain embodiments, one binding group is linked to the 5' end of the modified oligonucleotide, and one binding group is linked to the 3' end of the modified oligonucleotide. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more α₄ β_1/7 integrin ligands. In certain embodiments, the one or more α₄ β_1/7 integrin ligands are linked to the 5' end or 3' end of the oligonucleotide, or to the 5' end and 3' end of the oligonucleotide. In certain embodiments, the α₄ β_1/7 integrin ligand is selected from Formula XXXXXXII-XXXXXXXIV and Formula XXXXXXXIX-XXXXXXXIV, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the α₄ β_1/7 integrin ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the α₄ β_1/7 integrin ligand via a phosphorothioate group. In certain embodiments, the binding group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In some embodiments, the modified oligonucleotide is a second modified oligonucleotide. In some embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups) are linked to the internucleoside linkage of the modified oligonucleotide. In some embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises any one of Formula XXXV-Formula XXXXXVI. In some embodiments, the modified oligonucleotide comprises one or more α₄ β_1/7 integrin ligands and one or more lipids. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide. In certain embodiments, the one or more_α4β1 /₇ integrin ligands are linked to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more_α4β1/7 integrin ligands are linked to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more_α4β1 /₇ integrin ligands are linked to the 5' end and the 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more_α4β1/7 integrin ligands are selected from any one of Formula XXXXXXII-XXXXXXXIV and XXXXXXXIX-XXXXXXXIV, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide, and the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXXXIII-XXXXXXVI, or a salt, solvent or hydrate thereof. In certain embodiments, the one or more_α4β1/7 integrin ligands are selected from any one of Formula XXXXXXII-XXXXXXXIV and Formula XXXXXXXIX-XXXXXXXIV, or a salt, a solvate or a hydrate thereof, wherein R is a modified oligonucleotide, and the modified oligonucleotide also comprises any one of Formula XXXV-XXXXVI, or a salt, a solvate or a hydrate thereof, wherein R is a modified oligonucleotide.

在任一前述方法或用途中，在某些實施例中，化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In any of the foregoing methods or uses, in certain embodiments, the compound comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₈ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated_C22 hydrocarbon chain.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkages are between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。In certain embodiments, the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any one of Formula XXXV-Formula XXXXXVI.

在任一前述方法或用途中，在某些實施例中，化合物包含5'-膦酸酯修飾。舉例而言，在某些實施例中，經修飾之寡核苷酸包含一或多個在5'位具有膦酸酯修飾之糖。在某些實施例中，經修飾之寡核苷酸包含5'-膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷(例如5'末端)。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸為第一經修飾之寡核苷酸或反義寡核苷酸。In any of the foregoing methods or uses, in certain embodiments, the compound comprises a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., the 5' end) containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

在任一前述方法或用途中，化合物包含選自由表3中之IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸及長度為14至23個連接核苷且與該第一經修飾之寡核苷酸完全互補的第二經修飾之寡核苷酸。在某些實施例中，化合物包含選自表3中之IA Ref ID NO中之任一者的第一經修飾之寡核苷酸 及選自表3中之IS Ref ID NO中之任一者的第二經修飾之寡核苷酸。在某些實施例中，化合物係呈醫藥學上可接受之鹽形式。在某些實施例中，醫藥學上可接受之鹽為鈉鹽。在某些實施例中，醫藥學上可接受之鹽為鉀鹽。在某些實施例中，組合物包含如前述實施例中任一項之化合物以及醫藥學上可接受之載劑。In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs in Table 3 and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides and fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from any one of the IA Ref ID NOs in Table 3 and a second modified oligonucleotide selected from any one of the IS Ref ID NOs in Table 3. In certain embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, the composition comprises a compound as in any of the foregoing embodiments and a pharmaceutically acceptable carrier.

在任一前述方法或用途中，將化合物或包含任一前述實施例之化合物之組合物以治療有效量投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以足以遞送約1至100 mg/kg個體體重之劑量水準投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以約25 mg至約1,000 mg之固定劑量投與給個體。在某些實施例中，在一天內向個體投與一或多次組合物，直至該劑量水準或固定劑量。In any of the aforementioned methods or uses, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject in a therapeutically effective amount. In certain embodiments, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject at a dosage level sufficient to deliver about 1 to 100 mg/kg of the subject's body weight. In certain embodiments, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to a subject one or more times a day up to the dosage level or fixed dose.

在任一前述方法或用途中，每天、每週、每月、每季度或每年向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次(亦即每三個月一次)至約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次、約每六個月一次或約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。某些化合物In any of the foregoing methods or uses, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject daily, weekly, monthly, quarterly, or annually. In certain embodiments, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject from about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject about once a quarter, about once every six months, or about once a year.Certain compounds

在某些態樣中，本揭示案係關於包含寡聚化合物或由寡聚化合物組成之化合物。在某些實施例中，寡聚化合物包含與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of oligomeric compounds. In certain embodiments, the oligomeric compound comprises a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於包含經修飾之寡核苷酸或由經修飾之寡核苷酸組成之化合物。在某些實施例中，經修飾之寡核苷酸具有與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of modified oligonucleotides. In certain embodiments, the modified oligonucleotides have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於包含反義寡核苷酸或由反義寡核苷酸組成之化合物。在某些實施例中，反義寡核苷酸具有與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of antisense oligonucleotides. In certain embodiments, the antisense oligonucleotides have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於作為單股化合物之化合物。在某些實施例中，單股化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，此一寡聚化合物包含寡核苷酸及視情況結合基團或由寡核苷酸及視情況結合基團組成。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。在某些實施例中，寡核苷酸為反義寡核苷酸。在某些實施例中，單股化合物之寡核苷酸或經修飾之寡核苷酸包含自補核鹼基序列。In some aspects, the present disclosure relates to compounds that are single-stranded compounds. In some embodiments, the single-stranded compounds include or consist of oligomeric compounds. In some embodiments, such an oligomeric compound includes or consists of an oligonucleotide and, optionally, a binding group. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, the oligonucleotide of the single-stranded compound or the modified oligonucleotide includes a self-complementary nucleobase sequence.

在某些態樣中，本揭示案係關於作為雙股化合物之化合物。在某些實施例中，雙股化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，雙股化合物包含第一寡核苷酸及第二寡核苷酸。在某些實施例中，第一寡核苷酸具有與靶核酸互補之區域，且第二寡核苷酸具有與第一經修飾之寡核苷酸互補之區域。在某些實施例中，雙股化合物包含經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸具有與靶核酸互補之區域。在某些實施例中，雙股化合物包含第一經修飾之寡核苷酸及第二經修飾之寡核苷酸。在某些實施例中，第一經修飾之寡核苷酸具有與靶核酸互補之區域，且第二經修飾之寡核苷酸具有與第一經修飾之寡核苷酸互補之區域。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸為RNA寡核苷酸。在此等實施例中，經修飾之寡核苷酸中之胸腺嘧啶核鹼基經尿嘧啶核鹼基置換。In some aspects, the disclosure relates to compounds that are double-stranded compounds. In some embodiments, the double-stranded compound comprises or consists of an oligomeric compound. In some embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In some embodiments, the first oligonucleotide has a region that is complementary to the target nucleic acid, and the second oligonucleotide has a region that is complementary to the first modified oligonucleotide. In some embodiments, the double-stranded compound comprises a modified oligonucleotide. In some embodiments, the modified oligonucleotide has a region that is complementary to the target nucleic acid. In some embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a region that is complementary to the target nucleic acid, and the second modified oligonucleotide has a region that is complementary to the first modified oligonucleotide. In certain embodiments, the double-stranded oligonucleotide or modified oligonucleotide is an RNA oligonucleotide. In these embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase.

在某些實施例中，本文所闡述之化合物包含結合基團。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸包含結合基團。在某些實施例中，雙股化合物之第二寡核苷酸或第二經修飾之寡核苷酸包含結合基團。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸以及第二寡核苷酸或第二經修飾之寡核苷酸各自包含結合基團。In certain embodiments, the compounds described herein comprise a binding group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a binding group. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises a binding group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide and the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound each comprise a binding group.

在某些實施例中，化合物之長度為14-30個連接核苷。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸之長度為14-30個連接核苷。在某些實施例中，第二寡核苷酸或第二經修飾之寡核苷酸之長度為14-30個連接核苷。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸在該化合物之一端或兩端為平端。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸在該化合物之一端或兩端包括非互補懸突核苷。In some embodiments, the length of the compound is 14-30 linked nucleosides. In some embodiments, the length of the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14-30 linked nucleosides. In some embodiments, the length of the second oligonucleotide or the second modified oligonucleotide is 14-30 linked nucleosides. In some embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound is blunt-ended at one or both ends of the compound. In some embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound includes non-complementary overhanging nucleosides at one or both ends of the compound.

在某些實施例中，化合物具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少14個鄰接核鹼基之核鹼基序列。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸中之一者具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少14個鄰接核鹼基之核鹼基序列。In certain embodiments, the compound has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.

單股及雙股化合物之實例包括(但不限於)寡核苷酸、反義寡核苷酸、siRNA、靶向微小RNA之寡核苷酸、基於佔位之化合物(例如mRNA加工或轉譯阻斷化合物及剪接化合物)及單股RNAi化合物(例如小髮夾RNA (shRNA)、單股siRNA (ssRNA)及微小RNA模擬物)。Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, oligonucleotides targeting microRNAs, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimetics).

在某些實施例中，本文所闡述之化合物具有核鹼基序列，當該核鹼基序列以5’至3’方向書寫時，包含該序列所靶向之靶核酸之靶區域的反向互補序列。In certain embodiments, the compounds described herein have a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of a target region of a target nucleic acid to which the sequence is targeted.

在某些實施例中，本文所闡述之化合物包含長度為12至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為12至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為14至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為14至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為15至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為15至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19至23個連接亞單元之寡核苷酸。換言之，此等寡核苷酸分別為12至30個連接亞單元、12至23個連接亞單元、14至30個連接亞單元、14至23個連接亞單元、15至30個連接亞單元、15至23個連接亞單元、16至30個連接亞單元、16至23個連接亞單元、17至30個連接亞單元、17至23個連接亞單元、18至30個連接亞單元、18至23個連接亞單元、19至30個連接亞單元或19至23個連接亞單元。在某些實施例中，本文所闡述之化合物包含長度為14個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為20個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為21個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為22個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為23個連接亞單元之寡核苷酸。在其他實施例中，本文所闡述之化合物包含8至80個、12至50個、13至30個、13至50個、14至30個、14至50個、15至30個、15至50個、16至30個、16至50個、17至30個、17至50個、18至23個、18至24個、18至25個、18至50個、19至23個、19至30個、19至50個、20至23個或20至30個連接亞單元之寡核苷酸。在某些此類實施例中，本文所闡述之化合物包含長度為8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個連接亞單元或由上述值中之任兩者所界定範圍之寡核苷酸。In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 to 23 linked subunits. In other words, these oligonucleotides are 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits, respectively. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 20 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 21 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 22 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 23 linked subunits. In other embodiments, the compounds described herein comprise 8-80, 12-50, 13-30, 13-50, 14-30, 14-50, 15-30, 15-50, 16-30, 16-50, 17-30, 17-50, 18-23, 18-24, 18-25, 18-50, 19-23, 19-30, 19-50, 20-23, or 20-30 oligonucleotides linked to subunits. In certain such embodiments, the compounds described herein comprise an oligonucleotide having a length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked subunits, or a range defined by any two of the above values.

在某些實施例中，化合物可進一步包含額外部分，諸如結合基團或遞送部分。在某些實施例中，此等化合物為寡聚化合物，且額外部分連接至寡核苷酸。在某些實施例中，結合基團連接至寡核苷酸之核苷。In some embodiments, the compound may further comprise an additional moiety, such as a binding group or a delivery moiety. In some embodiments, these compounds are oligomeric compounds, and the additional moiety is linked to an oligonucleotide. In some embodiments, the binding group is linked to the nucleoside of the oligonucleotide.

在某些實施例中，化合物可縮短或截短。舉例而言，可自寡核苷酸之5’端(5’截短)或替代地3’端(3’截短)缺失一或多個亞單元。In certain embodiments, the compound may be shortened or truncated. For example, one or more subunits may be deleted from the 5' end (5' truncation) or alternatively the 3' end (3' truncation) of the oligonucleotide.

在某些實施例中，化合物可加長。舉例而言，一或多個亞單元可連接至寡核苷酸之3'端或5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至寡核苷酸之5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至寡核苷酸之3'端。在某些實施例中，至少一或多個亞單元可連接至雙股化合物之寡核苷酸之3'端或5'端，從而產生3'端及/或5'端懸突。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至雙股化合物之兩種寡核苷酸之5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至雙股化合物之兩種寡核苷酸之3'端。在某些實施例中，亞單元連接至雙股化合物之兩種寡核苷酸之同一端(例如，亞單元連接至一種寡核苷酸之3'端，且亞單元連接至另一寡核苷酸之5'端)。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量可相同或可不同。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量係相同的。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量係不同的。亞單元連接至雙股化合物之兩種寡核苷酸之同一端的此種情形可發生在雙股化合物之一端或兩端。在某些實施例中，連接至3'端及/或5'端之亞單元經修飾。In some embodiments, the compound can be elongated. For example, one or more subunits can be attached to the 3' end or the 5' end of the oligonucleotide. In some embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5' end of the oligonucleotide. In some embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of the oligonucleotide. In some embodiments, at least one or more subunits can be attached to the 3' end or 5' end of the oligonucleotide of the double-stranded compound, thereby generating a 3' and/or 5' overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is linked to the 5' end of both oligonucleotides of the double-stranded compound. In some embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is linked to the 3' end of both oligonucleotides of the double-stranded compound. In some embodiments, the subunits are linked to the same end of both oligonucleotides of the double-stranded compound (e.g., the subunit is linked to the 3' end of one oligonucleotide and the subunit is linked to the 5' end of the other oligonucleotide). In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide may be the same or different. In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide is the same. In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide is different. This situation where a subunit is connected to the same end of two oligonucleotides of a double-stranded compound can occur at one end or both ends of the double-stranded compound. In some embodiments, the subunits connected to the 3' end and/or the 5' end are modified.

在某些實施例中，本文所闡述之化合物為寡核苷酸。在某些實施例中，本文所闡述之化合物為經修飾之寡核苷酸。在某些實施例中，本文所闡述之化合物為反義寡核苷酸。在某些實施例中，本文所闡述之化合物為寡聚化合物。在某些實施例中，本文所闡述之化合物為RNAi化合物。在某些實施例中，本文所闡述之化合物為siRNA化合物。In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

在某些實施例中，本文所闡述之化合物可包含本文所闡述之靶向MAPT之寡核苷酸序列中之任一者。在某些實施例中，化合物可為雙股的。In certain embodiments, the compounds described herein may comprise any of the oligonucleotide sequences targeting MAPT described herein. In certain embodiments, the compounds may be double-stranded.

在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。在某些實施例中，化合物包含第二寡核苷酸。在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。In certain embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206.

在某些實施例中，化合物包含核糖核苷酸，對於本文所提供之任一序列，該等核糖核苷酸中之寡核苷酸用尿嘧啶(U)代替胸腺嘧啶(T)。在某些實施例中，化合物包含去氧核糖核苷酸，對於本文所提供之任一序列，該等去氧核糖核苷酸中之寡核苷酸用胸腺嘧啶(T)代替尿嘧啶(U)。某些機制In certain embodiments, the compounds comprise ribonucleotides in which oligonucleotides substitute uracil (U) for thymine (T) for any of the sequences provided herein. In certain embodiments, the compounds comprise deoxyribonucleotides in which oligonucleotides substitute thymine (T) for uracil (U) for any of the sequences provided herein.Certain mechanisms

在某些實施例中，本文所闡述之化合物包含經修飾之寡核苷酸或由經修飾之寡核苷酸組成。在某些實施例中，本文所闡述之化合物包含反義寡核苷酸或由反義寡核苷酸組成。在某些實施例中，化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，本文所闡述之化合物能夠與靶核酸雜交。在某些實施例中，本文所闡述之化合物選擇性地影響一或多種靶核酸。此等化合物包含如下核鹼基序列，該核鹼基序列與一或多種靶核酸雜交，從而產生一或多種期望活性，且不與一或多種非靶核酸雜交或與一或多種非靶核酸雜交之方式不會產生顯著不期望之活性。In certain embodiments, the compounds described herein comprise modified oligonucleotides or consist of modified oligonucleotides. In certain embodiments, the compounds described herein comprise antisense oligonucleotides or consist of antisense oligonucleotides. In certain embodiments, the compounds described herein comprise oligomeric compounds or consist of oligomeric compounds. In certain embodiments, the compounds described herein are capable of hybridizing with target nucleic acids. In certain embodiments, the compounds described herein selectively affect one or more target nucleic acids. These compounds comprise a nucleobase sequence that hybridizes with one or more target nucleic acids to produce one or more desired activities, and does not hybridize with one or more non-target nucleic acids or hybridizes with one or more non-target nucleic acids in a manner that does not produce significant undesirable activities.

在某些實施例中，本文所闡述之化合物與靶核酸雜交募集一或多種使靶核酸裂解之蛋白質。舉例而言，本文所闡述之某些化合物或該化合物之一部分裝載至RNA誘導之沈默複合物(RISC)中，最終導致靶核酸裂解。舉例而言，本文所闡述之某些化合物導致靶核酸由亞古爾蛋白(Argonaute)裂解。裝載至RISC中之化合物為RNAi化合物。RNAi化合物可為雙股(siRNA)或單股(ssRNA)。In certain embodiments, the compounds described herein hybridize with a target nucleic acid to recruit one or more proteins that cleave the target nucleic acid. For example, certain compounds described herein or a portion of the compounds are loaded into the RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein cause cleavage of the target nucleic acid by Argonaute. The compound loaded into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

在某些實施例中，本文所闡述之化合物與靶核酸雜交不募集裂解該靶核酸之蛋白質。在某些此類實施例中，化合物與靶核酸雜交改變該靶核酸之剪接。在某些實施例中，化合物與靶核酸雜交抑制該靶核酸與蛋白質或其他核酸之間的結合相互作用。在某些此類實施例中，化合物與靶核酸雜交改變RNA加工。在某些此類實施例中，化合物與靶核酸雜交改變該靶核酸之轉譯。In certain embodiments, the compounds described herein hybridize with target nucleic acids without recruiting proteins that cleave the target nucleic acids. In certain such embodiments, the compounds hybridize with target nucleic acids to alter the splicing of the target nucleic acids. In certain embodiments, the compounds hybridize with target nucleic acids to inhibit binding interactions between the target nucleic acids and proteins or other nucleic acids. In certain such embodiments, the compounds hybridize with target nucleic acids to alter RNA processing. In certain such embodiments, the compounds hybridize with target nucleic acids to alter the translation of the target nucleic acids.

可直接或間接觀察到化合物與靶核酸雜交所產生之活性。在某些實施例中，觀察或偵測活性涉及觀察或偵測靶核酸或由該靶核酸編碼的蛋白質之量的變化、核酸或蛋白質之剪接變異體之比率的變化及/或細胞或動物之表型變化。某些修飾The activity resulting from the hybridization of the compound with the target nucleic acid can be observed directly or indirectly. In certain embodiments, observing or detecting the activity involves observing or detecting a change in the amount of the target nucleic acid or a protein encoded by the target nucleic acid, a change in the ratio of splicing variants of the nucleic acid or protein, and/or a phenotypic change in a cell or animal.Certain Modifications

在某些態樣中，本揭示案係關於包含寡核苷酸或由寡核苷酸組成之化合物。寡核苷酸係由連接核苷組成。在某些實施例中，寡核苷酸可為未經修飾之RNA或DNA，或可經修飾。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。在某些實施例中，相對於未經修飾之RNA或DNA，經修飾之寡核苷酸包含至少一個經修飾之糖、經修飾之核鹼基或經修飾之核苷間鍵聯。在某些實施例中，寡核苷酸具有經修飾之核苷。經修飾之核苷可包含經修飾之糖、經修飾之核鹼基或經修飾之糖及經修飾之核鹼基二者。經修飾之寡核苷酸亦可包括末端修飾，例如5’端修飾及3’端修飾。糖修飾及模體In some aspects, the present disclosure relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides are composed of linked nucleosides. In some embodiments, the oligonucleotide can be unmodified RNA or DNA, or can be modified. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage relative to unmodified RNA or DNA. In some embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also include terminal modifications, such as a 5' end modification and a 3' end modification.Sugar modifications and motifs

在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，經修飾之糖為經修飾之雙環或三環糖。在某些實施例中，經修飾之糖為糖替代物。糖替代物可包含本文所闡述之一或多種取代。In certain embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In certain embodiments, the modified sugar is a modified bicyclic or tricyclic sugar. In certain embodiments, the modified sugar is a sugar surrogate. The sugar surrogate may comprise one or more substitutions described herein.

在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，呋喃糖基糖為核糖基糖。在某些實施例中，呋喃糖基糖包含一或多個取代基，包括(但不限於)在2’位、3’位、4’位及5’位之取代基。In some embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In some embodiments, the furanosyl sugar is a ribosyl sugar. In some embodiments, the furanosyl sugar comprises one or more substituents, including but not limited to substituents at the 2' position, 3' position, 4' position, and 5' position.

在某些實施例中，2’位取代基包括(但不限於) F及OCH₃(「OMe」、「O-甲基」或「甲氧基」)。在某些實施例中，適於經修飾之非雙環糖之2’位取代基包括(但不限於)鹵基、烯丙基、胺基、疊氮基、SH、CN、OCN、CF₃、OCF₃、F、Cl、Br、SCH₃、SOCH₃、SO₂CH₃、ONO₂、NO₂、N₃及NH₂。在某些實施例中，2’位取代基包括(但不限於) O-(C₁-C₁₀)烷氧基、烷氧基烷基、O-烷基、S-烷基、N-烷基、O-烯基、S-烯基、N-烯基、O-炔基、S-炔基、N-炔基、O-烷基-O-烷基、炔基，其中烷基、烯基及炔基可為經取代或未經取代之C₁至C₁₀烷基或C₂至C₁₀烯基及炔基。在某些實施例中，2’位取代基包括(但不限於)烷芳基、芳烷基、O-烷芳基及O-芳烷基。在某些實施例中，該等2’取代基可進一步經一或多個獨立地選自以下之取代基取代：羥基、烷氧基、羧基、苯甲基、苯基、硝基(NO₂)、硫醇、硫烷氧基、硫代烷基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，2’位取代基包括(但不限於) O[(CH₂)_nO]_mCH₃、O(CH₂)_nOCH₃、O(CH₂)_nCH₃、O(CH2)_nONH₂、O(CH₂)_nNH₂、O(CH₂)_nSCH₃及O(CH₂)_nON[(CH₂)_nCH₃)]₂，其中n及m獨立地為1至約10。在某些實施例中，2’位取代基包括(但不限於) OCH₂CH₂OCH₃(「MOE」)、O(CH₂)₂ON(CH₃)₂(「DMAOE」)、O(CH₂)₂O(CH₂)₂N(CH₃)₂(「DMAEOE」)及OCH₂C(=O)-N(H)CH₃(「NMA」)。In certain embodiments, 2'-position substituents include, but are not limited to, F and OCH₃ ("OMe", "O-methyl" or "methoxy"). In certain embodiments, 2'-position substituents suitable for modified non-bicyclic sugars include, but are not limited to, halogen, allyl, amine, azido, SH, CN, OCN, CF₃ , OCF₃ , F, Cl, Br, SCH₃ , SOCH₃ , SO₂ CH₃ , ONO₂ , NO₂ , N₃ and NH₂ . In some embodiments, the 2'-substituent includes, but is not limited to, O-(C₁ -C₁₀ ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. In some embodiments, the 2'-substituent includes, but is not limited to, alkaryl, aralkyl, O-alkaryl and O-aralkyl. In certain embodiments, the 2' substituents may be further substituted with one or more substituents independently selected from the group consisting of hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(_NO2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the 2' substituents include, but are not limited to, O[(_CH2 )_nO ]_mCH3 , O(_CH2 )_nOCH3 , O(_CH2)nCH3 , O_(CH2 )_nONH2 , O(_CH2 )_nNH2 , O(_CH2 )_{nSCH3,and O(CH2)nON[(CH2)nCH3)]2,whereinn} and m are independently₁ to about 10. In certain embodiments,_the 2'-_{substituent includes, but is not limited to, OCH2CH2OCH3(} "MOE"), O(_CH2 )_2ON (_CH3 )₂ ("DMAOE"), O(_CH2 )_2O (_CH2 )_2N (_CH3 )₂ ("DMAEOE"), and_OCH2C (=O)-N(H)_CH3 ("NMA").

在某些實施例中，適於經修飾之非雙環糖之4’位取代基包括(但不限於)烷氧基(例如甲氧基)、烷基及Manoharan等人，WO 2015/106128中所闡述之彼等取代基。在某些實施例中，適於經修飾之非雙環糖之5’位取代基包括(但不限於)甲基(「Me」或「CH₃」) (R或S)、乙烯基及甲氧基。在某些實施例中，5'修飾為5'-單磷酸酯((HO)₂(O)P-O-5')；5'-二磷酸酯((HO)₂(O)P-O-P(HO)(O)-O-5')；5'-三磷酸酯((HO)₂(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'-鳥苷帽(7-甲基化或非甲基化) (7m-G-O-5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'腺苷帽(Appp)，及任何經修飾或未經修飾之核苷酸帽結構(N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'-單硫代磷酸酯(硫代磷酸酯；(HO)₂(S)P-O-5')；5'-單二硫代磷酸酯(二硫代磷酸酯；(HO)(HS)(S)P-O-5')、5'硫代磷酸酯((HO)₂(O)P-S-5')；氧/硫置換之單磷酸酯、二磷酸酯及三磷酸酯之任何額外組合(例如5'-α-硫基三磷酸酯、5'-γ硫基三磷酸酯等)、5'-胺基磷酸酯((HO)₂(O)P-NH-5'、(HO)(NH₂)(O)P-O-5')、5'烷基膦酸酯(R=烷基=甲基、乙基、異丙基、丙基等，例如RP(OH)(O)-O-5'-)、5'烯基膦酸酯(亦即乙烯基、經取代之乙烯基)、(OH)₂(O)P-5'-CH₂-)、5'烷基醚膦酸酯(R=烷基醚=甲氧基甲基(MeOCH₂-)、乙氧基甲基等，例如RP(OH)(O)-O-5'-)。在某些實施例中，一或多個糖包含5'-膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，一或多個糖包含5'-乙烯基膦酸酯修飾。在某些實施例中，一或多個糖包含5'-伸乙基膦酸酯修飾。在某些實施例中，5'修飾位於寡核苷酸之末端。在某些實施例中，5'修飾位於反義寡核苷酸之末端。在某些實施例中，可將本文所闡述之2’位、4’位及5’位取代基添加至糖上之其他特定位置。在某些實施例中，此類取代基可添加至3’末端核苷上之糖的3’位或5’末端核苷之5’位。在某些實施例中，經修飾之非雙環糖可包含一個以上之非橋接糖取代基。在某些此類實施例中，經修飾之非雙環糖取代基包括(但不限於) 5’-Me-2’-F、5’-Me-2’-OMe (包括R及S異構物二者)。在某些實施例中，經修飾之糖取代基包括Migawa等人，WO 2008/101157及Rajeev等人，US2013/0203836中所闡述之彼等取代基。In certain embodiments, suitable 4'-position substituents for modified non-bicyclic sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. In certain embodiments, suitable 5'-position substituents for modified non-bicyclic sugars include, but are not limited to, methyl ("Me" or "CH₃ ") (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is 5'-monophosphate ((HO)₂ (O)PO-5');5'-diphosphate ((HO)₂ (O)POP(HO)(O)-O-5');5'-triphosphate ((HO)₂ (O)PO-(HO)(O)POP(HO)(O)-O-5');5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5');5' adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5');5'-monothioate(phosphorothioate; (HO)₂ any additional combination of oxygen/sulfur substituted monophosphates, diphosphates, and triphosphates (e.g., 5'-α-thiotriphosphate, 5'-γ-thiotriphosphate, etc.), 5'-phosphamidates ((HO)₂ (O)P-NH-5_' , (HO)(NH₂ )(O)PO-5'), 5'alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-), 5'alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)₂ (O)P-5'-CH₂ -), 5'alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH₂ -), ethoxymethyl, etc., such as RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylphosphonate modification. In certain embodiments, the 5' modification is located at the end of the oligonucleotide. In certain embodiments, the 5' modification is located at the end of the antisense oligonucleotide. In certain embodiments, the 2', 4', and 5' substituents described herein may be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, the modified non-bicyclic sugar may include more than one non-bridging sugar substituent. In certain such embodiments, the modified non-bicyclic sugar substituent includes, but is not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, the modified sugar substituent includes those described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

在某些實施例中，經修飾之糖為雙環糖。雙環糖係包含兩個環之經修飾之糖，其中經由連結第一環中的兩個原子之橋形成第二環，藉此形成雙環結構。在某些實施例中，雙環糖包含橋接取代基，該橋接取代基橋接呋喃糖基環之兩個原子以形成第二環。在某些實施例中，雙環糖不包含呋喃糖基部分。「雙環核苷」(「BNA」)係具有雙環糖之核苷。在某些實施例中，雙環糖在4’與2’呋喃糖環原子之間包含橋。在某些實施例中，雙環糖在5’與3’呋喃糖環原子之間包含橋。在某些此類實施例中，呋喃糖環為核糖環。在某些實施例中，4’至2’橋接取代基包括(但不限於) 4'-CH₂-2'、4'-(CH₂)₂-2'、4'- (CH₂)₃-2'、4'-CH₂-O-2' (「LNA」)、4'-CH₂-S-2'、4'-(CH₂)₂-O-2' (「ENA」)、4'-CH(CH₃)-O-2' (當呈S構形時，為「約束乙基」或「cEt」)、4’-CH2-O-CH₂-2’、4’-CH₂-N(R)-2’、4'- CH(CH₂OCH₃)-O-2' (「約束MOE」或「cMOE」)及其類似物(例如美國專利第7,399,845號)、4'-C(CH₃)(CH₃)-O-2'及其類似物(例如美國專利第8,278,283號)、4'-CH₂-N(OCH₃)-2'及其類似物(例如美國專利第8,278,425號)、4'-CH₂-O-N(CH₃)-2' (例如美國專利公開案第2004/0171570號)、4'-CH₂-N(R)-O-2' (其中R為H、C₁-C₁₂烷基或保護基團(例如美國專利第7,427,672號))、4'-CH₂-C(H)(CH₃)-2' (例如Chattopadhyaya等人，J. Org. Chem., 2009, 74, 118- 134)及4'-CH₂-C(=CH₂)-2'及其類似物(例如美國專利第8,278,426號)。前述文獻各自之全部內容在此係以引用的方式併入本文中。教示雙環核酸核苷酸之製備之其他代表性美國專利及美國專利公開案包括(但不限於)以下：美國專利第6,268,490號；第6,525,191號；第6,670,461號；第6,770,748號；第6,794,499號；第6,998,484號；第7,053,207號；第7,034,133號；第7,084,125號；第7,399,845號；第7,427,672號；第7,569,686號；第7,741,457號；第8,022,193號；第8,030,467號；第8,278,425號；第8,278,426號；第8,278,283號；US 2008/0039618；及US 2009/0012281、US 2013/0190383；及WO 2013/036868，其各自之全部內容在此係以引用的方式併入本文中。前述雙環核苷中之任一者均可製備成具有一或多種立體化學糖構形，包括例如α-L-呋喃核糖及β-D-呋喃核糖(例如，參見WO 99/14226)。除非另有指定，否則本文指定之雙環核苷係呈β-D構形。In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein a second ring is formed by a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not comprise a furanosyl moiety. A "bicyclic nucleoside"("BNA") is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the 4' to 2' bridging substituent includes, but is not limited to, 4'-_CH2-2 ', 4'-(_CH2 )_2-2 ', 4'-(_CH2 )_3-2 ', 4'-_CH2 -O-2'("LNA"),4'-CH2-_S -2', 4'-(_CH2 )₂ -O-2'("ENA"),4'-CH(_CH3 )-O-2'("constrainedethyl" or "cEt" when in the S configuration), 4'-CH2-O-_CH2-2 ', 4'-CH2_- N(R)-2', 4'-CH(_CH2OCH3 )-O-2'("constrainedMOE" or "cMOE") and the like (e.g., U.S. Patent No. 7,399,845), 4'-C(_CH3 )-O-2'("constrainedethyl" or "cEt"), and the like (e.g., U.S. Patent No. 7,399,845), and 4'-CH2-S-₂ '. )(CH₃ )-O-2′ and its analogs (e.g., U.S. Patent No. 8,278,283), 4′-CH₂ -N(OCH₃ )-2′ and its analogs (e.g., U.S. Patent No. 8,278,425), 4′-CH₂ -ON(CH₃ )-2′ (e.g., U.S. Patent Publication No. 2004/0171570), 4′-CH₂ -N(R)-O-2′ (wherein R is H, C₁ -C₁₂ alkyl or a protecting group (e.g., U.S. Patent No. 7,427,672)), 4′-CH₂ -C(H)(CH₃ )-2′ (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118- 134) and 4′-CH₂ -C(═CH₂ )-2' and its analogs (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing documents are hereby incorporated by reference. Other representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include (but are not limited to) the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7 ,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, US 2013/0190383; and WO 2013/036868, the entire contents of each of which are hereby incorporated by reference into this document. Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99/14226). Unless otherwise specified, the bicyclic nucleosides specified herein are in the β-D configuration.

在某些實施例中，經修飾之糖為糖替代物。在某些實施例中，糖替代物之氧原子經例如硫、碳或氮原子置換。在某些此類實施例中，糖替代物亦可包含如本文所闡述之橋接及/或非橋接取代基。在某些實施例中，糖替代物包含具有不為5個原子之環。在某些此類實施例中，糖替代物包含環丁基部分代替呋喃戊糖基糖。在某些實施例中，糖替代物包含六員環代替呋喃戊糖基糖。在某些實施例中，糖替代物包含四氫哌喃(「THP」)代替呋喃戊糖基糖。在某些實施例中，糖替代物包含嗎啉基代替呋喃戊糖基糖。教示此等經修飾之糖結構之製備之代表性美國專利包括(但不限於)美國專利第4,981,957號；第5,118,800號；第5,166,315號；第5,185,444號；第5,319,080號；第5,359,044號；第5,393,878號；第5,446,137號；第5,466,786號；第5,514,785號；第5,519,134號；第5,567,811號；第5,576,427號；第5,591,722號；第5,597,909號；第5,610,300號；第5,627,053號；第5,639,873號；第5,646,265號；第5,658,873號；第5,670,633號；第5,700,920號；第7,875,733號；第7,939,677號、第8,088,904號；第8,440,803號；及第9,005,906號，前述專利各自之全部內容在此係以引用的方式併入本文中。In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the oxygen atom of the sugar substitute is replaced by, for example, a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and/or non-bridging substituents as described herein. In certain embodiments, the sugar substitute includes a ring having not 5 atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a morpholinyl group replacing a furanopentosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5 ,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677; 8,088,904; 8,440,803; and 9,005,906, the entire contents of each of the foregoing patents are hereby incorporated by reference into this article.

在一些實施例中，糖替代物包含非環狀部分。在某些實施例中，糖替代物為解鎖核酸(「UNA」)。UNA係一種解鎖非環狀核酸，其中糖之任何鍵均已去除，從而形成解鎖「糖」殘基。在一個實例中，UNA亦涵蓋C1’-C4’之間的鍵(亦即C1’碳與C4’碳之間的共價碳-氧-碳鍵)已去除之單體。在另一實例中，糖之C2’-C3’鍵(亦即C2’碳與C3’碳之間的共價碳-碳鍵)已去除。教示UNA之製備之代表性美國公開案包括(但不限於)美國專利第8,314,227號；及美國專利公開案第2013/0096289號；第2013/0011922號；及第2011/0313020號，其各自之全部內容在此係以引用的方式併入本文中。在某些實施例中，糖替代物包含肽核酸(「PNA」)、非環狀丁基核酸(例如，參見Kumar等人，Org. Biomol. Chem., 2013, 11, 5853-5865)，以及Manoharan等人，US2013/130378中所闡述之核苷及寡核苷酸，該等文獻之全部內容在此係以引用的方式併入本文中。此項技術中已知可用於經修飾之核苷中之許多其他雙環及三環糖及糖替代物環系統。In some embodiments, the sugar surrogate comprises a non-cyclic portion. In certain embodiments, the sugar surrogate is an unblocked nucleic acid ("UNA"). UNA is an unblocked non-cyclic nucleic acid in which any bonds of the sugar have been removed, thereby forming an unblocked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' (i.e., the covalent carbon-oxygen-carbon bond between the C1' carbon and the C4' carbon) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between the C2' carbon and the C3' carbon) has been removed. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, each of which is hereby incorporated by reference in its entirety. In certain embodiments, the sugar surrogate comprises a peptide nucleic acid ("PNA"), a non-cyclic butyl nucleic acid (e.g., see Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides as described in Manoharan et al., US2013/130378, the entire contents of which are hereby incorporated by reference in its entirety. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

在某些態樣中，本揭示案係關於包含至少一種寡核苷酸之化合物，其中此種寡核苷酸之核苷包含一或多種類型之經修飾之糖及/或未經修飾之糖，該等糖以確定之模式或「糖模體」沿著寡核苷酸或其區域排列。在某些情況下，此等糖模體包括(但不限於)本文所闡述之糖修飾模式中之任一者。In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotides comprise one or more types of modified sugars and/or unmodified sugars arranged along the oligonucleotide or a region thereof in a defined pattern or "sugar motif". In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

在某些實施例中，寡核苷酸包含間隔體(gapmer)糖模體。間隔體寡核苷酸包含具有兩個外部「翼」區及一個中央或內部「空位」區之區域，或由該區域組成。空位區及翼區形成核苷鄰接序列，其中每一翼之大部分核苷糖不同於空位之大部分核苷糖。在某些實施例中，翼區包含大部分經修飾之糖，且空位包含大部分未經修飾之糖。在某些實施例中，空位之核苷為去氧核苷。具有間隔體糖模體之化合物闡述於例如美國專利8,790,919中，該專利之全部內容在此係以引用的方式併入本文中。In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external "wing" regions and a central or internal "gap" region. The gap region and the wing region form a nucleoside-adjacent sequence, wherein the majority of the nucleoside sugars of each wing are different from the majority of the nucleoside sugars of the gap. In certain embodiments, the wing region comprises a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleoside of the gap is a deoxynucleoside. Compounds with gapmer sugar motifs are described, for example, in U.S. Patent 8,790,919, the entire contents of which are incorporated herein by reference.

在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含三聯體糖模體。具有三聯體糖模體之寡核苷酸在三個連續核苷上包含三個相同之糖修飾。在某些實施例中，三聯體位於寡核苷酸之裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之三聯體糖模體。在某些實施例中，三聯體糖模體之相同糖修飾為2’-F修飾。具有三聯體糖模體之化合物揭示於例如美國專利10,668,170中，該專利之全部內容係以引用的方式併入本文中。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a triplet sugar motif. An oligonucleotide having a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds having triplet sugar motifs are disclosed, for example, in U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含四聯體糖模體。具有四聯體糖模體之寡核苷酸在四個連續核苷上包含四個相同之糖修飾。在某些實施例中，四聯體位於裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之四聯體糖模體。在某些實施例中，四聯體糖模體之相同糖修飾為2’-F修飾。對於具有長度為19-23個核苷酸之雙鏈體區域之雙股化合物，反義寡核苷酸之裂解位點通常位於距5’端10、11及12個位置附近。在某些實施例中，自有義寡核苷酸5’端之第一核苷計數，或自有義寡核苷酸5’端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於有義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。在某些實施例中，自反義寡核苷酸5’端之第一核苷計數，或自反義寡核苷酸5’端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於反義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。裂解位點可根據雙股化合物之雙鏈體區域長度而變化，且可相應地改變四聯體之位置。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a quadruplex sugar motif. An oligonucleotide having a quadruplex sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically located near 10, 11, and 12 positions from the 5' end. In certain embodiments, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or starting from the first paired nucleotide in the duplex region at the 5' end of the sense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the sense oligonucleotide. In certain embodiments, counting from the first nucleotide at the 5' end of the antisense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' end of the antisense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the antisense oligonucleotide. The cleavage site can vary depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex can be changed accordingly.

在某些實施例中，寡核苷酸包含交替性糖模體。在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含交替性糖模體。具有交替性糖模體之寡核苷酸包含至少兩種不同的糖修飾，其中包含第一糖修飾之一或多個連續核苷與包含第二糖修飾之一或多個連續核苷及包含第三糖修飾之一或多個連續核苷等等交替。舉例而言，若A、B及C各自代表核苷之一種修飾類型，則交替性模體可為「ABABABABABAB...」、「AABBAABBAABB...」、「AABAABAABAAB...」、「AAABAAABAAAB...」、「AAABBBAAABBB...」或「ABCABCABCABC...」等。在某些實施例中，交替性糖模體沿著寡核苷酸重複至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基。在某些實施例中，交替性糖模體包含兩種不同的糖修飾。在某些實施例中，交替性糖模體包含2’-OMe及2’-F糖修飾。In some embodiments, the oligonucleotide comprises an alternating sugar motif. In some embodiments, one or both oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, and so on. For example, if A, B, and C each represent a modification type of a nucleoside, the alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...", and the like. In some embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases along the oligonucleotide. In some embodiments, the alternating sugar motif comprises two different sugar modifications. In some embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

在某些實施例中，寡核苷酸之每一核苷獨立地經本文所提供之一或多種糖修飾修飾。在某些實施例中，雙股化合物之每一寡核苷酸獨立地具有一或多個本文所提供之糖模體。在某些實施例中，含有糖模體之寡核苷酸完全經修飾，此乃因除包含糖模體之核苷以外的每一核苷均包含糖修飾。核鹼基修飾及模體In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in that each nucleoside except the nucleoside containing the sugar motif contains a sugar modification.Nucleobase Modifications and Motifs

在某些實施例中，本文所闡述之化合物包含經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含一或多個包含經修飾之核鹼基的核苷。在某些實施例中，經修飾之寡核苷酸包含一或多個不包含核鹼基之核苷，稱為無鹼基核苷。In certain embodiments, the compounds described herein comprise modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise one or more nucleosides comprising modified nucleobases. In certain embodiments, the modified oligonucleotides comprise one or more nucleosides that do not comprise nucleobases, referred to as abasic nucleosides.

在某些實施例中，經修飾之核鹼基係選自：5-取代之嘧啶、6-氮雜嘧啶、烷基或炔基取代之嘧啶、烷基取代之嘌呤以及N-2、N-6及O-6取代之嘌呤。在某些實施例中，經修飾之核鹼基係選自：2-胺基丙基腺嘌呤、5-羥甲基胞嘧啶、5-甲基胞嘧啶、黃嘌呤、次黃嘌呤、2-胺基腺嘌呤、6-N-甲基鳥嘌呤、6-N-甲基腺嘌呤、2-丙基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶及2-硫胞嘧啶、5-丙炔基(C≡C-CH₃)尿嘧啶、5-丙炔基胞嘧啶、6-偶氮尿嘧啶、6-偶氮胞嘧啶、6-偶氮胸腺嘧啶、5-核糖基尿嘧啶(假尿嘧啶)、4-硫尿嘧啶、8-鹵基、8-胺基、8-硫醇、8-硫代烷基、8-羥基、8-氮雜及其他8-取代之嘌呤；5-鹵基、具體而言5-溴、5-三氟甲基、5-鹵基尿嘧啶及5-鹵基胞嘧啶；7-甲基鳥嘌呤、7-甲基腺嘌呤、2-F-腺嘌呤、2-胺基腺嘌呤、7-去氮鳥嘌呤、7-去氮腺嘌呤、3-去氮鳥嘌呤、3-去氮腺嘌呤、6-N-苯甲醯基腺嘌呤、2-N-異丁醯基鳥嘌呤、4-N-苯甲醯基胞嘧啶、4-N-苯甲醯基尿嘧啶、5-甲基4-N-苯甲醯基胞嘧啶、5-甲基4-N-苯甲醯基尿嘧啶、通用鹼基、疏水性鹼基、混雜鹼基、大小擴大之鹼基及氟化鹼基。其他經修飾之核鹼基包括三環嘧啶，諸如1,3-二氮雜吩噁嗪-2-酮、1,3-二氮雜吩噻嗪-2-酮及9-(2-胺基乙氧基)-1,3-二氮雜吩噁嗪-2-酮(G夾)。經修飾之核鹼基亦可包括嘌呤或嘧啶鹼基經其他雜環置換之彼等核鹼基，該等其他雜環例如7-去氮-腺嘌呤、7-去氮鳥苷、2-胺基吡啶及2-吡啶酮。In certain embodiments, the modified nucleobase is selected from: 5-substituted pyrimidine, 6-azapyrimidine, alkyl or alkynyl substituted pyrimidine, alkyl substituted purine, and N-2, N-6 and O-6 substituted purine. In certain embodiments, the modified nucleobase is selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH₃ )uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-aza and other 8-substituted purines; 5-halogen, specifically 5-bromo, 5-trifluoromethyl, 5-halogenuracil and 5-halogencytosine; 7-methylguanine, 7-methyladenine, 2 -F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, mixed bases, size-expanded bases, and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenathiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-H). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.

其他核鹼基包括以下文獻中所揭示之彼等核鹼基：美國專利3,687,808；Modified Nucleosides in Biochemistry, Biotechnology and Medicine，Herdewijn, P.編輯，Wiley-VCH, 2008；The Concise Encyclopedia Of Polymer Science And Engineering，第858-859頁; Kroschwitz, J.L.編輯，John Wiley & Sons, 1990, 858-859；Englisch等人，Angewandte Chemie，國際版，1991, 30, 613；Sanghvi, Y.S.，第15章，dsRNA Research and Applications，第289-302頁；Antisense Research and Applications, Crooke, S.T.及Lebleu, B.編輯，CRC Press, 1993, 273-288；Antisense Drug Technology, Crooke S.T.編輯，CRC Press, 2008, 163-166及442-443 (第6章及第15章)，該等文獻各自在此係以引用的方式併入本文中。Other nucleobases include those disclosed in the following references: U.S. Patent 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, J.L. ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, S.T. and Lebleu, B. ed., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S.T., ed., CRC Press, 2008, 163-166 and 442-443 (Chapter 6 and Chapter 15), each of which is hereby incorporated by reference.

教示某些上述經修飾之核鹼基以及其他經修飾之核鹼基之製備的公開案包括(但不限於)美國申請公開案第2003/0158403號及第2003/0175906號；美國專利4,845,205；5,130,302；5,134,066；5,175,273；5,367,066；5,432,272；5,434,257；5,457,187；5,459,255；5,484,908；5,502,177；5,525,711；5,552,540；5,587,469；5,594,121；5,596,091；5,614,617；5,645,985；5,681,941；5,811,534；5,750,692；5,948,903；5,587,470；5,457,191；5,763,588；5,830,653；5,808,027；6,005,096；6,015,886；6,147,200；6,166,197；6,166,199；6,222,025；6,235,887；6,380,368；6,528,640；6,639,062；6,617,438；7,045,610；7,427,672；及7,495,088，該等案件各自之全部內容在此係以引用的方式併入本文中。Publications teaching the preparation of some of the above modified nucleobases and other modified nucleobases include, but are not limited to, U.S. Application Publication Nos. 2003/0158403 and 2003/0175906; U.S. Patent Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066 ;5,432,272;5,434,257;5,457,187;5,459,255;5,484,908;5,502,177;5,5 25,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,98 5;5,681,941;5,811,534;5,750,692;5,948,903;5,587,470;5,457,191;5, 763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,166,1 and 7,495,088, each of which is hereby incorporated by reference in its entirety.

在某些實施例中，本文所闡述之化合物包含寡核苷酸。在某些實施例中，寡核苷酸包含以確定之模式或模體沿著寡核苷酸或其區域排列的經修飾及/或未經修飾之核鹼基。在某些實施例中，每一核鹼基均經修飾。在某些實施例中，核鹼基均不經修飾。在某些實施例中，每一嘌呤或每一嘧啶均經修飾。在某些實施例中，每一腺嘌呤均經修飾。在某些實施例中，每一鳥嘌呤均經修飾。在某些實施例中，每一胸腺嘧啶均經修飾。在某些實施例中，每一尿嘧啶均經修飾。在某些實施例中，每一胞嘧啶均經修飾。在某些實施例中，經修飾之寡核苷酸中之一些或所有胞嘧啶核鹼基為5-甲基胞嘧啶。In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides comprise modified and/or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in the modified oligonucleotides are 5-methylcytosine.

在某些實施例中，經修飾之寡核苷酸包含經修飾之核鹼基之嵌段。在某些此類實施例中，嵌段位於寡核苷酸之3’端。在某些實施例中，嵌段位於寡核苷酸之3’端的3個核苷內。在某些實施例中，嵌段位於寡核苷酸之5’端。在某些實施例中，嵌段位於寡核苷酸之5’端的3個核苷內。核苷間鍵聯修飾及模體In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 5' end of the oligonucleotide.InternucleosideLinkage Modifications and Motifs

3'至5'磷酸二酯鍵聯係RNA及DNA之天然核苷間鍵聯。在某些實施例中，本文所闡述之化合物具有一或多個經修飾(亦即非天然)之核苷間鍵聯。某些非天然核苷間鍵聯可賦予合意性質，諸如細胞攝取增強、對靶核酸之親和力增強且在核酸酶存在下穩定性增加。代表性經修飾之含磷核苷間鍵聯包括(但不限於)磷酸三酯、烷基膦酸酯(例如甲基膦酸酯)、胺基磷酸酯及硫代磷酸酯(「P=S」)及二硫代磷酸酯(「HS-P=S」)。代表性不含磷之核苷間連接基團包括(但不限於)亞甲基甲基亞胺基(-CH₂-N(CH₃)-O-CH₂)、硫代二酯、硫羰胺基甲酸酯(-O-C(=O)(NH)-S-)；矽氧烷(-O-SiH₂-O-)；及N,N'-二甲基肼(-CH₂-N((CH₃)-N((CH₃)-)。含磷及不含磷核苷間鍵聯之製備方法為熟習此項技術者所熟知。中性核苷間鍵聯包括(但不限於)磷酸三酯、甲基膦酸酯、MMI (3'-CH₂-N(CH₃)-O-5')、醯胺-3 (3'-CH₂-C(=O)-N(H)-5')、醯胺-4 (3'-CH₂-N(H)-C(=O)-5')、甲縮醛(3'-O-CH₂-O-5')、甲氧基丙基及硫基甲縮醛(3'-S-CH₂-O-5')。其他中性核苷間鍵聯包括非離子鍵聯，其包含矽氧烷(二烷基矽氧烷)、羧酸酯、羧醯胺、硫化物、磺酸酯及醯胺(例如，參見Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi及P.D. Cook編輯，ACS Symposium Series 580; 第3章及第4章，40-65)。其他中性核苷間鍵聯包括包含混合之N、O、S及CH₂組成部分的非離子鍵聯。The 3' to 5' phosphodiester bond links the natural internucleoside linkages of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified (i.e., non-natural) internucleoside linkages. Certain non-natural internucleoside linkages can impart desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified phosphorus-containing internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonate), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside linking groups include, but are not limited to, methylenemethylimine (-CH2_- N(_CH3 )-O-_CH2 ), thiodiester, thiocarbamate (-OC(=O)(NH)-S-); siloxane (-O-_SiH2 -O-); and N,N'-dimethylhydrazine (_-CH2 -N((_CH3 )-N((_CH3 )-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriester, methylphosphonate, MMI (3'-_CH2 -N(_CH3 )-O-5'), amide-3 (3'-_CH2 -C(=O)-N(H)-5'), amide-4 (3'-_CH2 -N(H)-C(=O)-5'), formaldehyde (3'-O-_CH2 -O-5'), methoxypropyl and thioformaldehyde (3'-S-_CH2 -O-5'). Other neutral internucleoside linkages include non-ionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates and amides (e.g., see Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Other neutral internucleoside linkages include non-ionic linkages including mixed N, O, S and_CH2 components.

在某些實施例中，本文所提供之化合物包含至少一個經修飾之核苷間鍵聯。經修飾之核苷間鍵聯可位於寡核苷酸之任何位置。對於雙股化合物，經修飾之核苷間鍵聯可位於雙股化合物之有義寡核苷酸內、反義寡核苷酸內或該兩種寡核苷酸內。In certain embodiments, the compounds provided herein comprise at least one modified internucleoside linkage. The modified internucleoside linkage may be located at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside linkage may be located in the sense oligonucleotide, the antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

在某些實施例中，核苷間鍵聯修飾可發生在寡核苷酸之每個核苷上。在某些實施例中，核苷間鍵聯修飾可沿著寡核苷酸以交替模式發生。在某些實施例中，基本上每一核苷間連接基團均為磷酸酯核苷間鍵聯(P=O)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團為硫代磷酸酯(P=S)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團獨立地選自硫代磷酸酯及磷酸酯核苷間鍵聯。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係相同的。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係不同的。在某些實施例中，雙股化合物包含6-8個經修飾之核苷間鍵聯。在某些實施例中，該6-8個經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，有義寡核苷酸在5’端及3’端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，反義寡核苷酸在5’端及3’端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linkage group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is a thiophosphate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from thiophosphate and phosphate internucleoside linkages. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or an alkylphosphonate internucleoside linkage.

在某些實施例中，雙股化合物包含懸突區。在某些實施例中，雙股化合物在懸突區中包含硫代磷酸酯或烷基膦酸酯核苷間鍵聯修飾。在某些實施例中，雙股化合物包含連接懸突核苷酸與靠近該懸突核苷酸之配對核苷酸之硫代磷酸酯或烷基膦酸酯核苷間鍵聯。舉例而言，在末端三個核苷之間可能存在至少兩個硫代磷酸酯核苷間鍵聯，其中該三個核苷中之兩個為懸突核苷，且第三個為靠近懸突核苷之配對核苷。該三個末端核苷可位於反義寡核苷酸之3’端、有義寡核苷酸之3’端、反義寡核苷酸之5’端或有義寡核苷酸之5’端。In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage connecting an overhang nucleotide and a paired nucleotide proximal to the overhang nucleotide. For example, there may be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, wherein two of the three nucleosides are overhang nucleosides and the third is a paired nucleoside proximal to the overhang nucleoside. The three terminal nucleosides may be located at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the sense oligonucleotide.

在某些實施例中，經修飾之寡核苷酸包含一或多個具有手性中心之核苷間鍵聯。代表性手性核苷間鍵聯包括(但不限於)烷基膦酸酯及硫代磷酸酯。可將包含具有手性中心之核苷間鍵聯的經修飾之寡核苷酸製備成包含立體隨機核苷間鍵聯的經修飾之寡核苷酸群體，或製備成包含呈特定立體化學構形之硫代磷酸酯鍵聯的經修飾之寡核苷酸群體。在某些實施例中，經修飾之寡核苷酸群體包含硫代磷酸酯核苷間鍵聯，其中所有該等硫代磷酸酯核苷間鍵聯均為立體隨機的。此等經修飾之寡核苷酸可使用可隨機選擇每一硫代磷酸酯鍵聯之立體化學構形之合成方法來生成。如熟習此項技術者所充分理解，每一個別寡核苷酸分子之每一個別硫代磷酸酯具有確定之立體構形。在某些實施例中，經修飾之寡核苷酸群體富集經修飾之寡核苷酸，該等經修飾之寡核苷酸包含一或多個呈特定獨立選擇之立體化學構形之特定硫代磷酸酯核苷間鍵聯。在某些實施例中，群體中至少65%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少70%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少80%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少90%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少99%之分子中存在特定硫代磷酸酯鍵聯之特定構形。經修飾之寡核苷酸之此類富集群體可使用此項技術中已知之合成方法來生成，例如以下文獻中所闡述之方法：Oka等人，JACS 125, 8307 (2003)；Wan等人，Nuc. Acid. Res. 42, 13456 (2014)；及WO 2017/015555。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Sp)構形之所指示硫代磷酸酯的經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Rp)構形之硫代磷酸酯的經修飾之寡核苷酸。結合基團In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages having a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as a modified oligonucleotide population comprising stereo-random internucleoside linkages, or as a modified oligonucleotide population comprising phosphorothioate linkages in a specific stereochemical configuration. In certain embodiments, the modified oligonucleotide population comprises phosphorothioate internucleoside linkages, wherein all of the phosphorothioate internucleoside linkages are stereo-random. Such modified oligonucleotides can be generated using a synthetic method that can randomly select the stereochemical configuration of each phosphorothioate linkage. As is well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereo configuration. In certain embodiments, a modified oligonucleotide population is enriched for modified oligonucleotides that contain one or more specific phosphorothioate internucleoside linkages in a specific independently selected stereochemical configuration. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, a specific conformation of a specific phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003); Wan et al., Nuc. Acid. Res. 42, 13456 (2014); and WO 2017/015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) conformation. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) conformation.Binding Group

在某些實施例中，本文所闡述之化合物包含一或多種寡核苷酸及視情況一或多種結合基團，或由其組成。結合基團可連接至寡核苷酸之任一端或兩端及/或連接在任一內部位置。在某些實施例中，結合基團連接在寡核苷酸之3’端。在某些實施例中，結合基團連接在寡核苷酸之5’端。在某些實施例中，寡核苷酸共價連接至一或多種結合基團。In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and optionally one or more binding groups. The binding group may be attached to either or both ends of the oligonucleotide and/or to any internal position. In certain embodiments, the binding group is attached to the 3' end of the oligonucleotide. In certain embodiments, the binding group is attached to the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide is covalently attached to one or more binding groups.

在某些實施例中，結合基團為連接至寡核苷酸之任一端或兩端之末端基團。在某些此類實施例中，末端基團連接在寡核苷酸之3’端。在某些此類實施例中，末端基團連接在寡核苷酸之5’端。在某些實施例中，末端基團包括(但不限於)封端基團、磷酸酯部分、保護基團、經修飾或未經修飾之核苷及兩個或更多個獨立地經修飾或未經修飾之核苷，諸如懸突。In some embodiments, the binding group is a terminal group attached to either or both ends of the oligonucleotide. In some such embodiments, the terminal group is attached to the 3' end of the oligonucleotide. In some such embodiments, the terminal group is attached to the 5' end of the oligonucleotide. In some embodiments, the terminal group includes (but is not limited to) a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more independently modified or unmodified nucleosides, such as an overhang.

在某些實施例中，結合基團使所連接之寡核苷酸之一或多種性質改質，包括(但不限於)藥效學、藥物動力學、穩定性、活性、半衰期、結合、吸收、組織分佈、細胞分佈、細胞攝取、電荷及清除。在某些實施例中，例如與不存在結合基團之化合物相比，此一結合基團增強化合物對選定靶標(例如分子、細胞或細胞類型、區室(例如細胞或器官區室)、組織、器官或身體區域)之親和力。在某些實施例中，結合基團賦予所連接之寡核苷酸新的性質，例如使得能夠偵測寡核苷酸之螢光團或報導基團。In some embodiments, the binding group modifies one or more properties of the linked oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance. In some embodiments, such a binding group enhances the affinity of the compound for a selected target (e.g., a molecule, a cell or cell type, a compartment (e.g., a cell or organ compartment), a tissue, an organ, or a body region), for example, compared to the compound in the absence of the binding group. In some embodiments, the binding group imparts a new property to the linked oligonucleotide, such as a fluorophore or reporter group that enables detection of the oligonucleotide.

在某些實施例中，結合基團包括(但不限於)嵌插物、報導分子、聚胺、聚醯胺、肽、碳水化合物、維生素部分、聚乙二醇、硫醚、聚醚、膽固醇、硫膽固醇、膽酸部分、葉酸鹽、脂質、磷脂、生物素、吩嗪、菲啶、蒽醌、金剛烷、吖啶、螢光黃、玫瑰紅、香豆素、螢光團及染料。In certain embodiments, binding groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterol, sulfosterol, bile acid moieties, folates, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescent yellow, rose bengal, coumarin, fluorescein, and dyes.

在某些實施例中，結合基團包括活性原料藥，例如阿司匹林(aspirin)、華法林(warfarin)、苯丁吡唑酮(phenylbutazone)、布洛芬、舒洛芬(suprofen)、芬布芬(fen-bufen)、酮洛芬(ketoprofen)、(S)-(+)-普拉洛芬(pranoprofen)、卡洛芬(carprofen)、丹磺醯肌胺酸(dansylsarcosine)、2,3,5-三碘苯甲酸、芬戈莫德(fingolimod)、氟芬那酸(flufenamic acid)、醛葉酸、苯并噻二嗪、氯噻嗪、二氮呯、吲哚美辛(indo-methicin)、巴比妥酸鹽(barbiturate)、頭孢菌素(cephalosporin)、磺胺藥、抗糖尿病藥、抗細菌劑或抗生素。In certain embodiments, the conjugated group comprises an active pharmaceutical ingredient, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folate, benzothiadiazine, chlorothiazide, diazepam, indomethicin, barbiturate, cephalosporin, sulfonamide, antidiabetic, antibacterial, or antibiotic.

在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包括(但不限於)凝集素、糖蛋白、脂質、蛋白質、肽、肽模擬物、受體配位體、抗體、促甲狀腺素、黑促素、表面活性劑蛋白A、碳水化合物、碳水化合物衍生物、經修飾之碳水化合物、碳水化合物群集、多糖、經修飾之多糖或多糖衍生物、黏蛋白碳水化合物、多價乳糖、多價半乳糖、N-乙醯基-半乳胺糖(GalNAc)、N-乙醯基葡萄糖胺多價甘露糖、多價岩藻糖、糖基化聚胺基酸、多價半乳糖、運鐵蛋白、雙膦酸酯、聚麩胺酸鹽、聚天冬胺酸鹽、脂質、膽固醇、類固醇、膽汁酸、葉酸鹽、維生素B12、維生素A、生物素或RGD肽或RGD肽模擬物。In certain embodiments, the binding group is a targeting moiety. In certain embodiments, targeting moieties include, but are not limited to, lectins, glycoproteins, lipids, proteins, peptides, peptide mimetics, receptor ligands, antibodies, thyrotropin, melanogaster, surfactant protein A, carbohydrates, carbohydrate derivatives, modified carbohydrates, carbohydrate clusters, polysaccharides, modified polysaccharides or polysaccharide derivatives, mucin carbohydrates, multivalent lactose, multivalent galactose, N-acetyl-galactosamine sugar (GalNAc), N-acetylglucosamine multivalent mannose, multivalent fucose, glycosylated polyamino acids, multivalent galactose, transferrin, bisphosphonates, polyglutamine, polyaspartate, lipids, cholesterol, steroids, bile acid, folate, vitamin B12, vitamin A, biotin, or RGD peptide or RGD peptide mimetic.

在某些實施例中，結合基團可包括(但不限於)以下參考文獻中所闡述之結合基團，諸如膽固醇(例如Letsinger等人，Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556)；膽酸(例如Manoharan等人，Biorg. Med. Chem. Let., 1994, 4:1053-1060)；硫醚，例如己基-S-三苯甲基硫醇(例如Manoharan等人，Αnn. NY. Acad. Sci., 1992, 660:306-309；Manoharan等人，Biorg. Med. Chem. Let., 1993, 3:2765-2770)；硫膽固醇(例如Oberhauser等人，Nucl. Acids Res., 1992, 20:533-538)；脂肪族鏈，例如十二烷-二醇或十一烷基殘餘物(例如Saison-Behmoaras等人，EMBO J, 1991, 10:1111-1118；Kabanov等人，FEBS Lett., 1990, 259:327-330；Svinarchuk等人，Biochimie, 1993, 75:49-54)；磷脂，例如二-十六烷基-外消旋-甘油或1,2-二-O-十六烷基-外消旋-甘油-3-H-膦酸三乙基-銨(例如Manoharan等人，Tetrahedron Lett., 1995, 36:3651-3654；Shea等人，Nucl. Acids Res., 1990, 18:3777-3783)；聚胺或聚乙二醇鏈(例如Manoharan等人，Nucleosides & Nucleotides, 1995, 14:969-973)；金剛烷乙酸(例如Manoharan等人，Tetrahedron Lett., 1995, 36:3651-3654)；棕櫚基(例如Mishra等人，Biochim. Biophys. Acta, 1995, 1264:229-237)；十八烷基胺或己基胺基-羰基羥膽固醇部分(例如Crooke等人，J. Pharmacol. Exp. Ther., 1996, 277:923-937)；生育酚(例如Nishina等人，Molecular Therapy Nucleic Acids, 2015, 4, e220及Nishina等人，Molecular Therapy, 2008, 16:734-740)；GalNAc及其他碳水化合物(例如Maier等人，Bioconjugate Chemistry, 2003, 14, 18-29；Rensen等人，J. Med. Chem. 2004, 47, 5798-5808；WO2009/073809及美國專利8,106,022；8,450,467及8,828,957；及WO2014/179445；WO2014/179620及美國專利9,127,276；9,181,549及10,844,379)，該等文獻各自係以全文引用的方式併入本文中。In certain embodiments, the binding group may include, but is not limited to, the binding groups described in the following references, such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556); cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4: 1053-1060); thioethers, such as hexyl-S-tritylthiol (e.g., Manoharan et al., Annals of New York, 1992, 660: 306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3: 2765-2770); thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538); aliphatic chains, such as dodecanediol or undecyl residues (e.g. Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54); phospholipids, such as di-hexadecyl-rac-glycerol or 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonic acid triethyl-ammonium (e.g. Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783); polyamine or polyethylene glycol chain (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973); adamantane acetic acid (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654); palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237); octadecylamine or hexylamino-carbonyl hydroxycholesterol moiety (e.g., Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937); tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al., Molecular Therapy, 2008, 16:734-740); GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WO2009/073809 and U.S. Pat. Nos. 8,106,022; 8,450,467 and 8,828,957; and WO2014/179445; WO2014/179620 and U.S. Pat. Nos. 9,127,276; 9,181,549 and 10,844,379), each of which is incorporated herein by reference in its entirety.

結合基團可經由結合連接體連接至寡核苷酸。在某些實施例中，結合連接體包含鏈結構，諸如烴基鏈，或重複單元之寡聚物或此等重複單元之組合。在某些實施例中，結合連接體包含一或多個選自以下之基團：烷基、胺基、側氧基、醯胺、二硫化物、聚乙二醇、醚、硫醚及羥基胺基。在某些實施例中，結合連接體包含至少一個磷基。在某些實施例中，結合連接體包含至少一個磷酸酯基。在某些實施例中，結合連接體包括至少一個中性連接基團。在某些實施例中，結合連接體包括(但不限於)吡咯啶、8-胺基-3,6-二氧雜辛酸(ADO)、4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸琥珀醯亞胺酯(SMCC)及6-胺基己酸(AHEX或AHA)。其他結合連接體包括(但不限於)經取代或未經取代之C₁-C₁₀烷基、經取代或未經取代之C₂-C₁₀烯基或經取代或未經取代之C₂-C₁₀炔基，其中較佳取代基之非限制性清單包括羥基、胺基、烷氧基、羧基、苯甲基、苯基、硝基、硫醇、硫烷氧基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，結合連接體包含1-10個連接體核苷。在某些實施例中，此等連接體核苷可為經修飾或未經修飾之核苷。通常期望連接體核苷在化合物到達靶組織後自化合物裂解。因此，本文之連接體核苷可經由可裂解鍵彼此連接及連接至化合物之其餘部分。在本文中，連接體核苷不視為寡核苷酸之一部分。因此，在化合物包含由指定數目或範圍之連接核苷組成及/或與參照核酸具有指定互補性百分比之寡核苷酸且化合物亦包含含有結合連接體(包含連接體核苷)之結合基團的實施例中，彼等連接體核苷不計入寡核苷酸之長度且不用於確定寡核苷酸對於參照核酸之互補性百分比。The binding group can be linked to the oligonucleotide via a binding linker. In some embodiments, the binding linker comprises a chain structure, such as an alkyl chain, or an oligomer of repeating units or a combination of such repeating units. In some embodiments, the binding linker comprises one or more groups selected from the following: alkyl, amine, pendoxy, amide, disulfide, polyethylene glycol, ether, thioether and hydroxylamine. In some embodiments, the binding linker comprises at least one phosphorus group. In some embodiments, the binding linker comprises at least one phosphate group. In some embodiments, the binding linker includes at least one neutral linking group. In certain embodiments, the conjugate linker includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxooctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include, but are not limited to, substituted or unsubstituted C₁ -C₁₀ alkyl, substituted or unsubstituted C₂ -C₁₀ alkenyl, or substituted or unsubstituted C₂ -C₁₀ alkynyl, wherein a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the conjugate linker comprises 1-10 linker nucleosides. In certain embodiments, these linker nucleosides may be modified or unmodified nucleosides. It is generally expected that the linker nucleosides will cleave from the compound after the compound reaches the target tissue. Therefore, the linker nucleosides herein may be linked to each other and to the rest of the compound via a cleavable bond. In this article, linker nucleosides are not considered part of an oligonucleotide. Therefore, in embodiments in which the compound comprises an oligonucleotide composed of a specified number or range of linker nucleosides and/or has a specified percentage of complementarity with a reference nucleic acid, and the compound also comprises a binding group containing a binding linker (including a linker nucleoside), those linker nucleosides are not included in the length of the oligonucleotide and are not used to determine the percentage of complementarity of the oligonucleotide to the reference nucleic acid.

在某些實施例中，結合基團及結合連接體以及其他修飾包括(但不限於)以下參考文獻中所闡述者：US 5,994,517；US 6,300,319；US 6,660,720；US 6,906,182；US 7,262,177；US 7,491,805；US 8,106,022；US 7,723,509；US 9,127,276；US 2006/0148740；US 2011/0123520；WO2013/033230；WO2012/037254；Biessen等人，J. Med. Chem. 1995, 38, 1846-1852；Lee等人，Bioorganic & Medicinal Chemistry 2011,19, 2494-2500；Rensen等人，J. Biol. Chem. 2001, 276, 37577-37584；Rensen等人，J. Med. Chem. 2004, 47, 5798-5808；Sliedregt等人，J. Med. Chem. 1999, 42, 609-618；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Lee, Carhohydr Res, 1978, 67, 509-514；Connolly等人，J Biol Chem, 1982, 257, 939-945；Pavia等人，Int J Pep Protein Res, 1983, 22, 539-548；Lee等人，Biochem, 1984, 23, 4255-4261；Lee等人，Glycoconjugate J, 1987, 4, 317-328；Toyokuni等人，Tetrahedron Lett, 1990, 31, 2673-2676；Biessen等人，J Med Chem, 1995, 38, 1538-1546；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Kim等人，Tetrahedron Lett, 1997, 38, 3487-3490；Lee等人，Bioconjug Chem, 1997, 8, 762-765；Kato等人，Glycohiol, 2001, 11, 821-829；Rensen等人，J Biol Chem, 2001, 276, 37577-37584；Lee等人，Methods Enzymol, 2003, 362, 38-43；Westerlind等人，Glycoconj J, 2004, 21, 227-241；Lee等人，Bioorg Med Chem Lett, 2006, 16(19), 5132-5135；Maierhofer等人，Bioorg Med Chem, 2007, 15, 7661-7676；Khorev等人，Bioorg Med Chem, 2008, 16, 5216-5231；Lee等人，Bioorg Med Chem, 2011, 19, 2494-2500；Kornilova等人，Analyt Biochem, 2012, 425, 43-46；Pujol等人，Angew Chemie Int Ed Engl, 2012, 51, 7445-7448；Biessen等人，J Med Chem, 1995, 38, 1846-1852；Sliedregt等人，J Med Chem, 1999, 42, 609-618；Rensen等人，J Med Chem, 2004, 47, 5798-5808；Rensen等人，Arterioscler Thromh Vase Biol, 2006, 26, 169-175；van Rossenberg等人，Gene Ther, 2004, 11, 457-464；Sato等人，JAm Chem Soc, 2004, 126, 14013-14022；Lee等人，J Org Chem, 2012, 77, 7564-7571；Biessen等人，FASEB J, 2000, 14, 1784-1792；Rajur等人，Bioconjug Chem, 1997, 8, 935-940；Duff等人，Methods Enzymol, 2000, 313, 297-321；Maier等人，Bioconjug Chem, 2003, 14, 18-29；Jayaprakash等人，Org Lett, 2010, 12, 5410-5413；Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128；Merwin等人，Bioconjug Chem, 1994, 5, 612-620；Tomiya等人，Bioorg Med Chem, 2013, 21, 5275-5281；國際申請案WO1998/013381；WO2011/038356；WO1997/046098；W02008/098788；W02004/101619；WO2012/037254；WO2011/120053；WO2011/100131；WO2011/163121；WO2012/177947；W02013/033230；W02013/075035；WO2012/083185；WO2012/083046；W02009/082607；WO2009/134487；W02010/144740；W02010/148013；WO1997/020563；W02010/088537；W02002/043771；W02010/129709；WO2012/068187；WO2009/126933；W02004/024757；WO2010/054406；WO2012/089352；WO2012/089602；WO2013/166121；WO2013/165816；美國專利4,751,219；7,582,744；8,552,163；8,137,695；6,908,903；6,383,812；7,262,177；6,525,031；5,994,517；6,660,720；6,300,319；7,723,509；8,106,022；7,491,805；7,491,805；8,541,548；8,344,125；8,313,772；8,349,308；8,450,467； 8,501,930；8,158,601；7,262,177；6,906,182；6,620,916；8,435,491；8,404,862；7,851,615；已公佈之美國專利申請公開案US2011/0097264；US2011/0097265；US2013/0004427；US2003/0119724；US2011/0207799；US2012/0035115；US2012/0230938；US2005/0164235；US2006/0183886；US2012/0136042；US2012/0095075；US2013/0109817；US2006/0148740；US2008/0206869；US2012/0165393；US2012/0101148；US2013/0121954；US2011/0123520；US2003/0077829；US2008/0108801；及US2009/0203132；該等參考文獻各自係以全文引用的方式併入本文中。某些結合基團In certain embodiments, the binding groups and binding linkers and other modifications include, but are not limited to, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006/0148740; US 2011/0123520; WO2013/033230; WO2012/037254; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998/013381; WO2011/038356; WO1997/046098; WO2008/098788; WO2004/101619; WO2012/037254; WO2011/120053; WO2011/100131; WO2011/163121; WO2012/177947; WO20 13/033230; W02013/075035; WO2012/083185; WO2012/083046; W02009/082607; WO2009/134487; W02010/144740; W02010/148013; WO1997/020563; W02010/088537; W02002/043771; W02010/129 709; WO2012/068187; WO2009/126933; W02004/024757; WO2010/054406; WO2012/089352; WO2012/089602; WO2013/166121; WO2013/165816; U.S. Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; published U.S. patent applications US2011/0097264; US2011/0097265; US2013/0004427; US2003/0119724; US2011/0207799; US2012/0035115; US2012/0230938; US2005/0164235; US2 006/0183886; US2012/0136042; US2012/0095075; US2013/0109817; US2006/0148740; US2008/0206869; US2012/0165393; US2012/0101148; US2013/0121954; US2011/0123520; US2003/0077829; US2008/0108801; and US2009/0203132; each of which is incorporated herein by reference in its entirety.Certain Binding Groups

在某些實施例中，本文所提供之化合物包含結合基團。在某些實施例中，本文所提供之寡核苷酸包含結合基團。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種TrkB配位體。In certain embodiments, the compounds provided herein include a binding group. In certain embodiments, the oligonucleotides provided herein include a binding group. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more TrkB ligands.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(I)或為其鹽、溶劑合物或水合物：式(I)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³及L⁴係如本文所闡述； R²為氫、-OR⁷、-SR⁸或-NR⁹R¹⁰； R³為氫、-OR¹¹、-SR¹²或-NR¹³R¹⁴； R⁴為氫、-OR¹⁵、-SR¹⁶或-NR¹⁷R¹⁸； R⁵為氫、-OR¹⁹、-SR²⁰或-NR²¹R²²； R⁶為氫、-OH、視情況經取代之-O-烷基、視情況經取代之-OAc、-NH₂、視情況經取代之-NHAc、-SH或=O； R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基、視情況經取代之雜芳基； Y為CH₂、NH、S或O；且 Z為視情況經取代之芳基或視情況經取代之雜芳基。In certain embodiments, the TrkB ligand of the modified oligonucleotide has formula (I) or is a salt, solvate or hydrate thereof: Formula (I), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ and L⁴ are as described herein; R² is hydrogen, -OR⁷ , -SR⁸ or -NR⁹ R¹⁰ ; R³ is hydrogen, -OR¹¹ , -SR¹² or -NR¹³ R¹⁴ ; R⁴ is hydrogen, -OR¹⁵ , -SR¹⁶ or -NR¹⁷ R¹⁸ ; R⁵ is hydrogen, -OR¹⁹ , -SR²⁰ or -NR²¹ R²² ; R⁶ is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH₂ , optionally substituted -NHAc, -SH or =O; R⁷ , R⁸ , R⁹ , R^R10 ,^R11 ,^R12 ,^R13 ,^R14 ,^R15 ,^R16 ,^R17 ,^R18 ,^R19 ,^R20 ,^R21 and^R22 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is_CH2 , NH, S or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

在某些實施例中，R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為烯基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為炔基。In certain embodiments, R⁷ , R⁸ , R⁹ , R¹⁰ , R¹¹ , R¹² , R¹³ , R¹⁴ , R¹⁵ , R¹⁶ , R¹⁷ , R¹⁸ , R¹⁹ , R²⁰ , R²¹ and R²² are each independently an unsaturated or partially unsaturated alkyl group which is optionally substituted. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkenyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkynyl group.

在某些實施例中，R²為OR⁷。在某些實施例中，R³為OR¹¹。在某些實施例中，R⁷及R¹¹各自獨立地為氫、視情況經取代之烷基或視情況經取代之烯基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為氫。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為烯基。在某些實施例中，R⁷為視情況經取代之烷基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烷基。在某些實施例中，R⁷為烯基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烯基。In certain embodiments, R² is OR⁷ . In certain embodiments, R³ is OR¹¹ . In certain embodiments, R⁷ and R¹¹ are each independently hydrogen, optionally substituted alkyl or optionally substituted alkenyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R 7 and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R 11 are each independently substituted alkyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently unsaturated or partially unsaturated alkyl, which may be substituted. In certain embodiments, one or both of R⁷ and R¹¹ are each independently alkenyl. In certain embodiments, R⁷ is optionally substituted alkyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkyl. In certain embodiments, R^{7 is alkenyl and R 11 is hydrogen. In certain embodiments, R 7is hydrogen and R 11isoptionally} substituted alkenyl.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(II-A)、式(II-B)、式(II-C)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³、L⁴及R¹係如本文所闡述。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (II-A), Formula (II-B), Formula (II-C), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ , L⁴ and R¹ are as described herein.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXVII)或為其鹽、溶劑合物或水合物：式(XXXXXVII)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R¹¹及R¹³各自獨立地不存在、為氫或視情況經取代之烷基； R¹²、R¹⁴及R¹⁵各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R¹⁶為氫、鹵素、-CN、-N₃、-SO_n16R^1A、-SO_v16NR^16BR^16C、-NHNR^16BR^16C、-ONR^16BR^16C、-NHC(O)NHNR^16BR^16C、-NHC(O)NR^16BR^16C、-N(O)_m16、-NR^16BR^16C、-C(O)R^16D、-C(O)OR^16D、-C(O)NR^16BR^16C、-OR^16A、-NR^16BSO₂R^16A、-NR^16BC(O)R^16D、-NR^16BC(O)OR^16D、-NR^16BOR^16D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基；及各自獨立地為單鍵或雙鍵，其中若為單鍵，則為雙鍵且R¹³不存在；且進一步其中若為單鍵，則為雙鍵且R¹¹不存在； R^16A、R^16B、R^16C、R^16D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基；鍵結至同一氮原子之R^16B及R^16C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； z3為0、1、2、3、4或5； n16為0、1、2、3或4；且 v16及m16各自獨立地為1或2。In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXVII) or is a salt, solvate or hydrate thereof: Formula (XXXXXVII), wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; R¹¹ and R¹³ are each independently absent, hydrogen or an optionally substituted alkyl group; R¹² , R¹⁴ and R¹⁵ are each independently hydrogen, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group,^an optionally substituted aryl group or an optionally substituted heteroaryl group; R¹⁶ is^hydrogen ,^ahalogen ,_-CN , -N₃ ,_-SON16R1A , -SOv16NR16BR16C ,^-NHNR16BR16C ,^-ONR16BR16C , -NHC(O)NHNR^16B R^16C , -NHC(O)NR^16B R^16C , -N(O)_m16 , -NR^16B R^16C , -C(O)R^16D , -C(O)OR^16D , -C(O)NR^16B R^16C , -OR^16A , -NR^16B SO₂ R^16A , -NR^16B C(O)R^16D , -NR^16B C(O)OR^16D , -NR^16B OR^16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and Each is independently a single key or a double key, where if is a single key, then is a double key and R¹³ does not exist; and further wherein if is a single key, then is a double bond and R¹¹ is absent; R^16A , R^16B , R^16C , R^16D are each independently hydrogen, halogen, -CF₃ , -CCl₃ , -CBr₃ , -CI₃ , -COOH, -CONH₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R^16B and R^16C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z3 is 0, 1, 2, 3, 4 or 5; n16 is 0, 1, 2, 3 or 4; and v16 and m16 are each independently 1 or 2.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXIX)或為其鹽、溶劑合物或水合物：式(XXXXXIX)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R¹⁷、R¹⁸及R¹⁹各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； z4為0、1或2；且 z5為0、1、2或3。In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXIX) or is a salt, solvate or hydrate thereof: Formula (XXXXXIX), wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; R¹⁷ , R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; z4 is 0, 1 or 2; and z5 is 0, 1, 2 or 3.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(XXXXXX)或為其鹽、溶劑合物或水合物：式(XXXXXX)， 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； R²⁰為氫、鹵素、-CN、-N₃、-SO_n20R^1A、-SO_v20NR^20BR^20C、-NHNR^20BR^20C、-ONR^20BR^20C、-NHC(O)NHNR^20BR^20C、-NHC(O)NR^20BR^20C、-N(O)_m20、-NR^20BR^20C、-C(O)R^20D、-C(O)OR^20D、-C(O)NR^20BR^20C、-OR^20A、-NR^20BSO₂R^20A、-NR^20BC(O)R^20D；-NR^20BC(O)OR^20D、-NR^20BOR^20D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²¹為氫、鹵素、-CN、-N₃、-SO_n21R^1A、-SO_v21NR^21BR^21C、-NHNR^21BR^21C、-ONR^21BR^21C、-NHC(O)NHNR^21BR^21C、-NHC(O)NR^21BR^21C、-N(O)_m21、-NR^21BR^21C、-C(O)R^21D、-C(O)OR^21D、-C(O)NR^21BR^21C、-OR^21A、-NR^21BSO₂R^21A、-NR^21BC(O)R^21D；-NR^21BC(O)OR^21D、-NR^21BOR^21D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²²及R²³各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R²⁴為氫、鹵素、-CN、-N₃、-SO_n24R^24A、-SO_v24NR^24BR^24C、-NHNR^24BR^24C、-ONR^24BR^24C、-NHC(O)NHNR^24BR^24C、-NHC(O)NR^24BR^24C、-N(O)_m24、-NR^24BR^24C、-C(O)R^24D、-C(O)OR^24D、-C(O)NR^24BR^24C、-OR^24A、-NR^24BSO₂R^24A、-NR^24BC(O)R^24D；-NR^24BC(O)OR^24D、-NR^24BOR^24D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R^20A、R^20B、R^20C、R^20D、R^21A、R^21B、R^21C、R^21D、R^24A、R^24B、R^24C及R^24D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 鍵結至同一氮原子之R^20B、R^20C、R^21B、R^21C、R^24B、R^24C、R^24B及R₂^4C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； n21、n22、n24、z6及z8各自獨立地為0、1、2、3或4； v20、v21、v24、m20、m21及m24各自獨立地為1或2；且 z7為0、1或2。In certain embodiments, the TrkB ligand of the modified oligonucleotide has the formula (XXXXXX) or is a salt, solvate or hydrate thereof: Formula (XXXXXX), wherein:^L1 ,^L2 ,^L3 ,^L4 and^R1are as described herein;^R20 is^hydrogen , halogen, -CN,_-N3 ,_-SON20R1A ,^{-SOv20NR20BR20C} , -NHNR20BR20C, -ONR20BR20C,^{-NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C,}_-N^{(O)20,-NR20BR20C,}_-C (^O )^R20D , -C(O^)OR20D_, -C(O^{)NR20BR20C,-OR20A,-NR20BSO2R20A} , -NR^20B C(O)R^20D ; -NR^20B C(O)OR^20D , -NR^20B OR^20D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted^aryl or optionally substituted_heteroaryl ; R^21is hydrogen, halogen, -CN,^-N₃ ,_-SON21R1A , -SOv21NR21BR21C^{,-NHNR21BR21C} ,^-ONR21BR21C ,^-NHC (^O )^NHNR21BR21C , -NHC(O^)NR21BR21C_R^{22andR​​​​​}_​^{​​​​​​​​R 23} is each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R²⁴ is hydrogen, halogen, -CN, -N₃ ,_-SON24R^24A , -SO_v24 NR^24B R^24C , -NHNR^24B R^24C , -ONR^24B R^24C , -NHC(O)NHNR^24B R^24C , -NHC(O)NR^24B R^24C , -N(O)_m24 , -NR^24B R^24C , -C(O)R^24D , -C(O)OR^24D , -C(O)NR^24B R^24C , -OR^24A , -NR^24B SO₂ R^24A , -NR^24B C(O)R^24D ; -NR^24B C(O)OR^24D , -NR^24B OR^24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R^20A , R^20B , R 20C , R^20D , R^21A , R^21B , R^21C , R^21D , R^24A ,^{RR 24B} , R^24C and R^24D are each independently hydrogen, halogen, -CF₃ , -CCl₃ , -CBr₃ , -CI₃ , -COOH, -CONH₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R^20B , R^20C , R^21B , R 21C^, R^24B , R^{24C, R 24Band} R^24C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl_; n21, n22, n24, z6 and z8 are each independently 0, 1, 2, 3 or 4; v20, v21, v24, m20, m21 and m24 are each independently 1 or 2; and z7 is 0, 1 or 2.

在某些實施例中，經修飾之寡核苷酸之CB₁配位體具有式(XXXXXXI)或為其鹽、溶劑合物或水合物：， 式(XXXXXXI) 其中： L¹、L²、L³、L⁴及R¹係如本文所闡述； X¹為NR¹⁰或CR¹¹R¹²； R¹⁰、R¹¹及R¹²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R¹⁹為氫、-SO_n19R^19A、-SO_v19NR^19BR^19C、-NHNR^19BR^19C、-ONR^19BR^19C、-NHC(O)NHNR^19BR^19C、-NHC(O)NR^19BR^19C、-NR^19BR^19C、-C(O)R^19D、-C(O)OR^19D、-C(O)NR^19BR^19C、-OR^19A、-NR^19BSO₂R^19A、-NR^19BC(O)R^19D、-NR^19BC(O)OR^19D、-NR^19BOR^19D、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基或視情況經取代之雜芳基； R^19A、R^19B、R^19C、R^19D各自獨立地為氫、鹵素、-CF₃、-CCl₃、-CBr₃、-CI₃、-COOH、-CONH₂、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基；其中鍵結至同一氮原子之R^19B及R^19C取代基可視情況接合形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基； n19為0、1、2、3或4；且 v19為1或2。In certain embodiments, the_CB1 ligand of the modified oligonucleotide has the formula (XXXXXXI) or is a salt, solvate or hydrate thereof: , Formula (XXXXXXI) wherein: L¹ , L² , L³ , L⁴ and R¹ are as described herein; X¹ is NR¹⁰ or CR¹¹ R¹² ; R¹⁰ , R¹¹ and R¹² are each independently hydrogen, optionally substituted alkyl, optionally substituted^heteroalkyl , optionally substituted^cycloalkyl , optionally substituted^{heterocycloalkyl} , optionally substituted aryl or optionally substituted^heteroaryl ;^R19 is hydrogen,_-SON19R19A ,_{-SOv19NR19BR19C}^{,-NHNR19BR19C} ,^-ONR19BR19C , -NHC(O)^NHNR19BR19C , -NHC(O)NR^19B R^19C , -NR^19B R^19C , -C(O)R^19D , -C(O)OR^19D , -C(O)NR^19B R^19C , -OR^19A , -NR^19B SO₂ R^19A , -NR^19B C(O)R^19D , -NR^19B C(O)OR^19D , -NR^19B OR^19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R^19A , R^19B , R^19C , R^R19D is each independently hydrogen, halogen,_-CF3 ,_-CCl3 ,_-CBr3 ,_-CI3 , -COOH,_-CONH2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; wherein^R19B and^R19C substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl as appropriate; n19 is 0, 1, 2, 3 or 4; and v19 is 1 or 2.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、聚乙二醇(PEG)、視情況經取代之雜烷基或視情況經取代之雜芳基；且 R³及R⁴各自獨立地為H、鹵素、視情況經取代之烷基或視情況經取代之-O-烷基。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXII) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, polyethylene glycol (PEG), an optionally substituted heteroalkyl group or an optionally substituted heteroaryl group; and R³ and R⁴ are each independently H, a halogen, an optionally substituted alkyl group or an optionally substituted -O-alkyl group.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXIII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXIII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²、R³、R⁴及R⁵各自獨立地為H、鹵素、視情況經取代之烷基、視情況經取代之-O-烷基、環烷基，或不存在； R⁸為視情況經取代之C₁-C₅烷基、視情況經取代之C₁-C₅伸烷基-(C₃-C₆)-環烷基或視情況經取代之(C₁-C₄)-伸烷基-(C₁-C₄)-烷氧基；且 R⁶及R⁷各自獨立地為H、鹵素、烷基或視情況經取代之烷基、視情況經取代之雜烷基、、、、、或。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXIII) or is a salt, solvate or hydrate thereof: Formula (XXXXXXIII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² , R³ , R⁴ and R⁵ are each independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent; R⁸ is optionally substituted C₁ -C₅ alkyl, optionally substituted C₁ -C₅ alkylene-(C₃ -C₆ )-cycloalkyl or optionally substituted (C₁ -C₄ )-alkylene-(C₁ -C₄ )-alkoxy; and R⁶ and R⁷ are each independently H, halogen, alkyl or optionally substituted alkyl, optionally substituted heteroalkyl, , , , , or .

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXIV)或為其鹽、溶劑合物或水合物：. 式(XXXXXXIV) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、-CONHR⁴、-CH₂OR⁴、-(CH₂)₂OR⁴、-CH₂NHCOR⁴或-OR⁴； R³為H、視情況經取代之烷基或視情況經取代之環烷基； R⁴為H、聚乙二醇、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基或視情況經取代之雜芳基； R⁵為-OH或不存在；且 X為H、視情況經取代之CH₂、視情況經取代之NH或環烷基。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXIV) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXIV) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, -CONHR⁴ , -CH₂ OR⁴ , -(CH₂ )₂ OR⁴ , -CH₂ NHCOR⁴ or -OR⁴ ; R³ is H, optionally substituted alkyl or optionally substituted cycloalkyl; R⁴ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; R⁵ is -OH or absent; and X is H, optionally substituted CH₂ , optionally substituted NH or cycloalkyl.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體具有式(XXXXXXXXIII)或為其鹽、溶劑合物或水合物：. 式(XXXXXXXXIII) 其中 L¹、L²、L³、L⁴及R¹係如本文所闡述； R²為H、-CONHR³、-CH₂OR³、-(CH₂)₂OR³、-CH₂NHCOR³或-OR³； R³之每一實例獨立地為H、聚乙二醇、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基或視情況經取代之雜芳基；且 X為H或鹵素。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide has the formula (XXXXXXXXIII) or is a salt, solvate or hydrate thereof: . Formula (XXXXXXXXIII) wherein L¹ , L² , L³ , L⁴ and R¹ are as described herein; R² is H, -CONHR³ , -CH₂ OR³ , -(CH₂ )₂ OR³ , -CH₂ NHCOR³ or -OR³ ; each instance of R³ is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; and X is H or a halogen.

在某些實施例中，L¹、L²、L³及L⁴各自獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體。In certain embodiments, L¹ , L² , L³ and L⁴ are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之雜芳基連接體。In certain embodiments, L¹ is an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之不飽和雜芳基、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L¹ is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L¹包含結構：。In certain embodiments,^L1 comprises the structure: .

在某些實施例中，L¹為視情況經取代之雜烷基連接體。在某些實施例中，視情況經取代之雜烷基連接體為視情況經取代之雜烷基或視情況經取代之C₁-C₁₀烷基鏈，其中一或多個碳原子經O、N或S置換。In certain embodiments, L¹ is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C₁ -C₁₀ alkyl chain in which one or more carbon atoms are replaced by O, N or S.

在某些實施例中，L¹包含結構：或。In certain embodiments,^L1 comprises the structure: or .

在某些實施例中，L¹包含結構：或-N(CH₃)-。In certain embodiments,^L1 comprises the structure: or -N(CH₃ )-.

在某些實施例中，L²為視情況經取代之PEG連接體。In certain embodiments,^L2 is an optionally substituted PEG linker.

在某些實施例中，PEG連接體之長度為五個PEG單元。在某些實施例中，PEG連接體之長度為四個PEG單元。在某些實施例中，PEG連接體之長度為三個PEG單元。In some embodiments, the length of the PEG conjugate is five PEG units. In some embodiments, the length of the PEG conjugate is four PEG units. In some embodiments, the length of the PEG conjugate is three PEG units.

在某些實施例中，L²為視情況經取代之烷基連接體。在某些實施例中，L²為視情況經取代之C_1-20烷基連接體。在某些實施例中，L²為視情況經取代之C₈烷基連接體。在某些實施例中，L³為視情況經取代之雜芳基連接體。In some embodiments,^L2 is an optionally substituted alkyl linker. In some embodiments,^L2 is an optionally substituted_C1-20 alkyl linker. In some embodiments,^L2 is an optionally substituted_C8 alkyl linker. In some embodiments,^L3 is an optionally substituted heteroaryl linker.

在某些實施例中，L³為視情況經取代之部分不飽和雜芳基連接體、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L³ is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L³包含結構：。In certain embodiments,^L3 comprises the structure: .

在某些實施例中，L⁴為視情況經取代之雜烷基連接體。在某些實施例中，雜烷基連接體經一或多個=O取代基取代。In certain embodiments,^L4 is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents.

在某些實施例中，雜烷基連接體包含兩個接合在一起形成視情況經取代之碳環基環之取代基。In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L¹-L²-L³-L⁴包含結構：、、、、、、、、、、、、、、、、、、或其鹽，其中X為O或S。In certain embodiments, L¹ -L² -L³ -L⁴ comprises the structure: , , , , , , , , , , , , , , , , , , or a salt thereof, wherein X is O or S.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)、式(XII)、式(XIII)、式(XIV)、式(XV)、式(XVI)、式(XVII)、式(XVIII)、式(XIX)、式(XX)、BA-129 式(XXI)、BA-169 式(XXII)、BA-170：異構物混合物 式(XXIII)、BA-173 式(XXIV)、BA-183 式(XXV)、BA-201 式(XXVI)、BA-203 式(XXVII)、BA-196 式(XXIX)BA-197 式(XXX)BA-198 式(XXXI)BA-225 式(XXXIII)BA-246 式(XXXIV)式(XXXXXXV)式(XXXXXXVI)式(XXXXXXVII)式(XXXXXXIX)式(XXXXXXX)式(XXXXXXXI)式(XXXXXXXII)式(XXXXXXXIII)式(XXXXXXXXV) 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), BA-129 (XXI), BA-169 (XXII), BA-170: isomer mixture formula (XXIII), BA-173 (XXIV), BA-183 (XXV), BA-201 type (XXVI), BA-203 type (XXVII), BA-196 Type (XXIX) BA-197 Type (XXX) BA-198 Type (XXXI) BA-225 Formula (XXXIII) BA-246 Type (XXXIV) Formula (XXXXXXV) Formula (XXXXXXVI) Formula (XXXXXXVII) Formula (XXXXXXIX) Formula (XXXXXXX) Formula (XXXXXXXI) Formula (XXXXXXXII) Formula (XXXXXXXIII) Formula (XXXXXXXXV) wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，經修飾之寡核苷酸之CB₁配位體係選自以下各式或其鹽、溶劑合物或水合物：式(XXXXXXXIV)式(XXXXXXXV)式(XXXXXXXVI)式(XXXXXXXVII)式(XXXXXXXVIII) 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the_CB1 ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (XXXXXXXIV) Formula (XXXXXXXV) Formula (XXXXXXXVI) Formula (XXXXXXXVII) Formula (XXXXXXXVIII) wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，經修飾之寡核苷酸之α₄β_1/7整聯蛋白配位體係選自以下各式或其鹽、溶劑合物或水合物：式(XXXXXXXIX)式(XXXXXXXX)式(XXXXXXXXI)式(XXXXXXXXII)式(XXXXXXXXIV) 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the α₄ β_1/7 integrin ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (XXXXXXXIX) Formula (XXXXXXXX) Formula (XXXXXXXXI) Formula (XXXXXXXXII) Formula (XXXXXXXXIV) wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，本文所提供之化合物包含結合基團。在某些實施例中，本文所提供之寡核苷酸包含結合基團。在某些實施例中，結合基團為脂質。在某些實施例中，本文所提供之經修飾之寡核苷酸之核苷間鍵聯包含一或多種脂質。In certain embodiments, the compounds provided herein comprise a binding group. In certain embodiments, the oligonucleotides provided herein comprise a binding group. In certain embodiments, the binding group is a lipid. In certain embodiments, the internucleoside linkages of the modified oligonucleotides provided herein comprise one or more lipids.

在某些實施例中，經修飾之寡核苷酸包含式(XXXV)，或其鹽、溶劑合物或水合物：式(XXXV)， 其中： Y為-C(=O)N(R^C)-或-N(R^C)C(=O)-； Q¹及Q³各自獨立地為-H、-OR⁴、配位體、連接體或脂質； Q²及Q⁴各自獨立地為鍵、、配位體、連接體或脂質； R^C獨立地為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基； 每一R⁹獨立地為經取代或未經取代之雜芳基； Z¹或Z²之每一實例獨立地為鍵、C₁-C₆伸烷基或C₂-C₆伸烯基；且 每一X獨立地為O或S； 或其鹽。In certain embodiments, the modified oligonucleotide comprises formula (XXXV), or a salt, solvate or hydrate thereof: Formula (XXXV), wherein: Y is -C(=O)N(^RC )- or -N(^RC )C(=O)-;^Q1 and^Q3 are each independently -H,^-OR4 , a ligand, a linker or a lipid;^Q2 and^Q4 are each independently a bond, , ligand, linker or lipid;^RC is independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(R6) or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ) or^-SR7 ;^R4 and^R5 are independently an oligonucleotide, or^R4 and^R5 are independently an^{oligonucleotide} .⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl; each R⁹ is independently substituted or unsubstituted heteroaryl; each instance of Z¹ or Z² is independently a bond, C₁ -C₆ alkylene, or C₂ -C₆ alkenylene; and each X is independently O or S; or a salt thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVI)，或其鹽、溶劑合物或水合物：式(XXXVI)， 其中： R^C為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVI), or a salt, solvate or hydrate thereof: Formula (XXXVI), wherein:^RC is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted^alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(^R6 ), or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ), or^-SR7 ;^R4 and^R5 are independently oligonucleotides, or^R4 and^R5 are joined together to form a single oligonucleotide; each R R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl ring; each R⁹ is independently substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVII)，或其鹽、溶劑合物或水合物：式(XXXVI)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVII), or a salt, solvate or hydrate thereof: Formula (XXXVI), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXVIII)，或其鹽、溶劑合物或水合物：式(XXXVIII)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXVIII), or a salt, solvate or hydrate thereof: Formula (XXXVIII), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXIX)，或其鹽、溶劑合物或水合物：式(XXXIX)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXIX), or a salt, solvate or hydrate thereof: Formula (XXXIX), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXX)，或其鹽、溶劑合物或水合物：式(XXXX)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the modified oligonucleotide comprises formula (XXXX), or a salt, solvate or hydrate thereof: Formula (XXXX), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXI)，或其鹽、溶劑合物或水合物：mUëmU式(XXXXI). 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXI), or a salt, solvate or hydrate thereof:mUëmU formula (XXXXI). wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXII)，或其鹽、溶劑合物或水合物：mAëmA式(XXXXII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXII), or a salt, solvate or hydrate thereof:mAëmA Formula (XXXXII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIII)，或其鹽、溶劑合物或水合物：mAëmU式(XXXXIII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIII), or a salt, solvate or hydrate thereof:mAëmU Formula (XXXXIII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIV)，或其鹽、溶劑合物或水合物：mAëmG式(XXXXIV) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIV), or a salt, solvate or hydrate thereof:mAëmG Formula (XXXXIV) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXV)，或其鹽、溶劑合物或水合物：mAëmC式(XXXXV) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXV), or a salt, solvate or hydrate thereof:mAëmC Formula (XXXXV) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVI)，或其鹽、溶劑合物或水合物：mUëmA式(XXXXVI) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVI), or a salt, solvate or hydrate thereof:Formula (XXXXVI ) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVII)，或其鹽、溶劑合物或水合物：mUëmG式(XXXXVII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVII), or a salt, solvate or hydrate thereof:mUëmG Formula (XXXXVII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXVIII)，或其鹽、溶劑合物或水合物：mUëfC式(XXXXVIII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXVIII), or a salt, solvate or hydrate thereof:Formula (XXXXVIII)wherein : R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXIX)，或其鹽、溶劑合物或水合物：fGëmU式(XXXXIX) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXIX), or a salt, solvate or hydrate thereof:fGëmU Formula (XXXXIX) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXX)，或其鹽、溶劑合物或水合物：mGëfG式(XXXXX) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXX), or a salt, solvate or hydrate thereof:mGëfG formula (XXXXX) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXXI)，或其鹽、溶劑合物或水合物：mGëmC式(XXXXXI) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXXI), or a salt, solvate or hydrate thereof:mGëmC Formula (XXXXXI) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含式(XXXXXII)，或其鹽、溶劑合物或水合物：mCëmA式(XXXXXII) 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the modified oligonucleotide comprises formula (XXXXXII), or a salt, solvate or hydrate thereof:mCëmA Formula (XXXXXII) wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，經修飾之寡核苷酸包含以下各式中之一者之核苷間鍵聯：式(XXXXXIII)、式(XXXXXIV)、式(XXXXXV)、式(XXXXXVI)。In certain embodiments, the modified oligonucleotide comprises an internucleoside linkage of one of the following formulas: Formula (XXXXXIII), Formula (XXXXXIV), Formula (XXXXXV), Formula (XXXXXVI).

在某些實施例中，任一前述實施例之化合物包含一或多個脂質結合基團。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之5’端或3’端。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之核苷間鍵聯以及5’端或3’端。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之核苷間鍵聯以及5’端及3’端。在某些實施例中，該一或多種配位體(例如一或多種TrkB配位體、一或多種CB₁配位體、一或多種α₄β_1/7整聯蛋白配位體)連接至經修飾之寡核苷酸之5’端或3’端，或經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種結合基團包含至少一種連接至經修飾之寡核苷酸之5’端或3’端或經修飾之寡核苷酸之5’端及3’端的配位體(例如至少一種TrkB配位體、至少一種CB₁配位體、至少一種α₄β_1/7整聯蛋白配位體)，以及至少一種脂質。在某些實施例中，該一或多種結合基團包含至少一種連接至經修飾之寡核苷酸之5’端或3’端或經修飾之寡核苷酸之5’端及3’端的配位體(例如至少一種TrkB配位體、至少一種CB₁配位體、至少一種α₄β_1/7整聯蛋白配位體)，以及一或多種連接至經修飾之寡核苷酸之一或多個核苷間鍵聯之脂質結合基團。在某些實施例中，經修飾之寡核苷酸包含配位體(例如TrkB配位體、CB₁配位體、α₄β_1/7整聯蛋白配位體)及脂質。在某些實施例中，經修飾之寡核苷酸包含一或多種配位體(例如一或多種TrkB配位體、一或多種CB₁配位體、一或多種α₄β_1/7整聯蛋白配位體)及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more lipid binding groups. In certain embodiments, the one or more lipid binding groups are linked to one or more internucleoside linkages of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the 5' end or 3' end of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the internucleoside linkages and the 5' end or 3' end of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the internucleoside linkages and the 5' end and 3' end of a modified oligonucleotide. In certain embodiments, the one or more ligands (e.g., one or more TrkB ligands, one or more CB₁ ligands, one or more α₄ β_1/7 integrin ligands) are linked to the 5' end or 3' end of the modified oligonucleotide, or to the 5' end and 3' end of the modified oligonucleotide. In certain embodiments, the one or more binding groups include at least one ligand (e.g., at least one TrkB ligand, at least one CB₁ ligand, at least one α₄ β_1/7 integrin ligand) linked to the 5' end or 3' end of the modified oligonucleotide, or to the 5' end and 3' end of the modified oligonucleotide, and at least one lipid. In certain embodiments, the one or more binding groups include at least one ligand (e.g., at least one TrkB ligand, at least one CB₁ ligand, at least one α₄ β_1/7 integrin ligand) linked to the 5' end or 3' end of the modified oligonucleotide or to both the 5' end and the 3' end of the modified oligonucleotide, and one or more lipid binding groups linked to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises a ligand (e.g., a TrkB ligand, a CB₁ ligand, an α₄ β_1/7 integrin ligand) and a lipid. In some embodiments, the modified oligonucleotide comprises one or more ligands (e.g., one or more TrkB ligands, one or more CB₁ ligands, one or more α₄ β_1/7 integrin ligands) and one or more lipids. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，任一前述實施例之化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₈ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated_C22 hydrocarbon chain.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkages are between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。在某些實施例中，經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。靶核酸及靶區域In certain embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXXXXIII-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any one of Formula XXXV-XXXXXVI.Target Nucleic Acid and Target Region

在某些實施例中，本文所闡述之化合物包含含有與靶核酸互補之區域的寡核苷酸或由其組成。在某些實施例中，靶核酸為內源性RNA分子。在某些實施例中，靶核酸編碼蛋白質。在某些實施例中，靶核酸係非編碼的。在某些此類實施例中，靶核酸係選自mRNA及前mRNA，包括內含子區、外顯子區及非轉譯區。在某些實施例中，靶RNA為mRNA。在某些實施例中，靶核酸為前mRNA。在某些此類實施例中，靶區域完全位於外顯子內。在某些此類實施例中，靶區域完全位於內含子內。在某些實施例中，靶區域跨內含子/外顯子接點。在某些實施例中，靶區域至少50%位於內含子內。In certain embodiments, the compounds described herein comprise or consist of oligonucleotides containing regions complementary to the target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from mRNA and pre-mRNA, including intronic regions, exonic regions, and non-translational regions. In certain embodiments, the target RNA is mRNA. In certain embodiments, the target nucleic acid is pre-mRNA. In certain such embodiments, the target region is completely within the exon. In certain such embodiments, the target region is completely within the intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, at least 50% of the target region is located within the intron.

在某些實施例中，本文所揭示之化合物與MAPT核酸雜交。最常見的雜交機制涉及核酸分子之互補核鹼基之間的氫鍵結。雜交可在不同條件下發生。雜交條件依賴於序列，且由待雜交核酸分子之性質及組成決定。確定序列是否與靶核酸特異性地雜交之方法為此項技術中所熟知。在某些實施例中，本文所提供之化合物與MAPT核酸特異性地雜交。In certain embodiments, the compounds disclosed herein hybridize with MAPT nucleic acids. The most common hybridization mechanism involves hydrogen bonding between complementary nucleobases of nucleic acid molecules. Hybridization can occur under different conditions. Hybridization conditions are sequence-dependent and determined by the properties and composition of the nucleic acid molecules to be hybridized. Methods for determining whether a sequence specifically hybridizes with a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein hybridize specifically with MAPT nucleic acids.

編碼MAPT之核苷酸序列包括(但不限於)以下： GenBank登錄號NM_001377265.1 (以SEQ ID NO: 1併入本文中)，及NT_010783.14之核苷酸2624000至2761000 (以SEQ ID NO: 2併入本文中)。互補性Nucleotide sequences encoding MAPT include, but are not limited to, the following: GenBank Accession No. NM_001377265.1 (incorporated herein as SEQ ID NO: 1), and nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2).

本文所提供之寡核苷酸可與特定核酸、靶區域、寡核苷酸或其部分具有確定之互補性百分比。非互補核鹼基係可容忍的，前提條件為寡核苷酸仍能夠與核酸、寡核苷酸或其部分特異性地雜交。在某些實施例中，本文所提供之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分至少或高達70%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%互補。在某些實施例中，本文所提供之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分互補70%至75%、75%至80%、80%至85%、85%至90%、90%至95%、95%至100%，或該等範圍之間的任何數值。可使用常規方法來確定寡核苷酸與靶核酸、靶區域、寡核苷酸或其指定部分之互補性百分比。舉例而言，寡核苷酸之20個核鹼基中有18個與靶區域互補，且因此將特異性地雜交之寡核苷酸將代表90%之互補性。在該實例中，其餘非互補核鹼基可與互補核鹼基成簇或間雜排列，且不需要彼此鄰接或與互補核鹼基鄰接。因此，具有4個非互補核鹼基(側翼為與靶核酸完全互補之兩個區域)之長度為18個核鹼基之寡核苷酸與靶核酸之總互補性為77.8%。寡核苷酸與靶核酸、靶區域、寡核苷酸或其指定部分之區域的互補性百分比可使用此項技術中已知之BLAST程式(基本局部比對搜索工具)常規地確定。在某些實施例中，本文所闡述之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分完全互補(亦即100%互補)。舉例而言，寡核苷酸可與靶核酸、靶區域、寡核苷酸或其指定部分完全互補。如本文所用，「完全互補」意指寡核苷酸之每一核鹼基與靶核酸、靶區域、寡核苷酸或其指定部分之相應核鹼基互補。舉例而言，20個核鹼基之寡核苷酸與長為400個核鹼基之靶序列完全互補，只要靶核酸之相應20個核鹼基部分與化合物完全互補即可。針對第一核酸及/或第二核酸之指定部分亦可使用「完全互補」。舉例而言，30個核鹼基之寡核苷酸之20個核鹼基部分可與長為400個核鹼基之靶序列之20個核鹼基區域「完全互補」。若靶序列具有20個核鹼基部分，其中每一核鹼基與30個核鹼基化合物之20個相應核鹼基部分互補，則該化合物之該20個核鹼基部分與靶序列完全互補。同時，整個30個核鹼基化合物可與靶序列完全互補或可不完全互補，此取決於該化合物之其餘10個核鹼基是否亦與靶序列互補。Oligonucleotides provided herein can have a defined complementarity percentage with a specific nucleic acid, target region, oligonucleotide or portion thereof. Non-complementary bases are tolerated provided that the oligonucleotide is still able to hybridize specifically with the nucleic acid, oligonucleotide or portion thereof. In certain embodiments, the oligonucleotides provided herein or a specified portion thereof are at least or up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementary with a target nucleic acid, target region, oligonucleotide or a specified portion thereof. In certain embodiments, the oligonucleotides provided herein or their designated portions are complementary to the target nucleic acid, target region, oligonucleotide or its designated portion by 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any value between these ranges. Conventional methods can be used to determine the complementarity percentage of the oligonucleotide and the target nucleic acid, target region, oligonucleotide or its designated portion. For example, 18 of the 20 nucleobases of the oligonucleotide are complementary to the target region, and therefore the oligonucleotides specifically hybridized will represent 90% complementarity. In this example, the remaining non-complementary nucleobases can be clustered or interspersed with complementary nucleobases, and do not need to be adjacent to each other or adjacent to complementary nucleobases. Thus, an oligonucleotide of 18 nucleobases in length with 4 non-complementary nucleobases flanked by two regions that are completely complementary to the target nucleic acid has a total complementarity of 77.8% with the target nucleic acid. The percent complementarity of an oligonucleotide with a target nucleic acid, target region, or region of an oligonucleotide or a designated portion thereof can be routinely determined using the BLAST program (Basic Local Alignment Search Tool) known in the art. In certain embodiments, an oligonucleotide or a designated portion thereof described herein is completely complementary (i.e., 100% complementary) to a target nucleic acid, target region, oligonucleotide, or a designated portion thereof. For example, an oligonucleotide can be completely complementary to a target nucleic acid, target region, oligonucleotide, or a designated portion thereof. As used herein, "completely complementary" means that each nucleobase of an oligonucleotide is complementary to the corresponding nucleobase of a target nucleic acid, target region, oligonucleotide, or a designated portion thereof. For example, a 20 nucleobase oligonucleotide is fully complementary to a target sequence that is 400 nucleobases in length as long as the corresponding 20 nucleobase portion of the target nucleic acid is fully complementary to the compound. "Fully complementary" may also be used with respect to a specified portion of the first nucleic acid and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase oligonucleotide may be "fully complementary" to a 20 nucleobase region of a target sequence that is 400 nucleobases in length. If the target sequence has a 20 nucleobase portion, each of which is complementary to the 20 corresponding nucleobase portions of a 30 nucleobase compound, then the 20 nucleobase portion of the compound is fully complementary to the target sequence. At the same time, the entire 30-nucleotide compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleotides of the compound are also complementary to the target sequence.

在某些實施例中，本文所闡述之寡核苷酸相對於靶核酸、靶區域、寡核苷酸或其指定部分包含一或多個失配核鹼基。在某些實施例中，本文所闡述之長度為或高達12、13、14、15、16、17、18、19、20、21、22或23個核鹼基之寡核苷酸相對於靶核酸或其指定部分包含不超過4個、不超過3個、不超過2個或不超過1個非互補核鹼基。在某些實施例中，本文所闡述之長度為或高達14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核鹼基之寡核苷酸相對於靶核酸、靶區域、寡核苷酸或其指定部分包含不超過6個、不超過5個、不超過4個、不超過3個、不超過2個或不超過1個非互補核鹼基。在某些實施例中，失配位於距寡核苷酸5’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位、12位、13位或14位處。在某些實施例中，失配位於距寡核苷酸3’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位或12位、13位或14位處。在某些實施例中，失配與靶核酸上之相應核鹼基形成搖擺鹼基對。舉例而言，在某些實施例中，失配形成選自以下之搖擺鹼基對：次黃嘌呤(肌苷核鹼基)與尿嘧啶(I:U鹼基對)；鳥嘌呤與尿嘧啶(G:U鹼基對)；次黃嘌呤與腺嘌呤(I:A鹼基對)；及次黃嘌呤與胞嘧啶(I:C鹼基對)。因此，在某些實施例中，寡核苷酸上之失配核鹼基包含次黃嘌呤、鳥嘌呤或尿嘧啶。In certain embodiments, the oligonucleotides described herein comprise one or more mismatched nucleobases relative to the target nucleic acid, target region, oligonucleotide, or a designated portion thereof. In certain embodiments, the oligonucleotides described herein having a length of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleobases or more comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase relative to the target nucleic acid or a designated portion thereof. In certain embodiments, the oligonucleotides described herein of length or up to 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase relative to the target nucleic acid, target region, oligonucleotide, or a designated portion thereof. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, or 14 from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a dangling base pair with the corresponding nucleobase on the target nucleic acid. For example, in certain embodiments, the mismatch forms a dangling base pair selected from the following: hypoxanthine (inosine nucleobase) and uracil (I:U base pair); guanine and uracil (G:U base pair); hypoxanthine and adenine (I:A base pair); and hypoxanthine and cytosine (I:C base pair). Thus, in certain embodiments, the mismatched nucleobase on the oligonucleotide comprises hypoxanthine, guanine, or uracil.

在某些實施例中，本文所闡述之寡核苷酸可與核酸之一部分互補。如本文所用，「部分」係指核酸區域內確定數量之鄰接核鹼基。「部分」亦可指寡核苷酸之確定數量之鄰接核鹼基。在某些實施例中，寡核苷酸與核酸之至少8個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少9個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少10個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少11個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少12個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少13個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少14個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少15個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少16個核鹼基之部分互補。亦考慮與核酸之至少9、10、17、18、19、20、21、22、23或更多個核鹼基之部分互補之寡核苷酸，或由該等值中之任兩者界定之範圍。在某些實施例中，寡核苷酸為反義寡核苷酸。在某些實施例中，將反義寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。在某些實施例中，寡核苷酸為有義寡核苷酸。在某些實施例中，將有義寡核苷酸之一部分與反義寡核苷酸之等長部分進行比較。在某些實施例中，將有義寡核苷酸之8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與反義寡核苷酸之等長部分進行比較。一致性In certain embodiments, the oligonucleotides described herein may complement a portion of a nucleic acid. As used herein, "portion" refers to a defined number of adjacent nucleobases within a region of a nucleic acid. "Portion" may also refer to a defined number of adjacent nucleobases of an oligonucleotide. In certain embodiments, an oligonucleotide complements a portion of at least 8 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 9 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 10 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 11 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 12 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 13 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 14 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 15 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 16 nucleobases of a nucleic acid. Oligonucleotides that complement a portion of at least 9, 10, 17, 18, 19, 20, 21, 22, 23 or more nucleobases of a nucleic acid are also contemplated, or ranges defined by any two of the equivalent values. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, a portion of an antisense oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide.Consistency

本文所提供之寡核苷酸亦可與特定核酸、靶區域、寡核苷酸或其指定部分具有確定之一致性百分比。如本文所用，若寡核苷酸具有相同的核鹼基配對能力，則其與本文所揭示之序列一致。舉例而言，含有胸苷代替所揭示RNA序列中之尿嘧啶之DNA將視為與該RNA序列一致，此乃因尿嘧啶及胸苷二者均與腺嘌呤配對。亦考慮本文所闡述化合物之縮短及加長形式，以及相對於本文所提供之化合物具有不同鹼基之化合物。不同鹼基可彼此毗鄰，或分散在整個化合物中。根據相對於與寡核苷酸相比較之序列具有相同鹼基配對之鹼基數，計算寡核苷酸之一致性百分比。在某些實施例中，本文所闡述之寡核苷酸或其部分與本文所揭示之核酸、寡核苷酸或其一部分中之一或多者之一致性為或至少為70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在某些實施例中，本文所闡述之寡核苷酸與特定核酸或寡核苷酸或其部分約70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致，或此等值之間的任何百分比。The oligonucleotides provided herein may also have a determined percent identity with a specific nucleic acid, a target region, an oligonucleotide or a designated portion thereof. As used herein, if an oligonucleotide has the same nucleobase pairing ability, it is consistent with the sequence disclosed herein. For example, a DNA containing thymidine instead of uracil in the disclosed RNA sequence will be considered consistent with the RNA sequence, because both uracil and thymidine are paired with adenine. Shortened and elongated forms of the compounds described herein are also considered, as well as compounds with different bases relative to the compounds provided herein. Different bases may be adjacent to each other or dispersed throughout the compound. The percent identity of the oligonucleotide is calculated based on the number of bases with the same base pairing relative to the sequence compared with the oligonucleotide. In certain embodiments, the oligonucleotides described herein or portions thereof are or are at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of the nucleic acids, oligonucleotides, or portions thereof disclosed herein. In certain embodiments, the oligonucleotides described herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a particular nucleic acid or oligonucleotide, or portion thereof, or any percentage in between these values.

在某些實施例中，寡核苷酸可具有一或多個失配核鹼基。在某些此類實施例中，失配位於距寡核苷酸5’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位、12位、13位或14位處。在某些此類實施例中，失配位於距寡核苷酸3’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位或12位、13位或14位處。在某些實施例中，將寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。在某些實施例中，寡核苷酸為有義寡核苷酸。在某些實施例中，將有義寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。醫藥組合物及調配物In some embodiments, an oligonucleotide may have one or more mismatched nucleobases. In some such embodiments, the mismatch is at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 positions from the 5' end of the oligonucleotide. In some such embodiments, the mismatch is at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 positions from the 3' end of the oligonucleotide. In some embodiments, a portion of an oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of a sense oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid.Pharmaceutical compositions and formulations

本文所闡述之化合物可與醫藥學上可接受之活性或惰性物質混合以供製備醫藥組合物或調配物。用於調配醫藥組合物之組合物及方法取決於多種準則，包括(但不限於)投與途徑、疾病程度或欲投與之劑量。某些實施例提供包含一或多種化合物或其鹽之醫藥組合物。在某些實施例中，化合物為反義寡核苷酸。在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸或由其組成。在某些此類實施例中，醫藥組合物包含一或多種化合物及適宜的醫藥學上可接受之稀釋劑或載劑。在某些實施例中，醫藥組合物包含一或多種化合物及無菌鹽水溶液。在某些實施例中，此醫藥組合物係由一種化合物及無菌鹽水溶液組成。在某些實施例中，無菌鹽水為醫藥級鹽水。在某些實施例中，醫藥組合物包含一或多種化合物及無菌水。在某些實施例中，醫藥組合物係由一種化合物及無菌水組成。在某些實施例中，無菌水為醫藥級水。在某些實施例中，醫藥組合物包含一或多種化合物及磷酸鹽緩衝鹽水(PBS)。在某些實施例中，醫藥組合物係由一種化合物及無菌PBS組成。在某些實施例中，無菌PBS為醫藥級PBS。The compounds described herein can be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. The compositions and methods for preparing pharmaceutical compositions depend on a variety of criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or their salts. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or is composed of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical composition comprises one or more compounds and a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises one or more compounds and a sterile saline solution. In some embodiments, the pharmaceutical composition is composed of a compound and a sterile saline solution. In some embodiments, the sterile saline is pharmaceutical grade saline. In some embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In some embodiments, the pharmaceutical composition is composed of a compound and sterile water. In some embodiments, the sterile water is pharmaceutical grade water. In some embodiments, the pharmaceutical composition comprises one or more compounds and phosphate buffered saline (PBS). In some embodiments, the pharmaceutical composition is composed of a compound and sterile PBS. In some embodiments, the sterile PBS is pharmaceutical grade PBS.

可藉由將本文所闡述之靶向MAPT之化合物與適宜的醫藥學上可接受之稀釋劑或載劑組合，將該化合物用於醫藥組合物中。在某些實施例中，醫藥學上可接受之稀釋劑為水，諸如適於注射之無菌水。因此，在一個實施例中，本文所闡述之方法中採用包含靶向MAPT之化合物及醫藥學上可接受之稀釋劑的醫藥組合物。在某些實施例中，醫藥學上可接受之稀釋劑為水。在某些實施例中，化合物包含本文所提供之一或多種經修飾之寡核苷酸或由其組成。The compound targeting MAPT described herein can be combined with a suitable pharmaceutically acceptable diluent or carrier to be used in a pharmaceutical composition. In certain embodiments, the pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Therefore, in one embodiment, a pharmaceutical composition comprising a compound targeting MAPT and a pharmaceutically acceptable diluent is used in the method described herein. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or is composed of one or more modified oligonucleotides provided herein.

包含本文所提供化合物之醫藥組合物涵蓋任何醫藥學上可接受之鹽、酯或此等酯之鹽，或在投與給動物、包括人類時能夠(直接或間接)提供其生物活性代謝物或殘餘物之任何其他寡核苷酸。在某些實施例中，化合物為反義寡核苷酸。在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸或由其組成。因此，舉例而言，本揭示案亦係關於化合物之醫藥學上可接受之鹽、前藥、此等前藥之醫藥學上可接受之鹽及其他生物等效形式。適宜的醫藥學上可接受之鹽包括(但不限於)鈉鹽及鉀鹽。前藥可包括在化合物之一端或兩端併入額外核苷，其在體內由內源性核酸酶裂解，形成活性化合物。在某些實施例中，化合物或組合物進一步包含醫藥學上可接受之載劑或稀釋劑。實例Pharmaceutical compositions comprising the compounds provided herein encompass any pharmaceutically acceptable salt, ester, or salt of such esters, or any other oligonucleotide capable of providing (directly or indirectly) its biologically active metabolites or residues when administered to animals, including humans. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Therefore, for example, the present disclosure also relates to pharmaceutically acceptable salts, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalent forms of the compound. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts. Prodrugs may include additional nucleosides incorporated into one or both ends of the compound, which are cleaved by endogenous nucleases in vivo to form active compounds. In certainembodiments , the compound or composition further comprises a pharmaceutically acceptable carrier or diluent.

以下實例闡述鑑別靶向MAPT之前導化合物之過程。某些化合物認定為具有高效能及耐受性。The following examples illustrate the process of identifying lead compounds targeting MAPT. Certain compounds were identified as having high potency and tolerability.

以下實例僅用於闡釋本文所闡述之化合物，而不意欲對其加以限制。本申請隨附之以下實例及相關序列表可將序列鑑別為「RNA」或「DNA」；然而，如本文所揭示，彼等序列可經化學修飾之任何組合修飾。熟習此項技術者將容易地瞭解，在某些情況下，將序列命名為「RNA」或「DNA」係任意的。舉例而言，可將包含含有2’-OH糖部分及胸腺嘧啶鹼基之核苷的寡核苷酸描述為具有經修飾之糖(2’-OH代替DNA之天然2’-H)的DNA或描述為具有經修飾之鹼基(甲基化尿嘧啶代替RNA之天然尿嘧啶)的RNA。因此，本文所提供之核酸序列(包括(但不限於)序列表中之彼等核酸序列)意欲涵蓋含有天然或經修飾之RNA及/或DNA之任何組合的核酸，包括(但不限於)具有經修飾之核鹼基的此等核酸。The following examples are intended only to illustrate the compounds described herein and are not intended to be limiting. The following examples and associated sequence listings accompanying this application may identify sequences as "RNA" or "DNA"; however, as disclosed herein, those sequences may be modified by any combination of chemical modifications. Those skilled in the art will readily appreciate that in certain circumstances, the naming of sequences as "RNA" or "DNA" is arbitrary. For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base may be described as a DNA with a modified sugar (2'-OH instead of the natural 2'-H of DNA) or as an RNA with a modified base (methylated uracil instead of the natural uracil of RNA). Therefore, the nucleic acid sequences provided herein (including but not limited to those in the sequence listing) are intended to encompass nucleic acids containing any combination of native or modified RNA and/or DNA, including but not limited to such nucleic acids with modified nucleobases.

本申請案中所引用之每一參考文獻均係以全文引用的方式併入本文中。表1化學命名法縮寫結構『m』2’-O-甲基糖修飾(例如mA、mG、mC、mU)『f』2’-F糖修飾(例如fA、fG、fC、fU)『*』硫代磷酸酯核苷間鍵聯『.』磷酸酯核苷間鍵聯『dQ』反向無鹼基去氧核糖『v』5’-乙烯基膦酸酯修飾『e』5’-伸乙基膦酸酯修飾『c6』5’或3’胺基改質劑C6『C16』C16脂質『C17』C17脂質『C18』C18脂質『C22』C22脂質『DBCO』二苯并環辛炔(DBCO)連接體『5’-L』5’配位體『3’-L』3’配位體『FIII』TrkB配位體式III，其中X為S『FIV』TrkB配位體式IV，其中X為S『FIV.』TrkB配位體式IV，其中X為O『FV』TrkB配位體式V，其中X為S『FVI』TrkB配位體式VI，其中X為S『FVII』TrkB配位體式VII，其中X為S『FVII.』TrkB配位體式VII，其中X為O『FX』TrkB配位體式X，其中X為S『FXIV』TrkB配位體式XIV，其中X為S『FXVI』TrkB配位體式XVI，其中X為S『FXX』TrkB配位體式XX，其中X為S『FXXI』TrkB配位體式XXI，其中X為S『FXXI.』TrkB配位體式XXI，其中X為O『FXXII』TrkB配位體式XXII，其中X為S『FXXIII』TrkB配位體式XXIII，其中X為S『FXXIV』TrkB配位體式XXIV，其中X為S『FXXV』TrkB配位體式XXV，其中X為S『FXXVI』TrkB配位體式XXVI，其中X為S『FXXVI.』TrkB配位體式XXVI，其中X為O『FXXVII』TrkB配位體式XXVII，其中X為S『FXXIX』TrkB配位體式XXIX，其中X為S『FXXX』TrkB配位體式XXX，其中X為S『FXXXI』TrkB配位體式XXXI，其中X為S『FXXXIII』TrkB配位體式XXXIII，其中X為S『FXXXIV』TrkB配位體式XXXIV，其中X為S『FIV』TrkB配位體式IV，其中X為S『FXII』TrkB配位體式XII，其中X為S『FXIV』TrkB配位體式XIV，其中X為S『FXV』TrkB配位體式XV，其中X為S『FXVI』TrkB配位體式XVI，其中X為S『FXXIV』TrkB配位體式XXIV，其中X為S『FXXXIII』TrkB配位體式XXXIII，其中X為S『FXXXXXXV』TrkB配位體式XXXXXXV，其中X為S『FXXXXXXVI』TrkB配位體式XXXXXXVI，其中X為S『FXXXXXXVII』TrkB配位體式XXXXXXVII，其中X為S『FXXXXXXIX』TrkB配位體式XXXXXXIX，其中X為S『FXXXXXXX』TrkB配位體式XXXXXXX，其中X為S『FXXXXXXXI』TrkB配位體式XXXXXXXI，其中X為S『FXXXXXXXII』TrkB配位體式XXXXXXXII，其中X為S『FXXXXXXXIII』TrkB配位體式XXXXXXXIII，其中X為S『FXXXXXXXIV』CB₁配位體式XXXXXXXIV，其中X為S『FXXXXXXXV』CB₁配位體式XXXXXXXV，其中X為S『FXXXXXXXVI』CB₁配位體式XXXXXXXVI，其中X為S『FXXXXXXXVII』CB₁配位體式XXXXXXXVII，其中X為S『FXXXXXXXVIII』CB₁配位體式XXXXXXXVIII，其中X為S『FXXXXXXXIX』α₄β_1/7整聯蛋白配位體式XXXXXXXIX，其中X為S『FXXXXXXXX』α₄β_1/7整聯蛋白配位體式XXXXXXXX，其中X為S『FXXXXXXXXI』α₄β_1/7整聯蛋白配位體式XXXXXXXXI，其中X為S『FXXXXXXXXII』α₄β_1/7整聯蛋白配位體式XXXXXXXXII，其中X為S『FXXXXXXXXIV』α₄β_1/7整聯蛋白配位體式XXXXXXXXIV，其中X為S『ê』核苷間鍵聯『ë』核苷間鍵聯『[ë1]』核苷間鍵聯『[ë2]』核苷間鍵聯『t6.mC』SC6mC保護基團表2化合物序列及SEQ ID NO: 1上之靶向位置化合物編號SEQ ID NO:1SEQ ID NO:1反義序列SEQ ID NO:有義序列SEQ ID NO:起始位點終止位點(5’-3’)(5’-3’)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表3化合物化學化合物5’-L經修飾之股(5’-3’)3’-LRef ID NO:SEQ ID 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reference cited in this application is incorporated herein by reference in its entirety.Table 1Chemical nomenclatureAbbreviationStructure 『m』 2'-O-methyl sugar modifications (e.g. mA, mG, mC, mU) 『f』 2'-F sugar modification (e.g. fA, fG, fC, fU) 『*』 Phosphorothioate internucleoside bonds 『.』 Phosphate internucleoside bonds 『dQ』 Reverse abasic deoxyribose 『v』 5'-Vinylphosphonate modification 『e』 5'-Ethylenephosphonate modification 『c6』 5' or 3' amino modifier C6 『C16』 C16 lipids 『C17』 C17 lipids 『C18』 C18 lipids 『C22』 C22 lipid 『DBCO』 Dibenzocyclooctyne (DBCO) linker 『5'-L』 5' ligand 『3'-L』 3' ligand 『FIII』 TrkB ligand formula III, where X is S 『FIV』 TrkB ligand formula IV, where X is S "FIV." TrkB ligand formula IV, where X is O 『FV』 TrkB ligand formula V, where X is S 『FVI』 TrkB ligand formula VI, where X is S 『FVII』 TrkB ligand formula VII, where X is S 『FVII.』 TrkB ligand formula VII, where X is O 『FX』 The TrkB ligand has the formula X, where X is S FXIV TrkB ligand formula XIV, where X is S FXVI TrkB ligand formula XVI, where X is S 『FXX』 The TrkB ligand has the formula XX, where X is S 『FXXI』 TrkB ligand formula XXI, where X is S 『FXXI.』 TrkB ligand formula XXI, where X is O 『FXXII』 TrkB ligand formula XXII, where X is S 『FXXIII』 TrkB ligand formula XXIII, where X is S 『FXXIV』 TrkB ligand formula XXIV, where X is S 『FXXV』 TrkB ligand formula XXV, where X is S 『FXXVI』 TrkB ligand formula XXVI, where X is S 『FXXVI.』 TrkB ligand formula XXVI, where X is O 『FXXVII』 TrkB ligand formula XXVII, where X is S 『FXXIX』 TrkB ligand formula XXIX, where X is S 『FXXX』 TrkB ligand formula XXX, where X is S 『FXXXI』 TrkB ligand formula XXXI, where X is S 『FXXXIII』 TrkB ligand formula XXXIII, where X is S 『FXXXIV』 TrkB ligand formula XXXIV, where X is S 『FIV』 TrkB ligand formula IV, where X is S FXII TrkB ligand formula XII, where X is S FXIV TrkB ligand formula XIV, where X is S FXV TrkB ligand formula XV, where X is S FXVI TrkB ligand formula XVI, where X is S 『FXXIV』 TrkB ligand formula XXIV, where X is S 『FXXXIII』 TrkB ligand formula XXXIII, where X is S 『FXXXXXXV』 TrkB ligand formula XXXXXXV, where X is S 『FXXXXXXVI』 TrkB ligand formula XXXXXXVI, where X is S 『FXXXXXXVII』 TrkB ligand formula XXXXXXVII, where X is S 『FXXXXXXIX』 TrkB ligand formula XXXXXXIX, where X is S "FXXXXXXX" The ligand formula of TrkB is XXXXXXX, where X is S 『FXXXXXXXI』 The TrkB ligand has the formula XXXXXXXI, where X is S 『FXXXXXXXII』 The TrkB ligand has the formula XXXXXXXII, where X is S 『FXXXXXXXIII』 The TrkB ligand formula is XXXXXXXIII, where X is S 『FXXXXXXXIV』 CB₁ ligand formula XXXXXXXIV, where X is S 『FXXXXXXXV』 CB₁ ligand formula XXXXXXXV, where X is S 『FXXXXXXXVI』 CB₁ ligand formula XXXXXXXVI, where X is S 『FXXXXXXXVII』 CB₁ ligand formula XXXXXXXVII, where X is S 『FXXXXXXXVIII』 CB₁ ligand formula XXXXXXXVIII, where X is S 『FXXXXXXXIX』 α₄ β_1/7 integrin ligand formula XXXXXXXIX, where X is S 『FXXXXXXXX』 α₄ β_1/7 integrin ligand formula XXXXXXXX, where X is S 『FXXXXXXXXI』 α₄ β_1/7 integrin ligand formula XXXXXXXXI, where X is S 『FXXXXXXXXII』 α₄ β_1/7 integrin ligand formula XXXXXXXXII, where X is S 『FXXXXXXXXIV』 α₄ β_1/7 integrin ligand formula XXXXXXXXIV, where X is S 『ê』 Internucleoside bonds 『ë』 Internucleoside bonds 『[ë1]』 Internucleoside bonds 『[ë2]』 Internucleoside bonds 『t6.mC』 SC6mC protection groupTable 2Compound sequence and target position on SEQ ID NO: 1Compound No.SEQ ID NO:1SEQ ID NO:1Antisense sequenceSEQ ID NO:Sense sequenceSEQ ID NO:Starting pointEnd point(5'-3')(5'-3') RD3168 1498 1520 UUUUUACUGACCAUGCGAGCUUU 11 AGCUCGCAUGGUCAGUAAAAA 81 RD3169 3648 3670 UUUACAAAGAGAAUUGGUUAGCC 12 CUAACCAAUUCUCUUUUGUAAA 82 RD3170 3649 3671 UCUUACAAAGAGAACUGGUUAGC 13 UAACCAGUUCUCUUUGUAAGA 83 RD3171 3652 3674 AGUCCUUACAAAGAGAACUGGUU 14 CCAGUUCUCUUUGUAAGGACU 84 RD3172 3836 3858 UGAUGAGGGGUAUAGGCAGUGAU 15 CACUGCCUAUACCCCUCAUCA 85 RD3173 4456 4478 AACAUCUAUGUAUAUGUUCAGCU 16 CUGAACAUAUACAUAGAUGUU 86 RD3174 5745 5767 UCUAAACCAUGAUUUUAGGCUGG 17 AGCCUAAAAUCAUGGUUUAGA 87 RD3175 5899 5921 UAUACAGUAUAUCUUAUCUAGCC 18 CUAGAUAAGAUAUACUGUAUA 88 RD3176 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD3177 5983 6005 AUAGCAAACAGGAUACAGUCUCA 20 AGACUGUAUCCUGUUUGCUAU 90 RD3178 6640 6662 ACCGAAGAAAUCAUGGGACUUGC twenty one AAGUCCCAUGAUUUCUUCGGU 91 RD3179 6711 6733 ACUAUAUAGACAUUCACAGACAG twenty two GUCUGUGAAUGUCUAUAUAGU 92 RD3180 1500 1522 UGCUUUUACUGACUAUGCGAGCU twenty three CUCGCAUAGUCAGUAAAAGCA 93 RD3181 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3182 1533 1555 UGGCUUUUUUGUCAUCGCUUCCA 25 GAAGCGAUGACAAAAAAGCCA 95 RD3183 1534 1556 UUGGCUUUUUUGUUAUCGCUUCC 26 AAGCGAUAACAAAAAAGCCAA 96 RD3184 1535 1557 UUUGGCUUUUUUGUCAUCGCUUC 27 AGCGAUGACAAAAAAGCCAAA 97 RD3185 2246 2268 UUCAACUGGUUUGUAGACUAUUU 28 AUAGUCUACAAACCAGUUGAA 98 RD3186 4452 4474 UCUAUGUAUAUGUUCAGCUGCUC 29 GCAGCUGAACAUAUACAUAGA 99 RD3187 4453 4475 AUCUAUGUAUAUGUUCAGCUGCU 30 CAGCUGAACAUAUACAUAGAU 100 RD3188 4455 4477 ACAUCUAUGUAUAUGUUCAGCUG 31 GCUGAACAUAUACAUAGAUGU 101 RD3189 4516 4538 UAAGCAUAAACAGACAAAUCCAA 32 GGAUUUGUCUGUUUAUGCUUA 102 RD3190 6714 6736 UACACUAUAUAGAUAUUCACAGA 33 UGUGAAUAUCUAUAUAGUGUA 103 RD3668 1502 1524 UUUGCUUUUACUGACCAUGCGAG 36 CGCAUGGUCAGUAAAAGCAAA 106 RD3745 1502 1524 UUUGCUUUUACUGACCAUGCGAG 37 UCGCAUGGUCAGUAAAAGCAAA 107 RD3746 1502 1524 UUUGCUUUUACUGACCAUGCGAG 38 CUCGCAUGGUCAGUAAAAGCAAA 108 RD3747 1503 1524 UUUGCUUUUACUGACCAUGCGA 39 UCGCAUGGUCAGUAAAAGCAAA 109 RD3748 1504 1524 UUUGCUUUUACUGACCAUGCG 40 CGCAUGGUCAGUAAAAGCAAA 110 RD3863 3836 3858 UGAUGAGGGGUAUAGGCAGUGAU 41 UCACUGCCUAUACCCCUCAUCA 111 RD3864 3837 3858 UGAUGAGGGGUAUAGGCAGUGA 42 UCACUGCCUAUACCCCUCAUCA 112 RD3865 5899 5921 UAUACAGUAUAUCUUAUCUAGCC 43 GCUAGAUAAGAUAUACUGUAUA 113 RD3866 6640 6662 ACCGAAGAAAUCAUGGGACUUGC 44 CAAGUCCCAUGAUUUCUUCGGU 114 RD3867 6641 6662 ACCGAAGAAAUCAUGGGACUUG 45 CAAGUCCCAUGAUUUCUUCGGU 115 RD3868 1500 1522 UGCUUUUACUGACUAUGCGAGCU 46 GCUCGCAUAGUCAGUAAAAGCA 116 RD3869 1501 1522 UGCUUUUACUGACUAUGCGAGC 47 GCUCGCAUAGUCAGUAAAAGCA 117 RD3870 4454 4474 UCUAUGUAUAUGUUCAGCUGC 48 GCAGCUGAACAUAUACAUAGA 118 RD3942 1499 1521 UCUUUUACUGACCAUGCGAGCUU 49 GCUCGCAUGGUCAGUAAAAGA 119 RD3943 2243 2265 AACUGGUUUGUAGACUAUUUGCA 50 GCAAAUAGUCUACAAACCAGUU 120 RD3944 2245 2267 UCAACUGGUUUGUAGACUAUUUG 51 AAAUAGUCUACAAACCAGUUGA 121 RD3945 3649 3671 UCUUACAAAGAGAACUGGUUAGC 52 CUAACCAGUUCUCUUUGUAAGA 122 RD3946 4457 4479 UAACAUCUAUGUAUAUGUUCAGC 53 CUGAACAUAUACAUAGAUGUUA 123 RD3947 4508 4530 AACAGACAAAUCCAACUACAACU 54 GUUGUAGUUGGAUUUGUCUGUU 124 RD3948 4512 4534 UAUAAACAGACAAAUCCAACUAC 55 UAGUUGGAUUUGUCUGUUUAUA 125 RD3949 4513 4535 UCAUAAACAGACAAAUCCAACUA 56 AGUUGGAUUUGUCUGUUUAUGA 126 RD3950 4515 4537 AAGCAUAAACAGAUAAAUCCAAC 57 UUGGAUUUAUCUGUUUAUGCUU 127 RD3951 4599 4621 ACCUCUUUACAAGUAUUUCAAGA 58 CUUGAAAUACUUGUAAAGAGGU 128 RD3952 4954 4976 UUGAUGCAGGAGUUGUAAGCCUC 59 AGGCUUACAACUCCUGCAUCAA 129 RD3953 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GCUUACAACUCCUGCAUCACA 130 RD3954 5117 5139 AUUCAUCCCAAUCUCUGCUGUGG 61 CACAGCAGAGAUUGGGAUGAAU 131 RD3955 5247 5269 AUGGAGUUUGUGCAAGGUCAGCG 62 CUGACCUUGCACAAACUCCAU 132 RD3956 5248 5270 UAUGGAGUUUGUGUAAGGUCAGC 63 CUGACCUUACACAAACUCCAUA 133 RD3957 5430 5452 AAAGCUCUAGCUGUACACGAAGC 64 CUUCGUGUACAGCUAGAGCUUU 134 RD3958 5900 5922 UCAUACAGUAUAUUCUAUCUAGC 65 CUAGAUAGAAUAUACUGUAUGA 135 RD3959 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD4139 1827 1849 UUUUUGCUGGAAUUCUGGUGGCG 67 GCCACCAGAAUUCCAGCAAAAA 137 RD4140 1885 1907 UGAUCCCCUGAUUUUGGAGGUUC 68 AACCUCCAAAAUCAGGGGAUCA 138 RD4141 4511 4533 AUAAACAGACAAAUCCAACUACA 69 GUAGUUGGAUUUGUCUGUUUAU 139 RD4142 4796 4818 UCUUCAGUCCUAAUCCUGUGCUU 70 AGCACAGGAUUAGGACUGAAGA 140 RD4143 4957 4979 UUUGUGAUGCAGGAGUUGUAAGC 71 CUUACAACUCCUGCAUCACAAA 141 RD4144 5767 5789 UUUAUCUGCCAGCACUGAUCACC 72 GUGAUCAGUGCUGGCAGAUAAA 142 RD4145 5902 5924 UGGCAUACAGUAUAUCCUAUCUA 73 AGAUAGGAUAUACUGUAUGCCA 143 RD3657 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD3658 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3659 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3663 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD3752 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD3753 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD3754 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3755 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3818 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3821 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3880 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3910 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3912 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3933 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD3969 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3970 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3973 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3977 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4044 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4060 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4066 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4110 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4137 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4147 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4149 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4151 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4155 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4156 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4157 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4173 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GCUUACAACUCCUGCAUCACA 130 RD4174 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GCUUACAACUCCUGCAUCACA 130 RD4176 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD4177 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD4179 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GCUUACAACUCCUGCAUCACA 130 RD4180 4956 4977 UGUGAUGCAGGAGUUGUAAGCC 144 GGCUUACAACUCCUGCAUCACA 150 RD4181 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4182 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GGCUUACAACUCCUGCAUCACA 150 RD4183 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD4184 1502 1523 UUGCUUUUACUGAUCAUGCGAG 146 CUCGCAUGAUCAGUAAAAGCAA 136 RD4185 1503 1523 UUGCUUUUACUGAUCAUGCGA 147 UCGCAUGAUCAGUAAAAGCAA 151 RD4186 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 UCGCAUGAUCAGUAAAAGCAA 151 RD4219 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4220 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4232 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GCUUACAACUCCUGCAUCACAC 152 RD4233 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAAC 153 RD4234 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4264 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4267 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4269 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4299 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4300 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4301 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4302 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4303 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4304 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4305 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4306 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4307 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4308 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4309 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4310 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4311 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4321 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4332 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4339 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4341 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4349 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4350 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4351 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4373 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4384 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4413 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4414 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4417 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4418 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4419 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD3806 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3810 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3837 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3978 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4153 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4154 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4205 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4218 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4221 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4222 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4223 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4224 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4225 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4226 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4227 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4228 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4229 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4230 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4347 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4348 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4363 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4369 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4370 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4386 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4390 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4421 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4452 4954 4976 UUGAUGCAGGAGUUGUAAGCCUC 59 AGGCUUACAACUCCUGCAUCAA 129 RD4453 4956 4978 UUGUGAUGCAGGAUUUGUAAGCC 177 GCUUACAAAUCCUGCAUCACAA 154 RD4454 4957 4979 UUUGUGAUGCAGGAGUUGUAAGC 71 CUUACAACUCCUGCAUCACAAA 141 RD4455 1500 1522 UGCUUUUACUGACUAUGCGAGCU twenty three CUCGCAUAGUCAGUAAAAGCA 93 RD4456 1502 1522 UGCUUUUACUGACUAUGCGAG 178 CUCGCAUAGUCAGUAAAAGCA 93 RD4457 1501 1522 UGCUUUUACUGACUAUGCGAGC 47 GCUCGCAUAGUCAGUAAAAGCA 116 RD4458 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 UAGAUAGGAUAUACUGUAUGCA 155 RD4460 5902 5923 UGCAUACAGUAUAUCCUAUCUA 179 UAGAUAGGAUAUACUGUAUGCA 155 RD4461 5903 5923 UGCAUACAGUAUAUCCUAUCU 180 AGAUAGGAUAUACUGUAUGCA 89 RD4462 4455 4477 ACAUCUAUGUAUAUGUUCAGCUG 31 AGCUGAACAUAUACAUAGAUGU 157 RD4463 4456 4477 ACAUCUAUGUAUAUGUUCAGCU 181 AGCUGAACAUAUACAUAGAUGU 157 RD4464 4457 4477 ACAUCUAUGUAUAUGUUCAGC 182 GCUGAACAUAUACAUAGAUGU 101 RD4497 2244 2266 UAACUGGUUUGUAGACUAUUUGC 183 CAAAUAGUCUACAAACCAGUUA 159 RD4498 3626 3648 UCUAAAGUCCCAGGUCUGCAAAG 184 UUUGCAGACCUGGGACUUUAGA 160 RD4499 4333 4355 UUAUGCAUGUGGAGCUGAGCAGC 185 CUGCUCAGCUCCACAUGCAUAA 161 RD4500 4424 4446 UAACAGACAGCAUGGCUUCCAGC 186 CUGGAAGCCAUGCUGUCUGUUA 162 RD4501 4428 4450 AGCAGAACAGACAGCAUGGCUUC 187 AAGCCAUGCUGUCUGUUCUGCU 163 RD4502 4796 4818 UCUUCAGUCCUAAUCCUGUGCUU 70 AGCACAGGAUUAGGACUGAAGA 140 RD4519 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4533 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4534 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4535 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4536 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4842 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4844 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4845 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4886 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4887 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4892 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4894 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4896 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4897 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4899 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4901 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4914 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD4944 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 UCACAUGGUCAGUAAAAGCAAA 164 RD4945 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 CUCACAUGGUCAGUAAAAGCAAA 165 RD4947 1502 1524 UUUGCUUUUACUGACCAUGCGGG 190 CCGCAUGGUCAGUAAAAGCAAA 166 RD4948 1502 1524 UUUGCUUUUACUGACCAUGCAAG 191 UUGCAUGGUCAGUAAAAGCAAA 167 RD4949 1503 1524 UUUGCUUUUACUGACCAUGUGA 192 CACAUGGUCAGUAAAAGCAAA 168 RD4950 1503 1524 UUUGCUUUUACUGACCAUGUGA 192 UCACAUGGUCAGUAAAAGCAAA 164 RD4951 1503 1524 UUUGCUUUUACUGACCAUGCGG 194 CCGCAUGGUCAGUAAAAGCAAA 166 RD4952 1503 1524 UUUGCUUUUACUGACCAUGCCA 195 UGGCAUGGUCAGUAAAAGCAAA 171 RD4954 1504 1524 UUUGCUUUUACUGACCAUGCC 196 GGCAUGGUCAGUAAAAGCAAA 172 RD4955 1502 1524 UUUGCUUUUACUGACCAUGUGGG 197 CACAUGGUCAGUAAAAGCAAA 168 RD4956 1502 1524 UUUGCUUUUACUGACCAUGUGGG 197 CCACAUGGUCAGUAAAAGCAAA 174 RD4957 1503 1524 UUUGCUUUUACUGACCAUGUGG 199 CCACAUGGUCAGUAAAAGCAAA 174 RD4958 1502 1524 UUUGCUUUUGCUGACCAUGCGAG 200 CGCAUGGUCAGCAAAAGCAAA 176 RD4959 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4975 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD3838 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4532 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4943 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 CACAUGGUCAGUAAAAGCAAA 168 RD4944 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 UCACAUGGUCAGUAAAAGCAAA 164 RD4946 1502 1524 UUUGCUUUUACUGACCAUGCGGG 190 CGCAUGGUCAGUAAAAGCAAA 94 RD4981 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD5019 4954 4976 UUGAUGCAGGAGUUGUAAGCCUC 59 AGGCUUACAACUCCUGCAUCAA 129 RD5020 4954 4976 UUGAUGCAGGAGUUGUAAGUCUC 209 AGACUUACAACUCCUGCAUCAA 201 RD5021 4954 4976 UUGAUGCAGGAGUUGUAAGCUUC 210 AAGCUUACAACUCCUGCAUCAA 202 RD5022 4956 4976 UUGAUGCAGGAGUUGUAAGUC 211 GACUUACAACUCCUGCAUCAA 203 RD5023 4956 4976 UUGAUGCAGGAGUUGUAAGCU 212 AGCUUACAACUCCUGCAUCAA 204 RD5024 4956 4978 UUGUGAUGCAGGAUUUGUAAGCC 177 GCUUACAAAUCCUGCAUCACAA 154 RD5025 4956 4978 UUGUGAUGCAGGAUUUGUAAGUC 213 ACUUACAAAUCCUGCAUCACAA 205 RD5026 4957 4978 UUGUGAUGCAGGAUUUGUAAGC 214 GCUUACAAAUCCUGCAUCACAA 154 RD5027 4957 4978 UUGUGAUGCAGGAUUUGUAAGU 215 ACUUACAAAUCCUGCAUCACAA 205 RD5028 4958 4978 UUGUGAUGCAGGAUUUGUAAG 216 CUUACAAAUCCUGCAUCACAA 206 RD5029 4956 4978 UUGUGAUGCAGGAUUUGUAAGCU 217 GCUUACAAAUCCUGCAUCACAA 154 RD5065 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 UCACAUGGUCAGUAAAAGCAAA 164 RD5262 1502 1524 UUUGCUUUUACUGACCAUGUGAG 188 UCACAUGGUCAGUAAAAGCAAA 164 RD5263 1504 1524 UUUGCUUUUACUGACCAUGCC 196 GGCAUGGUCAGUAAAAGCAAA 172 RD5286 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD5345 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD5350 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD5470 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5497 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5498 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5670 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3666 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3667 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3913 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3937 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD3941 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD3971 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD3995 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4157 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4235 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4267 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4269 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAAC 149 RD4310 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4336 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD4387 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4389 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4394 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4420 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD4518 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACAC 152 RD6027 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6028 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6029 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6030 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6031 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6032 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6034 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6035 1502 1524 UUUGCUUUUACUGACCAUGCGAG twenty four CGCAUGGUCAGUAAAAGCAAA 94 RD6036 5899 5921 UAUACAGUAUAUCUUAUCUAGCC 18 CUAGAUAAGAUAUACUGUAUA 88 RD6037 5899 5921 UAUACAGUAUAUCUUAUCUAGCC 18 CUAGAUAAGAUAUACUGUAUA 88 RD6039 5899 5921 UAUACAGUAUAUCUUAUCUAGCC 18 CUAGAUAAGAUAUACUGUAUA 88 RD6041 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD6042 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD6044 5901 5923 UGCAUACAGUAUAUCCUAUCUAG 19 AGAUAGGAUAUACUGUAUGCA 89 RD6046 4452 4474 UCUAUGUAUAUGUUCAGCUGCUC 29 GCAGCUGAACAUAUACAUAGA 99 RD6047 4452 4474 UCUAUGUAUAUGUUCAGCUGCUC 29 GCAGCUGAACAUAUACAUAGA 99 RD6049 4452 4474 UCUAUGUAUAUGUUCAGCUGCUC 29 GCAGCUGAACAUAUACAUAGA 99 RD6051 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD6052 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD6054 1501 1523 UUGCUUUUACUGAUCAUGCGAGC 66 CUCGCAUGAUCAGUAAAAGCAA 136 RD5470 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5946 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5947 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5948 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5954 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5955 4957 4977 UGUGAUGCAGGAGUUGUAAGC 145 GCUUACAACUCCUGCAUCACA 130 RD5956 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GGCUUACAACUCCUGCAUCACA 150 RD5967 4955 4977 UGUGAUGCAGGAGUUGUAAGCCU 60 GGCUUACAACUCCUGCAUCACA 150Table 3Compound ChemistryCompound5'-LModified strands (5'-3')3'-LRef ID NO:SEQ ID NO:RD3168 vU*fU*mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG.fA.mG.fC.mU*mU*mU IA1104 11FIII mA*mG.mC.mU.mC.mG.fC.mA.fU.fG.fG.fU.mC.mA.mG.mU.mA.mA.mA.mA*mA*dQ IS1389 81RD3169 vU*fU*mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fU.mU.fG.mG.fU.mU.fA.mG*mC*mC IA1105 12FIII mC*mU.mA.mA.mC.mC.fA.mA.fU.fU.fC.fU.mC.mU.mU.mU.mG.mU.mA.mA*mA*dQ IS1390 82RD3170 vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC IA1106 13FIII mU*mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ IS1391 83RD3171 vA*fG*mU.fC.mC.fU.mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fC.mU.fG.mG*mU*mU IA1127 14FV mC*mC.mA.mG.mU.mU.fC.mU.fC.fU.fU.fU.mG.mU.mA.mA.mG.mG.mA.mC*mU*dQ IS1319 84RD3172 vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU IA1108 15FV mC*mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ IS1320 85RD3173 vA*fA*mC.fA.mU.fC.mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG*mC*mU IA1128 16FV mC*mU.mG.mA.mA.mC.fA.mU.fA.fU.fA.fC.mA.mU.mA.mG.mA.mU.mG.mU*mU*dQ IS1321 86RD3174 vU*fC*mU.fA.mA.fA.mC.fC.mA.fU.mG.fA.mU.fU.mU.fU.mA.fG.mG.fC.mU*mG*mG IA1110 17FV mA*mG.mC.mC.mU.mA.fA.mA.fA.fU.fC.fA.mU.mG.mG.mU.mU.mU.mA.mG*mA*dQ IS1322 87RD3175 vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC IA1111 18FV mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ IS1323 88RD3176 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FV mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ IS1324 89RD3177 vA*fU*mA.fG.mC.fA.mA.fA.mC.fA.mG.fG.mA.fU.mA.fC.mA.fG.mU.fC.mU*mC*mA IA1129 20FV mA*mG.mA.mC.mU.mG.fU.mA.fU.fC.fC.fU.mG.mU.mU.mU.mG.mC.mU.mA*mU*dQ IS1325 90RD3178 vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC IA1130 twenty oneFV mA*mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ IS1326 91RD3179 vA*fC*mU.fA.mU.fA.mU.fA.mG.fA.mC.fA.mU.fU.mC.fA.mC.fA.mG.fA.mC*mA*mG IA1131 twenty twoFV mG*mU.mC.mU.mG.mU.fG.mA.fA.fU.fG.fU.mC.mU.mA.mU.mA.mU.mA.mG*mU*dQ IS1327 92RD3180 vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU IA1116 twenty threeFV mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ IS1339 93RD3181 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFV mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1340 94RD3182 vU*fG*mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU.fU.mC*mC*mA IA1118 25FV mG*mA.mA.mG.mC.mG.fA.mU.fG.fA.fC.fA.mA.mA.mA.mA.mA.mG.mC.mC*mA*dQ IS1341 95RD3183 vU*fU*mG.fG.mC.fU.mU.fU.mU.fU.mU.fG.mU.fU.mA.fU.mC.fG.mC.fU.mU*mC*mC IA1119 26FV mA*mA.mG.mC.mG.mA.fU.mA.fA.fC.fA.fA.mA.mA.mA.mA.mG.mC.mC.mA*mA*dQ IS1342 96RD3184 vU*fU*mU.fG.mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU*mU*mC IA1120 27FIII mA*mG.mC.mG.mA.mU.fG.mA.fC.fA.fA.fA.mA.mA.mA.mG.mC.mC.mA.mA*mA*dQ IS1405 97RD3185 vU*fU*mC.fA.mA.fC.mU.fG.mG.fU.mU.fU.mG.fU.mA.fG.mA.fC.mU.fA.mU*mU*mU IA1121 28FIII mA*mU.mA.mG.mU.mC.fU.mA.fC.fA.fA.fA.mC.mC.mA.mG.mU.mU.mG.mA*mA*dQ IS1406 98RD3186 vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC IA1122 29FV mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ IS1345 99RD3187 vA*fU*mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC.fU.mG*mC*mU IA1132 30FV mC*mA.mG.mC.mU.mG.fA.mA.fC.fA.fU.fA.mU.mA.mC.mA.mU.mA.mG.mA*mU*dQ IS1346 100RD3188 vA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC*mU*mG IA1133 31FV mG*mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG*mU*dQ IS1347 101RD3189 vU*fA*mA.fG.mC.fA.mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC*mA*mA IA1125 32FIII mG*mG.mA.mU.mU.mU.fG.mU.fC.fU.fG.fU.mU.mU.mA.mU.mG.mC.mU.mU*mA*dQ IS1410 102RD3190 vU*fA*mC.fA.mC.fU.mA.fU.mA.fU.mA.fG.mA.fU.mA.fU.mU.fC.mA.fC.mA*mG*mA IA1126 33FIII mU*mG.mU.mG.mA.mA.fU.mA.fU.fC.fU.fA.mU.mA.mU.mA.mG.mU.mG.mU*mA*dQ IS1411 103RD3658 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 34FIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 104RD3745 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 37FIII mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1490 107RD3746 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 38FIII mC*mU.mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1491 108RD3747 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mA IA1186 39FIII mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1490 109RD3748 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG IA1187 40FIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 110RD3863 vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU IA1108 41FIII mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ IS1520 111RD3864 vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU*mG*mA IA1223 42FIII mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ IS1520 112RD3865 vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC IA1111 43FIII mG*mC.mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ IS1521 113RD3866 vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC IA1130 44FIII mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ IS1522 114RD3867 vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU*mU*mG IA1224 45FIII mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ IS1522 115RD3868 vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU IA1116 46FIII mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ IS1523 116RD3869 vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA*mG*mC IA1225 47FIII mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ IS1523 117RD3870 vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU*fG*mC IA1226 48FIII mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ IS1407 118RD3942 vU*fC*mU.fU.mU.fU.mA.fC.mU.fG.mA.fC.mC.fA.mU.fG.mC.fG.mA.fG.mC*mU*mU IA1239 49FIII mG*mC.mU.mC.mG.mC.fA.mU.fG.fG.fU.fC.mA.mG.mU.mA.mA.mA.mA.mG*mA*dQ IS1539 119RD3943 vA*fA*mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU.fU.mG*mC*mA IA1241 50FIII mG*mC.mA.mA.mA.mU.mA.fG.mU.fC.fU.fA.fC.mA.mA.mA.mC.mC.mA.mG.mU*mU*dQ IS1541 120RD3944 vU*fC*mA.fA.mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU*mU*mG IA1242 51FIII mA*mA.mA.mU.mA.mG.mU.fC.mU.fA.fC.fA.fA.mA.mC.mC.mA.mG.mU.mU.mG*mA*dQ IS1542 121RD3945 vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC IA1106 52FIII mC*mU.mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ IS1543 122RD3946 vU*fA*mA.fC.mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA*mG*mC IA1243 53FIII mC*mU.mG.mA.mA.mC.mA.fU.mA.fU.fA.fC.fA.mU.mA.mG.mA.mU.mG.mU.mU*mA*dQ IS1544 123RD3947 vA*fA*mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU.fA.mC.fA.mA*mC*mU IA1244 54FIII mG*mU.mU.mG.mU.mA.mG.fU.mU.fG.fG.fA.fU.mU.mU.mG.mU.mC.mU.mG.mU*mU*dQ IS1545 124RD3948 vU*fA*mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU*mA*mC IA1245 55FIII mU*mA.mG.mU.mU.mG.mG.fA.mU.fU.fU.fG.fU.mC.mU.mG.mU.mU.mU.mA.mU*mA*dQ IS1546 125RD3949 vU*fC*mA.fU.mA.fA.mA.fC.mA.fG.mA.fC.mA.fA.mA.fU.mC.fC.mA.fA.mC*mU*mA IA1246 56FIII mA*mG.mU.mU.mG.mG.mA.fU.mU.fU.fG.fU.fC.mU.mG.mU.mU.mU.mA.mU.mG*mA*dQ IS1547 126RD3950 vA*fA*mG.fC.mA.fU.mA.fA.mA.fC.mA.fG.mA.fU.mA.fA.mA.fU.mC.fC.mA*mA*mC IA1247 57FIII mU*mU.mG.mG.mA.mU.mU.fU.mA.fU.fC.fU.fG.mU.mU.mU.mA.mU.mG.mC.mU*mU*dQ IS1548 127RD3951 vA*fC*mC.fU.mC.fU.mU.fU.mA.fC.mA.fA.mG.fU.mA.fU.mU.fU.mC.fA.mA*mG*mA IA1248 58FIII mC*mU.mU.mG.mA.mA.mA.fU.mA.fC.fU.fU.fG.mU.mA.mA.mA.mG.mA.mG.mG*mU*dQ IS1549 128RD3952 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC IA1249 59FIII mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA*mA*dQ IS1550 129RD3953 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1250 60FIII mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1551 130RD3954 vA*fU*mU.fC.mA.fU.mC.fC.mC.fA.mA.fU.mC.fU.mC.fU.mG.fC.mU.fG.mU*mG*mG IA1251 61FIII mC*mA.mC.mA.mG.mC.mA.fG.mA.fG.fA.fU.fU.mG.mG.mG.mA.mU.mG.mA.mA*mU*dQ IS1552 131RD3955 vA*fU*mG.fG.mA.fG.mU.fU.mU.fG.mU.fG.mC.fA.mA.fG.mG.fU.mC.fA.mG*mC*mG IA1252 62FIII mC*mU*mG.mA.mC.mC.fU.mU.fG.fC.fA.fC.mA.mA.mA.mC.mU.mC.mC.mA*mU*dQ IS1553 132RD3956 vU*fA*mU.fG.mG.fA.mG.fU.mU.fU.mG.fU.mG.fU.mA.fA.mG.fG.mU.fC.mA*mG*mC IA1253 63FIII mC*mU.mG.mA.mC.mC.mU.fU.mA.fC.fA.fC.fA.mA.mA.mC.mU.mC.mC.mA.mU*mA*dQ IS1554 133RD3957 vA*fA*mA.fG.mC.fU.mC.fU.mA.fG.mC.fU.mG.fU.mA.fC.mA.fC.mG.fA.mA*mG*mC IA1254 64FIII mC*mU.mU.mC.mG.mU.mG.fU.mA.fC.fA.fG.fC.mU.mA.mG.mA.mG.mC.mU.mU*mU*dQ IS1555 134RD3958 vU*fC*mA.fU.mA.fC.mA.fG.mU.fA.mU.fA.mU.fU.mC.fU.mA.fU.mC.fU.mA*mG*mC IA1255 65FIII mC*mU.mA.mG.mA.mU.mA.fG.mA.fA.fU.fA.fU.mA.mC.mU.mG.mU.mA.mU.mG*mA*dQ IS1556 135RD3959 vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1240 66FIII mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1557 136RD4139 vU*fU*mU.fU.mU.fG.mC.fU.mG.fG.mA.fA.mU.fU.mC.fU.mG.fG.mU.fG.mG*mC*mG IA1289 67FIII mG*mC.mC.mA.mC.mC.mA.fG.mA.fA.fU.fU.fC.mC.mA.mG.mC.mA.mA.mA.mA*mA*dQ IS1592 137RD4140 vU*fG*mA.fU.mC.fC.mC.fC.mU.fG.mA.fU.mU.fU.mU.fG.mG.fA.mG.fG.mU*mU*mC IA1290 68FIII mA*mA.mC.mC.mU.mC.mC.fA.mA.fA.fA.fU.fC.mA.mG.mG.mG.mG.mA.mU.mC*mA*dQ IS1593 138RD4141 vA*fU*mA.fA.mA.fC.mA.fG.mA.fC.mA.fA.mA.fU.mC.fC.mA.fA.mC.fU.mA*mC*mA IA1291 69FIII mG*mU.mA.mG.mU.mU.mG.fG.mA.fU.fU.fU.fG.mU.mC.mU.mG.mU.mU.mU.mA*mU*dQ IS1594 139RD4142 vU*fC*mU.fU.mC.fA.mG.fU.mC.fC.mU.fA.mA.fU.mC.fC.mU.fG.mU.fG.mC*mU*mU IA1292 70FIII mA*mG.mC.mA.mC.mA.mG.fG.mA.fU.fU.fA.fG.mG.mA.mC.mU.mG.mA.mA.mG*mA*dQ IS1595 140RD4143 vU*fU*mU.fG.mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*mG*mC IA1293 71FIII mC*mU.mU.mA.mC.mA.mA.fC.mU.fC.fC.fU.fG.mC.mA.mU.mC.mA.mC.mA.mA*mA*dQ IS1596 141RD4144 vU*fU*mU.fA.mU.fC.mU.fG.mC.fC.mA.fG.mC.fA.mC.fU.mG.fA.mU.fC.mA*mC*mC IA1294 72FIII mG*mU.mG.mA.mU.mC.mA.fG.mU.fG.fC.fU.fG.mG.mC.mA.mG.mA.mU.mA.mA*mA*dQ IS1597 142RD4145 vU*fG*mG.fC.mA.fU.mA.fC.mA.fG.mU.fA.mU.fA.mU.fC.mC.fU.mA.fU.mC*mU*mA IA1295 73FIII mA*mG.mA.mU.mA.mG.mG.fA.mU.fA.fU.fA.fC.mU.mG.mU.mA.mU.mG.mC.mC*mA*dQ IS1598 143RD3663 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FX mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ IS1397 89RD3668 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFX mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3657 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FIII mA*mG.mA.mUëmA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ IS1444 89RD3659 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD3752 eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1155 19FIII mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ IS1397 89RD3753 eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1155 19FIII mA*mG.mA.mUëmA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ IS1444 89RD3754 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3755 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD3818 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mAëmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1492 94RD3821 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mUëfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1495 94RD3880 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI c6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD3910 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1524 94RD3912 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3933 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIV IS1525 149RD3969 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourXXII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3970 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXX mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3973 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourXXIV mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3977 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFX mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4044 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIX IS1525 149RD4060 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FVII IS1525 149RD4066 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FVII IS1525 149RD4110 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA XXIII IS1525 149RD4137 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourXXV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4147 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourXXIII c6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD4149 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG[ë1]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1590 94RD4151 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG[ë2]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1591 94RD4155 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIV IS1599 149RD4156 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourDBCO c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIV IS1525 149RD4157 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIV IS1599 149RD4173 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1296 60FVI mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1600 130RD4174 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1296 60XXIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1600 130RD4176 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1297 66FVI mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1557 136RD4177 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1297 66XXIII mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1557 136RD4179 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1296 60FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1600 130RD4180 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG*mC*mC IA1298 144FIII mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1601 150RD4181 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1600 130RD4182 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1296 60FIII mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ IS1601 150RD4183 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1297 66FIII mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1557 136RD4184 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG*mA*mG IA1300 146FIII mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1557 136RD4185 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC*fG*mA IA1301 147FIII mU*mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1602 151RD4186 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1297 66FIII mU*mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ IS1602 151RD4219 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mUëmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1493 94RD4220 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mC.mA.mUëmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA FIV IS1618 149RD4232 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1296 60FIII mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA FIV IS1603 152RD4233 eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1297 66FIII mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA FIV IS1604 153RD4234 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFX mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA XXI IS1525 149RD4264 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFX mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD4267 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXIV mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4269 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA XXI IS1599 149RD4299 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mAëmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1492 94RD4300 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mUëmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1493 94RD4301 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mGëfG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1494 94RD4302 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mUëfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1495 94RD4303 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1496 94RD4304 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mAëmA.mA.mG.mC.mA.mA*mA*dQ IS1497 94RD4305 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mAëmA.mG.mC.mA.mA*mA*dQ IS1498 94RD4306 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mAëmG.mC.mA.mA*mA*dQ IS1499 94RD4307 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mGëmC.mA.mA*mA*dQ IS1500 94RD4308 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mCëmA.mA*mA*dQ IS1501 94RD4309 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ IS1502 94RD4310 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXV mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4311 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4321 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXX mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA XXVI IS1525 149RD4332 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourXXVII c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4339 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1633 94RD4341 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFX mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1633 94RD4349 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXX mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1633 94RD4350 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAëmA.mAëmA.mG.mC.mA.mA*mA*dQ IS1634 94RD4351 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFVI mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mAëmA.mA.mG.mC.mA.mA*mA*dQ IS1635 94RD4373 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FVI mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1639 152RD4384 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FX mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4413 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FIII mG*mC.mU.mUëmA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIV IS1638 152RD4414 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FIII mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIV IS1639 152RD4417 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FIV. mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIV IS1641 152RD4418 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FVII. mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FVII IS1641 152RD4419 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145XXI. mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC XXI IS1641 152RD3806 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourc6*mC*mG.mC.mAëmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1492 94RD3810 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mUëfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1495 94RD3837 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1445 94RD3978 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1524 94RD4153 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG[ë1]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1590 94RD4154 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG[ë2]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1591 94RD4218 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mUëmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1493 94RD4221 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mAëmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1492 94RD4222 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mGëfG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1494 94RD4223 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mUëfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1495 94RD4224 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1496 94RD4225 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mAëmA.mA.mG.mC.mA.mA*mA*dQ IS1497 94RD4226 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mAëmA.mG.mC.mA.mA*mA*dQ IS1498 94RD4227 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mAëmG.mC.mA.mA*mA*dQ IS1499 94RD4228 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mGëmC.mA.mA*mA*dQ IS1500 94RD4229 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mCëmA.mA*mA*dQ IS1501 94RD4230 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ IS1502 94RD4347 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAëmA.mAëmA.mG.mC.mA.mA*mA*dQ IS1634 94RD4348 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mAëmA.mA.mG.mC.mA.mA*mA*dQ IS1635 94RD4363 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mAëmA.mA.mA.mG.mC.mA.mA*mA*dQ IS1633 94RD4369 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145c6*mG*mC.mU.mUëmA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1638 152RD4370 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145c6*mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1639 152RD4386 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4390 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXVI mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4421 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXVI. t6.mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC FXXVI IS1641 152RD4452 eU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC IA1321 59c6*mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ*c6 IS1648 129RD4453 eU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mC IA1322 177FIII mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FIII IS1649 154RD4454 eU*fU*mU.fG.mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*mG*mC IA1323 71FIII mC*mU.mU.mA.mC.mA.mA.fC.mU.fC.fC.fU.fG.mC.mA.mU.mC.mA.mC.mA.mA.mA*dQ FIII IS1650 141RD4455 eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU IA1325 twenty threeFIII mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ FIII IS1660 93RD4456 eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG*fA*mG IA1326 178FIII mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ FIII IS1660 93RD4457 eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA*mG*mC IA1327 47FIII mG*mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ FIII IS1661 116RD4458 eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1155 19FIII mU*mA.mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ FIII IS1662 155RD4460 eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC*mU*mA IA1328 179FIII mU*mA.mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ FIII IS1662 155RD4461 eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU*fC*mU IA1329 180FIII mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ FIII IS1664 89RD4462 eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC*mU*mG IA1330 31FIII mA*mG.mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ FIII IS1665 157RD4463 eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG*mC*mU IA1331 181FIII mA*mG.mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ FIII IS1665 157RD4464 eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA*fG*mC IA1332 182FIII mG*mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ FIII IS1666 101RD4497 eU*fA*mA.fC.mU.fG.mG.fU.mU.fU.mG.fU.mA.fG.mA.fC.mU.fA.mU.fU.mU*mG*mC IA1335 183FIII mC*mA.mA.mA.mU.mA.mG.fU.mC.fU.fA.fC.fA.mA.mA.mC.mC.mA.mG.mU.mU.mA*dQ FIII IS1673 159RD4498 eU*fC*mU.fA.mA.fA.mG.fU.mC.fC.mC.fA.mG.fG.mU.fC.mU.fG.mC.fA.mA*mA*mG IA1336 184FIII mU*mU.mU.mG.mC.mA.mG.fA.mC.fC.fU.fG.fG.mG.mA.mC.mU.mU.mU.mA.mG.mA*dQ FIII IS1674 160RD4499 eU*fU*mA.fU.mG.fC.mA.fU.mG.fU.mG.fG.mA.fG.mC.fU.mG.fA.mG.fC.mA*mG*mC IA1337 185FIII mC*mU.mG.mC.mU.mC.mA.fG.mC.fU.fC.fC.fA.mC.mA.mU.mG.mC.mA.mU.mA.mA*dQ FIII IS1675 161RD4500 eU*fA*mA.fC.mA.fG.mA.fC.mA.fG.mC.fA.mU.fG.mG.fC.mU.fU.mC.fC.mA*mG*mC IA1338 186FIII mC*mU.mG.mG.mA.mA.mG.fC.mC.fA.fU.fG.fC.mU.mG.mU.mC.mU.mG.mU.mU.mA*dQ FIII IS1676 162RD4501 eA*fG*mC.fA.mG.fA.mA.fC.mA.fG.mA.fC.mA.fG.mC.fA.mU.fG.mG.fC.mU*mU*mC IA1339 187FIII mA*mA.mG.mC.mC.mA.mU.fG.mC.fU.fG.fU.fC.mU.mG.mU.mU.mC.mU.mG.mC.mU*dQ FIII IS1677 163RD4502 eU*fC*mU.fU.mC.fA.mG.fU.mC.fC.mU.fA.mA.fU.mC.fC.mU.fG.mU.fG.mC*mU*mU IA1340 70FIII mA*mG.mC.mA.mC.mA.mG.fG.mA.fU.fU.fA.fG.mG.mA.mC.mU.mG.mA.mA.mG.mA*dQ FIII IS1678 140RD4519 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4533 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.mC IS1679 149RD4534 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFIII mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ FIV. IS1679 149RD4535 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXV mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FXXX IS1640 152RD4536 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXVI mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FXXXI IS1640 152RD4842 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1685 94RD4844 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFVI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ IS1502 94RD4845 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIV IS1639 152RD4886 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C16 IS1640 152RD4887 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145C18*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIII IS1680 130RD4892 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC*mA*dQ*t6.mC IS1686 152RD4894 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC*mA*dQ*t6.mC FIV IS1686 152RD4896 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXV mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ FXV IS1683 130RD4897 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXVI mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ FXVI IS1683 130RD4899 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIV IS1684 149RD4901 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIII IS1688 130RD4914 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAëmC.mA*dQ FIII IS1683 130RD4944 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FIII mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1997 164RD4945 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FIII mC*mU.mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1998 165RD4947 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG IA1606 190FIII mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1999 166RD4948 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mA*mA*mG IA1607 191FIII mU*mU.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2000 167RD4949 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA IA1608 192FIII mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1996 168RD4950 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA IA1608 192FIII mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1997 164RD4951 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mG IA1616 194FIII mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1999 166RD4952 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mC*mA IA1617 195FIII mU*mG.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2001 171RD4954 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC IA1612 196FIII mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2002 172RD4955 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG IA1613 197FIII mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1996 168RD4956 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG IA1613 197FIII mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2003 174RD4957 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mG IA1614 199FIII mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2003 174RD4958 vU*fU*mU.fG.mC.fU.mU.fU.mU.fG.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1615 200FIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fC.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS2004 176RD4959 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXXXIV mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4975 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C22 IS1640 152RD3838 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4532 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mCëmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.mC IS1679 149RD4943 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FIII mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1996 168RD4944 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FIII mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1997 164RD4946 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG IA1606 190FIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FIII IS1685 94RD4981 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA*mA*dQ IS1502 94RD5019 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC IA1249 59FXXXI mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ FXXXI IS1648 129RD5020 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fU.mC*mU*mC IA1625 209FXXXI mA*mG.mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ FXXXI IS2016 201RD5021 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mU*mU*mC IA1626 210FXXXI mA*mA.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ FXXXI IS2017 202RD5022 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fU*mC IA1627 211FXXXI mG*mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ FXXXI IS2018 203RD5023 vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fC*mU IA1628 212FXXXI mA*mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ FXXXI IS2019 204RD5024 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mC IA1629 177FXXXI mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS1649 154RD5025 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mU*mC IA1630 213FXXXI mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS2020 205RD5026 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC IA1631 214FXXXI mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS1649 154RD5027 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA*mG*mU IA1632 215FXXXI mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS2020 205RD5028 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA*fA*mG IA1633 216FXXXI mC*mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS2021 206RD5029 vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mU IA1634 217FXXXI mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ FXXXI IS1649 154RD5065 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FXXXI mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAëmA.mA*dQ FXXXI IS1997 164RD5262 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG IA1605 188FXXXI mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ FXXXI IS2123 164RD5263 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC IA1612 196FXXXI mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ FXXXI IS2124 172RD5286 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFIII mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ FIII IS2006 94RD5345 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXI mC*mGëmC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ FXXXI IS2143 94RD5350 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD5470 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXXXI mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FXXXI IS2178 130RD5497 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*c6 IS1681 130RD5498 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FIII mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ FIII IS1681 130RD5670 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXI mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ FXXXI IS2006 94RD3666 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXXIV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3667 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXXIX c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3913 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXXVI c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3937 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXXIV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC FXXXXXXXV IS1525 149RD3941 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXXIX c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC FXXXXXXXXIV IS1525 149RD3971 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXX c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD3995 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXXVII c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4157 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC FIV IS1599 149RD4235 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXX c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC FXXXXXXXX IS1525 149RD4267 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXIV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4269 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourc6*mC*mG.mC.mA.mU.mG.fGëmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.mC FXXXXXXXII IS1599 149RD4310 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4336 eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1156 twenty fourFXXXXXXXXI c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ IS1402 94RD4387 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXXXXX c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4389 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXXXXXVII c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4394 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXXXXXXII c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD4420 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXXXXXX t6.mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC FXXXXXXXX IS1641 152RD4518 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXXXXXXXVIII c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.mC IS1640 152RD6027 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXV IS2006 94RD6028 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXVI c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXVI IS2006 94RD6029 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXVII c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXVII IS2006 94RD6030 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXIX c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXIX IS2006 94RD6031 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXIV c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXIV IS2006 94RD6032 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXXI c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXXI IS2006 94RD6034 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXXXXXII c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXXXXXII IS2006 94RD6035 vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG IA1117 twenty fourFXXXIII c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c6 FXXXIII IS2006 94RD6036 vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC IA1111 18FXVI c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 FXVI IS2458 88RD6037 vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC IA1111 18FXXXXXXXIX c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 FXXXXXXXIX IS2458 88RD6039 vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC IA1111 18FXXXXXXXVIII c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 FXXXXXXXVIII IS2458 88RD6041 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FXVI c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 FXVI IS1664 89RD6042 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FXXXXXXXIX c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 FXXXXXXXIX IS1664 89RD6044 vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG IA1112 19FXXXXXXXVIII c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c6 FXXXXXXXVIII IS1664 89RD6046 vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC IA1122 29FXVI c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 FXVI IS2459 99RD6047 vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC IA1122 29FXXXXXXXIX c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 FXXXXXXXIX IS2459 99RD6049 vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC IA1122 29FXXXXXXXVIII c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 FXXXXXXXVIII IS2459 99RD6051 vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1240 66FXVI c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 FXVI IS2460 136RD6052 vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1240 66FXXXXXXXIX c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 FXXXXXXXIX IS2460 136RD6054 vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC IA1240 66FXXXXXXXVIII c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*dQ*c6 FXXXXXXXVIII IS2460 136RD5470 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXVI AC6*mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 IS2178 130RD5946 fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXVI AC6*mG*mC.mU.mU.mAëmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS2178 130RD5947 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXVI AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS1681 130RD5948 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXVI AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS1681 130RD5954 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1603 145FXVI AC6*mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS1688 130RD5955 eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC IA1299 145FXVI AC6*mG*mCëmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS1688 130RD5956 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1250 60FXVI AC6*mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS2422 150RD5967 vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU IA1250 60FXVI AC6*mG*mGëmC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*AC6 FXVI IS2424 150Preparation of ligand

配位體BA-120、BA-128、BA-171、BA-168、BA-177、BA-210、BA-215、BA-236、BA-135、BA-136、BA-137、BA-144、BA-118、BA-196、BA-197、BA-198、BA-167、BA-216、BA-173、BA-183、BA-225、BA-129、BA-169、BA-170、BA-201及BA-203係如下文所闡述來製備。實例1：N-((3s,5s,7s)-金剛烷-1-基)-4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-6-(4-甲基六氫吡啶-1-基)-1,3,5-三嗪-2-胺(BA-120)之製備步驟1：2-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-4,6-二氯-1,3,5-三嗪Ligands BA-120, BA-128, BA-171, BA-168, BA-177, BA-210, BA-215, BA-236, BA-135, BA-136, BA-137, BA-144 , BA-118, BA- 196, BA-197, BA-198, BA-167, BA-216, BA-173, BA-183, BA-225, BA-129, BA-169, BA-170, BA-201 and BA-203 series Prepared as described below.Example 1: N-((3s,5s,7s)-adamantan-1-yl)-4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl) Preparation of6-(4-methylhexahydropyridin-1-yl)-1,3,5-triazine-2-amine (BA-120)Step 1 : 2-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)oxy)-4,6-dichloro-1,3,5-triazine

在0℃下經10 min向2,4,6-三氯-1,3,5-三嗪(1.0 g, 5.42 mmol)及NaHCO₃(911 mg, 10.84 mmol)於丙酮(8 mL)中之懸浮液中添加17-疊氮基-3,6,9,12,15-五氧雜十七烷-1-醇(1.67 g, 5.42 mmol)。移除冷卻浴，且將混合物在室溫下攪拌20小時。蒸發溶劑，且使所得殘餘物在水與DCM之間分配，以形成乳液。添加鹽水且分離有機相，用鹽水洗滌，乾燥，過濾，濃縮且藉由矽膠管柱層析使用於己烷中之0-100%乙酸乙酯梯度進行純化，得到標題化合物(1.48 g, 60%)。To a suspension of 2,4,6-trichloro-1,3,5-triazine (1.0 g, 5.42 mmol) and NaHCO₃ (911 mg, 10.84 mmol) in acetone (8 mL) was added 17-azido-3,6,9,12,15-pentaoxaheptadecan-1-ol (1.67 g, 5.42 mmol) at 0° C. over 10 min. The cooling bath was removed and the mixture was stirred at room temperature for 20 h. The solvent was evaporated and the resulting residue was partitioned between water and DCM to form an emulsion. Brine was added and the organic phase was separated, washed with brine, dried, filtered, concentrated and purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexanes to give the title compound (1.48 g, 60%).

MS (ESI)：m/z= 455.3 [M+H]⁺。步驟2：N-((3s,5s,7s)-金剛烷-1-基)-4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-6-氯-1,3,5-三嗪-2-胺MS (ESI):m/z = 455.3 [M+H]⁺ .Step 2 : N-((3s,5s,7s)-adamantan-1-yl)-4-((17-azino-3,6,9,12,15-pentaoxaheptadecanyl)oxy)-6-chloro-1,3,5-triazine-2-amine

在0℃下向2-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-4,6-二氯-1,3,5-三嗪(500 mg, 1.1 mmol)於THF (9.5 mL)中之混合物中逐滴添加金剛烷胺(166 mg, 0.151 ml, 1.1 mmol)及DIEA (0.29 mL, 1.65 mmol)於THF (1.2 mL)中之混合物。移除冷卻浴，且將混合物在室溫下攪拌隔夜，且接著濃縮並藉由矽膠管柱層析使用於己烷中之0-85%乙酸乙酯梯度進行純化，得到標題化合物(282 mg, 90%)。To a mixture of 2-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)oxy)-4,6-dichloro-1,3,5-triazine (500 mg, 1.1 mmol) in THF (9.5 mL) was added dropwise a mixture of adamantanamine (166 mg, 0.151 ml, 1.1 mmol) and DIEA (0.29 mL, 1.65 mmol) in THF (1.2 mL) at 0° C. The cooling bath was removed and the mixture was stirred at room temperature overnight and then concentrated and purified by silica gel column chromatography using a gradient of 0-85% ethyl acetate in hexanes to give the title compound (282 mg, 90%).

MS (ESI)m/z= 570.6 [M+H]⁺。步驟3：N-((3s,5s,7s)-金剛烷-1-基)-4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-6-(4-甲基六氫吡啶-1-基)-1,3,5-三嗪-2-胺MS (ESI)m/z = 570.6 [M+H]⁺ .Step 3 : N-((3s,5s,7s)-adamantan-1-yl)-4-((17-azino-3,6,9,12,15-pentaoxaheptadecanyl)oxy)-6-(4-methylhexahydropyridin-1-yl)-1,3,5-triazine-2-amine

在0℃下向於無水THF (0.76 ml)中之N-((3s,5s,7s)-金剛烷-1-基)-4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)-6-氯-1,3,5-三嗪-2-胺(50 mg, 0.088 mmol)逐滴添加4-甲基六氫吡啶(16 mL, 0.13 mmol)及DIEA (18 mL, 0.10 mmol)於THF (0.1 mL)中之混合物。將混合物在60℃下攪拌3小時，接著濃縮且藉由反相管柱層析使用於水(+0.1%甲酸)中之0-100%乙腈梯度純化殘餘物，得到標題化合物(36 mg, 65%)。To N-((3s,5s,7s)-adamantan-1-yl)-4-((17-azino-3,6,9,12,15-pentaoxaheptadecanyl)oxy)-6-chloro-1,3,5-triazin-2-amine (50 mg, 0.088 mmol) in anhydrous THF (0.76 ml) at 0 °C was added a mixture of 4-methylhexahydridine (16 mL, 0.13 mmol) and DIEA (18 mL, 0.10 mmol) in THF (0.1 mL) dropwise. The mixture was stirred at 60 °C for 3 h, then concentrated and the residue purified by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water (+0.1% formic acid) to give the title compound (36 mg, 65%).

MS (ESI)：m/z =  633.2 [M+H]⁺, 655.2 [M+Na]⁺。實例2：(S)-3-(4-(5-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)-2-(3,5-二氯異菸鹼醯胺基)丙酸(BA-128)之製備步驟1：(S)-2-(3,5-二氯異菸鹼醯胺基)-3-(4-(5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)丙酸第三丁酯MS (ESI): m/z = 633.2 [M+H]⁺ , 655.2 [M+Na]⁺ .Example 2: Preparation of (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisocyanamido)propionic acid (BA-128)Step 1 : (S)-2-(3,5-dichloroisocyanamide)-3-(4-(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoic acid tert-butyl ester

將(S)-2-(3,5-二氯異菸鹼醯胺基)-3-(4-(2-甲基-3-側氧基-5-((1-苯基-2,5,8,11-四氧雜十三烷-13-基)氧基)-2,3-二氫嗒嗪-4-基)苯基)丙酸第三丁酯(如Gong等人，「Synthesis and Biological Evaluation of Novel Pyridazinone-Based α4 Integrin Receptor Antagonists」,J. Med. Chem.,2006,49, 11, 3402-3411中所闡述來製備，0.81 g, 1.02 mmol)於甲醇(17 ml)中之溶液在Pd/C (0.11 g, 1.02 mmol)存在下在氫氣氣氛(1 atm)下攪拌2小時。藉由過濾去除觸媒，且將濾液濃縮並藉由矽膠管柱層析使用於DCM中之0-5% MeOH進行純化，獲得標題化合物(0.47 g, 66%)。A solution of (S)-2-(3,5-dichloroisosonicotinamido)-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-2,3-dihydropyridazin-4-yl)phenyl)propanoic acid tert-butyl ester (prepared as described in Gong et al., "Synthesis and Biological Evaluation of Novel Pyridazinone-Based α4 Integrin Receptor Antagonists",J. Med. Chem .,2006 ,49, 11 , 3402-3411, 0.81 g, 1.02 mmol) in methanol (17 ml) was heated in the presence of Pd/C (0.11 g, 1.02 mmol) under a hydrogen atmosphere (1 The reaction mixture was stirred at 400 °C for 2 h at 37 °C. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography using 0-5% MeOH in DCM to give the title compound (0.47 g, 66%).

MS (ESI) m/z 696.6 [M+H]⁺步驟2：(S)-2-(3,5-二氯異菸鹼醯胺基)-3-(4-(2-甲基-5-(2-(2-(2-(2-((甲基磺醯基)氧基)乙氧基)乙氧基)乙氧基)乙氧基)-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)丙酸第三丁酯MS (ESI) m/z 696.6 [M+H]⁺Step 2 : (S)-2-(3,5-dichloroisoxanamido)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoic acid tert-butyl ester

在0℃下將含甲磺醯氯(17 ul, 0.216 mmol)之DCM (1.4 ml)逐滴添加至(S)-2-(3,5-二氯異菸鹼醯胺基)-3-(4-(5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)丙酸第三丁酯(0.10 g, 0.144 mmol)於吡啶(1.4 ml)中之溶液中。將反應混合物在室溫下攪拌16 h，接著藉由添加水(10 ml)淬滅，且用DCM (3×10 ml)萃取。用飽和NaHCO₃溶液(10 ml)及鹽水(10 ml)洗滌有機層。使合併的有機萃取物經無水Na₂SO₄乾燥並濃縮，獲得呈褐色油狀物之標題化合物(0.11 g，定量)。Methanesulfonyl chloride (17 ul, 0.216 mmol) in DCM (1.4 ml) was added dropwise to a solution of (S)-tert-butyl 2-(3,5-dichloroisonicotinoyl)-3-(4-(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyrazin-4-yl)phenyl)propanoate (0.10 g, 0.144 mmol) in pyridine (1.4 ml) at 0°C. The reaction mixture was stirred at room temperature for 16 h, then quenched by the addition of water (10 ml) and extracted with DCM (3×10 ml). The organic layer was washed with saturated NaHCO₃ solution (10 ml) and brine (10 ml). The combined organic extracts were dried over anhydrous Na₂ SO₄ and concentrated to give the title compound (0.11 g, quantitative) as a brown oil.

MS (ESI) m/z 773.5 [M+H]⁺步驟3：(S)-3-(4-(5-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)-2-(3,5-二氯異菸鹼醯胺基)丙酸第三丁酯MS (ESI) m/z 773.5 [M+H]⁺Step 3 : (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisocyanamido)propanoic acid tert-butyl ester

向(S)-2-(3,5-二氯異菸鹼醯胺基)-3-(4-(2-甲基-5-(2-(2-(2-(2-((甲基磺醯基)氧基)乙氧基)乙氧基)乙氧基)乙氧基)-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)丙酸第三丁酯(0.11 mg, 0.143 mmol)於DMF (2.3 ml)中之溶液中添加NaN₃(21 mg, 0.316 mmol)，之後添加1滴水。將混合物在80℃下攪拌6小時，接著冷卻至室溫且在乙酸乙酯(20 ml)與水(20 ml)之間分配。分離有機相，且將水相用乙酸乙酯(2×15 ml)萃取兩次。將合併的有機萃取物用鹽水(×2)洗滌，乾燥，過濾，濃縮且藉由矽膠管柱層析使用於己烷中之0-100%乙酸乙酯梯度進行純化，得到呈澄清油狀物之標題化合物(85 mg, 82%)。To a solution of tert-butyl (S)-2-(3,5-dichloroisonicotinoyl)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyrazin-4-yl)phenyl)propanoate (0.11 mg, 0.143 mmol) in DMF (2.3 ml) was added_NaN3 (21 mg, 0.316 mmol) followed by 1 drop of water. The mixture was stirred at 80°C for 6 hours, then cooled to room temperature and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (2 x 15 ml). The combined organic extracts were washed with brine (x2), dried, filtered, concentrated and purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexanes to give the title compound as a clear oil (85 mg, 82%).

MS (ESI) m/z 721.6 [M+H]⁺步驟4：(S)-3-(4-(5-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)-2-(3,5-二氯異菸鹼醯胺基)丙酸MS (ESI) m/z 721.6 [M+H]⁺Step 4 : (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisocyanamido)propanoic acid

在0℃下向(S)-3-(4-(5-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-3-側氧基-2,3-二氫嗒嗪-4-基)苯基)-2-(3,5-二氯異菸鹼醯胺基)丙酸第三丁酯(25 mg, 0.035 mmol)於DCM (0.3 ml)中之溶液中逐滴添加TFA (0.14 ml)。移除冷卻浴，且將混合物在室溫下攪拌17小時，且接著濃縮並藉由矽膠管柱層析使用於DCM中之0-100%甲醇梯度進行純化，得到標題產物(16 mg, 69%)。To a solution of (S)-tert-butyl 3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyrazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoate (25 mg, 0.035 mmol) in DCM (0.3 ml) at 0°C was added TFA (0.14 ml) dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 17 h and then concentrated and purified by silica gel column chromatography using a gradient of 0-100% methanol in DCM to give the title product (16 mg, 69%).

MS (ESI) m/z 687.8 [M+Na]⁺MS (ESI) m/z 687.8 [M+Na]⁺

¹H NMR (500 MHz, DMSO-d₆)δ12.95 (s, 1H), 9.31 (d,J= 10 Hz, 1H), 8.63 (s, 2H), 8.20 (s, 1H), 7.42 (d,J= 10 Hz, 2H), 7.29 (d,J= 10 Hz, 2H), 4.78-4.72 (m, 1H), 4.36-4.32 (m, 2H), 3.66 (s, 5H), 3.57 (t,J= 5 Hz, 2H), 3.36 (t,J= 5 Hz, 2H), 3.53-3.47 (m, 8H), 3.20 (dd,J= 10, 5 Hz, 1H), 2.93 (q,J= 10 Hz, 1H)實例3：(3S)-3-(2-(4-(14-疊氮基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2’,4’,6’-三甲基-[1,1’-聯苯]-3-基)丙酸(BA-171)之製備步驟1：(E)-2-(4-(2-乙氧基乙烯基)-2-側氧基吡啶-1(2H)-基)-5-甲基己酸乙酯¹ H NMR (500 MHz, DMSO-d₆ )δ 12.95 (s, 1H), 9.31 (d,J = 10 Hz, 1H), 8.63 (s, 2H), 8.20 (s, 1H), 7.42 (d,J = 10 Hz, 2H), 7.29 (d,J = 10 Hz, 2H), 4.78-4.72 (m, 1H), 4.36-4.32 (m, 2H), 3.66 (s, 5H), 3.57 (t,J = 5 Hz, 2H), 3.36 (t,J = 5 Hz , 2H), 3.53-3.47 (m, 8H), 3.20 (dd,J = 10, 5 Hz, 1H), 2.93 (q,J = 10 Hz, 1H)Example 3: (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3- (2-(2-nitro-tetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-Preparation of[1,1'-biphenyl]-3-yl) propionic acid(BA-171)Step 1 : (E)-2-(4-(2-ethoxyvinyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanoic acid ethyl ester

在氮氣氣氛下在室溫下向2-(4-溴-2-側氧基吡啶-1-基)-5-甲基己酸乙酯(4.8 g, 14.54 mmol)及2-[(E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5.76 g, 29.081 mmol)於二噁烷(50 ml)及水(5 ml)中之攪拌溶液中添加K₂CO₃(4.02 g, 29.10 mmol)及Pd(PPh₃)₄(1.68 g, 1.45 mmol)。將所得混合物在氮氣氣氛下在70℃下攪拌隔夜。使混合物冷卻至室溫，且接著藉由添加水淬滅。用乙酸乙酯萃取所得混合物，且將合併的有機萃取物用鹽水洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用PE / EA (1:1)溶析進行純化，得到標題產物(含有頻哪醇)。藉由反相急速層析，利用以下條件進一步純化殘餘物：管柱，C18矽膠；移動相，含乙腈之水，在25 min內10%-100%梯度；偵測器，UV 254 nm。此產生呈褐色油狀物之2-(4-[(E)-2-乙氧基乙烯基]-2-側氧基吡啶-1-基-5-甲基己酸乙酯(4 g, 86%)。To a stirred solution of ethyl 2-(4-bromo-2-oxopyridin-1-yl)-5-methylhexanoate (4.8 g, 14.54 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.76 g, 29.081 mmol) in dioxane (50 ml) and water (5 ml) at room temperature under nitrogen atmosphere was added K₂ CO₃ (4.02 g, 29.10 mmol) and Pd(PPh₃ )₄ (1.68 g, 1.45 mmol). The resulting mixture was stirred at 70° C. under nitrogen atmosphere overnight. The mixture was cooled to room temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over anhydrous_Na2SO4, filtered, concentrated and purified by silica gel column chromatography, eluting with PE/EA (1:1) to give the title product (containing pinacol). The residue was further purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient 10%-100% in 25 min; detector, UV 254 nm. This yielded ethyl 2-(4-[(E)-2-ethoxyvinyl]-2-oxopyridin-1-yl-5-methylhexanoate (4 g, 86%) as a brown oil.

MS (ESI) m/z 322.1 [M+H]⁺MS (ESI) m/z 322.1 [M+H]⁺

¹H NMR (300 MHz, CDCl₃) δ 7.16 (m,J= 19.4, 10.1 Hz, 2H), 6.37 (s, 1H), 6.19 (d,J= 7.4 Hz, 1H), 5.60 (d,J= 13.0 Hz, 1H), 5.54 (m,J= 10.2, 5.6 Hz, 1H), 4.19 (q,J= 7.2 Hz, 2H), 3.94 (q,J= 7.1 Hz, 2H), 2.29 - 2.03 (m, 1H), 1.86 (d,J= 12.3 Hz, 1H), 1.57 (m,J= 13.3, 6.8 Hz, 1H), 1.35 (t,J= 7.0 Hz, 3H), 1.24 (m,J= 8.5, 7.8 Hz, 4H), 1.14 - 1.04 (m, 1H), 0.87 (m,J= 6.8, 3.0 Hz, 6H)步驟2：5-甲基-2-(2-側氧基-4-(2-側氧基乙基)吡啶-1(2H)-基)己酸乙酯¹ H NMR (300 MHz, CDCl₃ ) δ 7.16 (m,J = 19.4, 10.1 Hz, 2H), 6.37 (s, 1H), 6.19 (d,J = 7.4 Hz, 1H), 5.60 (d,J = 13.0 Hz, 1H), 5.54 (m,J = 10.2, 5.6 Hz, 1H), 4.19 (q,J = 7.2 Hz, 2H), 3.94 (q,J = 7.1 Hz, 2H), 2.29 - 2.03 (m, 1H), 1.86 (d,J = 12.3 Hz, 1H), 1.57 (m,J = 13.3, 6.8 Hz, 1H), 1.35 (t,J = 7.0 Hz, 3H), 1.24 (m,J = 8.5, 7.8 Hz, 4H), 1.14 - 1.04 (m, 1H), 0.87 (m,J = 6.8, 3.0 Hz, 6H)Step 2 : 5-Methyl-2-(2-oxo-4-(2-oxoethyl)pyridin-1(2H)-yl)hexanoic acid ethyl ester

將2-(4-[(E)-2-乙氧基乙烯基]-2-側氧基吡啶-1-基-5-甲基己酸乙酯(3.9 g, 12.134 mmol)及TFA (40 ml)在室溫下攪拌隔夜。在減壓下濃縮所得混合物。藉由矽膠管柱層析，用PE / EA (1:2)溶析純化殘餘物，得到呈黃色油狀物之標題化合物(1.9 g, 53%)。Ethyl 2-(4-[(E)-2-ethoxyvinyl]-2-oxopyridin-1-yl-5-methylhexanoate (3.9 g, 12.134 mmol) and TFA (40 ml) were stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1:2) to give the title compound (1.9 g, 53%) as a yellow oil.

MS (ESI) m/z 294.2MS (ESI) m/z 294.2

¹H NMR (300 MHz，氯仿-d) δ 9.76 (t,J= 2.0 Hz, 1H), 7.35 (d,J= 7.1 Hz, 1H), 6.54 - 6.47 (m, 1H), 6.14 (m,J= 7.2, 2.0 Hz, 1H), 5.56 (m,J= 10.1, 5.6 Hz, 1H), 4.21 (q,J= 7.1 Hz, 2H), 3.56 (d,J= 2.0, 0.8 Hz, 2H), 2.19 (m,J= 14.0, 11.1, 5.5 Hz, 1H), 1.88 (m,J= 18.8, 10.4, 4.8 Hz, 1H), 1.59 (m,J= 13.3, 6.7 Hz, 1H), 1.34 - 1.16 (m, 4H), 1.16 - 0.98 (m, 1H), 0.88 (q,J= 6.6, 3.1 Hz, 6H)步驟3：5-甲基-2-(2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1(2H)-基)己酸乙酯¹ H NMR (300 MHz, chloroform-d) δ 9.76 (t,J = 2.0 Hz, 1H), 7.35 (d,J = 7.1 Hz, 1H), 6.54 - 6.47 (m, 1H), 6.14 (m,J = 7.2, 2.0 Hz, 1H), 5.56 (m,J = 10.1, 5.6 Hz, 1H), 4.21 (q,J = 7.1 Hz, 2H), 3.56 (d,J = 2.0, 0.8 Hz, 2H), 2.19 (m,J = 14.0, 11.1, 5.5 Hz, 1H ), 1.88 (m,J = 18.8, 10.4, 4.8 Hz, 1H), 1.59 (m,J = 13.3, 6.7 Hz, 1H), 1.34 - 1.16 (m, 4H), 1.16 - 0.98 (m, 1H), 0.88 (q,J = 6.6, 3.1 Hz, 6H)Step 3 : 5- Methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxo-16-nitro-3-silicon 1(2H)-1(octadec-18-yl)pyridin-1(2H)-yl)hexanoic acid ethyl ester

向5-甲基-2-[2-側氧基-4-(2-側氧基乙基)吡啶-1-基]己酸乙酯(1.8 g, 6.136 mmol)於DCM (27 ml)中之攪拌溶液中添加15,15,16,16-四甲基-5,8,11,14-四氧雜-2-氮雜-15-矽雜十七烷(1.97 g, 6.127 mmol)、STAB (2.60 g, 12.268 mmol)。將所得混合物在室溫下攪拌2小時，藉由添加水(100 ml)淬滅且用DCM (3 × 120 ml)萃取。將合併的有機萃取物用鹽水(2 × 50 ml)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用DCM / MeOH (10:1)溶析進行純化，得到呈黃褐色油狀物之5-甲基-2-[2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1-基]己酸乙酯(1.6 g, 44%)。To a stirred solution of ethyl 5-methyl-2-[2-oxo-4-(2-oxoethyl)pyridin-1-yl]hexanoate (1.8 g, 6.136 mmol) in DCM (27 ml) was added 15,15,16,16-tetramethyl-5,8,11,14-tetraoxa-2-aza-15-silaheptadecane (1.97 g, 6.127 mmol), STAB (2.60 g, 12.268 mmol). The resulting mixture was stirred at room temperature for 2 hours, quenched by the addition of water (100 ml) and extracted with DCM (3×120 ml). The combined organic extracts were washed with brine (2 × 50 ml), dried over anhydrous_Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluting with DCM/MeOH (10:1) to give ethyl 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadec-18-yl)pyridin-1-yl]hexanoate (1.6 g, 44%) as a yellow-brown oil.

MS(ESI) m/z 599.3 [M+H]⁺MS (ESI) m/z 599.3 [M+H]⁺

¹HNMR (300 MHz，乙腈-d3) δ 7.25 (d,J= 7.1 Hz, 1H), 6.20 (s, 1H), 6.11 (m,J= 7.1, 2.0 Hz, 1H), 5.08 (m,J= 10.2, 5.4 Hz, 1H), 4.08 (q,J= 7.1 Hz, 2H), 3.66 (m,J= 5.7, 4.4 Hz, 2H), 3.57 - 3.47 (m, 11H), 3.47 - 3.37 (m, 3H), 2.68 - 2.48 (m, 4H), 2.24 (s, 3H), 2.15 - 1.99 (m, 1H), 1.90 (m, 1H), 1.48 (m,J= 13.4, 6.8 Hz, 1H), 1.25 - 1.11 (m, 5H),1.07-0.88 (m, 1H), 0.83 (s, 9H), 0.79 (m, J = 6.6, 3.0 Hz, 6H), 0.02 (s, 6H)步驟4：5-甲基-2-(2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1(2H)-基)己酸¹ HNMR (300 MHz, acetonitrile-d3) δ 7.25 (d,J = 7.1 Hz, 1H), 6.20 (s, 1H), 6.11 (m,J = 7.1, 2.0 Hz, 1H), 5.08 (m,J = 10.2, 5.4 Hz, 1H), 4.08 (q,J = 7.1 Hz, 2H), 3.66 (m,J = 5.7, 4.4 Hz, 2H), 3.57 - 3.47 (m, 11H), 3.47 - 3.37 (m, 3H), 2.68 - 2.48 (m, 4H ), 2.24 (s, 3H), 2.15 - 1.99 (m, 1H), 1.90 (m, 1H), 1.48 (m,J = 13.4, 6.8 Hz, 1H), 1.25 - 1.11 (m, 5H),1.07-0.88 (m, 1H), 0.83 (s, 9H), 0.79 (m, J = 6.6, 3.0 Hz, 6H), 0.02 (s, 6H)Step 4 : 5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7, 10,13-Tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridin-1(2H)-yl)hexanoic acid

向5-甲基-2-[2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1-基]己酸乙酯(1.4 g, 2.338 mmol)於THF (14 ml)及水(2.8 ml)中之攪拌溶液中添加氫氧化鋰(223.95 mg, 9.352 mmol)，且將所得混合物在室溫下攪拌2小時。接著在0℃下逐滴添加於水(14 ml)中之乙酸(0.71 g, 11.688 mmol)。用CH₃Cl (3 × 100 ml)萃取所得混合物。將合併的有機萃取物用鹽水(2 × 40 ml)洗滌，經無水MgSO₄乾燥，過濾並濃縮，提供呈黃色半固體之標題化合物(0.90 g, 67%)，其不經進一步純化即用於下一步驟中。To a stirred solution of ethyl 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadec-18-yl)pyridin-1-yl]hexanoate (1.4 g, 2.338 mmol) in THF (14 ml) and water (2.8 ml) was added lithium hydroxide (223.95 mg, 9.352 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Acetic acid (0.71 g, 11.688 mmol) in water (14 ml) was then added dropwise at 0°C. The resulting mixture was extracted with CH₃ Cl (3×100 ml). The combined organic extracts were washed with brine (2 x 40 ml), dried over anhydrous MgSO₄ , filtered and concentrated to provide the title compound as a yellow semisolid (0.90 g, 67%) which was used in the next step without further purification.

MS(ESI) m/z 571.3 [M+H]⁺步驟5：(3S)-3-(5-甲基-2-(2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1(2H)-基)己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯MS (ESI) m/z 571.3 [M+H]⁺Step 5 : (3S)-3-(5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecyl-18-yl)pyridin-1(2H)-yl)hexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid methyl ester

向(3S)-3-胺基-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基丙酸甲酯(600 mg, 2.017 mmol)及5-甲基-2-[2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1-基]己酸(1.15 g, 2.017 mmol)於DMF (12 ml)中之攪拌混合物中添加DIEA (782.27 mg, 6.051 mmol)、HBTU (765.13 mg, 2.017 mmol)及HOBT (27.26 mg, 0.202 mmol)，且將所得混合物在氮氣氣氛下在室溫下攪拌2 h，且接著藉由反相急速層析，利用以下條件進行純化：管柱，C18矽膠；移動相，含乙腈之水，在10 min內40%-100%梯度；在20 min內100%梯度；偵測器，UV 220 nm/305 nm，提供呈褐色油狀物之標題化合物(509.0 mg, 29%)。To a stirred mixture of (3S)-3-amino-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-ylpropanoic acid methyl ester (600 mg, 2.017 mmol) and 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadec-18-yl)pyridin-1-yl]hexanoic acid (1.15 g, 2.017 mmol) in DMF (12 ml) was added DIEA (782.27 mg, 6.051 mmol), HBTU (765.13 mg, 2.017 mmol) and HOBT (27.26 mg, 0.202 mmol), and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h, and then purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 40%-100% gradient in 10 min; 100% gradient in 20 min; detector, UV 220 nm/305 nm, to provide the title compound (509.0 mg, 29%) as a brown oil.

MS(ESI) m/z 850.6 [M+H]⁺MS (ESI) m/z 850.6 [M+H]⁺

¹H NMR (300 MHz, DMSO-d₆)δ8.95 (m,J= 27.0, 8.5, 5.6 Hz, 1H), 7.57 (m,J= 12.3, 7.3, 5.2 Hz, 1H), 7.45 - 7.19 (m, 2H), 7.12 - 6.86 (m, 4H), 6.18 (m,J= 21.3, 11.5, 5.6 Hz, 2H), 5.77 (d,J= 5.1 Hz, 1H), 5.34 (m,J= 61.7, 13.7, 5.9 Hz, 2H), 3.68 (q,J= 5.2 Hz, 2H), 3.63 - 3.39 (m, 15H), 3.32 (s, 2H), 2.83 (t,J= 6.5 Hz, 2H), 2.24 (m,J= 12.7, 5.5 Hz, 6H), 1.95 - 1.80 (m, 7H), 1.70 - 1.57 (m, 1H), 1.57 - 1.47 (m, 1H), 1.47-1.34 (m, 1H), 1.24 (d, J = 5.5 Hz, 2H), 1.15-0.96 (m, 1H), 0.93 - 0.79 (m, 13H), 0.72 (t, J = 6.0 Hz, 4H), 0.08 - 0.01 (m, 6H)步驟6：(3S)-3-(2-(4-(14-羥基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯¹ H NMR (300 MHz, DMSO-d₆ )δ 8.95 (m,J = 27.0, 8.5, 5.6 Hz, 1H), 7.57 (m,J = 12.3, 7.3, 5.2 Hz, 1H), 7.45 - 7.19 (m , 2H), 7.12 - 6.86 (m, 4H), 6.18 (m,J = 21.3, 11.5, 5.6 Hz, 2H), 5.77 (d,J = 5.1 Hz, 1H), 5.34 (m,J = 61.7, 13.7, 5.9 Hz, 2H), 3.68 (q,J = 5.2 Hz, 2H), 3.63 - 3.39 (m, 15H), 3.32 (s, 2H), 2.83 (t,J = 6.5 Hz, 2H), 2.24 (m,J = 12.7, 5.5 Hz, 6H), 1.95 - 1.80 (m, 7H), 1.70 - 1.57 (m , 1H), 1.57 - 1.47 (m, 1H), 1.47-1.34 (m, 1H), 1.24 (d, J = 5.5 Hz, 2H), 1.15-0.96 (m, 1H), 0.93 - 0.79 (m, 13H), 0.72 (t, J = 6.0 Hz, 4H), 0.08 - 0.01 (m, 6H)Step 6 ：(3S)-3-(2-(4-(14-hydroxy-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine- 1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid Methyl ester

向(3S)-3-(5-甲基-2-(2-側氧基-4-(2,2,3,3,16-五甲基-4,7,10,13-四氧雜-16-氮雜-3-矽雜十八烷-18-基)吡啶-1(2H)-基)己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯(0.25 g, 0.294 mmol)於THF (2 ml)中之溶液中逐滴添加TBAF (0.35 ml, 0.35 mmol，1 M於THF中)。將反應混合物在惰性氣氛下在室溫下攪拌2小時，且接著用飽和氯化銨溶液(15 ml)稀釋並用乙酸乙酯(3 × 15 ml)萃取。將合併的有機萃取物用鹽水(10 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由管柱層析使用於DCM中之0-15% MeOH進行純化，提供呈澄清油狀物之標題產物(0.12 mg, 55%)。To a solution of methyl (3S)-3-(5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxazol-16-aza-3-silaoctadecyl-18-yl)pyridin-1(2H)-yl)hexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.25 g, 0.294 mmol) in THF (2 ml) was added TBAF (0.35 ml, 0.35 mmol, 1 M in THF) dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 h and then diluted with saturated ammonium chloride solution (15 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (10 mL), dried over anhydrous_Na2SO4, filtered, concentrated and purified by column chromatography using 0-15% MeOH in DCM to provide the title product as a clear oil (0.12 mg, 55%).

MS (ESI) m/z 759.1 [M+Na]⁺步驟7：(3S)-3-(5-甲基-2-(4-(3-甲基-14-((甲基磺醯基)氧基)-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯MS (ESI) m/z 759.1 [M+Na]⁺Step 7 : (3S)-3-(5-methyl-2-(4-(3-methyl-14-((methylsulfonyl)oxy)-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)hexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid methyl ester

向(3S)-3-(2-(4-(14-羥基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯(0.12 g, 0.163 mmol)於DCM (1 ml)中之溶液中添加甲磺醯氯(0.016 ml, 0.212 mmol)及三乙胺(0.045 ml, 0.33 mmol)。將反應混合物在0℃下攪拌2小時，且接著用飽和碳酸氫鈉水溶液(10 ml)稀釋並用DCM (3 × 20 ml)萃取。將合併的有機萃取物用鹽水(10 ml)洗滌，經無水Na₂SO₄乾燥，過濾並在減壓下濃縮，獲得呈褐色油狀物之標題化合物(0.11 g, 83%)。To a solution of methyl (3S)-3-(2-(4-(14-hydroxy-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.12 g, 0.163 mmol) in DCM (1 ml) was added methanesulfonyl chloride (0.016 ml, 0.212 mmol) and triethylamine (0.045 ml, 0.33 mmol). The reaction mixture was stirred at 0°C for 2 h and then diluted with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with DCM (3 x 20 ml). The combined organic extracts were washed with brine (10 ml), dried_over anhydrous_Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (0.11 g, 83%) as a brown oil.

MS (ESI) m/z 815.1 [M+H]⁺步驟8：(3S)-3-(2-(4-(14-疊氮基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯MS (ESI) m/z 815.1 [M+H]⁺Step 8 : (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid methyl ester

向(3S)-3-(5-甲基-2-(4-(3-甲基-14-((甲基磺醯基)氧基)-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯(0.11 g, 0.135 mmol)於DMF (1 ml)中之溶液中添加疊氮化鈉(24 mg, 0.37 mmol)。將反應混合物在65℃下加熱2小時，且接著用水(15 ml)稀釋並用乙酸乙酯(3 × 15 ml)萃取。將合併的有機萃取物用鹽水(10 ml)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析使用於DCM中之0-15% MeOH梯度進行純化，提供呈澄清油狀物之標題化合物(45 mg, 44%)。To a solution of methyl (3S)-3-(5-methyl-2-(4-(3-methyl-14-((methylsulfonyl)oxy)-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)hexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.11 g, 0.135 mmol) in DMF (1 ml) was added sodium azide (24 mg, 0.37 mmol). The reaction mixture was heated at 65 °C for 2 h and then diluted with water (15 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous_Na2SO4, filtered, concentrated and purified by silica gel column chromatography using a 0-15% MeOH gradient in DCM to provide the title compound (45 mg, 44%) as a clear oil.

MS (ESI) m/z 762.2 [M+H]⁺步驟9：(3S)-3-(2-(4-(14-疊氮基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸MS (ESI) m/z 762.2 [M+H]⁺Step 9 : (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid

向(3S)-3-(2-(4-(14-疊氮基-3-甲基-6,9,12-三氧雜-3-氮雜十四烷基)-2-側氧基吡啶-1(2H)-基)-5-甲基己醯胺基)-3-(2',4',6'-三甲基-[1,1'-聯苯]-3-基)丙酸甲酯(45 mg, 0.059 mmol)於甲醇/水/二噁烷混合物(1.5 ml, 1:1:1)中之溶液中添加氫氧化鋰(4 mg, 0.177 mmol)，且將混合物在室溫下攪拌2小時。使溶劑在真空中蒸發，且將所得殘餘物用10%檸檬酸溶液處理並用乙酸乙酯(3 × 15 ml)萃取。將合併的有機萃取物用鹽水(5 ml)洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，提供呈澄清油狀物之標題化合物(30 mg, 75%)。To a solution of methyl (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (45 mg, 0.059 mmol) in a methanol/water/dioxane mixture (1.5 ml, 1:1:1) was added lithium hydroxide (4 mg, 0.177 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the resulting residue was treated with 10% citric acid solution and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (5 ml), dried_over anhydrous_Na2SO4 , filtered and concentrated to provide the title compound as a clear oil (30 mg, 75%).

MS (ESI) m/z 748.1 [M+H]⁺MS (ESI) m/z 748.1 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆)δ12.35 (bs, 1H), 9.00 (d,J= 10 Hz, 1H), 7.69 (d,J= 10 Hz, 1H), 7.37 (t,J= 10 Hz, 1H), 7.27 (d,J= 5 Hz, 1H), 7.06 (s, 1H), 6.99 (d,J= 5 Hz, 1H), 6.91 (s, 2H), 6.29 (s, 1H), 6.18 (d,J= 5 Hz, 1H), 5.47 (q,J= 5 Hz, 1H), 5.17 (q,J= 5 Hz, 1H), 4.09 (m, 3H), 2.64 (t, 5 Hz, 2H), 3.61-3.57 (m, 13H), 3.16 (s, 6H), 2.26 (s, 3H), 1.90 (s, 6H), 1.87-1.79 (m, 1H), 1.68-1.64 (m, 1H), 1.41-1.35 (m, 1H), 0.95-0.82 (m, 3H), 6.60 (d,J= 10 Hz, 6H)實例4：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊醯胺(BA-168)之製備步驟1：5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊酸乙酯¹ H NMR (500 MHz, DMSO-d₆ )δ 12.35 (bs, 1H), 9.00 (d,J = 10 Hz, 1H), 7.69 (d,J = 10 Hz, 1H), 7.37 (t,J = 10 Hz, 1H), 7.27 (d,J = 5 Hz, 1H), 7.06 (s, 1H), 6.99 (d,J = 5 Hz, 1H), 6.91 (s, 2H), 6.29 (s, 1H), 6.18 (d,J = 5 Hz, 1H), 5.47 ( q,J = 5 Hz, 1H), 5.17 (q,J = 5 Hz, 1H), 4.09 (m, 3H), 2.64 (t, 5 Hz, 2H), 3.61-3.57 (m, 13H), 3.16 (s, 6H), 2.26 (s, 3H), 1.90 (s, 6H), 1.87-1.79 (m, 1H), 1.68- 1.64 (m, 1H), 1.41-1.35 (m, 1H), 0.95-0.82 (m, 3H), 6.60 (d,J = 10 Hz, 6H)Example 4: N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-5-((6-(bis(4-chloro (phenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)hexahydropyridin-4-yl)amino)quinolin-8-yl)oxy)pentanamide ( Preparation of BA-168Step 1 : 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)hexahydropyridin-4-yl)amino) Ethyl quinolin-8-yl)oxy)pentanoate

向6-[雙(4-氯苯基)甲基]-4-[(1-三氟甲磺醯基六氫吡啶-4-基)胺基]喹啉-8-醇(2.0 g, 3.3 mmol，如J.Med. Chem.,2018, 61, 22, 10276-10298中所闡述來製備)及5-溴戊酸乙酯(0.75 g, 3.6 mmol)於DMF (5 mL)中之混合物中添加Cs₂CO₃(3.20 g, 9.8 mmol)，且將所得混合物在氮氣氣氛下在60℃下攪拌隔夜。添加乙酸乙酯(100 mL)，且用水(3 × 100 mL)洗滌混合物。使有機層經Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用DCM:甲醇(10:1, V/V)溶析進行純化，得到呈黃色固體之標題化合物(1.9 g, 78%)。To a mixture of 6-[bis(4-chlorophenyl)methyl]-4-[(1-trifluoromethanesulfonylhexahydropyridin-4-yl)amino]quinolin-8-ol (2.0 g, 3.3 mmol, prepared as described inJ.Med. Chem.,2018 , 61, 22, 10276-10298) and ethyl 5-bromovalerate (0.75 g, 3.6 mmol) in DMF (5 mL) was added_Cs2CO3 (3.20 g, 9.8 mmol), and the resulting mixture was stirred at 60 °C overnight under nitrogen atmosphere. Ethyl_acetate (100 mL) was added, and the mixture was washed with water (3 x 100 mL)._The organic layer was dried over_Na2SO4 , filtered, concentrated and purified by silica gel column chromatography eluting with DCM:methanol (10:1, v/v) to give the title compound (1.9 g, 78%) as a yellow solid.

MS (ESI)：m/z= 738.2 [M+H]⁺MS (ESI):m/z = 738.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d,J= 5.9 Hz, 1H), 7.82 (s, 1H), 7.57 - 7.47 (m, 1H), 7.45 - 7.32 (m, 4H), 7.31 (s, OH), 7.25 - 7.17 (m, 4H), 6.93 (s, 1H), 6.76 (d,J= 5.9 Hz, 1H), 5.71 (s, 1H), 4.08 - 3.98 (m, 4H), 3.98 - 3.86 (m, 4H), 3.40 (t,J= 12.7 Hz, 2H), 2.36 (t,J= 7.2 Hz, 2H), 2.10 (d,J= 12.7 Hz, 2H), 1.74 (s, 4H), 1.71 (s, 1H), 1.72 - 1.65 (m, 2H), 1.24 (s, 1H), 1.16 (t,J= 7.1 Hz, 3H)步驟2：5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊酸¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.37 (d,J = 5.9 Hz, 1H), 7.82 (s, 1H), 7.57 - 7.47 (m, 1H), 7.45 - 7.32 (m, 4H), 7.31 (s, OH), 7.25 - 7.17 (m, 4H), 6.93 (s, 1H), 6.76 (d,J = 5.9 Hz, 1H), 5.71 (s, 1H), 4.08 - 3.98 (m, 4H), 3.98 - 3.86 (m, 4H) , 3.40 (t,J = 12.7 Hz, 2H), 2.36 (t,J = 7.2 Hz, 2H), 2.10 (d,J = 12.7 Hz, 2H), 1.74 (s, 4H), 1.71 (s, 1H), 1.72 - 1.65 (m, 2H), 1.24 (s, 1H), 1.16 (t,J = 7.1 Hz , 3H)Step 2 : 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)hexahydropyridin-4-yl) (amino)quinolin-8-yl)oxy)pentanoic acid

將氫氧化鈉(1 M水溶液，7.8 mL, 25 mmol)添加至於THF (15 mL)中之5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊酸乙酯(1.9 g, 2.6 mmol)中，且將混合物在氮氣氣氛下在室溫下攪拌隔夜。用冰乙酸中和並淬滅反應物，且接著用乙酸乙酯(3 × 100 mL)萃取。將合併的有機萃取物用鹽水(3 × 100 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由反相急速層析(管柱，C18矽膠；移動相，含乙腈之水，在20 min內10%至100%梯度；偵測器，UV 254 nm.)進行純化，得到呈淺黃色固體之標題化合物(484 mg, 26%)。Sodium hydroxide (1 M aqueous solution, 7.8 mL, 25 mmol) was added to ethyl 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)hexahydropyridin-4-yl)amino)quinolin-8-yl)oxy)pentanoate (1.9 g, 2.6 mmol) in THF (15 mL), and the mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was neutralized and quenched with glacial acetic acid, and then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (3 × 100 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile in water, gradient 10% to 100% in 20 min; detector, UV 254 nm.) to give the title compound (484 mg, 26%) as a light yellow solid.

MS (ESI)：m/z= 710.0 [M+H]⁺MS (ESI):m/z = 710.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d,J= 5.3 Hz, 1H), 7.73 (s, 1H), 7.40 (d,J= 8.2 Hz, 4H), 7.21 (d,J= 8.2 Hz, 4H), 6.78 (d,J= 10.1 Hz, 2H), 6.65 (d,J= 5.6 Hz, 1H), 5.77 (s, 1H), 5.68 (s, 1H), 3.98 (t,J= 5.8 Hz, 2H), 3.88 (d,J= 13.4 Hz, 3H), 3.40 (t,J= 12.4 Hz, 2H), 2.31 (t,J= 7.0 Hz, 2H), 2.15 - 2.06 (m, 2H), 1.79 - 1.57 (m, 6H)步驟3：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊醯胺¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.35 (d,J = 5.3 Hz, 1H), 7.73 (s, 1H), 7.40 (d,J = 8.2 Hz, 4H), 7.21 (d,J = 8.2 Hz, 4H), 6.78 (d,J = 10.1 Hz, 2H), 6.65 (d,J = 5.6 Hz, 1H), 5.77 (s, 1H), 5.68 (s, 1H), 3.98 (t,J = 5.8 Hz, 2H), 3.88 (d,J = 13.4 Hz, 3H), 3.40 (t,J = 12.4 Hz, 2H), 2.31 (t,J = 7.0 Hz, 2H), 2.15 - 2.06 (m, 2H), 1.79 - 1.57 (m, 6H)Step 3 : N-(2-(2-(2-(2-azidoethoxy)ethoxy) 6-(bis(4-chlorophenyl)methyl)-4-((1-(trifluoromethyl)sulfonyl)hexahydropyridine-4-yl)-1-((((trifluoromethyl)sulfonyl)ethyl)-5-(((((trifluoromethyl)sulfonyl)hexahydropyridine-4-yl)-1-(((trifluoromethyl)sulfonyl)hexahydropyridine-4-yl)- 1-(2-Yl)amino)quinolin-8-yl)oxy)pentanamide

將5-((6-(雙(4-氯苯基)甲基)-4-((1-((三氟甲基)磺醯基)六氫吡啶-4-基)胺基)喹啉-8-基)氧基)戊酸(0.20 g, 0.44 mmol)、DIPEA (0.15 mL, 0.90 mmol)及胺(0.12 g, 0.55 mmol，1.25當量)於DMA (3 mL)中之溶液用HATU (0.34 g, 0.88 mmol)處理並攪拌3小時。用乙酸乙酯(50 mL)稀釋反應混合物，且用水(2 × 100 mL)洗滌。將有機層用飽和NaHCO₃(50 mL)及鹽水(50 mL)洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由矽膠層析(於己烷中之0至100%乙酸乙酯、之後為於乙酸乙酯中之0至40%甲醇，12 g Claricep管柱)進行純化，得到呈澄清油狀物之標題化合物(231 mg, 90%)。A solution of 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)hexahydropyridin-4-yl)amino)quinolin-8-yl)oxy)pentanoic acid (0.20 g, 0.44 mmol), DIPEA (0.15 mL, 0.90 mmol) and the amine (0.12 g, 0.55 mmol, 1.25 equiv) in DMA (3 mL) was treated with HATU (0.34 g, 0.88 mmol) and stirred for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 x 100 mL). The organic layer was washed with saturated_NaHCO3 (50 mL) and brine (50 mL), dried_overNa2SO4 , filtered, concentrated and purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes followed by 0 to 40% methanol in ethyl acetate, 12 g Claricep column) to give the title compound as a clear oil (231 mg, 90%).

MS (ESI)：m/z= 910.6 [M+H]⁺MS (ESI):m/z = 910.6 [M+H]⁺

¹H NMR (499 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.38 (d,J= 5.9 Hz, 1H), 7.82 (s, 1H), 7.48 - 7.29 (m, 4H), 7.25 - 7.17 (m, 4H), 6.92 (s, 1H), 6.78 (d,J= 6.0 Hz, 1H), 5.73 (d,J= 20.1 Hz, 2H), 4.07 - 3.85 (m, 6H), 3.59 - 3.53 (m, 2H), 3.53 - 3.45 (m, 4H), 3.38 (dt,J= 21.8, 5.4 Hz, 5H), 3.22 (q,J= 5.9 Hz, 2H), 2.19 (t,J= 6.8 Hz, 2H), 2.10 (dd,J= 13.5, 3.8 Hz, 2H), 1.70 (tt,J= 12.7, 7.9 Hz, 7H)實例5：(R)-(6-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)萘-1-基)(5-甲基-3-(嗎啉基甲基)-2,3-二氫-[1,4]噁嗪并[2,3,4-hi]吲哚-6-基)甲酮(BA-177)之製備步驟1：6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)-1-萘甲酸甲酯¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.45 (s, 1H), 8.38 (d,J = 5.9 Hz, 1H), 7.82 (s, 1H), 7.48 - 7.29 (m, 4H), 7.25 - 7.17 (m, 4H), 6.92 (s, 1H), 6.78 (d,J = 6.0 Hz, 1H), 5.73 (d,J = 20.1 Hz, 2H), 4.07 - 3.85 (m, 6H), 3.59 - 3.53 (m, 2H), 3.53 - 3.45 (m , 4H), 3.38 (dt,J = 21.8, 5.4 Hz, 5H), 3.22 (q,J = 5.9 Hz, 2H), 2.19 (t,J = 6.8 Hz, 2H), 2.10 (dd,J = 13.5, 3.8 Hz, 2H), 1.70 (tt,J = 12.7, 7.9 Hz, 7H )Example 5: (R)-(6-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)oxy)naphthalen-1-yl)(5-methyl 3-(oxolinylmethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indol-6- yl)methanone (BA-177) PreparationStep 1 : 6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedral-3-silaheneicosane-21-yl)oxy )-1-Naphthoic acid methyl ester

在室溫下向6-羥基萘-1-甲酸甲酯(5.0 g, 25 mmol)於乙腈(150 mL)中之攪拌溶液中添加K₂CO₃(5.13 g, 37.1 mmol)及4-甲基苯磺酸2,2,3,3-四甲基-4,7,10, 13,16,19-六氧雜-3-矽雜二十一烷-21-基酯(15.0 g, 27.2 mmol)。將所得混合物在氮氣氣氛下在70℃下攪拌隔夜，且接著使其冷卻至室溫。用乙酸乙酯(200 mL)稀釋混合物，用水(2 × 50 mL)及鹽水(2 × 50 mL)洗滌，經無水MgSO₄乾燥，過濾並濃縮，得到呈黃褐色油狀物之標題化合物。To a stirred solution of methyl 6-hydroxynaphthalene-1-carboxylate (5.0 g, 25 mmol) in acetonitrile (150 mL) was added K₂ CO₃ (5.13 g, 37.1 mmol) and 2,2,3,3-tetramethyl-4,7,10, 13,16,19-hexaoxana-3-silahenicosan-21-yl 4-methylbenzenesulfonate (15.0 g, 27.2 mmol) at room temperature. The resulting mixture was stirred at 70° C. overnight under a nitrogen atmosphere and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO₄ , filtered and concentrated to give the title compound as a tan oil.

MS (ESI)：m/z = 581 [M+H]⁺步驟2：N-甲氧基-N-甲基-6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)-1-萘甲醯胺MS (ESI): m/z = 581 [M+H]⁺Step 2 : N-methoxy-N-methyl-6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedral-3-silahenedecane-21-yl)oxy)-1-naphthylamide

在氬氣氣氛下在0℃下向6-[(2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基]萘-1-甲酸甲酯(15 g, 26 mmol)及N,O-二甲基羥胺鹽酸鹽(3.78 g, 38.7 mmol)於THF (300 mL)中之攪拌混合物中逐滴添加i-PrMgCl (99 mL, 129 mmol)。將所得混合物在氬氣氣氛下在0℃下攪拌1小時。藉由在室溫下添加飽和NH₄Cl (水溶液) (60 mL)淬滅反應物，且用乙酸乙酯(3 × 60 mL)萃取。將合併的有機萃取物用鹽水(2 × 20 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用CH₂Cl₂/ EA (1:1)溶析進行純化，得到呈黃色油狀物之標題化合物(9.6 g, 52%)。To a stirred mixture of methyl 6-[(2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxazolo-3-silannicosan-21-yl)oxy]naphthalene-1-carboxylate (15 g, 26 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.78 g, 38.7 mmol) in THF (300 mL) under an atmosphere of nitrogen at 0°C was added i-PrMgCl (99 mL, 129 mmol) dropwise. The resulting mixture was stirred at 0°C under an atmosphere of nitrogen for 1 hour. The reaction was quenched by the addition of saturated_NH4Cl (aq) (60 mL) at room temperature and extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over_{anhydrousNa2SO4} , filtered, concentrated and purified by silica gel column chromatography eluting with_CH2Cl2 /_EA (1:1) to give the title compound as a yellow oil (9.6 g, 52%).

MS (ESI)：m/z = 610 [M+H]⁺步驟3：1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)乙-1-酮MS (ESI): m/z = 610 [M+H]⁺Step 3 : 1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedralheneicosyl)oxy)naphthalen-1-yl)ethan-1-one

在氬氣氣氛下在室溫下向N-甲氧基-N-甲基-6-[(2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基]萘-1-甲醯胺(9.6 g, 16 mmol)於THF (38.4 mL)中之攪拌溶液中添加MeMgBr (157 mL, 157 mmol)。將所得混合物在室溫下攪拌1 h，藉由添加NH₄Cl水溶液(飽和) (50 mL)淬滅且用乙酸乙酯(3 × 100 mL)萃取。將合併的有機萃取物用鹽水(2 × 60 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用CH₂Cl₂/ EA (1:1)溶析進行純化，得到呈淺褐色油狀物之標題化合物(6.5 g, 72%)。To a stirred solution of N-methoxy-N-methyl-6-[(2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedralheneconyl-21-yl)oxy]naphthalene-1-carboxamide (9.6 g, 16 mmol) in THF (38.4 mL) was added MeMgBr (157 mL, 157 mmol) at room temperature under an atmosphere of hydrogen. The resulting mixture was stirred at room temperature for 1 h, quenched by the addition of aqueous_NH4Cl solution (saturated) (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (2 x 60 mL), dried over_{anhydrousNa2SO4} , filtered, concentrated and purified by silica gel column chromatography eluting with_CH2Cl2 /_EA (1:1) to give the title compound as a light brown oil (6.5 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d,J= 9.4 Hz, 1H), 8.05 - 7.92 (m, 2H), 7.53 (dd,J= 8.2, 7.3 Hz, 1H), 7.41 (d,J= 2.7 Hz, 1H), 7.26 (dd,J= 9.4, 2.7 Hz, 1H), 4.26 - 4.16 (m, 2H), 3.84 - 3.75 (m, 2H), 3.68 - 3.36 (m, 20H), 2.68 (s, 3H), 0.82 (s, 9H)¹ H NMR (300 MHz, DMSO-d₆ ) δ 8.54 (d,J = 9.4 Hz, 1H), 8.05 - 7.92 (m, 2H), 7.53 (dd,J = 8.2, 7.3 Hz, 1H), 7.41 ( d,J = 2.7 Hz, 1H), 7.26 (dd,J = 9.4, 2.7 Hz, 1H), 4.26 - 4.16 (m, 2H), 3.84 - 3.75 (m, 2H), 3.68 - 3.36 (m, 20H), 2.68 (s, 3H), 0.82 (s , 9H)

MS (ESI)：m/z= 565 (M+H)⁺。步驟4：3-羥基-1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)丁-1-酮MS (ESI):m/z = 565 (M+H)⁺ .Step 4 : 3-Hydroxy-1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedralheneicosane-21-yl)oxy)naphthalen-1-yl)butan-1-one

將1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)乙-1-酮(6.5 g, 11 mmol)於THF (260 mL)中之溶液在氮氣氣氛下在-40℃下用LiHMDS (15.9 mL, 0.796 mmol)處理10 min，之後在-40℃下分多次逐滴添加於THF中之CH₃CHO (4.2 mL, 44 mmol)。將所得混合物在氮氣氣氛下在-40℃下攪拌30 min，在-40℃下用NH₄Cl水溶液(飽和)淬滅且用乙酸乙酯(3 × 20 mL)萃取。將合併的有機萃取物用鹽水(3 × 20 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由反相急速層析進行純化：管柱，C18矽膠；移動相，含ACN之H₂O，在30 min內10%至95%梯度；偵測器，UV 254 nm，得到呈黃色油狀物之標題化合物(1.65 g, 24%)。A solution of 1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxa-3-silannicosan-21-yl)oxy)naphthalen-1-yl)ethan-1-one (6.5 g, 11 mmol) in THF (260 mL) was treated with LiHMDS (15.9 mL, 0.796 mmol) under nitrogen atmosphere at -40 °C for 10 min, followed by the addition of_CH3CHO (4.2 mL, 44 mmol) in THF dropwise in several portions at -40 °C. The resulting mixture was stirred at -40 °C for 30 min under nitrogen atmosphere, quenched with aqueous_NH4Cl solution (saturated) at -40 °C and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried_over anhydrous_Na2SO4 , filtered, concentrated and purified by reverse phase flash chromatography: column, C18 silica gel; mobile phase, ACN in_H2O , gradient 10% to 95% in 30 min; detector, UV 254 nm to give the title compound as a yellow oil (1.65 g, 24%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d,J= 9.4 Hz, 1H), 7.99 (d,J= 8.2 Hz, 1H), 7.88 (dd,J= 7.2, 1.2 Hz, 1H), 7.55 (t,J= 7.7 Hz, 1H), 7.43 (d,J= 2.7 Hz, 1H), 7.27 (dd,J= 9.4, 2.6 Hz, 1H), 4.72 (d,J= 5.0 Hz, 1H), 4.23 (dd,J= 5.7, 3.6 Hz, 2H), 4.23 - 4.11 (m, 1H), 3.85 - 3.79 (m, 2H), 3.74 (s, 1H), 3.70 - 3.59 (m, 4H), 3.63 - 3.53 (m, 2H), 3.57 - 3.47 (m, 13H), 3.43 (t,J= 5.2 Hz, 2H), 1.16 (d,J= 6.2 Hz, 3H), 0.85 (s, 9H)¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.37 (d,J = 9.4 Hz, 1H), 7.99 (d,J = 8.2 Hz, 1H), 7.88 (dd,J = 7.2, 1.2 Hz, 1H) , 7.55 (t,J = 7.7 Hz, 1H), 7.43 (d,J = 2.7 Hz, 1H), 7.27 (dd,J = 9.4, 2.6 Hz, 1H), 4.72 (d,J = 5.0 Hz, 1H), 4.23 (dd,J = 5.7, 3.6 Hz, 2H ), 4.23 - 4.11 (m, 1H), 3.85 - 3.79 (m, 2H), 3.74 (s, 1H), 3.70 - 3.59 (m, 4H), 3.63 - 3.53 (m, 2H), 3.57 - 3.47 (m, 13H), 3.43 (t,J = 5.2 Hz, 2H), 1.16 (d,J = 6.2 Hz, 3H), 0.85 (s, 9H)

MS (ESI)：m/z = 609 [M+H]⁺步驟5：1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)丁烷-1,3-二酮MS (ESI): m/z = 609 [M+H]⁺Step 5 : 1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxahedralheneicosane-21-yl)oxy)naphthalen-1-yl)butane-1,3-dione

將3-羥基-1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)丁-1-酮(1.5 g, 2.464 mmol)及戴斯-馬丁過碘烷(Dess-Martin periodinane) (1.36 g, 3.20 mmol)於CH₃Cl (20 mL)中之混合物在氮氣氣氛下在室溫下攪拌1小時。過濾所得混合物，且用DCM (3 × 20 mL)洗滌濾餅。將濾液濃縮，且藉由反相急速層析進行純化：管柱，C18矽膠；移動相，含ACN之H₂O，在30 min內10%至90%梯度；偵測器，UV 254 nm，得到呈黃色油狀物之標題化合物(1.1 g, 74%)。A mixture of 3-hydroxy-1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxa-3-silannicosan-21-yl)oxy)naphthalen-1-yl)butan-1-one (1.5 g, 2.464 mmol) and Dess-Martin periodinane (1.36 g, 3.20 mmol) in CH₃ Cl (20 mL) was stirred under nitrogen atmosphere at room temperature for 1 hour. The resulting mixture was filtered and the filter cake was washed with DCM (3×20 mL). The filtrate was concentrated and purified by reverse phase flash chromatography: column, C18 silica gel; mobile phase, ACN in_H2O , gradient 10% to 90% in 30 min; detector, UV 254 nm to give the title compound as a yellow oil (1.1 g, 74%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d,J= 9.3 Hz, 1H), 8.00 (d,J= 8.2 Hz, 1H), 7.65 (d,J= 1.2 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.45 (d,J= 2.7 Hz, 1H), 7.28 (dd,J= 9.4, 2.7 Hz, 1H), 4.29 - 4.16 (m, 2H), 3.83 (dd,J= 3.8, 2.2 Hz, 2H), 3.67 (d,J= 5.0 Hz, 2H), 3.62 (dd,J= 4.6, 1.9 Hz, 2H), 3.58 - 3.54 (m, 2H), 3.53 - 3.49 (m, 14H), 3.42 (dd,J= 6.0, 4.3 Hz, 2H), 2.21 (s, 3H), 0.85 (s, 12H)¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.34 (d,J = 9.3 Hz, 1H), 8.00 (d,J = 8.2 Hz, 1H), 7.65 (d,J = 1.2 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.45 (d,J = 2.7 Hz, 1H), 7.28 (dd,J = 9.4, 2.7 Hz, 1H), 4.29 - 4.16 (m, 2H), 3.83 (dd,J = 3.8, 2.2 Hz, 2H), 3.67 (d,J = 5.0 Hz, 2H), 3.62 (dd,J = 4.6, 1.9 Hz, 2H), 3.58 - 3.54 (m, 2H), 3.53 - 3.49 (m, 14H), 3.42 (dd,J = 6.0, 4.3 Hz, 2H), 2.21 (s, 3H), 0.85 (s, 12H)

MS (ESI)：m/z= 607 [M+H]⁺步驟6：(R)-(6-((17-羥基-3,6,9,12,15-五氧雜十七烷基)氧基)萘-1-基)(5-甲基-3-(嗎啉基甲基)-2,3-二氫-[1,4]噁嗪并[2,3,4-hi]吲哚-6-基)甲酮MS (ESI):m/z = 607 [M+H]⁺Step 6 : (R)-(6-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)oxy)naphthalen-1-yl)(5-methyl-3-(oxolinylmethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indol-6-yl)methanone

將(3R)-3-(嗎啉-4-基甲基)-2,3-二氫-1,4-苯并噁嗪-4-胺(900 mg, 3.610 mmol)、1-(6-((2,2,3,3-四甲基-4,7,10,13,16,19-六氧雜-3-矽雜二十一烷-21-基)氧基)萘-1-基)丁烷-1,3-二酮(1.10 g, 1.81 mmol)於乙醇(18 mL)中之混合物在氮氣氣氛下在室溫下攪拌20 min，之後在室溫下逐滴添加H₂SO₄(5%於乙醇中，3 mL)。將所得混合物在氮氣氣氛下在78℃下攪拌2小時，藉由在0℃下添加Na₂HCO₃(飽和)淬滅且用乙酸乙酯(3 × 30 mL)萃取。將合併的有機萃取物用鹽水(3 × 30 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由反相急速層析進行純化：管柱，C18矽膠；移動相，含ACN之H₂O，在30 min內10%至95%梯度；偵測器，UV 254 nm，得到呈黃色油狀物之標題化合物(704.6 mg, 27%)。A mixture of (3R)-3-(morpholin-4-ylmethyl)-2,3-dihydro-1,4-benzoxazin-4-amine (900 mg, 3.610 mmol), 1-(6-((2,2,3,3-tetramethyl-4,7,10,13,16,19-hexaoxa-3-silannicosan-21-yl)oxy)naphthalen-1-yl)butane-1,3-dione (1.10 g, 1.81 mmol) in ethanol (18 mL) was stirred under nitrogen atmosphere at room temperature for 20 min, and then_H2SO4 (₅ % in ethanol, 3 mL) was added dropwise at room temperature. The resulting mixture was stirred at 78 °C for 2 h under nitrogen atmosphere, quenched by addition_ofNa2HCO3 (saturated) at 0 °C and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (3 x 30 mL), dried_over anhydrous_Na2SO4 , filtered, concentrated and purified by reverse phase flash chromatography: column, C18 silica gel; mobile phase, ACN in_H2O , gradient 10% to 95% in 30 min; detector, UV 254 nm to afford the title compound as a yellow oil (704.6 mg, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 7.98 (d,J= 8.5 Hz, 1H), 7.72 (d,J= 9.4 Hz, 1H), 7.57 (t,J= 7.7 Hz, 1H), 7.47 (s, 1H), 7.39 - 7.30 (m, 1H), 7.15 (dd,J= 9.2, 3.0 Hz, 1H), 6.85 - 6.73 (m, 1H), 6.64 - 6.55 (m, 1H), 6.32 (d,J= 7.9 Hz, 1H), 4.88 (s, 1H), 4.73 (d,J= 11.6 Hz, 1H), 4.59-4.56 (m, 1H), 4.27 - 4.13 (m, 3H), 3.82 (s, 2H), 3.67 -3.50 (m,22H), 3.48 - 3.36 (m, 2H), 2.61 (dd,J= 12.7, 7.6 Hz, 1H), 2.49 - 2.18 (m, 8H)¹ H NMR (300 MHz, DMSO-d₆ ) δ 7.98 (d,J = 8.5 Hz, 1H), 7.72 (d,J = 9.4 Hz, 1H), 7.57 (t,J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.39 - 7.30 (m, 1H), 7.15 (dd,J = 9.2, 3.0 Hz, 1H), 6.85 - 6.73 (m, 1H), 6.64 - 6.55 (m, 1H), 6.32 (d,J = 7.9 Hz, 1H), 4.88 (s , 1H), 4.73 (d,J = 11.6 Hz, 1H), 4.59-4.56 (m, 1H), 4.27 - 4.13 (m, 3H), 3.82 (s, 2H), 3.67 -3.50 (m,2 2H), 3.48 - 3.36 (m, 2H), 2.61 (dd,J = 12.7, 7.6 Hz, 1H), 2.49 - 2.18 (m, 8H)

MS (ESI)：m/z= 707 [M+H]⁺步驟7：(R)-(6-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)氧基)萘-1-基)(5-甲基-3-(嗎啉基甲基)-2,3-二氫-[1,4]噁嗪并[2,3,4-hi]吲哚-6-基)甲酮MS (ESI):m/z = 707 [M+H]⁺Step 7 : (R)-(6-((17-azino-3,6,9,12,15-pentaoxaheptadecanyl)oxy)naphthalen-1-yl)(5-methyl-3-(oxolinylmethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indol-6-yl)methanone

在0℃下向(R)-(6-((17-羥基-3,6,9,12,15-五氧雜十七烷基)氧基)萘-1-基)(5-甲基-3-(嗎啉基甲基)-2,3-二氫-[1,4]噁嗪并[2,3,4-hi]吲哚-6-基)甲酮(0.25 g, 0.35 mmol)於無水二氯甲烷(3.5 mL)中之溶液中添加Et₃N (74 mL, 0.53 mmol)，之後添加MsCl (30 mL, 0.3 mmol)。使混合物緩慢升溫至室溫，且在1小時後，用飽和NaHCO₃淬滅反應物並用二氯甲烷(3 × 50 mL)萃取。將合併的有機萃取物用鹽水洗滌，經Na₂SO₄乾燥，過濾並濃縮，得到粗製甲磺酸鹽，其不經進一步純化即用於下一步驟中。在室溫下向該甲磺酸鹽於DMF (3.5 mL)中之溶液中添加NaN₃(69 mg, 1.06 mmol)，且接著將反應混合物加熱至90℃持續16小時，且接著冷卻至室溫。用水稀釋混合物，且用乙酸乙酯(3 × 100 mL)萃取。將合併的有機萃取物用鹽水洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由急速層析(25 g，20微米Biotage管柱)使用己烷/EtOAc 0-20%進行純化，得到呈褐色油狀物之標題化合物(232 mg, 67.4%)。To a solution of (R)-(6-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)oxy)naphthalen-1-yl)(5-methyl-3-(oxolinylmethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indol-6-yl)methanone (0.25 g, 0.35 mmol) in anhydrous dichloromethane (3.5 mL) at 0°C was added_Et3N (74 mL, 0.53 mmol) followed by MsCl (30 mL, 0.3 mmol). The mixture was allowed to slowly warm to room temperature and after 1 hour, the reaction was quenched with saturated_NaHCO3 and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine, dried_overNa2SO4 , filtered and concentrated to give the crude mesylate, which was used in the next step without further purification. To a solution of the mesylate in DMF (3.5 mL) was added_NaN3 (69 mg, 1.06 mmol) at room temperature, and the reaction mixture was then heated to 90 °C for 16 h, and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried_overNa2SO4 , filtered, concentrated and purified by flash chromatography (25 g, 20 micron Biotage column) using hexanes/EtOAc 0-20% to give the title compound as a brown oil (232 mg, 67.4%).

¹H NMR (500 MHz, DMSO-d₆) δ 7.97 (d,J= 10Hz, 1 H), 7.71 (d,J= 5Hz, 1 H), 7.57-7.54 (m, 1 H), 7.46 (d,J= 5Hz, 1 H), 7.34-7.32 (m, 1 H), 6.78 (t,J= 10Hz, 1 H), 6.58(d,J= 10 Hz, 1 H), 6.32 (d,J= 10Hz, 1 H), 4.88-4.85 (br, 1 H), 4.72 (d,J=10 Hz,1 H), 4.24-4.16 (m, 3 H), 3.82-3.80 (m, H), 4.01-3.99 (m, 2 H), 3.61-3.49 (m, 23 H), 3.37 - 3.34 (m, 18 H), 2.49-2.39 (m, 8 H)¹ H NMR (500 MHz, DMSO-d₆ ) δ 7.97 (d,J = 10Hz, 1 H), 7.71 (d,J = 5Hz, 1 H), 7.57-7.54 (m, 1 H), 7.46 (d ,J = 5Hz, 1 H), 7.34-7.32 (m, 1 H), 6.78 (t,J = 10Hz, 1 H), 6.58 (d,J = 10 Hz, 1 H), 6.32 (d,J = 10Hz, 1 H), 4.88-4.85 (br, 1 H), 4.72 (d ,J =10 Hz,1 H), 4.24-4.16 (m, 3 H), 3.82-3.80 (m, H), 4.01-3.99 (m, 2 H), 3.61-3.49 (m, 23 H), 3.37 - 3.34 (m, 18 H), 2.49-2.39 (m, 8 H)

MS (ESI)：m/z = 754.2 [M+Na]⁺實例6：4-(((2S,4S)-1-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸(BA-210)步驟1：4-(((2S,4S)-1-(2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯MS (ESI): m/z = 754.2 [M+Na]⁺Example 6: 4-(((2S,4S)-1-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoic acid (BA-210)Step 1 : Methyl 4-(((2S,4S)-1-(2-(4-(3-(4-(((tert-butyloxycarbonyl)amino)methyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoate

向2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙酸(如Tolomelli等人，「Dehydro-β-proline Containing α₄β₁Integrin Antagonists: Stereochemical Recognition in Ligand–Receptor Interplay」,ACS Med. Chem. Lett.2015,6,6, 701-706所闡述來製備；0.25 g, 0.626 mmol)於無水DMF (3 ml)中之溶液中添加4-(((2S,4S)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯(如Muro等人，「A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid」,Bioorg. Med. Chem.2009,17(3), 1232-43所闡述來製備，0.23 g, 0.626 mmol)、HATU (0.31 g, 0.814 mmol)及三乙胺(0.20 ml, 1.25 mmol)。將反應混合物在惰性氣氛下在室溫下攪拌3小時。添加水(15 ml)，且用DCM (3 × 20 ml)萃取混合物。將合併的有機萃取物用鹽水(10 ml)洗滌，經無水Na₂SO₄乾燥，濃縮且藉由矽膠管柱層析使用於己烷中之50%-100% EtOAc梯度進行純化，得到呈黃色油狀物之標題化合物(0.30 g, 76%)。To a solution of 2-(4-(3-(4-(((tert-butyloxycarbonyl)amino)methyl)phenyl)ureido)phenyl)acetic acid (prepared as described by Tolomelli et al., “Dehydro-β-proline Containing α₄ β₁ Integrin Antagonists: Stereochemical Recognition in Ligand–Receptor Interplay”,ACS Med. Chem. Lett.2015 ,6 ,6 , 701-706; 0.25 g, 0.626 mmol) in anhydrous DMF (3 ml) was added methyl 4-(((2S,4S)-4-fluoropyrrolidin-2-yl)methoxy)benzoate (prepared as described by Muro et al., “A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid”,Bioorg. Med. Chem .2009 ,17(3) , 1232-43, 0.23 g, 0.626 mmol), HATU (0.31 g, 0.814 mmol) and triethylamine (0.20 ml, 1.25 mmol). The reaction mixture was stirred at room temperature for 3 h under an inert atmosphere. Water (15 ml) was added and the mixture was extracted with DCM (3 × 20 ml). The combined organic extracts were washed with brine (10 ml), dried_over anhydrous_Na2SO4 , concentrated and purified by silica gel column chromatography using a gradient of 50%-100% EtOAc in hexanes to give the title compound (0.30 g, 76%) as a yellow oil.

MS (ESI) m/z 657.8 [M+Na]⁺步驟2：4-(((2S,4S)-1-(2-(4-(3-(4-(胺基甲基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯MS (ESI) m/z 657.8 [M+Na]⁺Step 2 : Methyl 4-(((2S,4S)-1-(2-(4-(3-(4-(aminomethyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoate

在0℃下向4-(((2S,4S)-1-(2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯(0.30 g, 0.473 mmol)於DCM (3 ml)中之溶液中逐滴添加TFA (0.3 ml)。移除冷卻浴，且將混合物在室溫下攪拌2小時，接著濃縮，定量得到呈黃色油狀物之標題化合物。To a solution of methyl 4-(((2S,4S)-1-(2-(4-(3-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoate (0.30 g, 0.473 mmol) in DCM (3 ml) at 0° C. was added TFA (0.3 ml) dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 2 h then concentrated to give the title compound quantitatively as a yellow oil.

MS (ESI) m/z 1069.3 [2M]⁺步驟3：4-(((2S,4S)-1-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯MS (ESI) m/z 1069.3 [2M]⁺Step 3 : 4-(((2S,4S)-1-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoic acid methyl ester

向4-(((2S,4S)-1-(2-(4-(3-(4-(胺基甲基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯(0.28 g, 0.43 mmol)於無水DMF (3 ml)中之溶液中添加1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸(0.125 g, 0.43 mmol)、HATU (0.21 g, 0.56 mmol)及三乙胺(0.18 ml, 1.29 mmol)。將反應混合物在惰性氣氛下在室溫下攪拌3小時，接著用水(20 ml)稀釋且用DCM (3 × 20 ml)萃取。將合併的有機萃取物用鹽水(10 ml)洗滌，經無水Na₂SO₄乾燥，濃縮且藉由矽膠管柱層析使用於己烷中之50%-100% EtOAc梯度進行純化，得到呈黃色油狀物之標題化合物(0.20 g, 57%)。To a solution of methyl 4-(((2S,4S)-1-(2-(4-(3-(4-(aminomethyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoate (0.28 g, 0.43 mmol) in anhydrous DMF (3 ml) was added 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid (0.125 g, 0.43 mmol), HATU (0.21 g, 0.56 mmol) and triethylamine (0.18 ml, 1.29 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 3 h, then diluted with water (20 ml) and extracted with DCM (3 x 20 ml). The combined organic extracts were washed with brine (10 ml), dried_over anhydrous_Na2SO4 , concentrated and purified by silica gel column chromatography using a gradient of 50%-100% EtOAc in hexanes to give the title compound as a yellow oil (0.20 g, 57%).

MS (ESI) m/z 808.9 [M+H]⁺步驟4：4-(((2S,4S)-1-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸MS (ESI) m/z 808.9 [M+H]⁺Step 4 : 4-(((2S,4S)-1-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoic acid

向4-(((2S,4S)-1-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)-4-氟吡咯啶-2-基)甲氧基)苯甲酸甲酯(0.20 g, 0.248 mmol)於甲醇/水/二噁烷(3 ml, 1:1:1)中之溶液中添加氫氧化鋰(20 mg, 0.744 mmol)，且在室溫下攪拌18小時。將反應混合物在減壓下濃縮，用檸檬酸溶液(10%)處理且用DCM (3 × 20 ml)萃取。將合併的有機萃取物用鹽水(5 ml)洗滌，經無水Na₂SO₄乾燥並濃縮，得到呈白色固體之標題化合物(0.19 g, 97%)。To a solution of methyl 4-(((2S,4S)-1-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecyl)phenyl)ureido)phenyl)acetyl)-4-fluoropyrrolidin-2-yl)methoxy)benzoate (0.20 g, 0.248 mmol) in methanol/water/dioxane (3 ml, 1:1:1) was added lithium hydroxide (20 mg, 0.744 mmol) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, treated with citric acid solution (10%) and extracted with DCM (3 x 20 ml). The combined organic extracts were washed with brine (5 ml), dried over_{anhydrousNa2SO4} and concentrated to give the title compound as a white solid (0.19 g, 97%).

MS (ESI) m/z 816.9 [M+Na]⁺MS (ESI) m/z 816.9 [M+Na]⁺

¹H NMR (500 MHz, DMSO-d₆)δ12.32 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.28 (t,J= 5.9 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.38 (d,J= 8.5 Hz, 4H), 7.15 (d,J= 8.4 Hz, 2H), 7.10 - 7.06 (m, 1H), 4.44 - 4.35 (m, 1H), 4.20 (d,J= 5.9 Hz, 2H), 3.94 - 3.76 (m, 3H), 3.67 - 3.46 (m, 17H), 3.40 - 3.35 (m, 3H), 2.75 (d,J= 15.4 Hz, 2H), 2.65 (d,J= 15.4 Hz, 2H), 2.37 (t,J= 6.4 Hz, 2H), 2.32 - 2.22 (m, 2H), 1.91 (s, 2H)實例7：(S)-2-(1-(4-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸(BA-215)之製備步驟1：(S)-2-(1-(4-(2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯¹ H NMR (500 MHz, DMSO-d₆ )δ 12.32 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.28 (t,J = 5.9 Hz, 1H), 7.89 - 7.85 ( m, 1H), 7.38 (d,J = 8.5 Hz, 4H), 7.15 (d,J = 8.4 Hz, 2H), 7.10 - 7.06 (m, 1H), 4.44 - 4.35 (m, 1H), 4.20 (d,J = 5.9 Hz, 2H), 3.94 - 3.76 (m, 3H), 3.67 - 3.46 (m, 17H), 3.40 - 3.35 (m, 3H), 2.75 (d,J = 15.4 Hz, 2H), 2.65 (d,J = 15.4 Hz, 2H), 2.37 (t,J = 6.4 Hz, 2H), 2.32 - 2.22 (m, 2H) , 1.91 (s, 2H)Example 7: (S)-2-(1-(4-(2-(4-(3-(4-(17-azido-3-oxo-6,9 ,12,15-tetraoxa-2-azaheptadecyl)phenyl)ureido)phenyl)acetyl)morpholine-3-carbonyl)hexahydropyridin-4-yl)acetic acid (BA -215)Step 1 : (S)-2-(1-(4-(2-(4-(3-(4-(((tert-butyloxycarbonyl)amino)methyl)phenyl)ureido)benzene (4-(2-( ...

向2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙酸(0.15 g, 0.36 mmol)於無水DMF (3 ml)中之溶液中添加(S)-2-(1-(嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯(如Chiba等人，「Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist」,Bioorg. & Med. Chem. Lett.,15,1, 41-45所闡述來製備；97 mg, 0.36 mmol)、HATU (0.18 g, 0.47 mmol)及三乙胺(0.10 ml)。將反應混合物在惰性氣氛下在室溫下攪拌3小時，且接著用水(20 ml)稀釋並用乙酸乙酯(3 × 20 ml)萃取。將合併的有機萃取物用鹽水(25 ml)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析使用於DCM中之0-20% MeOH梯度進行純化，得到呈黃色油狀物之標題化合物(0.18 g, 57%)。To a solution of 2-(4-(3-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)ureido)phenyl)acetic acid (0.15 g, 0.36 mmol) in anhydrous DMF (3 ml) were added (S)-methyl 2-(1-(morpholine-3-carbonyl)hexahydropyridin-4-yl)acetate (prepared as described by Chiba et al., “Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist”,Bioorg. & Med. Chem. Lett .,15 ,1 , 41-45; 97 mg, 0.36 mmol), HATU (0.18 g, 0.47 mmol) and triethylamine (0.10 ml). The reaction mixture was stirred at room temperature under an inert atmosphere for 3 h, and then diluted with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (25 ml), dried over_{anhydrousNa2SO4} , filtered, concentrated and purified by silica gel column chromatography using a gradient of 0-20% MeOH in DCM to give the title compound (0.18 g, 57%) as a yellow oil.

MS (ESI) m/z 652.6 [M+H]⁺。步驟2：(S)-2-(1-(4-(2-(4-(3-(4-(胺基甲基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯MS (ESI) m/z 652.6 [M+H]⁺ .Step 2 : (S)-methyl 2-(1-(4-(2-(4-(3-(4-(aminomethyl)phenyl)ureido)phenyl)acetyl)oxoline-3-carbonyl)hexahydropyridin-4-yl)acetate

在0℃下向(S)-2-(1-(4-(2-(4-(3-(4-(((第三丁氧基羰基)胺基)甲基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯(0.18 g, 0.276 mmol)於DCM (2 ml)中之溶液中逐滴添加TFA (0.3 ml)。移除冷卻浴，且將混合物在室溫下攪拌5小時，接著濃縮，定量得到呈黃色油狀物之標題化合物。To a solution of (S)-methyl 2-(1-(4-(2-(4-(3-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)ureido)phenyl)acetyl)morpholine-3-carbonyl)hexahydropyridin-4-yl)acetate (0.18 g, 0.276 mmol) in DCM (2 ml) at 0° C. was added TFA (0.3 ml) dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 5 h then concentrated to give the title compound quantitatively as a yellow oil.

MS (ESI) m/z 552.6 [M+H]⁺步驟3：(S)-2-(1-(4-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯MS (ESI) m/z 552.6 [M+H]⁺Step 3 : (S)-2-(1-(4-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)oxoline-3-carbonyl)hexahydropyridin-4-yl)acetate

向(S)-2-(1-(4-(2-(4-(3-(4-(胺基甲基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯(0.18 g, 0.276 mmol)於無水DMF (1.5 ml)中之溶液中添加1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸(80 mg, 0.276 mmol)、HATU (0.14 g, 0.36 mmol)及三乙胺(0.20 ml)。將反應混合物在惰性氣氛下在室溫下攪拌3小時，且接著用水(20 ml)稀釋並用DCM (3 × 20 ml)萃取。將合併的有機萃取物用鹽水(15 ml)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析使用於DCM中之0-20% MeOH梯度進行純化，得到呈黃色油狀物之標題化合物(0.11 g, 48%)。To a solution of (S)-methyl 2-(1-(4-(2-(4-(3-(4-(aminomethyl)phenyl)ureido)phenyl)acetyl)morpholine-3-carbonyl)hexahydropyridin-4-yl)acetate (0.18 g, 0.276 mmol) in anhydrous DMF (1.5 ml) were added 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid (80 mg, 0.276 mmol), HATU (0.14 g, 0.36 mmol) and triethylamine (0.20 ml). The reaction mixture was stirred at room temperature under an inert atmosphere for 3 h and then diluted with water (20 ml) and extracted with DCM (3 x 20 ml). The combined organic extracts were washed with brine (15 ml), dried over anhydrous_Na2SO4, filtered, concentrated and purified by silica gel column chromatography using a 0-20% MeOH gradient in DCM to give the title compound as a yellow oil (0.11 g, 48%).

MS (ESI) m/z 825.5 [M+H]⁺步驟4：(S)-2-(1-(4-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸MS (ESI) m/z 825.5 [M+H]⁺Step 4 : (S)-2-(1-(4-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)oxoline-3-carbonyl)hexahydropyridin-4-yl)acetic acid

向(S)-2-(1-(4-(2-(4-(3-(4-(17-疊氮基-3-側氧基-6,9,12,15-四氧雜-2-氮雜十七烷基)苯基)脲基)苯基)乙醯基)嗎啉-3-羰基)六氫吡啶-4-基)乙酸甲酯(0.11 g, 0.248 mmol)於甲醇/水/二噁烷(1.5 ml, 1:1:1)中之溶液中添加氫氧化鋰(10 mg, 0.40 mmol)，且在室溫下攪拌5小時。使溶劑在真空中蒸發，且將所得殘餘物用10%檸檬酸溶液處理，並藉由反相管柱層析(C18)使用於水(+0.1%甲酸)中之0-40% ACN梯度進行純化，得到呈白色固體之標題化合物(56 mg, 51%)。To a solution of (S)-methyl 2-(1-(4-(2-(4-(3-(4-(17-azido-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecanyl)phenyl)ureido)phenyl)acetyl)pyridin-4-yl)acetate (0.11 g, 0.248 mmol) in methanol/water/dioxane (1.5 ml, 1:1:1) was added lithium hydroxide (10 mg, 0.40 mmol) and stirred at room temperature for 5 hours. The solvent was evaporated i.vac. and the residue was treated with 10% citric acid solution and purified by reverse phase column chromatography (C18) using a gradient of 0-40% ACN in water (+0.1% formic acid) to give the title compound as a white solid (56 mg, 51%).

MS (ESI) m/z 811.9 [M+H]⁺MS (ESI) m/z 811.9 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆)δ12.13 (s, 1H) 8.64 (s, 1H), 8.61 (s, 1H), 8.28 (t,J= 5.9 Hz, 1H), 7.41 - 7.32 (m, 4H), 7.18 - 7.09 (m, 4H), 5.12 (s, 1H) 4.20 (d,J= 5.8 Hz, 2H), 3.87 - 3.72 (m, 4H), 3.68 - 3.52 (m, 13H), 3.52 - 3.46 (m, 10H), 3.38 (dd,J= 5.6, 4.3 Hz, 3H), 2.57 (s, 1H), 2.37 (t,J= 6.4 Hz, 2H), 2.21-2.08 (m, 2H), 2.15 (s, 2H), 1.68 (s, 2H)實例8：N-((3s,5s,7s)-金剛烷-1-基)-2-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-苯甲醯胺(BA-236)之製備步驟1：N-((3s,5s,7s)-金剛烷-1-基)-2-羥基苯甲醯胺¹ H NMR (500 MHz, DMSO-d₆ )δ 12.13 (s, 1H) 8.64 (s, 1H), 8.61 (s, 1H), 8.28 (t,J = 5.9 Hz, 1H), 7.41 - 7.32 (m , 4H), 7.18 - 7.09 (m, 4H), 5.12 (s, 1H) 4.20 (d,J = 5.8 Hz, 2H), 3.87 - 3.72 (m, 4H), 3.68 - 3.52 (m, 13H), 3.52 - 3.46 (m, 10H), 3.38 ( dd,J = 5.6, 4.3 Hz, 3H), 2.57 (s, 1H), 2.37 (t,J = 6.4 Hz, 2H), 2.21-2.08 (m, 2H), 2.15 (s, 2H), 1.68 (s, 2H)Example 8: N-((3s,5s,7s)-adamantane -1-yl)-2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-benzamide (BA-236) PreparationStep 1 : N-((3s,5s,7s)-adamantan-1-yl)-2-hydroxybenzamide

在室溫下向2-羥基苯甲酸(0.50 g, 3.620 mmol)於DCM (5 mL)及DMF (5 mL)中之攪拌溶液中添加HOBT (0.73 g, 5.430 mmol)、EDCI (1.04 g, 5.430 mmol)、三環[3.3.1.13,7]癸-1-胺(0.55 g, 3.620 mmol)及DIEA (1.40 g, 10.860 mmol)。將所得混合物在氮氣氣氛下在室溫下攪拌4小時。用水淬滅反應物且用乙酸乙酯萃取。將合併的有機萃取物用鹽水洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由層析C18 (ACN/H₂O)進行純化，得到呈黃色油狀物之標題化合物(280 mg, 28.5%)。To a stirred solution of 2-hydroxybenzoic acid (0.50 g, 3.620 mmol) in DCM (5 mL) and DMF (5 mL) was added HOBT (0.73 g, 5.430 mmol), EDCI (1.04 g, 5.430 mmol), tricyclo[3.3.1.13,7]decan-1-amine (0.55 g, 3.620 mmol) and DIEA (1.40 g, 10.860 mmol) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried_overNa2SO4 , filtered, concentrated and purified by chromatography on C18 (ACN/_H2O ) to give the title compound as a yellow oil (280 mg, 28.5%).

MS(ESI) m/z= 272.2 [M+H]⁺步驟2：N-((3s,5s,7s)-金剛烷-1-基)-2-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-苯甲醯胺MS (ESI) m/z = 272.2 [M+H]⁺Step 2 : N-((3s,5s,7s)-adamantan-1-yl)-2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-benzamide

在室溫下向2-羥基-N-(三環[3.3.1.13,7]癸-3-基)苯甲醯胺(0.28 g, 1.032 mmol)於乙腈(2.8 mL)中之攪拌溶液中添加Cs₂CO₃(0.67 g, 2.064 mmol)及11-疊氮基-1-碘-3,6,9-三氧雜十一烷(0.34 g, 1.032 mmol)。將所得混合物在室溫下攪拌16 h，且接著在氮氣下在50℃下攪拌4小時。用水淬滅反應物且用乙酸乙酯萃取。使合併的萃取物經硫酸鈉乾燥，過濾，濃縮且藉由層析C18 (ACN/H2O)進行純化，得到呈無色油狀物之標題化合物(252.1 mg, 51.2%)。To a stirred solution of 2-hydroxy-N-(tricyclo[3.3.1.13,7]dec-3-yl)benzamide (0.28 g, 1.032 mmol) in acetonitrile (2.8 mL) was added Cs₂ CO₃ (0.67 g, 2.064 mmol) and 11-azido-1-iodo-3,6,9-trioxaundecane (0.34 g, 1.032 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h, and then at 50 °C under nitrogen for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography on C18 (ACN/H2O) to give the title compound as a colorless oil (252.1 mg, 51.2%).

MS(ESI) m/z=473.3, [M+H]⁺MS (ESI) m/z = 473.3, [M + H]⁺

¹H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.87 - 7.86 (m, 1H), 7.46 - 7.44 (m, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.25 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.3 Hz, 2H), 3.59 - 3.56 (m, 6H), 3.54 (s, 4H), 3.42 - 3.34 (m, 2H), 2.06 (s, 9H), 1.67 (s, 6H)實例9：1-疊氮基-N-(3-(10,11-二氫-5H-二苯并[a,d][7]輪烯-5-亞基)丙基)-N-甲基-3,6,9,12-四氧雜十五烷-15-醯胺(BA-135)之製備¹ H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.87 - 7.86 (m, 1H), 7.46 - 7.44 (m, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.25 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.3 Hz, 2H), 3.59 - 3.56 (m, 6H), 3.54 (s, 4H), 3.42 - 3.34 (m, 2H), 2.06 (s, 9H), 1.67 (s, 6H)Example 9: 1-azido-N-(3-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-ylidene)propyl)-N - Preparation of methyl-3,6,9,12-tetraoxopentadecane-15-amide (BA-135)

向3-(10,11-二氫-5H-二苯并[a,d][7]輪烯-5-亞基)-N-甲基丙-1-胺HCl鹽(200 mg, 0.669 mmol, 1 eq)及DIPEA (0.23 mL, 1.338 mmol, 2 eq)於DMF (2 mL)中之攪拌溶液中添加1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸2,5-二側氧基吡咯啶-1-基酯(253 mg, 0.736 mmol, 1.1 eq)，且將混合物在室溫下攪拌30 min。LCMS顯示醯胺形成。添加水(20 mL)，且用DCM (2×50 m)萃取混合物。使合併的有機萃取物經乾燥，濃縮且藉由管柱層析(0-10% MeOH/DCM)進行純化，得到呈淡黃色油狀物之標題化合物(160 mg, 45%，95%純度)。To a stirred solution of 3-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-ylidene)-N-methylpropan-1-amine HCl salt (200 mg, 0.669 mmol, 1 eq) and DIPEA (0.23 mL, 1.338 mmol, 2 eq) in DMF (2 mL) was added 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid 2,5-dioxopyrrolidin-1-yl ester (253 mg, 0.736 mmol, 1.1 eq) and the mixture was stirred at room temperature for 30 min. LCMS showed amide formation. Water (20 mL) was added and the mixture was extracted with DCM (2×50 m). The combined organic extracts were dried, concentrated and purified by column chromatography (0-10% MeOH/DCM) to give the title compound as a light yellow oil (160 mg, 45%, 95% purity).

LCMS: m/z 537 [M+1]LCMS: m/z 537 [M+1]

¹H NMR (499 MHz, DMSO-d₆) δ 7.30 - 6.97 (m, 8H), 5.90 - 5.71 (m, 1H), 3.58 (ddd,J= 6.7, 4.0, 1.6 Hz, 3H), 3.56 - 3.42 (m, 10H), 3.42 - 3.35 (m, 4H), 3.32 (m, 2H)2.84 (s, 2H), 2.65 (s, 2H), 2.40 (d,J= 7.7 Hz, 2H), 2.26 (br。d,J= 35.2 Hz, 4H)實例10：1-疊氮基-N-(2-(5-羥基-1H-吲哚-2-基)乙基)-3,6,9,12-四氧雜十五烷-15-醯胺(BA-136)之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 7.30 - 6.97 (m, 8H), 5.90 - 5.71 (m, 1H), 3.58 (ddd,J = 6.7, 4.0, 1.6 Hz, 3H), 3.56 - 3.42 (m, 10H), 3.42 - 3.35 (m, 4H), 3.32 (m, 2H)2.84 (s, 2H), 2.65 (s, 2H), 2.40 (d,J = 7.7 Hz, 2H), 2.26 (br. d,J = 35.2 Hz, 4H)Example 10: 1-azido-N-(2-(5-hydroxy-1H-indol-2-yl)ethyl)-3,6,9,12-tetraoxopentadecane-15 - Preparation of amide (BA-136)

向2-(2-胺基乙基)-1H-吲哚-5-醇(55 mg, 0.313 mmol, 1 eq)及DIPEA (0.1 mL, 0.625 mmol, 2 eq)於DMF (1 mL)中之攪拌溶液中添加1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸2,5-二側氧基吡咯啶-1-基酯(118 mg, 0.344 mmol, 1.1 eq)，且將混合物在室溫下攪拌30 min.。LCMS顯示醯胺形成。添加水(20 mL)，且用DCM (2×50 mL)萃取混合物。使合併的有機萃取物經乾燥，濃縮，且藉由管柱層析(0-20% MeOH/DCM)進行純化，得到呈澄清油狀物之標題化合物(133 mg, 94%，95%純度)。To a stirred solution of 2-(2-aminoethyl)-1H-indol-5-ol (55 mg, 0.313 mmol, 1 eq) and DIPEA (0.1 mL, 0.625 mmol, 2 eq) in DMF (1 mL) was added 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid 2,5-dioxopyrrolidin-1-yl ester (118 mg, 0.344 mmol, 1.1 eq) and the mixture was stirred at room temperature for 30 min. LCMS showed amide formation. Water (20 mL) was added and the mixture was extracted with DCM (2×50 mL). The combined organic extracts were dried, concentrated, and purified by column chromatography (0-20% MeOH/DCM) to give the title compound (133 mg, 94%, 95% purity) as a clear oil.

LCMS, m/z 450 (M+1)LCMS, m/z 450 (M+1)

¹H NMR (499 MHz, DMSO-d₆) δ 10.46 (d,J= 2.5 Hz, 1H), 8.56 (s, 1H), 7.91 (t,J= 5.7 Hz, 1H), 7.11 (d,J= 8.6 Hz, 1H), 7.02 (d,J= 2.4 Hz, 1H), 6.81 (d,J= 2.3 Hz, 1H), 6.58 (dd,J= 8.6, 2.3 Hz, 1H), 3.63 - 3.56 (m, 4H), 3.56 - 3.44 (m, 12H), 3.37 (dd,J= 5.6, 4.3 Hz, 2H), 3.30 - 3.28 (m, 2H), 2.71 (t,J= 7.6 Hz, 2H), 2.31 (t,J= 7.6 Hz, 2H)實例11：N1-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-N3,N5-雙(2-羥基乙基)苯-1,3,5-三甲醯胺(BA-137)之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 10.46 (d,J = 2.5 Hz, 1H), 8.56 (s, 1H), 7.91 (t,J = 5.7 Hz, 1H), 7.11 (d,J = 8.6 Hz, 1H), 7.02 (d,J = 2.4 Hz, 1H), 6.81 (d,J = 2.3 Hz, 1H), 6.58 (dd,J = 8.6, 2.3 Hz, 1H), 3.63 - 3.56 (m, 4H), 3.56 - 3.44 (m, 12H), 3.37 (dd,J = 5.6, 4.3 Hz, 2H), 3.30 - 3.28 (m, 2H), 2.71 (t,J = 7.6 Hz, 2H), 2.31 (t,J = 7.6 Hz, 2H)Example 11: N1-(2-(2-(2-(2-azidoethoxy) Preparation of (ethoxy)ethoxy)ethyl)-N3,N5-bis(2-hydroxyethyl)benzene-1,3,5-trimethylamide (BA-137)

將苯-1,3,5-三甲酸三甲酯(0.5 g, 2.3 mmol, 1 eq)及2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙-1-胺(578 mg, 2.3 mmol, 1 eq)在150℃下攪拌2 h。藉由LCMS監測反應，其顯示單醯胺為主要產物，具有約20%二醯胺。使混合物冷卻並添加2-胺基乙-1-醇(1.4 mL, 22.9 mmol, 10 eq)，且將混合物在150℃下攪拌3 h。LCMS顯示三醯胺為主要產物。添加飽和氯化鈉溶液(20 mL)，且用DCM (5×100 m)萃取混合物。使合併的有機萃取物經乾燥，濃縮且藉由管柱層析(0-20% MeOH/DCM)進行純化，提供呈淡黃色油狀物之標題化合物(70 mg, 6%，95%純度)。Trimethyl benzene-1,3,5-tricarboxylate (0.5 g, 2.3 mmol, 1 eq) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine (578 mg, 2.3 mmol, 1 eq) were stirred at 150 °C for 2 h. The reaction was monitored by LCMS, which showed the monoamide as the major product with about 20% diamide. The mixture was cooled and 2-aminoethan-1-ol (1.4 mL, 22.9 mmol, 10 eq) was added, and the mixture was stirred at 150 °C for 3 h. LCMS showed the triamide as the major product. Saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with DCM (5 x 100 m). The combined organic extracts were dried, concentrated and purified by column chromatography (0-20% MeOH/DCM) to provide the title compound as a light yellow oil (70 mg, 6%, 95% purity).

LCMS, m/z 450 [M+1]LCMS, m/z 450 [M+1]

¹H NMR (499 MHz, DMSO-d₆) δ 8.70 (t,J= 5.6 Hz, 1H), 8.61 (t,J= 5.6 Hz, 2H), 8.44 - 8.39 (m, 3H), 4.76 (t,J= 5.6 Hz, 2H), 3.60 - 3.50 (m, 14H), 3.45 (q,J= 5.8 Hz, 2H), 3.41 - 3.33 (m, 6H)。實例12：N1-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-N3,N5-雙(2-羥基乙基)苯-1,3,5-三甲醯胺(BA-144)之製備步驟1：(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)胺基甲酸第三丁酯¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.70 (t,J = 5.6 Hz, 1H), 8.61 (t,J = 5.6 Hz, 2H), 8.44 - 8.39 (m, 3H), 4.76 (t,J = 5.6 Hz, 2H), 3.60 - 3.50 (m, 14H), 3.45 (q,J = 5.8 Hz, 2H), 3.41 - 3.33 (m, 6H).Example 12: Preparation of N1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-N3,N5-bis(2-hydroxyethyl)benzene-1,3,5-trimethylamide (BA-144)Step 1 : tert-butyl (2-((2-oxazolidinylcycloheptyl-3-yl)carbamoyl)phenyl)carbamate

向2-((第三丁氧基羰基)胺基)苯甲酸(2.01 g, 8.4 mmol)及3-胺基氮雜環庚-2-酮(1.19 g, 9.27 mmol，1.1當量)於DMF (10 mL)中之溶液中添加DIPEA (3.0 mL, 16.9 mmol，2當量)及HATU (4.8 g, 12.6 mmol，1.5當量)。將混合物在20℃下攪拌3 h。LCMS顯示期望產物。將混合物傾倒至水(260 mL)中，且將所得漿液短暫音波處理且在室溫下老化30 min。藉由過濾分離沈澱固體，用水(2× 50 mL)洗滌並風乾，得到呈灰白色固體之標題化合物(2.71g, 92%)。To a solution of 2-((tert-butoxycarbonyl)amino)benzoic acid (2.01 g, 8.4 mmol) and 3-aminoazacycloheptan-2-one (1.19 g, 9.27 mmol, 1.1 eq) in DMF (10 mL) was added DIPEA (3.0 mL, 16.9 mmol, 2 eq) and HATU (4.8 g, 12.6 mmol, 1.5 eq). The mixture was stirred at 20 °C for 3 h. LCMS showed the desired product. The mixture was poured into water (260 mL) and the resulting slurry was sonicated briefly and aged at room temperature for 30 min. The precipitated solid was isolated by filtration, washed with water (2 x 50 mL) and air-dried to give the title compound as an off-white solid (2.71 g, 92%).

LCMS：MS(+) m/z：348.3 [M+H]⁺LCMS: MS(+) m/z: 348.3 [M+H]⁺

¹H NMR (499 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.51 (d,J= 7.0 Hz, 1H), 8.18 (dd,J= 8.4, 1.2 Hz, 1H), 7.86 (dd,J= 7.4, 4.9 Hz, 1H), 7.76 (dd,J= 7.9, 1.5 Hz, 1H), 7.47 (ddd,J= 8.6, 7.3, 1.6 Hz, 1H), 7.08 (td,J= 7.6, 1.2 Hz, 1H), 4.60 (ddd,J= 11.3, 7.1, 1.7 Hz, 1H), 3.25 (ddd,J= 15.7, 11.2, 4.9 Hz, 1H), 3.10 (dt,J= 13.8, 6.3 Hz, 1H), 1.97 - 1.83 (m, 2H), 1.79 (dd,J= 14.2, 4.3 Hz, 1H), 1.71 (qt,J= 12.7, 3.5 Hz, 1H), 1.58 (qd,J= 13.1, 2.6 Hz, 1H), 1.46 (s, 9H), 1.32 - 1.18 (m, 1H)。步驟2：2-胺基-N-(2-側氧基氮雜環庚-3-基)苯甲醯胺(TFA鹽)¹ H NMR (499 MHz, DMSO-d₆ ) δ 10.52 (s, 1H), 8.51 (d,J = 7.0 Hz, 1H), 8.18 (dd,J = 8.4, 1.2 Hz, 1H), 7.86 (dd,J = 7.4, 4.9 Hz, 1H), 7.76 (dd,J = 7.9, 1.5 Hz, 1H), 7.47 (ddd,J = 8.6, 7.3, 1.6 Hz, 1H), 7.08 (td,J = 7.6, 1.2 Hz, 1H), 4.60 (ddd,J = 11.3 , 7.1, 1.7 Hz, 1H), 3.25 (ddd,J = 15.7, 11.2, 4.9 Hz, 1H), 3.10 (dt,J = 13.8, 6.3 Hz, 1H), 1.97 - 1.83 (m, 2H), 1.79 (dd,J = 14.2, 4.3 Hz, 1H), 1.71 (qt,J = 12.7, 3.5 Hz, 1H), 1.58 (qd,J = 13.1, 2.6 Hz, 1H), 1.46 (s, 9H), 1.32 - 1.18 (m, 1H).Step 2 : 2-amino-N-( 2-(2-((2-nitro-3-nitroheptan-3-yl)benzamide (TFA salt)

將TFA (6.0 mL, 78 mmol, 10 eq)添加至(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)胺基甲酸第三丁酯(2.71 g, 7.8 mmol)於DCM (20 mL)中之溶液中，且將混合物在20℃下攪拌18 h。LCMS資料顯示期望產物。將混合物濃縮至乾燥，重新溶解於DCM/EtOAc (1:1)中並重新濃縮，產生呈黏稠褐色油狀物之標題化合物(2.74g, 102%)。TFA (6.0 mL, 78 mmol, 10 eq) was added to a solution of tert-butyl (2-((2-oxazolidinylcyclohept-3-yl)carbamyl)phenyl)carbamate (2.71 g, 7.8 mmol) in DCM (20 mL), and the mixture was stirred at 20 °C for 18 h. LCMS data showed the desired product. The mixture was concentrated to dryness, redissolved in DCM/EtOAc (1:1) and re-concentrated to give the title compound (2.74 g, 102%) as a viscous brown oil.

LCMS：MS (+) m/z：248.9 [M+H]+LCMS: MS (+) m/z: 248.9 [M+H]+

¹H NMR (499 MHz, DMSO-d₆) δ 8.31 (d, J = 6.9 Hz, 1H), 7.91 (dd, J = 7.4, 4.9 Hz, 1H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.36 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 4.60 (dt, J = 10.4, 3.9 Hz, 1H), 3.23 (ddd, J = 15.7, 11.2, 4.9 Hz, 1H), 3.16 - 3.05 (m, 1H), 1.91 (tt, J = 16.0, 3.0 Hz, 2H), 1.78 (dt, J = 13.5, 4.2 Hz, 1H), 1.69 (qt, J = 15.4, 4.2 Hz, 1H), 1.62 - 1.51 (m, 1H), 1.32 - 1.18 (m, 1H)。步驟3：5-硝基-N-(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)苯并[b]噻吩-2-甲醯胺¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.31 (d, J = 6.9 Hz, 1H), 7.91 (dd, J = 7.4, 4.9 Hz, 1H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.36 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 4.60 (dt, J = 10.4, 3.9 Hz, 1H), 3.23 (ddd, J = 15.7, 11.2, 4.9 Hz, 1H), 3.16 - 3.05 (m, 1H), 1.91 (tt, J = 16.0, 3.0 Hz, 2H), 1.78 (dt, J = 13.5, 4.2 Hz, 1H), 1.69 (qt, J = 15.4, 4.2 Hz, 1H) , 1.62 - 1.51 (m, 1H), 1.32 - 1.18 (m, 1H).Step 3 : 5-nitro-N-(2-((2-oxazolidinone)-3-yl)-aminomethane (acyl)phenyl)benzo[b]thiophene-2-carboxamide

向5-硝基苯并[b]噻吩-2-甲酸(0.5 g, 2.1 mmol)及2-胺基-N-(2-側氧基氮雜環庚-3-基)苯甲醯胺(1 g, 3.2 mmol, 1.5 eq)於DMF (10 mL)中之溶液中添加DIPEA (1.6 mL, 9 mmol, 4 eq)及HATU (1.3 g, 3.4 mmol, 1.5 eq)。將反應混合物在20℃下攪拌18 h，在此期間形成灰白色沈澱物。將混合物傾倒至水(200 mL)中，且在渦旋下音波處理5-10 min。藉由過濾分離沈澱物，用水洗滌並風乾，得到呈灰色粉末之標題產物(340 mg, 33.5%)。To a solution of 5-nitrobenzo[b]thiophene-2-carboxylic acid (0.5 g, 2.1 mmol) and 2-amino-N-(2-oxazolidinyl)benzamide (1 g, 3.2 mmol, 1.5 eq) in DMF (10 mL) was added DIPEA (1.6 mL, 9 mmol, 4 eq) and HATU (1.3 g, 3.4 mmol, 1.5 eq). The reaction mixture was stirred at 20 °C for 18 h, during which time an off-white precipitate formed. The mixture was poured into water (200 mL) and sonicated under vortexing for 5-10 min. The precipitate was separated by filtration, washed with water and air-dried to give the title product as a grey powder (340 mg, 33.5%).

LCMS：MS(+) m/z：453.3 [M+H]+LCMS: MS(+) m/z: 453.3 [M+H]+

¹H NMR (499 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 7.1 Hz, 1H), 8.44 (dd, J = 8.3, 1.2 Hz, 1H), 8.41 - 8.34 (m, 2H), 8.30 (dd, J = 8.9, 2.3 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.60 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 4.69 (ddd, J = 11.3, 7.1, 1.7 Hz, 1H), 3.30 - 3.21 (m, 1H), 3.17 - 3.08 (m, 1H), 1.98 - 1.88 (m, 2H), 1.84 - 1.75 (m, 1H), 1.80 - 1.67 (m, 1H), 1.71 - 1.54 (m, 1H), 1.33 - 1.20 (m, 1H)。步驟4：5-胺基-N-(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)苯并[b]噻吩-2-甲醯胺¹ H NMR (499 MHz, DMSO-d₆ ) δ 12.41 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 7.1 Hz, 1H), 8.44 (dd, J = 8.3, 1.2 Hz, 1H), 8.41 - 8.34 (m, 2H), 8.30 (dd, J = 8.9, 2.3 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.60 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 4.69 (ddd, J = 11.3, 7.1, 1.7 Hz, 1H), 3.30 - 3.21 (m, 1H), 3.17 - 3.08 (m, 1H), 1.98 - 1.88 (m, 2H), 1.84 - 1.75 (m, 1H), 1.80 - 1.67 (m, 1H), 1.71 - 1.54 (m, 1H), 1.33 - 1.20 (m, 1H).Step 4 : 5-amino-N-(2-((2-oxo-nitrogen-cycloheptan-3-yl) (2-(4-(4-(2 ...

向5-硝基-N-(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)苯并[b]噻吩-2-甲醯胺(0.2 g, 0.44 mmol)及鋅金屬(0.057 g, 0.9 mmol, 2 eq)於甲醇(9 mL)及水(1 mL)中之懸浮液中添加氯化銨(0.059 g, 1.1 mmol, 2.5 eq)。將反應混合物在20℃下攪拌隔夜。用飽和NaHCO₃(5 mL)處理混合物，且在渦旋下音波處理，直至相對均質為止(鋅金屬仍存在於反應容器之底部)。過濾，用水洗滌並風乾，產生呈米色固體之標題化合物(178 mg, 95%)。To a suspension of 5-nitro-N-(2-((2-oxazolidinylcyclohept-3-yl)aminocarbonyl)phenyl)benzo[b]thiophene-2-carboxamide (0.2 g, 0.44 mmol) and zinc metal (0.057 g, 0.9 mmol, 2 eq) in methanol (9 mL) and water (1 mL) was added ammonium chloride (0.059 g, 1.1 mmol, 2.5 eq). The reaction mixture was stirred at 20 °C overnight. The mixture was treated with saturated NaHCO₃ (5 mL) and sonicated under vortexing until relatively homogeneous (zinc metal was still present at the bottom of the reaction vessel). Filter, wash with water and air-dry to give the title compound as a beige solid (178 mg, 95%).

LCMS：MS(+) m/z：423.4 [M+H]⁺LCMS: MS(+) m/z: 423.4 [M+H]⁺

¹H NMR (499 MHz, DMSO-d₆) δ 12.25 (s, 1H), 8.65 (d, J = 6.8 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.8 Hz, 2H), 7.78 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.25 (s, 2H), 4.94 (s, 1H), 4.80 (s, 1H), 4.71 (d, J = 7.7 Hz, 1H), 3.14 - 3.06 (m, 1H), 1.92 (s, 2H), 1.78 (s, 2H), 1.60 (d, J = 12.9 Hz, 1H), 1.34 - 1.16 (m, 1H)。步驟5：5-(1-疊氮基-3,6,9,12-四氧雜十五烷-15-醯胺基)-N-(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)苯并[b]噻吩-2-甲醯胺¹ H NMR (499 MHz, DMSO-d₆ ) δ 12.25 (s, 1H), 8.65 (d, J = 6.8 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.8 Hz, 2H), 7.78 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.25 (s, 2H), 4.94 (s, 1H), 4.80 (s, 1H), 4.71 (d, J = 7.7 Hz, 1H), 3.14 - 3.06 (m, 1H), 1.92 (s, 2H), 1.78 (s, 2H), 1.60 (d, J = 12.9 Hz, 1H), 1.34 - 1.16 (m, 1H).Step 5 : 5-(1-azido-3,6,9,12-tetraoxapentadecan-15-amido)-N-(2-((2-oxazocycloheptyl)-1-yl)-1-nitro-2-nitro-3-nitro-4-nitro-5-nitro-6-nitro-7-nitro-8-nitro-9-nitro-1-nitro-2-nitro-3-nitro-7-nitro-8-nitro-9-nitro-1-nitro-3 ... -3-yl)aminoformyl)phenyl)benzo[b]thiophene-2-carboxamide

向5-胺基-N-(2-((2-側氧基氮雜環庚-3-基)胺甲醯基)苯基)苯并[b]噻吩-2-甲醯胺(0.16 g, 0.4 mmol, 1.5 eq)於無水DMA (2 mL)中之混合物中添加DIPEA (0.13 mL, 0.77 mmol, 3 eq)及1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸2,5-二側氧基吡咯啶-1-基酯(0.1 g, 0.26 mmol)。將反應混合物在20℃下攪拌經週末，之後LCMS顯示部分轉化。添加HATU (0.5 g)，且將混合物攪拌隔夜。用DCM (60 mL)稀釋混合物，且用水(50 mL)、飽和NaHCO₃及飽和NaCl洗滌，經Na₂SO₄乾燥，濃縮，在矽膠上純化(0%-25% MeOH於EtOAc中)並在高真空下乾燥，得到呈米色固體之標題化合物(68 mg, 15%)。To a mixture of 5-amino-N-(2-((2-oxazolidin-3-yl)aminocarbonyl)phenyl)benzo[b]thiophene-2-carboxamide (0.16 g, 0.4 mmol, 1.5 eq) in anhydrous DMA (2 mL) was added DIPEA (0.13 mL, 0.77 mmol, 3 eq) and 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid 2,5-dioxopyrrolidin-1-yl ester (0.1 g, 0.26 mmol). The reaction mixture was stirred at 20 °C over the weekend after which LCMS showed partial conversion. HATU (0.5 g) was added and the mixture was stirred overnight. The mixture was diluted with DCM (60 mL) and washed with water (50 mL), saturated NaHCO₃ and saturated NaCl, dried over Na₂ SO₄ , concentrated, purified on silica gel (0%-25% MeOH in EtOAc) and dried under high vacuum to give the title compound as a beige solid (68 mg, 15%).

LCMS：MS(+) m/z：696.6 [M+H]⁺LCMS: MS(+) m/z: 696.6 [M+H]⁺

¹H NMR (499 MHz, DMSO-d₆) δ 12.37 (s, 1H), 10.16 (s, 1H), 8.66 (d,J= 7.1 Hz, 1H), 8.50 - 8.38 (m, 2H), 8.03 - 7.95 (m, 2H), 7.93 - 7.88 (m, 2H), 7.59 (ddd,J= 10.9, 7.3, 1.8 Hz, 2H), 7.26 (td,J= 7.6, 1.2 Hz, 1H), 4.76 - 4.66 (m, 1H), 3.74 (t,J= 6.2 Hz, 2H), 3.57 - 3.48 (m, 12H), 3.37 (d,J= 4.9 Hz, 1H), 3.11 (dd,J= 14.4, 7.5 Hz, 1H), 2.61 (t,J= 6.4 Hz, 2H), 1.97 - 1.88 (m, 2H), 1.83 - 1.68 (m, 1H), 1.60 (q,J= 11.9, 11.5 Hz, 1H), 1.27 (t,J= 13.1 Hz, 1H), 1.19 - 1.01 (m, 1H)實例13：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7,8-二羥基-4-側氧基色原烷-2-基)苯甲醯胺(BA-118)之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 12.37 (s, 1H), 10.16 (s, 1H), 8.66 (d,J = 7.1 Hz, 1H), 8.50 - 8.38 (m, 2H), 8.03 - 7.95 (m, 2H), 7.93 - 7.88 (m, 2H), 7.59 (ddd,J = 10.9, 7.3, 1.8 Hz, 2H), 7.26 (td,J = 7.6, 1.2 Hz, 1H), 4.76 - 4.66 (m, 1H), 3.74 (t,J = 6.2 Hz, 2H), 3.57 - 3.48 (m, 12H), 3.37 (d,J = 4.9 Hz, 1H), 3.11 (dd,J = 14.4, 7.5 Hz, 1H), 2.61 (t,J = 6.4 Hz, 2H), 1.97 - 1.88 (m, 2H), 1.83 - 1.68 (m, 1H), 1.60 (q,J = 11.9, 11.5 Hz, 1H), 1.27 (t,J = 13.1 Hz, 1H), 1.19 - 1.01 (m, 1H)Example 13: N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7,8-dihydroxy-4-oxochromane Preparation of 2-amino-2-yl)benzamide (BA-118)

將4-(7,8-二羥基-4-側氧基色原烷-2-基)苯甲酸2,5-二側氧基吡咯啶-1-基酯(144 mg, 0.365 mmol, 1 eq)及17-疊氮基-3,6,9,12,15-五氧雜十七烷-1-胺(223 mg, 0.73 mmol, 2 eq.)於DMF (2 mL)中之溶液在60℃下攪拌20 min。接著將混合物濃縮，且藉由急速層析使用乙酸乙酯/MeOH 0-5%作為溶析液純化粗製材料，得到呈褐色固體之標題化合物(160 mg, 75%)。A solution of 2,5-dioxopyrrolidin-1-yl 4-(7,8-dihydroxy-4-oxochroman-2-yl)benzoate (144 mg, 0.365 mmol, 1 eq) and 17-azido-3,6,9,12,15-pentaoxaheptadecan-1-amine (223 mg, 0.73 mmol, 2 eq.) in DMF (2 mL) was stirred at 60 °C for 20 min. The mixture was then concentrated and the crude material was purified by flash chromatography using ethyl acetate/MeOH 0-5% as eluent to give the title compound (160 mg, 75%) as a brown solid.

LCMS m/z 587 (M+1)LCMS m/z 587 (M+1)

¹H NMR (499 MHz, DMSO-d₆) δ 8.71 (t,J= 5.6 Hz, 1H), 8.25 (d,J= 8.6 Hz, 2H), 8.02 (d,J= 8.6 Hz, 2H),, 7.41 (d,J= 8.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d,J= 8.6 Hz, 1H),  3.60 - 3.48 (m, 20H), 3.45 (q, J = 5.8 Hz, 2H), 3.40 - 3.34 (m, 2H)實例14：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7-羥基-8-甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-196)、N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(8-羥基-7-甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-197)及N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7,8-二甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-198)之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.71 (t,J = 5.6 Hz, 1H), 8.25 (d,J = 8.6 Hz, 2H), 8.02 (d,J = 8.6 Hz, 2H),, 7.41 (d,J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d,J = 8.6 Hz, 1H), 3.60 - 3.48 (m, 20H), 3.45 (q, J = 5.8 Hz, 2H), 3.40 - 3.34 (m, 2H)Example 14: N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7-hydroxy-8-methoxy-4-oxo 2-Chromane-2-yl)benzamide (BA-196), N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(8 -hydroxy-7-methoxy-4-chlorochromen-2-yl)benzamide (BA-197) and N-(17-azido-3,6,9,12,15- Preparation of 4-(7,8-dimethoxy-4-hydroxychroman-2-yl)benzamide (BA-198)

向N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7,8-二羥基-4-側氧基色原烷-2-基)苯甲醯胺(400 mg, 0.683 mmol, 1 eq)及K₂CO₃(188 mg, 1.365 mmol, 2 eq)於DMF (10 mL)中之攪拌懸浮液中添加碘甲烷(0.043 mL, 0.683 mmol, 1 eq)，且將混合物在室溫下攪拌隔夜。LCMS顯示起始材料之混合物，為單甲基化及二甲基化的。將混合物濃縮，且藉由反相管柱層析使用含0.1%甲酸之0-60%水/MeCN作為溶析液進行純化，得到呈黃色黏性固體之三種產物：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7-羥基-8-甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-196)To a stirred suspension of N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7,8-dihydroxy-4-oxochroman-2-yl)benzamide (400 mg, 0.683 mmol, 1 eq) and K₂ CO₃ (188 mg, 1.365 mmol, 2 eq) in DMF (10 mL) was added iodomethane (0.043 mL, 0.683 mmol, 1 eq) and the mixture was stirred at room temperature overnight. LCMS showed a mixture of starting material, mono- and di-methylated. The mixture was concentrated and purified by reverse phase column chromatography using 0-60% water/MeCN containing 0.1% formic acid as the eluent to give three products as yellow viscous solids:N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7-hydroxy-8-methoxy-4-oxochroman-2-yl)benzamide (BA-196)

(50 mg，12%產率)，根據NMR，純度為85% (含有15%區域異構物)(50 mg, 12% yield), 85% pure by NMR (contains 15% regioisomer)

LCMS：m/z = 601 [M+1]LCMS: m/z = 601 [M+1]

¹H NMR (500 MHz, DMSO-d₆)  δ 10.66 (s, 1H), 8.71 (t, J = 5.5 Hz, 1H), 8.16 (d, J = 8.38 Hz, 2H), 8.04 (d, J = 8.38 Hz, 2H) 7.65 (d, J = 8.84 Hz, 1H), 7.03 (s, 1H), 7.02 (d, J = 8.84 Hz, 1H), 3.96 (s, 1H), 3.60 - 3.42 (m, 20H), 3.47 - 3.42 (m, 2H), 3.40 - 3.34 (m, 2H)。N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(8-羥基-7-甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-197)¹ H NMR (500 MHz, DMSO-d₆ ) δ 10.66 (s, 1H), 8.71 (t, J = 5.5 Hz, 1H), 8.16 (d, J = 8.38 Hz, 2H), 8.04 (d, J = 8.38 Hz, 2H) 7.65 (d, J = 8.84 Hz, 1H), 7.03 (s, 1H), 7.02 (d, J = 8.84 Hz, 1H), 3.96 (s, 1H), 3.60 - 3.42 (m, 20H), 3.47 - 3.42 (m, 2H), 3.40 - 3.34 (m, 2H).N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(8-hydroxy-7-methoxy-4-oxochromane-2 -yl)benzamide (BA-197)

(15 mg，4%產率)，根據NMR為65%純(含有35%區域異構物及二甲基化產物)(15 mg, 4% yield), 65% pure by NMR (contains 35% regioisomers and dimethylated product)

LCMS：m/z = 601 [M+1]LCMS: m/z = 601 [M+1]

¹H NMR (500 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.71 (q, J = 5.8 Hz, 1H), 8.23 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 3.95 (s, 3H), 3.62 - 3.42 (m, 24H), 3.39 - 3.35 (m, 2H)。N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7,8-二甲氧基-4-側氧基色原烷-2-基)苯甲醯胺(BA-198)¹ H NMR (500 MHz, DMSO-d₆ ) δ 9.75 (s, 1H), 8.71 (q, J = 5.8 Hz, 1H), 8.23 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 3.95 (s, 3H), 3.62 - 3.42 (m, 24H), 3.39 - 3.35 (m, 2H).N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7,8-dimethoxy-4-oxochromane-2- Benzyl) Benzamide (BA-198)

(100 mg，24%產率) 100%純(100 mg, 24% yield) 100% pure

LCMS：m/z = 615 [M+1]LCMS: m/z = 615 [M+1]

¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.60 - 3.42 (m, 22H), 3.40 - 3.34 (m, 2H)。實例15：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-4-(7,8-二羥基-4-側氧基色原烷-2-基)苯甲醯胺(BA-167)之製備¹ H NMR (500 MHz, DMSO-d₆ ) δ 8.71 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.60 - 3.42 (m, 22H), 3.40 - 3.34 (m, 2H).Example 15: N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-4-(7,8-dihydroxy-4-oxo Preparation of 2-chlorobenzoic acid benzylamine (BA-167)

將4-(7,8-二羥基-4-側氧基色原烷-2-基)苯甲酸2,5-二側氧基吡咯啶-1-基酯(665 mg, 1.684 mmol, 1 eq)及2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙-1-胺(440 mg, 2 mmol, 1.2 eq)及DIPEA (0.5 ml, 3.7 mmol, 2.2 eq)於THF (20 mL)中之懸浮液在60℃下攪拌3 h。將混合物濃縮，且將所得固體與甲醇一起研磨並過濾，得到呈米色固體之標題化合物(595 mg, 71%)，根據HPLC，純度＞95%。A suspension of 2,5-dioxopyrrolidin-1-yl 4-(7,8-dihydroxy-4-oxochroman-2-yl)benzoate (665 mg, 1.684 mmol, 1 eq) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine (440 mg, 2 mmol, 1.2 eq) and DIPEA (0.5 ml, 3.7 mmol, 2.2 eq) in THF (20 mL) was stirred at 60° C. for 3 h. The mixture was concentrated and the resulting solid was triturated with methanol and filtered to give the title compound (595 mg, 71%) as a beige solid with a purity of >95% by HPLC.

LCMS m/z 521 (M+Na)LCMS m/z 521 (M+Na)

¹H NMR (499 MHz, DMSO-d₆) δ 8.71 (t,J= 5.6 Hz, 1H), 8.25 (d, 8.6 Hz, 2H), 8.02 (d, 8.6 Hz, 2H), 7.41 (d,J= 8.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d,J= 8.7 Hz, 1H), 3.61 - 3.51 (m, 12H), 3.45 (q,J= 5.8 Hz, 2H), 3.39 - 3.35 (m, 2H)實例16：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(6-側氧基-6H-[1,3]二氧雜環戊烯并[4,5-h]色烯-8-基)苯甲醯胺(BA-216)之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.71 (t,J = 5.6 Hz, 1H), 8.25 (d, 8.6 Hz, 2H), 8.02 (d, 8.6 Hz, 2H), 7.41 (d,J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d,J = 8.7 Hz, 1H), 3.61 - 3.51 (m, 12H), 3.45 (q,J = 5.8 Hz, 2H), 3.39 - 3.35 (m, 2H)Example 16: N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(6-oxo-6H-[1,3]di Preparation of oxadiazine (4,5-h)chromen-8-yl)benzamide (BA-216)

在室溫下向N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(7,8-二羥基-4-側氧基-4H-色烯-2-基)苯甲醯胺(0.2 g, 0.341 mmol)於DMF (5 mL)中之溶液中添加K₂CO₃(94 mg, 0.682 mmol)，之後添加二碘甲烷(50 mL, 0.511 mmol)，且接著加熱至90℃持續12 h。接著使混合物冷卻，用DCM及水萃取，經Na₂SO₄乾燥，過濾，濃縮且藉由急速層析(管柱：Biotage sfar二氧化矽HCD Duo 5，20微米，25 g)，用0至15% DCM:MeOH (15 CV)溶析進行純化，得到呈淺棕色固體之標題化合物(128 mg, 64%)。To a solution of N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(7,8-dihydroxy-4-oxo-4H-chromen-2-yl)benzamide (0.2 g, 0.341 mmol) in DMF (5 mL) was added K₂ CO₃ (94 mg, 0.682 mmol) followed by diiodomethane (50 mL, 0.511 mmol) at room temperature and then heated to 90 °C for 12 h. The mixture was then cooled, extracted with DCM and water, dried over_Na2SO4 , filtered, concentrated and purified by flash chromatography (column: Biotage sfar silica HCD Duo₅ , 20 micron, 25 g) eluting with 0 to 15% DCM:MeOH (15 CV) to give the title compound as a light brown solid (128 mg, 64%).

MS(ESI) m/z= 621.1 [M+Na]⁺MS (ESI) m/z = 621.1 [M+Na]⁺

¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (t, J = 5.5 Hz, 1H), 8.10 (d, J = 10.0 Hz, 2H), 8.02 (d, J = 10.0Hz, 2H), 7.61 (d, J = 5.0 Hz,1H), 7.16 (d, J = 10 Hz, 1H), 7.05 (s, 1H), 3.59 - 3.36 (m, 24H), 3.33(s, 2H)實例17：(Z)-1-(3-((3-((1H-吡咯-2-基)亞甲基)-2-側氧基吲哚啉-6-基)胺基)-4-甲基苯基)-3-(3-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-氟-5-(三氟甲基)苯基)脲(BA-173)之製備步驟1：3-(苯甲基氧基)-2-氟-5-(三氟甲基)苯甲酸甲酯¹ H NMR (500 MHz, DMSO-d₆ ) δ 8.72 (t, J = 5.5 Hz, 1H), 8.10 (d, J = 10.0 Hz, 2H), 8.02 (d, J = 10.0Hz, 2H), 7.61 (d, J = 5.0 Hz,1H), 7.16 (d, J = 10 Hz, 1H), 7.05 (s, 1H), 3.59 - 3.36 (m, 24H), 3.33(s, 2H)Example 17: (Z)-1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolyl-6-yl)amino) -4-methylphenyl)-3-(3-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-fluoro-Preparation of5-(trifluoromethyl)phenyl)urea(BA-173)Step 1 : 3-(Benzyloxy)-2-fluoro-5-(trifluoromethyl)benzoic acid methyl ester

在氮氣氣氛下在室溫下向3-(苯甲基氧基)-2-氟-5-(三氟甲基)苯甲酸(4.9 g, 15.593 mmol, 1 eq)於甲醇(49.00 mL, 1210.243 mmol, 77.61 eq)中之溶液中添加兩滴H₂SO₄(305.85 mg, 3.119 mmol, 0.2 eq)。將所得混合物在氮氣氣氛下在室溫下攪拌隔夜。藉由添加NaHCO₃(飽和)淬滅反應物，且用乙酸乙酯(3 × 20 mL)萃取所得混合物。將合併的有機萃取物用鹽水(3 × 20 mL)洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，得到粗製標題化合物(5 g，粗製物)，其不經進一步純化即直接用於下一步驟中。To a solution of 3-(benzyloxy)-2-fluoro-5-(trifluoromethyl)benzoic acid (4.9 g, 15.593 mmol, 1 eq) in methanol (49.00 mL, 1210.243 mmol, 77.61 eq) was added two drops_ofH2SO4 (305.85 mg, 3.119 mmol, 0.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched by the addition of_NaHCO3 (saturated) and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried_over anhydrous_Na2SO4 , filtered and concentrated to give the crude title compound (5 g, crude), which was used directly in the next step without further purification.

LCMS-(M+H)⁺：329LCMS-(M+H)⁺ : 329

¹H NMR (400 MHz，氯仿-d) δ 7.79 (dd,J= 5.5, 2.3, 0.9 Hz, 1H), 7.48 - 7.32 (m, 6H), 5.19 (s, 2H), 3.96 (s, 3H)。步驟2：2-氟-3-羥基-5-(三氟甲基)苯甲酸甲酯¹ H NMR (400 MHz, chloroform-d ) δ 7.79 (dd,J = 5.5, 2.3, 0.9 Hz, 1H), 7.48 - 7.32 (m, 6H), 5.19 (s, 2H), 3.96 (s, 3H).Step 2 : Methyl 2-fluoro-3-hydroxy-5-(trifluoromethyl)benzoate

將3-(苯甲基氧基)-2-氟-5-(三氟甲基)苯甲酸甲酯(5 g, 15.232 mmol, 1 eq)及Pd/C (1.51 g, 14.189 mmol, 0.93 eq)於甲醇(150 mL)中之混合物在氫氣氣氛下在室溫下攪拌3小時。接著過濾混合物，且用甲醇(3×30 mL)洗滌濾餅。將濾液濃縮，得到呈白色固體之標題化合物(3.7 g，粗製物)。A mixture of methyl 3-(benzyloxy)-2-fluoro-5-(trifluoromethyl)benzoate (5 g, 15.232 mmol, 1 eq) and Pd/C (1.51 g, 14.189 mmol, 0.93 eq) in methanol (150 mL) was stirred under hydrogen atmosphere at room temperature for 3 hours. The mixture was then filtered and the filter cake was washed with methanol (3×30 mL). The filtrate was concentrated to give the title compound (3.7 g, crude) as a white solid.

LCMS：(M+H)⁺239步驟3：2-氟-3-((2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基)-5-(三氟甲基)苯甲酸甲酯LCMS: (M+H)⁺ 239Step 3 : Methyl 2-fluoro-3-((2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl)oxy)-5-(trifluoromethyl)benzoate

將2-氟-3-羥基-5-(三氟甲基)苯甲酸甲酯(3.7 g, 15.537 mmol, 1 eq)、K₂CO₃(3.22g, 23.306 mmol, 1.5 eq)及TBSO-PEG₃-OTs (7.18 g, 15.537 mmol, 1.0 eq)於乙腈(111 mL)中之混合物在氮氣氣氛下在70℃下攪拌隔夜。用水淬滅反應物，且用乙酸乙酯(3 × 50 mL)萃取所得混合物。將合併的有機萃取物用鹽水(3 × 50 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用EA/PE (30%)溶析進行純化，得到呈黃色油狀物之標題化合物(6 g, 58.4%)。A mixture of methyl 2-fluoro-3-hydroxy-5-(trifluoromethyl)benzoate (3.7 g, 15.537 mmol, 1 eq), K₂ CO₃ (3.22 g, 23.306 mmol, 1.5 eq) and TBSO-PEG₃ -OTs (7.18 g, 15.537 mmol, 1.0 eq) in acetonitrile (111 mL) was stirred at 70 °C overnight under nitrogen atmosphere. The reaction was quenched with water and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried_over anhydrous_Na2SO4 , filtered, concentrated and purified by silica gel column chromatography eluting with EA/PE (30%) to give the title compound (6 g, 58.4%) as a yellow oil.

LCMS：(M+H)⁺529LCMS: (M+H)⁺ 529

¹H NMR (400 MHz，氯仿-d) δ 7.83 - 7.77 (m, 1H), 7.43 (dd,J= 7.0, 2.3 Hz, 1H), 4.32 - 4.25 (m, 2H), 3.98 (s, 3H), 3.93 (dd,J= 5.5, 3.8 Hz, 2H), 3.82 - 3.68 (m, 4H), 3.72 - 3.65 (m, 6H), 3.57 (t,J= 5.5 Hz, 2H), 0.91 (s, 9H), 0.08 (s, 6H)步驟4：2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯甲酸¹ H NMR (400 MHz, chloroform-d ) δ 7.83 - 7.77 (m, 1H), 7.43 (dd,J = 7.0, 2.3 Hz, 1H), 4.32 - 4.25 (m, 2H), 3.98 (s, 3H), 3.93 (dd,J = 5.5, 3.8 Hz, 2H), 3.82 - 3.68 (m, 4H), 3.72 - 3.65 (m, 6H), 3.57 (t,J = 5.5 Hz, 2H), 0.91 (s, 9H), 0.08 (s, 6H)Step 4 ：2-Fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxo-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)benzoic acid

在氮氣氣氛下向2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯甲酸甲酯(5.59 g, 10.575 mmol, 1 eq)於THF (55 mL)中之溶液中逐滴添加氫氧化鋰水溶液(26.44 mL, 52.875 mmol, 5 eq)。將所得混合物在氮氣氣氛下攪拌2小時，且接著在室溫下逐滴添加乙酸(3.81 g, 63.450 mmol, 6 eq)。用乙酸乙酯(3 × 100 mL)萃取所得混合物。將合併的有機萃取物用鹽水(2 × 50 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用EA/PE (75%)溶析進行純化，得到呈黃色油狀物之標題化合物(4.0 g, 73.5%)。To a solution of methyl 2-fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxolane-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)benzoate (5.59 g, 10.575 mmol, 1 eq) in THF (55 mL) was added aqueous lithium hydroxide solution (26.44 mL, 52.875 mmol, 5 eq) dropwise under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere for 2 hours, and then acetic acid (3.81 g, 63.450 mmol, 6 eq) was added dropwise at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried_over anhydrous_Na2SO4 , filtered, concentrated and purified by silica gel column chromatography eluting with EA/PE (75%) to give the title compound (4.0 g, 73.5%) as a yellow oil.

LCMS：(M+H)⁺515步驟5：15-[2-氟-3-異氰酸基-5-(三氟甲基)苯氧基]-2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷LCMS: (M+H)⁺ 515Step 5 : 15-[2-Fluoro-3-isocyanato-5-(trifluoromethyl)phenoxy]-2,2,3,3-tetramethyl-4,7,10,13-tetraoxo-3-silapentadecane

將2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯甲酸(1.5 g, 2.915 mmol, 1 eq)、TEA (324.47 mg, 3.207 mmol, 1.1 eq)及DPPA (882.43 mg, 3.207 mmol, 1.1 eq)於甲苯(30 mL)中之溶液/混合物在氮氣氣氛下在室溫下攪拌隔夜。藉由添加水(5 mL)淬滅反應物，且用乙酸乙酯(3 × 50 mL)萃取。將合併的有機萃取物用鹽水(3 × 50 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用EA/PE (約30%)溶析進行純化，得到呈黃色油狀物之標題化合物(740 mg)。A solution/mixture of 2-fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)benzoic acid (1.5 g, 2.915 mmol, 1 eq), TEA (324.47 mg, 3.207 mmol, 1.1 eq) and DPPA (882.43 mg, 3.207 mmol, 1.1 eq) in toluene (30 mL) was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried_over anhydrous_Na2SO4 , filtered, concentrated and purified by silica gel column chromatography eluting with EA/PE (ca. 30%) to give the title compound as a yellow oil (740 mg).

LCMS：(M+H)⁺512步驟6：2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯胺LCMS: (M+H)⁺ 512Step 6 : 2-Fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxo-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)aniline

將15-[2-氟-3-異氰酸基-5-(三氟甲基)苯氧基]-2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷(750 mg, 1.466 mmol, 1 eq)於甲苯(20.45 mL, 192.237 mmol, 131.13 eq)中在氮氣氣氛下在80℃下加熱2小時，且接著濃縮，得到呈黃色油狀物之標題化合物(720 mg，粗製物)。15-[2-Fluoro-3-isocyanato-5-(trifluoromethyl)phenoxy]-2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecane (750 mg, 1.466 mmol, 1 eq) in toluene (20.45 mL, 192.237 mmol, 131.13 eq) was heated at 80 °C for 2 hours under nitrogen atmosphere and then concentrated to give the title compound as a yellow oil (720 mg, crude).

LCMS：(M+H)⁺486步驟7：2-(4-溴-2-硝基苯基)丙二酸1,3-二甲酯LCMS: (M+H)⁺ 486Step 7 : 2-(4-bromo-2-nitrophenyl)malonic acid 1,3-dimethyl ester

在氮氣氣氛下在室溫下向於DMSO-d₆(40 mL)中之4-溴-1-氟-2-硝基苯(4 g, 18.182 mmol, 1 eq)及丙二酸1,3-二甲酯(3.60 g, 27.249 mmol, 1.50 eq)中分多次添加NaH (872.67 mg, 21.818 mmol, 1.2 eq, 60%)。將所得混合物在氮氣氣氛下在60℃下加熱2 h，且接著在0℃下用飽和NH₄Cl (水溶液)/冰淬滅，並用乙酸乙酯(3 × 100 mL)萃取。將合併的有機萃取物用水(4×40 mL)及鹽水(2×40 mL)洗滌，經無水MgSO₄乾燥，過濾並濃縮，得到標題化合物(5.68 g，粗製物)。To 4-bromo-1-fluoro-2-nitrobenzene (4 g, 18.182 mmol, 1 eq) and 1,3-dimethyl malonate (3.60 g, 27.249 mmol, 1.50 eq) in DMSO-_d6 (40 mL) was added NaH (872.67 mg, 21.818 mmol, 1.2 eq, 60%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was heated at 60 °C for 2 h under nitrogen atmosphere, and then quenched with saturated_NH4Cl (aq)/ice at 0 °C and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water (4 x 40 mL) and brine (2 x 40 mL), dried over anhydrous MgSO₄ , filtered and concentrated to give the title compound (5.68 g, crude).

LCMS：(M+H)⁺332步驟8：(4-溴-2-硝基苯基)乙酸LCMS: (M+H)⁺ 332Step 8 : (4-bromo-2-nitrophenyl)acetic acid

將2-(4-溴-2-硝基苯基)丙二酸1,3-二甲酯(5.68 g, 17.103 mmol)於AcOH (57 mL)及HCl (57 mL)中之溶液在氬氣氣氛下在110℃下加熱隔夜。使混合物冷卻至室溫，且接著濃縮。藉由添加CH₂Cl₂產生沈澱分離產物，得到呈灰色固體之標題化合物(2.9 g, 60.5%)。A solution of 1,3-dimethyl 2-(4-bromo-2-nitrophenyl)malonate (5.68 g, 17.103 mmol) in AcOH (57 mL) and HCl (57 mL₎ was heated at 110 °C overnight under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and then concentrated. The product precipitated by addition of_CH2Cl2 to give the title compound as a grey solid (2.9 g, 60.5%).

LCMS：(M+H)⁺260步驟9：2-(4-溴-2-硝基苯基)乙酸乙酯LCMS: (M+H)⁺ 260Step 9 : Ethyl 2-(4-bromo-2-nitrophenyl)acetate

將(4-溴-2-硝基苯基)乙酸(2.9 g, 10.729 mmol, 1 eq)及H₂SO₄(0.42 mL, 7.939 mmol, 0.74 eq)於乙醇中之溶液/混合物在氬氣氣氛下在85℃下攪拌2 h。在0℃下用NaHCO₃淬滅反應物，且用乙酸乙酯萃取。將合併的有機萃取物用鹽水洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，得到呈褐色油狀物之標題化合物(2.9 g, 87.3%)。A solution/mixture of (4-bromo-2-nitrophenyl)acetic acid (2.9 g, 10.729 mmol, 1 eq) and H₂ SO₄ (0.42 mL, 7.939 mmol, 0.74 eq) in ethanol was stirred at 85 °C for 2 h under an atmosphere of argon. The reaction was quenched with NaHCO₃ at 0 °C and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na₂ SO₄ , filtered and concentrated to give the title compound (2.9 g, 87.3%) as a brown oil.

LCMS：(M+H)⁺288步驟10：2-{4-[(2-甲基-5-硝基苯基)胺基]-2-硝基苯基}乙酸乙酯LCMS: (M+H)⁺ 288Step 10 : Ethyl 2-{4-[(2-methyl-5-nitrophenyl)amino]-2-nitrophenyl}acetate

在氮氣氣氛下向2-(4-溴-2-硝基苯基)乙酸乙酯(2.9 g, 10.066 mmol, 1 eq)及2-胺基-4-硝基甲苯(2.30 g, 15.099 mmol, 1.5 eq)於甲苯中之溶液中添加Pd(OAc)₂(0.23 g, 1.007 mmol, 0.1 eq)及xantphos (1.16 g, 2.013 mmol, 0.2 eq)，之後在室溫下分多次添加Cs₂CO₃(8.20 g, 25.165 mmol, 2.5 eq)。將所得混合物在氮氣氣氛下在80℃下加熱3 h，且接著冷卻至室溫並用乙酸乙酯(3 × 50 mL)萃取。將合併的有機萃取物用鹽水(3 × 50 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用EA/PE溶析進行純化，得到 呈黃色油狀物之標題化合物(2.4 g, 66.35%)。To a solution of ethyl 2-(4-bromo-2-nitrophenyl)acetate (2.9 g, 10.066 mmol, 1 eq) and 2-amino-4-nitrotoluene (2.30 g, 15.099 mmol, 1.5 eq) in toluene was added Pd(OAc)₂ (0.23 g, 1.007 mmol, 0.1 eq) and xantphos (1.16 g, 2.013 mmol, 0.2 eq) under nitrogen atmosphere, followed by addition of Cs₂ CO₃ (8.20 g, 25.165 mmol, 2.5 eq) in portions at room temperature. The resulting mixture was heated at 80 °C for 3 h under nitrogen atmosphere, and then cooled to room temperature and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried over anhydrous_Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluting with EA/PE to give the title compound as a yellow oil (2.4 g, 66.35%).

LCMS：(M+H)⁺360步驟11：6-[(5-胺基-2-甲基苯基)胺基]-1,3-二氫吲哚-2-酮LCMS: (M+H)⁺ 360Step 11 : 6-[(5-amino-2-methylphenyl)amino]-1,3-dihydroindol-2-one

將2-{4-[(2-甲基-5-硝基苯基)胺基]-2-硝基苯基}乙酸乙酯(2.4 g, 5.566 mmol, 1 eq)及Pd/C (598.23 mg, 5.622 mmol, 1.01 eq)於乙酸(40 mL)及THF (20 mL)中之溶液/混合物在氫氣氣氛下在室溫下攪拌隔夜。過濾所得混合物，且用THF (3×30 mL)洗滌濾餅。將濾液濃縮，且藉由反相急速層析進行純化：管柱，C18矽膠；移動相，含ACN之水，在30 min內10%至95%梯度；偵測器，UV 254 nm，得到呈黃色油狀物之標題化合物(1 g, 70.9%)。A solution/mixture of ethyl 2-{4-[(2-methyl-5-nitrophenyl)amino]-2-nitrophenyl}acetate (2.4 g, 5.566 mmol, 1 eq) and Pd/C (598.23 mg, 5.622 mmol, 1.01 eq) in acetic acid (40 mL) and THF (20 mL) was stirred under hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with THF (3×30 mL). The filtrate was concentrated and purified by reverse phase flash chromatography: column, C18 silica gel; mobile phase, ACN in water, gradient 10% to 95% in 30 min; detector, UV 254 nm to give the title compound as a yellow oil (1 g, 70.9%).

LCMS：(M+H)⁺254LCMS: (M+H)⁺ 254

¹H NMR (400 MHz，氯仿-d) δ 7.69 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 6.2, 2.2 Hz, 2H), 6.50 (d, J = 2.1 Hz, 1H), 6.33 (dd, J = 8.0, 2.4 Hz, 1H), 5.33 (s, 1H), 3.47 (s, 2H), 2.13 (s, 3H), 2.01 (d, J = 1.8 Hz, 2H)步驟12：1-{2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯基}-3-{4-甲基-3-[(2-側氧基-1,3-二氫吲哚-6-基)胺基]苯基}脲¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 6.2, 2.2 Hz, 2H), 6.50 (d, J = 2.1 Hz, 1H), 6.33 (dd, J = 8.0, 2.4 Hz, 1H), 5.33 (s, 1H), 3.47 (s, 2H), 2.13 (s, 3H), 2.01 (d, J = 1.8 Hz, 2H)Step 12 ：1-{2-fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxo-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)phenyl}-3-{4-methyl-3-[(2-oxo-1,3-dihydroindol-6-yl)amino]phenyl}urea

在氮氣氣氛下在0℃下向2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯胺(720 mg, 1.483 mmol, 1.00 eq)及三光氣(175.99 mg, 0.593 mmol, 0.4 eq)於THF (4 mL, 49.371 mmol, 239.74 eq)中之溶液中添加DIEA (574.91 mg, 4.449 mmol, 3 eq)，且接著在0℃下攪拌15 min。在0℃下逐滴/分多次添加6-[(5-胺基-2-甲基苯基)胺基]-1,3-二氫吲哚-2-酮(751.16 mg, 2.966 mmol，2.00 eq於THF中)，且將混合物在氮氣氣氛下在0℃下攪拌30 min。在0℃下用NaHCO₃淬滅反應物，且用乙酸乙酯(3 × 50 mL)萃取。將合併的有機萃取物用鹽水(3 × 50 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由矽膠管柱層析，用EA/PE (70%)溶析進行純化，得到呈黃色油狀物之標題化合物(700 mg, 61.7%)。To a solution of 2-fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)aniline (720 mg, 1.483 mmol, 1.00 eq) and triphosgene (175.99 mg, 0.593 mmol, 0.4 eq) in THF (4 mL, 49.371 mmol, 239.74 eq) was added DIEA (574.91 mg, 4.449 mmol, 3 eq) at 0°C under nitrogen atmosphere and then stirred at 0°C for 15 min. 6-[(5-amino-2-methylphenyl)amino]-1,3-dihydroindol-2-one (751.16 mg, 2.966 mmol, 2.00 eq in THF) was added dropwise/multiple times at 0°C, and the mixture was stirred at 0°C for 30 min under nitrogen atmosphere. The reaction was quenched with NaHCO₃ at 0°C and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by silica gel column chromatography eluting with EA/PE (70%) to give the title compound (700 mg, 61.7%) as a yellow oil.

LCMS：(M+H)⁺765步驟13：1-[2-氟-3-(2-{2-[2-(2-羥基乙氧基)乙氧基]乙氧基}乙氧基)-5-(三氟甲基)苯基]-3-(4-甲基-3-{[(3Z)-2-側氧基-3-(1H-吡咯-2-基亞甲基)-1H-吲哚-6-l]胺基}苯基)脲LCMS: (M+H)⁺ 765Step 13 : 1-[2-Fluoro-3-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)-5-(trifluoromethyl)phenyl]-3-(4-methyl-3-{[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-1]amino}phenyl)urea

將1-{2-氟-3-[(2,2,3,3-四甲基-4,7,10,13-四氧雜-3-矽雜十五烷-15-基)氧基]-5-(三氟甲基)苯基}-3-{4-甲基-3-[(2-側氧基-1,3-二氫吲哚-6-基)胺基]苯基}脲(700 mg, 0.915 mmol, 1 eq)、吡咯-2-甲醛(104.44 mg, 1.098 mmol, 1.2 eq)及六氫吡啶(155.85 mg, 1.830 mmol, 2.0 eq)於乙醇(7 mL)中之溶液在氮氣氣氛下在80℃下加熱2小時。將所得混合物在減壓下濃縮，且用THF (7 mL)稀釋。添加TBAF (358.92 mg, 1.373 mmol, 1.5 eq)，且將所得混合物在氮氣氣氛下在室溫下攪拌2小時。接著用乙酸乙酯(3 × 20 mL)萃取混合物，且將合併的有機萃取物用鹽水(3 × 20 mL)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由反相急速層析進行純化：管柱，C18矽膠；移動相，含ACN之水，在30 min內10%至95%梯度；偵測器，UV 254 nm，得到呈紅色固體之標題化合物(545.4 mg, 80.3%)。A solution of 1-{2-fluoro-3-[(2,2,3,3-tetramethyl-4,7,10,13-tetraoxo-3-silapentadecan-15-yl)oxy]-5-(trifluoromethyl)phenyl}-3-{4-methyl-3-[(2-oxo-1,3-dihydroindol-6-yl)amino]phenyl}urea (700 mg, 0.915 mmol, 1 eq), pyrrole-2-carbaldehyde (104.44 mg, 1.098 mmol, 1.2 eq) and hexahydropyridine (155.85 mg, 1.830 mmol, 2.0 eq) in ethanol (7 mL) was heated at 80° C. for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and diluted with THF (7 mL). TBAF (358.92 mg, 1.373 mmol, 1.5 eq) was added and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was then extracted with ethyl acetate (3 × 20 mL) and the combined organic extracts were washed with brine (3 × 20 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by reverse phase flash chromatography: column, C18 silica gel; mobile phase, ACN in water, 10% to 95% gradient in 30 min; detector, UV 254 nm to give the title compound (545.4 mg, 80.3%) as a red solid.

LCMS：(M+H)⁺728LCMS: (M+H)⁺ 728

¹H NMR (300 MHz, DMSO-d₆) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (s, 1H), 8.72 (d,J= 3.0 Hz, 1H), 8.19 (dd,J= 6.3, 1.9 Hz, 1H), 7.60 (s, 1H), 7.48 - 7.39 (m, 2H), 7.35 (d,J= 2.1 Hz, 1H), 7.25 (s, 1H), 7.14 (dd,J= 8.2, 5.6 Hz, 2H), 7.04 (dd,J= 8.1, 2.1 Hz, 1H), 6.73 - 6.66 (m, 1H), 6.57 (dd,J= 8.4, 2.0 Hz, 1H), 6.47 (d,J= 2.0 Hz, 1H), 6.30 (q,J= 2.7 Hz, 1H), 4.56 (t,J= 5.4 Hz, 1H), 4.28 (t,J= 4.4 Hz, 2H), 3.77 (dd,J= 5.5, 3.4 Hz, 2H), 3.60 (dd,J= 5.8, 3.1 Hz, 2H), 3.57 - 3.50 (m, 2H), 3.55 - 3.43 (m, 2H), 3.43 - 3.35 (m, 2H), 3.33 (s, 4H), 2.15 (s, 3H)步驟14：(Z)-甲磺酸2-(2-(2-(2-(3-(3-(3-((3-((1H-吡咯-2-基)亞甲基)-2-側氧基吲哚啉-6-基)胺基)-4-甲基苯基)脲基)-2-氟-5-(三氟甲基)苯氧基)乙氧基)乙氧基)乙氧基)乙酯¹ H NMR (300 MHz, DMSO-d₆ ) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (s, 1H), 8.72 (d,J = 3.0 Hz, 1H), 8.19 (dd,J = 6.3, 1.9 Hz, 1H), 7.60 (s, 1H), 7.48 - 7.39 (m, 2H), 7.35 (d,J = 2.1 Hz, 1H), 7.25 (s, 1H), 7.14 (dd,J = 8.2, 5.6 Hz, 2H), 7.04 ( dd,J = 8.1, 2.1 Hz, 1H), 6.73 - 6.66 (m, 1H), 6.57 (dd,J = 8.4, 2.0 Hz, 1H), 6.47 (d,J = 2.0 Hz, 1H), 6.30 (q,J = 2.7 Hz, 1H), 4.56 (t,J = 5.4 Hz, 1H), 4.28 (t,J = 4.4 Hz, 2H), 3.77 (dd,J = 5.5, 3.4 Hz, 2H), 3.60 (dd,J = 5.8, 3.1 Hz, 2H), 3.57 - 3.50 (m, 2H), 3.55 - 3.43 (m, 2H), 3.43 - 3.35 ( m, 2H), 3.33 (s, 4H), 2.15 (s, 3H)Step14 ：(Z)-methanesulfonic acid 2-(2-(2-(2-(3-(3-(3-((3-((1H-pyrrol-2-yl)methylene)-2-yl (6-(trifluoromethyl)phenoxy)ethoxy)ethoxy)ethyl) 2-(2-(2-oxy)ethyl)ester

向1-[2-氟-3-(2-{2-[2-(2-羥基乙氧基)乙氧基]乙氧基}乙氧基)-5-(三氟甲基)苯基]-3-(4-甲基-3-{[(3Z)-2-側氧基-3-(1H-吡咯-2-基亞甲基)-1H-吲哚-6-l]胺基}苯基)脲(200 mg, 0.275 mmol, 1 eq)及三乙胺(0.1 ml, 0.7 mmol, 2.6 eq)於無水DCM (2 mL)中之混合物中添加甲磺醯氯(0.025 mL, 0.33 mmol, 1.2 eq)。將溶液在室溫下攪拌30 min。LCMS顯示形成含有約20%二甲磺醯基之期望產物。用飽和NaHCO₃水溶液(5 mL)淬滅反應物，用DCM 2×50 mL萃取，濃縮，且藉由管柱層析使用0-20% MeOH/DCM進行純化，得到呈褐色膠狀物之標題化合物(170 mg)。To a mixture of 1-[2-fluoro-3-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)-5-(trifluoromethyl)phenyl]-3-(4-methyl-3-{[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-1]amino}phenyl)urea (200 mg, 0.275 mmol, 1 eq) and triethylamine (0.1 ml, 0.7 mmol, 2.6 eq) in anhydrous DCM (2 mL) was added methanesulfonyl chloride (0.025 mL, 0.33 mmol, 1.2 eq). The solution was stirred at room temperature for 30 min. LCMS showed the formation of the desired product containing about 20% of the dimesylyl group. The reaction was quenched with saturated aqueous NaHCO₃ (5 mL), extracted with DCM 2×50 mL, concentrated, and purified by column chromatography using 0-20% MeOH/DCM to give the title compound as a brown gum (170 mg).

LCMS (m/z = 806 M+1)LCMS (m/z = 806 M+1)

¹H NMR (499 MHz, DMSO-d₆) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (d, J = 4.0 Hz, 1H), 8.71 (d, J = 2.9 Hz, 1H), 8.18 (dd, J = 6.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.25 (td, J = 2.6, 1.5 Hz, 1H), 7.13 (dd, J = 9.8, 6.9 Hz, 2H), 7.01 (ddd, J = 25.8, 8.2, 2.2 Hz, 1H), 6.77 - 6.67 (m, 1H), 6.57 (dd, J = 8.3, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.29 (dt, J = 3.6, 2.4 Hz, 1H), 4.32 - 4.25 (m, 4H), 3.80 - 3.74 (m, 2H), 3.68 - 3.63 (m, 2H), 3.62 - 3.54 (m, 5H), 3.54 (dd, J = 5.1, 2.0 Hz, 4H), 3.16 (s, 3H), 2.15 (d, J = 2.7 Hz, 3H)步驟15：(Z)-1-(3-((3-((1H-吡咯-2-基)亞甲基)-2-側氧基吲哚啉-6-基)胺基)-4-甲基苯基)-3-(3-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-氟-5-(三氟甲基)苯基)脲¹ H NMR (499 MHz, DMSO-d₆ ) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (d, J = 4.0 Hz, 1H), 8.71 (d, J = 2.9 Hz, 1H) , 8.18 (dd, J = 6.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.25 (td, J = 2.6, 1.5 Hz, 1H), 7.13 (dd, J = 9.8, 6.9 Hz, 2H), 7.01 (ddd, J = 25.8, 8.2, 2.2 Hz, 1H), 6.77 - 6.67 (m, 1H), 6.57 (dd, J = 8.3, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.29 (dt, J = 3.6, 2.4 Hz, 1H), 4.32 - 4.25 (m, 4H), 3.80 - 3.74 (m, 2H), 3.68 - 3.63 (m, 2H), 3.62 - 3.54 (m, 5H), 3.54 (dd, J = 5.1, 2.0 Hz, 4H), 3.16 ( s, 3H), 2.15 (d, J = 2.7 Hz, 3H)Step15 ：(Z)-1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolyl-6-yl)amino)-4-methyl phenyl)-3-(3-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-fluoro-5-(trifluoro methyl)phenyl)urea

將於無水DMF (1 mL)中之(Z)-甲磺酸2-(2-(2-(2-(3-(3-(3-((3-((1H-吡咯-2-基)亞甲基)-2-側氧基吲哚啉-6-基)胺基)-4-甲基苯基)脲基)-2-氟-5-(三氟甲基)苯氧基)乙氧基)乙氧基)乙氧基)乙酯(170 mg, 0.211 mmol, 1 eq)及疊氮化鈉(41 mg, 0.634 mmol, 3 eq)在50℃下加熱12 h。使混合物冷卻並用5 mL水稀釋，用DCM (20 mL)萃取，經Na₂SO₄乾燥，過濾，濃縮且藉由管柱層析使用0-20% MeOH/DCM進行純化，得到呈磚紅色固體之標題化合物(60 mg, 34%) (98% HPLC純度)。(Z)-methanesulfonic acid 2-(2-(2-(2-(3-(3-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)amino)-4-methylphenyl)ureido)-2-fluoro-5-(trifluoromethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl methanesulfonate (170 mg, 0.211 mmol, 1 eq) and sodium azide (41 mg, 0.634 mmol, 3 eq) in anhydrous DMF (1 mL) were heated at 50 °C for 12 h. The mixture was cooled and diluted with 5 mL of water, extracted with DCM (20 mL), dried_overNa2SO4 , filtered, concentrated and purified by column chromatography using 0-20% MeOH/DCM to give the title compound (60 mg, 34%) as a brick-red solid (98% HPLC purity).

LCMS m/z-775 (M⁺+Na)LCMS m/z-775 (M⁺ +Na)

¹H NMR (499 MHz, DMSO-d₆) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 6.3, 2.1 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 2.2 Hz, 1H), 7.25 (td, J = 2.6, 1.4 Hz, 1H), 7.13 (dd, J = 10.7, 7.9 Hz, 2H), 7.04 (dd, J = 8.2, 2.2 Hz, 1H), 6.70 (dt, J = 3.7, 1.7 Hz, 1H), 6.57 (dd, J = 8.3, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.29 (dt, J = 3.6, 2.4 Hz, 1H), 4.30 - 4.25 (m, 2H), 3.80 - 3.74 (m, 2H), 3.62 - 3.57 (m, 4H), 3.57 - 3.49 (m, 6H), 3.37 (dd, J = 5.6, 4.3 Hz, 3H), 2.15 (s, 3H)。實例18：2-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-8-(4-(甲基胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮(BA-183)之製備步驟1：4-(苯甲基(甲基)胺基)苯甲酸甲酯¹ H NMR (499 MHz, DMSO-d₆ ) δ 13.15 (s, 1H), 10.70 (s, 1H), 9.09 (s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 6.3, 2.1 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 2.2 Hz, 1H), 7.25 (td, J = 2.6, 1.4 Hz, 1H), 7.13 (dd, J = 10.7, 7.9 Hz, 2H), 7.04 (dd, J = 8.2, 2.2 Hz, 1H), 6.70 (dt, J = 3.7, 1.7 Hz, 1H), 6.57 (dd, J = 8.3, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.29 (dt, J = 3.6, 2.4 Hz , 1H), 4.30 - 4.25 (m, 2H), 3.80 - 3.74 (m, 2H), 3.62 - 3.57 (m, 4H), 3.57 - 3.49 (m, 6H), 3.37 (dd, J = 5.6, 4.3 Hz, 3H), 2.15 (s , 3H).Example 18: 2-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-8-(4-(methylamino)phenyl)chromeno[7 Preparation of 8-d] imidazol-6(3H)-one (BA-183)Step 1 : Methyl 4-(Benzyl(methyl)amino)benzoate

將4-(甲基胺基)苯甲酸甲酯(10 g, 60.54 mmol, 1 eq)、溴甲苯(12.42 g, 72.64 mmol, 8.63 mL, 1.2 eq)及K₂CO₃(25.10 g, 181.61 mmol, 3 eq)於DMF (100 mL)中之溶液在80℃下攪拌2小時。接著將混合物濃縮，添加水(600 mL)且用DCM (800 mL × 3)萃取。使合併的有機萃取物經Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；120 g SepaFlash®二氧化矽急速管柱)，使用0~10%乙酸乙酯/石油醚梯度，80 mL/min)進行純化，得到呈黃色固體之標題化合物(14.3 g, 92.5%)。A solution of methyl 4-(methylamino)benzoate (10 g, 60.54 mmol, 1 eq), benzyl bromide (12.42 g, 72.64 mmol, 8.63 mL, 1.2 eq) and K₂ CO₃ (25.10 g, 181.61 mmol, 3 eq) in DMF (100 mL) was stirred at 80° C. for 2 hours. The mixture was then concentrated, water (600 mL) was added and extracted with DCM (800 mL×3)._The combined organic extracts were dried over_Na2SO4 , filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column) using a 0-10% ethyl acetate/petroleum ether gradient, 80 mL/min) to give the title compound as a yellow solid (14.3 g, 92.5%).

MS ES⁺：256.0MS ES⁺ : 256.0

¹H NMR (400 MHz, DMSO-d₆) δ = 7.77 - 7.70 (m, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.16 (m, 3H), 6.75 (d, J = 9.1 Hz, 2H), 4.68 (s, 2H), 3.74 (s, 3H), 3.11 (s, 3H)步驟2：4-(苯甲基(甲基)胺基)苯甲酸¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.77 - 7.70 (m, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.16 (m, 3H), 6.75 (d, J = 9.1 Hz, 2H), 4.68 (s, 2H), 3.74 (s, 3H), 3.11 (s, 3H)Step 2 : 4-(Benzyl(methyl)amino)benzoic acid

向4-[苯甲基(甲基)胺基]苯甲酸甲酯(14.3 g, 56.01 mmol, 1 eq)於THF (100 mL)中之溶液中添加氫氧化鋰(1 M於水中，560 mL, 10 eq)，且將混合物在25℃下攪拌0.5小時。用1 M HCl調整pH，直至在0℃下沈澱出白色固體。用水(200 mL)稀釋混合物並過濾，且在減壓下乾燥濾餅，得到呈白色固體之標題化合物(13.49 g, 99.8%)，其不經進一步純化即使用。To a solution of methyl 4-[benzyl(methyl)amino]benzoate (14.3 g, 56.01 mmol, 1 eq) in THF (100 mL) was added lithium hydroxide (1 M in water, 560 mL, 10 eq) and the mixture was stirred at 25 °C for 0.5 h. The pH was adjusted with 1 M HCl until a white solid precipitated at 0 °C. The mixture was diluted with water (200 mL) and filtered, and the filter cake was dried under reduced pressure to give the title compound as a white solid (13.49 g, 99.8%) which was used without further purification.

MS ES⁺：241.9MS ES⁺ : 241.9

¹H NMR (400 MHz, DMSO-d₆) δ = 7.73 (d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 2H), 7.28 - 7.12 (m, 3H), 6.73 (d, J = 8.9 Hz, 2H), 4.67 (s, 2H), 3.10 (s, 3H)。步驟3：4-(苯甲基(甲基)胺基)苯甲酸3-乙醯胺基-6-乙醯基-2-硝基苯酯¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.73 (d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 2H), 7.28 - 7.12 (m, 3H), 6.73 (d, J = 8.9 Hz, 2H), 4.67 (s, 2H), 3.10 (s, 3H).Step 3 : 3-Acetamido-6-acetyl-2-nitrophenyl 4-(Benzyl(methyl)amino)benzoate

在25℃下向4-[苯甲基(甲基)胺基]苯甲酸(1.5 g, 6.22 mmol, 1 eq)及N-(4-乙醯基-3-羥基-2-硝基-苯基)乙醯胺(1.48 g, 6.22 mmol, 1 eq)於DCM (15 mL)中之混合物中一次性添加EDCI (2.38 g, 12.43 mmol, 2 eq)及DMAP (151.90 mg, 1.24 mmol, 0.2 eq)。將混合物在25℃下攪拌2小時，且接著在減壓下濃縮，並藉由急速矽膠層析(ISCO®；20 g SepaFlash®二氧化矽急速管柱，0~35%乙酸乙酯/石油醚梯度溶析液，50 mL/min)進行純化，得到呈黃色固體之標題化合物(1.2 g, 41.8%)。To a mixture of 4-[benzyl(methyl)amino]benzoic acid (1.5 g, 6.22 mmol, 1 eq) and N-(4-acetyl-3-hydroxy-2-nitro-phenyl)acetamide (1.48 g, 6.22 mmol, 1 eq) in DCM (15 mL) at 25 °C were added EDCI (2.38 g, 12.43 mmol, 2 eq) and DMAP (151.90 mg, 1.24 mmol, 0.2 eq) in one portion. The mixture was stirred at 25 °C for 2 h, and then concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-35% ethyl acetate/petroleum ether gradient, 50 mL/min) to give the title compound (1.2 g, 41.8%) as a yellow solid.

MS ES⁺：462.2步驟4：7-胺基-2-(4-(苯甲基(甲基)胺基)苯基)-8-硝基-4H-色烯-4-酮MS ES⁺ : 462.2Step 4 : 7-amino-2-(4-(benzyl(methyl)amino)phenyl)-8-nitro-4H-chromen-4-one

在氮氣氣氛下在0℃下向於THF (15 mL)中之4-[苯甲基(甲基)胺基]苯甲酸(3-乙醯胺基-6-乙醯基-2-硝基-苯基)酯(1.2 g, 2.60 mmol, 1 eq)一次性添加NaH (312.02 mg, 7.80 mmol，60%純度，3 eq)。將混合物在0℃-25℃下攪拌1小時，且接著傾倒至NH₄Cl水溶液(600 mL)中，並用乙酸乙酯(800 mL × 3)萃取。將合併的有機層濃縮，得到粗產物(1.2 g，粗製物)，其不經進一步純化即用於下一步驟中。在25℃下向粗製(1.2 g, 2.60 mmol, 1 eq)於乙酸(12 mL)中之混合物中一次性添加H₂SO₄(0.36 mL)。將混合物加熱至110℃持續30分鐘，且接著藉由添加水溶液淬滅。藉由在0℃下添加NaHCO₃(800 ml)將pH調整至pH=7，且接著用乙酸乙酯(400 mL × 3)萃取。使合併的有機萃取物經Na₂SO₄乾燥，過濾並在減壓下濃縮，得到呈黃色固體之標題化合物(600 mg，粗製物)，其不經進一步純化即用於下一步驟。To 4-[benzyl(methyl)amino]benzoic acid (3-acetamido-6-acetyl-2-nitro-phenyl) ester (1.2 g, 2.60 mmol, 1 eq) in THF (15 mL) was added NaH (312.02 mg, 7.80 mmol, 60% purity, 3 eq) in one portion at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C-25°C for 1 hour, and then poured into NH₄ Cl aqueous solution (600 mL), and extracted with ethyl acetate (800 mL×3). The combined organic layers were concentrated to give the crude product (1.2 g, crude), which was used in the next step without further purification. To a mixture of the crude (1.2 g, 2.60 mmol, 1 eq) in acetic acid (12 mL) was added H₂ SO₄ (0.36 mL) in one portion at 25 °C. The mixture was heated to 110 °C for 30 min, and then quenched by adding aqueous solution. The pH was adjusted to pH = 7 by adding NaHCO₃ (800 ml) at 0 °C, and then extracted with ethyl acetate (400 mL x 3). The combined organic extracts were dried over Na₂ SO₄ , filtered and concentrated under reduced pressure to give the title compound (600 mg, crude) as a yellow solid, which was used in the next step without further purification.

MS ES⁺：402.0步驟5：7,8-二胺基-2-(4-(甲基胺基)苯基)-4H-色烯-4-酮MS ES⁺ : 402.0Step 5 : 7,8-Diamino-2-(4-(methylamino)phenyl)-4H-chromen-4-one

使7-胺基-2-[4-[苯甲基(甲基)胺基]苯基]-8-硝基-色烯-4-酮(300 mg, 747.36 μmol, 1 eq)、Pd/C (300 mg，10%純度)及Pd(OH)₂(300 mg，20%純度)於甲醇(5 mL)中之混合物脫氣並用H₂(×3)吹掃，且接著將混合物在H₂氣氛(15 Psi)下在25℃下攪拌1小時。過濾反應混合物並在減壓下濃縮，得到呈黃色固體之標題化合物二胺60(200 mg, 95.1%)，其不經進一步純化即用於下一步驟。A mixture of 7-amino-2-[4-[benzyl(methyl)amino]phenyl]-8-nitro-chromen-4-one (300 mg, 747.36 μmol, 1 eq), Pd/C (300 mg, 10% purity) and Pd(OH)₂ (300 mg, 20% purity) in methanol (5 mL) was degassed and purged with_H2 (×3), and then the mixture was stirred under_H2 atmosphere (15 Psi) at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound diamine60 (200 mg, 95.1%) as a yellow solid, which was used in the next step without further purification.

MS ES⁺：282.1。步驟6：1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-酸第三丁酯MS ES⁺ : 282.1.Step 6 : 1-phenyl-2,5,8,11,14,17-hexaoxaeicosane-20-oic acid tert-butyl ester

在氮氣氣氛下向丙-2-烯酸第三丁酯(585.42 mg, 4.57 mmol, 662.99 uL, 1.5 eq)於THF (10 mL)中之溶液中添加NaOMe (5.4 M, 5.64 uL, 0.01 eq)，之後添加2-[2-[2-[2-(2-苯甲基氧基乙氧基)乙氧基]乙氧基]乙氧基]乙醇(1 g, 3.05 mmol, 1 eq)。將反應混合物在25℃下攪拌8小時，且接著藉由添加水(30 mL)淬滅並在乙酸乙酯(50 mL)與鹽水(20 mL)之間分配。用乙酸乙酯(2×40 mL)進一步萃取水相，且將合併的有機萃取物用鹽水(2×50 mL)洗滌，經Na₂SO₄乾燥，過濾且藉由急速矽膠層析(ISCO®；20 g SepaFlash®二氧化矽急速管柱，0~30%乙酸乙酯/石油醚梯度溶析液，50 mL/min)進行純化，得到呈黃色油狀物之標題化合物(960 mg, 69.0%)。To a solution of tert-butyl prop-2-enoate (585.42 mg, 4.57 mmol, 662.99 uL, 1.5 eq) in THF (10 mL) was added NaOMe (5.4 M, 5.64 uL, 0.01 eq) followed by 2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (1 g, 3.05 mmol, 1 eq) under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 8 hours and then quenched by the addition of water (30 mL) and partitioned between ethyl acetate (50 mL) and brine (20 mL). The aqueous phase was further extracted with ethyl acetate (2×40 mL), and the combined organic extracts were washed with brine (2×50 mL), dried over Na₂ SO₄ , filtered and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% ethyl acetate/petroleum ether gradient, 50 mL/min) to give the title compound as a yellow oil (960 mg, 69.0%).

MS ES⁺：456。MS ES⁺ :456.

¹H NMR (400 MHz, DMSO-d₆) δ = 7.41 - 7.19 (m, 5H), 4.48 (s, 2H), 3.59 - 3.48 (m, 22H), 2.41 (t, J = 6.3 Hz, 2H), 1.39 (s, 9H)。步驟7：1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-酸¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.41 - 7.19 (m, 5H), 4.48 (s, 2H), 3.59 - 3.48 (m, 22H), 2.41 (t, J = 6.3 Hz, 2H), 1.39 (s, 9H).Step 7 : 1-phenyl-2,5,8,11,14,17-hexaoxaeicosanoic acid

將1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-酸第三丁酯(640 mg, 1.40 mmol, 1 eq)於HCl/二噁烷(3 mL)中之溶液在25℃下攪拌0.5小時。將反應混合物在減壓下濃縮，得到呈黃色油狀物之標題化合物(600 mg，粗製物)，其不經進一步純化即用於下一步驟。A solution of tert-butyl 1-phenyl-2,5,8,11,14,17-hexaoxaeicosane-20-ate (640 mg, 1.40 mmol, 1 eq) in HCl/dioxane (3 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (600 mg, crude) as a yellow oil, which was used in the next step without further purification.

MS ES⁺：401.2步驟8：N-(8-胺基-2-(4-(甲基胺基)苯基)-4-側氧基-4H-色烯-7-基)-1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-醯胺MS ES⁺ : 401.2Step 8 : N-(8-amino-2-(4-(methylamino)phenyl)-4-oxo-4H-chromen-7-yl)-1-phenyl-2,5,8,11,14,17-hexaoxaeicosan-20-amide

在0℃下向7,8-二胺基-2-[4-(甲基胺基)苯基]色烯-4-酮(290 mg, 1.03 mmol, 1 eq)及1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-酸(412.83 mg, 1.03 mmol, 1 eq)於DMF (2 mL)中之混合物中一次性添加DIPEA (399.71 mg, 3.09 mmol, 538.69 μL, 3 eq)及HATU (587.97 mg, 1.55 mmol, 1.5 eq)。將混合物在25℃下攪拌0.5小時，且接著濃縮並藉由急速矽膠層析(ISCO®；12 g SepaFlash®二氧化矽急速管柱，0~10%乙酸乙酯/石油醚梯度溶析液，40 mL/min)進行純化，得到呈黃色油狀物之標題化合物(490 mg, 71.6%)。To a mixture of 7,8-diamino-2-[4-(methylamino)phenyl]chromen-4-one (290 mg, 1.03 mmol, 1 eq) and 1-phenyl-2,5,8,11,14,17-hexaoxaeicosanoic acid (412.83 mg, 1.03 mmol, 1 eq) in DMF (2 mL) at 0 °C were added DIPEA (399.71 mg, 3.09 mmol, 538.69 μL, 3 eq) and HATU (587.97 mg, 1.55 mmol, 1.5 eq) in one portion. The mixture was stirred at 25 °C for 0.5 h, and then concentrated and purified by flash silica chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-10% ethyl acetate/petroleum ether gradient, 40 mL/min) to give the title compound as a yellow oil (490 mg, 71.6%).

MS ES⁺：664.4步驟9：8-(4-(甲基胺基)苯基)-2-(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)色烯并[7,8-d]咪唑-6(3H)-酮MS ES⁺ : 664.4Step 9 : 8-(4-(Methylamino)phenyl)-2-(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)chromeno[7,8-d]imidazol-6(3H)-one

將於乙酸(10 mL)中之N-(8-胺基-2-(4-(甲基胺基)苯基)-4-側氧基-4H-色烯-7-基)-1-苯基-2,5,8,11,14,17-六氧雜二十烷-20-醯胺(490 mg, 738.22 μmol, 1 eq)加熱至110℃持續30分鐘。藉由在0℃下添加NaHCO₃水溶液(300 mL)至pH = 7-8淬滅反應物，且接著用乙酸乙酯(3×200 mL)萃取。使合併的有機萃取物經Na₂SO₄乾燥，過濾並濃縮，得到呈黃色油狀物之標題化合物(300 mg，粗製物)，其不經進一步純化即用於下一步驟。N-(8-amino-2-(4-(methylamino)phenyl)-4-oxo-4H-chromen-7-yl)-1-phenyl-2,5,8,11,14,17-hexaoxoeicosane-20-amide (490 mg, 738.22 μmol, 1 eq) in acetic acid (10 mL) was heated to 110 °C for 30 min. The reaction was quenched by adding aqueous NaHCO₃ (300 mL) to pH = 7-8 at 0 °C and then extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried over Na₂ SO₄ , filtered and concentrated to give the title compound (300 mg, crude) as a yellow oil, which was used in the next step without further purification.

MS ES⁺：646.2步驟10：2-(17-羥基-3,6,9,12,15-五氧雜十七烷基)-8-(4-(甲基胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮MS ES⁺ : 646.2Step 10 : 2-(17-Hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)-8-(4-(methylamino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one

使2-[2-[2-[2-[2-[2-(2-苯甲基氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]-8-[4-(甲基胺基)苯基]-3H-哌喃并[2,3-e]苯并咪唑-6-酮(300 mg, 464.58 umol, 1 eq)及Pd(OH)₂(255.32 mg, 363.61 μmol，20%純度)於甲醇(10 mL)中之混合物脫氣並用H₂氣(×3)吹掃，且接著將混合物在H₂氣氛(15 Psi)下在25℃下攪拌1小時。接著過濾混合物，濃縮且藉由急速矽膠層析(ISCO®；12 g SepaFlash®二氧化矽急速管柱，0~10%乙酸乙酯/石油醚梯度溶析液，40 mL/min)進行純化，得到呈黃色油狀物之標題化合物(185 mg, 71.7%)。A mixture of 2-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-8-[4-(methylamino)phenyl]-3H-pyrano[2,3-e]benzimidazol-6-one (300 mg, 464.58 umol, 1 eq) and Pd(OH)₂ (255.32 mg, 363.61 μmol, 20% purity) in methanol (10 mL) was degassed and purged with_H2 gas (×3), and then the mixture was stirred under_H2 atmosphere (15 Psi) at 25 °C for 1 hour. The mixture was then filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-10% ethyl acetate/petroleum ether gradient, 40 mL/min) to give the title compound (185 mg, 71.7%) as a yellow oil.

MS ES⁺：556.2步驟11：2-(17-氯-3,6,9,12,15-五氧雜十七烷基)-8-(4-(甲基胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮MS ES⁺ : 556.2Step 11 : 2-(17-chloro-3,6,9,12,15-pentaoxaheptadecanyl)-8-(4-(methylamino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one

在0℃下向2-[2-[2-[2-[2-[2-(2-羥基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]-8-[4-(甲基胺基)苯基]-3H-哌喃并[2,3-e]苯并咪唑-6-酮(240 mg, 431.95 μmol, 1 eq)於CHCl₃(0.5 mL)中之溶液中逐滴添加SOCl₂(513.89 mg, 4.32 mmol, 313.35 μL, 10 eq)。將混合物在60℃下加熱10 min，且接著藉由在0℃下添加NaHCO₃水溶液(5 ml)至pH = 7-8淬滅反應物，且接著用乙酸乙酯(30 mL × 3)萃取。使合併的有機萃取物經Na₂SO₄乾燥，過濾，濃縮且藉由製備型HPLC ((Welch Xtimate C18 150 × 30 mm × 5 um)；移動相A [水(NH₃H₂O+NH₄HCO₃)-ACN]；移動相B：乙腈，流量：25 mL/min，梯度條件自14% B至54%)進行純化。使所分離之殘餘物在乙腈(2 mL)與水(10 mL)之間分配，且將溶液凍乾至乾燥，得到呈黃色油狀物之標題化合物(25.02 mg, 9.6%，95.5%純度)。To a solution of 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-8-[4-(methylamino)phenyl]-3H-pyrano[2,3-e]benzimidazol-6-one (240 mg, 431.95 μmol, 1 eq) in CHCl₃ (0.5 mL) was added SOCl₂ (513.89 mg, 4.32 mmol, 313.35 μL, 10 eq) dropwise at 0° C. The mixture was heated at 60° C. for 10 min, and then the reaction was quenched by adding aqueous NaHCO₃ solution (5 ml) at 0° C. to pH = 7-8, and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over_Na2SO4, filtered, concentrated and purified by preparative HPLC ((Welch Xtimate C18 150×30 mm×5 um); mobile phase A [water (_NH3H2O +_NH4HCO3 )-ACN]; mobile phase B:_acetonitrile , flow rate: 25 mL/min, gradient condition from 14% B to 54%). The separated residue was partitioned between acetonitrile (₂ mL) and water (10 mL), and the solution was lyophilized to dryness to give the title compound (25.02 mg, 9.6%, 95.5% purity) as a yellow oil.

MS ES⁺：574.5MS ES⁺ : 574.5

¹H NMR (400 MHz, DMSO-d₆) δ = 8.02 - 7.86 (m, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.55 (q, J =4.6 Hz, 1H), 3.91 (t, J = 6.6 Hz, 2H), 3.71 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 3.52 (dd, J = 2.9, 5.4 Hz, 4H), 3.48 - 3.43 (m, 10H), 3.17 (br t, J = 6.6 Hz, 2H),2.78 (d, J = 4.9 Hz, 3H)。步驟12：2-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-8-(4-(甲基胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.02 - 7.86 (m, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.76 (s , 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.55 (q, J =4.6 Hz, 1H), 3.91 (t, J = 6.6 Hz, 2H), 3.71 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 3.52 (dd, J = 2.9, 5.4 Hz, 4H), 3.48 - 3.43 (m, 10H), 3.17 (br t, J = 6.6 Hz, 2H), 2.78 (d, J = 4.9 Hz, 3H).Step 12 : 2-(17-azido-3,6,9,12,15-pentaoxadeca Heptadecyl)-8-(4-(methylamino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one

將於無水DMF (1 mL)中之2-(17-氯-3,6,9,12,15-五氧雜十七烷基)-8-(4-(甲基胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮(57 mg, 0.099 mmol, 1 eq)及疊氮化鈉(32 mg, 0.497 mmol, 5 eq)在70℃下加熱12 h。使混合物冷卻並用鹽水(20 mL)稀釋，用DCM (50 mL)萃取，經Na₂SO₄乾燥，過濾，濃縮且藉由管柱層析使用0-10% MeOH/DCM進行純化，得到呈黃色膠狀物之標題化合物(29:71互變異構混合物) (51 mg, 88%)，LCMS及HPLC純度＞95%。2-(17-Chloro-3,6,9,12,15-pentaoxaheptadecyl)-8-(4-(methylamino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one (57 mg, 0.099 mmol, 1 eq) and sodium azide (32 mg, 0.497 mmol, 5 eq) in anhydrous DMF (1 mL) were heated at 70 °C for 12 h. The mixture was cooled and diluted with brine (20 mL), extracted with DCM (50 mL), dried_overNa2SO4 , filtered, concentrated and purified by column chromatography using 0-10% MeOH/DCM to give the title compound (29:71 tautomeric mixture) (51 mg, 88%) as a yellow gum with LCMS and HPLC purity >95%.

LCMS m/z 580, 603 (M+Na)LCMS m/z 580, 603 (M+Na)

¹H NMR (499 MHz, DMSO-d₆) δ 12.83 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 6.76 (s, 1H), 6.73 - 6.67 (m, 2H), 6.56 (q, J = 4.9 Hz, 1H), 3.91 (t, J = 6.6 Hz, 2H), 3.60 - 3.40 (m, 18H), 3.36 (dd, J = 5.6, 4.3 Hz, 2H), 3.17 (t, J = 6.6 Hz, 2H), 2.78 (d, J = 4.9 Hz, 3H)。實例19：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(8-羥基-4-甲氧基喹啉-2-基)苯甲醯胺(BA-225)之製備步驟1：4-(8-羥基-4-甲氧基喹啉-2-基)苯甲酸甲酯¹ H NMR (499 MHz, DMSO-d₆ ) δ 12.83 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 6.76 (s, 1H), 6.73 - 6.67 (m, 2H), 6.56 (q, J = 4.9 Hz, 1H), 3.91 (t, J = 6.6 Hz, 2H), 3.60 - 3.40 (m, 18H), 3.36 (dd, J = 5.6, 4.3 Hz, 2H), 3.17 (t , J = 6.6 Hz, 2H), 2.78 (d, J = 4.9 Hz, 3H).Example 19: N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(8-hydroxy-4-methoxyquinolin-2-yl) Preparation of Benzylamine (BA-225)Step 1 : 4-(8-hydroxy-4-methoxyquinolin-2-yl)benzoic acid methyl ester

向1-(2-胺基-3-羥基苯基)乙-1-酮(2.15g, 14.2 mmol)於甲醇(30 mL)中之溶液中添加4-甲醯基苯甲酸甲酯(7.0 g, 43 mmol)，之後添加硫酸(650 mL, 12 mmol)，且將混合物在回流下加熱48小時。接著將混合物濃縮，且藉由急速管柱層析(管柱：Biotage sfar二氧化矽HCD Duo 5，20微米，100 g)，利用於己烷中之0至100% EA (15 CV)溶析進行純化，得到呈黃色固體之標題化合物(495 mg, 11%)。To a solution of 1-(2-amino-3-hydroxyphenyl)ethan-1-one (2.15 g, 14.2 mmol) in methanol (30 mL) was added methyl 4-formylbenzoate (7.0 g, 43 mmol) followed by sulfuric acid (650 mL, 12 mmol) and the mixture was heated at reflux for 48 hours. The mixture was then concentrated and purified by flash column chromatography (column: Biotage sfar silica HCD Duo 5, 20 micron, 100 g) eluting with 0 to 100% EA (15 CV) in hexanes to give the title compound (495 mg, 11%) as a yellow solid.

MS(ESI) m/z= 310 [M+H]⁺。MS (ESI) m/z = 310 [M+H]⁺ .

¹H NMR (500 MHz, DMSO-d₆) δ 9.67 (br, 1H), 8.01 (d, J = 10.0Hz, 2H), 7.66 (s, 1H), 7.54 (d, J = 10 Hz, 2H), 7.39 (t, J = 10 Hz,1H), 7.12 (d, J = 10 Hz, 1H), 4.19(s, 3H), 3.89(s, 3H)。步驟2：N-(17-疊氮基-3,6,9,12,15-五氧雜十七烷基)-4-(8-羥基-4-甲氧基喹啉-2-基)苯甲醯胺¹ H NMR (500 MHz, DMSO-d₆ ) δ 9.67 (br, 1H), 8.01 (d, J = 10.0Hz, 2H), 7.66 (s, 1H), 7.54 (d, J = 10 Hz, 2H), 7.39 (t, J = 10 Hz,1H), 7.12 (d, J = 10 Hz, 1H), 4.19(s, 3H), 3.89(s, 3H).Step 2 : N-(17-azido-3,6,9,12,15-pentaoxaheptadecanyl)-4-(8-hydroxy-4-methoxyquinolin-2-yl)benzamide

向4-(8-羥基-4-甲氧基喹啉-2-基)苯甲酸甲酯(495 mg, 1.6 mmol)於THF:H₂O (6 mL:1 mL, v/v)中之溶液中添加氫氧化鋰(192 mg, 8.35 mmol)，且將混合物在室溫下攪拌3小時。接著將混合物濃縮且溶解於DMF (8 mL)中。在室溫下添加HATU (1.03g, 2.72 mmol)及N₃-PEG₅-NH₂(686 mg, 2.24 mmol)，之後添加DIPEA (0.9 mL, 4.8 mmol)並攪拌30分鐘。用水稀釋反應混合物並用DCM萃取。使合併的有機萃取物經Na₂SO₄乾燥，過濾，濃縮且藉由急速管柱層析(管柱：Biotage sfar二氧化矽HCD Duo 5，20微米，50 g)，利用MeOH:DCM (0至20%, v/v, 10 CV)溶析進行純化，得到呈褐色固體之標題化合物(770 mg, 83%)。To a solution of methyl 4-(8-hydroxy-4-methoxyquinolin-2-yl)benzoate (495 mg, 1.6 mmol) in THF:H₂ O (6 mL:1 mL, v/v) was added lithium hydroxide (192 mg, 8.35 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated and dissolved in DMF (8 mL). HATU (1.03 g, 2.72 mmol) and N₃ -PEG₅ -NH₂ (686 mg, 2.24 mmol) were added at room temperature followed by DIPEA (0.9 mL, 4.8 mmol) and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over_Na2SO4, filtered, concentrated and purified by flash column chromatography (column: Biotage sfar silica HCD Duo 5, 20 micron, 50 g) eluting with MeOH:DCM (0 to 20%, v/v, 10 CV) to give the title compound (770 mg, 83%) as a brown solid.

MS(ESI) m/z= 584.0 [M+H]⁺MS(ESI) m/z= 584.0 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (br, 1H), 8.68 (t, J = 5 Hz, 1H), 8.01 (d, J = 10.0 Hz, 2H), 7.66 (s,1H), 7.54 (d, J = 10 Hz, 1H), 7.39 (t, J = 10 Hz,1H), 7.12 (d, J = 10 Hz, 1H), 4.19(s, 3H), 3.59-3.38 (m, 24H)實例20：8-((1-(10-疊氮基癸基)-1H-1,2,3-三唑-4-基)甲氧基)-7-羥基-2-苯基-4H-色烯-4-酮(BA-129)之製備步驟1：7-羥基-2-苯基-8-(丙-2-炔-1-基氧基)-4H-色烯-4-酮¹ H NMR (500 MHz, DMSO-d₆ ) δ 9.55 (br, 1H), 8.68 (t, J = 5 Hz, 1H), 8.01 (d, J = 10.0 Hz, 2H), 7.66 (s,1H) , 7.54 (d, J = 10 Hz, 1H), 7.39 (t, J = 10 Hz,1H), 7.12 (d, J = 10 Hz, 1H), 4.19(s, 3H), 3.59-3.38 (m, 24H)Example 20: 8-((1-(10-azidodecyl)-1H-1,2,3-triazol-4-yl)methoxy)-7-hydroxy-2-phenyl- Preparation of 4H-chromen-4-one (BA-129)Step 1 : 7-Hydroxy-2-phenyl-8-(prop-2-yn-1-yloxy)-4H-chromen-4-one

向7,8-二羥基-2-苯基-4H-色烯-4-酮(1.5 g, 5.906 mmol, 1 eq)及K₂CO₃(0.815 g, 5.906 mmol, 1 eq)於DMF (20 mL)中之攪拌懸浮液中添加炔丙基溴(0.447 mL, 5.906 mmol, 1 eq)，且將混合物在室溫下攪拌隔夜。添加水(100 mL)，形成沈澱物，藉由過濾去除該沈澱物。用DCM (2×100 mL)萃取濾液，且使合併的萃取物經Na₂SO₄乾燥，過濾，濃縮，且將所得固體與甲醇一起研磨，藉由過濾分離，且在高真空下乾燥，獲得呈白色固體之標題化合物(500 mg, 29%)。To a stirred suspension of 7,8-dihydroxy-2-phenyl-4H-chromen-4-one (1.5 g, 5.906 mmol, 1 eq) and K₂ CO₃ (0.815 g, 5.906 mmol, 1 eq) in DMF (20 mL) was added propargyl bromide (0.447 mL, 5.906 mmol, 1 eq) and the mixture was stirred at room temperature overnight. Water (100 mL) was added to form a precipitate which was removed by filtration. The filtrate was extracted with DCM (2 x 100 mL) and the combined extracts were dried_overNa2SO4 , filtered, concentrated, and the resulting solid was triturated with methanol, isolated by filtration, and dried under high vacuum to give the title compound as a white solid (500 mg, 29%).

LCMS：m/z = 293 M+1LCMS: m/z = 293 M+1

¹H NMR (499 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.17 - 8.09 (m, 2H), 7.68 (d,J= 8.8 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.03 (d,J= 8.8 Hz, 1H), 6.94 (s, 1H), 4.90 (d,J= 2.5 Hz, 2H), 3.54 (t,J= 2.4 Hz, 1H)。¹H NMR (499 MHz, CD₃OD) δ 8.15 - 8.07 (m, 2H), 7.80 (d,J= 8.9 Hz, 1H), 7.63 - 7.53 (m, 3H), 7.03 (d,J= 8.9 Hz, 1H), 6.85 (s, 1H), 4.95 (d,J= 2.5 Hz, 2H), 2.91 (t,J= 2.4 Hz, 1H)步驟2：8-((1-(10-溴癸基)-1H-1,2,3-三唑-4-基)甲氧基)-7-羥基-2-苯基-4H-色烯-4-酮¹ H NMR (499 MHz, DMSO-d₆ ) δ 10.85 (s, 1H), 8.17 - 8.09 (m, 2H), 7.68 (d,J = 8.8 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.03 (d,J = 8.8 Hz, 1H), 6.94 (s, 1H), 4.90 (d,J = 2.5 Hz, 2H), 3.54 (t,J = 2.4 Hz, 1H).¹ H NMR (499 MHz, CD₃ OD) δ 8.15 - 8.07 (m, 2H), 7.80 (d,J = 8.9 Hz, 1H), 7.63 - 7.53 (m, 3H), 7.03 (d,J = 8.9 Hz , 1H), 6.85 (s, 1H), 4.95 (d,J = 2.5 Hz, 2H), 2.91 (t,J = 2.4 Hz, 1H)Step 2 : 8-((1-(10-bromodecyl) -1H-1,2,3-triazol-4-yl)methoxy)-7-hydroxy-2-phenyl-4H-chromen-4-one

在室溫下向7-羥基-2-苯基-8-(丙-2-炔-1-基氧基)-4H-色烯-4-酮(0.15 g, 0.514 mmol, 1 eq)及1-疊氮基-10-溴癸烷(0.162 g, 0.616 mmol, 1.2 eq)於THF (5 mL)中之溶液中添加CuSO₄·5H₂O (64 mg, 0.257 mmol, 0.5 eq)於水(1 mL)中之溶液，之後添加抗壞血酸鈉(76 mg, 0.385 mmol, 0.75 eq)於水(1 mL)中之溶液。將反應物在室溫下攪拌2小時，且接著用DCM (50 mL)稀釋並用NaHCO₃(50 mL)洗滌。用DCM (2×100 mL)萃取水相，且使有機萃取物經Na₂SO₄乾燥，過濾，濃縮且藉由層析0-100% EtOAc/己烷進行純化，得到呈膠狀物之標題化合物(280 mg, 98%)。To a solution of 7-hydroxy-2-phenyl-8-(prop-2-yn-1-yloxy)-4H-chromen-4-one (0.15 g, 0.514 mmol, 1 eq) and 1-azido-10-bromodecane (0.162 g, 0.616 mmol, 1.2 eq) in THF (5 mL) was added a solution of CuSO₄ ·5H₂ O (64 mg, 0.257 mmol, 0.5 eq) in water (1 mL) followed by a solution of sodium ascorbate (76 mg, 0.385 mmol, 0.75 eq) in water (1 mL) at room temperature. The reaction was stirred at room temperature for 2 hours and then diluted with DCM (50 mL) and washed with NaHCO₃ (50 mL). The aqueous phase was extracted with DCM (2 x 100 mL) and the organic extracts were dried_overNa2SO4 , filtered, concentrated and purified by chromatography 0-100% EtOAc/hexanes to give the title compound as a gum (280 mg, 98%).

LCMS：m/z = 554 (M+)步驟3：8-((1-(10-疊氮基癸基)-1H-1,2,3-三唑-4-基)甲氧基)-7-羥基-2-苯基-4H-色烯-4-酮LCMS: m/z = 554 (M+)Step 3 : 8-((1-(10-azidodecyl)-1H-1,2,3-triazol-4-yl)methoxy)-7-hydroxy-2-phenyl-4H-chromen-4-one

將8-((1-(10-溴癸基)-1H-1,2,3-三唑-4-基)甲氧基)-7-羥基-2-苯基-4H-色烯-4-酮(0.275 g, 0.496 mmol, 1 eq)及疊氮化鈉(74 mg, 2.482 mmol, 5 eq)於無水DMF (5 mL)中之溶液在氬氣下加熱至60℃持續2小時。使混合物冷卻至室溫，用飽和碳酸氫鹽水溶液(50 mL)稀釋且用乙酸乙酯(100 mL)萃取。將合併的有機萃取物用鹽水(100 mL)洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由矽膠層析，用0-100% EtOAc/己烷溶析進行純化，得到呈米色固體之標題化合物(220 mg, 84%)。根據HPLC，純度為99%。A solution of 8-((1-(10-bromodecyl)-1H-1,2,3-triazol-4-yl)methoxy)-7-hydroxy-2-phenyl-4H-chromen-4-one (0.275 g, 0.496 mmol, 1 eq) and sodium azide (74 mg, 2.482 mmol, 5 eq) in anhydrous DMF (5 mL) was heated to 60 °C under nitrogen for 2 hours. The mixture was cooled to room temperature, diluted with saturated aqueous bicarbonate solution (50 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried_overNa2SO4 , filtered, concentrated and purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give the title compound as a beige solid (220 mg, 84%). Purity was 99% by HPLC.

LCMS m/z 517 (M+1)LCMS m/z 517 (M+1)

¹H NMR (499 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.10 (s, 1H), 8.01 - 7.94 (m, 2H), 7.65 (d,J= 8.8 Hz, 1H), 7.61 - 7.52 (m, 3H), 7.04 (d,J= 8.7 Hz, 1H), 6.87 (s, 1H), 5.26 (s, 2H), 4.20 (t,J= 7.0 Hz, 2H), 3.30 (t,J= 7.0 Hz, 2H), 1.59 (p,J= 7.1 Hz, 2H), 1.51 (dq,J= 8.3, 6.8 Hz, 2H), 1.32 - 1.07 (m, 10H), 1.04 (q,J= 6.9 Hz, 2H)。實例21：8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮(BA-169)之製備步驟1至4步驟1：4-甲基苯磺酸1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基酯¹ H NMR (499 MHz, DMSO-d₆ ) δ 10.80 (s, 1H), 8.10 (s, 1H), 8.01 - 7.94 (m, 2H), 7.65 (d,J = 8.8 Hz, 1H), 7.61 - 7.52 (m, 3H), 7.04 (d,J = 8.7 Hz, 1H), 6.87 (s, 1H), 5.26 (s, 2H), 4.20 (t,J = 7.0 Hz, 2H), 3.30 (t,J = 7.0 Hz, 2H), 1.59 (p,J = 7.1 Hz, 2H), 1.51 (dq,J = 8.3, 6.8 Hz, 2H), 1.32 - 1.07 (m, 10H), 1.04 (q,J = 6.9 Hz, 2H).Example 21: 8-(4-((17-azido-3,6,9,12,15-pentaoxadeca Preparation of (heptaalkyl)(methyl)amino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one (BA-169) Steps 1 to 4Step 1 : 1-phenyl-2,5,8,11,14,17-hexaoxanodecane-19-yl 4-methylbenzenesulfonate

向2-[2-[2-[2-[2-(2-苯甲基氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙醇(5 g, 13.42 mmol, 1eq)於DCM (100 mL)中之溶液中添加TEA (2.72 g, 26.85 mmol, 3.74 mL, 2eq)、4-甲苯磺醯氯(2.82 g, 14.77 mmol, 1.1eq)及DMAP (164.01 mg, 1.34 mmol, 0.1eq)。將混合物在30℃下攪拌5小時，在減壓下濃縮且藉由急速矽膠層析(ISCO®；40 g SepaFlash®二氧化矽急速管柱，0~50%乙酸乙酯/石油醚梯度溶析液，100 mL/min)純化殘餘物，得到呈無色油狀物之標題化合物(6.5 g，92%產率)。To a solution of 2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (5 g, 13.42 mmol, 1eq ) in DCM (100 mL) was added TEA (2.72 g, 26.85 mmol, 3.74 mL, 2eq ), 4-toluenesulfonyl chloride (2.82 g, 14.77 mmol, 1.1eq ) and DMAP (164.01 mg, 1.34 mmol, 0.1eq ). The mixture was stirred at 30 °C for 5 h, concentrated under reduced pressure and the residue was purified by flash silica chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-50% ethyl acetate/petroleum ether gradient, 100 mL/min) to give the title compound as a colorless oil (6.5 g, 92% yield).

MS ES⁺：527.1。MS ES⁺ :527.1.

¹H NMR (400 MHz, CDCl₃) δ = 7.80 (d, J = 8.3 Hz, 2H), 7.38 - 7.32 (m, 6H), 7.31 - 7.28 (m, 1H), 4.57 (s, 2H), 4.18 - 4.14 (m, 2H), 3.69 - 3.62 (m, 18H), 3.58 (s, 4H), 2.45 (s, 3H)。步驟2：4-((1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸乙酯¹ H NMR (400 MHz, CDCl₃ ) δ = 7.80 (d, J = 8.3 Hz, 2H), 7.38 - 7.32 (m, 6H), 7.31 - 7.28 (m, 1H), 4.57 (s, 2H), 4.18 - 4.14 (m, 2H), 3.69 - 3.62 (m, 18H), 3.58 (s, 4H), 2.45 (s, 3H).Step 2 : Ethyl 4-((1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)benzoate

向4-甲基苯磺酸1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基酯(3.25 g, 6.17 mmol, 1eq)及4-胺基苯甲酸乙酯(1.02 g, 6.17 mmol, 1.29 mL, 1eq)於DMF (10 mL)中之溶液中添加K₂CO₃(2.56 g, 18.51 mmol, 3eq)及KI (1.02 g, 6.17 mmol, 1eq)。將混合物在微波下在180℃下攪拌3小時。使混合物冷卻至室溫，濃縮且藉由急速矽膠層析(ISCO®；80 g SepaFlash®二氧化矽急速管柱，0~60%乙酸乙酯/石油醚梯度溶析液，100 mL/min)純化殘餘物，得到呈黃色油狀物之標題化合物(2 g, 31%)。To a solution of 1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl 4-methylbenzenesulfonate (3.25 g, 6.17 mmol, 1eq ) and ethyl 4-aminobenzoate (1.02 g, 6.17 mmol, 1.29 mL, 1eq ) in DMF (10_mL ) was added_K2CO3 (2.56 g, 18.51 mmol, 3eq ) and KI (1.02 g, 6.17 mmol, 1eq ). The mixture was stirred under microwave at 180 °C for 3 h. The mixture was cooled to room temperature, concentrated and the residue was purified by flash silica chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0-60% ethyl acetate/petroleum ether gradient, 100 mL/min) to give the title compound as a yellow oil (2 g, 31%).

MS ES⁺：520.2。MS ES⁺ :520.2.

¹H NMR (400 MHz, CDCl₃) δ = 7.91 - 7.82 (m, 2H), 7.34 (d,J= 4.4 Hz, 4H), 7.32 - 7.28 (m, 1H), 6.62 (d,J= 8.6 Hz, 2H), 4.56 (s, 2H), 4.32 (q,J= 7.1 Hz, 2H), 3.72 (t,J= 5.1 Hz, 2H), 3.67 - 3.64 (m, 18H), 3.64 - 3.61 (m, 2H), 3.35 (t,J= 5.1 Hz, 2H), 1.37 (t,J= 7.1 Hz, 3H)。步驟3：4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸乙酯¹ H NMR (400 MHz, CDCl₃ ) δ = 7.91 - 7.82 (m, 2H), 7.34 (d,J = 4.4 Hz, 4H), 7.32 - 7.28 (m, 1H), 6.62 (d,J = 8.6 Hz , 2H), 4.56 (s, 2H), 4.32 (q,J = 7.1 Hz, 2H), 3.72 (t,J = 5.1 Hz, 2H), 3.67 - 3.64 (m, 18H), 3.64 - 3.61 (m, 2H), 3.35 (t,J = 5.1 Hz , 2H), 1.37 (t,J = 7.1 Hz, 3H).Step 3 : Ethyl 4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)benzoate

在氮氣氣氛下在0℃下向4-((1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸乙酯(1 g, 1.92 mmol, 1eq)於THF (10 mL)中之溶液中添加NaH (115.46 mg, 2.89 mmol，60%純度，1.5eq)。攪拌0.5小時後，添加碘甲烷(1.37 g, 9.62 mmol, 599.02 uL, 5eq)，且將混合物在氮氣下在25℃下攪拌4小時。重複上述反應，且將兩次反應物一起後處理。藉由在0℃下添加NH₄Cl水溶液(20 mL)淬滅反應混合物，且接著用水(50 mL)稀釋並用乙酸乙酯(3 × 50 mL)萃取。將合併的有機萃取物用鹽水(100 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；40 g SepaFlash®二氧化矽急速管柱，0~60%乙酸乙酯/石油醚梯度溶析液，100 mL/min)進行純化，得到呈黃色油狀物之標題化合物(1.7 g, 83%)。To a solution of ethyl 4-((1-phenyl-2,5,8,11,14,17-hexaoxanononadecan-19-yl)amino)benzoate (1 g, 1.92 mmol, 1eq ) in THF (10 mL) was added NaH (115.46 mg, 2.89 mmol, 60% purity, 1.5eq ) at 0° C. under nitrogen atmosphere. After stirring for 0.5 h, iodomethane (1.37 g, 9.62 mmol, 599.02 uL, 5eq ) was added and the mixture was stirred at 25° C. under nitrogen for 4 h. The above reaction was repeated and both reactions were worked up together. The reaction mixture was quenched by adding aqueous NH₄ Cl solution (20 mL) at 0° C., and then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (100 mL×1), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-60% ethyl acetate/petroleum ether gradient, 100 mL/min) to give the title compound (1.7 g, 83%) as a yellow oil.

MS ES⁺：534.7MS ES⁺ : 534.7

¹H NMR (400 MHz, CDCl₃) δ = 7.94 - 7.87 (m, 2H), 7.34 (d, J = 4.4 Hz, 4H), 7.31 - 7.28 (m, 1H), 6.70 (d, J = 9.0 Hz, 2H), 4.57 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.70 - 3.59 (m, 24H), 3.07 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H)步驟4：4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸¹ H NMR (400 MHz, CDCl₃ ) δ = 7.94 - 7.87 (m, 2H), 7.34 (d, J = 4.4 Hz, 4H), 7.31 - 7.28 (m, 1H), 6.70 (d, J = 9.0 Hz, 2H), 4.57 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.70 - 3.59 (m, 24H), 3.07 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H)Step 4 : 4-(Methyl(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)benzoic acid

向4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸乙酯(1.2 g, 2.25 mmol, 1eq)於THF (12 mL)中之溶液中添加NaOH (269.82 mg, 6.75 mmol, 3eq)於水(4 mL)中之溶液。將混合物在65℃下攪拌2小時且接著冷卻至室溫，濃縮，用水(10 mL)稀釋，用1 N HCl酸化至pH=5-6並用乙酸乙酯(20 mL × 3)萃取。將合併的有機萃取物用鹽水(40 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，得到呈黃色油狀物之標題化合物(1.1 g，粗製物)，其不經進一步純化即用於下一步驟中。To a solution of ethyl 4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxanodec-19-yl)amino)benzoate (1.2 g, 2.25 mmol, 1eq ) in THF (12 mL) was added a solution of NaOH (269.82 mg, 6.75 mmol, 3eq ) in water (4 mL). The mixture was stirred at 65 °C for 2 hours and then cooled to room temperature, concentrated, diluted with water (10 mL), acidified with 1 N HCl to pH = 5-6 and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (40 mL x 1), dried over anhydrous_Na2SO4, filtered and concentrated to give the title compound (1.1 g, crude) as a yellow oil, which was used in the next step without further purification.

MS ES⁺：506.1。 步驟5至9步驟5：1-(4-氟-2-羥基-3-硝基苯基)乙-1-酮MS ES⁺ : 506.1. Steps 5 to 9Step 5 : 1-(4-Fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one

在0℃下向H₂SO₄溶液(80 mL)中添加1-(4-氟-2-羥基-苯基)乙酮(20 g, 129.75 mmol, 1 eq)，經30 min逐滴添加HNO₃(15.63 g, 168.68 mmol, 11.16 mL，68%純度，1.3 eq)。將混合物在25℃下攪拌1小時，且接著添加冰-水(800 ml)，且接著用DCM (800 mL × 3)萃取混合物。將合併的有機萃取物用鹽水(500 mL)洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；120 g SepaFlash®二氧化矽急速管柱，0~10%乙酸乙酯/石油醚梯度溶析液，80 mL/min)進行純化，得到呈黃色固體之標題化合物(13.4 g，粗製物)。步驟6：1-(2-(苯甲基氧基)-4-氟-3-硝基苯基)乙-1-酮To_{H2SO4solution} (80 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (20 g, 129.75 mmol, 1 eq) at 0°C,_HNO3 (15.63 g, 168.68 mmol, 11.16 mL, 68% purity, 1.3 eq) was added dropwise over 30 min. The mixture was stirred at 25°C for 1 hour, and then ice-water (800 ml) was added, and then the mixture was extracted with DCM (800 mL x 3). The combined organic extracts were washed with brine (500 mL), dried_overNa2SO4 , filtered, concentrated and purified by flash silica chromatography (ISCO®; 120 g SepaFlash® silica flash column, 0-10% ethyl acetate/petroleum ether gradient, 80 mL/min) to give the title compound as a yellow solid (13.4 g, crude).Step 6 : 1-(2-(Benzyloxy)-4-fluoro-3-nitrophenyl)ethan-1-one

將1-(4-氟-2-羥基-3-硝基-苯基)乙酮(13.4 g, 67.29 mmol, 1 eq)、K₂CO₃(18.60 g, 134.58 mmol, 2 eq)及溴甲基苯(12.66 g, 74.02 mmol, 8.79 mL, 1.1 eq)於乙腈(130 mL)中之溶液在70℃下加熱8小時。將混合物濃縮，且藉由急速矽膠層析(ISCO®；80 g SepaFlash®二氧化矽急速管柱，0~10%乙酸乙酯/石油醚梯度溶析液，65 mL/min)進行純化，得到呈黃色固體之標題化合物(11.5 g, 59%)。A solution of 1-(4-fluoro-2-hydroxy-3-nitro-phenyl)ethanone (13.4 g, 67.29 mmol, 1 eq), K₂ CO₃ (18.60 g, 134.58 mmol, 2 eq) and bromomethylbenzene (12.66 g, 74.02 mmol, 8.79 mL, 1.1 eq) in acetonitrile (130 mL) was heated at 70° C. for 8 hours. The mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0-10% ethyl acetate/petroleum ether gradient, 65 mL/min) to give the title compound (11.5 g, 59%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ = 8.07 (dd, J = 6.4, 8.9 Hz, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.45 - 7.33 (m, 5H), 5.06 (s, 2H), 2.61 (s, 3H)。步驟7：1-(4-胺基-2-(苯甲基氧基)-3-硝基苯基)乙-1-酮¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.07 (dd, J = 6.4, 8.9 Hz, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.45 - 7.33 (m, 5H), 5.06 (s, 2H), 2.61 (s, 3H).Step 7 : 1-(4-amino-2-(benzyloxy)-3-nitrophenyl)ethan-1-one

在25℃下向1-(2-(苯甲基氧基)-4-氟-3-硝基苯基)乙-1-酮(11.5 g, 39.76 mmol, 1 eq)於乙腈(100 mL)中之溶液中逐滴添加NH₃·H₂O (83.60 g, 596.35 mmol, 91.87 mL，25%純度，15 eq)。將混合物在50℃下加熱2小時且接著濃縮，得到呈黃色油狀物之標題化合物(8.5 g，粗製物)，其不經進一步純化即用於下一步驟。To a solution of 1-(2-(benzyloxy)-4-fluoro-3-nitrophenyl)ethan-1-one (11.5 g, 39.76 mmol, 1 eq) in acetonitrile (100 mL) was added NH₃ ·H₂ O (83.60 g, 596.35 mmol, 91.87 mL, 25% purity, 15 eq) dropwise at 25° C. The mixture was heated at 50° C. for 2 h and then concentrated to give the title compound as a yellow oil (8.5 g, crude) which was used in the next step without further purification.

MS ES⁺：286.9MS ES⁺ : 286.9

¹H NMR (400 MHz, DMSO-d₆) δ = 7.69 (d, J = 9.0 Hz, 1H), 7.48 - 7.30 (m, 5H), 6.82 (s, 2H), 6.70 (d, J = 9.1 Hz, 1H), 4.94 (s, 2H), 2.46 (s, 3H)步驟8：N-(4-乙醯基-3-(苯甲基氧基)-2-硝基苯基)乙醯胺¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.69 (d, J = 9.0 Hz, 1H), 7.48 - 7.30 (m, 5H), 6.82 (s, 2H), 6.70 (d, J = 9.1 Hz, 1H), 4.94 (s, 2H), 2.46 (s, 3H)Step 8 : N-(4-acetyl-3-(benzyloxy)-2-nitrophenyl)acetamide

向1-(4-胺基-2-苯甲基氧基-3-硝基-苯基)乙酮(8.5 g, 29.69 mmol, 1 eq)及乙醯氯(2.56 g, 32.66 mmol, 2.33 mL, 1.1 eq)之溶液中添加甲苯(80 mL)，且將混合物在120℃下攪拌8小時且接著濃縮，得到呈黃色油狀物之標題化合物(9g，粗製物)，其不經進一步純化即用於下一步驟。To a solution of 1-(4-amino-2-benzyloxy-3-nitro-phenyl)ethanone (8.5 g, 29.69 mmol, 1 eq) and acetyl chloride (2.56 g, 32.66 mmol, 2.33 mL, 1.1 eq) was added toluene (80 mL), and the mixture was stirred at 120 °C for 8 h and then concentrated to give the title compound (9 g, crude) as a yellow oil which was used in the next step without further purification.

MS ES⁺：329.3MS ES⁺ : 329.3

¹H NMR (400 MHz, CDCl₃) δ = 13.74 (s, 1H), 8.94 (br s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.09 (s,3H), 2.66 (s, 3H), 2.27 (s, 3H)。步驟9：N-(4-乙醯基-3-羥基-2-硝基苯基)乙醯胺¹ H NMR (400 MHz, CDCl₃ ) δ = 13.74 (s, 1H), 8.94 (br s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.09 (s,3H), 2.66 (s, 3H), 2.27 (s, 3H).Step 9 : N-(4-acetyl-3-hydroxy-2-nitrophenyl)acetamide

在氮氣氣氛下在-78℃下向N-(4-乙醯基-3-苯甲基氧基-2-硝基-苯基)乙醯胺(9 g, 27.41 mmol, 1 eq)於DCM (90 mL)中之溶液中逐滴添加BBr₃溶液(1 M, 32.89 mL, 1.2 eq)，且接著將混合物在-78℃下攪拌1小時。添加冰-水(1500 ml)，且用DCM (1000 mL × 3)萃取混合物。將合併的有機萃取物用鹽水(500 mL)洗滌，經Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；80 g SepaFlash®二氧化矽急速管柱，0~20%乙酸乙酯/石油醚梯度溶析液，80 mL/min)進行純化，得到呈黃色固體之標題化合物(5.5 g, 84%)。To a solution of N-(4-acetyl-3-benzyloxy-2-nitro-phenyl)acetamide (9 g, 27.41 mmol, 1 eq) in DCM (90 mL) was added BBr₃ solution (1 M, 32.89 mL, 1.2 eq) dropwise under nitrogen at -78 °C, and then the mixture was stirred at -78 °C for 1 hour. Ice-water (1500 ml) was added, and the mixture was extracted with DCM (1000 mL × 3). The combined organic extracts were washed with brine (500 mL), dried_overNa2SO4 , filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0-20% ethyl acetate/petroleum ether gradient, 80 mL/min) to give the title compound as a yellow solid (5.5 g, 84%).

MS ES⁺：239.0MS ES⁺ : 239.0

¹H NMR (400 MHz, DMSO-d₆) δ = 13.30 (s, 1H), 10.40 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 2.74 (s, 3H), 2.16 (s, 3H) 步驟10至16步驟10：4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸3-乙醯胺基-6-乙醯基-2-硝基苯酯¹ H NMR (400 MHz, DMSO-d₆ ) δ = 13.30 (s, 1H), 10.40 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 2.74 (s, 3H), 2.16 (s, 3H) Steps 10 to 16Step 10 : 4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)benzoic acid 3-acetamido-6-acetyl-2-nitrophenyl ester

向4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸(1.4 g, 2.77 mmol, 1eq)於DCM (10 mL)中之溶液中添加EDCI (1.06 g, 5.54 mmol, 2eq)、DMAP (67.66 mg, 553.80 μmol, 0.2eq)及N-(4-乙醯基-3-羥基-2-硝基苯基)乙醯胺(659.56 mg, 2.77 mmol, 1eq)。將混合物在25℃下攪拌2小時，且接著濃縮並藉由急速矽膠層析(ISCO®；20 g SepaFlash®二氧化矽急速管柱，0~100%乙酸乙酯/石油醚梯度溶析液，100 mL/min)進行純化，得到呈黃色油狀物之標題化合物(1 g, 50%)。To a solution of 4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxanononadecan-19-yl)amino)benzoic acid (1.4 g, 2.77 mmol, 1eq ) in DCM (10 mL) were added EDCI (1.06 g, 5.54 mmol, 2eq ), DMAP (67.66 mg, 553.80 μmol, 0.2eq ) and N-(4-acetyl-3-hydroxy-2-nitrophenyl)acetamide (659.56 mg, 2.77 mmol, 1eq ). The mixture was stirred at 25 °C for 2 h, and then concentrated and purified by flash silica chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-100% ethyl acetate/petroleum ether gradient, 100 mL/min) to give the title compound as a yellow oil (1 g, 50%).

MS ES⁺：726.6MS ES⁺ : 726.6

¹H NMR (400 MHz, CDCl₃) δ = 8.75 (s, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.01 (dd, J = 6.2, 8.9 Hz, 3H), 7.34 (d, J = 4.5 Hz, 4H), 6.75 - 6.71 (m, 2H), 4.57 (s, 2H), 3.67 - 3.62 (m, 24H), 3.11 (s, 3H), 2.53 (s, 3H), 2.26 (s, 3H)。步驟11：N-(3-羥基-4-(3-(4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯基)-3-側氧基丙醯基)-2-硝基苯基)乙醯胺¹ H NMR (400 MHz, CDCl₃ ) δ = 8.75 (s, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.01 (dd, J = 6.2, 8.9 Hz, 3H), 7.34 (d, J = 4.5 Hz, 4H), 6.75 - 6.71 (m, 2H), 4.57 (s, 2H), 3.67 - 3.62 (m, 24H), 3.11 (s, 3H), 2.53 (s, 3H), 2.26 (s, 3H).Step 11 : N-(3-hydroxy-4-(3-(4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxanodecane-19-yl) (amino)phenyl)-3-oxopropionyl)-2-nitrophenyl)acetamide

向4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯甲酸3-乙醯胺基-6-乙醯基-2-硝基苯酯(1 g, 1.38 mmol, 1eq)於吡啶(15 mL)中之溶液中添加KOH (386.52 mg, 6.89 mmol, 5eq)，且將混合物在60℃下攪拌2小時。冷卻至室溫後，用1 N HCl將混合物酸化至pH=5-6，且接著用水(20 mL)稀釋並用乙酸乙酯(20 mL × 3)萃取。將合併的有機萃取物用鹽水(40 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，得到呈黃色油狀物之標題化合物(1.3 g，粗製物)，其不經進一步純化即用於下一步驟中。To a solution of 3-acetamido-6-acetyl-2-nitrophenyl 4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)benzoate (1 g, 1.38 mmol, 1eq ) in pyridine (15 mL) was added KOH (386.52 mg, 6.89 mmol, 5eq ), and the mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the mixture was acidified to pH=5-6 with 1 N HCl, and then diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (40 mL x 1), dried over anhydrous_Na2SO4, filtered and concentrated to give the title compound (1.3 g, crude) as a yellow oil, which was used in the next step without further purification.

MS ES⁺：726.2。步驟12：7-胺基-2-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-8-硝基-4H-色烯-4-酮MS ES⁺ : 726.2.Step 12 : 7-amino-2-(4-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-8-nitro-4H-chromen-4-one

向N-(3-羥基-4-(3-(4-(甲基(1-苯基-2,5,8,11,14,17-六氧雜十九烷-19-基)胺基)苯基)-3-側氧基丙醯基)-2-硝基苯基)乙醯胺(1.3 g, 1.79 mmol, 1eq)於乙酸(20 mL)中之溶液中添加H₂SO₄(175.68 mg, 1.79 mmol, 95.48 μL, 1eq)。將混合物在110℃下加熱0.5小時，且接著冷卻至室溫。用NaHCO₃水溶液將反應中和至pH=7-8，且接著用乙酸乙酯(20 mL × 3)萃取。將合併的有機萃取物用鹽水(40 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮，且將所得殘餘物溶解於二噁烷(20 mL)及HCl (20 mL)中。將混合物在110℃下加熱1小時且接著濃縮，得到呈褐色膠狀物之標題化合物(1 g，粗製物)，其不經進一步純化即用於下一步驟中。To a solution of N-(3-hydroxy-4-(3-(4-(methyl(1-phenyl-2,5,8,11,14,17-hexaoxonadecan-19-yl)amino)phenyl)-3-oxopropanoyl)-2-nitrophenyl)acetamide (1.3 g, 1.79 mmol, 1eq ) in acetic acid (20 mL) was added H₂ SO₄ (175.68 mg, 1.79 mmol, 95.48 μL, 1eq ). The mixture was heated at 110 °C for 0.5 h, and then cooled to room temperature. The reaction was neutralized with aqueous NaHCO₃ to pH = 7-8, and then extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (40 mL x 1), dried over anhydrous_Na2SO4, filtered, concentrated, and the resulting residue was dissolved in dioxane (20 mL) and HCl (20 mL). The mixture was heated at 110 °C for 1 hour and then concentrated to give the title compound (1 g, crude) as a brown gum, which was used in the next step without further purification.

MS ES⁺：576.3。步驟13：7,8-二胺基-2-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-4H-色烯-4-酮MS ES⁺ : 576.3.Step 13 : 7,8-Diamino-2-(4-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-4H-chromen-4-one

在氮氣氣氛下向7-胺基-2-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-8-硝基-4H-色烯-4-酮(1 g, 1.74 mmol, 1eq)於甲醇(30 mL)中之溶液中添加Pd/C (10%, 0.5 g)。使懸浮液脫氣並用氫氣(× 3)吹掃。將混合物在氫氣(15 Psi)下在25℃下攪拌2小時且接著過濾並將濾液濃縮，得到呈黃色膠狀物之標題化合物(950 mg，粗製物)，其不經進一步純化即用於下一步驟中。To a solution of 7-amino-2-(4-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-8-nitro-4H-chromen-4-one (1 g, 1.74 mmol, 1eq ) in methanol (30 mL) was added Pd/C (10%, 0.5 g) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen (× 3). The mixture was stirred under hydrogen (15 Psi) at 25° C. for 2 h and then filtered and the filtrate was concentrated to give the title compound (950 mg, crude) as a yellow gum which was used in the next step without further purification.

MS ES⁺：546.2步驟14：8-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基) (甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮MS ES⁺ : 546.2Step 14 : 8-(4-((17-Hydroxy-3,6,9,12,15-pentaoxaheptadecanyl) (methyl)amino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one

向77,8-二胺基-2-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-4H-色烯-4-酮(850 mg, 1.56 mmol, 1eq)於乙腈(20 mL)中之溶液中添加三甲氧基甲烷(181.85 mg, 1.71 mmol, 187.86 uL, 1.1eq)及碘(39.54 mg, 155.79 μmol, 0.1eq)。將混合物在25℃下攪拌1小時，且接著藉由添加NaHSO₃水溶液(20 mL)淬滅，並用乙酸乙酯(20 mL × 3)萃取。將合併的有機萃取物用鹽水(40 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；20 g SepaFlash®二氧化矽急速管柱，0~15% MeOH/DCM梯度溶析液，100 mL/min)進行純化，得到呈紅色膠狀物之標題化合物(500 mg，58%產率)。To a solution of 7,7,8-diamino-2-(4-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-4H-chromen-4-one (850 mg, 1.56 mmol, 1eq ) in acetonitrile (20 mL) were added trimethoxymethane (181.85 mg, 1.71 mmol, 187.86 uL, 1.1eq ) and iodine (39.54 mg, 155.79 μmol, 0.1eq ). The mixture was stirred at 25 °C for 1 hour, and then quenched by the addition of aqueous NaHSO₃ solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (40 mL × 1), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-15% MeOH/DCM gradient eluent, 100 mL/min) to give the title compound (500 mg, 58% yield) as a red gum.

MS ES⁺：556.3MS ES⁺ : 556.3

¹H NMR (400 MHz, DMSO-d₆) δ = 8.71 (br s, 1H), 8.04 (br d, J = 6.9 Hz, 2H), 7.87 (br d, J = 4.5 Hz, 1H), 7.66 (br s, 1H), 7.55 - 7.00 (m, 1H), 6.86 (br d, J = 8.1 Hz, 3H), 3.62 (br s, 4H), 3.47 (br s, 18H), 3.38 (br s, 2H), 3.16 (s, 1H), 3.05 (br s, 3H)。步驟15：8-(4-((17-氯-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.71 (br s, 1H), 8.04 (br d, J = 6.9 Hz, 2H), 7.87 (br d, J = 4.5 Hz, 1H), 7.66 ( br s, 1H), 7.55 - 7.00 (m, 1H), 6.86 (br d, J = 8.1 Hz, 3H), 3.62 (br s, 4H), 3.47 (br s, 18H), 3.38 (br s, 2H), 3.16 (s, 1H), 3.05 (br s, 3H).Step 15 : 8-(4-((17-chloro-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)chromeno[7,8- d] imidazol-6(3H)-one

向8-(4-((17-羥基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮(450 mg, 809.91 μmol, 1eq)於DCM (20 mL)中之溶液中添加SOCl₂(8.10 mmol, 587.53 μL, 10eq)。將混合物在25℃下攪拌1小時，且接著傾倒至飽和NaHCO₃水溶液(30 mL)中並用乙酸乙酯(30 mL × 3)萃取。將合併的有機萃取物用鹽水(60 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；12 g SepaFlash®)，使用0-10% MeOH/DCM梯度，80 mL/min進行純化，得到呈褐色膠狀物之作為互變異構物混合物之標題化合物(350 mg, 69%)，其為91.7%純。To a solution of 8-(4-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one (450 mg, 809.91 μmol, 1eq ) in DCM (20 mL) was added SOCl₂ (8.10 mmol, 587.53 μL, 10eq ). The mixture was stirred at 25 °C for 1 h, and then poured into saturated aqueous NaHCO₃ solution (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with brine (60 mL x 1), dried over anhydrous_Na2SO4, filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®) using a 0-10% MeOH/DCM gradient at 80 mL/min to afford the title compound as a mixture of tautomeric isomers as a brown gum (350 mg, 69%), which was 91.7% pure.

MS ES⁺：574.1MS ES⁺ : 574.1

¹H NMR (400 MHz, DMSO-d₆) δ = 9.56 (s, 1H), 8.16 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J = 9.0 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.66 - 3.58 (m, 6H), 3.55 - 3.46 (m, 16H), 3.06 (s, 3H)步驟16：8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮¹ H NMR (400 MHz, DMSO-d₆ ) δ = 9.56 (s, 1H), 8.16 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J = 9.0 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.66 - 3.58 (m, 6H), 3.55 - 3.46 (m, 16H), 3.06 (s, 3H)Step 16 ：8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one

將於無水DMF (1 mL)中之8-(4-((17-氯-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)色烯并[7,8-d]咪唑-6(3H)-酮(180 mg, 0.314 mmol, 1 eq)及疊氮化鈉(102 mg, 1.568 mmol, 5 eq)在70℃下加熱12小時。使混合物冷卻，用水(10 mL)稀釋，用DCM (50 mL)萃取，經Na₂SO₄乾燥，過濾，濃縮且藉由管柱層析使用0-20% MeOH/DCM進行純化，得到呈黃色膠狀物之作為互變異構混合物(28:72)之標題化合物(50 mg, 25%)，根據LCMS，其純度＞95%。8-(4-((17-Chloro-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one (180 mg, 0.314 mmol, 1 eq) and sodium azide (102 mg, 1.568 mmol, 5 eq) in anhydrous DMF (1 mL) were heated at 70 °C for 12 h. The mixture was cooled, diluted with water (10 mL), extracted with DCM (50 mL), dried_overNa2SO4 , filtered, concentrated and purified by column chromatography using 0-20% MeOH/DCM to afford the title compound (50 mg, 25%) as a yellow gum as a tautomeric mixture (28:72) with a purity >95% by LCMS.

LCMS m/z = 681 (M⁺+1)LCMS m/z = 681 (M⁺⁺ 1)

¹H NMR (499 MHz, DMSO-d₆) δ 13.09 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 9.1 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.91 - 6.81 (m, 2H), 6.83 (s, 1H), 3.67 - 3.60 (m, 3H), 3.58 - 3.54 (m, 2H), 3.54 - 3.47 (m, 18H), 3.36 (m, 2H), 3.05 (s, 3H)實例22：8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮(BA-170及互變異構物BA-201)之製備步驟1：8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮¹ H NMR (499 MHz, DMSO-d₆ ) δ 13.09 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 9.1 Hz, 2H) , 7.85 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.91 - 6.81 (m, 2H), 6.83 (s, 1H), 3.67 - 3.60 (m, 3H), 3.58 - 3.54 (m, 2H), 3.54 - 3.47 ( m, 18H), 3.36 (m, 2H), 3.05 (s, 3H)Example 22: 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methyl Preparation of chromeno[7,8-d]imidazol-6(3H)-one (BA-170 and its tautomer BA-201)Step 1 : 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methylchromatographic Olen[7,8-d]imidazol-6(3H)-one

向7,8-二胺基-2-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-4H-色烯-4-酮(700 mg, 1.28 mmol, 1eq)於乙腈(15 mL)中之溶液中添加1,1,1-三甲氧基乙烷(169.55 mg, 1.41 mmol, 1.1eq)及碘(32.56 mg, 128.29 μmol, 25.84 μL, 0.1eq)。將混合物在25℃下攪拌1小時，且接著藉由添加NaHSO₃水溶液(20 mL)淬滅，並用乙酸乙酯(20 mL × 3)萃取。將合併的有機萃取物用鹽水(40 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾，濃縮且藉由急速矽膠層析(ISCO®；20 g SepaFlash®二氧化矽急速管柱，0~15% MeOH/DCM梯度溶析液，100 mL/min)進行純化，得到呈褐色膠狀物之標題化合物(470 mg, 64%)。To a solution of 7,8-diamino-2-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-4H-chromen-4-one (700 mg, 1.28 mmol, 1eq ) in acetonitrile (15 mL) were added 1,1,1-trimethoxyethane (169.55 mg, 1.41 mmol, 1.1eq ) and iodine (32.56 mg, 128.29 μmol, 25.84 μL, 0.1eq ). The mixture was stirred at 25° C. for 1 hour, and then quenched by the addition of aqueous NaHSO₃ solution (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (40 mL × 1), dried over anhydrous Na₂ SO₄ , filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-15% MeOH/DCM gradient eluent, 100 mL/min) to give the title compound (470 mg, 64%) as a brown gum.

MS ES⁺：570.2步驟2：8-(4-((17-氯-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮MS ES⁺ : 570.2Step 2 : 8-(4-((17-chloro-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one

向8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮(400 mg, 702.19 umol, 1eq)於DCM (6 mL)中之溶液中添加SOCl₂(835.40 mg, 7.02 mmol, 509.39 μL, 10eq)。將混合物在25℃下攪拌4小時，且接著傾倒至飽和NaHCO₃水溶液(40 mL)中，並用乙酸乙酯(40 mL × 3)萃取。將合併的有機萃取物用鹽水(80 mL × 1)洗滌，經無水Na₂SO₄乾燥，過濾並濃縮，得到呈褐色膠狀物之作為互變異構物混合物之標題化合物(320 mg, 71%)。To a solution of 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one (400 mg, 702.19 umol, 1eq ) in DCM (6 mL) was added SOCl₂ (835.40 mg, 7.02 mmol, 509.39 μL, 10eq ). The mixture was stirred at 25 °C for 4 h, and then poured into saturated aqueous NaHCO₃ solution (40 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with brine (80 mL x 1), dried over anhydrous_Na2SO4, filtered and concentrated to give the title compound as a mixture of tautomeric isomers as a brown gum (320 mg, 71%).

MS ES⁺：588.3MS ES⁺ : 588.3

¹H NMR (400 MHz, DMSO-d₆) δ = 8.08 - 7.85 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.50 (br d, J = 8.3 Hz, 1H), 6.87 (br d, J = 8.9 Hz, 2H), 6.79 (s, 1H), 3.70 - 3.66 (m, 2H), 3.66 - 3.60 (m, 6H), 3.54 - 3.47 (m, 16H), 3.05 (s, 3H), 2.61 (s, 3H)。步驟3：8-(4-((17-疊氮基-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.08 - 7.85 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.50 (br d, J = 8.3 Hz, 1H), 6.87 ( br d, J = 8.9 Hz, 2H), 6.79 (s, 1H), 3.70 - 3.66 (m, 2H), 3.66 - 3.60 (m, 6H), 3.54 - 3.47 (m, 16H), 3.05 (s, 3H), 2.61 (s, 3H).Step 3 : 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methylchromatographic Olen[7,8-d]imidazol-6(3H)-one

將於無水DMF (2 mL)中之8-(4-((17-氯-3,6,9,12,15-五氧雜十七烷基)(甲基)胺基)苯基)-2-甲基色烯并[7,8-d]咪唑-6(3H)-酮(310 mg, 0.527 mmol, 1 eq)及疊氮化鈉(171 mg, 2.63 mmol, 5 eq)在70℃下加熱12小時。使混合物冷卻，用水(20 mL)稀釋且用DCM (100 mL)萃取。使有機萃取物經Na₂SO₄乾燥，過濾，濃縮且藉由管柱層析(0-20% MeOH/DCM)進行純化，得到呈深橙色膠狀物之作為互變異構物混合物BA-170:BA-201 (30:70)之標題化合物(120 mg, 38%)，純度＞95%。8-(4-((17-Chloro-3,6,9,12,15-pentaoxaheptadecanyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one (310 mg, 0.527 mmol, 1 eq) and sodium azide (171 mg, 2.63 mmol, 5 eq) in anhydrous DMF (2 mL) were heated at 70 °C for 12 h. The mixture was cooled, diluted with water (20 mL) and extracted with DCM (100 mL). The organic extract_was dried over_Na2SO4 , filtered, concentrated and purified by column chromatography (0-20% MeOH/DCM) to afford the title compound (120 mg, 38%) as a dark orange gum as a mixture of tautomeric isomers BA-170:BA-201 (30:70) with a purity >95%.

LCMS m/z = 595 (M+1)LCMS m/z = 595 (M+1)

¹H NMR證實互變異構結構： BA-170異構物，其中7-NH質子出現在進一步低場之δ13.38處；及 BA-201異構物，其中9-NH質子出現在高場之δ12.98處¹ H NMR confirmed the tautomeric structures: BA-170 isomer, in which the 7-NH proton appears further downfield atδ 13.38; and BA-201 isomer, in which the 9-NH proton appears upfield atδ 12.98

藉由急速管柱層析進一步純化BA-170互變異構混合物(80 mg)，獲得呈深橙色膠狀物之純BA-201 (50 mg)。The BA-170 tautomeric mixture (80 mg) was further purified by flash column chromatography to obtain pure BA-201 (50 mg) as a dark orange gum.

BA-170：¹H NMR：(499 MHz, DMSO-d₆) δ 13.38, 12.85 (2s, 1H), 8.09, 7.94 (d,J= 8.7 Hz, 2H), 7.77, 7.72 (d,J= 8.5 Hz, 1H), 7.54, 7.47 (d,J= 8.5 Hz, 1H), 6.88, 6.85 (d, J = 9.0 Hz, 2H), 6.81, 6.79 (s, 1H), 3.67 - 3.62 (m, 2H), 3.58 - 3.54 (m, 2H), 3.54 - 3.45 (m, 16H), 3.38 - 3.35 (m, 2H), 3.06, 3.05 (s, 3H), 2.63, 2.60 (s, 3H)。BA-170:¹ H NMR: (499 MHz, DMSO-d₆ ) δ 13.38, 12.85 (2s, 1H), 8.09, 7.94 (d,J = 8.7 Hz, 2H), 7.77, 7.72 (d,J = 8.5 Hz, 1H), 7.54, 7.47 (d,J = 8.5 Hz, 1H), 6.88, 6.85 (d, J = 9.0 Hz, 2H), 6.81, 6.79 (s, 1H), 3.67 - 3.62 (m, 2H), 3.58 - 3.54 (m, 2H ), 3.54 - 3.45 (m, 16H), 3.38 - 3.35 (m, 2H), 3.06, 3.05 (s, 3H), 2.63, 2.60 (s, 3H).

BA-201：¹H NMR (499 MHz, DMSO-d₆) δ 12.98 (s, 1H), 7.98 (d,J= 8.7 Hz, 2H), 7.76 (d,J= 8.5 Hz, 1H), 7.50 (d,J= 8.5 Hz, 1H), 6.87 (d,J= 9.0 Hz, 2H), 6.80 (s, 1H), 3.62 (m, 4H), 3.58 - 3.54 (m, 2H), 3.54 - 3.45 (m, 16H), 3.40 - 3.34 (m, 2H), 3.05 (s, 3H), 2.61 (s, 3H)。實例23：N-(18-疊氮基-3,6,9,12,15-五氧雜十八烷基)-4-(7,8-雙(烯丙基氧基)-4-側氧基-4H-色烯-2-基)苯甲醯胺(BA-203)BA-201:¹ H NMR (499 MHz, DMSO-d₆ ) δ 12.98 (s, 1H), 7.98 (d,J = 8.7 Hz, 2H), 7.76 (d,J = 8.5 Hz, 1H), 7.50 ( d,J = 8.5 Hz, 1H), 6.87 (d,J = 9.0 Hz, 2H), 6.80 (s, 1H), 3.62 (m, 4H), 3.58 - 3.54 (m, 2H), 3.54 - 3.45 (m, 16H), 3.40 - 3.34 (m, 2H), 3.05 ( s, 3H), 2.61 (s, 3H).Example 23: N-(18-azido-3,6,9,12,15-pentaoxoctadecyl)-4-(7,8-bis(allyloxy)-4- Oxy-4H-chromen-2-yl)benzamide (BA-203)

在室溫下向N-(18-疊氮基-3,6,9,12,15-五氧雜十八烷基)-4-(7,8-二羥基-4-側氧基-4H-色烯-2-基)苯甲醯胺(BA-118, 200 mg, 0.34 mmol, 1 eq)於DMF (5 mL)中之溶液中添加K₂CO₃(94 mg, 0.68 mmol, 2 eq)，之後添加烯丙基溴(35.2 uL, 0.408 mmol, 1.2 eq)，且接著將混合物加熱至80℃持續3小時。接著過濾混合物，使過量DMF與庚烷共沸。藉由急速層析(25 g biotage 20微米) 0至10% DCM/MeOH 10 CV進行純化，得到呈黃色油狀物之標題化合物(140 mg, 62%)。To a solution of N-(18-azido-3,6,9,12,15-pentaoxaoctadecyl)-4-(7,8-dihydroxy-4-oxo-4H-chromen-2-yl)benzamide (BA-118, 200 mg, 0.34 mmol, 1 eq) in DMF (5 mL) was added K₂ CO₃ (94 mg, 0.68 mmol, 2 eq) followed by allyl bromide (35.2 uL, 0.408 mmol, 1.2 eq) at room temperature and the mixture was then heated to 80° C. for 3 hours. The mixture was then filtered and the excess DMF was azeotroped with heptane. Purification by flash chromatography (25 g biotage 20 micron) 0 to 10% DCM/MeOH 10 CV gave the title compound as a yellow oil (140 mg, 62%).

LCMS：m/z 689 (M⁺+Na)LCMS: m/z 689 (M⁺ +Na)

¹H NMR (499 MHz, DMSO-d₆) δ 8.71 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 6.13 (dddt, J = 24.8, 16.0, 10.4, 5.4 Hz, 2H), 5.51 - 5.39 (m, 2H), 5.32 (d, J = 10.6 Hz, 1H), 5.27 (d, J = 10.4 Hz, 1H), 4.79 (d, J = 5.0 Hz, 2H), 4.70 (d, J = 5.9 Hz, 2H), 3.60 - 3.48 (m, 20H), 3.45 (q, J = 6.0 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H)。配位體結合之寡核苷酸之製備¹ H NMR (499 MHz, DMSO-d₆ ) δ 8.71 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 6.13 (dddt, J = 24.8, 16.0, 10.4, 5.4 Hz, 2H), 5.51 - 5.39 (m, 2H), 5.32 (d, J = 10.6 Hz, 1H), 5.27 (d, J = 10.4 Hz, 1H), 4.79 (d, J = 5.0 Hz, 2H), 4.70 (d, J = 5.9 Hz, 2H), 3.60 - 3.48 (m, 20H), 3.45 (q, J = 6.0 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H). Preparation ofligand-conjugatedoligonucleotides

屬於本揭示案範圍內之例示性配位體結合之寡核苷酸可根據以下程序來合成。Exemplary ligand-conjugated oligonucleotides within the scope of the present disclosure can be synthesized according to the following procedure.

在一些情況下，一種配位體(下文所闡述之一般程序中之配位體A)與寡核苷酸之5'端結合。In some cases, a ligand (ligand A in the general procedures described below) is bound to the 5' end of the oligonucleotide.

在一些情況下，兩種相同的配位體(配位體A及配位體A)與寡核苷酸之5'端及3'端結合。In some cases, two identical ligands (Ligand A and Ligand A) are bound to the 5' and 3' ends of the oligonucleotide.

在一些情況下，兩種不同的配位體(配位體A及配位體B)與寡核苷酸之5’端及3'端結合。In some cases, two different ligands (Ligand A and Ligand B) are bound to the 5' and 3' ends of the oligonucleotide.

在一些情況下，一種配位體(配位體A)與寡核苷酸之3'端結合。實例24：A型一般程序I -配位體與有義股之5’端結合步驟1：5'-DBCO官能化之有義股In some cases, one ligand (ligand A) is bound to the 3' end of the oligonucleotide.Example 24: Type A General Procedure I - Ligand Binding to the 5' End of the Sense StrandStep 1 : 5'-DBCO functionalized sense strand

將磷酸鈉緩衝液(10% V/V, 1 M, pH 7)及乙腈(20%-50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液，藉由凍乾乾燥且將乾燥之5'- DBCO官能化之有義股在無RNA酶之水中重構。步驟2：5’-配位體結合之有義股Sodium phosphate buffer (10% V/V, 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation and the aqueous solution was purified by reverse phase HPLC, dried by freeze drying and the dried 5'-DBCO functionalized sense strand was reconstituted in RNase-free water.Step 2 : 5'-ligand bound sense strand

將配位體A-N₃(2 eq)於DMSO或THF中之溶液添加至5’-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。實例25：B型一般程序I -配位體與有義股之5’端結合步驟1：5'-DBCO官能化之有義股A solution of ligand AN₃ (2 eq) in DMSO or THF was added to a solution of 5'-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 25: Type B General Procedure I - Ligand conjugation to the 5' end of the sense strandStep 1 : 5'-DBCO functionalized sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由用磷酸鈉緩衝液(100 mM, pH 7, 3×)截留分子量去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，藉由反相HPLC純化溶液，藉由凍乾乾燥且將乾燥產物在無RNA酶之水中重構。步驟2：5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by using a sodium phosphate buffer (100 mM, pH 7, 3×) molecular weight cutoff. A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation, the solution was purified by reverse phase HPLC, dried by freeze drying, and the dried product was reconstituted in RNase-free water.Step 2 : 5'-ligand-bound sense strand

向5’-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N₃(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。實例26：A型一般程序II -雙-同-3',5'-配位體結合之有義股步驟1：3’,5’-雙-DBCO修飾之有義股To a solution of the 5'-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN₃ (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 26: Type A General Procedure II - Bi-homo -3',5'-ligand conjugated sense strandStep 1 : 3',5'-Bis-DBCO modified sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20%-50% V/V)添加至3’,5’胺官能化之有義股之水溶液中。接著添加DBCO-NHS (3 eq)於DMSO或CH₃CN中之溶液，且藉由LCMS及HPLC監測反應。完成後，藉由反相HPLC純化產物，藉由凍乾乾燥，且在無RNA酶之水中重構。步驟2：3’,5’-雙結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 3',5' amine functionalized sense strand. A solution of DBCO-NHS (3 eq) in DMSO or CH₃ CN was then added and the reaction was monitored by LCMS and HPLC. Upon completion, the product was purified by reverse phase HPLC, dried by lyophilization, and reconstituted in RNase-free water.Step 2 : 3',5'-double conjugated sense strand

將配位體A-N₃(3 eq)於DMSO或CH₃CN中之溶液添加至3’,5’-雙-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化3’,5’-雙結合之有義股，藉由凍乾乾燥，在無RNA酶之水中重構，且使用Amicon^®Ultra-15離心過濾器(3K，5次)去鹽。實例27：B型一般程序II -雙-同-5',3'-配位體結合之有義股步驟1：3’,5’-雙-DBCO修飾之有義股A solution of ligand AN₃ (3 eq) in DMSO or CH₃ CN was added to a solution of 3',5'-bis-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3',5'-bis-conjugated sense strand was purified by reverse phase HPLC, dried by lyophilization, reconstituted in RNase-free water, and desalted using an Amicon^® Ultra-15 centrifugal filter (3K, 5 times).Example 27: Type B General Procedure II - Bi-homo -5',3'-ligand conjugated sense strandStep 1 : 3',5'-Bis-DBCO modified sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’, 3’-雙(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構。步驟2：3’,5’-雙結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5', 3'-bis(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP) (25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried double-DBCO modified sense strand was reconstituted in RNase-free water.Step 2 : 3',5'-double conjugated sense strand

向5’,3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N₃(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。實例28：C型一般程序II -雙-同-5',3'-配位體結合之有義股步驟1：5'-DBCO / 3'-(C6-SS-C6)-mC官能化之有義股To a solution of 5',3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN₃ (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 28: Type C General Procedure II - Bis-homo -5',3'-ligand conjugated sense strandStep 1 : 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20% -50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液。將產物流份合併，藉由凍乾乾燥，且將乾燥之N-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟2。步驟2：5',3'-雙DBCO官能化之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20% -50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, and the aqueous solution was purified by reverse phase HPLC. The product fractions were combined, dried by freeze drying, and the dried N-DBCO-modified sense strand was reconstituted in RNase-free water for use in step 2.Step 2 : 5',3'-Bis-DBCO-functionalized sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-DBCO / 3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟3。步驟3：雙-同-5',3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense strand was reconstituted in RNase-free water for use in step 3.Step 3 : Bi-homo -5',3'-ligand bound sense strand

向5’-, 3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N₃(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。藉由HPLC及LCMS確認產物。實例29：D型一般程序II -雙-同-5',3'-配位體結合之有義股步驟1：5'-(C6-SS-C6)-mC / 3'-DBCO官能化之有義股To a solution of 5'-, 3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN₃ (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-ligand-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.Example 29: General Procedure II for Form D - Bis-homo -5', 3'-ligand-conjugated sense strandStep 1 : 5'-(C6-SS-C6)-mC/3'-DBCO functionalized sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20% -50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液。將產物流份合併，藉由凍乾乾燥，且將乾燥之N-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟2。步驟2：5',3'-雙DBCO官能化之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20% -50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, and the aqueous solution was purified by reverse phase HPLC. The product fractions were combined, dried by freeze drying, and the dried N-DBCO-modified sense strand was reconstituted in RNase-free water for use in step 2.Step 2 : 5',3'-Bis-DBCO-functionalized sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-DBCO / 3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟3。步驟3：雙-同-5',3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense strand was reconstituted in RNase-free water for use in step 3.Step 3 : Bi-homo -5',3'-ligand bound sense strand

向5’-, 3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N₃(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。藉由HPLC及LCMS確認產物。實例30：A型一般程序III -雙-雜-3',5'-配位體結合之有義股步驟1：5’-結合之3’-(C6-SS-C6)-mC官能化之有義股To a solution of 5'-, 3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN₃ (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.Example 30: Type A General Procedure III - Bis-hetero -3',5'-ligand conjugated sense strandStep 1 : 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand

將配位體A-N₃(2 eq)於DMSO中之溶液添加至5’-DBCO修飾之有義股(1 eq，關於製備參見上文)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon^®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。步驟2：5’-結合之3’-DBCO修飾之有義股A solution of ligand AN₃ (2 eq) in DMSO was added to an aqueous solution of 5'-DBCO-modified sense strand (1 eq, see above for preparation) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an^Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Step 2 : 5'-conjugated 3'-DBCO-modified sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-結合之3’-(C6-SS-C6)-mC官能化之有義股(1 eq)於水中之溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之5’-結合之3’-DBCO修飾之有義股在磷酸鈉緩衝液(100 mM)中重構以用於步驟3。步驟3：雙-異-3',5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to a solution of 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand (1 eq) in water. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by HPLC and LCMS. Upon completion, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 5'-conjugated 3'-DBCO modified sense strand was reconstituted in sodium phosphate buffer (100 mM) for use in step 3.Step 3 : Bis-iso -3',5'-ligand conjugated sense strand

將配位體B-N₃(2 eq)於DMSO中之溶液添加至5’-結合之3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon^®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-, 3’-結合之有義股。實例31：B型一般程序III -雙-雜-3',5'-配位體結合之有義股步驟1：5'-(C6-SS-C6)-mC, 3’-結合之有義股A solution of ligand_BN3 (2 eq) in DMSO was added to an aqueous solution of 5'-conjugated 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an^Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 31: Type B General Procedure III - Bis-Hybrid -3',5'-Ligand Conjugated Sense StrandStep 1 : 5'-(C6-SS-C6)-mC, 3'-conjugated sense strand

將配位體A-N₃(2 eq)於DMSO中之溶液添加至3'-DBCO修飾之有義股(1 eq，關於製備參見上文)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon^®Ultra-15離心過濾器(3K，5次)截留分子量來純化3’-結合之有義股。步驟2：5’-DBCO, 3’-結合之有義股A solution of ligand AN₃ (2 eq) in DMSO was added to an aqueous solution of 3'-DBCO-modified sense strand (1 eq, see above for preparation) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon^® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Step 2 : 5'-DBCO, 3'-conjugated sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-結合之3’-(C6-SS-C6)-mC官能化之有義股(1 eq)於水中之溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之5’-結合之3’-DBCO修飾之有義股在磷酸鈉緩衝液(100 mM)中重構以用於步驟3。步驟3：雙-異-3',5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to a solution of 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand (1 eq) in water. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by HPLC and LCMS. Upon completion, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 5'-conjugated 3'-DBCO modified sense strand was reconstituted in sodium phosphate buffer (100 mM) for use in step 3.Step 3 : Bis-iso -3',5'-ligand conjugated sense strand

將配位體B-N₃(2 eq)於DMSO中之溶液添加至5’-結合之3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon^®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-, 3’-結合之有義股。實例32：A型一般程序IV -配位體與有義股之3’端結合步驟1：3’- DBCO修飾之有義股A solution of ligand_BN3 (2 eq) in DMSO was added to an aqueous solution of 5'-conjugated 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an^Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 32: Type A General Procedure IV - Ligand conjugation to the 3' end of the sense strandStep 1 : 3'-DBCO modified sense strand

將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH=7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之3’-DBCO修飾之有義股在100 mM磷酸鈉緩衝液中重構以用於步驟2。步驟2：3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP, 25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH=7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by HPLC and LCMS. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 3'-DBCO modified sense strand was reconstituted in 100 mM sodium phosphate buffer for use in step 2.Step 2 : 3'-ligand bound sense strand

將配位體A-N₃(3 eq)於DMSO中之溶液添加至3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5×)截留分子量來純化3’-結合之有義股。實例33：B型一般程序IV -配位體與有義股之3’端結合步驟1：3'-DBCO官能化之有義股A solution of ligand AN₃ (3 eq) in DMSO was added to an aqueous solution of 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5x) molecular weight cutoff.Example 33: Type B General Procedure IV - Ligand conjugation to the 3' end of the sense strandStep 1 : 3'-DBCO functionalization of the sense strand

將磷酸鈉緩衝液(10% V/V, 1 M, pH 7)及乙腈(20%-50% V/V)添加至3’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之DBCO修飾之有義股在無RNA酶之水中重構。步驟2：3’-配位體結合之有義股Sodium phosphate buffer (10% V/V, 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 3'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried DBCO-modified sense strand was reconstituted in RNase-free water.Step 2 : 3'-ligand-bound sense strand

將配位體A-N₃(2 eq)於DMSO或THF中之溶液添加至3’-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化3’-結合之有義股。實例34：雙-5'-, 3'-結合之有義股RD3937 5' BA-120 / 3' BA-120 FXXXXXXXIV+IS1525+FXXXXXXXV SEQ: RD3181 / 5'EPA solution of ligand AN₃ (2 eq) in DMSO or THF was added to a solution of 3'-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Example 34: Double-5'-, 3'-conjugated sense strand RD3937 5' BA-120 / 3' BA-120 FXXXXXXXIV+IS1525+FXXXXXXXV SEQ: RD3181 / 5'EP

根據C型一般程序II，使BA-120與寡有義股結合。產物製備純度為90%，且由HPLC證實。BA-120 was conjugated to the oligosense strand according to General Procedure II, Type C. The product was prepared with 90% purity and confirmed by HPLC.

LCMS：m/z: 9418.9 (計算值9420.6g/mol)實例35：單5'結合之有義股RD3666 5' BA-120 FXXXXXXXIV+IS1402 SEQ: RD3181 / 5'VPLCMS: m/z: 9418.9 (calcd. 9420.6 g/mol)Example 35: Single 5' sense strand RD3666 5' BA-120 FXXXXXXXIV+IS1402 SEQ: RD3181 / 5'VP

根據A型一般程序I，使BA-120與寡有義股結合。產物製備純度為92%，由HPLC證實。BA-120 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 92% purity as confirmed by HPLC.

LCMS：m/z 8342.7 (計算值8344.2 g/mol)實例36：單5'結合之有義股RD3913 5' BA-168 FXXXXXXXVI+IS1402 SEQ: RD3181 / 5'EPLCMS: m/z 8342.7 (calcd. 8344.2 g/mol)Example 36: Single 5' sense strand RD3913 5' BA-168 FXXXXXXXVI+IS1402 SEQ: RD3181 / 5'EP

根據A型一般程序I，使BA-168與寡有義股結合。產物製備純度為92%，由HPLC證實。BA-168 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 92% purity as confirmed by HPLC.

LCMS：m/z: 8620.5 (計算值8622.2 g/mol)實例37：單5'結合之有義股RD3995 5' BA-177 FXXXXXXXVII+IS1402 SEQ: RD3181 / 5'EPLCMS: m/z: 8620.5 (calcd. 8622.2 g/mol)Example 37: Single 5' sense strand RD3995 5' BA-177 FXXXXXXXVII+IS1402 SEQ: RD3181 / 5'EP

根據A型一般程序I，使BA-177與寡有義股結合。產物製備純度為97%，由HPLC證實。BA-177 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 97% purity as confirmed by HPLC.

LCMS：m/z: 8441.8 (計算值8443.3 g/mol)實例38：單5'結合之有義股RD4389 5' BA-177 FXXXXXXXVII+IS1640 SEQ: RD3953 / 5'EPLCMS: m/z: 8441.8 (calcd. 8443.3 g/mol)Example 38: Single 5' conjugated sense strand RD4389 5' BA-177 FXXXXXXXVII+IS1640 SEQ: RD3953 / 5'EP

根據A型一般程序I，使BA-177與寡有義股結合。產物製備純度為93%，由HPLC證實。BA-177 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 93% purity as confirmed by HPLC.

LCMS：m/z: 8900.7 (計算值8898.9 g/mol)實例39：雙5'-, 3'-結合之有義股RD6054 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2460+LK0181 5'VPLCMS: m/z: 8900.7 (calcd. 8898.9 g/mol)Example 39: Double 5'-, 3'-linked sense strand RD6054 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2460+LK0181 5'VP

根據A型一般程序II，使BA-236與寡有義股結合。產物製備純度為93%，且由HPLC證實。BA-236 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 93% purity and confirmed by HPLC.

LCMS：m/z: 9401.6 (計算值9403.2 g/mol) 及實例40：雙5'-, 3'-結合之有義股RD6039 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2458+FXXXXXXXVIIILCMS: m/z: 9401.6 (calcd. 9403.2 g/mol) andExample 40: Double 5'-, 3'-conjugated sense strand RD6039 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2458+FXXXXXXXVIII

根據A型一般程序II，使BA-236與寡有義股結合。產物製備純度為95%，且由HPLC證實。BA-236 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 95% purity and confirmed by HPLC.

LCMS：m/z: 9045.3 (計算值9046.9g/mol) 及實例41：雙5'-, 3'-結合之有義股RD6044 5' BA-236 / 3' BA-236 FXXXXXXXVIII+ IS1664+FXXXXXXXVIIILCMS: m/z: 9045.3 (calcd. 9046.9 g/mol) andExample 41: Double 5'-, 3'-conjugated sense strand RD6044 5' BA-236 / 3' BA-236 FXXXXXXXVIII+ IS1664+FXXXXXXXVIII

根據A型一般程序II，使BA-236與寡有義股結合。產物製備純度為97%，且由HPLC證實。BA-236 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 97% purity and confirmed by HPLC.

LCMS：m/z: 9100.4 (計算值9102.0g/mol) 及實例42：雙5'-, 3'-結合之有義股RD6049 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2459+FXXXXXXXVIIILCMS: m/z: 9100.4 (calcd. 9102.0 g/mol) andExample 42: Double 5'-, 3'-conjugated sense strand RD6049 5' BA-236 / 3' BA-236 FXXXXXXXVIII+IS2459+FXXXXXXXVIII

根據A型一般程序II，使BA-236與寡有義股結合。產物製備純度為92%，且由HPLC證實。BA-236 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 92% purity and confirmed by HPLC.

LCMS：m/z: 9082.3 (計算值9084.0g/mol)實例43：單5'結合之有義股RD4518 5' BA-236 FXXXXXXXVIII+IS1640 SEQ: RD3953 / 5'EPLCMS: m/z: 9082.3 (calcd. 9084.0 g/mol)Example 43: Single 5' sense strand RD4518 5' BA-236 FXXXXXXXVIII+IS1640 SEQ: RD3953 / 5'EP

根據A型一般程序類型I，使BA-120與寡有義股結合。產物製備純度為95%，由HPLC證實。BA-120 was conjugated to the oligosense strand according to Type A General Procedure Type I. The product was prepared with 95% purity as confirmed by HPLC.

LCMS：m/z: 8641.4 (計算值8639.7 g/mol)實例44：單5'結合之有義股RD3941 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS1525+FXXXXXXXXIV SEQ: RD3181 / 5'EPLCMS: m/z: 8641.4 (calcd. 8639.7 g/mol)Example 44: Single 5' sense strand RD3941 5' BA-128 / 3' BA-128 FXXXXXXXIX + IS1525 + FXXXXXXXXIV SEQ: RD3181 / 5' EP

根據C型一般程序II，使BA-128與寡有義股結合。產物製備純度為96%，由HPLC證實。BA-128 was conjugated to the oligosense strand according to General Procedure II, Type C. The product was prepared with 96% purity as confirmed by HPLC.

LCMS：m/z: 9482.4 (計算值9483.4 g/mol)(AC6)*(mC)*(mG)(mC)(mA)(mU)(mG)(fG)(mU)(fC)(fA)(fG)(fU)(mA)(mA)(mA)(mA)(mG)(mC)(mA)(mA)*(mA)*(SC6)(mC)IA1156(eU)*(fU)*(mU)(fG)(mC)(fU)(mU)(fU)(mU)(fA)(mC)(fU)(mG)(fA)(mC)(fC)(mA)(fU)(mG)(fC)(mG)*(mA)*(mG)實例45：雙-5'-, 3'-結合之有義股RD6037 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2458+FXXXXXXXIXLCMS: m/z: 9482.4 (calcd. 9483.4 g/mol) (AC6)*(mC)*(mG)(mC)(mA)(mU)(mG)(fG)(mU)(fC)(fA)(fG)(fU)(mA)(mA)(mA)(mA)(mG)(mC)(mA)(mA)*(mA)*(SC6)(mC) IA1156 (eU )*(fU)*(mU)(fG)(mC)(fU)(mU)(fU)(mU)(fA)(mC)(fU)(mG)(fA)(mC)(fC)(mA)(fU)(mG)(fC)(mG)*(mA)*(mG)Example 45: Double-5'-, 3'-conjugated sense strand RD6037 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2458+FXXXXXXXIX

根據A型一般程序II，使BA-128與寡有義股結合。產物製備純度為97%，且由HPLC證實。BA-128 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 97% purity and confirmed by HPLC.

LCMS：m/z: 9429.1 (計算值9430.7 g/mol) 及實例46：雙-5'-, 3'-結合之有義股RD6047 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2459+FXXXXXXXIXLCMS: m/z: 9429.1 (calcd. 9430.7 g/mol) andExample 46: Bis-5'-, 3'-conjugated sense strand RD6047 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2459+FXXXXXXXIX

根據A型一般程序II，使BA-128與寡有義股結合。產物製備純度為90%，且由HPLC證實。BA-128 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 90% purity and confirmed by HPLC.

LCMS：m/z: 9466.1 (計算值9467.8 g/mol) 及實例47：雙-5'-, 3'-結合之有義股RD6042 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS1664+FXXXXXXXIXLCMS: m/z: 9466.1 (calcd. 9467.8 g/mol) andExample 47: Bis-5'-, 3'-conjugated sense strand RD6042 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS1664+FXXXXXXXIX

根據A型一般程序II，使BA-128與寡有義股結合。產物製備純度為98%，且由HPLC證實。BA-128 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 98% purity and confirmed by HPLC.

LCMS：m/z: 9785.3 (計算值9485.8 g/mol) 及實例48：雙-5'-, 3'-結合之有義股RD6052 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2460+FXXXXXXXIXLCMS: m/z: 9785.3 (calcd. 9485.8 g/mol) andExample 48: Bis-5'-, 3'-conjugated sense strand RD6052 5' BA-128 / 3' BA-128 FXXXXXXXIX+IS2460+FXXXXXXXIX

根據A型一般程序II，使BA-128與寡有義股結合。產物製備純度為90%，且由HPLC證實。BA-128 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 90% purity and confirmed by HPLC.

LCMS：m/z: 9785.3 (計算值9787.0 g/mol)實例49：單5'結合之有義股RD3667 5' BA-128 FXXXXXXXIX+IS1402 SEQ: RD3181 / 5'VPLCMS: m/z: 9785.3 (calcd. 9787.0 g/mol)Example 49: Single 5' sense strand RD3667 5' BA-128 FXXXXXXXIX+IS1402 SEQ: RD3181 / 5'VP

根據A型一般程序I，使BA-128與寡有義股結合。產物製備純度為97%，由HPLC證實。BA-128 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 97% purity as confirmed by HPLC.

LCMS：m/z: 8374.4 (計算值8375.9 g/mol)實例50：單5'結合之有義股RD3971 5' BA-171 FXXXXXXX+IS1402 SEQ: RD3181 / 5'EPLCMS: m/z: 8374.4 (calcd. 8375.9 g/mol)Example 50: Single 5' sense strand RD3971 5' BA-171 FXXXXXXX+IS1402 SEQ: RD3181 / 5'EP

根據A型一般程序I，使BA-171與寡有義股結合。產物製備純度為98%，由HPLC證實。BA-171 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 98% purity as confirmed by HPLC.

LCMS：m/z: 8456.9 (計算值8458.4 g/mol) 及實例51：單5'結合之有義股RD4387 5' BA-171 FXXXXXXX+IS1640 SEQ: RD3953 / 5'EPLCMS: m/z: 8456.9 (calcd. 8458.4 g/mol) andExample 51: Single 5' conjugated sense strand RD4387 5' BA-171 FXXXXXXX+IS1640 SEQ: RD3953 / 5'EP

根據A型一般程序I，使BA-171與寡有義股結合。產物製備純度為89%，由HPLC證實。BA-171 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 89% purity as confirmed by HPLC.

LCMS：m/z: 8915.8 (計算值8914.0 g/mol)實例52：雙5'-, 3'-結合之有義股RD4235 5' BA-171 /3' BA-171 FXXXXXXX+IS1525+FXXXXXXXX SEQ: RD3181 / 5'EPLCMS: m/z: 8915.8 (calcd. 8914.0 g/mol)Example 52: Double 5'-, 3'-linked sense strand RD4235 5' BA-171 /3' BA-171 FXXXXXXX+IS1525+FXXXXXXXX SEQ: RD3181 / 5'EP

根據C型一般程序II，使BA-171與寡有義股結合。產物製備純度為89%，由HPLC證實。BA-171 was conjugated to the oligosense strand according to General Procedure II, Type C. The product was prepared with 89% purity as confirmed by HPLC.

LCMS：m/z: 9664.9 (計算值9666.9 g/mol)實例53：雙5'-, 3'-結合之有義股RD4420 5' BA-171 /3' BA-171 FXXXXXXXX+IS1641+FXXXXXXXX SEQ: RD3953 / 5'EPLCMS: m/z: 9664.9 (calcd. 9666.9 g/mol)Example 53: Double 5'-, 3'-binding sense strand RD4420 5' BA-171 /3' BA-171 FXXXXXXXX+IS1641+FXXXXXXXX SEQ: RD3953 / 5'EP

根據B型一般程序II，使BA-171與寡有義股結合。產物製備純度為98%，由HPLC證實。BA-171 was conjugated to the oligosense strand according to General Procedure II, Type B. The product was prepared with 98% purity as confirmed by HPLC.

LCMS：m/z: 9794.2 (計算值9795.9 g/mol)實例54：單5'結合之有義股RD4336 5' BA-210 FXXXXXXXXI+IS1402 SEQ: RD3181 / 5'EPLCMS: m/z: 9794.2 (calcd. 9795.9 g/mol)Example 54: Single 5' sense strand RD4336 5' BA-210 FXXXXXXXXI+IS1402 SEQ: RD3181 / 5'EP

根據A型一般程序I，使BA-210與寡有義股結合。製備純度為96%，由HPLC證實。BA-210 was conjugated to the oligosense strand according to Type A General Procedure I. The purity of the preparation was 96% as confirmed by HPLC.

LCMS：m/z: 8503.5 (計算值8505.3 g/mol)實例55：單5'結合之有義股RD4394 5' BA-215 FXXXXXXXXII+IS1640 SEQ: RD3953 / 5'EPLCMS: m/z: 8503.5 (calcd. 8505.3 g/mol)Example 55: Single 5' sense strand RD4394 5' BA-215 FXXXXXXXXII+IS1640 SEQ: RD3953 / 5'EP

根據A型一般程序I，使BA-215與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-215 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z: 8977.9 (計算值8979.7 g/mol)實例56：雙5'-, 3'-結合之有義股RD6027 5' BA-135 /3' BA-135 FXXXXXXV+IS2006+FXXXXXXV SEQ: RD3181 / 5'VPLCMS: m/z: 8977.9 (calcd. 8979.7 g/mol)Example 56: Double 5'-, 3'-binding sense strand RD6027 5' BA-135 /3' BA-135 FXXXXXXV+IS2006+FXXXXXXV SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-135與寡有義股結合。產物製備純度為87%，由HPLC證實。BA-135 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 87% purity as confirmed by HPLC.

LCMS：m/z 9249.5，(計算值9251.3 g/mol)實例57：雙5'-, 3'-結合之有義股RD6028 5' BA-136 /3' BA-136 FXXXXXXVI+IS2006+FXXXXXXVI SEQ: RD3181 / 5'VPLCMS: m/z 9249.5, (calcd. 9251.3 g/mol)Example 57: Double 5'-, 3'-binding sense strand RD6028 5' BA-136 /3' BA-136 FXXXXXXVI+IS2006+FXXXXXXVI SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-136與寡有義股結合。產物製備純度為97%，由HPLC證實。BA-136 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 97% purity as confirmed by HPLC.

LCMS：m/z 9075.2，(計算值9077.0 g/mol)實例58：雙5'-, 3'-結合之有義股RD6029 5' BA-137 /3' BA-137 FXXXXXXVII+IS2006+FXXXXXXVII SEQ: RD3181 / 5'VPLCMS: m/z 9075.2, (calcd. 9077.0 g/mol)Example 58: Double 5'-, 3'-binding sense strand RD6029 5' BA-137 /3' BA-137 FXXXXXXVII+IS2006+FXXXXXXVII SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-137與寡有義股結合。產物製備純度為92%，由HPLC證實。BA-137 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 92% purity as confirmed by HPLC.

LCMS：m/z 9169.2，(計算值9171.0 g/mol)實例59：雙5'-, 3'-結合之有義股RD6030 5' BA-144 /3' BA-144 FXXXXXXIX+IS2006+FXXXXXXIX SEQ: RD3181 / 5'VPLCMS: m/z 9169.2, (calcd. 9171.0 g/mol)Example 59: Double 5'-, 3'-binding sense strand RD6030 5' BA-144 /3' BA-144 FXXXXXXIX+IS2006+FXXXXXXIX SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-144與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-144 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z 9567.7，(計算值9569.5 g/mol)實例60：雙5'-, 3'-結合之有義股RD6031 5' BA-173 /3' BA-173 FXXIV+IS2006+FXXIV SEQ: RD3181 / 5'VPLCMS: m/z 9567.7, (calcd. 9569.5 g/mol)Example 60: Double 5'-, 3'-binding sense strand RD6031 5' BA-173 /3' BA-173 FXXIV+IS2006+FXXIV SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-173與寡有義股結合。產物製備純度為81%，由HPLC證實。BA-173 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 81% purity as confirmed by HPLC.

LCMS：m/z 9681.5，(計算值9683.4 g/mol)實例61：雙5'-, 3'-結合之有義股RD6032 5' BA-183 /3' BA-183 FXXXXXXXI+IS2006+FXXXXXXXI SEQ: RD3181 / 5'VPLCMS: m/z 9681.5, (calcd. 9683.4 g/mol)Example 61: Double 5'-, 3'-binding sense strand RD6032 5' BA-183 /3' BA-183 FXXXXXXXI+IS2006+FXXXXXXXI SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-183與寡有義股結合。產物製備純度為86%，由HPLC證實。BA-183 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 86% purity as confirmed by HPLC.

LCMS：m/z 9337.4，(計算值9339.2 g/mol)實例62：雙5'-, 3'-結合之有義股RD6034 5' BA-216 /3' BA-216 FXXXXXXXII+IS2006+FXXXXXXXII SEQ: RD3181 / 5'VPLCMS: m/z 9337.4, (calcd. 9339.2 g/mol)Example 62: Double 5'-, 3'-binding sense strand RD6034 5' BA-216 /3' BA-216 FXXXXXXXII+IS2006+FXXXXXXXII SEQ: RD3181 / 5'VP

根據A型一般程序II，使BA-216與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-216 was conjugated to the oligosense strand according to General Procedure II Type A. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z 9373.3，(計算值9375.2 g/mol)實例63：雙5'-, 3'-結合之有義股RD6036 5' BA-198 /3' BA-198 FXVI+IS2458+FXVI SEQ: RD3175 / 5'VPLCMS: m/z 9373.3, (calcd. 9375.2 g/mol)Example 63: Double 5'-, 3'-binding sense strand RD6036 5' BA-198 /3' BA-198 FXVI+IS2458+FXVI SEQ: RD3175 / 5'VP

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為98%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 98% purity as confirmed by HPLC.

LCMS：m/z 9329.4，(計算值9331.0 g/mol) 及實例64：雙5'-, 3'-結合之有義股RD6041 5' BA-198 /3' BA-198 FXVI+ IS1664+FXVI SEQ: RD3176/ 5'VPLCMS: m/z 9329.4, (calcd. 9331.0 g/mol) andExample 64: Double 5'-, 3'-conjugated sense strand RD6041 5' BA-198 /3' BA-198 FXVI+ IS1664+FXVI SEQ: RD3176/ 5'VP

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為93%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 93% purity as confirmed by HPLC.

LCMS：m/z 9384.4，(計算值9386.1 g/mol) 及實例65：雙5'-, 3'-結合之有義股RD6046 5' BA-198 /3' BA-198 FXVI+ IS2459+FXVI SEQ: RD3186/ 5'VPLCMS: m/z 9384.4, (calcd. 9386.1 g/mol) andExample 65: Double 5'-, 3'-conjugated sense strand RD6046 5' BA-198 /3' BA-198 FXVI+ IS2459+FXVI SEQ: RD3186/ 5'VP

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為90%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 90% purity as confirmed by HPLC.

LCMS：m/z 9366.4，(計算值9368.1 g/mol) 及實例66：雙5'-, 3'-結合之有義股RD6051 5' BA-198 /3' BA-198 FXVI+ IS2460+FXVI SEQ: RD3959/ 5'VPLCMS: m/z 9366.4, (calcd. 9368.1 g/mol) andExample 66: Double 5'-, 3'-conjugated sense strand RD6051 5' BA-198 /3' BA-198 FXVI+ IS2460+FXVI SEQ: RD3959/ 5'VP

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z 9685.6，(計算值9687.3 g/mol)實例67：雙5'-, 3'-結合之有義股RD6035 5' BA-225 /3' BA-225 FXXXIII+IS2006+FXXXIIILCMS: m/z 9685.6, (calcd. 9687.3 g/mol)Example 67: Double 5'-, 3'-linked sense strand RD6035 5' BA-225 /3' BA-225 FXXXIII+IS2006+FXXXIII

根據A型一般程序II，使BA-225與寡有義股結合。產物製備純度為80%，由HPLC證實。BA-225 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 80% purity as confirmed by HPLC.

LCMS：m/z 9343.4，(計算值9345.2 g/mol)實例68：單5'-結合之有義股RD4267 5' BA-196 FXIV+IS1402LCMS: m/z 9343.4, (calcd. 9345.2 g/mol)Example 68: Single 5'-conjugated sense strand RD4267 5' BA-196 FXIV+IS1402

根據A型一般程序I，使BA-196與寡有義股結合。產物製備純度為95%，由HPLC證實。BA-196 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 95% purity as confirmed by HPLC.

LCMS：m/z 8310.5，(計算值8311.4 g/mol)實例69：單5'-結合之有義股RD4310 5' BA-197 FXV+IS1402LCMS: m/z 8310.5, (calcd. 8311.4 g/mol)Example 69: Single 5'-conjugated sense strand RD4310 5' BA-197 FXV+IS1402

根據A型一般程序I，使BA-197與寡有義股結合。產物製備純度為95%，由HPLC證實。BA-197 was conjugated to the oligosense strand according to Type A General Procedure I. The product was prepared with 95% purity as confirmed by HPLC.

LCMS：m/z 8310.4，(計算值8312.0 g/mol)實例70：單3'-結合之有義股RD4157 3' BA-118 IS1599+FIVLCMS: m/z 8310.4, (calcd. 8312.0 g/mol)Example 70: Single 3'-conjugated sense strand RD4157 3' BA-118 IS1599+FIV

根據A型一般程序IV，使BA-118與寡有義股結合。產物製備純度為86%，由HPLC證實。BA-118 was conjugated to the oligosense strand according to General Procedure IV, Type A. The product was prepared with 86% purity as confirmed by HPLC.

LCMS：m/z 8652.1，(計算值8653.4 g/mol)實例71：單3'-結合之有義股RD4269 3' BA-129 IS1599+FXXXXXXXIIILCMS: m/z 8652.1, (calcd. 8653.4 g/mol)Example 71: Single 3'-conjugated sense strand RD4269 3' BA-129 IS1599+FXXXXXXXIII

根據A型一般程序IV，使BA-129與寡有義股結合。產物製備純度為97%，由HPLC證實。BA-129 was conjugated to the oligosense strand according to General Procedure IV, Type A. The product was prepared with 97% purity as confirmed by HPLC.

LCMS：m/z 8582.1，(計算值8583.8 g/mol)實例72：雙5'-, 3'-結合之有義股RD5470 5' BA-198 /3' BA-198 FXVI+IS2178+FXVI SEQ: RD3953/ 5'VP IA1603LCMS: m/z 8582.1, (calcd. 8583.8 g/mol)Example 72: Double 5'-, 3'-binding sense strand RD5470 5' BA-198 /3' BA-198 FXVI+IS2178+FXVI SEQ: RD3953/ 5'VP IA1603

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為95%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 95% purity as confirmed by HPLC.

LCMS：m/z 9414.8，(計算值9416.5 g/mol)實例73：雙5'-, 3'-結合之有義股RD5946 5' BA-198 /3' BA-198 FXVI+IS2178+FXVI SEQ: RD3953/ 5'EP IA1299LCMS: m/z 9414.8, (calcd. 9416.5 g/mol)Example 73: Double 5'-, 3'-conjugated sense strand RD5946 5' BA-198 /3' BA-198 FXVI+IS2178+FXVI SEQ: RD3953/ 5' EP IA1299

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為95%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 95% purity as confirmed by HPLC.

LCMS：m/z 9414.8，(計算值9416.5 g/mol)實例74：雙5'-, 3'-結合之有義股RD5947 5' BA-198 /3' BA-198 FXVI+IS1681+FXVI SEQ: RD3953/ 5'VP IA1603LCMS: m/z 9414.8, (calcd. 9416.5 g/mol)Example 74: Double 5'-, 3'-conjugated sense strand RD5947 5' BA-198 /3' BA-198 FXVI+IS1681+FXVI SEQ: RD3953/ 5' VP IA1603

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z 9215.3，(計算值9217.0 g/mol)實例75：雙5'-, 3'-結合之有義股RD5948 5' BA-198 /3' BA-198 FXVI+IS1681+FXVI SEQ: RD3953/ 5'EP IA1299LCMS: m/z 9215.3, (calcd. 9217.0 g/mol)Example 75: Double 5'-, 3'-conjugated sense strand RD5948 5' BA-198 /3' BA-198 FXVI+IS1681+FXVI SEQ: RD3953/ 5' EP IA1299

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為94%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 94% purity as confirmed by HPLC.

LCMS：m/z 9215.3，(計算值9217.0 g/mol)實例76：雙5'-, 3'-結合之有義股RD5954 5' BA-198 /3' BA-198 FXVI+IS1688+FXVI SEQ: RD3953/ 5'VP IA1603LCMS: m/z 9215.3, (calcd. 9217.0 g/mol)Example 76: Double 5'-, 3'-conjugated sense strand RD5954 5' BA-198 /3' BA-198 FXVI+IS1688+FXVI SEQ: RD3953/ 5' VP IA1603

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為93%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 93% purity as confirmed by HPLC.

LCMS：m/z 9414.7，(計算值9415.5 g/mol)實例77：雙5'-, 3'-結合之有義股RD5955 5' BA-198 /3' BA-198 FXVI+IS1688+FXVI SEQ: RD3953/ 5'EP IA1299LCMS: m/z 9414.7, (calcd. 9415.5 g/mol)Example 77: Double 5'-, 3'-conjugated sense strand RD5955 5' BA-198 /3' BA-198 FXVI+IS1688+FXVI SEQ: RD3953/ 5' EP IA1299

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為93%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 93% purity as confirmed by HPLC.

LCMS：m/z 9414.7，(計算值9415.5 g/mol)實例78：雙5'-, 3'-結合之有義股RD5956 5' BA-198 /3' BA-198 FXVI+IS2422+FXVI SEQ: RD3953/ 5'VP IA1250LCMS: m/z 9414.7, (calcd. 9415.5 g/mol)Example 78: Double 5'-, 3'-conjugated sense strand RD5956 5' BA-198 /3' BA-198 FXVI+IS2422+FXVI SEQ: RD3953/ 5' VP IA1250

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為87%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 87% purity as confirmed by HPLC.

LCMS：m/z 9774.1，(計算值9775.7 g/mol)實例79：雙5'-, 3'-結合之有義股RD5967 5' BA-198 /3' BA-198 FXVI+IS2424+FXVI SEQ: RD3953/ 5'VP IA1250LCMS: m/z 9774.1, (calcd. 9775.7 g/mol)Example 79: Double 5'-, 3'-conjugated sense strand RD5967 5' BA-198 /3' BA-198 FXVI+IS2424+FXVI SEQ: RD3953/ 5'VP IA1250

根據A型一般程序II，使BA-198與寡有義股結合。產物製備純度為87%，由HPLC證實。BA-198 was conjugated to the oligosense strand according to General Procedure II, Type A. The product was prepared with 87% purity as confirmed by HPLC.

LCMS：m/z 9774.1，(計算值9775.7 g/mol)實例80：使用醯胺連接體合成配位體結合之寡核苷酸LCMS: m/z 9774.1, (calcd. 9775.7 g/mol)Example 80: Synthesis of ligand-boundoligonucleotides using amide linkers

使用醯胺連接體與配位體結合之寡核苷酸可使用以下方法來合成：Oligonucleotides conjugated to ligands using amide linkers can be synthesized using the following methods:

上文合成方法可用於合成例如以下在5'端及/或3'端包含配位體之寡核苷酸：實例81：合成寡核苷酸之一般程序The above synthesis method can be used to synthesize, for example, the following oligonucleotides comprising a ligand at the 5' end and/or the 3' end:Example 81: General Procedure for SynthesizingOligonucleotides

使用寡核苷酸合成儀Oligopilot100 (Cytiva Life Sciences)在固相上合成股。將固體支持物(CPG, 80-90 μmol/g, 500A，來自LGC-Biosearch Technologies, Petaluma, CA)裝載至150-300 μmol規模。RNA及2'修飾之RNA亞磷醯胺係購自Hongene Biotech (Union City, CA)。The oligonucleotide synthesizer Oligopilot100 (Cytiva Life Sciences) was used to synthesize the strands on the solid phase. The solid support (CPG, 80-90 μmol/g, 500A, from LGC-Biosearch Technologies, Petaluma, CA) was loaded to a scale of 150-300 μmol. RNA and 2'-modified RNA phosphoramidites were purchased from Hongene Biotech (Union City, CA).

所使用之2'-O-甲基亞磷醯胺為： 5'-O-(4,4'-二甲氧基三苯甲基)-N⁶-苯甲醯基-2'-O-甲基-腺苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N⁴-乙醯基-2'-O-甲基-胞苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N²-異丁醯基-2'-O-甲基-鳥苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-2'-O-甲基-尿苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺。The 2'-O-methylphosphoamidoamines used were: 5'-O-(4,4'-dimethoxytrityl)-N⁶ -benzoyl-2'-O-methyl-adenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamido 5'-O-(4,4'-dimethoxytrityl)-N⁴ -acetyl-2'-O-methyl-cytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamido 5'-O-(4,4'-dimethoxytrityl)-N² -isobutyryl-2'-O-methyl-guanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite 5'-O-(4,4'-dimethoxytrityl)-2'-O-methyl-uridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite.

所使用之2'-氟亞磷醯胺為： 5'-O-(4,4'-二甲氧基三苯甲基)-N⁶-苯甲醯基-2'-氟腺苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N⁴-乙醯基-2'-氟胞苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N²-異丁醯基-2'-氟鳥苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-2'-氟尿苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺。The 2'-fluorophosphamides used are: 5'-O-(4,4'-dimethoxytrityl)-N⁶ -benzoyl-2'-fluoroadenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphamide 5'-O-(4,4'-dimethoxytrityl)-N⁴ -acetyl-2'-fluorocytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphamide 5'-O-(4,4'-dimethoxytrityl)-N² -isobutyryl-2'-fluoroguanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite 5'-O-(4,4'-dimethoxytrityl)-2'-fluorouridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite.

為產生硫代磷酸酯鍵聯，使用3-((二甲基胺基-亞甲基)胺基)-3H-1,2,4-二噻唑-3-硫酮(DDTT. 來自Chemgenes, Wilmington, MA之0.1 M溶液)持續4-6分鐘。為產生磷酸二酯鍵聯，使用I₂O於吡啶/水中之溶液(0.05 M，來自Sigma Aldrich, St Louis, MO)。在氧化/硫化後，使用含20% n-甲基咪唑之乙腈與含40%乙酸酐/60%二甲基吡啶之乙腈的混合物(Sigma Aldrich, St Louis, MO)使連接至CPG之任何未反應鏈乙醯化。To generate phosphorothioate linkages, 3-((dimethylamino-methylene)amino)-3H-1,2,4-dithiazole-3-thione (DDTT. 0.1 M solution from Chemgenes, Wilmington, MA) was used for 4-6 minutes. To generate phosphodiester linkages,_I2O in pyridine/water (0.05 M from Sigma Aldrich, St Louis, MO) was used. After oxidation/sulfidation, any unreacted chain attached to CPG was acetylated using a mixture of 20% n-methylimidazole in acetonitrile and 40% acetic anhydride/60% lutidine in acetonitrile (Sigma Aldrich, St Louis, MO).

將亞磷醯胺溶解於無水乙腈(0.2 M)中，且添加分子篩(4A)並放置隔夜(Sigma Aldrich, St. Louis, MO)。對於寡核苷酸鏈，使用5-(乙基硫基)-1H-四唑(ETT，0.6 M於乙腈中，來自Sigma Aldrich)作為活化劑溶液。偶合時間為6分鐘，每步3.0當量進行。偶合前，使用二氯乙酸於二氯甲烷中之溶液(3% Deblock, Sigma Aldrich)處理支持物結合之寡核苷酸，且用無水乙腈洗滌。支持物結合之寡聚物之裂解及去保護The phosphoramidite was dissolved in anhydrous acetonitrile (0.2 M) and molecular sieves (4A) were added and left overnight (Sigma Aldrich, St. Louis, MO). For the oligonucleotide chain, 5-(ethylthio)-1H-tetrazole (ETT, 0.6 M in acetonitrile, from Sigma Aldrich) was used as the activator solution. The coupling time was 6 min and 3.0 equivalents were performed per step. Prior to coupling, the support-bound oligonucleotides were treated with a solution of dichloroacetic acid in dichloromethane (3% Deblock, Sigma Aldrich) and washed with anhydrous acetonitrile.Cleavage and deprotection of support-bound oligomers

固相合成完成後，將支持物用AMA溶液在65℃下處理20分鐘，該AMA溶液為1:1體積之NH₄OH:CH₃NH₂溶液(Fisher Scientific, Spectrum Chemicals)。接著使溶液蒸發。純化前，在分析型HPLC及LCMS上實施過程中分析，以測定粗純度、鑑別目標質量並監測去保護之完成。LCMS方法After solid phase synthesis, the support was treated with AMA solution at 65°C for 20 minutes. The AMA solution was a 1:1 volumetric NH₄ OH:CH₃ NH₂ solution (Fisher Scientific, Spectrum Chemicals). The solution was then evaporated. Prior to purification, in-process analysis was performed on analytical HPLC and LCMS to determine crude purity, identify target mass, and monitor the completion of deprotection.LCMSMethod

使用Waters XBridge寡核苷酸BEH C18管柱，130 Å, 2.5 μm, 2.1 mm × 50 mm (P/N 186003952)管柱與緩衝溶液：400 mM HFIP + 15 mM TEA (緩衝液A)及100%甲醇(緩衝液B)，梯度為5%-50%緩衝液B，2分鐘，70℃，流量為0.5 mL/分鐘。藉由切向流過濾(TFF)濃縮A Waters XBridge Oligonucleotide BEH C18 column, 130 Å, 2.5 μm, 2.1 mm × 50 mm (P/N 186003952) was used with the following buffers: 400 mM HFIP + 15 mM TEA (buffer A) and 100% methanol (buffer B), with a gradient of 5%-50% buffer B over 2 min at 70°C at a flow rate of 0.5 mL/min.Concentration by tangential flow filtration (TFF)

使用Pall Minimate EVO系統(產品ID：OAPMPUNV)，使用帶有3k Omega膜之Pall Minimate TFF卡匣囊式容器濃縮粗製寡聚物。純化Crude oligomers wereconcentrated using the Pall Minimate EVO system (Product ID: OAPMPUNV) using a Pall Minimate TFF cartridge capsule with 3k Omega membrane.

使用反相HPLC實施純化。所用管柱為Phenomenex Clarity 5 μm Oligo-RP AXIOS, 250 × 30 mm (P/N: 00G-4442-U0-AX)。緩衝溶液混合物為100 mM TEAA、5% ACN，pH為7.0 (緩衝液A)及1:1乙腈:甲醇(緩衝液B)。梯度為5%-30%緩衝液B，60分鐘，60℃，流量為20 mL/分鐘。Purification was performed using reverse phase HPLC. The column used was a Phenomenex Clarity 5 μm Oligo-RP AXIOS, 250 × 30 mm (P/N: 00G-4442-U0-AX). The buffer mixture was 100 mM TEAA, 5% ACN, pH 7.0 (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient was 5%-30% buffer B, 60 min, 60°C, and the flow rate was 20 mL/min.

純化後，藉由反相UPLC對流份進行分析。所用管柱為Waters ACQUITY UPLC寡核苷酸BEH C18 1.7 μm, 2.1 × 50 mm (P/N: 186003949)。緩衝溶液混合物為100 mM TEAA、5% ACN，pH為7.0 (緩衝液A)及1:1乙腈:甲醇(緩衝液B)。梯度設為5%-30%緩衝液B，5分鐘，80℃，流量為1.0 mL/分鐘。所純化匯集物(pool)之最低規格為85%。去鹽After purification, the fractions were analyzed by reverse phase UPLC. The column used was Waters ACQUITY UPLC Oligonucleotide BEH C18 1.7 μm, 2.1 × 50 mm (P/N: 186003949). The buffer solution mixture was 100 mM TEAA, 5% ACN, pH 7.0 (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient was set to 5%-30% buffer B, 5 minutes, 80°C, and the flow rate was 1.0 mL/min. The minimum specification of the purified pool was 85%.Desalination

在匯集物確立後，即使用Pall Minimate EVO系統(產品ID：OAPMPUNV)對寡聚物進行去鹽。所用卡匣為帶有3k Omega膜之Pall Minimate TFF囊式容器(產品ID：OA003C12)。收集滲餘物進行凍乾或直接退火。雙股siRNA之製備實例82：退火之一般程序After the pool is established, the oligomers are desalted using the Pall Minimate EVO system (Product ID: OAPMPUNV). The cartridge used is a Pall Minimate TFF capsule container with 3k Omega membrane (Product ID: OA003C12). The permeate is collected and freeze-dried or directly annealed. Example 82of double-stranded siRNA preparation:General procedure for annealing

如本文所闡述製備配位體結合之RNA有義股。Ligand-bound RNA sense strands were prepared as described herein.

根據熟習此項技術者所熟知之程序製備RNA反義股。藉由Nanodrop測定有義股及反義股二者之濃度。藉由混合等莫耳量之有義股與反義股製備雙股siRNA。藉由RP-HPLC (一種非變性方法)監測退火過程。退火後，雙鏈體混合物中之反義股不超過5%。藉由在Nanodrop上量測溶液吸光度測定雙鏈體濃度。實例83：製備含有碳鏈之二核苷酸亞醯胺之一般程序Prepare RNA antisense strands according to procedures well known to those skilled in the art. Determine the concentration of both sense and antisense strands by Nanodrop. Prepare double-stranded siRNA by mixing equal molar amounts of sense and antisense strands. Monitor the annealing process by RP-HPLC, a non-denaturing method. After annealing, the antisense strand in the duplex mixture does not exceed 5%. Determine the duplex concentration by measuring the absorbance of the solution on Nanodrop. Example 83:General procedure for preparingdinucleotide amidescontaining carbon chains

步驟1：將N,N-二異丙基乙胺(DIPEA, 3 eq)添加至視情況鹼保護之3-(5-[「A/C/G/U」]-5-(DMTrO-甲基)-2-[F/OMe"]-四氫呋喃-3-基)乙酸(1 eq)、視情況鹼保護之1-[「A/C/G/U」]-2-[F/OMe"]-5-((十七烷基胺基)甲基)四氫呋喃-3-醇(1.15 eq)及HATU (1.5 eq)於DMF中之攪拌溶液中。將混合物在室溫下攪拌2 h，且接著逐滴添加至水或飽和碳酸氫鈉水溶液中。藉由過濾分離所得沈澱固體，用水洗滌，乾燥，重新溶解於乙酸乙酯中且藉由層析進行純化。Step 1 : N,N-diisopropylethylamine (DIPEA, 3 eq) was added to a stirred solution of optionally alkali-protected 3-(5-["A/C/G/U"]-5-(DMTrO-methyl)-2-[F/OMe"]-tetrahydrofuran-3-yl)acetic acid (1 eq), optionally alkali-protected 1-["A/C/G/U"]-2-[F/OMe"]-5-((heptadecanamido)methyl)tetrahydrofuran-3-ol (1.15 eq) and HATU (1.5 eq) in DMF. The mixture was stirred at room temperature for 2 h, and then added dropwise to water or saturated aqueous sodium bicarbonate solution. The resulting precipitated solid was isolated by filtration, washed with water, dried, redissolved in ethyl acetate and purified by chromatography.

步驟2：將N, N-二異丙基氯亞磷醯胺(3 eq)逐滴添加至乙醇(1 eq)及二異丙基乙胺(6 eq)於DCM中之攪拌溶液中。將反應混合物在室溫下攪拌3小時，接著用飽和碳酸氫鈉水溶液淬滅，且用DCM萃取。將合併的萃取物用鹽水洗滌，經Na₂SO₄乾燥，濃縮，藉由層析純化並在高真空下乾燥。Step 2 : N, N-diisopropylphosphoramidite chloride (3 eq) was added dropwise to a stirred solution of ethanol (1 eq) and diisopropylethylamine (6 eq) in DCM. The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined extracts were washed with brine, dried over_Na2SO4, concentrated, purified by chromatography and dried under high vacuum.

根據上文所概述之一般程序，製備下表中含有碳鏈之二核苷酸亞醯胺。化合物名稱結構NB編號ID(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-氟-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-152fGëmU'(2R,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((2-((2S,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-137mAëmA'(2R,3R,4R,5R)-5-(4-苯甲醯胺基-2-側氧基嘧啶-1(2H)-基)-2-((2-((2S,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-146mAëmC'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-167mAëmG'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-165mAëmU'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(4-苯甲醯胺基-2-側氧基嘧啶-1(2H)-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-145mCëmA'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-氟-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-180mGëfG'(2R,3R,4R,5R)-5-(4-苯甲醯胺基-2-側氧基嘧啶-1(2H)-基)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-179mGëmC'(2R,3R,4R,5R)-5-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-144mUëmA'(2R,3R,4R,5R)-5-(4-乙醯胺基-2-側氧基嘧啶-1(2H)-基)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-115mUëmC'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(2-異丁醯胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-126mUëmG'(2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基)-N-十七烷基乙醯胺基)甲基)-5-(2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)-4-甲氧基四氫呋喃-3-基(2-氰基乙基)二異丙基亞磷醯胺NB-114mUëmU'The carbon chain containing dinucleotide imides shown in the table below were prepared according to the general procedure outlined above.Compound NameStructureNBNumberID (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(2,4-oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-152 fGëmU' (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((2-((2S,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-137 mAëmA' (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((2-((2S,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-146 mAëmC' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(6-benzylamino-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-167 mAëmG' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(6-benzylamino-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-165 mAëmU' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(6-benzamido-9H-purin-9-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-145 mCëmA' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-fluoro-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-180 mGëfG' (2R,3R,4R,5R)-5-(4-benzylamino-2-oxopyrimidin-1(2H)-yl)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-179 mGëmC' (2R,3R,4R,5R)-5-(6-benzylamino-9H-purin-9-yl)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-144 mUëmA' (2R,3R,4R,5R)-5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-115 mUëmC' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-126 mUëmG' (2R,3R,4R,5R)-2-((2-((2S,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl)-N-heptadecylacetamido)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphamide NB-114 mUëmU'

所製備之包含C鏈之二核苷酸亞醯胺之分析資料：亞磷醯胺ID說明產率純度*質量(m/z)³¹P NMR(202 MHz, DMSO-d₆)NB-152fGëmU'白色 固體74%95%1399 M⁺+Naδ 149.86, 149.68, 149.48, 149.29NB-137mAëmA'白色 固體52%＞95%1556 M+Naδ 150.22, 149.78, 149.63NB-146mAëmC'1532 M+ Naδ 149.98, 149.73,149.68, 149.22NB-167mAëmG'δ 150.45, 150.40, 150.20, 149.98NB-165mAëmU'1429 M+Na⁺δ 149.82, 149.71, 149.48, 149.28NB-145mCëmA'1532 M+ Naδ 150.14, 149.85, 149.78, 147.94NB-180mGëfG'灰白色 固體62%94%1486 M+δ 150.72, 150.58, 150.51, 150.19,150.00NB-179mGëmC'灰白色 固體59%98%1514 M+Naδ 150.00, 149.77, 149.20NB-144mUëmA'1407 M+ Hδ 150.49, 150.42, 150.21,150.03, 149.83, 147.74, 149.60NB-115mUëmC'白色 固體59%96%1344 M+Naδ 149.94, 149.66, 149.24NB-126mUëmG'米色 固體84%98%1413 M+Naδ 150.46, 150.31, 150.00。NB-114mUëmU'白色 固體75%95%1302 M+Naδ 149.81, 149.69, 149.47, 149.34*藉由HPLC測定純度實例84：經修飾之寡核苷酸在hMAPT基因轉殖小鼠中靶向人類MAPT之效應Analytical data of the prepared dinucleotide imide containing C chain:PhosphamideIDinstructionProductivityPurity*Mass (m/z)³¹P NMR(202 MHz, DMSO-d₆ ) NB-152 fGëmU' White solid 74% 95% 1399 M⁺ +Na δ 149.86, 149.68, 149.48, 149.29 NB-137 mAëmA' White solid 52% >95% 1556 M+Na δ 150.22, 149.78, 149.63 NB-146 mAëmC' 1532 M+ Na δ 149.98, 149.73,149.68, 149.22 NB-167 mAëmG' δ 150.45, 150.40, 150.20, 149.98 NB-165 mAëmU' 1429 M+Na⁺ δ 149.82, 149.71, 149.48, 149.28 NB-145 mCëmA' 1532 M+ Na δ 150.14, 149.85, 149.78, 147.94 NB-180 mGëfG' Off-white solid 62% 94% 1486 M+ δ 150.72, 150.58, 150.51, 150.19,150.00 NB-179 mGëmC' Off-white solid 59% 98% 1514 M+Na δ 150.00, 149.77, 149.20 NB-144 mUëmA' 1407 M+ H δ 150.49, 150.42, 150.21,150.03, 149.83, 147.74, 149.60 NB-115 mUëmC' White solid 59% 96% 1344 M+Na δ 149.94, 149.66, 149.24 NB-126 mUëmG' Beige solid 84% 98% 1413 M+Na δ 150.46, 150.31, 150.00. NB-114 mUëmU' White solid 75% 95% 1302 M+Na δ 149.81, 149.69, 149.47, 149.34 *Purity was determined by HPLCExample 84: Effect of modifiedoligonucleotides targeting human MAPT inhMAPTgene transgenic mice

在活體內人類MAPT基因轉殖小鼠PD研究中評估化合物。動物在第1天藉由大池內(ICM)或IT或ICV接受單一媒劑或0.2 mg (10 mg/kg)劑量(n=3隻/組)。每天觀察動物之行為變化。在第15天或第29天收集腦區域，且將組織立即置於均質管中，快速冷凍，接著保持在-80℃以用於基因表現分析。Compounds were evaluated in an in vivo human MAPT transgenic mouse PD study. Animals received a single vehicle or 0.2 mg (10 mg/kg) dose (n=3/group) intracisternal (ICM) or IT or ICV on day 1. Animals were observed daily for behavioral changes. Brain regions were collected on day 15 or day 29, and tissues were immediately placed in homogenizer tubes, snap frozen, and then kept at -80°C for gene expression analysis.

根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl人類MAPT TaqMan基因表現分析(Thermo Fisher：Hs00213484_m1, FAM)、1 μl小鼠GAPDH TaqMan基因表現分析(Thermo Fisher：Mm99999915_g1, VIC) 及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，以95℃持續15秒且60℃持續1分鐘進行40個循環。結果在以下各表中呈現為相對於媒劑對照之CTNNB1抑制百分比。RNA isolation was performed according to the instructions of the RNeasy Micro Kit (Qiagen catalog number 74004). After RNA isolation, the 96-well plate was placed on ice while preparing the qRT-PCR reaction. 2 μl of RNA was added to a reaction mixture containing 5 μl of TaqMan Fast Virus 1-Step Master Mix (Thermo Fisher catalog number 44444432), 1 μl of Human MAPT TaqMan Gene Expression Assay (Thermo Fisher: Hs00213484_m1, FAM), 1 μl of Mouse GAPDH TaqMan Gene Expression Assay (Thermo Fisher: Mm99999915_g1, VIC) and 11 μl of RT-PCR grade nuclease-free water in a MicroAmp Optical 96-well plate (0.2 mL). qPCR was performed using a QuantStudio3 qPCR machine using the following cycles: 50°C for 1 minute, 95°C for 20 seconds, 95°C for 15 seconds and 60°C for 1 minute for 40 cycles. The results are presented in the following tables as percent inhibition of CTNNB1 relative to vehicle control.

結果在下表4中呈現為相對於媒劑對照之hMAPT抑制百分比。表4平均MAPT抑制研究編號化合物D15D15D15D15D15D15D15D15D15CBMCTXHPCSTRBSCERVTHORLUMBSC7號RD3168261790428號RD31692283120408號RD3170373137425027266號RD317131453331135號RD31723031433231296號RD3173723331222125號RD317404142327305號RD31752358604856425號RD31765068686864646號RD31774233815256348376號RD317817284716435149487號RD317912202510204552465號RD318038385047463814號RD318119442432555962575號RD31822529303338355號RD31831422303146267號RD31843312222717號RD31852365號RD31863949535356438號RD318726911535061287號RD3188282551748號RD318926404445238號RD31901609A號RD3658444947316465696913號RD3745481715124016101213號RD3746451618211516713號RD3747592029265037373113號RD3748441115165146424621號RD38638621號RD38643122號RD3865192029291522號RD3866332539293022號RD3867313325292221號RD386820186131121號RD386928107191822號RD3870212822222153號RD3933626569666967656930號RD3942383330444128號RD3943383235444128號RD3944391718273428號RD3945111318222628號RD3946152334242130號RD3947404346423430號RD39482168172730號RD3949201725252430號RD3950302428252831號RD3951151927347331號RD3952283832356831號RD3953445354464629號RD3954172829號RD3955213741203129號RD395621344718429號RD3957241434031號RD3958284137326331號RD3959444753614747號RD4139251921201247號RD414051724253447號RD414195447號RD414225151334347號RD4143212735371248號RD414419131801148號RD414533454527365號RD31813547545153496號RD31722330557292210號RD366815733445066695911號RD3663223926739444312號RD375212149231212號RD37532326936812號RD3754325047386171607312號RD3755385350252861495316號RD3806312238307371727016號RD3810534752357467676417號RD3818413826174869605518號RD3658284249535418號RD3658385271697120號RD3658423330275922號RD3821596563607224號RD3754625662605724號RD3912576173716924號RD3969445466666624號RD3970456868676824號RD3973252749427325號RD3755596274627326號RD3754424264535626號RD3910525270656926號RD3978301836313332號RD3912574959527432號RD3912516778706733號RD3933647578747435號RD3658576063656836號RD3977516974741937號RD3970395448395537號RD3970305751626438號RD4044685574677439號RD4060777664676940號RD4066525469566840號RD4110495066636944號RD3837807681728744號RD3880625968568544號RD4147676472687245號RD4156414551634046號RD4149455064603446號RD4151444362492646號RD415325262931346號RD41543127353848號RD4137554456595649號RD4173414051375349號RD4174283841374649號RD4181505760515850號RD4176274836574350號RD4177283834404150號RD4184394547574151號RD4218535563696751號RD4221636372737751號RD4222645169666951號RD4223666773737951號RD4224696881768252號RD4225977184799252號RD4226956879749152號RD4227874044467452號RD4229977283799052號RD4230966080707553號RD4155643664606468656954號RD38376076777454號RD39774956706854號RD40604575707354號RD41575860666054號RD41793343534155號RD4180143735393155號RD418252528171855號RD4183222628364455號RD4185232942354855號RD4186253533464357號RD4321544762626857號RD4232274158444757號RD4233373842455257號RD4234596275698058號RD4267575166686260號RD4264585774647560號RD4269545269587861號RD4205353230293061號RD4219404547455361號RD4220403639344661號RD4225646472717861號RD4229675270717862號RD4310566369717462號RD4311576165686363號RD4300212626312163號RD4305233537342563號RD4306616872676564號RD4299425763707164號RD4301524357626164號RD4302615867727264號RD4307647581787865號RD4303495564566965號RD4304616469647565號RD4309647181627465號RD4347505158536665號RD4348584665707066號RD4308886521707566號RD43328454-6436566號RD43636865-2697667號RD4339516659496867號RD4341565355486767號RD4349535467497268號RD4384394251414170號RD4350334352374770號RD4351565657516671號RD436943235263071號RD4370263028243871號RD4373293430143371號RD4417485052495372號RD4418294754404872號RD4419355662434673號RD4413484846174073號RD441450394212389A號RD3657113537242127589A號RD3659354746635859579B號RD365855765945686468659B號RD36583430164755469B號RD3658213066737552號RD4228955580819175號RD4390275246413575號RD4421313850454976號RD4452424343355776號RD4453394248395576號RD4454343243353977號RD4460353142264277號RD4386375955445277號RD45194852574478號RD4455332443434878號RD4456291227363078號RD4457272018423078號RD4458283346342978號RD4461331718333778號RD4462234147432679號RD4463263041142579號RD4464193941183079號RD449712181961979號RD4498129151180號RD44992518143380號RD450014191480號RD45011482號RD4535134652404682號RD4536235457454983號RD4534584365587283號RD450251510883號RD4533574457537283號RD4532535867667684號RD488613145084號RD488751125485號RD4845252439193585號RD4844675573688087號RD4899464757496788號RD3754555969727388號RD3755463860547388號RD3933416666627188號RD4155534564587388號RD3838405056595788號RD3837736679697289號RD4842545765617589號RD4914415157434889號RD4944484955456889號RD4945453949416389號RD4947524959487190號RD4948432145304690號RD4949554267586690號RD4950482649386390號RD4951593768567390號RD4952513558485991號RD4954455871565291號RD4955404647465291號RD4956613748465991號RD4957604858556391號RD4958443644415092號RD4892534957424792號RD4894536265545392號RD4896536067525092號RD4897486260504793號RD4901384755364794號RD4975244045284294號RD49592845564944102號RD49434655655664106號RD49446361705973102號RD4946505567607296號RD49816146665671103號RD50191726312134103號RD50203344443239103號RD50212318171636103號RD50223532372538103號RD50234838472741103號RD50244145443446105號RD50253538493946105號RD50262340543839105號RD50272631383939105號RD50283031353440105號RD50293327383941106號RD50653136313231115號RD52633046514141115號RD52863942625762115號RD53456055686073114號RD53505444575460化合物 (第15天)CBMCTXHPCSTRCERVRD3666563455171RD3667164425042RD39134753726362RD39375841686076RD39413656546164RD39717672737780RD39955463767113RD415758606660-21RD42355272727576RD42675751666862RD42695452695878RD43105663697174RD43365358716270RD43874254524237RD43894763564946RD43944159564451RD44202948522738RD45184056655116RD60276250646675RD60285934646461RD60296055656566RD60305050646372RD60313651665665RD60324650616354RD6036-7303529-20RD60376355440-12RD60412456593634RD60424161543045RD60464740452632RD60473449453234RD60515252494557RD60524340523534RD60546349643760研究編號化合物D29D29D29D29D29D29D29D29D29CBMCTXHPCSTRBSSCCERVTHORLUMB7號RD316857364825444346448號RD31693158號RD3170101818215714136號RD31711210151045號RD31723018261124436號RD3173362217554233105號RD3174018455號RD31751340342737665號RD31765022331847536號RD3177403871484033326號RD31783855340614946377號RD317925101824212023165號RD318038433738708914號RD318149342723475949505號RD318228273241545號RD31833427242948527號RD318432221910262117297號RD318527156836105號RD31861218221941388號RD318714231322636156537號RD318816232510292224188號RD318911164604944468號RD3190121163041279A號RD3658464453607271655913號RD3745603743415750565913號RD3746463945564538475313號RD3747634843545467706313號RD3748503727496873786321號RD3863121號RD38641821號RD3868521號RD38699353號RD393351556860665357465號RD3181496151ND88ND10號RD3668617351667580767611號RD36635756626812號RD3752272124274258513412號RD3753334044385473726612號RD3754423826187068745512號RD3755474760558985887816號RD3806325047417216號RD3810345350297417號RD3818251333193018號RD3658554263594118號RD3658663877712920號RD3658402930397432號RD3912455649307232號RD3912707373557537號RD3970446343545237號RD3970486568777753號RD4155622570627263746554號RD3837465871707354號RD3977606267666854號RD406049597069739A號RD365721102117493637819A號RD3659512538347067645688號RD3754595763696788號RD3755576272717788號RD3933587875747488號RD4155476364627888號RD3838223230545388號RD38375469717472106號RD49444763614954106號RD50655455605172115號RD52635351525154115號RD52865466676468114號RD53506166597071RD3666CBMCTXHPCSTRCERVBSTHORLUMB第15天563455171737477第29天4053456070616260RD3667CBMCTXHPCSTRBSCERVTHORLUMB第15天164425054425955第29天3232432443464752RD3971CBMCTXHPCSTRCERV第15天7672737780第29天5662636274研究編號化合物D43D43D43D43D43D43D43D43D43CBMCTXHPCSTRBSSCCERVTHORLUMB10號RD3668617351667580767611號RD366357566268106號RD49444763614954106號RD50655455605172114號RD53505747625659CBM小腦CTX額葉皮質HPC海馬體STR紋狀體BS腦幹CERV頸脊髓THOR胸脊髓LUMB腰脊髓SC脊髓D15第15天D29第29天實例85：經修飾之寡核苷酸在非人類靈長類動物中靶向人類MAPT之效應The results are presented in Table 4 below as percentage inhibition of hMAPT relative to vehicle control.Table 4Average MAPT inhibitionStudy No. Compound D15 D15 D15 D15 D15 D15 D15 D15 D15 CBM CTX HPC STR BS CERV THOR LUMB SC No. 7 RD3168 26 17 9 0 42 No. 8 RD3169 twenty two 8 31 20 40 No. 8 RD3170 37 31 37 42 50 27 26 No. 6 RD3171 3 14 5 33 31 13 No. 5 RD3172 30 31 43 32 31 29 No. 6 RD3173 7 twenty three 33 12 twenty two 12 No. 5 RD3174 0 4 14 twenty three 27 30 No. 5 RD3175 twenty three 58 60 48 56 42 No. 5 RD3176 50 68 68 68 64 64 No. 6 RD3177 4 twenty three 38 15 25 63 48 37 No. 6 RD3178 17 28 47 16 43 51 49 48 No. 7 RD3179 12 20 25 10 20 45 52 46 No. 5 RD3180 38 38 50 47 46 38 No. 14 RD3181 19 44 twenty four 32 55 59 62 57 No. 5 RD3182 25 29 30 33 38 35 No. 5 RD3183 14 twenty two 30 31 46 26 No. 7 RD3184 33 12 twenty two 27 1 No. 7 RD3185 twenty three 6 No. 5 RD3186 39 49 53 53 56 43 No. 8 RD3187 26 9 11 53 50 61 28 No. 7 RD3188 28 25 5 1 74 No. 8 RD3189 26 40 44 45 twenty three No. 8 RD3190 16 0 No. 9A RD3658 44 49 47 31 64 65 69 69 No. 13 RD3745 48 17 15 12 40 16 10 12 No. 13 RD3746 45 16 18 twenty one 15 16 7 No. 13 RD3747 59 20 29 26 50 37 37 31 No. 13 RD3748 44 11 15 16 51 46 42 46 No. 21 RD3863 8 6 No. 21 RD3864 3 1 No. 22 RD3865 19 20 29 29 15 No. 22 RD3866 33 25 39 29 30 No. 22 RD3867 31 33 25 29 twenty two No. 21 RD3868 20 18 6 13 11 No. 21 RD3869 28 10 7 19 18 No. 22 RD3870 twenty one 28 twenty two twenty two twenty one No. 53 RD3933 62 65 69 66 69 67 65 69 No. 30 RD3942 38 33 30 44 41 No. 28 RD3943 38 32 35 44 41 No. 28 RD3944 39 17 18 27 34 No. 28 RD3945 11 13 18 twenty two 26 No. 28 RD3946 15 twenty three 34 twenty four twenty one No. 30 RD3947 40 43 46 42 34 No. 30 RD3948 twenty one 6 8 17 27 No. 30 RD3949 20 17 25 25 twenty four No. 30 RD3950 30 twenty four 28 25 28 No. 31 RD3951 15 19 27 34 73 No. 31 RD3952 28 38 32 35 68 No. 31 RD3953 44 53 54 46 46 No. 29 RD3954 1 7 28 No. 29 RD3955 twenty one 37 41 20 31 No. 29 RD3956 twenty one 34 47 18 4 No. 29 RD3957 twenty four 14 34 0 No. 31 RD3958 28 41 37 32 63 No. 31 RD3959 44 47 53 61 47 No. 47 RD4139 25 19 twenty one 20 12 No. 47 RD4140 5 17 twenty four 25 34 No. 47 RD4141 9 5 4 No. 47 RD4142 25 15 13 34 3 No. 47 RD4143 twenty one 27 35 37 12 No. 48 RD4144 19 13 18 0 11 No. 48 RD4145 33 45 45 27 36 No. 5 RD3181 35 47 54 51 53 49 No. 6 RD3172 twenty three 30 5 57 29 twenty two No. 10 RD3668 1 57 33 44 50 66 69 59 No. 11 RD3663 twenty two 39 26 7 39 44 43 No. 12 RD3752 12 14 9 twenty three 12 No. 12 RD3753 twenty three 26 9 36 8 No. 12 RD3754 32 50 47 38 61 71 60 73 No. 12 RD3755 38 53 50 25 28 61 49 53 No. 16 RD3806 31 twenty two 38 30 73 71 72 70 No. 16 RD3810 53 47 52 35 74 67 67 64 No. 17 RD3818 41 38 26 17 48 69 60 55 No. 18 RD3658 28 42 49 53 54 No. 18 RD3658 38 52 71 69 71 No. 20 RD3658 42 33 30 27 59 No. 22 RD3821 59 65 63 60 72 No. 24 RD3754 62 56 62 60 57 No. 24 RD3912 57 61 73 71 69 No. 24 RD3969 44 54 66 66 66 No. 24 RD3970 45 68 68 67 68 No. 24 RD3973 25 27 49 42 73 No. 25 RD3755 59 62 74 62 73 No. 26 RD3754 42 42 64 53 56 No. 26 RD3910 52 52 70 65 69 No. 26 RD3978 30 18 36 31 33 No. 32 RD3912 57 49 59 52 74 No. 32 RD3912 51 67 78 70 67 No. 33 RD3933 64 75 78 74 74 No. 35 RD3658 57 60 63 65 68 No. 36 RD3977 51 69 74 74 19 No. 37 RD3970 39 54 48 39 55 No. 37 RD3970 30 57 51 62 64 No. 38 RD4044 68 55 74 67 74 No. 39 RD4060 77 76 64 67 69 No. 40 RD4066 52 54 69 56 68 No. 40 RD4110 49 50 66 63 69 No. 44 RD3837 80 76 81 72 87 No. 44 RD3880 62 59 68 56 85 No. 44 RD4147 67 64 72 68 72 No. 45 RD4156 41 45 51 63 40 No. 46 RD4149 45 50 64 60 34 No. 46 RD4151 44 43 62 49 26 No. 46 RD4153 25 26 29 31 3 No. 46 RD4154 31 27 35 38 No. 48 RD4137 55 44 56 59 56 No. 49 RD4173 41 40 51 37 53 No. 49 RD4174 28 38 41 37 46 No. 49 RD4181 50 57 60 51 58 No. 50 RD4176 27 48 36 57 43 No. 50 RD4177 28 38 34 40 41 No. 50 RD4184 39 45 47 57 41 No. 51 RD4218 53 55 63 69 67 No. 51 RD4221 63 63 72 73 77 No. 51 RD4222 64 51 69 66 69 No. 51 RD4223 66 67 73 73 79 No. 51 RD4224 69 68 81 76 82 No. 52 RD4225 97 71 84 79 92 No. 52 RD4226 95 68 79 74 91 No. 52 RD4227 87 40 44 46 74 No. 52 RD4229 97 72 83 79 90 No. 52 RD4230 96 60 80 70 75 No. 53 RD4155 64 36 64 60 64 68 65 69 No. 54 RD3837 60 76 77 74 No. 54 RD3977 49 56 70 68 No. 54 RD4060 45 75 70 73 No. 54 RD4157 58 60 66 60 No. 54 RD4179 33 43 53 41 No. 55 RD4180 14 37 35 39 31 No. 55 RD4182 5 25 28 17 18 No. 55 RD4183 twenty two 26 28 36 44 No. 55 RD4185 twenty three 29 42 35 48 No. 55 RD4186 25 35 33 46 43 No. 57 RD4321 54 47 62 62 68 No. 57 RD4232 27 41 58 44 47 No. 57 RD4233 37 38 42 45 52 No. 57 RD4234 59 62 75 69 80 No. 58 RD4267 57 51 66 68 62 No. 60 RD4264 58 57 74 64 75 No. 60 RD4269 54 52 69 58 78 No. 61 RD4205 35 32 30 29 30 No. 61 RD4219 40 45 47 45 53 No. 61 RD4220 40 36 39 34 46 No. 61 RD4225 64 64 72 71 78 No. 61 RD4229 67 52 70 71 78 No. 62 RD4310 56 63 69 71 74 No. 62 RD4311 57 61 65 68 63 No. 63 RD4300 twenty one 26 26 31 twenty one No. 63 RD4305 twenty three 35 37 34 25 No. 63 RD4306 61 68 72 67 65 No. 64 RD4299 42 57 63 70 71 No. 64 RD4301 52 43 57 62 61 No. 64 RD4302 61 58 67 72 72 No. 64 RD4307 64 75 81 78 78 No. 65 RD4303 49 55 64 56 69 No. 65 RD4304 61 64 69 64 75 No. 65 RD4309 64 71 81 62 74 No. 65 RD4347 50 51 58 53 66 No. 65 RD4348 58 46 65 70 70 No. 66 RD4308 88 65 twenty one 70 75 No. 66 RD4332 84 54 -6 43 65 No. 66 RD4363 68 65 -2 69 76 No. 67 RD4339 51 66 59 49 68 No. 67 RD4341 56 53 55 48 67 No. 67 RD4349 53 54 67 49 72 No. 68 RD4384 39 42 51 41 41 No. 70 RD4350 33 43 52 37 47 No. 70 RD4351 56 56 57 51 66 No. 71 RD4369 4 32 35 26 30 No. 71 RD4370 26 30 28 twenty four 38 No. 71 RD4373 29 34 30 14 33 No. 71 RD4417 48 50 52 49 53 No. 72 RD4418 29 47 54 40 48 No. 72 RD4419 35 56 62 43 46 No. 73 RD4413 48 48 46 17 40 No. 73 RD4414 50 39 42 12 38 No. 9A RD3657 11 35 37 twenty four twenty one 27 58 No. 9A RD3659 35 47 46 63 58 59 57 No. 9B RD3658 55 76 59 45 68 64 68 65 No. 9B RD3658 34 30 16 47 55 46 No. 9B RD3658 twenty one 30 66 73 75 No. 52 RD4228 95 55 80 81 91 No. 75 RD4390 27 52 46 41 35 No. 75 RD4421 31 38 50 45 49 No. 76 RD4452 42 43 43 35 57 No. 76 RD4453 39 42 48 39 55 No. 76 RD4454 34 32 43 35 39 No. 77 RD4460 35 31 42 26 42 No. 77 RD4386 37 59 55 44 52 No. 77 RD4519 48 52 57 44 No. 78 RD4455 33 twenty four 43 43 48 No. 78 RD4456 29 12 27 36 30 No. 78 RD4457 27 20 18 42 30 No. 78 RD4458 28 33 46 34 29 No. 78 RD4461 33 17 18 33 37 No. 78 RD4462 twenty three 41 47 43 26 No. 79 RD4463 26 30 41 14 25 No. 79 RD4464 19 39 41 18 30 No. 79 RD4497 12 18 19 6 19 No. 79 RD4498 12 9 15 11 No. 80 RD4499 25 18 14 33 No. 80 RD4500 14 19 14 No. 80 RD4501 14 No. 82 RD4535 13 46 52 40 46 No. 82 RD4536 twenty three 54 57 45 49 No. 83 RD4534 58 43 65 58 72 No. 83 RD4502 5 15 10 8 No. 83 RD4533 57 44 57 53 72 No. 83 RD4532 53 58 67 66 76 No. 84 RD4886 13 1 4 50 No. 84 RD4887 51 12 54 No. 85 RD4845 25 twenty four 39 19 35 No. 85 RD4844 67 55 73 68 80 No. 87 RD4899 46 47 57 49 67 No. 88 RD3754 55 59 69 72 73 No. 88 RD3755 46 38 60 54 73 No. 88 RD3933 41 66 66 62 71 No. 88 RD4155 53 45 64 58 73 No. 88 RD3838 40 50 56 59 57 No. 88 RD3837 73 66 79 69 72 No. 89 RD4842 54 57 65 61 75 No. 89 RD4914 41 51 57 43 48 No. 89 RD4944 48 49 55 45 68 No. 89 RD4945 45 39 49 41 63 No. 89 RD4947 52 49 59 48 71 No. 90 RD4948 43 twenty one 45 30 46 No. 90 RD4949 55 42 67 58 66 No. 90 RD4950 48 26 49 38 63 No. 90 RD4951 59 37 68 56 73 No. 90 RD4952 51 35 58 48 59 No. 91 RD4954 45 58 71 56 52 No. 91 RD4955 40 46 47 46 52 No. 91 RD4956 61 37 48 46 59 No. 91 RD4957 60 48 58 55 63 No. 91 RD4958 44 36 44 41 50 No. 92 RD4892 53 49 57 42 47 No. 92 RD4894 53 62 65 54 53 No. 92 RD4896 53 60 67 52 50 No. 92 RD4897 48 62 60 50 47 No. 93 RD4901 38 47 55 36 47 No. 94 RD4975 twenty four 40 45 28 42 No. 94 RD4959 28 45 56 49 44 No. 102 RD4943 46 55 65 56 64 No. 106 RD4944 63 61 70 59 73 No. 102 RD4946 50 55 67 60 72 No. 96 RD4981 61 46 66 56 71 No. 103 RD5019 17 26 31 twenty one 34 No. 103 RD5020 33 44 44 32 39 No. 103 RD5021 twenty three 18 17 16 36 No. 103 RD5022 35 32 37 25 38 No. 103 RD5023 48 38 47 27 41 No. 103 RD5024 41 45 44 34 46 No. 105 RD5025 35 38 49 39 46 No. 105 RD5026 twenty three 40 54 38 39 No. 105 RD5027 26 31 38 39 39 No. 105 RD5028 30 31 35 34 40 No. 105 RD5029 33 27 38 39 41 No. 106 RD5065 31 36 31 32 31 No. 115 RD5263 30 46 51 41 41 No. 115 RD5286 39 42 62 57 62 No. 115 RD5345 60 55 68 60 73 No. 114 RD5350 54 44 57 54 60Compound (Day 15) CBM CTX HPC STR CERV RD3666 5 63 45 51 71 RD3667 1 64 42 50 42 RD3913 47 53 72 63 62 RD3937 58 41 68 60 76 RD3941 36 56 54 61 64 RD3971 76 72 73 77 80 RD3995 54 63 76 71 13 RD4157 58 60 66 60 -twenty one RD4235 52 72 72 75 76 RD4267 57 51 66 68 62 RD4269 54 52 69 58 78 RD4310 56 63 69 71 74 RD4336 53 58 71 62 70 RD4387 42 54 52 42 37 RD4389 47 63 56 49 46 RD4394 41 59 56 44 51 RD4420 29 48 52 27 38 RD4518 40 56 65 51 16 RD6027 62 50 64 66 75 RD6028 59 34 64 64 61 RD6029 60 55 65 65 66 RD6030 50 50 64 63 72 RD6031 36 51 66 56 65 RD6032 46 50 61 63 54 RD6036 -7 30 35 29 -20 RD6037 6 35 54 40 -12 RD6041 twenty four 56 59 36 34 RD6042 41 61 54 30 45 RD6046 47 40 45 26 32 RD6047 34 49 45 32 34 RD6051 52 52 49 45 57 RD6052 43 40 52 35 34 RD6054 63 49 64 37 60Study No. Compound D29 D29 D29 D29 D29 D29 D29 D29 D29 CBM CTX HPC STR BS SC CERV THOR LUMB No. 7 RD3168 57 36 48 25 44 43 46 44 No. 8 RD3169 31 5 No. 8 RD3170 10 18 18 twenty one 5 7 14 13 No. 6 RD3171 12 10 15 10 4 No. 5 RD3172 30 18 26 11 twenty four 43 No. 6 RD3173 36 twenty two 17 55 42 33 10 No. 5 RD3174 0 18 45 No. 5 RD3175 13 40 34 27 37 66 No. 5 RD3176 50 twenty two 33 18 47 53 No. 6 RD3177 40 38 7 1 48 40 33 32 No. 6 RD3178 38 55 34 0 61 49 46 37 No. 7 RD3179 25 10 18 twenty four twenty one 20 twenty three 16 No. 5 RD3180 38 43 37 38 70 89 No. 14 RD3181 49 34 27 twenty three 47 59 49 50 No. 5 RD3182 28 27 32 41 54 No. 5 RD3183 34 27 twenty four 29 48 52 No. 7 RD3184 32 twenty two 19 10 26 twenty one 17 29 No. 7 RD3185 27 1 5 6 8 3 6 10 No. 5 RD3186 12 18 twenty two 19 41 38 No. 8 RD3187 14 twenty three 13 twenty two 63 61 56 53 No. 7 RD3188 16 twenty three 25 10 29 twenty two twenty four 18 No. 8 RD3189 11 16 4 60 49 44 46 No. 8 RD3190 12 1 16 30 41 27 No. 9A RD3658 46 44 53 60 72 71 65 59 No. 13 RD3745 60 37 43 41 57 50 56 59 No. 13 RD3746 46 39 45 56 45 38 47 53 No. 13 RD3747 63 48 43 54 54 67 70 63 No. 13 RD3748 50 37 27 49 68 73 78 63 No. 21 RD3863 1 No. 21 RD3864 18 No. 21 RD3868 5 No. 21 RD3869 9 3 No. 53 RD3933 51 55 68 60 66 53 57 46 No. 5 RD3181 49 61 51 ND 88 ND No. 10 RD3668 61 73 51 66 75 80 76 76 No. 11 RD3663 57 56 62 68 No. 12 RD3752 27 twenty one twenty four 27 42 58 51 34 No. 12 RD3753 33 40 44 38 54 73 72 66 No. 12 RD3754 42 38 26 18 70 68 74 55 No. 12 RD3755 47 47 60 55 89 85 88 78 No. 16 RD3806 32 50 47 41 72 No. 16 RD3810 34 53 50 29 74 No. 17 RD3818 25 13 33 19 30 No. 18 RD3658 55 42 63 59 41 No. 18 RD3658 66 38 77 71 29 No. 20 RD3658 40 29 30 39 74 No. 32 RD3912 45 56 49 30 72 No. 32 RD3912 70 73 73 55 75 No. 37 RD3970 44 63 43 54 52 No. 37 RD3970 48 65 68 77 77 No. 53 RD4155 62 25 70 62 72 63 74 65 No. 54 RD3837 46 58 71 70 73 No. 54 RD3977 60 62 67 66 68 No. 54 RD4060 49 59 70 69 73 No. 9A RD3657 twenty one 10 twenty one 17 49 36 37 81 No. 9A RD3659 51 25 38 34 70 67 64 56 No. 88 RD3754 59 57 63 69 67 No. 88 RD3755 57 62 72 71 77 No. 88 RD3933 58 78 75 74 74 No. 88 RD4155 47 63 64 62 78 No. 88 RD3838 twenty two 32 30 54 53 No. 88 RD3837 54 69 71 74 72 No. 106 RD4944 47 63 61 49 54 No. 106 RD5065 54 55 60 51 72 No. 115 RD5263 53 51 52 51 54 No. 115 RD5286 54 66 67 64 68 No. 114 RD5350 61 66 59 70 71RD3666 CBM CTX HPC STR CERV BS THOR LUMB Day 15 5 63 45 51 71 73 74 77 Day 29 40 53 45 60 70 61 62 60RD3667 CBM CTX HPC STR BS CERV THOR LUMB Day 15 1 64 42 50 54 42 59 55 Day 29 32 32 43 twenty four 43 46 47 52RD3971 CBM CTX HPC STR CERV Day 15 76 72 73 77 80 Day 29 56 62 63 62 74Study No. Compound D43 D43 D43 D43 D43 D43 D43 D43 D43 CBM CTX HPC STR BS SC CERV THOR LUMB No. 10 RD3668 61 73 51 66 75 80 76 76 No. 11 RD3663 57 56 62 68 No. 106 RD4944 47 63 61 49 54 No. 106 RD5065 54 55 60 51 72 No. 114 RD5350 57 47 62 56 59CBM Cerebellum CTX Frontal cortex HPC Hippocampus STR Texture BS Brain stem CERV Cervical spinal cord THOR Thoracic spinal cord LUMB Lumbar spinal cord SC spinal cord D15 Day 15 D29 Day 29Example 85: Modified oligonucleiGlycosideAcids target humans in nonhuman primatesMAPTEffect

在活體內食蟹猴PD研究中評估某些化合物。動物在第1天經由腰部鞘內注射以2 mL人工腦脊髓液(aCSF)體積接受單次60 mg劑量。每天觀察動物之行為變化。如下文所指示，在投藥後收集每一動物之腦區域，且將組織立即置於均質管中，快速冷凍，且接著保持在-80℃直至分析。Certain compounds were evaluated in an in vivo cynomolgus monkey PD study. Animals received a single 60 mg dose via lumbar intrathecal injection in a 2 mL volume of artificial cerebral spinal fluid (aCSF) on day 1. Animals were observed daily for behavioral changes. Brain regions were collected from each animal after dosing, and tissues were immediately placed in homogenizer tubes, flash frozen, and then kept at -80°C until analysis, as indicated below.

根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl食蟹猴MAPT TaqMan基因表現分析(Thermo Fisher：Mf00902189_m1, FAM)、1 μl食蟹猴ARL1 TaqMan基因表現分析(Thermo Fisher：Mf02795431_m1, VIC) 及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，以95℃持續15秒且60℃持續1分鐘進行40個循環。RNA isolation was performed according to the instructions of the RNeasy Micro Kit (Qiagen catalog number 74004). After RNA isolation, the 96-well plate was placed on ice while preparing the qRT-PCR reaction. 2 μl of RNA was added to a reaction mixture containing 5 μl of TaqMan Fast Virus 1-Step Master Mix (Thermo Fisher catalog number 44444432), 1 μl of Cynomolgus MAPT TaqMan Gene Expression Assay (Thermo Fisher: Mf00902189_m1, FAM), 1 μl of Cynomolgus ARL1 TaqMan Gene Expression Assay (Thermo Fisher: Mf02795431_m1, VIC) and 11 μl of RT-PCR grade nuclease-free water in a MicroAmp Optical 96-well plate (0.2 mL). qPCR was performed using a QuantStudio3 qPCR machine using the following cycles: 50°C for 1 min, 95°C for 20 sec, 95°C for 15 sec and 60°C for 1 min for 40 cycles.

結果在下表5中呈現為相對於對照(來自同一動物之投藥前水準)之MAPT RNA抑制百分比。由於鞘內注射變化，某些動物可能接受較低之劑量，且因此可能結果顯示出較低抑制。在投藥後1 h、6 h及24 h量測CSF中所存在之測試化合物之量。表6顯示投用RD4845之兩隻動物之CSF化合物濃度(μg/mL)。表5腦及脊髓中之MAPT RNA抑制百分比化合物RD3659RD3933RD4155RD4845RD4844RD4842動物IDC2002C01re1C01re2C2001C01re3C01re1C01re2C1001C1002C1002終止日52434343435757573546額葉皮質93317662718391326385顳葉皮質95568689958596395095海馬體8695848837592535380紋狀體58332529365481612250小腦8527343462495468腦幹541064646486648686頸脊髓87486472857285777093腰脊髓91788189887891859497表6CSF化合物濃度RD4845CSF化合物(ug/mL)投藥後小時C01re1C01re21h3554127506h459164724h2348SEQ ID NO: 1等效內容及範圍The results are presented in Table 5 below as percent inhibition of MAPT RNA relative to control (pre-dose levels from the same animal). Due to intrathecal injection variations, some animals may receive a lower dose and therefore may show lower inhibition as a result. The amount of test compound present in the CSF was measured 1 h, 6 h and 24 h after dosing. Table 6 shows the CSF compound concentrations (μg/mL) for two animals dosed with RD4845.Table 5Percent inhibition of MAPT RNA in brain and spinal cordCompoundRD3659RD3933RD4155RD4845RD4844RD4842Animal IDC2002C01re1C01re2C2001C01re3C01re1C01re2C1001C1002C1002End Date52434343435757573546Frontal cortex 93 31 76 62 71 83 91 32 63 85Temporal cortex 95 56 86 89 95 85 96 39 50 95Hippocampus 86 9 58 48 83 75 92 53 53 80Texture 58 33 25 29 36 54 81 61 twenty two 50Cerebellum 85 27 34 34 62 49 54 68Brain stem 54 10 64 64 64 86 64 86 86Cervical spinal cord 87 48 64 72 85 72 85 77 70 93Lumbar spinal cord 91 78 81 89 88 78 91 85 94 97Table 6CSFcompound concentrationRD4845CSFcompounds(ug/mL)Hours after administrationC01re1C01re21h 3554 127506h 459 164724h twenty three 48SEQ ID NO: 1Equivalent content and scope

應理解，本揭示案不限於本文明確闡述之任何或所有特定實施例，且因此當然可有所變化。亦應理解，本文所用之術語僅係出於描述特定實施例之目的，而不意欲具有限制性。It should be understood that the present disclosure is not limited to any or all of the specific embodiments explicitly described herein, and therefore may of course vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

除非另有定義，否則本文所用之所有技術及科學術語均具有與熟習本揭示案所屬領域技術者所通常理解相同之含義。儘管與本文所闡述之任何方法及材料類似或等同者亦可用於實踐或測試本揭示案，但現闡述較佳方法及材料。如熟習此項技術者將易於明瞭，且根據本文所用術語應理解，在本文中定義詞語或術語之情形下，該等詞語或術語之適用性不應限於緊接在定義之前或之後的實施例，而是應在語境允許之情形下在整個本揭示案中使用。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used to practice or test this disclosure, preferred methods and materials are now described. As will be readily apparent to those skilled in the art and understood from the terms used herein, where a word or term is defined herein, the applicability of such word or term should not be limited to the embodiments immediately preceding or following the definition, but should be used throughout this disclosure as the context permits.

本說明書中所引用之所有出版物及專利經引用以揭示並闡述與所引用出版物相關之方法及/或材料。所有此等出版物及專利均係以引用方式併入本文中，如同每一個別出版物或專利明確且個別地指示以引用方式併入一般。此種以引用方式併入明確地限於所引用出版物及專利中所闡述之方法及/或材料，且不延伸至來自所引用出版物及專利之任何詞典式定義(亦即，所引用出版物及專利中的在本揭示案中未再明確重複之任何詞典式定義不應視為如此，且不應解讀為定義隨附申請專利範圍中出現之任何術語)。若任何併入之參考文獻與本揭示案之間存在衝突，則應以本揭示案為準。另外，本揭示案中屬於先前技術內之任何特定實施例可明確地自任一或多項技術方案中排除。由於認為此等實施例為熟習此項技術者所已知，故可將其排除，即使本文中未明確陳述該排除。出於任何原因，無論是否與先前技術之存在相關，本揭示案之任何特定實施例均可自任何技術方案中排除。All publications and patents cited in this specification are cited to disclose and describe methods and/or materials related to the cited publications. All such publications and patents are incorporated herein by reference as if each individual publication or patent was expressly and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any dictionary definitions from the cited publications and patents (i.e., any dictionary definitions in the cited publications and patents that are not expressly repeated in this disclosure should not be regarded as such and should not be interpreted as defining any term appearing in the scope of the attached patent applications). In the event of a conflict between any incorporated reference and this disclosure, this disclosure shall control. In addition, any specific embodiment of the present disclosure that is within the prior art may be explicitly excluded from any one or more technical solutions. Such embodiments may be excluded because they are considered to be known to those skilled in the art, even if the exclusion is not explicitly stated herein. Any specific embodiment of the present disclosure may be excluded from any technical solution for any reason, whether or not it is related to the existence of prior art.

對任何出版物之引用係由於其揭示內容早於申請日，而不應解釋為承認本揭示案無權因先前揭示內容而早於此出版物。此外，所提供之公開日期可能與實際公開日期不同，可能需要獨立確認。The citation of any publication for its disclosure prior to the filing date should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Furthermore, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

如熟習此項技術者在閱讀本揭示案後將明瞭，本文所闡述及闡釋之個別實施例中之每一者具有分立之組件及特徵，該等組件及特徵可在不背離本揭示案之範圍或精神之情形下容易地與其他若干實施例中之任一者之特徵分離或組合。任何所列舉之方法可按所列舉事件之順序或按在邏輯上可能之任何其他順序來實施。As will be apparent to those skilled in the art after reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be easily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of this disclosure. Any recited method may be implemented in the order of the recited events or in any other order that is logically possible.

在申請專利範圍中，除非指示相反情形或自上下文中另外明顯可見，否則諸如「一種/個(a、an)」及「該(the)」等冠詞可意指一種/個或一種/個以上。除非上下文另有明確指示或要求，否則無論性別代詞(例如男性、女性、無性、其他等)在本文中何處使用，該代詞均應解釋為性別中性的(例如，解釋為同等地指所有性別)，而不考慮隱含性別。除非上下文另有明確指示或要求，否則無論在本文中何處使用，單數形式使用之詞語包括複數，且複數形式使用之詞語包括單數。除非指示相反情形或自上下文中另外明顯可見，否則若一個、一個以上或所有群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關，則在群組之一或多個成員之間包括「或」之技術方案或描述視為滿足條件的。本揭示案包括其中恰好一個群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關之實施例。本揭示案包括其中一個以上或所有群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關之實施例。In the claims, unless otherwise indicated or otherwise apparent from the context, articles such as "a," "an," and "the" may mean one or more than one. Unless the context clearly indicates or requires otherwise, wherever a gender pronoun (e.g., masculine, feminine, asexual, other, etc.) is used herein, the pronoun should be construed as gender neutral (e.g., construed as referring equally to all genders) without regard to implied gender. Unless the context clearly indicates or requires otherwise, wherever used herein, words used in the singular include the plural, and words used in the plural include the singular. Unless indicated to the contrary or otherwise apparent from the context, a technical solution or description including an "or" between one or more members of a group is deemed to satisfy the condition if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The present disclosure includes embodiments in which exactly one of the group members is present in, used in, or otherwise related to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or process.

此外，本揭示案涵蓋將來自所列示技術方案中之一或多者之一或多種限制、要素、條款及說明性術語引入至另一技術方案中之所有變化形式、組合及排列。舉例而言，附屬於另一技術方案之任一技術方案可經修改以包括在附屬於同一基礎技術方案之任何其他技術方案中找到之一或多種限制。倘若以列表形式(例如，以馬庫什群組(Markush group)格式)呈現要素，則亦揭示該等要素之每一亞組，且可自該群組移除任何要素。應理解，一般而言，倘若稱本揭示案或本揭示案之態樣包含特定要素及/或特徵，則本揭示案之某些實施例或本揭示案之態樣係由此等要素及/或特徵組成，或基本上由其組成。出於簡潔性目的，在本文中不以同樣的語言明確陳述彼等實施例。亦應注意，術語「包含」及「含有」意欲為開放性的且允許包括其他要素或步驟。在給出範圍之情形下，除非另有指定，否則端點包括在此等範圍中。此外，除非另有指示或自上下文及熟習此項技術者之理解另外明顯可見，否則表述為範圍之值可在本揭示案之不同實施例中假設所陳述範圍內之任一具體值或子範圍，直至該範圍之下限單位之十分之一，除非上下文另外明確指示。In addition, this disclosure covers all variations, combinations and arrangements of one or more restrictions, elements, clauses and explanatory terms from one or more of the listed technical solutions introduced into another technical solution. For example, any technical solution attached to another technical solution can be modified to include one or more restrictions found in any other technical solution attached to the same basic technical solution. If the elements are presented in a list form (for example, in a Markush group format), each subgroup of these elements is also disclosed, and any element can be removed from the group. It should be understood that, in general, if it is said that this disclosure or the aspect of this disclosure includes specific elements and/or features, then some embodiments of this disclosure or the aspect of this disclosure are composed of these elements and/or features, or are basically composed of them. For the purpose of brevity, they are not clearly stated in the same language herein. It should also be noted that the terms "comprising" and "containing" are intended to be open ended and allow for the inclusion of other elements or steps. Where ranges are given, the endpoints are included in such ranges unless otherwise specified. In addition, unless otherwise indicated or otherwise apparent from the context and the understanding of one skilled in the art, values expressed as ranges may assume any specific value or sub-range within the stated range in different embodiments of the present disclosure, up to one tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

熟習此項技術者將認識到，或能夠僅使用常規實驗確定本文所闡述具體實施例之許多等效形式。本文所闡述之本發明實施例之範圍不意欲限於以上說明，而是如隨附申請專利範圍中所陳述。熟習此項技術者應瞭解，在不背離如以下申請專利範圍中所定義之本揭示案之精神或範圍之情形下，可對本說明作出各種變化及修改。Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but rather to that set forth in the accompanying claims. Those skilled in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the disclosure as defined in the following claims.

圖1顯示包含一或多種配位體之本揭示案之例示性化合物。圖2顯示包含一或多種原肌凝蛋白受體激酶B (TrkB)配位體之本揭示案之例示性化合物。圖3顯示包含一或多種1型大麻素受體(CB₁)配位體之本揭示案之例示性化合物。圖4顯示包含一或多種α₄β_1/7整聯蛋白配位體之本揭示案之例示性化合物。Figure 1 shows exemplary compounds of the present disclosure comprising one or more ligands.Figure 2 shows exemplary compounds of the present disclosure comprising one or more ligands for tropomyosin receptor kinase B (TrkB).Figure 3 shows exemplary compounds of the present disclosure comprising one or more cannabinoid receptor type 1 (_CB1 ) ligands.Figure 4 shows exemplary compounds of the present disclosure comprising one or more_α4β1/7 integrin ligands.

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Claims (177)

Translated fromChinese

一種化合物，其包含長度為14至30個連接核苷之經修飾之寡核苷酸，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個鄰接核鹼基之核鹼基序列。A compound comprising a modified oligonucleotide having a length of 14 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 adjacent nucleobases of any nucleobase sequence of SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.一種化合物，其包含長度為14至23個連接核苷之經修飾之寡核苷酸，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之核鹼基序列之核鹼基序列。A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.一種化合物，其包含經修飾之寡核苷酸，該經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者組成之群的核鹼基序列。A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.如請求項1至3中任一項之化合物，其中該經修飾之寡核苷酸與SEQ ID NO: 1或2至少80%、至少85%、至少90%或至少95%互補。The compound of any one of claims 1 to 3, wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary to SEQ ID NO: 1 or 2.如請求項1至4中任一項之化合物，其中該經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。The compound of any one of claims 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項1至5中任一項之化合物，其中該化合物為雙股的。The compound of any one of claims 1 to 5, wherein the compound is bistranded.一種化合物，其包含長度為14至23個連接核苷之第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及長度為14至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide having a length of 14 to 23 linked nucleosides, wherein the first modified oligonucleotide has a sequence comprising SEQ ID NO: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NO: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 of any one of the nucleobase sequence of at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases; and a second modified oligonucleotide of 14 to 23 linked nucleosides in length, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.一種化合物，其包含長度為14至23個連接核苷之第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217或SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之核鹼基序列之核鹼基序列；及長度為14至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide of 14 to 23 linked nucleosides in length, the first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206; and a second modified oligonucleotide of 14 to 23 linked nucleosides in length, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.一種化合物，其包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217以及SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206; and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide of 19 to 23 linked nucleosides in length.如請求項7至9中任一項之化合物，其中該第一經修飾之寡核苷酸在其長度上與SEQ ID NO: 1或2具有至少80%、至少85%、至少90%或至少95%之互補性或一致性。A compound as in any one of claims 7 to 9, wherein the first modified oligonucleotide has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in its length.如請求項7至10中任一項之化合物，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2中同該第一經修飾之寡核苷酸長度相同之區域具有至少1個、至少2個、至少3個失配。The compound of any one of claims 7 to 10, wherein the first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with a region of SEQ ID NO: 1 or 2 that is the same length as the first modified oligonucleotide.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為14至23個連接核苷。The compound of any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 14 to 23 linked nucleosides.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為19至23個連接核苷。The compound of any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 19 to 23 linked nucleosides.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為21至23個連接核苷。The compound of any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 linked nucleosides in length.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸完全互補。A compound as in any one of claims 7 to 11, wherein the first modified oligonucleotide and the second modified oligonucleotide are completely complementary to each other.如請求項7至15中任一項之化合物，其中該第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。The compound of any one of claims 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項7至16中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。The compound of any one of claims 7 to 16, wherein the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項5、16及17中任一項之化合物，其中該經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。The compound of any one of claims 5, 16 and 17, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.如請求項18之化合物，其中該硫代磷酸酯核苷間鍵聯或該甲基膦酸酯核苷間鍵聯位於該第一經修飾之寡核苷酸或該第二經修飾之寡核苷酸的3’末端或位於該第一經修飾之寡核苷酸的5’末端。A compound as claimed in claim 18, wherein the phosphorothioate nucleoside linkage or the methylphosphonate nucleoside linkage is located at the 3' end of the first modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.如請求項5、16及17中任一項之化合物，其中該經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。The compound of any one of claims 5, 16 and 17, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar.如請求項20之化合物，其中該經修飾之糖包含2’-F修飾。The compound of claim 20, wherein the modified sugar comprises a 2'-F modification.如請求項20之化合物，其中該經修飾之糖包含2’-OMe修飾。The compound of claim 20, wherein the modified sugar comprises a 2'-OMe modification.如請求項7至15中任一項之化合物，其中該第一經修飾之寡核苷酸之每一核苷包含經修飾之糖。The compound of any one of claims 7 to 15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.如請求項7至15中任一項之化合物，其中該第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。The compound of any one of claims 7 to 15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.如請求項23或24之化合物，其中該經修飾之糖包含選自由鹵素、烷氧基及雙環糖或其組合組成之群的修飾。The compound of claim 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar or a combination thereof.如請求項25之化合物，其中該經修飾之糖包含選自由LNA、cEt、2’-MOE、2’-F、2’-OMe及2’-去氧或其組合組成之群的修飾。A compound as claimed in claim 25, wherein the modified sugar comprises a modification selected from the group consisting of LNA, cEt, 2’-MOE, 2’-F, 2’-OMe and 2’-deoxy or a combination thereof.如請求項26之化合物，其中該第一經修飾之寡核苷酸包含不超過十個2’-F糖修飾。The compound of claim 26, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.如請求項27之化合物，其中該第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。A compound as claimed in claim 27, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.如任一前述請求項之化合物，其包含結合基團。A compound as claimed in any preceding claim, comprising a binding group.如請求項29之化合物，其中該結合基團連接至該經修飾之寡核苷酸之5’端。A compound as claimed in claim 29, wherein the binding group is linked to the 5' end of the modified oligonucleotide.如請求項29或30之化合物，其中該結合基團包含靶向部分。A compound as claimed in claim 29 or 30, wherein the binding group comprises a targeting moiety.如請求項31之化合物，其中該靶向部分包含一或多種選自一或多種原肌凝蛋白受體B (TrkB)配位體、一或多種1型大麻素受體(CB₁)配位體及一或多種α₄β_1/7整聯蛋白配位體之配位體。The compound of claim 31, wherein the targeting moiety comprises one or more ligands selected from one or more tropomyosin receptor B (TrkB) ligands, one or more type 1 cannabinoid receptor (_CB1 ) ligands, and one or more_α4β1/7 integrin ligands.如請求項32之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 32, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之5’端。The compound of claim 33, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end of the modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之3’端。The compound of claim 33, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 3' end of the modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之5’端及3’端。The compound of claim 33, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end and the 3' end of the modified oligonucleotide.如請求項33之化合物，其中： 該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者； 該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者；且 該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。The compound of claim 33, wherein: the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII and Formula XXXXXXIX-XXXXXXIII; the one or more_CB1 ligands are selected from any one of Formula XXXXXXI and Formula XXXXXXXIV-XXXXXXXXXVIII; and the one or more_α4β1/7 integrin ligands are selected from any one of Formula XXXXXXII-XXXXXXIV and Formula XXXXXXXIX-XXXXXXXXXIV.如請求項29至37中任一項之化合物，其中該結合基團包含一或多種脂質。A compound as in any one of claims 29 to 37, wherein the binding group comprises one or more lipids.如請求項38之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 38, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項38或39之化合物，其中該一或多種脂質連接至該經修飾之寡核苷酸之核苷間鍵聯。The compound of claim 38 or 39, wherein the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide.如請求項40之化合物，其中該經修飾之寡核苷酸之該核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。The compound of claim 40, wherein the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXIII to Formula XXXXXVI.如請求項38至40中任一項之化合物，其中該經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。The compound of any one of claims 38 to 40, wherein the modified oligonucleotide comprises any one of Formula XXXV to Formula XXXXXVI.如請求項32至42中任一項之化合物，其中該經修飾之寡核苷酸包含一或多種TrkB配位體、一或多種CB₁配位體或一或多種α₄β_1/7整聯蛋白配位體。The compound of any one of claims 32 to 42, wherein the modified oligonucleotide comprises one or more TrkB ligands, one or more_CB1 ligands, or one or more_α4β1/7 integrin ligands.如請求項43之化合物，其中該經修飾之寡核苷酸包含一或多種TrkB配位體。The compound of claim 43, wherein the modified oligonucleotide comprises one or more TrkB ligands.如請求項44之化合物，其中該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者。The compound of claim 44, wherein the one or more TrkB ligands are selected from any one of Formula I-Formula XXXIV, Formula XXXXXVII, Formula XXXXXIX-Formula XXXXXX, Formula XXXXXXV-Formula XXXXXXVII, and Formula XXXXXXIX-Formula XXXXXXXIII.如請求項45之化合物，其中該一或多種TrkB配位體係選自式XXIX-式XXXI及式XXXXXXV中之任一者。The compound of claim 45, wherein the one or more TrkB ligands are selected from any one of Formula XXIX-Formula XXXI and Formula XXXXXXV.如請求項44至46中任一項之化合物，其中該經修飾之寡核苷酸包含一種或兩種TrkB配位體。A compound as in any one of claims 44 to 46, wherein the modified oligonucleotide comprises one or two TrkB ligands.如請求項44至46中任一項之化合物，其中該經修飾之寡核苷酸包含至少兩種TrkB配位體。A compound as in any one of claims 44 to 46, wherein the modified oligonucleotide comprises at least two TrkB ligands.如請求項48之化合物，其中該至少兩種TrkB配位體係相同的。The compound of claim 48, wherein the at least two TrkB ligands are the same.如請求項48之化合物，其中該至少兩種TrkB配位體係不同的。The compound of claim 48, wherein the at least two TrkB ligands are different.如請求項43之化合物，其中該經修飾之寡核苷酸包含一或多種CB₁配位體。The compound of claim 43, wherein the modified oligonucleotide comprises one or more_CB1 ligands.如請求項51之化合物，其中該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者。The compound of claim 51, wherein the one or more_CB1 ligands are selected from any one of Formula XXXXXXXI and Formula XXXXXXXIV to Formula XXXXXXXVIII.如請求項52之化合物，其中該一或多種CB₁配位體係選自式XXXXXXXIV-式XXXXXXXVI中之任一者。The compound of claim 52, wherein the one or more_CB1 ligands are selected from any one of Formula XXXXXXXIV to Formula XXXXXXXVI.如請求項51至53中任一項之化合物，其中該經修飾之寡核苷酸包含一種或兩種CB₁配位體。A compound as claimed in any one of claims 51 to 53, wherein the modified oligonucleotide comprises one or two_CB1 ligands.如請求項51至53中任一項之化合物，其中該經修飾之寡核苷酸包含至少兩種CB₁配位體。The compound of any one of claims 51 to 53, wherein the modified oligonucleotide comprises at least two_CB1 ligands.如請求項55之化合物，其中該至少兩種CB₁配位體係相同的。The compound of claim 55, wherein the at least two_CB1 ligands are the same.如請求項55之化合物，其中該至少兩種CB₁配位體係不同的。The compound of claim 55, wherein the at least two_CB1 ligands are different.如請求項43之化合物，其中該經修飾之寡核苷酸包含一或多種α₄β_1/7整聯蛋白配位體。The compound of claim 43, wherein the modified oligonucleotide comprises one or more α₄ β_1/7 integrin ligands.如請求項58之化合物，其中該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。The compound of claim 58, wherein the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXII to Formula XXXXXXXIV and Formula XXXXXXXIX to Formula XXXXXXXIV.如請求項59之化合物，其中該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXXXI、式XXXXXXXXII及式XXXXXXXXIV中之任一者。The compound of claim 59, wherein the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXXI, Formula XXXXXXXXII and Formula XXXXXXXXIV.如請求項58至60中任一項之化合物，其中該經修飾之寡核苷酸包含一種或兩種α₄β_1/7整聯蛋白配位體。A compound as in any one of claims 58 to 60, wherein the modified oligonucleotide comprises one or two_α4β1/7 integrin ligands.如請求項58至60中任一項之化合物，其中該經修飾之寡核苷酸包含至少兩種α₄β_1/7整聯蛋白配位體。The compound of any one of claims 58 to 60, wherein the modified oligonucleotide comprises at least two_α4β1/7 integrin ligands.如請求項62之化合物，其中該至少兩種α₄β_1/7整聯蛋白配位體係相同的。The compound of claim 62, wherein the at least two_α4β1/7 integrin ligands are the same.如請求項62之化合物，其中該至少兩種α₄β_1/7整聯蛋白配位體係不同的。The compound of claim 62, wherein the at least two_α4β1/7 integrin ligands are different.如請求項44至64中任一項之化合物，其中該經修飾之寡核苷酸包含一或多種脂質。The compound of any one of claims 44 to 64, wherein the modified oligonucleotide comprises one or more lipids.如請求項65之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 65, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項44至66中任一項之化合物，其中該經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。The compound of any one of claims 44 to 66, wherein the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.如請求項67之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。The compound of claim 67, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain.如請求項68之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈，視情況其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。The compound of claim 68, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain, and optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain.如請求項69之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。The compound of claim 69, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain or a saturated or unsaturated_C22 hydrocarbon chain.如請求項67至70中任一項之化合物，其中該一或多個經取代或未經取代之烷基或烯基連接至該經修飾之寡核苷酸之核苷間鍵聯。The compound of any one of claims 67 to 70, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups are attached to the internucleoside linkage of the modified oligonucleotide.如請求項71之化合物，其中該核苷間鍵聯位於距該經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。The compound of claim 71, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 5' end of the modified oligonucleotide.如請求項72之化合物，其中該核苷間鍵聯位於距該經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。The compound of claim 72, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 5' end of the modified oligonucleotide.如請求項71之化合物，其中該核苷間鍵聯位於距該經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。The compound of claim 71, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide.如請求項74之化合物，其中該核苷間鍵聯位於距該經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。The compound of claim 74, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide.如請求項71至75中任一項之化合物，其中該經修飾之寡核苷酸之該核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。A compound as in any one of claims 71 to 75, wherein the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXXXXIII-Formula XXXXXVI.如請求項65至76中任一項之化合物，其中該經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。The compound of any one of claims 65 to 76, wherein the modified oligonucleotide comprises any one of Formula XXXV to Formula XXXXXVI.如請求項1至6中任一項之化合物，其中該經修飾之寡核苷酸包含5'-膦酸酯修飾。The compound of any one of claims 1 to 6, wherein the modified oligonucleotide comprises a 5'-phosphonate modification.如請求項7至77中任一項之化合物，其中該第一經修飾之寡核苷酸包含5'-膦酸酯修飾。The compound of any one of claims 7 to 77, wherein the first modified oligonucleotide comprises a 5'-phosphonate modification.如請求項78或79之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。The compound of claim 78 or 79, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylephosphonate modification.一種化合物，其包含： 包含5'-膦酸酯修飾之第一經修飾之寡核苷酸，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及 包含一或多種配位體之第二經修飾之寡核苷酸。A compound comprising:a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; anda second modified oligonucleotide comprising one or more ligands.如請求項81之化合物，其中該第一經修飾之寡核苷酸包含含有該5'-膦酸酯修飾之5'末端核苷。The compound of claim 81, wherein the first modified oligonucleotide comprises a 5'-terminal nucleoside containing the 5'-phosphonate modification.如請求項81或82之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。The compound of claim 81 or 82, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylephosphonate modification.如請求項81至83中任一項之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。The compound of any one of claims 81 to 83, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification.如請求項81至83中任一項之化合物，其中該5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。The compound of any one of claims 81 to 83, wherein the 5'-phosphonate modification is a 5'-ethylephosphonate modification.如請求項81至85中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種選自一或多種原肌凝蛋白受體B (TrkB)配位體、一或多種1型大麻素受體(CB₁)配位體及一或多種α₄β_1/7整聯蛋白配位體之配位體。A compound as in any one of claims 81 to 85, wherein the second modified oligonucleotide comprises one or more ligands selected from one or more tropomyosin receptor B (TrkB) ligands, one or more type 1 cannabinoid receptor (_CB1 ) ligands and one or more_α4β1/7 integrin ligands.如請求項86之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該第二經修飾之寡核苷酸之5’端。The compound of claim 86, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end of the second modified oligonucleotide.如請求項86之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該第二經修飾之寡核苷酸之3’端。The compound of claim 86, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 3' end of the second modified oligonucleotide.如請求項86之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該第二經修飾之寡核苷酸之5’端及3’端。The compound of claim 86, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end and the 3' end of the second modified oligonucleotide.如請求項86之化合物，其中： 該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者； 該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者；且 該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。The compound of claim 86, wherein: the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII and Formula XXXXXXIX-XXXXXXIII; the one or more_CB1 ligands are selected from any one of Formula XXXXXXI and Formula XXXXXXXIV-XXXXXXXXXVIII; and the one or more_α4β1/7 integrin ligands are selected from any one of Formula XXXXXXII-XXXXXXIV and Formula XXXXXXXIX-XXXXXXXXXIV.如請求項81至90中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種TrkB配位體。The compound of any one of claims 81 to 90, wherein the second modified oligonucleotide comprises one or more TrkB ligands.如請求項91之化合物，其中該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者。The compound of claim 91, wherein the one or more TrkB ligands are selected from any one of Formula I-Formula XXXIV, Formula XXXXXVII, Formula XXXXXIX-Formula XXXXXX, Formula XXXXXXV-Formula XXXXXXVII, and Formula XXXXXXIX-Formula XXXXXXXIII.如請求項92之化合物，其中該一或多種TrkB配位體係選自式XXIX-式XXXI及式XXXXXXV中之任一者。The compound of claim 92, wherein the one or more TrkB ligands are selected from any one of Formula XXIX-Formula XXXI and Formula XXXXXXV.如請求項91至93中任一項之化合物，其中該第二經修飾之寡核苷酸包含一種或兩種TrkB配位體。A compound as in any one of claims 91 to 93, wherein the second modified oligonucleotide comprises one or two TrkB ligands.如請求項91至93中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少兩種TrkB配位體。The compound of any one of claims 91 to 93, wherein the second modified oligonucleotide comprises at least two TrkB ligands.如請求項95之化合物，其中該至少兩種TrkB配位體係相同的。The compound of claim 95, wherein the at least two TrkB ligands are the same.如請求項95之化合物，其中該至少兩種TrkB配位體係不同的。The compound of claim 95, wherein the at least two TrkB ligands are different.如請求項81至90中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種CB₁配位體。The compound of any one of claims 81 to 90, wherein the second modified oligonucleotide comprises one or more_CB1 ligands.如請求項98之化合物，其中該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者。The compound of claim 98, wherein the one or more_CB1 ligands are selected from any one of Formula XXXXXXXI and Formula XXXXXXXIV to Formula XXXXXXXVIII.如請求項99之化合物，其中該一或多種CB₁配位體係選自式XXXXXXXIV-式XXXXXXXVI中之任一者。The compound of claim 99, wherein the one or more_CB1 ligands are selected from any one of Formula XXXXXXXIV to Formula XXXXXXXVI.如請求項98至100中任一項之化合物，其中該第二經修飾之寡核苷酸包含一種或兩種CB₁配位體。The compound of any one of claims 98 to 100, wherein the second modified oligonucleotide comprises one or two_CB1 ligands.如請求項98至100中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少兩種CB₁配位體。The compound of any one of claims 98 to 100, wherein the second modified oligonucleotide comprises at least two_CB1 ligands.如請求項102之化合物，其中該至少兩種CB₁配位體係相同的。The compound of claim 102, wherein the at least two_CB1 ligands are the same.如請求項102之化合物，其中該至少兩種CB₁配位體係不同的。The compound of claim 102, wherein the at least two_CB1 ligands are different.如請求項81至90中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種α₄β_1/7整聯蛋白配位體。The compound of any one of claims 81 to 90, wherein the second modified oligonucleotide comprises one or more_α4β1/7 integrin ligands.如請求項105之化合物，其中該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。The compound of claim 105, wherein the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXII to Formula XXXXXXXIV and Formula XXXXXXXIX to Formula XXXXXXXIV.如請求項106之化合物，其中該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXXXI、式XXXXXXXXII及式XXXXXXXXIV中之任一者。The compound of claim 106, wherein the one or more α₄ β_1/7 integrin ligands are selected from any one of Formula XXXXXXXXI, Formula XXXXXXXXII and Formula XXXXXXXXIV.如請求項105至107中任一項之化合物，其中該第二經修飾之寡核苷酸包含一種或兩種α₄β_1/7整聯蛋白配位體。The compound of any one of claims 105 to 107, wherein the second modified oligonucleotide comprises one or two α₄ β_1/7 integrin ligands.如請求項105至107中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少兩種α₄β_1/7整聯蛋白配位體。The compound of any one of claims 105 to 107, wherein the second modified oligonucleotide comprises at least two_α4β1/7 integrin ligands.如請求項109之化合物，其中該至少兩種α₄β_1/7整聯蛋白配位體係相同的。The compound of claim 109, wherein the at least two_α4β1/7 integrin ligands are the same.如請求項109之化合物，其中該至少兩種α₄β_1/7整聯蛋白配位體係不同的。The compound of claim 109, wherein the at least two_α4β1/7 integrin ligands are different.如請求項81至111中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種脂質。A compound as in any one of claims 81 to 111, wherein the second modified oligonucleotide comprises one or more lipids.如請求項81至111中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。The compound of any one of claims 81 to 111, wherein the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.如請求項113之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。The compound of claim 113, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain.如請求項114之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈，視情況其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。The compound of claim 114, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain, and optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain.如請求項115之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。The compound of claim 115, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain or a saturated or unsaturated_C22 hydrocarbon chain.如請求項113至116中任一項之化合物，其中該一或多個經取代或未經取代之烷基或烯基連接至該第二經修飾之寡核苷酸之核苷間鍵聯。The compound of any one of claims 113 to 116, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to the internucleoside linkage of the second modified oligonucleotide.如請求項117之化合物，其中該核苷間鍵聯位於距該第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。The compound of claim 117, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 5' end of the second modified oligonucleotide.如請求項118之化合物，其中該核苷間鍵聯位於距該第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。The compound of claim 118, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 5' end of the second modified oligonucleotide.如請求項117之化合物，其中該核苷間鍵聯位於距該第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。The compound of claim 117, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the second modified oligonucleotide.如請求項120之化合物，其中該核苷間鍵聯位於距該第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。The compound of claim 120, wherein the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the second modified oligonucleotide.如請求項117至121中任一項之化合物，其中該第二經修飾之寡核苷酸之該核苷間鍵聯係選自式XXXXXIII-式XXXXXVI中之任一者。The compound of any one of claims 117 to 121, wherein the internucleoside bond of the second modified oligonucleotide is selected from any one of Formula XXXXXIII to Formula XXXXXVI.如請求項112至122中任一項之化合物，其中該第二經修飾之寡核苷酸包含式XXXV-式XXXXXVI中之任一者。The compound of any one of claims 112 to 122, wherein the second modified oligonucleotide comprises any one of Formula XXXV to Formula XXXXXVI.如請求項81至123中任一項之化合物，其中該第一經修飾之寡核苷酸之長度為14至30個連接核苷。The compound of any one of claims 81 to 123, wherein the first modified oligonucleotide has a length of 14 to 30 linked nucleosides.如請求項81至124中任一項之化合物，其中該第二經修飾之寡核苷酸之長度為14至30個連接核苷，其具有與該第一經修飾之寡核苷酸互補之區域。A compound as in any one of claims 81 to 124, wherein the second modified oligonucleotide is 14 to 30 linked nucleosides in length and has a region that is complementary to the first modified oligonucleotide.如請求項81至125中任一項之化合物，其中該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-73、144-147、177-188、190-192、194-197、199-200及209-217中之任一者之至少14個鄰接核鹼基之核鹼基序列。The compound of any one of claims 81 to 125, wherein the first modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.如請求項81至126中任一項之化合物，其中該第二經修飾之寡核苷酸具有包含SEQ ID NO: 81-143、149-155、157、159-168、171-172、174、176及201-206中之任一者之至少14個鄰接核鹼基之核鹼基序列。The compound of any one of claims 81 to 126, wherein the second modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176, and 201-206.如請求項81至127中任一項之化合物，其中該第一經修飾之寡核苷酸係選自表3中IA Ref ID NO中之任一者。The compound of any one of claims 81 to 127, wherein the first modified oligonucleotide is selected from any one of IA Ref ID NOs in Table 3.如請求項81至128中任一項之化合物，其中該第二經修飾之寡核苷酸係選自表3中IS Ref ID NO中之任一者。The compound of any one of claims 81 to 128, wherein the second modified oligonucleotide is selected from any one of the IS Ref ID NOs in Table 3.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸，及與該第一經修飾之寡核苷酸完全互補的長度為14至21個連接核苷之第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3, and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides that is completely complementary to the first modified oligonucleotide.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸，及選自由表3中IS Ref ID NO中之任一者組成之群的第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3, and a second modified oligonucleotide selected from the group consisting of any one of IS Ref ID NOs in Table 3.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸及/或選自由表3中IS Ref ID NO中之任一者組成之群的第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3 and/or a second modified oligonucleotide selected from the group consisting of any one of IS Ref ID NOs in Table 3.如請求項130、131或132之化合物，其包含結合基團。The compound of claim 130, 131 or 132, comprising a binding group.如請求項133之化合物，其中該結合基團連接至該第一經修飾之寡核苷酸或該第二經修飾之寡核苷酸之5’端。A compound as claimed in claim 133, wherein the binding group is linked to the 5' end of the first modified oligonucleotide or the second modified oligonucleotide.如請求項133或134之化合物，其中該結合基團包含靶向部分。A compound as claimed in claim 133 or 134, wherein the binding group comprises a targeting moiety.如請求項135之化合物，其中該靶向部分包含一或多種選自一或多種原肌凝蛋白受體B (TrkB)配位體、一或多種1型大麻素受體(CB₁)配位體及一或多種α₄β_1/7整聯蛋白配位體之配位體。The compound of claim 135, wherein the targeting moiety comprises one or more ligands selected from one or more tropomyosin receptor B (TrkB) ligands, one or more type 1 cannabinoid receptor (_CB1 ) ligands, and one or more_α4β1/7 integrin ligands.如請求項136之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 136, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項137之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之5’端。The compound of claim 137, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end of the modified oligonucleotide.如請求項137之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之3’端。The compound of claim 137, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 3' end of the modified oligonucleotide.如請求項137之化合物，其中該一或多種TrkB配位體、該一或多種CB₁配位體或該一或多種α₄β_1/7整聯蛋白配位體連接至該經修飾之寡核苷酸之5’端及3’端。The compound of claim 137, wherein the one or more TrkB ligands, the one or more_CB1 ligands or the one or more_α4β1/7 integrin ligands are linked to the 5' end and the 3' end of the modified oligonucleotide.如請求項137之化合物，其中： 該一或多種TrkB配位體係選自式I-式XXXIV、式XXXXXVII、式XXXXXIX-式XXXXXX、式XXXXXXV-式XXXXXXVII及式XXXXXXIX-式XXXXXXXIII中之任一者； 該一或多種CB₁配位體係選自式XXXXXXI及式XXXXXXXIV-式XXXXXXXVIII中之任一者；且 該一或多種α₄β_1/7整聯蛋白配位體係選自式XXXXXXII-式XXXXXXIV及式XXXXXXXIX-式XXXXXXXXIV中之任一者。The compound of claim 137, wherein: the one or more TrkB ligands are selected from any one of Formula I-XXXIV, Formula XXXXXVII, Formula XXXXXIX-XXXXXX, Formula XXXXXXV-XXXXXXVII and Formula XXXXXXIX-XXXXXXIII; the one or more_CB1 ligands are selected from any one of Formula XXXXXXI and Formula XXXXXXXIV-XXXXXXXXXVIII; and the one or more_α4β1/7 integrin ligands are selected from any one of Formula XXXXXXII-XXXXXXIV and Formula XXXXXXXIX-XXXXXXXXXIV.如前述請求項中任一項之化合物，其中該化合物係呈醫藥學上可接受之鹽形式。A compound as claimed in any preceding claim, wherein the compound is in the form of a pharmaceutically acceptable salt.如請求項142之化合物，其中該醫藥學上可接受之鹽為鈉鹽。The compound of claim 142, wherein the pharmaceutically acceptable salt is a sodium salt.如請求項142之化合物，其中該醫藥學上可接受之鹽為鉀鹽。The compound of claim 142, wherein the pharmaceutically acceptable salt is a potassium salt.一種組合物，其包含如任一前述請求項之化合物或經修飾之寡核苷酸以及醫藥學上可接受之載劑。A composition comprising a compound or modified oligonucleotide as claimed in any preceding claim and a pharmaceutically acceptable carrier.一種用於療法中之組合物，其包含如任一前述請求項之化合物或經修飾之寡核苷酸。A composition for use in therapy, comprising a compound or modified oligonucleotide as claimed in any preceding claim.一種治療、預防或改善個體之與MAPT相關之疾病、病症或疾患之方法，其包括向該個體投與靶向MAPT之化合物，藉此治療、預防或改善該疾病、病症或疾患。A method for treating, preventing or ameliorating a disease, disorder or condition associated with MAPT in an individual comprises administering a compound targeting MAPT to the individual, thereby treating, preventing or ameliorating the disease, disorder or condition.一種向個體投與如請求項1至144中任一項之化合物或經修飾之寡核苷酸或如請求項146之組合物的方法。A method of administering the compound or modified oligonucleotide of any one of claims 1 to 144 or the composition of claim 146 to a subject.如請求項147或148之方法，其中該疾病、病症或疾患為神經退化性疾病，包括tau蛋白病變、阿茲海默氏病(Alzheimer’s disease)、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群(Dravet’s Syndrome)。The method of claim 147 or 148, wherein the disease, disorder or condition is a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy or Dravet's Syndrome.如請求項147至149中任一項之方法，其中投與該化合物抑制或減少或改善神經退化性疾病，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。The method of any one of claims 147 to 149, wherein administration of the compound inhibits or reduces or ameliorates a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy or Dravet syndrome.一種抑制細胞中之MAPT表現之方法，其包括使該細胞與靶向MAPT之化合物接觸，藉此抑制該細胞中之MAPT表現。A method for inhibiting MAPT expression in a cell comprises contacting the cell with a compound targeting MAPT, thereby inhibiting MAPT expression in the cell.如請求項151之方法，其中該細胞係在個體之腦中。The method of claim 151, wherein the cell is in the brain of the individual.如請求項152之方法，其中該個體患有神經退化性疾病或處於患有神經退化性疾病之風險下，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。The method of claim 152, wherein the individual has or is at risk for a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), epilepsy, or Dravet syndrome.一種減少或抑制個體之神經退化性疾病、包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群之方法，其包括向該個體投與靶向MAPT之化合物，藉此減少或抑制該個體之神經退化性疾病，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。A method for reducing or inhibiting a neurodegenerative disease in an individual, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), epilepsy, or Dravet syndrome, comprising administering to the individual a compound targeting MAPT, thereby reducing or inhibiting the neurodegenerative disease in the individual, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), epilepsy, or Dravet syndrome.如請求項154之方法，其中該個體患有神經退化性疾病或處於患有神經退化性疾病之風險下，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。The method of claim 154, wherein the individual has or is at risk for a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy, or Dravet syndrome.如請求項147至155中任一項之方法，其中該化合物為靶向MAPT之化合物。The method of any one of claims 147 to 155, wherein the compound is a compound targeting MAPT.如請求項147至156中任一項之方法，其中該化合物或該經修飾之寡核苷酸為如請求項1至144中任一項之化合物或經修飾之寡核苷酸或如請求項146之組合物。The method of any one of claims 147 to 156, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 144 or the composition of claim 146.如請求項157之方法，其中非經腸投與該化合物或該組合物。The method of claim 157, wherein the compound or the composition is administered parenterally.如請求項157之方法，其中藉由鞘內投與來投與該化合物或該組合物。The method of claim 157, wherein the compound or the composition is administered by intrathecal administration.一種靶向MAPT之化合物之用途，其用於治療、預防或改善與MAPT相關之疾病、病症或疾患。A use of a compound targeting MAPT for treating, preventing or ameliorating a disease, disorder or condition associated with MAPT.如請求項160之用途，其中該疾病、病症或疾患為神經退化性疾病，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。The use of claim 160, wherein the disease, disorder or condition is a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy or Dravet syndrome.如請求項160或161之用途，其中該化合物為靶向MAPT之化合物。The use of claim 160 or 161, wherein the compound is a compound targeting MAPT.如請求項160至162中任一項之用途，其中該化合物或該經修飾之寡核苷酸為如請求項1至144中任一項之化合物或經修飾之寡核苷酸或如請求項146之組合物。The use of any one of claims 160 to 162, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 144 or the composition of claim 146.一種靶向MAPT之化合物之用途，其用於製造用以治療、預防或改善與MAPT相關之疾病、病症或疾患的藥劑。A use of a compound targeting MAPT for manufacturing a medicament for treating, preventing or ameliorating a disease, disorder or condition associated with MAPT.如請求項164之用途，其中該疾病為神經退化性疾病，包括tau蛋白病變、阿茲海默氏病、額顳葉失智症(FTD)、FTDP-17、進行性核上性麻痺(PSP)、慢性創傷性腦病變(CTE)、皮質基底節退化症(CBD)、癲癇或德拉韋氏症候群。The use of claim 164, wherein the disease is a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), cortical basal degeneration (CBD), epilepsy or Dravet syndrome.如請求項164或165之用途，其中該化合物為靶向MAPT之化合物。The use of claim 164 or 165, wherein the compound is a compound targeting MAPT.如請求項164至166中任一項之用途，其中該化合物或該經修飾之寡核苷酸為如請求項1至144中任一項之化合物或經修飾之寡核苷酸或如請求項146之組合物。The use of any one of claims 164 to 166, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 144 or the composition of claim 146.如任一前述請求項之方法或用途，其中約每三個月一次至約每年一次向個體投與該化合物或該組合物。The method or use of any preceding claim, wherein the compound or the composition is administered to the subject about once every three months to about once a year.如任一前述請求項之方法或用途，其中約每三個月一次、約每六個月一次或約每年一次向個體投與該化合物或該組合物。The method or use of any preceding claim, wherein the compound or the composition is administered to the subject about once every three months, about once every six months, or about once a year.一種向個體之腦遞送治療性寡核苷酸之方法，該方法包括向該個體投與如請求項1至144中任一項之化合物或其立體異構物、互變異構物、前藥或鹽或如請求項146之組合物。A method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound of any one of claims 1 to 144 or a stereoisomer, tautomer, prodrug or salt thereof, or a composition of claim 146.如請求項170之方法，其中將該治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。The method of claim 170, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of striatum, cerebellum, brain stem, hippocampus, frontal cortex, and spinal cord.一種治療或改善個體之疾病、病症或其症狀之方法，該方法包括向該個體投與如請求項1至144中任一項之化合物或其立體異構物、互變異構物、前藥或鹽或如請求項146之組合物。A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 144 or a stereoisomer, tautomer, prodrug or salt thereof, or a composition of claim 146.如請求項172之方法，其中該疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。The method of claim 172, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.如請求項172或173之方法，其中該疾病、病症或其症狀為阿茲海默氏病或其症狀。The method of claim 172 or 173, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.如請求項170至174中任一項之方法，其中該投與為鞘內投與或腦室內(ICV)投與。The method of any one of claims 170 to 174, wherein the administration is intrathecal administration or intracerebroventricular (ICV) administration.一種向個體之細胞或組織活體內遞送一或多種貨物分子之方法，其包括向該個體投與如請求項1至144中任一項之化合物或如請求項146之組合物。A method for delivering one or more cargo molecules into cells or tissues of a subject in vivo, comprising administering to the subject a compound of any one of claims 1 to 144 or a composition of claim 146.如請求項176之方法，其中該細胞或組織為CNS細胞或組織。The method of claim 176, wherein the cell or tissue is a CNS cell or tissue.