CFTR相關疾病及病症可定義為尤其包括囊腫纖維化以及選自以下之其他CFTR相關疾病及病症：
● 慢性支氣管炎；鼻竇炎；便秘；胰臟炎；胰臟功能不全；由先天性雙側輸精管缺乏(congenital bilateral absence of the vas deferens；CBAVD)引起之男性不孕症；輕度肺病；過敏性支氣管與肺的麴菌病(allergic bronchopulmonary aspergillosis；ABPA)；肝病；凝血-血纖維蛋白溶解不足，諸如蛋白C不足；及糖尿病；
● 哮喘；COPD；吸菸誘發之COPD；及乾眼病；及
● 特發性胰臟炎；遺傳性肺氣腫；遺傳性血色素沈著症；溶酶體貯積病，尤其諸如I-細胞疾病假賀勒病(Hurler)；黏多醣貯積症；桑多霍夫/塔伊-薩克斯病(Sandhoff/Tay-Sachs)；成骨不全；法布立病(Fabry disease)；休格倫氏病(Sjogren's disease)；骨質疏鬆症；骨質減少；骨癒合及骨生長(包括骨修復、骨再生、減少骨骼再吸收及增加骨骼沈積)；氯離子通道病，諸如先天性肌強直病(湯姆森及貝克爾形式(Thomson and Becker forms))；3型貝特氏症候群(Bartter's syndrome)；癲癇症；溶酶體貯積病；原發性纖毛運動困難(Primary Ciliary Dyskinesia；PCD)-纖毛之結構及/或功能之遺傳性病症之術語(包括PCD伴隨內臟逆位，亦稱為卡塔格內氏症候群(Kartagener syndrome)、PCD無內臟逆位及纖毛發育不全)；全面性癲癇伴隨熱驚厥附加(generalized epilepsy with fibrile seizures plus；GEFS+)；一般癲癇伴隨熱及無熱驚厥；肌強直；先天性肌剛痙病；鉀惡化肌強直；高鉀血週期性麻痹；長QT症候群(LQTS)；LQTS/布魯加達氏症候群(Brugada syndrome)；體染色體顯性LQTS伴隨耳聾；體染色體隱性LQTS；LQTS伴隨畸形特徵；先天性及後天性LQTS；擴張型心肌症；體染色體顯性LQTS；骨質石化病；及3型貝特氏症候群。
CFTR-associated diseases and disorders may be defined to include inter alia cystic fibrosis and other CFTR-associated diseases and disorders selected from:
● Chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic Allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolytic insufficiencies, such as protein C insufficiency; and diabetes mellitus;
● asthma; COPD; smoking-induced COPD; and dry eye disease; and
● Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; lysosomal storage disorders, especially such as the I-cell disorder pseudo-Hurler; mucopolysaccharidosis; Sandhoff/Tay-Sachs; Osteogenesis Imperfecta; Fabry disease; Sjogren's disease; Osteoporosis; Osteopenia; Bone healing and bone growth (including bone repair, bone regeneration, decreased bone resorption, and increased bone deposition); chloride channelopathies, such as myotonia congenita (Thomson and Becker forms); Bett syndrome type 3 (Bartter's syndrome); epilepsy; lysosomal storage disease; Primary Ciliary Dyskinesia (PCD) - term for an inherited disorder of the structure and/or function of cilia (including PCD with situs inversus, Also known as Kartagener syndrome, PCD without inversus and ciliary hypoplasia); generalized epilepsy with fibrile seizures plus (GEFS+); generalized epilepsy with febrile and afebrile Convulsions; Myotonia; Myotonia congenita; Potassium exacerbated myotonia; Hyperkalemic periodic paralysis; Long QT syndrome (LQTS); LQTS/Brugada syndrome; Autosomal dominant LQTS with Deafness; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Betts syndrome type 3.
術語「囊腫纖維化治療」係指囊腫纖維化之任何治療且尤其包括降低囊腫纖維化之嚴重程度及/或減少囊腫纖維化之症狀之治療。The term "cystic fibrosis treatment" refers to any treatment of cystic fibrosis and especially includes treatments that reduce the severity of cystic fibrosis and/or reduce the symptoms of cystic fibrosis.
術語「囊腫纖維化」係指任何形式之囊腫纖維化，尤其係指與一或多個基因突變相關之囊腫纖維化。較佳地，此類囊腫纖維化與CFTR遷移缺陷(II類突變)或CFTR穩定性降低(VI類突變) [特定言之，CFTR遷移缺陷/II類突變]相關，其中應理解，此類CFTR遷移缺陷或CFTR穩定性降低可能與相同或任何其他類別之另一致病突變相關。此類其他致病CFTR基因突變包含I類突變(無功能性CFTR蛋白)、(另一) II類突變(CFTR遷移缺陷)、III類突變(CFTR調節缺陷)、IV類突變(CFTR傳導缺陷)、V類突變(歸因於剪接缺陷之較少CFTR蛋白)及/或(另一) VI類突變(歸因於CFTR穩定性降低之較少CFTR蛋白)。該一或多個基因突變可例如包含至少一個選自以下之突變：F508del、A561E及N1303K，以及I507del、R560T、R1066C及V520F；特定言之F508del。除以上列舉的以外，其他CFTR基因突變包含例如G85E、R347P、L206W及M1101K。該基因突變可為異型接合、純合或複合異型接合的。該基因突變尤其為異型接合的，其包含一個F508del突變。其他CFTR基因突變(其尤其為III及/或IV類突變)包含G551D、R117H、D1152H、A455E、S549N、R347H、S945L及R117C。The term "cystic fibrosis" refers to any form of cystic fibrosis, especially cystic fibrosis associated with one or more genetic mutations. Preferably, such cystic fibrosis is associated with defects in CFTR migration (class II mutations) or reduced CFTR stability (class VI mutations) [specifically, CFTR migration defects/class II mutations], wherein it is understood that such CFTR Migration defects or reduced CFTR stability may be associated with another pathogenic variant of the same or any other class. Such other pathogenic CFTR gene mutations include class I mutations (no functional CFTR protein), (another) class II mutations (defects in CFTR migration), class III mutations (defects in CFTR regulation), class IV mutations (defects in CFTR conduction) , class V mutations (less CFTR protein due to splicing defects) and/or (another) class VI mutations (less CFTR protein due to reduced CFTR stability). The one or more genetic mutations may for example comprise at least one mutation selected from the group consisting of: F508del, A561E and N1303K, and I507del, R560T, R1066C and V520F; in particular F508del. In addition to those listed above, other CFTR gene mutations include, for example, G85E, R347P, L206, and M1101K. The gene mutation may be heterozygous, homozygous, or compound heterozygous. The genetic mutation is particularly heterozygous, comprising a F508del mutation. Other CFTR gene mutations, which are especially Class III and/or IV mutations, include G551D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.
囊腫纖維化/與囊腫纖維化相關之某種基因突變之嚴重程度以及其校正功效一般可藉由測試由CFTR實現之氯離子運輸來量測。舉例而言，在患者中，汗水中氯離子平均含量可用於此類評定。Cystic fibrosis/cystic fibrosis-associated mutations The severity and corrective efficacy of certain gene mutations can generally be measured by testing chloride ion transport by CFTR. For example, in a patient, the average chloride ion content in sweat can be used for such an assessment.
術語「囊腫纖維化之症狀」尤其係指汗水中較高的氯離子濃度；囊腫纖維化之症狀進一步包含慢性支氣管炎；鼻竇炎；便秘；胰臟炎；胰臟功能不全；由先天性雙側輸精管缺乏(CBAVD)引起之男性不孕症；輕度肺病；過敏性支氣管與肺的麴菌病(ABPA)；肝病；凝血-血纖維蛋白溶解不足，諸如蛋白C不足；及/或糖尿病。The term "symptoms of cystic fibrosis" especially refers to high chloride ion concentration in sweat; symptoms of cystic fibrosis further include chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; Male infertility due to vas deferens deficiency (CBAVD); mild lung disease; allergic bronchial and pulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolytic insufficiency, such as protein C insufficiency; and/or diabetes.
為了避免任何疑問，若化合物描述為適用於治療某些疾病，則此類化合物同樣適用於製備用於治療該等疾病之藥物。同樣，此類化合物亦適合於用於治療此類疾病之方法，且包含向有需要之個體投與有效量之此類化合物。For the avoidance of any doubt, where compounds are described as being useful in the treatment of certain diseases, such compounds are also suitable for use in the manufacture of medicaments for the treatment of such diseases. Likewise, such compounds are also suitable for use in methods of treating such diseases comprising administering an effective amount of such compounds to a subject in need thereof.
如本文所用，術語「個體」係指哺乳動物，尤其人類。As used herein, the term "individual" refers to mammals, especially humans.
本發明進一步係關於一種治療囊腫纖維化之方法，其包含向有需要之個體投與有效量之巨環(尤其17員或18員巨環)或其醫藥學上可接受之鹽；其中該巨環之環核心包含一個芳族部分(諸如伸芳基或5員至10員伸雜芳基，其中該芳族部分尤其(i)經由羰基及(ii)經由氧原子與分子之其餘部分/該巨環之環成員結合，其中該羰基及該氧原子尤其以1,2-二基或以1,3-二基關係與該芳族部分連接)、至少一個β-胺基酸(其中該β-胺基酸尤其經由其胺基與羰基結合，該羰基與該芳族部分連接)及至少一個N-烷基化之α-胺基酸(其中該N-烷基化之α-胺基酸尤其經由其N-烷基化之胺基與該β-胺基酸之羰基結合，且其中此類α-胺基酸尤其為甘胺酸或攜帶烴取代基之天然或非天然胺基酸)；其中該巨環為人類CFTR之II類突變的校正劑(其中尤其校正該CFTR，特定言之人類F508del-CFTR之摺疊、穩定性、降解及/或遷移)，其中較佳地以至少與魯瑪卡托(lumacaftor)可達成的相同功效來校正該CFTR的活性(其中該活性/功效可根據下文實驗部分中揭示的方法測試)。The present invention further relates to a method for treating cystic fibrosis, which comprises administering an effective amount of a macrocycle (especially a 17-membered or 18-membered macrocycle) or a pharmaceutically acceptable salt thereof to an individual in need; wherein the macrocycle The ring core of the ring comprises an aromatic moiety (such as an aryl or a 5- to 10-membered heteroaryl, wherein the aromatic moiety is in particular (i) via a carbonyl group and (ii) via an oxygen atom with the rest of the molecule/the Ring members of a macrocycle in which the carbonyl and the oxygen atom are especially linked to the aromatic moiety in a 1,2-diyl or in a 1,3-diyl relationship), at least one β-amino acid (wherein the β - an amino acid in particular bonded via its amine group to a carbonyl group which is attached to the aromatic moiety) and at least one N-alkylated α-amino acid (wherein the N-alkylated α-amino acid In particular via its N-alkylated amine group bonded to the carbonyl of the β-amino acid, and wherein such α-amino acid is especially glycine or a natural or unnatural amino acid bearing a hydrocarbon substituent) ; wherein the macrocycle is a correction agent for class II mutations in human CFTR (wherein in particular correcting the folding, stability, degradation and/or migration of the CFTR, in particular the human F508del-CFTR), wherein preferably at least with Lu The same efficacy can be achieved with lumacaftor to correct the activity of the CFTR (wherein the activity/efficacy can be tested according to the method disclosed in the experimental section below).
此外，關於式(II)化合物(無論關於化合物本身、其鹽、含有化合物或其鹽之組合物或化合物或其鹽之用途等)所指示之任何較佳情況及(子)實施例在細節上作必要修改後將適用於式(I)化合物。In addition, any preferences and (sub)embodiments indicated for the compound of formula (II) (whether in relation to the compound itself, its salt, a composition containing the compound or its salt, or the use of the compound or its salt, etc.) are in detail This applies mutatis mutandis to compounds of formula (I).
式 (I) / 式 (II) 化合物之製備 ：可藉由熟知文獻方法、下文給出之方法、下文實驗部分中給出之方法或類似方法製備式(I)、式(II)、式(I
E)、式(II
E)之化合物。雖然最佳反應條件可隨用所用特定反應物或溶劑而改變，但此類條件可由熟習此項技術者藉由常規最佳化程序來決定。在一些情況下，進行以下反應流程及/或反應步驟之次序可變化以促進反應或避免非所需要之反應產物。在下文所概述之一般反應順序中，通用基團
R
1 、
R
2 、
R
3 、
R
4 、
Ar
1 及
Ar
2 如對於式(I)、式(II)、式(I
E)、式(II
E)所定義。本文所用之其他縮寫明確定義，或如實驗部分中定義。在一些情況下，通用基團
R
1 、
R
2 、
R
3 、
R
4 、
Ar
1 及
Ar
2 可能不與以下流程中所說明之組合體相容且因此將需要使用保護基(protecting group；PG)。保護基之使用為此項技術中熟知的(參見例如「Protective Groups in Org. Synthesis」, T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999)。出於此論述之目的，將假定此類保護基視需要存在於適當位置上。在一些情況下，最終產物可進一步例如藉由操縱取代基進行改質以得到新的最終產物。此等操縱可包括但不限於熟習此項技術者通常已知之還原、氧化、烷基化、醯化、水解及過渡金屬催化之交叉偶合反應。所得化合物亦可以本身已知之方式轉變成鹽，尤其醫藥學上可接受之鹽。
Preparation of compounds of formula (I) / formula (II) : formula (I), formula (II), formula ( I E ), compounds of formula (II E ). While optimal reaction conditions may vary with the particular reactants or solvent employed, such conditions can be determined by one skilled in the art by routine optimization procedures. In some cases, the following reaction schemes are performed and/or the order of reaction steps can be varied to facilitate the reaction or to avoid undesired reaction products. In the general reaction sequence outlined below, the general groups R 1 , R 2 , R 3 , R 4 , Ar 1 and Ar 2 are as for formula (I), formula (II), formula ( IE ), formula ( II E ) defined. Other abbreviations used herein are explicitly defined, or as defined in the experimental section. In some cases, the generic groups R 1 , R 2 , R 3 , R 4 , Ar 1 and Ar 2 may not be compatible with the combinations illustrated in the schemes below and thus will require the use of protecting groups (PG ). The use of protecting groups is well known in the art (see eg "Protective Groups in Org. Synthesis", TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are optionally present in place. In some cases, the final product can be further modified, eg, by manipulating substituents, to obtain a new final product. Such manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal catalyzed cross-coupling reactions commonly known to those skilled in the art. The compounds obtained can also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.
本發明之式(I)、式(II)、式(I
E)及式(II
E)之化合物可根據下文所概述之一般反應順序製備。
Compounds of formula (I), formula (II), formula (I E ) and formula (II E ) of the present invention can be prepared according to the general reaction sequence outlined below.
按照以下描繪之流程中之一者製備式(I)化合物。
反應流程 A Compounds of formula (I) are prepared according to one of the schemes depicted below. Reaction scheme A
反應流程 A ：可利用外消旋或鏡像異構性富集之胺基酸建構嵌段進行合成。分別按照文獻中或
反應流程 I及
J中充分描述之程序製備之合適保護的胺建構嵌段
A及酸
B- 酸，在溶劑(如THF、DMF或NMP)中，在鹼(諸如TEA或DIPEA)存在下，在-20℃與+75℃之間的溫度下，較佳地在室溫，用肽偶合劑(諸如HATU、COMU、T3P、PyBop或EDCI/HOBt)處理，產生對應醯胺中間物
AB。中間物
AB之胺官能基之去保護根據熟習此項技術者已知方法達成，例如藉由用含4M HCl之二㗁烷處理或較佳地用TFA (在Boc保護基之情況下)處理，或用哌啶或二乙胺(在Fmoc保護基之情況下)處理，或適當處理(在其他保護基，諸如Cbz或Alloc保護基之情況下)。接著，根據上文針對
AB中間物之形成已描述之肽偶合條件，使去保護的中間物
AB- 胺與按照文獻中或實驗部分中描述之程序製備之合適保護的酸
C反應。接著，在最終肽偶合巨內醯胺化之前，將所得直鏈中間物
ABC去保護。在一些情況下，依序移除保護基PG1及PG3，但其較佳在一個單步中同時移除。舉例而言，
tBu酯及Boc保護基藉由用含4M HCl之二㗁烷或較佳地TFA處理移除，或可替代地烯丙酯及Alloc保護基可藉由如文獻中充分報導之鈀催化劑處理移除。接著，在標準條件下將直鏈
ABC去保護的中間物環化(cylised)，亦即可在稀釋條件，諸如小於
ABC起始材料於溶劑(如DMF或NMP)或溶劑混合物(如DMF/DCM (1:1))中之0.1M溶液中，在鹼(諸如TEA或DIPEA)存在下，在-20℃與+75℃之間的溫度下，較佳地在室溫，用偶合劑(諸如COMU、T3P、PyBop、EDCI/HOBt，或較佳地HATU)處理中間物，得到對應巨環
cABC。視不同殘基之性質而定，可能需要一些其餘的去保護步驟以得到最終產物。藉由製備型HPLC，用標準反相或(必要時)對掌性相管柱進行最終純化，得到呈純立體異構物形式之目標化合物。
Reaction Scheme A : It can be synthesized using racemic or enantiomerically enriched amino acid building blocks. Suitably protected amine building block A and acid B- acid prepared following procedures well described in the literature or in Reaction Schemes I and J , respectively, in a solvent such as THF, DMF or NMP, in a base such as TEA or DIPEA ) in the presence of a peptide coupling reagent such as HATU, COMU, T3P, PyBop or EDCI/HOBt at a temperature between -20°C and +75°C, preferably at room temperature, yields the corresponding amide intermediate object AB . Deprotection of the amine function of intermediate AB is achieved according to methods known to those skilled in the art, for example by treatment with 4M HCl in dioxane or preferably with TFA (in the case of the Boc protecting group), Either with piperidine or diethylamine (in the case of the Fmoc protecting group), or appropriately in the case of other protecting groups such as Cbz or Alloc protecting groups. The deprotected intermediate AB- amine is then reacted with an appropriately protected acid C prepared according to procedures described in the literature or in the experimental section according to the peptide coupling conditions described above for the formation of the AB intermediate. The resulting linear intermediate ABC is then deprotected prior to final peptide coupling macrolactamylation. In some cases, protecting groups PG1 and PG3 are removed sequentially, but are preferably removed simultaneously in a single step. For example, the tBu ester and Boc protecting groups are removed by treatment with 4M HCl in dioxane or preferably TFA, or alternatively the Allyl ester and Alloc protecting groups can be removed by Palladium catalyst treatment removed. Next, the linear ABC deprotected intermediate is cylised under standard conditions, that is, dilute conditions, such as less than the ABC starting material, in a solvent (such as DMF or NMP) or a solvent mixture (such as DMF/DCM (1:1)) in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at room temperature, with a coupling agent such as COMU, T3P, PyBop, EDCI/HOBt, or preferably HATU) treat the intermediate to obtain the corresponding macrocyclic cABC . Depending on the nature of the various residues, some additional deprotection steps may be required to obtain the final product. Final purification by preparative HPLC using standard reverse phase or (if necessary) chiral phase columns afforded the title compound as the pure stereoisomer.
反應流程 B ：在
反應流程 A之修改版本中，可逐步地引入
C部分，一次一個胺基酸。根據上文已描述之肽偶合條件處理先前
反應流程 A中所描述之
AB中間物及市售或按照文獻中或下文實驗部分中描述之程序製備的第一胺基酸
D-1，形成對應肽鍵。
ABD-1之胺官能基之選擇性去保護，諸如藉由用哌啶或二乙胺處理移除Fmoc基團，或藉由在溶劑(如EtOAc、THF或二㗁烷)中在催化劑(諸如Pd/C或Pd(OH)
2/C)上氫解移除Cbz保護基，或較佳地藉由用含4M HCl之二㗁烷或用TFA處理移除Boc保護基，分別得到游離胺或其銨鹽，準備好在類似肽偶合步驟中與第二胺基酸
D-2偶合。三個所描述之偶合/去保護/偶合步驟得到與先前
反應流程 A中所描述相同的直鏈中間物
ABC。合成得到所需巨環
cABC之其餘步驟與上文描述相同。
反應流程 B 反應流程 C Reaction Scheme B : In a modified version of Reaction Scheme A , part C can be introduced stepwise, one amino acid at a time. The AB intermediate previously described in Reaction Scheme A and the first amino acid D-1 , either commercially available or prepared according to procedures described in the literature or in the experimental section below, were treated according to the peptide coupling conditions described above to form the corresponding peptides key. Selective deprotection of the amine function of ABD-1 , such as by removal of the Fmoc group by treatment with piperidine or diethylamine, or by reaction in a solvent such as EtOAc, THF or dioxane over a catalyst such as Hydrogenolysis on Pd/C or Pd(OH) 2 /C) removes the Cbz protecting group, or preferably removes the Boc protecting group by treatment with 4M HCl in dioxane or with TFA to give the free amine or Its ammonium salt, is ready for coupling with the second amino acid D-2 in a similar peptide coupling step. The three described coupling/deprotection/coupling steps lead to the same linear intermediate ABC as previously described in Reaction Scheme A. The remaining steps for the synthesis of the desired macrocyclic cABC are the same as described above. Reaction scheme B Reaction scheme C
反應流程 C ：在一替代方法中，可修改建構直鏈中間物
ABC之順序。根據上文已描述之肽偶合條件，在溶劑(如THF、DMF或NMP)中，在鹼(諸如TEA或DIPEA)存在下，在-20℃與+75℃之間的溫度下，較佳地在室溫，用試劑(諸如HATU、COMU、T3P、PyBop或EDCI/HOBt)處理按照文獻中或分別
反應流程 K 及 J中描述之程序製備的合適保護的建構嵌段
C及胺
B- 胺。根據熟習此項技術者已知之方法，例如藉由在甲醇水溶液中，在0℃直至50℃範圍內之溫度下，用NaOH或LiOH處理(對於甲基或乙酯而言)，或較佳地藉由在溶劑(如EtOAc、THF或二㗁烷)中，在催化劑(諸如Pd/C或Pd(OH)
2/C)上氫解(對於苯甲酯而言)，來達成中間物
BC之酸官能基的去保護，亦即移除PG4。接著，根據先前已描述之肽偶合條件，使去保護的中間物
BC- 酸與按照文獻中或
反應流程 I中描述之程序製備之合適保護的胺建構嵌段
A反應。接著可將所得直鏈
ABC去保護且環化，得到如
反應流程 A中所描述之最終產物
cABC。
反應流程 D Reaction Scheme C : In an alternative approach, the order of construction of the linear intermediate ABC can be modified. According to the peptide coupling conditions already described above, in a solvent such as THF, DMF or NMP, in the presence of a base such as TEA or DIPEA, at a temperature between -20°C and +75°C, preferably Appropriately protected building block C and amine B- amine prepared following procedures described in the literature or in Reaction Schemes K and J , respectively, are treated at room temperature with reagents such as HATU, COMU, T3P, PyBop or EDCI/HOBt. According to methods known to those skilled in the art, for example by treatment with NaOH or LiOH (for methyl or ethyl esters) in aqueous methanol at temperatures ranging from 0°C to 50°C, or preferably Intermediate BC is achieved by hydrogenolysis (for the benzyl ester) over a catalyst such as Pd/C or Pd(OH) 2 /C in a solvent such as EtOAc, THF or dioxane. Deprotection of the acid function, ie removal of PG4. Next, the deprotected intermediate BC- acid is reacted with an appropriately protected amine building block A prepared according to the procedures described in the literature or in Reaction Scheme I according to the peptide coupling conditions described previously. The resulting linear ABC can then be deprotected and cyclized to give the final product cABC as described in Reaction Scheme A. Reaction scheme D
反應流程 D ：如在自
反應流程 A移動至
反應流程 B時為此種情況，
反應流程 C中之
C部分可類似地逐步引入，一次一個胺基酸。根據上文已描述之肽偶合條件，處理按照文獻中、或實驗部分中或
反應流程 J中描述之程序製備之合適保護的酸
D-1及胺
B- 胺。
BD-1之胺官能基之選擇性去保護，亦即移除PG5，諸如在酸性條件下移除Cbz保護基，或更佳地，用含4M HCl之二㗁烷或較佳地用TFA處理來移除Boc保護基，得到對應銨鹽而無需移除正交保護基PG4。接著可在類似肽偶合步驟中使所得中間物胺與第二胺基酸
D-2偶合。三個所描述之偶合/去保護/偶合步驟得到與先前
反應流程 C中所描述之物質相同的受保護的中間物
BC，在該階段可如上文所描述進行合成之其餘部分。
反應流程 E Reaction Scheme D : As is the case when moving from Reaction Scheme A to Reaction Scheme B , part C in Reaction Scheme C can similarly be introduced stepwise, one amino acid at a time. Suitably protected acids D-1 and amines B- amine prepared according to the procedures described in the literature, or in the Experimental section or in Reaction Scheme J , were treated according to the peptide coupling conditions already described above. Selective deprotection of the amine function of BD-1 , i.e. removal of PG5, such as removal of the Cbz protecting group under acidic conditions, or better, treatment with dioxane containing 4M HCl or preferably TFA To remove the Boc protecting group, the corresponding ammonium salt was obtained without removing the orthogonal protecting group PG4. The resulting intermediate amine can then be coupled with a second amino acid D-2 in a similar peptide coupling step. The three described coupling/deprotection/coupling steps lead to the same protected intermediate BC as previously described in Reaction Scheme C , at which stage the remainder of the synthesis can be carried out as described above. Reaction scheme E
反應流程 E ：在
反應流程 C之另一變化形式中，建構嵌段
A- 胺在β-三級丁酯存在下受到2個羧酸官能基上之合適的正交保護基(諸如α-苯甲酯或α-甲酯)的雙重保護。接著，按照
反應流程 C中描述之序列，得到對應直鏈中間物
ABC。使用TFA對天冬胺酸側鏈及Boc胺進行雙重去保護，且隨後藉由先前已描述之方法進行環化，得到仍在
A上受到保護之環化的中間物
cABC。可藉由在甲醇/水中，在0℃至50℃範圍內之溫度下，用NaOH或LiOH處理(對於甲酯或乙酯而言)，或較佳地藉由在溶劑(如EtOAc、THF或二㗁烷)中在催化劑(諸如Pd/C或Pd(OH)
2/C)上對苯甲酯進行氫解，來實現天冬胺酸主鏈羧酸的去保護，亦即移除PG6。接著，根據上文已描述之肽偶合條件，使去保護的中間物
cABC- 酸與市售或按照文獻中或實驗部分中所描述之程序製備之胺
AM偶合，得到目標化合物。此策略對於製備用於探索
AM部分之文庫尤其有效。
反應流程 F Reaction Scheme E : In another variation of Reaction Scheme C , the building block A- amine is protected in the presence of β-tertiary butyl ester with a suitable orthogonal protecting group (such as α-benzene methyl ester or α-methyl ester) double protection. Then, according to the sequence described in Reaction Scheme C , the corresponding linear intermediate ABC is obtained. Double deprotection of the aspartic acid side chain and the Boc amine using TFA, and subsequent cyclization by methods previously described gave the cyclized intermediate cABC still protected on A. This can be achieved by treatment with NaOH or LiOH (for methyl or ethyl esters) in methanol/water at temperatures ranging from 0°C to 50°C, or preferably by treatment in a solvent such as EtOAc, THF or Deprotection of the aspartate backbone carboxylic acid, ie removal of PG6, is achieved by hydrogenolysis of benzyl esters in dioxane over a catalyst such as Pd/C or Pd(OH) 2 /C. Next, the deprotected intermediate cABC- acid is coupled with commercially available or prepared amine AM according to the peptide coupling conditions already described above to obtain the target compound. This strategy is especially effective for preparing libraries for exploring AM segments. Reaction scheme F
反應流程 F ：反應流程 E中描述之逐步引入
A部分之策略可以不同順序施加，得到相同的
cABC- 酸中間物，如
反應流程 F中所說明。在β-烯丙酯存在下，受2個羧酸官能基上之合適的正交保護基(諸如α-苯甲酯或α-甲酯)的雙重保護的受保護的
A- 胺可以與
反應流程 A中所描述相同的順序，與所需的
B- 酸及
C建構嵌段偶合，得到對應直鏈中間物
ABC。使用TFA (在Boc保護基之情況下)依序對胺保護基PG3去保護，隨後藉由在溶劑(如DCM)中，用1,3-二甲基巴比妥酸(巴比妥酸)及Pd(PPh
3)
4處理來移除天冬胺酸側鏈保護基PG1 (在烯丙基保護基之情況下)，僅如上文已描述進行環化，得到仍在
A上受保護的中間物
cABC，如已在
反應流程 E中描述。合成得到所需巨環
cABC之其餘步驟與上文已描述相同。
反應流程 G Reaction Scheme F : The strategy for stepwise introduction of part A described in Reaction Scheme E can be applied in a different order to give the same cABC- acid intermediate as illustrated in Reaction Scheme F. In the presence of β-allyl esters, double protected A- amines , doubly protected by suitable orthogonal protecting groups on the 2 carboxylic acid functions such as α-benzyl or α-methyl esters, can be reacted with The same sequence as described in Scheme A , coupled with the desired B- acid and C building block, affords the corresponding linear intermediate ABC . Sequential deprotection of the amine protecting group PG3 using TFA (in the case of the Boc protecting group) followed by 1,3-dimethylbarbituric acid (barbituric acid) in a solvent such as DCM and Pd(PPh 3 ) 4 treatment to remove the aspartic acid side chain protecting group PG1 (in the case of the allyl protecting group), and only cyclization as already described above gives the intermediate still protected on A The substance cABC , as already described in Reaction Scheme E. The remaining steps for the synthesis of the desired macrocyclic cABC are the same as those described above. Reaction scheme G
反應流程 G ：在
反應流程 F之變化形式中且與
反應流程 B及
D非常相似，部分
C可逐步引入，一次一個胺基酸。此外，胺基酸
D-1自身可藉由在已經組裝的
ABD1前驅物上引入所需側鏈R1來逐步建構。根據已描述之肽偶合條件，已在
反應流程 F中描述之胺去保護的
AB中間物可與
D-1之未經取代之胺基酸前驅物(諸如NH-Boc或較佳地NH-硝基苯磺醯基-胺基酸)偶合。接著可藉由在鹼(諸如K
2CO
3)存在下，用所需烷基鹵(諸如溴化物或較佳地碘化物)處理，或較佳地經由根據熟習此項技術者熟知之標準條件進行的與所需醇之光延反應(Mitsunobu reaction)，例如藉由在溶劑(諸如THF或二㗁烷)中，在-80℃直至60℃範圍內之溫度下，用DEAD或DIAD與磷化氫配體(如三苯膦)處理，來將NH-硝基苯磺醯基官能基烷基化。接著可藉由在溶劑(如DMF)中，在鹼(諸如K
2CO
3)存在下，用硫酚進行標準處理來移除硝基苯磺醯基活化/保護基，得到對應去保護的中間物。可根據
反應流程 B中所說明之條件，使胺基酸
D-2與此中間物偶合。三個所描述之偶合/去保護/偶合步驟得到與先前
反應流程 F中所描述相同的去保護的直鏈中間物
ABC。合成得到所需巨環
cABC之其餘步驟與上文已描述相同。
反應流程 H Reaction Scheme G : In a variation of Reaction Scheme F and very similar to Reaction Schemes B and D , part C can be introduced stepwise, one amino acid at a time. In addition, amino acid D-1 itself can be constructed stepwise by introducing the desired side chain R1 on the already assembled ABD1 precursor. According to the described peptide coupling conditions, the amine-deprotected AB intermediate already described in Reaction Scheme F can be reacted with an unsubstituted amino acid precursor of D-1 such as NH-Boc or preferably NH-Nitridine phenylsulfonyl-amino acid) coupling. This can be followed by treatment with the desired alkyl halide (such as bromide or preferably iodide) in the presence of a base (such as K2CO3 ), or preferably via standard conditions well known to those skilled in the art A Mitsunobu reaction with the desired alcohol is carried out, for example by using DEAD or DIAD with phosphine in a solvent such as THF or dioxane at temperatures ranging from -80°C to 60°C Ligand (such as triphenylphosphine) to alkylate the NH-nitrobenzenesulfonyl functional group. The nitrobenzenesulfonyl activating/protecting group can then be removed by standard treatment with thiophenol in a solvent such as DMF in the presence of a base such as K2CO3 to give the corresponding deprotected intermediate thing. Amino acid D-2 can be coupled with this intermediate according to the conditions illustrated in Reaction Scheme B. The three described coupling/deprotection/coupling steps lead to the same deprotected linear intermediate ABC as described in Reaction Scheme F previously. The remaining steps for the synthesis of the desired macrocyclic cABC are the same as those described above. Reaction scheme H
反應流程 H ：在
反應流程 F之其他改編中，
A- 胺建構嵌段之α-羧酸保護基可為固相，諸如聚合物連接之載體(support)，從而使得能夠根據熟習聚合物負載之肽合成技術者熟知之確立方法，進行環化的巨環前驅物之逐步固相肽合成。舉例而言，可藉由在允許聚合物珠粒之合適腫脹之溶劑混合物(諸如DCM/DMF)中，用HOBt及DMAP以及偶合劑(諸如DCC或DIC)處理，在Wang樹脂上引入胺基酸
A- 酸，其在胺官能基上由例如Fmoc保護基且在β-羧酸官能基上由例如烯丙酯合適的正交保護。隨後Fmoc保護基之去保護，之後在聚合物肽合成之標準條件下進行肽偶合的順序，允許逐步引入不同建構嵌段
B- 酸、
D1及最後合適保護的
D2(如例如alloc保護的
D2)，得到聚合物負載的直鏈肽
ABC，類似於
反應流程 F中描述之直鏈肽。可藉由潛在地在1,3-二甲基巴比妥酸存在下，用鈀催化劑處理，來達成烯丙酯及N-alloc保護基之雙重去保護，得到仍負載的直鏈肽。可在此等情況下實現在標準肽偶合條件下之環化而無寡聚物形成之風險。接著可藉由酸處理(諸如用TFA/H
2O (95/5)之混合物)，自聚合物載體釋放出已在
反應流程 F中描述之巨環
cABC- 酸。接著可使用如上文所描述之偶合條件，使釋放的
cABC - 酸與適當
AM胺偶合，得到目標化合物。
反應流程 I Reaction Scheme H : In other adaptations of Reaction Scheme F , the α-carboxylic acid protecting group of the A- amine building block can be a solid phase, such as a polymer-linked support, enabling Stepwise solid-phase peptide synthesis of cyclized macrocyclic precursors is carried out by an established method well known to those skilled in peptide synthesis. For example, amino acids can be introduced on Wang resin by treatment with HOBt and DMAP and coupling agents such as DCC or DIC in a solvent mixture that allows for suitable swelling of the polymer beads such as DCM/DMF A- Acid , suitably orthogonally protected on the amine function by eg Fmoc protecting group and on the β-carboxylic acid function by eg allyl ester. Subsequent deprotection of the Fmoc protecting group, followed by a sequence of peptide couplings under standard conditions for polymer peptide synthesis, allows the stepwise introduction of the different building blocks B- acid , D1 and finally a suitably protected D2 (such as e.g. alloc-protected D2 ) , to obtain a polymer-loaded linear peptide ABC similar to the linear peptide described in Reaction Scheme F. Double deprotection of the allyl ester and the N-alloc protecting group can be achieved by treatment with a palladium catalyst, potentially in the presence of 1,3-dimethylbarbituric acid, to give the still supported linear peptide. Cyclization under standard peptide coupling conditions can be achieved in such cases without risk of oligomer formation. The macrocyclic cABC- acids already described in Reaction Scheme F can then be liberated from the polymeric support by acid treatment, such as with a mixture of TFA/ H2O (95/5). The released cABC - acid can then be coupled with the appropriate AM amine using coupling conditions as described above to give the target compound. Reaction scheme I
建構嵌段
A為市售的，如文獻中所描述來製備，或可如
反應流程 I中所說明來製備。根據標準肽偶合條件，藉由在溶劑(如THF、DMF或NMP)中，在鹼(諸如TEA或DIPEA)存在下，在-20℃與+75℃之間的溫度下，較佳地在室溫，用COMU或T3P、HATU、PyBop或另一肽偶合劑處理，使合適正交保護的
A- 酸，諸如N-Fmoc之β-三級丁酯或N-Boc天冬胺酸之β-烯丙酯與所需
AM胺偶合。接著，所得中間物可在保護基化學物質領域中充分確立之標準條件下，在胺官能性上選擇地去保護而無需移除β-酯保護基PG1。在β-三級丁酯存在下用哌啶或二乙胺特定處理以移除N-Fmoc，或在β-烯丙酯存在下用TFA或含4M HCl之二㗁烷處理以移除N-Boc，分別獲得呈其游離鹼或其銨鹽形式之目標建構嵌段
A。
反應流程 J Building block A is commercially available, prepared as described in the literature, or can be prepared as illustrated in Reaction Scheme I. According to standard peptide coupling conditions, by in a solvent (such as THF, DMF or NMP), in the presence of a base (such as TEA or DIPEA), at a temperature between -20 ° C and +75 ° C, preferably at room temperature Warm, treatment with COMU or T3P, HATU, PyBop or another peptide coupler to render a suitable orthogonally protected A- acid , such as β-tertiary butyl ester of N-Fmoc or β-tertiary butyl ester of N-Boc aspartic acid The allyl ester is coupled with the desired AM amine. The resulting intermediate can then be selectively deprotected on the amine functionality without removal of the β-ester protecting group PG1 under standard conditions well established in the field of protecting group chemistry. Specific treatment with piperidine or diethylamine in the presence of β-tertiary butyl esters to remove N-Fmoc, or treatment with TFA or dioxane with 4M HCl in the presence of β-allyl esters to remove N- Boc, the target building block A is obtained in the form of its free base or its ammonium salt, respectively. Reaction flow J
建構嵌段
B、
B- 酸或
B- 胺如文獻中所描述來製備，或可如
反應流程 J中所說明來製備。在羧酸官能基上作為酯(諸如甲酯、乙酯或苯甲酯)保護之適當柳酸衍生物為市售的或如文獻中所描述來製備，或可如實驗部分中所描述來製備。類似地，胺官能基上由Boc或Cbz基團保護之胺基醇為市售的或如文獻中所描述容易地由對應胺基酸製備，或亦可如實驗部分中所描述來製備。胺基醇之醇官能基可在鹼(諸如DIPEA或TEA)存在下，用甲磺醯氯或甲苯磺醯氯或類似活化劑處理後活化，且使其在溶劑(諸如THF或DMF)中與柳酸酯衍生物之苯酚官能基反應，得到雙重保護的
B建構嵌段。替代地，兩個建構嵌段可根據光延方法，藉由在溶劑(諸如THF或二㗁烷)中，在-20℃直至60℃範圍內之溫度下，用磷化氫配體(如三苯膦)及DEAD或DIAD試劑處理而一起反應。接著，所得正交保護的中間物可在酸官能基上或在胺官能基上選擇地去保護，以分別獲得對應建構嵌段
B- 酸或
B- 胺。舉例而言，甲酯用NaOH水溶液或LiOH溶液皂化或苯甲酯在鈀催化劑(諸如炭負載之Pd或Pd(OH)
2)上進行氫解，獲得對應
B- 酸。替代地，藉由用TFA處理進行Boc去保護或對Cbz保護之胺進行氫解(在甲酯之情況下)，得到對應
B- 胺。
反應流程 K Building blocks B , B- acid or B- amine are prepared as described in the literature, or can be prepared as illustrated in Reaction Scheme J. Suitable salicylic acid derivatives protected on the carboxylic acid function as esters such as methyl, ethyl or benzyl esters are commercially available or prepared as described in the literature or can be prepared as described in the experimental section . Similarly, aminoalcohols protected on the amine function by Boc or Cbz groups are commercially available or readily prepared from the corresponding amino acids as described in the literature, or can also be prepared as described in the experimental section. The alcohol function of the aminoalcohol can be activated after treatment with methanesulfonyl chloride or toluenesulfonyl chloride or a similar activator in the presence of a base such as DIPEA or TEA, and allowed to react in a solvent such as THF or DMF with The phenol functional group of the salicylate derivative reacts to obtain a doubly protected B building block. Alternatively, the two building blocks can be synthesized according to the Mitsunobu method by using a phosphine ligand such as triphenyl Phosphine) and DEAD or DIAD reagent treatment to react together. The resulting orthogonally protected intermediate can then be selectively deprotected at the acid function or at the amine function to obtain the corresponding building block B- acid or B- amine , respectively. For example, saponification of methyl esters with aqueous NaOH or LiOH solutions or hydrogenolysis of benzyl esters over a palladium catalyst such as Pd on charcoal or Pd(OH) 2 affords the corresponding B- acids . Alternatively, Boc deprotection by treatment with TFA or hydrogenolysis of the Cbz protected amine (in the case of the methyl ester) affords the corresponding B- amine . Reaction scheme K
可如
反應流程 K中所說明由關鍵中間物
D-1 胺製備建構嵌段
C。中間物
D-1為市售的或如文獻中所描述來製備，或可如此流程中所說明來製備。可使合適PG8保護的溴乙酸酯衍生物(諸如甲酯、乙酯或苯甲酯)在溶劑(如MeCN、丙酮或DMF)中，在鹼(諸如K
2CO
3或DIPEA)存在下，在室溫直至80℃範圍內之溫度下，與適當胺R1NH
2反應，得到胺
D-1。替代地，可使合適PG8保護的胺基酸酯衍生物(諸如甲酯、乙酯或苯甲酯)在溶劑(諸如DCM或THF)中，在催化量之DMAP存在下，與氯化硝基磺醯苯反應，得到對應N-硝基苯磺醯基保護的胺。接著，可藉由如上文已描述之光延方法，亦即藉由在溶劑(諸如THF或二㗁烷)中，在0℃直至80℃範圍內之溫度下，在所需醇R1OH存在下，與磷化氫配體(如三苯膦)及DEAD或DIAD試劑反應，來實現磺醯胺氮之烷基化。隨後，可藉由在溶劑(如DMF或DCM)中，在鹼(諸如K
2CO
3)存在下，用硫酚處理來達成硝基苯磺醯基之裂解，得到胺建構嵌段
D-1。與市售，或根據如上文所描述之標準肽偶合方法如文獻中所描述來製備之
D-2胺基酸偶合。接著，可藉由用NaOH水溶液或LiOH溶液處理(在甲酯或乙酯之情況下)，或藉由在鈀催化劑(諸如炭負載之Pd或Pd(OH)
2)上對苯甲酯進行氫解，來實現酯之去保護，得到目標
C建構嵌段。
Building block C can be prepared from the key intermediate D-1 amine as illustrated in Reaction Scheme K. Intermediate D-1 is commercially available or prepared as described in the literature, or can be prepared as illustrated in such schemes. A suitable PG8-protected bromoacetate derivative (such as methyl ester, ethyl ester or benzyl ester) can be made in a solvent (such as MeCN , acetone or DMF) in the presence of a base (such as K2CO3 or DIPEA), Reaction with the appropriate amine R1NH2 at a temperature ranging from room temperature up to 80°C affords amine D-1 . Alternatively, a suitable PG8-protected amino acid ester derivative (such as methyl, ethyl, or benzyl ester) can be reacted with nitrochloride in the presence of a catalytic amount of DMAP in a solvent (such as DCM or THF). The reaction of sulfonyl benzene affords the corresponding N-nitrobenzene sulfonyl protected amine. Subsequently, by the Mitsunobu method as already described above, ie by the presence of the desired alcohol R1OH in a solvent such as THF or dioxane at a temperature ranging from 0°C to 80°C, with Phosphine ligands (such as triphenylphosphine) react with DEAD or DIAD reagents to achieve alkylation of the sulfonamide nitrogen. Subsequent cleavage of the nitrobenzenesulfonyl group can be achieved by treatment with thiophenol in the presence of a base such as K2CO3 in a solvent such as DMF or DCM to give the amine building block D-1 . Coupling with D-2 amino acids is commercially available, or prepared as described in the literature according to standard peptide coupling methods as described above. The benzyl ester can then be hydrogenated by treatment with aqueous NaOH or LiOH solution (in the case of the methyl or ethyl ester), or by hydrogenation of the benzyl ester over a palladium catalyst such as Pd on carbon or Pd(OH) 2 . Solution, to achieve the deprotection of the ester, to obtain the target C building blocks.
提供以下實例以說明本發明。此等實例僅為說明性的且不應視為以任何方式限制本發明。The following examples are provided to illustrate the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.
實驗部分Experimental part
I. 化學方法所有溫度均以℃為單位陳述。市售起始材料未經進一步純化即按原樣使用。除非另外規定，否則所有反應均在烘乾的玻璃器皿中，在氮氣氛圍下進行。化合物藉由矽膠急驟管柱層析或藉由製備型HPLC來純化。描述於本發明中之化合物藉由使用列於以下之條件的LC-MS資料(滯留時間t
R以min為單位給出；獲自質譜之分子量以g/mol為單位給出)表徵。在本發明化合物呈現為構形異構物之混合物的情況下，尤其在其LC-MS譜中可見，給出最大量構形異構物之滯留時間。
I. Chemical Methods All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. All reactions were performed in oven-dried glassware under a nitrogen atmosphere unless otherwise specified. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. The compounds described in the present invention were characterized by LC-MS data (retention times tR are given in min; molecular weights obtained from mass spectra are given in g/mol) using the conditions listed below. In cases where the compounds of the invention appear as mixtures of conformers, this is seen especially in their LC-MS spectra, giving the retention times of the most abundant conformers.
分析型 LC-MS 設備 ：HPLC泵：二元梯度泵，Agilent G4220A或等效物
自動取樣器：Gilson LH215 (具有Gilson 845z注射器)或等效物
管柱隔室：Dionex TCC-3000RS或等效物
脫氣器：Dionex SRD-3200或等效物
補給泵：Dionex HPG-3200SD或等效物
DAD偵測器：Agilent G4212A或等效物
MS偵測器：單四極質量分析器，Thermo Finnigan MSQPlus或等效物
ELS偵測器：Sedere SEDEX 90或等效物
Analytical LC-MS equipment : HPLC Pump: Binary gradient pump, Agilent G4220A or equivalent Autosampler: Gilson LH215 (with Gilson 845z syringe) or equivalent Column compartment: Dionex TCC-3000RS or equivalent Degasser: Dionex SRD-3200 or equivalent Makeup pump: Dionex HPG-3200SD or equivalent DAD Detector: Agilent G4212A or equivalent MS Detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPlus or etc. Effect ELS detector: Sedere SEDEX 90 or equivalent
在酸性條件下進行之LC-MS
方法 A：管柱：Zorbax SB水溶液(3.5 μm，4.6 × 50 mm)。條件：MeCN [溶離劑A]；水+ 0.04% TFA [溶離劑B]。梯度：95% B → 5% B，1.5 min (流速：4.5 mL/min)。偵測：UV/Vis + MS。
LC-MS Method A under acidic conditions: Column: Zorbax SB aqueous solution (3.5 μm, 4.6 × 50 mm). Conditions: MeCN [Eluent A]; Water + 0.04% TFA [Eluent B]. Gradient: 95% B → 5% B over 1.5 min (flow rate: 4.5 mL/min). Detection: UV/Vis + MS.
方法 B：管柱：Zorbax RRHD SB水溶液(1.8 μm，2.1 × 50 mm)。條件：MeCN [溶離劑A]；水+ 0.04% TFA [溶離劑B]。梯度：95% B → 5% B，2.0 min (流速：0.8 mL/min)。偵測：UV/Vis + MS。
Method B : Column: Zorbax RRHD SB aqueous solution (1.8 μm, 2.1 × 50 mm). Conditions: MeCN [Eluent A]; Water + 0.04% TFA [Eluent B]. Gradient: 95% B → 5% B, 2.0 min (flow rate: 0.8 mL/min). Detection: UV/Vis + MS.
方法 C：管柱：Waters XBridge C18 (5 μm，4.6 × 30 mm)。條件：MeCN [溶離劑A]；水+ 0.04% TFA [溶離劑B]。梯度：95% B → 5% B，1.5 min (流速：4.5 mL/min)。偵測：UV/Vis + MS。
Method C : Column: Waters XBridge C18 (5 μm, 4.6 × 30 mm). Conditions: MeCN [Eluent A]; Water + 0.04% TFA [Eluent B]. Gradient: 95% B → 5% B over 1.5 min (flow rate: 4.5 mL/min). Detection: UV/Vis + MS.
方法 D：管柱：Waters BEH C18 (2.1 × 50mm，2.5μm)。條件：MeCN [溶離劑A]；水+ 0.04% TFA [溶離劑B]。梯度：95% B → 5% B，2.0 min (流速：0.8 mL/min)。偵測：UV/Vis + MS。
Method D : Column: Waters BEH C18 (2.1 × 50mm, 2.5μm). Conditions: MeCN [Eluent A]; Water + 0.04% TFA [Eluent B]. Gradient: 95% B → 5% B, 2.0 min (flow rate: 0.8 mL/min). Detection: UV/Vis + MS.
方法 E：管柱：Waters XBridge C18 (2.5 μm，4.6 × 30 mm)。條件：MeCN [溶離劑A]；水+ 0.04% TFA [溶離劑B]。梯度：95% B → 5% B，1.5 min (流速：4.5 mL/min)。偵測：UV/Vis + MS。
Method E : Column: Waters XBridge C18 (2.5 μm, 4.6 × 30 mm). Conditions: MeCN [Eluent A]; Water + 0.04% TFA [Eluent B]. Gradient: 95% B → 5% B over 1.5 min (flow rate: 4.5 mL/min). Detection: UV/Vis + MS.
方法 F：管柱：Waters XSelect CSH C18 (3.5 μm，2.1 × 30 mm)。條件：MeCN + 0.1%甲酸[溶離劑A]；水+ 0.1%甲酸[溶離劑B]。梯度：95% B → 2% B，1.6 min (流速1 mL/min)，偵測：UV/Vis + MS。
Method F : Column: Waters XSelect CSH C18 (3.5 μm, 2.1 × 30 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; water + 0.1% formic acid [eluent B]. Gradient: 95% B → 2% B, 1.6 min (flow rate 1 mL/min), detection: UV/Vis + MS.
方法 G：管柱：Waters Atlantis T3 (3.0 μm，2.1 × 50 mm)。條件：MeCN + 0.1%甲酸[溶離劑A]；水+ 0.1%甲酸[溶離劑B]。梯度：95% B → 2% B，5 min (流速0.8 mL/min)。偵測：UV/Vis + MS。
Method G : Column: Waters Atlantis T3 (3.0 μm, 2.1 × 50 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; water + 0.1% formic acid [eluent B]. Gradient: 95% B → 2% B, 5 min (flow rate 0.8 mL/min). Detection: UV/Vis + MS.
方法 H：Waters Acquity二元溶劑管理器，MS：Waters SQ偵測器或Xevo TQD或SYNAPT G2 MS，DAD：Acquity UPLC PDA偵測器，ELSD：Acquity UPLC ELSD。來自Waters之管柱ACQUITY UPLC CSH C18 1.7μm 2.1x50 mm，在Acquity UPLC管柱管理器中恆溫在60℃。溶離劑：A：H
2O + 0.05%甲酸；B：MeCN + 0.045%甲酸。方法：梯度：2% B → 98% B，2.0 min。流速：1.0 mL/min。偵測：UV 214 nm及ELSD，以及MS，t
R以min為單位給出。
Method H : Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector or Xevo TQD or SYNAPT G2 MS, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column ACQUITY UPLC CSH C18 1.7 μm 2.1 x 50 mm from Waters, thermostated at 60° C. in an Acquity UPLC column manager. Dissolution agent: A: H 2 O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2% B → 98% B, 2.0 min. Flow rate: 1.0 mL/min. Detection: UV 214 nm and ELSD, and MS, tR is given in min.
在鹼性條件下進行之LC-MS
方法 I：管柱：Waters BEH C18 (2.5μm，2.1 × 50mm)。條件：水NH
3[c(NH
3) = 13 mmol/l] [溶離劑A]；MeCN [溶離劑B]。梯度：5% B → 95% B，2 min (流速0.8 mL/min)。偵測：UV/Vis + MS。
LC-MS method I under alkaline conditions: Column: Waters BEH C18 (2.5μm, 2.1 × 50mm). Conditions: water NH 3 [c(NH 3 ) = 13 mmol/l] [eluent A]; MeCN [eluent B]. Gradient: 5% B → 95% B, 2 min (flow rate 0.8 mL/min). Detection: UV/Vis + MS.
方法 J ：管柱：Waters XSelect CSH C18 (3.5μm，2.1 × 30mm)。條件：95% MeCN + 5% Water/NH
4HCO
3[c(NH
4HCO
3) = 10 mmol/l] [溶離劑A]；水/NH
4HCO
3[c(NH
4HCO
3) = 10 mmol/l] [溶離劑B]。梯度：95% B → 2% B，1.6 min (流速1mL/min)，偵測：UV/Vis + MS。
Method J : Column: Waters XSelect CSH C18 (3.5 μm, 2.1 × 30mm). Conditions: 95% MeCN + 5% Water/NH 4 HCO 3 [c(NH 4 HCO 3 ) = 10 mmol/l] [Eluent A]; Water/NH 4 HCO 3 [c(NH 4 HCO 3 ) = 10 mmol/l] [Eluent B]. Gradient: 95% B → 2% B, 1.6 min (flow rate 1mL/min), detection: UV/Vis + MS.
GC-MSAgilent 6890N/管柱：RXi-5MS 20m，ID 180 μm，df 0.18 μm；速度50 cm/s，He載氣；100℃ → 250℃，4.5 min；偵測：MS。
GC-MS Agilent 6890N/column: RXi-5MS 20m, ID 180 μm, df 0.18 μm; speed 50 cm/s, He carrier gas; 100°C → 250°C, 4.5 min; detection: MS.
製備型 HPLC 設備 ：配備有Gilson LH215、Dionex SRD-3200脫氣器之Gilson 333/334 HPLC泵，
Dionex ISO-3100A補給泵，Dionex DAD-3000 DAD偵測器，單一四極質量分析器MS偵測器，Thermo Finnigan MSQ Plus，MRA100-000分流器，Polymer Laboratories PL-ELS1000 ELS偵測器
Preparative HPLC equipment : Gilson 333/334 HPLC pump equipped with Gilson LH215, Dionex SRD-3200 degasser, Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector, single quadrupole mass analyzer MS detector , Thermo Finnigan MSQ Plus, MRA100-000 shunt, Polymer Laboratories PL-ELS1000 ELS detector
在鹼性條件下進行之製備型 HPLC管柱：Waters XBridge (10 μm，75 × 30 mm)。條件：MeCN [溶離劑A]；水+0.5% NH
4OH (25%水溶液) [溶離劑B]；梯度參見
製備型 HPLC 表 1(流速：75 mL/min)，視待純化之化合物之極性來決定溶離劑A之起始百分比(x)。偵測：UV/Vis + MS
製備型 HPLC 表 1 t (min)
0
0.01
4.0
6.0
6.2
6.6
溶離劑A (%)
x
x
95
95
x
x
溶離劑B (%)
100-x
100-x
5
5
100-x
100-x
Preparative HPLC column under alkaline conditions: Waters XBridge (10 μm, 75 × 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH 4 OH (25% in water) [eluent B]; gradient see Preparative HPLC Table 1 (flow rate: 75 mL/min), depending on the polarity of the compound to be purified To determine the initial percentage of eluent A (x). Detection: UV/Vis + MS Preparative HPLC Table 1 t (min) 0 0.01 4.0 6.0 6.2 6.6
Solvent A (%) x x 95 95 x x
Solvent B (%) 100-x 100-x 5 5 100-x 100-x
在酸性條件下進行之製備型 HPLC管柱：Waters Atlantis T3 (10 μm，75 × 30 mm)。條件：MeCN [溶離劑A]；水+0.5% HCO
2H [溶離劑B]；梯度參見
製備型 HPLC 表 2(流速：75 mL/min)，視待純化之化合物之極性來決定溶離劑A之起始百分比(x)。偵測：UV/Vis + MS
製備型 HPLC 表 2 t (min)
0
0.01
4.0
6.0
6.2
6.6
溶離劑A (%)
x
x
95
95
x
x
溶離劑B (%)
100-x
100-x
5
5
100-x
100-x
Preparative HPLC column under acidic conditions: Waters Atlantis T3 (10 μm, 75 × 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCO 2 H [eluent B]; gradient see Preparative HPLC Table 2 (flow rate: 75 mL/min), depending on the polarity of the compound to be purified to determine the eluent A The starting percentage (x). Detection: UV/Vis + MS Preparative HPLC Table 2 t (min) 0 0.01 4.0 6.0 6.2 6.6
Solvent A (%) x x 95 95 x x
Solvent B (%) 100-x 100-x 5 5 100-x 100-x
用於對掌性分離之製備型HPLC 在大多數情況下，可根據熟習此項技術者熟知之標準方法，藉由標準製備型規模HPLC分離或純化所需非鏡像異構物。在一些情況下，建議使用對掌性層析管柱來分離非鏡像異構物之複雜混合物。使用對掌性固定相管柱，諸如Chiralpak IA、IB或IC管柱，基於固定的直鏈澱粉或纖維素對掌性相，利用基於比率在9:1至1:9變化之MeCN與EtOH或MeOH之混合物的等度溶離劑，得到最好結果。為了補償所純化化合物中之可電離官能基之存在，可將調節劑添加至溶劑混合物中，該溶劑混合物諸如0.1% 二乙胺(對於鹼性衍生物而言)或0.1%甲酸(對於酸性衍生物而言)。在一些情況下，使用超臨界流體層析，其使用與上文所描述相同的對掌性固定相管柱，利用由50%至90%超臨界二氧化碳與EtOH、MeOH或1:1 EtOH:MeCN混合物構成之等度溶離劑。偵測：UV/Vis。Preparative HPLC for Chiral Separation In most cases, the desired diastereomer can be separated or purified by standard preparative-scale HPLC according to standard methods well known to those skilled in the art. In some cases, anti-chiral columns are recommended for the separation of complex mixtures of diastereomers. Use chiral stationary phase columns, such as Chiralpak IA, IB or IC columns, based on immobilized amylose or cellulose chiral phases, using MeCN and EtOH or An isocratic eluent of a mixture of MeOH gives the best results. To compensate for the presence of ionizable functional groups in purified compounds, modifiers can be added to solvent mixtures such as 0.1% diethylamine (for basic derivatives) or 0.1% formic acid (for acidic derivatives) in terms of things). In some cases, supercritical fluid chromatography was used using the same chiral stationary phase column as described above, utilizing a mixture of 50% to 90% supercritical carbon dioxide with EtOH, MeOH, or 1:1 EtOH:MeCN Isocratic dissolving agent for the mixture. Detection: UV/Vis.
縮寫(如上文或下文中所使用)： AcOH 乙酸
Ac
2O 乙酸酐
Alloc 烯丙氧基羰基
anh. 無水
aq. 水性/水溶液
atm 氛圍
BnBr 溴甲苯
Boc 三級丁氧基羰基
Boc
2O 二碳酸二三級丁酯
BOP (苯并三唑-1-基氧基)-三(二甲胺基)-六氟磷酸鏻
BuLi 正丁基鋰
CDI 1,1'-羰基二咪唑
CD
3I 碘甲烷-d3
CHCl
3氯仿
COMU (1-氰基-2-乙氧基-2-側氧基亞乙基胺氧基)二甲胺基-(N-𠰌啉基)-碳正離子六氟磷酸鹽
Cu(OAc)
2乙酸銅(II)
d 天
DBU 1,8-二氮雜雙環[5.4.0]十一碳-7-烯
DCC
N,N'-二環己基碳化二亞胺
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DEAD 偶氮二甲酸二乙酯
DIAD 偶氮二甲酸二異丙酯
DIBAL/DIBAL-H 氫化二異丁基鋁
DIC
N,N'-二異丙基碳化二亞胺
DIPEA 二異丙基-乙胺，惠尼格氏鹼(Hünig's base)
DMAP 4-二甲基胺基吡啶
DMF 二甲基甲醯胺
DMSO 二甲基甲醯胺
DPPA 二苯基磷醯基疊氮化物
dppf 1,1'-雙(二苯基膦基)二茂鐵
EDC 1-乙基-3-(3-二甲胺基丙基)碳化二亞胺
Et 乙基
Et
2O 二乙醚
EtOAc 乙酸乙酯
EtOH 乙醇
蒸發(evaporated) 真空蒸發
Ex. 實例
FC 矽膠急驟層析
FDPP 二苯基磷酸五氟苯基酯
Fmoc 9-茀基甲氧基羰基
h 小時
HATU 六氟磷酸(1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物
Hept 庚烷
Hex 己烷
HOBT 1-羥基苯并三唑
HPLC 高效液相層析
HV 高真空條件
i Bu 異丁基
i Pr 異丙基
iPrOH 異丙醇
i PrOAc 乙酸異丙酯
KO
t Bu 三級丁醇鉀
LAH 氫化鋰鋁
LC-MS 液相層析-質譜
Lit. 文獻
M mol/l
mCPBA 間氯過氧苯甲酸
Me 甲基
MeCN 乙腈
MeI 碘甲烷
米氏酸(Meldrum's acid) 2,2-二甲基-1,3-二㗁烷-4,6-二酮
MeOH 甲醇
mL 毫升
min 分鐘
mix. 混合物
MOM 甲氧基甲基
MW 微波
NaBH(OAc)
3三乙醯氧基硼氫化鈉
NCS N-氯丁二醯亞胺
NMP N-甲基-2-吡咯啶酮
nosyl 4-硝基苯磺醯基
n Pr 正丙基
OAc 乙酸酯基
org. 有機
Pd(
t Bu
3P)
2雙(三-三級丁基膦)鈀(0)
Pd(OAc)
2乙酸鈀(II)
Pd/C 鈀/活性炭
Pd(OH)
2/C 氫氧化鈀/活性炭(皮爾曼氏催化劑(Pearlman's catalyst))
Pd
2(dba)
3三(二苯亞甲基丙酮)二鈀(0)
PdCl
2(PPh
3)
2雙(三苯基膦)二氯化鈀(II)
Pd(dppf)Cl
2[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)
Pd(dppf)Cl
2·DCM [1,1'-雙(二苯膦基)-二茂鐵]二氯化鈀(II)與二氯甲烷之錯合物
Pd(PPh
3)
4四(三苯基膦)鈀(0)
Ph 苯基
PhMe 甲苯
PPh
3三苯基膦
prep. 製備型
PTFE 聚四氟乙烯
PyBOP 六氟磷酸(苯并三唑-1-基-氧基)-三吡咯啶基-鏻
PyClop 六氟磷酸氯三吡咯啶鏻
rac 外消旋
RM 反應混合物
羅謝爾鹽(Rochelle's salt) 酒石酸鈉鉀
RT 室溫
RuPhos 2-二環己基膦基-2',6'-二異丙氧基聯苯
s 秒
sat. 飽和
Selectfluor 1-氯甲基-4-氟-1,4-重氮雙環[2.2.2]辛烷雙(四氟硼酸鹽)
SM 起始材料
soln. 溶液
TBAF 氟化四丁銨
TBDMSCl 三級丁基二甲基矽基氯
TBME 三級丁基甲基醚
tBu 三級丁基(
tert-butyl/
tertiary butyl)
TEA 三甲基胺
Tf 三氟甲烷磺醯基
TFA 三氟乙酸
THF 四氫呋喃
TLC 薄層層析
TMEDA N,N,N',N'-四甲基乙二胺
TMS 三甲基矽基
tosyl 對甲苯-磺醯基
T
3P 正丙基膦酸酐
t
R滯留時間
triflate 三氟甲烷磺酸酯
pTsOH 對甲苯磺酸
Xantphos 4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃
XPhos 2-二環己基膦-2',4',6'-三異丙基聯苯
Abbreviations (as used above or below): AcOH Acetic acid Ac2O Acetic anhydride Alloc Allyloxycarbonyl anh. Anhydrous aq. Tertiary butyl ester BOP (Benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate BuLi n-Butyl lithium CDI 1,1'-carbonyldiimidazole CD 3 I Iodomethane- d3 CHCl 3 Chloroform COMU (1-cyano-2-ethoxy-2-oxoethyleneamineoxy)dimethylamino-(N-𠰌linyl)-carbenium hexafluorophosphate Cu (OAc) 2 Copper(II) acetate d DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC N,N' -dicyclohexylcarbodiimide DCE 1,2- Dichloroethane DCM Dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL/DIBAL-H Diisobutylaluminum hydride DIC N,N'- diisopropylcarbodiimide DIPEA Diisopropyl-Ethylamine, Whitney Grignard Base (Hünig's base) DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethylformamide DPPA Diphenylphosphorylazide dppf 1,1'-bis(diphenylphosphine base) ferrocene EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Et ethyl Et 2 O diethyl ether EtOAc ethyl acetate EtOH ethanol evaporated vacuum evaporated Ex. Example FC silica gel flash chromatography FDPP pentafluorophenyl diphenyl phosphate Fmoc 9-fenylmethoxycarbonyl h h HATU hexafluorophosphate (1-[bis(dimethylamino)methylene]-1H-1, 2,3-Triazolo[4,5-b]pyridinium 3-oxide Hept Heptane Hex Hexane HOBT 1-Hydroxybenzotriazole HPLC High-performance liquid chromatography HV High vacuum conditions Bu Isobutyli Pr isopropyl iPrOH Isopropanoli PrOAc Isopropyl acetate KO t Bu Potassium tertiary butoxide LAH Lithium aluminum hydride LC-MS Liquid chromatography-mass spectrometry Lit. Literature M mol/l m CPBA m-Chloroperbenzoic acid Me Methyl MeCN Acetonitrile MeI iodomethane Meldrum's acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeOH methanol mL ml min min mix. mixture MOM methoxymethyl MW microwave NaBH (OAc) 3 sodium triacetyloxyborohydride NCS N-chlorobutadiimide NMP N-methyl-2-pyrrolidone nosyl 4-nitrobenzenesulfonyl n Pr n-propyl OAc acetate Group org. Organic Pd( t Bu 3 P) 2 bis(tri-tertiary butylphosphine) palladium(0) Pd(OAc) 2 palladium(II) acetate Pd/C palladium/activated carbon Pd( OH) 2 /C palladium hydroxide/activated carbon (Pearlman's catalyst) Pd2 (dba) 3tris (dibenzylideneacetone)dipalladium(0) PdCl2 ( PPh3 ) 2bis (tris DCM _ Complex of [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride and dichloromethane Pd(PPh 3 ) 4Tetrakis (triphenylphosphine)palladium(0) Ph Phenyl PhMe Toluene PPh 3 Triphenylphosphine prep. Prep. PTFE Polytetrafluoroethylene PyBOP Hexafluorophosphate (Benzotriazol-1-yl-oxy)-tripyrrolidinyl-phosphonium PyClop Chlorotrifluorophosphate Pyrrolidinium phosphonium rac racemic RM reaction mixture Rochelle's salt sodium potassium tartrate RT room temperature RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyls sec sat. Saturated Selectfluor 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) SM Starting material soln. Solution TBAF Tetrabutylammonium fluoride TBDMSCl Tertiary butyl Dimethylsilyl Chloride TBME Tertiary butyl methyl ether t Bu Tertiary butyl ( tert -butyl/ tert iary butyl) TEA Trimethylamine Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC TMEDA N,N,N',N'-Tetramethylethylenediamine TMS trimethylsilyl tosyl p-toluene-sulfonyl T 3 P n-propylphosphonic anhydride t R retention time triflate trifluoromethanesulfonate pTsOH p-toluenesulfonic acid Xantphos 4, 5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran XPhos 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl
A-前驅物及中間物之製備
A- Preparation of precursors and intermediates
胺： 市售的胺描繪於表AM-1中。
表 AM-1 胺 名稱
AM-1.1 3,4-亞甲基二氧苯乙胺.鹽酸
AM-1.2 2-(1,3-二氫-異苯并呋喃-5-基)-乙胺
AM-1.3 2-(1,3-苯并㗁唑-2-基)乙胺.鹽酸
AM-1.4 3-甲氧基苯乙胺
AM-1.5 4-甲氧基苯乙胺
AM-1.6 苯乙胺
AM-1.7 3,5-二甲氧基苯乙胺
AM-1.8 2-(對甲苯基)乙胺
AM-1.9 3-甲基苯乙胺
AM-1.10 4-乙基苯乙胺
AM-1.11 2-(4-三級丁基苯基)乙胺
AM-1.12 4-溴苯乙胺
AM-1.13 2-氟苯乙胺
AM-1.14 2-(3-氯苯基)乙胺
AM-1.15 3-溴苯乙胺
AM-1.16 3,4-二甲基苯乙胺
AM-1.17 2,4-二甲基苯乙胺
AM-1.18 2-甲基苯乙胺
AM-1.19 2,3-二甲氧基苯乙胺
AM-1.20 3-氟苯乙胺
AM-1.21 4-氟苯乙胺
AM-1.22 2-(2,6-二氟苯基)乙-1-胺
AM-1.23 2-(3-苯基-[1,2,4]㗁二唑-5-基)-乙胺.鹽酸
AM-1.24 [2-(5-甲基-1,2,4-㗁二唑-3-基)乙基]胺.鹽酸
AM-1.25 [2-(5-乙基-1,2,4-㗁二唑-3-基)乙基]胺.鹽酸
AM-1.26 2-(5-環丙基-1,2,4-㗁二唑-3-基)乙-1-胺.鹽酸
AM-1.27 2-(5-甲基-1,2-㗁唑-4-基)乙-1-胺.鹽酸
AM-1.28 2-(1-甲基-1H-吡唑-4-基)乙胺
AM-1.29 2-(5-三級丁基-1,2,4-㗁二唑-3-基)乙胺.鹽酸
AM-1.30 2-(5-三級丁基-1,2-㗁唑-3-基)乙-1-胺
AM-1.31 2-(5-甲基-1,2-㗁唑-3-基)乙-1-胺.鹽酸
AM-1.32 2-(1,2-噻唑-5-基)乙-1-胺.鹽酸
AM-1.33 2-(5-環丙基-1,2-㗁唑-3-基)乙-1-胺
AM-1.34 2-(3,5-二氟苯基)乙-1-胺
AM-1.35 2-(3-環丙基-1,2,4-㗁二唑-5-基)乙-1-胺.鹽酸
AM-1.36 [2-(5-環丁基-1,2,4-㗁二唑-3-基)乙基]胺.鹽酸
AM-1.37 2-(1,4-二甲基-1
H-吡唑-3-基)乙-1-胺
AM-1.38 2,2-二氟-2-苯基乙胺.鹽酸
AM-1.39 2-(3-甲基-[1,2,4]㗁二唑-5-基)-乙胺.鹽酸
AM-1.40 2-(3-甲基-1,2-㗁唑-5-基)乙-1-胺.鹽酸
AM-1.41 2-[4-(二氟甲氧基)苯基]乙-1-胺
AM-1.42 2-吡𠯤-2-基-乙胺
AM-1.43 2-嘧啶-4-基-乙胺.鹽酸
AM-1.44 2-(嘧啶-5-基)乙-1-胺.2鹽酸
AM-1.45 3-(二氟甲氧基)丙-1-胺
AM-1.46 1-(2-胺基乙氧基)-2-甲氧基乙烷
AM-1.47 2-(4-甲基-1,3-噻唑-2-基)乙-1-胺
AM-1.48 2-(5-甲基-1,3-噻唑-2-基)乙-1-胺
AM-1.49 2-{4
H,5
H,6
H-環戊[d][1,3]噻唑-2-基}乙-1-胺
AM-1.50 2-(1,2-苯并㗁唑-3-基)乙-1-胺.鹽酸
AM-1.51 8-甲氧基-3,4-二氫-2
H-1-苯并哌喃-3-胺
AM-1.52 2-(3-甲氧基苯氧基)乙胺
AM-1.53 2-(4-甲氧基苯氧基)乙胺
AM-1.54 4-(2-胺基乙基)苯甲腈.鹽酸
AM-1.55 2-(3,5-二甲基異㗁唑-4-基)乙胺
AM-1.56 2-(2-異丙基-1,3-噻唑-4-基)乙胺.鹽酸
AM-1.57 2-(3-(二氟甲氧基)苯基)乙-1-胺
AM-1.58 2-(3-乙氧基苯基)乙-1-胺
AM-1.59 外消旋-2-(5,5-二甲基四氫-2H-哌喃-2-基)乙-1-胺
AM-1.60 4-(2-胺基乙基)-N,N-二甲基苯胺
AM-1.61 2-(噻吩-2-基)乙-1-胺
AM-1.62 2-(5-甲氧基吡啶-2-基)乙-1-胺
AM-1.63 2-(呋喃-2-基)乙-1-胺
AM-1.64 外消旋-2-(四氫-2
H-哌喃-2-基)乙-1-胺
AM-1.65 3-甲氧基丙-1-胺
AM-1.66 2-(3,5-二甲基-1
H-吡唑-1-基)乙-1-胺
AM-1.67 外消旋-2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-2-基)乙-1-胺.鹽酸
AM-1.68 5-甲氧基戊-1-胺
AM-1.69 2-(4-(1
H-吡唑-1-基)苯基)乙-1-胺
AM-1.70 2-(6-甲氧基吡啶-2-基)乙-1-胺
AM-1.71 4-(2-胺基乙基)-2-甲氧基苯胺
AM-1.72 3-苯基丙-1-胺
AM-1.73 2-(2,3-二氫苯并呋喃-5-基)乙-1-胺.鹽酸
AM-1.74 2-(2-甲氧基吡啶-4-基)乙-1-胺.鹽酸
AM-1.75 (2,3-二氫苯并呋喃-2-基)甲胺
AM-1.76 3-(2-胺基乙基)苯甲腈
AM-1.77 2-(3-(三氟甲基)苯基)乙-1-胺
AM-1.78 2-(3-(甲基磺醯基)苯基)乙-1-胺
AM-1.79 2-(4-(N-𠰌啉基)苯基)乙-1-胺
AM-1.80 (1-(3,4-二甲氧基苯基)環丙基)甲胺.鹽酸
AM-1.81 2-(4-溴-1H-吡唑-1-基)乙胺.鹽酸
AM-1.82 2,2-二氟-2-(3-甲氧基苯基)乙-1-胺
AM-1.83 2-(5-異丙基-1,2,4-㗁二唑-3-基)乙-1-胺.鹽酸
AM-1.84 2-(3-(三氟甲基)異㗁唑-5-基)乙-1-胺
AM-1.85 2-(3-(三氟甲基)-1,2,4-㗁二唑-5-基)乙-1-胺.鹽酸
AM-1.86 丁-3-炔-1-胺.鹽酸
AM-1.87 3-胺基丙酸苯甲酯4-甲基苯磺酸鹽
AM-1.88 (S)-2-胺基-1-苯基乙-1-醇
AM-1.89 2-(3-環丙基-1,2,4-㗁二唑-5-基)-2,2-二氟乙-1-胺
AM-1.90 2-胺基-1-(3-環丙基-1,2,4-㗁二唑-5-基)乙-1-醇
AM-1.91 2-(2
H-苯并[d][1,2,3]三唑-2-基)乙-1-胺
AM-1.92 3-(三氟甲氧基)丙-1-胺
AM-1.93 2-([1,2,4]三唑并[1,5-a]嘧啶-2-基)乙-1-胺
AM-1-94 2-(1-(2-甲氧基乙基)-1
H-吡唑-4-基)乙-1-胺
AM-1.95 2-(6-甲氧基吡啶-3-基)乙-1-胺
Amines: Commercially available amines are depicted in Table AM-1. Table AM-1 amine name
AM-1.1 3,4-Methylenedioxyphenethylamine. Hydrochloric acid
AM-1.2 2-(1,3-Dihydro-isobenzofuran-5-yl)-ethylamine
AM-1.3 2-(1,3-Benzazol-2-yl)ethylamine. Hydrochloric acid
AM-1.4 3-methoxyphenethylamine
AM-1.5 4-methoxyphenethylamine
AM-1.6 Phenylethylamine
AM-1.7 3,5-Dimethoxyphenethylamine
AM-1.8 2-(p-Tolyl)ethylamine
AM-1.9 3-Methylphenethylamine
AM-1.10 4-Ethylphenethylamine
AM-1.11 2-(4-tertiary butylphenyl) ethylamine
AM-1.12 4-Bromophenethylamine
AM-1.13 2-Fluorophenethylamine
AM-1.14 2-(3-Chlorophenyl)ethylamine
AM-1.15 3-Bromophenethylamine
AM-1.16 3,4-Dimethylphenethylamine
AM-1.17 2,4-Dimethylphenethylamine
AM-1.18 2-Methylphenethylamine
AM-1.19 2,3-Dimethoxyphenethylamine
AM-1.20 3-Fluorophenethylamine
AM-1.21 4-Fluorophenethylamine
AM-1.22 2-(2,6-Difluorophenyl)ethan-1-amine
AM-1.23 2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-ethylamine. Hydrochloric acid
AM-1.24 [2-(5-Methyl-1,2,4-oxadiazol-3-yl)ethyl]amine. Hydrochloric acid
AM-1.25 [2-(5-Ethyl-1,2,4-oxadiazol-3-yl)ethyl]amine. Hydrochloric acid
AM-1.26 2-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)ethan-1-amine. Hydrochloric acid
AM-1.27 2-(5-methyl-1,2-oxazol-4-yl)ethan-1-amine.hydrochloric acid
AM-1.28 2-(1-Methyl-1H-pyrazol-4-yl)ethylamine
AM-1.29 2-(5-Tertiary butyl-1,2,4-oxadiazol-3-yl)ethylamine. Hydrochloric acid
AM-1.30 2-(5-tertiary butyl-1,2-oxazol-3-yl)ethan-1-amine
AM-1.31 2-(5-methyl-1,2-oxazol-3-yl)ethan-1-amine.hydrochloric acid
AM-1.32 2-(1,2-thiazol-5-yl)ethan-1-amine.hydrochloric acid
AM-1.33 2-(5-Cyclopropyl-1,2-oxazol-3-yl)ethan-1-amine
AM-1.34 2-(3,5-Difluorophenyl)ethan-1-amine
AM-1.35 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-amine.hydrochloric acid
AM-1.36 [2-(5-Cyclobutyl-1,2,4-oxadiazol-3-yl)ethyl]amine. Hydrochloric acid
AM-1.37 2-(1,4-Dimethyl-1 H -pyrazol-3-yl)ethan-1-amine
AM-1.38 2,2-Difluoro-2-phenylethylamine. Hydrochloric acid
AM-1.39 2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-ethylamine. Hydrochloric acid
AM-1.40 2-(3-methyl-1,2-oxazol-5-yl)ethan-1-amine.hydrochloric acid
AM-1.41 2-[4-(Difluoromethoxy)phenyl]ethan-1-amine
AM-1.42 2-Pyramide-2-yl-ethylamine
AM-1.43 2-Pyrimidin-4-yl-ethylamine. Hydrochloric acid
AM-1.44 2-(pyrimidin-5-yl)ethan-1-amine.2 hydrochloric acid
AM-1.45 3-(Difluoromethoxy)propan-1-amine
AM-1.46 1-(2-aminoethoxy)-2-methoxyethane
AM-1.47 2-(4-Methyl-1,3-thiazol-2-yl)ethan-1-amine
AM-1.48 2-(5-Methyl-1,3-thiazol-2-yl)ethan-1-amine
AM-1.49 2-{4 H ,5 H ,6 H -cyclopenta[d][1,3]thiazol-2-yl}ethan-1-amine
AM-1.50 2-(1,2-Benzazol-3-yl)ethan-1-amine. Hydrochloric acid
AM-1.51 8-Methoxy-3,4-dihydro- 2H -1-benzopyran-3-amine
AM-1.52 2-(3-Methoxyphenoxy)ethylamine
AM-1.53 2-(4-Methoxyphenoxy)ethylamine
AM-1.54 4-(2-Aminoethyl)benzonitrile. Hydrochloric acid
AM-1.55 2-(3,5-Dimethylisozazol-4-yl)ethylamine
AM-1.56 2-(2-Isopropyl-1,3-thiazol-4-yl)ethylamine. Hydrochloric acid
AM-1.57 2-(3-(Difluoromethoxy)phenyl)ethan-1-amine
AM-1.58 2-(3-ethoxyphenyl)ethan-1-amine
AM-1.59 rac-2-(5,5-Dimethyltetrahydro-2H-pyran-2-yl)ethan-1-amine
AM-1.60 4-(2-aminoethyl)-N,N-dimethylaniline
AM-1.61 2-(thiophen-2-yl)ethan-1-amine
AM-1.62 2-(5-Methoxypyridin-2-yl)ethan-1-amine
AM-1.63 2-(furan-2-yl)ethan-1-amine
AM-1.64 rac-2-(tetrahydro-2 H -pyran-2-yl)ethan-1-amine
AM-1.65 3-methoxypropan-1-amine
AM-1.66 2-(3,5-Dimethyl-1 H -pyrazol-1-yl)ethan-1-amine
AM-1.67 rac-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethan-1-amine.hydrochloric acid
AM-1.68 5-methoxypentan-1-amine
AM-1.69 2-(4-( 1H -pyrazol-1-yl)phenyl)ethan-1-amine
AM-1.70 2-(6-Methoxypyridin-2-yl)ethan-1-amine
AM-1.71 4-(2-Aminoethyl)-2-methoxyaniline
AM-1.72 3-Phenylpropan-1-amine
AM-1.73 2-(2,3-dihydrobenzofuran-5-yl)ethan-1-amine.hydrochloric acid
AM-1.74 2-(2-methoxypyridin-4-yl)ethan-1-amine.hydrochloric acid
AM-1.75 (2,3-Dihydrobenzofuran-2-yl)methanamine
AM-1.76 3-(2-Aminoethyl)benzonitrile
AM-1.77 2-(3-(Trifluoromethyl)phenyl)ethan-1-amine
AM-1.78 2-(3-(Methylsulfonyl)phenyl)ethan-1-amine
AM-1.79 2-(4-(N-𠰌linyl)phenyl)ethan-1-amine
AM-1.80 (1-(3,4-dimethoxyphenyl)cyclopropyl)methanamine.hydrochloric acid
AM-1.81 2-(4-Bromo-1H-pyrazol-1-yl)ethylamine. Hydrochloric acid
AM-1.82 2,2-Difluoro-2-(3-methoxyphenyl)ethan-1-amine
AM-1.83 2-(5-isopropyl-1,2,4-oxadiazol-3-yl)ethan-1-amine.hydrochloric acid
AM-1.84 2-(3-(trifluoromethyl)isozazol-5-yl)ethan-1-amine
AM-1.85 2-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine.hydrochloric acid
AM-1.86 But-3-yn-1-amine. Hydrochloric acid
AM-1.87 Benzyl 3-Aminopropionate 4-Methylbenzenesulfonate
AM-1.88 (S)-2-Amino-1-phenylethan-1-ol
AM-1.89 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-2,2-difluoroethane-1-amine
AM-1.90 2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-ol
AM-1.91 2-( 2H -Benzo[d][1,2,3]triazol-2-yl)ethan-1-amine
AM-1.92 3-(Trifluoromethoxy)propan-1-amine
AM-1.93 2-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethan-1-amine
AM-1-94 2-(1-(2-methoxyethyl)-1 H -pyrazol-4-yl)ethan-1-amine
AM-1.95 2-(6-Methoxypyridin-3-yl)ethan-1-amine
非市售的胺如下文所描述合成。Non-commercially available amines were synthesized as described below.
2- 𠳭 唍 -6- 基 - 乙胺 . 鹽酸 (AM-2.1). 步驟 1 ：向6-溴𠳭烷(600 mg，2.73 mmol)及Cs
2CO
3(2.67 g，8.19 mmol)於PhMe (9.2 mL)及水(3 mL)中之室溫溶液中添加
N-[2-(三氟甲硼烷基)乙基]胺基甲酸三級丁酯鉀(693 mg，2.76 mmol)。在藉由鼓泡氬氣通入溶液來將反應混合物脫氣之後，添加RuPhos 95% (134 mg，0.273 mmol)及Pd(OAc)
2(30.7 mg，0.137 mmol)，且在95℃攪拌所得混合物18 h。將混合物冷卻至室溫，接著添加水及EtOAc，且經由矽藻土過濾反應混合物。濾液用EtOAc (3×)萃取，用鹽水洗滌，乾燥(MgSO
4)，過濾且濃縮。藉由FC (用5%至25% EtOAc/庚烷溶離)純化，得到呈淡黃色固體狀之(2-𠳭唍-6-基-乙基)-胺基甲酸三級丁酯(543 mg，72%)。LC-MS B：t
R= 0.97 min；[M+H]
+= 222.04。
2- Bromo - 6- yl - ethylamine . Hydrochloric acid (AM-2.1). Step 1 : Add 6-bromo-6-alkane (600 mg, 2.73 mmol) and Cs 2 CO 3 (2.67 g, 8.19 mmol) in PhMe ( 9.2 mL) and water (3 mL) was added potassium tert-butyl N- [2-(trifluoroboryl)ethyl]carbamate (693 mg, 2.76 mmol). After degassing the reaction mixture by bubbling argon through the solution, RuPhos 95% (134 mg, 0.273 mmol) and Pd(OAc) 2 (30.7 mg, 0.137 mmol) were added, and the resulting mixture was stirred at 95 °C 18 h. The mixture was cooled to room temperature, then water and EtOAc were added, and the reaction mixture was filtered through celite. The filtrate was extracted with EtOAc (3x), washed with brine, dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 5% to 25% EtOAc/heptane) afforded tertiary-butyl (2-EtO-6-yl-ethyl)-carbamate (543 mg, 72%). LC-MS B: tR = 0.97 min; [M+H] + = 222.04.
步驟 2 ：向(2-𠳭唍-6-基-乙基)-胺基甲酸三級丁酯(540 mg，1.95 mmol)於二㗁烷(0.5 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(4 mL)。在室溫攪拌反應混合物4 h，接著真空濃縮混合物，得到呈白色固體狀之
AM-2.1(412 mg，99%)。LC-MS B：t
R= 0.51 min；[M+H]
+= 219.41.
Step 2 : To a room temperature solution of tert-butyl (2-𠳭-6-yl-ethyl)-carbamate (540 mg, 1.95 mmol) in dioxane (0.5 mL) was added 4 M HCl dioxane (4 mL). The reaction mixture was stirred at room temperature for 4 h, then the mixture was concentrated in vacuo to afford AM-2.1 (412 mg, 99%) as a white solid. LC-MS B: tR = 0.51 min; [M+H] + = 219.41.
下表AM-2中列出類似於針對
AM-2.1所描述之2步驟順序由對應起始材料製備之胺。
表 AM-2 胺 SM 名稱 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
AM-2.2 2-苯并呋喃-6-基-乙胺.鹽酸
0.5
B
203.35
[+MeCN]
AM-2.3 2-(4-甲基-3,4-二氫-2H-苯并[1,4]㗁 𠯤-7-基)-乙胺
0.45
B
193.40
AM-2.4 2-𠳭唍-7-基-乙胺.鹽酸
0.51
B
178.43
AM-2.5 2-(2,3-二氫-苯并呋喃-6-基)-乙胺.鹽酸
0.46
B
164.12
AM-2.6 2-(2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙胺.鹽酸
0.46
B
180.26
AM-2.7 2-(4-[1,2,3]三唑-2-基-苯基)-乙胺.鹽酸
0.49
B
189.39
AM-2.8 2-(3-[1,2,3]三唑-2-基-苯基)-乙胺.鹽酸
0.50
B
189.38
AM-2.9 2-(3-甲基-4-[1,2,3]三唑-2-基-苯基)-乙胺.鹽酸
0.76
I
203.32
AM-2.10 2-(1-環丙基-1
H-吡唑-4-基)-乙胺.鹽酸
0.50
I
152.26
AM-2.11 2-(3-嘧啶-2-基-苯基)-乙胺.鹽酸
0.48
B
200.36
AM-2.12 2-(4-嘧啶-2-基-苯基)-乙胺.鹽酸
0.47
B
200.37
AM-2.13 2-(2-氟-6-甲基-苯基)-乙胺.鹽酸
0.76
I
154.24
AM-2.14 2-(2,6-二氟-3-甲基-苯基)-乙胺.鹽酸
0.80
I
172.14
AM-2.15 2-(3-氟-4-甲氧基-苯基)-乙胺.鹽酸
0.67
I
170.18
AM-2.16 2-(2,3-二氟-苯基)-乙胺.鹽酸
0.70
I
158.21
AM-2.17 2-(4-氟-3-甲氧基-苯基)-乙胺.鹽酸
0.73
I
170.17
AM-2.18 2-(2-氟-5-甲基-苯基)-乙胺.鹽酸
0.78
I
154.17
AM-2.19 2-(4-甲氧基-3-甲基-苯基)-乙胺.鹽酸
0.81
I
166.12
AM-2.20 2-(2,4-二氟-苯基)-乙胺.鹽酸
0.71
I
158.22
AM-2.21 2-(2,3,4,5-四氫苯并[b]㗁呯-8-基)乙-1-胺.鹽酸
0.55
B
192.43
The amines prepared from the corresponding starting materials are listed in Table AM-2 below in a similar 2-step sequence as described for AM-2.1 . Table AM-2 amine SM name t R [min] LC-MS method MS- data m/z [M+H] +
AM-2.2 2-Benzofuran-6-yl-ethylamine. Hydrochloric acid 0.5 B 203.35 [+MeCN]
AM-2.3 2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]㗁𠯤-7-yl)-ethylamine 0.45 B 193.40
AM-2.4 2-𠳭唍-7-yl-ethylamine. Hydrochloric acid 0.51 B 178.43
AM-2.5 2-(2,3-Dihydro-benzofuran-6-yl)-ethylamine. Hydrochloric acid 0.46 B 164.12
AM-2.6 2-(2,3-Dihydro-benzo[1,4]dioxine-6-yl)-ethylamine. Hydrochloric acid 0.46 B 180.26
AM-2.7 2-(4-[1,2,3]triazol-2-yl-phenyl)-ethylamine. Hydrochloric acid 0.49 B 189.39
AM-2.8 2-(3-[1,2,3]triazol-2-yl-phenyl)-ethylamine. Hydrochloric acid 0.50 B 189.38
AM-2.9 2-(3-Methyl-4-[1,2,3]triazol-2-yl-phenyl)-ethylamine. Hydrochloric acid 0.76 I 203.32
AM-2.10 2-(1-Cyclopropyl-1 H -pyrazol-4-yl)-ethylamine. Hydrochloric acid 0.50I 152.26
AM-2.11 2-(3-Pyrimidin-2-yl-phenyl)-ethylamine. Hydrochloric acid 0.48 B 200.36
AM-2.12 2-(4-Pyrimidin-2-yl-phenyl)-ethylamine. Hydrochloric acid 0.47 B 200.37
AM-2.13 2-(2-Fluoro-6-methyl-phenyl)-ethylamine. Hydrochloric acid 0.76 I 154.24
AM-2.14 2-(2,6-Difluoro-3-methyl-phenyl)-ethylamine. Hydrochloric acid 0.80I 172.14
AM-2.15 2-(3-Fluoro-4-methoxy-phenyl)-ethylamine. Hydrochloric acid 0.67I 170.18
AM-2.16 2-(2,3-Difluoro-phenyl)-ethylamine. Hydrochloric acid 0.70I 158.21
AM-2.17 2-(4-Fluoro-3-methoxy-phenyl)-ethylamine. Hydrochloric acid 0.73I 170.17
AM-2.18 2-(2-Fluoro-5-methyl-phenyl)-ethylamine. Hydrochloric acid 0.78 I 154.17
AM-2.19 2-(4-Methoxy-3-methyl-phenyl)-ethylamine. Hydrochloric acid 0.81I 166.12
AM-2.20 2-(2,4-Difluoro-phenyl)-ethylamine. Hydrochloric acid 0.71I 158.22
AM-2.21 2-(2,3,4,5-tetrahydrobenzo[b]oxan-8-yl)ethan-1-amine.hydrochloric acid 0.55 B 192.43
2-(3-(1,1-二氟乙基)苯基)乙-1-胺鹽酸鹽(AM-2.22)
步驟 1 ：在添加Cs
2CO
3(884 mg，2.71 mmol)及Pd(dppf)Cl
2.DCM (74 mg，0.09 mmol)之前，用Ar對1-溴-3-(1,1-二氟乙基)苯(200 mg，0.91 mmol)及(2-((三級丁氧基羰基)胺基)乙基)三氟硼酸鉀(273 mg，1.09 mmol)於PhMe (7 mL)及H
2O (2 mL)中之混合物進行脫氣10 min。用Ar對反應混合物另外脫氣2 min且接著加熱至100℃持續2 h。在冷卻至室溫之後，將反應混合物分配於NH
4Cl飽和水溶液與DCM之間且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用20%至100% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之(3-(1,1-二氟乙基)苯乙基)胺基甲酸三級丁酯。LC-MS J：t
R= 2.17 min；[M+H]
+= 208.1。
2-(3-(1,1-difluoroethyl)phenyl)ethan-1-amine hydrochloride (AM-2.22) step 1 : After adding Cs 2 CO 3 (884 mg, 2.71 mmol) and Pd ( dppf)Cl 2 .DCM (74 mg, 0.09 mmol), p-1-bromo-3-(1,1-difluoroethyl)benzene (200 mg, 0.91 mmol) and (2-((tertiary A mixture of butoxycarbonyl)amino)ethyl)potassium trifluoroborate (273 mg, 1.09 mmol) in PhMe (7 mL) and H2O (2 mL) was degassed for 10 min. The reaction mixture was degassed with Ar for another 2 min and then heated to 100 °C for 2 h. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous NH4Cl and DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 20% to 100% EtOAc/heptane) to afford tert-butyl (3-(1,1-difluoroethyl)phenethyl)carbamate as a white solid . LC-MS J: tR = 2.17 min; [M+H] + = 208.1.
步驟 2 ：類似於對於AM-2.1步驟2所描述之程序，由(3-(1,1-二氟乙基)苯乙基)胺基甲酸三級丁酯製備標題化合物。LC-MS J：t
R= 1.77 min；[M+H]
+= 186.1。
Step 2 : In analogy to the procedure described for AM-2.1 Step 2, the title compound was prepared from tert-butyl (3-(1,1-difluoroethyl)phenethyl)carbamate. LC-MS J: tR = 1.77 min; [M+H] + = 186.1.
2-(2-環丙基-2
H-1,2,3-三唑-4-基)乙-1-胺鹽酸鹽(AM-2.23)
步驟 1 ：向4,5-二溴-2
H-1,2,3-三唑(1.5 g，6.61 mmol)、環丙基硼酸(1.17 g，13.2 mmol)、Na
2CO
3(1.4 g，13.2 mmol)及2,2'-聯吡啶(1.04 g，6.61 mmol)於DCE (15 mL)及2-甲基呋喃(15 mL)中之混合物中添加Cu(OAc)
2(1.23 g，6.61 mmol)，且將反應混合物加熱至80℃持續48 h。過濾反應混合物，且用EtOAc沖洗濾餅。濾液用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至30% EtOAc/庚烷溶離)純化粗產物，得到呈黃色固體狀之4,5-二溴-2-環丙基-2
H-1,2,3-三唑。LC-MS D：t
R= 0.92 min；無電離。
2-(2-cyclopropyl- 2H -1,2,3-triazol-4-yl)ethan-1-amine hydrochloride (AM-2.23) step 1 : to 4,5-dibromo-2 H -1,2,3-triazole (1.5 g, 6.61 mmol), cyclopropylboronic acid (1.17 g, 13.2 mmol), Na 2 CO 3 (1.4 g, 13.2 mmol) and 2,2'-bipyridine ( 1.04 g, 6.61 mmol) in a mixture of DCE (15 mL) and 2-methylfuran (15 mL) was added Cu(OAc) 2 (1.23 g, 6.61 mmol) and the reaction mixture was heated to 80 °C for 48 h. The reaction mixture was filtered, and the filter cake was rinsed with EtOAc. The filtrate was washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 30% EtOAc/heptane) to give 4,5-dibromo-2-cyclopropyl- 2H -1,2,3-triazole as a yellow solid . LC-MS D: tR = 0.92 min; no ionization.
步驟 2 ：按照對於AM-2.1步驟1所描述之程序，由4,5-二溴-2-環丙基-2
H-1,2,3-三唑製備(2-(5-溴-2-環丙基-2
H-1,2,3-三唑-4-基)乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 0.91 min；[M+H]
+= 331.06。
Step 2 : Prepare (2-(5- bromo -2 -Tertiary-butyl cyclopropyl- 2H -1,2,3-triazol-4-yl)ethyl)carbamate. LC-MS B: tR = 0.91 min; [M+H] + = 331.06.
步驟 3 ：在添加10% Pd/C (23 mg，5 mol%)之前，將(2-(5-溴-2-環丙基-2
H-1,2,3-三唑-4-基)乙基)胺基甲酸三級丁酯(110 mg，0.33 mmol)於EtOH (3 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌16 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到呈白色固體狀之(2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)胺基甲酸三級丁酯。LC-MS I：t
R= 0.83 min；[M+H]
+= 253.28。
Step 3 : (2-(5-bromo-2-cyclopropyl-2H - 1,2,3-triazol-4-yl ) Ethyl) tert-butyl carbamate (110 mg, 0.33 mmol) in EtOH (3 mL) was evacuated/purged with N2 (3x). The reaction mixture was evacuated/flushed with H2 (3x) and stirred under H2 atmosphere for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford (2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)amino as a white solid. Tertiary butyl formate. LC-MS I: tR = 0.83 min; [M+H] + = 253.28.
步驟 4 ：類似於對於AM-2.1步驟2所描述之程序，由(2-(2-環丙基-2
H-1,2,3-三唑-4-基)乙基)胺基甲酸三級丁酯製備標題化合物。LC-MS I：t
R= 0.46 min；[M+H]
+= 153.24。
Step 4 : Similar to the procedure described for AM-2.1 Step 2, from (2-(2-cyclopropyl- 2H -1,2,3-triazol-4-yl)ethyl)carbamate Butyl ester to prepare the title compound. LC-MS I: tR = 0.46 min; [M+H] + = 153.24.
2-(3,4-二氫-2
H-苯并[b][1,4]二㗁呯-7-基)-乙胺.鹽酸(AM-3.1).
步驟 1 ：向多巴胺鹽酸鹽(2.0 g，10.5 mmol)及NaHCO
3(886 mg，10.5 mmol)於THF (50 mL)中之室溫懸浮液中添加二碳酸二三級丁酯(2.33 g，10.5 mmol)，且在室溫攪拌混合物2 h。產物用EtOAc (3×)萃取，且經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用5% MeOH/DCM溶離)純化，得到呈白色固體狀之(3,4-二羥基苯乙基)胺基甲酸三級丁酯(2.34 g，88%)。LC-MS I：t
R= 0.64 min; [M-H]
-= 252.00。
2-(3,4-Dihydro- 2H -benzo[b][1,4]bis-7-yl)-ethylamine. Hydrochloric acid (AM-3.1). Step 1 : To dopamine hydrochloride (2.0 g, 10.5 mmol) and NaHCO 3 (886 mg, 10.5 mmol) in THF (50 mL) were added ditertiary butyl dicarbonate (2.33 g, 10.5 mmol) at room temperature, and The mixture was stirred for 2 h. The product was extracted with EtOAc (3x), and the combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 5% MeOH/DCM) afforded tert-butyl (3,4-dihydroxyphenethyl)carbamate (2.34 g, 88%) as a white solid. LC-MS I: tR = 0.64 min; [MH] - = 252.00.
步驟 2 ：向(3,4-二羥基苯乙基)胺基甲酸三級丁酯(2.24 g，8.86 mmol)及K
2CO
3(3.13 g，22.2 mmol)於DMF (10 mL)中之室溫懸浮液中添加1,3-二溴丙烷(1.01 mL，9.75 mmol)，且在室溫攪拌所得混合物隔夜。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈略微淺棕色油狀之(2-(3,4-二氫-2
H-苯并[b][1,4]二㗁呯-7-基)乙基)胺基甲酸三級丁酯(1.25 g，48%)。LC-MS I：t
R= 0.98 min；[M+H]
+= 294.05。
Step 2 : Add tert-butyl (3,4-dihydroxyphenethyl)carbamate (2.24 g, 8.86 mmol) and K 2 CO 3 (3.13 g, 22.2 mmol) in DMF (10 mL) To the warm suspension was added 1,3-dibromopropane (1.01 mL, 9.75 mmol), and the resulting mixture was stirred at room temperature overnight. Direct purification of the reaction mixture by preparative HPLC (basic) afforded (2-(3,4-dihydro- 2H -benzo[b][1,4]bisoxane- tert-butyl 7-yl)ethyl)carbamate (1.25 g, 48%). LC-MS I: tR = 0.98 min; [M+H] + = 294.05.
步驟 3 ：向(2-(3,4-二氫-2
H-苯并[b][1,4]二㗁呯-7-基)乙基)胺基甲酸三級丁酯(1.25 g，4.28 mmol)於二㗁烷(20 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(5.4 mL)。在室溫攪拌反應混合物18 h，接著真空濃縮混合物，得到呈白色固體狀之
AM-3.1(931 mg，100%)。LC-MS I：t
R= 0.68 min；[M+H]
+= 194.13。
Step 3 : Add tertiary butyl (2-(3,4-dihydro- 2H -benzo[b][1,4]dioxane-7-yl)ethyl)carbamate (1.25 g, To a room temperature solution of 4.28 mmol) in dioxane (20 mL) was added 4 M HCl in dioxane (5.4 mL). The reaction mixture was stirred at room temperature for 18 h, then the mixture was concentrated in vacuo to afford AM-3.1 (931 mg, 100%) as a white solid. LC-MS I: tR = 0.68 min; [M+H] + = 194.13.
2-(3-(甲氧基-d3)苯基)乙-1-胺.鹽酸(AM-3.2)
步驟 1 ：向(3-羥基苯乙基)胺基甲酸三級丁酯(638 mg，2.7 mmol)及K
2CO
3(557 mg，4.0 mmol)於DMF (5 mL)中之室溫混合物中添加CD
3I (0.25 mL，4.0 mmol)，且將反應混合物加熱至50℃持續36 h。將反應混合物冷卻至室溫且分配於H
2O與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到粗產物，藉由FC (用0%至100% EtOAc/庚烷溶離)純化該粗產物，得到呈無色油狀之(3-(甲氧基-d3)苯乙基)胺基甲酸三級丁酯。LC-MS J：t
R= 2.09 min；[M+H-Me]
+= 240.1。
2-(3-(Methoxy-d3)phenyl)ethan-1-amine.hydrochloride (AM-3.2) Step 1 : To (3-hydroxyphenethyl)carbamate tertiary butyl ester (638 mg, 2.7 mmol) and K2CO3 (557 mg, 4.0 mmol) in DMF (5 mL) at room temperature were added CD3I (0.25 mL, 4.0 mmol) and the reaction mixture was heated to 50 °C for 36 h . The reaction mixture was cooled to room temperature and partitioned between H2O and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give the crude product which was purified by FC (eluted with 0% to 100% EtOAc/heptane) to give a colorless oil (3-(methoxy-d3)phenethyl)carbamate tertiary butyl ester. LC-MS J: tR = 2.09 min; [M+H-Me] + = 240.1.
步驟 2 ：類似於對於AM-2.1步驟2所描述之程序，由(3-(甲氧基-d3)苯乙基)胺基甲酸三級丁酯製備標題化合物。LC-MS J：t
R= 1.47 min；[M+H]
+= 155.1。
Step 2 : In analogy to the procedure described for AM-2.1 Step 2, the title compound was prepared from tert-butyl (3-(methoxy-d3)phenethyl)carbamate. LC-MS J: tR = 1.47 min; [M+H] + = 155.1.
2-(2-氟-4-甲氧基-苯基)-乙胺.鹽酸(AM-4.1)
步驟 1 ：向2-氟-4-甲氧基苯甲醛(1.25 g，7.95 mmol)於硝基甲烷(16 mL)中之室溫溶液中添加分子篩4A (100 mg)，接著添加丁胺(0.1 mL，0.938 mmol)及乙酸(0.01 mL，1.62 mmol)，且將混合物加熱至90℃持續1 h。濃縮反應混合物且將殘餘物分配於EtOAc與水之間。有機層用水及鹽水洗滌且真空濃縮。藉由FC (用0%至20% EtOAc/庚烷溶離)純化，得到呈淺黃色固體狀之2-氟-4-甲氧基-1-2-硝基-乙烯基-苯(1.06 g，68%)。LC-MS B：t
R= 0.92 min；無電離。
2-(2-Fluoro-4-methoxy-phenyl)-ethylamine. Hydrochloric acid (AM-4.1) Step 1 : To 2-fluoro-4-methoxybenzaldehyde (1.25 g, 7.95 mmol) in nitric acid To a room temperature solution in methyl methane (16 mL) was added molecular sieve 4A (100 mg), followed by butylamine (0.1 mL, 0.938 mmol) and acetic acid (0.01 mL, 1.62 mmol), and the mixture was heated to 90 °C for 1 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine and concentrated in vacuo. Purification by FC (eluted with 0% to 20% EtOAc/heptane) afforded 2-fluoro-4-methoxy-1-2-nitro-vinyl-benzene (1.06 g, 68%). LC-MS B: tR = 0.92 min; no ionization.
步驟 2 ：向NaBH
4(996 mg，25.8 mmol)於THF (40 mL)中之0℃溶液中添加三氟化硼乙醚合物(4.19 mL，32.3 mmol)。在0℃攪拌混合物10 min，接著在室溫攪拌15 min，之後逐滴添加2-氟-4-甲氧基-1-2-硝基-乙烯基-苯(1.06 g，5.38 mmol)於THF (10 mL)中之溶液，且使混合物在70℃回流3 h，接著使其達到室溫隔夜。在逐滴添加2 N HCl (35 mL，69.9 mmol)之前，將反應混合物冷卻至0℃。在添加之後，在0℃攪拌混合物10 min，接著在室溫攪拌15 min，之後將混合物加熱至80℃持續1 h。將反應混合物冷卻至室溫且蒸發有機溶劑，且將其餘的水層冷卻至0℃，之後用10% NaOH水溶液鹼化。產物用EtOAc (3×)萃取，且經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮。將在HV下充分乾燥之殘餘物溶解於DCM (10 mL)中且冷卻至0℃，之後添加含4 M HCl之二㗁烷(1.61 mL，6.45 mmol)，且攪拌所得混合物1 h。濃縮反應混合物且用Et
2O (2×)濕磨，得到呈米色粉末狀之
AM-4.1(957 mg，87%)標題化合物。LC-MS B：t
R= 0.49 min；[M+H]
+= 170.08。
Step 2 : To a solution of NaBH4 (996 mg, 25.8 mmol) in THF (40 mL) at 0 °C was added boron trifluoride etherate (4.19 mL, 32.3 mmol). The mixture was stirred at 0 °C for 10 min, then at room temperature for 15 min, after which 2-fluoro-4-methoxy-1-2-nitro-vinyl-benzene (1.06 g, 5.38 mmol) in THF was added dropwise (10 mL), and the mixture was refluxed at 70 °C for 3 h, then allowed to reach room temperature overnight. The reaction mixture was cooled to 0 °C before 2 N HCl (35 mL, 69.9 mmol) was added dropwise. After the addition, the mixture was stirred at 0 °C for 10 min, followed by 15 min at room temperature, after which the mixture was heated to 80 °C for 1 h. The reaction mixture was cooled to room temperature and the organic solvent was evaporated, and the remaining aqueous layer was cooled to 0 °C before being basified with 10% aqueous NaOH. The product was extracted with EtOAc (3x), and the combined org. layers were washed with brine, dried ( MgSO4 ), filtered and concentrated. The residue dried well under HV was dissolved in DCM (10 mL) and cooled to 0 °C before adding 4 M HCl in dioxane (1.61 mL, 6.45 mmol) and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated and triturated with Et2O (2x) to afford the title compound AM-4.1 (957 mg, 87%) as a beige powder. LC-MS B: tR = 0.49 min; [M+H] + = 170.08.
2-(4-溴-2,6-二氟-苯基)-乙胺(AM-4.2) 類似於對於
AM-4.1所描述之合成，由4-溴-2,6-二氟苯甲醛製備標題化合物。LC-MS B：t
R= 0.53 min；[M+H]
+= 235.98。
2-(4-Bromo-2,6-difluoro-phenyl)-ethylamine (AM-4.2) Prepared from 4-bromo-2,6-difluorobenzaldehyde in analogy to the synthesis described for AM-4.1 title compound. LC-MS B: tR = 0.53 min; [M+H] + = 235.98.
2-(2,6-二氟-4-甲氧基-苯基)-乙胺(AM-4.3)
步驟 1 ：向2,6-二氟-4-甲氧基苯甲醛(1.0 g，5.69 mmol)於硝基甲烷(7 mL)中之室溫溶液中添加乙酸銨(179 mg，2.28 mmol)，且使所得混合物回流40 min。蒸發反應混合物，且將殘餘物分配於水與DCM之間。水層用DCM (2×)萃取，且經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈橙色油狀之1,3-二氟-5-甲氧基-2-(2-硝基-乙烯基)-苯(1.25 g)，其按原樣用於下一步驟。LC-MS B：t
R= 0.96 min；[M+H]
+= 216.12。
2-(2,6-Difluoro-4-methoxy-phenyl)-ethylamine (AM-4.3) Step 1 : To 2,6-difluoro-4-methoxybenzaldehyde (1.0 g, 5.69 To a room temperature solution of mmol) in nitromethane (7 mL) was added ammonium acetate (179 mg, 2.28 mmol), and the resulting mixture was refluxed for 40 min. The reaction mixture was evaporated, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM (2×), and the combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated to give 1,3-difluoro-5-methoxy- 2-(2-Nitro-vinyl)-benzene (1.25 g), which was used as such in the next step. LC-MS B: tR = 0.96 min; [M+H] + = 216.12.
步驟 2 ：類似於對於AM-4.1步驟2所描述之程序，由1,3-二氟-5-甲氧基-2-(2-硝基-乙烯基)-苯製備標題化合物。LC-MS B：t
R= 0.51 min；[M+H]
+= 188.32。
Step 2 : The title compound was prepared from 1,3-difluoro-5-methoxy-2-(2-nitro-vinyl)-benzene analogously to the procedure described for AM-4.1 Step 2. LC-MS B: tR = 0.51 min; [M+H] + = 188.32.
2-(3,4-二氟-苯基)-乙胺.鹽酸AM-4.4
步驟 1 ：類似於對於
AM-4.1 步驟1所描述之程序，製備1,2-二氟-4-(2-硝基-乙烯基)-苯。LC-MS C：t
R= 0.75 min；無電離。
2-(3,4-Difluoro-phenyl)-ethylamine.HCl AM-4.4 Step 1 : Similar to the procedure described for AM-4.1 Step 1, 1,2-difluoro-4-(2- Nitro-vinyl)-benzene. LC-MS C: tR = 0.75 min; no ionization.
步驟 2 ：向LiAlH
4(1.06 g，26.65 mmol)於THF (35 mL)中之0℃懸浮液中添加濃H
2SO
4(0.710 mL)。在攪拌20 min之後，逐滴添加1,2-二氟-4-(2-硝基-乙烯基)-苯(1.10 g，5.97 mmol)於THF (5 mL)中之溶液且持續攪拌10 min，之後移除冷卻浴，且將反應混合物緩慢加熱至平緩回流。在5 min之後，將混合物冷卻至0℃且藉由逐滴添加
i PrOH (4.4 mL)，隨後添加2 M NaOH水溶液(3.1 mL)來小心地水解。過濾所得懸浮液，且用THF沖洗濾餅。濃縮濾液，且將游離胺溶解於含有
i PrOH (0.72 mL)之Et
2O (20 mL)中且用含2 M HCl之Et
2O (11.4 mL)酸化。過濾所得懸浮液，且用Et
2O洗滌濾餅，得到呈白色固體狀之標題化合物(440 mg，38%)，該標題化合物在HV下進一步乾燥。LC-MS C：t
R= 0.40 min；[M+H]
+= 199.3。
Step 2 : To a 0° C. suspension of LiAlH 4 (1.06 g, 26.65 mmol) in THF (35 mL) was added concentrated H 2 SO 4 (0.710 mL). After stirring for 20 min, a solution of 1,2-difluoro-4-(2-nitro-vinyl)-benzene (1.10 g, 5.97 mmol) in THF (5 mL) was added dropwise and stirring was continued for 10 min , after which the cooling bath was removed, and the reaction mixture was slowly heated to gentle reflux. After 5 min, the mixture was cooled to 0 °C and carefully hydrolyzed by dropwise addition of iPrOH (4.4 mL) followed by 2 M aqueous NaOH (3.1 mL). The resulting suspension was filtered, and the filter cake was rinsed with THF. The filtrate was concentrated, and the free amine was dissolved in Et2O (20 mL) containing iPrOH (0.72 mL) and acidified with 2M HCl in Et2O (11.4 mL). The resulting suspension was filtered, and the filter cake was washed with Et2O to give the title compound (440 mg, 38%) as a white solid, which was further dried under HV. LC-MS C: tR = 0.40 min; [M+H] + = 199.3.
2-(4,5-二甲基異㗁唑-3-基)乙-1-胺(AM-5.1)
步驟 1 ：在Dean Stark設備中，於乙醯乙酸乙酯(1.46 mL，11.4 mmol)及吡咯啶(1.92 mL，22.8 mmol)於PhMe (50 mL)中之室溫溶液中添加
pTsOH單水合物(11.1 mg，0.06 mmol)，且使所得混合物回流2 h。移除揮發物，且呈橙色油狀之3-吡咯啶-1-基-丁-2-烯酸乙酯(2.03 g，97%)按原樣用於下一步驟。LC-MS B：t
R= 0.39 min；[M+H]
+= 184.45。
2-(4,5-Dimethylisoxazol-3-yl)ethan-1-amine (AM-5.1) Step 1 : In the Dean Stark apparatus, in ethyl acetate (1.46 mL, 11.4 mmol) To a room temperature solution of pyrrolidine (1.92 mL, 22.8 mmol) in PhMe (50 mL) was added pTsOH monohydrate (11.1 mg, 0.06 mmol), and the resulting mixture was refluxed for 2 h. The volatiles were removed and ethyl 3-pyrrolidin-1-yl-but-2-enoate (2.03 g, 97%) as an orange oil was used as such in the next step. LC-MS B: tR = 0.39 min; [M+H] + = 184.45.
步驟 2 ：向3-(Boc-胺基)-1-丙醇(4.88 mL，27.7 mmol)及DIPEA (14.2 mL，083 mmol)於DCM (83.1 mL)中之0℃溶液中逐滴添加SO
3-吡啶錯合物(11.0 g，69.2 mmol)於DMSO (39.3 mL)中之溶液。在0℃攪拌反應混合物1 h，接著在室溫攪拌1 h。混合物用HCl及水稀釋，接著用DCM (3×)萃取。經合併之有機萃取物用水及鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮，得到呈無色油狀之(3-側氧基-丙基)-胺基甲酸三級丁酯(4.81 g，100%)，其按原樣用於下一步驟。
Step 2 : To a 0° C. solution of 3-(Boc-amino)-1-propanol (4.88 mL, 27.7 mmol) and DIPEA (14.2 mL, 083 mmol) in DCM (83.1 mL) was added SO 3 dropwise - A solution of pyridine complex (11.0 g, 69.2 mmol) in DMSO (39.3 mL). The reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 1 h. The mixture was diluted with HCl and water, then extracted with DCM (3x). The combined organic extracts were washed with water and brine, dried ( Na2SO4 ), filtered and concentrated to afford (3-oxo-propyl)-carbamate tert-butyl ester (4.81 g, 100%), which was used as such in the next step.
步驟 3 ：向(3-側氧基-丙基)-胺基甲酸三級丁酯(4.81 g，0.028 mol)於EtOH (100 mL)中之劇烈攪拌溶液中添加羥胺鹽酸鹽(3.90 g，0.06 mol)於H
2O (25 mL)中之溶液及乙酸鈉(9.20 g，0.11 mol)於H
2O (25 mL)中之溶液。在室溫攪拌所得懸浮液18 h且接著在50℃另外攪拌3 h。移除揮發物，且將殘餘物分配於EtOAc與水之間。分離各層，且用EtOAc進一步萃取水層。經合併之有機萃取物用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用50% EtOAc/庚烷溶離)來純化，得到呈無色油狀之(3-羥基亞胺基-丙基)-胺基甲酸三級丁酯(4.5 g，86%)。LC-MS B：t
R= 0.58 min；[M+H]
+= 189.43。
Step 3 : To a vigorously stirred solution of (3-oxo-propyl)-carbamic acid tert-butyl ester (4.81 g, 0.028 mol) in EtOH (100 mL) was added hydroxylamine hydrochloride (3.90 g, 0.06 mol) in H2O (25 mL) and sodium acetate (9.20 g, 0.11 mol) in H2O (25 mL). The resulting suspension was stirred at room temperature for 18 h and then at 50 °C for an additional 3 h. Volatiles were removed, and the residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was further extracted with EtOAc. The combined org. extracts were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by FC (elution with 50% EtOAc/heptane) afforded tert-butyl (3-hydroxyimino-propyl)-carbamate (4.5 g, 86%) as a colorless oil. LC-MS B: tR = 0.58 min; [M+H] + = 189.43.
步驟 4 ：向(3-羥基亞胺基-丙基)-胺基甲酸三級丁酯(2.80 g，14.9 mmol)於DCM (80 mL)中之室溫溶液中添加NCS (2.23 g，16.4 mmol)，且在室溫攪拌所得混合物2 h。蒸發混合物且藉由FC (用50% EtOAc/庚烷溶離)直接純化，得到呈橙色油狀之(3-氯-3-(羥基亞胺基)丙基)胺基甲酸三級丁酯(2.02 g，61%)。LC-MS B：t
R= 0.72 min; [M(
35Cl)+H]
+= 223.37。
Step 4 : To a room temperature solution of (3-hydroxyimino-propyl)-carbamate tert-butyl ester (2.80 g, 14.9 mmol) in DCM (80 mL) was added NCS (2.23 g, 16.4 mmol ), and the resulting mixture was stirred at room temperature for 2 h. The mixture was evaporated and directly purified by FC (elution with 50% EtOAc/heptane) to afford tert-butyl (3-chloro-3-(hydroxyimino)propyl)carbamate (2.02 g, 61%). LC-MS B: tR = 0.72 min; [M( 35 Cl)+H] + = 223.37.
步驟 5 ：向(3-氯-3-(羥基亞胺基)丙基)胺基甲酸三級丁酯(2.02 g，9.07 mmol)於DCM (15 mL)中之室溫溶液中添加3-吡咯啶-1-基-丁-2-烯酸乙酯(1.83 g，10 mmol)於DCM (15 mL)中之溶液，隨後添加TEA (2.56 mL，0.0181 mol)，且攪拌所得混合物15 min。濃縮反應混合物，且藉由FC (用50% EtOAc/庚烷溶離)直接純化殘餘物，得到仍含有起始材料之3-(2-三級丁氧基羰基胺基-乙基)-5-甲基-異㗁唑-4-甲酸乙酯(1.60 g)，因此將產物溶解於DCM中且用2 M HCl水溶液洗滌。有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮，得到呈微黃色油狀之3-(2-三級丁氧基羰基胺基-乙基)-5-甲基-異㗁唑-4-甲酸乙酯(1.25 g，46%)。LC-MS B：t
R= 0.93 min；[M+H]
+= 299.30。
Step 5 : To a room temperature solution of tert-butyl (3-chloro-3-(hydroxyimino)propyl)carbamate (2.02 g, 9.07 mmol) in DCM (15 mL) was added 3-pyrrole A solution of pyridin-1-yl-but-2-enoic acid ethyl ester (1.83 g, 10 mmol) in DCM (15 mL) was then added with TEA (2.56 mL, 0.0181 mol) and the resulting mixture was stirred for 15 min. The reaction mixture was concentrated and the residue was directly purified by FC (elution with 50% EtOAc/heptane) to afford 3-(2-tert-butoxycarbonylamino-ethyl)-5- Methyl-isoxazole-4-carboxylic acid ethyl ester (1.60 g), so the product was dissolved in DCM and washed with 2 M aq. HCl. The organic layer was washed with brine, dried ( Na2SO4 ), filtered and concentrated to give 3-(2-tert-butoxycarbonylamino-ethyl)-5-methyl-iso Ethyl azole-4-carboxylate (1.25 g, 46%). LC-MS B: tR = 0.93 min; [M+H] + = 299.30.
步驟 6 ：向3-(2-三級丁氧基羰基胺基-乙基)-5-甲基-異㗁唑-4-甲酸乙酯(500 mg，1.68 mmol)於Et
2O (5 mL)中之0℃溶液中逐滴添加含LAH (76 mg，2.01 mmol)之Et
2O (15 mL)。添加之後，將所得混合物升溫至室溫且攪拌1.5 h。將混合物冷卻至0℃且極小心地用EtOAc淬滅，隨後添加羅謝爾鹽飽和水溶液。將所得混合物升溫至室溫且接著劇烈攪拌30 min，其後形成兩個層。分離各層，且用EtOAc (2×)再萃取水層。經合併之有機萃取物用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發。藉由FC (用50% EtOAc/庚烷溶離)，隨後製備型HPLC (鹼性)純化，得到呈白色固體狀之[2-(4-羥基甲基-5-甲基-異㗁唑-3-基)-乙基]-胺基甲酸三級丁酯(135 mg，31%)。LC-MS I：t
R= 0.67 min；[M+H]
+= 257.20。
Step 6 : Add ethyl 3-(2-tertiary butoxycarbonylamino-ethyl)-5-methyl-isoxazole-4-carboxylate (500 mg, 1.68 mmol) in Et 2 O (5 mL ) in 0 °C solution was added dropwise with LAH (76 mg, 2.01 mmol) in Et2O (15 mL). After the addition, the resulting mixture was warmed to room temperature and stirred for 1.5 h. The mixture was cooled to 0 °C and quenched with EtOAc very carefully, followed by the addition of saturated aqueous Rochelle salt. The resulting mixture was warmed to room temperature and then stirred vigorously for 30 min, after which two layers formed. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried ( Na2SO4 ), filtered and evaporated. Purification by FC (elution with 50% EtOAc/heptane) followed by preparative HPLC (basic) afforded [2-(4-hydroxymethyl-5-methyl-isoxazole-3) as a white solid -yl)-ethyl]-tert-butyl carbamate (135 mg, 31%). LC-MS I: tR = 0.67 min; [M+H] + = 257.20.
步驟 7 ：向[2-(4-羥基甲基-5-甲基-異㗁唑-3-基)-乙基]-胺基甲酸三級丁酯(100 mg，0.39 mmol)於二㗁烷(2 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(1 mL，3.99 mmol)，且在室溫攪拌所得混合物6 d。濃縮混合物，得到呈無色油狀之2-(4-氯甲基-5-甲基-異㗁唑-3-基)-乙胺(鹽酸鹽) (77 mg，93%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.56 min；無電離。
Step 7 : To [2-(4-hydroxymethyl-5-methyl-isoxazol-3-yl)-ethyl]-carbamic acid tertiary butyl ester (100 mg, 0.39 mmol) in dioxane To a room temperature solution in (2 mL) was added 4 M HCl in dioxane (1 mL, 3.99 mmol), and the resulting mixture was stirred at room temperature for 6 d. The mixture was concentrated to give 2-(4-chloromethyl-5-methyl-isozazol-3-yl)-ethylamine (hydrochloride) (77 mg, 93%) as a colorless oil, which was obtained as received for the next step. LC-MS I: tR = 0.56 min; no ionization.
步驟 8 ：向2-(4-氯甲基-5-甲基-異㗁唑-3-基)-乙胺(鹽酸鹽) (19 mg，0.09 mmol)於EtOH (0.5 mL)及EtOAc (0.5 mL)中之室溫溶液(經脫氣)中添加Pd/C (10 mg，0.01 mmol)。在H
2氛圍下在室溫攪拌反應混合物30 min。過濾混合物，且蒸發濾液，得到呈黃色固體狀之
AM-5.1(45 mg，89%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.51 min；[M+H]
+= 141.20。
Step 8 : Add 2-(4-chloromethyl-5-methyl-isoxazol-3-yl)-ethylamine (hydrochloride) (19 mg, 0.09 mmol) in EtOH (0.5 mL) and EtOAc ( To a room temperature solution (degassed) in 0.5 mL) was added Pd/C (10 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 30 min under H2 atmosphere. The mixture was filtered, and the filtrate was evaporated to give AM-5.1 (45 mg, 89%) as a yellow solid, which was used as such in the next step. LC-MS I: tR = 0.51 min; [M+H] + = 141.20.
2-(3-環丙基異㗁唑-5-基)乙-1-胺.鹽酸(AM-5.2)
步驟 1 ：向丁-3-炔-1-醇(22.9 mL，318 mmol)、異吲哚啉-1,3-二酮(44.5 g，302 mmol)及PPh
3(83 g，318 mmol)於THF (1500 mL)中之0℃溶液中逐滴添加DIAD (61.7 mL，318 mmol)於THF (350 mL)中之溶液，且攪拌反應混合物1 h。真空濃縮反應混合物，且將殘餘物溶解於PhMe (370 mL)中，之後緩慢添加MeOH (210 mL)。將反應混合物冷卻至室溫，且添加MeOH直至白色固體沈澱。部分濃縮反應混合物，之後藉由過濾收集固體，用冷PhMe洗滌，且接著空氣乾燥，得到2-(丁-3-炔-1-基)異吲哚啉-1,3-二酮。LC-MS F：t
R= 1.81 min；無電離。
2-(3-Cyclopropylisozazol-5-yl)ethan-1-amine.hydrochloric acid (AM-5.2) step 1 : to but-3-yn-1-ol (22.9 mL, 318 mmol), iso To a solution of indoline-1,3-dione (44.5 g, 302 mmol) and PPh 3 (83 g, 318 mmol) in THF (1500 mL) at 0 °C was added dropwise DIAD (61.7 mL, 318 mmol) solution in THF (350 mL), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in PhMe (370 mL), after which MeOH (210 mL) was added slowly. The reaction mixture was cooled to room temperature, and MeOH was added until a white solid precipitated. The reaction mixture was partially concentrated, after which the solid was collected by filtration, washed with cold PhMe, and then air dried to give 2-(but-3-yn-1-yl)isoindoline-1,3-dione. LC-MS F: tR = 1.81 min; no ionization.
步驟 2 ：向羥胺.鹽酸(37.2 g，535 mmol)於H
2O (125 mL)中之室溫溶液中小心地添加Na
2CO
3(22.7 g，214 mmol)，隨後減緩添加環丙烷甲醛(26.7 mL，357 mmol)於EtOH (100 mL)中之溶液。攪拌反應混合物1 h且接著分配於H
2O與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到粗產物，該粗產物自正庚烷再結晶，得到呈白色固體狀之E/Z-環丙烷甲醛肟。LC-MS F：t
R= 2.13 及2.30 min；無電離。
Step 2 : To a room temperature solution of hydroxylamine.HCl (37.2 g, 535 mmol) in H 2 O (125 mL) was carefully added Na 2 CO 3 (22.7 g, 214 mmol), followed by slow addition of cyclopropanecarbaldehyde (26.7 mL, 357 mmol) in EtOH (100 mL). The reaction mixture was stirred for 1 h and then partitioned between H2O and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give the crude product which was recrystallized from n-heptane to give E/Z-cyclopropanecarbaldehyde oxime as a white solid. LC-MS F: t R = 2.13 and 2.30 min; no ionization.
步驟 3 ：向環丙烷甲醛肟(19.3 g，226 mmol)及吡啶(0.83 mL，10.3 mmol)於DMF (100 mL)中之0℃溶液中逐份添加NCS (34.3 g，257 mmol)，且攪拌反應混合物3 h。添加2-(丁-3-炔-1-基)異吲哚啉-1,3-二酮(21.0 g，103 mmol)於DMF (100 mL)中之溶液，隨後添加TEA (28.7 mL，206 mmol)，且攪拌反應混合物3 h。將反應混合物分配於H
2O與DCM之間且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到粗產物，該粗產物用MeOH濕磨，得到呈白色固體狀之2-(2-(3-環丙基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮。LC-MS J：t
R= 1.91 min；[M+H]
+= 283.1。
Step 3 : To a solution of cyclopropaneformaldoxime (19.3 g, 226 mmol) and pyridine (0.83 mL, 10.3 mmol) in DMF (100 mL) at 0 °C was added NCS (34.3 g, 257 mmol) portionwise, and stirred The reaction mixture was 3 h. A solution of 2-(but-3-yn-1-yl)isoindoline-1,3-dione (21.0 g, 103 mmol) in DMF (100 mL) was added followed by TEA (28.7 mL, 206 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was partitioned between H2O and DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give the crude product which was triturated with MeOH to give 2-(2-(3-cyclopropyl (isozazol-5-yl)ethyl)isoindoline-1,3-dione. LC-MS J: tR = 1.91 min; [M+H] + = 283.1.
步驟 4 ：向2-(2-(3-環丙基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(28.0 g，97 mmol)於EtOH (100 mL)中之室溫懸浮液中添加肼.H
2O (9.44 mL，194 mmol)，且將反應混合物加熱至80℃持續5 h。將反應混合物冷卻至室溫且過濾，用EtOH洗滌。真空濃縮濾液，且將殘餘物懸浮於Et
2O中且再過濾，用Et
2O洗滌。部分濃縮濾液，之後添加含1M HCl之Et
2O (100 mL)，且過濾沈澱並真空乾燥，得到呈白色固體狀之標題化合物。LC-MS J：t
R= 1.42 min；[M+H]
+= 153.1。
Step 4 : Dissolve 2-(2-(3-cyclopropylisozazol-5-yl)ethyl)isoindoline-1,3-dione (28.0 g, 97 mmol) in EtOH (100 mL) To the room temperature suspension in hydrazine.H2O (9.44 mL, 194 mmol) was added, and the reaction mixture was heated to 80 °C for 5 h. The reaction mixture was cooled to room temperature and filtered, washing with EtOH. The filtrate was concentrated in vacuo, and the residue was suspended in Et2O and filtered again, washing with Et2O . The filtrate was partially concentrated before addition of 1M HCl in Et2O (100 mL), and the precipitate was filtered and dried in vacuo to give the title compound as a white solid. LC-MS J: tR = 1.42 min; [M+H] + = 153.1.
2-(3-(二氟甲基)異㗁唑-5-基)乙-1-胺(AM-5.3)
步驟 1 ：向丁-3-炔-1-醇(1.0 mL，14.3 mmol)於THF (25 mL)中之室溫溶液中添加咪唑(1.94 g，28.5 mmol)，隨後添加TBDMSCl (2.58 g，17.1 mmol)，且攪拌反應混合物16 h。添加
iPr
2O (25 mL)，且過濾沈澱並用額外
iPr
2O洗滌。濾液用NaHCO
3飽和水溶液、鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈無色油狀之(丁-3-炔-1-基氧基)(三級丁基)二甲基矽烷。
1H NMR (CDCl
3)
δ: 3.76 (t,
J= 7.1 Hz, 2H), 2.43 (td,
J= 7.1, 2.7 Hz, 2 H), 1.98 (t,
J= 2.7 Hz, 1 H), 0.92 (s, 9 H), 0.10 (s, 6 H)。
2-(3-(Difluoromethyl)isozazol-5-yl)ethan-1-amine (AM-5.3) Step 1 : To but-3-yn-1-ol (1.0 mL, 14.3 mmol) in To a room temperature solution in THF (25 mL) was added imidazole (1.94 g, 28.5 mmol), followed by TBDMSCl (2.58 g, 17.1 mmol), and the reaction mixture was stirred for 16 h. iPr2O (25 mL) was added, and the precipitate was filtered and washed with additional iPr2O . The filtrate was washed with saturated aqueous NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give (but-3-yn-1-yloxy)(tert-butyl)dimethyl silane. 1 H NMR (CDCl 3 ) δ : 3.76 (t, J = 7.1 Hz, 2H), 2.43 (td, J = 7.1, 2.7 Hz, 2 H), 1.98 (t, J = 2.7 Hz, 1 H), 0.92 (s, 9H), 0.10 (s, 6H).
步驟 2 ：向(丁-3-炔-1-基氧基)(三級丁基)二甲基矽烷(1.85 g，9.0 mmol)於THF (15 mL)中之-78℃溶液中添加nBuLi (1.6 M於己烷中，7.9 mL，12.6 mmol)，且將反應混合物升溫至-15℃且攪拌15 min，之後冷卻回至-40℃。接著逐滴添加二氟乙酸乙酯(1.24 mL，11.7 mmol)，隨後添加三氟化硼醚合物(1.55 mL，12.2 mmol)，且將反應混合物升溫至室溫且攪拌16 h。反應物用冷的NH
4Cl飽和水溶液淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用20%至50% DCM/庚烷溶離)純化粗產物，得到呈黃色油狀之6-((三級丁基二甲基矽基)氧基)-1,1-二氟己-3-炔-2-酮。
1H NMR (CDCl
3)
δ: 5.73 (t,
J= 54.2 Hz, 1 H), 3.82 (t,
J= 6.5 Hz, 2H), 2.68 (t,
J= 6.6 Hz, 2H), 0.89 (s, 9 H), 0.08 (s, 6 H)。
Step 2 : To a -78 °C solution of (but-3-yn-1-yloxy)(tertiary butyl)dimethylsilane (1.85 g, 9.0 mmol) in THF (15 mL) was added nBuLi ( 1.6 M in hexanes, 7.9 mL, 12.6 mmol), and the reaction mixture was warmed to -15 °C and stirred for 15 min before cooling back to -40 °C. Ethyl difluoroacetate (1.24 mL, 11.7 mmol) was then added dropwise, followed by boron trifluoride etherate (1.55 mL, 12.2 mmol), and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with cold saturated aqueous NH4Cl and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 20% to 50% DCM/heptane) to afford 6-((tertiarybutyldimethylsilyl)oxy)-1,1-difluoro as a yellow oil Hex-3-yn-2-one. 1 H NMR (CDCl 3 ) δ : 5.73 (t, J = 54.2 Hz, 1 H), 3.82 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H), 0.89 (s, 9 H), 0.08 (s, 6 H).
步驟 3 ：向6-((三級丁基二甲基矽基)氧基)-1,1-二氟己-3-炔-2-酮(2.22 g，8.5 mmol)於THF (20 mL)中之室溫溶液中添加羥胺鹽酸鹽(0.71 g，10.2 mmol)，隨後添加CuO (121 mg，0.85 mmol)，且攪拌反應混合物16 h。添加NaHCO
3(0.85 g，10.2 mmol)，且攪拌反應混合物1 h，之後經由短矽膠墊(用1:1 Et
2O:THF溶離)過濾反應混合物，得到5-(2-((三級丁基二甲基矽基)氧基)乙基)-3-(二氟甲基)異㗁唑及2-(3-(二氟甲基)異㗁唑-5-基)乙-1-醇之混合物。
Step 3 : Add 6-((tertiary butyldimethylsilyl)oxy)-1,1-difluorohex-3-yn-2-one (2.22 g, 8.5 mmol) in THF (20 mL) To the room temperature solution in China was added hydroxylamine hydrochloride (0.71 g, 10.2 mmol), followed by CuO (121 mg, 0.85 mmol), and the reaction mixture was stirred for 16 h. NaHCO 3 (0.85 g, 10.2 mmol) was added, and the reaction mixture was stirred for 1 h, after which time the reaction mixture was filtered through a short pad of silica gel (eluted with 1:1 Et 2 O:THF) to give 5-(2-((tert-butyl Dimethylsilyl)oxy)ethyl)-3-(difluoromethyl)isoxazol and 2-(3-(difluoromethyl)isoxazol-5-yl)ethan-1-ol the mixture.
步驟 4 ：向5-(2-((三級丁基二甲基矽基)氧基)乙基)-3-(二氟甲基)異㗁唑及2-(3-(二氟甲基)異㗁唑-5-基)乙-1-醇(2.35 g，8.5 mmol，估算)於THF (50 mL)及Et
2O (50 mL)中之室溫溶液中添加TBAF (1.0 M於THF中，6.0 mL，6.0 mmol)，且攪拌反應混合物16 h。將反應混合物分配於NH
4Cl飽和水溶液與EtOAc之間且萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至6% MeOH/DCM溶離)純化粗產物，得到呈黃色油狀之2-(3-(二氟甲基)異㗁唑-5-基)乙-1-醇。
1H NMR (DMSO)
δ: 7.23 (t,
J= 53.2 Hz, 1H), 6.64 (s, 1 H), 4.93 (t,
J= 5.3 Hz, 1H), 3.72 (q,
J= 6.0 Hz, 2H), 2.96 (t,
J= 6.3 Hz, 2H)。
Step 4 : To 5-(2-((tertiary butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)isoxazole and 2-(3-(difluoromethyl) )isozazol-5-yl)ethan-1-ol (2.35 g, 8.5 mmol, est.) in THF (50 mL) and Et 2 O (50 mL) at room temperature was added TBAF (1.0 M in THF , 6.0 mL, 6.0 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 6% MeOH/DCM) to afford 2-(3-(difluoromethyl)isoxazol-5-yl)ethan-1-ol as a yellow oil. 1 H NMR (DMSO) δ : 7.23 (t, J = 53.2 Hz, 1H), 6.64 (s, 1 H), 4.93 (t, J = 5.3 Hz, 1H), 3.72 (q, J = 6.0 Hz, 2H ), 2.96 (t, J = 6.3 Hz, 2H).
步驟 5 ：向2-(3-(二氟甲基)異㗁唑-5-基)乙-1-醇(412 mg，2.5 mmol)、異吲哚啉-1,3-二酮(409 mg，2.8 mmol)及PPh
3(7.95 g，3.0 mmol)於THF (20 mL)中之0℃溶液中逐滴添加DIAD (0.59 mL，3.0 mmol)於THF (2 mL)中之溶液，且攪拌反應混合物16 h。真空濃縮反應混合物，且藉由FC (用0%至30% EtOAc/庚烷溶離)純化殘餘物，得到2-(2-(3-(二氟甲基)異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮。LC-MS J：t
R= 1.98 min；[M+H]
+= 293.1。
Step 5 : Add 2-(3-(difluoromethyl)isozazol-5-yl)ethan-1-ol (412 mg, 2.5 mmol), isoindoline-1,3-dione (409 mg , 2.8 mmol) and PPh 3 (7.95 g, 3.0 mmol) in THF (20 mL) at 0 °C was added dropwise to a solution of DIAD (0.59 mL, 3.0 mmol) in THF (2 mL), and the reaction was stirred Mixture 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by FC (eluted with 0% to 30% EtOAc/heptane) to afford 2-(2-(3-(difluoromethyl)isoxazol-5-yl)ethan base) isoindoline-1,3-dione. LC-MS J: tR = 1.98 min; [M+H] + = 293.1.
步驟 6 ：向2-(2-(3-(二氟甲基)異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(113 mg，0.39 mmol)於EtOH (4 mL)中之室溫懸浮液中添加肼.H
2O (380 μL，0.77 mmol)，且將反應混合物加熱至80℃持續2 h。將反應混合物冷卻至室溫且過濾，用EtOH洗滌。真空濃縮濾液，且將殘餘物懸浮於Et
2O中且再過濾，用Et
2O洗滌。真空濃縮濾液，得到呈白色固體狀之標題化合物。LC-MS I：t
R= 0.53 min；[M+H+MeCN]
+= 204.32。
Step 6 : Add 2-(2-(3-(difluoromethyl)isozazol-5-yl)ethyl)isoindoline-1,3-dione (113 mg, 0.39 mmol) in EtOH ( To a room temperature suspension in 4 mL), hydrazine.H 2 O (380 μL, 0.77 mmol) was added, and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered, washing with EtOH. The filtrate was concentrated in vacuo, and the residue was suspended in Et2O and filtered again, washing with Et2O . The filtrate was concentrated in vacuo to afford the title compound as a white solid. LC-MS I: tR = 0.53 min; [M+H+MeCN] + = 204.32.
2-(2,4,6-三氟-苯基)-乙胺.鹽酸(AM-6.1) 向2,4,6-三氟苯基乙腈(1.00 g，5.73 mmol)於THF (10 mL)中之0℃溶液中逐滴添加甲硼烷四氫呋喃錯合物於THF (15.5 mL，15.5 mmol)中之1M溶液，且在室溫攪拌反應混合物隔夜。將反應混合物冷卻至0℃，之後逐滴添加MeOH(5 mL)，接著在室溫攪拌溶液1 h，之後濃縮。將殘餘物冷卻至0℃，接著逐滴添加含1.25 M HCl之MeOH (15.0 mL)，且在室溫攪拌所得懸浮液2天，接著移除溶劑，且在Et
2O中濕磨殘餘物。產物藉由過濾分離且用Et
2O洗滌，得到呈白色固體狀之
AM-6.1(833 mg，69%)。LC-MS B：t
R= 0.45 min；[M+H]
+= 176.26。
2-(2,4,6-Trifluoro-phenyl)-ethylamine. Hydrochloric acid (AM-6.1) was dissolved in 2,4,6-trifluorophenylacetonitrile (1.00 g, 5.73 mmol) in THF (10 mL) A 1 M solution of borane tetrahydrofuran complex in THF (15.5 mL, 15.5 mmol) was added dropwise to a solution at 0 °C in China, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C before MeOH (5 mL) was added dropwise and the solution was stirred at room temperature for 1 h before being concentrated. The residue was cooled to 0 °C, then 1.25 M HCl in MeOH (15.0 mL) was added dropwise, and the resulting suspension was stirred at room temperature for 2 days, then the solvent was removed and the residue was triturated in Et2O . The product was isolated by filtration and washed with Et2O to afford AM-6.1 (833 mg, 69%) as a white solid. LC-MS B: tR = 0.45 min; [M+H] + = 176.26.
2-[3-(3-甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙胺(AM-7.1)
步驟 1 ：向3-甲氧基苯甲腈(1.0 g，7.36 mmol)於MeOH (15 mL)中之室溫溶液中添加NaHCO
3(1.55 g，18.4 mmol)，隨後添加羥胺鹽酸鹽(1.29 g，18.4 mmol)，且使所得白色懸浮液回流(70℃)隔夜。濃縮混合物，且殘餘物用EtOAc稀釋且用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈黃色油狀之
N-羥基-3-甲氧基-苯甲脒(1.67 g，137%)，其按原樣用於下一步驟。LC-MS B ：t
R= 0.38 min；[M+H]
+= 167.11。
2-[3-(3-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamine (AM-7.1) step 1 : to 3-methoxybenzyl To a room temperature solution of nitrile (1.0 g, 7.36 mmol) in MeOH (15 mL) was added NaHCO3 (1.55 g, 18.4 mmol) followed by hydroxylamine hydrochloride (1.29 g, 18.4 mmol) and the resulting white suspension The solution was refluxed (70°C) overnight. The mixture was concentrated and the residue was diluted with EtOAc and washed with brine, dried (MgSO 4 ), filtered and concentrated to give N -hydroxy-3-methoxy-benzamidine (1.67 g, 137% ), which was used as-is in the next step. LC-MS B: tR = 0.38 min; [M+H] + = 167.11.
步驟 2 ：向Boc-β-ala-OH (1.73 g，9.06 mmol)、
N-羥基-3-甲氧基-苯甲脒(1.67 g，9.06 mmol)及DIPEA (4.65 mL，27.2 mmol)於DCM (45 mL)中之0℃溶液中添加TBTU (3.49 g，10.9 mmol)。移除冰浴，且在室溫攪拌混合物18 h。濃縮反應混合物，且將殘餘物分配於EtOAc (50 mL)與水(50 mL)之間，且過濾出所得固體，得到中間物(2-{[[羥基亞胺基]-(3-甲氧基-苯基)-甲基]-胺甲醯基}-乙基)-胺基甲酸三級丁酯(1.856 g，61%)。向此白色固體中添加二㗁烷(50 mL)，且使反應混合物回流(90℃) 24 h。濃縮混合物，得到呈無色油狀之{2-[3-(3-甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙基}-胺基甲酸三級丁酯(1.90 g，109%)，其按原樣用於下一步驟。LC-MS B ：t
R= 0.95 min；[M+H]
+= 320.12。
Step 2 : Add Boc-β-ala-OH (1.73 g, 9.06 mmol), N -hydroxy-3-methoxy-benzamidine (1.67 g, 9.06 mmol) and DIPEA (4.65 mL, 27.2 mmol) in DCM To a 0°C solution in (45 mL) was added TBTU (3.49 g, 10.9 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc (50 mL) and water (50 mL), and the resulting solid was filtered off to give intermediate (2-{[[hydroxyimino]-(3-methoxy yl-phenyl)-methyl]-carbamoyl}-ethyl)-tert-butyl carbamate (1.856 g, 61%). To this white solid was added dioxane (50 mL), and the reaction mixture was refluxed (90 °C) for 24 h. The mixture was concentrated to give {2-[3-(3-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-carbamic acid tris as a colorless oil Butyl ester (1.90 g, 109%) was used as such in the next step. LC-MS B: tR = 0.95 min; [M+H] + = 320.12.
步驟 3 ：向{2-[3-(3-甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙基}-胺基甲酸三級丁酯(1.915 g，6.0 mmol)於DCM (40 mL)中之室溫溶液中添加TFA (4.59 mL，60 mmol)，且在室溫攪拌混合物1 d。混合物用NaHCO
3飽和水溶液(50 mL)中和，接著添加DCM (50 mL)。分離兩個層，且水層用DCM (50 mL)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮，得到呈黃色油狀之
AM-7.1(1.14 g，86%)。LC-MS B ：t
R= 0.54 min；[M+H]
+= 220.22。
Step 3 : To {2-[3-(3-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-carbamic acid tertiary butyl ester (1.915 g, 6.0 mmol) in DCM (40 mL) was added TFA (4.59 mL, 60 mmol) and the mixture was stirred at room temperature for 1 d. The mixture was neutralized with saturated aqueous NaHCO 3 (50 mL), followed by the addition of DCM (50 mL). The two layers were separated, and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated to give AM-7.1 (1.14 g, 86%) as a yellow oil. LC-MS B: tR = 0.54 min; [M+H] + = 220.22.
2-[3-(3,5-二甲基-苯基)-[1,2,4]㗁二唑-5-基]-乙胺(AM-7.2) 按照對於
AM-7.1所描述之3步驟合成，由3,5-二甲基苯甲腈製備標題化合物。LC-MS E：t
R= 0.53 min；[M+H]
+= 218.22。
2-[3-(3,5-Dimethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamine (AM-7.2) As described for AM-7.1 3 Step synthesis, the title compound was prepared from 3,5-dimethylbenzonitrile. LC-MS E: tR = 0.53 min; [M+H] + = 218.22.
2-[3-(2-三氟甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙胺.鹽酸(AM-7.3)
步驟 1 及 2 ：按照對於
AM-7.1步驟1及2所描述之合成，由3,2-三氟甲氧基-苯甲腈製備標題化合物，得到{2-[3-(2-三氟甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙基}-胺基甲酸三級丁酯。LC-MS E：t
R= 0.88 min；[M+H]
+= 318.04。
2-[3-(2-Trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-Ethylamine. Hydrochloric acid (AM-7.3) Steps 1 and 2 : Follow the procedure for AM-7.1 Synthesis as described in steps 1 and 2 to prepare the title compound from 3,2-trifluoromethoxy-benzonitrile to give {2-[3-(2-trifluoromethoxy-phenyl)- [1,2,4]Oxadiazol-5-yl]-ethyl}-carbamate tertiary butyl ester. LC-MS E: tR = 0.88 min; [M+H] + = 318.04.
步驟 3 ：向{2-[3-(2-三氟甲氧基-苯基)-[1,2,4]㗁二唑-5-基]-乙基}-胺基甲酸三級丁酯(425 mg，1.14 mmol)於二㗁烷(3 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(6 mL)，且在室溫攪拌混合物18 h。濃縮反應混合物，得到呈淺棕色油狀之
AM-7.3(0.41 g，119%)。LC-MS E：t
R= 0.53 min；[M+H]
+= 273.93。
Step 3 : To {2-[3-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-carbamic acid tertiary butyl ester (425 mg, 1.14 mmol) in dioxane (3 mL) at room temperature was added 4 M HCl in dioxane (6 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to afford AM-7.3 (0.41 g, 119%) as a light brown oil. LC-MS E: tR = 0.53 min; [M+H] + = 273.93.
2-[5-(2-三氟甲氧基-苯基)-4
H-[1,2,4]三唑-3-基]-乙胺(AM-8.1)
步驟 1 ：向
N-(2-氰基乙基)胺基甲酸三級丁酯(1.20 g，7.05 mmol)及2-(三氟甲氧基)苯甲酸醯肼(1.55 g，7.05 mmol)於正丁醇(50 mL)中之室溫溶液中添加K
2CO
3(487 mg，3.53 mmol)，且將所得懸浮液加熱至120℃持續6.5 h，接著在室溫攪拌隔夜，且再加熱至120℃持續另外4.5 h。濃縮混合物，且殘餘物用DCM稀釋且用1 N HCl酸化。分離兩個層，且水層用DCM萃取。濃縮經合併之有機層且藉由FC (用10%至30% EtOAc/庚烷溶離)純化，得到呈無色油狀之{2-[5-(2-三氟甲氧基-苯基)-4
H-[1,2,4]三唑-3-基]-乙基}-胺基甲酸三級丁酯(678 mg，26%)。LC-MS A：t
R= 0.80 min；[M+H]
+= 373.15。
2-[5-(2-trifluoromethoxy-phenyl) -4H- [1,2,4]triazol-3-yl]-ethylamine (AM-8.1) step 1 : to N- ( tertiary butyl 2-cyanoethyl)carbamate (1.20 g, 7.05 mmol) and hydrazine 2-(trifluoromethoxy)benzoate (1.55 g, 7.05 mmol) in n-butanol (50 mL) To the room temperature solution in China was added K2CO3 (487 mg, 3.53 mmol), and the resulting suspension was heated to 120 °C for 6.5 h, then stirred at room temperature overnight, and reheated to 120 °C for another 4.5 h . The mixture was concentrated, and the residue was diluted with DCM and acidified with 1 N HCl. The two layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were concentrated and purified by FC (elution with 10% to 30% EtOAc/heptane) to afford {2-[5-(2-trifluoromethoxy-phenyl)- 4 H- [1,2,4]triazol-3-yl]-ethyl}-carbamic acid tert-butyl ester (678 mg, 26%). LC-MS A: tR = 0.80 min; [M+H] + = 373.15.
步驟 2 ：向{2-[5-(2-三氟甲氧基-苯基)-4
H-[1,2,4]三唑-3-基]-乙基}-胺基甲酸三級丁酯(678 mg，1.82 mmol)於DCM (20 mL)中之0℃溶液中逐滴添加含4 M HCl之二㗁烷(30 mL，30 mmol)。在室溫攪拌所得反應混合物2 h，接著濃縮反應混合物，得到呈黃色油狀之
AM-8.1(515 mg，104%)，其按原樣用於下一步驟。LC-MS A：t
R= 0.52 min；[M+H]
+= 273.14。
Step 2 : To {2-[5-(2-trifluoromethoxy-phenyl) -4H- [1,2,4]triazol-3-yl]-ethyl}-carbamic acid tertiary To a solution of butyl ester (678 mg, 1.82 mmol) in DCM (20 mL) at 0 °C was added 4 M HCl in dioxane (30 mL, 30 mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 2 h, then the reaction mixture was concentrated to afford AM-8.1 (515 mg, 104%) as a yellow oil, which was used as such in the next step. LC-MS A: tR = 0.52 min; [M+H] + = 273.14.
2-(3-甲氧基-4-[1,2,3]三唑-2-基-苯基)-乙胺.鹽酸(AM-9.1)
步驟 1 ：1
H-1,2,3-三唑(5.0 g，0.072 mmol)用水(35 mL)稀釋且加熱至50℃，之後逐滴添加Br
2(23.1 g，0.145 mmol) (放熱)。油浴用水浴替換以將內部溫度保持在低於50℃。在15 min之後，所得橙色懸浮液用2 M NaOH水溶液(5 mL)及40%亞硫酸氫鈉溶液(2 mL)淬滅。接著，添加32% NaOH水溶液直至pH 7，隨後添加額外40%亞硫酸氫鈉溶液(10 mL)。歸因於放熱，在過濾懸浮液之前，將其冷卻至室溫。用水(3 × 10 mL)沖洗餅，且濃縮濾液，得到呈略微淺黃色固體狀之4,5-二溴-2
H-[1,2,3]三唑(14.86 g，90%)。
2-(3-Methoxy-4-[1,2,3]triazol-2-yl-phenyl)-ethylamine. Hydrochloric acid (AM-9.1) step 1 : 1 H -1,2,3- Triazole (5.0 g, 0.072 mmol) was diluted with water (35 mL) and heated to 50 °C before adding Br2 (23.1 g, 0.145 mmol) dropwise (exotherm). The oil bath was replaced with a water bath to keep the internal temperature below 50 °C. After 15 min, the resulting orange suspension was quenched with 2 M aqueous NaOH (5 mL) and 40% sodium bisulfite solution (2 mL). Next, 32% aqueous NaOH was added until pH 7, followed by an additional 40% sodium bisulfite solution (10 mL). Due to the exotherm, the suspension was cooled to room temperature before being filtered. The cake was washed with water (3 x 10 mL), and the filtrate was concentrated to give 4,5-dibromo- 2H- [1,2,3]triazole (14.86 g, 90%) as a slightly pale yellow solid.
步驟 2 ：向2-氟-5-硝基苯甲醚(5.00 g，28.6 mmol)於DMF (40 mL)中之室溫溶液中添加K
2CO
3(3.96 g，28.6 mmol)及4,5-二溴-2H-[1,2,3]三唑(6.50 g，28.6 mmol)，且在45℃攪拌混合物3 d。混合物用H
2O稀釋且過濾出所形成沈澱，用水洗滌且在HV下乾燥所收集固體，得到呈白色固體狀之4,5-二溴-2-(2-甲氧基-4-硝基-苯基)-2
H-[1,2,3]三唑(7.51 g，69%)。LC-MS B：t
R= 1.03 min；無電離。
Step 2 : To a room temperature solution of 2-fluoro-5-nitroanisole (5.00 g, 28.6 mmol) in DMF (40 mL) was added K 2 CO 3 (3.96 g, 28.6 mmol) and 4,5 -Dibromo-2H-[1,2,3]triazole (6.50 g, 28.6 mmol), and the mixture was stirred at 45 °C for 3 d. The mixture was diluted with H2O and the formed precipitate was filtered off, the collected solid was washed with water and dried under HV to give 4,5-dibromo-2-(2-methoxy-4-nitro- Phenyl) -2H- [1,2,3]triazole (7.51 g, 69%). LC-MS B: tR = 1.03 min; no ionization.
步驟 3 ：向4,5-二溴-2-(2-甲氧基-4-硝基-苯基)-2
H-[1,2,3]三唑(7.4 g，0.020 mol)於MeOH (70 mL)中之室溫溶液(經脫氣)中添加Pd(OH)
2(20%，1.04 g，1.96 mmol)，且在H
2氛圍下在室溫攪拌所得混合物2 h。經由矽藻土過濾混合物，其接著大量地用MeOH洗滌。濃縮濾液且藉由FC (首先用EtOAc/庚烷溶離，接著用100% EtOAc溶離且最終用10% MeOH/DCM溶離)純化。藉由製備型HPLC (鹼性)再純化所分離產物(130%)，得到呈棕色油狀之3-甲氧基-4-[1,2,3]三唑-2-基-苯胺(2.87 g，75%)。LC-MS I：t
R= 0.53 min；[M+H]
+= 191.33。
Step 3 : To 4,5-dibromo-2-(2-methoxy-4-nitro-phenyl) -2H- [1,2,3]triazole (7.4 g, 0.020 mol) in MeOH To a room temperature solution (degassed) in (70 mL) was added Pd(OH) 2 (20%, 1.04 g, 1.96 mmol), and the resulting mixture was stirred at room temperature under H 2 atmosphere for 2 h. The mixture was filtered through Celite, which was then washed extensively with MeOH. The filtrate was concentrated and purified by FC (first with EtOAc/heptane, then with 100% EtOAc and finally with 10% MeOH/DCM). The isolated product (130%) was repurified by preparative HPLC (basic) to give 3-methoxy-4-[1,2,3]triazol-2-yl-aniline (2.87 g, 75%). LC-MS I: tR = 0.53 min; [M+H] + = 191.33.
步驟 4 ：向CuBr
2(537 mg，2.41 mmol)於MeCN (3 mL)中之60℃溶液中緩慢添加亞硝酸三級丁酯(0.314 mL，2.65 mmol)。逐滴添加3-甲氧基-4-[1,2,3]三唑-2-基-苯胺(500 mg，2.41 mmol)於MeCN (3 mL)中之溶液，且在添加之後，使混合物達到室溫。混合物用胺基磺酸(47 mg，0.48 mmol)於水(1 mL)中之溶液淬滅，隨後添加2 M HCl水溶液(3 mL)。在添加EtOAc且分離各層之前，蒸發MeCN。有機層用2 M HCl水溶液、水及鹽水洗滌，接著經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用10%至20% EtOAc/己烷溶離)純化，得到呈黃色油狀之2-(4-溴-2-甲氧基苯基)-2
H-1,2,3-三唑(0.27 g，46%)。LC-MS I：t
R= 0.87 min；[M+H]
+= 254.13。
Step 4 : To a 60 °C solution of CuBr2 (537 mg, 2.41 mmol) in MeCN (3 mL) was slowly added tert-butyl nitrite (0.314 mL, 2.65 mmol). A solution of 3-methoxy-4-[1,2,3]triazol-2-yl-aniline (500 mg, 2.41 mmol) in MeCN (3 mL) was added dropwise, and after the addition, the mixture was allowed to Bring to room temperature. The mixture was quenched with a solution of sulfamic acid (47 mg, 0.48 mmol) in water (1 mL), followed by the addition of 2 M aqueous HCl (3 mL). MeCN was evaporated before EtOAc was added and the layers were separated. The organic layer was washed with 2M aq. HCl, water and brine, then dried (Na 2 SO 4 ), filtered and concentrated. Purification by FC (eluted with 10% to 20% EtOAc/hexanes) afforded 2-(4-bromo-2-methoxyphenyl) -2H -1,2,3-tris as a yellow oil Azole (0.27 g, 46%). LC-MS I: tR = 0.87 min; [M+H] + = 254.13.
步驟 5 及 6 ：按照對於
AM-2.1所描述之2步驟順序，由2-(4-溴-2-甲氧基苯基)-2H-1,2,3-三唑製備標題化合物。LC-MS I：t
R= 0.61 min；[M+H]
+= 260.26。
Steps 5 and 6 : The title compound was prepared from 2-(4-bromo-2-methoxyphenyl)-2H-1,2,3-triazole following the 2-step sequence described for AM-2.1 . LC-MS I: tR = 0.61 min; [M+H] + = 260.26.
2-(4-吡𠯤-2-基-苯基)-乙胺(AM-10.1)
步驟 1 ：向4-(2-硝基乙基)苯基硼酸(200 mg，1.03 mmol)及2-溴吡𠯤(168 mg，1.03 mmol)於二㗁烷(8 mL)中之室溫溶液中添加含2 M K
2CO
3之水(2 mL)。溶液用氬氣脫氣2 min，接著添加Pd(PPh
3)
4(35.6 mg，0.0308 mmol)，且將混合物加熱至80℃持續18 h。向混合物中添加水及EtOAc。分離各層，且水層用EtOAc再萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (EtOAc/庚烷2:3)純化，得到呈黃色油狀之2-[4-(2-硝基-乙基)-苯基]-吡𠯤(88 mg，37%)。LC-MS B：t
R= 0.84 min；[M+H]
+= 230.10。
2-(4-Pyr-2-yl-phenyl)-ethylamine (AM-10.1) Step 1 : Add 4-(2-nitroethyl)phenylboronic acid (200 mg, 1.03 mmol) and 2- To a room temperature solution of pyrimbromide (168 mg, 1.03 mmol) in dioxane (8 mL) was added 2 MK 2 CO 3 in water (2 mL). The solution was degassed with argon for 2 min, then Pd( PPh3 ) 4 (35.6 mg, 0.0308 mmol) was added, and the mixture was heated to 80 °C for 18 h. Water and EtOAc were added to the mixture. The layers were separated, and the aqueous layer was re-extracted with EtOAc. The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (EtOAc/heptane 2:3) afforded 2-[4-(2-nitro-ethyl)-phenyl]-pyridine (88 mg, 37%) as a yellow oil. LC-MS B: tR = 0.84 min; [M+H] + = 230.10.
步驟 2 ：向2-[4-(2-硝基-乙基)-苯基]-吡𠯤(88 mg，0.384 mmol)於EtOH/THF中之室溫溶液中添加Pd/C (10%，13.5 mg，0.019 mmol)，且在H
2氛圍下在室溫攪拌混合物18 h。過濾混合物且濃縮。藉由製備型HPLC (鹼性)純化，得到呈黃色固體狀之
AM-10.1(65 mg，85%)。LC-MS B：t
R= 0.48 min；[M+H]
+= 200.20。
Step 2 : To a room temperature solution of 2-[4-(2-nitro-ethyl)-phenyl]-pyridine (88 mg, 0.384 mmol) in EtOH/THF was added Pd/C (10%, 13.5 mg, 0.019 mmol), and the mixture was stirred at room temperature under H 2 atmosphere for 18 h. The mixture was filtered and concentrated. Purification by preparative HPLC (basic) afforded AM-10.1 (65 mg, 85%) as a yellow solid. LC-MS B: tR = 0.48 min; [M+H] + = 200.20.
2-(3-吡𠯤-2-基-苯基)-乙胺(AM-10.2) 按照對於
AM-10.1所描述之2步驟程序，由(3-(2-硝基乙基)苯基)硼酸製備標題化合物。LC-MS B：t
R= 0.48 min；[M+H]
+= 200.19。
2-(3-Pyroxyl-2-yl-phenyl)-ethylamine (AM-10.2) Following the 2-step procedure described for AM-10.1 , from (3-(2-nitroethyl)phenyl) Boronic acid to prepare the title compound. LC-MS B: tR = 0.48 min; [M+H] + = 200.19.
2-(7-甲氧基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙胺.鹽酸(AM-11.1)
步驟 1 ：向2,3-二氫-1,4-苯并二氧雜環己烯-6-醇(8.0 g，50 mmol)於DMF (80 mL)中之室溫溶液中逐份添加NBS (8.89 g，50 mmol)，且攪拌混合物2 h，之後添加額外NBS (3.0 g)且攪拌混合物另外30 min。混合物用水稀釋且用EtOAc (3×)萃取。經合併之有機萃取物用水(2×)、鹽水洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離)純化，得到呈紅色油狀之7-溴-2,3-二氫-苯并[1,4]二氧雜環己烯-6-醇(5.98 g，90%)。LC-MS B：t
R= 0.74 min；無電離。
2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine. Hydrochloric acid (AM-11.1) Step 1 : To 2, To a room temperature solution of 3-dihydro-1,4-benzodioxin-6-ol (8.0 g, 50 mmol) in DMF (80 mL) was added NBS (8.89 g, 50 mmol) in portions ), and the mixture was stirred for 2 h, after which additional NBS (3.0 g) was added and the mixture was stirred for another 30 min. The mixture was diluted with water and extracted with EtOAc (3x). The combined org. extracts were washed with water (2x), brine, dried over a phase separator and concentrated. Purification by FC (eluted with 0% to 30% EtOAc/heptane) afforded 7-bromo-2,3-dihydro-benzo[1,4]dioxine-6 as a red oil - Alcohol (5.98 g, 90%). LC-MS B: tR = 0.74 min; no ionization.
步驟 2 ：向7-溴-2,3-二氫-苯并[1,4]二氧雜環己烯-6-醇(5.981 g，25.9 mmol)及Cs
2CO
3(10.12 g，31.1 mmol)於DMF (60 mL)中之室溫溶液中添加MeI (3.26 mL，51.8 mmol)，且攪拌混合物1.5 h。混合物用水稀釋且用Et
2O (3×)萃取。經合併之有機層用水、鹽水洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離)純化，得到呈白色粉末狀之6-溴-7-甲氧基-2,3-二氫-苯并[1,4]二氧雜環己烯(5.85 g，92%)。LC-MS B：t
R= 0.90 min；[M+H]
+= 244.13。
Step 2 : To 7-bromo-2,3-dihydro-benzo[1,4]dioxin-6-ol (5.981 g, 25.9 mmol) and Cs 2 CO 3 (10.12 g, 31.1 mmol ) in DMF (60 mL) was added MeI (3.26 mL, 51.8 mmol) and the mixture was stirred for 1.5 h. The mixture was diluted with water and extracted with Et2O (3x). The combined organic layers were washed with water, brine, dried over a phase separator and concentrated. Purification by FC (elution with 0% to 30% EtOAc/heptane) afforded 6-bromo-7-methoxy-2,3-dihydro-benzo[1,4]dioxyl as a white powder Heterocyclohexene (5.85 g, 92%). LC-MS B: tR = 0.90 min; [M+H] + = 244.13.
步驟 3 及 4 ：按照對於
AM-2.1所描述之2步驟程序，由6-溴-7-甲氧基-2,3-二氫-苯并[1,4]二氧雜環己烯製備標題化合物。LC-MS B：t
R= 0.52 min；[M+H]
+= 210.24。
Steps 3 and 4 : The title was prepared from 6-bromo-7-methoxy-2,3-dihydro-benzo[1,4]dioxine following the 2-step procedure described for AM-2.1 compound. LC-MS B: tR = 0.52 min; [M+H] + = 210.24.
2-(7-氯-5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙胺.鹽酸(AM-12.1)
步驟 1 ：向3-甲基兒茶酚(5.0 g，40.3 mmol)及K
2CO
3(22.27 g，161 mmol)於DMF (70 mL)中之室溫溶液中添加1,2-二溴乙烷(8.85 mL，101 mmol)，且攪拌所得混合物18 h。混合物用水稀釋且用Et
2O (3×)萃取。經合併之有機層用水及鹽水洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至25% EtOAc/庚烷溶離)純化，得到呈無色油狀之5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯(3.05 g，50%)。LC-MS B：t
R= 0.83 min；無電離。
2-(7-Chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine. Hydrochloric acid (AM-12.1) Step 1 : To a room temperature solution of 3-methylcatechol (5.0 g, 40.3 mmol) and K 2 CO 3 (22.27 g, 161 mmol) in DMF (70 mL) was added 1,2-dibromoethane (8.85 mL, 101 mmol), and the resulting mixture was stirred for 18 h. The mixture was diluted with water and extracted with Et2O (3x). The combined organic layers were washed with water and brine, dried over a phase separator and concentrated. Purification by FC (eluted with 0% to 25% EtOAc/heptane) afforded 5-methyl-2,3-dihydro-benzo[1,4]dioxine as a colorless oil ( 3.05 g, 50%). LC-MS B: tR = 0.83 min; no ionization.
步驟 2 ：向5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯(2.864 g，19.1 mmol)於THF (60 mL)中之0℃溶液中逐份添加NBS (3.39 g，19.1 mmol)，且在室溫攪拌反應混合物18 h。向混合物中添加NBS (286 mg)且繼續攪拌另外30 min。混合物用水稀釋且用EtOAc (3×)萃取。經合併之有機萃取物用水(2×)、鹽水洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離)純化，得到呈淺橙色油狀之6-溴-5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯(4.40 g，100%)。LC-MS B：t
R= 0.96 min；無電離。
Step 2 : To a 0 °C solution of 5-methyl-2,3-dihydro-benzo[1,4]dioxine (2.864 g, 19.1 mmol) in THF (60 mL) in portions NBS (3.39 g, 19.1 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. NBS (286 mg) was added to the mixture and stirring was continued for another 30 min. The mixture was diluted with water and extracted with EtOAc (3x). The combined org. extracts were washed with water (2x), brine, dried over a phase separator and concentrated. Purification by FC (eluted with 0% to 30% EtOAc/heptane) afforded 6-bromo-5-methyl-2,3-dihydro-benzo[1,4]dioxyl as a light orange oil Heterocyclohexenes (4.40 g, 100%). LC-MS B: tR = 0.96 min; no ionization.
步驟 3 ：按照對於
AM-2.1步驟1所描述之反應，由6-溴-5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯製備[2-(5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙基]-胺基甲酸三級丁酯。LC-MS B：t
R= 0.95 min；無電離。
Step 3 : Preparation of [2-( tertiary-butyl 5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamate. LC-MS B: tR = 0.95 min; no ionization.
步驟 4 ：向[2-(5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙基]-胺基甲酸三級丁酯(600 mg，2.05 mmol)於DMF (10 mL)中之室溫溶液中逐份添加NCS (307 mg，2.25 mmol)，且將混合物加熱至50℃持續18 h。混合物用水稀釋且用EtOAc (3×)萃取。經合併之有機萃取物用水、鹽水洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至20% EtOAc/庚烷溶離)純化，得到呈略微橙色油狀之[2-(7-氯-5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙基]-胺基甲酸三級丁酯(581 mg，87%)。
Step 4 : To [2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamic acid tertiary butyl ester To a room temperature solution of (600 mg, 2.05 mmol) in DMF (10 mL) was added NCS (307 mg, 2.25 mmol) in portions, and the mixture was heated to 50 °C for 18 h. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed with water, brine, dried over a phase separator and concentrated. Purification by FC (eluted with 0% to 20% EtOAc/heptane) afforded [2-(7-chloro-5-methyl-2,3-dihydro-benzo[1, 4] Dioxin-6-yl)-ethyl]-carbamic acid tert-butyl ester (581 mg, 87%).
步驟 5 ：按照對於
AM-2.1步驟2所描述之反應，由[2-(7-氯-5-甲基-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙基]-胺基甲酸三級丁酯製備標題化合物。LC-MS B：t
R= 0.58 min；[M+H]
+= 228.11。
Step 5 : Following the reaction described for AM-2.1 Step 2, from [2-(7-chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxine- 6-yl)-ethyl]-carbamic acid tert-butyl ester to prepare the title compound. LC-MS B: tR = 0.58 min; [M+H] + = 228.11.
2-(7-氯-2,3-二氫-苯并[1,4]二氧雜環己烯-6-基)-乙胺.鹽酸(AM-12.2) 按照對於
AM-12.1步驟3至5所描述之3步驟反應順序，由6-溴-2,3-二氫苯并[b][1,4]二氧雜環己烯製備標題化合物。LC-MS B：t
R= 0.54 min；[M+H]
+= 214.22。
2-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine.hydrochloric acid (AM-12.2) Follow steps 3 to 1 for AM-12.1 The 3-step reaction sequence described in 5 prepared the title compound from 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine. LC-MS B: tR = 0.54 min; [M+H] + = 214.22.
2-(3-甲氧基異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-13.1)
步驟 1 ：向3-(3-甲氧基異㗁唑-5-基)丙酸(1.0 g，5.55 mmol)及TEA (0.93 mL，6.66 mmol)於PhMe (25 mL)中之室溫溶液中逐滴添加DPPA (1.32 mL，6.1 mmol)，且將反應混合物加熱至100℃持續1.5 h。添加2-甲基丙-2-醇(1.06 mL，11.1 mmol)，且將反應混合物加熱至回流持續16 h。將反應混合物冷卻至室溫且分配於NaHCO
3飽和水溶液與EtOAc之間，並分離各層。水相用EtOAc (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至100% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之(2-(3-甲氧基異㗁唑-5-基)乙基)胺基甲酸三級丁酯。LC-MS F：t
R= 1.80 min；[M+H]
+= 243.1。
2-(3-methoxyisozol-5-yl)ethan-1-amine hydrochloride (AM-13.1) step 1 : to 3-(3-methoxyisozol-5-yl)propane To a room temperature solution of acid (1.0 g, 5.55 mmol) and TEA (0.93 mL, 6.66 mmol) in PhMe (25 mL) was added DPPA (1.32 mL, 6.1 mmol) dropwise, and the reaction mixture was heated to 100 °C for 1.5 h. 2-Methylpropan-2-ol (1.06 mL, 11.1 mmol) was added, and the reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous NaHCO 3 and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2x), and the combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 100% EtOAc/heptane) to afford (2-(3-methoxyisozazol-5-yl)ethyl)carbamate tris(2-(3-methoxyisozazol-5-yl)ethyl)carbamate as a colorless oil grade butyl ester. LC-MS F: tR = 1.80 min; [M+H] + = 243.1.
步驟 2 ：類似於對於AM-2.1步驟2所描述之程序，由(2-(3-甲氧基異㗁唑-5-基)乙基)胺基甲酸三級丁酯製備標題化合物。LC-MS B：t
R= 0.28 min；[M+H]
+= 143.09。
Step 2 : In analogy to the procedure described for AM-2.1 Step 2, the title compound was prepared from tert-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate. LC-MS B: tR = 0.28 min; [M+H] + = 143.09.
2-(3-(甲氧基-d3)異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-13.2)
步驟 1 ：向戊-4-炔酸(5.0 g，51 mmol)於EtOH (50 mL)中之室溫溶液中添加H
2SO
4(136 μL，2.55 mmol)，且將反應混合物加熱至70℃持續2 h。將反應混合物分配於水與EtOAc之間，且分離各層。有機相用H
2O (2×)洗滌，之後添加KHCO
3(10.21 g，102 mmol)於H
2O (25 mL)中之溶液，隨後逐滴添加二溴化羥基碳醯亞胺(10.34 g，51 mmol)於EtOAc (200 mL)中之溶液。在室溫攪拌反應混合物48 h，且接著用H
2O、鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用1%至15% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之3-(3-溴異㗁唑-5-基)丙酸乙酯。LC-MS F：t
R= 1.87 min；[M+H]
+= 247.0。
2-(3-(Methoxy-d3)isozazol-5-yl)ethan-1-amine hydrochloride (AM-13.2) step 1 : pent-4-ynoic acid (5.0 g, 51 mmol) To a room temperature solution in EtOH ( 50 mL) was added H2SO4 (136 μL, 2.55 mmol), and the reaction mixture was heated to 70 °C for 2 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic phase was washed with H 2 O (2×), then a solution of KHCO 3 (10.21 g, 102 mmol) in H 2 O (25 mL) was added, followed by dropwise addition of hydroxycarbimide dibromide (10.34 g , 51 mmol) in EtOAc (200 mL). The reaction mixture was stirred at room temperature for 48 h, and then washed with H2O , brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (elution with 1% to 15% EtOAc/heptane) to afford ethyl 3-(3-bromoisoxazol-5-yl)propionate as a white solid. LC-MS F: tR = 1.87 min; [M+H] + = 247.0.
步驟 2 ：在冰浴中，向甲醇-d3 (11.53 mL，285 mmol)中逐份添加Na (1.15 g，50 mmol)，且當所有固體溶解時，添加3-(3-溴異㗁唑-5-基)丙酸乙酯(1.0 g，4.0 mmol)，且在微波爐中在110℃照射所得溶液75 min。反應混合物用H
2O稀釋且接著倒入2M HCl (35 mL)中並用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用5%至10% MeOH/DCM溶離)純化粗產物，得到呈白色固體狀之3-(3-(甲氧基-d3)異㗁唑-5-基)丙酸。LC-MS F：t
R= 1.07 min；[M+H]
+= 175.0。
Step 2 : To methanol-d3 (11.53 mL, 285 mmol) was added Na (1.15 g, 50 mmol) portionwise in an ice bath, and when all solids were dissolved, 3-(3-bromoisoxazole- 5-yl) ethyl propionate (1.0 g, 4.0 mmol), and the resulting solution was irradiated in a microwave oven at 110° C. for 75 min. The reaction mixture was diluted with H2O and then poured into 2M HCl (35 mL) and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 5% to 10% MeOH/DCM) to afford 3-(3-(methoxy-d3)isozazol-5-yl)propanoic acid as a white solid. LC-MS F: tR = 1.07 min; [M+H] + = 175.0.
步驟 3-4 ：類似於對於AM-13.1所描述之程序，由3-(3-(甲氧基-d3)異㗁唑-5-基)丙酸製備標題化合物。LC-MS F：t
R= 0.13 min；[M+H]
+= 146.0。
Step 3-4 : The title compound was prepared from 3-(3-(methoxy-d3)isoxazol-5-yl)propionic acid in analogy to the procedure described for AM-13.1. LC-MS F: tR = 0.13 min; [M+H] + = 146.0.
2-(4-(3-甲氧基丙基)-1
H-吡唑-1-基)乙-1-胺二鹽酸鹽(AM-14.1)
步驟 1 ：胺基甲酸,
N-[2-(4-溴-1H-吡唑-1-基)乙基]-, 1,1-二甲基乙酯(300 mg，1.03 mmol)及反式-3-甲氧基-1-丙烯基硼酸酯(0.71 mL，1.07 mmol)於二㗁烷(3 mL)及H
2O (3 mL)中之混合物用Ar脫氣10 min，之後添加Cs
2CO
3(1.18 g，3.62 mmol)及Pd(dppf)Cl
2.DCM (25.3 mg，0.03 mmol)。反應混合物用Ar脫氣另外2 min且接著在微波爐中在90℃照射20 min (冷卻功能開啟)。在冷卻至室溫之後，將反應混合物分配於水與DCM之間且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(Mg
2SO
4)，過濾且真空蒸發。藉由製備型HPLC (酸性，5%至95%)純化粗產物，得到呈無色油狀之(2-(4-(3-甲氧基丙-1-烯-1-基)-1H-吡唑-1-基)乙基)胺基甲酸三級丁酯(187 mg，64%)。LC-MS B：t
R= 0.78 min；[M+H]
+= 282.29。
2-(4-(3-methoxypropyl) -1H -pyrazol-1-yl)ethan-1-amine dihydrochloride (AM-14.1) step 1 : carbamic acid, N- [2 -(4-Bromo-1H-pyrazol-1-yl)ethyl]-, 1,1-dimethylethyl ester (300 mg, 1.03 mmol) and trans-3-methoxy-1-propenyl boric acid A mixture of ester (0.71 mL, 1.07 mmol) in dioxane (3 mL) and H 2 O (3 mL) was degassed with Ar for 10 min, after which Cs 2 CO 3 (1.18 g, 3.62 mmol) and Pd( dppf) Cl2.DCM (25.3 mg, 0.03 mmol). The reaction mixture was degassed with Ar for another 2 min and then irradiated in a microwave oven at 90 °C for 20 min (cooling function on). After cooling to room temperature, the reaction mixture was partitioned between water and DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried ( Mg2SO4 ), filtered and evaporated in vacuo . The crude product was purified by preparative HPLC (acidic, 5% to 95%) to afford (2-(4-(3-methoxyprop-1-en-1-yl)-1H-pyridine) as a colorless oil (Azol-1-yl)ethyl)carbamate tert-butyl ester (187 mg, 64%). LC-MS B: tR = 0.78 min; [M+H] + = 282.29.
步驟 2 ：向(2-(4-(3-甲氧基丙-1-烯-1-基)-1H-吡唑-1-基)乙基)胺基甲酸三級丁酯(180 mg，0.64 mmol)於MeOH中之室溫溶液中添加Pd/C (10%，34 mg，0.032 mmol)，且在H
2氛圍下在室溫攪拌混合物1 h。過濾混合物且濃縮，得到呈無色油狀之(2-(4-(3-甲氧基丙基)-1H-吡唑-1-基)乙基)胺基甲酸三級丁酯(180 mg，99%)。LC-MS B：t
R= 0.78 min；[M+H]
+= 284.28。
Step 2 : To (2-(4-(3-methoxyprop-1-en-1-yl)-1H-pyrazol-1-yl)ethyl)carbamate (180 mg, 0.64 mmol) to a room temperature solution in MeOH was added Pd/C (10%, 34 mg, 0.032 mmol), and the mixture was stirred at room temperature under H 2 atmosphere for 1 h. The mixture was filtered and concentrated to afford tert-butyl (2-(4-(3-methoxypropyl)-1H-pyrazol-1-yl)ethyl)carbamate (180 mg, 99%). LC-MS B: tR = 0.78 min; [M+H] + = 284.28.
步驟 3 ：向(2-(4-(3-甲氧基丙基)-1
H-吡唑-1-基)乙基)胺基甲酸三級丁酯(175 mg，0.62 mmol)於二㗁烷(5 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(4.4 mL，6.18 mmol)，且攪拌所得混合物30 min。真空濃縮反應混合物，得到呈無色油狀之標題化合物
AM-14.1(157 mg，99%)。LC-MS B：t
R= 0.42 min；[M+H]
+= 184.40。
Step 3 : Add (2-(4-(3-methoxypropyl) -1H -pyrazol-1-yl)ethyl)carbamate (175 mg, 0.62 mmol) to tertiary butyl To a room temperature solution in alkanes (5 mL) was added 4 M HCl in dioxane (4.4 mL, 6.18 mmol), and the resulting mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo to afford the title compound AM-14.1 (157 mg, 99%) as a colorless oil. LC-MS B: tR = 0.42 min; [M+H] + = 184.40.
2-(4-環丙基-1H-吡唑-1-基)乙-1-胺二鹽酸鹽(AM-15.1)
步驟 1 ：胺基甲酸, N-[2-(4-溴-1H-吡唑-1-基)乙基]-, 1,1-二甲基乙酯(500 mg，1.72 mmol)及環丙基硼酸(459 mg，5.34 mmol)於THF (10 mL)中之混合物用Ar脫氣10 min，之後添加Cs
2CO
3(1.97 g，6.03 mmol)及Pd(dppf)Cl
2.DCM (42.2 mg，0.052 mmol)。反應混合物用Ar脫氣另外2 min且接著在微波爐中在70℃照射30 min (冷卻功能開啟)。在冷卻至室溫之後，將反應混合物分配於水與DCM之間且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(Mg
2SO
4)，過濾且真空蒸發。藉由FC (用15%至50% EtOAc/庚烷溶離，在EtOAc/庚烷1:1中R
f= 0.48)純化粗產物，得到呈無色油狀之(2-(4-環丙基-1H-吡唑-1-基)乙基)胺基甲酸三級丁酯(187 mg，64%)。LC-MS B：t
R= 0.78 min；[M+H]
+= 282.29。
2-(4-Cyclopropyl-1H-pyrazol-1-yl)ethan-1-amine dihydrochloride (AM-15.1) step 1 : carbamic acid, N-[2-(4-bromo-1H A mixture of -pyrazol-1-yl)ethyl]-, 1,1-dimethylethyl ester (500 mg, 1.72 mmol) and cyclopropylboronic acid (459 mg, 5.34 mmol) in THF (10 mL) After degassing with Ar for 10 min, Cs2CO3 (1.97 g, 6.03 mmol) and Pd(dppf) Cl2.DCM (42.2 mg, 0.052 mmol) were added. The reaction mixture was degassed with Ar for another 2 min and then irradiated in a microwave oven at 70 °C for 30 min (cooling function on). After cooling to room temperature, the reaction mixture was partitioned between water and DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried ( Mg2SO4 ), filtered and evaporated in vacuo . Purification of the crude product by FC (elution with 15% to 50% EtOAc/heptane, Rf = 0.48 in EtOAc/heptane 1:1) afforded (2-(4-cyclopropyl- tert-butyl 1H-pyrazol-1-yl)ethyl)carbamate (187 mg, 64%). LC-MS B: tR = 0.78 min; [M+H] + = 282.29.
步驟 2 ：在室溫，向(2-(4-環丙基-1H-吡唑-1-基)乙基)胺基甲酸三級丁酯(580 mg，2.31 mmol)中添加含5 M HCl之
i PrOH (2.3 mL，11.5 mmol)，且攪拌反應混合物30 min。真空濃縮反應混合物，得到呈無色油狀之標題化合物
AM-15.1(157 mg，99%)。LC-MS B：t
R= 0.42 min；[M+H]
+= 184.40。
Step 2 : To tert-butyl (2-(4-cyclopropyl-1H-pyrazol-1-yl)ethyl)carbamate (580 mg, 2.31 mmol) was added 5 M HCl at room temperature i PrOH (2.3 mL, 11.5 mmol), and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo to afford the title compound AM-15.1 (157 mg, 99%) as a colorless oil. LC-MS B: tR = 0.42 min; [M+H] + = 184.40.
2-(4-甲氧基-1
H-吡唑-1-基)乙-1-胺二鹽酸鹽(AM-16.1)
步驟 1 ：於4-甲氧基-1
H-吡唑鹽酸鹽(1.00 g，7.06 mmol)及Cs
2CO
3(6.97 g，21.2 mmol)於MeCN (16.3 mL)中之室溫懸浮液中添加
N-(2-溴乙基)胺基甲酸三級丁酯(1.61 g，7.06 mmol)，且將反應混合物加熱至80℃持續18 h。使反應混合物達到室溫，接著將其過濾，且用DCM沖洗濾餅。藉由FC (用20%至60% EtOAc/庚烷溶離，其中R
f= 0.18 (庚烷/EtOAc 1:1))純化，得到呈白色固體狀之(2-(4-甲氧基-1
H-吡唑-1-基)乙基)胺基甲酸三級丁酯(1.473 g，87%)。
2-(4-Methoxy-1 H -pyrazol-1-yl)ethan-1-amine dihydrochloride (AM-16.1) step 1 : in 4-methoxy-1 H -pyrazole hydrochloride To a room temperature suspension of salt (1.00 g, 7.06 mmol) and Cs2CO3 (6.97 g, 21.2 mmol) in MeCN ( 16.3 mL) was added tertiary-butyl N- (2-bromoethyl)carbamate (1.61 g, 7.06 mmol), and the reaction mixture was heated to 80 °C for 18 h. The reaction mixture was allowed to come to room temperature, then it was filtered and the filter cake was rinsed with DCM. Purification by FC (elution with 20% to 60% EtOAc/heptane, where Rf = 0.18 (heptane/EtOAc 1:1)) gave (2-(4-methoxy-1) as a white solid (H -pyrazol-1-yl)ethyl)carbamate (1.473 g, 87%).
步驟 2 ：向(2-(4-甲氧基-1
H-吡唑-1-基)乙基)胺基甲酸三級丁酯(1.47 g，5.53 mmol)於DCM (9.5 mL)中之0℃懸浮液中添加含4 M HCl之二㗁烷(13.8 mL，55.3 mmol)，且使反應混合物達到室溫隔夜。濃縮反應混合物且與DCM一起在HV下共蒸發，得到呈灰白色固體狀之標題化合物
AM-16.1(1.36 g，94%)。LC-MS B：t
R= 0.36 min；無電離。
Step 2 : Add (2-(4-methoxy- 1H -pyrazol-1-yl)ethyl)carbamate (tert-butyl) (1.47 g, 5.53 mmol) to 0 in DCM (9.5 mL) To the suspension was added 4 M HCl in dioxane (13.8 mL, 55.3 mmol) and the reaction mixture was allowed to reach room temperature overnight. The reaction mixture was concentrated and co-evaporated with DCM under HV to afford the title compound AM-16.1 (1.36 g, 94%) as an off-white solid. LC-MS B: tR = 0.36 min; no ionization.
2-(5- 環丙基 -2
H-
四唑 -2- 基 ) 乙 -1- 胺鹽酸鹽 (AM-16.2)按照對於
AM-16.1所描述之反應順序，使用K
2CO
3替代Cs
2CO
3，由5-環丙基-2
H-1,2,3,4-四唑製備標題化合物。LC-MS I：t
R= 0.44 min；[M+H]
+= 154.25。
2-(5- Cyclopropyl - 2H - tetrazol -2- yl ) ethan - 1- amine hydrochloride (AM-16.2) Follow the reaction sequence described for AM-16.1 , using K2CO3 instead of Cs 2 CO 3 , The title compound was prepared from 5-cyclopropyl-2 H -1,2,3,4-tetrazole. LC-MS I: tR = 0.44 min; [M+H] + = 154.25.
2-(3- 乙炔基苯基 ) 乙 -1- 胺 .TFA (AM-17.1) 步驟 1 ：類似於對於AM-3.1步驟1所描述之程序，由2-(3-溴苯基)乙-1-胺製備(3-溴苯乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 1.00 min；[M+H-Me]
+= 285.12。
2-(3- Ethynylphenyl ) ethan -1- amine.TFA (AM-17.1) Step 1 : Similar to the procedure described for AM-3.1 Step 1, 2-(3-bromophenyl)ethan-1- Preparation of tertiary-butyl (3-bromophenethyl)carbamate from 1-amine. LC-MS B: tR = 1.00 min; [M+H-Me] + = 285.12.
步驟 2 ：在60℃攪拌(3-溴苯乙基)胺基甲酸三級丁酯(10.51 g，35 mmol)、三甲基矽基乙炔(14.8 mL，105 mmol)、XPhos Pd G2 (1.38 g，1.75 mmol)及TEA (14.6 mL，105 mmol)於DMF (120 mL)中之經脫氣混合物18 h。將反應混合物分配於水與Et
2O之間，且分離各層。水相用Et
2O (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至60% EtOAc/庚烷溶離)純化粗產物，得到呈棕色油狀之(3-((三甲基矽基)乙炔基)苯乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 1.13 min；[M+H-
t Bu]
+= 262.27。
Step 2 : Stir tert-butyl (3-bromophenethyl)carbamate (10.51 g, 35 mmol), trimethylsilylacetylene (14.8 mL, 105 mmol), XPhos Pd G2 (1.38 g , 1.75 mmol) and TEA (14.6 mL, 105 mmol) in DMF (120 mL) was degassed for 18 h. The reaction mixture was partitioned between water and Et2O , and the layers were separated. The aqueous phase was re - extracted with Et2O (2x), and the combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 60% EtOAc/heptane) to afford tert-butyl (3-((trimethylsilyl)ethynyl)phenethyl)carbamate as a brown oil ester. LC-MS B: tR = 1.13 min; [M+H- tBu ] + = 262.27.
步驟 3 ：向(3-((三甲基矽基)乙炔基)苯乙基)胺基甲酸三級丁酯(10.36 g，32.6 mmol)於DCM (100 mL)中之室溫溶液中添加TFA (15 mL，196 mmol)，且攪拌反應混合物1 h，之後真空濃縮。將殘餘物與DCM (2×)一起共蒸發，得到呈黃色固體狀之標題化合物。LC-MS B：t
R= 0.49 min；[M+H]
+= 146.19。
Step 3 : To a room temperature solution of tert-butyl (3-((trimethylsilyl)ethynyl)phenethyl)carbamate (10.36 g, 32.6 mmol) in DCM (100 mL) was added TFA (15 mL, 196 mmol), and the reaction mixture was stirred for 1 h before being concentrated in vacuo. The residue was co-evaporated with DCM (2x) to give the title compound as a yellow solid. LC-MS B: tR = 0.49 min; [M+H] + = 146.19.
2-(3- 甲氧基 -1,2,4- 㗁二唑 -5- 基 ) 乙 -1- 胺鹽酸鹽 (AM-18.1) 步驟 1 ：向boc-β-Ala-OH (5.0 g，25.9 mmol)、o-甲基異脲硫酸氫鹽(4.5 g，25.9 mmol)及DIPEA (18.1 mL，104 mmol)於DMF (150 mL)中之室溫溶液中添加HATU (11.82 g，31.1 mmol)，且在室溫攪拌反應混合物1.5 h。向反應混合物中添加水及EtOAc，接著分離兩個層，且無機層用EtOAc (2×)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮，得到粗產物，藉由FC (用20%至100% EtOAc/庚烷溶離)純化該粗產物，得到呈白色固體狀之(3-((亞胺基(甲氧基)甲基)胺基)-3-側氧基丙基)胺基甲酸三級丁酯。LC-MS I：t
R= 0.64 min；[M+H]
+= 246.36。
2-(3- methoxy -1,2,4- oxadiazol -5- yl ) ethan -1- amine hydrochloride (AM-18.1) step 1 : to boc-β-Ala-OH (5.0 g , 25.9 mmol), o-methylisourea bisulfate (4.5 g, 25.9 mmol) and DIPEA (18.1 mL, 104 mmol) in DMF (150 mL) at room temperature were added HATU (11.82 g, 31.1 mmol ), and the reaction mixture was stirred at room temperature for 1.5 h. Water and EtOAc were added to the reaction mixture, then the two layers were separated, and the inorganic layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give the crude product, which was purified by FC (eluted with 20% to 100% EtOAc/heptane) to give a white Tertiary-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate as a solid. LC-MS I: tR = 0.64 min; [M+H] + = 246.36.
步驟 2 ：向(3-((亞胺基(甲氧基)甲基)胺基)-3-側氧基丙基)胺基甲酸三級丁酯(6.19 g，24.7 mmol)及NBS (10.56 g，59.3 mmol)於EtOAc (120 mL)中之室溫溶液中添加1,8-二氮雜雙環[5.4.0]十一碳-7-烯(8.96 mL，59.3 mmol)，且攪拌反應混合物5 h。添加額外1,8-二氮雜雙環[5.4.0]十一碳-7-烯(1.85 mL，12.4 mmol)及NBS (2.2 g，12.4 mmol)，且繼續攪拌16 h。過濾懸浮液，且濾液用水、NaHCO
3飽和水溶液及鹽水洗滌，之後蒸發至乾燥。藉由FC (用20%至100% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之((2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)胺基甲酸三級丁酯。LC-MS I：t
R= 0.75 min；[M+H]
+= 244.33。
Step 2 : Add tertiary butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate (6.19 g, 24.7 mmol) and NBS (10.56 g, 59.3 mmol) to a room temperature solution in EtOAc (120 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.96 mL, 59.3 mmol) and the reaction mixture was stirred 5 h. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (1.85 mL, 12.4 mmol) and NBS (2.2 g, 12.4 mmol) were added and stirring was continued for 16 h. The suspension was filtered, and the filtrate was washed with water, saturated aqueous NaHCO 3 and brine before being evaporated to dryness. The crude product was purified by FC (eluted with 20% to 100% EtOAc/heptane) to afford ((2-(3-methoxy-1,2,4-oxadiazol-5-yl) as a colorless oil ) ethyl) tertiary butyl carbamate. LC-MS I: t R = 0.75 min; [M+H] + = 244.33.
步驟 3 ：向(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)胺基甲酸三級丁酯(150 mg，0.62 mmol)於DCM (2 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(0.62 mL，2.47 mmol)，且在室溫攪拌反應混合物4天，接著在50℃攪拌6 h。蒸發混合物，得到呈白色固體狀之標題化合物
A-18.1(79 mg，71%)。LC-MS I：t
R=0.35 min；[M+H]
+= 144.21。
Step 3 : Add tertiary-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL ) in dioxane (0.62 mL, 2.47 mmol) was added, and the reaction mixture was stirred at room temperature for 4 days, then at 50 °C for 6 h. The mixture was evaporated to give the title compound A-18.1 (79 mg, 71%) as a white solid. LC-MS I: tR = 0.35 min; [M+H] + = 144.21.
2-(4- 環丙基 -2
H-1,2,3-
三唑 -2- 基 ) 乙 -1- 胺鹽酸鹽 (AM-19.1) 步驟 1 ：向
N-[2-(4-溴-2
H-1,2,3-三唑-2-基)乙基]胺基甲酸三級丁酯(291 mg，1 mmol)、環丙基硼酸(112 mg，1.3 mmol)、磷酸三鉀(758 mg，3.5 mmol)及三環己基膦(45.1 mg，0.156 mmol)於甲苯(22 mL)及水(0.22 mL)中之室溫溶液中添加Pd(OAc)
2(17.1 mg，0.076 mmol)。將混合物加熱至100℃持續18 h。將反應混合物冷卻至室溫，接著過濾混合物，且濃縮濾液。藉由FC (用5%至40% EtOAc/庚烷溶離，其中在庚烷/EtOAc 7:3中，R
f= 0.27)純化，得到呈黃色油狀之(2-(4-環丙基-2
H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯(194 mg，77%)。LC-MS B：t
R= 0.82 min；[M+H]
+= 253.34。
2-(4- cyclopropyl - 2H -1,2,3- triazol -2- yl ) ethan -1- amine hydrochloride (AM-19.1) step 1 : to N- [2-(4- Bromo- 2H -1,2,3-triazol-2-yl)ethyl]carbamate (291 mg, 1 mmol), cyclopropylboronic acid (112 mg, 1.3 mmol), triphosphate To a room temperature solution of potassium (758 mg, 3.5 mmol) and tricyclohexylphosphine (45.1 mg, 0.156 mmol) in toluene (22 mL) and water (0.22 mL) was added Pd(OAc) 2 (17.1 mg, 0.076 mmol ). The mixture was heated to 100 °C for 18 h. The reaction mixture was cooled to room temperature, then the mixture was filtered, and the filtrate was concentrated. Purification by FC (elution with 5% to 40% EtOAc/heptane, where Rf = 0.27 in heptane/EtOAc 7:3) afforded (2-(4-cyclopropyl- tert-butyl 2 H -1,2,3-triazol-2-yl)ethyl)carbamate (194 mg, 77%). LC-MS B: tR = 0.82 min; [M+H] + = 253.34.
步驟 2 ：向(2-(4-環丙基-2
H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯(550 mg，1.96 mmol)於DCM (3.4 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(4.9 mL，19.6 mmol)。在室溫攪拌反應混合物30 min，接著濃縮反應混合物，得到呈白色固體狀之標題化合物
AM-19.1(432 mg，98%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.37 min；[M+H]
+= 153.11。
Step 2 : Add tertiary-butyl (2-(4-cyclopropyl- 2H -1,2,3-triazol-2-yl)ethyl)carbamate (550 mg, 1.96 mmol) in DCM ( To a room temperature solution in 3.4 mL) was added 4 M HCl in dioxane (4.9 mL, 19.6 mmol). The reaction mixture was stirred at room temperature for 30 min, then the reaction mixture was concentrated to afford the title compound AM-19.1 (432 mg, 98%) as a white solid, which was used as such in the next step. LC-MS B: tR = 0.37 min; [M+H] + = 153.11.
2-(2- 胺基乙基 )-2H-1,2,3- 三唑 -4- 甲腈三氟乙酸鹽 (AM-19.2) 步驟 1 ：向
N-[2-(4-溴-2
H-1,2,3-三唑-2-基)乙基]胺基甲酸三級丁酯(429 mg，1.47 mmol)於1,2-二甲氧基乙烷(7 mL)中之室溫溶液中添加乙烯基硼酸酐吡啶錯合物(355 mg，1.47 mmol)及2 M K
2CO
3水溶液(2.5 mL)，且反應混合物用Ar吹掃10 min，之後添加Pd(PPh
3)
4(34.8 mg，0.03 mmol)。將混合物加熱至80℃持續18 h。將反應混合物冷卻至室溫，過濾，且將濾液分配於水與EtOAc之間，且分離各層。水相用EtOAc (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (酸性)純化粗產物，得到呈棕色油狀之(2-(4-乙烯基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 0.81 min；[M+H]
+= 239.14。
2-(2- Aminoethyl )-2H-1,2,3- triazole -4- carbonitrile trifluoroacetate (AM-19.2) step 1 : to N- [2-(4-bromo-2 H -1,2,3-triazol-2-yl)ethyl]carbamate (429 mg, 1.47 mmol) in 1,2-dimethoxyethane (7 mL) Vinylboronic anhydride pyridine complex (355 mg, 1.47 mmol) and 2 M K 2 CO 3 aqueous solution (2.5 mL) were added to warm solution, and the reaction mixture was purged with Ar for 10 min, after which Pd(PPh 3 ) 4 ( 34.8 mg, 0.03 mmol). The mixture was heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2x), and the combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (acidic) to give (2-(4-vinyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate tertiary grade as a brown oil. butyl ester. LC-MS B: tR = 0.81 min; [M+H] + = 239.14.
步驟 2 ：向(2-(4-乙烯基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯(118 mg，0.50 mmol)於水:丙酮之1:1混合物(6 mL)中之室溫溶液中添加KMnO
4(401 mg，1.0 mmol)，且攪拌反應混合物18 h。過濾反應混合物且真空蒸發，且藉由製備型HPLC (酸性)純化粗產物，得到呈白色固體狀之2-(2-((三級丁氧基羰基)胺基)乙基)-2H-1,2,3-三唑-4-甲酸。LC-MS B：t
R= 0.61 min；[M+H]
+= 257.11。
Step 2 : Add (2-(4-vinyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate (118 mg, 0.50 mmol) in water:acetone To a room temperature solution in a 1:1 mixture (6 mL) was added KMnO 4 (401 mg, 1.0 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was filtered and evaporated in vacuo, and the crude product was purified by preparative HPLC (acidic) to give 2-(2-((tertiary-butoxycarbonyl)amino)ethyl)-2H-1 as a white solid ,2,3-triazole-4-carboxylic acid. LC-MS B: tR = 0.61 min; [M+H] + = 257.11.
步驟 3 ：向2-(2-((三級丁氧基羰基)胺基)乙基)-2H-1,2,3-三唑-4-甲酸(66 mg，0.26 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (294 mg，0.77 mmol)，且攪拌反應混合物1 h，之後添加25% NH
3水溶液(0.99 mL，6.4 mmol)且繼續攪拌1 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之(2-(4-胺甲醯基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 0.58 min；[M+H]
+= 256.13。
Step 3 : Add 2-(2-((tertiary butoxycarbonyl)amino)ethyl)-2H-1,2,3-triazole-4-carboxylic acid (66 mg, 0.26 mmol) in DMF (1 mL) at room temperature was added HATU (294 mg, 0.77 mmol) and the reaction mixture was stirred for 1 h, after which 25% aqueous NH 3 (0.99 mL, 6.4 mmol) was added and stirring was continued for 1 h. The reaction mixture was directly purified by preparative HPLC (basic) to afford (2-(4-aminoformyl-2H-1,2,3-triazol-2-yl)ethyl)amine as a white solid Tertiary butyl formate. LC-MS B: tR = 0.58 min; [M+H] + = 256.13.
步驟 4 ：向(2-(4-胺甲醯基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯(49 mg，0.19 mmol)於DCM (2 mL)中之室溫溶液中添加柏傑斯試劑(Burgess reagent) (97 mg，0.38 mmol)，且攪拌反應混合物18 h。將反應混合物倒入水中，用DCM稀釋且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (酸性)純化粗產物，得到呈無色油狀之(2-(4-氰基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯。LC-MS B：t
R= 0.80 min；[M+H]
+= 238.14。
Step 4 : Add tertiary-butyl (2-(4-aminoformyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate (49 mg, 0.19 mmol) in DCM ( 2 mL) was added Burgess reagent (97 mg, 0.38 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was poured into water, diluted with DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (acidic) to give (2-(4-cyano-2H-1,2,3-triazol-2-yl)ethyl)carbamate tertiary grade as a colorless oil. butyl ester. LC-MS B: tR = 0.80 min; [M+H] + = 238.14.
步驟 5 ：類似於對於AM-17.1步驟3所描述之程序，由(2-(4-氰基-2H-1,2,3-三唑-2-基)乙基)胺基甲酸三級丁酯製備標題化合物。LC-MS B：t
R= 0.22 min；[M+H]
+= 138.16。
Step 5 : Similar to the procedure described for AM-17.1 Step 3, tertiary butyl (2-(4-cyano-2H-1,2,3-triazol-2-yl)ethyl)carbamate Esters to prepare the title compound. LC-MS B: tR = 0.22 min; [M+H] + = 138.16.
2-(4- 乙炔基 -5- 甲基 -2H-1,2,3- 三唑 -2- 基 ) 乙 -1- 胺 (AM-19.3) 步驟 1 ：向4,5-二溴-2H-1,2,3-三唑(4.0 g，17.6 mmol)於DMF (120 mL)中之0℃溶液中逐份添加NaH於礦物油中之60%分散液(1.48 g，37 mmol)，且將反應混合物升溫至室溫且攪拌30 min，之後冷卻回至0℃。逐份添加N-(2-溴乙基)鄰苯二甲醯亞胺(9.9 g，37 mmol)，且將反應混合物升溫至室溫且攪拌42 h。將反應混合物淬滅至冰水中，且藉由過濾收集沈澱。濾餅用Et
2O洗滌，得到呈白色固體狀之2-(2-(4,5-二溴-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮。LC-MS I：t
R= 0.98 min；無電離。
2-(4- ethynyl -5- methyl -2H-1,2,3- triazol -2- yl ) ethan -1- amine (AM-19.3) step 1 : to 4,5-dibromo-2H - To a 0°C solution of 1,2,3-triazole (4.0 g, 17.6 mmol) in DMF (120 mL) was added a 60% dispersion of NaH in mineral oil (1.48 g, 37 mmol) in portions, and The reaction mixture was warmed to room temperature and stirred for 30 min before cooling back to 0 °C. N-(2-Bromoethyl)phthalimide (9.9 g, 37 mmol) was added portionwise, and the reaction mixture was warmed to room temperature and stirred for 42 h. The reaction mixture was quenched into ice water, and the precipitate was collected by filtration. The filter cake was washed with Et2O to give 2-(2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl)isoindoline- 1,3-diketones. LC-MS I: tR = 0.98 min; no ionization.
步驟 2 ：向2-(2-(4,5-二溴-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮(500 mg，1.25 mmol)及Pd(dppf)Cl
2.DCM (10 mg，0.013 mmol)於二㗁烷(2 mL)中之室溫溶液中逐滴添加ZnMe
2(2 M於PhMe中，0.50 mL，1.0 mmol)，且將反應混合物加熱至70℃並攪拌3 h。真空濃縮反應混合物，且將殘餘物分配於水與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (鹼性)純化粗產物，得到呈白色固體狀之2-(2-(4-溴-5-甲基-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮。LC-MS I：t
R= 0.92 min；無電離。
Step 2 : To 2-(2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl)isoindoline-1,3-dione (500 mg, 1.25 mmol) and Pd(dppf)Cl 2 .DCM (10 mg, 0.013 mmol) in dioxane (2 mL) at room temperature was added dropwise ZnMe 2 (2 M in PhMe, 0.50 mL, 1.0 mmol ), and the reaction mixture was heated to 70 °C and stirred for 3 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (basic) to give 2-(2-(4-bromo-5-methyl-2H-1,2,3-triazol-2-yl)ethane as a white solid base) isoindoline-1,3-dione. LC-MS I: tR = 0.92 min; no ionization.
步驟 3 ：在70℃攪拌2-(2-(4-溴-5-甲基-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮(85 mg，0.25 mmol)、(三級丁基二甲基矽基)乙炔(73 mg，0.51 mmol)、XPhos Pd G2 (20 mg，0.03 mmol)及KOAc (75 mg，0.76 mmol)於DMF (2 mL)中之經脫氣混合物30 min。經由Whatman過濾器過濾反應混合物且藉由製備型HPLC (鹼性)直接純化，得到呈白色固體狀之2-(2-(4-((三級丁基二甲基矽基)乙炔基)-5-甲基-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮。LC-MS I：t
R= 1.32 min；[M+H]
+= 395.29。
Step 3 : Stir 2-(2-(4-bromo-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)isoindoline-1,3-di Ketone (85 mg, 0.25 mmol), (tertiary butyldimethylsilyl) acetylene (73 mg, 0.51 mmol), XPhos Pd G2 (20 mg, 0.03 mmol) and KOAc (75 mg, 0.76 mmol) in DMF (2 mL) for 30 min. The reaction mixture was filtered through a Whatman filter and directly purified by preparative HPLC (basic) to give 2-(2-(4-((tertiarybutyldimethylsilyl)ethynyl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)isoindoline-1,3-dione. LC-MS I: tR = 1.32 min; [M+H] + = 395.29.
步驟 4 ：向2-(2-(4-((三級丁基二甲基矽基)乙炔基)-5-甲基-2H-1,2,3-三唑-2-基)乙基)異吲哚啉-1,3-二酮(32 mg，0.08 mmol)於EtOH (1 mL)中之室溫溶液中添加單水合肼(0.18 mL，2.43 mmol)，且將反應混合物加熱至回流持續2.5 h。將反應混合物冷卻至室溫且添加MeCN。過濾所得懸浮液，且丟棄濾餅。真空濃縮濾液，得到呈黃色油狀之2-(4-((三級丁基二甲基矽基)乙炔基)-5-甲基-2H-1,2,3-三唑-2-基)乙-1-胺。LC-MS I：t
R= 1.14 min；[M+H+MeCN]
+= 306.14。
Step 4 : To 2-(2-(4-((tertiary butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl ) To a room temperature solution of isoindoline-1,3-dione (32 mg, 0.08 mmol) in EtOH (1 mL) was added hydrazine monohydrate (0.18 mL, 2.43 mmol) and the reaction mixture was heated to reflux Lasts 2.5 hours. The reaction mixture was cooled to room temperature and MeCN was added. The resulting suspension was filtered, and the filter cake was discarded. The filtrate was concentrated in vacuo to afford 2-(4-((tertiarybutyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazol-2-yl as a yellow oil ) ethyl-1-amine. LC-MS I: tR = 1.14 min; [M+H+MeCN] + = 306.14.
步驟 5 ：向2-(4-((三級丁基二甲基矽基)乙炔基)-5-甲基-2H-1,2,3-三唑-2-基)乙-1-胺(26 mg，0.1 mmol)於EtOH (0.75 mL)中之室溫溶液中添加1 M NaOH水溶液(0.25 mL，0.25 mmol)，且將反應混合物加熱至60℃持續3 h。在添加水及DCM之前，濃縮反應混合物。分離各層，且水相用DCM (1×)萃取。經合併之有機層經相分離器乾燥且真空濃縮，得到呈黃色油狀之標題化合物。LC-MS I：t
R= 0.51 min；[M+H]
+= 151.22。
Step 5 : To 2-(4-((tertiary butyldimethylsilyl)ethynyl)-5-methyl-2H-1,2,3-triazol-2-yl)eth-1-amine (26 mg, 0.1 mmol) in EtOH (0.75 mL) was added 1 M aqueous NaOH (0.25 mL, 0.25 mmol) and the reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated before adding water and DCM. The layers were separated and the aqueous phase was extracted with DCM (1x). The combined organic layers were dried over a phase separator and concentrated in vacuo to give the title compound as a yellow oil. LC-MS I: tR = 0.51 min; [M+H] + = 151.22.
2-(4- 氟 -3- 甲氧基異㗁唑 -5- 基 ) 乙 -1- 胺鹽酸鹽 (AM-20.1) 步驟 1 ：在微波管中，向
AM-13.1(402 mg，2.25 mmol)及DIPEA (0.47 mL，2.7 mmol)於二㗁烷(12 mL)中之室溫懸浮液中添加鄰苯二甲酸酐(354 mg，2.36 mmol)。將管密封且加熱至100℃持續48 h。向反應混合物中添加水，且混合物用1 M HCl酸化，且產物用EtOAc萃取，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色固體狀之2-(2-(3-甲氧基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(718 mg)，其按原樣用於下一步驟。LC-MS B：t
R=0.85 min；[M+H]
+= 273.09。
2-(4- Fluoro -3- methoxyisoxazol -5- yl ) ethan -1- amine hydrochloride (AM-20.1) Step 1 : In a microwave tube, add AM-13.1 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL) at room temperature was added phthalic anhydride (354 mg, 2.36 mmol). The tube was sealed and heated to 100 °C for 48 h. Water was added to the reaction mixture, and the mixture was acidified with 1 M HCl, and the product was extracted with EtOAc, dried (MgSO 4 ), filtered and concentrated to give 2-(2-(3-methoxyiso (azol-5-yl)ethyl)isoindoline-1,3-dione (718 mg), which was used as such in the next step. LC-MS B: tR = 0.85 min; [M+H] + = 273.09.
步驟 2 ：向2-(2-(3-甲氧基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(710 mg，2.61 mmol)於四亞甲基碸(21.7 mL，226 mmol)中之40℃溶液中添加Selectfluor (1.07 g，2.87 mmol)，且將反應混合物加熱至120℃持續18 h。將所得深棕色溶液冷卻至約50℃，接著將反應混合物倒入預攪拌的H
2O (30 mL)中，隨後倒入EtOAc (10 mL)中。分離兩個層，且無機層用EtOAc (5 mL)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由製備型HPLC (酸性)純化，得到呈無色油狀之2-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(89 mg，12%)。LC-MS B：t
R= 0.90 min；[M+H]
+= 291.02。
Step 2 : To 2-(2-(3-methoxyisozol-5-yl)ethyl)isoindoline-1,3-dione (710 mg, 2.61 mmol) in tetramethylene To a solution of Selectfluor (21.7 mL, 226 mmol) at 40 °C was added Selectfluor (1.07 g, 2.87 mmol) and the reaction mixture was heated to 120 °C for 18 h. The resulting dark brown solution was cooled to about 50 °C and the reaction mixture was poured into pre-stirred H2O (30 mL) followed by EtOAc (10 mL). The two layers were separated, and the inorganic layer was extracted with EtOAc (5 mL). The combined org. layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by preparative HPLC (acidic) afforded 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3 as a colorless oil - Diketones (89 mg, 12%). LC-MS B: tR = 0.90 min; [M+H] + = 291.02.
步驟 3 ：向2-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)異吲哚啉-1,3-二酮(85 mg，0.293 mmol)於EtOH (3 mL)中之室溫溶液中添加單水合肼(0.222 mL，2.93 mmol)，且將反應混合物加熱至80℃持續1 h。將反應混合物冷卻至室溫，且形成白色沈澱。添加乙醚，且濕磨固體(副產物)，之後過濾出。濃縮濾液，得到呈無色油狀之標題化合物
AM-20.1(40 mg，85%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.33 min；[M+H]
+= 161.08。
Step 3 : Add 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.293 mmol) in EtOH To a room temperature solution in (3 mL) hydrazine monohydrate (0.222 mL, 2.93 mmol) was added, and the reaction mixture was heated to 80 °C for 1 h. The reaction mixture was cooled to room temperature and a white precipitate formed. Diethyl ether was added and the solid (by-product) was triturated before being filtered off. The filtrate was concentrated to afford the title compound AM-20.1 (40 mg, 85%) as a colorless oil, which was used as such in the next step. LC-MS B: tR = 0.33 min; [M+H] + = 161.08.
用於合成建構嵌段for the synthesis of building blocks
AA
之通用方法general method
11
(
S)-3-
胺基 -4-((3- 甲氧基苯乙基 ) 胺基 )-4- 側氧基丁酸三級丁酯 (A-1.1) 步驟 1 ：向Fmoc-L-天冬胺酸β-三級丁酯(5.0 g，11.9 mmol)、3-甲氧基苯乙胺(AM-1.4，2.0 g，13.1 mmol)及DIPEA (4.08 mL，23.8 mmol)於DMF (40 mL)中之室溫溶液中添加HATU (4.53 g，11.9 mmol)，且攪拌反應混合物1 h。將反應混合物分配於水與EtOAc之間，且分離各層。水相用EtOAc (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用20%至80% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之(S)-3-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯。LC-MS B：t
R= 1.12 min；[M+H]
+= 545.11。
( S )-3- Amino -4-((3- methoxyphenethyl ) amino )-4- oxobutanoic acid tertiary butyl ester (A-1.1) step 1 : to Fmoc-L- β-tertiary butyl aspartate (5.0 g, 11.9 mmol), 3-methoxyphenethylamine (AM-1.4, 2.0 g, 13.1 mmol) and DIPEA (4.08 mL, 23.8 mmol) in DMF (40 mL) was added HATU (4.53 g, 11.9 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2x), and the combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 20% to 80% EtOAc/heptane) to afford (S)-3-(((( 9H -Fetil-9-yl)methoxy)carbonyl as a white solid )amino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid tertiary butyl ester. LC-MS B: tR = 1.12 min; [M+H] + = 545.11.
步驟 2 ：向(S)-3-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯(5.45 g，9.9 mmol)於DCM (60 mL)中之室溫溶液中添加哌啶(4.95 mL，49.5 mmol)，且攪拌反應混合物2 h。真空濃縮反應混合物，且藉由FC (用100:2:0.5 DCM:MeOH:NH
3溶離)直接純化殘餘物，得到呈無色油狀之標題化合物。LC-MS B：t
R= 0.67 min；[M+H]
+= 323.34。
Step 2 : To (S)-3-(((( 9H -fluorene-9-yl)methoxy)carbonyl)amino)-4-((3-methoxyphenethyl)amino)- To a room temperature solution of tert-butyl 4-oxobutanoate (5.45 g, 9.9 mmol) in DCM (60 mL) was added piperidine (4.95 mL, 49.5 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo, and the residue was directly purified by FC (eluted with 100:2:0.5 DCM:MeOH:NH 3 ) to give the title compound as a colorless oil. LC-MS B: tR = 0.67 min; [M+H] + = 323.34.
下表A-1中列舉類似於上文對於A-1.1描述之2-步驟順序來製備之建構嵌段A。
表 A-1 編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
A-1.2
2-(𠳭唍-7-基)乙-1-胺鹽酸鹽(AM-2.4)
(
S)-3-胺基-4-((2-(𠳭唍-7-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.86
I
349.21
A-1.3
2-(2,3-二氫苯并呋喃-6-基)乙-1-胺鹽酸鹽(AM-2.5)
(
S)-3-胺基-4-((2-(2,3-二氫苯并呋喃-6-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.81
I
335.24
A-1.4
2-(4-溴苯基)乙-1-胺(AM-1.12)
(
S)-3-胺基-4-((4-溴苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.90
I
371.13
A-1.5
2-(2,3,4,5-四氫苯并[b]㗁呯-8-基)乙-1-胺鹽酸鹽(AM-2.21)
(
S)-3-胺基-4-側氧基-4-((2-(2,3,4,5-四氫苯并[b]㗁呯-8-基)乙基)胺基)丁酸三級丁酯
0.93
I
363.21
A-1.6
2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙-1-胺鹽酸鹽(AM-2.6)
(
S)-3-胺基-4-((2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.66
B
351.47
A-1.7
2-(4-(2H-1,2,3-三唑-2-基)苯基)乙-1-胺鹽酸鹽(AM2.7)
(
S)-4-((4-(2H-1,2,3-三唑-2-基)苯乙基)胺基)-3-胺基-4-側氧基丁酸三級丁酯
0.69
B
360.45
A-1.8
2-(3-甲基異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-1.40)
(
S)-3-胺基-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.64
I
298.26
A-1.9
2-(3-溴苯基)乙-1-胺
(
S)-3-胺基-4-((3-溴苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.73
B
371.36
A-1.10
2-(3-(二氟甲氧基)苯基)乙-1-胺(AM-1.57)
(
S)-3-胺基-4-((3-(二氟甲氧基)苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.73
B
359.45
A-1.11
2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙-1-胺(AM-1.49)
(
S)-3-胺基-4-((2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.64
B
340.15
A-1.12
2-(3-乙氧基苯基)乙-1-胺(AM-1.58)
(
S)-3-胺基-4-((3-乙氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.90
I
337.25
A-1.13
(
RS)-2-(5,5-二甲基四氫-2H-哌喃-2-基)乙-1-胺(AM-1.59)
(
S)-3-胺基-4-((2-((
RS)-5,5-二甲基四氫-2H-哌喃-2-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.88
I
329.27
A-1.14
2-(苯并[d][1,3]二氧呃-5-基)乙-1-胺鹽酸鹽
(
S)-3-胺基-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.67
B
337.20
A-1.15
2-(3,5-二甲氧基苯基)乙-1-胺(AM-1.7)
(
S)-3-胺基-4-((3,5-二甲氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.69
B
353.20
A-1.16
2-(苯并[d]㗁唑-2-基)乙-1-胺鹽酸鹽(AM-1.3)
(
S)-3-胺基-4-((2-(苯并[d]㗁唑-2-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.65
B
334.35
A-1.17
2-(3-(2H-1,2,3-三唑-2-基)苯基)乙-1-胺鹽酸鹽(AM-2.8)
(
S)-4-((3-(2H-1,2,3-三唑-2-基)苯乙基)胺基)-3-胺基-4-側氧基丁酸三級丁酯
0.69
B
360.51
A-1.18
2-(5-環丙基異㗁唑-3-基)乙-1-胺(AM-1.33)
(
S)-3-胺基-4-((2-(5-環丙基異㗁唑-3-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.76
I
324.27
A-1.19
2-(5-環丙基-1,2,4-㗁二唑-3-基)乙-1-胺鹽酸鹽(AM-1.26)
(
S)-3-胺基-4-((2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.70
I
325.31
A-1.20
2-(2,6-二氟苯基)乙-1-胺(AM-1.22)
(
S)-3-胺基-4-((2,6-二氟苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.87
I
329.26
A-1.21
2-(4-(嘧啶-2-基)苯基)乙-1-胺鹽酸鹽(AM-2.12)
(
S)-3-胺基-4-側氧基-4-((4-(嘧啶-2-基)苯乙基)胺基)丁酸三級丁酯
0.66
B
371.22
A-1.22
2-(3-環丙基-1,2,4-㗁二唑-5-基)乙-1-胺鹽酸鹽(AM-1.35)
(
S)-3-胺基-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.72
I
325.29
A-1.23
2-(3-(甲氧基-d3)苯基)乙-1-胺(AM-3.2)
(
S)-3-胺基-4-((3-(甲氧基-d3)苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.82
I
326.33
A-1.24
2-(3-環丙基異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-5.2)
(
S)-3-胺基-4-((2-(3-環丙基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.73
I
324.31
A-1.25
4-乙基苯乙胺(AM-1.10)
(
S)-3-胺基-4-((4-乙基苯乙基)胺基)-4-側氧基丁酸三級丁酯
0.98
I
321.38
A-1.26
2-(3-(1,1-二氟乙基)苯基)乙-1-胺(AM-2.22)
(
S)-3-胺基-4-((3-(1,1-二氟乙基)苯乙基)胺基)-4-側氧基丁酸三級丁酯
2.0
J
357.1
A-1.27
2-(3-(嘧啶-2-基)苯基)乙-1-胺二鹽酸鹽(AM-2.11)
(S)-3-胺基-4-側氧基-4-((3-(嘧啶-2-基)苯乙基)胺基)丁酸三級丁酯
0.66
B
371.23
A-1.28
2-(3-甲氧基異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-13.1)
(
S)-3-胺基-4-((2-(3-甲氧基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.68
I
314.36
A-1.29
2-(3-(甲氧基-d3)異㗁唑-5-基)乙-1-胺鹽酸鹽(AM-13.2)
(
S)-3-胺基-4-((2-(3-(甲氧基-d3)異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.67
I
317.39
A-1.30
2-(2-環丙基-2H-1,2,3-三唑-4-基)乙-1-胺鹽酸鹽(AM-2.23)
(S)-3-胺基-4-((2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.69
I
324.36
A-1.31
2-(3-(三氟甲基)異㗁唑-5-基)乙-1-胺(AM-1.84)
(
S)-3-胺基-4-側氧基-4-((2-(3-(三氟甲基)異㗁唑-5-基)乙基)胺基)丁酸三級丁酯
0.85
I
352.23
A-1.32
2-(3-(二氟甲基)異㗁唑-5-基)乙-1-胺(AM-5.3)
(
S)-3-胺基-4-((2-(3-(二氟甲基)異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.75
I
334.32
A-1.33
丁-3-炔-1-胺鹽酸鹽(AM-1.86)
(
S)-3-胺基-4-(丁-3-炔-1-基胺基)-4-側氧基丁酸三級丁酯
1.63
J
185.1
(-
t Bu)
A-1.34
3-胺基丙酸苯甲酯4-甲基苯磺酸鹽(AM-1.87)
(
S)-3-胺基-4-((3-(苯甲氧基)-3-側氧基丙基)胺基)-4-側氧基丁酸三級丁酯
1.84
J
351.2
A-1.35 (
S)-2-胺基-1-苯基乙-1-醇(AM-1.88)
(
S)-3-胺基-4-(((
S)-2-羥基-2-苯基乙基)胺基)-4-側氧基丁酸三級丁酯
0.70
I
309.31
A-1.36 2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙-1-胺鹽酸鹽(AM-18.1)
(
S)-3-胺基-4-((2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.62
I
315.44
A-1.37 2-(5-環丙基-2
H-四唑-2-基)乙-1-胺鹽酸鹽(AM-16.2)
(
S)-3-胺基-4-((2-(5-環丙基-2H-四唑-2-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.96
I
325.47
A-1.38 2-(4-環丙基-2
H-1,2,3-三唑-2-基)乙-1-胺鹽酸鹽(AM-19.1)
(
S)-3-胺基-4-((2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.59
B
324.03
A-1.39 2-胺基-1-(3-環丙基-1,2,4-㗁二唑-5-基)乙-1-醇(AM-1.90)
(
S)-3-胺基-4-(((
R)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)胺基)-4-側氧基丁酸三級丁酯
(在F-moc去保護之前進行對掌性分離)
0.53
A
341.28
A-1.40 2-胺基-1-(3-環丙基-1,2,4-㗁二唑-5-基)乙-1-醇(AM-1.90)
(
S)-3-胺基-4-(((
S)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)胺基)-4-側氧基丁酸三級丁酯
(在F-moc去保護之前進行對掌性分離)
0.53
A
341.23
A-1.41 2-(2
H-苯并[d][1,2,3]三唑-2-基)乙-1-胺(AM-1.91)
(
S)-4-((2-(2
H-苯并[d][1,2,3]三唑-2-基)乙基)胺基)-3-胺基-4-側氧基丁酸三級丁酯
0.61
A
334.26
A-1.42 3-(三氟甲氧基)丙-1-胺(AM-1.92)
(
S)-3-胺基-4-側氧基-4-((3-(三氟甲氧基)丙基)胺基)丁酸三級丁酯
0.63
A
315.24
A-1.43 3-(二氟甲氧基)丙-1-胺(AM-1.45)
(
S)-3-胺基-4-((3-(二氟甲氧基)丙基)胺基)-4-側氧基丁酸三級丁酯
0.59
A
297.28
A-1.44 2-([1,2,4]三唑并[1,5-a]嘧啶-2-基)乙-1-胺(AM-1.93)
(S)-4-((2-([1,2,4]三唑并[1,5-a]嘧啶-2-基)乙基)胺基)-3-胺基-4-側氧基丁酸三級丁酯
0.46
A
335.33
A-1.45 2-(1-(2-甲氧基乙基)-1
H-吡唑-4-基)乙-1-胺(AM-1.94)
(
S)-3-胺基-4-((2-(1-(2-甲氧基乙基)-1
H-吡唑-4-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.53
A
341.31
A-1.46 2-(4-氟-3-甲氧基異㗁唑-5-基)乙-1-胺鹽酸鹽
(AM-20.1)
(
S)-3-胺基-4-((2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯
0.71
I
332.50
Listed in Table A-1 below are building blocks A prepared analogously to the 2-step sequence described above for A-1.1. Table A-1 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
A-1.2 2-(𠳭唍-7-yl)ethan-1-amine hydrochloride (AM-2.4) ( S )-3-Amino-4-((2-(𠳭唍-7-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.86I 349.21
A-1.3 2-(2,3-Dihydrobenzofuran-6-yl)ethan-1-amine hydrochloride (AM-2.5) ( S )-3-Amino-4-((2-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.81I 335.24
A-1.4 2-(4-Bromophenyl)ethan-1-amine (AM-1.12) ( S )-3-Amino-4-((4-bromophenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.90I 371.13
A-1.5 2-(2,3,4,5-Tetrahydrobenzo[b]oxan-8-yl)ethan-1-amine hydrochloride (AM-2.21) ( S) -3-amino-4-oxo-4-((2-(2,3,4,5-tetrahydrobenzo[b]oxan-8-yl)ethyl)amino) Tertiary butyl butyrate 0.93 I 363.21
A-1.6 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine hydrochloride (AM-2.6) ( S )-3-amino-4-((2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)amino)- Tertiary butyl 4-oxobutyrate 0.66 B 351.47
A-1.7 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-amine hydrochloride (AM2.7) ( S )-4-((4-(2H-1,2,3-triazol-2-yl)phenethyl)amino)-3-amino-4-oxobutanoic acid tertiary butyl ester 0.69 B 360.45
A-1.8 2-(3-Methylisozol-5-yl)ethan-1-amine hydrochloride (AM-1.40) ( S )-3-Amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.64I 298.26
A-1.9 2-(3-Bromophenyl)ethan-1-amine ( S )-3-Amino-4-((3-bromophenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.73 B 371.36
A-1.10 2-(3-(Difluoromethoxy)phenyl)ethan-1-amine (AM-1.57) ( S )-3-Amino-4-((3-(difluoromethoxy)phenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.73 B 359.45
A-1.11 2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)ethan-1-amine (AM-1.49) ( S )-3-Amino-4-((2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.64 B 340.15
A-1.12 2-(3-ethoxyphenyl)ethan-1-amine (AM-1.58) ( S )-3-Amino-4-((3-ethoxyphenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.90I 337.25
A-1.13 ( RS )-2-(5,5-Dimethyltetrahydro-2H-pyran-2-yl)ethan-1-amine (AM-1.59) ( S )-3-amino-4-((2-(( RS )-5,5-dimethyltetrahydro-2H-pyran-2-yl)ethyl)amino)-4-oxo tertiary butyl butyrate 0.88 I 329.27
A-1.14 2-(Benzo[d][1,3]dioxer-5-yl)ethan-1-amine hydrochloride ( S )-3-amino-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary Butyl ester 0.67 B 337.20
A-1.15 2-(3,5-dimethoxyphenyl)ethan-1-amine (AM-1.7) ( S )-3-Amino-4-((3,5-dimethoxyphenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.69 B 353.20
A-1.16 2-(Benzo[d]oxazol-2-yl)ethan-1-amine hydrochloride (AM-1.3) ( S )-3-Amino-4-((2-(benzo[d]oxazol-2-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.65 B 334.35
A-1.17 2-(3-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-amine hydrochloride (AM-2.8) ( S )-4-((3-(2H-1,2,3-triazol-2-yl)phenethyl)amino)-3-amino-4-oxobutanoic acid tertiary butyl ester 0.69 B 360.51
A-1.18 2-(5-Cyclopropylisozazol-3-yl)ethan-1-amine (AM-1.33) ( S )-3-Amino-4-((2-(5-cyclopropylisoxazol-3-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.76 I 324.27
A-1.19 2-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)ethan-1-amine hydrochloride (AM-1.26) ( S )-3-amino-4-((2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.70I 325.31
A-1.20 2-(2,6-Difluorophenyl)ethan-1-amine (AM-1.22) ( S )-3-Amino-4-((2,6-difluorophenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.87I 329.26
A-1.21 2-(4-(pyrimidin-2-yl)phenyl)ethan-1-amine hydrochloride (AM-2.12) ( S )-3-Amino-4-oxo-4-((4-(pyrimidin-2-yl)phenethyl)amino)butanoic acid tertiary butyl ester 0.66 B 371.22
A-1.22 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (AM-1.35) ( S )-3-amino-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.72I 325.29
A-1.23 2-(3-(Methoxy-d3)phenyl)ethan-1-amine (AM-3.2) ( S )-3-Amino-4-((3-(methoxy-d3)phenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.82I 326.33
A-1.24 2-(3-Cyclopropylisozol-5-yl)ethan-1-amine hydrochloride (AM-5.2) ( S )-3-Amino-4-((2-(3-cyclopropylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.73I 324.31
A-1.25 4-Ethylphenethylamine (AM-1.10) ( S )-3-Amino-4-((4-ethylphenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.98 I 321.38
A-1.26 2-(3-(1,1-difluoroethyl)phenyl)ethan-1-amine (AM-2.22) ( S )-3-Amino-4-((3-(1,1-difluoroethyl)phenethyl)amino)-4-oxobutanoic acid tertiary butyl ester 2.0J 357.1
A-1.27 2-(3-(Pyrimidin-2-yl)phenyl)ethan-1-amine dihydrochloride (AM-2.11) (S)-3-Amino-4-oxo-4-((3-(pyrimidin-2-yl)phenethyl)amino)butanoic acid tertiary butyl ester 0.66 B 371.23
A-1.28 2-(3-Methoxyisozazol-5-yl)ethan-1-amine hydrochloride (AM-13.1) ( S )-3-Amino-4-((2-(3-methoxyisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.68 I 314.36
A-1.29 2-(3-(Methoxy-d3)isozazol-5-yl)ethan-1-amine hydrochloride (AM-13.2) ( S )-3-amino-4-((2-(3-(methoxy-d3)isoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.67I 317.39
A-1.30 2-(2-Cyclopropyl-2H-1,2,3-triazol-4-yl)ethan-1-amine hydrochloride (AM-2.23) (S)-3-amino-4-((2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)amino)-4-oxobutane tertiary butyl acid 0.69 I 324.36
A-1.31 2-(3-(Trifluoromethyl)isozazol-5-yl)ethan-1-amine (AM-1.84) ( S )-3-Amino-4-oxo-4-((2-(3-(trifluoromethyl)isoxazol-5-yl)ethyl)amino)butanoic acid tertiary butyl ester 0.85I 352.23
A-1.32 2-(3-(Difluoromethyl)isozazol-5-yl)ethan-1-amine (AM-5.3) ( S )-3-amino-4-((2-(3-(difluoromethyl)isozazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.75I 334.32
A-1.33 But-3-yn-1-amine hydrochloride (AM-1.86) ( S )-3-Amino-4-(but-3-yn-1-ylamino)-4-oxobutanoic acid tertiary butyl ester 1.63J 185.1 ( -t Bu)
A-1.34 Benzyl 3-aminopropionate 4-methylbenzenesulfonate (AM-1.87) ( S )-3-Amino-4-((3-(Benzyloxy)-3-oxopropyl)amino)-4-oxobutanoic acid tertiary butyl ester 1.84J 351.2
A-1.35 ( S )-2-Amino-1-phenylethan-1-ol (AM-1.88) ( S )-3-Amino-4-((( S )-2-hydroxy-2-phenylethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.70I 309.31
A-1.36 2-(3-Methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (AM-18.1) ( S )-3-amino-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.62I 315.44
A-1.37 2-(5-Cyclopropyl- 2H -tetrazol-2-yl)ethan-1-amine hydrochloride (AM-16.2) ( S )-3-Amino-4-((2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.96 I 325.47
A-1.38 2-(4-Cyclopropyl- 2H -1,2,3-triazol-2-yl)ethan-1-amine hydrochloride (AM-19.1) ( S )-3-amino-4-((2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)amino)-4-oxobutane tertiary butyl acid 0.59 B 324.03
A-1.39 2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-ol (AM-1.90) ( S )-3-amino-4-((( R )-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxyethyl)amino) - tertiary butyl 4-oxobutanoate (chiral separation prior to F-moc deprotection) 0.53A 341.28
A-1.40 2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-ol (AM-1.90) ( S )-3-amino-4-((( S )-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxyethyl)amino) - tertiary butyl 4-oxobutanoate (chiral separation prior to F-moc deprotection) 0.53A 341.23
A-1.41 2-( 2H -Benzo[d][1,2,3]triazol-2-yl)ethan-1-amine (AM-1.91) ( S )-4-((2-(2 H -benzo[d][1,2,3]triazol-2-yl)ethyl)amino)-3-amino-4-oxo Tertiary butyl butyrate 0.61A 334.26
A-1.42 3-(Trifluoromethoxy)propan-1-amine (AM-1.92) ( S )-3-Amino-4-oxo-4-((3-(trifluoromethoxy)propyl)amino)butanoic acid tertiary butyl ester 0.63A 315.24
A-1.43 3-(Difluoromethoxy)propan-1-amine (AM-1.45) ( S )-3-Amino-4-((3-(difluoromethoxy)propyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.59A 297.28
A-1.44 2-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethan-1-amine (AM-1.93) (S)-4-((2-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethyl)amino)-3-amino-4-oxo tertiary butyl butyrate 0.46A 335.33
A-1.45 2-(1-(2-methoxyethyl)-1 H -pyrazol-4-yl)ethan-1-amine (AM-1.94) ( S )-3-amino-4-((2-(1-(2-methoxyethyl)-1 H -pyrazol-4-yl)ethyl)amino)-4-oxo Tertiary butyl butyrate 0.53A 341.31
A-1.46 2-(4-Fluoro-3-methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM-20.1) ( S )-3-amino-4-((2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester 0.71I 332.50
用於合成建構嵌段for the synthesis of building blocks
AA
之通用方法general method
22
L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(A-2.1)
步驟 1 ：向Boc-L-天冬胺酸-β-烯丙酯(5.0 g，17.7 mmol)及KHCO
3(1.8 g，17.7 mmol)於DMF (30 mL)中之室溫混合物中添加溴甲苯(2.15 mL，17.7 mmol)，且攪拌反應混合物16 h。真空濃縮反應混合物，且將殘餘物分配於H
2O與EtOAC之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之(三級丁氧基羰基)-L-天冬胺酸4-烯丙酯1-苯甲酯。LC-MS B：t
R= 1.01 min；[M+H]
+= 364.45。
L-aspartic acid 4-allyl ester 1-benzyl ester hydrochloride (A-2.1) step 1 : add Boc-L-aspartic acid-β-allyl ester (5.0 g, 17.7 mmol) and To a room temperature mixture of KHCO3 (1.8 g, 17.7 mmol) in DMF (30 mL) was added bromotoluene (2.15 mL, 17.7 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and EtOAC and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give (tertiary butoxycarbonyl) -L -aspartic acid 4-allyl ester 1- Benzyl esters. LC-MS B: tR = 1.01 min; [M+H] + = 364.45.
步驟 2 ：向(三級丁氧基羰基)-L-天冬胺酸4-烯丙酯1-苯甲酯(6.43 g，17.7 mmol)於二㗁烷(40 mL)中之溶液中添加含4M HCl之二㗁烷(17.7 mL，71 mmol)，且在室溫攪拌反應混合物5 h。真空移除揮發物，且殘餘物用Et
2O濕磨，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 0.61 min；[M+H]
+= 264.34。
Step 2 : To a solution of (tertiary butoxycarbonyl)-L-aspartic acid 4-allyl ester 1-benzyl ester (6.43 g, 17.7 mmol) in dioxane (40 mL) was added 4M HCl dioxane (17.7 mL, 71 mmol), and the reaction mixture was stirred at room temperature for 5 h. The volatiles were removed in vacuo, and the residue was triturated with Et2O to give the title compound as a white solid. LC-MS B: tR = 0.61 min; [M+H] + = 264.34.
(
S)-3-胺基-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽(A-2.2)
步驟 1 ：類似於對於A-1.1步驟1所描述之程序，由(S)-4-(烯丙氧基)-2-((三級丁氧基羰基)胺基)-4-側氧基丁酸製備(
S)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-3-((三級丁氧基羰基)胺基)-4-側氧基丁酸烯丙酯。LC-MS B：t
R= 0.94 min；[M+H]
+= 421.16。
( S )-3-amino-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-4-oxobutanoic acid allyl Ester hydrochloride (A-2.2) step 1 : similar to the procedure described for A-1.1 step 1, from (S)-4-(allyloxy)-2-((tertiary butoxycarbonyl) Amino)-4-oxobutanoic acid preparation ( S )-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-3- Allyl ((tertiary butoxycarbonyl)amino)-4-oxobutanoate. LC-MS B: tR = 0.94 min; [M+H] + = 421.16.
步驟 2 ：類似於對於A-2.1步驟2所描述之程序，由(S)-4-(烯丙氧基)-2-((三級丁氧基羰基)胺基)-4-側氧基丁酸製備標題化合物。LC-MS B：t
R= 0.61 min；[M+H]
+= 321.20。
Step 2 : Similar to the procedure described for A-2.1 Step 2, from (S)-4-(allyloxy)-2-((tertiary butoxycarbonyl)amino)-4-oxo Butyric acid to prepare the title compound. LC-MS B: tR = 0.61 min; [M+H] + = 321.20.
下表A-2中列舉類似於上文對於A-2.2描述之2-步驟順序來製備之建構嵌段A。
表A-2
編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
A-2.3
(
S)-4-(烯丙氧基)-2-((三級丁氧基羰基)胺基)-4-側氧基丁酸
(
S)-3-胺基-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽
0.74
I
307.21
A-2.4
(
S)-4-(烯丙氧基)-2-((三級丁氧基羰基)胺基)-4-側氧基丁酸
(
S)-3-胺基-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽
0.57
I
282.21
Listed in Table A-2 below are building blocks A prepared analogously to the 2-step sequence described above for A-2.2. Table A-2 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
A-2.3 ( S )-4-(allyloxy)-2-((tertiary butoxycarbonyl)amino)-4-oxobutanoic acid ( S )-3-Amino-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl hydrochloride 0.74I 307.21
A-2.4 ( S )-4-(allyloxy)-2-((tertiary butoxycarbonyl)amino)-4-oxobutanoic acid ( S )-3-Amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid allyl hydrochloride 0.57I 282.21
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
11
(
R)-2-(2-胺基-3-苯基丙氧基)-4,6-二甲氧基苯甲酸苯甲酯鹽酸鹽(B-1.1)
步驟 1 ：向2-羥基-4,6-二甲氧基苯甲酸(3 g，14.4 mmol)於DMF (40 mL)中之溶液中添加KHCO
3(1.6 g，15.8 mmol)及溴甲苯(2.1 mL，17.3 mmol)，且攪拌反應混合物16 h。過濾反應混合物且真空濃縮濾液。將殘餘物分配於水與EtOAc之間且萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用5%至40% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之2-羥基-4,6-二甲氧基苯甲酸苯甲酯。LC-MS B：t
R= 1.04 min；[M+H]
+= 289.23。
( R )-2-(2-Amino-3-phenylpropoxy)-4,6-dimethoxybenzoic acid benzyl ester hydrochloride (B-1.1) step 1 : to 2-hydroxy- To a solution of 4,6-dimethoxybenzoic acid (3 g, 14.4 mmol) in DMF (40 mL) was added KHCO 3 (1.6 g, 15.8 mmol) and bromotoluene (2.1 mL, 17.3 mmol) and stirred The reaction mixture was 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 5% to 40% EtOAc/heptane) to afford benzyl 2-hydroxy-4,6-dimethoxybenzoate as a white solid. LC-MS B: tR = 1.04 min; [M+H] + = 289.23.
步驟 2 ：向2-羥基-4,6-二甲氧基苯甲酸酯(3.16 g，10.7 mmol)、(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯(4.12 g，16.1 mmol)及PPh
3(4.27 g，16.1 mmol)於THF (40 mL)中之0℃混合物中添加DIAD (3.0 mL，15 mmol)，且在室溫攪拌反應混合物16 h。濃縮混合物，且藉由FC (用20%至100% EtOAc/庚烷溶離)直接純化殘餘物，得到呈無色油狀之(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4,6-二甲氧基苯甲酸苯甲酯。LC-MS B：t
R= 1.16 min；[M+H]
+= 522.26。
Step 2 : To 2-hydroxy-4,6-dimethoxybenzoate (3.16 g, 10.7 mmol), ( R )-(1-hydroxy-3-phenylpropan-2-yl)carbamate To a mixture of tertiary butyl ester (4.12 g, 16.1 mmol) and PPh3 (4.27 g, 16.1 mmol) in THF (40 mL) at 0 °C was added DIAD (3.0 mL, 15 mmol) and the reaction mixture was stirred at room temperature 16 h. The mixture was concentrated and the residue was directly purified by FC (eluted with 20% to 100% EtOAc/heptane) to afford ( R )-2-(2-((tertiary butoxycarbonyl)amine as a colorless oil phenyl)-3-phenylpropoxy)-4,6-dimethoxybenzoic acid benzyl ester. LC-MS B: tR = 1.16 min; [M+H] + = 522.26.
步驟 3 ：向(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4,6-二甲氧基苯甲酸苯甲酯(4.64 g，8.63 mmol)於二㗁烷(40 mL)中之溶液中添加含4M HCl之二㗁烷(21 mL，86.3 mmol)，且在室溫攪拌反應混合物5 h。真空移除揮發物，且殘餘物用Et
2O (3×)濕磨，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 0.84 min；[M+H]
+= 422.36。
Step 3 : To ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-4,6-dimethoxybenzoic acid benzyl ester (4.64 g, 8.63 mmol) in dioxane (40 mL) was added 4M HCl in dioxane (21 mL, 86.3 mmol), and the reaction mixture was stirred at room temperature for 5 h. The volatiles were removed in vacuo, and the residue was triturated with Et2O (3x) to give the title compound as a white solid. LC-MS B: tR = 0.84 min; [M+H] + = 422.36.
下表B-1中列舉類似於上文對於B-1.1描述之3-步驟順序製備之建構嵌段B。在鹽酸鹽具有高度吸濕性之情況下，使胺經受鹼性處理以釋放其游離鹼。
表B-1
編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
B-1.2
2-羥基-6-甲基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-6-甲基苯甲酸苯甲酯
2.28
J
376.2
B-1.3
2-羥基-5-甲基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-5-甲基苯甲酸苯甲酯
1.83
F
376.2
B-1.4
2-羥基-4-甲基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-4-甲基苯甲酸苯甲酯
1.83
F
376.2
B-1.5
2-羥基-6-甲氧基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-6-甲氧基苯甲酸苯甲酯鹽酸鹽
1.06
I
392.14
B-1.6
2-羥基-5-甲氧基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-5-甲氧基苯甲酸苯甲酯
2.26
J
392.2
B-1.7
2-羥基-4-甲氧基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-4-甲氧基苯甲酸苯甲酯
2.88
F
392.2
B-1.8
5-氯-2-羥基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-5-氯苯甲酸苯甲酯
1.80
F
396.1
B-1.9
5-氟-2-羥基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-5-氟苯甲酸苯甲酯
2.29
J
380.2
B-1.10
4-羥基-6-甲基菸鹼酸
(
R)-4-(2-胺基-3-苯基丙氧基)-6-甲基菸鹼酸苯甲酯二鹽酸鹽
2.08
J
377.1
B-1.11
2-羥基-4,5-二甲氧基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-4,5-二甲氧基苯甲酸苯甲酯
1.75
F
422.2
B-1.12
3-羥基-2-萘甲酸
(
R)-3-(2-胺基-3-苯基丙氧基)-2-萘甲酸苯甲酯鹽酸鹽
1.83
F
412.2
B-1.13
2-羥基-1-萘甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-1-萘甲酸苯甲酯鹽酸鹽
0.88
B
412.37
B-1.14
3-羥基喹啉-4-甲酸
(
R)-3-(2-胺基-3-苯基丙氧基)喹啉-4-甲酸苯甲酯二鹽酸鹽
0.83
B
413.34
B-1.16
6-羥基-2H-1,3-苯并二氧呃-5-甲酸
(
R)-6-(2-胺基-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸苯甲酯鹽酸鹽
0.84
B
406.13
B-1.19
6-氟-3-羥基喹啉-4-甲酸
(
R)-3-(2-胺基-3-苯基丙氧基)-6-氟喹啉-4-甲酸苯甲酯二鹽酸鹽
1.12
I
431.24
B-1.20
8-氟-3-羥基喹啉-4-甲酸
(
R)-3-(2-胺基-3-苯基丙氧基)-8-氟喹啉-4-甲酸苯甲酯二鹽酸鹽
0.83
B
431.19
B-1.21
2-氟-6-羥基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-6-氟苯甲酸苯甲酯鹽酸鹽
0.83
B
380.15
B-1.22
2-羥基-4-甲氧基苯甲酸
(
R)-2-(2-胺基-3-苯基丙氧基)-4-甲氧基苯甲酸苯甲酯鹽酸鹽
0.87
B
392.27
B-1.23
3-羥基喹啉-4-甲酸
(
S)-3-(2-胺基-3-苯基丙氧基)喹啉-4-甲酸苯甲酯二鹽酸鹽
1.07
I
413.24
B-1.26
6-氯-3-羥基喹啉-4-甲酸
(
R)-3-(2-胺基-3-苯基丙氧基)-6-氯喹啉-4-甲酸苯甲酯二鹽酸鹽
0.94
D
447.09
Listed in Table B-1 below are building blocks B prepared in a 3-step sequence analogous to that described above for B-1.1. In the case of hydrochlorides which are highly hygroscopic, the amine is subjected to alkaline treatment to release its free base. Table B-1 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
B-1.2 2-Hydroxy-6-methylbenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-6-methylbenzoic acid benzyl ester 2.28J 376.2
B-1.3 2-Hydroxy-5-methylbenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-5-methylbenzoic acid benzyl ester 1.83 F 376.2
B-1.4 2-Hydroxy-4-methylbenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-4-methylbenzoic acid benzyl ester 1.83 F 376.2
B-1.5 2-Hydroxy-6-methoxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-6-methoxybenzoic acid benzyl ester hydrochloride 1.06 I 392.14
B-1.6 2-Hydroxy-5-methoxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-5-methoxybenzoic acid benzyl ester 2.26J 392.2
B-1.7 2-Hydroxy-4-methoxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-4-methoxybenzoic acid benzyl ester 2.88 F 392.2
B-1.8 5-chloro-2-hydroxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-5-chlorobenzoic acid benzyl ester 1.80F 396.1
B-1.9 5-fluoro-2-hydroxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-5-fluorobenzoic acid benzyl ester 2.29J 380.2
B-1.10 4-Hydroxy-6-methylnicotinic acid ( R )-4-(2-Amino-3-phenylpropoxy)-6-methylnicotinic acid benzyl ester dihydrochloride 2.08J 377.1
B-1.11 2-Hydroxy-4,5-dimethoxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-4,5-dimethoxybenzoic acid benzyl ester 1.75F 422.2
B-1.12 3-Hydroxy-2-naphthoic acid ( R )-3-(2-Amino-3-phenylpropoxy)-2-naphthoic acid benzyl hydrochloride 1.83 F 412.2
B-1.13 2-Hydroxy-1-naphthoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-1-naphthoic acid benzyl hydrochloride 0.88 B 412.37
B-1.14 3-Hydroxyquinoline-4-carboxylic acid ( R )-3-(2-Amino-3-phenylpropoxy)quinoline-4-carboxylic acid benzyl ester dihydrochloride 0.83 B 413.34
B-1.16 6-Hydroxy-2H-1,3-benzodioxer-5-carboxylic acid ( R )-6-(2-Amino-3-phenylpropoxy)benzo[d][1,3]dioxer-5-carboxylic acid benzyl ester hydrochloride 0.84 B 406.13
B-1.19 6-fluoro-3-hydroxyquinoline-4-carboxylic acid ( R )-3-(2-Amino-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylic acid benzyl ester dihydrochloride 1.12 I 431.24
B-1.20 8-fluoro-3-hydroxyquinoline-4-carboxylic acid ( R )-3-(2-Amino-3-phenylpropoxy)-8-fluoroquinoline-4-carboxylic acid benzyl ester dihydrochloride 0.83 B 431.19
B-1.21 2-fluoro-6-hydroxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-6-fluorobenzoic acid benzyl ester hydrochloride 0.83 B 380.15
B-1.22 2-Hydroxy-4-methoxybenzoic acid ( R )-2-(2-Amino-3-phenylpropoxy)-4-methoxybenzoic acid benzyl ester hydrochloride 0.87 B 392.27
B-1.23 3-Hydroxyquinoline-4-carboxylic acid ( S )-3-(2-Amino-3-phenylpropoxy)quinoline-4-carboxylic acid benzyl ester dihydrochloride 1.07 I 413.24
B-1.26 6-Chloro-3-hydroxyquinoline-4-carboxylic acid ( R )-3-(2-Amino-3-phenylpropoxy)-6-chloroquinoline-4-carboxylic acid benzyl ester dihydrochloride 0.94D 447.09
(
R)-2-(2-胺基-3-苯基丙氧基)-6-乙氧基苯甲酸苯甲酯鹽酸鹽(B-1.17)
步驟 1 ：向2,6-二羥基苯甲酸(1.0 g，6.3 mmol)及NaHCO
3(582 mg，6.9 mmol)於DMF (16 mL)中之室溫混合物中添加溴甲苯(0.92 mL，7.6 mmol)，且將反應混合物加熱至60℃持續6 h。將反應混合物分配於水與EtOAc之間且萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至10% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之2,6-二羥基苯甲酸苯甲酯。LC-MS B：t
R= 0.98 min；[M+H]
+= 245.35。
( R )-2-(2-amino-3-phenylpropoxy)-6-ethoxybenzoic acid benzyl hydrochloride (B-1.17) step 1 : to 2,6-dihydroxybenzene To a room temperature mixture of formic acid (1.0 g, 6.3 mmol) and NaHCO3 (582 mg, 6.9 mmol) in DMF (16 mL) was added bromotoluene (0.92 mL, 7.6 mmol) and the reaction mixture was heated to 60 °C for 6 h. The reaction mixture was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 10% EtOAc/heptane) to afford benzyl 2,6-dihydroxybenzoate as a colorless oil. LC-MS B: tR = 0.98 min; [M+H] + = 245.35.
步驟 2 ：向2,6-二羥基苯甲酸苯甲酯(376 mg，1.1 mmol)及Cs
2CO
3(351 mg，1.1 mmol)於DMF (15 mL)中之室溫混合物中添加碘乙烷(0.086 mL，1.1 mmol)，且攪拌反應混合物16 h。將反應混合物分配於水與EtOAc之間，且分離各層。水相用EtOAc (2×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至10% EtOAc/庚烷溶離)純化粗產物，得到呈黃色固體狀之2-乙氧基-6-羥基苯甲酸苯甲酯。LC-MS B：t
R= 1.01 min；[M+H]
+= 273.29。
Step 2 : To a room temperature mixture of benzyl 2,6-dihydroxybenzoate (376 mg, 1.1 mmol) and Cs2CO3 (351 mg, 1.1 mmol) in DMF (15 mL) was added iodoethane (0.086 mL, 1.1 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2x ) , and the combined org. layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 10% EtOAc/heptane) to afford benzyl 2-ethoxy-6-hydroxybenzoate as a yellow solid. LC-MS B: tR = 1.01 min; [M+H] + = 273.29.
步驟 3-4 ：按照對於B-1.1所描述之步驟2及3，由2-乙氧基-6-羥基苯甲酸苯甲酯製備標題化合物。LC-MS B：t
R= 0.85 min；[M+H]
+= 406.40。
Step 3-4 : The title compound was prepared from benzyl 2-ethoxy-6-hydroxybenzoate following steps 2 and 3 described for B-1.1. LC-MS B: tR = 0.85 min; [M+H] + = 406.40.
(
R)-4-(2-胺基-3-苯基丙氧基)-2-甲氧基菸鹼酸苯甲酯(B-1.18)
步驟 1 ：向4-羥基-2-甲氧基菸鹼酸(452 mg，2.7 mmol)於DMF (5 mL)中之溶液中添加CDI (615 mg，3.8 mmol)，且將反應混合物加熱至60℃持續2 h。在冷卻至0℃之後，添加額外DMF (5 mL)、苯甲醇(0.5 mL，4.8 mmol)及NaH (118 mg，2.95 mmol)，且將反應混合物升溫至室溫並攪拌16 h。將反應混合物分配於1N HCl與DCM之間，且分離各層。水相用DCM (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至35% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之4-羥基-2-甲氧基菸鹼酸苯甲酯。LC-MS F：t
R= 2.07 min；[M+H]
+= 260.0。
( R )-4-(2-amino-3-phenylpropoxy)-2-methoxynicotinic acid benzyl ester (B-1.18) step 1 : to 4-hydroxy-2-methoxy To a solution of niacin (452 mg, 2.7 mmol) in DMF (5 mL) was added CDI (615 mg, 3.8 mmol) and the reaction mixture was heated to 60 °C for 2 h. After cooling to 0 °C, additional DMF (5 mL), benzyl alcohol (0.5 mL, 4.8 mmol) and NaH (118 mg, 2.95 mmol) were added, and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was partitioned between 1N HCl and DCM, and the layers were separated. The aqueous phase was re-extracted with DCM (1×), and the combined org. layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 35% EtOAc/heptane) to afford benzyl 4-hydroxy-2-methoxynicotinate as a white solid. LC-MS F: tR = 2.07 min; [M+H] + = 260.0.
步驟 2 ：類似於對於B-1.1步驟2所描述之程序，由4-羥基-2-甲氧基菸鹼酸苯甲酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基菸鹼酸苯甲酯。LC-MS J：t
R= 2.34 min；[M+H]
+= 493.2。
Step 2 : Similar to the procedure described for B-1.1 Step 2, from 4-hydroxy-2-methoxynicotinic acid benzyl ester and ( R )-(1-hydroxy-3-phenylpropan-2- Base) tertiary butyl carbamate to prepare ( R )-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinic acid benzene methyl ester. LC-MS J: tR = 2.34 min; [M+H] + = 493.2.
步驟 3 ：向(
R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基菸鹼酸苯甲酯(235 mg，0.48 mmol)於DCM (6 mL)中之0℃溶液中添加TFA (3.65 mL，4.77 mmol)，且將反應混合物升溫至室溫且攪拌3 h。真空濃縮反應混合物，且將殘餘物分配於DCM與NaHCO
3飽和水溶液之間，並分離各層。水相用DCM (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之標題化合物。LC-MS I：t
R= 1.01 min；[M+H]
+= 393.15。
Step 3 : To ( R )-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinic acid benzyl ester (235 mg, To a 0 °C solution of 0.48 mmol) in DCM (6 mL) TFA (3.65 mL, 4.77 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and saturated aqueous NaHCO 3 , and the layers were separated. The aqueous phase was re-extracted with DCM (1×), and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give the title compound as a yellow oil. LC-MS I: tR = 1.01 min; [M+H] + = 393.15.
(
R)-2-(2-((三級丁氧基羰基)胺基)-3-(吡啶-2-基)丙氧基)-1-萘甲酸(B-1.24)
步驟 1 ：類似於對於B-1.1步驟1所描述之程序，由2-羥基-1-萘甲酸製備2-羥基-1-萘甲酸苯甲酯。LC-MS B：t
R= 1.08 min；[M+H]
+= 279.51。
( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-(pyridin-2-yl)propoxy)-1-naphthoic acid (B-1.24) Step 1 : Similar to For the procedure described in Step 1 of B-1.1, benzyl 2-hydroxy-1-naphthoate was prepared from 2-hydroxy-1-naphthoic acid. LC-MS B: tR = 1.08 min; [M+H] + = 279.51.
步驟 2 ：向LAH (85 mg，2.2 mmol)於Et
2O (13 mL)中之0℃懸浮液中添加(
R)-2-((三級丁氧基羰基)胺基)-3-(吡啶-2-基)丙酸(500 mg，1.8 mmol)，且將反應混合物升溫至室溫並攪拌1 h。將反應混合物冷卻至0℃且用EtOAc淬滅，之後添加羅謝爾鹽飽和水溶液且維持劇烈攪拌30 min，其後分離各層。水相用EtOAc (3×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之(
R)-(1-羥基-3-(吡啶-2-基)丙-2-基)胺基甲酸三級丁酯。LC-MS I：t
R= 0.63 min；[M+H]
+= 253.22。
Step 2 : To a suspension of LAH (85 mg, 2.2 mmol) in Et2O (13 mL) at 0 °C was added ( R )-2-((tertiary butoxycarbonyl)amino)-3-( pyridin-2-yl)propanoic acid (500 mg, 1.8 mmol), and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and quenched with EtOAc before adding saturated aqueous Rochelle salt and maintaining vigorous stirring for 30 min, after which the layers were separated. The aqueous phase was re-extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give ( R )-(1-hydroxy-3- (pyridin-2-yl)propan-2-yl)carbamate tertiary butyl ester. LC-MS I: tR = 0.63 min; [M+H] + = 253.22.
步驟 3 ：類似於對於B-1.1步驟2所描述之程序，由以上步驟1及2之產物製備(
R)-2-(2-((三級丁氧基羰基)胺基)-3-(吡啶-2-基)丙氧基)-1-萘甲酸苯甲酯。LC-MS I：t
R= 1.23 min；[M+H]
+= 514.18。
Step 3 : Similar to the procedure described for B-1.1 Step 2, ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-( Pyridin-2-yl)propoxy)-1-naphthoic acid benzyl ester. LC-MS I: tR = 1.23 min; [M+H] + = 514.18.
步驟 4 ：在添加10% Pd/C (18 mg，10 mol%)之前，將(
R)-2-(2-((三級丁氧基羰基)胺基)-3-(吡啶-2-基)丙氧基)-1-萘甲酸苯甲酯(108 mg，0.17 mmol)於MeOH (3 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌2 h。反應混合物經由矽藻土墊過濾，且真空濃縮濾液，得到呈白色固體狀之標題化合物。LC-MS I：t
R= 0.48 min；[M+H]
+= 423.23。
Step 4 : Before adding 10% Pd/C (18 mg, 10 mol%), ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-(pyridine-2- A solution of benzyl)-propoxy)-1-naphthoate (108 mg, 0.17 mmol) in MeOH (3 mL) was evacuated/purged with N2 (3x). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford the title compound as a white solid. LC-MS I: tR = 0.48 min; [M+H] + = 423.23.
(
R)-3-(3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙氧基)喹啉-4-甲酸(B-1.25)
步驟 1 ：向(
R)-3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙酸(128 mg，0.4 mmol)於MeOH (2 mL)中之0℃溶液中添加TMS-重氮甲烷(2 M於Et
2O中，0.6 mL，1.2 mmol)之溶液，且將反應混合物升溫至室溫並攪拌2 h。隨後藉由製備型HPLC (鹼性)純化反應混合物，得到呈白色固體狀之(
R)-3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙酸甲酯。LC-MS I：t
R= 1.08 min；[M+H]
+= 336.25。
( R )-3-(3-(benzo[b]thiophen-3-yl)-2-((tertiary butoxycarbonyl)amino)propoxy)quinoline-4-carboxylic acid (B-1.25 ) Step 1 : To ( R )-3-(benzo[b]thiophen-3-yl)-2-((tertiary butoxycarbonyl)amino)propanoic acid (128 mg, 0.4 mmol) in MeOH ( To a 0 °C solution in 2 mL) was added a solution of TMS-diazomethane (2 M in Et2O , 0.6 mL, 1.2 mmol), and the reaction mixture was warmed to room temperature and stirred for 2 h. Subsequent purification of the reaction mixture by preparative HPLC (basic) gave ( R )-3-(benzo[b]thiophen-3-yl)-2-((tertiary butoxycarbonyl) as a white solid Amino) methyl propionate. LC-MS I: tR = 1.08 min; [M+H] + = 336.25.
步驟 2 ：向
R)-3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙酸甲酯(130 mg，0.39 mmol)於EtOH (1 mL)及H
2O (1 mL)中之0℃混合物中添加NaBH
4(30 mg，0.78 mmol)，且將反應混合物升溫至室溫並攪拌16 h。隨後藉由製備型HPLC (鹼性)純化反應混合物，得到呈無色油狀之(R)-(1-(苯并[b]噻吩-3-基)-3-羥基丙-2-基)胺基甲酸三級丁酯。LC-MS I：t
R= 0.97 min；[M+H]
+= 308.16。
Step 2 : To R )-methyl 3-(benzo[b]thiophen-3-yl)-2-((tertiary butoxycarbonyl)amino)propanoate (130 mg, 0.39 mmol) in EtOH ( 1 mL) and H 2 O (1 mL) at 0° C. was added NaBH 4 (30 mg, 0.78 mmol), and the reaction mixture was warmed to room temperature and stirred for 16 h. Subsequent purification of the reaction mixture by preparative HPLC (basic) afforded (R)-(1-(benzo[b]thiophen-3-yl)-3-hydroxypropan-2-yl)amine as a colorless oil Tertiary butyl formate. LC-MS I: tR = 0.97 min; [M+H] + = 308.16.
步驟 3 ：類似於對於B-1.1步驟1所描述之程序，由3-羥基喹啉-4-甲酸製備3-羥基喹啉-4-甲酸苯甲酯。LC-MS B：t
R= 0.95 min；[M+H]
+= 280.19。
Step 3 : Benzyl 3-hydroxyquinoline-4-carboxylate was prepared from 3-hydroxyquinoline-4-carboxylic acid in analogy to the procedure described for B-1.1 Step 1. LC-MS B: tR = 0.95 min; [M+H] + = 280.19.
步驟 4 ：類似於對於B-1.1步驟2所描述之程序，由以上步驟2及3之產物製備(
R)-3-(3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙氧基)喹啉-4-甲酸苯甲酯。LC-MS I：t
R= 0.85 min；[M+H]
+= 569.24。
Step 4 : Similar to the procedure described for B-1.1 Step 2, ( R )-3-(3-(benzo[b]thiophen-3-yl)-2-( Benzyl (tertiary butoxycarbonyl)amino)propoxy)quinoline-4-carboxylate. LC-MS I: tR = 0.85 min; [M+H] + = 569.24.
步驟 5 ：向(
R)-3-(3-(苯并[b]噻吩-3-基)-2-((三級丁氧基羰基)胺基)丙氧基)喹啉-4-甲酸苯甲酯(136 mg，0.24 mmol)於2:1 THF:H
2O (3 mL)中之混合物中添加LiOH.H
2O (20 mg，0.48 mmol)，且將反應混合物加熱至50℃持續16 h。真空濃縮反應混合物，且將殘餘物分配於1M HCl水溶液與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色固體狀之標題化合物。LC-MS B：t
R= 0.96 min；[M+H]
+= 479.23。
Step 5 : To ( R )-3-(3-(benzo[b]thiophen-3-yl)-2-((tertiary butoxycarbonyl)amino)propoxy)quinoline-4-carboxylic acid To a mixture of benzyl ester (136 mg, 0.24 mmol) in 2:1 THF:H 2 O (3 mL) was added LiOH.H 2 O (20 mg, 0.48 mmol) and the reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 1M aqueous HCl and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give the title compound as a yellow solid. LC-MS B: tR = 0.96 min; [M+H] + = 479.23.
(
R)-3-(2-胺基-3-苯基丙氧基)-5-氟喹啉-4-甲酸苯甲酯二鹽酸鹽(B-1.27)
步驟 1 ：向KOH (18.6 g，331 mmol)於水(80 mL)中之室溫溶液中添加4-氟吲哚啉-2,3-二酮(4.8 g，27.6 mmol)，隨後添加溴丙酮酸(6.47 g，38 mmol)，且攪拌反應混合物16 h。添加額外KOH (4.6 g，83 mmol)及溴丙酮酸(2.88 g，17.3 mmol)，且繼續攪拌另外16 h。將反應混合物倒入1M HCl水溶液中，且所得沈澱藉由過濾收集且用水及EtOAc洗滌，且接著在真空烘箱中在40℃乾燥，得到呈棕色固體狀之5-氟-3-羥基喹啉-4-甲酸。LC-MS B：t
R= 0.39 min；[M+H]
+= 208.09。
( R )-3-(2-amino-3-phenylpropoxy)-5-fluoroquinoline-4-carboxylic acid benzyl ester dihydrochloride (B-1.27) step 1 : to KOH (18.6 g , 331 mmol) in water (80 mL) was added 4-fluoroindoline-2,3-dione (4.8 g, 27.6 mmol) followed by bromopyruvate (6.47 g, 38 mmol) , and the reaction mixture was stirred for 16 h. Additional KOH (4.6 g, 83 mmol) and bromopyruvate (2.88 g, 17.3 mmol) were added and stirring was continued for another 16 h. The reaction mixture was poured into 1M aqueous HCl, and the resulting precipitate was collected by filtration and washed with water and EtOAc, and then dried in a vacuum oven at 40 °C to give 5-fluoro-3-hydroxyquinoline- 4-Formic acid. LC-MS B: tR = 0.39 min; [M+H] + = 208.09.
步驟 2-4 ：按照如對於B-1.1所描述之反應順序，由5-氟-3-羥基喹啉-4-甲酸製備標題化合物。LC-MS B：t
R= 0.83 min；[M+H]
+= 431.14。
Step 2-4 : Following the reaction sequence as described for B-1.1, the title compound was prepared from 5-fluoro-3-hydroxyquinoline-4-carboxylic acid. LC-MS B: tR = 0.83 min; [M+H] + = 431.14.
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
22
(
R)-2-(2-胺基-3-苯基丙氧基)-6-氟苯甲酸甲酯鹽酸鹽(B-2.1)
步驟 1 ：類似於對於B-1.1步驟2所描述之程序，由2-氟-6-羥基苯甲酸甲酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-6-氟苯甲酸甲酯。LC-MS J：t
R= 2.28 min；[M-Boc+H]
+= 304.1。
( R )-2-(2-Amino-3-phenylpropoxy)-6-fluorobenzoic acid methyl ester hydrochloride (B-2.1) step 1 : similar to that described for B-1.1 step 2 Procedure, Preparation of ( R ) -2- (2 -((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-6-fluorobenzoic acid methyl ester. LC-MS J: tR = 2.28 min; [M-Boc+H] + = 304.1.
步驟 2 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS J：t
R= 1.95 min；[M+H]
+= 304.1。
Step 2 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS J: tR = 1.95 min; [M+H] + = 304.1.
下表B-2列舉類似於上文對於B-2.1描述之2-步驟順序製備之建構嵌段B。在鹽酸鹽具有高度吸濕性之情況下，使胺經受鹼性處理以釋放其游離鹼。
表B-2
編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
B-2.2
2-氯-6-羥基苯甲酸乙酯
(
R)-2-(2-胺基-3-苯基丙氧基)-6-氯苯甲酸乙酯鹽酸鹽
2.05
J
334.1
B-2.3
4-羥基-2-甲基噻唑-5-甲酸乙酯
(
R)-4-(2-胺基-3-苯基丙氧基)-2-甲基噻唑-5-甲酸乙酯鹽酸鹽
2.00
J
321.1
B-2.4
3-羥基噻吩-2-甲酸甲酯
(R)-3-(2-胺基-3-苯基丙氧基)噻吩-2-甲酸甲酯鹽酸鹽
1.94
J
292.0
B-2.13
2-羥基-5-甲氧基苯甲酸甲酯
(
R)-2-(2-胺基-3-苯基丙氧基)-5-甲氧基苯甲酸甲酯鹽酸鹽
0.73
B
316.31
B-2.14
2-羥基苯甲酸乙酯
(
R)-2-(2-胺基-3-苯基丙氧基)苯甲酸乙酯鹽酸鹽
0.99
I
300.29
Table B-2 below lists building block B prepared in a 2-step sequence similar to that described above for B-2.1. In the case of hydrochlorides which are highly hygroscopic, the amine is subjected to alkaline treatment to release its free base. Table B-2 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
B-2.2 Ethyl 2-chloro-6-hydroxybenzoate ( R )-2-(2-Amino-3-phenylpropoxy)-6-chlorobenzoic acid ethyl ester hydrochloride 2.05J 334.1
B-2.3 4-Hydroxy-2-methylthiazole-5-carboxylic acid ethyl ester ( R )-4-(2-Amino-3-phenylpropoxy)-2-methylthiazole-5-carboxylic acid ethyl ester hydrochloride 2.00J 321.1
B-2.4 3-Hydroxythiophene-2-carboxylic acid methyl ester (R)-3-(2-Amino-3-phenylpropoxy)thiophene-2-carboxylic acid methyl ester hydrochloride 1.94J 292.0
B-2.13 Methyl 2-Hydroxy-5-methoxybenzoate ( R )-2-(2-Amino-3-phenylpropoxy)-5-methoxybenzoic acid methyl ester hydrochloride 0.73 B 316.31
B-2.14 Ethyl 2-Hydroxybenzoate ( R )-2-(2-Amino-3-phenylpropoxy) ethyl benzoate hydrochloride 0.99 I 300.29
(
R)-6-(2-胺基-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-7-甲酸甲酯鹽酸鹽(B-2.5)
步驟 1 ：向2,6-二羥基苯甲酸甲酯(1.0 g，6.0 mmol)於乙酸(10 mL)中之0℃溶液中小心地添加硝酸(0.36 mL，6.0 mmol)，且將反應混合物升溫至室溫並攪拌1 h。將反應混合物倒入冷水中，且沈澱藉由過濾收集且用額外冷水洗滌，之後真空乾燥，得到呈粉色固體狀之2,6-二羥基-3-硝基苯甲酸甲酯。LC-MS B：t
R= 0.75 min；無電離。
1H NMR (DMSO)
δ: 11.73 (s, 1 H), 10.94 (s, 1 H), 8.05 (d,
J= 9.4 Hz, 1 H), 6.60 (d,
J= 9.4 Hz, 1 H), 3.81 (s, 3 H)。
( R )-6-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-7-carboxylic acid methyl ester hydrochloride (B-2.5) step 1 : to To a 0°C solution of methyl 2,6-dihydroxybenzoate (1.0 g, 6.0 mmol) in acetic acid (10 mL) was added nitric acid (0.36 mL, 6.0 mmol) carefully, and the reaction mixture was warmed to room temperature and stirred 1 h. The reaction mixture was poured into cold water and the precipitate was collected by filtration and washed with additional cold water before drying in vacuo to give methyl 2,6-dihydroxy-3-nitrobenzoate as a pink solid. LC-MS B: tR = 0.75 min; no ionization. 1 H NMR (DMSO) δ : 11.73 (s, 1 H), 10.94 (s, 1 H), 8.05 (d, J = 9.4 Hz, 1 H), 6.60 (d, J = 9.4 Hz, 1 H), 3.81 (s, 3H).
步驟 2 ：向2,6-二羥基-3-硝基苯甲酸甲酯(500 mg，2.3 mmol)於原乙酸三乙酯(13.5 mL，72 mmol)中之懸浮液中添加含4M HCl之二㗁烷(1.45 mL，5.8 mmol)，且將反應混合物抽成真空/用N
2(3×)吹掃，之後添加10% Pd/C (173 mg，7 mol%)。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌16 h。反應混合物經由矽藻土墊過濾，且真空濃縮濾液，得到呈黃色固體狀之6-羥基-2-甲基苯并[d]㗁唑-7-甲酸甲酯。LC-MS B：t
R= 0.78 min；[M+H]
+= 208.32。
1H NMR (DMSO)
δ: 10.69 (s, 1 H), 7.76 (d,
J= 8.7 Hz, 1 H), 6.96 (d,
J= 8.7 Hz, 1 H), 3.97 (s, 3 H), 2.60 (s, 3 H)。
Step 2 : To a suspension of methyl 2,6-dihydroxy-3-nitrobenzoate (500 mg, 2.3 mmol) in triethyl orthoacetate (13.5 mL, 72 mmol) was added 4M HCl in bis Oxane (1.45 mL, 5.8 mmol) and the reaction mixture was evacuated/flushed with N2 (3x) before adding 10% Pd/C (173 mg, 7 mol%). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a yellow solid. LC-MS B: tR = 0.78 min; [M+H] + = 208.32. 1 H NMR (DMSO) δ : 10.69 (s, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 3.97 (s, 3 H), 2.60 (s, 3 H).
步驟 3-4 ：按照對於B-2.1所描述之反應順序，由6-羥基-2-甲基苯并[d]㗁唑-7-甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.69 min；[M+H]
+= 341.35。注意：標題化合物不穩定且不應儲存較長時段。
Step 3-4 : The title compound was prepared from methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate following the reaction sequence described for B-2.1. LC-MS B: tR = 0.69 min; [M+H] + = 341.35. Note: The title compound is unstable and should not be stored for extended periods of time.
(
R)-6-(2-胺基-3-苯基丙氧基)苯并[d]㗁唑-7-甲酸甲酯鹽酸鹽(B-2.6) 按照對於B-2.5所描述之反應順序，在步驟2中用原乙酸三乙酯替代原甲酸三甲酯製備標題化合物。LC-MS B：t
R= 0.66 min；[M+H]
+= 327.27。注意：標題化合物不穩定且不應儲存較長時段。
( R )-6-(2-Amino-3-phenylpropoxy)benzo[d]oxazole-7-carboxylic acid methyl ester hydrochloride (B-2.6) Follow the reaction described for B-2.5 Sequentially, the title compound was prepared in Step 2 by substituting triethyl orthoacetate for trimethyl orthoformate. LC-MS B: tR = 0.66 min; [M+H] + = 327.27. Note: The title compound is unstable and should not be stored for extended periods of time.
(
R)-6-(2-胺基-3-苯基丙氧基)-1-甲基-1H-苯并[d]咪唑-7-甲酸甲酯二鹽酸鹽(B-2.7)
步驟 1 ：向2,6-二氟-3-硝基苯甲酸甲酯(5.0 g，22.6 mmol)於MeOH (40 mL)中之室溫溶液中添加甲胺(2 M於MeOH中，7.9 mL，15.8 mmol)，且攪拌反應混合物1 h。真空濃縮反應混合物，且將殘餘物懸浮於
i PrOH及水之混合物中，之後過濾。濾餅用水洗滌且經乾燥，之後藉由FC (用0%至20% EtOAc/庚烷溶離)純化，得到呈黃色固體狀之6-氟-2-(甲基胺基)-3-硝基苯甲酸甲酯。LC-MS B：t
R= 0.87 min；[M+H]
+= 229.38。
( R )-6-(2-Amino-3-phenylpropoxy)-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid methyl ester dihydrochloride (B-2.7) step 1 : To a room temperature solution of methyl 2,6-difluoro-3-nitrobenzoate (5.0 g, 22.6 mmol) in MeOH (40 mL) was added methylamine (2 M in MeOH, 7.9 mL, 15.8 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in a mixture of iPrOH and water, then filtered. The filter cake was washed with water and dried before purification by FC (elution with 0% to 20% EtOAc/heptane) to give 6-fluoro-2-(methylamino)-3-nitro as a yellow solid Methyl benzoate. LC-MS B: tR = 0.87 min; [M+H] + = 229.38.
步驟 2 ：向Boc-D-苯基丙胺醇(2.93 g，11.4 mmol)於THF (60 mL)中之0℃溶液中逐份添加NaH於礦物油中之60%分散液(549 mg，13.7 mmol)，且在攪拌10 min之後，添加6-氟-2-(甲基胺基)-3-硝基苯甲酸甲酯(2.4 g，10.4 mmol)於THF (10 mL)中之溶液。將反應混合物升溫至室溫且攪拌1 h，之後冷卻回至0℃，且用水淬滅。真空蒸發THF，且其餘的水相用額外水稀釋並用EtOAc (3×)萃取。經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至30% EtOAc/庚烷溶離)純化粗產物，得到呈黃色固體狀之(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-(甲基胺基)-3-硝基苯甲酸甲酯。LC-MS B：t
R= 1.09 min；[M+H]
+= 460.26。
Step 2 : To a 0°C solution of Boc-D-phenylpropanol (2.93 g, 11.4 mmol) in THF (60 mL) was added a 60% dispersion of NaH in mineral oil (549 mg, 13.7 mmol ), and after stirring for 10 min, a solution of methyl 6-fluoro-2-(methylamino)-3-nitrobenzoate (2.4 g, 10.4 mmol) in THF (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h before being cooled back to 0 °C and quenched with water. THF was evaporated in vacuo, and the remaining aqueous phase was diluted with additional water and extracted with EtOAc (3x). The combined organic layers were washed with brine , dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 30% EtOAc/heptane) to afford ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3- as a yellow solid Phenylpropoxy)-2-(methylamino)-3-nitrobenzoic acid methyl ester. LC-MS B: tR = 1.09 min; [M+H] + = 460.26.
步驟 3-4 ：按照對於B-2.6所描述之氫化/環化，隨後Boc-裂解之反應順序，由(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-(甲基胺基)-3-硝基苯甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.54 min；[M+H]
+= 340.41。
Step 3-4 : Following the reaction sequence of hydrogenation/cyclization as described for B-2.6 followed by Boc-cleavage, from ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3 -Phenylpropoxy)-2-(methylamino)-3-nitrobenzoic acid methyl ester The title compound was prepared. LC-MS B: tR = 0.54 min; [M+H] + = 340.41.
(
R)-6-(2-胺基-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-5-甲酸甲酯鹽酸鹽(B-2.8) 按照對於B-2.5所描述之反應順序，由2,4-二羥基苯甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.70 min；[M+H]
+= 341.39。
( R )-6-(2-Amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-5-carboxylic acid methyl ester hydrochloride (B-2.8) According to B- The reaction sequence described in 2.5 prepared the title compound from methyl 2,4-dihydroxybenzoate. LC-MS B: tR = 0.70 min; [M+H] + = 341.39.
(
R)-6-(2-胺基-3-苯基丙氧基)-1,2-二甲基-1H-苯并[d]咪唑-7-甲酸甲酯鹽酸鹽(B-2.9) 按照對於B-2.7所描述之反應順序，使用原乙酸三乙酯替代原甲酸三甲酯，由2,6-二氟-3-硝基苯甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.50 min；[M+H]
+= 354.45。
( R )-6-(2-Amino-3-phenylpropoxy)-1,2-dimethyl-1H-benzo[d]imidazole-7-carboxylic acid methyl ester hydrochloride (B-2.9 ) The title compound was prepared from methyl 2,6-difluoro-3-nitrobenzoate following the reaction sequence described for B-2.7, using triethyl orthoacetate instead of trimethyl orthoformate. LC-MS B: tR = 0.50 min; [M+H] + = 354.45.
(
R)-2-(2-胺基-3-苯基丙氧基)咪唑并[1,2-a]吡啶-3-甲酸乙酯二鹽酸鹽(B-2.10)
步驟 1 ：將2-胺基吡啶(7.08 g，75 mmol)懸浮於溴丙二酸二乙酯(38.5 mL，226 mmol)中且加熱至100℃持續1.5 h。將反應混合物分配於水與EtOAc之間，且分離各層。丟棄有機相，且水相經冷凍乾燥，得到粗產物，藉由製備型HPLC (鹼性)純化該粗產物，得到呈奶白色固體狀之2-羥基咪唑并[1,2-a]吡啶-3-甲酸乙酯。LC-MS J：t
R= 0.41 min；[M+H]
+= 207.1。
( R )-2-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester dihydrochloride (B-2.10) step 1 : the 2 -Aminopyridine (7.08 g, 75 mmol) was suspended in diethyl bromomalonate (38.5 mL, 226 mmol) and heated to 100 °C for 1.5 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic phase was discarded, and the aqueous phase was lyophilized to give the crude product, which was purified by preparative HPLC (basic) to give 2-hydroxyimidazo[1,2-a]pyridine- 3-Ethyl carboxylate. LC-MS J: tR = 0.41 min; [M+H] + = 207.1.
步驟 2-3 ：類似於對於B-2.1所描述之程序，由2-羥基咪唑并[1,2-a]吡啶-3-甲酸乙酯製備標題化合物。LC-MS I：t
R= 0.91 min；[M+H]
+= 340.28。
Step 2-3 : The title compound was prepared from ethyl 2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate in analogy to the procedure described for B-2.1. LC-MS I: tR = 0.91 min; [M+H] + = 340.28.
(
R)-5-(2-胺基-3-苯基丙氧基)-2,3-二氫苯并呋喃-4-甲酸甲酯鹽酸鹽(B-2.11)
步驟 1-2 ：2,5-二羥基苯甲酸甲酯(1.02 g，6.1 mmol)及MgSO
4(2.1 g，17.5 mmol)於Et
2O (10 mL)中之懸浮液用氬氣吹掃10 min，之後添加Ag
2O (3.46 g，14.9 mmol)，且攪拌反應混合物16 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到粗產物3,6-二氧雜環己-1,4-二烯-1-甲酸甲酯，將該粗產物再溶解於PhMe (50 mL)中，之後添加正丁基乙烯基醚(1.7 mL，13.1 mmol)，且將反應混合物加熱至45℃持續19 h。將反應混合物倒入水中，且分離各相。水相用EtOAc (3×)萃取，且經合併之有機相用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用1%至50% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之2-丁氧基-5-羥基-2,3-二氫苯并呋喃-4-甲酸甲酯。LC-MS J：t
R= 2.23 min；[M+H]
+= 267.1。
( R )-5-(2-amino-3-phenylpropoxy)-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester hydrochloride (B-2.11) step 1-2 : 2 , A suspension of methyl 5-dihydroxybenzoate (1.02 g, 6.1 mmol) and MgSO 4 (2.1 g, 17.5 mmol) in Et 2 O (10 mL) was purged with argon for 10 min before adding Ag 2 O (3.46 g, 14.9 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to give the crude product, methyl 3,6-dioxane-1,4-diene-1-carboxylate, which was redissolved in PhMe (50 mL), then n-butyl vinyl ether (1.7 mL, 13.1 mmol) was added, and the reaction mixture was heated to 45 °C for 19 h. The reaction mixture was poured into water, and the phases were separated. The aqueous phase was extracted with EtOAc (3x), and the combined organic phases were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo . The crude product was purified by FC (eluted with 1% to 50% EtOAc/heptane) to give 2-butoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylic acid methanolate as a white solid ester. LC-MS J: tR = 2.23 min; [M+H] + = 267.1.
步驟 3 ：向2-丁氧基-5-羥基-2,3-二氫苯并呋喃-4-甲酸甲酯(761 mg，2.86 mmol)於PhMe (25 mL)中之溶液中添加TFA (0.9 mL，11.75 mmol)，且將反應混合物加熱至回流持續4.5 h。將反應混合物倒入水中，且分離各相。水相用EtOAc (3×)萃取，且經合併之有機相用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至50% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之5-羥基苯并呋喃-4-甲酸甲酯。LC-MS J：t
R= 2.00 min；無電離。
1H NMR (DMSO)
δ: 10.83 (bs, 1 H), 8.12 (d,
J= 2.2 Hz, 1 H), 7.82 (d,
J= 8.9 Hz, 1 H), 7.19 (d,
J= 2.1 Hz, 1 H), 6.95 (d,
J= 8.9 Hz, 1 H), 4.00 (s, 3 H)。
Step 3 : To a solution of methyl 2-butoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate (761 mg, 2.86 mmol) in PhMe (25 mL) was added TFA (0.9 mL, 11.75 mmol), and the reaction mixture was heated to reflux for 4.5 h. The reaction mixture was poured into water, and the phases were separated. The aqueous phase was extracted with EtOAc (3x), and the combined organic phases were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo . The crude product was purified by FC (eluted with 0% to 50% EtOAc/heptane) to afford methyl 5-hydroxybenzofuran-4-carboxylate as a white solid. LC-MS J: t R = 2.00 min; no ionization. 1 H NMR (DMSO) δ : 10.83 (bs, 1 H), 8.12 (d, J = 2.2 Hz, 1 H), 7.82 (d, J = 8.9 Hz, 1 H), 7.19 (d, J = 2.1 Hz , 1 H), 6.95 (d, J = 8.9 Hz, 1 H), 4.00 (s, 3 H).
步驟 4 ：在添加10% Pd/C (109 mg，5 mol%)之前，將5-羥基苯并呋喃-4-甲酸甲酯(395 mg，2.06 mmol)及AcOH (1.3 mL，22.5 mmol)於EtOAc (20 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌21 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到呈白色固體狀之6-羥基-2-甲基苯并[d]㗁唑-7-甲酸甲酯。LC-MS F：t
R= 1.88 min；[M+H]
+= 195.0。
Step 4 : Methyl 5-hydroxybenzofuran-4-carboxylate (395 mg, 2.06 mmol) and AcOH (1.3 mL, 22.5 mmol) were dissolved in The solution in EtOAc (20 mL) was evacuated/purged with N2 (3x). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 21 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a white solid. LC-MS F: tR = 1.88 min; [M+H] + = 195.0.
步驟 5-6 ：類似於對於B-2.1所描述之程序，由5-羥基-2,3-二氫苯并呋喃-4-甲酸甲酯製備標題化合物。LC-MS J：t
R= 1.97 min；[M+H]
+= 328.1。
Step 5-6 : The title compound was prepared from methyl 5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate in analogy to the procedure described for B-2.1. LC-MS J: tR = 1.97 min; [M+H] + = 328.1.
(
R)-3-(2-胺基-3-苯基丙氧基)-6-甲氧基吡啶甲酸甲酯鹽酸鹽(B-2.12)
步驟 1 ：向3-羥基吡啶甲酸甲酯(0.94 g，6.1 mmol)於DMF (20 mL)中之室溫溶液中添加Cs
2CO
3(2.4 g，7.4 mmol)及BnBr (1.31 mL，11.1 mmol)，且將反應混合物加熱至70℃持續2 h。真空濃縮反應混合物，且將殘餘物分配於水與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用30%至45% EtOAc/庚烷溶離)純化粗產物，得到呈棕色油狀之3-(苯甲氧基)吡啶甲酸甲酯。LC-MS J：t
R= 1.86 min；[M+H]
+= 244.0。
( R )-3-(2-amino-3-phenylpropoxy)-6-methoxypicolinate methyl ester hydrochloride (B-2.12) step 1 : to 3-hydroxypicolinate methyl ester ( To a room temperature solution of 0.94 g, 6.1 mmol) in DMF (20 mL) Cs2CO3 (2.4 g, 7.4 mmol) and BnBr (1.31 mL, 11.1 mmol) were added and the reaction mixture was heated to 70 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 30% to 45% EtOAc/heptane) to afford methyl 3-(benzyloxy)picolinate as a brown oil. LC-MS J: tR = 1.86 min; [M+H] + = 244.0.
步驟 2 ：向3-(苯甲氧基)吡啶甲酸甲酯(1.19 g，4.9 mmol於DCM (10 mL)中之0℃溶液中添加
mCPBA (1.51 g，6.1 mmol)，且將反應混合物升溫至室溫並攪拌16 h。將反應混合物分配於NaHSO
3飽和水溶液與DCM之間且萃取。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用NaHCO
3飽和水溶液洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈棕色固體狀之3-(苯甲氧基)-2-(甲氧基羰基)吡啶1-氧化物。LC-MS J：t
R= 1.72 min；[M+H]
+= 260.0。
Step 2 : To a 0°C solution of methyl 3-(benzyloxy)picolinate (1.19 g, 4.9 mmol in DCM (10 mL) was added m CPBA (1.51 g, 6.1 mmol) and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was partitioned between saturated aqueous NaHSO 3 and DCM and extracted. The layers were separated and the aqueous phase was re-extracted with DCM ( 2 ×). Washed, dried over Na2SO4 , filtered and evaporated in vacuo to give 3-(benzyloxy)-2-(methoxycarbonyl)pyridine 1-oxide as a brown solid. LC-MS J: tR = 1.72 min; [M+H] + = 260.0.
步驟 3 ：向3-(苯甲氧基)-2-(甲氧基羰基)吡啶1-氧化物(1.27 g，4.9 mmol)中添加Ac
2O (7.0 mL，74.2 mmol)，且將反應混合物加熱至100℃持續1 h。添加額外Ac
2O (7 mL，74.2 mmol)且繼續加熱2 h。添加EtOH (10 mL)，且將反應混合物加熱至回流持續1 h，之後冷卻至室溫隔夜。真空濃縮反應混合物，且將殘餘物與PhMe (1×)一起共沸，之後添加含2M NaOH之MeOH (10 mL)，且將反應混合物加熱至80℃持續3 h。真空蒸發MeOH，且其餘的水溶液用1M HCl酸化，之後用DCM (4×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈棕色固體狀之3-(苯甲氧基)-6-羥基吡啶甲酸。LC-MS G：t
R= 2.74 min；[M+H]
+= 246.0。
Step 3 : To 3-(benzyloxy)-2-(methoxycarbonyl)pyridine 1-oxide (1.27 g, 4.9 mmol) was added Ac 2 O (7.0 mL, 74.2 mmol), and the reaction mixture Heat to 100 °C for 1 h. Additional Ac2O (7 mL, 74.2 mmol) was added and heating was continued for 2 h. EtOH (10 mL) was added, and the reaction mixture was heated to reflux for 1 h before cooling to room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was azeotroped with PhMe (1×) before 2M NaOH in MeOH (10 mL) was added and the reaction mixture was heated to 80 °C for 3 h. MeOH was evaporated in vacuo, and the remaining aqueous solution was acidified with 1M HCl, then extracted with DCM (4x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 3-(benzyloxy)-6-hydroxypicolinic acid as a brown solid. LC-MS G: tR = 2.74 min; [M+H] + = 246.0.
步驟 4 ：向3-(苯甲氧基)-6-羥基吡啶甲酸(1.0 g，4.1 mmol)於丙酮(60 mL)中之懸浮液中添加Ag
2CO
3(4.5 g，16.3 mmol)及MeI(0.56 mL，9.0 mmol)，且將反應混合物加熱至回流持續2 h。將反應混合物冷卻至室溫且用1 M HCl酸化，之後真空濃縮。將殘餘物分配於水與DCM之間且萃取。過濾各層且分離，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用10%至70% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之3-(苯甲氧基)-6-甲氧基吡啶甲酸甲酯。LC-MS J：t
R= 1.98 min；[M+H]
+= 274.2。
Step 4 : To a suspension of 3-(benzyloxy)-6-hydroxypicolinic acid (1.0 g, 4.1 mmol) in acetone (60 mL ) was added Ag2CO3 (4.5 g, 16.3 mmol) and MeI (0.56 mL, 9.0 mmol), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and acidified with 1 M HCl, then concentrated in vacuo. The residue was partitioned between water and DCM and extracted. The layers were filtered and separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 10% to 70% EtOAc/heptane) to afford methyl 3-(benzyloxy)-6-methoxypicolinate as a colorless oil. LC-MS J: tR = 1.98 min; [M+H] + = 274.2.
步驟 5 ：在添加10% Pd/C (157 mg，5 mol%)之前，將3-(苯甲氧基)-6-甲氧基吡啶甲酸甲酯(847 mg，2.94 mmol)於EtOH (20 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌2 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到呈白色固體狀之3-羥基-6-甲氧基吡啶甲酸甲酯。LC-MS J：t
R= 1.48 min；無電離。
Step 5 : Methyl 3-(benzyloxy)-6-methoxypicolinate (847 mg, 2.94 mmol) was dissolved in EtOH (20 The solution in mL) was evacuated/purged with N2 (3x). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford methyl 3-hydroxy-6-methoxypicolinate as a white solid. LC-MS J: tR = 1.48 min; no ionization.
步驟 6-7 ：類似於對於B-2.1所描述之程序，由3-羥基-6-甲氧基吡啶甲酸甲酯製備標題化合物。LC-MS J：t
R= 1.85 min；[M+H]
+= 317.2。
Step 6-7 : The title compound was prepared from methyl 3-hydroxy-6-methoxypicolinate in analogy to the procedure described for B-2.1. LC-MS J: tR = 1.85 min; [M+H] + = 317.2.
(
R)-5-(2-胺基-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-4-甲酸甲酯鹽酸鹽(B-2.15) 按照對於B-2.5所描述之反應順序，由2,5-二羥基苯甲酸甲酯製備標題化合物。LC-MS D：t
R= 0.63 min；[M+H]
+= 341.37。
( R )-5-(2-Amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-4-carboxylic acid methyl ester hydrochloride (B-2.15) According to B- The reaction sequence described in 2.5 prepared the title compound from methyl 2,5-dihydroxybenzoate. LC-MS D: tR = 0.63 min; [M+H] + = 341.37.
(
R)-3-(2-胺基-3-苯基丙氧基)異喹啉-4-甲酸甲酯二鹽酸鹽(B-2.16)
步驟 1 ：向異喹啉-3-胺(1.0 g，6.9 mmol)於DCM (20 mL)及EtOH (10 mL)中之0℃溶液中逐份添加NBS (1.30 g，7.3 mmol)，且攪拌反應混合物30 min，之後升溫至室溫隔夜。真空濃縮反應混合物，且殘餘物用DCM濕磨且過濾。真空濃縮濾液，且藉由FC (用25%至40% EtOAc/庚烷溶離)純化殘餘物，得到呈棕色固體狀之4-溴異喹啉-3-胺。隨後用
i Pr
2O濕磨進一步提高其純度。LC-MS J：t
R= 1.84 min；[M+H]
+= 223.0。
( R )-3-(2-amino-3-phenylpropoxy)isoquinoline-4-carboxylic acid methyl ester dihydrochloride (B-2.16) step 1 : to isoquinolin-3-amine ( 1.0 g, 6.9 mmol) in DCM (20 mL) and EtOH (10 mL) at 0 °C was added NBS (1.30 g, 7.3 mmol) portionwise, and the reaction mixture was stirred for 30 min before warming to room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was triturated with DCM and filtered. The filtrate was concentrated in vacuo, and the residue was purified by FC (eluted with 25% to 40% EtOAc/heptane) to afford 4-bromoisoquinolin-3-amine as a brown solid. Subsequent wet milling with iPr2O further enhanced its purity . LC-MS J: tR = 1.84 min; [M+H] + = 223.0.
步驟 2 ：在添加Pd(dppf)Cl
2(261 mg，0.36 mmol)之前，將4-溴異喹啉-3-胺(796 mg，3.6 mmol)及DIPEA (1.87 mL，10.7 mmol)於DMF (10 mL)及MeOH (5 mL)中之溶液抽成真空/用CO (3×)吹掃。將反應混合物抽成真空/用CO (3×)吹掃，且在CO氛圍下在75℃攪拌20 h。將反應混合物冷卻至室溫且真空濃縮，且將殘餘物分配於水與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色固體狀之3-胺基異喹啉-4-甲酸甲酯。LC-MS J：t
R= 1.78 min；[M+H]
+= 203.1。
Step 2 : 4 -Bromoisoquinolin-3-amine (796 mg, 3.6 mmol) and DIPEA (1.87 mL, 10.7 mmol) were dissolved in DMF ( 10 mL) and MeOH (5 mL) was evacuated/purged with CO (3×). The reaction mixture was evacuated/surged with CO (3x) and stirred at 75 °C for 20 h under a CO atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give methyl 3-aminoisoquinoline-4-carboxylate as a yellow solid. LC-MS J: tR = 1.78 min; [M+H] + = 203.1.
步驟 3 ：向3-胺基異喹啉-4-甲酸甲酯(330 mg，1.63 mmol)於2.5M H
2SO
4水溶液(4 mL，10 mmol)中之0℃懸浮液中添加NaNO
2(135 mg，2.0 mmol)於H
2O (0.6 mL)中之溶液，且攪拌反應混合物1.5 h。反應混合物藉由添加2M NaOH水溶液中和且用EtOAc (4×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色固體狀之3-羥基異喹啉-4-甲酸甲酯。LC-MS F：t
R= 1.52 min；[M+H]
+= 204.0。
Step 3 : To a 0°C suspension of methyl 3-aminoisoquinoline- 4 -carboxylate (330 mg, 1.63 mmol) in 2.5M aqueous H2SO4 (4 mL, 10 mmol) was added NaNO2 (135 mg, 2.0 mmol) in H 2 O (0.6 mL), and the reaction mixture was stirred for 1.5 h. The reaction mixture was neutralized by addition of 2M aqueous NaOH and extracted with EtOAc (4x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give methyl 3-hydroxyisoquinoline-4-carboxylate as a yellow solid. LC-MS F: tR = 1.52 min; [M+H] + = 204.0.
步驟 4-5 ：按照對於B-2.1所描述之反應順序，由3-羥基異喹啉-4-甲酸甲酯製備標題化合物。LC-MS J：t
R= 1.97 min；[M+H]
+= 337.2。
Step 4-5 : The title compound was prepared from 3-hydroxyisoquinoline-4-carboxylic acid methyl ester following the reaction sequence described for B-2.1. LC-MS J: tR = 1.97 min; [M+H] + = 337.2.
(
R)-6-(2-
胺基 -3- 苯基丙氧基 ) 咪唑并 [1,2-a] 吡啶 -5- 甲酸甲酯二鹽酸鹽 (B-2.17) 步驟 1 ：向甲基-3-羥基吡啶甲酸酯(2.41 g，15.7 mmol)於水110 mL)中之0℃溶液中逐滴添加Br
2(0.81 mL，15.7 mmol)，且將反應混合物升溫至室溫並攪拌隔夜。反應混合物用40%亞硫酸氫鈉水溶液淬滅且用DCM (2×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈白色固體狀之6-溴-3-羥基吡啶甲酸甲酯。LC-MS G：t
R= 3.19 min；[M+H]
+= 231.9。
( R )-6-(2- Amino -3- phenylpropoxy ) imidazo [1,2-a] pyridine -5- carboxylic acid methyl ester dihydrochloride (B-2.17) step 1 : tomethane To a solution of Br2 (0.81 mL, 15.7 mmol) in H2O (2.41 g, 15.7 mmol) in water (110 mL) at 0 °C was added dropwise, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with 40% aqueous sodium bisulfite and extracted with DCM (2x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give methyl 6-bromo-3-hydroxypicolinate as a white solid. LC-MS G: tR = 3.19 min; [M+H] + = 231.9.
步驟 2 ：類似於對於B-1.1步驟2所描述之程序，由6-溴-3-羥基吡啶甲酸甲酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(R)-6-溴-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯。LC-MS F：t
R= 2.16 min；[M+H-
t Bu]
+= 409.0。
Step 2 : Similar to the procedure described for B-1.1 Step 2, methyl 6-bromo-3-hydroxypicolinate and ( R )-(1-hydroxy-3-phenylpropan-2-yl)amino Preparation of (R)-methyl 6-bromo-3-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)picolinate from tert-butyl formate. LC-MS F: tR = 2.16 min; [M+H- tBu ] + = 409.0.
步驟 3 ：向(R)-6-溴-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯(5.0 g，10.5 mmol)、胺基甲酸苯甲酯(1.67 g，11.1 mmol)及Cs
2CO
3(5.15 g，15.8 mmol)於二㗁烷(130 mL)中之室溫混合物中添加Pd
2(dba)
3(483 mg，0.53 mmol)及XPhos (201 mg，0.42 mmol)，且將反應混合物加熱至95℃並攪拌48 h。將反應混合物冷卻至室溫，過濾，且真空濃縮濾液，之後藉由FC (用0%至40% EtOAc/庚烷溶離)純化，得到呈橙色固體之(R)-6-(((苯甲氧基)羰基)胺基)-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯。LC-MS F：t
R= 2.24 min；[M+H]
+= 536.2。
Step 3 : To (R)-methyl 6-bromo-3-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (5.0 g, 10.5 mmol), To a room temperature mixture of benzyl carbamate (1.67 g, 11.1 mmol) and Cs 2 CO 3 (5.15 g, 15.8 mmol) in dioxane (130 mL) was added Pd 2 (dba) 3 (483 mg, 0.53 mmol) and XPhos (201 mg, 0.42 mmol), and the reaction mixture was heated to 95°C and stirred for 48 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo before purification by FC (eluted with 0% to 40% EtOAc/heptane) to afford (R)-6-((((Benzene) as an orange solid (oxy)carbonyl)amino)-3-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)picolinate methyl ester. LC-MS F: tR = 2.24 min; [M+H] + = 536.2.
步驟 4 ：在添加10% Pd/C (70 mg，0.07 mmol)之前，(R)-6-(((苯甲氧基)羰基)胺基)-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯(1.43 g，2.19 mmol)於EtOH (20 mL)中之溶液用N
2/真空(3×)吹掃。在另外惰性化三次之後，連接H
2氣球，且在55℃攪拌反應混合物1 h。經由矽藻土塞過濾混合物，用EtOH沖洗。濃縮濾液，得到呈黃色油狀之(R)-6-胺基-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯。LC-MS J：t
R= 2.00 min；[M+H]
+= 402.2。
Step 4 : (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tertiary butoxy A solution of methyl (carbonyl)amino)-3-phenylpropoxy)picolinate (1.43 g, 2.19 mmol) in EtOH (20 mL) was purged with N2 /vacuum (3x). After three additional inertizations, a H2 balloon was attached and the reaction mixture was stirred at 55 °C for 1 h. The mixture was filtered through a plug of celite, rinsing with EtOH. The filtrate was concentrated to afford (R)-methyl 6-amino-3-(2-((tertiary-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate as a yellow oil. LC-MS J: tR = 2.00 min; [M+H] + = 402.2.
步驟 5 ：向(R)-6-胺基-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)吡啶甲酸甲酯(0.50 g，1.25 mmol)及NaHCO
3(209 mg，2.49 mmol)於EtOH (15 mL)中之混合物中添加50% 2-氯乙醛水溶液(0.475 mL，3.74 mmol)，且將反應混合物加熱至70℃並攪拌5 h。真空濃縮反應混合物，且將殘餘物分配於水與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用50%至100% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之(R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)咪唑并[1,2-a]吡啶-5-甲酸甲酯。LC-MS I：t
R= 1.01 min；[M+H]
+= 426.52。
Step 5 : To (R)-methyl 6-amino-3-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (0.50 g, 1.25 mmol) and NaHCO 3 (209 mg, 2.49 mmol) in EtOH (15 mL) was added 50% aqueous 2-chloroacetaldehyde (0.475 mL, 3.74 mmol), and the reaction mixture was heated to 70° C. and stirred for 5 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 50% to 100% EtOAc/heptane) to afford (R)-6-(2-((tertiary butoxycarbonyl)amino)-3- as a white solid phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylic acid methyl ester. LC-MS I: tR = 1.01 min; [M+H] + = 426.52.
步驟 6 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS J：t
R= 1.83 min；[M+H]
+= 326.2。
Step 6 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS J: tR = 1.83 min; [M+H] + = 326.2.
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
33
(
R)-4-(2-胺基-3-苯基丙氧基)菸鹼酸乙酯二鹽酸鹽(B-3.1)
步驟 1 ：向4-羥基菸鹼酸(5.0 g，34.9 mmol)於EtOH (50 mL)中之0℃溶液中逐滴添加H
2SO
4(1.86 mL，34.9 mmol)，且將反應混合物加熱至回流持續3 d。在真空濃縮之後，向殘餘物中小心地添加NaHCO
3飽和水溶液，且過濾出固體並乾燥，得到呈灰白色固體狀之4-羥基菸鹼酸乙酯。LC-MS D：t
R= 0.37 min；[M+H]
+= 168.05。
( R )-4-(2-Amino-3-phenylpropoxy)nicotinic acid ethyl ester dihydrochloride (B-3.1) Step 1 : Add 4-hydroxynicotinic acid (5.0 g, 34.9 mmol ) in EtOH (50 mL) at 0 °C was added H2SO4 (1.86 mL, 34.9 mmol) dropwise, and the reaction mixture was heated to reflux for 3 d. After concentration in vacuo, saturated aqueous NaHCO 3 was carefully added to the residue, and the solid was filtered off and dried to give ethyl 4-hydroxynicotinate as an off-white solid. LC-MS D: tR = 0.37 min; [M+H] + = 168.05.
步驟 2 ：類似於對於B-1.1步驟2所描述之程序，由4-羥基菸鹼酸乙酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)菸鹼酸乙酯。LC-MS J：t
R= 2.17 min；[M+H]
+= 401.2。
Step 2 : Similar to the procedure described for B- 1.1 Step 2, a tertiary Preparation of ( R )-ethyl 4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)nicotinate from butyl ester. LC-MS J: tR = 2.17 min; [M+H] + = 401.2.
步驟 3 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS B：t
R= 0.52 min；[M+H]
+= 301.28。
Step 3 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS B: tR = 0.52 min; [M+H] + = 301.28.
下表B-3中列舉類似於上文對於
B-3.1描述之3-步驟順序製備之建構嵌段B。在鹽酸鹽具有高度吸濕性之情況下，使胺經受鹼性處理以釋放其游離鹼。
表B-3
編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
B-3.2
3-羥基異菸鹼酸
(
R)-3-(2-胺基-3-苯基丙氧基)異菸鹼酸乙酯二鹽酸鹽
1.88
J
301.1
Listed in Table B-3 below are building blocks B prepared in a 3-step sequence similar to that described above for B-3.1. In the case of hydrochlorides which are highly hygroscopic, the amine is subjected to alkaline treatment to release its free base. Table B-3 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
B-3.2 3-Hydroxyisonicotinic acid ( R )-3-(2-Amino-3-phenylpropoxy)isonicotinic acid ethyl ester dihydrochloride 1.88J 301.1
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
44
(
R)-2-(2-胺基-3-苯基丙氧基)-6-(三氟甲氧基)苯甲酸苯甲酯鹽酸鹽(B-4.1)
步驟 1 ：向NaH (1.35 g，33.7 mmol)於THF (50 mL)中之室溫懸浮液中逐滴添加3-(三氟甲氧基)苯酚(5.0 g，28.1 mmol)於THF (40 mL)中之溶液，且攪拌所得混合物15 min，之後逐滴添加溴化甲氧基甲基(2.98 mL，36.5 mmol)。在攪拌1 h之後，反應混合物藉由添加Na
2CO
3飽和水溶液淬滅，用一些水稀釋且用
i Pr
2O萃取。有機相用NaHCO
3、鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈無色油狀之1-(甲氧基甲氧基)-3-(三氟甲氧基)苯。LC-MS J：t
R= 2.13 min；無電離。
( R )-2-(2-amino-3-phenylpropoxy)-6-(trifluoromethoxy)benzoic acid benzyl hydrochloride (B-4.1) step 1 : to NaH (1.35 g, 33.7 mmol) in THF (50 mL) was added dropwise to a solution of 3-(trifluoromethoxy)phenol (5.0 g, 28.1 mmol) in THF (40 mL) and stirred The resulting mixture was left for 15 min, after which methoxymethyl bromide (2.98 mL, 36.5 mmol) was added dropwise. After stirring for 1 h, the reaction mixture was quenched by addition of saturated aqueous Na2CO3 , diluted with some water and extracted with iPr2O . The organic phase was washed with NaHCO3 , brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 1-(methoxymethoxy)-3-(trifluoromethoxy)benzene as a colorless oil. LC-MS J: tR = 2.13 min; no ionization.
步驟 2 ：向sBuLi (1.4 M於環己烷中，12.54 mL，17.55 mmol)於THF (10 mL)及環己烷(15 mL)之混合物中之-78℃溶液中逐滴添加1-(甲氧基甲氧基)-3-(三氟甲氧基)苯(3.0 g，13.5 mmol)於THF (7 mL)中之溶液，且攪拌反應混合物1.5 h。將反應混合物淬滅至新鮮碾磨之乾冰上且接著升溫至室溫。在攪拌15 min之後，添加幾滴MeOH，之後真空濃縮反應混合物。將中間物甲酸鋰溶解於DMF (20 mL)中，之後添加KHCO
3(0.41 g，4.1 mmol)及溴甲苯(1.93 mL，16.2 mmol)，且攪拌反應混合物18 h。過濾反應混合物且真空濃縮濾液。將殘餘物分配於水與EtOAc之間且萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至15% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之2-(甲氧基甲氧基)-6-(三氟甲氧基)苯甲酸苯甲酯。LC-MS J：t
R= 2.24 min；[M+H]
+= 357.1。
Step 2 : To a -78 °C solution of sBuLi (1.4 M in cyclohexane, 12.54 mL, 17.55 mmol) in a mixture of THF (10 mL) and cyclohexane (15 mL) was added 1-(methanol) dropwise Oxymethoxy)-3-(trifluoromethoxy)benzene (3.0 g, 13.5 mmol) in THF (7 mL), and the reaction mixture was stirred for 1.5 h. The reaction mixture was quenched onto freshly ground dry ice and then allowed to warm to room temperature. After stirring for 15 min, a few drops of MeOH were added, after which the reaction mixture was concentrated in vacuo. The intermediate lithium formate was dissolved in DMF (20 mL), after which KHCO 3 (0.41 g, 4.1 mmol) and bromotoluene (1.93 mL, 16.2 mmol) were added, and the reaction mixture was stirred for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 15% EtOAc/heptane) to give 2-(methoxymethoxy)-6-(trifluoromethoxy)benzoic acid benzyl as a colorless oil ester. LC-MS J: tR = 2.24 min; [M+H] + = 357.1.
步驟 3 ：向2-(甲氧基甲氧基)-6-(三氟甲氧基)苯甲酸苯甲酯(1.39 g，3.9 mmol)於DCM (20 mL)中之溶液中添加TFA (2 mL，26.1 mmol)，且攪拌所得混合物1 h。真空濃縮反應混合物，且將殘餘物與DCM (2×)一起共蒸發，得到呈白色固體狀之2-羥基-6-(三氟甲氧基)苯甲酸苯甲酯。LC-MS J：t
R= 2.22 min; [M-H]
-= 311.0。
Step 3 : To a solution of benzyl 2-(methoxymethoxy)-6-(trifluoromethoxy)benzoate (1.39 g, 3.9 mmol) in DCM (20 mL) was added TFA (2 mL, 26.1 mmol), and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was co-evaporated with DCM (2x) to give benzyl 2-hydroxy-6-(trifluoromethoxy)benzoate as a white solid. LC-MS J: tR = 2.22 min; [MH] - = 311.0.
步驟 4 ：類似於對於B-1.1步驟2所描述之程序，由2-羥基-6-(三氟甲氧基)苯甲酸苯甲酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-6-(三氟甲氧基)苯甲酸苯甲酯。LC-MS J：t
R= 2.50 min；[M-Boc+H]
+= 446.1。
Step 4 : Similar to the procedure described for B-1.1 Step 2, from 2-hydroxy-6-(trifluoromethoxy)benzoic acid benzyl ester and ( R )-(1-hydroxy-3-phenylpropane Preparation of ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-6-(trifluoromethane Oxy) benzyl benzoate. LC-MS J: tR = 2.50 min; [M-Boc+H] + = 446.1.
步驟 5 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS J：t
R= 2.30 min；[M+H]
+= 446.1。
Step 5 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS J: tR = 2.30 min; [M+H] + = 446.1.
下表B-4中列舉類似於上文對於
B-4.1描述之5-步驟順序製備之建構嵌段B。在鹽酸鹽具有高度吸濕性之情況下，使胺經受鹼性處理以釋放其游離鹼。
表B-4
編號 起始材料 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
B-4.2
苯并[d][1,3]二氧呃-5-醇
(
R)-5-(2-胺基-3-苯基丙氧基)苯并[d][1,3]二氧呃-4-甲酸苯甲酯鹽酸鹽
2.09
J
406.1
B-4.3
苯并[d][1,3]二氧呃-2,2-d2-5-醇
(
R)-5-(2-胺基-3-苯基丙氧基)苯并[d][1,3]二氧呃-4-甲酸苯甲酯-2,2-d2鹽酸鹽
2.16
J
408.2
B-4.4
2,2-二氟苯并[d][1,3]二氧呃-5-醇
(
R)-5-(2-胺基-3-苯基丙氧基)-2,2-二氟苯并[d][1,3]二氧呃-4-甲酸苯甲酯鹽酸鹽
2.31
J
442.1
Listed in Table B-4 below are building blocks B prepared in a 5-step sequence similar to that described above for B-4.1. In the case of hydrochlorides which are highly hygroscopic, the amine is subjected to alkaline treatment to release its free base. Table B-4 serial number starting material product t R [min] LC-MS method MS- data m/z [M+H] +
B-4.2 Benzo[d][1,3]dioxer-5-ol ( R )-5-(2-Amino-3-phenylpropoxy)benzo[d][1,3]dioxer-4-carboxylic acid benzyl ester hydrochloride 2.09J 406.1
B-4.3 Benzo[d][1,3]dioxer-2,2-d2-5-ol ( R )-5-(2-Amino-3-phenylpropoxy)benzo[d][1,3]dioxer-4-benzoic acid benzyl ester-2,2-d2 hydrochloride 2.16J 408.2
B-4.4 2,2-Difluorobenzo[d][1,3]dioxer-5-ol ( R )-5-(2-Amino-3-phenylpropoxy)-2,2-difluorobenzo[d][1,3]dioxer-4-carboxylate benzyl hydrochloride 2.31J 442.1
(
R)-4-(2-胺基-3-苯基丙氧基)-2-甲基菸鹼酸乙酯二鹽酸鹽(B-4.5)
步驟 1 ：向2-氯-4-羥基吡啶(1.0 g，7.72 mmol)於DMF (20 mL)中之0℃溶液中添加NaH (370 mg，9.26 mmol)，且將反應混合物升溫至室溫並攪拌15 min，之後冷卻回至0℃。添加氯甲基甲基醚(1.17 mL，15.4 mmol)，且將反應混合物升溫至室溫並攪拌1 h。反應混合物藉由添加Na
2CO
3飽和水溶液淬滅，用一些水稀釋且用Et
2O萃取。有機相用NaHCO
3、鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到粗產物，藉由FC (用20%至100% EtOAc/庚烷溶離)純化該粗產物，得到呈無色油狀之2-氯-4-(甲氧基甲氧基)吡啶。LC-MS I：t
R= 0.72 min；[M+H]
+= 174.09。
( R )-4-(2-amino-3-phenylpropoxy)-2-methylnicotinic acid ethyl ester dihydrochloride (B-4.5) step 1 : to 2-chloro-4-hydroxyl To a 0°C solution of pyridine (1.0 g, 7.72 mmol) in DMF (20 mL) was added NaH (370 mg, 9.26 mmol) and the reaction mixture was warmed to room temperature and stirred for 15 min before cooling back to 0°C. Chloromethyl methyl ether (1.17 mL, 15.4 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched by adding saturated aqueous Na2CO3 , diluted with some water and extracted with Et2O . The organic phase was washed with NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give the crude product which was purified by FC (eluted with 20% to 100% EtOAc/heptane) to give a colorless oil 2-chloro-4-(methoxymethoxy)pyridine. LC-MS I: tR = 0.72 min; [M+H] + = 174.09.
步驟 2 ：向2-氯-4-(甲氧基甲氧基)吡啶(413 mg，2.36 mmol)於THF (7 mL)中之-78℃溶液中添加nBuLi (2.5 M於己烷中，1.18 mL，2.94 mmol)，且在攪拌30 min之後，經由導管向氯甲酸乙酯(0.23 mL，2.36 mmol)於THF (4 mL)中之-78℃溶液中添加該反應混合物且在-78℃攪拌1 h。將反應混合物升溫至室溫且攪拌2 h，之後用NaHCO
3淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用10%至70% EtOAc/庚烷溶離)純化粗產物，得到呈黃色油狀之2-氯-4-(甲氧基甲氧基)菸鹼酸乙酯。LC-MS B：t
R= 0.82 min；[M+H]
+= 246.29。
Step 2 : To a solution of 2-chloro-4-(methoxymethoxy)pyridine (413 mg, 2.36 mmol) in THF (7 mL) at -78 °C was added nBuLi (2.5 M in hexane, 1.18 mL, 2.94 mmol), and after stirring for 30 min, the reaction mixture was added via cannula to a -78°C solution of ethyl chloroformate (0.23 mL, 2.36 mmol) in THF (4 mL) and stirred at -78°C 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h before being quenched with NaHCO 3 and extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 10% to 70% EtOAc/heptane) to afford ethyl 2-chloro-4-(methoxymethoxy)nicotinate as a yellow oil. LC-MS B: tR = 0.82 min; [M+H] + = 246.29.
步驟 3 ：向2-氯-4-(甲氧基甲氧基)菸鹼酸乙酯(120 mg，0.46 mmol)及Pd(dppf)Cl
2.DCM (3.8 mg，0.005 mmol)於二㗁烷(2 mL)中之室溫溶液中逐滴添加ZnMe
2(2 M於PhMe中，0.46 mL，0.93 mmol)，且將反應混合物加熱至90℃並攪拌1 h。真空濃縮反應混合物，且將殘餘物分配於水與EtOAc之間並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (鹼性)純化粗產物，得到呈無色油狀之4-(甲氧基甲氧基)-2-甲基菸鹼酸乙酯。LC-MS I：t
R= 0.71 min；[M+H]
+= 226.18。
Step 3 : Ethyl 2-chloro-4-(methoxymethoxy)nicotinate (120 mg, 0.46 mmol) and Pd(dppf)Cl 2 .DCM (3.8 mg, 0.005 mmol) in dioxane To a room temperature solution in (2 mL) ZnMe2 (2 M in PhMe, 0.46 mL, 0.93 mmol) was added dropwise, and the reaction mixture was heated to 90 °C and stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (basic) to afford ethyl 4-(methoxymethoxy)-2-methylnicotinate as a colorless oil. LC-MS I: tR = 0.71 min; [M+H] + = 226.18.
步驟 4 ：向4-(甲氧基甲氧基)-2-甲基菸鹼酸乙酯(50 mg，0.22 mmol)於二㗁烷(1 mL)中之室溫溶液中添加含4M HCl之二㗁烷(0.55 mL)，且攪拌反應混合物16 h。真空移除揮發物，且將殘餘物懸浮於Et
2O中且濃縮，得到呈白色固體狀之4-羥基-2-甲基菸鹼酸乙酯鹽酸鹽。LC-MS I：t
R= 0.30 min；[M+H]
+= 182.23。
Step 4 : To a room temperature solution of ethyl 4-(methoxymethoxy)-2-methylnicotinate (50 mg, 0.22 mmol) in dioxane (1 mL) was added 4M HCl in Dioxane (0.55 mL), and the reaction mixture was stirred for 16 h. The volatiles were removed in vacuo, and the residue was suspended in Et2O and concentrated to give ethyl 4-hydroxy-2-methylnicotinate hydrochloride as a white solid. LC-MS I: tR = 0.30 min; [M+H] + = 182.23.
步驟 5 ：類似於對於B-1.1步驟2所描述之程序，由4-羥基-2-甲基菸鹼酸乙酯鹽酸鹽及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲基菸鹼酸乙酯。LC-MS B：t
R= 0.82 min；[M+H]
+= 415.41。
Step 5 : Similar to the procedure described for B-1.1 Step 2, from 4-hydroxy-2-methylnicotinic acid ethyl ester hydrochloride and ( R )-(1-hydroxy-3-phenylpropan-2 Preparation of ( R )-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methylnicotinic acid from tertiary butyl carbamate ester. LC-MS B: tR = 0.82 min; [M+H] + = 415.41.
步驟 6 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS B：t
R= 0.52 min；[M+H]
+= 315.32。
Step 6 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS B: tR = 0.52 min; [M+H] + = 315.32.
(
R)-6-(2-胺基-3-苯基丙氧基)-2,3-二氫苯并呋喃-7-甲酸苯甲酯鹽酸鹽(B-4.6)
步驟 1 ：向6-羥基苯并呋喃-3(2H)-酮(8.0 g，53.3 mmol)於DMF (80 mL)中之室溫溶液中添加溴甲苯(8.9 mL，74.6 mmol)及K
2CO
3(14.7 g，107 mmol)，且攪拌反應混合物2 h。將反應混合物倒入冷水中，且沈澱藉由過濾收集並在真空烘箱中在40℃乾燥48 h。分離出呈橙色固體狀之6-(苯甲氧基)苯并呋喃-3(2H)-酮。LC-MS J：t
R= 2.03 min；[M+H]
+= 241.0。
( R )-6-(2-amino-3-phenylpropoxy)-2,3-dihydrobenzofuran-7-benzoic acid benzyl hydrochloride (B-4.6) step 1 : to 6 To a room temperature solution of -hydroxybenzofuran-3(2H)-one (8.0 g, 53.3 mmol) in DMF (80 mL) was added bromotoluene (8.9 mL, 74.6 mmol) and K 2 CO 3 (14.7 g, 107 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was poured into cold water, and the precipitate was collected by filtration and dried in a vacuum oven at 40 °C for 48 h. 6-(Benzyloxy)benzofuran-3(2H)-one was isolated as an orange solid. LC-MS J: tR = 2.03 min; [M+H] + = 241.0.
步驟 2 ：向AlCl
3(6.87 g，51.5 mmol)及LiAlH
4(19.5 mL，46.8 mmol，2.4M於THF中)於THF (200 mL)中之0℃溶液中逐份添加6-(苯甲氧基)苯并呋喃-3(2H)-酮(11.25 g，46.8 mmol)，且將反應混合物升溫至室溫並攪拌2 h。將反應混合物冷卻至0℃且用0.5M NaOH水溶液(400 mL)淬滅並用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈橙色油狀之6-(苯甲氧基)苯并呋喃。GC-MS MC：t
R= 4.74 min; [M]
+= 224.1。注意：含有呈次要副產物之6-(苯甲氧基)-2,3-二氫苯并呋喃。
Step 2 : To a 0 °C solution of AlCl3 (6.87 g, 51.5 mmol) and LiAlH4 (19.5 mL, 46.8 mmol, 2.4M in THF) in THF (200 mL) was added 6-(benzyloxy yl)benzofuran-3(2H)-one (11.25 g, 46.8 mmol), and the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C and quenched with 0.5M aqueous NaOH (400 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 6-(benzyloxy)benzofuran as an orange oil. GC-MS MC: tR = 4.74 min; [M] + = 224.1. Note: Contains 6-(benzyloxy)-2,3-dihydrobenzofuran as a minor by-product.
步驟 3 ：按照對於B-2.11步驟4所描述之程序，由6-(苯甲氧基)苯并呋喃製備2,3-二氫苯并呋喃-6-醇。GC-MS MC：t
R= 3.38 min; [M]
+= 136.1。
Step 3 : Following the procedure described for B-2.11 Step 4, 2,3-dihydrobenzofuran-6-ol was prepared from 6-(benzyloxy)benzofuran. GC-MS MC: tR = 3.38 min; [M] + = 136.1.
步驟 4-8 ：類似於對於B-4.1所描述之程序，由2,3-二氫苯并呋喃-6-醇製備標題化合物。LC-MS J：t
R= 2.30 min；[M+H]
+= 446.1。
Step 4-8 : The title compound was prepared from 2,3-dihydrobenzofuran-6-ol in analogy to the procedure described for B-4.1. LC-MS J: tR = 2.30 min; [M+H] + = 446.1.
(
R)-6-(2-胺基-3-苯基丙氧基)喹啉-5-甲酸苯甲酯二鹽酸鹽(B-4.7)
步驟 1 ：向喹啉-6-醇(1.0 g，6.9 mmol)及NaOAc (0.62 g，7.6 mmol)於AcOH (15 mL)中之室溫溶液中添加Br
2(0.37 mL，7.2 mmol)於AcOH (5 mL)中之溶液，且攪拌反應混合物30 min。反應混合物用NaHSO
3飽和水溶液淬滅且用2M NaOH水溶液及Na
2CO
3中和，之後用EtOAc (2×)萃取。經合併之有機萃取物用鹽水洗滌且真空濃縮。將殘餘物溶解於PhMe中且真空濃縮(2×)，得到呈棕色固體狀之5-溴喹啉-6-醇。LC-MS J：t
R= 1.16 min；[M+H]
+= 221.9。
( R )-6-(2-amino-3-phenylpropoxy)quinoline-5-carboxylic acid benzyl ester dihydrochloride (B-4.7) step 1 : to quinoline-6-alcohol (1.0 g, 6.9 mmol) and NaOAc (0.62 g, 7.6 mmol) in AcOH (15 mL) at room temperature was added a solution of Br2 (0.37 mL, 7.2 mmol) in AcOH (5 mL) and the reaction mixture was stirred 30 min. The reaction mixture was quenched with sat. aq. NaHSO 3 and neutralized with 2M aq. NaOH and Na 2 CO 3 before extracting with EtOAc (2×). The combined organic extracts were washed with brine and concentrated in vacuo. The residue was dissolved in PhMe and concentrated in vacuo (2x) to afford 5-bromoquinolin-6-ol as a brown solid. LC-MS J: tR = 1.16 min; [M+H] + = 221.9.
步驟 2 ：類似於對於B-4.1步驟1所描述之程序，由5-溴喹啉-6-醇製備5-溴-6-(甲氧基甲氧基)喹啉。LC-MS J：t
R= 2.30 min；[M+H]
+= 446.1。
Step 2 : Preparation of 5-bromo-6-(methoxymethoxy)quinoline from 5-bromoquinolin-6-ol in analogy to the procedure described for B-4.1 Step 1. LC-MS J: tR = 2.30 min; [M+H] + = 446.1.
步驟 3 ：向5-溴-6-(甲氧基甲氧基)喹啉(2.45 g，9.1 mmol)於THF (50 mL)中之-78℃溶液中逐滴添加nBuLi (1.6 M於己烷中，5.7 mL，9.1 mmol)，且攪拌反應混合物30 min。反應混合物用新鮮碾磨之乾冰(12 g，273 mmol)淬滅，且接著升溫至室溫並30 min。真空濃縮反應混合物，且將中間物甲酸鋰溶解於DMF (30 mL)中，之後添加溴甲苯(1.3 mL，11 mmol)，且將反應混合物加熱至60℃持續10 min。將反應混合物冷卻至室溫且分配於NaHCO
3飽和水溶液與EtOAc之間，並萃取。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用30%至100% EtOAc/庚烷溶離)純化粗產物，得到呈黃色油狀之6-(甲氧基甲氧基)喹啉-5-甲酸苯甲酯。LC-MS J：t
R= 2.02 min；[M+H]
+= 324.1。
Step 3 : To a solution of 5-bromo-6-(methoxymethoxy)quinoline (2.45 g, 9.1 mmol) in THF (50 mL) at -78 °C was added dropwise nBuLi (1.6 M in hexane , 5.7 mL, 9.1 mmol), and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with freshly ground dry ice (12 g, 273 mmol), and then allowed to warm to room temperature for 30 min. The reaction mixture was concentrated in vacuo, and the intermediate lithium formate was dissolved in DMF (30 mL), after which bromotoluene (1.3 mL, 11 mmol) was added, and the reaction mixture was heated to 60 °C for 10 min. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous NaHCO 3 and EtOAc, and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 30% to 100% EtOAc/heptane) to afford benzyl 6-(methoxymethoxy)quinoline-5-carboxylate as a yellow oil. LC-MS J: tR = 2.02 min; [M+H] + = 324.1.
步驟 4-6 ：類似於對於B-4.1步驟3-5所描述之程序，由6-(甲氧基甲氧基)喹啉-5-甲酸苯甲酯製備標題化合物。LC-MS B：t
R= 0.77 min；[M+H]
+= 413.16。
Step 4-6 : The title compound was prepared from benzyl 6-(methoxymethoxy)quinoline-5-carboxylate in analogy to the procedure described for B-4.1 Steps 3-5. LC-MS B: tR = 0.77 min; [M+H] + = 413.16.
(
R)-7-(2-胺基-3-苯基丙氧基)喹啉-8-甲酸苯甲酯二鹽酸鹽(B-4.8)
步驟 1 ：向喹啉-7-醇(10 g，68.9 mmol)於AcOH (20 mL)中之溶液中添加DCM (40 mL)，且將所得懸浮液冷卻至0℃，之後緩慢添加Br
2(3.87 mL，75 mmol)於AcOH (20 mL)中之溶液，且攪拌反應混合物2 h。懸浮液用EtOAc稀釋且過濾，且過濾殘餘物用EtOAc及Et
2O洗滌並在40℃真空乾燥，得到呈棕色固體狀之8-溴喹啉-7-醇氫溴酸鹽。LC-MS J：t
R= 0.27 min；[M+H]
+= 225.9。
( R )-7-(2-amino-3-phenylpropoxy)quinoline-8-carboxylic acid benzyl ester dihydrochloride (B-4.8) step 1 : to quinoline-7-alcohol (10 g, 68.9 mmol) in AcOH (20 mL) was added DCM (40 mL), and the resulting suspension was cooled to 0 °C before slowly adding Br2 (3.87 mL, 75 mmol) in AcOH (20 mL) solution, and the reaction mixture was stirred for 2 h. The suspension was diluted with EtOAc and filtered, and the filter residue was washed with EtOAc and Et2O and dried in vacuo at 40 °C to give 8-bromoquinolin-7-ol hydrobromide as a brown solid. LC-MS J: tR = 0.27 min; [M+H] + = 225.9.
步驟 2-6 ：類似於對於B-4.7步驟2-6所描述之程序，由8-溴喹啉-7-醇氫溴酸鹽製備標題化合物。LC-MS J：t
R= 2.07 min；[M+H]
+= 413.1。
Step 2-6 : The title compound was prepared from 8-bromoquinolin-7-ol hydrobromide in analogy to the procedure described for B-4.7 Step 2-6. LC-MS J: tR = 2.07 min; [M+H] + = 413.1.
(
R)-6-(2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲酸苯甲酯二鹽酸鹽(B-4.9) 類似於對於B-4.7所描述之程序，由3-氟喹啉-6-醇製備標題化合物。LC-MS J：t
R= 2.16 min；[M+H]
+= 431.2。
( R )-6-(2-Amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid benzyl ester dihydrochloride (B-4.9) Similar to that described for B-4.7 The title compound was prepared from 3-fluoroquinolin-6-ol using the following procedure. LC-MS J: tR = 2.16 min; [M+H] + = 431.2.
(
R)-2-(2-胺基-3-苯基丙氧基)-4-甲氧基菸鹼酸苯甲酯鹽酸鹽(B-4.10)
步驟 1 ：類似於對於B-4.7步驟-3所描述之程序，由2-氟-4-甲氧基吡啶製備2-氟-4-甲氧基菸鹼酸苯甲酯。LC-MS F：t
R= 1.96 min；[M+H]
+= 262.0。
( R )-2-(2-Amino-3-phenylpropoxy)-4-methoxynicotinic acid benzyl ester hydrochloride (B-4.10) step 1 : similar to the step for B-4.7 Benzyl 2-fluoro-4-methoxynicotinate was prepared from 2-fluoro-4-methoxypyridine by the procedure described in -3. LC-MS F: tR = 1.96 min; [M+H] + = 262.0.
步驟 2 ：向2-氟-4-甲氧基菸鹼酸苯甲酯(600 mg，2.3 mmol)及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯(577 mg，2.3 mmol)於THF (20 mL)中之0℃溶液中添加KO
t Bu (258 mg，2.3 mmol)於THF (3.5 mL)中之溶液，且將反應混合物升溫至室溫並攪拌30 min。真空濃縮反應混合物，且藉由FC (用10%至45% EtOAc/庚烷溶離)純化殘餘物，得到呈無色油狀之(R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4-甲氧基菸鹼酸苯甲酯。LC-MS F：t
R= 2.30 min；[M+H]
+= 493.1。
Step 2 : Add 2-fluoro-4-methoxynicotinic acid benzyl ester (600 mg, 2.3 mmol) and ( R )-(1-hydroxy-3-phenylpropan-2-yl)carbamic acid tris To a solution of butyl ester (577 mg, 2.3 mmol) in THF (20 mL) at 0 °C was added a solution of KOtBu (258 mg, 2.3 mmol) in THF (3.5 mL) and the reaction mixture was warmed to room temperature. Warm and stir for 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by FC (eluting with 10% to 45% EtOAc/heptane) to afford (R)-2-(2-((tert-butoxycarbonyl) as a colorless oil Amino)-3-phenylpropoxy)-4-methoxynicotinic acid benzyl ester. LC-MS F: tR = 2.30 min; [M+H] + = 493.1.
步驟 3 ：類似於對於B-1.1步驟3所描述之程序，由(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4-甲氧基菸鹼酸苯甲酯製備標題化合物。LC-MS F：t
R= 1.76 min；[M+H]
+= 393.1。
Step 3 : Similar to the procedure described for B-1.1 Step 3, from ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-4- Benzyl methoxynicotinate to prepare the title compound. LC-MS F: tR = 1.76 min; [M+H] + = 393.1.
(
R)-5-(2-胺基-3-苯基丙氧基)-2-甲氧基異菸鹼酸苯甲酯三氟乙酸鹽(B-4.11)
步驟 1 ：類似於對於B-4.1步驟1所描述之程序，由6-甲氧基吡啶-3-醇製備2-甲氧基-5-(甲氧基甲氧基)吡啶。LC-MS J：t
R= 1.67 min；[M+H]
+= 170.1。
( R )-5-(2-Amino-3-phenylpropoxy)-2-methoxyisonicotinic acid benzyl trifluoroacetate (B-4.11) step 1 : similar to that for B- 4.1 Procedure described in step 1, 2-methoxy-5-(methoxymethoxy)pyridine was prepared from 6-methoxypyridin-3-ol. LC-MS J: tR = 1.67 min; [M+H] + = 170.1.
步驟 2-5 ：類似於對於B-4.7步驟3-6所描述之程序，在Boc裂解步驟中用HCl替代TFA，由2-甲氧基-5-(甲氧基甲氧基)吡啶製備標題化合物。LC-MS J：t
R= 2.16 min；[M+H]
+= 393.1。
Steps 2-5 : Similar to the procedure described for B-4.7 Steps 3-6, substituting HCl for TFA in the Boc cleavage step, the title was prepared from 2-methoxy-5-(methoxymethoxy)pyridine compound. LC-MS J: tR = 2.16 min; [M+H] + = 393.1.
(
R)-4-(2-胺基-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸乙酯(B-4.12)
步驟 1 ：按照對於B-4.6步驟1所描述之程序，由6-甲基吡啶-2,4-二醇製備4-(苯甲氧基)-6-甲基吡啶-2-醇。LC-MS I：t
R= 0.71 min; [2M+H]
+= 431.31。
( R )-4-(2-Amino-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid ethyl ester (B-4.12) Step 1 : Follow the steps for B-4.6 4-(Benzyloxy)-6-methylpyridin-2-ol was prepared from 6-picoline-2,4-diol by the procedure described in 1. LC-MS I: tR = 0.71 min; [2M+H] + = 431.31.
步驟 2 ：向4-(苯甲氧基)-6-甲基吡啶-2-醇(500 mg，2.32 mmol)及Ag
2CO
3(1.29 g，4.65 mmol)於DCM (20 mL)中之室溫混合物中添加MeI (0.438 mL，6.97 mmol)，且在微波爐中在100℃照射反應混合物1 h。過濾反應混合物，且用DCM洗滌固體，之後真空濃縮濾液，且藉由FC (用20%至100% EtOAc/庚烷溶離)純化殘餘物，得到呈無色油狀之4-(苯甲氧基)-2-甲氧基-6-甲基吡啶。LC-MS I：t
R= 1.07 min；[M+H]
+= 230.25。
Step 2 : Addition of 4-(benzyloxy)-6-methylpyridin-2-ol (500 mg, 2.32 mmol) and Ag 2 CO 3 (1.29 g, 4.65 mmol) in DCM (20 mL) To the warm mixture was added MeI (0.438 mL, 6.97 mmol), and the reaction mixture was irradiated in a microwave oven at 100 °C for 1 h. The reaction mixture was filtered and the solid was washed with DCM before the filtrate was concentrated in vacuo and the residue was purified by FC (elution with 20% to 100% EtOAc/heptane) to give 4-(benzyloxy) as a colorless oil -2-Methoxy-6-methylpyridine. LC-MS I: tR = 1.07 min; [M+H] + = 230.25.
步驟 3 ：向4-(苯甲氧基)-2-甲氧基-6-甲基吡啶(1.66 g，7.3 mmol)於THF (25 mL)中之-78℃溶液中逐滴添加nBuLi (2.5 M於己烷中，3.63 mL，9.1 mmol)，且攪拌反應混合物30 min，之後逐滴添加氯甲酸乙酯(0.70 mL，7.3 mmol)。將反應混合物升溫至室溫且藉由添加NaHCO
3飽和水溶液淬滅並用EtOAc萃取。分離各層，且水相用EtOAc (2×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用20%EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之4-(苯甲氧基)-2-甲氧基-6-甲基菸鹼酸乙酯。LC-MS I：t
R= 1.11 min；[M+H]
+= 302.29。
Step 3 : To a solution of 4-(benzyloxy)-2-methoxy-6-picoline (1.66 g, 7.3 mmol) in THF (25 mL) at -78 °C was added dropwise nBuLi (2.5 M in hexanes, 3.63 mL, 9.1 mmol), and the reaction mixture was stirred for 30 min, after which ethyl chloroformate (0.70 mL, 7.3 mmol) was added dropwise. The reaction mixture was warmed to room temperature and quenched by addition of saturated aqueous NaHCO 3 and extracted with EtOAc. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x), and the combined org. layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo . The crude product was purified by FC (eluted with 20% EtOAc/heptane) to afford ethyl 4-(benzyloxy)-2-methoxy-6-methylnicotinate as a colorless oil. LC-MS I: tR = 1.11 min; [M+H] + = 302.29.
步驟 4-6 ：類似於對於B-2.12步驟5-7所描述之程序，由4-(苯甲氧基)-2-甲氧基-6-甲基菸鹼酸乙酯製備標題化合物。注意：使用TFA替代HCl進行Boc-裂解，且在鹼性處理之後分離出呈其游離鹼形式之標題化合物。LC-MS I：t
R= 0.97 min；[M+H]
+= 345.32。
Step 4-6 : The title compound was prepared from ethyl 4-(benzyloxy)-2-methoxy-6-methylnicotinate in analogy to the procedure described for B-2.12 Steps 5-7. Note: Boc-cleavage was performed using TFA instead of HCl and the title compound was isolated in its free base form after basic treatment. LC-MS I: tR = 0.97 min; [M+H] + = 345.32.
(
R)-4-(2-胺基-3-苯基丙氧基)-2-(甲氧基-d3)-6-甲基菸鹼酸乙酯(B-4.13) 類似於對於B-4.12所描述之程序，在步驟2中用CD
3I替代MeI製備標題化合物。LC-MS I：t
R= 0.97 min；[M+H]
+= 348.35。
( R )-4-(2-amino-3-phenylpropoxy)-2-(methoxy-d3)-6-methylnicotinic acid ethyl ester (B-4.13) is similar to that for B- The title compound was prepared by the procedure described in 4.12, substituting CD3I for MeI in step 2. LC-MS I: tR = 0.97 min; [M+H] + = 348.35.
(
R)-6-(2-
胺基 -3- 苯基丙氧基 )-8- 甲基喹啉 -5- 甲酸苯甲酯 (B-4.14) 步驟 1 ：向4-甲氧基-2-甲基苯胺(5.0 g，35.7 mmol)於EtOH (50 mL)中之室溫溶液中添加米氏酸(6.04 g，41.1 mmol)及原甲酸三乙酯(6.06 mL，35.7 mmol)，且將反應混合物加熱至80℃持續2 h。將反應混合物冷卻至室溫，且沈澱藉由過濾收集，用EtOH洗滌，且在HV下經乾燥，得到呈白色固體狀之5-(((4-甲氧基-2-甲基苯基)胺基)亞甲基)-2,2-二甲基-1,3-二㗁烷-4,6-二酮。LC-MS B：t
R= 0.90 min；[M+H]
+= 292.13。
( R )-6-(2- amino -3- phenylpropoxy )-8- methylquinoline -5- benzoic acid benzyl ester (B-4.14) step 1 : to 4-methoxy-2 -To a room temperature solution of methylaniline (5.0 g, 35.7 mmol) in EtOH (50 mL) was added Michaelis acid (6.04 g, 41.1 mmol) and triethylorthoformate (6.06 mL, 35.7 mmol), and the The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to room temperature, and the precipitate was collected by filtration, washed with EtOH, and dried under HV to give 5-(((4-methoxy-2-methylphenyl) as a white solid Amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. LC-MS B: tR = 0.90 min; [M+H] + = 292.13.
步驟 2 ：將5-(((4-甲氧基-2-甲基苯基)胺基)亞甲基)-2,2-二甲基-1,3-二㗁烷-4,6-二酮(8.19 g，28.1 mmol)溶解於Dowtherm A (50 mL)中，且加熱至250℃持續5 min。將反應混合物冷卻至室溫且用Et
2O稀釋，且沈澱藉由過濾收集且用Et
2O洗滌，之後在HV下乾燥，得到呈棕色固體狀之6-甲氧基-8-甲基喹啉-4-醇。LC-MS B：t
R= 0.58 min；[M+H]
+= 190.21。
Step 2 : 5-(((4-methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6- Diketone (8.19 g, 28.1 mmol) was dissolved in Dowtherm A (50 mL) and heated to 250 °C for 5 min. The reaction mixture was cooled to room temperature and diluted with Et20 , and the precipitate was collected by filtration and washed with Et20 before drying under HV to give 6-methoxy-8-methylquinone as a brown solid Lin-4-ol. LC-MS B: tR = 0.58 min; [M+H] + = 190.21.
步驟 3 ：向6-甲氧基-8-甲基喹啉-4-醇(3.91 g，20.7 mmol)於DMF (75 mL)中之室溫溶液中添加三溴化磷(2.16 mL，22.7 mmol)，且將反應混合物加熱至45℃持續1 h。將反應混合物冷卻至室溫，用水稀釋，且藉由添加NaHCO
3飽和水溶液將pH調整至8。沈澱藉由過濾收集且溶解於EtOAc中，用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用10% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之4-溴-6-甲氧基-8-甲基喹啉。LC-MS B：t
R= 0.82 min；[M+H]
+= 254.03。
Step 3 : To a room temperature solution of 6-methoxy-8-methylquinolin-4-ol (3.91 g, 20.7 mmol) in DMF (75 mL) was added phosphorus tribromide (2.16 mL, 22.7 mmol ), and the reaction mixture was heated to 45 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and the pH was adjusted to 8 by addition of saturated aqueous NaHCO 3 . The precipitate was collected by filtration and dissolved in EtOAc, washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 10% EtOAc/heptane) to afford 4-bromo-6-methoxy-8-methylquinoline as a white solid. LC-MS B: tR = 0.82 min; [M+H] + = 254.03.
步驟 4 ：向4-溴-6-甲氧基-8-甲基喹啉(7.2 g，28.5 mmol)於THF中之-78℃溶液中逐滴添加nBuLi (1.6 M於己烷中，35.7 mL，57.1 mmol)，且攪拌反應混合物30 min。反應物用NH
4Cl飽和水溶液淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用20% EtOAc/庚烷溶離)純化粗產物，得到呈黃色油狀之6-甲氧基-8-甲基喹啉。LC-MS B：t
R= 0.49 min；[M+H]
+= 174.26。
Step 4 : To a -78°C solution of 4-bromo-6-methoxy-8-methylquinoline (7.2 g, 28.5 mmol) in THF was added dropwise nBuLi (1.6 M in hexane, 35.7 mL , 57.1 mmol), and the reaction mixture was stirred for 30 min. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (elution with 20% EtOAc/heptane) to afford 6-methoxy-8-methylquinoline as a yellow oil. LC-MS B: tR = 0.49 min; [M+H] + = 174.26.
步驟 5 ：類似於對於B-4.7步驟1所描述之程序，由6-甲氧基-8-甲基喹啉製備5-溴-6-甲氧基-8-甲基喹啉。LC-MS B：t
R= 0.74 min；[M+H]
+= 252.09。
Step 5 : 5-Bromo-6-methoxy-8-methylquinoline was prepared from 6-methoxy-8-methylquinoline in analogy to the procedure described for B-4.7 Step 1. LC-MS B: tR = 0.74 min; [M+H] + = 252.09.
步驟 6 ：向5-溴-6-甲氧基-8-甲基喹啉(3.57 g，14.2 mmol)於DCM (70 mL)中之0℃溶液中逐滴添加BBr
3(1 M於DCM中，42.5 mL，42.5 mmol)。移除冷卻浴，且在室溫攪拌反應混合物2 h。將反應混合物小心地淬滅至冷MeOH中且真空濃縮。將殘餘物與PhMe、EtOAc及DCM一起共蒸發，得到呈黃色固體狀之5-溴-8-甲基喹啉-6-醇。LC-MS B：t
R= 0.55 min；[M+H]
+= 238.01。
Step 6 : To a 0°C solution of 5-bromo-6-methoxy-8-methylquinoline (3.57 g, 14.2 mmol) in DCM (70 mL) was added BBr3 (1 M in DCM) dropwise , 42.5 mL, 42.5 mmol). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was carefully quenched into cold MeOH and concentrated in vacuo. The residue was co-evaporated with PhMe, EtOAc and DCM to give 5-bromo-8-methylquinolin-6-ol as a yellow solid. LC-MS B: tR = 0.55 min; [M+H] + = 238.01.
步驟 7 ：類似於對於B-1.1步驟2所描述之程序，由5-溴-8-甲基喹啉-6-醇及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-(1-((5-溴-8-甲基喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯。LC-MS B：t
R= 1.10 min；[M+H]
+= 472.94。
Step 7 : Similar to the procedure described for B-1.1 Step 2, from 5-bromo-8-methylquinolin-6-ol and ( R )-(1-hydroxyl-3-phenylpropan-2-yl ) carbamate tertiary butyl ester preparation ( R )-(1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamic acid Tertiary butyl ester. LC-MS B: tR = 1.10 min; [M+H] + = 472.94.
步驟 8 ：向(
R)-(1-((5-溴-8-甲基喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯(185 mg，0.39 mmol)於THF (2 mL)中之-78℃溶液中逐滴添加nBuLi (1.6 M於己烷中，0.54 mL，0.86 mmol)，且攪拌反應混合物30 min，之後逐滴添加氯甲酸苯甲酯(0.058 mL，0.41 mmol)。將反應混合物升溫至室溫且藉由添加NaHCO
3飽和水溶液淬滅並用EtOAc萃取。分離各層，且水相用EtOAc (2×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (酸性)純化粗產物，得到呈白色固體狀之(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-8-甲基喹啉-5-甲酸苯甲酯。LC-MS B：t
R= 1.11 min；[M+H]
+= 527.33。
Step 8 : To ( R )-(1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate tertiary butyl ester ( 185 mg, 0.39 mmol) in THF (2 mL) at -78 °C was added dropwise with nBuLi (1.6 M in hexane, 0.54 mL, 0.86 mmol), and the reaction mixture was stirred for 30 min before chlorine was added dropwise. Benzyl formate (0.058 mL, 0.41 mmol). The reaction mixture was warmed to room temperature and quenched by addition of saturated aqueous NaHCO 3 and extracted with EtOAc. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x), and the combined org. layers were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo . The crude product was purified by preparative HPLC (acidic) to afford ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-8 as a white solid -Methylquinoline-5-benzoic acid benzyl ester. LC-MS B: tR = 1.11 min; [M+H] + = 527.33.
步驟 9 ：向
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-8-甲基喹啉-5-甲酸苯甲酯(550 mg，1.04 mmol)於DCM (5 mL)中之室溫溶液中添加TFA (4.0 mL，52.2 mmol)，且攪拌反應混合物1 h。真空濃縮反應混合物，且將殘餘物與DCM ( 2×)一起共蒸發，之後藉由製備型HPLC (鹼性)純化，得到呈黃色油狀之標題化合物。LC-MS B：t
R= 0.78 min；[M+H]
+= 427.23。
Step 9 : To R )-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylic acid benzyl ester (550 mg , 1.04 mmol) in DCM (5 mL) was added TFA (4.0 mL, 52.2 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was co-evaporated with DCM (2x) before purification by preparative HPLC (basic) to afford the title compound as a yellow oil. LC-MS B: tR = 0.78 min; [M+H] + = 427.23.
(
R)-4-(2-
胺基 -3- 苯基丙氧基 )-2- 甲氧基 -6- 甲基菸鹼酸苯甲酯 (B-4.15) 步驟 1 ：向(R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸乙酯
(B-4.12 ， 步驟 5)(42 g，94.5 mmol)於MeOH (300 mL)中之室溫溶液中添加16% NaOH水溶液(100 mL，472 mmol)，且加熱至90℃持續4 h。將反應混合物冷卻至室溫且真空濃縮。其餘的水相用
i PrOAc (3×)萃取，且丟棄有機相。將水相冷卻至0℃且用1M HCl水溶液酸化，且過濾沈澱並用水洗滌。將固體溶解於DCM中，且分離其餘的水，之後有機相經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之(R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸。LC-MS B：t
R= 0.94 min；[M+H]
+= 417.20。
( R )-4-(2- amino -3- phenylpropoxy )-2- methoxy -6- methylnicotinic acid benzyl ester (B-4.15) step 1 : to (R)- 4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid ethyl ester (B-4.12 , step 5) (42 g, 94.5 mmol) in MeOH (300 mL) was added 16% aqueous NaOH (100 mL, 472 mmol) and heated to 90 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The remaining aqueous phase was extracted with iPrOAc (3x), and the organic phase was discarded. The aqueous phase was cooled to 0°C and acidified with 1M aqueous HCl, and the precipitate was filtered and washed with water. The solid was dissolved in DCM and the remaining water was separated, after which the organic phase was dried over Na2SO4 , filtered and evaporated in vacuo to give (R)-4-(2-((tertiarybutoxy Carbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid. LC-MS B: tR = 0.94 min; [M+H] + = 417.20.
步驟 2 ：向(R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸(2.0 g，4.8 mmol)於DMF (8 mL)中之室溫溶液中添加K
2CO
3(1.33 g，9.6 mmol)及BnBr (0.51 mL，4.3 mmol)，且將反應混合物加熱至40℃並攪拌4 h。將反應混合物倒入水中且用TBME (2×)萃取。經合併之有機萃取物用水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈無色油狀之(R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸苯甲酯。LC-MS B：t
R= 1.17 min；[M+H]
+= 507.24。
Step 2 : To (R)-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid (2.0 g, 4.8 mmol) to a room temperature solution in DMF (8 mL) were added K2CO3 (1.33 g, 9.6 mmol) and BnBr (0.51 mL, 4.3 mmol), and the reaction mixture was heated to 40 °C and stirred for 4 h. The reaction mixture was poured into water and extracted with TBME (2x). The combined organic extracts were washed with water, dried over Na2SO4 , filtered and evaporated in vacuo to afford (R)-4-(2-((tertiary-butoxycarbonyl)amino)-3 as a colorless oil -phenylpropoxy)-2-methoxy-6-methylnicotinic acid benzyl ester. LC-MS B: tR = 1.17 min; [M+H] + = 507.24.
步驟 3 ：類似於對於B-1.1步驟3所描述之程序，由(R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸苯甲酯製備標題化合物。注意：使用TFA替代HCl進行Boc-裂解，且在鹼性處理之後分離出呈其游離鹼形式之標題化合物。LC-MS B：t
R= 0.79 min；[M+H]
+= 407.22。
Step 3 : Similar to the procedure described for B-1.1 Step 3, from (R)-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2- Benzyl Methoxy-6-methylnicotinate Preparation of the title compound. Note: Boc-cleavage was performed using TFA instead of HCl and the title compound was isolated in its free base form after basic treatment. LC-MS B: tR = 0.79 min; [M+H] + = 407.22.
(
R)-4-(2-
胺基 -3- 苯基丙氧基 )-6- 甲氧基 -2- 甲基嘧啶 -5- 甲酸苯甲酯三氟乙酸鹽 (B-4.16) 步驟 1 ：向DIPEA (7.74 mL，55.2 mmol)於THF (35 mL)中之-78℃溶液中逐滴添加nBuLi (1.6 M於己烷中，34.5 mL，55.2 mmol)，且攪拌反應混合物5 min。向新鮮製備之LDA中逐滴添加4,6-二氯-2-甲基嘧啶(5.0 g，30.7 mmol)於THF (40 mL)中之溶液，且繼續在-78℃攪拌1 h。反應混合物用新鮮碾磨之乾冰(20 g，454 mmol)淬滅且攪拌5 min，之後經過20 min升溫至室溫且再攪拌15 min。真空濃縮反應混合物，得到呈棕色固體狀之4,6-二氯-2-甲基嘧啶-5-甲酸鋰，其未經純化即進一步使用。LC-MS J：t
R= 0.16 min；[M-H]
-= 204.9。
( R )-4-(2- Amino -3- phenylpropoxy )-6- methoxy -2- methylpyrimidine -5- carboxylic acid benzyl trifluoroacetate (B-4.16) step 1 : To a -78 °C solution of DIPEA (7.74 mL, 55.2 mmol) in THF (35 mL) was added nBuLi (1.6 M in hexane, 34.5 mL, 55.2 mmol) dropwise and the reaction mixture was stirred for 5 min. A solution of 4,6-dichloro-2-methylpyrimidine (5.0 g, 30.7 mmol) in THF (40 mL) was added dropwise to freshly prepared LDA and stirring was continued at -78 °C for 1 h. The reaction mixture was quenched with freshly ground dry ice (20 g, 454 mmol) and stirred for 5 min before warming to room temperature over 20 min and stirring for an additional 15 min. The reaction mixture was concentrated in vacuo to afford lithium 4,6-dichloro-2-methylpyrimidine-5-carboxylate as a brown solid, which was used further without purification. LC-MS J: tR = 0.16 min; [MH] - = 204.9.
步驟 2 ：向4,6-二氯-2-甲基嘧啶-5-甲酸鋰(6.54 g，30.7 mmol)於DMF (50 mL)中之室溫溶液中添加KHCO
3(6.15 g，61.4 mmol)及BnBr (10.95 mL，92 mmol)，且攪拌反應混合物18 h。反應混合物藉由添加H
2O及鹽水淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至5% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之4,6-二氯-2-甲基嘧啶-5-甲酸苯甲酯。LC-MS J：t
R= 2.13 min；[M+H]
+= 296.9。
Step 2 : To a room temperature solution of lithium 4,6-dichloro-2-methylpyrimidine-5-carboxylate (6.54 g, 30.7 mmol) in DMF (50 mL) was added KHCO 3 (6.15 g, 61.4 mmol) and BnBr (10.95 mL, 92 mmol), and the reaction mixture was stirred for 18 h. The reaction mixture was quenched by addition of H2O and brine and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 5% EtOAc/heptane) to afford benzyl 4,6-dichloro-2-methylpyrimidine-5-carboxylate as a colorless oil. LC-MS J: tR = 2.13 min; [M+H] + = 296.9.
步驟 3 ：向4,6-二氯-2-甲基嘧啶-5-甲酸苯甲酯(2.68 g，5.41 mmol)於THF (15 mL)中之0℃溶液中逐滴添加NaOMe (於MeOH中之30%溶液，1.0 mL，5.41 mmol)，且攪拌反應混合物1 h。反應混合物用1M HCl水溶液淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至7% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之4-氯-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯。LC-MS J：t
R= 2.15 min；[M+H]
+= 293.1。
Step 3 : To a 0°C solution of 4,6-dichloro-2-methylpyrimidine-5-carboxylate benzyl ester (2.68 g, 5.41 mmol) in THF (15 mL) was added NaOMe (in MeOH) dropwise 30% solution of , 1.0 mL, 5.41 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 7% EtOAc/heptane) to afford benzyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate as a colorless oil. LC-MS J: tR = 2.15 min; [M+H] + = 293.1.
步驟 4 ：向烯丙醇(0.21 mL，3.1 mmol)於THF (10 mL)中之0℃溶液中添加NaH (於礦物油中之60%分散液，128 mg，3.21 mmol)，且攪拌所得懸浮液10 min，之後將其緩慢添加至4-氯-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯於THF (15 mL)中之-10℃溶液中，且攪拌反應混合物1 h。反應混合物用1M HCl水溶液淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至10% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之4-(烯丙氧基)-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯。LC-MS J：t
R= 2.24 min；[M+H]
+= 315.1。
Step 4 : To a 0°C solution of allyl alcohol (0.21 mL, 3.1 mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil, 128 mg, 3.21 mmol) and the resulting suspension was stirred solution for 10 min, after which it was slowly added to a -10 °C solution of benzyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate in THF (15 mL), and the reaction mixture was stirred 1 h. The reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc (3x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 10% EtOAc/heptane) to give 4-(allyloxy)-6-methoxy-2-methylpyrimidine-5-carboxylic acid as a colorless oil Benzyl esters. LC-MS J: tR = 2.24 min; [M+H] + = 315.1.
步驟 5 ：向4-(烯丙氧基)-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯(170 mg，0.54 mmol)及1,3-二甲基巴比妥酸(127 mg，0.81 mmol)於MeCN (10 mL)中之室溫溶液(經脫氣)中添加Pd(PPh
3)
4(43.7 mg，0.038 mmol)，且將反應混合物加熱至50℃持續2.5 h。過濾反應混合物且濃縮，得到呈灰色固體狀之4-羥基-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯。LC-MS J：t
R= 1.63 min；[M+H]
+= 275.1。
Step 5 : Add 4-(allyloxy)-6-methoxy-2-methylpyrimidine-5-carboxylic acid benzyl ester (170 mg, 0.54 mmol) and 1,3-dimethylbarbituric acid (127 mg, 0.81 mmol) in MeCN (10 mL) at room temperature (degassed) was added Pd( PPh3 ) 4 (43.7 mg, 0.038 mmol) and the reaction mixture was heated to 50 °C for 2.5 h . The reaction mixture was filtered and concentrated to afford benzyl 4-hydroxy-6-methoxy-2-methylpyrimidine-5-carboxylate as a gray solid. LC-MS J: tR = 1.63 min; [M+H] + = 275.1.
步驟 6 及 7 ：類似於對於B-1.1步驟2及3所描述之程序，在Boc裂解步驟中用HCl替代TFA，由4-羥基-6-甲氧基-2-甲基嘧啶-5-甲酸苯甲酯製備標題化合物。LC-MS J：t
R= 2.17 min；[M+H]
+= 408.2。
Steps 6 and 7 : Similar to the procedure described for B-1.1 Steps 2 and 3, replacing TFA with HCl in the Boc cleavage step, from 4-hydroxy-6-methoxy-2-methylpyrimidine-5-carboxylic acid Benzyl ester to prepare the title compound. LC-MS J: tR = 2.17 min; [M+H] + = 408.2.
(
R)-4-(2-
胺基 -3- 苯基丙氧基 )-2,6- 二甲氧基菸鹼酸乙酯 (B-4.17) 步驟 1 ：向2,4,6-三氟吡啶(1.0 g，7.14 mmol)於DMF (4 mL)中之-78℃溶液中添加苯甲醇(0.82 mL，7.85 mmol)及KO
t Bu (867 mg，7.5 mmol)於DMF (4 mL)中之溶液，且攪拌反應混合物10 min。反應混合物用水淬滅且升溫至0℃，之後過濾。過濾之殘餘物自庚烷再結晶，得到呈白色固體狀之4-(苯甲氧基)-2,6-二氟吡啶。LC-MS B：t
R= 0.99 min；[M+H]
+= 222.27。
( R )-4-(2- amino -3- phenylpropoxy )-2,6- dimethoxynicotinic acid ethyl ester (B-4.17) step 1 : to 2,4,6-tri To a solution of fluoropyridine (1.0 g, 7.14 mmol) in DMF (4 mL) at -78 °C was added benzyl alcohol (0.82 mL, 7.85 mmol) and KOtBu (867 mg, 7.5 mmol) in DMF (4 mL) solution, and the reaction mixture was stirred for 10 min. The reaction mixture was quenched with water and warmed to 0 °C before being filtered. The filtered residue was recrystallized from heptane to afford 4-(benzyloxy)-2,6-difluoropyridine as a white solid. LC-MS B: tR = 0.99 min; [M+H] + = 222.27.
步驟 2 ：將4-(苯甲氧基)-2,6-二氟吡啶(1.71 g，7.56 mmol)於NaOMe (25 wt%於MeOH中，6.9 mL，30.2 mmol)中之懸浮液加熱至60℃持續18 h。真空濃縮反應混合物，且將殘餘物分配於水與TBME之間，且分離各層。水相用TBME (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈無色油狀之4-(苯甲氧基)-2,6-二甲氧基吡啶。LC-MS B：t
R= 1.02 min；[M+H]
+= 246.29。
Step 2 : A suspension of 4-(benzyloxy)-2,6-difluoropyridine (1.71 g, 7.56 mmol) in NaOMe (25 wt% in MeOH, 6.9 mL, 30.2 mmol) was heated to 60 ℃ for 18 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and TBME, and the layers were separated. The aqueous phase was re-extracted with TBME (2×), and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give 4-(benzyloxy)-2 as a colorless oil. ,6-Dimethoxypyridine. LC-MS B: tR = 1.02 min; [M+H] + = 246.29.
步驟 3-6 ：類似於對於B-4.12步驟3-6所描述之程序，由4-(苯甲氧基)-2,6-二甲氧基吡啶製備標題化合物。注意：使用TFA替代HCl進行Boc-裂解，且在鹼性處理之後分離出呈其游離鹼形式之標題化合物。LC-MS B：t
R= 0.73 min；[M+H]
+= 361.23。
Step 3-6 : The title compound was prepared from 4-(benzyloxy)-2,6-dimethoxypyridine in analogy to the procedure described for B-4.12 Step 3-6. Note: Boc-cleavage was performed using TFA instead of HCl and the title compound was isolated in its free base form after basic treatment. LC-MS B: tR = 0.73 min; [M+H] + = 361.23.
(S)-6-(2- 胺基 -3- 苯基丙氧基 )-3- 氟喹啉 -5- 甲酸苯甲酯二鹽酸鹽 (B-4.18)類似於對於B-4.7所描述之程序，且在光延步驟中使用(
S)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯，由3-氟喹啉-6-醇製備標題化合物。LC-MS I：t
R= 1.07 min；[M+H]
+= 431.08。
(S)-Benzyl 6-(2- amino -3- phenylpropoxy )-3- fluoroquinoline -5- carboxylate dihydrochloride (B-4.18) is similar to that described for B-4.7 The title compound was prepared from 3-fluoroquinolin-6-ol using ( S )-(1-hydroxy-3-phenylpropan-2-yl)carbamate tert-butyl ester in the Mitsunobu procedure. LC-MS I: tR = 1.07 min; [M+H] + = 431.08.
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
55
(
R)-2-(2-胺基-3-苯基丙氧基)-6-(甲氧基-d3)苯甲酸苯甲酯鹽酸鹽(B-5.1)
步驟 1 ：向2,6-二羥基苯甲酸(3.0 g，19.7 mmol)於1,2-二甲氧基乙烷(15 mL)中之0℃溶液中添加DMAP (120 mg，0.99 mmol)，隨後逐滴添加丙酮(1.9 mL，25.8 mmol)及亞硫醯二氯(1.85 mL，25.2 mmol)，且攪拌反應混合物30 min，之後升溫至室溫且攪拌16 h。反應混合物藉由添加NaHCO
3飽和水溶液淬滅且用Et
2O (4×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至50% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之5-羥基-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮。LC-MS F：t
R= 1.93 min；[M+H]
+= 195.1。
( R )-2-(2-amino-3-phenylpropoxy)-6-(methoxy-d3)benzoic acid benzyl hydrochloride (B-5.1) step 1 : to 2,6 To a solution of -dihydroxybenzoic acid (3.0 g, 19.7 mmol) in 1,2-dimethoxyethane (15 mL) at 0 °C was added DMAP (120 mg, 0.99 mmol), followed by dropwise addition of acetone (1.9 mL, 25.8 mmol) and thionyl dichloride (1.85 mL, 25.2 mmol), and the reaction mixture was stirred for 30 min, then warmed to room temperature and stirred for 16 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO 3 and extracted with Et 2 O (4×). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 50% EtOAc/heptane) to give 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3] as a white solid Dioxin-4-one. LC-MS F: tR = 1.93 min; [M+H] + = 195.1.
步驟 2 ：向5-羥基-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮(1.76 g，8.6 mmol)及K
2CO
3(1.79 g，12.9 mmol)於DMF (25 mL)中之溶液中添加CD
3I (0.8 mL，12.9 mmol)，且將反應混合物加熱至50℃持續1 h。將反應混合物分配於水與EtOAc之間，且分離各層。水相用EtOAc (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用10%至100% EtOAc/庚烷溶離)純化粗產物，得到呈灰白色固體狀之5-(甲氧基-d3)-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮。LC-MS J：t
R= 1.82 min；[M+H]
+= 212.1。
Step 2 : Addition of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxine-4-one (1.76 g, 8.6 mmol) and K 2 CO 3 (1.79 g, 12.9 mmol) in DMF (25 mL) was added CD3I (0.8 mL, 12.9 mmol) and the reaction mixture was heated to 50 °C for 1 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (1×), and the combined org. layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 10% to 100% EtOAc/heptane) to afford 5-(methoxy-d3)-2,2-dimethyl-4H-benzo[d3] as an off-white solid ][1,3]dioxin-4-one. LC-MS J: tR = 1.82 min; [M+H] + = 212.1.
步驟 3 ：向苯甲醇(1.7 mL，16.3 mmol)於DMF 45 mL)中之溶液中添加NaH (0.65 g，16.3 mmol)，且攪拌反應混合物30 min，之後添加5-(甲氧基-d3)-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮(1.72 g，8.1 mmol)於DMF(5 mL)中之溶液且繼續攪拌1 h。將反應混合物分配於1N HCl與EtOAc之間，且分離各層。水相用EtOAc (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至50% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之2-羥基-6-(甲氧基-d3)苯甲酸苯甲酯。LC-MS J：t
R= 2.13 min；[M+H]
+= 262.1。
Step 3 : To a solution of benzyl alcohol (1.7 mL, 16.3 mmol) in DMF (45 mL) was added NaH (0.65 g, 16.3 mmol) and the reaction mixture was stirred for 30 min before adding 5-(methoxy-d3) - A solution of 2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (1.72 g, 8.1 mmol) in DMF (5 mL) and continued stirring 1 h. The reaction mixture was partitioned between 1N HCl and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (1×), and the combined org. layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 50% EtOAc/heptane) to afford benzyl 2-hydroxy-6-(methoxy-d3)benzoate as a colorless oil. LC-MS J: tR = 2.13 min; [M+H] + = 262.1.
步驟 4 ：類似於對於B-1.1步驟2所描述之程序，由2-羥基-6-(甲氧基-d3)苯甲酸苯甲酯及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-6-(甲氧基-d3)苯甲酸苯甲酯。LC-MS J：t
R= 2.39 min；[M-Boc+H]
+= 395.2。
Step 4 : Similar to the procedure described for B-1.1 Step 2, from 2-hydroxy-6-(methoxy-d3)benzyl benzoate and ( R )-(1-hydroxy-3-phenylpropane Preparation of ( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-6-(methoxy -d3) Benzyl benzoate. LC-MS J: tR = 2.39 min; [M-Boc+H] + = 395.2.
步驟 5 ：類似於對於B-1.1步驟3所描述之程序，製備標題化合物。LC-MS J：t
R= 2.15 min；[M+H]
+= 395.1。
Step 5 : The title compound was prepared analogously to the procedure described for B-1.1 Step 3. LC-MS J: tR = 2.15 min; [M+H] + = 395.1.
(
R)-2-(2-胺基-3-苯基丙氧基)-6-(二氟甲氧基)苯甲酸苯甲酯鹽酸鹽(B-5.2)
步驟 1 ：向5-羥基-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮(B-5.1步驟1，1.58 g，8.1 mmol)於MeCN (12 mL)中之0℃溶液中添加KOH (4.57 g，81 mmol)於水(12 mL)中之溶液，且攪拌二相反應混合物5 min，之後逐滴添加二乙基膦酸溴二氟甲酯(2.0 mL，11.4 mmol)。在攪拌1.5 h之後，添加EtOAc (25 mL)且分離各相。水相用EtOAc (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈棕色油狀之5-(二氟甲氧基)-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮。LC-MS J：t
R= 2.0 min；[M+H]
+= 245.1。
( R )-2-(2-amino-3-phenylpropoxy)-6-(difluoromethoxy)benzoic acid benzyl hydrochloride (B-5.2) step 1 : to 5-hydroxy -2,2-Dimethyl-4H-benzo[d][1,3]dioxin-4-one (B-5.1 Step 1, 1.58 g, 8.1 mmol) in MeCN (12 mL) A solution of KOH (4.57 g, 81 mmol) in water (12 mL) was added to a solution at 0 °C in , and the biphasic reaction mixture was stirred for 5 min, after which bromodifluoromethyl diethylphosphonate (2.0 mL, 11.4 mmol). After stirring for 1.5 h, EtOAc (25 mL) was added and the phases were separated. The aqueous phase was re-extracted with EtOAc (1×), and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give 5-(difluoromethoxy)-2 as a brown oil. , 2-Dimethyl-4H-benzo[d][1,3]dioxine-4-one. LC-MS J: tR = 2.0 min; [M+H] + = 245.1.
步驟 2-4 ：按照對於B-5.1所描述之反應順序，由5-(二氟甲氧基)-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮製備標題化合物。LC-MS J：t
R= 2.20 min；[M+H]
+= 428.1。
Step 2-4 : Following the reaction sequence described for B-5.1, 5-(difluoromethoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxa Cyclohexen-4-one Preparation of the title compound. LC-MS J: tR = 2.20 min; [M+H] + = 428.1.
(
R)-6-(2-胺基-3-苯基丙氧基)-2-甲基苯并呋喃-7-甲酸甲酯鹽酸鹽(B-5.3)
步驟 1 ：向5-羥基-2,2-二甲基-4H-苯并[d][1,3]二氧雜環己烯-4-酮(B-5.1步驟1，3.0 g，15.4 mmol)於丙酮(60 mL)中之室溫溶液中添加K
2CO
3(2.38 g，17.2 mmol)及3-溴丙炔(於PhMe中之80%溶液，1.67 mL，15.5 mmol)，且將反應混合物加熱至55℃持續21 h。濃縮混合物，且將殘餘物分配於水與EtOAc之間。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用5%至35% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之2,2-二甲基-5-(丙-2-炔-1-基氧基)-4H-苯并[d][1,3]二氧雜環己烯-4-酮。LC-MS J：t
R= 1.83 min；[M+H]
+= 233.1。
( R )-6-(2-amino-3-phenylpropoxy)-2-methylbenzofuran-7-carboxylic acid methyl ester hydrochloride (B-5.3) step 1 : to 5-hydroxy- 2,2-Dimethyl-4H-benzo[d][1,3]dioxin-4-one (B-5.1 step 1, 3.0 g, 15.4 mmol) in acetone (60 mL) To a room temperature solution of K2CO3 (2.38 g, 17.2 mmol) and 3 -bromopropyne (80% solution in PhMe, 1.67 mL, 15.5 mmol) were added, and the reaction mixture was heated to 55 °C for 21 h . The mixture was concentrated, and the residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. Purification of the crude product by FC (elution with 5% to 35% EtOAc/heptane) afforded 2,2-dimethyl-5-(prop-2-yn-1-yloxy)- 4H-Benzo[d][1,3]dioxin-4-one. LC-MS J: tR = 1.83 min; [M+H] + = 233.1.
步驟 2 ：向2,2-二甲基-5-(丙-2-炔-1-基氧基)-4H-苯并[d][1,3]二氧雜環己烯-4-酮(1.53 g，6.6 mmol)於DMF (15 mL)中之0℃溶液中添加NaOMe (於MeOH中之30%溶液，1.9 mL，10.1 mmol)，且將反應混合物升溫至室溫並攪拌1 h。反應混合物用1M HCl水溶液淬滅且用EtOAc (3×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈米色固體狀之2-羥基-6-(丙-2-炔-1-基氧基)苯甲酸甲酯。LC-MS J：t
R= 1.79 min；[M+H]
+= 207.0。
Step 2 : To 2,2-dimethyl-5-(prop-2-yn-1-yloxy)-4H-benzo[d][1,3]dioxine-4-one (1.53 g, 6.6 mmol) in DMF (15 mL) at 0 °C was added NaOMe (30% solution in MeOH, 1.9 mL, 10.1 mmol), and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 2-hydroxy-6-(prop-2-yn-1-yloxy)benzoic acid methyl as a beige solid ester. LC-MS J: tR = 1.79 min; [M+H] + = 207.0.
步驟 3 ：2-羥基-6-(丙-2-炔-1-基氧基)苯甲酸甲酯(1.33 g，6.5 mmol)CsF (1.5 g，9.9 mmol)及二乙基苯胺(18 mL)之混合物用N
2吹掃，之後在微波爐中在200℃照射55 min。反應混合物用EtOAc稀釋且用1M HCl水溶液洗滌。水相用EtOAc (2×)萃取，且經合併之有機萃取物用1M HCl、鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用1%至15% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之6-羥基-2-甲基苯并呋喃-7-甲酸甲酯。LC-MS F：t
R= 1.98 min；[M+H]
+= 207.0。
Step 3 : Methyl 2-hydroxy-6-(prop-2-yn-1-yloxy)benzoate (1.33 g, 6.5 mmol) CsF (1.5 g, 9.9 mmol) and diethylaniline (18 mL) The mixture was purged with N2 and then irradiated in a microwave oven at 200 °C for 55 min. The reaction mixture was diluted with EtOAc and washed with 1M aq. HCl. The aqueous phase was extracted with EtOAc ( 2x), and the combined org. extracts were washed with 1M HCl, brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (elution with 1% to 15% EtOAc/heptane) to afford methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate as a white solid. LC-MS F: tR = 1.98 min; [M+H] + = 207.0.
步驟 4-5 ：類似於對於B-1.1步驟2-3所描述之程序，由6-羥基-2-甲基苯并呋喃-7-甲酸甲酯製備標題化合物。LC-MS J：t
R= 1.98 min；[M+H]
+= 340.1。
Step 4-5 : The title compound was prepared from methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate in analogy to the procedure described for B-1.1 Step 2-3. LC-MS J: tR = 1.98 min; [M+H] + = 340.1.
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
66
(
R)-6-(2-胺基-3-苯基丙氧基)-3-甲基苯并[d]異㗁唑-7-甲酸甲酯鹽酸鹽(B-6.1)
步驟 1 ：向3-甲基-1,2-苯并異㗁唑-6-醇(2.0 g，13.4 mmol)於AcOH (40 mL)中之溶液中添加六亞甲基四胺(8.1 g，57.1 mmol)，且將反應混合物加熱至100℃持續2 h。添加2M HCl水溶液(40 mL)，且在100℃繼續攪拌30 min。反應混合物用冰浴冷卻，且藉由過濾收集所得固體。真空濃縮濾液且再冷卻至0℃，之後再次藉由過濾收集固體。將兩個產物(crop)合併且真空乾燥，得到呈米色粉末狀之6-羥基-3-甲基苯并[d]異㗁唑-7-甲醛。LC-MS B：t
R= 0.72 min；無電離。
1H NMR (DMSO)
δ: 11.67 (s, 1 H), 10.43 (s, 1 H), 7.94 (d,
J= 8.7 Hz, 1 H), 7.03 (d,
J= 8.7 Hz, 1 H)。
( R )-6-(2-amino-3-phenylpropoxy)-3-methylbenzo[d]isoxazole-7-carboxylic acid methyl ester hydrochloride (B-6.1) step 1 : To a solution of 3-methyl-1,2-benzisoxazol-6-ol (2.0 g, 13.4 mmol) in AcOH (40 mL) was added hexamethylenetetramine (8.1 g, 57.1 mmol) , and the reaction mixture was heated to 100 °C for 2 h. Aqueous 2M HCl (40 mL) was added and stirring was continued at 100 °C for 30 min. The reaction mixture was cooled with an ice bath, and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo and recooled to 0 °C before the solid was again collected by filtration. The two crops were combined and dried in vacuo to give 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde as a beige powder. LC-MS B: tR = 0.72 min; no ionization. 1 H NMR (DMSO) δ : 11.67 (s, 1 H), 10.43 (s, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H).
步驟 2 ：向6-羥基-3-甲基苯并[d]異㗁唑-7-甲醛(1.09 g，6.1 mmol)於THF (40 mL)及三級丁醇(12 mL)中之室溫溶液中一次性添加2-甲基-2-丁烯(7.33 mL，69.2 mmol)，隨後添加NaClO
2(2.06 g，18.2 mmol)及NaH
2PO
4.2H
2O (4.3 g，27.3 mmol)於H
2O (12 mL)中之溶液，且在室溫攪拌反應混合物30 min。固體藉由過濾收集，用冷的1M HCl水溶液洗滌且真空乾燥，得到呈白色固體狀之6-羥基-3-甲基苯并[d]異㗁唑-7-甲酸。LC-MS B：t
R= 0.63 min；[M+H]
+= 194.31。
Step 2 : Add 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde (1.09 g, 6.1 mmol) to room temperature in THF (40 mL) and tertiary butanol (12 mL) 2-Methyl-2-butene (7.33 mL, 69.2 mmol) was added to the solution at one time, followed by NaClO 2 (2.06 g, 18.2 mmol) and NaH 2 PO 4 .2H 2 O (4.3 g, 27.3 mmol) in solution in H2O (12 mL), and the reaction mixture was stirred at room temperature for 30 min. The solid was collected by filtration, washed with cold 1M aqueous HCl and dried in vacuo to afford 6-hydroxy-3-methylbenzo[d]isoxazole-7-carboxylic acid as a white solid. LC-MS B: tR = 0.63 min; [M+H] + = 194.31.
步驟 3-5 ：按照對於B-3.1所描述之反應順序，由6-羥基-3-甲基苯并[d]異㗁唑-7-甲酸製備標題化合物。LC-MS B：t
R= 0.70 min；[M+H]
+= 341.38。
Step 3-5 : The title compound was prepared from 6-hydroxy-3-methylbenzo[d]isoxazole-7-carboxylic acid following the reaction sequence described for B-3.1. LC-MS B: tR = 0.70 min; [M+H] + = 341.38.
(
R)-5-(2-胺基-3-苯基丙氧基)-1-甲基-1H-吲唑-4-甲酸甲酯鹽酸鹽(B-6.2) 按照對於B-6.1所描述之反應順序，由1-甲基-1H-吲唑-5-醇製備標題化合物。LC-MS B：t
R= 0.70 min；[M+H]
+= 340.36。
( R )-5-(2-Amino-3-phenylpropoxy)-1-methyl-1H-indazole-4-carboxylic acid methyl ester hydrochloride (B-6.2) According to B-6.1 The reaction sequence described prepared the title compound from 1-methyl-1H-indazol-5-ol. LC-MS B: tR = 0.70 min; [M+H] + = 340.36.
用於合成建構嵌段for the synthesis of building blocks
BB
之通用方法general method
77
(
R)-6-(2-胺基-3-苯基丙氧基)異喹啉-5-甲酸甲酯二鹽酸鹽(B-7.1)
步驟 1 ：在水浴中，向異喹啉-6-醇(2.0 g，13.8 mmol)於CHCl
3(30 mL)中之懸浮液中逐滴添加Br
2(0.78 mL，15.2 mmol)，且攪拌反應混合物2 h。添加EtOAc，且固體藉由過濾收集並用EtOAc及接著庚烷洗滌。過濾殘餘物藉由懸浮於NaHCO
3飽和水溶液中中和且再過濾，之後用H
2O及接著庚烷洗滌。將過濾殘餘物懸浮於MeCN中且真空蒸發，得到呈棕色固體狀之5-溴異喹啉-6-醇。LC-MS J：t
R= 0.33 min；[M+H]
+= 224.0。
( R )-6-(2-Amino-3-phenylpropoxy)isoquinoline-5-carboxylic acid methyl ester dihydrochloride (B-7.1) step 1 : in a water bath, add isoquinoline- To a suspension of 6-alcohol (2.0 g, 13.8 mmol) in CHCl 3 (30 mL) was added Br 2 (0.78 mL, 15.2 mmol) dropwise, and the reaction mixture was stirred for 2 h. EtOAc was added and the solid was collected by filtration and washed with EtOAc and then heptane. The filtered residue was neutralized by suspending in sat. aq. NaHCO 3 and re-filtered before washing with H 2 O and then heptane. The filtered residue was suspended in MeCN and evaporated in vacuo to give 5-bromoisoquinolin-6-ol as a brown solid. LC-MS J: tR = 0.33 min; [M+H] + = 224.0.
步驟 2 ：類似於對於B-1.1步驟2所描述之程序，由5-溴異喹啉-6-醇及(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯製備(
R)-(1-((5-溴異喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯。LC-MS J：t
R= 2.28 min；[M+H]
+= 457.1。
Step 2 : Similar to the procedure described for B-1.1 Step 2, from 5-bromoisoquinolin-6-ol and ( R )-(1-hydroxyl-3-phenylpropan-2-yl)carbamic acid Tertiary butyl ester Preparation of tertiary butyl ( R )-(1-((5-bromoisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate. LC-MS J: tR = 2.28 min; [M+H] + = 457.1.
步驟 3 ：DIPEA (0.76 mL，4.4 mmol)於MeOH (3 mL)中之溶液用Ar吹掃，之後添加Pd(OAc)
2(74 mg，0.33 mmol)及Xantphos (190 mg，0.33 mmol)，且將催化劑混合物加熱至70℃持續20 min。在單獨的燒瓶中，(
R)-(1-((5-溴異喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯(1.0 g，2.19 mmol)於MeOH (40 mL)中之溶液首先用Ar吹掃，之後用CO吹掃，且接著在CO氛圍下加熱至70℃，之後經由注射器添加熱的催化劑溶液，且攪拌反應混合物20 h。將反應混合物冷卻至室溫且真空濃縮，且將殘餘物分配於NaHCO
3飽和水溶液與DCM之間並萃取。分離各層，且水相用DCM (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用25%至80% EtOAc/庚烷溶離)純化粗產物，得到呈黑色固體之(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)異喹啉-5-甲酸甲酯。LC-MS J：t
R= 2.11 min；[M+H]
+= 437.2。
Step 3 : A solution of DIPEA (0.76 mL, 4.4 mmol) in MeOH (3 mL) was purged with Ar, after which Pd(OAc) 2 (74 mg, 0.33 mmol) and Xantphos (190 mg, 0.33 mmol) were added, and The catalyst mixture was heated to 70 °C for 20 min. In a separate flask, ( R )-(1-((5-bromoisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (1.0 g , 2.19 mmol) in MeOH (40 mL) was first purged with Ar, then with CO, and then heated to 70 °C under a CO atmosphere, after which the hot catalyst solution was added via syringe, and the reaction mixture was stirred for 20 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO 3 and DCM and extracted. The layers were separated, and the aqueous phase was re-extracted with DCM (1×), and the combined org. layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 25% to 80% EtOAc/heptane) to afford ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3-benzene as a black solid Methyl propoxy)isoquinoline-5-carboxylate. LC-MS J: tR = 2.11 min; [M+H] + = 437.2.
步驟 4 ：類似於對於B-1.1步驟3所描述之程序，由(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)異喹啉-5-甲酸甲酯製備標題化合物。LC-MS J：t
R= 1.83 min；[M+H]
+= 337.2。
Step 4 : Similar to the procedure described for B-1.1 Step 3, from ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)isoquinoline - Methyl 5-carboxylate to prepare the title compound. LC-MS J: tR = 1.83 min; [M+H] + = 337.2.
(
R)-6-(2-
胺基 -3- 苯基丙氧基 )-3- 甲基異喹啉 -5- 甲酸苯甲酯二鹽酸鹽 (B-7.2) 步驟 1 ：向2-羥基-4-甲氧基苯甲醛(16 g，105 mmol)及吡啶(42.5 mL，526 mmol)於DCM (70 mL)中之-10℃溶液中逐滴添加三氟甲烷磺酸酐(26.2 mL，158 mmol)，且攪拌反應混合物30 min。反應混合物用冰水淬滅且用1M HCl水溶液酸化，之後用EtOAc (2×)萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之三氟甲烷磺酸2-甲醯基-5-甲氧基苯酯。
1H NMR (400 MHz, CDCl
3) δ 10.13 (s, 1H), 7.95 (d,
J= 8.8 Hz, 1H), 7.03 (dd,
J= 8.7, 2.3 Hz, 1H), 6.88 (d,
J= 2.3 Hz, 1H), 3.93 (s, 3H)。
( R )-6-(2- Amino -3- phenylpropoxy )-3- methylisoquinoline -5- formic acid benzyl ester dihydrochloride (B-7.2) step 1 : to 2- To a solution of hydroxy-4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL) at -10 °C was added dropwise trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol), and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with ice water and acidified with 1M aqueous HCl before extraction with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 10.13 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.7, 2.3 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H).
步驟 2 ：三氟甲烷磺酸2-甲醯基-5-甲氧基苯酯(19.6 g，66.4 mmol)及TEA (93 mL，664 mmol)於DMF (400 mL)中之室溫溶液用Ar吹掃30 min。依次添加丙-1-炔(1 M於DMF中，133 mL，133 mmol)、CuI (1.27 g，6.64 mmol)及Pd(PPh
3)
4(5.0 g，4.33 mmol)，且封閉攪拌反應混合物2 h。反應混合物經由矽藻土墊過濾且部分地真空濃縮濾液，之後用EtOAc稀釋，且依次用1M KHSO
4溶液及鹽水洗滌並真空濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離)純化粗產物，得到呈黃色固體狀之4-甲氧基-2-(丙-1-炔-1-基)苯甲醛。LC-MS J：t
R= 1.80 min；[M+H]
+= 175.1。
Step 2 : A room temperature solution of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) was washed with Ar Purge for 30 min. Prop-1-yne (1 M in DMF, 133 mL, 133 mmol), CuI (1.27 g, 6.64 mmol) and Pd(PPh 3 ) 4 (5.0 g, 4.33 mmol) were added sequentially, and the reaction mixture was closed and stirred 2 h. The reaction mixture was filtered through a pad of Celite and the filtrate was partially concentrated in vacuo before being diluted with EtOAc and washed sequentially with 1M KHSO 4 solution and brine and concentrated in vacuo. The crude product was purified by FC (eluted with 0% to 30% EtOAc/heptane) to afford 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde as a yellow solid. LC-MS J: tR = 1.80 min; [M+H] + = 175.1.
步驟 3 ：在高壓釜中，4-甲氧基-2-(丙-1-炔-1-基)苯甲醛(10.3 g，58.8 mmol)於MeOH (350 mL)中之室溫溶液用Ar吹掃5 min。添加含7M NH
3之MeOH (150 mL，1050 mmol)，且在2巴下將反應混合物加熱至65℃持續4 h。真空濃縮反應混合物，且將殘餘物與DCM (2×)一起共蒸發，得到呈棕色固體狀之6-甲氧基-3-甲基異喹啉。LC-MS J：t
R= 1.81 min；[M+H]
+= 174.1。
Step 3 : In an autoclave, a room temperature solution of 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde (10.3 g, 58.8 mmol) in MeOH (350 mL) was blown with Ar Sweep for 5 min. 7M NH3 in MeOH (150 mL, 1050 mmol) was added and the reaction mixture was heated to 65 °C at 2 bar for 4 h. The reaction mixture was concentrated in vacuo, and the residue was co-evaporated with DCM (2x) to give 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS J: tR = 1.81 min; [M+H] + = 174.1.
步驟 4 ：向6-甲氧基-3-甲基異喹啉(5.0 g，27.7 mmol)於DCM (100 mL)中之-78℃溶液中逐滴添加BBr
3(1 M於DCM中，55.4 mL，55.4 mmol)。移除冷卻浴，且在室溫攪拌反應混合物30 h。將反應混合物小心地淬滅至冷MeOH中且真空濃縮。將殘餘物與PhMe、EtOAc及DCM一起共蒸發，得到呈棕色固體狀之3-甲基異喹啉-6-醇。LC-MS J：t
R= 1.10 min；[M+H]
+= 160.1。
Step 4 : To a -78°C solution of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL) was added BBr 3 (1 M in DCM, 55.4 mL, 55.4 mmol). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 h. The reaction mixture was carefully quenched into cold MeOH and concentrated in vacuo. The residue was co-evaporated with PhMe, EtOAc and DCM to give 3-methylisoquinolin-6-ol as a brown solid. LC-MS J: tR = 1.10 min; [M+H] + = 160.1.
步驟 5-6 ：按照對於B-7.1所描述之步驟1及2，由3-甲基異喹啉-6-醇製備(R)-(1-((5-溴-3-甲基異喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯。LC-MS J：t
R= 2.20 min；[M+H]
+= 471.1。
Step 5-6 : Preparation of (R)-(1-((5-bromo-3-methylisoquinoline (Phenyl-6-yl)oxy)-3-phenylpropan-2-yl)carbamate tertiary butyl ester. LC-MS J: tR = 2.20 min; [M+H] + = 471.1.
步驟 7 ：(R)-(1-((5-溴-3-甲基異喹啉-6-基)氧基)-3-苯基丙-2-基)胺基甲酸三級丁酯(2.5 g，5.30 mmol)、苯甲醇(2.76 mL，26.5 mmol)及DIPEA (2.78 mL，15.9 mmol)於PhMe (20 mL)中之室溫溶液用Ar吹掃10 min。接著，反應混合物用CO吹掃且在CO氛圍下加熱至88℃，之後經由注射泵(3 mL/h)添加Pd(
t Bu
3P)
2(271 mg，0.53 mmol)於PhMe (5.5 mL)中之溶液。升溫至95℃且在CO氛圍下攪拌反應混合物24 h。將反應混合物冷卻至室溫且真空濃縮，且將殘餘物分配於NaHCO
3飽和水溶液與EtOAc之間並萃取。分離各層，且水相用EtOAc (1×)再萃取，且經合併之有機層用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用5%至65% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之(R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-3-甲基異喹啉-5-甲酸苯甲酯。LC-MS J：t
R= 2.19 min；[M+H]
+= 527.2。
Step 7 : (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate tertiary butyl ester ( A room temperature solution of 2.5 g, 5.30 mmol), benzyl alcohol (2.76 mL, 26.5 mmol) and DIPEA (2.78 mL, 15.9 mmol) in PhMe (20 mL) was purged with Ar for 10 min. Next, the reaction mixture was purged with CO and heated to 88 °C under CO atmosphere, after which Pd( tBu3P ) 2 (271 mg, 0.53 mmol ) in PhMe (5.5 mL) was added via syringe pump (3 mL/h) solution in. The temperature was raised to 95 °C and the reaction mixture was stirred under CO atmosphere for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO 3 and EtOAc and extracted. The layers were separated, and the aqueous phase was re-extracted with EtOAc (1×), and the combined org. layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 5% to 65% EtOAc/heptane) to afford (R)-6-(2-((tertiary butoxycarbonyl)amino)-3- phenylpropoxy)-3-methylisoquinoline-5-carboxylic acid benzyl ester. LC-MS J: tR = 2.19 min; [M+H] + = 527.2.
步驟 8 ：類似於對於B-1.1步驟3所描述之程序，由(R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-3-甲基異喹啉-5-甲酸苯甲酯製備標題化合物。LC-MS J：t
R= 1.95 min；[M+H]
+= 427.2。
Step 8 : Similar to the procedure described for B-1.1 Step 3, from (R)-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-3- Benzyl methylisoquinoline-5-carboxylate to prepare the title compound. LC-MS J: tR = 1.95 min; [M+H] + = 427.2.
建構嵌段building blocks
B-B-
酸之合成acid synthesis
(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸(B-酸-1)
步驟 1 ：類似於對於B-1.1步驟1所描述之程序，由6-羥基苯并[d][1,3]二氧呃-5-甲酸製備6-羥基苯并[d][1,3]二氧呃-5-甲酸苯甲酯。LC-MS I：t
R= 1.12 min；[M+H]
+= 272.94。
( R )-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxer-5-carboxylic acid (B- Acid-1) Step 1 : Preparation of 6-hydroxybenzo[d] from 6-hydroxybenzo[d][1,3]dioxer-5-carboxylic acid similar to the procedure described for B-1.1 step 1 [1,3]Benzyl dioxer-5-carboxylate. LC-MS I: tR = 1.12 min; [M+H] + = 272.94.
步驟 2 ：類似於對於B-1.1步驟2所描述之程序，由6-羥基苯并[d][1,3]二氧呃-5-甲酸苯甲酯製備(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸苯甲酯。LC-MS I：t
R= 1.27 min；[M+H]
+= 506.02。
Step 2 : Similar to the procedure described for B-1.1 Step 2, prepare ( R )-6-(2- ((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxer-5-carboxylic acid benzyl ester. LC-MS I: tR = 1.27 min; [M+H] + = 506.02.
步驟 3 ：類似於對於B-1.24步驟4所描述之程序，由(
R)-6-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸苯甲酯製備標題化合物。LC-MS I：t
R= 0.53 min；[M+H]
+= 416.01。
Step 3 : Similar to the procedure described for B-1.24 Step 4, from ( R )-6-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)benzo[ d] [1,3]Benzyl dioxer-5-carboxylate Preparation of the title compound. LC-MS I: tR = 0.53 min; [M+H] + = 416.01.
(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲酸(B-酸-2) 按照如對於B-酸-1所描述之3-步驟順序，由2-羥基-4,5-二甲氧基苯甲酸製備標題化合物。LC-MS B：t
R= 0.98 min；[M+H]
+= 432.18。
( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-4,5-dimethoxybenzoic acid (B-acid-2) according to The title compound was prepared from 2-hydroxy-4,5-dimethoxybenzoic acid in the 3-step sequence described for B-acid-1. LC-MS B: tR = 0.98 min; [M+H] + = 432.18.
(
R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-6-甲氧基苯甲酸(B-酸-3) 按照如對於B-酸-1所描述之3-步驟順序，由2-羥基-6-甲氧基苯甲酸製備標題化合物。LC-MS I：t
R= 0.52 min；[M+H]
+= 401.88。
( R )-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-6-methoxybenzoic acid (B-acid-3) according to as for B- The title compound was prepared from 2-hydroxy-6-methoxybenzoic acid in a 3-step sequence as described in Acid-1. LC-MS I: tR = 0.52 min; [M+H] + = 401.88.
(
R)-6-(2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸(B-酸-4)
步驟 1 ：類似於對於B-1.1步驟2所描述之程序，用(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸苯甲酯替代(
R)-(1-羥基-3-苯基丙-2-基)胺基甲酸三級丁酯，由6-羥基苯并[d][1,3]二氧呃-5-甲酸苯甲酯製備(
R)-6-(2-(((苯甲氧基)羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸苯甲酯。LC-MS I：t
R= 1.27 min；[M+H]
+= 540.20。
( R )-6-(2-((((9H-Fil-9-yl)methoxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]di Oxygen-5-carboxylic acid (B-acid-4) step 1 : similar to the procedure described for B-1.1 step 2 with ( R )-(1-hydroxy-3-phenylpropan-2-yl)amine Benzyl carbamate was substituted for ( R )-(1-hydroxy-3-phenylpropan-2-yl) tertiary butyl carbamate from 6-hydroxybenzo[d][1,3]dioxer - Preparation of 5-benzyl carboxylate ( R )-6-(2-(((benzyloxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]di Benzyl oxyer-5-carboxylate. LC-MS I: tR = 1.27 min; [M+H] + = 540.20.
步驟 2 ：在添加10% Pd/C (473 mg，10 mol%)之前，將(
R)-6-(2-(((苯甲氧基)羰基)胺基)-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸苯甲酯(2.4 g，4.45 mmol)於THF (40 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌2 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到呈白色固體狀之(
R)-6-(2-胺基-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸。LC-MS B：t
R= 0.65 min；[M+H]
+= 316.13。
Step 2 : Before adding 10% Pd/C (473 mg, 10 mol%), ( R )-6-(2-((((benzyloxy)carbonyl)amino)-3-phenylpropoxy A solution of benzyl)benzo[d][1,3]dioxer-5-carboxylate (2.4 g, 4.45 mmol) in THF (40 mL) was evacuated/blown with N 2 (3×) sweep. The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford ( R )-6-(2-amino-3-phenylpropoxy)benzo[d][1,3] as a white solid Dioxoer-5-carboxylic acid. LC-MS B: tR = 0.65 min; [M+H] + = 316.13.
步驟 3 ：向(
R)-6-(2-胺基-3-苯基丙氧基)苯并[d][1,3]二氧呃-5-甲酸(1.35 g，4.28 mmol)及Na
2CO
3(926 mg，8.56 mmol)於二㗁烷(40 mL)及水(8 mL)之混合物中之室溫溶液中添加N-(9-茀基甲氧基羰基氧基)丁二醯亞胺(1.45 g，4.28 mmol)，且攪拌反應混合物16 h。真空濃縮反應混合物，且將殘餘物分配於1M HCl與EtOAc之間並萃取。過濾各層且分離，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由FC (用0%至5% MeOH/DCM溶離)純化粗產物，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 1.09 min；[M+H]
+= 538.24。
Step 3 : To ( R )-6-(2-amino-3-phenylpropoxy)benzo[d][1,3]dioxer-5-carboxylic acid (1.35 g, 4.28 mmol) and Na To a room temperature solution of 2 CO 3 (926 mg, 8.56 mmol) in a mixture of dioxane (40 mL) and water (8 mL) was added N-(9-fenylmethoxycarbonyloxy)butanediyl imine (1.45 g, 4.28 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 1M HCl and EtOAc and extracted. The layers were filtered and separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 0% to 5% MeOH/DCM) to afford the title compound as a white solid. LC-MS B: tR = 1.09 min; [M+H] + = 538.24.
(R)-2-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-1-萘甲酸(B-酸-5) 按照如對於B-酸-1所描述之3-步驟順序，由2-羥基-1-萘甲酸製備標題化合物。LC-MS B：t
R= 1.02 min；[M+H]
+= 422.33。
(R)-2-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-1-naphthoic acid (B-acid-5) Follow the procedure as for B-acid-1 The title compound was prepared from 2-hydroxy-1-naphthoic acid in a 3-step sequence as described. LC-MS B: tR = 1.02 min; [M+H] + = 422.33.
(R)-3-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)喹啉-4-甲酸(B-酸-6) 按照如對於B-酸-1所描述之3-步驟順序，由3-羥基喹啉-4-甲酸製備標題化合物。LC-MS B：t
R= 0.88 min；[M+H]
+= 423.35。
(R)-3-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylic acid (B-acid-6) according to as for B-acid- The title compound was prepared from 3-hydroxyquinoline-4-carboxylic acid according to the 3-step sequence described in 1. LC-MS B: tR = 0.88 min; [M+H] + = 423.35.
(
R)-4-(2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基菸鹼酸(B-酸-7) 按照如對於B-酸-1所描述之3-步驟順序，由4-羥基-2-甲氧基菸鹼酸製備標題化合物。LC-MS B：t
R= 0.90 min；[M+H]
+= 403.20。
( R )-4-(2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinic acid (B-acid-7) Follow the procedure as for B - The 3-step sequence described in Acid-1 for the preparation of the title compound from 4-hydroxy-2-methoxynicotinic acid. LC-MS B: tR = 0.90 min; [M+H] + = 403.20.
(R)-6-(2-((( 烯丙氧基 ) 羰基 ) 胺基 )-3- 苯基丙氧基 )-3- 氟喹啉 -5- 甲酸 (B- 酸 -8) 步驟 1 ：在N
2下，將(R)-6-(2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲酸苯甲酯二鹽酸鹽
(B-4.9)(0.46 g，0.92 mmol)溶解於MeOH (10 mL)中；在添加10% Pd/C (50 mg)之前，容器用N
2/真空(3×)吹掃。在惰性化三次之後，連接H
2氣球，且在H
2氛圍下攪拌反應混合物1 h。經由玻璃纖維過濾器過濾非均勻反應混合物(用甲醇/THF洗滌)。接著，減壓濃縮濾液至乾燥，得到0.43 g呈粗黃色油狀之(R)-6-(2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲酸，其按原樣用於下一步驟。LC-MS B：t
R= 0.62 min；[M+H]
+= 341.21。
(R)-6-(2-((( allyloxy ) carbonyl ) amino )-3- phenylpropoxy )-3- fluoroquinoline - 5- carboxylic acid (B- acid -8) step 1 : Under N 2 , (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-formyl benzyl dihydrochloride (B-4.9) ( 0.46 g, 0.92 mmol) was dissolved in MeOH (10 mL); the vessel was purged with N 2 /vacuum (3×) before adding 10% Pd/C (50 mg). After inertization three times, a H2 balloon was attached and the reaction mixture was stirred under H2 atmosphere for 1 h. The heterogeneous reaction mixture was filtered through a glass fiber filter (washed with methanol/THF). Then, the filtrate was concentrated to dryness under reduced pressure to obtain 0.43 g of (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid as a crude yellow oil, which Used as is for the next step. LC-MS B: tR = 0.62 min; [M+H] + = 341.21.
步驟 2 ：將(R)-6-(2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲酸(436 mg，1.28 mmol)溶解於THF (10 mL)及水(10 mL)中。向所得輕懸浮液中添加NaHCO
3(430 mg，5.12 mmol)，隨後添加氯甲酸烯丙酯(0.155 mL，1.41 mmol)。在室溫攪拌反應混合物1 h。將反應混合物稀釋/分配於水與EtOAc之間，且小心地用一些HCl (2N)酸化降至pH~3。分離各層且用EtOAc (2×)進一步萃取無機層。經合併之有機萃取物用酸化水及鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈黃色油狀之標題化合物(0.39 g)。在此階段無純化。LC-MS B：t
R= 0.94 min；[M+H]
+= 425.23。
Step 2 : Dissolve (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid (436 mg, 1.28 mmol) in THF (10 mL) and water (10 mL). To the resulting light suspension was added NaHCO3 (430 mg, 5.12 mmol) followed by allyl chloroformate (0.155 mL, 1.41 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted/partitioned between water and EtOAc and carefully acidified with some HCl (2N) down to pH~3. The layers were separated and the inorganic layer was further extracted with EtOAc (2x). The combined organic extracts were washed with acidified water and brine, dried over Na2SO4 , filtered and evaporated in vacuo to give the title compound (0.39 g) as a yellow oil. No purification at this stage. LC-MS B: tR = 0.94 min; [M+H] + = 425.23.
(R)-4-(2-((( 烯丙氧基 ) 羰基 ) 胺基 )-3- 苯基丙氧基 )-2- 甲氧基 -6- 甲基菸鹼酸 (B- 酸 -9)按照對於B-酸-8所描述之2-步驟順序，由(R)-4-(2-胺基-3-苯基丙氧基)-2-甲氧基-6-甲基菸鹼酸苯甲酯
(B-4.15)製備呈無色油狀之標題化合物。LC-MS B：t
R= 0.89 min；[M+H]
+= 401.07。
(R)-4-(2-((( allyloxy ) carbonyl ) amino )-3- phenylpropoxy ) -2- methoxy -6- methylnicotinic acid (B- acid- 9) Following the 2-step sequence described for B-acid-8, from (R)-4-(2-amino-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid Benzyl acid base (B-4.15) produces the title compound as a colorless oil. LC-MS B: tR = 0.89 min; [M+H] + = 401.07.
用於合成建構嵌段C之通用方法1General method for the synthesis of building block C 1
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基甘胺酸(C-1.1)
步驟 1 ：向Boc-
N-甲基甘胺酸(7.12 g，36.9 mmol)於丙酮(100 mL)中之室溫溶液中添加K
2CO
3(7.15 g，51.7 mmol)，隨後逐滴添加溴甲苯(4.93 mL，40.6 mmol)。將所得混合物加熱至45℃且攪拌16 h。將混合物冷卻至室溫，之後過濾，且濃縮濾液，得到
N-(三級丁氧基羰基)-
N-甲基甘胺酸苯甲酯，其未經純化即使用。LC-MS B：t
R= 0.99 min；[M+H]
+= 280.36。
N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methylglycine (C-1.1) step 1 : to Boc- N -methylglycine To a room temperature solution of the amine acid (7.12 g, 36.9 mmol) in acetone (100 mL ) was added K2CO3 (7.15 g, 51.7 mmol) followed by dropwise addition of bromotoluene (4.93 mL, 40.6 mmol). The resulting mixture was heated to 45 °C and stirred for 16 h. The mixture was cooled to room temperature before being filtered, and the filtrate was concentrated to afford benzyl N- (tert-butoxycarbonyl) -N -methylglycine, which was used without purification. LC-MS B: tR = 0.99 min; [M+H] + = 280.36.
步驟 2 ：向
N-(三級丁氧基羰基)-
N-甲基甘胺酸苯甲酯(11.0 g，34.2 mmol)於二㗁烷(10 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(34.3 mL，0.137 mol)，且攪拌所得混合物2 h。過濾懸浮液且用Et
2O (2×)洗滌，得到呈白色固體狀之甲基甘胺酸苯甲酯鹽酸鹽。LC-MS B：t
R= 0.48 min；[M+H]
+= 180.49。
Step 2 : To a room temperature solution of N- (tertiary butoxycarbonyl) -N -methylglycine benzyl ester (11.0 g, 34.2 mmol) in dioxane (10 mL) was added 4 M HCl dioxane (34.3 mL, 0.137 mol), and the resulting mixture was stirred for 2 h. The suspension was filtered and washed with Et2O (2x) to afford benzyl methylglycine hydrochloride as a white solid. LC-MS B: tR = 0.48 min; [M+H] + = 180.49.
步驟 3 ：向Boc-
N-甲基-L-白胺酸(9.07 g，36.9 mmol)、HATU (14.03 g，36.9 mmol)及DIPEA (9.48 mL，55.4 mmol)於DMF (70 mL)中之預攪拌的室溫溶液中添加甲基甘胺酸苯甲酯鹽酸鹽(7.96 g，36.9 mmol)及DIPEA (9.48 mL，55.4 mmol)於DMF (30 mL)中之溶液，且攪拌所得混合物2 h。濃縮混合物，且將殘餘物分配於水與EtOAc之間。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(MgSO
4)，過濾且蒸發，得到粗產物，用Et
2O濕磨該粗產物，得到呈無色油狀之
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基甘胺酸苯甲酯。LC-MS B：t
R= 1.11 min；[M+H]
+= 407.47。
Step 3 : Add Boc- N -methyl-L-leucine (9.07 g, 36.9 mmol), HATU (14.03 g, 36.9 mmol) and DIPEA (9.48 mL, 55.4 mmol) in DMF (70 mL) To the stirred room temperature solution was added a solution of benzyl methylglycine hydrochloride (7.96 g, 36.9 mmol) and DIPEA (9.48 mL, 55.4 mmol) in DMF (30 mL), and the resulting mixture was stirred for 2 h . The mixture was concentrated, and the residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and evaporated to give a crude product which was triturated with Et 2 O to give N- ( N- (tert-butyl Oxycarbonyl) -N -methyl-L-leucyl) -N -methylglycine benzyl ester. LC-MS B: tR = 1.11 min; [M+H] + = 407.47.
步驟 4 ：在添加10% Pd/C (1.82 g，1.7 mmol)之前，
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基甘胺酸苯甲酯(14.2 g，34.2 mmol)於EtOH (200 ml)中之溶液用N
2/真空(3×)吹掃。在另外惰性化三次之後，連接H
2氣球，且攪拌反應混合物2.5 h。濃縮混合物且經由矽藻土塞過濾，用EtOH沖洗。濃縮濾液，得到呈無色油狀之標題化合物。LC-MS B：t
R= 0.84 min；[M+H]
+= 317.31。
Step 4 : Before adding 10% Pd/C (1.82 g, 1.7 mmol), N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl A solution of benzyl glycinate (14.2 g, 34.2 mmol) in EtOH (200 ml) was purged with N2 /vacuum (3x). After three additional inertizations, a H2 balloon was attached and the reaction mixture was stirred for 2.5 h. The mixture was concentrated and filtered through a plug of celite, rinsing with EtOH. The filtrate was concentrated to afford the title compound as a colorless oil. LC-MS B: tR = 0.84 min; [M+H] + = 317.31.
(
S)-1-(2-((三級丁氧基羰基) (甲基)胺基)-
N,4-二甲基戊醯胺基)環丙烷-1-甲酸(C-1.2)
步驟 1 ：向THF (600 mL)之室溫溶液中添加KtOBu (49.6 g，0.43 mol)。向以上懸浮液中添加1-(Boc-胺基)環丙烷甲酸(40.0 g，0.195 mol)於THF (400 mL)中之溶液，接著小心地添加硫酸二甲酯(dimethylsulfate) (19.6 mL，0.205 mol) (放熱)，且在室溫攪拌反應混合物2 h，之後添加硫酸二甲酯(1 mL，0.01 mol)，且繼續在室溫另外攪拌1 h。反應物用H
2O (400 mL)淬滅且用32% HCl水溶液(80 mL)酸化。分離各層，且水層用DCM (500 mL)萃取。將經合併之有機層濃縮至減少的體積，接著有機層用H
2O (300 mL)洗滌，之後濃縮。向油性殘餘物中添加庚烷，且使所得懸浮液在室溫靜置隔夜。次日上午，過濾混合物，且用庚烷(30 mL)沖洗所得固體且乾燥，得到呈白色固體狀之1-(三級丁氧基羰基-甲基-胺基)-環丙烷甲酸(21.5 g，51%)。LC-MS B：t
R= 0.71 min；[M+H]
+= 216.39。
( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)cyclopropane-1-carboxylic acid (C-1.2) step 1 : To a room temperature solution in THF (600 mL) was added KtOBu (49.6 g, 0.43 mol). To the above suspension was added a solution of 1-(Boc-amino)cyclopropanecarboxylic acid (40.0 g, 0.195 mol) in THF (400 mL), followed by careful addition of dimethylsulfate (19.6 mL, 0.205 mol) (exothermic), and the reaction mixture was stirred at room temperature for 2 h, after which dimethyl sulfate (1 mL, 0.01 mol) was added and stirring was continued for an additional 1 h at room temperature. The reaction was quenched with H2O (400 mL) and acidified with 32% aqueous HCl (80 mL). The layers were separated, and the aqueous layer was extracted with DCM (500 mL). The combined organic layers were concentrated to a reduced volume, and the organic layer was washed with H2O (300 mL) before being concentrated. Heptane was added to the oily residue, and the resulting suspension was allowed to stand overnight at room temperature. The next morning, the mixture was filtered and the resulting solid was rinsed with heptane (30 mL) and dried to give 1-(tertiary butoxycarbonyl-methyl-amino)-cyclopropanecarboxylic acid (21.5 g , 51%). LC-MS B: tR = 0.71 min; [M+H] + = 216.39.
步驟 2-5 ：按照對於
C-1.1步驟1-4所描述之反應順序，由1-(三級丁氧基羰基-甲基-胺基)-環丙烷甲酸製備標題化合物。LC-MS B：t
R= 0.87 min；[M+H]
+= 343.26。
Step 2-5 : The title compound was prepared from 1-(tert-butoxycarbonyl-methyl-amino)-cyclopropanecarboxylic acid following the reaction sequence described for C-1.1 Steps 1-4. LC-MS B: tR = 0.87 min; [M+H] + = 343.26.
1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-1,2,3,6-四氫吡啶-2-甲酸(C-1.3)
步驟 1 ：向(
S)-
N-Boc-1,2,3,6-四氫-2-吡啶甲酸(400 mg，1.72 mmol)於MeOH (5 mL)中之0℃溶液中添加H
2SO
4(92 μL，1.72 mmol)，且將所得混合物加熱至回流持續4 h。將反應混合物緩慢倒入飽和NaHCO
3之0℃溶液中且用EtOAc (3×)萃取。經合併之有機萃取物經乾燥(MgSO
4)，過濾且濃縮，得到呈橙色油狀之(
S)-1,2,3,6-四氫吡啶-2-甲酸甲酯。LC-MS I：t
R= 0.46 min；[M+H]
+= 142.16。
1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (C-1.3) step 1 : To a 0 °C solution of ( S ) -N -Boc-1,2,3,6-tetrahydro-2-pyridinecarboxylic acid (400 mg, 1.72 mmol) in MeOH (5 mL) was added H2SO4 ( 92 μL, 1.72 mmol), and the resulting mixture was heated to reflux for 4 h. The reaction mixture was poured slowly into a 0 °C solution of saturated NaHCO 3 and extracted with EtOAc (3×). The combined organic extracts were dried ( MgSO4 ), filtered and concentrated to afford ( S )-methyl 1,2,3,6-tetrahydropicolinate as an orange oil. LC-MS I: tR = 0.46 min; [M+H] + = 142.16.
步驟 2 及 3 ：按照對於
C-2.1所描述之反應順序，由Boc-
N-甲基-L-白胺酸及(
S)-1,2,3,6-四氫吡啶-2-甲酸酯製備標題化合物。LC-MS B：t
R= 0.92 min；[M+H]
+= 355.34。觀測到四氫吡啶2位置之差向異構，且進一步使用呈非鏡像異構物之混合物形式之此建構嵌段。
Steps 2 and 3 : According to the reaction sequence described for C-2.1 , from Boc- N -methyl-L-leucine and ( S )-1,2,3,6-tetrahydropyridine-2-carboxylic acid Esters to prepare the title compound. LC-MS B: tR = 0.92 min; [M+H] + = 355.34. Epimerization of the tetrahydropyridine 2 position was observed and this building block was further used as a mixture of diastereomers.
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-丙胺酸(C-1.4)
步驟 1 ：向(三級丁氧基羰基)-D-丙胺酸(2.01 g，10.62 mmol於THF (10 mL)中之0℃溶液中添加MeI (1.0 mL，16.06 mmol)，接著添加NaH (1.08 g，27.1 mmol)。在0℃30 min之後，將反應混合物升溫至室溫且繼續攪拌3 h。混合物用水淬滅且用0.5 M KHSO
4(pH 2)酸化。分離各層，且水層用EtOAc (3 × 20 mL)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發，得到呈棕色油狀之
N-(三級丁氧基羰基)-
N-甲基-D-丙胺酸，其按原樣用於下一步驟。
N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl-D-alanine (C-1.4) step 1 : to (tertiary butoxy To a 0°C solution of (2.01 g, 10.62 mmol) in THF (10 mL) was added MeI (1.0 mL, 16.06 mmol) followed by NaH (1.08 g, 27.1 mmol). At 0°C After 30 min, the reaction mixture was warmed to room temperature and stirring was continued for 3 h. The mixture was quenched with water and acidified with 0.5 M KHSO4 (pH 2). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give N- (tert-butoxycarbonyl) -N -methyl-D-alanine as a brown oil, which was obtained according to Used as such in the next step.
步驟 2-5 ：按照對於
C-1.1步驟1-4所描述之4-步驟反應順序，由
N-(三級丁氧基羰基)-
N-甲基-D-丙胺酸製備標題化合物。LC-MS F：t
R= 1.98 min；[M+H]
+= 331.20。
1H NMR (400 MHz, DMSO) δ 5.03 - 4.46 (m, 2H), 2.95 - 2.83 (m, 2H), 2.75 - 2.54 (m, 4H), 1.58 - 1.44 (m, 2H), 1.41 (s, 10H), 1.31 - 1.23 (m, 3H), 1.23 - 1.17 (m, 1H), 0.94 - 0.84 (m, 6H)。
Step 2-5 : The title compound was prepared from N- (tertiary butoxycarbonyl) -N -methyl-D-alanine following the 4-step reaction sequence described for C-1.1 Steps 1-4. LC-MS F: tR = 1.98 min; [M+H] + = 331.20. 1 H NMR (400 MHz, DMSO) δ 5.03 - 4.46 (m, 2H), 2.95 - 2.83 (m, 2H), 2.75 - 2.54 (m, 4H), 1.58 - 1.44 (m, 2H), 1.41 (s, 10H), 1.31 - 1.23 (m, 3H), 1.23 - 1.17 (m, 1H), 0.94 - 0.84 (m, 6H).
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
22
(
R)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基) 𠰌啉-3-甲酸(C-2.1)
步驟 1 ：向Boc-
N-甲基-L-白胺酸(3.0 g，12.2 mmol)、(
R)-𠰌啉-3-甲酸甲酯(1.85 g，12.2 mmol)及DIPEA (6.3 mL，36.6 mmol)於DMF (30 mL)中之室溫溶液中逐份添加HATU (4.64 g，12.2 mmol)，且攪拌所得混合物1 h。添加水，且混合物用EtOAc (3×)萃取。經合併之有機萃取物依次用NaHCO
3飽和水溶液、水及鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用0%至100% EtOAc/庚烷溶離)純化，得到呈無色油狀之(
R)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)𠰌啉-3-甲酸甲酯。LC-MS B：t
R= 0.97 min；[M+H]
+= 373.50。
( R )-4-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) 𠰌line-3-carboxylic acid (C-2.1) step 1 : to Boc- N -form Base-L-leucine (3.0 g, 12.2 mmol), ( R )-𠰌line-3-carboxylic acid methyl ester (1.85 g, 12.2 mmol) and DIPEA (6.3 mL, 36.6 mmol) in DMF (30 mL) To the room temperature solution of HATU (4.64 g, 12.2 mmol) was added portionwise, and the resulting mixture was stirred for 1 h. Water was added, and the mixture was extracted with EtOAc (3x). The combined org. extracts were washed sequentially with saturated aqueous NaHCO 3 , water and brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by FC (eluted with 0% to 100% EtOAc/heptane) afforded ( R )-4-( N- (tertiary butoxycarbonyl) -N -methyl-L-white as a colorless oil Amino) ???line-3-carboxylic acid methyl ester. LC-MS B: tR = 0.97 min; [M+H] + = 373.50.
步驟 2 ：向(
R)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)𠰌啉-3-甲酸甲酯(4.37 g，11.7 mmol)於MeOH (55 mL)中之室溫溶液中添加2 M NaOH水溶液(11.7 mL，22.6 mmol)，且在室溫攪拌混合物4.5 h。真空移除揮發物，且殘餘物水溶液用2 M HCl水溶液中和，之後用DCM (3×)萃取。經合併之有機層經乾燥(Na
2SO
4)，過濾且真空蒸發，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 0.86 min；[M+H]
+= 359.49。
Step 2 : To ( R )-4-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-methyl-3-carboxylate (4.37 g, 11.7 mmol) in To a room temperature solution in MeOH (55 mL) was added 2 M aqueous NaOH (11.7 mL, 22.6 mmol), and the mixture was stirred at room temperature for 4.5 h. The volatiles were removed in vacuo, and the aqueous residue was neutralized with 2 M aqueous HCl before extraction with DCM (3x). The combined organic layers were dried ( Na2SO4 ), filtered and evaporated in vacuo to give the title compound as a white solid. LC-MS B: tR = 0.86 min; [M+H] + = 359.49.
下表C-2中列舉類似於上文對於
C-2.1描述之2-步驟順序，由對應起始材料製備之建構嵌段C。
表C-2
編號 SM A SM B 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-2.2 Boc-
N-甲基-L-白胺酸
(R)-哌啶-2-甲酸甲酯鹽酸鹽
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌啶-2-甲酸
0.93
B
357.51
C-2.3 Boc-
N-甲基-L-白胺酸
(S)-吡咯啶-3-甲酸甲酯鹽酸鹽
(
S)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)吡咯啶-3-甲酸
0.82
B
343.51
C-2.4 Boc-
N-甲基-L-白胺酸
3-甲氧基-1-(甲基胺基)環丁烷-1-甲酸甲酯鹽酸鹽
呈立體異構物之混合物形式
Aurum Pharmatech TR33962
(
S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-甲氧基環丁烷-1-甲酸
0.89
B
387.24
C-2.5 D2-1.1 (
R)-哌啶-2-甲酸甲酯鹽酸鹽
(
R)-1-((
S)-2-((三級丁氧基羰基)胺基)-3-環戊基丙醯基)哌啶-2-甲酸
0.98
B
383.42
C-2.6 D2-1.1 (R)-𠰌啉-3-甲酸甲酯
(R)-4-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙醯基)𠰌啉-3-甲酸
0.92
B
385.25
C-2.7 Boc-
N-甲基-L-白胺酸
1-胺基環丙烷甲酸甲酯
(
S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)環丙烷-1-甲酸
0.83
B
329.39
C-2.8 Boc-
N-甲基-L-白胺酸
(
S)-哌啶-2-甲酸甲酯鹽酸鹽
(
S)-1-[(S)-2-(
N-(三級丁氧基羰基)-
N-甲基-胺基)-4-甲基-戊醯基]-L-白胺醯基)哌啶-2-甲酸
0.54
I
357.33
C-2.9 Boc-
N-甲基-L-白胺酸
4,4-二氟哌啶-2-甲酸甲酯鹽酸鹽
1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4,4-二氟哌啶-2-甲酸
0.56
I
393.28
C-2.10 Boc-
N-甲基-L-白胺酸
1,2,3,4-四氫-1-異喹啉甲酸乙酯鹽酸鹽，CAS 106181-28-6，AstaTech批次C2130-078
2-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-1,2,3,4-四氫異喹啉-1-甲酸
0.57
I
405.25
C-2.11 Boc-
N-甲基-L-白胺酸
1,2,3,4-四氫-異喹啉-3-甲酸甲酯(鹽酸鹽)
2-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-1,2,3,4-四氫異喹啉-3-甲酸
0.56
I
405.31
C-2.12 Boc-
N-甲基-L-白胺酸
2-(甲基胺基)-2-苯基-乙酸甲酯(鹽酸鹽)
2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-N,4-二甲基戊醯胺基)-2-苯基乙酸
0.98
B
393.30
C-2.15 Boc-
N-甲基-L-白胺酸
4,4,4-三氟-2-(甲基胺基)丁酸甲酯(鹽酸鹽)
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4,4,4-三氟丁酸
0.56
I
399.27
C-2.16 Boc-
N-甲基-L-白胺酸
3-環丁氧基-2-(甲基胺基)丙酸甲酯鹽酸鹽
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
O-環丁基-
N-甲基絲胺酸
0.99
A
401.22
C-2.17 Boc-
N-甲基-L-白胺酸
氮𠰢-2-甲酸甲酯鹽酸鹽
1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)氮𠰢-2-甲酸
0.95
A
371.30
Listed in Table C-2 below are the building blocks C prepared from the corresponding starting materials analogously to the 2-step sequence described above for C-2.1. Table C-2 serial number SM A SM B product t R [min] LC-MS method MS- data m/z [M+H] +
C-2.2 Boc- N -methyl-L-leucine (R)-Piperidine-2-carboxylic acid methyl ester hydrochloride ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)piperidine-2-carboxylic acid 0.93 B 357.51
C-2.3 Boc- N -methyl-L-leucine (S)-Pyrrolidine-3-carboxylic acid methyl ester hydrochloride ( S )-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)pyrrolidine-3-carboxylic acid 0.82 B 343.51
C-2.4 Boc- N -methyl-L-leucine Methyl 3-methoxy-1-(methylamino)cyclobutane-1-carboxylate hydrochloride as a mixture of stereoisomers Aurum Pharmatech TR33962 ( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-methoxycyclobutane-1- formic acid 0.89 B 387.24
C-2.5 D2-1.1 ( R )-Piperidine-2-carboxylic acid methyl ester hydrochloride ( R )-1-(( S )-2-((tertiary butoxycarbonyl)amino)-3-cyclopentylpropionyl)piperidine-2-carboxylic acid 0.98 B 383.42
C-2.6 D2-1.1 (R)-Methyl 𠰌line-3-carboxylate (R )-4-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentylpropionyl)𠰌line-3-carboxylic acid 0.92 B 385.25
C-2.7 Boc- N -methyl-L-leucine Methyl 1-aminocyclopropanecarboxylate ( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino)-4-methylpentamido)cyclopropane-1-carboxylic acid 0.83 B 329.39
C-2.8 Boc- N -methyl-L-leucine ( S )-Piperidine-2-carboxylic acid methyl ester hydrochloride ( S )-1-[(S)-2-( N -(tertiary butoxycarbonyl) -N -methyl-amino)-4-methyl-pentyl]-L-leucyl ) piperidine-2-carboxylic acid 0.54I 357.33
C-2.9 Boc- N -methyl-L-leucine 4,4-Difluoropiperidine-2-carboxylic acid methyl ester hydrochloride 1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4,4-difluoropiperidine-2-carboxylic acid 0.56 I 393.28
C-2.10 Boc- N -methyl-L-leucine Ethyl 1,2,3,4-tetrahydro-1-isoquinolinecarboxylate hydrochloride, CAS 106181-28-6, AstaTech Batch C2130-078 2-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid 0.57I 405.25
C-2.11 Boc- N -methyl-L-leucine Methyl 1,2,3,4-tetrahydro-isoquinoline-3-carboxylate (hydrochloride) 2-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 0.56 I 405.31
C-2.12 Boc- N -methyl-L-leucine 2-(Methylamino)-2-phenyl-acetic acid methyl ester (hydrochloride) 2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanylamino)-2-phenylacetic acid 0.98 B 393.30
C-2.15 Boc- N -methyl-L-leucine Methyl 4,4,4-trifluoro-2-(methylamino)butyrate (hydrochloride) ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamylamino)-4,4,4-tri flubutyric acid 0.56 I 399.27
C-2.16 Boc- N -methyl-L-leucine Methyl 3-cyclobutoxy-2-(methylamino)propionate hydrochloride N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -O -cyclobutyl- N -methylserine 0.99A 401.22
C-2.17 Boc- N -methyl-L-leucine Methyl nitrogen 𠰢-2-carboxylate hydrochloride 1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)nitrogen-2-carboxylic acid 0.95A 371.30
6-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-6-氮雜螺[2.5]辛烷-5-甲酸(C-2.13)
步驟 1 ：向市售的6-氮雜螺[2.5]辛烷-5-甲酸鹽酸鹽於MeOH (2 mL)中之0℃溶液中添加(三甲基矽基)重氮甲烷溶液(2.0 M於己烷中，0.75 mL，1.49 mmol)。將反應混合物升溫至室溫且攪拌30 min。濃縮混合物，得到外消旋-6-氮雜-螺[2.5]辛烷-5-甲酸甲酯，其按原樣用於下一步驟。LC-MS I：t
R= 0.66 min；[M+H]
+= 170.18。
6-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-6-azaspiro[2.5]octane-5-carboxylic acid (C-2.13) step 1 : to To a solution of commercially available 6-azaspiro[2.5]octane-5-carboxylate hydrochloride in MeOH (2 mL) at 0 °C was added a solution of (trimethylsilyl)diazomethane (2.0 M in in alkanes, 0.75 mL, 1.49 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. The mixture was concentrated to afford rac-methyl 6-aza-spiro[2.5]octane-5-carboxylate, which was used as such in the next step. LC-MS I: tR = 0.66 min; [M+H] + = 170.18.
步驟 2 及 3 ：按照對於
C-2.1所描述之2-步驟程序，由外消旋-6-氮雜-螺[2.5]辛烷-5-甲酸甲酯製備標題化合物。LC-MS I：t
R= 1.27 min；[M+H]
+= 397.34。
Steps 2 and 3 : The title compound was prepared from rac-methyl 6-aza-spiro[2.5]octane-5-carboxylate following the 2-step procedure described for C-2.1 . LC-MS I: tR = 1.27 min; [M+H] + = 397.34.
O-苯甲基-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基絲胺酸(C-2.14)
步驟 1 ：向O-苯甲基-N-甲基-DL-絲胺酸(3.10 g，14.8 mmol)於DCM (20 mL)中之0℃溶液中添加亞硫醯二氯，且在60℃攪拌反應混合物16 h。將混合物倒入冰水中且用DCM (3×)萃取。經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且真空濃縮。藉由FC (用0%至20% EtOAc/庚烷溶離)純化，得到呈無色油狀之O-苯甲基-N-甲基絲胺酸甲酯。LC-MS B：t
R= 0.53 min；[M+H]
+= 224.04.
O-benzyl- N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methylserine (C-2.14) step 1 : to O - To a solution of Benzyl-N-methyl-DL-serine (3.10 g, 14.8 mmol) in DCM (20 mL) at 0 °C was added thionyl dichloride and the reaction mixture was stirred at 60 °C for 16 h . The mixture was poured into ice water and extracted with DCM (3x). The combined org. layers were washed with brine, dried ( MgSO4 ), filtered and concentrated in vacuo. Purification by FC (elution with 0% to 20% EtOAc/heptane) afforded O-benzyl-N-methylserine methyl ester as a colorless oil. LC-MS B: tR = 0.53 min; [M+H] + = 224.04.
步驟 2 及 3 ：按照對於
C-2.1所描述之2-步驟程序，由O-苯甲基-
N-甲基絲胺酸甲酯製備標題化合物。LC-MS B：t
R= 1.01 min；[M+H]
+= 437.30。
Steps 2 and 3 : The title compound was prepared from O-benzyl- N -methylserine methyl ester following the 2-step procedure described for C-2.1 . LC-MS B: tR = 1.01 min; [M+H] + = 437.30.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
33
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-甲基哌𠯤-2-甲酸(C-3.1)
步驟 1 ：向(2
R)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(2.0 g，8.2 mmol)於MeOH (40 mL)中之室溫溶液中添加乙酸鈉(3.36 g，41 mmol)，隨後添加TFA (0.63 mL，8.2 mmol)及37%甲醛水溶液(2.92 mL，39 mmol)，且攪拌所得混合物30 min。在逐份添加NaBH
3CN (1.74 g，26.3 mmol)之前，將混合物冷卻至0℃。將混合物升溫至室溫且攪拌5 h，之後濃縮。將殘餘物分配於EtOAc與1 M NaOH水溶液之間且萃取。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發，得到呈無色油狀之(
R)-4-甲基哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯。LC-MS I：t
R= 0.81 min；[M+H]
+= 259.22。
( R )-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-methylpiperone-2-carboxylic acid (C-3.1) step 1 : to To a room temperature solution of (2 R )-piperone-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (2.0 g, 8.2 mmol) in MeOH (40 mL) was added sodium acetate (3.36 g, 41 mmol), followed by TFA (0.63 mL, 8.2 mmol) and 37% aqueous formaldehyde (2.92 mL, 39 mmol), and the resulting mixture was stirred for 30 min. The mixture was cooled to 0 °C before adding NaBH3CN (1.74 g, 26.3 mmol) in portions. The mixture was warmed to room temperature and stirred for 5 h before being concentrated. The residue was partitioned between EtOAc and 1 M aqueous NaOH and extracted. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give ( R )-4-methylpiperone-1,2-dicarboxylic acid 1-(tri grade butyl ester) 2-methyl ester. LC-MS I: tR = 0.81 min; [M+H] + = 259.22.
步驟 2 ：類似於對於
C-1.1步驟2所描述之程序，由(
R)-4-甲基哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯製備(
R)-4-甲基哌𠯤-2-甲酸甲酯二鹽酸鹽。LC-MS I：t
R= 0.34 min；[M+H]
+= 159.16。
Step 2 : Preparation of ( R ) from (R)-4-methylpiperone-1,2-dicarboxylic acid 1-(tert - butyl)2-methyl ester similar to the procedure described for C-1.1 step 2 -Methyl 4-methylpiperone-2-carboxylate dihydrochloride. LC-MS I: tR = 0.34 min; [M+H] + = 159.16.
步驟 3 及 4 ：按照對於
C-2.1所描述之2-步驟反應順序，由Boc-
N-甲基-L-白胺酸及(
R)-4-甲基哌𠯤-2-甲酸甲酯二鹽酸鹽製備標題化合物。LC-MS B：t
R= 0.67 min；[M+H]
+= 372.51。
Steps 3 and 4 : According to the 2-step reaction sequence described for C-2.1 , from Boc- N -methyl-L-leucine and ( R )-4-methylpiperone-2-carboxylic acid methyl ester di Hydrochloride salt to prepare the title compound. LC-MS B: tR = 0.67 min; [M+H] + = 372.51.
下表C-3中列舉類似於上文對於
C-3.1描述之4-步驟順序，由對應起始材料製備之建構嵌段C。
表C-3
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-3.2 乙醛
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-乙基哌𠯤-2-甲酸
0.56
I
386.00
C-3.3 丙酮
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-異丙基哌𠯤-2-甲酸
0.71
B
400.51
C-3.4 異丁醛
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-異丁基哌𠯤-2-甲酸
0.75
B
414.45
C-3.5 環丁酮
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-環丁基哌𠯤-2-甲酸
0.73
B
412.48
C-3.6 環丙酮
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-(環丙基甲基)哌𠯤-2-甲酸
0.56
I
412.30
Listed in Table C-3 below are the building blocks C prepared from the corresponding starting materials in analogy to the 4-step sequence described above for C-3.1. Table C-3 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
C-3.2 Acetaldehyde ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-ethylpiperone-2-carboxylic acid 0.56 I 386.00
C-3.3 acetone ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-isopropylpiperazine-2-carboxylic acid 0.71 B 400.51
C-3.4 Isobutyraldehyde ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-isobutylpiperone-2-carboxylic acid 0.75 B 414.45
C-3.5 Cyclobutanone ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-cyclobutylpiperone-2-carboxylic acid 0.73 B 412.48
C-3.6 Cyclopropanone ( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-(cyclopropylmethyl)pipera-2-carboxylic acid 0.56 I 412.30
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-環丙基哌𠯤-2-甲酸(鹽酸鹽) (C-3.7)
步驟 1 ：向(
R)-1-Boc-哌𠯤-2-甲酸甲酯(1.54 g，6.30 mmol)於MeOH (30 mL)及THF (30 mL)中之室溫溶液中添加(1-乙氧基環丙氧基)三甲基矽烷(2.6 mL，12.80 mmol)、NaBH
3CN (0.66 g，9.98 mmol)及AcOH (0.5 mL，8.74 mmol)，且將所得混合物加熱至60℃持續16 h。向冷卻的混合物中添加水(5 mL)，隨後添加1 M NaOH水溶液(10 mL)，且在攪拌15 min之後，減壓移除揮發物。殘餘物用DCM (2×)萃取，且經合併之有機萃取物用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發，得到呈無色油狀之(
R)-4-環丙基哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯。LC-MS B：t
R= 0.58 min；[M+H]
+= 285.31。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-cyclopropylpiperone-2-carboxylic acid (hydrochloride) (C- 3.7) Step 1 : To a room temperature solution of ( R )-1-Boc-piperone-2-carboxylate (1.54 g, 6.30 mmol) in MeOH (30 mL) and THF (30 mL) was added (1 -ethoxycyclopropoxy)trimethylsilane (2.6 mL, 12.80 mmol), NaBH 3 CN (0.66 g, 9.98 mmol) and AcOH (0.5 mL, 8.74 mmol), and the resulting mixture was heated to 60°C for 16 h. To the cooled mixture was added water (5 mL), followed by 1 M aqueous NaOH (10 mL), and after stirring for 15 min, the volatiles were removed under reduced pressure. The residue was extracted with DCM (2x) and the combined org. extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give ( R )-4-cyclopropylpiperide as a colorless oil 𠯤-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester. LC-MS B: tR = 0.58 min; [M+H] + = 285.31.
步驟 2-4 ：按照如對於
C-3.1步驟2至4所描述之3-步驟順序，由(
R)-4-環丙基哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯製備標題化合物。LC-MS B：t
R= 0.73 min；[M+H]
+= 398.43。
Step 2-4 : Following the 3-step sequence as described for C-3.1 steps 2 to 4, from ( R )-4-cyclopropylpiperone-1,2-dicarboxylic acid 1-(tertiary butyl ester) 2-Methyl ester to prepare the title compound. LC-MS B: tR = 0.73 min; [M+H] + = 398.43.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
44
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(𠳭唍-3-基甲基)甘胺酸(C-4.1)
步驟 1 ：向Boc-
N-甲基-L-白胺酸(135 mg，0.55 mmol)、
IM-1.3(155 mg，0.5 mmol)及DIPEA (0.34 mL，2 mmol)於DMF (2 mL)中之室溫溶液中添加HATU (219 mg，0.58 mmol)，且攪拌所得混合物1 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到
N-(
N-(三級丁氧基羰基)
-N-甲基-L-白胺醯基)-
N-((𠳭唍-3-基)甲基)甘胺酸苯甲酯(218 mg，81%)。LC-MS I：t
R= 1.35 min；[M+H]
+= 539.23。
N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (𠳭锍-3-ylmethyl)glycine (C-4.1) step 1 : To Boc- N -methyl-L-leucine (135 mg, 0.55 mmol), IM-1.3 (155 mg, 0.5 mmol) and DIPEA (0.34 mL, 2 mmol) in DMF (2 mL) at room temperature To the solution was added HATU (219 mg, 0.58 mmol), and the resulting mixture was stirred for 1 h. The reaction mixture was directly purified by preparative HPLC (basic) to give N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(((𠳭唍-3 -yl)methyl)benzylglycine (218 mg, 81%). LC-MS I: tR = 1.35 min; [M+H] + = 539.23.
步驟 2 ：向
N-(
N-(三級丁氧基羰基)
-N-甲基-L-白胺醯基)-
N-((𠳭唍-3-基)甲基)甘胺酸苯甲酯(218 mg，0.4 mmol)於THF/H
2O (2:1) (2 mL)中之室溫溶液中添加LiOH (52.9 mg，1.26 mmol)，且在室溫攪拌混合物隔夜。真空移除揮發物，且殘餘物水溶液用2 M HCl水溶液酸化，之後用EtOAc (3×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且蒸發，得到呈白色固體狀之標題化合物
C-4.1(200 mg，71%)。LC-MS I：t
R= 0.62 min；[M+H]
+= 449.25。
Step 2 : To N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(((𠳭锍-3-yl)methyl)glycine benzyl To a room temperature solution of the ester (218 mg, 0.4 mmol) in THF/ H2O (2:1) (2 mL) was added LiOH (52.9 mg, 1.26 mmol) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo, and the aqueous residue was acidified with 2 M aqueous HCl, then extracted with EtOAc (3x). The combined organic layers were dried ( MgSO4 ), filtered and evaporated to give the title compound C-4.1 (200 mg, 71%) as a white solid. LC-MS I: tR = 0.62 min; [M+H] + = 449.25.
下表C-4中列舉類似於上文對於
C-4.1描述之2-步驟順序，由對應起始材料製備之建構嵌段C。
表C-4
編號 SM A SM B 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-4.2 Boc-
N-甲基-L-白胺酸
IM-1.1 N-(2-(三級丁氧基)乙基)-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)甘胺酸
0.99
B
403.46
C-4.3 Boc-
N-甲基-L-白胺酸
IM-1.2 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-((3-甲基四氫呋喃-3-基)甲基)甘胺酸
0.93
D
402.26
C-4.4 Boc-
N-甲基-L-白胺酸
IM-1.4 N-(2-(7-氧雜雙環[2.2.1]庚-2-基)乙基)-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)甘胺酸
0.95
D
427.39
C-4.5 Boc-
N-甲基-L-白胺酸
IM-1.5 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(5,5-二甲基四氫呋喃-2-基)乙基)甘胺酸
1.12
D
441.36
C-4.6 Boc-
N-甲基-L-白胺酸
IM-1.6 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(四氫呋喃-2-基)乙基)甘胺酸
0.97
D
401.25
C-4.7 Boc-
N-甲基-L-白胺酸
IM-1.7 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(四氫-2
H-哌喃-3-基)乙基)甘胺酸
0.97
D
415.42
C-4.8 Boc-
N-甲基-L-白胺酸
IM-1.8 N-(2-(2,9-二氧雜螺[5.5]十一烷-3-基)乙基)-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)甘胺酸
1.00
D
485.31
C-4.9 Boc-
N-甲基-L-白胺酸
IM-1.9 N-(2-(1,4-二㗁烷-2-基)乙基)-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)甘胺酸
0.88
D
403.4
C-4.10 Boc-
N-甲基-L-白胺酸
IM-1.10 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸
1.05
D
415.43
C-4.11 Boc-
N-甲基-L-白胺酸
IM-1.11 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(3-甲氧基環丁基)乙基)甘胺酸
0.54-0.58
I
415.25
C-4.12 D2-1.3 IM-1.12 N-(2-((三級丁氧基羰基)(甲基)胺基)戊-4-炔醯基)-
N-(2-環己基乙基)甘胺酸
0.58
I
395.22
Listed in Table C-4 below are the building blocks C prepared from the corresponding starting materials in analogy to the 2-step sequence described above for C-4.1. Table C-4 serial number SM A SM B product t R [min] LC-MS method MS- data m/z [M+H] +
C-4.2 Boc- N -methyl-L-leucine IM-1.1 N- (2-(tertiary butoxy)ethyl) -N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)glycine 0.99 B 403.46
C-4.3 Boc- N -methyl-L-leucine IM-1.2 N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -((3-methyltetrahydrofuran-3-yl)methyl)glycine 0.93D 402.26
C-4.4 Boc- N -methyl-L-leucine IM-1.4 N -(2-(7-oxabicyclo[2.2.1]hept-2-yl)ethyl) -N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl base) glycine 0.95D 427.39
C-4.5 Boc- N -methyl-L-leucine IM-1.5 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(5,5-dimethyltetrahydrofuran-2-yl)ethyl)glycol amino acid 1.12D 441.36
C-4.6 Boc- N -methyl-L-leucine IM-1.6 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(tetrahydrofuran-2-yl)ethyl)glycine 0.97D 401.25
C-4.7 Boc- N -methyl-L-leucine IM-1.7 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(tetrahydro-2 H -pyran-3-yl)ethyl)glycerin amino acid 0.97D 415.42
C-4.8 Boc- N -methyl-L-leucine IM-1.8 N -(2-(2,9-dioxaspiro[5.5]undec-3-yl)ethyl) -N- ( N- (tertiary butoxycarbonyl) -N -methyl-L- leucyl)glycine 1.00D 485.31
C-4.9 Boc- N -methyl-L-leucine IM-1.9 N -(2-(1,4-Dioxane-2-yl)ethyl) -N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)glycine acid 0.88D 403.4
C-4.10 Boc- N -methyl-L-leucine IM-1.10 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(tetrahydro-2 H -pyran-2-yl)ethyl)glycol amino acid 1.05D 415.43
C-4.11 Boc- N -methyl-L-leucine IM-1.11 N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(3-methoxycyclobutyl)ethyl)glycine 0.54-0.58I 415.25
C-4.12 D2-1.3 IM-1.12 N -(2-((tertiary butoxycarbonyl)(methyl)amino)pent-4-ynyl) -N- (2-cyclohexylethyl)glycine 0.58 I 395.22
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
55
(
S)-2-(2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-2,3-二氫-1
H-茚-2-甲酸(C-5.1)
步驟 1 ：向Boc-
N-甲基-L-白胺酸(800 mg，3.25 mmol)、2-胺基-二氫茚-2-甲酸甲酯鹽酸鹽(764 mg，3.25 mmol)及DIPEA (2.23 mL，13 mmol)於DMF (8 mL)中之室溫溶液中添加HATU (1.24 g，3.25 mmol)。在室溫攪拌反應混合物1 h，接著用水(20 mL)及DCM (50 mL)稀釋。分離各層，且水層用DCM (2 × 50 mL)萃取。經合併之有機層用鹽水(20 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用20%至55% EtOAc/庚烷溶離，在EtOAc/庚烷3:7中，R
f= 0.34)純化，得到呈無色油狀之(S)-2-(2-((三級丁氧基羰基)胺基)-4-甲基戊醯胺基)-2,3-二氫-1
H-茚-2-甲酸甲酯(1.07 g，79%)。LC-MS B：t
R= 1.07min；[M+H]
+= 419.17。
( S )-2-(2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-2,3-dihydro-1 H -indene -2-Formic acid (C-5.1) Step 1 : Add Boc- N -methyl-L-leucine (800 mg, 3.25 mmol), 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (764 mg, 3.25 mmol) and DIPEA (2.23 mL, 13 mmol) in DMF (8 mL) at room temperature was added HATU (1.24 g, 3.25 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with water (20 mL) and DCM (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined org. layers were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 20% to 55% EtOAc/heptane, Rf = 0.34 in EtOAc/heptane 3:7) gave (S)-2-(2-(( tertiary butoxycarbonyl)amino)-4-methylpentamido)-2,3-dihydro- 1H -indene-2-carboxylic acid methyl ester (1.07 g, 79%). LC-MS B: tR = 1.07min; [M+H] + = 419.17.
步驟 2 ：向(S)-2-(2-((三級丁氧基羰基)胺基)-4-甲基戊醯胺基)-2,3-二氫-1
H-茚-2-甲酸甲酯(200 mg，0.478 mmol)於DMF (6 mL)中之0℃溶液中添加NaH (36.6 mg，0.956 mmol)。在10 min攪拌之後，添加MeI (60 μL，0.96 mmol)且移除冰浴。在室溫攪拌混合物1 h，接著將反應混合物分配於2 N HCl (6 mL)與DCM (75 mL)之間，且分離各層。水層用DCM (2 × 75 mL)再萃取，且經合併之有機層用鹽水(30 mL)洗滌，經乾燥(Na
2SO
4)，過濾且蒸發。藉由FC (用35%至80% EtOAc/庚烷溶離)純化粗產物，得到呈無色油狀之(S)-2-(2-((三級丁氧基羰基)胺基)-
N,4-二甲基戊醯胺基)-2,3-二氫-1
H-茚-2-甲酸甲酯。LC-MS B：t
R= 1.11 min；[M+H]
+= 433.07。
Step 2 : To (S)-2-(2-((tertiary butoxycarbonyl)amino)-4-methylpentamido)-2,3-dihydro- 1H -indene-2- To a solution of methyl formate (200 mg, 0.478 mmol) in DMF (6 mL) at 0 °C was added NaH (36.6 mg, 0.956 mmol). After stirring for 10 min, MeI (60 μL, 0.96 mmol) was added and the ice bath was removed. The mixture was stirred at room temperature for 1 h, then the reaction mixture was partitioned between 2 N HCl (6 mL) and DCM (75 mL), and the layers were separated. The aqueous layer was re-extracted with DCM (2 x 75 mL), and the combined org. layers were washed with brine (30 mL), dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by FC (eluted with 35% to 80% EtOAc/heptane) to afford (S)-2-(2-((tertiary butoxycarbonyl)amino) -N as a colorless oil, 4-Dimethylpentamido)-2,3-dihydro- 1H -indene-2-carboxylic acid methyl ester. LC-MS B: tR = 1.11 min; [M+H] + = 433.07.
步驟 3 ：向(S)-2-(2-((三級丁氧基羰基)胺基)-
N,4-二甲基戊醯胺基)-2,3-二氫-1
H-茚-2-甲酸甲酯(90 mg，2.08 mmol)於MeOH (30 mL)中之室溫溶液中添加4 M NaOH溶液(21 mL，83.2 mmol)，且在50℃攪拌反應混合物4 h。將反應混合物冷卻至室溫，接著混合物用DCM (100 mL)稀釋且用2 M HCl溶液(10 mL)酸化。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(30 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色泡沫狀之標題化合物
C-5.1(796 mg，91%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.01 min；[M+H]
+= 419.09。
Step 3 : To (S)-2-(2-((tertiary butoxycarbonyl)amino) -N ,4-dimethylpentanylamino)-2,3-dihydro-1 H -indene - To a room temperature solution of methyl 2-carboxylate (90 mg, 2.08 mmol) in MeOH (30 mL) was added 4 M NaOH solution (21 mL, 83.2 mmol), and the reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, then the mixture was diluted with DCM (100 mL) and acidified with 2 M HCl solution (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO 4 ), filtered and concentrated to give the title compound C-5.1 (796 mg, 91%) as a white foam, which was used as such in the next step step. LC-MS B: tR = 1.01 min; [M+H] + = 419.09.
下表C-5中列舉類似於上文對於
C-5.1描述之3-步驟順序，由對應起始材料製備之建構嵌段C。
表C-5
編號 SM A SM B 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-5.2 Boc-
N-甲基-L-白胺酸
α-胺基異丁酸甲酯鹽酸鹽
(S)-2-(2-((三級丁氧基羰基)(甲基)胺基)-N,4-二甲基戊醯胺基)-2-甲基丙酸
0.88
B
345.26
C-5.3 Boc-
N-甲基-L-
白胺酸
2-胺基-2-環丙基乙酸甲酯(鹽酸鹽)
2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-N,4-二甲基戊醯胺基)-2-環丙基乙酸
0.91
B
357.32
C-5.4 Boc-
N-甲基-L-
白胺酸
1-胺基-3,3-二氟環丁烷-1-甲酸甲酯(鹽酸鹽)
(S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-N,4-二甲基戊醯胺基)-3,3-二氟環丁烷-1-甲酸
0.95
B
393.30
Listed in Table C-5 below are the building blocks C prepared from the corresponding starting materials in analogy to the 3-step sequence described above for C-5.1. Table C-5 serial number SM A SM B product t R [min] LC-MS method MS- data m/z [M+H] +
C-5.2 Boc- N -methyl-L-leucine Methyl α-aminoisobutyrate hydrochloride (S)-2-(2-((tertiary butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanylamino)-2-methylpropionic acid 0.88 B 345.26
C-5.3 Boc- N -methyl-L-leucine Methyl 2-amino-2-cyclopropylacetate (hydrochloride) 2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanylamino)-2-cyclopropylacetic acid 0.91 B 357.32
C-5.4 Boc- N -methyl-L-leucine Methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate (hydrochloride) (S)-1-(2-((tertiary butoxycarbonyl)(methyl)amino)-N,4-dimethylpentamido)-3,3-difluorocyclobutane-1 - formic acid 0.95 B 393.30
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
66
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-(3-羥基丙基)哌𠯤-2-甲酸鹽酸鹽(C-6.1)
步驟 1 ：向(R)-哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(1.0 g，4.01 mmol)及苯甲基3-溴丙基醚(0.95 mL，5.22 mmol)於MeCN (10 mL)中之室溫溶液中添加K
2CO
3(1.66 g，12 mmol)，且在60℃攪拌所得混合物17 h。向反應混合物中添加水(20 mL)及DCM (75 mL)，接著分離兩個層，且水層用DCM (2 × 50 mL)萃取。經合併之有機萃取物用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用5%至25% EtOAc/庚烷溶離)純化，得到呈無色油狀之(
R)-4-(3-苯甲氧基-丙基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(1.58 g，100%)。LC-MS B：t
R= 0.75 min；[M+H]
+= 393.43。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-(3-hydroxypropyl)piperazine-2-carboxylate hydrochloride (C-6.1) Step 1 : Add (R)-piperyl-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester (1.0 g, 4.01 mmol) and benzyl 3-bromopropyl To a room temperature solution of ether (0.95 mL, 5.22 mmol) in MeCN ( 10 mL) was added K2CO3 (1.66 g, 12 mmol), and the resulting mixture was stirred at 60 °C for 17 h. Water (20 mL) and DCM (75 mL) were added to the reaction mixture, then the two layers were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined org. extracts were washed with brine (50 mL), dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 5% to 25% EtOAc/heptane) afforded ( R )-4-(3-benzyloxy-propyl)-piperazine-1,2-bis as a colorless oil 1-tert-butyl 2-methyl formate (1.58 g, 100%). LC-MS B: tR = 0.75 min; [M+H] + = 393.43.
步驟 2 ：向(R)-4-(3-苯甲氧基-丙基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(1.57 g，4 mmol)於二㗁烷(7 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(5 mL，20 mmol)，且在50℃攪拌所得混合物2 h。將反應混合物冷卻至室溫，接著用DCM (100 mL)稀釋，且添加K
2CO
3飽和水溶液(20 mL)。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(100 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈無色油狀之(R)-4-(3-苯甲氧基-丙基)-哌𠯤-2-甲酸甲酯(1.06 g，91%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.53 min；[M+H]
+= 293.32。
Step 2 : Add (R)-4-(3-benzyloxy-propyl)-piperone-1,2-dicarboxylic acid 1-tertiary butyl ester 2-methyl ester (1.57 g, 4 mmol) in di To a room temperature solution in dioxane (7 mL) was added dioxane (5 mL, 20 mmol) containing 4 M HCl, and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature, then diluted with DCM (100 mL), and saturated aqueous K 2 CO 3 (20 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO 4 ), filtered and concentrated to give (R)-4-(3-benzyloxy-propyl)-piperone as a colorless oil - Methyl 2-carboxylate (1.06 g, 91%) which was used as such in the next step. LC-MS B: tR = 0.53 min; [M+H] + = 293.32.
步驟 3 ：向Boc-
N-甲基-L-白胺酸(880 mg，3.58 mmol)、(
R)-4-(3-苯甲氧基-丙基)-哌𠯤-2-甲酸甲酯(1.05 g，3.58 mmol)及DIPEA (1.84 mL，10.7 mmol)於DMF (11 mL)中之室溫溶液中添加HATU (1.36 g，3.58 mmol)。在室溫攪拌所得混合物1 h，反應混合物用DCM (100 mL)及水(10 mL)稀釋。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用15%至42% EtOAc/庚烷溶離)純化，得到呈無色油狀之(R)-4-(3-(苯甲氧基)丙基)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-2-甲酸甲酯(1.67 g，90%)。LC-MS B：t
R= 0.90 min；[M+H]
+= 520.39。
Step 3 : To Boc- N -methyl-L-leucine (880 mg, 3.58 mmol), ( R )-4-(3-benzyloxy-propyl)-piperone-2-formic acid methyl ester (1.05 g, 3.58 mmol) and DIPEA (1.84 mL, 10.7 mmol) in DMF (11 mL) at room temperature was added HATU (1.36 g, 3.58 mmol). The resulting mixture was stirred at room temperature for 1 h, and the reaction mixture was diluted with DCM (100 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (eluted with 15% to 42% EtOAc/heptane) afforded (R)-4-(3-(benzyloxy)propyl)-1-( N- (tri Butoxycarbonyl) -N -methyl-L-leucyl)piperone-2-carboxylic acid methyl ester (1.67 g, 90%). LC-MS B: tR = 0.90 min; [M+H] + = 520.39.
步驟 4 ：向(R)-4-(3-(苯甲氧基)丙基)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-2-甲酸甲酯(1.66 g，3.19 mmol)於MeOH (60 mL)中之室溫溶液中添加2 M NaOH溶液(32 mL，63.9 mmol)，且在50℃攪拌反應混合物1 h。將反應混合物冷卻至室溫，且反應混合物用DCM (100 mL)稀釋且用25% HCl水溶液(10 mL)酸化。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(100 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色固體狀之(
R)-4-(3-苯甲氧基-丙基)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌𠯤-2-甲酸(1.47 g，85%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.84 min；[M+H]
+= 506.36。
Step 4 : To (R)-4-(3-(benzyloxy)propyl)-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)piper To a room temperature solution of methyl ?-2-carboxylate (1.66 g, 3.19 mmol) in MeOH (60 mL) was added 2 M NaOH solution (32 mL, 63.9 mmol), and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature, and the reaction mixture was diluted with DCM (100 mL) and acidified with 25% aqueous HCl (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO 4 ), filtered and concentrated to give ( R )-4-(3-benzyloxy-propyl)-1- as a white solid. [( S )-2-(tertiary butoxycarbonyl-methyl-amino)-4-methyl-pentyl]-piperone-2-carboxylic acid (1.47 g, 85%), which was used as received in the next step. LC-MS B: tR = 0.84 min; [M+H] + = 506.36.
步驟 5 ：在添加10% Pd/C (171 mg，0.16 mmol)之前，(
R)-4-(3-苯甲氧基-丙基)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌𠯤-2-甲酸(1.74 g，3.21 mmol)於EtOH (20 mL)中之溶液用N
2/真空(3×)惰性化。在另外惰性化三次之後，連接H
2氣球，且在室溫攪拌反應混合物18 h。濃縮混合物且經由矽藻土塞過濾，用EtOH沖洗。濃縮濾液，得到呈白色固體狀之標題化合物
C-6.1(1.14 g，79%)。LC-MS B：t
R= 0.67 min；[M+H]
+= 416.34。
Step 5 : Before adding 10% Pd/C (171 mg, 0.16 mmol), ( R )-4-(3-benzyloxy-propyl)-1-[( S )-2-(tertiary butane Oxycarbonyl-methyl-amino)-4-methyl-pentyl]-piperone-2-carboxylic acid (1.74 g, 3.21 mmol) in EtOH (20 mL) was washed with N2 /vacuum (3 ×) Inertization. After three additional inertizations, a H2 balloon was attached and the reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and filtered through a plug of celite, rinsing with EtOH. The filtrate was concentrated to afford the title compound C-6.1 (1.14 g, 79%) as a white solid. LC-MS B: tR = 0.67 min; [M+H] + = 416.34.
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-(2-羥基乙基)哌𠯤-2-甲酸鹽酸鹽(C-6.2) 按照對於
C-6.1所描述之5-步驟順序，在步驟1中使用苯甲基2-溴乙基醚替代苯甲基3-溴丙基醚製備標題化合物。LC-MS B：t
R= 0.67 min；[M+H]
+= 402.07。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-(2-hydroxyethyl)piperone-2-carboxylate hydrochloride (C-6.2) The title compound was prepared following the 5-step sequence described for C-6.1 , using benzyl 2-bromoethyl ether in step 1 instead of benzyl 3-bromopropyl ether. LC-MS B: tR = 0.67 min; [M+H] + = 402.07.
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-(2-甲氧基乙基)哌𠯤-2-甲酸鹽酸鹽(C-6.3)
步驟 1 ：向(R)-哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(4.00 g，16 mmol)及DIPEA (8.41 mL，48.1 mmol)於MeCN (87 mL)中之室溫溶液中添加1-溴-2-甲氧基乙烷(4.31 mL，44.9 mmol)。在80℃攪拌所得混合物18 h。濃縮混合物，且將殘餘物分配於水(10 mL)與DCM (50 mL)之間。分離各層，且水層用DCM (2 × 75 mL)再萃取。經合併之有機萃取物用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且蒸發，得到呈橙色油狀之(R)-4-(2-甲氧基-乙基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯。LC-MS B：t
R= 0.54 min；[M+H]
+= 303.36。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-(2-methoxyethyl)piperone-2-carboxylate Salt (C-6.3) Step 1 : Add (R)-pipera-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester (4.00 g, 16 mmol) and DIPEA (8.41 mL, 48.1 mmol) to a room temperature solution in MeCN (87 mL) was added 1-bromo-2-methoxyethane (4.31 mL, 44.9 mmol). The resulting mixture was stirred at 80 °C for 18 h. The mixture was concentrated, and the residue was partitioned between water (10 mL) and DCM (50 mL). The layers were separated, and the aqueous layer was re-extracted with DCM (2 x 75 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO 4 ), filtered and evaporated to give (R)-4-(2-methoxy-ethyl)-piperone as an orange oil - 1-tertiary butyl 2-methyl 1,2-dicarboxylate. LC-MS B: tR = 0.54 min; [M+H] + = 303.36.
步驟 2 至 4 ：按照對於
C-6.1步驟2至4所描述之反應順序，由(
R)-4-(2-甲氧基-乙基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯製備標題化合物。LC-MS B：t
R= 0.71 min；[M+H]
+= 416.36。
Steps 2 to 4 : Following the reaction sequence described for C-6.1 Steps 2 to 4, from ( R )-4-(2-methoxy-ethyl)-pipera-1,2-dicarboxylic acid 1-tri Butyl ester 2-methyl ester to prepare the title compound. LC-MS B: tR = 0.71 min; [M+H] + = 416.36.
(
S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-
N-(3-甲氧基丙基)-4-甲基戊醯胺基)環丙烷-1-甲酸(C-6.4)
步驟 1 ：按照對於
C-6.3步驟1所描述之反應，由1-胺基環丙烷甲酸甲酯及1-溴-3-甲氧基丙烷製備1-(3-甲氧基-丙基胺基)-環丙烷甲酸甲酯。LC-MS B：t
R= 0.39 min；[M+H]
+= 188.43。
( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino) -N- (3-methoxypropyl)-4-methylpentamylamino)cyclopropane- 1-Formic acid (C -6.4 ) Step 1 : Prepare 1-(3- Methoxy-propylamino)-methyl cyclopropanecarboxylate. LC-MS B: tR = 0.39 min; [M+H] + = 188.43.
步驟 2 及 3 ：按照對於
C-6.1步驟3及4所描述之反應順序，由1-(3-甲氧基-丙基胺基)-環丙烷甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.91 min；[M+H]
+= 401.30。
Steps 2 and 3 : Following the reaction sequence described for C-6.1 Steps 3 and 4, the title compound was prepared from 1-(3-methoxy-propylamino)-cyclopropanecarboxylic acid methyl ester. LC-MS B: tR = 0.91 min; [M+H] + = 401.30.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
77
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-((2,2,2-三氯乙氧基)羰基)哌𠯤-2-甲酸(C-7.1)
步驟 1 ：向(R)-哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(2.0 g，8.02 mmol)及DIPEA (2.88 mL，16.5 mmol)於DCM (40 mL)中之室溫溶液中添加氯甲酸2,2,2-三氯乙酯(1.2 mL，8.54 mmol)。在室溫攪拌所得混合物45 min。反應混合物用DCM (100 mL)及水(20 mL)稀釋。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用20%至60% EtOAc/庚烷溶離，在EtOAc/庚烷1:1中R
f= 0.3)純化，得到呈白色固體狀之(R)-哌𠯤-1,2,4-三甲酸1-(三級丁酯)2-甲酯4-(2,2,2-三氯乙酯) (2.90 g，74%)。LC-MS B：t
R= 1.13 min；[M+H]
+= 545.75。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-((2,2,2-trichloroethoxy)carbonyl)piper 𠯤-2-Formic acid (C-7.1) Step 1 : To (R)-pipera 𠯤-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester (2.0 g, 8.02 mmol) and DIPEA (2.88 mL, 16.5 mmol) in DCM (40 mL) was added 2,2,2-trichloroethyl chloroformate (1.2 mL, 8.54 mmol). The resulting mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with DCM (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 20% to 60% EtOAc/heptane, Rf = 0.3 in EtOAc/heptane 1:1) afforded (R)-piperone-1,2,4 as a white solid - 1-(tert-butyl) 2-methyl tricarboxylate 4-(2,2,2-trichloroethyl ester) (2.90 g, 74%). LC-MS B: tR = 1.13 min; [M+H] + = 545.75.
步驟 2 至 4 ：按照對於
C-6.1步驟2至4所描述之反應順序，由(R)-哌𠯤-1,2,4-三甲酸1-(三級丁酯)2-甲酯4-(2,2,2-三氯乙酯)製備標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 531.98。
Steps 2 to 4 : According to the reaction sequence described for C-6.1 Steps 2 to 4, from (R)-pipera-1,2,4-tricarboxylic acid 1-(tertiary butyl) 2-methyl ester 4- (2,2,2-Trichloroethyl ester) to prepare the title compound. LC-MS B: tR = 1.03 min; [M+H] + = 531.98.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
88
(
R)-1-(
N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-4-苯基哌𠯤-2-甲酸(C-8.1)
步驟 1 ：向(R)-哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(1.00 g，4.01 mmol)及苯基硼酸(749 mg，4.01 mmol)於DCM (20 mL)中之室溫溶液中添加Cu(OAc)
2(749 mg，6.2 mmol)，且在室溫攪拌所得混合物隔夜。反應混合物用DCM稀釋且用冷水(20 mL)及鹽水(20 mL)洗滌。有機層經乾燥(MgSO
4)，過濾且蒸發。藉由製備型HPLC (鹼性)純化，得到呈無色油狀之(R)-4-苯基-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(337 mg，26%)。LC-MS B：t
R= 1.02 min；[M+H]
+= 321.13。
( R )-1-( N- (tertiary butoxycarbonyl)-N-methyl-L-leucyl)-4-phenylpipera-2-carboxylic acid (C-8.1) step 1 : to (R)-piperone-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.00 g, 4.01 mmol) and phenylboronic acid (749 mg, 4.01 mmol) in DCM (20 mL) To a room temperature solution of Cu(OAc) 2 (749 mg, 6.2 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with cold water (20 mL) and brine (20 mL). The organic layer was dried ( MgSO4 ), filtered and evaporated. Purification by preparative HPLC (basic) afforded 1-tert-butyl 2-methyl (R)-4-phenyl-piperone-1,2-dicarboxylate as a colorless oil (337 mg, 26 %). LC-MS B: tR = 1.02 min; [M+H] + = 321.13.
步驟 2 ：向(R)-4-苯基-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(337 mg，1.06 mmol)於DCM (40 mL)中之溶液中添加TFA (0.8 mL，10.6 mmol)，且攪拌所得混合物24 h。反應混合物用DCM (10 mL)稀釋且用NaHCO
3飽和水溶液(30 mL)中和。分離各層，且水層用DCM (20 mL)再萃取。經合併之有機萃取物經乾燥(Na
2SO
4)，過濾且濃縮，得到呈淺黃色油狀之(
R)-4-苯基-哌𠯤-2-甲酸甲酯(232 mg，100%)。LC-MS B：t
R= 0.52 min；[M+H]
+= 221.32。
Step 2 : To a solution of (R)-4-phenyl-piperone-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (337 mg, 1.06 mmol) in DCM (40 mL) was added TFA (0.8 mL, 10.6 mmol), and the resulting mixture was stirred for 24 h. The reaction mixture was diluted with DCM (10 mL) and neutralized with saturated aqueous NaHCO 3 (30 mL). The layers were separated, and the aqueous layer was re-extracted with DCM (20 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated to give ( R )-methyl 4-phenyl-piperazine-2-carboxylate (232 mg, 100%) as a light yellow oil . LC-MS B: tR = 0.52 min; [M+H] + = 221.32.
步驟 3 及 4 ：按照對於
C-2.1所描述之反應順序，由Boc-
N-甲基-L-白胺酸及(
R)-4-苯基-哌𠯤-2-甲酸甲酯製備標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 433.9。
Steps 3 and 4 : Preparation of the title compound from Boc- N -methyl-L-leucine and ( R )-4-phenyl-piperone-2-carboxylic acid methyl ester following the reaction sequence described for C-2.1 . LC-MS B: tR = 1.03 min; [M+H] + = 433.9.
(RS)-1-(N-( 三級丁氧基羰基 )-N- 甲基 -L- 白胺醯基 )-4-(5- 氟吡啶 -2- 基 ) 哌 𠯤 -2- 甲酸 (C-8.2) 步驟 1 ：將(2R)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(2500 mg，10 mmol)、2-溴-5-氟吡啶(2161 mg，12 mmol)、三(二苯亞甲基丙酮)二鈀(0) (473 mg,，0.501 mmol)及氯化1,3-雙(2,6-二異丙基苯基)咪唑鎓(426 mg，1 mmol)於甲苯(30 mL)中之混合物進行脫氣且用氬氣惰性化。接著，將反應混合物加熱直至100℃持續4h30min以達到完全轉化，如藉由LC-MS所監測。將溶液冷卻回至室溫且經由玻璃纖維過濾器過濾。向所得濾液中添加水且收集有機層；接著，無機相進一步用EtOAc (2×)萃取。經合併之有機相依次用NH
4Cl飽和水溶液、NaHCO
3飽和水溶液及鹽水洗滌，經MgSO
4乾燥，接著減壓濃縮。藉由FC (0%至30% EtOAc/庚烷)純化粗物質，得到呈黃色油狀之(R)-4-(5-氟吡啶-2-基)哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(2.21 g)。LC-MS B：t
R= 0.92 min；[M+H]
+= 340.16。
(RS)-1-(N-( tertiary butoxycarbonyl )-N- methyl -L- leucyl ) -4-(5- fluoropyridin -2- yl ) piperazine -2-carboxylic acid ( C-8.2) Step 1 : Mix (2R)-piperone-1,2-dicarboxylic acid 1-tertiary butyl 2-methyl ester (2500 mg, 10 mmol), 2-bromo-5-fluoropyridine (2161 mg , 12 mmol), tris(dibenzylideneacetone)dipalladium(0) (473 mg, 0.501 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride ( 426 mg, 1 mmol) in toluene (30 mL) was degassed and inertized with argon. Then, the reaction mixture was heated up to 100°C for 4h30min to achieve complete conversion as monitored by LC-MS. The solution was cooled back to room temperature and filtered through a glass fiber filter. Water was added to the resulting filtrate and the organic layer was collected; then, the inorganic phase was further extracted with EtOAc (2x). The combined organic phases were washed sequentially with saturated aqueous NH4Cl , saturated aqueous NaHCO3 and brine, dried over MgSO4 , and concentrated under reduced pressure. The crude material was purified by FC (0% to 30% EtOAc/heptane) to afford (R)-4-(5-fluoropyridin-2-yl)piperoxo-1,2-dicarboxylic acid 1 as a yellow oil - (tertiary butyl) 2-methyl ester (2.21 g). LC-MS B: tR = 0.92 min; [M+H] + = 340.16.
步驟 2-4 ：按照對於
C-8.1所描述之反應2至4之反應順序，由boc-
N-甲基-L-白胺酸及(R)-4-(5-氟吡啶-2-基)哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯製備標題化合物。在4步驟順序結束時，在哌𠯤對掌性中心處觀測到廣泛差向異構。LC-MS B：t
R= 0.96 min；[M+H]
+= 453.37。
Step 2-4 : According to the reaction sequence of reactions 2 to 4 described for C-8.1 , from boc- N -methyl-L-leucine and (R)-4-(5-fluoropyridin-2-yl ) 1-(tert-butyl) 2-methyl piper-1,2-dicarboxylate The title compound was prepared. At the end of the 4-step sequence, extensive epimerization was observed at the chiral center of the piperone. LC-MS B: tR = 0.96 min; [M+H] + = 453.37.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
99
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-(吡啶-3-基磺醯基)哌𠯤-2-甲酸(C-9.1)
步驟 1 ：向(R)-哌𠯤-1,2-二甲酸1-(三級丁酯)2-甲酯(2.00 g，8.02 mmol)及TEA (3.37 mL，24.1 mmol)於DCM (80 mL)中之室溫溶液中添加吡啶-3-磺醯氯(2.33 g，12.8 mmol)，且在室溫攪拌所得混合物1 h。反應混合物用DCM (75 mL)及水(10 mL)稀釋。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用80%至85% EtOAc/庚烷，在EtOAc/庚烷7:3中R
f= 0.42溶離)純化，得到呈白色泡沫狀之(
R)-4-(吡啶-3-磺醯基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(3.06 g，99%)。LC-MS B：t
R= 0.89 min；[M+H]
+= 386.16。
( R )-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-(pyridin-3-ylsulfonyl)piperone-2-carboxylic acid ( C-9.1) Step 1 : To (R)-piperone-1,2-dicarboxylic acid 1-(tertiary butyl) 2-methyl ester (2.00 g, 8.02 mmol) and TEA (3.37 mL, 24.1 mmol) in To a room temperature solution in DCM (80 mL) was added pyridine-3-sulfonyl chloride (2.33 g, 12.8 mmol), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (75 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (eluted with 80% to 85% EtOAc/heptane, Rf = 0.42 in EtOAc/heptane 7:3) afforded ( R )-4-(pyridine-3-sulfo as a white foam Acyl)-piperone-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (3.06 g, 99%). LC-MS B: tR = 0.89 min; [M+H] + = 386.16.
步驟 2 ：向(
R)-4-(吡啶-3-磺醯基)-哌𠯤-1,2-二甲酸1-三級丁酯2-甲酯(3.0 g，7.78 mmol)於二㗁烷(10 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(9.73 mL，38.9 mmol)。在50℃攪拌所得混合物2 h。過濾懸浮液，且用TBME (20 mL)沖洗固體，得到呈白色固體狀之(
R)-4-(吡啶-3-基磺醯基)哌𠯤-2-甲酸甲酯二鹽酸鹽(3.12 g，112%)。LC-MS B：t
R= 0.44 min；[M+H]
+= 286.15。
Step 2 : Add ( R )-4-(pyridine-3-sulfonyl)-piperone-1,2-dicarboxylic acid 1-tertiary butyl ester 2-methyl ester (3.0 g, 7.78 mmol) in dioxane To a room temperature solution in (10 mL) was added dioxane (9.73 mL, 38.9 mmol) containing 4 M HCl. The resulting mixture was stirred at 50 °C for 2 h. The suspension was filtered and the solid was rinsed with TBME (20 mL) to give ( R )-4-(pyridin-3-ylsulfonyl)piperoxo-2-carboxylic acid methyl ester dihydrochloride (3.12 g, 112%). LC-MS B: tR = 0.44 min; [M+H] + = 286.15.
步驟 3 及 4 ：按照對於
C-2.1所描述之反應順序，由Boc-
N-甲基-L-白胺酸及(
R)-4-(吡啶-3-基磺醯基)哌𠯤-2-甲酸甲酯二鹽酸鹽製備標題化合物。LC-MS B：t
R= 0.93 min；[M+H]
+= 499.27。
Steps 3 and 4 : According to the reaction sequence described for C-2.1 , from Boc- N -methyl-L-leucine and ( R )-4-(pyridin-3-ylsulfonyl)piperone-2 - Methyl formate dihydrochloride Preparation of the title compound. LC-MS B: tR = 0.93 min; [M+H] + = 499.27.
(
R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-((5-甲氧基吡啶-3-基)磺醯基)哌𠯤-2-甲酸(C-9.2) 按照對於
C-9.1所描述之4-步驟順序，在步驟1中使用5-甲氧基-吡啶-3-磺醯氯替代吡啶-3-磺醯氯製備標題化合物。LC-MS B：t
R= 0.96 min；[M+H]
+= 529.10。
( R )-1-( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-((5-methoxypyridin-3-yl)sulfonyl) Piperidine-2-carboxylic acid (C-9.2) Follow the 4-step sequence described for C-9.1 , using 5-methoxy-pyridine-3-sulfonyl chloride instead of pyridine-3-sulfonyl chloride in step 1 Preparation of the title compound. LC-MS B: tR = 0.96 min; [M+H] + = 529.10.
用於合成建構嵌段 C 之通用方法 10下表C-10中列舉類似於上文對於
C-1.1步驟3及4描述之順序，由對應起始材料製備之建構嵌段C。
表C-10
編號 SM A SM B 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-10.1 D2-1.1 IM-2.2 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙醯基)-
N-(((R)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.55-0.62
I
427.25
C-10.2 D2-1.1 IM-2.1 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙醯基)-
N-(((S)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.59-0.61
I
427.24
C-10.3 D2-1.2 IM-2.2 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環己基丙醯基)-
N-(((R)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.58-0.66
I
441.28
C-10.4 D2-1.2 IM-2.1 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環己基丙醯基)-
N-(((S)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.59-0.64
I
441.27
C-10.5 D2-2.1 IM-2.1 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙醯基)-
N-(((S)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.55-0.59
I
413.22
C-10.6 D2-2.1 IM-2.2 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙醯基)-
N-(((R)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.53-0.60
I
413.20
C-10.7 D2-1.4 IM-2.2 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丙基丙醯基)-N-(((R)-四氫-2H-哌喃-2-基)甲基)甘胺酸
0.48-0.53
I
399.21
C-10.8 D2-1.4 IM-2.3 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丙基丙醯基)-
N-(2-((S)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.51-0.56
I
413.3
C-10.9 D2-1.4 IM-2.4 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丙基丙醯基)-
N-(2-((R)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.52-0.58
I
413.23
C-10.10 D2-2.1 IM-2.3 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙醯基)-
N-(2-((S)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.55-0.60
I
427.34
C-10.11 D2-2.1 IM-2.4 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙醯基)-
N-(2-((R)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.55-0.60
I
427.33
C-10.12 Boc-
N-甲基-L-白胺酸
IM-2.3 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-((S)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.53-0.61
I
415.25
C-10.13 Boc-
N-甲基-L-白胺酸
IM-2.4 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-((R)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.53-0.61
I
415.25
C-10.14 D2-1.1 IM-1.10 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙醯基)-
N-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸
1.01
B
441.39
C-10.15 D2-1.2 IM-1.10 N-((S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環己基丙醯基)-
N-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.61-0.65
I
455.31
C-10.16 D2-1.1 IM-1.12 (S)-
N-(2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙醯基)-
N-(2-環己基乙基)甘胺酸
0.70
I
439.29
C-10.17 D2-1.2 IM-1.12 (S)-
N-(2-((三級丁氧基羰基)(甲基)胺基)-3-環己基丙醯基)-
N-(2-環己基乙基)甘胺酸
0.73
I
453.34
C-10.18 D2-2.1 IM-1.12 (S)-
N-(2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙醯基)-
N-(2-環己基乙基)甘胺酸
0.67
I
425.28
C-10.19 Boc-
N-甲基-L-白胺酸
IM-1.12 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-環己基乙基)甘胺酸
0.72
I
413.26
C-10.20 Boc-
N-甲基-L-白胺酸
IM-2.2 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(((R)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.51-0.59
I
401.89
C-10.21 Boc-
N-甲基-L-白胺酸
IM-2.1 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(((S)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.54
I
401.87
C-10.22 Boc-
N-甲基-L-白胺酸
IM-1.10 N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸
1.05
B
415.43
C-10.23 Boc-
N-甲基-甘胺酸
IM-1.12
N-(
N-(三級丁氧基羰基)-
N-甲基甘胺醯基)-
N-(2-環己基乙基)甘胺酸
2.09
F
無電離
C-10.24 Boc-
N-甲基-L-丙胺酸
IM-1.12
N-(
N-(三級丁氧基羰基)-
N-甲基-L-丙胺醯基)-
N-(2-環己基乙基)甘胺酸
2.20
F
371.20
C-10.25 Boc-
N-甲基-L-白胺酸
IM-1.15
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(3-苯基丙基)甘胺酸
1.78-1.84
J
421.20
C-10.26 D2-1.4
IM-1.12
(S)-
N-(2-((三級丁氧基羰基)(甲基)胺基)-3-環丙基丙醯基)-
N-(2-環己基乙基)甘胺酸
0.63
I
411.28
General Method 10 for the Synthesis of Building Block C Building block C prepared from the corresponding starting materials is listed in Table C-10 below, analogous to the sequence described above for C-1.1 steps 3 and 4. Table C-10 serial number SM A SM B product t R [min] LC-MS method MS- data m/z [M+H] +
C-10.1 D2-1.1 IM-2.2 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentylpropionyl) -N -(((R)-tetrahydro-2 H - pyran-2-yl)methyl)glycine 0.55-0.62I 427.25
C-10.2 D2-1.1 IM-2.1 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentylpropionyl) -N -(((S)-tetrahydro-2 H - pyran-2-yl)methyl)glycine 0.59-0.61I 427.24
C-10.3 D2-1.2 IM-2.2 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclohexylpropionyl) -N -(((R)-tetrahydro-2 H -piper pyran-2-yl)methyl)glycine 0.58-0.66I 441.28
C-10.4 D2-1.2 IM-2.1 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclohexylpropionyl) -N -(((S)-tetrahydro-2 H -piper pyran-2-yl)methyl)glycine 0.59-0.64I 441.27
C-10.5 D2-2.1 IM-2.1 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionyl) -N -(((S)-tetrahydro-2 H - pyran-2-yl)methyl)glycine 0.55-0.59I 413.22
C-10.6 D2-2.1 IM-2.2 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionyl) -N -(((R)-tetrahydro-2 H - pyran-2-yl)methyl)glycine 0.53-0.60I 413.20
C-10.7 D2-1.4 IM-2.2 N-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopropylpropionyl)-N-(((R)-tetrahydro-2H-piper pyran-2-yl)methyl)glycine 0.48-0.53I 399.21
C-10.8 D2-1.4 IM-2.3 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopropylpropionyl) -N- (2-((S)-tetrahydro-2 H -pyran-2-yl)ethyl)glycine 0.51-0.56I 413.3
C-10.9 D2-1.4 IM-2.4 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopropylpropionyl) -N- (2-((R)-tetrahydro-2 H -pyran-2-yl)ethyl)glycine 0.52-0.58I 413.23
C-10.10 D2-2.1 IM-2.3 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionyl) -N- (2-((S)-tetrahydro-2 H -pyran-2-yl)ethyl)glycine 0.55-0.60I 427.34
C-10.11 D2-2.1 IM-2.4 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionyl) -N- (2-((R)-tetrahydro-2 H -pyran-2-yl)ethyl)glycine 0.55-0.60I 427.33
C-10.12 Boc- N -methyl-L-leucine IM-2.3 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(2-((S)-tetrahydro-2 H -pyran-2-yl) Ethyl)glycine 0.53-0.61I 415.25
C-10.13 Boc- N -methyl-L-leucine IM-2.4 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(2-((R)-tetrahydro-2 H -pyran-2-yl) Ethyl)glycine 0.53-0.61I 415.25
C-10.14 D2-1.1 IM-1.10 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentylpropionyl) -N- (2-(tetrahydro-2 H -pyran -2-yl)ethyl)glycine 1.01 B 441.39
C-10.15 D2-1.2 IM-1.10 N -((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclohexylpropionyl) -N- (2-(tetrahydro-2 H -pyranyl- 2-yl)ethyl)glycine 0.61-0.65I 455.31
C-10.16 D2-1.1 IM-1.12 (S) -N- (2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentylpropionyl) -N- (2-cyclohexylethyl)glycine 0.70I 439.29
C-10.17 D2-1.2 IM-1.12 (S) -N- (2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclohexylpropionyl) -N- (2-cyclohexylethyl)glycine 0.73I 453.34
C-10.18 D2-2.1 IM-1.12 (S) -N- (2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionyl) -N- (2-cyclohexylethyl)glycine 0.67I 425.28
C-10.19 Boc- N -methyl-L-leucine IM-1.12 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-cyclohexylethyl)glycine 0.72I 413.26
C-10.20 Boc- N -methyl-L-leucine IM-2.2 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(((R)-tetrahydro-2 H -pyran-2-yl)methyl ) Glycine 0.51-0.59I 401.89
C-10.21 Boc- N -methyl-L-leucine IM-2.1 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(((S)-tetrahydro-2 H -pyran-2-yl)methyl ) Glycine 0.54I 401.87
C-10.22 Boc- N -methyl-L-leucine IM-1.10 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (2-(tetrahydro-2 H -pyran-2-yl)ethyl)glycol amino acid 1.05 B 415.43
C-10.23 Boc- N -methyl-glycine IM-1.12 N- ( N- (tertiary butoxycarbonyl) -N -methylglycyl) -N- (2-cyclohexylethyl)glycine 2.09 F No ionization
C-10.24 Boc- N -methyl-L-alanine IM-1.12 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-propanyl) -N -(2-cyclohexylethyl)glycine 2.20F 371.20
C-10.25 Boc- N -methyl-L-leucine IM-1.15 N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -(3-phenylpropyl)glycine 1.78-1.84J 421.20
C-10.26 D2-1.4 IM-1.12 (S) -N- (2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopropylpropionyl) -N- (2-cyclohexylethyl)glycine 0.63 I 411.28
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1111
(
S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基-
N-甲基丙醯胺基)環丙烷-1-甲酸(C-11.1)
步驟 1 ：向1-胺基環丙烷甲酸甲酯(3.25 g，27.7 mmol)及NaHCO
3(9.64 g，115 mmol)於DCM (30 mL)及H
2O (30 mL)中之室溫溶液中添加氯甲酸苯甲酯(4.6 mL，30.6 mmol)。在室溫攪拌所得混合物。在2 h之後，分離兩個層，且水層用DCM (2 × 30 mL)萃取。濃縮經合併之有機萃取物，得到呈黃色固體狀之1-苯甲氧基羰基胺基-環丙烷甲酸甲酯(7.28 g，106%)。LC-MS B：t
R= 0.79 min；[M+H]
+= 250.37。
( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentyl- N -methylacrylamide)cyclopropane-1-carboxylic acid (C- 11.1) Step 1 : Methyl 1-aminocyclopropanecarboxylate (3.25 g, 27.7 mmol) and NaHCO 3 (9.64 g, 115 mmol) in DCM (30 mL) and H 2 O (30 mL) were dissolved at room temperature To the solution was added benzyl chloroformate (4.6 mL, 30.6 mmol). The resulting mixture was stirred at room temperature. After 2 h, the two layers were separated, and the aqueous layer was extracted with DCM (2 x 30 mL). The combined organic extracts were concentrated to give methyl 1-benzyloxycarbonylamino-cyclopropanecarboxylate (7.28 g, 106%) as a yellow solid. LC-MS B: tR = 0.79 min; [M+H] + = 250.37.
步驟 2 ：向DMF (45 mL)之0℃溶液中添加NaH (1.85 g，46.3 mmol)，隨後添加1-苯甲氧基羰基胺基-環丙烷甲酸甲酯(7.28 g，29.2 mmol)於DMF (30 mL)中之溶液。在45 min之後，添加MeI (5.5 mL，87.5 mmol)，且將混合物升溫至室溫隔夜。將反應混合物分配於H
2O (50 mL)與EtOAc (150 mL)之間，且分離各層。水層用EtOAc (2 × 75 mL)再萃取，且經合併之有機層用鹽水(40 mL)洗滌，經乾燥(MgSO
4)，過濾且蒸發，得到呈橙色液體狀之1-(苯甲氧基羰基-甲基-胺基)-環丙烷甲酸甲酯(7.70 g，100%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.88 min；[M+H]
+= 264.33。
Step 2 : To a 0°C solution in DMF (45 mL) was added NaH (1.85 g, 46.3 mmol), followed by methyl 1-benzyloxycarbonylamino-cyclopropanecarboxylate (7.28 g, 29.2 mmol) in DMF (30 mL). After 45 min, MeI (5.5 mL, 87.5 mmol) was added, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (150 mL), and the layers were separated. The aqueous layer was re-extracted with EtOAc (2 x 75 mL), and the combined organic layers were washed with brine (40 mL), dried (MgSO 4 ), filtered and evaporated to give 1-(benzyloxy) as an orange liquid. ((2)-methylcarbonyl-methyl-amino)-cyclopropanecarboxylate (7.70 g, 100%), which was used as such in the next step. LC-MS B: tR = 0.88 min; [M+H] + = 264.33.
步驟 3 ：在添加10% Pd/C (606 mg，0.57 mmol)之前，1-(苯甲氧基羰基-甲基-胺基)-環丙烷甲酸甲酯(4.00 g，11.4 mmol)於MeOH (18 mL)中之溶液用N
2/真空(3×)惰性化。在另外惰性化三次之後，連接H
2氣球，且攪拌反應混合物18 h。濃縮混合物且經由矽藻土塞過濾，用EtOH沖洗。濃縮濾液(小心的，產物為揮發性)，得到1-甲基胺基-環丙烷甲酸甲酯(653 mg，44%)。LC-MS B：t
R= 0.26 min；[M+H]
+= 130.24。
Step 3 : 1-(Benzyloxycarbonyl-methyl-amino)-cyclopropanecarboxylic acid methyl ester (4.00 g, 11.4 mmol) was dissolved in MeOH ( The solution in 18 mL) was inertized with N2 /vacuum (3x). After three additional inertizations, a H2 balloon was attached and the reaction mixture was stirred for 18 h. The mixture was concentrated and filtered through a plug of celite, rinsing with EtOH. The filtrate was concentrated (caution, product was volatile) to give methyl 1-methylamino-cyclopropanecarboxylate (653 mg, 44%). LC-MS B: tR = 0.26 min; [M+H] + = 130.24.
步驟 4 及 5 ：按照對於
C-2.1所描述之2-步驟順序，由
D2-1.1及1-甲基胺基-環丙烷甲酸甲酯製備標題化合物。LC-MS B：t
R= 0.92 min；[M+H]
+= 369.29。
Steps 4 and 5 : The title compound was prepared from D2-1.1 and methyl 1-methylamino-cyclopropanecarboxylate following the 2-step sequence described for C-2.1 . LC-MS B: tR = 0.92 min; [M+H] + = 369.29.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1212
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-(3-甲氧基丙基)-D-丙胺酸(C-12.1)
步驟 1 ：向D-丙胺酸甲酯鹽酸鹽(600 mg，4.3 mmol)、3-甲氧基-丙醛(429 mg，4.73 mmol)、分子篩3A (450 mg)及AcOH (0.295 mL，5.16 mmol)於MeOH (19 mL)中之室溫溶液中添加NaH
3BCN (398 mg，6.02 mmol)。在室溫攪拌所得混合物35 min。濃縮混合物，且向殘餘物中添加DCM。有機層用飽和NaHCO
3洗滌，且水層用DCM再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈無色油狀之(
R)-2-(3-甲氧基-丙基胺基)-丙酸甲酯(615 mg，82%)。LC-MS B: t
R= 0.33；[M+H]
+= 176.50。
N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N- (3-methoxypropyl)-D-alanine (C-12.1) step 1 : D-alanine methyl ester hydrochloride (600 mg, 4.3 mmol), 3-methoxy-propionaldehyde (429 mg, 4.73 mmol), molecular sieve 3A (450 mg) and AcOH (0.295 mL, 5.16 mmol) To a room temperature solution in MeOH (19 mL) was added NaH3BCN (398 mg, 6.02 mmol). The resulting mixture was stirred at room temperature for 35 min. The mixture was concentrated, and DCM was added to the residue. The organic layer was washed with saturated NaHCO 3 , and the aqueous layer was re-extracted with DCM. The combined organic extracts were washed with brine, dried ( MgSO4 ), filtered and concentrated to give ( R )-2-(3-methoxy-propylamino)-propionic acid methyl ester as a colorless oil (615 mg, 82%). LC-MS B: tR = 0.33; [M+H] + = 176.50.
步驟 2 及 3 ：按照對於
C-2.1所描述之2-步驟順序，由(
R)-2-(3-甲氧基-丙基胺基)-丙酸甲酯製備標題化合物。LC-MS B：t
R= 0.91 min；[M+H]
+= 389.42。
Steps 2 and 3 : The title compound was prepared from ( R )-2-(3-methoxy-propylamino)-propionic acid methyl ester following the 2-step sequence described for C-2.1 . LC-MS B: tR = 0.91 min; [M+H] + = 389.42.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1313
(
S)-1-(2-((三級丁氧基羰基)(甲基)胺基)-
N-(2-甲氧基乙基)-4-甲基戊醯胺基)環丙烷-1-甲酸(C-13.1)
步驟 1 ：向1-三級丁氧基羰基胺基-環丙烷甲酸(7.00 g，33.0 mmol)及K
2CO
3(6.92 g，49.6 mmol)於MeCN (320 mL)中之懸浮液中添加溴甲苯(4.41 mL，36.4 mmol)。將所得混合物加熱至60℃持續15 h。濃縮反應混合物，且向殘餘物中添加EtOAc及水。分離有機層且用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色固體狀之1-三級丁氧基羰基胺基-環丙烷甲酸苯甲酯(9.97 g，104%)。LC-MS B：t
R= 0.95 min；[M+H]
+= 292.31。
( S )-1-(2-((tertiary butoxycarbonyl)(methyl)amino) -N- (2-methoxyethyl)-4-methylpentamylamino)cyclopropane- 1-Formic acid (C-13.1) Step 1 : Add 1-tertiary butoxycarbonylamino-cyclopropanecarboxylic acid (7.00 g, 33.0 mmol) and K 2 CO 3 (6.92 g, 49.6 mmol) in MeCN (320 mL ) was added bromotoluene (4.41 mL, 36.4 mmol). The resulting mixture was heated to 60 °C for 15 h. The reaction mixture was concentrated, and to the residue were added EtOAc and water. The organic layer was separated and washed with brine, dried (MgSO 4 ), filtered and concentrated to give benzyl 1-tert-butoxycarbonylamino-cyclopropanecarboxylate (9.97 g, 104%) as a white solid. LC-MS B: tR = 0.95 min; [M+H] + = 292.31.
步驟 2 ：向1-三級丁氧基羰基胺基-環丙烷甲酸苯甲酯(9.97 g，33.0 mmol)於DCM (20 mL)中之室溫懸浮液中添加含4 M HCl之二㗁烷(84.0 mL，336 mmol)，且在室溫攪拌所得混合物1.5 h。濃縮反應混合物且在HV下與DCM一起共蒸發，得到呈白色固體狀之1-胺基-環丙烷甲酸苯甲酯鹽酸鹽(7.93 g，105%)。LC-MS B：t
R= 0.50 min；[M+H]
+= 192.34。
Step 2 : To a room temperature suspension of benzyl 1-tert-butoxycarbonylamino-cyclopropanecarboxylate (9.97 g, 33.0 mmol) in DCM (20 mL) was added 4 M HCl in dioxane (84.0 mL, 336 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and co-evaporated with DCM under HV to give 1-amino-cyclopropanecarboxylate benzyl hydrochloride (7.93 g, 105%) as a white solid. LC-MS B: tR = 0.50 min; [M+H] + = 192.34.
步驟 3 ：向1-胺基-環丙烷甲酸苯甲酯鹽酸鹽(7.93 g，33.0 mmol)及TEA (13.9 mL，99.1 mmol)於DCM (70 mL)中之0℃懸浮液中逐份添加2-硝基苯磺醯氯(8.30 g，36.4 mmol)。在30 min之後移除冰浴，且在室溫攪拌混合物1.5 h。將反應混合物分配於飽和NaHCO
3與DCM之間，且分離各層。水層用DCM再萃取，且經合併之有機層用鹽水(40 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (EtOAc/庚烷3:7至1:1，在EtOAc/庚烷3:7中R
f= 0.21)純化，得到呈橙色油狀之1-(2-硝基-苯磺醯基胺基)-環丙烷甲酸苯甲酯(12.05 g，97%)。LC-MS B：t
R= 0.96 min；[M+H]
+= 377.29。
Step 3 : To a suspension of 1-amino-cyclopropanecarboxylate benzyl hydrochloride (7.93 g, 33.0 mmol) and TEA (13.9 mL, 99.1 mmol) in DCM (70 mL) at 0 °C was added portionwise 2-Nitrobenzenesulfonyl chloride (8.30 g, 36.4 mmol). The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between saturated NaHCO 3 and DCM, and the layers were separated. The aqueous layer was re-extracted with DCM, and the combined org. layers were washed with brine (40 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (EtOAc/heptane 3:7 to 1:1, Rf = 0.21 in EtOAc/heptane 3:7) gave 1-(2-nitro-benzenesulfonyl as orange oil Amino)-benzyl cyclopropanecarboxylate (12.05 g, 97%). LC-MS B: tR = 0.96 min; [M+H] + = 377.29.
步驟 4 ：向1-(2-硝基-苯磺醯基胺基)-環丙烷甲酸苯甲酯(2.00 g，5.31 mmol)、2-甲氧基-乙醇(0.635 mL，7.97 mmol)及PPh
3(2.83 g，10.2 mmol)於THF (55 mL)中之0℃溶液中逐滴添加DIAD (2.1 mL，10.2 mmol)。在0℃攪拌所得混合物5 min，接著在室溫攪拌3 h。濃縮混合物且藉由FC (EtOAc/庚烷，3:7至1:1，在EtOAc/1:1中R
f= 0.39)純化，得到呈黃色油狀之1-((
N-(2-甲氧基乙基)-2-硝基苯基)磺醯胺基)環丙烷-1-甲酸苯甲酯(3.55 g，154%)。LC-MS B：t
R= 1.03 min；[M+H]
+= 435.20。
Step 4 : Add 1-(2-nitro-benzenesulfonylamino)-cyclopropanecarboxylic acid benzyl ester (2.00 g, 5.31 mmol), 2-methoxy-ethanol (0.635 mL, 7.97 mmol) and PPh To a solution of 3 (2.83 g, 10.2 mmol) in THF (55 mL) at 0 °C was added DIAD (2.1 mL, 10.2 mmol) dropwise. The resulting mixture was stirred at 0 °C for 5 min, then at room temperature for 3 h. The mixture was concentrated and purified by FC (EtOAc/heptane, 3:7 to 1:1, Rf = 0.39 in EtOAc/1:1) to give 1-(( N- (2-methanol) as a yellow oil oxyethyl)-2-nitrophenyl)sulfonamido)cyclopropane-1-carboxylic acid benzyl ester (3.55 g, 154%). LC-MS B: tR = 1.03 min; [M+H] + = 435.20.
步驟 5 ：向1-((N-(2-甲氧基乙基)-2-硝基苯基)磺醯胺基)環丙烷-1-甲酸苯甲酯(3.55 g，5.31 mmol)及K
2CO
3(1.18 g，8.5 mmol)於DMF (28 mL)中之室溫溶液中逐滴添加硫酚(0.844 mL，7.97 mmol)。在室溫攪拌所得混合物2 h。將混合物分配於EtOAc與水之間。分離有機層，經乾燥(MgSO
4)，過濾且濃縮，直至僅存在DMF。藉由製備型HPLC (鹼性)純化，得到呈無色油狀之1-(2-甲氧基-乙基胺基)-環丙烷甲酸苯甲酯(848 mg，64%)。LC-MS B：t
R= 0.58 min；[M+H]
+= 250.33。
Step 5 : Add 1-((N-(2-methoxyethyl)-2-nitrophenyl)sulfonamido)cyclopropane-1-carboxylic acid benzyl ester (3.55 g, 5.31 mmol) and K To a room temperature solution of 2CO3 (1.18 g, 8.5 mmol) in DMF (28 mL) was added thiophenol (0.844 mL, 7.97 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, dried ( MgSO4 ), filtered and concentrated until only DMF was present. Purification by preparative HPLC (basic) afforded benzyl 1-(2-methoxy-ethylamino)-cyclopropanecarboxylate (848 mg, 64%) as a colorless oil. LC-MS B: tR = 0.58 min; [M+H] + = 250.33.
步驟 6 及 7 ：按照對於
C-1.1步驟3及4所描述之反應順序，由1-(2-甲氧基-乙基胺基)-環丙烷甲酸苯甲酯製備標題化合物。LC-MS B：t
R= 0.91 min；[M+H]
+= 389.42。
Steps 6 and 7 : Following the reaction sequence described for C-1.1 Steps 3 and 4, the title compound was prepared from 1-(2-methoxy-ethylamino)-cyclopropanecarboxylic acid benzyl ester. LC-MS B: tR = 0.91 min; [M+H] + = 389.42.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1414
(
R)-1-(
N-(三級丁氧基羰基)-
N-乙基-L-白胺醯基)哌啶-2-甲酸(C-14.1)
步驟 1 ：向Fmoc-Leu-OH (3.00 g，8.23 mmol)及
pTsOH.H
2O (145 mg，0.82 mmol)於PhMe (150 mL)中之室溫溶液中添加乙醛(2.33 mL，41.2 mmol)，且用Dean Stark設備使所得混合物回流19 h。在4 h及6 h之後，再次添加乙醛(2.33 mL，41.2 mmol)。在將混合物分配於EtOAc與NaHCO
3飽和水溶液之間之前，將其冷卻至室溫。分離各相，且水相用EtOAc (2×)再萃取。經合併之有機層經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用5%至20% EtOAc/庚烷溶離)純化，得到呈黃色油狀之(4
S)-4-異丁基-(2
R,
S)-2-甲基-5-側氧基㗁唑啶-3-甲酸(9
H-茀-9-基)甲酯。LC-MS B：t
R= 1.13 min；[M+H]
+= 380.15。
( R )-1-( N- (tertiary butoxycarbonyl) -N -ethyl-L-leucyl)piperidine-2-carboxylic acid (C-14.1) step 1 : to Fmoc-Leu-OH (3.00 g, 8.23 mmol) and pTsOH.H 2 O (145 mg, 0.82 mmol) in PhMe (150 mL) at room temperature were added acetaldehyde (2.33 mL, 41.2 mmol) and used Dean Stark apparatus The resulting mixture was refluxed for 19 h. After 4 h and 6 h, acetaldehyde (2.33 mL, 41.2 mmol) was added again. The mixture was cooled to room temperature before partitioning between EtOAc and saturated aqueous NaHCO 3 . The phases were separated and the aqueous phase was re-extracted with EtOAc (2x). The combined org. layers were dried (Na 2 SO 4 ), filtered and concentrated. Purification by FC (eluted with 5% to 20% EtOAc/heptane) afforded ( 4S )-4-isobutyl-( 2R , S )-2-methyl-5-pentane as a yellow oil Oxyxazolidine-3-carboxylic acid ( 9H -fluorene-9-yl)methyl ester. LC-MS B: tR = 1.13 min; [M+H] + = 380.15.
步驟 2 ：向(4
S)-4-異丁基-(2
R,
S)-2-甲基-5-側氧基㗁唑啶-3-甲酸(9
H-茀-9-基)甲酯(3.0 g，8.0 mmol)於DCM (30 mL)中之室溫溶液中添加TFA (31.3 mL，0.40 mol)，隨後添加三乙基矽烷(3.89 mL，23.9 mmol)，且攪拌所得混合物19 h。濃縮混合物且與DCM (2×)一起共蒸發。藉由FC (用50% EtOAc/庚烷+1% AcOH溶離)純化，得到呈黃色油狀之
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-乙基-L-白胺酸。LC-MS B：t
R= 1.05 min；[M+H]
+= 382.16。
Step 2 : To (4 S )-4-isobutyl-(2 R , S )-2-methyl-5-oxazolidine-3-carboxylic acid (9 H -fluorene-9-yl) methyl To a room temperature solution of the ester (3.0 g, 8.0 mmol) in DCM (30 mL) was added TFA (31.3 mL, 0.40 mol) followed by triethylsilane (3.89 mL, 23.9 mmol) and the resulting mixture was stirred for 19 h . The mixture was concentrated and coevaporated with DCM (2x). Purification by FC (eluted with 50% EtOAc/heptane + 1% AcOH) afforded N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -ethyl as a yellow oil -L-leucine. LC-MS B: tR = 1.05 min; [M+H] + = 382.16.
步驟 3 ：按照對於
C-2.1 步驟1所描述之程序，由
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-乙基-L-白胺酸及(
R)-哌啶-2-甲酸甲酯鹽酸鹽製備(
R)-1-(
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-乙基-L-白胺醯基)哌啶-2-甲酸甲酯。LC-MS I：t
R= 1.36 min；[M+H]
+= 507.33。
Step 3 : Following the procedure described for C-2.1 Step 1, from N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -ethyl-L-leucine and ( R )-piperidine-2-carboxylic acid methyl ester hydrochloride preparation ( R )-1-( N -((( 9H -fen-9-yl)methoxy)carbonyl) -N -ethyl-L-white Amino)piperidine-2-carboxylic acid methyl ester. LC-MS I: tR = 1.36 min; [M+H] + = 507.33.
步驟 4 ：攪拌(
R)-1-(
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-乙基-L-白胺醯基)哌啶-2-甲酸甲酯(1.98 g，3.91 mmol)及2 M NaOH水溶液(3.9 mL，7.82 mmol)於MeOH (7.8 mL)中之室溫溶液18 h。真空蒸發MeOH，且殘餘物用水稀釋並用EtOAc (3×)萃取。丟棄經合併之有機萃取物，且將水相蒸發至乾燥，得到呈白色固體狀之(
R)-1-(乙基-L-白胺醯基)哌啶-2-甲酸。LC-MS B：t
R= 0.55 min；[M+H]
+= 271.30。
Step 4 : Stirring ( R )-1-( N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -ethyl-L-leucyl)piperidine-2-carboxylic acid A room temperature solution of the methyl ester (1.98 g, 3.91 mmol) and 2 M aqueous NaOH (3.9 mL, 7.82 mmol) in MeOH (7.8 mL) for 18 h. MeOH was evaporated in vacuo, and the residue was diluted with water and extracted with EtOAc (3x). The combined organic extracts were discarded, and the aqueous phase was evaporated to dryness to afford ( R )-1-(ethyl-L-leucyl)piperidine-2-carboxylic acid as a white solid. LC-MS B: tR = 0.55 min; [M+H] + = 271.30.
步驟 5 ：向(
R)-1-(乙基-L-白胺醯基)哌啶-2-甲酸(1.06 g，3.92 mmol)於DMF (3.5 mL)及1 M NaOH水溶液(3.9 mL，3.92 mmol)中之室溫溶液中添加Boc酸酐(898 mg，4.12 mmol)於DMF (3.5 mL)中之溶液。在19 h之後，添加TEA (1.09 mL，7.84 mmol)，且在另外5 h之後，添加額外Boc酸酐(170 mg，0.78 mmol)且繼續攪拌1 h。反應混合物用2 M HCl水溶液酸化且用TBME (2×)萃取。經合併之有機萃取物用水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由製備型HPLC (酸性)純化，得到呈無色油狀之標題化合物
C-14.1。LC-MS B：t
R= 0.98 min；[M+H]
+= 371.21。
Step 5 : Dissolve ( R )-1-(ethyl-L-leucyl)piperidine-2-carboxylic acid (1.06 g, 3.92 mmol) in DMF (3.5 mL) and 1 M aqueous NaOH (3.9 mL, 3.92 mmol) was added a solution of Boc anhydride (898 mg, 4.12 mmol) in DMF (3.5 mL). After 19 h, TEA (1.09 mL, 7.84 mmol) was added and after another 5 h, additional Boc anhydride (170 mg, 0.78 mmol) was added and stirring was continued for 1 h. The reaction mixture was acidified with 2 M aqueous HCl and extracted with TBME (2x). The combined org. extracts were washed with water, dried ( Na2SO4 ) , filtered and concentrated. Purification by preparative HPLC (acidic) afforded the title compound C-14.1 as a colorless oil. LC-MS B: tR = 0.98 min; [M+H] + = 371.21.
用於合成建構嵌段C之通用方法16General method for the synthesis of building block C 16
N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(2-環己基乙基)甘胺酸(C-16.1)
步驟 1 及 2 ：按照對於
C-4.1步驟1及2所描述之程序，由
D2-3.1及
IM-1.12製備標題化合物。LC-MS I：t
R= 0.64 min；[M+H]
+= 397.29。
N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N- (2-cyclohexylethyl)glycine (C-16.1) step 1 and 2 : The title compound was prepared from D2-3.1 and IM-1.12 following the procedure described for C-4.1 steps 1 and 2. LC-MS I: tR = 0.64 min; [M+H] + = 397.29.
下表C-16中列舉類似於上文對於
C-16.1描述之順序，由
D2-3.1及對應起始材料製備之建構嵌段C。
表 C-16 編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-16.2 IM-2.5 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(((
S)-𠳭唍-3-基)甲基)甘胺酸
0.56
I
433.14
C-16.3 IM-2.6 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(((
R)-𠳭唍-3-基)甲基)甘胺酸
0.56
I
433.17
C-16.4 IM-2.2 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(((
R)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.50
I
385.18
C-16.5 IM-2.1 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(((
S)-四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.49
I
385.17
C-16.6 IM -2.3 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(2-((
S)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.52-0.54
I
399.21
C-16.7 IM-2.4 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-(2-((
R)-四氫-2
H-哌喃-2-基)乙基)甘胺酸
0.52-0.54
I
399.21
C-16.8 IM-1.16 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-((2,3-二氫苯并呋喃-2-基)甲基)甘胺酸
0.95
B
419.37
C-16.9 IM-1.14 N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-((6,6-二甲基四氫-2
H-哌喃-2-基)甲基)甘胺酸
0.98
B
413.43
Listed in Table C-16 below are building blocks C prepared from D2-3.1 and corresponding starting materials in a sequence similar to that described above for C-16.1. Table C-16 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
C-16.2 IM-2.5 N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((( S )-𠳭-3-yl)methyl)glycine 0.56 I 433.14
C-16.3 IM-2.6 N -( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((( R )-𠳭-3-yl)methyl)glycine 0.56 I 433.17
C-16.4 IM-2.2 N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((( R )-tetrahydro-2 H -pyran-2-yl)methyl base) glycine 0.50I 385.18
C-16.5 IM-2.1 N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((( S )-tetrahydro-2 H -pyran-2-yl)methyl base) glycine 0.49 I 385.17
C-16.6 IM-2.3 N -( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -(2-(( S )-tetrahydro-2 H -pyran-2-yl ) ethyl) glycine 0.52-0.54I 399.21
C-16.7 IM-2.4 N -( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -(2-(( R )-tetrahydro-2 H -pyran-2-yl ) ethyl) glycine 0.52-0.54I 399.21
C-16.8 IM-1.16 N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((2,3-dihydrobenzofuran-2-yl)methyl)glycerin amino acid 0.95 B 419.37
C-16.9 IM-1.14 N -( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -((6,6-dimethyltetrahydro-2 H -pyran-2- base) methyl) glycine 0.98 B 413.43
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1717
N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-苯丙胺酸(C-17.1)
步驟 1 ：向
IM-3.1(200 mg，0.682 mmol)、
D2-3.1(156 mg，0.682 mmol)及DIPEA (0.36 mmol，2.05 mmol)於DCM (3 mL)中之室溫溶液中添加PyClop (352 mg，0.82 mmol)，且將反應混合物加熱至40℃隔夜。向反應混合物中添加水(5 mL),且用DCM (2×)萃取產物。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC純化，得到
N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-苯基丙胺酸甲酯。LC-MS B：t
R= 1.06 min；[M+H]
+= 405.19。
N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -methyl-D-phenylalanine (C-17.1) step 1 : to IM-3.1 ( 200 mg, 0.682 mmol), D2-3.1 (156 mg, 0.682 mmol) and DIPEA (0.36 mmol, 2.05 mmol) in DCM (3 mL) at room temperature were added PyClop (352 mg, 0.82 mmol), and The reaction mixture was heated to 40°C overnight. Water (5 mL) was added to the reaction mixture, and the product was extracted with DCM (2×). The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC afforded N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -methyl-D-phenylalanine methyl ester. LC-MS B: tR = 1.06 min; [M+H] + = 405.19.
步驟 2 ：向
N-(
N-((烯丙氧基)羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-苯基丙胺酸甲酯(193 mg，0.478 mmol)於THF/MeOH/H
2O 2/1/1之溶劑混合物(2.5 mL)中之室溫溶液中添加LiOH.H
2O (40.1 mg，0.96 mmol)，且將反應混合物加熱至100℃持續15 h。蒸發THF及MeOH，且殘餘物用1 M HCl酸化至pH 1，接著用EtOAc (3×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且蒸發，得到
C-17.1，其按原樣用於下一步驟。LC-MS I：t
R= 0.53-0.56 min；[M+H]
+= 391.23。
Step 2 : To N- ( N -((allyloxy)carbonyl) -N -methyl-L-leucyl) -N -methyl-D-phenylalanine methyl ester (193 mg, 0.478 mmol) to a room temperature solution in a solvent mixture of THF/MeOH/ H2O2 /1/1 (2.5 mL) was added LiOH.H2O (40.1 mg, 0.96 mmol) and the reaction mixture was heated to 100 °C Last for 15 hours. THF and MeOH were evaporated, and the residue was acidified to pH 1 with 1 M HCl, then extracted with EtOAc (3x). The combined organic layers were dried ( MgSO4 ), filtered and evaporated to give C-17.1 which was used as such in the next step. LC-MS I: tR = 0.53-0.56 min; [M+H] + = 391.23.
下表C-17中列舉類似於上文對於
C-17.1描述之順序，由
D2-3.1及對應起始材料製備之建構嵌段C。
表 C-17 編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-17.2 IM-3.2 (
R)-2-((
S)-2-(((烯丙氧基)羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-環己基丙酸
1.03
B
397.25
C-17.3 IM-3.3 (
R)-2-((
S)-2-(((烯丙氧基)羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-2-環戊基乙酸
0.96
B
369.13
C-17.4 1-(甲基胺基)環戊烷-1-甲酸甲酯
(
S)-1-(2-(((烯丙氧基)羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環戊烷-1-甲酸
0.89
B
355.23
C-17.5 IM-4.1 (
S)-1-(2-(((烯丙氧基)羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3,3-二氟環丁烷-1-甲酸
1.00
B
391.17
Listed in Table C-17 below are building blocks C prepared from D2-3.1 and corresponding starting materials in a sequence similar to that described above for C-17.1. Table C-17 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
C-17.2 IM-3.2 ( R )-2-(( S )-2-(((allyloxy)carbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-cyclohexylpropionic acid 1.03 B 397.25
C-17.3 IM-3.3 ( R )-2-(( S )-2-(((allyloxy)carbonyl)(methyl)amino) -N ,4-dimethylpentamido)-2-cyclopentylacetic acid 0.96 B 369.13
C-17.4 Methyl 1-(methylamino)cyclopentane-1-carboxylate ( S )-1-(2-(((allyloxy)carbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)cyclopentane-1-carboxylic acid 0.89 B 355.23
C-17.5 IM-4.1 ( S )-1-(2-(((allyloxy)carbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3,3-difluorocyclobutane- 1-Formic acid 1.00 B 391.17
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
1818
2-((S)-2-((三級丁氧基羰基) (甲基)胺基)-
N,4-二甲基戊醯胺基)- 3(4,4-二氟環己基)丙酸(C-18.1)
步驟 1 ：向2-(三級丁氧基羰基胺基)-3-(4,4-二氟環己基)丙酸(1.0 g，3.25 mmol)於THF (20 mL)中之0℃懸浮液中添加NaH於礦物油中之60%分散液(374 mg，9.76 mmol)。在0℃攪拌反應混合物10 min，接著在室溫另外攪拌10 min。將反應混合物冷卻回至0℃，且逐滴添加MeI (0.614 mL，9.76 mmol)，且將反應混合物升溫至室溫隔夜。添加水及EtOAc，接著分離兩個層。水層用EtOAc (2×)洗滌，且經合併之有機層經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離)純化，得到呈無色油狀之甲基-2-((三級丁氧基羰基)(甲基)胺基)-3-(4,4-二氟環己基)丙酸酯(434 mg，40%)。LC-MS B：t
R= 1.04 min；[M+H]
+= 336.26。
2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3(4,4-difluorocyclohexyl) Propionic acid (C-18.1) Step 1 : Add 2-(tertiary butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propionic acid (1.0 g, 3.25 mmol) in THF (20 mL ) was added a 60% dispersion of NaH in mineral oil (374 mg, 9.76 mmol). The reaction mixture was stirred at 0 °C for 10 min, then at room temperature for an additional 10 min. The reaction mixture was cooled back to 0 °C, and MeI (0.614 mL, 9.76 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. Water and EtOAc were added, then the two layers were separated. The aqueous layer was washed with EtOAc (2x), and the combined org. layers were dried ( Na2SO4 ), filtered and concentrated. Purification by FC (eluted with 0% to 30% EtOAc/heptane) afforded methyl-2-((tertiary butoxycarbonyl)(methyl)amino)-3-(4 , 4-difluorocyclohexyl)propionate (434 mg, 40%). LC-MS B: tR = 1.04 min; [M+H] + = 336.26.
步驟 2 ：向甲基-2-((三級丁氧基羰基)(甲基)胺基)-3-(4,4-二氟環己基)丙酸酯(300 mg，0.61 mmol)於DCM (10 mL)中之室溫溶液中添加TFA (0.99 mL，12.9 mmol)，且在室溫攪拌反應混合物2 h。真空移除揮發物，且將殘餘物與DCM (3×)一起共蒸發，得到甲基-3-(4,4-二氟環己基)-2-(甲基胺基)丙酸酯2,2,2-三氟乙酸鹽，其按原樣用於下一步驟。LC-MS B：t
R= 0.56 min；[M+H]
+= 236.31。
Step 2 : To methyl-2-((tertiary butoxycarbonyl)(methyl)amino)-3-(4,4-difluorocyclohexyl)propionate (300 mg, 0.61 mmol) in DCM To a room temperature solution in (10 mL) was added TFA (0.99 mL, 12.9 mmol), and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was co-evaporated with DCM (3x) to give methyl-3-(4,4-difluorocyclohexyl)-2-(methylamino)propionate 2, 2,2-Trifluoroacetate, which was used as such in the next step. LC-MS B: tR = 0.56 min; [M+H] + = 236.31.
步驟 3 及 4 ：按照對於
C-2.1步驟1及2所描述之反應順序，由甲基-3-(4,4-二氟環己基)-2-(甲基胺基)丙酸酯2,2,2-三氟乙酸鹽及Boc-
N-甲基-L-白胺酸製備標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 449.27。
Steps 3 and 4 : According to the reaction sequence described for C-2.1 steps 1 and 2, from methyl-3-(4,4-difluorocyclohexyl)-2-(methylamino)propionate 2, 2,2-Trifluoroacetate and Boc- N -methyl-L-leucine to prepare the title compound. LC-MS B: tR = 1.03 min; [M+H] + = 449.27.
下表C-18中列舉類似於上文對於
C-18.1描述之4-步驟順序，由Boc-
N-甲基-L-白胺酸及對應SM製備之建構嵌段C。替代地，在步驟2中，可在含4 M HCl之二㗁烷替代TFA存在下進行Boc去保護。
表C-18
編號 SM 步驟1 SM 步驟3 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-18.2 Boc-
O-苯甲基-D-高絲胺酸
Boc-
N-甲基-L-白胺酸
O-苯甲基-
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-高絲胺酸
1.02
B
451.22.
C-18.3 Boc-D-Val-OH
Boc-
N-甲基-L-白胺酸
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-纈胺酸
0.96
B
359.33
C-18.4 Boc-D-Leu-OH
Boc-
N-甲基-L-白胺酸
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-白胺酸
1.00
B
373.33
C-18.5 (
R)-
N-Boc-2-胺基丁酸
+ Boc-
N-甲基-L-白胺酸
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)丁酸
0.92
B
345.31
C-18.6 (
R)-Boc-2-胺基-4,4-二氟-丁酸
+ Boc-
N-甲基-L-白胺酸
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4,4-二氟丁酸
0.93
B
381.26
C-18.7 (R)-N-Boc-2-胺基-3-環丙基丙酸
Boc
-N-甲基-L-白胺酸
(R)-2-(
(S)-2-((三級丁氧基羰基)(甲基)胺基)
-N,4-二甲基戊醯胺基)-3-環丙基丙酸
0.98
B
371.53
C-18.8 (R)-N-Boc-2-胺基-3-環丁基丙酸
Boc
-N-甲基-L-白胺酸
(R)-2-(
(S)-2-((三級丁氧基羰基)(甲基)胺基)
-N,4-二甲基戊醯胺基)-3-環丁基丙酸
1.00
B
385.20
C-18.9 外消旋
-N-Boc-
O-乙基-高絲胺酸
Boc
-N-甲基-L-白胺酸
(RS)
-N-(N-(三級丁氧基羰基)
-N-甲基-L-白胺醯基)-O-乙基
-N-甲基高絲胺酸
0.92
B
389.37
C-18.10 (R)-N-Boc-2-胺基-4,4-二甲基戊酸
+ Boc
-N-甲基-L-白胺酸
(R)-2-(
(S)-2-((三級丁氧基羰基)(甲基)胺基)
-N,4-二甲基戊醯胺基)-4,4-二甲基戊酸
1.03
B
387.26
+步驟1中使用之SM由市售的無保護胺基酸，使用標準boc保護條件合成。
Listed in Table C-18 below is a 4-step sequence similar to that described above for C-18.1 , building block C prepared from Boc- N -methyl-L-leucine and the corresponding SM. Alternatively, in step 2, Boc deprotection can be performed in the presence of bisoxane containing 4 M HCl instead of TFA. Table C-18 serial number SM step 1 SM step 3 product t R [min] LC-MS method MS- data m/z [M+H] +
C-18.2 Boc- O -Benzyl-D-homoserine Boc- N -methyl-L-leucine O -benzyl- N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl-D-homoserine 1.02 B 451.22.
C-18.3 Boc-D-Val-OH Boc- N -methyl-L-leucine N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl-D-valine 0.96 B 359.33
C-18.4 Boc-D-Leu-OH Boc- N -methyl-L-leucine N -( N -(tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl-D-leucine 1.00 B 373.33
C-18.5 ( R )- N -Boc-2-aminobutyric acid + Boc- N -methyl-L-leucine ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)butanoic acid 0.92 B 345.31
C-18.6 ( R )-Boc-2-amino-4,4-difluoro-butanoic acid + Boc- N -methyl-L-leucine ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamylamino)-4,4-difluorobutane acid 0.93 B 381.26
C-18.7 (R)-N -Boc-2-amino-3-cyclopropylpropionic acid Boc -N -methyl-L-leucine (R) -2-( (S) -2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-cyclopropylpropionic acid 0.98 B 371.53
C-18.8 (R)-N -Boc-2-amino-3-cyclobutylpropionic acid Boc -N -methyl-L-leucine (R) -2-( (S) -2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-cyclobutylpropionic acid 1.00 B 385.20
C-18.9 rac -N- Boc- O -ethyl-homoserine Boc -N -methyl-L-leucine (RS) -N -(N-(tertiary butoxycarbonyl) -N -methyl-L-leucyl)-O-ethyl -N -methylhomoserine 0.92 B 389.37
C-18.10 (R)-N -Boc-2-amino-4,4-dimethylpentanoic acid + Boc -N -methyl-L-leucine (R) -2-( (S) -2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamidyl)-4,4-dimethyl Valeric acid 1.03 B 387.26
+ The SM used in step 1 was synthesized from commercially available unprotected amino acids using standard boc protection conditions.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
11
1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-苯基哌啶-2-甲酸(C-19.1)
步驟 1 ：向4-苯基-哌啶-1,2-二甲酸1-三級丁酯(1.0 g，3.11 mmol)及MeI (0.775 mL，12.4 mmol)於DMF (8 mL)中之室溫溶液中添加K
2CO
3(860 mg，6.22 mmol)，且在室溫攪拌反應混合物20 min。向反應混合物中添加水(10 mL)及DCM (100 mL)，接著分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈黃色油狀之4-苯基哌啶-1,2-二甲酸1-
(三級丁酯)2-甲酯(1.14 g，105%)。LC-MS B：t
R= 1.03 min；[M+H]
+= 320.29。
1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-phenylpiperidine-2-carboxylic acid (C-19.1) step 1 : to 4-phenyl To a room temperature solution of -piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.0 g, 3.11 mmol) and MeI (0.775 mL, 12.4 mmol) in DMF (8 mL) was added K 2 CO 3 ( 860 mg, 6.22 mmol), and the reaction mixture was stirred at room temperature for 20 min. Water (10 mL) and DCM (100 mL) were added to the reaction mixture, then the layers were separated and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated to give 1- ( tert-butyl 4-phenylpiperidine-1,2-dicarboxylate as a yellow oil ) 2-methyl ester (1.14 g, 105%). LC-MS B: tR = 1.03 min; [M+H] + = 320.29.
步驟 2 ：向4-苯基哌啶-1,2-二甲酸1-(三級丁酯)2-甲酯(1.10 g，3.44 mmol)於
i PrOH (5 mL)中之室溫溶液中添加含5 M HCl之
i PrOH (3.44 mL，17.2 mmol)，且在室溫攪拌反應混合物2 h，接著在50℃攪拌30 min。濃縮混合物，得到呈黃色粉末之甲基-4-苯基哌啶-2-甲酸酯鹽酸鹽(878 mg，100%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.56 min；[M+H]
+= 220.35。
Step 2 : To a room temperature solution of 4-phenylpiperidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl ester (1.10 g, 3.44 mmol) in iPrOH (5 mL) was added 5 M HCl in iPrOH (3.44 mL, 17.2 mmol), and the reaction mixture was stirred at room temperature for 2 h, then at 50 °C for 30 min. The mixture was concentrated to give methyl-4-phenylpiperidine-2-carboxylate hydrochloride (878 mg, 100%) as a yellow powder, which was used as such in the next step. LC-MS B: tR = 0.56 min; [M+H] + = 220.35.
步驟 3 及 4 ：按照對於
C-2.1步驟1及2所描述之反應順序，由甲基-4-苯基哌啶-2-甲酸酯鹽酸鹽及Boc-
N-甲基-L-白胺酸製備標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 449.27。
Steps 3 and 4 : According to the reaction sequence described for C-2.1 steps 1 and 2, from methyl-4-phenylpiperidine-2-carboxylate hydrochloride and Boc- N -methyl-L-white amino acid to prepare the title compound. LC-MS B: tR = 1.03 min; [M+H] + = 449.27.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
2020
(R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸(C-20.1)
步驟 1 ：向Boc-D-Glu-Ome (1.00 g，3.64 mmol)、
N-羥基乙脒(296 mg，4 mmol)及DIPEA (1.87 mL，10.9 mmol)於DCM (10 mL)中之室溫溶液中添加HATU (1.52 g，4 mmol)，且在室溫攪拌反應混合物30 min。濃縮混合物，得到所需中間物。LC-MS B：t
R= 0.82 min；[M+H]
+= 380.29。將粗中間物溶解於二㗁烷(10 mL)中且在80℃攪拌隔夜。向反應混合物中添加水(10 mL)及DCM (100 mL)，接著分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用10%至20% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:9中R
f= 0.12)純化，得到呈無色油狀之(R)-2-((三級丁氧基羰基)胺基)-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯(952 mg，72%)。LC-MS B：t
R= 1.04 min；[M+H]
+= 362.25。
(R)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-4-(3-phenyl -1,2,4-oxadiazol-5-yl)butanoic acid (C-20.1) step 1 : Add Boc-D-Glu-Ome (1.00 g, 3.64 mmol), N -hydroxyacetamidine (296 mg, 4 mmol) and DIPEA (1.87 mL, 10.9 mmol) in DCM (10 mL) at room temperature was added HATU (1.52 g, 4 mmol) and the reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated to afford the desired intermediate. LC-MS B: tR = 0.82 min; [M+H] + = 380.29. The crude intermediate was dissolved in dioxane (10 mL) and stirred at 80 °C overnight. Water (10 mL) and DCM (100 mL) were added to the reaction mixture, then the layers were separated and the aqueous layer was extracted with DCM (2 x 75 mL). The combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 10% to 20% EtOAc/heptane with Rf = 0.12 in EtOAc/heptane 1:9) afforded (R)-2-((tertiary butane) as a colorless oil Oxycarbonyl)amino)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid methyl ester (952 mg, 72%). LC-MS B: tR = 1.04 min; [M+H] + = 362.25.
步驟 2 ：按照對於
C-19.1步驟2所描述之程序，由(R)-2-((三級丁氧基羰基)胺基)-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯製備(R)-2-胺基-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯鹽酸鹽。
Step 2 : Following the procedure described for C-19.1 Step 2, from (R)-2-((tertiary butoxycarbonyl)amino)-4-(3-phenyl-1,2,4-㗁Preparation of methyl (R)-2-amino-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyrate hydrochloride from methyl oxadiazol-5-yl)butyrate .
步驟 3 ：按照對於
C-2.1步驟1所描述之反應，由(R)-2-胺基-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯鹽酸鹽及Boc-
N-甲基-L-白胺酸製備(R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯。LC-MS B：t
R= 1.10 min；[M+H]
+= 489.22。
Step 3 : Following the reaction described for C-2.1 Step 1, from (R)-2-amino-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid methyl Preparation of ester hydrochloride and Boc- N -methyl-L-leucine (R)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-4- Methylpentamido)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid methyl ester. LC-MS B: tR = 1.10 min; [M+H] + = 489.22.
步驟 4 ：向(R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-4-(3-苯基-1,2,4-㗁二唑-5-基)丁酸甲酯(920 mg，1.88 mmol)於DMF (9 mL)中之0℃溶液中添加NaH (216 mg，5.65 mmol)。在5 min攪拌之後，向0℃溶液中添加MeI (0.469 mL，7.53 mmol)，接著移除冰浴，且在室溫攪拌反應混合物4 h。藉由LC/MS，反應對照顯示，在甲基化期間亦出現皂化(tR不同於SM)。向反應混合物中添加水(15 mL)及TBME (20 mL)，接著分離各層且水層用TBME (1 × 20 mL)洗滌。水層用2 M HCl (10 mL)處理且用DCM (2 × 20 mL)萃取。經合併之DCM層用鹽水(10 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈黃色油狀之標題化合物
C-20.1(688 mg，75%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.03 min；[M+H]
+= 489.24。
Step 4 : To (R)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)-4-methylpentamido)-4-(3-phenyl To a solution of methyl-1,2,4-oxadiazol-5-yl)butanoate (920 mg, 1.88 mmol) in DMF (9 mL) at 0 °C was added NaH (216 mg, 5.65 mmol). After stirring for 5 min, MeI (0.469 mL, 7.53 mmol) was added to the 0 °C solution, then the ice bath was removed, and the reaction mixture was stirred at room temperature for 4 h. By LC/MS, reaction controls showed that saponification also occurs during methylation (tR differs from SM). Water (15 mL) and TBME (20 mL) were added to the reaction mixture, then the layers were separated and the aqueous layer was washed with TBME (1 x 20 mL). The aqueous layer was treated with 2 M HCl (10 mL) and extracted with DCM (2 x 20 mL). The combined DCM layers were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated to give the title compound C-20.1 (688 mg, 75%) as a yellow oil, which was used as such in the next step step. LC-MS B: tR = 1.03 min; [M+H] + = 489.24.
表C-20中列舉根據上文對於
C-20.1描述之4-步驟順序製備之建構嵌段C。在皂化在甲基化條件期間不發生之情況下，添加額外步驟以將酯皂化為羧酸(4 N NaOH於MeOH中，類似於
C-5.1之步驟3)。
表 C-20 編號 SM羥基乙醯脒*
步驟4 之條件 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-20.2 -20℃
3 min
(
R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-環丙基-1,2,4-㗁二唑-5-基)丁酸
0.97
A
453.21
C-20.3 -20℃
20 min
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-環戊基-1,2,4-㗁二唑-5-基)丁酸
1.0
A
481.19
C-20.4 0℃至RT
在RT 10 min
(
R)-2-((
S)-2-(
(三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-(三級丁基)-1,2,4-㗁二唑-5-基)丁酸
1.03
A
469.22
C-20.5 0℃
20 min
(
R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-甲基-1,2,4-㗁二唑-5-基)丁酸
0.89
A
427.25
*若不為市售的，則經由標準條件，由其對應腈合成羥基乙醯脒。
Listed in Table C-20 are building blocks C prepared according to the 4-step sequence described above for C-20.1. In cases where saponification did not occur during the methylation conditions, an additional step was added to saponify the ester to the carboxylic acid (4 N NaOH in MeOH, similar to step 3 of C-5.1 ). Table C-20 serial number SM Hydroxyacetamide* Conditions of Step 4 product t R [min] LC-MS method MS- data m/z [M+H] +
C-20.2 -20°C 3 min ( R )-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-4-(3-cyclopropane 1,2,4-oxadiazol-5-yl)butanoic acid 0.97A 453.21
C-20.3 -20°C 20min ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-4-(3-cyclopentyl 1,2,4-oxadiazol-5-yl)butanoic acid 1.0A 481.19
C-20.4 0°C to RT for 10 min at RT ( R )-2-(( S )-2-( ( tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamylamino)-4-(3-(tri Butyl)-1,2,4-oxadiazol-5-yl)butanoic acid 1.03 A 469.22
C-20.5 0°C 20 min ( R )-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-4-(3-methyl -1,2,4-oxadiazol-5-yl)butanoic acid 0.89A 427.25
*If not commercially available, hydroxyacetamides were synthesized from their corresponding nitriles via standard conditions.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
21twenty one
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N,O-二甲基高絲胺酸(C-21.1)
步驟 1 ：向Boc-D-高絲胺酸(2.0 g，8.85 mmol)及K
2CO
3(1.85 g，13.3 mmol)於DMF (30 mL)中之室溫溶液中添加MeI (0.67 mL，10.6 mmol)，且在室溫攪拌反應混合物16 h。將混合物倒入冰水中且用EtOAc (3×)萃取。經合併之有機層用水及鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈淺黃色固體狀之(R)-(2-側氧基四氫呋喃-3-基)胺基甲酸三級丁酯(2.07 g，116%)。LC-MS B：t
R= 0.60 min；無電離。
N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-N ,O -dimethylhomoserine (C-21.1) step 1 : to Boc-D- To a room temperature solution of homoserine (2.0 g, 8.85 mmol) and K 2 CO 3 (1.85 g, 13.3 mmol) in DMF (30 mL) was added MeI (0.67 mL, 10.6 mmol) and the reaction was stirred at room temperature Mixture 16 h. The mixture was poured into ice water and extracted with EtOAc (3x). The combined organic layers were washed with water and brine, dried (MgSO 4 ), filtered and concentrated to afford (R)-(2-oxotetrahydrofuran-3-yl)carbamic acid tert-butyl as a light yellow solid Ester (2.07 g, 116%). LC-MS B: tR = 0.60 min; no ionization.
步驟 2 ：向(R)-(2-側氧基四氫呋喃-3-基)胺基甲酸三級丁酯(2.0 g，8.6 mmol)於DCM (20 mL)中之室溫溶液中添加TFA (3.29 mL，43 mmol)，且在室溫攪拌反應混合物6 h。真空移除揮發物，與DCM (3×)一起共蒸發，得到粗物質(R)-3-胺基二氫呋喃-2(3H)-酮2,2,2-三氟乙酸鹽(3.0 g，160%)，其按原樣用於下一步驟。藉由LC-MS，未能偵測到產物形成，僅有SM消失。
Step 2 : To a room temperature solution of tert-butyl (R)-(2-oxotetrahydrofuran-3-yl)carbamate (2.0 g, 8.6 mmol) in DCM (20 mL) was added TFA (3.29 mL, 43 mmol), and the reaction mixture was stirred at room temperature for 6 h. Volatiles were removed in vacuo and co-evaporated with DCM (3×) to give crude (R)-3-aminodihydrofuran-2(3H)-one 2,2,2-trifluoroacetate salt (3.0 g , 160%), which was used as such in the next step. By LC-MS, no product formation could be detected, only SM disappeared.
步驟 3 ：向(R)-3-胺基二氫呋喃-2(3
H)-酮2,2,2-三氟乙酸鹽(3.00 g)、Boc-
N-甲基-L-白胺酸(3.70 g，14.6 mmol)及DIPEA (7.16 mL，41.8 mmol)於DMF (20 mL)中之室溫溶液中添加HATU (5.83 g，15.3 mmol)，且攪拌反應混合物1 h。將混合物分配於水與EtOAc之間，且分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用水及鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發。藉由FC (用50% EtOAc/庚烷溶離)純化，得到呈無色油狀之甲基((S)-4-甲基-1-側氧基-1-(((R)-2-側氧基四氫呋喃-3-基)胺基)戊-2-基)胺基甲酸三級丁酯(2.21 g，75%)。LC-MS B：t
R= 0.87 min；[M+H]
+= 329.28。
Step 3 : Add (R)-3-aminodihydrofuran-2( 3H )-one 2,2,2-trifluoroacetate (3.00 g), Boc- N -methyl-L-leucine (3.70 g, 14.6 mmol) and DIPEA (7.16 mL, 41.8 mmol) in DMF (20 mL) at room temperature was added HATU (5.83 g, 15.3 mmol) and the reaction mixture was stirred for 1 h. The mixture was partitioned between water and EtOAc, and the layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried ( Na2SO4 ), filtered and evaporated. Purification by FC (elution with 50% EtOAc/heptane) afforded methyl((S)-4-methyl-1-oxo-1-(((R)-2-oxo-1-(((R)-2-oxo) as a colorless oil tert-butyloxytetrahydrofuran-3-yl)amino)pentan-2-yl)carbamate (2.21 g, 75%). LC-MS B: tR = 0.87 min; [M+H] + = 329.28.
步驟 4 ：向甲基((S)-4-甲基-1-側氧基-1-(((R)-2-側氧基四氫呋喃-3-基)胺基)戊-2-基)胺基甲酸三級丁酯(2.21 g，6.73 mmol)於二㗁烷(20 mL)中之室溫溶液中添加8 M NaOH水溶液(1.7 mL，13.5 mmol)，且在50℃攪拌反應混合物1 h。將反應混合物濃縮至乾燥，接著將粗物質溶解於DCM中且用2 N HCl水溶液酸化(pH 3)。分離各層，且水層用DCM (3×)萃取。經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈無色油狀之
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基高絲胺酸(2.40 g，100%)，其按原樣用於下一步驟。在內酯開環期間發生差向異構。LC-MS B：t
R= 0.75 min；[M+H]
+= 347.30。
Step 4 : To methyl ((S)-4-methyl-1-oxo-1-(((R)-2-oxotetrahydrofuran-3-yl)amino)pentan-2-yl) To a room temperature solution of tert-butyl carbamate (2.21 g, 6.73 mmol) in dioxane (20 mL) was added 8 M aqueous NaOH (1.7 mL, 13.5 mmol), and the reaction mixture was stirred at 50 °C for 1 h . The reaction mixture was concentrated to dryness, then the crude material was dissolved in DCM and acidified (pH 3) with 2 N aqueous HCl. The layers were separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated to afford N- (tertiary butoxycarbonyl) -N -methyl-L-leucylhoseramine as a colorless oil Acid (2.40 g, 100%), which was used as such in the next step. Epimerization occurs during lactone ring opening. LC-MS B: tR = 0.75 min; [M+H] + = 347.30.
步驟 5 ：向
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基高絲胺酸(2.40 mg，6.93 mmol)於DMF (50 mL)中之室溫溶液中逐份添加NaH於礦物油中之60%分散液(796 mg，20.8 mmol)，接著添加MeI (1.74 mL，27.7 mmol)，且繼續在室溫攪拌1 h。將混合物分配於水與EtOAc之間。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用水及鹽水洗滌，經乾燥(Na
2SO
4)，過濾且蒸發。藉由FC (用100% EtOAc溶離)純化，得到呈淺黃色油狀之
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N,
O-二甲基高絲胺酸甲酯(692 mg，26%)。LC-MS B：t
R= 0.99 min；[M+H]
+= 389.26。
Step 5 : To a room temperature solution of N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl homoserine (2.40 mg, 6.93 mmol) in DMF (50 mL) A 60% dispersion of NaH in mineral oil (796 mg, 20.8 mmol) was added, followed by MeI (1.74 mL, 27.7 mmol), and stirring was continued at room temperature for 1 h. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried ( Na2SO4 ), filtered and evaporated. Purification by FC (elution with 100% EtOAc) afforded N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N , O- as a pale yellow oil Dimethylhomoserine methyl ester (692 mg, 26%). LC-MS B: tR = 0.99 min; [M+H] + = 389.26.
步驟 6 ：向
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-N,O-二甲基高絲胺酸甲酯(692 mg，1.78 mmol，1 eq)於二㗁烷(20 mL)中之室溫溶液中添加8 M NaOH水溶液(1.7 mL，3.56 mmol)，且在50℃攪拌反應混合物1 h。將反應混合物濃縮至乾燥，接著將粗物質溶解於DCM中且用2 N HCl水溶液酸化(pH 3)。分離各層，且水層用DCM (3×)萃取。經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈無色油狀之標題化合物
C-21.1(750 mg，112%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.88 min；[M+H]
+= 375.32。
Step 6 : To N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-N,O-dimethyl homoserine methyl ester (692 mg, 1.78 mmol, 1 eq) To a room temperature solution in dioxane (20 mL) was added 8 M aqueous NaOH (1.7 mL, 3.56 mmol), and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated to dryness, then the crude material was dissolved in DCM and acidified (pH 3) with 2 N aqueous HCl. The layers were separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated to give the title compound C-21.1 (750 mg, 112%) as a colorless oil, which was used as such in the next step. LC-MS B: tR = 0.88 min; [M+H] + = 375.32.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
22twenty two
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3-(5- 氟吡啶 -2- 基 )-1,2,4- 㗁二唑 -5- 基 ) 丙酸 (C-22.1) 步驟 1 ：向Boc-D-Asp-OMe (10.00 g，38.8 mmol)及DIPEA (26.6 mL，155 mmol)於DMF (71 mL)中之室溫溶液中添加溴甲苯(4.71 mL，38.8 mmol)，且將反應混合物加熱至50℃持續2 h。使溶液達到室溫，接著添加水及Et
2O且分離各層。無機層用Et
2O (1×)萃取。經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用0%至30% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:4中R
f= 0.24)純化，得到呈無色油狀之(三級丁氧基羰基)-D-天冬胺酸4-苯甲酯1-甲酯(12.7 g，97%)。LC-MS B：t
R= 0.97 min；[M+H]
+= 337.96。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamylamino )-3-(3-(5 -Fluoropyridin -2- yl )-1,2,4- oxadiazol -5- yl ) propionic acid (C-22.1) step 1 : add Boc-D - Asp-OMe (10.00 g, 38.8 mmol) and DIPEA To a room temperature solution of (26.6 mL, 155 mmol) in DMF (71 mL) was added bromotoluene (4.71 mL, 38.8 mmol), and the reaction mixture was heated to 50 °C for 2 h. The solution was allowed to come to room temperature, then water and Et2O were added and the layers were separated. The inorganic layer was extracted with Et2O (1x). The combined org. layers were washed with brine, dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 0% to 30% EtOAc/heptane with Rf = 0.24 in EtOAc/heptane 1:4) afforded (tertiary butoxycarbonyl)-D- Aspartic acid 4-benzyl 1-methyl ester (12.7 g, 97%). LC-MS B: tR = 0.97 min; [M+H] + = 337.96.
步驟 2 ：向(三級丁氧基羰基)-D-天冬胺酸4-苯甲酯1-甲酯(8.19 g，24 mmol)於二㗁烷(42.3 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(57.9 mL，240 mmol)，且將所得反應混合物加熱至50℃持續30 min。使混合物達到室溫，接著濃縮，得到淺黃色固體之D-天冬胺酸4-苯甲酯1-甲酯鹽酸鹽(6.90 g，92%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.53 min；[M+H]
+= 238.30。
Step 2 : To a room temperature solution of (tertiary butoxycarbonyl)-D-aspartic acid 4-benzyl ester 1-methyl ester (8.19 g, 24 mmol) in dioxane (42.3 mL) was added 4 M HCl in dioxane (57.9 mL, 240 mmol), and the resulting reaction mixture was heated to 50 °C for 30 min. The mixture was allowed to reach room temperature, then concentrated to give 4-benzyl D-aspartate 1-methyl ester hydrochloride (6.90 g, 92%) as a pale yellow solid, which was used as such in the next step. LC-MS B: tR = 0.53 min; [M+H] + = 238.30.
步驟 3 ：向D-天冬胺酸4-苯甲酯1-甲酯鹽酸鹽(6.84 g，22.1 mmol)、boc-
N-甲基-L-白胺酸(5.58 g，22.1 mmol)及DIPEA (19.9 mL，110 mmol)於MeCN (83 mL)中之室溫溶液中添加HATU (10.38 g，26.5 mmol)。在室溫攪拌所得混合物10 min。向反應混合物中添加水(135 mL)及DCM (315 mL)，接著分離各層，且無機層用DCM萃取。經合併之有機層用鹽水(50 mL)洗滌，經相分離器乾燥且濃縮。藉由FC (用0%至40% EtOAc溶離)純化，得到呈淺黃色油狀之
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基-D-天冬胺酸4-苯甲酯1-甲酯(9.70 g，94%)。LC-MS B：t
R= 1.10 min；[M+H]
+= 465.03。
Step 3 : Add D-aspartic acid 4-benzyl ester 1-methyl ester hydrochloride (6.84 g, 22.1 mmol), boc- N -methyl-L-leucine (5.58 g, 22.1 mmol) and To a room temperature solution of DIPEA (19.9 mL, 110 mmol) in MeCN (83 mL) was added HATU (10.38 g, 26.5 mmol). The resulting mixture was stirred at room temperature for 10 min. Water (135 mL) and DCM (315 mL) were added to the reaction mixture, then the layers were separated, and the inorganic layer was extracted with DCM. The combined organic layers were washed with brine (50 mL), dried over a phase separator and concentrated. Purification by FC (eluted with 0% to 40% EtOAc) afforded N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl-D-asparagine as a pale yellow oil Acid 4-benzyl 1-methyl ester (9.70 g, 94%). LC-MS B: tR = 1.10 min; [M+H] + = 465.03.
步驟 4 ：向
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基-D-天冬胺酸4-苯甲酯1-甲酯(4.53 g，8.83 mmol)及MeI (2.22 mL，35.3 mmol)於DMF (73 mL)中之-20℃溶液中添加NaH (1.02 g，26.5 mmol)。在-20℃攪拌所得溶液15 min，接著用1 M HCl水溶液(224 mL)淬滅且用乙酸異丙酯稀釋。分離各層，且無機層用乙酸異丙酯(1×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用10%至40% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:1中R
f= 0.31)純化，得到呈淺黃色油狀之
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-天冬胺酸4-苯甲酯1-甲酯(3.9 g，92%)。LC-MS B：t
R= 1.11 min；[M+H]
+= 479.16。
Step 4 : To N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl-D-aspartic acid 4-benzyl ester 1-methyl ester (4.53 g, 8.83 mmol) and To a solution of MeI (2.22 mL, 35.3 mmol) in DMF (73 mL) at -20 °C was added NaH (1.02 g, 26.5 mmol). The resulting solution was stirred at -20 °C for 15 min, then quenched with 1 M aqueous HCl (224 mL) and diluted with isopropyl acetate. The layers were separated, and the inorganic layer was extracted with isopropyl acetate (1x). The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 10% to 40% EtOAc/heptane with Rf = 0.31 in EtOAc/heptane 1:1) afforded N- ( N- (tertiary butoxy 4-benzyl) -N -methyl-L-leucyl) -N -methyl-D-aspartic acid 4-benzyl 1-methyl ester (3.9 g, 92%). LC-MS B: tR = 1.11 min; [M+H] + = 479.16.
步驟 5 ：向
N-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-
N-甲基-D-天冬胺酸4-苯甲酯1-甲酯(3.89 g，7.28 mmol)於MeOH (34 mL)中之室溫溶液中添加Pd/C (10%，387 mg，0.364 mmol)，且在H
2氛圍下在室溫攪拌反應混合物1 h。過濾反應混合物且濃縮，得到呈無色油狀之(
R)-3-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-甲氧基-4-側氧基丁酸(3.2 g，114%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.89 min；[M+H]
+= 389.33。
Step 5 : To N- ( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl) -N -methyl-D-aspartic acid 4-benzyl ester 1-methyl To a room temperature solution of the ester (3.89 g, 7.28 mmol) in MeOH (34 mL) was added Pd/C (10%, 387 mg, 0.364 mmol), and the reaction mixture was stirred at room temperature under H 2 atmosphere for 1 h. The reaction mixture was filtered and concentrated to afford ( R )-3-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentane as a colorless oil. Amino)-4-methoxy-4-oxobutanoic acid (3.2 g, 114%), which was used as such in the next step. LC-MS B: tR = 0.89 min; [M+H] + = 389.33.
步驟 6 ：向
R)-3-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-甲氧基-4-側氧基丁酸(1.00 g，2.5 mmol)、5-氟-
N'-羥基吡啶甲脒(631 mg，3.75 mmol)及DIPEA (1.28 mL，7.49 mmol)於DCM (2.8 mL)中之室溫溶液中添加PyBOP (1.73 g，3.25 mmol)。在室溫攪拌所得反應混合物10 min。真空移除溶劑，且將殘餘物再溶解於二㗁烷(2.8 mL)中。將所得混合物加熱至100℃持續3.5 h，接著加熱至90℃隔夜。次日上午，另外加熱升高至100℃持續8 h。使反應混合物達到室溫，之後真空濃縮，接著添加水及DCM。分離各層，且無機層用DCM (1×)萃取。經合併之有機層經相分離器乾燥且濃縮。藉由FC (用10%至50% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:1中R
f= 0.36)純化，得到呈微黃色固體狀之(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)丙酸甲酯(931 g，73%)。LC-MS B：t
R= 1.04 min；[M+H]
+= 508.18。
Step 6 : To R )-3-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-4-methoxy 4-oxobutanoic acid (1.00 g, 2.5 mmol), 5-fluoro- N' -hydroxypicolinamidine (631 mg, 3.75 mmol) and DIPEA (1.28 mL, 7.49 mmol) in DCM (2.8 mL) To the room temperature solution in China was added PyBOP (1.73 g, 3.25 mmol). The resulting reaction mixture was stirred at room temperature for 10 min. The solvent was removed in vacuo, and the residue was redissolved in dioxane (2.8 mL). The resulting mixture was heated to 100 °C for 3.5 h, then to 90 °C overnight. The next morning, additional heating was raised to 100 °C for 8 h. The reaction mixture was allowed to reach room temperature before being concentrated in vacuo, followed by the addition of water and DCM. The layers were separated, and the inorganic layer was extracted with DCM (1x). The combined organic layers were dried over a phase separator and concentrated. Purification by FC (elution with 10% to 50% EtOAc/heptane with Rf = 0.36 in EtOAc/heptane 1:1) gave ( R )-2-(( S ) as a yellowish solid -2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-(3-(5-fluoropyridin-2-yl)-1 , 2,4-oxadiazol-5-yl)propanoic acid methyl ester (931 g, 73%). LC-MS B: tR = 1.04 min; [M+H] + = 508.18.
步驟 7 ：向(
R)-2-((
S)-2-(
(三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)丙酸甲酯(1.50 g，2.96 mmol)於MeOH (15 mL)中之室溫溶液中添加4 M NaOH溶液(3.70 mL，14.8 mmol)，且在室溫攪拌反應混合物15 min。反應混合物用DCM (50 mL)稀釋且用2 M HCl溶液(20 mL)酸化。分離各層，且無機層用DCM萃取。經合併之有機層用鹽水(30 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈灰白色泡沫狀之標題化合物
C-22.1(1.40 g，96%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.95 min；[M+H]
+= 494.18。
Step 7 : To ( R )-2-(( S )-2-( ( tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamylamino)-3-( 3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanoic acid methyl ester (1.50 g, 2.96 mmol) in MeOH (15 mL) at room temperature 4 M NaOH solution (3.70 mL, 14.8 mmol) was added, and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with DCM (50 mL) and acidified with 2 M HCl solution (20 mL). The layers were separated, and the inorganic layer was extracted with DCM. The combined organic layers were washed with brine (30 mL), dried (MgSO 4 ), filtered and concentrated to afford the title compound C-22.1 (1.40 g, 96%) as an off-white foam, which was used as such in the next step step. LC-MS B: tR = 0.95 min; [M+H] + = 494.18.
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3-( 三氟甲基 )-1,2,4- 㗁二唑 -5- 基 ) 丙酸 (C-22.2)按照對於
C-22.1所描述之7-步驟順序，在步驟6中使用市售的2,2,2-三氟-
N'-羥基乙醯脒替代5-氟-
N'-羥基吡啶甲脒製備標題化合物。LC-MS B：t
R= 1.02 min；[M+H]
+= 467.11。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamido )-3-(3-( tri Fluoromethyl )-1,2,4- oxadiazol -5- yl ) propanoic acid (C-22.2) Follow the 7-step sequence described for C-22.1 , using commercially available 2,2 , 2-trifluoro- N' -hydroxyacetamidine was substituted for 5-fluoro- N' -hydroxypicolinamidine to prepare the title compound. LC-MS B: tR = 1.02 min; [M+H] + = 467.11.
下表C-22中列舉根據上文對於
C-22.1描述之7-步驟順序製備之建構嵌段C。在步驟6中，使用(
R)-3-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-甲氧基-4-側氧基丁酸及其對應羥基乙醯脒。對於
C-22.5而言，類似於
C-22.1，在步驟1中使用boc-D-Glu-OMe替代boc-D-Asp-OMe，且在步驟6中使用如表C-22中所概述之對應羥基乙醯脒來進行合成。
表C-22
編號 SM羥基乙醯脒*
產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-22.3 (
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-(二氟甲基)-1,2,4-㗁二唑-5-基)丙酸
0.95
A
449.10
C-22.4 *
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-(4-(2-甲氧基乙基)苯基)-1,2,4-㗁二唑-5-基)丙酸
1.06
A
533.17
C-22.5 *
(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-4-(3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)丁酸
0.97
A
508.21
*若不為市售的，則經由標準條件，由其對應腈合成羥基乙醯脒。
Building block C prepared according to the 7-step sequence described above for C-22.1 is listed in Table C-22 below. In step 6, use ( R )-3-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-4 -Methoxy-4-oxobutanoic acid and its corresponding hydroxyacetamide. For C-22.5 , similar to C-22.1 , boc-D-Glu-OMe was used instead of boc-D-Asp-OMe in step 1, and the correspondence as outlined in Table C-22 was used in step 6. hydroxyacetamide for synthesis. Table C-22 serial number SM Hydroxyacetamide* product t R [min] LC-MS method MS- data m/z [M+H] +
C-22.3 ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-(3-(di Fluoromethyl)-1,2,4-oxadiazol-5-yl)propionic acid 0.95A 449.10
C-22.4 * ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-(3-(4 -(2-Methoxyethyl)phenyl)-1,2,4-oxadiazol-5-yl)propionic acid 1.06 A 533.17
C-22.5 * ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamylamino)-4-(3-(5 -Fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)butanoic acid 0.97A 508.21
*If not commercially available, hydroxyacetamides were synthesized from their corresponding nitriles via standard conditions.
用於合成建構嵌段for the synthesis of building blocks
CC
之通用方法general method
C-23C-23
2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3,3- 二氟吡咯啶 -1- 基 ) 丙酸 (C-23.1) 步驟 1 ：在2 h內向(三級丁氧基羰基)-L-絲胺酸苯甲酯(1.50 g，5.08 mmol)及MeI (1.59 mL，25.4 mmol)於THF (30 mL)中之0℃溶液中以四份添加NaH (1.02 g，25.4 mmol)。移除冰浴，且在室溫攪拌反應混合物2 h。將混合物冷卻至0℃，接著小心地添加水(強烈的氣體釋放)。混合物用Et
2O洗滌且丟棄有機層。水層用10%檸檬酸溶液酸化，接著用EtOAc (2×)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮，得到2-((三級丁氧基羰基)(甲基)胺基)丙烯酸(1.178 g)。向此粗材料中添加丙酮(30 mL)，隨後添加K
2CO
3(1.81 g，13.08 mmol)及溴甲苯(1.04 mL，8.72 mmol。在50℃攪拌混合物50 min，接著懸浮液用水稀釋，經部分濃縮以移除丙酮，接著用EtOAc (3×)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由FC (用5%至100% EtOAc/庚烷溶離)純化，得到呈黃色油狀之2-((三級丁氧基羰基)(甲基)胺基)丙烯酸苯甲酯(760 mg，59%)。LC-MS J：t
R= 2.13 min；[M+H]
+=無電離。
2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamido )-3-(3,3 -difluoropyrrolidine -1- yl ) propionic acid (C-23.1) step 1 : (tertiary butoxycarbonyl)-L-serine benzyl ester (1.50 g, 5.08 mmol) and MeI (1.59 mL, 25.4 mmol) in THF (30 mL) at 0 °C was added NaH (1.02 g, 25.4 mmol) in four portions. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C., followed by careful addition of water (strong gas evolution). The mixture was washed with Et2O and the organic layer was discarded. The aqueous layer was acidified with 10% citric acid solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried ( Na2SO4 ), filtered and concentrated to give 2-((tert-butoxycarbonyl)(methyl)amino)acrylic acid (1.178 g). To this crude material was added acetone (30 mL) followed by K2CO3 (1.81 g, 13.08 mmol) and bromotoluene (1.04 mL, 8.72 mmol. The mixture was stirred at 50 °C for 50 min, then the suspension was diluted with water and washed with Partial concentration to remove acetone followed by extraction with EtOAc (3x). The combined organic layers were washed with brine , dried ( Na2SO4 ), filtered and concentrated. Heptane eluting) and purified to obtain benzyl 2-((tertiary butoxycarbonyl)(methyl)amino)acrylate (760 mg, 59%) as a yellow oil. LC-MS J: t R = 2.13 min; [M+H] + = no ionization.
步驟 2 ：向3,3-二氟吡咯啶鹽酸鹽(493 mg，3.43 mmol)於2-丙醇(0.69 mL)及水(61.8 µl，3.43 mmol)中之溶液中添加K
2CO
3(378 mg，3.78 mmol)，接著添加2-((三級丁氧基羰基)(甲基)胺基)丙烯酸苯甲酯(200 mg，0.686 mmol)，將所得反應混合物加熱至60℃持續18 h。濃縮溶液，接著添加NaHCO
3飽和溶液及EtOAc。收集有機層，且無機層用EtOAc (2×)萃取。經合併之有機層用鹽水洗滌，經乾燥(Na
2SO
4)，過濾且濃縮。藉由製備型HPLC (鹼性)純化，得到呈淺黃色油狀之2-((三級丁氧基羰基)(甲基)胺基)-3-(3,3-二氟吡咯啶-1-基)丙酸苯甲酯(321 mg，117%)。LC-MS J：t
R= 2.11 min；[M+H]
+= 399.20
Step 2 : To a solution of 3,3-difluoropyrrolidine hydrochloride (493 mg, 3.43 mmol) in 2-propanol (0.69 mL) and water (61.8 μl, 3.43 mmol) was added K 2 CO 3 ( 378 mg, 3.78 mmol), followed by the addition of benzyl 2-((tertiary butoxycarbonyl)(methyl)amino)acrylate (200 mg, 0.686 mmol) and the resulting reaction mixture was heated to 60 °C for 18 h . The solution was concentrated, followed by the addition of saturated NaHCO 3 solution and EtOAc. The organic layer was collected and the inorganic layer was extracted with EtOAc (2x). The combined org. layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by preparative HPLC (basic) afforded 2-((tertiary butoxycarbonyl)(methyl)amino)-3-(3,3-difluoropyrrolidine-1 as a pale yellow oil -yl) benzyl propionate (321 mg, 117%). LC-MS J: tR = 2.11 min; [M+H] + = 399.20
步驟 3 ：向2-((三級丁氧基羰基)(甲基)胺基)-3-(3,3-二氟吡咯啶-1-基)丙酸苯甲酯(0.140 g，0.320 mmol)於DCM (2.0 mL)中之室溫溶液中添加TFA (2.0 mL，26.0 mmol)，且在室溫攪拌反應混合物2 h。真空移除揮發物，且將殘餘物與DCM (2×)一起共蒸發，得到呈油狀之3-(3,3-二氟吡咯啶-1-基)-2-(甲基胺基)丙酸苯甲酯TFA鹽，其按原樣用於下一步驟。
Step 3 : Benzyl 2-((tertiary butoxycarbonyl)(methyl)amino)-3-(3,3-difluoropyrrolidin-1-yl)propionate (0.140 g, 0.320 mmol ) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was co-evaporated with DCM (2x) to give 3-(3,3-difluoropyrrolidin-1-yl)-2-(methylamino) as an oil Benzyl propionate TFA salt, which was used as such in the next step.
步驟 4 及 5 ：按照對於
C-1.1步驟3及4所描述之反應順序，由Boc-
N-甲基-L-白胺酸及3-(3,3-二氟吡咯啶-1-基)-2-(甲基胺基)丙酸苯甲酯TFA鹽製備標題化合物。LC-MS F：t
R= 1.93 min；[M+H]
+= 436.20。
Steps 4 and 5 : According to the reaction sequence described for C-1.1 steps 3 and 4, from Boc- N -methyl-L-leucine and 3-(3,3-difluoropyrrolidin-1-yl) -Benzyl 2-(methylamino)propionate TFA salt The title compound was prepared. LC-MS F: tR = 1.93 min; [M+H] + = 436.20.
2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-( 吡咯啶 -1- 基 ) 丙酸 (C-23.2)按照對於
C-23.1所描述之5-步驟順序，在步驟2中使用以下條件製備標題化合物。向2-((三級丁氧基羰基)(甲基)胺基)丙烯酸苯甲酯(500 mg，1.716 mmol)於EtOH (10 mL)中之室溫溶液中添加吡咯啶(0.213 mL，2.57 mmol)，且將反應混合物加熱至50℃持續1.5 h。濃縮反應混合物且藉由製備型HPLC直接純化，得到呈透明油狀之所需中間物(53 mg，76%)。按照步驟3至5 (如對於C-23.1所描述)，得到所需標題化合物
C-23.2。LC-MS J：t
R= 1.69 min；[M+H]
+= 400.30
2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentanylamino )-3-( pyrrolidin -1- yl ) propane Acid (C-23.2) Following the 5-step sequence described for C-23.1 , the title compound was prepared in Step 2 using the following conditions. To a room temperature solution of benzyl 2-((tertiary butoxycarbonyl)(methyl)amino)acrylate (500 mg, 1.716 mmol) in EtOH (10 mL) was added pyrrolidine (0.213 mL, 2.57 mmol), and the reaction mixture was heated to 50 °C for 1.5 h. The reaction mixture was concentrated and directly purified by preparative HPLC to give the desired intermediate (53 mg, 76%) as a clear oil. Following steps 3 to 5 (as described for C-23.1) afforded the desired title compound C-23.2 . LC-MS J: t R = 1.69 min; [M+H] + = 400.30
用於合成建構嵌段C之通用方法24General method for the synthesis of building block C 24
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3- 苯基 -1,2,4- 㗁二唑 -5- 基 ) 丙酸 (C-24.1)按照對於
C-20.1所描述之4-步驟順序，在步驟1中使用Boc-D-Asp-OMe替代Boc-D-Glu-OMe製備標題化合物。在大多數情況下，添加皂化步驟(4 N NaOH於MeOH中)。LC-MS A：t
R= 1.04 min；[M+H]
+= 475.23
表C-24
編號 SM羥基乙醯脒*
產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
C-24.2 *
(
R)-2-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-(2-甲氧基乙基)-1,2,4-㗁二唑-5-基)丙酸
1.00
A
471.42
C-24.3 (
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-甲基-1,2,4-㗁二唑-5-基)丙酸
0.88
A
413.25
*若不為市售的，則經由標準條件，由其對應腈合成羥基乙醯脒。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamido )-3-(3- phenyl -1,2,4- oxadiazol -5- yl ) propionic acid (C-24.1) Follow the 4-step sequence described for C-20.1 , using Boc-D-Asp-OMe in step 1 instead of Boc- D-Glu-OMe to prepare the title compound. In most cases, a saponification step (4 N NaOH in MeOH) was added. LC-MS A: t R = 1.04 min; [M+H] + = 475.23 Table C-24 serial number SM Hydroxyacetamide* product t R [min] LC-MS method MS- data m/z [M+H] +
C-24.2 * ( R )-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-(3-(2 -Methoxyethyl)-1,2,4-oxadiazol-5-yl)propionic acid 1.00A 471.42
C-24.3 ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-(3-methyl -1,2,4-oxadiazol-5-yl)propionic acid 0.88A 413.25
*If not commercially available, hydroxyacetamides were synthesized from their corresponding nitriles via standard conditions.
用於合成建構嵌段C之通用方法25General method for the synthesis of building block C 25
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3- 甲氧基異㗁唑 -5- 基 ) 丙酸 (C-25.1) 步驟 1 ：向3-甲氧基-1,2-㗁唑-5-甲酸(4.98 g，33.1 mmol)及TEA (5.29 mL，38.0 mmol)於THF (132 mL)中之0℃溶液中逐滴添加氯甲酸乙酯(3.54 mL，36.4 mmol)。在0℃攪拌反應混合物1.5 h，接著在0℃逐滴添加NaBH
4(3.79 g，99.2 mmol)於水(53 mL)中之溶液，且在0℃攪拌所得反應混合物10 min。使反應混合物升溫至室溫，接著添加DCM，且分離兩個層。無機層用DCM (2×)萃取，且經合併之有機層用鹽水洗滌，經乾燥(經由相分離器)且濃縮。藉由FC (用10%至50% EtOAc/庚烷溶離，其中在庚烷/EtOAc 1:1中R
f= 0.38)純化，得到呈無色油狀之(3-甲氧基異㗁唑-5-基)甲醇(1.39 g，33%)。LC-MS A：t
R= 0.39 min；[M+H]
+= 130.10。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamido )-3-(3- methoxy Isoxazol -5- yl ) propionic acid (C-25.1) step 1 : Add 3-methoxy-1,2-oxazole-5-carboxylic acid (4.98 g, 33.1 mmol) and TEA (5.29 mL, 38.0 mmol) in THF (132 mL) was added ethyl chloroformate (3.54 mL, 36.4 mmol) dropwise. The reaction mixture was stirred at 0°C for 1.5 h, then a solution of NaBH4 (3.79 g, 99.2 mmol) in water (53 mL) was added dropwise at 0°C, and the resulting reaction mixture was stirred at 0°C for 10 min. The reaction mixture was allowed to warm to room temperature, then DCM was added, and the two layers were separated. The inorganic layer was extracted with DCM (2x), and the combined organic layers were washed with brine, dried (via phase separator) and concentrated. Purification by FC (elution with 10% to 50% EtOAc/heptane with Rf = 0.38 in heptane/EtOAc 1:1) afforded (3-methoxyisoxazole-5) as a colorless oil -yl) methanol (1.39 g, 33%). LC-MS A: tR = 0.39 min; [M+H] + = 130.10.
步驟 2 ：向(3-甲氧基異㗁唑-5-基)甲醇(1.39 g，10.8 mmol)於Et
2O (115 mL)中之0℃溶液中逐滴添加PBr
3(1.03 mL，10.8 mmol)。移除冰浴，且在室溫攪拌反應混合物48 h。反應混合物用EtOAc及Na
2CO
3飽和水溶液稀釋。分離各層，且無機層用EtOAc (1×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮，得到呈略微黃色油狀之5-(溴甲基)-3-甲氧基異㗁唑(1.65 g，80%)，其按原樣用於下一步驟。LC-MS A：t
R= 0.71 min；[M+H]
+=無電離。
Step 2 : To a solution of (3-methoxyisoxazol-5-yl)methanol (1.39 g, 10.8 mmol) in Et2O (115 mL) at 0 °C was added PBr3 (1.03 mL, 10.8 mL) dropwise mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with EtOAc and saturated aqueous Na2CO3 . The layers were separated, and the inorganic layer was extracted with EtOAc (1x). The combined organic layers were dried (MgSO 4 ), filtered and concentrated to give 5-(bromomethyl)-3-methoxyisoxazole (1.65 g, 80%) as a slightly yellow oil, which was obtained as received. for the next step. LC-MS A: tR = 0.71 min; [M+H] + = no ionization.
步驟 3 ：向(
S)-2,5-二氫-3,6-二甲氧基-2-異丙基吡𠯤(1.5 mL，8.1 mmol)於THF (74 mL)中之-75℃溶液中逐滴添加n-BuLi (1.6 M於己烷中，6.03 mL，9.53 mmol)。攪拌所得溶液30 min，接著添加5-(溴甲基)-3-甲氧基異㗁唑(1.64 g，8.1 mmol於THF (60 mL)中之溶液，且在-75℃攪拌反應混合物1.5 h。向反應混合物中添加1 M NH
4Cl水溶液(86 mL)及Et
2O，且分離兩個層，且無機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用0%至20% EtOAc/庚烷溶離，在庚烷/EtOAc 4:1中R
f= 0.32)純化，得到呈略微黃色油狀之5-(((2
R,5
S)-5-異丙基-3,6-二甲氧基-2,5-二氫吡𠯤-2-基)甲基)-3-甲氧基異㗁唑(1.30 g，55%)。LC-MS A：t
R= 0.91 min；[M+H]
+= 296.24。
Step 3 : To a -75°C solution of ( S )-2,5-dihydro-3,6-dimethoxy-2-isopropylpyridine (1.5 mL, 8.1 mmol) in THF (74 mL) n-BuLi (1.6 M in hexane, 6.03 mL, 9.53 mmol) was added dropwise in . The resulting solution was stirred for 30 min, then a solution of 5-(bromomethyl)-3-methoxyisoxazole (1.64 g, 8.1 mmol in THF (60 mL) was added, and the reaction mixture was stirred at -75 °C for 1.5 h Aq. 1 M NH 4 Cl (86 mL) and Et 2 O were added to the reaction mixture, and the two layers were separated, and the inorganic layer was dried (MgSO 4 ), filtered, and concentrated. By FC (0% to 20 % EtOAc/heptane and purification in heptane/EtOAc 4:1 ( Rf = 0.32) gave 5-((( 2R , 5S )-5-isopropyl-3, 6-dimethoxy-2,5-dihydropyr-2-yl)methyl)-3-methoxyisoxazole (1.30 g, 55%). LC-MS A: t R = 0.91 min ;[M+H] + = 296.24.
步驟 4 ：向5-(((2
R,5
S)-5-異丙基-3,6-二甲氧基-2,5-二氫吡𠯤-2-基)甲基)-3-甲氧基異㗁唑(1.31 g，4.1 mmol)於MeCN (41.4 mL)中之室溫溶液中添加1 M HCl水溶液(8.1 mL，8.21 mmol)。在室溫攪拌反應混合物30 min，接著移除溶劑，且殘餘物用1 M NH
3水溶液處理直至pH=9。向反應混合物中添加DCM，且分離兩個層。無機層用DCM (1×)萃取，且經合併之有機層經乾燥(經由相分離器)且濃縮。藉由FC (用0至2% MeOH/DCM (含有0.5% NH
4OH)溶離，其中在DCM/MeOH/NH
4OH 100:2:0.5中R
f= 0.20)純化，得到呈黃色油狀之(
R)-2-胺基-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(756 mg，92%)。LC-MS A：t
R= 0.35 min；[M+H]
+= 201.34。
Step 4 : To 5-(((2 R ,5 S )-5-isopropyl-3,6-dimethoxy-2,5-dihydropyr-2-yl)methyl)-3- To a room temperature solution of methoxyisoxazole (1.31 g, 4.1 mmol) in MeCN (41.4 mL) was added 1 M aqueous HCl (8.1 mL, 8.21 mmol). The reaction mixture was stirred at room temperature for 30 min, then the solvent was removed and the residue was treated with 1 M aqueous NH 3 until pH=9. DCM was added to the reaction mixture, and the two layers were separated. The inorganic layer was extracted with DCM (1×), and the combined organic layers were dried (via phase separator) and concentrated. Purification by FC (elution with 0 to 2% MeOH/DCM (containing 0.5% NH4OH ) with Rf = 0.20 in DCM/MeOH/ NH4OH 100:2:0.5) afforded the product as a yellow oil ( R )-methyl 2-amino-3-(3-methoxyisoxazol-5-yl)propanoate (756 mg, 92%). LC-MS A: tR = 0.35 min; [M+H] + = 201.34.
步驟 5 ：向(
R)-2-胺基-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(750 mg，3.50 mmol)、boc-
N-甲基-L-白胺酸(886 mg，3.5 mmol)及DIPEA (1.8 mL，10.5 mmol)於MeCN (12.8 mL)中之室溫溶液中添加HATU (1.648 g，4.20 mmol)。在室溫攪拌反應混合物10 min，接著添加水及DCM，且分離各層。無機層用DCM (1×)萃取，且經合併之有機層經乾燥(經由相分離器)且濃縮。藉由FC (用10%至40% EtOAc/庚烷溶離，其中在庚烷/EtOAc 7:3中R
f=0.23)純化，得到呈無色油狀之(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(1.40 g，94%)。LC-MS A：t
R= 0.99 min；[M+H]
+= 428.19。
Step 5 : To ( R )-2-amino-3-(3-methoxyisoxazol-5-yl)propionic acid methyl ester (750 mg, 3.50 mmol), boc- N -methyl-L- To a room temperature solution of leucine (886 mg, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) in MeCN (12.8 mL) was added HATU (1.648 g, 4.20 mmol). The reaction mixture was stirred at room temperature for 10 min, then water and DCM were added, and the layers were separated. The inorganic layer was extracted with DCM (1×), and the combined organic layers were dried (via phase separator) and concentrated. Purification by FC (elution with 10% to 40% EtOAc/heptane, where R f =0.23 in heptane/EtOAc 7:3) afforded ( R )-2-(( S )- 2-((tertiary butoxycarbonyl)(methyl)amino)-4-methylpentanylamino)-3-(3-methoxyisoxazol-5-yl)propionic acid methyl ester ( 1.40 g, 94%). LC-MS A: tR = 0.99 min; [M+H] + = 428.19.
步驟 6 ：向(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(1.40 g，3.27 mmol)及MeI (0.82 mL，13.1 mmol)於DMF (28 mL)中之-20℃溶液中添加NaH (376 mg，9.82 mmol)。在-20℃攪拌反應混合物11 min，接著反應混合物用1 M HCl水溶液(84 mL)，隨後添加Et
2O來淬滅。分離各層，且無機層用Et
2O (1×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用5%至40% EtOAc/庚烷溶離，其中在庚烷/EtOAc 7:3中R
f= 0.26)純化，得到呈淺黃色油狀之(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(1.30 g，90%)。LC-MS A：t
R= 1.03 min；[M+H]
+= 442.20。
Step 6 : To ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino)-4-methylpentamylamino)-3-(3-methyl Oxyisoxazol-5-yl) propionate (1.40 g, 3.27 mmol) and MeI (0.82 mL, 13.1 mmol) in DMF (28 mL) at -20°C were added NaH (376 mg, 9.82 mmol). The reaction mixture was stirred at -20 °C for 11 min, then the reaction mixture was quenched with 1 M aqueous HCl (84 mL), followed by addition of Et2O . The layers were separated, and the inorganic layer was extracted with Et2O (1x). The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 5% to 40% EtOAc/heptane with Rf = 0.26 in heptane/EtOAc 7:3) gave ( R )-2-(( S ) as a light yellow oil -2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-(3-methoxyisoxazol-5-yl)propane methyl ester (1.30 g, 90%). LC-MS A: tR = 1.03 min; [M+H] + = 442.20.
步驟 7 ：向(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(3-甲氧基異㗁唑-5-基)丙酸甲酯(1.303 g，2.86 mmol)於MeOH (41.2 mL)中之室溫溶液中添加4 M NaOH水溶液(28.8 mL，114 mmol)。將反應混合物加熱至50℃且在此溫度攪拌10 min，接著使反應混合物達到室溫。添加2 M HCl水溶液(165 mL)及DCM (105 mL)，分離各層，且無機層用DCM (1×)萃取。經合併之有機層經乾燥(經由相分離器)且濃縮，得到呈無色油狀之標題化合物(1.20 g，99%)。LC-MS A：t
R= 0.92 min；[M+H]
+= 428.17。
Step 7 : To ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-( To a room temperature solution of methyl 3-methoxyisozazol-5-yl)propanoate (1.303 g, 2.86 mmol) in MeOH (41.2 mL) was added 4 M aqueous NaOH (28.8 mL, 114 mmol). The reaction mixture was heated to 50 °C and stirred at this temperature for 10 min, then the reaction mixture was allowed to reach room temperature. 2M aqueous HCl (165 mL) and DCM (105 mL) were added, the layers were separated, and the inorganic layer was extracted with DCM (1×). The combined organic layers were dried (via a phase separator) and concentrated to give the title compound (1.20 g, 99%) as a colorless oil. LC-MS A: tR = 0.92 min; [M+H] + = 428.17.
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(3-( 三級丁基 ) 異㗁唑 -5- 基 ) 丙酸 (C-25.2)按照對於
C-25.1所描述之7-步驟順序，在步驟1中使用3-三級丁基-1,2-㗁唑-5-甲酸替代3-甲氧基-1,2-㗁唑-5-甲酸製備標題化合物。LC-MS A：t
R= 1.14 min；[M+H]
+= 468.46。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentanylamino )-3-(3-( tri tertiary butyl ) isoxazol -5- yl ) propionic acid (C-25.2) Follow the 7-step sequence described for C-25.1 , using 3-tertiary butyl-1,2-oxazole in step 1 -5-carboxylic acid in place of 3-methoxy-1,2-oxazole-5-carboxylic acid to prepare the title compound. LC-MS A: tR = 1.14 min; [M+H] + = 468.46.
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(5-( 三級丁基 )-1,2,4- 㗁二唑 -3- 基 ) 丙酸 (C-25.3)按照對於
C-25.1所描述之步驟3至步驟7，在步驟3中使用5-(三級丁基)-3-(氯甲基)-1,2,4-㗁二唑替代5-(溴甲基)-3-甲氧基異㗁唑製備標題化合物。LC-MS A：t
R= 1.00 min；[M+H]
+= 455.09。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentanylamino )-3-(5-( tri Butyl )-1,2,4- oxadiazol -3- yl ) propanoic acid (C-25.3) Follow steps 3 to 7 as described for C-25.1 , using 5-(tertiary Butyl)-3-(chloromethyl)-1,2,4-oxadiazole was substituted for 5-(bromomethyl)-3-methoxyisoxazole to prepare the title compound. LC-MS A: tR = 1.00 min; [M+H] + = 455.09.
用於合成建構嵌段C之通用方法26General method for the synthesis of building block C 26
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(4- 苯基 -1
H-1,2,3-
三唑 -1- 基 ) 丙酸 (26.1) 步驟 1 ：向3-疊氮基-
N-Boc-D-丙胺酸甲酯(850 mg，3.48 mmol)、苯基乙炔(0.39 mL，3.48 mmol)及(+)-L-抗壞血酸鈉(141 mg，0.696 mmol)於tBuOH/H
2O之1:1混合物(11.9 mL)中之室溫溶液中添加乙酸銅(II) (66.5 mg，0.348 mmol)，接著在室溫攪拌反應混合物20 min。反應混合物用DCM及鹽水稀釋，分離各層，且有機層經乾燥(用相分離器)且濃縮，得到呈略微淺黃色固體狀之(R)-2-((三級丁氧基羰基)胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(1.07 g，89%)。LC-MS A：t
R= 0.89 min；[M+H]
+= 347.19。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4- dimethylpentamido )-3-(4- phenyl -1H -1,2,3- triazol -1- yl ) propionic acid (26.1) Step 1 : Add 3-azido- N -Boc-D-alanine methyl ester (850 mg, 3.48 mmol), To a room temperature solution of phenylacetylene (0.39 mL, 3.48 mmol) and (+)-sodium L-ascorbate (141 mg, 0.696 mmol) in a 1:1 mixture of tBuOH/ H2O (11.9 mL) was added copper acetate (II) (66.5 mg, 0.348 mmol), then the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with DCM and brine, the layers were separated, and the organic layer was dried (with a phase separator) and concentrated to afford (R)-2-((tertiary butoxycarbonyl)amino as a slightly pale yellow solid )-methyl 3-(4-phenyl- 1H -1,2,3-triazol-1-yl)propanoate (1.07 g, 89%). LC-MS A: tR = 0.89 min; [M+H] + = 347.19.
步驟 2 ：向(
R)-2-((三級丁氧基羰基)胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(1.06 g，3.07 mmol)於二㗁烷(5.4 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(7.6 mL，30.7 mmol)。將反應混合物加熱至50℃持續30 min。使反應混合物達到室溫，接著濃縮反應混合物，得到淺黃色固體之(
R)-2-胺基-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯二鹽酸鹽(980 mg，100%)。LC-MS A：t
R= 0.49 min；[M+H]
+= 247.28。
Step 2 : To ( R )-2-((tertiary butoxycarbonyl)amino)-3-(4-phenyl- 1H -1,2,3-triazol-1-yl)propanoic acid methyl To a room temperature solution of the ester (1.06 g, 3.07 mmol) in dioxane (5.4 mL) was added 4 M HCl in dioxane (7.6 mL, 30.7 mmol). The reaction mixture was heated to 50 °C for 30 min. The reaction mixture was allowed to reach room temperature, and then the reaction mixture was concentrated to obtain ( R )-2-amino-3-(4-phenyl- 1H -1,2,3-triazol-1-yl) as a light yellow solid Methyl propionate dihydrochloride (980 mg, 100%). LC-MS A: tR = 0.49 min; [M+H] + = 247.28.
步驟 3 ：向(
R)-2-胺基-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯二鹽酸鹽(975 mg，3.05 mmol)、boc-
N-甲基-L-白胺酸(773 mg，3.05 mmol)及DIPEA (2.61 mL，15.3 mmol)於MeCN (10.9 mL)中之室溫溶液中添加HATU (1.437 g，3.67 mmol)。在室溫攪拌反應混合物10 min，接著添加水及DCM。分離各層，無機層用DCM (1×)萃取，且經合併之有機層經乾燥(經由相分離器)且濃縮。藉由FC (用20%至60% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:1中R
f= 0.28)純化，得到呈橙色油狀之(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(1.90 g，130%)。LC-MS A：t
R= 1.04 min；[M+H]
+= 474.17。
Step 3 : To ( R )-2-amino-3-(4-phenyl- 1H -1,2,3-triazol-1-yl)propanoic acid methyl ester dihydrochloride (975 mg, 3.05 mmol), boc- N -methyl-L-leucine (773 mg, 3.05 mmol) and DIPEA (2.61 mL, 15.3 mmol) in MeCN (10.9 mL) at room temperature were added HATU (1.437 g, 3.67 mmol). The reaction mixture was stirred at room temperature for 10 min, then water and DCM were added. The layers were separated, the inorganic layer was extracted with DCM (1x), and the combined organic layers were dried (via a phase separator) and concentrated. Purification by FC (elution with 20% to 60% EtOAc/heptane with Rf = 0.28 in EtOAc/heptane 1:1) afforded ( R )-2-(( S )- 2-((tertiary butoxycarbonyl)(methyl)amino)-4-methylpentanylamino)-3-(4-phenyl-1 H -1,2,3-triazole-1 -yl) methyl propionate (1.90 g, 130%). LC-MS A: tR = 1.04 min; [M+H] + = 474.17.
步驟 4 ：向(
R)-2-((
S)-2-
(三級丁氧基羰基)(甲基)胺基)-4-甲基戊醯胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(1.772 g，3.32 mmol)及MeI (0.834 mL，13.3 mmol)於DMF (28.2 mL)中之-20℃溶液中添加NaH (381 mg，9.95 mmol)。在-20℃攪拌反應混合物17 min，接著用1 M HCl水溶液(84.6 mL)及Et
2O淬滅。分離各層，且無機層用Et
2O (1×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用0%至60% EtOAc/庚烷溶離，其中在庚烷/EtOAc 4:6中R
f= 0.52)純化，得到呈黃色油狀之(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(612 mg，39%)。LC-MS A：t
R= 1.07 min；[M+H]
+= 488.19。
Step 4 : To ( R )-2-(( S )-2- ( tertiary butoxycarbonyl)(methyl)amino)-4-methylpentamylamino)-3-(4-phenyl -1H -1,2,3-triazol-1-yl)propionic acid methyl ester (1.772 g, 3.32 mmol) and MeI (0.834 mL, 13.3 mmol) in DMF (28.2 mL) in a -20°C solution NaH (381 mg, 9.95 mmol) was added. The reaction mixture was stirred at -20 °C for 17 min, then quenched with 1 M aqueous HCl (84.6 mL) and Et2O . The layers were separated, and the inorganic layer was extracted with Et2O (1x). The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 0% to 60% EtOAc/heptane with Rf = 0.52 in heptane/EtOAc 4:6) afforded ( R )-2-(( S )- 2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)-3-(4-phenyl-1 H -1,2,3-tri (azol-1-yl) propionate methyl ester (612 mg, 39%). LC-MS A: tR = 1.07 min; [M+H] + = 488.19.
步驟 5 ：向(
R)-2-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)-3-(4-苯基-1
H-1,2,3-三唑-1-基)丙酸甲酯(607 mg，1.02 mmol)於MeOH (14.4 mL)中之室溫溶液中添加4 M NaOH水溶液(10.3 mL，40.7 mmol)。將反應混合物加熱至50℃持續12 min，接著使其達到室溫，之後添加2 M HCl水溶液(59 mL)及DCM (35 mL)。分離各層，且無機層用DCM (1×)萃取。經合併之有機層經乾燥(經由相分離器)且濃縮。藉由製備型HPLC (酸性條件)純化，得到呈白色泡沫狀之標題化合物(337 mg，70%)。LC-MS A：t
R= 0.97 min；[M+H]
+= 474.18。
Step 5 : To ( R )-2-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentamido)-3-( To a room temperature solution of methyl 4-phenyl- 1H -1,2,3-triazol-1-yl)propanoate (607 mg, 1.02 mmol) in MeOH (14.4 mL) was added 4 M aqueous NaOH ( 10.3 mL, 40.7 mmol). The reaction mixture was heated to 50 °C for 12 min, then allowed to reach room temperature, after which 2 M aqueous HCl (59 mL) and DCM (35 mL) were added. The layers were separated, and the inorganic layer was extracted with DCM (1x). The combined org. layers were dried (via a phase separator) and concentrated. Purification by preparative HPLC (acidic conditions) afforded the title compound (337 mg, 70%) as a white foam. LC-MS A: tR = 0.97 min; [M+H] + = 474.18.
(
R)-2-((
S)-2-((
三級 丁氧基羰基 )( 甲基 ) 胺基 )-
N,4-
二甲基戊醯胺基 )-3-(4-(5- 氟吡啶 -2- 基 )-1
H-1,2,3-
三唑 -1- 基 ) 丙酸 (C-26.2)按照對於
C-26.1所描述之5-步驟順序，在步驟1中使用2-乙炔基-5-氟吡啶替代苯基乙炔製備標題化合物。LC-MS A：t
R= 0.94 min；[M+H]
+= 493.36。
( R )-2-(( S )-2-(( tertiary butoxycarbonyl )( methyl ) amino ) -N ,4 -dimethylpentamylamino )-3-(4-(5 -Fluoropyridin -2- yl ) -1H -1,2,3- triazol -1- yl ) propanoic acid (C-26.2) was used in step 1 following the 5 - step sequence described for C-26.1 2-Ethynyl-5-fluoropyridine was substituted for phenylacetylene to prepare the title compound. LC-MS A: tR = 0.94 min; [M+H] + = 493.36.
用於合成建構嵌段C之通用方法27General method for the synthesis of building block C 27
N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-O-環己基-N-甲基-D-高絲胺酸(C-27.1)
步驟 1 ：在0℃，向氫化鈉(於油中之懸浮液，60%) (1017 mg，26.5 mmol)於DMF (10 mL)中之懸浮液中逐滴添加Boc-D-高絲胺酸(3000 mg，13.3 mmol)於DMF (10 mL)中之溶液，且攪拌溶液20 min。向此溶液中添加碘化四丁基銨(49.5 mg，0.133 mmol)，且攪拌所得混合物30 min，且添加3-溴環己烯(2 mL，15.6 mmol)。在室溫攪拌2 h之後，添加碘化鈉(2010 mg，13.3 mmol)，且在室溫攪拌反應混合物隔夜。添加水及EtOAc，且分離2個相。無機層進一步用EtOAc (2×)萃取。經合併之有機層經Na
2SO
4乾燥，過濾且濃縮，得到呈棕色油狀之N-(三級丁氧基羰基)-O-(環己-2-烯-1-基)-D-高絲胺酸(3.06g)，其按原樣用於下一步驟。LC-MS B. t
R= 0.86 min；[M+H]
+= 300.33。
N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-O-cyclohexyl-N-methyl-D-homoserine (C-27.1) step 1 : To a suspension of sodium hydride (in oil, 60%) (1017 mg, 26.5 mmol) in DMF (10 mL) was added dropwise Boc-D-homoserine (3000 mg, 13.3 mmol) in DMF (10 mL), and the solution was stirred for 20 min. To this solution was added tetrabutylammonium iodide (49.5 mg, 0.133 mmol), and the resulting mixture was stirred for 30 min, and 3-bromocyclohexene (2 mL, 15.6 mmol) was added. After stirring at room temperature for 2 h, sodium iodide (2010 mg, 13.3 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Water and EtOAc were added and the 2 phases were separated. The inorganic layer was further extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4 , filtered and concentrated to give N-(tert-butoxycarbonyl)-O-(cyclohex-2-en-1 - yl)-D- as a brown oil Homoserine (3.06 g), which was used as such in the next step. LC-MS B. tR = 0.86 min; [M+H] + = 300.33.
步驟 2 ：在氬氣下，將N-(三級丁氧基羰基)-O-(環己-2-烯-1-基)-D-高絲胺酸(3060 mg，10.2 mmol)溶解於DCM (10 mL)及MeOH (10 mL)之混合物中。將此溶液冷卻至0℃，且緩慢添加三甲基矽基重氮甲烷(大約10%於己烷中，大約0.6 mol/L) (21 mL，12.3 mmol)。在室溫攪拌溶液1 h。移除溶劑至乾燥。粗材料經由分離柱(Isolute)吸收且經由FC純化，其使用100:0至60:40之庚烷/EtOAc之梯度，得到0.9 g呈淺黃色油狀之N-(三級丁氧基羰基)-O-(環己-2-烯-1-基)-D-高絲胺酸甲酯。LC-MS B：t
R= 0.98 min；[M+H]
+= 314.34。
Step 2 : N-(tert-butoxycarbonyl)-O-(cyclohex-2-en-1-yl)-D-homoserine (3060 mg, 10.2 mmol) was dissolved in DCM under argon (10 mL) and MeOH (10 mL). This solution was cooled to 0 °C, and trimethylsilyldiazomethane (ca. 10% in hexane, ca. 0.6 mol/L) (21 mL, 12.3 mmol) was added slowly. The solution was stirred at room temperature for 1 h. Solvent was removed to dryness. The crude material was taken up through an Isolute and purified by FC using a gradient of heptane/EtOAc from 100:0 to 60:40 to afford 0.9 g of N-(tertiary butoxycarbonyl) as a pale yellow oil -O-(cyclohex-2-en-1-yl)-D-homoserine methyl ester. LC-MS B: tR = 0.98 min; [M+H] + = 314.34.
步驟 3 ：在N
2下，將N-(三級丁氧基羰基)-O-(環己-2-烯-1-基)-D-高絲胺酸甲酯(900 mg，2.87 mmol)溶解於MeOH (20 mL)中；在添加10% Pd/C (90 mg)之前，容器用N
2/真空(3×)吹掃。在惰性化三次之後，連接H
2氣球，且在H
2氛圍下攪拌反應混合物1 h。經由玻璃纖維過濾器過濾非均勻反應混合物(用甲醇/THF洗滌)。接著減壓濃縮濾液至乾燥，得到0.82 g呈無色油狀之N-(三級丁氧基羰基)-O-環己基-D-高絲胺酸甲酯，其按原樣用於下一步驟。LC-MS B：t
R= 1.01 min；[M+H]
+= 316.37。
Step 3 : N-(tertiary butoxycarbonyl)-O-(cyclohex-2-en-1-yl)-D - homoserine methyl ester (900 mg, 2.87 mmol) was dissolved under N2 in MeOH (20 mL); the vessel was purged with N2 /vacuum (3x) before adding 10% Pd/C (90 mg). After inertization three times, a H2 balloon was attached and the reaction mixture was stirred under H2 atmosphere for 1 h. The heterogeneous reaction mixture was filtered through a glass fiber filter (washed with methanol/THF). The filtrate was then concentrated to dryness under reduced pressure to afford 0.82 g of N-(tert-butoxycarbonyl)-O-cyclohexyl-D-homoserine methyl ester as a colorless oil, which was used as such in the next step. LC-MS B: tR = 1.01 min; [M+H] + = 316.37.
步驟 4 ：在氬氣下，向N-(三級丁氧基羰基)-O-環己基-D-高絲胺酸甲酯(820 mg，2.6 mmol)及碘甲烷(0.245 mL，3.9 mmol)於DMF(8 mL)中之室溫溶液中逐份添加氫化鈉(於礦物油中之60%分散液) (149 mg，3.9 mmol)，且攪拌所得混合物1 h。將反應混合物分配於水與EtOAc之間。分離各層且用EtOAc (2×)進一步萃取無機層。經合併之有機萃取物用水及鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到0.84 g呈淺黃色油狀之N-(三級丁氧基羰基)-O-環己基-N-甲基-D-高絲胺酸甲酯。在此階段無純化。LC-MS B：t
R= 1.06 min；[M+H]
+= 330.37。
Step 4 : Under argon, add N-(tertiary butoxycarbonyl)-O-cyclohexyl-D-homoserine methyl ester (820 mg, 2.6 mmol) and iodomethane (0.245 mL, 3.9 mmol) in Sodium hydride (60% dispersion in mineral oil) (149 mg, 3.9 mmol) was added portionwise to a room temperature solution in DMF (8 mL), and the resulting mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc. The layers were separated and the inorganic layer was further extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried over Na2SO4 , filtered and evaporated in vacuo to give 0.84 g of N-(tertiary butoxycarbonyl)-O-cyclohexyl-N- Methyl-D-homoserine methyl ester. No purification at this stage. LC-MS B: tR = 1.06 min; [M+H] + = 330.37.
步驟 5 至 7 ：按照對於
C-18.1步驟2至4所描述之反應順序，由Boc-
N-甲基-L-白胺酸及N-(三級丁氧基羰基)-O-環己基-N-甲基-D-高絲胺酸甲酯製備呈無色油狀之標題化合物。LC-MS B：t
R= 1.06 min；[M+H]
+= 443.44。
Steps 5 to 7 : According to the reaction sequence described for C-18.1 steps 2 to 4, from Boc- N -methyl-L-leucine and N-(tertiary butoxycarbonyl)-O-cyclohexyl- N-Methyl-D-homoserine methyl ester Preparation of the title compound as a colorless oil. LC-MS B: tR = 1.06 min; [M+H] + = 443.44.
N-(N-( 三級丁氧基羰基 )-N- 甲基 -L- 白胺醯基 )-N- 甲基 -O- 苯基 -D- 高絲胺酸 (C-27.2) 步驟 1 ：向在室溫之(R)-4-溴-2-[[(三級丁氧基)羰基]胺基]丁酸三級丁酯(300 mg，0.843 mmol)於DMF (2 mL)中之溶液中添加苯酚(0.0786 mL，0.885 mmol)及K
2CO
3(349 mg，2.53 mmol)。在60℃攪拌反應混合物1小時。添加水及EtOAc，且分離2個相。無機層進一步用EtOAc (2×)萃取。經合併之有機層經Na
2SO
4乾燥，過濾且濃縮。粗物質經由分離柱吸收，且藉由FC (庚烷/EtOAc，100/0至50/50)純化產物，得到呈淺黃色油狀之N-(三級丁氧基羰基)-O-苯基-D-高絲胺酸三級丁酯(267 mg)。LC-MS B：t
R= 1.08 min；[M+H]
+= 352.32。
N-(N-( tertiary butoxycarbonyl )-N- methyl -L- leucyl )-N- methyl -O- phenyl -D- homoserine (C-27.2) step 1 : To (R)-4-bromo-2-[[(tertiary butoxy)carbonyl]amino]butanoic acid tertiary butyl ester (300 mg, 0.843 mmol) in DMF (2 mL) at room temperature To the solution were added phenol (0.0786 mL, 0.885 mmol) and K 2 CO 3 (349 mg, 2.53 mmol). The reaction mixture was stirred at 60°C for 1 hour. Water and EtOAc were added and the 2 phases were separated. The inorganic layer was further extracted with EtOAc (2x). The combined org. layers were dried over Na2SO4 , filtered and concentrated. The crude material was taken up through a separation column and the product was purified by FC (heptane/EtOAc, 100/0 to 50/50) to give N-(tertiary butoxycarbonyl)-O-phenyl as a light yellow oil - D-homoserine tertiary butyl ester (267 mg). LC-MS B: tR = 1.08 min; [M+H] + = 352.32.
步驟 2 ：在氬氣下，向N-(三級丁氧基羰基)-O-苯基-D-高絲胺酸三級丁酯(267 mg，0.76 mmol)及碘甲烷(0.0717 mL，1.14 mmol)於DMF (5 mL)中之室溫溶液中逐份添加氫化鈉(於礦物油中之60%分散液) (43.7 mg，1.14 mmol)，且攪拌所得混合物1 h。將反應混合物分配於水與EtOAc之間。分離各層，且水相用EtOAc (2×)再萃取。經合併之有機萃取物用水及鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈淡橙色油狀之N-(三級丁氧基羰基)-N-甲基-O-苯基-D-高絲胺酸三級丁酯(226 mg)。此步驟中無純化。LC-MS B：t
R= 1.13 min；[M+H]
+= 366.31。
Step 2 : Under argon, add N-(tertiary butoxycarbonyl)-O-phenyl-D-homoserine tertiary butyl ester (267 mg, 0.76 mmol) and iodomethane (0.0717 mL, 1.14 mmol ) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil) (43.7 mg, 1.14 mmol) portionwise, and the resulting mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was re-extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried over Na2SO4 , filtered and evaporated in vacuo to give N-(tert-butoxycarbonyl)-N-methyl-O-phenyl as a pale orange oil - D-homoserine tertiary butyl ester (226 mg). No purification in this step. LC-MS B: tR = 1.13 min; [M+H] + = 366.31.
步驟 3 ：向N-(三級丁氧基羰基)-N-甲基-O-苯基-D-高絲胺酸三級丁酯(226 mg，0.618 mmol)於DCM (5 mL)中之室溫溶液中添加TFA (0.474 mL，6.18 mmol)，且在室溫攪拌所得混合物6 h。充分真空移除揮發物；將所得殘餘物溶解回DCM中以另外重複共蒸發過程2次，得到呈棕色油狀之呈(R)-1-羧基-N-甲基-3-苯氧基丙-1-銨之(1:1) 2,2,2-三氟乙酸鹽形式之粗產物(266 mg)，其按原樣用於下一步驟。LC-MS B：t
R= 0.44 min; [2M+H]
+= 419.36。
Step 3 : Add N-(tertiary-butoxycarbonyl)-N-methyl-O-phenyl-D-homoserine tertiary-butyl ester (226 mg, 0.618 mmol) in DCM (5 mL) To the warm solution was added TFA (0.474 mL, 6.18 mmol), and the resulting mixture was stirred at room temperature for 6 h. The volatiles were removed under full vacuum; the resulting residue was dissolved back into DCM to repeat the co-evaporation process 2 more times to afford (R)-1-carboxy-N-methyl-3-phenoxypropane as a brown oil. - The crude product (266 mg) as the (1:1) 2,2,2-trifluoroacetate salt of 1-ammonium, which was used as such in the next step. LC-MS B: tR = 0.44 min; [2M+H] + = 419.36.
步驟 4 ：在室溫向(R)-1-羧基-N-甲基-3-苯氧基丙-1-銨2,2,2-三氟乙酸鹽(266 mg，1.27 mmol)於MeOH (5 mL)中之溶液中添加亞硫醯二氯(0.375 mL，5.08 mmol)。在60℃攪拌反應混合物16 h。將混合物倒入冰水中且用DCM (3×)萃取。經合併之有機層用鹽水洗滌，經MgSO
4乾燥，過濾且減壓濃縮，得到呈無色油狀之粗物質N-甲基-O-苯基-D-高絲胺酸甲酯(101 mg)。在此階段無純化。LC-MS B：t
R= 0.54 min；[M+H]
+= 224.31。
Step 4 : Add (R)-1-carboxy-N-methyl-3-phenoxypropan-1-ammonium 2,2,2-trifluoroacetate (266 mg, 1.27 mmol) in MeOH ( 5 mL) was added thionyl dichloride (0.375 mL, 5.08 mmol). The reaction mixture was stirred at 60 °C for 16 h. The mixture was poured into ice water and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give crude N-methyl-O-phenyl-D-homoserine methyl ester (101 mg) as a colorless oil. No purification at this stage. LC-MS B: tR = 0.54 min; [M+H] + = 224.31.
步驟 5 及 6 ：按照對於
C-2.1 步驟1及2所描述之反應順序，由Boc-
N-甲基-L-白胺酸及N-甲基-O-苯基-D-高絲胺酸甲酯製備呈無色油狀之標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 437.31。
Steps 5 and 6 : According to the reaction sequence described for C-2.1 steps 1 and 2, from Boc- N -methyl-L-leucine and N-methyl-O-phenyl-D-homoserine Ester Preparation of the title compound as a colorless oil. LC-MS B: tR = 1.03 min; [M+H] + = 437.31.
用於合成建構嵌段C之通用方法28General method for the synthesis of building block C 28
(RS)-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-O-(5-甲基吡𠯤-2-基)高絲胺酸(C-28.1)
步驟 1-3 ：在藉由FC (0至100% EtOAc/庚烷)純化之後，對於
C-18.2所描述之3種第一反應之順序得到呈無色油狀之關鍵中間物O-苯甲基-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-D-高絲胺酸甲酯。LC-MS B：t
R= 1.12 min；[M+H]
+= 465.38。
(RS)-N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-O-(5-methylpyr-2-yl) Homoserine (C-28.1) steps 1-3 : After purification by FC (0 to 100% EtOAc/heptane), the sequence of the 3 first reactions described for C-18.2 afforded Homoserine as a colorless oil The key intermediate is O-benzyl-N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-homoserine methyl ester. LC-MS B: tR = 1.12 min; [M+H] + = 465.38.
步驟 4 ：在N
2下，將O-苯甲基-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-D-高絲胺酸甲酯(5500 mg，11.8 mmol)溶解於MeOH (100 mL)中；在添加Pd(OH)
2/C (20 wt%) (830 mg)之前，容器用N
2/真空(3×)吹掃。在惰性化三次之後，連接H
2氣球，且在H
2氛圍下攪拌反應混合物16 h。經由玻璃纖維過濾器過濾非均勻反應混合物(用甲醇/THF洗滌)。接著減壓濃縮濾液至乾燥，得到4.36 g呈無色油狀之N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-D-高絲胺酸甲酯，其按原樣用於下一步驟。LC-MS B：t
R= 0.87 min；[M+H]
+= 375.07。
Step 4 : Under N 2 , add O-benzyl-N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-Kose Amino acid methyl ester (5500 mg, 11.8 mmol) was dissolved in MeOH (100 mL); the vessel was flooded with N2 /vacuum (3×) before adding Pd(OH) 2 /C (20 wt%) (830 mg) purge. After inertization three times, a H2 balloon was attached and the reaction mixture was stirred under H2 atmosphere for 16 h. The heterogeneous reaction mixture was filtered through a glass fiber filter (washed with methanol/THF). The filtrate was then concentrated to dryness under reduced pressure to obtain 4.36 g of N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D- Homoserine methyl ester, which was used as such in the next step. LC-MS B: tR = 0.87 min; [M+H] + = 375.07.
步驟 5 ：向2-羥基-5-甲基吡𠯤(80 mg，0.69 mmol)、N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-D-高絲胺酸甲酯(271 mg，0.725 mmol)、NEt3 (0.0962 mL，0.69 mmol)及聚合物負載之三苯基膦(1.32 mmol/g) (787 mg，1.04 mmol)於THF (30 mL)中之冷凍懸浮液中逐滴添加DIAD (0.194 mL，0.966 mmol)。在室溫攪拌所得反應混合物1 h。過濾出聚合物。向濾液中添加水，且所得無機層用EtO
2(3×)萃取。經合併之有機萃取物用鹽水洗滌，經MgSO
4乾燥，過濾且真空蒸發。藉由FC (50%至100% EtOAc/庚烷)純化，得到呈白色固體狀之差向異構物(RS)-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-O-(5-甲基吡𠯤-2-基)高絲胺酸甲酯之混合物(376 mg)。LC-MS B：t
R= 1.07及1.08 min；[M+H]
+= 467.47。
Step 5 : Add 2-hydroxy-5-methylpyrrole (80 mg, 0.69 mmol), N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N -Methyl-D-homoserine acid methyl ester (271 mg, 0.725 mmol), NEt3 (0.0962 mL, 0.69 mmol) and polymer-supported triphenylphosphine (1.32 mmol/g) (787 mg, 1.04 mmol) in To a frozen suspension in THF (30 mL) was added dropwise DIAD (0.194 mL, 0.966 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The polymer was filtered off. Water was added to the filtrate, and the resulting inorganic layer was extracted with EtO2 (3x). The combined org. extracts were washed with brine, dried over MgSO4 , filtered and evaporated in vacuo. Purification by FC (50% to 100% EtOAc/heptane) afforded the epimer (RS)-N-(N-(tert-butoxycarbonyl)-N-methyl- Mixture of L-leucyl)-N-methyl-O-(5-methylpyrhal-2-yl)homoserine methyl ester (376 mg). LC-MS B: tR = 1.07 and 1.08 min; [M+H] + = 467.47.
步驟 6 ：向差向異構物(RS)-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-O-(5-甲基吡𠯤-2-基)高絲胺酸甲酯(376 mg，0.806 mmol)於二㗁烷(10 mL)中之混合物中添加1M NaOH (1.6 mL，1.61 mmol)。在50℃攪拌反應混合物1 h；接著使其返回至室溫且用0.5 ml NH
4Cl飽和溶液處理。將所得混合物濃縮至乾燥。將粗殘餘物分配於DCM與水之間，且收集DCM層。無機層用幾滴2N HCl水溶液(降至pH ~ 3)酸化且用DCM (3×)萃取。經合併之有機層用酸化鹽水洗滌，經MgSO
4乾燥且減壓濃縮，得到呈無色油狀之標題化合物(RS)-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-N-甲基-O-(5-甲基吡𠯤-2-基)高絲胺酸
(C-28.1)(334 mg)，其按原樣用於隨後步驟中。LC-MS B：t
R= 0.94 及0.95 min；[M+H]
+= 453.47。
Step 6 : To the epimer (RS)-N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-O-(5- To a mixture of methylpyryl-2-yl)homoserine (376 mg, 0.806 mmol) in dioxane (10 mL) was added 1M NaOH (1.6 mL, 1.61 mmol). The reaction mixture was stirred at 50 °C for 1 h; then allowed to return to room temperature and treated with 0.5 ml of a saturated solution of NH4Cl . The resulting mixture was concentrated to dryness. The crude residue was partitioned between DCM and water, and the DCM layer was collected. The inorganic layer was acidified with a few drops of 2N aqueous HCl (down to pH~3) and extracted with DCM (3x). The combined organic layers were washed with acidified brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound (RS)-N-(N-(tertiary-butoxycarbonyl)-N-methyl- L-leucyl)-N-methyl-O-(5-methylpyrha-2-yl)homoserine (C-28.1) (334 mg), which was used as it is in the subsequent step. LC-MS B: tR = 0.94 and 0.95 min; [M+H] + = 453.47.
(RS)-N-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)-O-(2-甲氧基吡啶-4-基)-N-甲基高絲胺酸(C-28.2)
按照對於
C-28.1所描述之6-步驟順序，在步驟5中使用市售的2-甲氧基-4-吡啶酚替代2-羥基-5-甲基吡𠯤製備標題化合物，得到呈無色油狀之不可區分的差向異構物之混合物的
C-28.2。LC-MS B：t
R= 0.76 min；[M+H]
+= 468.47。
(RS)-N-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-O-(2-methoxypyridin-4-yl)-N-methyl Homoserine (C-28.2) Follow the 6-step sequence described for C-28.1 , using commercially available 2-methoxy-4-pyridinol in place of 2-hydroxy-5-methylpyridine in step 5 The title compound was prepared to afford C-28.2 as a mixture of indistinguishable epimers as a colorless oil. LC-MS B: tR = 0.76 min; [M+H] + = 468.47.
用於合成建構嵌段C之通用方法29General method for the synthesis of building block C 29
(R)-2-((S)-2-(( 三級丁氧基羰基 )( 甲基 ) 胺基 )-N,4- 二甲基戊醯胺基 )-3,3- 二甲基丁酸 (C-29.1) 步驟 1 ：向中3-甲基-D-纈胺酸甲酯(1080 mg，7.14 mmol)於二㗁烷(20 mL)中之淡黃色溶液中添加1 M NaOH (14.3 mL，14.3 mmol)。接著，所得混合物用Boc
2O (1.84 mL，7.85 mmol)處理且在室溫攪拌24 h。減壓濃縮混合物，且將殘餘物分配於NH
4Cl飽和水溶液與DCM之間。無機層進一步用DCM (2×)萃取，且經合併之有機萃取物經MgSO
4乾燥且減壓濃縮。將粗殘餘物再溶解於MeCN中且用庚烷洗滌，接著與Et
2O一起共蒸發，得到呈無色油狀之(R)-2-((三級丁氧基羰基)胺基)-3,3-二甲基丁酸甲酯(1.08 g)。在此階段無進一步純化。LC-MS B：t
R= 0.92 min；[M+H]
+= 246.22及[2M+H]
+= 491.27。
(R)-2-((S)-2-(( tertiary butoxycarbonyl )( methyl ) amino )-N,4 -dimethylpentanylamino )-3,3- dimethyl Butyric acid (C-29.1) Step 1 : To a pale yellow solution of 3-methyl-D-valine methyl ester (1080 mg, 7.14 mmol) in dioxane (20 mL) was added 1 M NaOH ( 14.3 mL, 14.3 mmol). Then, the resulting mixture was treated with Boc2O (1.84 mL, 7.85 mmol) and stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between saturated aqueous NH4Cl and DCM. The inorganic layer was further extracted with DCM (2x), and the combined org. extracts were dried over MgSO 4 and concentrated under reduced pressure. The crude residue was redissolved in MeCN and washed with heptane, then co-evaporated with Et2O to afford (R)-2-((tertiary butoxycarbonyl)amino)-3 as a colorless oil , Methyl 3-dimethylbutyrate (1.08 g). No further purification at this stage. LC-MS B: tR = 0.92 min; [M+H] + = 246.22 and [2M+H] + = 491.27.
步驟 2 ：在氬氣下，在室溫，向(R)-2-((三級丁氧基羰基)胺基)-3,3-二甲基丁酸甲酯(1080 mg，4.4 mmol)及碘甲烷(0.415 mL，6.6 mmol)於DMF (17 mL)中之溶液中逐份添加氫化鈉(於礦物油中之60%分散液) (253 mg，6.6 mmol)。在室溫攪拌所得混合物1 h。反應混合物藉由小心的添加NH
4Cl飽和水溶液淬滅，且水層用EtOAc (3×)萃取。經合併之有機萃取物用硫代硫酸鹽飽和水溶液洗滌，接著用鹽水洗滌，經MgSO
4乾燥，過濾且減壓蒸發，得到呈淺黃色液體狀之(R)-2-((三級丁氧基羰基)(甲基)胺基)-3,3-二甲基丁酸甲酯(1.58 g)，其按原樣用於下一步驟。LC-MS B：t
R= 1.01 min；[M+H]
+= 260.23。
Step 2 : To (R)-methyl 2-((tertiary butoxycarbonyl)amino)-3,3-dimethylbutanoate (1080 mg, 4.4 mmol) under argon at room temperature And to a solution of iodomethane (0.415 mL, 6.6 mmol) in DMF (17 mL) was added sodium hydride (60% dispersion in mineral oil) (253 mg, 6.6 mmol) in portions. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by careful addition of saturated aqueous NH4Cl , and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with saturated aqueous thiosulfate followed by brine, dried over MgSO , filtered and evaporated under reduced pressure to give (R)-2-((tertiary butoxy (methyl)amino)-3,3-dimethylbutyrate (1.58 g), which was used as such in the next step. LC-MS B: tR = 1.01 min; [M+H] + = 260.23.
步驟 3-5 ：按照對於
C-18.1步驟2至4所描述之反應順序，由Boc-
N-甲基-L-白胺酸及(R)-2-((三級丁氧基羰基)(甲基)胺基)-3,3-二甲基丁酸甲酯製備呈灰白色固體狀之標題化合物；藉由FC (0%至100% EtOAc/庚烷，用ELSD監測)純化。LC-MS B：t
R= 1.02 min；[M+H]
+= 373.32。
Step 3-5 : According to the reaction sequence described for C-18.1 steps 2 to 4, from Boc- N -methyl-L-leucine and (R)-2-((tertiary butoxycarbonyl)( Methyl)amino)-3,3-dimethylbutyrate produced the title compound as an off-white solid; purified by FC (0% to 100% EtOAc/heptane, monitored by ELSD). LC-MS B: tR = 1.02 min; [M+H] + = 373.32.
(R)-2-((S)-2-(( 三級丁氧基羰基 )( 甲基 ) 胺基 )-N,4- 二甲基戊醯胺基 )-4- 苯基丁酸 (C-29.2)按照對於
C-29.1所描述之5-步驟順序，在步驟1中以市售的(R)-2-胺基-4-苯基丁酸乙酯鹽酸鹽替代3-甲基-D-纈胺酸甲酯起始製備標題化合物，得到呈黃色油狀之
C-29.2。LC-MS B：t
R= 1.03 min；[M+H]
+= 421.38。
(R)-2-((S)-2-(( tertiary butoxycarbonyl )( methyl ) amino )-N,4- dimethylpentanylamino )-4- phenylbutanoic acid ( C-29.2) Follow the 5-step sequence described for C-29.1 , substituting commercial (R)-2-amino-4-phenylbutanoic acid ethyl ester hydrochloride for 3-methyl in step 1 - D-Valine methyl ester The title compound was prepared starting from C-29.2 as a yellow oil. LC-MS B: tR = 1.03 min; [M+H] + = 421.38.
建構嵌段D
building block D
O-苯甲基-
N-(三級丁氧基羰基)-
N-甲基絲胺酸(D1-1.1) 步驟1：向Boc-D-Ser-(Bzl)-OH (271 mg，0.9 mmol)及
pTsOH (15.8 mg，0.09 mmol)於PhMe (9 mL)中之室溫溶液中添加多聚甲醛(579 mg，4.5 mmol)，且在Dean Stark設備中使反應混合物回流隔夜。混合物用NaHCO
3水溶液洗滌，分離有機層，經乾燥(MgSO
4)且減壓濃縮。藉由FC (0%至70% EtOAc/庚烷溶離)純化，得到呈白色固體狀之(R)-4-((苯甲氧基)甲基)-5-側氧基㗁唑啶-3-甲酸三級丁酯(178 mg，65%)。LC-MS B：t
R= 0.98 min；[M+H]
+= 308.09。
O -benzyl- N- (tertiary butoxycarbonyl) -N -methylserine (D1-1.1) Step 1: Add Boc-D-Ser-(Bzl)-OH (271 mg, 0.9 mmol ) and pTsOH (15.8 mg, 0.09 mmol) in PhMe (9 mL) at room temperature was added paraformaldehyde (579 mg, 4.5 mmol) and the reaction mixture was refluxed overnight in a Dean Stark apparatus. The mixture was washed with aqueous NaHCO 3 , the organic layer was separated, dried (MgSO 4 ) and concentrated under reduced pressure. Purification by FC (0% to 70% EtOAc/heptane elution) afforded (R)-4-((benzyloxy)methyl)-5-oxazolidine-3 as a white solid - Tertiary butyl formate (178 mg, 65%). LC-MS B: tR = 0.98 min; [M+H] + = 308.09.
步驟2：向(R)-4-((苯甲氧基)甲基)-5-側氧基㗁唑啶-3-甲酸三級丁酯(179 mg，0.581 mmol)及三乙基矽烷(0.5 mL，3.1 mmol)於CHCl
3(3 mL)中之室溫溶液中添加TFA (2.0 mL，26.1 mmol)，且在室溫攪拌反應混合物3 h。濃縮混合物，且將殘餘物再溶解於TBME中且用NaHCO
3水溶液萃取。水層用1 N HCl酸化至pH 3且用TBME萃取。濃縮有機層，得到呈白色固體狀之
O-苯甲基-
N-甲基-DL-絲胺酸，其按原樣用於下一步驟。LC-MS B：t
R= 0.43 min；[M+H]
+=210.34。
Step 2: Add (R)-4-((benzyloxy)methyl)-5-oxazolidine-3-carboxylic acid tertiary butyl ester (179 mg, 0.581 mmol) and triethylsilane ( To a room temperature solution of 0.5 mL, 3.1 mmol) in CHCl3 (3 mL) was added TFA (2.0 mL, 26.1 mmol), and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated, and the residue was redissolved in TBME and extracted with aqueous NaHCO 3 . The aqueous layer was acidified to pH 3 with 1 N HCl and extracted with TBME. The organic layer was concentrated to afford O- benzyl- N -methyl-DL-serine as a white solid, which was used as such in the next step. LC-MS B: tR = 0.43 min; [M+H] + = 210.34.
步驟 3 ：向
O-苯甲基-
N-甲基-D-絲胺酸(122 mg，0.581 mmol)及TEA (0.404 mL，2.9 mmol)於THF (6 mL)中之室溫溶液中添加二碳酸二三級丁酯(128 mg，0.581 mmol)，且在室溫攪拌反應混合物隔夜。濃縮混合物且向殘餘物中添加TBME及水。分離各層，且水層用10%檸檬酸酸化(pH 5)。水層用TBME (3×)萃取，且經合併之有機層經乾燥(MgSO
4)，過濾且濃縮，得到呈黏稠黃色油狀之標題化合物
D1-1.1(136 mg，76%)。LC-MS B：t
R= 0.88 min；[M+H]
+=310.17。在此合成步驟期間或在更早步驟中是否發生外消旋化不確定。外消旋混合物按原樣用於下一步驟。
Step 3 : To a room temperature solution of O -benzyl- N -methyl-D-serine (122 mg, 0.581 mmol) and TEA (0.404 mL, 2.9 mmol) in THF (6 mL) was added di Ditert-butyl carbonate (128 mg, 0.581 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and TBME and water were added to the residue. The layers were separated, and the aqueous layer was acidified (pH 5) with 10% citric acid. The aqueous layer was extracted with TBME (3×), and the combined organic layers were dried (MgSO 4 ), filtered and concentrated to give the title compound D1-1.1 (136 mg, 76%) as a viscous yellow oil. LC-MS B: tR = 0.88 min; [M+H] + = 310.17. It is uncertain whether racemization occurred during this synthetic step or in an earlier step. The racemic mixture was used as such in the next step.
下表D1-1中列舉類似於上文對於
D1-1.1描述之順序，由對應起始材料製備之建構嵌段D1。
表D1-1
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
D1-1.2 Boc-D-Ser-(tBu)-OH
N-(三級丁氧基羰基)-
O-(三級丁基)-
N-甲基絲胺酸
外消旋發生
0.85
B
276.22
Listed in Table D1-1 below are the building blocks D1 prepared from the corresponding starting materials in analogy to the sequence described above for D1-1.1 . Table D1-1 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
D1-1.2 Boc-D-Ser-(tBu)-OH N- (tertiary butoxycarbonyl) -O- (tertiary butyl) -N -methylserine racemization occurs 0.85 B 276.22
N-(((9
H-茀-9-基)氧基)羰基)-
N-(3,3-二甲基丁基)甘胺酸(D1-2.1)
步驟 1 ：在迪恩-斯達克設備(Dean-Stark apparatus)中，向Fmoc-Gly-OH (1.0 g，3.36 mmol)及3,3-二甲基丁醛(0.489 mL，3.7 mmol)於PhMe (60 mL)中之室溫懸浮液中添加pTsOH (65.3 mg，0.336 mmol)，且在110℃使所得渾濁混合物回流4 h。在冷卻至室溫之後，反應混合物用EtOAc稀釋，且產物用NaHCO
3飽和水溶液(2×)洗滌。有機層經乾燥(MgSO
4)，過濾且濃縮，得到呈淺黃色固體狀之2-新戊基-5-側氧基㗁唑啶-3-甲酸(9
H-茀-9-基)甲酯(0.99 g，78%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.13 min；[M+H]
+= 380.19。
N -((( 9H -Fetrene-9-yl)oxy)carbonyl) -N- (3,3-Dimethylbutyl)glycine (D1-2.1) Step 1 : In Dean-Star In a Dean-Stark apparatus, add Fmoc-Gly-OH (1.0 g, 3.36 mmol) and 3,3-dimethylbutyraldehyde (0.489 mL, 3.7 mmol) in PhMe (60 mL) to room temperature To the suspension was added pTsOH (65.3 mg, 0.336 mmol), and the resulting cloudy mixture was refluxed at 110 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, and the product was washed with saturated aqueous NaHCO 3 (2×). The organic layer was dried ( MgSO4 ), filtered and concentrated to give ( 9H -fen-9-yl)methyl 2-neopentyl-5-oxazolidine-3-carboxylate as a light yellow solid (0.99 g, 78%), which was used as such in the next step. LC-MS B: tR = 1.13 min; [M+H] + = 380.19.
步驟 2 ：向2-新戊基-5-側氧基㗁唑啶-3-甲酸(9
H-茀-9-基)甲酯(980 mg，2.58 mmol)及三乙基矽烷(1.25 mL，7.75 mmol)於DCM (13 mL)中之室溫溶液中添加TFA (4.94 mL，64.6 mmol)，且在室溫攪拌所得混合物隔夜。反應混合物用DCM稀釋且用水(2×)洗滌。有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用0%至50% EtOAc/庚烷+ 0.5% AcOH溶離)純化，得到呈無色固體狀之標題化合物
D1-2.1(866 mg，88%)。LC-MS B：t
R= 1.05 min；[M+H]
+= 382.18。
Step 2 : To 2-neopentyl-5-oxazolidine-3-carboxylic acid ( 9H -fen-9-yl)methyl ester (980 mg, 2.58 mmol) and triethylsilane (1.25 mL, 7.75 mmol) in DCM (13 mL) was added TFA (4.94 mL, 64.6 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water (2x). The organic layer was dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 0% to 50% EtOAc/heptane + 0.5% AcOH) afforded the title compound D1-2.1 (866 mg, 88%) as a colorless solid. LC-MS B: tR = 1.05 min; [M+H] + = 382.18.
下表D1-2中列舉類似於上文對於
D1-2.1描述之順序，由對應起始材料製備之建構嵌段D (Fmoc保護的)。在步驟2中，在一些情況下，省略三乙基矽烷。
表D1-2
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
D1-2.2 2-環己基乙醛
N-(((9
H-茀-9-基)甲氧基)羰基)-N-(2-環己基乙基)甘胺酸
1.10
B
408.23
D1-2.3 多聚甲醛
(S)-2-((((9
H-茀-9-基)甲氧基)羰基)(甲基)胺基)-3-環丁基丙酸
1.04
B
380.40
Listed in Table D1-2 below are building blocks D (Fmoc protected) prepared from the corresponding starting materials in a sequence analogous to that described above for D1-2.1 . In Step 2, triethylsilane was omitted in some cases. Table D1-2 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
D1-2.2 2-Cyclohexylacetaldehyde N -((( 9H -Fetil-9-yl)methoxy)carbonyl)-N-(2-cyclohexylethyl)glycine 1.10B 408.23
D1-2.3 Paraformaldehyde (S)-2-(((( 9H -Ferne-9-yl)methoxy)carbonyl)(methyl)amino)-3-cyclobutylpropionic acid 1.04 B 380.40
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-苯乙基甘胺酸(D1-2.4)
步驟 1 ：向苯基乙醛(0.78 mL，6 mmol)及甘胺酸三級丁酯鹽酸鹽(1.0 g，6 mmol)於MeOH (40 mL)中之室溫溶液中添加TEA (1.67 mL，12 mmol)。在室溫1 h之後，添加NaBH(OAc)
3(2.68 g，12 mmol)，且在室溫攪拌反應混合物隔夜。過濾反應混合物，濃縮且分配於EtOAc與NaHCO
3水溶液之間。分離有機層，且水層用EtOAc萃取。經合併之有機層用鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用50% EtOAc/庚烷溶離)純化，得到呈無色油狀之苯乙基甘胺酸三級丁酯(0.193 g，14%)。LC-MS D t
R= 0.63 min；[M+H]
+= 236.45。
N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -phenylethylglycine (D1-2.4) Step 1 : Addition of phenylacetaldehyde (0.78 mL, 6 mmol) and To a room temperature solution of tert-butyl glycine hydrochloride (1.0 g, 6 mmol) in MeOH (40 mL) was added TEA (1.67 mL, 12 mmol). After 1 h at room temperature, NaBH(OAc) 3 (2.68 g, 12 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, concentrated and partitioned between EtOAc and aqueous NaHCO 3 . The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined org. layers were washed with brine, dried ( MgSO4 ), filtered and concentrated. Purification by FC (elution with 50% EtOAc/heptane) afforded tert-butyl phenethylglycine (0.193 g, 14%) as a colorless oil. LC-MS D t R = 0.63 min; [M+H] + = 236.45.
步驟 2 ：向苯乙基甘胺酸三級丁酯(193 mg，0.82 mmol)及碳酸鈉(261 mg，2.46 mmol)於二㗁烷(5 mL)及水(3 mL)中之室溫懸浮液中添加
N-(9-茀基甲氧基羰基氧基)丁二醯亞胺(417 mg，1.23 mmol)，且在室溫攪拌反應混合物隔夜。蒸發二㗁烷且將殘餘物分配於EtOAc與水之間。有機層經乾燥(MgSO
4)，過濾且濃縮，得到
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-苯乙基甘胺酸三級丁酯(0.484 g，129%)，其按原樣用於下一步驟。LC-MS D t
R= 1.34 min；[M+H]
+= 458.29。
Step 2 : Suspend tertiary butyl phenethylglycine (193 mg, 0.82 mmol) and sodium carbonate (261 mg, 2.46 mmol) in dioxane (5 mL) and water (3 mL) at room temperature To the solution was added N- (9-fenylmethoxycarbonyloxy)succinimide (417 mg, 1.23 mmol), and the reaction mixture was stirred at room temperature overnight. Dioxane was evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried (MgSO 4 ), filtered and concentrated to give tert-butyl N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -phenylethylglycine (0.484 g , 129%), which was used as such in the next step. LC-MS D t R = 1.34 min; [M+H] + = 458.29.
步驟 3 ：向
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-苯乙基甘胺酸三級丁酯(484 mg，0.505 mmol)於DCM (2 mL)中之0℃溶液中添加TFA (0.4 mL，5.05 mmol)，且在室溫攪拌所得反應混合物隔夜。濃縮混合物，且藉由FC (用DCM/MeOH 19:1溶離)純化粗產物，得到呈無色油狀之標題化合物
D1-2.4(0.266 g，131%)。LC-MS D t
R= 1.09 min；[M+H]
+= 402.17。
Step 3 : Add N -((( 9H -fluorene-9-yl)methoxy)carbonyl) -N -phenylethylglycine tert-butyl ester (484 mg, 0.505 mmol) in DCM (2 mL) TFA (0.4 mL, 5.05 mmol) was added to the solution at 0 °C in China, and the resulting reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the crude product was purified by FC (elution with DCM/MeOH 19:1) to afford the title compound D1-2.4 (0.266 g, 131%) as a colorless oil. LC-MS D t R = 1.09 min; [M+H] + = 402.17.
下表D1-2中列舉類似於上文對於
D1-2.4描述之順序，由對應起始材料製備之建構嵌段D (Fmoc保護的)。
表D1-2
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
D1-2.5 3-(苯甲氧基)丙醛
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-(3-(苯甲氧基)丙基)甘胺酸
1.11
B
446.30.
D1-2.6 2-(㗁烷-4-基)乙醛
N-(((9
H-茀-9-基)甲氧基)羰基)-
N-(2-(四氫-2H-哌喃-4-基)乙基)甘胺酸
0.95
D
410.43
Listed in Table D1-2 below are building block D (Fmoc protected) prepared from the corresponding starting materials in a sequence similar to that described above for D1-2.4 . Table D1-2 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
D1-2.5 3-(Benzyloxy)propanal N -((( 9H -Oxyl-9-yl)methoxy)carbonyl) -N- (3-(benzyloxy)propyl)glycine 1.11B 446.30.
D1-2.6 2-(Oxane-4-yl)acetaldehyde N -((( 9H -Fluene-9-yl)methoxy)carbonyl) -N- (2-(tetrahydro-2H-pyran-4-yl)ethyl)glycine 0.95D 410.43
1-(( 三級丁氧基羰基 )( 甲基 ) 胺基 ) 環丁烷 -1- 甲酸為市售的且簡稱為
D1-3.0。
1-(( Tertiary butoxycarbonyl )( methyl ) amino ) cyclobutane -1- carboxylic acid is commercially available and is abbreviated as D1-3.0 .
2-((三級丁氧基羰基)(甲基)胺基)-3-環戊基丙酸(D1-4.1) 向2-{[(三級丁氧基)羰基]胺基}-3-環戊基丙酸(432 mg，1.63 mmol)於THF (8 mL)中之0℃溶液中添加NaH (187 mg，4.88 mmol)，接著添加MeI (0.51 mL，8.13 mmol)，且使反應混合物達到室溫，同時攪拌10 h。反應混合物用H
2O淬滅且用EtOAc萃取，得到標題化合物
D1-4.1(318 mg，72%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.94 min；[M+H]
+= 272.30。
2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopentyl propionic acid (D1-4.1) to 2-{[(tertiary butoxycarbonyl)amino}-3 - To a solution of cyclopentylpropionic acid (432 mg, 1.63 mmol) in THF (8 mL) at 0 °C was added NaH (187 mg, 4.88 mmol), followed by MeI (0.51 mL, 8.13 mmol), and the reaction mixture was allowed to Bring to room temperature while stirring for 10 h. The reaction mixture was quenched with H 2 O and extracted with EtOAc to afford the title compound D1-4.1 (318 mg, 72%), which was used as such in the next step. LC-MS B: tR = 0.94 min; [M+H] + = 272.30.
下表D1-4中列舉類似於上文對於
D1-4.1描述之方法，由對應起始材料製備之建構嵌段
D1。
表D1-4
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
D1-4.2 (R)-2-((三級丁氧基羰基)胺基)-3-(萘-1-基)丙酸
(R)-2-((三級丁氧基羰基)(甲基)胺基)-3-(萘-1-基)丙酸
0.51
I
330.23
D1-4.3 (三級丁氧基羰基)-D-纈胺酸
N-(三級丁氧基羰基)-
N-甲基-D-纈胺酸
0.39
I
232.30
D1-4.4 (三級丁氧基羰基)-D-白胺酸
N-(三級丁氧基羰基)-
N-甲基-D-白胺酸
0.45
I
246.31
D1-4.5 (R)-2-((三級丁氧基羰基)胺基)-3-環己基丙酸
(R)-2-((三級丁氧基羰基)(甲基)胺基)-3-環己基丙酸
0.57
I
286.34
D1-4.6 2-((三級丁氧基羰基)胺基)-4,4-二氟丁酸
2-((三級丁氧基羰基)(甲基)胺基)-4,4-二氟丁酸
0.37
I
無質量
The building blocks D1 prepared from the corresponding starting materials analogously to the methods described above for D1-4.1 are listed in Tables D1-4 below. Table D1-4 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
D1-4.2 (R)-2-((tertiary butoxycarbonyl)amino)-3-(naphthalen-1-yl)propionic acid (R)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-(naphthalene-1-yl)propionic acid 0.51 I 330.23
D1-4.3 (Tertiary Butoxycarbonyl)-D-Valine N- (tertiary butoxycarbonyl) -N -methyl-D-valine 0.39 I 232.30
D1-4.4 (tertiary butoxycarbonyl)-D-leucine N -(tertiary butoxycarbonyl) -N -methyl-D-leucine 0.45I 246.31
D1-4.5 (R)-2-((tertiary butoxycarbonyl)amino)-3-cyclohexylpropionic acid (R)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclohexylpropionic acid 0.57I 286.34
D1-4.6 2-((tertiary butoxycarbonyl)amino)-4,4-difluorobutanoic acid 2-((tertiary butoxycarbonyl)(methyl)amino)-4,4-difluorobutanoic acid 0.37I no quality
(S)-2-(三級丁氧基羰基-甲基-胺基)-3-環戊基-丙酸(D2-1.1) 向(S)-2-((三級丁氧基羰基)胺基)-3-環戊基丙酸(2.0 g，7.62 mmol)於THF (32 mL)中之0℃溶液中添加NaH (914 mg，22.9 mmol)。在5 min之後，添加MeI (1.9 mL，30.5 mmol)，且移除冰浴，並在室溫攪拌混合物隔夜。反應物用DCM (100 mL)稀釋且用2 M HCl水溶液淬滅(27 mL→pH=1)。分離各層，且水層用DCM (2 × 100 mL)萃取。經合併之有機層用鹽水(100 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈橙色油狀之標題化合物(2.28 g，110%)。LC-MS B：t
R= 0.94 min；[M+H]
+= 272.30。
(S)-2-(tertiary butoxycarbonyl-methyl-amino)-3-cyclopentyl-propionic acid (D2-1.1) to (S)-2-((tertiary butoxycarbonyl) To a solution of amino)-3-cyclopentylpropanoic acid (2.0 g, 7.62 mmol) in THF (32 mL) at 0 °C was added NaH (914 mg, 22.9 mmol). After 5 min, MeI (1.9 mL, 30.5 mmol) was added, and the ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM (100 mL) and quenched with 2 M aqueous HCl (27 mL→pH=1). The layers were separated, and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO 4 ), filtered and concentrated to give the title compound (2.28 g, 110%) as an orange oil. LC-MS B: tR = 0.94 min; [M+H] + = 272.30.
下表D2-1中列舉類似於上文對於
D2-1.1描述之方法，由對應起始材料製備之建構嵌段
D2。
表D2-1
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
D2-1.2 Boc-β-環己基-L-丙胺酸單水合物
(S)-2-(三級丁氧基羰基-甲基-胺基)-3-環己基-丙酸
0.98
B
286.31
D2-1.3 (2
S)-2-{[(三級丁氧基)羰基]胺基}-3-環戊基丙酸
(S)-2-((三級丁氧基羰基)(甲基)胺基)戊-4-炔酸
0.94
B
272.33.
D2-1.4 (S)-2-(Boc-胺基)-3-環丙基丙酸
(S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丙基丙酸
0.81
B
244.34
Listed in Table D2-1 below are the building blocks D2 prepared from the corresponding starting materials analogously to the methods described above for D2-1.1 . Table D2-1 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
D2-1.2 Boc-β-cyclohexyl-L-alanine monohydrate (S)-2-(tertiary butoxycarbonyl-methyl-amino)-3-cyclohexyl-propionic acid 0.98 B 286.31
D2-1.3 (2 S )-2-{[(tertiary butoxy)carbonyl]amino}-3-cyclopentylpropionic acid (S)-2-((tertiary butoxycarbonyl)(methyl)amino)pent-4-ynoic acid 0.94 B 272.33.
D2-1.4 (S)-2-(Boc-amino)-3-cyclopropylpropionic acid (S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclopropylpropionic acid 0.81 B 244.34
(S)-2-((三級丁氧基羰基)(甲基)胺基)-3-環丁基丙酸(D2-2.1)
步驟 1 ：向Boc-Ala(β-環丁基)-OH二異丙基胺(1.0 g，2.84 mmol)於H
2O中之室溫溶液中添加檸檬酸，以將pH降至4，接著游離甲酸用DCM (3×)萃取，得到Boc-Ala(β-環丁基)-OH (692 mg，2.84 mmol)，其按原樣用於下一步驟。
(S)-2-((tertiary butoxycarbonyl)(methyl)amino)-3-cyclobutylpropionic acid (D2-2.1) step 1 : to Boc-Ala(β-cyclobutyl)- To a room temperature solution of OH diisopropylamine (1.0 g, 2.84 mmol) in H2O was added citric acid to lower the pH to 4, then the free formic acid was extracted with DCM (3x) to give Boc-Ala ( β-cyclobutyl)-OH (692 mg, 2.84 mmol), which was used as such in the next step.
步驟 2 ：向Boc-Ala(β-環丁基)-OH (692 mg，2.84 mmol)於THF (10 mL)中之0℃溶液中添加NaH (於礦物油中之60%分散液，341 mg，8.53 mmol)，隨後逐滴添加MeI (1.43 mL，22.8 mmol)。在室溫攪拌所得混合物18 h。反應混合物用水淬滅且用TBME (3×)萃取。水層用檸檬酸酸化至pH 4且用EtOAc (3×)萃取。經合併之EtOAc層經乾燥(MgSO
4)，過濾且濃縮，得到
D2-2.1(801 mg，109%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.89 min；[M+H]
+= 258.08。
Step 2 : To a solution of Boc-Ala(β-cyclobutyl)-OH (692 mg, 2.84 mmol) in THF (10 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 341 mg , 8.53 mmol), followed by the dropwise addition of MeI (1.43 mL, 22.8 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with TBME (3x). The aqueous layer was acidified to pH 4 with citric acid and extracted with EtOAc (3x). The combined EtOAc layers were dried (MgSO 4 ), filtered and concentrated to afford D2-2.1 (801 mg, 109%) which was used as such in the next step. LC-MS B: tR = 0.89 min; [M+H] + = 258.08.
N-((烯丙氧基)羰基)-
N-甲基-L-白胺酸(D2-3.1)
步驟 1 ：向Boc-
N-Me-Leu-OH (2.78 g，11 mmol)於DCM (20 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(11 mL，44 mmol)。在室溫攪拌混合物2 h。濃縮反應混合物，得到(
S)-4-甲基-2-甲基胺基-戊酸(2.14 g)，其按原樣用於下一步驟。
N -((allyloxy)carbonyl) -N -methyl-L-leucine (D2-3.1) step 1 : Boc- N -Me-Leu-OH (2.78 g, 11 mmol) in DCM ( To a room temperature solution in 20 mL) was added dioxane (11 mL, 44 mmol) containing 4 M HCl. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to afford ( S )-4-methyl-2-methylamino-pentanoic acid (2.14 g), which was used as such in the next step.
步驟 2 ：向含(
S)-4-甲基-2-甲基胺基-戊酸(1.59 g，11 mmol)及Na
2CO
3(4.08 g，38.5 mmol)之二㗁烷/H
2O 3/5 (48 mL)中添加氯甲酸烯丙酯(1.27 mL，11.6 mmol)。在室溫攪拌混合物隔夜，接著反應混合物用EtOAc稀釋且使用2 M HCl水溶液酸化至pH 2。分離各層，且水層用EtOAc (2×)萃取。經合併之有機層經乾燥(Na
2SO
4)，過濾且濃縮，得到
D2-3.1(2.5 g，99%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.80 min；[M+H]
+= 230.43。
Step 2 : Add ( S )-4-methyl-2-methylamino-pentanoic acid (1.59 g, 11 mmol) and Na 2 CO 3 (4.08 g, 38.5 mmol) to dioxane/H 2 O To 3/5 (48 mL) was added allyl chloroformate (1.27 mL, 11.6 mmol). The mixture was stirred at room temperature overnight, then the reaction mixture was diluted with EtOAc and acidified to pH 2 using 2 M aqueous HCl. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated to afford D2-3.1 (2.5 g, 99%) which was used as such in the next step. LC-MS B: tR = 0.80 min; [M+H] + = 230.43.
中間物intermediate
(2-(三級丁氧基)乙基)甘胺酸苯甲酯(IM-1.1) 向2-(三級丁氧基)乙-1-胺(493 mg，4 mmol)於MeCN (3 mL)中之溶液中逐滴添加溴乙酸苯甲酯(0.165 mL，1 mmol)於MeCN (2 mL)中之溶液，且在室溫攪拌反應混合物50 min。過濾出沈澱，且藉由製備型HPLC (鹼性)直接純化濾液，得到呈無色油狀之
IM-1.1(214 mg，81%)。LC-MS I：t
R= 0.93 min；[M+H]
+= 266.25。
(2-(tertiary butoxy)ethyl)benzyl glycinate (IM-1.1) to 2-(tertiary butoxy)ethan-1-amine (493 mg, 4 mmol) in MeCN (3 A solution of benzyl bromoacetate (0.165 mL, 1 mmol) in MeCN (2 mL) was added dropwise to a solution in mL) and the reaction mixture was stirred at room temperature for 50 min. The precipitate was filtered off and the filtrate was directly purified by preparative HPLC (basic) to afford IM-1.1 (214 mg, 81%) as a colorless oil. LC-MS I: tR = 0.93 min; [M+H] + = 266.25.
下表IM-1中列舉類似於上文對於
IM-1.1描述之方法，由對應起始材料製備之中間物。
表IM-1
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
IM-1.2 C-(3-甲基-四氫-呋喃-3-基)-甲胺
(
R)-((3-甲基四氫呋喃-3-基)甲基)甘胺酸苯甲酯
0.82
I
264.21
IM-1.3 1-(3,4-二氫-2
H-𠳭唏-3-基)甲胺
外消旋-(
R)-(𠳭唍-3-基甲基)甘胺酸苯甲酯
1.03
I
312.23
IM-1.4 2-{7-氧雜雙環[2.2.1]庚-2-基}乙-1-胺
(2-(7-氧雜雙環[2.2.1]庚-2-基)乙基)甘胺酸苯甲酯
0.82
I
289.97
IM-1.5 2-{5-氧雜螺[3.4]辛-6-基}乙-1-胺
(2-(5-氧雜螺[3.4]辛-6-基)乙基)甘胺酸苯甲酯
0.99
I
304.21
IM-1.6 2-(氧雜環戊烷-2-基)乙-1-胺
(2-(四氫呋喃-2-基)乙基)甘胺酸苯甲酯
0.81
I
264.23
IM-1.7 2-(㗁烷-3-基)乙-1-胺
(2-(四氫-2
H-哌喃-3-基)乙基)甘胺酸苯甲酯
0.85
I
278.24
IM-1.8 2-{2,9-二氧雜螺[5.5]十一烷-3-基}乙-1-胺
(2-(2,9-二氧雜螺[5.5]十一烷-3-基)乙基)甘胺酸苯甲酯
0.87
I
348.22
IM-1.9 1,4-二㗁烷-2-甲胺.鹽酸
((1,4-二㗁烷-2-基)甲基)甘胺酸苯甲酯
0.71
I
266.16
IM-1.10 2-(四氫哌喃-2-基)乙胺.鹽酸
(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸苯甲酯
0.90
I
278.21
IM-1.11 2-(3-甲氧基環丁基)乙-1-胺
(2-(3-甲氧基環丁基)乙基)甘胺酸苯甲酯
0.88
I
278.20
IM-1.12 2-環己基乙胺
(2-環己基乙基)甘胺酸苯甲酯
1.19
I
276.26
IM-1.13 (四氫-2
H-哌喃-3-基)甲胺
((四氫-2
H-哌喃-3-基)甲基)甘胺酸苯甲酯
0.81
I
264.33
IM-1.14 (6,6-二甲基四氫-2H-哌喃-2-基)甲胺
[(6,6-二甲基-四氫-哌喃-2-基甲基)-胺基]-乙酸苯甲酯
1.02
I
292.32
IM-1.15 AM-1.72
(3-苯基丙基)甘胺酸苯甲酯
2.18
J
284.2
IM-1.16 AM-1.75
((2,3-二氫苯并呋喃-2-基)甲基)甘胺酸苯甲酯
0.99
I
298.29
Listed in Table IM-1 below are intermediates prepared from the corresponding starting materials analogously to the methods described above for IM-1.1 . Table IM-1 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
IM-1.2 C-(3-Methyl-tetrahydro-furan-3-yl)-methylamine ( R )-((3-methyltetrahydrofuran-3-yl)methyl)glycine benzyl ester 0.82I 264.21
IM-1.3 1-(3,4-Dihydro-2 H- 𠳭-3-yl)methylamine rac-( R )-(𠳭唍-3-ylmethyl)glycinate benzyl ester 1.03 I 312.23
IM-1.4 2-{7-oxabicyclo[2.2.1]hept-2-yl}ethan-1-amine (2-(7-Oxabicyclo[2.2.1]hept-2-yl)ethyl)glycine benzyl ester 0.82I 289.97
IM-1.5 2-{5-oxaspiro[3.4]oct-6-yl}ethan-1-amine Benzyl (2-(5-oxaspiro[3.4]oct-6-yl)ethyl)glycine 0.99 I 304.21
IM-1.6 2-(oxolan-2-yl)ethan-1-amine (2-(tetrahydrofuran-2-yl)ethyl)glycine benzyl ester 0.81I 264.23
IM-1.7 2-(Oxan-3-yl)ethan-1-amine (2-(Tetrahydro- 2H -pyran-3-yl)ethyl)glycine benzyl ester 0.85I 278.24
IM-1.8 2-{2,9-Dioxaspiro[5.5]undec-3-yl}ethan-1-amine Benzyl (2-(2,9-dioxaspiro[5.5]undec-3-yl)ethyl)glycine 0.87I 348.22
IM-1.9 1,4-Dioxane-2-methylamine. Hydrochloric acid ((1,4-Dioxan-2-yl)methyl)glycine benzyl ester 0.71I 266.16
IM-1.10 2-(Tetrahydropyran-2-yl)ethylamine. Hydrochloric acid (2-(Tetrahydro- 2H -pyran-2-yl)ethyl)glycine benzyl ester 0.90I 278.21
IM-1.11 2-(3-Methoxycyclobutyl)ethan-1-amine (2-(3-Methoxycyclobutyl)ethyl)glycine benzyl ester 0.88 I 278.20
IM-1.12 2-cyclohexylethylamine (2-Cyclohexylethyl)benzyl glycinate 1.19 I 276.26
IM-1.13 (Tetrahydro-2 H -pyran-3-yl)methylamine ((Tetrahydro- 2H -pyran-3-yl)methyl)glycine benzyl ester 0.81I 264.33
IM-1.14 (6,6-Dimethyltetrahydro-2H-pyran-2-yl)methanamine [(6,6-Dimethyl-tetrahydro-pyran-2-ylmethyl)-amino]-benzyl acetate 1.02 I 292.32
IM-1.15 AM-1.72 (3-Phenylpropyl)benzylglycine 2.18J 284.2
IM-1.16 AM-1.75 ((2,3-Dihydrobenzofuran-2-yl)methyl)glycine benzyl ester 0.99 I 298.29
(
S)-((四氫-2
H-哌喃-2-基)甲基)甘胺酸苯甲酯(IM-2.1)
步驟 1 ：向四氫哌喃-2-甲醇(6.0 g，50.1 mmol)於THF (300 mL)中之0℃溶液中添加NaH (於礦物油中之60%分散液，2.41 g，60.1 mmol)。將反應混合物升溫至室溫，且在攪拌30 min之後，添加溴甲苯(7.29 mL，60.1 mmol)，且在室溫攪拌混合物隔夜。添加NH
4Cl飽和水溶液，且混合物用EtOAc (2×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (庚烷/EtOAc 1:0至9:1)純化，得到呈無色油狀之外消旋-2-((苯甲氧基)甲基)四氫-2
H-哌喃(10.3 g，100%)。
( S )-((Tetrahydro- 2H -pyran-2-yl)methyl)glycine benzyl ester (IM-2.1) Step 1 : To tetrahydropyran-2-methanol (6.0 g, 50.1 mmol) in THF (300 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 2.41 g, 60.1 mmol). The reaction mixture was warmed to room temperature, and after stirring for 30 min, bromotoluene (7.29 mL, 60.1 mmol) was added, and the mixture was stirred at room temperature overnight. Sat. aq. NH4Cl was added, and the mixture was extracted with EtOAc (2x). The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (heptane/EtOAc 1:0 to 9:1) gave rac-2-((benzyloxy)methyl)tetrahydro- 2H -pyran (10.3 g, 100%).
步驟 2 ：對掌性分離，得到(
R)-2-((苯甲氧基)甲基)四氫-2
H-哌喃及(
S)-2-((苯甲氧基)甲基)四氫-2
H-哌喃，其按原樣用於下一步驟。藉由旋光性指定組態。
Step 2 : Chiral separation to obtain ( R )-2-((benzyloxy)methyl)tetrahydro- 2H -pyran and ( S )-2-((benzyloxy)methyl) Tetrahydro- 2H -pyran, which was used as such in the next step. Configuration is specified by optical activity.
步驟 3 ：向(
S)-2-((苯甲氧基)甲基)四氫-2
H-哌喃(4.92 g，23.9 mmol)於MeOH (100 mL)中之室溫溶液中添加10% Pd/C (2.54 g，2.39 mmol)，且在H
2氛圍下在室溫攪拌反應混合物3 h。過濾反應混合物且減壓濃縮濾液。藉由Kugelrohr蒸餾純化，得到呈無色油狀之(
S)-(四氫-2
H-哌喃-2-基)甲醇(2.54 g，92%)。
Step 3 : To a room temperature solution of ( S )-2-((benzyloxy)methyl)tetrahydro- 2H -pyranan (4.92 g, 23.9 mmol) in MeOH (100 mL) was added 10% Pd/C (2.54 g, 2.39 mmol), and the reaction mixture was stirred at room temperature under H 2 atmosphere for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by Kugelrohr distillation afforded ( S )-(tetrahydro- 2H -pyran-2-yl)methanol (2.54 g, 92%) as a colorless oil.
步驟 4 ：向H-Gly-OBzl HCl (6.11 g，30 mmol)及TEA (8.77 mL，63 mmol)於DCM (45 mL)中之0℃溶液中逐份添加2-硝基苯磺醯氯(7.54 g，33 mmol)。將混合物升溫至室溫且攪拌1 h。濃縮反應混合物，接著向殘餘物中添加EtOAc及水。分離各層，且用EtOAc萃取水層。經合併之有機層經乾燥(MgSO
4)，過濾且濃縮。藉由FC (庚烷/EtOAc 0:1至1:1)純化，得到呈白色固體狀之((2-硝基苯基)磺醯基)甘胺酸苯甲酯(10.56 g，100%)。LC-MS B：t
R= 0.93 min；[M+H]
+= 351.26。
Step 4 : To a solution of H-Gly-OBzl HCl (6.11 g, 30 mmol) and TEA (8.77 mL, 63 mmol) in DCM (45 mL) at 0 °C was added portionwise 2-nitrobenzenesulfonyl chloride ( 7.54 g, 33 mmol). The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated, then EtOAc and water were added to the residue. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined org. layers were dried ( MgSO4 ), filtered and concentrated. Purification by FC (heptane/EtOAc 0:1 to 1:1) gave ((2-nitrophenyl)sulfonyl)glycine benzyl ester (10.56 g, 100%) as a white solid . LC-MS B: tR = 0.93 min; [M+H] + = 351.26.
步驟 5 ：向((2-硝基苯基)磺醯基)甘胺酸苯甲酯(1.75 g，5 mmol)、(
S)-2-((苯甲氧基)甲基)四氫-2
H-哌喃(639 mg，5.5 mmol)及PPh
3(1.66 g，6 mmol)於THF (50 mL)中之室溫溶液中添加DIAD (1 mL，5 mmol)，且攪拌反應混合物1 h。濃縮反應混合物且藉由製備型HPLC (鹼性)直接純化，得到呈淡淺棕色油狀之(
S)-
N-(2-(
N-(2-(苯甲氧基)-2-側氧基乙基)-
N-((四氫-2
H-哌喃-2-基)甲基)胺磺醯基)苯基)-
N-側氧基羥基銨(2.1 g，94%)。LC-MS I：t
R= 1.11 min；[M+H]
+= 449.12。
Step 5 : To ((2-nitrophenyl)sulfonyl)glycine benzyl ester (1.75 g, 5 mmol), ( S )-2-((benzyloxy)methyl)tetrahydro- To a room temperature solution of 2 H -pyran (639 mg, 5.5 mmol) and PPh 3 (1.66 g, 6 mmol) in THF (50 mL) was added DIAD (1 mL, 5 mmol), and the reaction mixture was stirred for 1 h . The reaction mixture was concentrated and directly purified by preparative HPLC (basic) to afford ( S ) -N- (2-( N- (2-(benzyloxy)-2-oxo) as light brown oil Ethyl) -N -((tetrahydro- 2H -pyran-2-yl)methyl)sulfamoyl)phenyl) -N -oxohydroxyl ammonium (2.1 g, 94%). LC-MS I: tR = 1.11 min; [M+H] + = 449.12.
步驟 6 ：向(
S)-
N-(2-(
N-(2-(苯甲氧基)-2-側氧基乙基)-
N-((四氫-2
H-哌喃-2-基)甲基)胺磺醯基)苯基)-
N-側氧基羥基銨(2.10 g，4.69 mmol)及K
2CO
3(992 mg，7.03 mmol)於DMF (25 mL)中之室溫懸浮液中添加硫酚(0.681 mL，6.56 mmol)。在室溫攪拌反應混合物1 h，接著過濾出固體，且濃縮濾液並藉由製備型HPLC (鹼性)純化，得到呈無色油狀之
IM-2.1(976 mg，79%)。LC-MS I：t
R= 0.88 min；[M+H]
+= 264.22。
Step 6 : To ( S ) -N- (2-( N- (2-(benzyloxy)-2-oxoethyl) -N -((tetrahydro- 2H -pyran-2- (yl)methyl)sulfamoyl)phenyl) -N -oxohydroxyl ammonium (2.10 g, 4.69 mmol) and K 2 CO 3 (992 mg, 7.03 mmol) in DMF (25 mL) at room temperature To the suspension was added thiophenol (0.681 mL, 6.56 mmol). The reaction mixture was stirred at room temperature for 1 h, then the solid was filtered off, and the filtrate was concentrated and purified by preparative HPLC (basic) to afford IM-2.1 (976 mg, 79%) as a colorless oil. LC-MS I: tR = 0.88 min; [M+H] + = 264.22.
下表IM-2中列舉類似於對於
IM-2.1所描述之順序製備之中間物。
表IM-2
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
IM-2.2 (
R)-(四氫-2
H-哌喃-2-基)甲醇
(參見
IM-2.1步驟1至3)
(R)-((四氫-2
H-哌喃-2-基)甲基)甘胺酸苯甲酯
0.88
I
264.21
IM-2.3 (S)-2-(四氫-2
H-哌喃-2-基)乙-1-醇
(類似於
IM-2.1步驟1至3合成)
(S)-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸苯甲酯
0.90
I
278.24
IM-2.4 (R)-2-(四氫-2
H-哌喃-2-基)乙-1-醇
(類似於
IM-2.1步驟1至3合成)
(R)-(2-(四氫-2
H-哌喃-2-基)乙基)甘胺酸苯甲酯
0.90
I
278.25
IM-2.5 (S)-𠳭唍-3-基甲醇
(S)-(𠳭唍-3-基甲基)甘胺酸苯甲酯
1.05
I
312.23
IM-2.6 (R)-𠳭唍-3-基甲醇
(R)-(𠳭唍-3-基甲基)甘胺酸苯甲酯
1.05
I
312.25
Intermediates prepared in a sequence similar to that described for IM-2.1 are listed in Table IM-2 below. Table IM-2 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
IM-2.2 ( R )-(tetrahydro- 2H -pyran-2-yl)methanol (see IM-2.1 steps 1 to 3) (R)-((Tetrahydro-2 H -pyran-2-yl)methyl)glycine benzyl ester 0.88 I 264.21
IM-2.3 (S)-2-(tetrahydro- 2H -pyran-2-yl)ethan-1-ol (synthesized similarly to IM-2.1 steps 1 to 3) (S)-(2-(Tetrahydro-2 H -pyran-2-yl)ethyl)glycine benzyl ester 0.90I 278.24
IM-2.4 (R)-2-(tetrahydro- 2H -pyran-2-yl)ethan-1-ol (synthesized similarly to IM-2.1 steps 1 to 3) (R)-(2-(Tetrahydro-2 H -pyran-2-yl)ethyl)glycine benzyl ester 0.90I 278.25
IM-2.5 (S)-𠳭唍-3-ylmethanol (S)-(𠳭唍-3-ylmethyl)glycine benzyl ester 1.05 I 312.23
IM-2.6 (R)-𠳭唍-3-ylmethanol (R)-(𠳭唍-3-ylmethyl)glycine benzyl ester 1.05 I 312.25
甲基-D-苯基丙胺酸甲酯(IM-3.1).
步驟 1 ：向Boc-D-Phe-OH (458 mg，1.73 mmol)於DMF (8 mL)中之0℃溶液中添加NaH (於礦物油中之60%分散液，265 mg，6.92 mmol)，接著添加MeI (0.05 mL，0.8 mmol)，且將反應混合物升溫至室溫隔夜。蒸發溶劑，且藉由FC純化粗產物，得到
N-(三級丁氧基羰基)-
N-甲基-D-苯基丙胺酸甲酯。
Methyl-D-phenylalanine methyl ester (IM-3.1). Step 1 : To a solution of Boc-D-Phe-OH (458 mg, 1.73 mmol) in DMF (8 mL) at 0 °C was added NaH ( 60% dispersion in mineral oil, 265 mg, 6.92 mmol), then MeI (0.05 mL, 0.8 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The solvent was evaporated and the crude product was purified by FC to give N- (tert-butoxycarbonyl) -N -methyl-D-phenylalanine methyl ester.
步驟 2 ：向
N-(三級丁氧基羰基)-
N-甲基-D-苯基丙胺酸甲酯(200 mg，0.682 mmol)於DCM (3 mL)中之0℃溶液中添加含4 M HCl之二㗁烷(0.24 mL，0.682 mmol)，且在室溫攪拌混合物2 h。真空濃縮反應混合物，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 0.46 min；[M+H]
+= 194.21。
Step 2 : To a 0°C solution of N- (tertiary butoxycarbonyl) -N -methyl-D-phenylalanine methyl ester (200 mg, 0.682 mmol) in DCM (3 mL) was added 4 M HCl bisoxane (0.24 mL, 0.682 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound as a white solid. LC-MS B: tR = 0.46 min; [M+H] + = 194.21.
下表IM-3中列舉類似於上文對於
IM-3.1描述之順序，由對應起始材料製備之中間物。
表IM-3
編號 SM 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
IM-3.2 Boc-β-環己基-D-丙胺酸單水合物
(R)-3-環己基-2-(甲基胺基)丙酸甲酯
0.58
B
200.39
IM-3.3 Boc-D-環戊基-甘胺酸
(R)-2-環戊基-2-(甲基胺基)乙酸甲酯(鹽酸鹽)
0.45
B
172.00
Listed in Table IM-3 below are intermediates prepared from the corresponding starting materials in analogy to the sequence described above for IM-3.1 . Table IM-3 serial number SM product t R [min] LC-MS method MS- data m/z [M+H] +
IM-3.2 Boc-β-cyclohexyl-D-alanine monohydrate (R)-3-Cyclohexyl-2-(methylamino)propionic acid methyl ester 0.58 B 200.39
IM-3.3 Boc-D-cyclopentyl-glycine (R)-2-Cyclopentyl-2-(methylamino)acetic acid methyl ester (hydrochloride) 0.45 B 172.00
3,3-二氟-1-甲基胺基-環丁烷甲酸甲酯(IM-4.1)
步驟 1 ：向1-{[(三級丁氧基)羰基](甲基)胺基}-3,3-二氟環丁烷-1-甲酸(100 mg，0.36 mmol)於MeOH (1 mL)中之0℃溶液中添加含2.0 M (三甲基矽基)重氮甲烷之Et
2O (0.27 mL，0.54 mmol)。將反應混合物升溫至室溫且繼續攪拌6 h。濃縮反應混合物且藉由FC (庚烷/EtOAc 4:1)純化，得到呈透明油狀之1-((三級丁氧基羰基)(甲基)胺基)-3,3-二氟環丁烷-1-甲酸甲酯(52 mg，52%)。LC-MS I：t
R= 0.98 min；[M+H]
+= 280.25。
3,3-Difluoro-1-methylamino-cyclobutanecarboxylic acid methyl ester (IM-4.1) step 1 : to 1-{[(tertiary butoxy)carbonyl](methyl)amino}- To a solution of 3,3-difluorocyclobutane-1-carboxylic acid (100 mg, 0.36 mmol) in MeOH (1 mL) at 0 °C was added 2.0 M (trimethylsilyl)diazomethane in Et2O (0.27 mL, 0.54 mmol). The reaction mixture was warmed to room temperature and stirring was continued for 6 h. The reaction mixture was concentrated and purified by FC (heptane/EtOAc 4:1) to give 1-((tertiary butoxycarbonyl)(methyl)amino)-3,3-difluorocyclo as a clear oil Butane-1-carboxylic acid methyl ester (52 mg, 52%). LC-MS I: tR = 0.98 min; [M+H] + = 280.25.
步驟 2 ：按照
IM-3.1步驟2中描述之程序，由1-((三級丁氧基羰基)(甲基)胺基)-3,3-二氟環丁烷-1-甲酸甲酯製備標題化合物
IM-4.1。LC-MS I：t
R= 0.57 min；[M+H]
+= 180.31。
Step 2 : Prepared from methyl 1-((tertiary butoxycarbonyl)(methyl)amino)-3,3-difluorocyclobutane-1-carboxylate following the procedure described in IM-3.1 Step 2 Title compound IM-4.1 . LC-MS I: tR = 0.57 min; [M+H] + = 180.31.
2((2-硝基苯)磺醯胺基)乙酸(IM-5.1) 向甘胺酸(1.89 g，25 mmol)及32% NaOH水溶液(5 mL，50 mmol)於H
2O (20 mL)中之60℃溶液中逐份添加2-硝基苯磺醯氯(5.71 g，25 mmol)。在完成添加之後，在60℃攪拌反應混合物30 min，之後冷卻至0℃。混合物用濃HCl酸化至pH 1，且藉由過濾分離所形成沈澱，得到呈白色固體狀之
IM-5.1(4.34 g，67%)。LC-MS B：t
R= 0.6 min；[M+H]
+= 261.25。
2((2-nitrophenyl)sulfonylamino)acetic acid (IM-5.1) to glycine (1.89 g, 25 mmol) and 32% NaOH aqueous solution (5 mL, 50 mmol) in H 2 O (20 mL ) was added 2-nitrobenzenesulfonyl chloride (5.71 g, 25 mmol) in portions at 60 °C. After complete addition, the reaction mixture was stirred at 60 °C for 30 min before cooling to 0 °C. The mixture was acidified to pH 1 with concentrated HCl, and the formed precipitate was isolated by filtration to afford IM-5.1 (4.34 g, 67%) as a white solid. LC-MS B: tR = 0.6 min; [M+H] + = 261.25.
市售 磺醯氯表SCI
磺醯氯 名稱
SCl-1 苯磺醯氯
SCl-2 吡啶-3-磺醯氯
SCl-3 吡啶-2-磺醯氯
SCl-4 吡啶-4-磺醯氯
SCl-5 3-甲氧基苯磺醯氯
SCl-6 3-(三氟甲氧基)苯磺醯氯
SCl-7 2-氟-5-甲氧基苯磺醯氯
SCl-8 5-甲氧基吡啶-3-磺醯氯
SCl-9 4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁 𠯤-7-磺醯氯
SCl-10 2-側氧基-2,3-二氫苯并[d]㗁唑-6-磺醯氯
SCl-11 苯基甲烷磺醯氯
SCl-12 喹啉-7-基甲烷磺醯氯
SCl-13 甲烷磺醯氯
SCl-14 2-甲氧基乙烷-1-磺醯氯
SCl-15 3-甲氧基丙烷-1-磺醯氯
SCl-16 2-(二甲基胺基)乙烷-1-磺醯氯
SCl-17 四氫-2H-哌喃-4-磺醯氯
SCl-18 (四氫-2H-哌喃-4-基)甲烷磺醯氯
SCl-19 2-(N-𠰌啉基)乙烷-1-磺醯氯
SCl-20 3-(N-𠰌啉基)丙烷-1-磺醯氯
Commercially available sulfonyl chloride form SCI Sulfonyl chloride name
SCl-1 Benzenesulfonyl chloride
SCl-2 Pyridine-3-sulfonyl chloride
SCl-3 Pyridine-2-sulfonyl chloride
SCl-4 Pyridine-4-sulfonyl chloride
SCl-5 3-Methoxybenzenesulfonyl chloride
SCl-6 3-(Trifluoromethoxy)benzenesulfonyl chloride
SCl-7 2-Fluoro-5-methoxybenzenesulfonyl chloride
SCl-8 5-Methoxypyridine-3-sulfonyl chloride
SCl-9 4-Methyl-3,4-dihydro-2H-benzo[b][1,4]㗁𠯤-7-sulfonyl chloride
SCl-10 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride
SCl-11 Phenylmethanesulfonyl chloride
SCl-12 Quinolin-7-ylmethanesulfonyl chloride
SCl-13 Methanesulfonyl chloride
SCl-14 2-Methoxyethane-1-sulfonyl chloride
SCl-15 3-Methoxypropane-1-sulfonyl chloride
SCl-16 2-(Dimethylamino)ethane-1-sulfonyl chloride
SCl-17 Tetrahydro-2H-pyran-4-sulfonyl chloride
SCl-18 (Tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride
SCl-19 2-(N-𠰌linyl)ethane-1-sulfonyl chloride
SCl-20 3-(N-𠰌linyl)propane-1-sulfonyl chloride
攜帶carry
羧酸carboxylic acid
基團之巨環之合成Synthesis of radical macrocycles
(9
S,13
S,19a
R,22
R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16
H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲酸(MC-COOH-1)
步驟 1 ：向
B-1.14(5.0 g，10.3 mmol)、
C-2.2(3.67 g，10.3 mmol)及DIPEA (5.29 mL，30.9 mmol)於DMF (100 mL)中之室溫溶液中添加HATU (4.12 g，10.3 mmol)。在室溫攪拌所得混合物10 min，接著將混合物分配於水與EtOAc之間。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(MgSO
4)，過濾且蒸發，得到呈白色固體狀之3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-甲酸苯甲酯(8.78 g，114%)，其按原樣用於下一步驟。LC-MS I：t
R= 1.43 min；[M+H]
+= 751.46。
(9 S ,13 S ,19a R ,22 R )-22-benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9, 10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro- 16H -pyrido[2',1':6,7][1]oxygen Hetero[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxylic acid (MC-COOH-1) Step 1 : Add HATU ( 4.12 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 10 min, then the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried ( MgSO4 ), filtered and evaporated to give 3-[( R )-2-({( R )-1-[( S )-2 as a white solid -(tertiary butoxycarbonyl-methyl-amino)-4-methyl-pentyl]-piperidine-2-carbonyl}-amino)-3-phenyl-propoxy]-quinoline - Benzyl 4-carboxylate (8.78 g, 114%), which was used as such in the next step. LC-MS I: tR = 1.43 min; [M+H] + = 751.46.
步驟 2 ：在添加Pd/C (604 mg，0.567 mmol)之前，將3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-甲酸苯甲酯(8.79 g，11.3 mmol)於EtOH (100 mL)中之室溫溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌18 h。過濾反應混合物，且用EtOH沖洗濾餅。濃縮濾液，得到呈灰白色固體狀之3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-甲酸(7.81 g，104%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.68 min；[M+H]
+= 661.20。
Step 2 : Before adding Pd/C (604 mg, 0.567 mmol), 3-[( R )-2-({( R )-1-[( S )-2-(tertiary butoxycarbonyl- Methyl-amino)-4-methyl-pentyl]-piperidine-2-carbonyl}-amino)-3-phenyl-propoxy]-quinoline-4-carboxylic acid benzyl ester (8.79 g, 11.3 mmol) in EtOH (100 mL) at room temperature was evacuated/sparged with N2 (3x). The reaction mixture was evacuated/flushed with H2 (3x) and stirred under H2 atmosphere for 18 h. The reaction mixture was filtered, and the filter cake was rinsed with EtOH. The filtrate was concentrated to afford 3-[( R )-2-({( R )-1-[( S )-2-(tertiary butoxycarbonyl-methyl-amino)-4- Methyl-pentyl]-piperidine-2-carbonyl}-amino)-3-phenyl-propoxy]-quinoline-4-carboxylic acid (7.81 g, 104%), which was used as such in the following one step. LC-MS I: tR = 0.68 min; [M+H] + = 661.20.
步驟 3 ：向Fmoc-L-天冬胺酸β-三級丁酯(10.0 g，23.8 mmol)及KHCO
3(2.65 g，26.2 mmol)於DMF (60 mL)中之室溫溶液中添加溴甲苯(3.46 mL，28.6 mmol)，且在室溫攪拌所得混合物18 h。濃縮混合物，且向殘餘物中添加EtOAc及水。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機層用水及鹽水洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色粉末狀之(
S)-2-(9
H-茀-9-基甲氧基羰基胺基)-丁二酸1-苯甲酯4-三級丁酯(12.21 g，102%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.19 min；[M+H]
+= 502.28。
Step 3 : To a room temperature solution of Fmoc-L-aspartic acid β-tert-butyl ester (10.0 g, 23.8 mmol) and KHCO3 (2.65 g, 26.2 mmol) in DMF (60 mL) was added bromotoluene (3.46 mL, 28.6 mmol), and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated, and to the residue were added EtOAc and water. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried (MgSO 4 ), filtered and concentrated to give ( S )-2-( 9H -tertil-9-ylmethoxycarbonylamino)- as a white powder 1-Benzyl 4-tert-butyl succinate (12.21 g, 102%) which was used as such in the next step. LC-MS B: tR = 1.19 min; [M+H] + = 502.28.
步驟 4 ：向(S)-2-(9
H-茀-9-基甲氧基羰基胺基)-丁二酸1-苯甲酯4-三級丁酯(12.21 g，23.6 mmol)於DCM (150 mL)中之室溫溶液中添加哌啶(11.8 mL，118 mmol)。在室溫攪拌所得混合物2 h。在40℃真空濃縮混合物，得到白色固體，其用庚烷濕磨。過濾出固體且藉由FC (用10%至100% EtOAc/庚烷溶離)純化，得到呈淺黃色油狀之(
S)-2-胺基-丁二酸1-苯甲酯4-三級丁酯(5.44 g，82%)。LC-MS B：t
R= 0.68 min；[M+H]
+= 280.36。
Step 4 : Add (S)-2-( 9H -tertil-9-ylmethoxycarbonylamino)-succinic acid 1-benzyl 4-tert-butyl ester (12.21 g, 23.6 mmol) in DCM To a room temperature solution in (150 mL) was added piperidine (11.8 mL, 118 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo at 40 °C to give a white solid which was triturated with heptane. The solid was filtered off and purified by FC (eluting with 10% to 100% EtOAc/heptane) to afford ( S )-2-amino-succinic acid 1-benzyl ester 4-tert as a pale yellow oil Butyl ester (5.44 g, 82%). LC-MS B: tR = 0.68 min; [M+H] + = 280.36.
步驟 5 ：向3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-甲酸(6.63 g，9.03 mmol)、(
S)-2-胺基-丁二酸1-苯甲酯4-三級丁酯(2.55 g，9.03 mmol)及DIPEA (4.64 mL，27.1 mmol)於DMF (100 mL)中之室溫溶液中添加HATU (3.61 g，9.03 mmol)。在室溫攪拌所得混合物1 h，接著將混合物分配於水與EtOAc之間。分離各層，且水層用EtOAc (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經乾燥(MgSO
4)，過濾且蒸發，得到呈粉色固體狀之(
S)-2-({3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-羰基}-胺基)-丁二酸1-苯甲酯4-三級丁酯(7.54 g)，其按原樣用於下一步驟。LC-MS I：t
R= 1.44 min；[M+H]
+= 922.70。
Step 5 : To 3-[( R )-2-({( R )-1-[( S )-2-(tertiary butoxycarbonyl-methyl-amino)-4-methyl-pentanoyl Base]-piperidine-2-carbonyl}-amino)-3-phenyl-propoxy]-quinoline-4-carboxylic acid (6.63 g, 9.03 mmol), ( S )-2-amino-butanedi To a room temperature solution of 1-benzyl acid 4-tert-butyl ester (2.55 g, 9.03 mmol) and DIPEA (4.64 mL, 27.1 mmol) in DMF (100 mL) was added HATU (3.61 g, 9.03 mmol). The resulting mixture was stirred at room temperature for 1 h, then the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried ( MgSO4 ), filtered and evaporated to give ( S )-2-({3-[( R )-2-({( R )- 1-[( S )-2-(tertiary butoxycarbonyl-methyl-amino)-4-methyl-pentyl]-piperidine-2-carbonyl}-amino)-3-phenyl -propoxy]-quinoline-4-carbonyl}-amino)-1-benzyl 4-tert-butyl succinate (7.54 g), which was used as such in the next step. LC-MS I: tR = 1.44 min; [M+H] + = 922.70.
步驟 6 ：向(
S)-2-({3-[(
R)-2-({(
R)-1-[(
S)-2-(三級丁氧基羰基-甲基-胺基)-4-甲基-戊醯基]-哌啶-2-羰基}-胺基)-3-苯基-丙氧基]-喹啉-4-羰基}-胺基)-丁二酸1-苯甲酯4-三級丁酯(7.54 g，5.64 mmol)於DCM (150 mL)中之室溫溶液中添加TFA (69.1 mL，897 mmol)。攪拌所得混合物3 h，接著濃縮且與DCM (2×)一起共蒸發。將殘餘物溶解於DMF (100 mL)中，且向溶液中添加DIPEA (7.72 mL，45.1 mmol)及HATU (2.57 g，6.77 mmol)。在室溫攪拌混合物1 h，接著將混合物分配於水與EtOAc之間。分離各層，且水溶液用EtOAc (2×)再萃取。經合併之有機萃取物用水(2×)及鹽水(2×)洗滌，經乾燥(MgSO
4)，過濾且蒸發。藉由FC (用100% EtOAc溶離)純化，得到呈粉色固體狀之(9
S,13
S,19a
R,22
R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16
H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲酸苯甲酯(2.45 g，58%)。LC-MS I：t
R= 1.20 min；[M+H]
+= 748.48。
Step 6 : To ( S )-2-({3-[( R )-2-({( R )-1-[( S )-2-(tertiary butoxycarbonyl-methyl-amino) -4-Methyl-pentyl]-piperidine-2-carbonyl}-amino)-3-phenyl-propoxy]-quinoline-4-carbonyl}-amino)-succinic acid 1- To a room temperature solution of benzyl 4-tert-butyl ester (7.54 g, 5.64 mmol) in DCM (150 mL) was added TFA (69.1 mL, 897 mmol). The resulting mixture was stirred for 3 h, then concentrated and co-evaporated with DCM (2x). The residue was dissolved in DMF (100 mL), and to the solution were added DIPEA (7.72 mL, 45.1 mmol) and HATU (2.57 g, 6.77 mmol). The mixture was stirred at room temperature for 1 h, then the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous re-extracted with EtOAc (2x). The combined org. extracts were washed with water (2x) and brine (2x), dried ( MgSO4 ), filtered and evaporated. Purification by FC (eluted with 100% EtOAc) afforded ( 9S , 13S , 19aR , 22R )-22-benzyl-13-isobutyl-12-methyl-7 as a pink solid ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16 H -Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxylic acid Benzyl ester (2.45 g, 58%). LC-MS I: tR = 1.20 min; [M+H] + = 748.48.
步驟 7 ：在添加Pd/C (157 mg，0.147 mmol)之前，將(9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲酸苯甲酯(2.45 g，2.95 mmol)於EtOH (25 mL)中之懸浮液抽成真空/用H
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌24 h。過濾混合物，且用EtOH沖洗濾餅。濃縮濾液且藉由FC (用4% MeOH/DCM溶離)純化，得到呈灰白色固體狀之標題化合物(1.57 g，81%)。LC-MS I：t
R= 0.54 min；[M+H]
+= 658.42。
Step 7 : Add (9S,13S,19aR,22R)-22-benzyl-13-isobutyl-12-methyl-7,11,14 before adding Pd/C (157 mg, 0.147 mmol) ,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2 ',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxylic acid benzyl ester (2.45 g, 2.95 mmol) in EtOH (25 mL) was evacuated/flushed with H2 (3x). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 24 h. The mixture was filtered, and the filter cake was rinsed with EtOH. The filtrate was concentrated and purified by FC (eluting with 4% MeOH/DCM) to afford the title compound (1.57 g, 81%) as an off-white solid. LC-MS I: tR = 0.54 min; [M+H] + = 658.42.
下表MC-COOH-A中列舉類似於上文對於
MC-COOH-1描述之7-步驟順序，由對應起始材料製備之羧酸。
表 MC-COOH-A 編號 結構 BB-B BB-C 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
MC-COOH-2 B-1.11 C-1.1 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
0.84
B
627.16
MC-COOH-3 B-2.7 C-2.2 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲酸
0.51
I
661.46
MC-COOH-4 B-1.13 C-2.1 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲酸
0.92
B
659.25
MC-COOH-5 B-1.14 C-2.1 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲酸
0.84
B
660.32
MC-COOH-6 B-1.19 C-1.2 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲酸
0.92
B
662.19
MC-COOH-7 B-1.14 C-1.2 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲酸
0.52
I
644.27
MC-COOH-15 B-1.5 C-10.19 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
0.66
I
693.46
MC-COOH-16 B-1.16 C-1.1 (4R,10S,14S)-4-苯甲基-107R,13S,17S)-7-苯甲基-13-異丁基-8,11,14-二甲基-6,9,12,1615,19-四側氧基-2,20,22-三氧雜-56,7,8,9,10,11,15-四氮雜-三環[12,13,14,15.7.0.019,23]二十四碳-1(,16,17),,18,23-三烯-14-19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸
0.45
I
610.87
MC-COOH-24 B-1.18 C-2.2 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲酸
0.54
I
638.27
MC-COOH-25 B-1.19 C-2.2 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲酸
0.55
I
676.40
MC-COOH-26 B-4.15 C-2.2 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲酸
0.52
I
652.17
MC-COOH-27 B-1.18 C-1.4 (3
R,6
R,9
S,13
S)-3-苯甲基-9-異丁基-16-甲氧基-6,7,10-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
1.66
J
612.20
MC-COOH-28 B-1.19 C-22.1 (3
S,7
S,10
R,13
R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲酸
0.97
813.14
MC-COOH-29 B-4.15 C-22.2 (3
R,6
R,9
S,13
S)-3-苯甲基-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
0.97
762.31
MC-COOH-30 B-1.19 C-5.4 (3'S,7'S,13'R)-13'-苯甲基-3,3,20'-三氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲酸
0.97
B
712.07
Carboxylic acids prepared from the corresponding starting materials are listed in Table MC-COOH-A below, analogous to the 7-step sequence described above for MC-COOH-1 . Form MC-COOH-A serial number structure BB-B BB-C product t R [min] LC-MS method MS- data m/z [M+H] +
MC-COOH-2 B-1.11 C-1.1 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-7,10-dimethyl-5,8,11,15-tetraoxo- 2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14] Tetraazacyclohexadecene-13-carboxylic acid 0.84 B 627.16
MC-COOH-3 B-2.7 C-2.2 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-5,11-dimethyl-6,10,13,19-tetraoxo-6,7,8,9 ,10,11,12,13,16,17,18,18a,19,20,21,22-Hexadecahydro-5H,15H-imidazo[4',5':5,6]benzo[1 ,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxylic acid 0.51 I 661.46
MC-COOH-4 B-1.13 C-2.1 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5, 6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxylic acid 0.92 B 659.25
MC-COOH-5 B-1.14 C-2.1 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11, 12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa [4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxylic acid 0.84 B 660.32
MC-COOH-6 B-1.19 C-1.2 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetrahydrooxy-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-Spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-carboxylic acid 0.92 B 662.19
MC-COOH-7 B-1.14 C-1.2 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-Dimethyl-1',5',8',11'-Tetraoxo -2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane- 1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-carboxylic acid 0.52I 644.27
MC-COOH-15 B-1.5 C-10.19 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7 ,10,14] Tetraazacyclohexadecene-13-carboxylic acid 0.66 I 693.46
MC-COOH-16 B-1.16 C-1.1 (4R,10S,14S)-4-Benzyl-107R,13S,17S)-7-Benzyl-13-isobutyl-8,11,14-dimethyl-6,9,12,1615 ,19-tetraaza-tricyclo[12,13,14,15.7.0.019,23 ]tetracos-1(,16,17),,18,23-triene-14-19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo [1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid 0.45I 610.87
MC-COOH-24 B-1.18 C-2.2 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6, 7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxylic acid 0.54I 638.27
MC-COOH-25 B-1.19 C-2.2 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9, 10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa [4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxylic acid 0.55I 676.40
MC-COOH-26 B-4.15 C-2.2 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5 ,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3', 4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxylic acid 0.52I 652.17
MC-COOH-27 B-1.18 C-1.4 (3 R ,6 R ,9 S ,13 S )-3-Benzyl-9-isobutyl-16-methoxy-6,7,10-trimethyl-5,8,11,15- Four-sided oxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa [4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid 1.66J 612.20
MC-COOH-28 B-1.19 C-22.1 (3 S ,7 S ,10 R ,13 R )-13-benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazole -5-yl)methyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7, 8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -3-Formic acid 0.97 813.14
MC-COOH-29 B-4.15 C-22.2 (3 R ,6 R ,9 S ,13 S )-3-Benzyl-9-isobutyl-16-methoxy-7,10,18-trimethyl-5,8,11,15- Four-sided oxy-6-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formic acid 0.97 762.31
MC-COOH-30 B-1.19 C-5.4 (3'S,7'S,13'R)-13'-Benzyl-3,3,20'-trifluoro-7'-isobutyl-6',9'-dimethyl-1',5', 8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro -1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]- 3'-Formic acid 0.97 B 712.07
(7R,13S,17S)-7-苯甲基-11-(3,3-二甲基丁基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸(MC-COOH-8)
根據用於固相合成之通用方法進行合成。使Wang樹脂(153 mg，0.135 mmol)在DMF (5 mL)中膨脹1 h。排出溶劑，且樹脂用
Fmoc-Asp(OAll)-OH(272 mg，0.675 mmol)、TBTU (214 mg，0.648 mmol)、DIPEA (0.236 mL，1.35 mmol)於DMF (3 mL)中之溶液處理3 h。藉由用20%哌啶於DMF (3 mL)中之溶液處理樹脂(2 × 5 min)進行Fmoc去保護。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。樹脂用
B- 酸 -4(394 mg，0.675 mmol)、TBTU (214 mg，0.648 mmol)、HOBt (103 mg，0.675 mmol)及DIPEA (0.236 mL，1.35 mmol)於DMF (3 mL)中之溶液處理3 h。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。藉由用20%哌啶於DMF (3 mL)中之溶液處理樹脂(2 × 5 min)進行Fmoc去保護。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。接著，樹脂用
D1-2.1(257 mg，0.675 mmol)、TBTU (214 mg，0.648 mmol)、HOBt (103 mg，0.675 mmol)及DIPEA (0.236 mL，1.35 mmol)於DMF (3 mL)中之溶液處理3 h。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。藉由用20%哌啶於DMF (3 mL)中之溶液處理樹脂(2 × 5 min)進行Fmoc去保護。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。接著，樹脂用
Fmoc-NMeLeu-OH(253 mg，0.675 mmol)、TBTU (214 mg，0.648 mmol)、HOBt (103 mg，0.675 mmol)及DIPEA (0.236 ml，1.35 mmol)於DMF (3 mL)中之溶液處理3 h。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。藉由用哌啶/DBU/DMF (1/1/48) (2 × 3 mL × 5 min)之溶液處理樹脂(2 × 5 min)進行Fmoc去保護。過濾之後，樹脂用DMF (3 × 4 mL)及DCM (3 × 4 mL)洗滌。接著，樹脂用Pd(PPh
3)
4(78 mg，0.0675 mmol)及1,3-二甲基巴比妥酸(106 mg，0.675 mmol)於THF中之溶液處理10 h。過濾之後，樹脂依次用0.5% DIPEA於DMF中之溶液(4 × 3 mL)及0.5%二乙基二硫胺基甲酸鈉於DMF中之溶液(4 × 3 mL)及最後用DMF (4 × 3 mL)洗滌。藉由用五氟二苯基亞膦酸苯酯(104 mg，0.27 mmol)於DMF/DCM (2 mL)中之溶液處理樹脂5 h進行直鏈肽之環化。最後，使用TFA於DCM中之溶液(1/1，3 mL)由樹脂裂解巨環2 h。在藉由製備型HPLC (酸性)純化粗混合物之後，得到呈白色固體狀之標題化合物
MC-COOH-8(22 mg，26%)。LC-MS D t
R= 1.03 min；[M+H]
+= 681.31。
(7R,13S,17S)-7-Benzyl-11-(3,3-dimethylbutyl)-13-isobutyl-14-methyl-9,12,15,19-tetraoxo Group-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5':4, 5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid (MC-COOH-8)
下表MC-COOH-B中列舉類似於上文對於
MC-COOH-8描述之固相合成，由對應起始材料製備之羧酸。
表 MC-COOH-B 編號 結構 SM BB-B SM BB-D1 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
MC-COOH-9 B- 酸-4 D1-2.2 (7R,13S,17S)-7-苯甲基-11-(2-環己基乙基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸
1.11
D
707.31
MC-COOH-10 B- 酸-4 D1-2.4 (7R,13S,17S)-7-苯甲基-13-異丁基-14-甲基-9,12,15,19-四側氧基-11-苯乙基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸
0.98
D
701.21
MC-COOH-11 B- 酸-4 D1-2.5 (7R,13S,17S)-7-苯甲基-11-(3-(苯甲氧基)丙基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸
1.00
D
745.31
MC-COOH-17 B- 酸-4 D1-2.6 (7R,13S,17S)-7-苯甲基-13-異丁基-14-甲基-9,12,15,19-四側氧基-11-(2-(四氫-2H-哌喃-4-基)乙基)-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸
0.84
D
709.34
Carboxylic acids prepared from the corresponding starting materials are listed in Table MC-COOH-B below in a solid phase synthesis similar to that described above for MC-COOH-8 . Form MC-COOH-B serial number structure SM BB-B SM BB-D1 product t R [min] LC-MS method MS- data m/z [M+H] +
MC-COOH-9 B- acid-4 D1-2.2 (7R,13S,17S)-7-Benzyl-11-(2-cyclohexylethyl)-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-6 ,7,8,9,10,11,12,13,14,15,16,17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzene And[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid 1.11D 707.31
MC-COOH-10 B- acid-4 D1-2.4 (7R,13S,17S)-7-Benzyl-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-11-phenylethyl-6,7,8, 9,10,11,12,13,14,15,16,17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2 -p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid 0.98D 701.21
MC-COOH-11 B- acid-4 D1-2.5 (7R,13S,17S)-7-Benzyl-11-(3-(Benzyloxy)propyl)-13-isobutyl-14-methyl-9,12,15,19-tetra Oxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5':4 ,5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid 1.00D 745.31
MC-COOH-17 B- acid-4 D1-2.6 (7R,13S,17S)-7-Benzyl-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-11-(2-(tetrahydro-2H-piper Fen-4-yl)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17,18,19-tetrahydro-[1,3]dioxo[ 4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid 0.84D 709.34
(7R,13S,17S)-7-苯甲基-13-(環丁基甲基)-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲酸(MC-COOH-12)
根據對於
MC-COOH-8所描述之固相方法，使用
B- 酸 -4製備標題化合物。用市售的
N -(((9
H-
茀 -9- 基 ) 甲氧基 ) 羰基 )-
N-
甲基甘胺酸替換
D1-2.1，
且用 Fmoc-NMeLeu-OH替換
D1-2.3。LC-MS B t
R= 0.87 min；[M+H]
+= 623.25。
(7R,13S,17S)-7-Benzyl-13-(cyclobutylmethyl)-11,14-dimethyl-9,12,15,19-tetraoxo-6,7,8,9 ,10,11,12,13,14,15,16,17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxylic acid (MC-COOH-12) The title compound was prepared using B- acid -4 according to the solid phase method described for MC-COOH-8 . D1-2.1 was replaced with commercially available N -((( 9H - fluorene -9- yl ) methoxy ) carbonyl ) -N - methylglycine and D1-2.3 was replaced with Fmoc-NMeLeu-OH . LC-MS B t R = 0.87 min; [M+H] + = 623.25.
(3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-(環丙基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸(MC-COOH-13)
步驟 1 ：向
B- 酸 -2(7.46 g，17.3 mmol)、
A-2.1(5.70 g，19 mmol)及DIPEA (11.9 mL，69.7 mmol)於DMF (80 mL)中之室溫溶液中添加HATU (7.45 g，19 mmol)，且在室溫攪拌反應混合物2 h。蒸發溶劑且藉由FC (用DCM至DCM/MeOH 9:1溶離)純化粗產物，得到(2-((R)-2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(11.71 g，100%)。LC-MS I：t
R= 1.24 min；[M+H]
+= 677.42。
(3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-(cyclopropylmethyl)-17,18-dimethoxy-10-methyl-5 ,8,11,15-Tetrahydrobenzo[p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid (MC-COOH-13) Step 1 : To a room temperature solution of B- acid -2 (7.46 g, 17.3 mmol), A-2.1 (5.70 g, 19 mmol) and DIPEA (11.9 mL, 69.7 mmol) in DMF (80 mL) was added HATU (7.45 g, 19 mmol), and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by FC (eluted with DCM to DCM/MeOH 9:1) to give (2-((R)-2-((tertiary butoxycarbonyl)amino)-3-phenyl Propoxy)-4,5-dimethoxybenzoyl)-4-allyl-L-aspartic acid 1-benzyl ester hydrochloride (11.71 g, 100%). LC-MS I: tR = 1.24 min; [M+H] + = 677.42.
步驟 2 ：向含(2-((R)-2-胺基-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(11.712 g，17.3 mmol)之DCM (135 mL)中添加含4 M HCl之二㗁烷(34.5 mL，138 mmol)。在室溫攪拌混合物4 h且蒸發，得到呈白色固體狀之(2-((R)-2-胺基-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(11.71 g，100%)，其按原樣用於下一步驟。LC-MS I：t
R= 1.07 min；[M+H]
+= 577.36。
Step 2 : Add (2-((R)-2-amino-3-phenylpropoxy)-4,5-dimethoxybenzoyl)-L-aspartic acid 4-ene Propyl ester 1-benzomethyl ester hydrochloride (11.712 g, 17.3 mmol) in DCM (135 mL) was added 4 M HCl in dioxane (34.5 mL, 138 mmol). The mixture was stirred at room temperature for 4 h and evaporated to give (2-((R)-2-amino-3-phenylpropoxy)-4,5-dimethoxybenzoyl as a white solid )-4-allyl-L-aspartate 1-benzyl ester hydrochloride (11.71 g, 100%), which was used as such in the next step. LC-MS I: tR = 1.07 min; [M+H] + = 577.36.
步驟 3 ：將
IM-5.1(639 mg，2.44 mmol)、(2-((R)-2-胺基-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(1.695 g，2.44 mmol)、HATU (956 mg，2.44 mmol)及DIPEA (2.44 mL，14.3 mmol)溶解於DMF (12 mL)中。在室溫攪拌混合物2 h。蒸發溶劑且藉由FC (用0-5% MeOH/DCM溶離)純化粗混合物，得到呈無色油狀之(4,5-二甲氧基-2-((R)-2-(2-((2-硝基苯基)磺醯胺基)乙醯胺基)-3-苯基丙氧基)苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(964 mg，48%)。LC-MS B：t
R= 1.1 min；[M+H]
+= 819.32。
Step 3 : Mix IM-5.1 (639 mg, 2.44 mmol), (2-((R)-2-amino-3-phenylpropoxy)-4,5-dimethoxybenzoyl) -L-aspartic acid 4-allyl ester 1-benzyl hydrochloride (1.695 g, 2.44 mmol), HATU (956 mg, 2.44 mmol) and DIPEA (2.44 mL, 14.3 mmol) were dissolved in DMF (12 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude mixture was purified by FC (eluted with 0-5% MeOH/DCM) to afford (4,5-dimethoxy-2-((R)-2-(2-( (2-nitrophenyl)sulfonylamino)acetamido)-3-phenylpropoxy)benzoyl)-L-aspartic acid 4-allyl ester 1-benzyl ester ( 964 mg, 48%). LC-MS B: tR = 1.1 min; [M+H] + = 819.32.
步驟 4 ：向(4,5-二甲氧基-2-((R)-2-(2-((2-硝基苯基)磺醯胺基)乙醯胺基)-3-苯基丙氧基)苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(864 mg，0.88 mmol)、2-環己基乙醇(0.136 mL，0.968 mmol)及PPh
3(267 mg，0.968 mmol)於DCM (5 mL)中之室溫溶液(經脫氣)中添加DIAD (227 mg，0.968 mmol)。在室溫攪拌反應混合物1 h，接著蒸發溶劑且藉由FC (用0%至10% EtOAc/庚烷溶離)純化粗產物，得到呈白色固體狀之(2-((R)-2-(2-((
N-(2-環己基乙基)-2-硝基苯基)磺醯胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(810 mg，89%)。LC-MS B：t
R= 1.24 min；[M+H]
+= 929.38。
Step 4 : To (4,5-dimethoxy-2-((R)-2-(2-((2-nitrophenyl)sulfonamido)acetamido)-3-phenyl Propoxy) benzoyl) -L-aspartate 4-allyl 1-benzyl ester (864 mg, 0.88 mmol), 2-cyclohexyl ethanol (0.136 mL, 0.968 mmol) and PPh 3 ( To a room temperature solution (degassed) of 267 mg, 0.968 mmol) in DCM (5 mL) was added DIAD (227 mg, 0.968 mmol). The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the crude product was purified by FC (eluted with 0% to 10% EtOAc/heptane) to afford (2-((R)-2-( 2-((( N- (2-cyclohexylethyl)-2-nitrophenyl)sulfonamido)acetamido)-3-phenylpropoxy)-4,5-dimethoxy Benzoyl)-4-allyl-L-aspartate 1-benzyl ester (810 mg, 89%). LC-MS B: tR = 1.24 min; [M+H] + = 929.38.
步驟 5 ：向(2-((R)-2-(2-((
N-(2-環己基乙基)-2-硝基苯基)磺醯胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(811 mg，0.8 mmol)及硫酚(0.116 mL，1.12 mmol)於DMF (4 mL)中之室溫溶液中添加K
2CO
3(169 mg，1.2 mmol)。在室溫攪拌反應混合物1 h，接著蒸發溶劑且藉由製備型HPLC (鹼性)純化粗產物，得到呈無色油狀之(2-((R)-2-(2-((2-環己基乙基)胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(665 mg，112%)。LC-MS B：t
R= 0.99 min；[M+H]
+= 744.41。
Step 5 : To (2-((R)-2-(2-(( N- (2-cyclohexylethyl)-2-nitrophenyl)sulfonamido)acetamido)-3- Phenylpropoxy)-4,5-dimethoxybenzoyl)-L-aspartate 4-allyl 1-benzyl ester (811 mg, 0.8 mmol) and thiophenol (0.116 mL , 1.12 mmol) in DMF (4 mL ) was added K2CO3 (169 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the crude product was purified by preparative HPLC (basic) to afford (2-((R)-2-(2-((2-cyclo Hexylethyl)amino)acetamido)-3-phenylpropoxy)-4,5-dimethoxybenzoyl)-L-aspartic acid 4-allyl ester 1-phenyl Methyl ester (665 mg, 112%). LC-MS B: tR = 0.99 min; [M+H] + = 744.41.
步驟 6 ：向(2-((R)-2-(2-((2-環己基乙基)胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(133 mg，0.098 mmol)、
D2-1.4(28.6 mg，0.117 mmol)及DIPEA (0.0934 mL，0.545 mmol)於DMF (2 mL)中之室溫溶液中添加HATU (42.2 mg，0.108 mmol)。在室溫攪拌反應混合物1 h，接著蒸發溶劑且藉由製備型HPLC (鹼性)純化粗產物，得到呈白色固體狀之(2-(((6S,12R)-12-苯甲基-8-(2-環己基乙基)-6-(環丙基甲基)-2,2,5-三甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(104 mg，97.1%)。LC-MS B：t
R= 1.29 min；[M+H]
+= 969.66。
Step 6 : To (2-((R)-2-(2-((2-cyclohexylethyl)amino)acetamido)-3-phenylpropoxy)-4,5-dimethyl Oxybenzoyl)-L-aspartic acid 4-allyl ester 1-benzyl ester (133 mg, 0.098 mmol), D2-1.4 (28.6 mg, 0.117 mmol) and DIPEA (0.0934 mL, 0.545 mmol ) in DMF (2 mL) was added HATU (42.2 mg, 0.108 mmol). The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the crude product was purified by preparative HPLC (basic) to give (2-(((6S,12R)-12-benzyl-8) as a white solid -(2-cyclohexylethyl)-6-(cyclopropylmethyl)-2,2,5-trimethyl-4,7,10-trioxy-3-oxa-5,8, 11-Triazatridecan-13-yl)oxy)-4,5-dimethoxybenzoyl)-L-aspartate 4-allyl 1-benzyl ester (104 mg , 97.1%). LC-MS B: tR = 1.29 min; [M+H] + = 969.66.
步驟 7 ：向含(2-(((6S,12R)-12-苯甲基-8-(2-環己基乙基)-6-(環丙基甲基)-2,2,5-三甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-4,5-二甲氧基苯甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(104 mg，0.104 mmol)之DCM (3 mL)中添加含4 M HCl之二㗁烷(2.0 mL，2.0 mmol)。在室溫攪拌反應混合物4 h，接著蒸發溶劑，且將粗殘餘物溶解於經脫氣DCM (3 mL)中並用Pd(PPh
3)
4(12.3 mg，0.0104 mmol)及1,3-二甲基巴比妥酸(32.9 mg，0.208 mmol)處理。在室溫攪拌反應混合物1 h，接著經由Whatman過濾器過濾且蒸發溶劑，得到呈無色油狀之(S)-4-(苯甲氧基)-3-(2-((R)-2-(2-((S)-
N-(2-環己基乙基)-3-環丙基-2-(甲基胺基)丙醯胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯胺基)-4-側氧基丁酸(104 mg，120%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.94 min；[M+H]
+= 829.36。
Step 7 : To the Methyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)oxy)-4,5-dimethoxybenzyl Acyl)-L-aspartate 4-allyl 1-benzyl ester (104 mg, 0.104 mmol) in DCM (3 mL) was added dioxane (2.0 mL, 2.0 mmol) containing 4 M HCl . The reaction mixture was stirred at room temperature for 4 h, then the solvent was evaporated, and the crude residue was dissolved in degassed DCM (3 mL) and washed with Pd(PPh 3 ) 4 (12.3 mg, 0.0104 mmol) and 1,3-dimethyl Based on barbituric acid (32.9 mg, 0.208 mmol) treatment. The reaction mixture was stirred at room temperature for 1 h, then filtered through a Whatman filter and the solvent was evaporated to give (S)-4-(benzyloxy)-3-(2-((R)-2- (2-((S) -N- (2-cyclohexylethyl)-3-cyclopropyl-2-(methylamino)propionylamino)acetamido)-3-phenylpropoxy (104 mg, 120%)-4,5-dimethoxybenzamido)-4-oxobutanoic acid (104 mg, 120%), which was used as such in the next step. LC-MS B: tR = 0.94 min; [M+H] + = 829.36.
步驟 8 ：向(S)-4-(苯甲氧基)-3-(2-((R)-2-(2-((S)-
N-(2-環己基乙基)-3-環丙基-2-(甲基胺基)丙醯胺基)乙醯胺基)-3-苯基丙氧基)-4,5-二甲氧基苯甲醯胺基)-4-側氧基丁酸(40 mg，0.05 mmol)於DCM中之室溫溶液中添加FDPP (38 mg，0.14 mmol)。將反應混合物加熱至50℃持續12 h，接著蒸發溶劑且藉由製備型HPLC (鹼性)純化粗產物，得到呈白色固體狀之(3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-(環丙基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15 十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸苯甲酯(11 mg，13%)。LC-MS B：t
R= 1.18 min；[M+H]
+= 811.43。
Step 8 : To (S)-4-(benzyloxy)-3-(2-((R)-2-(2-((S) -N- (2-cyclohexylethyl)-3- Cyclopropyl-2-(methylamino)propionylamino)acetamido)-3-phenylpropoxy)-4,5-dimethoxybenzamido)-4-side To a room temperature solution of oxybutyric acid (40 mg, 0.05 mmol) in DCM was added FDPP (38 mg, 0.14 mmol). The reaction mixture was heated to 50 °C for 12 h, then the solvent was evaporated and the crude product was purified by preparative HPLC (basic) to give (3R,9S,13S)-3-benzyl-7- as a white solid. (2-cyclohexylethyl)-9-(cyclopropylmethyl)-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3, 4,5,6,7,8,9,10,11,12,13,14,15 Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-13-carboxylate benzyl ester (11 mg, 13%). LC-MS B: tR = 1.18 min; [M+H] + = 811.43.
步驟 9 ：向(3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-(環丙基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15 十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸苯甲酯(14 mg，0.017 mmol)於MeOH (2 mL)中之室溫溶液(經脫氣)中添加Pd/C (10%，1.84 mg，0.0017 mmol)。在H
2氛圍下在室溫攪拌反應混合物1 h，接著經由Whatman過濾器過濾混合物，且濃縮，得到呈無色油狀之標題化合物
MC-COOH-13(14 mg，113%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.01 min；[M+H]
+= 721.35。
Step 9 : To (3R,9S,13S)-3-benzyl-7-(2-cyclohexylethyl)-9-(cyclopropylmethyl)-17,18-dimethoxy-10- Methyl-5,8,11,15-Tetrahydrobenzo[p ][1] A room temperature solution of oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylate benzyl ester (14 mg, 0.017 mmol) in MeOH (2 mL) (via degassed) was added Pd/C (10%, 1.84 mg, 0.0017 mmol). The reaction mixture was stirred at room temperature under H atmosphere for 1 h, then the mixture was filtered through a Whatman filter, and concentrated to give the title compound MC-COOH-13 (14 mg, 113%) as a colorless oil, which was used as such. in the next step. LC-MS B: tR = 1.01 min; [M+H] + = 721.35.
(3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-(環戊基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸(MC-COOH-14)
類似於對於
MC-COOH-13所描述之程序，在步驟6中用
D2-1.1替換
D2-1.4製備標題化合物。LC-MS B：t
R= 1.19 min；[M+H]
+= 896.38。
(3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-(cyclopentylmethyl)-17,18-dimethoxy-10-methyl-5 ,8,11,15-Tetrahydrobenzo[p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid (MC-COOH-14) The title compound was prepared analogously to the procedure described for MC-COOH-13 , substituting D2-1.1 for D2-1.4 in step 6. LC-MS B: tR = 1.19 min; [M+H] + = 896.38.
(3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(2-((RS)-四氫-2H-哌喃-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸(MC-COOH-18)
步驟 1-6 ：類似於對於
MC-COOH-13所描述之程序，按照步驟1-6，其中在步驟4中使用2-(四氫-2
H-哌喃-2-基)乙醇替代2-環己基乙醇，且在步驟5中使用
D2-3.1替代
D2-1.4來製備該中間物。
(3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-( 2-((RS)-tetrahydro-2H-pyran-2-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid (MC-COOH-18) Step 1-6 : Similar to the procedure described for MC-COOH-13, step 1-6 was followed, wherein in step 4 2-(tetrahydro- 2H -pyran-2-yl)ethanol was used instead of 2- Cyclohexyl ethanol, and this intermediate was prepared in step 5 using D2-3.1 instead of D2-1.4 .
步驟 7 ：向來自步驟6之中間物(242 mg，0.252 mmol)及1,3-二甲基巴比妥酸(79.6 mg，0.505 mmol)於DCM (2 mL)中之室溫溶液(經脫氣)中添加Pd(PPh
3)
4(29.8 mg，0.025 mmol)，且在室溫攪拌反應混合物1.5 h。過濾反應混合物且濃縮且按原樣用於下一步驟。LC-MS I：t
R= 0.68 min；[M+H]
+= 833.60。
Step 7 : To a room temperature solution of the intermediate from step 6 (242 mg, 0.252 mmol) and 1,3-dimethylbarbituric acid (79.6 mg, 0.505 mmol) in DCM (2 mL) Pd(PPh 3 ) 4 (29.8 mg, 0.025 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was filtered and concentrated and used as such in the next step. LC-MS I: tR = 0.68 min; [M+H] + = 833.60.
步驟 8 及 9 ：按照對於
MC-COOH-13步驟8及9所描述之程序，製備標題化合物
MC-COOH-18。LC-MS I：t
R= 0.53/0.54 min；[M+H]
+= 725.50。
Steps 8 and 9 : Following the procedure described for MC-COOH-13 Steps 8 and 9, the title compound MC-COOH-18 was prepared. LC-MS I: tR = 0.53/0.54 min; [M+H] + = 725.50.
(3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-7-(3-甲氧基-3-甲基丁基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸(MC-COOH-19)
類似於對於
MC-COOH-18所描述之9-步驟合成，製備標題化合物。在步驟4中，使用3-甲氧基-3-甲基-1-丁醇替代2-(四氫-2
H-哌喃-2-基)乙醇。LC-MS B：t
R= 0.90 min；[M+H]
+= 713.36。
(3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-7-(3-methoxy-3-methylbutyl)-10-methyl -5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p] [1]Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid (MC-COOH-19) The title compound was prepared analogously to the 9-step synthesis described for MC-COOH-18 . In step 4, 3-methoxy-3-methyl-1-butanol was used instead of 2-(tetrahydro- 2H -pyran-2-yl)ethanol. LC-MS B: tR = 0.90 min; [M+H] + = 713.36.
(3S,7S,13R)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2
H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸(MC-COOH-20)
步驟 1 及 2 ：按照
MC-COOH-13步驟1及2之合成，使用
A-2.1及
B- 酸 -5，製備(2-((R)-2-胺基-3-苯基丙氧基)-1-萘甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽。LC-MS B：t
R= 0.9 min；[M+H]
+= 567.28。
(3S,7S,13R)-13-Benzyl-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-9-(((R)-tetrahydro-2 H -pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2 -p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylic acid (MC-COOH-20) Steps 1 and 2 : According to the synthesis of MC-COOH-13 steps 1 and 2, use A-2.1 and B- acid -5 to prepare (2-((R)-2-amino-3-phenylpropoxy )-1-naphthoyl)-L-aspartic acid 4-allyl 1-benzyl ester hydrochloride. LC-MS B: tR = 0.9 min; [M+H] + = 567.28.
步驟 3 ：向(2-((R)-2-胺基-3-苯基丙氧基)-1-萘甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯鹽酸鹽(127 mg，0.20 mmol)、
C-16.4(84.6 mg，0.22 mmol)及DIPEA (0.14 mL，0.8 mmol)於DMF (3 mL)中之室溫溶液中添加HATU (87.5 mg，0.23 mmol)，且在室溫攪拌反應混合物2 h。蒸發溶劑且藉由製備型HPLC (鹼性)純化粗產物，得到(2-(((2R,8S)-2-苯甲基-8-異丁基-9-甲基-4,7,10-三側氧基-6-(((R)-四氫-2
H-哌喃-2-基)甲基)-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(142 mg，76%)。LC-MS I：t
R= 1.34 min；[M+H]
+= 933.56。
Step 3 : To (2-((R)-2-amino-3-phenylpropoxy)-1-naphthoyl)-L-aspartate 4-allyl 1-benzyl ester To a room temperature solution of hydrochloride (127 mg, 0.20 mmol), C-16.4 (84.6 mg, 0.22 mmol) and DIPEA (0.14 mL, 0.8 mmol) in DMF (3 mL) was added HATU (87.5 mg, 0.23 mmol ), and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by preparative HPLC (basic) to give (2-(((2R,8S)-2-benzyl-8-isobutyl-9-methyl-4,7,10 -Trilateral oxy-6-(((R)-tetrahydro-2 H -pyran-2-yl)methyl)-11-oxa-3,6,9-triazatetradecane-13 -en-1-yl)oxy)-1-naphthoyl)-L-aspartate 4-allyl 1-benzyl ester (142 mg, 76%). LC-MS I: tR = 1.34 min; [M+H] + = 933.56.
步驟 4 ：向(2-(((2R,8S)-2-苯甲基-8-異丁基-9-甲基-4,7,10-三側氧基-6-(((R)-四氫-2
H-哌喃-2-基)甲基)-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘甲醯基)-L-天冬胺酸4-烯丙酯1-苯甲酯(145 mg，0.152 mmol)及1,3-二甲基巴比妥酸(47.8 mg，0.30 mmol)於DCM (3 mL)中之室溫溶液(經脫氣)中添加Pd(PPh
3)
4(29.8 mg，0.025 mmol)，且在室溫攪拌反應混合物1 h。過濾反應混合物且濃縮且按原樣用於下一步驟。LC-MS I：t
R= 0.68 min；[M+H]
+= 809.52。
Step 4 : To (2-(((2R,8S)-2-benzyl-8-isobutyl-9-methyl-4,7,10-three pendant oxy-6-(((R) -Tetrahydro- 2H -pyran-2-yl)methyl)-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-1- Naphthyl)-L-aspartate 4-allyl 1-benzyl ester (145 mg, 0.152 mmol) and 1,3-dimethylbarbituric acid (47.8 mg, 0.30 mmol) in DCM To a room temperature solution (degassed) in (3 mL) was added Pd( PPh3 ) 4 (29.8 mg, 0.025 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and concentrated and used as such in the next step. LC-MS I: tR = 0.68 min; [M+H] + = 809.52.
步驟 5 及 6 ：按照對於
MC-COOH-13所描述之步驟8及9，製備標題化合物
MC-COOH-20。LC-MS D：t
R= 0.98 min；[M+H]
+= 701.10。
Steps 5 and 6 : Following steps 8 and 9 as described for MC-COOH-13 , the title compound MC-COOH-20 was prepared. LC-MS D: tR = 0.98 min; [M+H] + = 701.10.
下表MC-COOH-C中列舉類似於上文對於
MC-COOH-20描述之合成，由對應起始材料製備之羧酸。
表 MC-COOH-C 編號 結構 SM BB-B SM BB-C 產物 t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
MC-COOH-21 B- 酸-5 C-16.5 (3S,7S,13R)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸
1.00
D
709.01
MC-COOH-22 B- 酸-2 C-16.4 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
0.92
B
711.34
MC-COOH-23 B- 酸-2 C-16.5 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲酸
0.94
B
711.34
Carboxylic acids prepared from the corresponding starting materials are listed in Table MC-COOH-C below in a synthesis similar to that described above for MC-COOH-20 . Form MC-COOH-C serial number structure SM BB-B SM BB-C product t R [min] LC-MS method MS- data m/z [M+H] +
MC-COOH-21 B- acid-5 C-16.5 (3S,7S,13R)-13-Benzyl-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-9-(((S)-tetrahydro-2H -Pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylic acid 1.00D 709.01
MC-COOH-22 B- acid-2 C-16.4 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-( ((R)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-deca Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid 0.92 B 711.34
MC-COOH-23 B- acid-2 C-16.5 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-( ((S)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-deca Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxylic acid 0.94 B 711.34
式(I)化合物之合成
Synthesis of compounds of formula (I)
通用方法：GM-1 向含有對應胺
AM之各管中添加對應
MC-COOH(0.05 mmol)及DIPEA (0.15 mmol)於DMF (0.5 mL)中之儲備溶液。在攪拌2 min之後，向各管中添加另外的HATU (0.05 mmol)於DMF (0.5 mL)中之儲備溶液，且在室溫振盪所得混合物1 h。藉由製備型HPLC (鹼性)直接純化混合物，且在Genevac HT12真空離心機中在40℃乾燥各級分，得到預期產物。在一些情況下，使用對掌性層析來獲得呈純立體異構物形式之所需產物。
General method: GM-1 To each tube containing the corresponding amine AM was added the corresponding stock solution of MC-COOH (0.05 mmol) and DIPEA (0.15 mmol) in DMF (0.5 mL). After stirring for 2 min, additional stock solution of HATU (0.05 mmol) in DMF (0.5 mL) was added to each tube, and the resulting mixture was shaken at room temperature for 1 h. The mixture was purified directly by preparative HPLC (basic) and the fractions were dried in a Genevac HT12 vacuum centrifuge at 40°C to give the expected product. In some cases, chiral chromatography was used to obtain the desired product as a pure stereoisomer.
通用方法：GM-2General Method: GM-2
實例222：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-
N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
步驟 1 ：向
B-1.13(239 mg，0.53 mmol)、
C-2.1(203 mg，0.53 mmol)及DIPEA (0.27 mL，1.58 mmol)於DMF (5 mL)中之室溫溶液中添加HATU (201 mg，0.53 mmol)，且攪拌反應混合物30 min。接著，藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸苯甲酯。LC-MS I：t
R= 1.40 min；[M+H]
+= 752.46。
Example 222: (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl- N- (3-methoxyphenethyl)-21-methyl-5,16,20,23 -Tetrahydrooxy-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p] [1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide Step 1 : To B-1.13 (239 mg, 0.53 mmol), C-2.1 (203 mg, 0.53 mmol) and DIPEA (0.27 mL, 1.58 mmol) in DMF (5 mL) at room temperature were added HATU (201 mg, 0.53 mmol), and The reaction mixture was stirred for 30 min. The reaction mixture was then directly purified by preparative HPLC (basic) to give 2-((R)-2-((R)-4-(N-(tertiary butoxycarbonyl)- Benzyl N-methyl-L-leucyl)-3-formylamino)-3-phenylpropoxy)-1-naphthoate. LC-MS I: tR = 1.40 min; [M+H] + = 752.46.
步驟 2 ：在添加10% Pd/C (22 mg，5 mol%)之前，將2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸苯甲酯(308 mg，0.41 mmol)於EtOH (3 mL)中之溶液抽成真空/用N
2(3×)吹掃。將反應混合物抽成真空/用H
2(3×)吹掃且在H
2氛圍下攪拌2 h。經由矽藻土墊過濾反應混合物，且真空濃縮濾液，得到呈白色固體狀之2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸。LC-MS I：t
R= 0.65 min；[M+H]
+= 662.38。
Step 2 : Before adding 10% Pd/C (22 mg, 5 mol%), 2-((R)-2-((R)-4-(N-(tertiary butoxycarbonyl)-N -Methyl-L-leucyl)-(3-formylamino)-3-phenylpropoxy)-1-naphthoic acid benzyl ester (308 mg, 0.41 mmol) in EtOH (3 mL ) was evacuated/purged with N 2 (3×). The reaction mixture was evacuated/surged with H2 (3x) and stirred under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford 2-((R)-2-((R)-4-(N-(tertiary-butoxycarbonyl)-N- Methyl-L-leucyl)-3-formylamino)-3-phenylpropoxy)-1-naphthoic acid. LC-MS I: tR = 0.65 min; [M+H] + = 662.38.
步驟 3 ：向2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸(160 mg，0.24 mmol)、
A-1.1(78 mg，0.24 mmol)及DIPEA (82 μL，0.48 mmol)於DMF (3 mL)中之室溫溶液中添加HATU (96 mg，0.24 mmol)，且攪拌反應混合物1 h。接著，藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之(S)-3-(2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯。LC-MS I：t
R= 1.36 min；[M+H]
+= 966.74。
Step 3 : To 2-((R)-2-((R)-4-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl)-3-methyl Amino)-3-phenylpropoxy)-1-naphthoic acid (160 mg, 0.24 mmol), A-1.1 (78 mg, 0.24 mmol) and DIPEA (82 μL, 0.48 mmol) in DMF (3 mL ) was added to a room temperature solution of HATU (96 mg, 0.24 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was then directly purified by preparative HPLC (basic) to afford (S)-3-(2-((R)-2-((R)-4-(N-(tri Butoxycarbonyl)-N-methyl-L-leucylamino)-( (3-Methoxyphenethyl)amino)-4-oxobutanoic acid tertiary butyl ester. LC-MS I: tR = 1.36 min; [M+H] + = 966.74.
步驟 4 ：向(S)-3-(2-((R)-2-((R)-4-(N-(三級丁氧基羰基)-N-甲基-L-白胺醯基)𠰌啉-3-甲醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸三級丁酯(174 mg，0.18 mmol)於DCM (5 mL)中之室溫溶液中添加TFA (2.1 mL，28 mmol)，且攪拌反應混合物2 h。真空濃縮反應混合物，且將殘餘物再溶解於DCM中且再次真空濃縮(2×)。將殘餘物溶解於DMF (4 mL)中，之後添加DIPEA (0.24 mL，1.4 mmol)及HATU (80 mg，0.21 mmol，且攪拌反應混合物1 h。接著，藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之標題化合物。LC-MS I：t
R= 1.09 min；[M+H]
+= 792.45。
Step 4 : To (S)-3-(2-((R)-2-((R)-4-(N-(tertiary butoxycarbonyl)-N-methyl-L-leucyl )𠰌line-3-formylamino)-3-phenylpropoxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxo To a room temperature solution of ter-butylbutyrate (174 mg, 0.18 mmol) in DCM (5 mL) was added TFA (2.1 mL, 28 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo, and the residue was redissolved in DCM and concentrated in vacuo again (2x). The residue was dissolved in DMF (4 mL), after which DIPEA (0.24 mL, 1.4 mmol) and HATU (80 mg, 0.21 mmol) were added, and the reaction mixture was stirred for 1 h. Then, by preparative HPLC (basic) directly The reaction mixture was purified to give the title compound as a white solid.LC-MS I: tR = 1.09 min; [M+H] + = 792.45.
注意 ：在以上步驟1之產物為甲酯或乙酯而非所描述之苯甲酯(例如下文實例228)之情況下，在室溫或加熱直至80℃，在MeOH中使用10 eq. 2M NaOH水溶液進行鹼性水解。接著，隨後反應順序保持與實例222所描述相同。在一些情況下，使用對掌性層析來獲得呈純立體異構物形式之所需產物。
Note : In cases where the product of step 1 above was a methyl or ethyl ester rather than the benzyl ester as described (e.g. Example 228 below), use 10 eq. 2M NaOH in MeOH at room temperature or by heating up to 80°C The aqueous solution is subjected to alkaline hydrolysis. Then, the subsequent reaction sequence remained the same as described in Example 222. In some cases, chiral chromatography was used to obtain the desired product as a pure stereoisomer.
通用方法：GM-3General Method: GM-3
實例689：(3'S,7'S,13'R)-13'-苯甲基-
N-(2-(3-環丙基異㗁唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'
H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
步驟 1 ：向
B-1.19(200 mg，0.396 mmol)、
D1-3.0(95 mg，0.415 mmol)及DIPEA (0.34 mL，1.98 mmol)於DMF (4 mL)中之室溫溶液中添加HATU (169 mg，0.435 mmol)，且攪拌反應混合物16 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到3-((R)-2-{[1-(三級丁氧基羰基-甲基-胺基)-環丁烷羰基]-胺基}-3-苯基-丙氧基)-6-氟-喹啉-4-甲酸苯甲酯(220 mg，87%)，其按原樣用於下一步驟。
Example 689: (3'S,7'S,13'R)-13'-Benzyl- N- (2-(3-cyclopropylisoxazol-5-yl)ethyl)-20'-fluoro-7'-Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide Step 1 : To B-1.19 (200 mg, 0.396 mmol), D1-3.0 (95 mg, 0.415 mmol) and DIPEA (0.34 mL, 1.98 mmol) in DMF (4 mL) at room temperature was added HATU (169 mg, 0.435 mmol), and the reaction mixture was stirred for 16 h. Direct purification of the reaction mixture by preparative HPLC (basic) afforded 3-((R)-2-{[1-(tertiary butoxycarbonyl-methyl-amino)-cyclobutanecarbonyl]-amine (220 mg, 87%), which was used as such in the next step.
步驟 2 ：向3-((R)-2-{[1-(三級丁氧基羰基-甲基-胺基)-環丁烷羰基]-胺基}-3-苯基-丙氧基)-6-氟-喹啉-4-甲酸苯甲酯(220 mg，0.385 mmol)於DCM (2 mL)中之室溫溶液中添加含4.0 M HCl之二㗁烷(0.385 mL，1.54 mmol)，且在室溫攪拌反應混合物2 h。蒸發溶劑且粗物質(R)-6-氟-3-(2-(1-(甲基胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)喹啉-4-甲酸苯甲酯(195 mg)按原樣用於下一步驟。
Step 2 : To 3-((R)-2-{[1-(tertiary butoxycarbonyl-methyl-amino)-cyclobutanecarbonyl]-amino}-3-phenyl-propoxy To a room temperature solution of )-6-fluoro-quinoline-4-carboxylate benzyl ester (220 mg, 0.385 mmol) in DCM (2 mL) was added 4.0 M HCl in dioxane (0.385 mL, 1.54 mmol) , and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude material (R)-6-fluoro-3-(2-(1-(methylamino)cyclobutane-1-carboxamido)-3-phenylpropoxy)quinoline- 4-Benzyl carboxylate (195 mg) was used as such in the next step.
步驟 3 ：向(R)-6-氟-3-(2-(1-(甲基胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)喹啉-4-甲酸苯甲酯(195 mg，0.385 mmol)、Boc-
N-甲基-L-白胺酸(99.4 mg，0.404 mmol)及DIPEA (0.33 mL，1.93 mmol)於DMF (4 mL)中之室溫溶液中添加HATU (164 mg，0.423 mmol)，且在室溫攪拌反應混合物16 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲酸苯甲酯(207 mg，70%)。LC-MS I：t
R= 1.45-1.48 min；[M+H]
+= 769.48。
Step 3 : To (R)-6-fluoro-3-(2-(1-(methylamino)cyclobutane-1-formamido)-3-phenylpropoxy)quinoline-4 - Chamber of benzyl formate (195 mg, 0.385 mmol), Boc- N -methyl-L-leucine (99.4 mg, 0.404 mmol) and DIPEA (0.33 mL, 1.93 mmol) in DMF (4 mL) To the warm solution was added HATU (164 mg, 0.423 mmol), and the reaction mixture was stirred at room temperature for 16 h. Direct purification of the reaction mixture by preparative HPLC (basic) afforded 3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-Dimethylpentamylamino)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylic acid benzyl ester (207 mg, 70%). LC-MS I: tR = 1.45-1.48 min; [M+H] + = 769.48.
步驟 4 ：向3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲酸苯甲酯(207 mg，0.270 mmol)於THF/H
2O 2/1 (3 mL)中之室溫溶液中添加LiOH.H
2O (35.1 mg，0.84 mmol)，且在60℃攪拌反應混合物3 d。蒸發THF，且殘餘物用1 M HCl酸化至pH 1並用EtOAc (3×)萃取。經合併之有機層經乾燥(MgSO
4)，過濾且蒸發，得到粗物質3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲酸(182 mg)，其按原樣用於下一步驟。LC-MS I：t
R= 0.70 min；[M+H]
+= 679.45。
Step 4 : To 3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanamide Base) cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-benzoic acid benzyl ester (207 mg, 0.270 mmol) in THF/H 2 O 2/ To a room temperature solution in 1 (3 mL) was added LiOH.H 2 O (35.1 mg, 0.84 mmol), and the reaction mixture was stirred at 60° C. for 3 d. THF was evaporated and the residue was acidified to pH 1 with 1 M HCl and extracted with EtOAc (3x). The combined organic layers were dried (MgSO 4 ), filtered and evaporated to give crude 3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl)(methyl )amino) -N ,4-dimethylpentanylamino)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylic acid (182 mg ), which was used as-is in the next step. LC-MS I: tR = 0.70 min; [M+H] + = 679.45.
步驟 5 ：向3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲酸(45.5 mg，0.067 mmol)、
A-1.24(22 mg，0.07 mmol)及DIPEA (0.0573 mL，0.335 mmol)於DMF (2 mL)中之室溫溶液中添加HATU (28.6 mg，0.0737 mmol)，且在室溫攪拌反應混合物16 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到(S)-3-(3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-環丙基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(44 mg，67%)。LC-MS B：t
R= 1.24 min；[M+H]
+= 984.40。
Step 5 : To 3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanamide yl)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylic acid (45.5 mg, 0.067 mmol), A-1.24 (22 mg, 0.07 mmol) And to a room temperature solution of DIPEA (0.0573 mL, 0.335 mmol) in DMF (2 mL) was added HATU (28.6 mg, 0.0737 mmol) and the reaction mixture was stirred at room temperature for 16 h. Direct purification of the reaction mixture by preparative HPLC (basic) afforded (S)-3-(3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl) (Methyl)amino) -N ,4-dimethylpentanylamino)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-methanol Amino)-4-((2-(3-cyclopropylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (44 mg, 67%) . LC-MS B: tR = 1.24 min; [M+H] + = 984.40.
步驟 6 ：向(S)-3-(3-((R)-2-(1-((S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-環丙基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(44 mg，0.045 mmol)於DMF (2 mL)中之室溫溶液中添加TFA (2 mL，26 mmol)，且在室溫攪拌所得混合物2 h。濃縮混合物且與DCM (2×)一起共蒸發，得到(S)-4-((2-(3-環丙基異㗁唑-5-基)乙基)胺基)-3-(3-((R)-2-(1-((S)-
N,4-二甲基-2-(甲基胺基)戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲醯胺基)-4-側氧基丁酸三氟乙酸鹽(53 mg)，其按原樣用於下一步驟。LC-MS I：t
R= 0.58 min；[M+H]
+= 828.28。
Step 6 : To (S)-3-(3-((R)-2-(1-((S)-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4 -Dimethylpentamylamino)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoroquinoline-4-formamido)-4-((2- A room temperature solution of (3-cyclopropylisozazol-5-yl)ethyl)amino)-4-oxobutanoic acid tert-butyl ester (44 mg, 0.045 mmol) in DMF (2 mL) TFA (2 mL, 26 mmol) was added to , and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and co-evaporated with DCM (2x) to give (S)-4-((2-(3-cyclopropylisoxazol-5-yl)ethyl)amino)-3-(3- ((R)-2-(1-((S) -N ,4-Dimethyl-2-(methylamino)pentamido)cyclobutane-1-carboxamido)-3- Phenylpropoxy)-6-fluoroquinoline-4-formamido)-4-oxobutanoic acid trifluoroacetate (53 mg), which was used as such in the next step. LC-MS I: tR = 0.58 min; [M+H] + = 828.28.
步驟 7 ：向(S)-4-((2-(3-環丙基異㗁唑-5-基)乙基)胺基)-3-(3-((R)-2-(1-((S)-
N,4-二甲基-2-(甲基胺基)戊醯胺基)環丁烷-1-甲醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲醯胺基)-4-側氧基丁酸三氟乙酸鹽(53 mg)及DIPEA (0.162 mL，0.945 mmol)於DMF (0.5 mL)/DCM (4.5 mL)中之室溫溶液中添加HATU (108 mg，0.283 mmol)，且在室溫攪拌反應混合物16 h。濃縮反應混合物且藉由製備型HPLC (鹼性)純化，得到呈固體狀之標題化合物(30 mg)。LC-MS I：t
R= 1.07 min；[M+H]
+= 810.29。
Step 7 : To (S)-4-((2-(3-cyclopropylisoxazol-5-yl)ethyl)amino)-3-(3-((R)-2-(1- ((S) -N ,4-Dimethyl-2-(methylamino)pentanylamino)cyclobutane-1-formamido)-3-phenylpropoxy)-6-fluoro Quinoline-4-formamido)-4-oxobutanoic acid trifluoroacetate (53 mg) and DIPEA (0.162 mL, 0.945 mmol) in DMF (0.5 mL)/DCM (4.5 mL) To the warm solution was added HATU (108 mg, 0.283 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by preparative HPLC (basic) to afford the title compound (30 mg) as a solid. LC-MS I: tR = 1.07 min; [M+H] + = 810.29.
通用方法：GM-4General Method: GM-4
實例700：(3S,7S,13R)-
N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(((S)-𠳭唍-3-基)甲基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
步驟 1 及 2 ：按照對於
GM-5步驟1及2所描述之合成，使用
A-2.2及
B- 酸 -5製備(S)-3-(2-((R)-2-胺基-3-苯基丙氧基)-1-萘醯胺基)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽。LC-MS B：t
R= 0.88 min；[M+H]
+= 624.23。
Example 700: (3S,7S,13R) -N- (2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-((( S)-𠳭唍-3-yl)methyl)-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6, 7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -3-Formamide Steps 1 and 2 : Following the synthesis described for GM-5 Steps 1 and 2, ( S ) -3- ( 2- ( (R)- 2-amino-3-phenylpropoxy)-1-naphthylamino)-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl) Amino)-4-oxobutanoic acid allyl hydrochloride. LC-MS B: tR = 0.88 min; [M+H] + = 624.23.
步驟 3 ：向(S)-3-(2-((R)-2-胺基-3-苯基丙氧基)-1-萘醯胺基)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽(66 mg，0.1 mmol)、
C-16.2(47.6 mg，0.11 mmol)及DIPEA (0.051 mL，0.3 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (41.8 mg，0.11 mmol)，且在室溫攪拌反應混合物30 min。藉由製備型HPLC (酸性)純化，得到呈白色固體狀之(S)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-3-(2-(((2R,8S)-2-苯甲基-6-(((S)-𠳭唍-3-基)甲基)-8-異丁基-9-甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘醯胺基)-4-側氧基丁酸烯丙酯(87 mg，84%)。LC-MS I：t
R= 1.33 min；[M+H]
+= 1038.74。
Step 3 : To (S)-3-(2-((R)-2-amino-3-phenylpropoxy)-1-naphthylamide)-4-((2-(benzo[ d] [1,3]dioxer-5-yl)ethyl)amino)-4-oxobutanoic acid allyl hydrochloride (66 mg, 0.1 mmol), C-16.2 (47.6 mg, 0.11 mmol) and DIPEA (0.051 mL, 0.3 mmol) in DMF (1 mL) at room temperature was added HATU (41.8 mg, 0.11 mmol) and the reaction mixture was stirred at room temperature for 30 min. Purification by preparative HPLC (acidic) afforded (S)-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino as a white solid )-3-(2-(((2R,8S)-2-benzyl-6-(((S)-𠳭唍-3-yl)methyl)-8-isobutyl-9-methyl -4,7,10-Trilateral oxy-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-1-naphthylamide)- Allyl 4-oxobutyrate (87 mg, 84%). LC-MS I: tR = 1.33 min; [M+H] + = 1038.74.
步驟 4 ：向(S)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-3-(2-(((2R,8S)-2-苯甲基-6-(((S)-𠳭唍-3-基)甲基)-8-異丁基-9-甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘醯胺基)-4-側氧基丁酸烯丙酯(87.7 mg，0.082 mmol)及1,3-二甲基巴比妥酸(25.8 mg，0.163 mmol)於DCM (1 mL)中之室溫溶液中添加Pd(Ph
3)
4(9.63 mg，0.0082 mmol)，且在室溫攪拌反應混合物2 h。濃縮反應混合物，得到(S)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-3-(2-((R)-2-(2-((S)-
N-(((S)-𠳭唍-3-基)甲基)-4-甲基-2-(甲基胺基)戊醯胺基)乙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-側氧基丁酸，其按原樣用於下一步驟。LC-MS I：t
R= 0.69 min；[M+H]
+= 914.75。
Step 4 : To (S)-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-3-(2-(((2R, 8S)-2-Benzyl-6-(((S)-𠳭唍-3-yl)methyl)-8-isobutyl-9-methyl-4,7,10-three pendant oxy- Allyl 11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-1-naphthylamido)-4-oxobutanoate (87.7 mg, 0.082 mmol) and 1,3-dimethylbarbituric acid (25.8 mg, 0.163 mmol) in DCM (1 mL) at room temperature were added Pd(Ph 3 ) 4 (9.63 mg, 0.0082 mmol) , and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give (S)-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-3-(2-((R) -2-(2-((S) -N -(((S)-𠳭锍-3-yl)methyl)-4-methyl-2-(methylamino)pentylamino)acetyl Amino)-3-phenylpropoxy)-1-naphthylamino)-4-oxobutanoic acid, which was used as such in the next step. LC-MS I: tR = 0.69 min; [M+H] + = 914.75.
步驟 5 ：向(S)-4-((2-(苯并[d][1,3]二氧呃-5-基)乙基)胺基)-3-(2-((R)-2-(2-((S)-
N-(((S)-𠳭唍-3-基)甲基)-4-甲基-2-(甲基胺基)戊醯胺基)乙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-側氧基丁酸(74.7 mg，0.082 mmol)及DIPEA (70 µL，0.41 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (31.1 mg，0.082 mmol)，且在室溫攪拌反應混合物30 min。藉由製備型HPLC (鹼性)純化，得到呈白色固體狀之標題化合物(49.6 mg，97%)。LC-MS I：t
R= 1.19 min；[M+H]
+= 896.69。
Step 5 : To (S)-4-((2-(benzo[d][1,3]dioxer-5-yl)ethyl)amino)-3-(2-((R)- 2-(2-((S) -N -(((S)-𠳭-3-yl)methyl)-4-methyl-2-(methylamino)pentamylamino)acetamide yl)-3-phenylpropoxy)-1-naphthylamino)-4-oxobutanoic acid (74.7 mg, 0.082 mmol) and DIPEA (70 µL, 0.41 mmol) in DMF (1 mL) To a room temperature solution of HATU (31.1 mg, 0.082 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. Purification by preparative HPLC (basic) afforded the title compound (49.6 mg, 97%) as a white solid. LC-MS I: tR = 1.19 min; [M+H] + = 896.69.
實例976：(3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-10-(2-乙氧基乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
步驟 1 ：在氬氣下，向
B- 酸 -8(394 mg，0.928 mmol)、
A-1.22(361 mg，1.11 mmol)及DIPEA (0.477 mL，2.78 mmol)於DMF (5 mL)中之室溫溶液中添加HATU (424 mg，1.11 mmol)，且攪拌所得混合物1 h。將反應混合物分配於水與EtOAc之間。分離各層且用EtOAc (2×)進一步萃取無機層。經合併之有機萃取物用水及鹽水洗滌，經Na
2SO
4乾燥，過濾且減壓蒸發，得到粗產物；其藉由FC純化，用0%至100% EtOAc/庚烷溶離，得到呈米色固體狀之(S)-3-(6-((R)-2-(((烯丙氧基)羰基)胺基)-3-苯基丙氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(334 mg)。LC-MS B：t
R= 1.09 min；[M+H]
+= 731.48。
Example 976: (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-10 -(2-ethoxyethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16, 17-f] Quinoline-3-formamide Step 1 : Under argon, add B- acid -8 (394 mg, 0.928 mmol), A-1.22 (361 mg, 1.11 mmol) and DIPEA (0.477 mL, To a room temperature solution of 2.78 mmol) in DMF (5 mL) HATU (424 mg, 1.11 mmol) was added, and the resulting mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc. The layers were separated and the inorganic layer was further extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried over Na2SO4 , filtered and evaporated under reduced pressure to give the crude product; which was purified by FC eluting with 0% to 100% EtOAc/heptane to give a beige solid (S)-3-(6-((R)-2-(((allyloxy)carbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-methyl Amino)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (334 mg). LC-MS B: tR = 1.09 min; [M+H] + = 731.48.
步驟 2 ：在氬氣氛圍下，將(S)-3-(6-((R)-2-(((烯丙氧基)羰基)胺基)-3-苯基丙氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(334 mg，0.457 mmol)溶解於MeOH (10 mL)中，且向溶液中添加1,3-二甲基巴比妥酸(144 mg，0.914 mmol)，接著添加Pd(PPh
3)
4(27.2 mg，0.0229 mmol)。在室溫攪拌反應混合物1小時以達到完全轉化。減壓蒸發反應混合物，且藉由FC純化所得粗物質，用0%至20% MeOH/DCM溶離，得到呈棕色油狀之(S)-3-(6-((R)-2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(142 mg)。LC-MS B：t
R= 0.81 min；[M+H]
+= 647.46。
Step 2 : Under argon atmosphere, (S)-3-(6-((R)-2-(((allyloxy)carbonyl)amino)-3-phenylpropoxy)-3 -Fluoroquinoline-5-formamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-side Tert-butyl oxybutyrate (334 mg, 0.457 mmol) was dissolved in MeOH (10 mL), and to the solution was added 1,3-dimethylbarbituric acid (144 mg, 0.914 mmol), followed by Pd( PPh3 ) 4 (27.2 mg, 0.0229 mmol). The reaction mixture was stirred at room temperature for 1 hour to achieve complete conversion. The reaction mixture was evaporated under reduced pressure and the resulting crude material was purified by FC eluting with 0% to 20% MeOH/DCM to afford (S)-3-(6-((R)-2-amino) as a brown oil -3-phenylpropoxy)-3-fluoroquinoline-5-formamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl )ethyl)amino)-4-oxobutanoic acid tert-butyl ester (142 mg). LC-MS B: tR = 0.81 min; [M+H] + = 647.46.
步驟 3 ：在氬氣下，向
C-18.9(85.5 mg，0.22 mmol)、(S)-3-(6-((R)-2-胺基-3-苯基丙氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(142 mg，0.22 mmol)及DIPEA (0.113 mL，0.66 mmol)於DMF (2 mL)中之室溫溶液中添加HATU (100 mg，0.264 mmol)，且攪拌反應混合物1 h。將混合物分配於水與EtOAc之間。分離各層且用EtOAc (2×)進一步萃取無機層。經合併之有機萃取物用水及鹽水洗滌，經Na
2SO
4乾燥，過濾且減壓蒸發，得到粗產物。藉由FC純化，用50% EtOAc/庚烷溶離，得到呈白色粉末狀之(S)-3-(6-(((6S,9RS,12R)-12-苯甲基-9-(2-乙氧基乙基)-6-異丁基-2,2,5,8-四甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(114 mg)。LC-MS B：t
R= 1.25 min；[M+H]+ = 1017.93。
Step 3 : Under argon, add C-18.9 (85.5 mg, 0.22 mmol), (S)-3-(6-((R)-2-amino-3-phenylpropoxy)-3- Fluoroquinoline-5-formamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxo To a room temperature solution of tert-butyl butyrate (142 mg, 0.22 mmol) and DIPEA (0.113 mL, 0.66 mmol) in DMF (2 mL) was added HATU (100 mg, 0.264 mmol), and the reaction mixture was stirred 1 h. The mixture was partitioned between water and EtOAc. The layers were separated and the inorganic layer was further extracted with EtOAc (2x). The combined organic extracts were washed with water and brine, dried over Na2SO4 , filtered and evaporated under reduced pressure to give crude product. Purification by FC, eluting with 50% EtOAc/heptane afforded (S)-3-(6-(((6S,9RS,12R)-12-benzyl-9-(2- Ethoxyethyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxy-3-oxa-5,8,11-triaza Tridecan-13-yl)oxy)-3-fluoroquinoline-5-formamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazole-5 -yl)ethyl)amino)-4-oxobutanoic acid tert-butyl ester (114 mg). LC-MS B: tR = 1.25 min; [M+H]+ = 1017.93.
步驟 4 ：按照對於
GM-2 步驟 4所描述之條件，由(S)-3-(6-(((6S,9RS,12R)-12-苯甲基-9-(2-乙氧基乙基)-6-異丁基-2,2,5,8-四甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-3-氟喹啉-5-甲醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯製備呈白色粉末狀之標題化合物。LC-MS I：t
R= 1.06 min；[M+H]
+= 843.73。
Step 4 : According to the conditions described for GM-2 step 4 , from (S)-3-(6-(((6S,9RS,12R)-12-benzyl-9-(2-ethoxyethyl Base)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-three pendant oxy-3-oxa-5,8,11-triazatridecyl- 13-yl)oxy)-3-fluoroquinoline-5-formamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl tert-butyl)amino)-4-oxobutanoate The title compound was prepared as a white powder. LC-MS I: tR = 1.06 min; [M+H] + = 843.73.
通用方法：GM-5General Method: GM-5
實例713：(3S,7S,10R,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-
N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
步驟 1 ：向
A-2.3(1.0 g，2.95 mmol)、
B- 酸 -5(1.26 g，2.95 mmol)及DIPEA (2.1 mL，11.9 mmol)於DCM (10 mL)中之室溫溶液中添加HATU (1.15 g，2.95 mmol)，且在室溫攪拌反應混合物隔夜。添加NaHCO
3飽和水溶液，且混合物用DCM萃取。濃縮有機層，且藉由FC (用0%至50% EtOAc/庚烷溶離)純化粗產物，得到(S)-3-(2-((R)-2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(1.65 g，79%)。LC-MS B：t
R= 1.16 min；[M+H]
+= 710.37。
Example 713: (3S,7S,10R,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl- N- (3-methoxyphenethyl) -6,9-Dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- Tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide Step 1 : To A-2.3 (1.0 g , 2.95 mmol), B- acid -5 (1.26 g, 2.95 mmol) and DIPEA (2.1 mL, 11.9 mmol) in DCM (10 mL) at room temperature were added HATU (1.15 g, 2.95 mmol), and in The reaction mixture was stirred overnight at room temperature. Sat. aq. NaHCO 3 was added, and the mixture was extracted with DCM. The organic layer was concentrated, and the crude product was purified by FC (eluted with 0% to 50% EtOAc/heptane) to afford (S)-3-(2-((R)-2-((tertiary butoxycarbonyl )amino)-3-phenylpropoxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl ( 1.65 g, 79%). LC-MS B: tR = 1.16 min; [M+H] + = 710.37.
步驟 2 ：向含(S)-3-(2-((R)-2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(1.65 g，2.33 mmol)之DCM (10 mL)中添加含4 M HCl之二㗁烷(2.33 mL，9.31 mmol)，且在室溫攪拌反應混合物2 h。濃縮混合物，得到(S)-3-(2-((R)-2-胺基-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(1.7 g，120%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.08 min；[M+H]
+= 610.43。
Step 2 : to (S)-3-(2-((R)-2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-1-naphthylamide) - To allyl 4-((3-methoxyphenethyl)amino)-4-oxobutanoate (1.65 g, 2.33 mmol) in DCM (10 mL) was added 4 M HCl in dihydrogen Alkane (2.33 mL, 9.31 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give (S)-3-(2-((R)-2-amino-3-phenylpropoxy)-1-naphthylamido)-4-((3-methoxybenzene Allyl ethyl)amino)-4-oxobutyrate (1.7 g, 120%), which was used as such in the next step. LC-MS B: tR = 1.08 min; [M+H] + = 610.43.
步驟 3 ：向(S)-3-(2-((R)-2-胺基-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(64.6 mg，0.1 mmol)、
D1-1.1(34 mg，0.11 mmol)及DIPEA (0.051 mL，0.3 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (42.7 mg，0.11 mmol)，且在室溫攪拌反應混合物30 min。藉由製備型HPLC (酸性)純化，得到呈主要差向異構物形式之(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-((三級丁氧基羰基)(甲基)胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(47 mg，52%)。LC-MS B：t
R= 1.22 min；[M+H]
+= 901.13。亦分離出次要差向異構物(S)-3-(2-((R)-2-((S)-3-(苯甲氧基)-2-((三級丁氧基羰基)(甲基)胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(21 mg，24%)。LC-MS B：t
R= 1.24 min；[M+H]
+= 901.14。
Step 3 : To (S)-3-(2-((R)-2-amino-3-phenylpropoxy)-1-naphthylamide)-4-((3-methoxybenzene Ethyl)amino)-4-oxobutyric acid allyl ester (64.6 mg, 0.1 mmol), D1-1.1 (34 mg, 0.11 mmol) and DIPEA (0.051 mL, 0.3 mmol) in DMF (1 mL) To the room temperature solution in HATU (42.7 mg, 0.11 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. Purification by preparative HPLC (acidic) afforded (S)-3-(2-((R)-2-((R)-3-(benzyloxy)- 2-((tertiary butoxycarbonyl)(methyl)amino)acrylamide)-3-phenylpropoxy)-1-naphthylamide)-4-((3-methoxy Allyl phenethyl)amino)-4-oxobutyrate (47 mg, 52%). LC-MS B: tR = 1.22 min; [M+H] + = 901.13. The minor epimer (S)-3-(2-((R)-2-((S)-3-(benzyloxy)-2-((tertiary butoxycarbonyl )(methyl)amino)acrylamide)-3-phenylpropoxy)-1-naphthylamide)-4-((3-methoxyphenethyl)amino)-4- Allyl oxybutyrate (21 mg, 24%). LC-MS B: tR = 1.24 min; [M+H] + = 901.14.
步驟 4 ：向(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-((三級丁氧基羰基)(甲基)胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(47 mg，0.051 mmol)於DCM (1 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(0.1 mL，0.4 mmol)，且在室溫攪拌反應混合物1 h。濃縮反應混合物，得到呈白色固體狀之(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-(甲基胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽(42.8 mg，100%)，其按原樣用於下一步驟。LC-MS B：t
R= 0.97 min；[M+H]
+= 801.05。
Step 4 : To (S)-3-(2-((R)-2-((R)-3-(benzyloxy)-2-((tertiary butoxycarbonyl)(methyl)amine Base) propionylamino)-3-phenylpropoxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid To a room temperature solution of the propyl ester (47 mg, 0.051 mmol) in DCM (1 mL) was added 4 M HCl in dioxane (0.1 mL, 0.4 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (S)-3-(2-((R)-2-((R)-3-(benzyloxy)-2-(methylamino)propionyl) as a white solid Amino)-3-phenylpropoxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl hydrochloride Salt (42.8 mg, 100%), which was used as such in the next step. LC-MS B: tR = 0.97 min; [M+H] + = 801.05.
步驟 5 ：向(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-(甲基胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯鹽酸鹽(42.8 mg，0.0511 mmol)、
D2-3.1(12.9 mg，0.056 mmol)及DIPEA (0.026 mL，0.153 mmol)於DMF (0.5 mL)中之室溫溶液中添加HATU (21.8 mg，0.056 mmol)，且在室溫攪拌反應混合物1 h。藉由製備型HPLC (酸性)純化，得到呈白色固體狀之(S)-3-(2-(((2R,5R,8S)-2-苯甲基-5-((苯甲氧基)甲基)-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(41.5 mg，80%)。LC-MS B：t
R= 1.26 min；[M+H]
+= 1012.27。
Step 5 : To (S)-3-(2-((R)-2-((R)-3-(benzyloxy)-2-(methylamino)propionylamino)-3- Phenylpropoxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl hydrochloride (42.8 mg, 0.0511 mmol), D2-3.1 (12.9 mg, 0.056 mmol) and DIPEA (0.026 mL, 0.153 mmol) in DMF (0.5 mL) were added to a room temperature solution of HATU (21.8 mg, 0.056 mmol), and the reaction was stirred at room temperature Mixture 1 h. Purification by preparative HPLC (acidic) afforded (S)-3-(2-(((2R,5R,8S)-2-benzyl-5-((benzyloxy)) as a white solid Methyl)-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-ene -1-yl)oxy)-1-naphthylamino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl ester (41.5 mg, 80% ). LC-MS B: tR = 1.26 min; [M+H] + = 1012.27.
步驟 6 ：向(S)-3-(2-(((2R,5R,8S)-2-苯甲基-5-((苯甲氧基)甲基)-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸烯丙酯(41.5 mg，0.04 mmol)及1,3-二甲基巴比妥酸(12.9 mg，0.08 mmol)於DCM (1 mL)中之室溫溶液中添加Pd(Ph
3)
4(4.83 mg，0.004 mmol)，且在室溫攪拌反應混合物1 h。濃縮反應混合物，得到(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-((S)-
N,4-二甲基-2-(甲基胺基)戊醯胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸，其按原樣用於下一步驟。LC-MS B：t
R= 0.94 min；[M+H]
+= 888.15。
Step 6 : To (S)-3-(2-(((2R,5R,8S)-2-benzyl-5-((benzyloxy)methyl)-8-isobutyl-6, 9-Dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-1-naphthalene Amino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoic acid allyl ester (41.5 mg, 0.04 mmol) and 1,3-dimethylbarbital To a room temperature solution of the acid (12.9 mg, 0.08 mmol) in DCM (1 mL) was added Pd( Ph3 ) 4 (4.83 mg, 0.004 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give (S)-3-(2-((R)-2-((R)-3-(benzyloxy)-2-((S) -N ,4-dimethyl- 2-(Methylamino)pentylamino)propionylamino)-3-phenylpropoxy)-1-naphthylamido)-4-((3-methoxyphenethyl)amine yl)-4-oxobutanoic acid, which was used as such in the next step. LC-MS B: tR = 0.94 min; [M+H] + = 888.15.
步驟 7 ：向(S)-3-(2-((R)-2-((R)-3-(苯甲氧基)-2-((S)-
N,4-二甲基-2-(甲基胺基)戊醯胺基)丙醯胺基)-3-苯基丙氧基)-1-萘醯胺基)-4-((3-甲氧基苯乙基)胺基)-4-側氧基丁酸(36.4 mg，0.041 mmol)及DIPEA (35.1 µL，0.205 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (15.9 mg，0.041 mmol)，且在室溫攪拌反應混合物20 min。藉由製備型HPLC (酸性)純化，得到呈淡黃色固體狀之標題化合物(29.3 mg，82%)。LC-MS B：t
R= 1.18 min；[M+H]
+= 870.1。
Step 7 : To (S)-3-(2-((R)-2-((R)-3-(benzyloxy)-2-((S) -N ,4-dimethyl-2 -(Methylamino)pentylamino)propionylamino)-3-phenylpropoxy)-1-naphthylamido)-4-((3-methoxyphenethyl)amino )-4-oxobutanoic acid (36.4 mg, 0.041 mmol) and DIPEA (35.1 µL, 0.205 mmol) in DMF (1 mL) at room temperature were added HATU (15.9 mg, 0.041 mmol), and The reaction mixture was stirred warmly for 20 min. Purification by preparative HPLC (acidic) afforded the title compound (29.3 mg, 82%) as a light yellow solid. LC-MS B: tR = 1.18 min; [M+H] + = 870.1.
通用方法：GM-6General Method: GM-6
實例722：(3S,7S,10R,13R)-10,13-二苯甲基-20-氟-7-異丁基-6,9-二甲基-
N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
步驟 1 ：向
B-1.19(227 mg，0.45 mmol)、
C-17.1(178 mg，0.45 mmol)及DIPEA (0.39 mL，0.3 mmol)於DMF (4 mL)中之室溫溶液中添加HATU (192 mg，0.49 mmol)，且在室溫攪拌反應混合物16 h。藉由製備型HPLC (鹼性)純化，得到3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲酸苯甲酯(269 mg，70%)。LC-MS I：t
R= 1.42 min；[M+H]
+= 803.46。
Example 722: (3S,7S,10R,13R)-10,13-Benzhydryl-20-fluoro-7-isobutyl-6,9-dimethyl- N- (2-(3-methyl Isoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13 ,14-tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecen[17,16-c]quinoline-3-formamide Step 1 : to B To a room temperature solution of -1.19 (227 mg, 0.45 mmol), C-17.1 (178 mg, 0.45 mmol) and DIPEA (0.39 mL, 0.3 mmol) in DMF (4 mL) was added HATU (192 mg, 0.49 mmol) , and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative HPLC (basic) afforded 3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl-4,7 , 10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4-carboxylic acid benzyl ester (269 mg, 70%). LC-MS I: tR = 1.42 min; [M+H] + = 803.46.
步驟 2 ：向3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲酸苯甲酯(269 mg)於THF/H
2O 2/1 (3 mL)中之室溫溶液中添加LiOH.H
2O (35.1 mg，0.84 mmol)，且在60℃攪拌反應混合物3 d。蒸發THF，且殘餘物用1 M HCl酸化至pH 1並用EtOAc (3×)萃取。有機層經合併，經乾燥(MgSO
4)，過濾且蒸發，得到3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲酸(250 mg，105%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.71/0.72 min；[M+H]
+= 713.42。藉由LC-MS可見之雙重峰指示，出現一個對掌性中心之差向異構。
Step 2 : To 3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl-4,7,10-three pendant oxy- 11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4-carboxylic acid benzyl ester (269 mg) in THF/H To a room temperature solution in 2 O 2/1 (3 mL) was added LiOH.H 2 O (35.1 mg, 0.84 mmol), and the reaction mixture was stirred at 60° C. for 3 d. THF was evaporated and the residue was acidified to pH 1 with 1 M HCl and extracted with EtOAc (3x). The organic layers were combined, dried (MgSO 4 ), filtered and evaporated to give 3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl Base-4,7,10-three pendant oxy-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4 - Formic acid (250 mg, 105%) which was used as such in the next step. LC-MS I: tR = 0.71/0.72 min; [M+H] + = 713.42. One epimerization to the chiral center was indicated by the doublet visible by LC-MS.
步驟 3 ：向3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲酸(114 mg，0.23 mmol)、
A-1.8(78.1 mg，0.24 mmol)及DIPEA (0.19 mL，1.13 mmol)於DMF (4 mL)中之室溫溶液中添加HATU (96 mg，0.25 mmol)，且在室溫攪拌反應混合物16 h。藉由製備型HPLC (酸性)純化，得到(S)-3-(3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(187 mg，56%)。LC-MS B：t
R= 1.21 min；[M+H]
+= 992.37。
Step 3 : To 3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl-4,7,10-three pendant oxy- 11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4-carboxylic acid (114 mg, 0.23 mmol), A-1.8 (78.1 mg, 0.24 mmol) and DIPEA (0.19 mL, 1.13 mmol) in DMF (4 mL) at room temperature were added HATU (96 mg, 0.25 mmol) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative HPLC (acidic) afforded (S)-3-(3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-di Methyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline- 4-formamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (187 mg, 56 %). LC-MS B: tR = 1.21 min; [M+H] + = 992.37.
步驟 4 ：向(S)-3-(3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(187 mg，0.189 mmol)於DCM (3 mL)中之室溫溶液中添加TFA (2 mL，26 mmol)，且在室溫攪拌所得混合物2 h。濃縮混合物且與DCM (2×)一起共蒸發，得到(S)-3-(3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸(180 mg)，其按原樣用於下一步驟。LC-MS I：t
R= 0.66/0.68 min；[M+H]
+= 936.3。藉由LC-MS可見之雙重峰指示，出現一個對掌性中心之差向異構。
Step 4 : To (S)-3-(3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl-4,7, 10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4-formamido) -4-((2-(3-Methylisozazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (187 mg, 0.189 mmol) in DCM (3 mL ) was added TFA (2 mL, 26 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and co-evaporated with DCM (2x) to afford (S)-3-(3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6, 9-Dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoro Quinoline-4-formamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid (180 mg), which Used as is for the next step. LC-MS I: tR = 0.66/0.68 min; [M+H] + = 936.3. One epimerization to the chiral center was indicated by the doublet visible by LC-MS.
步驟 5 ：向(S)-3-(3-(((2R,5R,8S)-2,5-二苯甲基-8-異丁基-6,9-二甲基-4,7,10-三側氧基-11-氧雜-3,6,9-三氮雜十四碳-13-烯-1-基)氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸(177 mg，0.19 mmol)及1,3-二甲基巴比妥酸(59.6 mg，0.38 mmol)於DCM (1 mL)中之室溫溶液中添加Pd(Ph
3)
4(22.3 mg，0.019 mmol)，且在室溫攪拌反應混合物1 h。濃縮反應混合物，得到(S)-3-(3-((R)-2-((R)-2-((S)-N,4-二甲基-2-(甲基胺基)戊醯胺基)-3-苯基丙醯胺基)-3-苯基丙氧基)-6-氟喹啉-4-甲醯胺基)-4-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-4-側氧基丁酸(165 mg)，其按原樣用於下一步驟。LC-MS I：t
R= 0.64 min；[M+H]
+= 852.59。
Step 5 : To (S)-3-(3-(((2R,5R,8S)-2,5-benzhydryl-8-isobutyl-6,9-dimethyl-4,7, 10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)-6-fluoroquinoline-4-formamido) -4-((2-(3-Methylisozol-5-yl)ethyl)amino)-4-oxobutanoic acid (177 mg, 0.19 mmol) and 1,3-dimethylbutyric acid To a room temperature solution of bituric acid (59.6 mg, 0.38 mmol) in DCM (1 mL) was added Pd( Ph3 ) 4 (22.3 mg, 0.019 mmol), and the reaction mixture was stirred at room temperature for 1 h. Concentration of the reaction mixture afforded (S)-3-(3-((R)-2-((R)-2-((S)-N,4-dimethyl-2-(methylamino)pentane Amino)-3-phenylpropanylamino)-3-phenylpropanyloxy)-6-fluoroquinoline-4-formamido)-4-((2-(3-methyliso (azol-5-yl)ethyl)amino)-4-oxobutanoic acid (165 mg), which was used as such in the next step. LC-MS I: tR = 0.64 min; [M+H] + = 852.59.
步驟 6 ：按照對於
GM-5步驟7所描述之合成，合成標題化合物。LC-MS I：t
R= 1.11min；[M+H]
+= 834.77。
Step 6 : Following the synthesis described for GM-5 Step 7, the title compound was synthesized. LC-MS I: tR = 1.11 min; [M+H] + = 834.77.
通用方法：GM-7General Method: GM-7
實例724：(3R,6RS,9S,13S)-3-苯甲基-6-((苯甲氧基)甲基)-
N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
步驟 1 ：向
A-1.22(1.25 g，3.86 mmol)、
B- 酸 -7(1.55 g，3.86 mmol)及DIPEA (2.0 mL，11.6 mmol)於DCM (30 mL)中之室溫懸浮液中添加HATU (1.49 g，3.86 mmol)，接著添加DMF (5 mL)，得到透明溶液。在室溫攪拌反應混合物隔夜。濃縮反應混合物且藉由FC (用0%至100% EtOAc/庚烷溶離)純化，得到(S)-3-(4-((R)-2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(2.79 g，100%)。LC-MS I：t
R= 1.12 min；[M+H]
+= 709.20。
Example 724: (3R,6RS,9S,13S)-3-Benzyl-6-((benzyloxy)methyl) -N- (2-(3-cyclopropyl-1,2,4- (Odiazol-5-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4 ,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-13-carboxamide Step 1 : To A-1.22 (1.25 g, 3.86 mmol), B- acid -7 (1.55 g, 3.86 mmol) and DIPEA (2.0 mL, 11.6 mmol) in To a room temperature suspension in DCM (30 mL) was added HATU (1.49 g, 3.86 mmol) followed by DMF (5 mL) to give a clear solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by FC (elution with 0% to 100% EtOAc/heptane) to afford (S)-3-(4-((R)-2-((tertiary butoxycarbonyl)amino )-3-phenylpropoxy)-2-methoxynicotinylamino)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl) Ethyl)amino)-4-oxobutanoic acid tert-butyl ester (2.79 g, 100%). LC-MS I: tR = 1.12 min; [M+H] + = 709.20.
步驟 2 ：向含(S)-3-(4-((R)-2-((三級丁氧基羰基)胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(2.79 g，3.94 mmol)之DCM (30 mL)及MeOH (5 mL)中添加含4 M HCl之二㗁烷(2.0 mL，8.0 mmol)。在室溫攪拌反應混合物48 h。濃縮混合物，得到呈黃色固體狀之(S)-3-(4-((R)-2-胺基-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯鹽酸鹽(2.55 g，100%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.90 min；[M+H]
+= 609.35。
Step 2 : Add (S)-3-(4-((R)-2-((tertiary butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotine Amino)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (2.79 g, 3.94 mmol) in DCM (30 mL) and MeOH (5 mL) was added 4 M HCl in dioxane (2.0 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated to afford (S)-3-(4-((R)-2-amino-3-phenylpropoxy)-2-methoxynicotinamido)-4 as a yellow solid -((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl hydrochloride (2.55 g , 100%), which was used as such in the next step. LC-MS I: tR = 0.90 min; [M+H] + = 609.35.
步驟 3 ：向(S)-3-(4-((R)-2-胺基-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯鹽酸鹽(304 mg，0.33 mmol)、
D1-1.1(96 mg，0.30 mmol)及DIPEA (0.15 mL，0.9 mmol)於DMF (3 mL)中之室溫溶液中添加HATU (128 mg，0.33 mmol)，且在室溫攪拌反應混合物15 min。藉由製備型HPLC (鹼性)純化，得到呈白色固體狀之(S)-3-(4-((R)-2-(3-(苯甲氧基)-2-((三級丁氧基羰基)(甲基)胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(108 mg，40%)。LC-MS I：t
R= 1.23 min；[M+H]
+= 900.76。
Step 3 : To (S)-3-(4-((R)-2-amino-3-phenylpropoxy)-2-methoxynicotinylamido)-4-((2- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl hydrochloride (304 mg, 0.33 mmol), To a room temperature solution of D1-1.1 (96 mg, 0.30 mmol) and DIPEA (0.15 mL, 0.9 mmol) in DMF (3 mL) was added HATU (128 mg, 0.33 mmol), and the reaction mixture was stirred at room temperature for 15 min . Purification by preparative HPLC (basic) afforded (S)-3-(4-((R)-2-(3-(benzyloxy)-2-((tertiary butane) as a white solid Oxycarbonyl)(methyl)amino)propionylamino)-3-phenylpropoxy)-2-methoxynicotinylamido)-4-((2-(3-cyclopropyl -1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid tertiary butyl ester (108 mg, 40%). LC-MS I: tR = 1.23 min; [M+H] + = 900.76.
步驟 4 ：向(S)-3-(4-((R)-2-(3-(苯甲氧基)-2-((三級丁氧基羰基)(甲基)胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(108 mg，0.12 mmol)於MeOH (1 mL)中之室溫溶液中添加含4 M HCl之二㗁烷(0.06 mL，0.24 mmol)，且在室溫攪拌反應混合物48 h。濃縮反應混合物，得到呈白色固體狀之(S)-3-(4-((R)-2-((RS)-3-(苯甲氧基)-2-(甲基胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯鹽酸鹽(101 mg，100%)，其按原樣用於下一步驟。LC-MS I：t
R= 1.05 min；[M+H]
+= 800.64。
Step 4 : To (S)-3-(4-((R)-2-(3-(benzyloxy)-2-((tertiary butoxycarbonyl)(methyl)amino)propionyl Amino)-3-phenylpropoxy)-2-methoxynicotinylamino)-4-((2-(3-cyclopropyl-1,2,4-oxadiazole-5- To a room temperature solution of tert-butyl)-ethyl)amino)-4-oxobutanoate (108 mg, 0.12 mmol) in MeOH (1 mL) was added dioxane (0.06 mL, 0.24 mmol), and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated to afford (S)-3-(4-((R)-2-((RS)-3-(benzyloxy)-2-(methylamino)propionyl as a white solid Amino)-3-phenylpropoxy)-2-methoxynicotinylamino)-4-((2-(3-cyclopropyl-1,2,4-oxadiazole-5- yl)ethyl)amino)-4-oxobutanoic acid tert-butyl hydrochloride (101 mg, 100%), which was used as such in the next step. LC-MS I: tR = 1.05 min; [M+H] + = 800.64.
步驟 5 ：向(S)-3-(4-((R)-2-(3-(苯甲氧基)-2-(甲基胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯鹽酸鹽(100 mg，0.12 mmol)、Boc-
N-甲基-L-白胺酸(36.4 mg，0.14 mmol)及DIPEA (0.08 mL，0.48 mmol)於DMF (1.2 mL)中之室溫溶液中添加HATU (56.4 mg，0.14 mmol)，且在室溫攪拌反應混合物15 min。藉由製備型HPLC (鹼性)純化，得到呈白色固體狀之(S)-3-(4-(((6S,9RS,12R)-12-苯甲基-9-((苯甲氧基)甲基)-6-異丁基-2,2,5,8-四甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(60 mg，49%)。LC-MS I：t
R= 1.38 min；[M+H]
+= 1027.94。
Step 5 : To (S)-3-(4-((R)-2-(3-(benzyloxy)-2-(methylamino)propionylamino)-3-phenylpropoxy Base)-2-methoxynicotinylamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4 -Oxybutyric acid tertiary butyl hydrochloride (100 mg, 0.12 mmol), Boc- N -methyl-L-leucine (36.4 mg, 0.14 mmol) and DIPEA (0.08 mL, 0.48 mmol) in To a room temperature solution in DMF (1.2 mL) was added HATU (56.4 mg, 0.14 mmol), and the reaction mixture was stirred at room temperature for 15 min. Purification by preparative HPLC (basic) afforded (S)-3-(4-(((6S,9RS,12R)-12-benzyl-9-((benzyloxy )Methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-three-oxo-3-oxa-5,8,11-triazepine Carbon-13-yl)oxy)-2-methoxynicotinylamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl tert-butyl)amino)-4-oxobutanoate (60 mg, 49%). LC-MS I: tR = 1.38 min; [M+H] + = 1027.94.
步驟 6 ：向(S)-3-(4-(((6S,9RS,12R)-12-苯甲基-9-((苯甲氧基)甲基)-6-異丁基-2,2,5,8-四甲基-4,7,10-三側氧基-3-氧雜-5,8,11-三氮雜十三碳-13-基)氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸三級丁酯(60.3 mg，0.06 mmol)於DCM (1 mL)中之室溫溶液中添加TFA (0.6 mL，7.83 mmol)，且在室溫攪拌所得混合物1 h。濃縮混合物且與DCM (2×)一起共蒸發，得到(S)-3-(4-((R)-2-(3-(苯甲氧基)-2-((S)-N,4-二甲基-2-(甲基胺基)戊醯胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸(55 mg，100%)，其按原樣用於下一步驟。LC-MS I：t
R= 0.64 min；[M+H]
+= 871.79。
Step 6 : To (S)-3-(4-(((6S,9RS,12R)-12-benzyl-9-((benzyloxy)methyl)-6-isobutyl-2, 2,5,8-Tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecyl-13-yl)oxy)-2-methane Oxynicotinylamido)-4-((2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid To a room temperature solution of tert-butyl ester (60.3 mg, 0.06 mmol) in DCM (1 mL) was added TFA (0.6 mL, 7.83 mmol), and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated and co-evaporated with DCM (2x) to give (S)-3-(4-((R)-2-(3-(benzyloxy)-2-((S)-N,4 -Dimethyl-2-(methylamino)pentamido)propionamido)-3-phenylpropoxy)-2-methoxynicotinamido)-4-((2 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid (55 mg, 100%), which was used as such in the following one step. LC-MS I: tR = 0.64 min; [M+H] + = 871.79.
步驟 7 ：向(S)-3-(4-((R)-2-(3-(苯甲氧基)-2-((S)-
N,4-二甲基-2-(甲基胺基)戊醯胺基)丙醯胺基)-3-苯基丙氧基)-2-甲氧基菸鹼醯胺基)-4-((2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)胺基)-4-側氧基丁酸(51.1 mg，0.06 mmol)及DIPEA (50 µL，0.29 mmol)於DMF (1 mL)中之室溫溶液中添加HATU (23 mg，0.046 mmol)，且在室溫攪拌反應混合物30 min。藉由製備型HPLC (鹼性)純化，得到呈淡黃色固體狀之標題化合物(29.3 mg，82%)。LC-MS 036：t
R= 1.08 min；[M+H]
+= 853.34。
Step 7 : To (S)-3-(4-((R)-2-(3-(benzyloxy)-2-((S) -N ,4-dimethyl-2-(methyl Amino)pentylamino)propionylamino)-3-phenylpropoxy)-2-methoxynicotinylamino)-4-((2-(3-cyclopropyl-1, 2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoic acid (51.1 mg, 0.06 mmol) and DIPEA (50 µL, 0.29 mmol) in DMF (1 mL) To the solution at room temperature was added HATU (23 mg, 0.046 mmol), and the reaction mixture was stirred at room temperature for 30 min. Purification by preparative HPLC (basic) afforded the title compound (29.3 mg, 82%) as a light yellow solid. LC-MS 036: tR = 1.08 min; [M+H] + = 853.34.
通用方法：GM-8General Method: GM-8
實例725：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-
N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1
H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
步驟 1 ：向
C-7.1(2.48 g，4.65 mmol)、
B-1.13(2.37 g，4.65 mmol)及DIPEA (2.4 mL，14 mmol)於MeCN (14.5 mL)中之室溫溶液中添加HATU (1.86 g，4.89 mmol)，且在室溫攪拌反應混合物30 min。向反應混合物中添加水(10 mL)及DCM (100 mL)，且分離各層。水層用DCM (2 × 75 mL)萃取，且經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用15%至45% EtOAc/庚烷溶離，在EtOAc/庚烷3:7中R
f= 0.45)純化，得到呈白色泡沫狀之(R)-3-(((R)-1-((1-((苯甲氧基)羰基)萘-2-基)氧基)-3-苯基丙-2-基)胺甲醯基)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-1-甲酸2,2,2-三氯乙酯(2.25 g，52%)。LC-MS B：t
R= 1.33 min；[M+H]
+= 927.11。
Instance 725: (4aR,7R,18S,22S)-7-benzyl-22-isobutyl-21-methyl- N- (2-(3-methylisoxazol-5-yl)ethyl )-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro -1 H -naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl Amine Step 1 : To a room temperature solution of C-7.1 (2.48 g, 4.65 mmol), B-1.13 (2.37 g, 4.65 mmol) and DIPEA (2.4 mL, 14 mmol) in MeCN (14.5 mL) was added HATU ( 1.86 g, 4.89 mmol), and the reaction mixture was stirred at room temperature for 30 min. Water (10 mL) and DCM (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 x 75 mL), and the combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 15% to 45% EtOAc/heptane, Rf = 0.45 in EtOAc/heptane 3:7) afforded (R)-3-(((R)- 1-((1-((Benzyloxy)carbonyl)naphthalen-2-yl)oxy)-3-phenylpropan-2-yl)aminoformyl)-4-( N- (tertiary butyl Oxycarbonyl) -N -methyl-L-leucyl)piperone-1-carboxylic acid 2,2,2-trichloroethyl ester (2.25 g, 52%). LC-MS B: tR = 1.33 min; [M+H] + = 927.11.
步驟 2 ：向(R)-3-(((R)-1-((1-((苯甲氧基)羰基)萘-2-基)氧基)-3-苯基丙-2-基)胺甲醯基)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-1-甲酸2,2,2-三氯乙酯(2.24 g，2.42 mmol)於MeOH (20 mL)中之室溫溶液(經脫氣)中添加Pd/C (129 mg，0.121 mmol)。在H
2氛圍下在室溫攪拌反應混合物18 h。過濾混合物且濃縮濾液，得到呈白色泡沫狀之2-((R)-2-((R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-((2,2,2-三氯乙氧基)羰基)哌𠯤-2-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸(2.01 g，100%)，其按原樣用於下一步驟。LC-MS B：t
R= 1.21 min；[M+H]
+= 836.91。
Step 2 : To (R)-3-(((R)-1-((1-((benzyloxy)carbonyl)naphthalene-2-yl)oxy)-3-phenylpropan-2-yl )carbamoyl)-4-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)piperone-1-carboxylic acid 2,2,2-trichloroethyl ester ( To a room temperature solution (degassed) of 2.24 g, 2.42 mmol) in MeOH (20 mL) was added Pd/C (129 mg, 0.121 mmol). The reaction mixture was stirred at room temperature under H2 atmosphere for 18 h. The mixture was filtered and the filtrate was concentrated to give 2-((R)-2-((R)-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucylamide as a white foam Base)-4-((2,2,2-trichloroethoxy)carbonyl)piperone-2-formamido)-3-phenylpropoxy)-1-naphthoic acid (2.01 g, 100 %), which was used as-is in the next step. LC-MS B: tR = 1.21 min; [M+H] + = 836.91.
步驟 3 ：向2-((R)-2-((R)-1-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)-4-((2,2,2-三氯乙氧基)羰基)哌𠯤-2-甲醯胺基)-3-苯基丙氧基)-1-萘甲酸(600 mg，0.718 mmol)、
A-1.8(256 mg，0.86 mmol)及DIPEA (0.369 mL，2.15 mmol)於MeCN (6 mL)中之室溫溶液中添加HATU (355 mg，0.933 mmol)，且在室溫攪拌反應混合物1 h。向反應混合物中添加水(8 mL)及DCM (80 mL)，接著分離各層。水層用DCM (2 × 75 mL)萃取，且經合併之有機層用鹽水(10 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用20%至60% EtOAc/庚烷溶離，其中在EtOAc/庚烷1:1中R
f= 0.26)純化，得到呈白色泡沫狀之(R)-3-(((R)-1-((1-(((S)-4-(三級丁氧基)-1-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-1,4-二側氧基丁-2-基)胺甲醯基)萘-2-基)氧基)-3-苯基丙-2-基)胺甲醯基)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-1-甲酸2,2,2-三氯乙酯(512 mg，64%)。LC-MS B：t
R= 1.30 min；[M+H]
+= 1116.18。
Step 3 : To 2-((R)-2-((R)-1-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)-4-((2 ,2,2-trichloroethoxy)carbonyl)piperone-2-formamido)-3-phenylpropoxy)-1-naphthoic acid (600 mg, 0.718 mmol), A-1.8 (256 mg, 0.86 mmol) and DIPEA (0.369 mL, 2.15 mmol) in MeCN (6 mL) at room temperature was added HATU (355 mg, 0.933 mmol) and the reaction mixture was stirred at room temperature for 1 h. Water (8 mL) and DCM (80 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 x 75 mL), and the combined org. layers were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 20% to 60% EtOAc/heptane with Rf = 0.26 in EtOAc/heptane 1:1) afforded (R)-3-(((R) -1-((1-(((S)-4-(tertiary butoxy)-1-((2-(3-methylisozol-5-yl)ethyl)amino)-1 ,4-Dioxobut-2-yl)carbamoyl)naphthalene-2-yl)oxy)-3-phenylpropan-2-yl)carbamoyl)-4-( N- ( tertiary butoxycarbonyl) -N -methyl-L-leucyl)piperone-1-carboxylate 2,2,2-trichloroethyl ester (512 mg, 64%). LC-MS B: tR = 1.30 min; [M+H] + = 1116.18.
步驟 4 ：向(R)-3-(((R)-1-((1-(((S)-4-(三級丁氧基)-1-((2-(3-甲基異㗁唑-5-基)乙基)胺基)-1,4-二側氧基丁-2-基)胺甲醯基)萘-2-基)氧基)-3-苯基丙-2-基)胺甲醯基)-4-(
N-(三級丁氧基羰基)-
N-甲基-L-白胺醯基)哌𠯤-1-甲酸2,2,2-三氯乙酯(500 mg，0.448 mmol)於DCM (5 mL)中之室溫溶液中添加TFA (1.73 mL，22.4 mmol)，且在室溫攪拌反應混合物3 h。濃縮混合物且與DCM一起共蒸發，之後在HV下乾燥。LC-MS B t
R=0.89 min；[M+H]
+= 960.02。將經乾燥之殘餘物溶解於MeCN (5 mL)中，接著添加DIPEA (0.384 mL，2.24 mmol)及HATU (256 mg，0.672 mmol)，且在室溫攪拌反應混合物30 min。向反應混合物中添加水(10 mL)及DCM (100 mL)，且分離各層。水層用DCM (2 × 75 mL)萃取，且經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用35%至100% EtOAc/庚烷溶離，在EtOAc/庚烷7:3中R
f= 0.28)純化，得到呈白色泡沫狀之(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-18-((2-(3-甲基異㗁唑-5-基)乙基)胺甲醯基)-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤並[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸2,2,2-三氯乙酯(293 mg，69%)。LC-MS B：t
R= 1.13 min；[M+H]
+= 940.04。
Step 4 : To (R)-3-(((R)-1-((1-(((S)-4-(tertiary butoxy)-1-((2-(3-methyliso (Zazol-5-yl)ethyl)amino)-1,4-dioxobutan-2-yl)aminoformyl)naphthalene-2-yl)oxy)-3-phenylpropan-2 -yl)carbamoyl)-4-( N- (tertiary butoxycarbonyl) -N -methyl-L-leucyl)pipera-1-carboxylic acid 2,2,2-trichloroethyl To a room temperature solution of the ester (500 mg, 0.448 mmol) in DCM (5 mL) was added TFA (1.73 mL, 22.4 mmol), and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated and coevaporated with DCM before drying under HV. LC-MS BtR = 0.89 min; [M+H] + = 960.02. The dried residue was dissolved in MeCN (5 mL), then DIPEA (0.384 mL, 2.24 mmol) and HATU (256 mg, 0.672 mmol) were added, and the reaction mixture was stirred at room temperature for 30 min. Water (10 mL) and DCM (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 x 75 mL), and the combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 35% to 100% EtOAc/heptane, Rf = 0.28 in EtOAc/heptane 7:3) afforded (4aR,7R,18S,22S)-7- Benzyl-22-isobutyl-21-methyl-18-((2-(3-methylisoxazol-5-yl)ethyl)carbamoyl)-5,16,20,23 -Tetrahydro-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphtho[1,2 -p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylate 2,2,2-trichloroethyl ester ( 293 mg, 69%). LC-MS B: tR = 1.13 min; [M+H] + = 940.04.
步驟 5 ：向(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-18-((2-(3-甲基異㗁唑-5-基)乙基)胺甲醯基)-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3
H-萘并[1,2-p]吡𠯤並[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸2,2,2-三氯乙酯(260 mg，0.269 mmol)及AcOH (0.339 mL，5.92 mmol)於DCM (5 mL)中之室溫溶液中添加鋅粉(176 mg，2.69 mmol)，且在室溫攪拌反應混合物1 h。向反應混合物中添加飽和NaHCO
3(10 mL)及DCM (50 mL)，且分離各層。水層用DCM (2 × 25 mL)萃取，且經合併之有機層用鹽水(10 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮，得到呈白色泡沫狀之標題化合物(215 mg，104%)。LC-MS B：t
R= 0.80 min；[M+H]
+= 765.67。
Step 5 : To (4aR,7R,18S,22S)-7-benzyl-22-isobutyl-21-methyl-18-((2-(3-methylisoxazol-5-yl) Ethyl)carbamoyl)-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21, 22,23-Hexadecahydro-3 H -naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadeca To a room temperature solution of 2,2,2-trichloroethyl carbene-3-carboxylate (260 mg, 0.269 mmol) and AcOH (0.339 mL, 5.92 mmol) in DCM (5 mL) was added zinc powder (176 mg , 2.69 mmol), and the reaction mixture was stirred at room temperature for 1 h. Sat. NaHCO 3 (10 mL) and DCM (50 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 x 25 mL), and the combined organic layers were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated to give the title compound as a white foam (215 mg, 104 %). LC-MS B: tR = 0.80 min; [M+H] + = 765.67.
通用方法：GM-9General Method: GM-9
實例761：(8'R,14'S,18'S)-8'-苯甲基-14'-異丁基-2',12',15'-三甲基-10',13',16',20'-四側氧基-N-(2-(3-苯基異㗁唑-5-基)乙基)-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'
H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺
步驟 1 ：類似於對於實例222步驟1所描述之程序，由
B-2.5(302 mg，0.65 mmol)及
C-1.2(221 mg，0.65 mmol)製備6-((
R)-2-(1-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丙烷-1-甲醯胺基)-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-7-甲酸甲酯。LC-MS J：t
R= 2.30 min；[M+H]
+= 665.3。
Example 761: (8'R,14'S,18'S)-8'-benzyl-14'-isobutyl-2',12',15'-trimethyl-10',13',16',20 '-Tetraoxo-N-(2-(3-phenylisoxazol-5-yl)ethyl)-7',8',9',10',13',14',15', 16',17',18',19',20'-Dodecahydro-12' H -spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[ 1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-carboxamide Step 1 : Similar to the procedure described for Example 222 Step 1 , from B-2.5 (302 mg, 0.65 mmol) and C-1.2 (221 mg, 0.65 mmol) to prepare 6-(( R )-2-(1-(( S )-2-((tertiary butoxy Carbonyl)(methyl)amino) -N ,4-dimethylpentamido)cyclopropane-1-formamido)-3-phenylpropoxy)-2-methylbenzo[d ] azole-7-carboxylic acid methyl ester. LC-MS J: tR = 2.30 min; [M+H] + = 665.3.
步驟 2 ：攪拌6-((
R)-2-(1-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-N,4-二甲基戊醯胺基)環丙烷-1-甲醯胺基)-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-7-甲酸甲酯(315 mg，0.47 mmol)及2M NaOH水溶液(4.74 mL，9.48 mmol)於MeOH (10 mL)中之室溫溶液16 h。真空濃縮反應混合物，且將殘餘物分配於水與EtOAc之間，且分離各層。水相用EtOAc (2×)再萃取，且經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發，得到呈白色固體狀之6-((
R)-2-(1-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丙烷-1-甲醯胺基)-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-7-甲酸。LC-MS J：t
R= 1.82 min；[M+H]
+= 651.2。
Step 2 : Stir 6-(( R )-2-(1-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamide Base) cyclopropane-1-formamido)-3-phenylpropoxy)-2-methylbenzo[d]oxazole-7-methyl carboxylate (315 mg, 0.47 mmol) and 2M NaOH aqueous solution (4.74 mL, 9.48 mmol) in MeOH (10 mL) at room temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2x), and the combined organic extracts were washed with brine , dried over Na2SO4 , filtered and evaporated in vacuo to give 6-(( R )-2-( 1-(( S )-2-((tertiary butoxycarbonyl)(methyl)amino) -N ,4-dimethylpentanylamino)cyclopropane-1-formamido)-3 -phenylpropoxy)-2-methylbenzo[d]oxazole-7-carboxylic acid. LC-MS J: tR = 1.82 min; [M+H] + = 651.2.
步驟 3 及 4 ：類似於如對於實例222步驟3-4所描述之反應順序，由6-((
R)-2-(1-((
S)-2-((三級丁氧基羰基)(甲基)胺基)-
N,4-二甲基戊醯胺基)環丙烷-1-甲醯胺基)-3-苯基丙氧基)-2-甲基苯并[d]㗁唑-7-甲酸及
A-1.33製備(8'R,14'S,18'S)-8'-苯甲基-N-(丁-3-炔-1-基)-14'-異丁基-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'
H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺。LC-MS J：t
R= 1.97 min；[M+H]
+= 699.2。
Steps 3 and 4 : Similar to the reaction sequence as described for Example 222 Steps 3-4, from 6-(( R )-2-(1-(( S )-2-((tertiary butoxycarbonyl) (Methyl)amino) -N ,4-Dimethylpentamylamino)cyclopropane-1-formamido)-3-phenylpropoxy)-2-methylbenzo[d]㗁Preparation of azole-7-carboxylic acid and A-1.33 (8'R,14'S,18'S)-8'-benzyl-N-(but-3-yn-1-yl)-14'-isobutyl-2',12',15'-trimethyl-10',13',16',20'-tetraoxo-7',8',9',10',13',14',15',16',17',18',19',20'-Dodecahydro-12' H -spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1 ,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-formamide. LC-MS J: tR = 1.97 min; [M+H] + = 699.2.
步驟 5 ：向(
E)-苯甲醛肟(48 mg，0.40 mmol)於DMF (0.5 mL)中之室溫溶液中添加NCS (64 mg，0.48 mmol)，且攪拌反應混合物16 h。將反應混合物分配於水與Et
2O之間，且分離各層。水相用Et
2O (2×)再萃取，且經合併之有機萃取物用鹽水洗滌且經空氣流乾燥，得到(
Z)-N-羥基亞胺苄基氯。
注意：化合物不穩定且直接用於下一步驟。
Step 5 : To a room temperature solution of ( E )-benzaldehyde oxime (48 mg, 0.40 mmol) in DMF (0.5 mL) was added NCS (64 mg, 0.48 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and Et2O , and the layers were separated. The aqueous phase was re-extracted with Et2O (2x), and the combined organic extracts were washed with brine and dried over an air stream to afford ( Z )-N-hydroxyiminobenzyl chloride. Note: The compound is unstable and used directly in the next step.
步驟 6 ：攪拌(8'R,14'S,18'S)-8'-苯甲基-N-(丁-3-炔-1-基)-14'-異丁基-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'
H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺(45 mg，0.06 mmol)、(
Z)-N-羥基亞胺苄基氯(30 mg，0.19 mmol)CuI (0.2 mg，1.29 μmol)及K
2CO
3(36 mg，0.26 mmol)於THF (1 mL)中之室溫混合物48 h。真空濃縮反應混合物且再溶解於DMF中，之後藉由製備型HPLC (鹼性)直接純化，得到呈白色固體狀之標題化合物。LC-MS H：t
R= 1.19 min；[M+H]
+= 818.8。
Step 6 : Stir (8'R,14'S,18'S)-8'-Benzyl-N-(but-3-yn-1-yl)-14'-isobutyl-2',12',15'-Trimethyl-10',13',16',20'-tetraoxo-7',8',9',10',13',14',15',16',17',18',19',20'-Dodecahydro-12' H -spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2-p][ 1] Oxa[4,7,10,14]tetraazacycloheptacene]-18'-formamide (45 mg, 0.06 mmol), ( Z )-N-hydroxyiminobenzyl chloride ( A room temperature mixture of 30 mg, 0.19 mmol) CuI (0.2 mg, 1.29 μmol) and K 2 CO 3 (36 mg, 0.26 mmol) in THF (1 mL) for 48 h. The reaction mixture was concentrated in vacuo and redissolved in DMF before direct purification by preparative HPLC (basic) to afford the title compound as a white solid. LC-MS H: tR = 1.19 min; [M+H] + = 818.8.
實例762：(8'R,14'S,18'S)-8'-苯甲基-14'-異丁基-N-(2-(3-異丙基異㗁唑-5-基)乙基)-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺 類似於對於實例761步驟6所描述之程序，由(8'R,14'S,18'S)-8'-苯甲基-
N-(丁-3-炔-1-基)-14'-異丁基-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'
H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺(實例761步驟1-4)及(
Z)-
N-羥基異丁醯亞胺基氯(由(
E)-異丁醛肟製備，參見實例761步驟5)製備標題化合物。LC-MS H：t
R= 1.14 min；[M+H]
+= 784.6。
Example 762: (8'R,14'S,18'S)-8'-Benzyl-14'-isobutyl-N-(2-(3-isopropylisoxazol-5-yl)ethyl)- 2',12',15'-Trimethyl-10',13',16',20'-Tetraoxo-7',8',9',10',13',14',15',16',17',18',19',20'-Dodecahydro-12'H-spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-formamide Analogously to the procedure described for Example 761 Step 6, (8'R,14'S,18'S)-8'-Benzyl- N- (but-3-yn-1-yl)-14'-isobutyl-2',12',15'-trimethyl -10',13',16',20'-Tetra-oxo-7',8',9',10',13',14',15',16',17',18',19',20'-Dodecahydro-12'H-spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-formamide (steps 1-4 of Example 761) and ( Z ) -N -hydroxyisobutyrylimide chloride (from ( E )-Isobutyraldehyde oxime preparation, see Example 761 step 5) to prepare the title compound. LC-MS H: tR = 1.14 min; [M+H] + = 784.6.
實例763：(3'S,7'S,13'R)-13'-苯甲基-
N-(2-(3-苯甲基-1,2,4-㗁二唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'
H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
步驟 1-4 ：類似於對於實例222步驟1-4所描述之反應順序，由
B-1.14、
C-1.2及
A-1.34製備3-((3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺基)丙酸苯甲酯。LC-MS J：t
R= 2.07 min；[M+H]
+= 805.4。
Example 763: (3'S,7'S,13'R)-13'-Benzyl- N- (2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl)- 7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7 ',8',9',11',12',13',14'-Dodecahydro-1' H -spiro[cyclopropane-1,10'-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide Step 1-4 : Similar to the reaction sequence described for Example 222 Step 1-4, from B -1.14 , C-1.2 and A-1.34 to prepare 3-((3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoneBenzyl]-3'-formamido)propionate. LC-MS J: tR = 2.07 min; [M+H] + = 805.4.
步驟 5 ：按照對於實例222步驟2所描述之氫化程序，由3-((3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺基)丙酸苯甲酯製備3-((3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺基)丙酸。LC-MS J：t
R= 1.63 min；[M+H]
+= 715.3。
Step 5 : Following the hydrogenation procedure described for Example 222 Step 2, 3-((3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-6',9'-di Methyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12', 13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17, Preparation of 3-((3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-6 from 16-c]quinoline]-3'-formamido)benzyl propionate ',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9', 11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacycloheptadeca Carbaeno[17,16-c]quinoline]-3'-formamido)propionic acid. LC-MS J: tR = 1.63 min; [M+H] + = 715.3.
步驟 6 ：向苯甲基氰(1.0 mL，8.5 mmol)於MeOH (20 mL)中之室溫溶液中添加羥胺.鹽酸(1.19 g，17.1 mmol)，隨後添加NaOH (0.68 g，17.1 mmol)於水(5 mL)中之溶液，且攪拌反應混合物16 h。真空濃縮反應混合物，且使殘餘物與PhMe (2×)一起共蒸發，得到呈無色油狀之N'-羥基-2-苯基乙醯脒。
注意：直接按原樣用於下一步驟。
Step 6 : To a room temperature solution of benzylcyanide (1.0 mL, 8.5 mmol) in MeOH (20 mL) was added hydroxylamine.HCl (1.19 g, 17.1 mmol), followed by NaOH (0.68 g, 17.1 mmol) in solution in water (5 mL), and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo, and the residue was co-evaporated with PhMe (2x) to afford N'-hydroxy-2-phenylacetamide as a colorless oil. NOTE: Use directly as-is in the next step.
步驟 7 ：向3-((3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺基)丙酸(50 mg，0.07 mmol)及DIPEA (35 μL，0.20 mmol)於NMP (1 mL)中之室溫溶液中添加HATU (38 mg，0.10 mmol)，且攪拌反應混合物10 min，之後添加N'-羥基-2-苯基乙醯脒(33 mg，0.22 mmol)於NMP (200 μL)中之溶液且繼續攪拌30 min。接著將反應混合物加熱至80℃持續16 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之標題化合物。LC-MS H：t
R= 1.22 min；[M+H]
+= 829.8。
Step 7 : To 3-((3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-6',9'-dimethyl-1',5',8', 11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-methane To a room temperature solution of amido)propionic acid (50 mg, 0.07 mmol) and DIPEA (35 μL, 0.20 mmol) in NMP (1 mL) was added HATU (38 mg, 0.10 mmol), and the reaction mixture was stirred for 10 min , after which a solution of N'-hydroxy-2-phenylacetamide (33 mg, 0.22 mmol) in NMP (200 μL) was added and stirring was continued for 30 min. The reaction mixture was then heated to 80 °C for 16 h. The reaction mixture was directly purified by preparative HPLC (basic) to afford the title compound as a white solid. LC-MS H: tR = 1.22 min; [M+H] + = 829.8.
實例764：(3'S,7'S,13'R)-13'-苯甲基-
N-(2-(3-(環丙基甲基)-1,2,4-㗁二唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'
H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
步驟 1 ：向2-環丙基乙腈(100 mg，1.23 mmol)於EtOH (1.5 mL)中之室溫溶液中添加50%羥胺水溶液(0.19 mL，1.48 mmol)，且將反應混合物加熱至回流持續24 h。真空濃縮反應混合物，且使殘餘物與PhMe (2×)一起共蒸發，得到呈無色油狀之2-環丙基-N'-羥基乙醯脒。
注意：直接按原樣用於下一步驟。
Example 764: (3'S,7'S,13'R)-13'-Benzyl- N- (2-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl) Ethyl)-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5', 6',7',8',9',11',12',13',14'-dodecahydro-1' H -spiro[cyclopropane-1,10'-[1]oxa[4, 7,10,14] Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide Step 1 : Add 2-cyclopropylacetonitrile (100 mg, 1.23 mmol) to To a room temperature solution in EtOH (1.5 mL) was added 50% aqueous hydroxylamine (0.19 mL, 1.48 mmol), and the reaction mixture was heated to reflux for 24 h. The reaction mixture was concentrated in vacuo, and the residue was co-evaporated with PhMe (2x) to give 2-cyclopropyl-N'-hydroxyacetamide as a colorless oil. NOTE: Use directly as-is in the next step.
步驟 2-7 ：類似於對於實例763步驟7所描述之程序，由3-((3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'
H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺基)丙酸(實例763步驟1-5)及2-環丙基-
N'-羥基乙醯脒製備標題化合物。LC-MS H：t
R= 1.17 min；[M+H]
+= 793.7。
Steps 2-7 : Similar to the procedure described for Example 763 Step 7, from 3-((3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-6',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamido)propanoic acid (Example 763, steps 1-5) and 2-cyclopropyl- N' -hydroxyacetamide The title compound was prepared. LC-MS H: tR = 1.17 min; [M+H] + = 793.7.
下表MC-1中列舉如上文通用方法1 (
GM-1)中所描述，由其對應建構嵌段
MC-COOH(SM-A)及
胺(SM-B)製備之通式(I)化合物。在下表中，*表示在合成期間分離之實例化合物，歸因於對掌性中心之差向異構，其最常藉由對最終合成步驟進行製備型HPLC純化以次要差向異構物形式分離。在某些情況下，鏡像異構性或非鏡像異構性純建構嵌段在合成期間進行差向異構，且分離呈差向異構物之混合物形式之實例化合物。
表MC-1 (GM-1)
實例 SM-A MC-COOH SM-B AM t
R[min]
LC-MS 方法 MS- 資料m/z [M+H]
+
1 MC-COOH-8
AM-1.1
1.14 (I)
828.23
2 MC-COOH-9
AM-1.1
1.23 (D)
854.37
3 MC-COOH-2
AM-2.1
1.00 (I)
786.23
4 MC-COOH-2
AM-2.2
0.99 (I)
770.2
5 MC-COOH-10
AM-1.1
1.12 (D)
848.27
6 MC-COOH-11
AM-1.1
1.14 (D)
892.29
7 MC-COOH-12
AM-1.1
1.00 (B)
770.46
8 MC-COOH-2
AM-2.3
0.98 (D)
801.37
9 MC-COOH-13
AM-1.1
1.13 (B)
868.35
10 MC-COOH-14
AM-1.1
1.19 (B)
896.38
11 MC-COOH-15
AM-2.1
1.27 (I)
852.27
12 MC-COOH-15
AM-3.1
1.24 (I)
868.28
13 MC-COOH-15
AM-1.2
1.20 / 1.22 (I)
838.25
14 MC-COOH-15
AM-2.2
1.26 (I)
836.24
15 MC-COOH-15
AM-2.5
1.24 (I)
838.25
16 MC-COOH-15
AM-1.3
1.21 / 1.22 (I)
837.22
17 MC-COOH-3
AM-1.4
1.06 (I)
794.64
18 MC-COOH-15
AM-1.42
1.11 (I)
798.49
19 MC-COOH-15
AM-1.43
1.09 (I)
798.5
20 MC-COOH-15
AM-1.44
1.09 (I)
798.47
21 MC-COOH-15
AM-1.45
1.19 (I)
800.56
22 MC-COOH-15
AM-1.46
1.14 (I)
794.56
23 MC-COOH-3
AM-1.47
0.97 (I)
785.28
24 MC-COOH-3
AM-1.48
0.97 (I)
785.28
25 MC-COOH-3
AM-1.5
1.04 (I)
794.32
26 MC-COOH-3
AM-1.57
1.07 (I)
830.22
27 MC-COOH-3
AM-1.6
1.06 (I)
764.32
28 MC-COOH-3
AM-2.8
1.04 (I)
831.34
29 MC-COOH-3
AM-1.49
1.05 (I)
811.63
30 MC-COOH-3
AM-1.50
1.05 (I)
805.67
31 MC-COOH-3
AM-2.7
1.06 (I)
831.68
32 MC-COOH-4
AM-1.51
1.09 (I)
820.61
33 MC-COOH-4
AM-1.52
1.08 (I)
808.38
34 MC-COOH-4
AM-1.53
1.07 (I)
808.38
35 MC-COOH-4
AM-11.1
1.06 (I)
850.42
36 MC-COOH-4
AM-12.1
1.16 (I)
868.42
37 MC-COOH-4
AM-12.2
1.11 (I)
854.38
38 MC-COOH-4
AM-1.50
1.06 (B)
803.39
39 MC-COOH-4
AM-2.6
1.04 (I)
820.39
40 MC-COOH-4
AM-1.54
1.03 (I)
787.41
41 MC-COOH-4
AM-2.8
1.07 (I)
829.31
42 MC-COOH-4
AM-2.5
1.06 (I)
804.39
43 MC-COOH-4
AM-1.55
0.99 (I)
781.29
44 MC-COOH-4
AM-1.25
1.00 (B)
782.26
45 MC-COOH-4
AM-1.26
1.02 (B)
794.43
46 MC-COOH-5
AM-1.56
1.01 (I)
812.24
47 MC-COOH-5
AM-1.10
1.1 (I)
791.27
48 MC-COOH-5
AM-1.11
1.18 (I)
819.32
49 MC-COOH-5
AM-1.12
1.08 (I)
841.18
50 MC-COOH-5
AM-1.13
1.01 (I)
781.16
51 MC-COOH-5
AM-1.14
1.06 (I)
797.12
52 MC-COOH-5
AM-1.15
1.07 (I)
841.14
53 MC-COOH-5
AM-2.6
0.96 (I)
821.25
54 MC-COOH-5
AM-2.5
0.98 (I)
805.26
55 MC-COOH-5
AM-2.7
0.99 (I)
830.17
56 MC-COOH-5
AM-2.8
0.98 (I)
830.16
57 MC-COOH-5
AM-1.7
0.99 (I)
823.32
58 MC-COOH-5
AM-1.6
1.01 (I)
763.28
59 MC-COOH-5
AM-4.1
1.01 (I)
811.26
60 MC-COOH-5
AM-1.8
1.05 (I)
777.28
61 MC-COOH-5
AM-1.16
1.09 (I)
791.3
62 MC-COOH-5
AM-1.9
1.05 (I)
777.28
63 MC-COOH-5
AM-1.17
1.1 (I)
791.3
64 MC-COOH-5
AM-1.18
1.05 (I)
777.28
65 MC-COOH-5
AM-1.19
1.00 (I)
823.29
66 MC-COOH-5
AM-1.20
1.01 (I)
781.17
67 MC-COOH-5
AM-1.21
1.02 (I)
781.16
68 MC-COOH-5
AM-1.22
1.03 (I)
799.25
69 MC-COOH-5
AM-1.23
1.01 (I)
831.25
70 MC-COOH-4
AM-5.1
1.03 (I)
781.51
71 MC-COOH-1
AM-1.7
1.08 (I)
821.36
72 MC-COOH-1
AM-1.22
1.12 (I)
797.15
73 MC-COOH-1
AM-6.1
1.15 (I)
815.31
74 MC-COOH-1
AM-4.3
1.14 (I)
827.3
75 MC-COOH-1
AM-4.4
1.13 (I)
797.18
76 MC-COOH-1
AM-1.23
1.1 (I)
829.23
77 MC-COOH-1
AM-1.6
1.11 (I)
761.3
78 MC-COOH-1
AM-1.24
0.95 (I)
767.29
79 MC-COOH-1
AM-1.25
1.00 (I)
781.22
80 MC-COOH-1
AM-1.26
1.02 (I)
793.34
81 MC-COOH-1
AM-1.19
1.09 (I)
821.41
82 MC-COOH-1
AM-1.27
0.99 (I)
766.04
83 MC-COOH-1
AM-1.28
0.92 (I)
765.21
84 MC-COOH-1
AM-1.5
1.09 (I)
791.31
85 MC-COOH-1
AM-1.29
1.1 (I)
809.37
86 MC-COOH-1
AM-7.2
1.14 (B)
857.37
87 MC-COOH-1
AM-7.3
1.14 (B)
913.34
88 MC-COOH-1
AM-8.1
1.02 (B)
912.5
89 MC-COOH-1
AM-1.30
1.17 (I)
808.81
90* MC-COOH-1
AM-1.30
1.12 (I)
808.75
91 MC-COOH-1
AM-2.17
1.09 (I)
809.26
92 MC-COOH-1
AM-2.18
1.15 (I)
793.22
93 MC-COOH-1
AM-9.1
1.03 (I)
858.29
94 MC-COOH-1
AM-2.20
1.13 (I)
797.06
95 MC-COOH-1
AM-2.19
1.14 (I)
805.28
96 MC-COOH-1
AM-1.9
1.15 (I)
775.22
97 MC-COOH-1
AM-2.16
1.12 (I)
797.15
98 MC-COOH-1
AM-1.31
0.99 (I)
765.98
99 MC-COOH-1
AM-4.2
1.22 (I)
875.17
100 MC-COOH-1
AM-2.15
1.08 (I)
809.23
101 MC-COOH-16
AM-3.1
0.99 (I)
785.90
102 MC-COOH-1
AM-2.14
1.17 (I)
811.24
103 MC-COOH-1
AM-1.32
0.98 (I)
768.14
104 MC-COOH-1
AM-2.13
1.16 (I)
793.25
105 MC-COOH-1
AM-1.33
1.04 (I)
792.25
106 MC-COOH-5
AM-1.33
0.97 (I)
794.61
107 MC-COOH-5
AM-1.30
1.06 (I)
810.62
108 MC-COOH-7
AM-1.6
1.08 (I)
747.6
109 MC-COOH-7
AM-1.7
1.05 (I)
807.65
110 MC-COOH-7
AM-1.22
1.09 (I)
783.58
111 MC-COOH-7
AM-1.5
1.05 (I)
777.59
112 MC-COOH-7
AM-1.9
1.12 (I)
761.6
113 MC-COOH-7
AM-4.4
1.10 (I)
783.56
114 MC-COOH-7
AM-1.25
0.96 (I)
767.59
115 MC-COOH-7
AM-1.26
0.98 (I)
779.59
116 MC-COOH-7
AM-1.29
1.07 (I)
795.63
117 MC-COOH-7
AM-1.31
0.96 (I)
752.55
118 MC-COOH-7
AM-1.33
1.01 (I)
778.63
119 MC-COOH-7
AM-1.30
1.10 (I)
794.66
120 MC-COOH-7
AM-1.34
1.10 (I)
783.58
121 MC-COOH-7
AM-1.35
0.99 (I)
779.62
122 MC-COOH-1
AM-2.12
1.05 (I)
839.3
123 MC-COOH-1
AM-2.11
1.03 (I)
839.29
124 MC-COOH-1
AM-2.10
0.97 (I)
791.27
125 MC-COOH-1
AM-2.9
1.10 (I)
842.32
126 MC-COOH-1
AM-1.34
1.16 (I)
797.48
127 MC-COOH-1
AM-1.35
1.06 (I)
793.51
128 MC-COOH-1
AM-1.36
1.10 (I)
807.56
129 MC-COOH-1
AM-1.37
1.00 (I)
779.55
130 MC-COOH-5
AM-7.1
1.01 (I)
861.95
131 MC-COOH-6
AM-1.4
1.09 (I)
795.52
132 MC-COOH-6
AM-1.22
1.11 (I)
801.5
133 MC-COOH-6
AM-10.1
1.03 (I)
843.54
134 MC-COOH-6
AM-10.2
1.02 (I)
843.54
135 MC-COOH-6
AM-2.7
1.09 (I)
832.56
136 MC-COOH-6
AM-2.8
1.08 (I)
832.54
137 MC-COOH-6
AM-2.12
1.05 (I)
843.55
138 MC-COOH-6
AM-2.11
1.03 (I)
843.56
139 MC-COOH-6
AM-2.10
0.96 (I)
795.57
140 MC-COOH-6
AM-1.35
1.02 (I)
797.37
141 MC-COOH-6
AM-1.31
0.98 (I)
770.52
142 MC-COOH-6
AM-1.33
1.03 (I)
796.55
143 MC-COOH-6
AM-1.28
0.91 (I)
769.53
144 MC-COOH-6
AM-1.26
1.00 (I)
797.41
145 MC-COOH-7
AM-1.38
1.10 (I)
783.54
146 MC-COOH-6
AM-1.39
0.95 (I)
771.46
147 MC-COOH-6
AM-1.40
1.00 (B)
770.08
148 MC-COOH-2
AM-2.4
1.00 (I)
786.58
149 MC-COOH-15
AM-2.6
1.22 (I)
854.25
150 MC-COOH-15
AM-1.57
1.27 (I)
862.14
151 MC-COOH-16
AM-1.19
0.99 (I)
774.16
152 MC-COOH-2
AM-1.73
0.96 (I)
772.18
153 MC-COOH-16
AM-1.5
1.15 (H)
744.7
154 MC-COOH-17
AM-1.1
1.03 (B)
856.32
155 MC-COOH-18
AM-1.1
1.25 (H)
872.7
156 MC-COOH-19
AM-1.1
1.21 (H)
860.9
157 MC-COOH-15
AM-1.59
1.33 (I)
832.92
158 MC-COOH-15
AM-1.74
1.19 (I)
827.34
159 MC-COOH-22
AM-1.1
1.05 (B)
858.41
160 MC-COOH-23
AM-1.1
1.07 (B)
858.42
161 MC-COOH-2
AM-2.21
1.23 (H)
800.8
162 MC-COOH-20
AM-1.1
1.32 (H)
848.8
163 MC-COOH-21
AM-1.1
1.33 (H)
848.8
164 MC-COOH-20
AM-1.4
1.33 (H)
834.8
165 MC-COOH-21
AM-1.4
1.36 (H)
834.8
166 MC-COOH-6
AM-1.80
1.26 (H)
851.7
167 MC-COOH-6
AM-1.78
1.12 (H)
843.7
168 MC-COOH-6
AM-1.76
1.21 (H)
790.7
169 MC-COOH-6
AM-1.77
1.34 (H)
833.7
170 MC-COOH-6
AM-1.79
1.20 (H)
850.7
171 MC-COOH-25
AM-1.83
1.27 (H)
813.7
172 MC-COOH-6
AM-15.1
1.16 (H)
795.6
173 MC-COOH-6
AM-1.81
1.17 (H)
833.5
174 MC-COOH-6
AM-14.1
1.13 (H)
827.7
175 MC-COOH-7
AM-1.82
1.26 (H)
813.7
176 MC-COOH-24
AM-2.10
1.08 (H)
771.8
177 MC-COOH-24
AM-1.84
1.24 (H)
800.6
178 MC-COOH-24
AM-1.85
1.22 (H)
801.6
179 MC-COOH-24
AM-15.1
1.14 (H)
771.7
180 MC-COOH-24
AM-1.4
1.20 (H)
771.7
181 MC-COOH-24
AM-2.12
1.17 (H)
819.7
182 MC-COOH-24
AM-1.23
1.23 (H)
809.7
183 MC-COOH-24
AM-1.6
1.22 (H)
741.7
184 MC-COOH-24
AM-1.12
1.30 (H)
819.6
185 MC-COOH-24
AM-1.5
1.20 (H)
771.7
186 MC-COOH-24
AM-1.9
1.26 (H)
755.7
187 MC-COOH-24
AM-2.23
1.11 (H)
772.6
188 MC-COOH-6
AM-16.1
1.07 (H)
785.6
189 MC-COOH-24
AM-17.1
1.23 (H)
765.6
190 MC-COOH-24
AM-1.49
1.19 (H)
788.7
191 MC-COOH-24
AM-5.3
1.16 (H)
782.7
192 MC-COOH-2
AM-1.8
1.20 (H)
744.7
193 MC-COOH-2
AM-1.5
1.13 (H)
760.7
194 MC-COOH-2
AM-1.58
1.19 (H)
774.7
195 MC-COOH-2
AM-1.4
1.14 (H)
760.7
196 MC-COOH-2
AM-1.13
1.16 (H)
748.6
197 MC-COOH-2
AM-1.60
0.94 (H)
773.8
198 MC-COOH-15
AM-1.1
1.42 (H)
840.7
199 MC-COOH-15
AM-1.4
1.44 (H)
826.8
200 MC-COOH-15
AM-3.2
1.45 (H)
829.7
201 MC-COOH-15
AM-1.58
1.48 (H)
840.7
202 MC-COOH-15
AM-1.8
1.50 (H)
810.7
203 MC-COOH-15
AM-1.60
1.24 (H)
839.7
204 MC-COOH-15
AM-1.13
1.46 (H)
814.7
205 MC-COOH-15
AM-1.7
1.44 (H)
856.8
206 MC-COOH-15
AM-1.61
1.44 (H)
802.7
207 MC-COOH-15
AM-1.62
1.18 (H)
827.7
208 MC-COOH-15
AM-1.63
1.40 (H)
786.6
209 MC-COOH-15
AM-1.66
1.35 (H)
814.8
210 MC-COOH-15
AM-1.65
1.33 (H)
764.6
211 MC-COOH-15
AM-1.6
1.45 (H)
796.7
212 MC-COOH-15
AM-1.64
1.42 (H)
804.7
213 MC-COOH-15
AM-1.67
1.46 (H)
854.8
214 MC-COOH-15
AM-1.40
1.34 (H)
801.8
215 MC-COOH-15
AM-1.10
1.53 (H)
824.8
216 MC-COOH-15
AM-1.68
1.38 (H)
792.8
217 MC-COOH-15
AM-1.69
1.43 (H)
862.8
218 MC-COOH-15
AM-1.71
1.24 (H)
841.8
219 MC-COOH-15
AM-1.5
1.44 (H)
826.8
220 MC-COOH-15
AM-1.70
1.42 (H)
827.7
221 MC-COOH-5
AM-1.84
1.18 (H)
822.6
765 MC-COOH-27
AM-20.1
1.07 (H)
754.4
766 MC-COOH-26
AM-20.1
1.19 (H)
794.5
767 MC-COOH-24
AM-20.1
1.14 (H)
780.4
830 MC-COOH-6
AM-1.94
0.99 (H)
813.4
831 MC-COOH-24
AM-1.89
1.17 (H)
809.4
832 MC-COOH-24
AM-1.91
1.08 (H)
782.4
833 MC-COOH-24
AM-16.2
1.05 (H)
773.4
834 MC-COOH-26
AM-19.3
1.11 (H)
784.4
835 MC-COOH-26
AM-16.2
1.09 (H)
787.4
836 MC-COOH-26
AM-19.2
1.08 (H)
771.4
837 MC-COOH-28
AM-19.1
1.15 (H)
947.4
838 MC-COOH-30
AM-16.2
1.15 (H)
847.4
839 MC-COOH-30
AM-13.1
1.13 (H)
836.4
840 MC-COOH-28
AM-1.91
1.16 (H)
957.4
841 MC-COOH-30
AM-1.35
1.17 (H)
847.4
842 MC-COOH-28
AM-1.88
1.11 (H)
932.4
843 MC-COOH-28
AM-1.95
1.14 (H)
947.4
844 MC-COOH-28
AM-1.93
0.98 (H)
958.4
845 MC-COOH-28
AM-1.65
1.09 (H)
884.4
846 MC-COOH-28
AM-1.92
1.21 (H)
938.4
847 MC-COOH-28
AM-1.62
0.96 (H)
947.4
848 MC-COOH-29
AM-1.88
1.18 (H)
881.4
849 MC-COOH-29
AM-1.35
1.20 (H)
897.4
850 MC-COOH-24
AM-1.45
1.06 (H)
745.4
example SM-A MC-COOH SM- BAM t R [min] LC-MS method MS- data m/z [M+H] +
1 MC-COOH-8 AM-1.1 1.14 (I) 828.23
2 MC-COOH-9 AM-1.1 1.23 (D) 854.37
3 MC-COOH-2 AM-2.1 1.00 (I) 786.23
4 MC-COOH-2 AM-2.2 0.99 (I) 770.2
5 MC-COOH-10 AM-1.1 1.12 (D) 848.27
6 MC-COOH-11 AM-1.1 1.14 (D) 892.29
7 MC-COOH-12 AM-1.1 1.00 (B) 770.46
8 MC-COOH-2 AM-2.3 0.98 (D) 801.37
9 MC-COOH-13 AM-1.1 1.13 (B) 868.35
10 MC-COOH-14 AM-1.1 1.19 (B) 896.38
11 MC-COOH-15 AM-2.1 1.27 (I) 852.27
12 MC-COOH-15 AM-3.1 1.24 (I) 868.28
13 MC-COOH-15 AM-1.2 1.20 / 1.22 (I) 838.25
14 MC-COOH-15 AM-2.2 1.26 (I) 836.24
15 MC-COOH-15 AM-2.5 1.24 (I) 838.25
16 MC-COOH-15 AM-1.3 1.21 / 1.22 (I) 837.22
17 MC-COOH-3 AM-1.4 1.06 (I) 794.64
18 MC-COOH-15 AM-1.42 1.11 (I) 798.49
19 MC-COOH-15 AM-1.43 1.09 (I) 798.5
20 MC-COOH-15 AM-1.44 1.09 (I) 798.47
twenty one MC-COOH-15 AM-1.45 1.19 (I) 800.56
twenty two MC-COOH-15 AM-1.46 1.14 (I) 794.56
twenty three MC-COOH-3 AM-1.47 0.97 (I) 785.28
twenty four MC-COOH-3 AM-1.48 0.97 (I) 785.28
25 MC-COOH-3 AM-1.5 1.04 (I) 794.32
26 MC-COOH-3 AM-1.57 1.07 (I) 830.22
27 MC-COOH-3 AM-1.6 1.06 (I) 764.32
28 MC-COOH-3 AM-2.8 1.04 (I) 831.34
29 MC-COOH-3 AM-1.49 1.05 (I) 811.63
30 MC-COOH-3 AM-1.50 1.05 (I) 805.67
31 MC-COOH-3 AM-2.7 1.06 (I) 831.68
32 MC-COOH-4 AM-1.51 1.09 (I) 820.61
33 MC-COOH-4 AM-1.52 1.08 (I) 808.38
34 MC-COOH-4 AM-1.53 1.07 (I) 808.38
35 MC-COOH-4 AM-11.1 1.06 (I) 850.42
36 MC-COOH-4 AM-12.1 1.16 (I) 868.42
37 MC-COOH-4 AM-12.2 1.11 (I) 854.38
38 MC-COOH-4 AM-1.50 1.06 (B) 803.39
39 MC-COOH-4 AM-2.6 1.04 (I) 820.39
40 MC-COOH-4 AM-1.54 1.03 (I) 787.41
41 MC-COOH-4 AM-2.8 1.07 (I) 829.31
42 MC-COOH-4 AM-2.5 1.06 (I) 804.39
43 MC-COOH-4 AM-1.55 0.99 (I) 781.29
44 MC-COOH-4 AM-1.25 1.00 (B) 782.26
45 MC-COOH-4 AM-1.26 1.02 (B) 794.43
46 MC-COOH-5 AM-1.56 1.01 (I) 812.24
47 MC-COOH-5 AM-1.10 1.1 (I) 791.27
48 MC-COOH-5 AM-1.11 1.18 (I) 819.32
49 MC-COOH-5 AM-1.12 1.08 (I) 841.18
50 MC-COOH-5 AM-1.13 1.01 (I) 781.16
51 MC-COOH-5 AM-1.14 1.06 (I) 797.12
52 MC-COOH-5 AM-1.15 1.07 (I) 841.14
53 MC-COOH-5 AM-2.6 0.96 (I) 821.25
54 MC-COOH-5 AM-2.5 0.98 (I) 805.26
55 MC-COOH-5 AM-2.7 0.99 (I) 830.17
56 MC-COOH-5 AM-2.8 0.98 (I) 830.16
57 MC-COOH-5 AM-1.7 0.99 (I) 823.32
58 MC-COOH-5 AM-1.6 1.01 (I) 763.28
59 MC-COOH-5 AM-4.1 1.01 (I) 811.26
60 MC-COOH-5 AM-1.8 1.05 (I) 777.28
61 MC-COOH-5 AM-1.16 1.09 (I) 791.3
62 MC-COOH-5 AM-1.9 1.05 (I) 777.28
63 MC-COOH-5 AM-1.17 1.1 (I) 791.3
64 MC-COOH-5 AM-1.18 1.05 (I) 777.28
65 MC-COOH-5 AM-1.19 1.00 (I) 823.29
66 MC-COOH-5 AM-1.20 1.01 (I) 781.17
67 MC-COOH-5 AM-1.21 1.02 (I) 781.16
68 MC-COOH-5 AM-1.22 1.03 (I) 799.25
69 MC-COOH-5 AM-1.23 1.01 (I) 831.25
70 MC-COOH-4 AM-5.1 1.03 (I) 781.51
71 MC-COOH-1 AM-1.7 1.08 (I) 821.36
72 MC-COOH-1 AM-1.22 1.12 (I) 797.15
73 MC-COOH-1 AM-6.1 1.15 (I) 815.31
74 MC-COOH-1 AM-4.3 1.14 (I) 827.3
75 MC-COOH-1 AM-4.4 1.13 (I) 797.18
76 MC-COOH-1 AM-1.23 1.1 (I) 829.23
77 MC-COOH-1 AM-1.6 1.11 (I) 761.3
78 MC-COOH-1 AM-1.24 0.95 (I) 767.29
79 MC-COOH-1 AM-1.25 1.00 (I) 781.22
80 MC-COOH-1 AM-1.26 1.02 (I) 793.34
81 MC-COOH-1 AM-1.19 1.09 (I) 821.41
82 MC-COOH-1 AM-1.27 0.99 (I) 766.04
83 MC-COOH-1 AM-1.28 0.92 (I) 765.21
84 MC-COOH-1 AM-1.5 1.09 (I) 791.31
85 MC-COOH-1 AM-1.29 1.1 (I) 809.37
86 MC-COOH-1 AM-7.2 1.14 (B) 857.37
87 MC-COOH-1 AM-7.3 1.14 (B) 913.34
88 MC-COOH-1 AM-8.1 1.02 (B) 912.5
89 MC-COOH-1 AM-1.30 1.17 (I) 808.81
90* MC-COOH-1 AM-1.30 1.12 (I) 808.75
91 MC-COOH-1 AM-2.17 1.09 (I) 809.26
92 MC-COOH-1 AM-2.18 1.15 (I) 793.22
93 MC-COOH-1 AM-9.1 1.03 (I) 858.29
94 MC-COOH-1 AM-2.20 1.13 (I) 797.06
95 MC-COOH-1 AM-2.19 1.14 (I) 805.28
96 MC-COOH-1 AM-1.9 1.15 (I) 775.22
97 MC-COOH-1 AM-2.16 1.12 (I) 797.15
98 MC-COOH-1 AM-1.31 0.99 (I) 765.98
99 MC-COOH-1 AM-4.2 1.22 (I) 875.17
100 MC-COOH-1 AM-2.15 1.08 (I) 809.23
101 MC-COOH-16 AM-3.1 0.99 (I) 785.90
102 MC-COOH-1 AM-2.14 1.17 (I) 811.24
103 MC-COOH-1 AM-1.32 0.98 (I) 768.14
104 MC-COOH-1 AM-2.13 1.16 (I) 793.25
105 MC-COOH-1 AM-1.33 1.04 (I) 792.25
106 MC-COOH-5 AM-1.33 0.97 (I) 794.61
107 MC-COOH-5 AM-1.30 1.06 (I) 810.62
108 MC-COOH-7 AM-1.6 1.08 (I) 747.6
109 MC-COOH-7 AM-1.7 1.05 (I) 807.65
110 MC-COOH-7 AM-1.22 1.09 (I) 783.58
111 MC-COOH-7 AM-1.5 1.05 (I) 777.59
112 MC-COOH-7 AM-1.9 1.12 (I) 761.6
113 MC-COOH-7 AM-4.4 1.10 (I) 783.56
114 MC-COOH-7 AM-1.25 0.96 (I) 767.59
115 MC-COOH-7 AM-1.26 0.98 (I) 779.59
116 MC-COOH-7 AM-1.29 1.07 (I) 795.63
117 MC-COOH-7 AM-1.31 0.96 (I) 752.55
118 MC-COOH-7 AM-1.33 1.01 (I) 778.63
119 MC-COOH-7 AM-1.30 1.10 (I) 794.66
120 MC-COOH-7 AM-1.34 1.10 (I) 783.58
121 MC-COOH-7 AM-1.35 0.99 (I) 779.62
122 MC-COOH-1 AM-2.12 1.05 (I) 839.3
123 MC-COOH-1 AM-2.11 1.03 (I) 839.29
124 MC-COOH-1 AM-2.10 0.97 (I) 791.27
125 MC-COOH-1 AM-2.9 1.10 (I) 842.32
126 MC-COOH-1 AM-1.34 1.16 (I) 797.48
127 MC-COOH-1 AM-1.35 1.06 (I) 793.51
128 MC-COOH-1 AM-1.36 1.10 (I) 807.56
129 MC-COOH-1 AM-1.37 1.00 (I) 779.55
130 MC-COOH-5 AM-7.1 1.01 (I) 861.95
131 MC-COOH-6 AM-1.4 1.09 (I) 795.52
132 MC-COOH-6 AM-1.22 1.11 (I) 801.5
133 MC-COOH-6 AM-10.1 1.03 (I) 843.54
134 MC-COOH-6 AM-10.2 1.02 (I) 843.54
135 MC-COOH-6 AM-2.7 1.09 (I) 832.56
136 MC-COOH-6 AM-2.8 1.08 (I) 832.54
137 MC-COOH-6 AM-2.12 1.05 (I) 843.55
138 MC-COOH-6 AM-2.11 1.03 (I) 843.56
139 MC-COOH-6 AM-2.10 0.96 (I) 795.57
140 MC-COOH-6 AM-1.35 1.02 (I) 797.37
141 MC-COOH-6 AM-1.31 0.98 (I) 770.52
142 MC-COOH-6 AM-1.33 1.03 (I) 796.55
143 MC-COOH-6 AM-1.28 0.91 (I) 769.53
144 MC-COOH-6 AM-1.26 1.00 (I) 797.41
145 MC-COOH-7 AM-1.38 1.10 (I) 783.54
146 MC-COOH-6 AM-1.39 0.95 (I) 771.46
147 MC-COOH-6 AM-1.40 1.00 (B) 770.08
148 MC-COOH-2 AM-2.4 1.00 (I) 786.58
149 MC-COOH-15 AM-2.6 1.22 (I) 854.25
150 MC-COOH-15 AM-1.57 1.27 (I) 862.14
151 MC-COOH-16 AM-1.19 0.99 (I) 774.16
152 MC-COOH-2 AM-1.73 0.96 (I) 772.18
153 MC-COOH-16 AM-1.5 1.15 (H) 744.7
154 MC-COOH-17 AM-1.1 1.03 (B) 856.32
155 MC-COOH-18 AM-1.1 1.25 (H) 872.7
156 MC-COOH-19 AM-1.1 1.21 (H) 860.9
157 MC-COOH-15 AM-1.59 1.33 (I) 832.92
158 MC-COOH-15 AM-1.74 1.19 (I) 827.34
159 MC-COOH-22 AM-1.1 1.05 (B) 858.41
160 MC-COOH-23 AM-1.1 1.07 (B) 858.42
161 MC-COOH-2 AM-2.21 1.23 (H) 800.8
162 MC-COOH-20 AM-1.1 1.32 (H) 848.8
163 MC-COOH-21 AM-1.1 1.33 (H) 848.8
164 MC-COOH-20 AM-1.4 1.33 (H) 834.8
165 MC-COOH-21 AM-1.4 1.36 (H) 834.8
166 MC-COOH-6 AM-1.80 1.26 (H) 851.7
167 MC-COOH-6 AM-1.78 1.12 (H) 843.7
168 MC-COOH-6 AM-1.76 1.21 (H) 790.7
169 MC-COOH-6 AM-1.77 1.34 (H) 833.7
170 MC-COOH-6 AM-1.79 1.20 (H) 850.7
171 MC-COOH-25 AM-1.83 1.27 (H) 813.7
172 MC-COOH-6 AM-15.1 1.16 (H) 795.6
173 MC-COOH-6 AM-1.81 1.17 (H) 833.5
174 MC-COOH-6 AM-14.1 1.13 (H) 827.7
175 MC-COOH-7 AM-1.82 1.26 (H) 813.7
176 MC-COOH-24 AM-2.10 1.08 (H) 771.8
177 MC-COOH-24 AM-1.84 1.24 (H) 800.6
178 MC-COOH-24 AM-1.85 1.22 (H) 801.6
179 MC-COOH-24 AM-15.1 1.14 (H) 771.7
180 MC-COOH-24 AM-1.4 1.20 (H) 771.7
181 MC-COOH-24 AM-2.12 1.17 (H) 819.7
182 MC-COOH-24 AM-1.23 1.23 (H) 809.7
183 MC-COOH-24 AM-1.6 1.22 (H) 741.7
184 MC-COOH-24 AM-1.12 1.30 (H) 819.6
185 MC-COOH-24 AM-1.5 1.20 (H) 771.7
186 MC-COOH-24 AM-1.9 1.26 (H) 755.7
187 MC-COOH-24 AM-2.23 1.11 (H) 772.6
188 MC-COOH-6 AM-16.1 1.07 (H) 785.6
189 MC-COOH-24 AM-17.1 1.23 (H) 765.6
190 MC-COOH-24 AM-1.49 1.19 (H) 788.7
191 MC-COOH-24 AM-5.3 1.16 (H) 782.7
192 MC-COOH-2 AM-1.8 1.20 (H) 744.7
193 MC-COOH-2 AM-1.5 1.13 (H) 760.7
194 MC-COOH-2 AM-1.58 1.19 (H) 774.7
195 MC-COOH-2 AM-1.4 1.14 (H) 760.7
196 MC-COOH-2 AM-1.13 1.16 (H) 748.6
197 MC-COOH-2 AM-1.60 0.94 (H) 773.8
198 MC-COOH-15 AM-1.1 1.42 (H) 840.7
199 MC-COOH-15 AM-1.4 1.44 (H) 826.8
200 MC-COOH-15 AM-3.2 1.45 (H) 829.7
201 MC-COOH-15 AM-1.58 1.48 (H) 840.7
202 MC-COOH-15 AM-1.8 1.50 (H) 810.7
203 MC-COOH-15 AM-1.60 1.24 (H) 839.7
204 MC-COOH-15 AM-1.13 1.46 (H) 814.7
205 MC-COOH-15 AM-1.7 1.44 (H) 856.8
206 MC-COOH-15 AM-1.61 1.44 (H) 802.7
207 MC-COOH-15 AM-1.62 1.18 (H) 827.7
208 MC-COOH-15 AM-1.63 1.40 (H) 786.6
209 MC-COOH-15 AM-1.66 1.35 (H) 814.8
210 MC-COOH-15 AM-1.65 1.33 (H) 764.6
211 MC-COOH-15 AM-1.6 1.45 (H) 796.7
212 MC-COOH-15 AM-1.64 1.42 (H) 804.7
213 MC-COOH-15 AM-1.67 1.46 (H) 854.8
214 MC-COOH-15 AM-1.40 1.34 (H) 801.8
215 MC-COOH-15 AM-1.10 1.53 (H) 824.8
216 MC-COOH-15 AM-1.68 1.38 (H) 792.8
217 MC-COOH-15 AM-1.69 1.43 (H) 862.8
218 MC-COOH-15 AM-1.71 1.24 (H) 841.8
219 MC-COOH-15 AM-1.5 1.44 (H) 826.8
220 MC-COOH-15 AM-1.70 1.42 (H) 827.7
221 MC-COOH-5 AM-1.84 1.18 (H) 822.6
765 MC-COOH-27 AM-20.1 1.07 (H) 754.4
766 MC-COOH-26 AM-20.1 1.19 (H) 794.5
767 MC-COOH-24 AM-20.1 1.14 (H) 780.4
830 MC-COOH-6 AM-1.94 0.99 (H) 813.4
831 MC-COOH-24 AM-1.89 1.17 (H) 809.4
832 MC-COOH-24 AM-1.91 1.08 (H) 782.4
833 MC-COOH-24 AM-16.2 1.05 (H) 773.4
834 MC-COOH-26 AM-19.3 1.11 (H) 784.4
835 MC-COOH-26 AM-16.2 1.09 (H) 787.4
836 MC-COOH-26 AM-19.2 1.08 (H) 771.4
837 MC-COOH-28 AM-19.1 1.15 (H) 947.4
838 MC-COOH-30 AM-16.2 1.15 (H) 847.4
839 MC-COOH-30 AM-13.1 1.13 (H) 836.4
840 MC-COOH-28 AM-1.91 1.16 (H) 957.4
841 MC-COOH-30 AM-1.35 1.17 (H) 847.4
842 MC-COOH-28 AM-1.88 1.11 (H) 932.4
843 MC-COOH-28 AM-1.95 1.14 (H) 947.4
844 MC-COOH-28 AM-1.93 0.98 (H) 958.4
845 MC-COOH-28 AM-1.65 1.09 (H) 884.4
846 MC-COOH-28 AM-1.92 1.21 (H) 938.4
847 MC-COOH-28 AM-1.62 0.96 (H) 947.4
848 MC-COOH-29 AM-1.88 1.18 (H) 881.4
849 MC-COOH-29 AM-1.35 1.20 (H) 897.4
850 MC-COOH-24 AM-1.45 1.06 (H) 745.4
下表MC-2中列舉類似於對應通用方法2 (
GM-2) (參見實例222)，由對應建構嵌段A、B及C製備之通式(I)化合物。
表 MC-2 (GM-2) 實例 A B C t
R[min]
LC-MS 方法H MS- 資料m/z [M+H]
+
223 A-1.14
B-1.16
C-1.1
1.13
758.6
224 A-1.1
B-1.16
C-1.1
1.15
744.7
225 A-1.12
B-1.16
C-1.1
1.21
758.7
226 A-1.6
B-1.16
C-1.1
1.11
772.5
227 A-1.25
B-1.16
C-1.1
1.27
742.6
228 A-1.14
B-2.13
C-1.1
1.14
744.5
229 A-1.14
B-1.3
C-1.1
1.17
728.6
230 A-1.1
B-1.3
C-1.1
1.20
714.7
231 A-1.1
B-2.13
C-1.1
1.17
730.7
232 A-1.1
B-1.22
C-1.1
1.16
730.7
233 A-1.1
B-1.4
C-1.1
1.19
714.7
234 A-1.14
B-1.9
C-1.1
1.16
732.5
235 A-1.14
B-1.2
C-1.1
1.15
728.5
236 A-1.14
B-1.12
C-1.1
1.22
764.7
237 A-1.1
B-1.8
C-1.1
1.22
732.7 [M-H]
-
238 A-1.1
B-1.12
C-1.1
1.25
750.6
239 A-1.25
B-1.5
C-1.1
1.24
728.6
240 A-1.1
B-2.4
C-1.1
1.13
706.6
241 A-1.1
B-2.3
C-1.1
1.13
721.6
242 A-1.14
B-5.1
C-10.19
1.42
843.8
243 A-1.1
B-5.1
C-10.19
1.45
829.7
244 A-1.23
B-5.1
C-10.19
1.44
832.9
245 A-1.2
B-2.13
C-1.1
1.21
756.7
246 A-1.14
B-1.2
C-10.19
1.46
824.7
247 A-1.1
B-1.2
C-10.19
1.49
810.7
248 A-1.14
B-2.13
C-10.19
1.44
840.8
249 A-1.1
B-2.13
C-10.19
1.47
826.8
250 A-1.14
B-1.12
C-10.19
1.51
860.7
251 A-1.1
B-1.12
C-10.19
1.53
846.7
252 A-1.25
B-3.1
C-1.1
1.04
699.5
253 A-1.14
B-1.8
C-10.19
1.49
844.6
254 A-1.1
B-1.8
C-10.19
1.51
828.8 [M-H]
-
255 A-1.14
B-1.1
C-10.19
1.42
870.7
256 A-1.1
B-1.1
C-10.19
1.44
856.9
257 A-1.14
B-1.5
C-10.23
1.24
784.6
258 A-1.1
B-1.5
C-10.23
1.26
770.7
259 A-1.4
B-1.5
C-2.1
1.22
820.5
260 A-1.5
B-1.5
C-2.1
1.22
812.7
261 A-1.2
B-3.1
C-10.19
1.31
823.7
262 A-1.3
B-3.1
C-10.19
1.26
809.7
263 A-1.14
B-1.5
C-10.24
1.28
798.8
264 A-1.1
B-1.5
C-10.24
1.29
784.8
265 A-1.14
B-3.2
C-10.19
1.36
811.7
266 A-1.1
B-3.2
C-10.19
1.39
797.7
267 A-1.14
B-1.13
C-10.19
1.49
860.7
268 A-1.1
B-1.13
C-10.19
1.51
846.7
269 A-1.14
B-1.13
C-1.1
1.20
764.7
270 A-1.14
B-1.10
C-10.19
1.16
825.8
271 A-1.1
B-1.10
C-10.19
1.18
811.7
272 A-1.14
B-1.1
C-10.24
1.27
828.7
273 A-1.1
B-1.1
C-10.24
1.30
814.6
274 A-1.14
B-1.5
C-10.26
1.38
838.7
275 A-1.2
B-1.1
C-10.19
1.47
882.9
276 A-1.3
B-1.1
C-10.19
1.44
868.8
277 A-1.1
B-2.1
C-1.1
1.14
718.6
278 A-1.14
B-2.1
C-1.1
1.11
732.6
279 A-1.14
B-2.2
C-1.1
1.15
746.7 [M-H]
-
280 A-1.1
B-1.17
C-2.2
1.30
784.6
281 A-1.14
B-1.18
C-10.19
1.37
841.7
282 A-1.1
B-1.18
C-10.19
1.39
827.8
283 A-1.6
B-1.17
C-2.2
1.27
812.8
284 A-1.14
B-1.13
C-10.2
1.37
874.8
285 A-1.14
B-1.13
C-10.4
1.42
888.8
286 A-1.14
B-1.13
C-10.1
1.39
874.8
287 A-1.14
B-1.13
C-10.3
1.44
888.8
288 A-1.14
B-1.13
C-10.14
1.38
888.8
289 A-1.14
B-1.13
C-10.15
1.43
902.8
290 A-1.14
B-1.13
C-10.16
1.54
886.8
291 A-1.14
B-1.13
C-10.17
1.58
900.9
292 A-1.14
B-1.13
C-10.18
1.50
872.7
293 A-1.1
B-1.13
C-10.2
1.40
860.7
294 A-1.1
B-1.13
C-10.4
1.45
874.7
295 A-1.1
B-1.13
C-10.1
1.42
860.7
296 A-1.1
B-1.13
C-10.3
1.47
874.7
297 A-1.1
B-1.13
C-4.10
1.35
848.7
298 A-1.1
B-1.13
C-10.14
1.41
874.8
299 A-1.1
B-1.13
C-10.15
1.46
888.9
300 A-1.1
B-1.13
C-10.16
1.57
872.8
301 A-1.1
B-1.13
C-10.17
1.60
886.9
302 A-1.1
B-1.13
C-10.18
1.53
858.7
303 A-1.1
B-1.13
C-10.19
1.51
846.8
304 A-1.14
B-1.5
C-4.10
1.24
842.7
305 A-1.14
B-1.5
C-10.20
1.26
828.7
306 A-1.14
B-1.5
C-10.21
1.24
828.6
307 A-1.14
B-1.5
C-10.1
1.32
854.8
308 A-1.14
B-1.5
C-10.2
1.30
854.8
309 A-1.14
B-1.5
C-10.4
1.35
868.7
310 A-1.1
B-1.5
C-4.10
1.27
828.7
311 A-1.1
B-1.5
C-10.20
1.28
814.7
312 A-1.1
B-1.5
C-10.21
1.26
814.7
313 A-1.1
B-1.5
C-10.1
1.35
840.7
314 A-1.1
B-1.5
C-10.4
1.38
854.7
315 A-1.1
B-1.14
C-10.19
1.43
847.8
316 A-1.23
B-1.14
C-10.19
1.43
850.8
317 A-1.1
B-4.1
C-1.1
1.23
784.6
318 A-1.14
B-1.14
C-1.1
1.10
765.5
319 A-1.1
B-1.14
C-1.1
1.12
751.6
320 A-1.23
B-1.14
C-1.1
1.12
754.6
321 A-1.14
B-4.2
C-1.1
1.09
758.6
322 A-1.14
B-4.3
C-1.1
1.09
760.5
323 A-1.1
B-4.2
C-1.1
1.12
744.6
324 A-1.1
B-4.3
C-1.1
1.11
746.6
325 A-1.15
B-1.13
C-2.1
1.25
822.7
326 A-1.14
B-1.13
C-2.1
1.23
806.7
327 A-1.16
B-1.13
C-2.1
1.21
803.7
328 A-1.15
B-2.7
C-2.2
1.04
824.8
329 A-1.14
B-2.7
C-2.2
1.01
808.6
330 A-1.14
B-1.13
C-4.4
1.26
874.7
331 A-1.14
B-1.13
C-4.5
1.38
888.8
332 A-1.14
B-1.13
C-4.6
1.27
848.8
333 A-1.14
B-1.13
C-4.7
1.27
862.7
334 A-1.14
B-1.13
C-4.8
1.29
932.8
335 A-1.14
B-1.13
C-4.2
1.35
850.7
336 A-1.14
B-1.13
C-4.11
1.29
862.7
337 A-1.14
B-1.13
C-10.5
1.33
860.6
338 A-1.14
B-1.13
C-10.6
1.35
860.7
339 A-1.14
B-1.13
C-4.12
1.38
842.8
340 A-1.14
B-1.13
C-10.7
1.29
846.8
341 A-1.14
B-1.13
C-10.26
1.45
858.8
342 A-1.1
B-2.6
C-2.8
1.19
781.6
343 A-1.1
B-2.6
C-2.2
1.22
781.7
344 A-1.8
B-1.14
C-10.19
1.32
822.7
345 A-1.14
B-4.2
C-10.19
1.41
854.7
346 A-1.1
B-4.2
C-10.19
1.43
840.7
347 A-1.23
B-4.2
C-10.19
1.43
843.7
348 A-1.1
B-2.7
C-3.7
0.96
835.8
349 A-1.14
B-1.20
C-1.1
1.12
783.5
350 A-1.1
B-1.20
C-1.1
1.14
769.6
351 A-1.1
B-2.15
C-2.2
1.22
795.6
352 A-1.1
B-2.5
C-3.3
0.78
838.8
353 A-1.1
B-2.7
C-3.3
0.68
837.7
354 A-1.1
B-1.13
C-6.3
0.97
849.7
355 A-1.1
B-1.13
C-3.5
0.97
845.7
356 A-1.1
B-1.13
C-3.7
1.246
831.8
357* A-1.1
B-1.13
C-3.7
1.17
831.7
358 A-1.14
B-1.13
C-10.8
1.29
860.8
359 A-1.14
B-1.13
C-10.9
1.28
860.7
360 A-1.14
B-1.13
C-10.10
1.34
874.8
361 A-1.14
B-1.13
C-10.11
1.34
874.8
362 A-1.14
B-1.13
C-10.12
1.33
862.8
363 A-1.14
B-1.13
C-10.13
1.33
862.8
364 A-1.1
B-2.7
C-3.4
0.82
851.7
365 A-1.1
B-1.14
C-2.2
1.27
791.8
366 A-1.1
B-1.14
C-2.8
1.24
791.7
367 A-1.8
B-1.14
C-2.2
1.15
766.6
368 A-1.15
B-2.15
C-2.2
1.22
825.7
369 A-1.1
B-1.13
C-7.1
1.44
965.7
370 A-1.11
B-1.13
C-2.1
1.23
809.6
371 A-1.10
B-1.13
C-2.1
1.29
828.7
372 A-1.1
B-1.14
C-3.4
0.97
848.7
373* A-1.1
B-1.14
C-3.4
0.95
848.7
374 A-1.1
B-1.14
C-3.3
0.84
834.6
375 A-1.8
B-1.14
C-3.3
0.74
809.7
376 A-1.1
B-1.13
C-1.3
1.34
788.6
377 A-1.15
B-2.9
C-2.2
0.94
838.8
378 A-1.9
B-1.13
C-2.1
1.16方法I
842.52
379 A-1.14
B-2.5
C-10.19
1.38
865.8
380 A-1.1
B-2.5
C-10.19
1.41
851.7
381 A-1.23
B-2.5
C-10.19
1.41
854.7
382 A-1.14
B-1.20
C-10.19
1.42
879.8
383 A-1.1
B-1.20
C-10.19
1.44
865.7
384 A-1.23
B-1.20
C-10.19
1.44
868.8
385 A-1.1
B-1.13
C-1.2
1.30
776.6
386 A-1.1
B-1.13
C-2.7
1.31
762.6
387 A-1.7
B-1.13
C-2.1
1.26
829.8
388* A-1.1
B-1.14
C-3.7
1.14
832.7
389 A-1.1
B-1.14
C-3.7
1.13
832.7
390* A-1.1
B-1.14
C-3.5
0.93
846.8
391 A-1.1
B-1.14
C-3.5
0.89
846.7
392* A-1.14
B-1.14
C-3.7
1.13
846.8
393 A-1.14
B-1.14
C-3.7
1.13
846.8
394* A-1.14
B-1.14
C-3.5
0.91
860.8
395 A-1.14
B-1.14
C-3.5
0.88
860.8
396 A-1.1
B-1.13
C-6.4
1.34
834.8
397 A-1.12
B-1.13
C-2.1
1.31
806.8
398 A-1.10
B-1.14
C-3.7
1.20
868.8
399* A-1.10
B-1.14
C-3.7
1.18
868.7
400 A-1.12
B-1.14
C-3.7
1.22
846.8
401* A-1.12
B-1.14
C-3.7
1.20
846.8
402 A-1.8
B-1.14
C-3.7
1.01
805.8 [M-H]
-
403* A-1.8
B-1.14
C-3.7
1.03
807.7
404 A-1.11
B-1.14
C-3.7
1.14
849.8
405* A-1.11
B-1.14
C-3.7
1.16
849.8
406 A-1.1
B-2.8
C-2.2
1.27
795.8
407 A-1.1
B-2.8
C-2.1
1.13
797.6
408 A-1.14
B-4.4
C-1.1
1.20
794.6
409 A-1.1
B-4.4
C-1.1
1.22
780.6
410 A-1.8
B-2.5
C-10.19
1.230
826.8
411 A-1.8
B-1.20
C-10.19
1.34
840.8
412 A-1.1
B-1.14
C-2.1
1.16
793.6
413* A-1.1
B-1.14
C-2.1
1.16
793.6
414 A-1.10
B-1.14
C-6.3
0.94
886.7
415 A-1.11
B-1.14
C-6.3
0.87
867.7
416 A-1.1
B-1.13
C-6.2
0.90
835.6
417 A-1.1
B-2.5
C-3.7
1.09
836.6
418 A-1.12
B-2.5
C-3.7
1.15
850.7
419 A-1.10
B-2.5
C-3.7
1.14
872.7
420 A-1.11
B-2.5
C-3.7
1.07
853.6
421 A-1.6
B-2.5
C-3.7
1.07
864.8
422 A-1.26
B-2.5
C-10.19
1.46
885.8
423 A-1.1
B-6.2
C-2.2
1.25
794.6
424 A-1.1
B-6.2
C-2.1
1.13
796.7
425 A-1.1
B-2.5
C-3.6
0.81
850.7
426 A-1.10
B-2.5
C-3.6
0.86
886.7
427 A-1.12
B-2.5
C-3.6
0.85
864.7
428 A-1.7
B-2.5
C-3.6
0.82
887.8
429 A-1.8
B-6.2
C-2.2
1.13
769.6
430 A-1.14
B-2.10
C-1.1
1.11
754.7
431 A-1.1
B-1.13
C-12.1
1.35
822.7
432 A-1.8
B-1.14
C-11.1
1.16
778.7
433 A-1.1
B-1.14
C-1.2
1.21
777.6
434 A-1.8
B-1.14
C-1.2
1.08
752.7
435 A-1.8
B-2.5
C-2.6
1.06
798.7
436 A-1.8
B-2.5
C-2.5
1.19
796.6
437* A-1.8
B-2.5
C-2.5
1.16
796.8
438 A-1.1
B-1.18
C-1.2
1.13
757.6
439 A-1.1
B-1.20
C-1.2
1.23
795.7
440 A-1.8
B-1.20
C-1.2
1.09
770.6
441 A-1.1
B-4.7
C-1.1
1.01
751.7
442 A-1.1
B-2.10
C-1.2
1.19
766.6
443 A-1.8
B-1.20
C-2.2
1.17
784.7
444 A-1.8
B-4.5
C-2.2
0.83
730.6
445 A-1.8
B-1.14
C-10.20
1.13
810.6
446 A-1.8
B-1.14
C-10.12
1.13
824.7
447 A-1.1
B-4.6
C-1.2
1.18
768.6
448 A-1.8
B-2.10
C-1.2
1.06
741.6
449 A-1.1
B-2.10
C-1.1
1.12
740.5
450 A-1.1
B-2.11
C-1.1
1.17
742.6
451 A-1.1
B-1.13
C-6.1
0.89
849.7
452 A-1.8
B-1.13
C-6.1
0.78
824.7
453 A-1.17
B-1.14
C-1.2
1.21
814.8
454 A-1.7
B-1.14
C-1.2
1.21
814.6
455 A-1.8
B-4.6
C-2.2
1.13
757.6
456 A-1.1
B-4.6
C-2.2
1.25
782.6
457 A-1.1
B-1.13
C-13.1
1.33
820.7
458 A-1.8
B-1.14
C-7.1
1.25
941.6
459 A-1.1
B-1.14
C-3.1
0.82
806.8
460 A-1.1
B-4.7
C-1.2
1.09
777.7
461 A-1.17
B-1.14
C-2.2
1.27
828.7
462 A-1.17
B-1.14
C-2.8
1.24
828.7
463 A-1.7
B-1.14
C-2.2
1.28
828.8
464 A-1.7
B-1.14
C-2.8
1.24
828.6
465 A-1.1
B-7.1
C-1.1
0.82
751.6
466 A-1.17
B-1.18
C-2.2
1.21
808.7
467 A-1.17
B-1.18
C-2.8
1.17
808.6
468 A-1.7
B-1.18
C-2.2
1.21
808.7
469 A-1.1
B-2.10
C-2.2
1.25
780.6
470 A-1.8
B-2.10
C-2.2
1.12
755.6
471 A-1.1
B-4.8
C-1.2
0.89
777.7
472 A-1.7
B-4.7
C-2.2
1.16
828.8
473 A-1.7
B-4.7
C-2.8
1.13
828.6
474 A-1.8
B-4.7
C-2.2
1.02
766.7
475 A-1.8
B-1.13
C-9.1
1.15
907.7
476 A-1.24
B-1.14
C-1.2
1.14
778.7
477 A-1.8
B-1.18
C-2.2
1.09
746.7
478 A-1.20
B-1.18
C-2.2
1.24
777.7
479 A-1.8
B-1.13
C-9.2
1.19
937.7
480 A-1.8
B-1.19
C-2.2
1.19
784.7
481 A-1.7
B-1.19
C-2.2
1.32
846.7
482 A-1.20
B-2.5
C-2.2
1.26
801.6
483 A-1.19
B-1.18
C-2.2
1.12
773.6
484 A-1.20
B-2.10
C-2.2
1.28
786.7
485 A-1.20
B-2.7
C-2.2
1.06
800.6
486 A-1.19
B-4.7
C-2.2
1.07
793.8
487 A-1.8
B-1.23
C-2.2
1.12
766.7
488 A-1.1
B-2.12
C-1.2
1.15
757.6
489 A-1.19
B-1.19
C-2.1
1.12
813.7
490 A-1.20
B-6.2
C-2.2
1.28
800.6
491 A-1.20
B-4.6
C-2.2
1.28
788.6
492 A-1.7
B-1.13
C-2.4
1.32
857.8
493 A-1.7
B-1.14
C-2.4
1.23
858.7
494 A-1.1
B-7.1
C-1.2
0.91
777.7
495 A-1.8
B-1.14
C-5.1
1.24
828.6
496 A-1.21
B-1.14
C-1.2
1.18
825.8
497 A-1.18
B-1.20
C-2.8
1.20
810.6
498 A-1.19
B-1.20
C-2.2
1.20
811.6
499 A-1.24
B-1.20
C-2.2
1.22
810.6
500 A-1.24
B-1.20
C-2.8
1.18
810.6
501 A-1.22
B-1.20
C-2.2
1.22
811.7
502 A-1.27
B-1.14
C-1.2
1.15
825.7
503 A-1.1
B-1.14
C-5.2
1.21
779.7
504 A-1.18
B-4.7
C-2.2
1.11
792.8
505 A-1.22
B-4.7
C-2.2
1.07
793.6
506 A-1.8
B-1.14
C-14.1
1.20
780.8
507 A-1.1
B-4.9
C-1.1
1.14
769.5
508 A-1.8
B-1.13
C-5.3
1.22
765.7
509 A-1.1
B-1.14
C-8.1
1.36
868.7
510 A-1.8
B-1.14
C-8.1
1.26
843.8
511 A-1.22
B-1.18
C-2.2
1.14
773.7
512 A-1.18
B-1.18
C-2.2
1.16
772.7
513 A-1.1
B-4.10
C-1.1
1.07
731.6
514 A-1.24
B-4.7
C-2.2
1.09
792.7
515 A-1.22
B-4.11
C-2.2
1.21
773.7
516 A-1.19
B-4.11
C-2.2
1.19
773.7
517 A-1.24
B-2.12
C-2.2
1.16
772.7
518 A-1.18
B-2.12
C-2.2
1.18
772.6
519 A-1.24
B-1.19
C-1.2
1.18
796.6
520 A-1.19
B-1.19
C-2.8
1.18
811.7
521 A-1.22
B-1.19
C-2.8
1.20
811.7
522 A-1.7
B-1.20
C-2.2
1.29
846.7
523 A-1.24
B-1.18
C-2.2
1.15
772.7
524 A-1.24
B-1.19
C-8.1
1.34
887.7
525 A-1.22
B-1.19
C-8.1
1.33
888.7
526 A-1.18
B-4.11
C-2.2
1.22
772.7
527 A-1.8
B-1.26
C-2.2
1.23
800.6
528 A-1.1
B-1.26
C-2.2
1.36
823.9 [M-H]
-
529 A-1.22
B-2.12
C-2.2
1.16
773.7
530 A-1.1
B-2.16
C-1.1
1.20
751.6
531 A-1.1
B-5.3
C-1.1
1.19
754.7
532 A-1.24
B-5.3
C-1.1
1.11
755.6
533 A-1.28
B-4.12
C-2.2
1.01方法I
776.7
534 A-1.8
B-1.27
C-2.2
1.14
784.6
535 A-1.1
B-1.27
C-2.2
1.07方法B
809.26
536 A-1.1
B-2.5
C-8.1
1.32
872.7
537 A-1.1
B-1.19
C-2.3
1.15
795.6
538 A-1.1
B-1.18
C-8.1
1.30
848.8
539 A-1.19
B-1.19
C-18.1
1.34
903.8
540 A-1.19
B-1.19
C-18.1
1.30
903.8
541 A-1.19
B-4.9
C-2.2
1.21
811.6
542 A-1.8
B-1.18
C-8.1
1.20
823.7
543 A-1.24
B-4.7
C-1.2
1.01
778.6
544 A-1.19
B-4.7
C-1.2
0.99
779.7
545 A-1.24
B-4.9
C-1.2
1.16
796.6
546 A-1.19
B-4.9
C-1.2
1.14
797.6
547 A-1.8
B-1.14
C-18.3
1.19
768.6
548 A-1.8
B-1.14
C-18.4
1.25
782.6
549* A-1.1
B-1.18
C-8.1
1.30
848.8
550* A-1.8
B-1.18
C-8.1
1.19
823.8
551 A-1.1
B-5.3
C-1.2
1.25
780.8
552 A-1.24
B-5.3
C-1.2
1.19
781.7
553 A-1.19
B-5.3
C-1.2
1.17
782.7
554 A-1.22
B-5.3
C-1.2
1.17
782.6
555 A-1.1
B-2.16
C-1.2
1.28
777.6
556 A-1.24
B-2.16
C-1.2
1.21
778.7
557 A-1.19
B-1.18
C-18.1
1.20
865.8
558 A-1.19
B-1.18
C-18.1
1.24
865.7
559 A-1.31
B-1.14
C-2.2
1.29
820.6
560 A-1.31
B-1.19
C-2.2
1.33
838.6
561 A-1.19
B-5.3
C-1.1
1.09
756.6
562 A-1.22
B-5.3
C-1.1
1.10
756.6
563 A-1.19
B-1.27
C-2.2
1.17
811.6
564 A-1.8
B-1.14
C-2.14
1.26
846.6
565 A-1.18
B-4.12
C-2.2
1.21
786.6
566 A-1.8
B-1.14
C-21.1
1.09
784.6
567 A-1.19
B-4.12
C-2.2
1.17
787.6
568 A-1.31
B-4.12
C-2.2
1.28
814.7
569 A-1.1
B-1.18
C-2.10
1.24
819.6
570 A-1.8
B-1.18
C-3.4
0.80
803.7
571 A-1.19
B-1.18
C-20.1
1.26
905.8
572* A-1.1
B-1.14
C-1.4
1.19
765.7
573 A-1.8
B-1.14
C-1.4
1.09
740.7
574 A-1.24
B-1.14
C-1.4
1.15
766.7
575 A-1.1
B-5.3
C-1.4
1.25
768.7
576 A-1.8
B-5.3
C-1.4
1.12
743.7
577* A-1.19
B-1.18
C-20.1
1.22
905.7
578 A-1.8
B-1.14
C-18.2
1.27
860.7
579* A-1.8
B-1.14
C-18.2
1.23
860.7
580 A-1.28
B-4.12
C-2.13
1.24
802.6
581 A-1.28
B-4.13
C-2.2
1.15
779.6
582 A-1.28
B-1.18
C-10.19
1.30
818.7
583 A-1.14
B-1.4
C-1.1
1.16
728.6
584 A-1.1
B-2.13
C-2.3
1.16
756.7
585 A-1.14
B-1.11
C-10.19
1.41
870.7
586 A-1.1
B-1.11
C-10.19
1.44
856.7
587 A-1.1
B-2.13
C-2.2
1.30
770.6
588 A-1.1
B-2.13
C-2.1
1.17
772.6
589 A-1.14
B-3.1
C-10.19
1.24
811.6
590 A-1.1
B-3.1
C-10.19
1.26
797.7
591 A-1.1
B-1.5
C-2.2
1.25
770.6
592 A-1.3
B-3.1
C-2.8
1.04
753.7
593 A-1.3
B-3.1
C-2.2
1.05
753.7
594 A-1.6
B-3.1
C-2.2
1.03
769.7
595 A-1.1
B-1.13
C-1.1
1.22
750.6
596 A-1.2
B-1.11
C-10.19
1.48
882.8
597 A-1.3
B-1.11
C-10.19
1.43
868.8
598 A-1.1
B-2.5
C-1.1
1.08
755.5
599 A-1.2
B-1.13
C-10.19
1.54
872.9
600 A-1.3
B-1.13
C-10.19
1.51
856.8 [M-H]
-
601 A-1.1
B-1.1
C-2.8
1.24
800.8
602 A-1.1
B-1.1
C-2.2
1.26
800.7
603 A-1.1
B-1.13
C-2.2
1.37
790.8
604 A-1.1
B-1.13
C-2.8
1.34
790.8
605 A-1.1
B-1.5
C-3.2
0.79
799.8
606 A-1.8
B-1.13
C-2.8
1.22
765.7
607 A-1.8
B-1.13
C-2.2
1.24
765.6
608 A-1.8
B-1.13
C-2.1
1.13
767.6
609 A-1.8
B-1.1
C-2.2
1.14
775.6
610 A-1.14
B-1.14
C-10.19
1.41
861.7
611 A-1.1
B-1.5
C-3.3
0.81
813.8
612 A-1.1
B-1.5
C-3.4
0.95
827.7
613 A-1.15
B-1.13
C-3.4
1.05
877.8
614 A-1.1
B-2.5
C-2.2
1.23
795.6
615 A-1.1
B-2.5
C-2.8
1.20
795.8
616 A-1.14
B-5.2
C-1.1
1.15
780.5
617 A-1.8
B-1.13
C-3.4
0.94
822.7
618 A-1.15
B-1.13
C-3.3
0.92
863.8
619 A-1.1
B-2.5
C-3.4
0.95
852.8
620 A-1.8
B-2.5
C-3.4
0.84
827.8
621* A-1.8
B-2.5
C-3.4
0.83
827.8
622 A-1.8
B-1.14
C-3.4
0.86
823.7
623 A-1.8
B-1.13
C-3.3
0.82
808.7
624 A-1.1
B-6.1
C-2.1
1.12
797.6
625 A-1.10
B-2.5
C-2.1
1.15
833.7
626 A-1.14
B-1.13
C-10.25
1.39
868.8
627 A-1.6
B-1.20
C-2.1
1.15
839.7
628 A-1.1
B-2.5
C-1.2
1.17
781.7
629 A-1.8
B-6.1
C-2.2
1.14
770.7
630 A-1.8
B-6.1
C-2.5
1.21
796.6
631* A-1.8
B-6.1
C-2.5
1.18
796.6
632 A-1.8
B-2.5
C-2.2
1.10
770.6
633 A-1.8
B-1.13
C-2.4
1.19
795.7
634 A-1.20
B-6.1
C-2.2
1.28
801.7
635 A-1.20
B-6.1
C-2.8
1.25
801.7
636 A-1.20
B-1.19
C-2.2
1.34
815.7
637 A-1.19
B-1.19
C-2.2
1.23
811.7
638 A-1.18
B-1.20
C-2.2
1.23
810.6
639 A-1.18
B-1.19
C-2.2
1.26
810.7
640 A-1.24
B-1.19
C-2.2
1.25
810.7
641 A-1.22
B-1.19
C-2.2
1.24
811.8
642 A-1.24
B-1.14
C-2.2
1.20
792.6
643 A-1.18
B-1.19
C-2.1
1.15
812.6
644 A-1.24
B-1.19
C-2.1
1.13
812.6
645 A-1.22
B-1.19
C-2.1
1.13
813.7
646 A-1.22
B-1.14
C-14.1
1.25
807.7
647 A-1.1
B-4.11
C-1.1
1.14
731.5
648 A-1.24
B-4.11
C-1.2
1.14
758.7
649 A-1.19
B-4.11
C-1.2
1.12
759.7
650 A-1.1
B-4.11
C-1.2
1.21
757.6
651 A-1.7
B-1.21
C-2.2
1.28
795.7
652 A-1.24
B-4.11
C-2.2
1.21
772.7
653 A-1.7
B-4.3
C-2.2
1.26
823.7
654 A-1.8
B-1.13
C-1.2
1.18
751.7
655 A-1.24
B-4.9
C-2.2
1.23
810.6
656 A-1.22
B-4.12
C-2.2
1.19
787.6
657 A-1.22
B-4.13
C-2.2
1.19
790.7
658 A-1.24
B-4.12
C-2.2
1.19
786.6
659 A-1.24
B-4.13
C-2.2
1.19
789.7
660 A-1.24
B-1.27
C-2.2
1.19
810.8
661 A-1.24
B-1.18
C-18.1
1.22
864.8
662 A-1.24
B-1.18
C-18.1
1.26
864.7
663 A-1.24
B-1.18
C-2.9
1.12
808.6
664 A-1.18
B-4.13
C-2.2
1.21
789.7
665 A-1.30
B-1.19
C-2.2
1.22
810.8
666 A-1.19
B-4.13
C-2.2
1.17
790.7
667 A-1.31
B-4.12
C-2.8
1.25
814.7
668 A-1.24
B-1.18
C-2.13
1.23
798.7
669 A-1.24
B-1.18
C-2.13
1.18
798.8
670 差向異構物 1 A-1.24
B-1.18
C-19.1
1.23
848.8
671 差向異構物 2 A-1.24
B-1.18
C-19.1
1.26
848.8
672 差向異構物 3 A-1.24
B-1.18
C-19.1
1.28
848.7
673 差向異構物 4 A-1.24
B-1.18
C-19.1
1.30
848.7
674 差向異構物 1 A-1.24
B-1.14
C-19.1
1.27
868.7
675 差向異構物 2 A-1.24
B-1.14
C-19.1
1.31
868.7
676 差向異構物 3 A-1.24
B-1.14
C-19.1
1.33
868.7
677 差向異構物 4 A-1.24
B-1.14
C-19.1
1.35
868.7
678 A-1.8
B-1.18
C-2.11
1.15
794.6
679 A-1.8
B-1.18
C-2.10
1.14
794.6
680 A-1.1
B-1.14
C-1.4
1.21
765.7
681 A-1.19
B-1.18
C-2.12
1.19
809.6
682 A-1.18
B-1.18
C-18.1
1.27
864.7
683 A-1.8
B-4.12
C-2.13
1.22
786.6
684 A-1.28
B-4.12
C-2.13
1.20
802.7
685 A-1.30
B-4.13
C-2.2
1.16
789.6
686 A-1.28
B-1.14
C-1.2
1.09
768.6
687 A-1.14
B-2.14
C-1.1
1.13
714.7
688 A-1.6
B-2.14
C-1.1
1.12
728.7
768 A-1.1
B-1.18
C-1.4
1.12
745.5
769 A-1.28
B-4.9
C-2.2
1.18
800.5
770 A-1.28
B-4.9
C-2.8
1.14
800.4
771 A-1.28
B-1.18
C-1.4
1.02
736.4
772 A-1.28
B-4.15
C-1.4
1.07
750.5
773 A-1.8
B-4.15
C-18.2
1.11
748.5
774 A-1.1
B-4.15
C-18.2
1.23
773.5
775 A-1.8
B-4.15
C-18.6
1.13
784.5
776 A-1.28
B-1.18
C-2.15
1.14
804.4
777 A-1.24
B-4.9
C-2.8
1.18
810.5
778 A-1.38
B-4.9
C-2.2
1.22
810.5
779 A-1.38
B-4.9
C-2.8
1.18
810.5
780 A-1.22
B-4.9
C-2.2
1.22
811.5
781 A-1.18
B-4.9
C-2.2
1.23
810.5
782 A-1.19
B-1.18
C-22.1
1.11
910.5
783 A-1.28
B-1.18
C-22.1
1.09
899.5
784 A-1.28
B-4.15
C-18.2
1.12
764.5
785 A-1.28
B-4.15
C-18.6
1.14
800.5
786 A-1.28
B-4.9
C-1.4
1.11
774.4
787 A-1.38
B-4.9
C-1.4
1.15
784.5
788 A-1.1
B-2.17
C-1.4
0.88
754.5
789 A-1.28
B-2.17
C-1.4
0.80
745.5
790 A-1.24
B-2.17
C-1.4
0.83
755.5
791 A-1.28
B-4.15
C-2.15
1.19
818.4
792* A-1.28
B-4.15
C-2.15
1.17
818.4
793 A-1.19
B-4.9
C-2.8
1.16
811.5
794 A-1.19
B-4.9
C-22.1
1.19
948.5
795 A-1.28
B-4.9
C-22.1
1.17
937.5
796 A-1.28
B-7.2
C-2.2
0.86
796.5
797 A-1.24
B-4.9
C-1.4
1.16
784.5
798 A-1.18
B-4.9
C-1.4
1.17
784.5
799 A-1.19
B-4.9
C-1.4
1.13
785.5
800 A-1.22
B-4.9
C-1.4
1.15
785.4
801 A-1.19
B-4.9
C-18.6
1.20
835.5
802* A-1.19
B-4.9
C-18.6
1.17
835.5
803 A-1.19
B-4.9
C-18.2
1.18
799.4
804 A-1.37
B-4.9
C-22.1
1.18
948.5
805 A-1.30
B-4.9
C-2.2
1.19
810.3
806 A-1.37
B-4.15
C-2.15
1.21
829.5
807 A-1.8
B-4.9
C-22.1
1.16
921.5
808 A-1.22
B-4.9
C-22.1
1.20
948.5
809 A-1.28
B-1.19
C-22.2
1.28
910.4
810* A-1.28
B-1.19
C-22.2
1.25
910.4
811 A-1.19
B-1.19
C-22.2
1.31
921.5
812* A-1.19
B-1.19
C-22.2
1.28
921.5
813 A-1.19
B-1.19
C-22.1
1.20
948.5
814* A-1.19
B-1.19
C-22.1
1.18
948.5
815 A-1.28
B-1.19
C-22.1
1.18
937.5
816* A-1.28
B-1.19
C-22.1
1.16
937.5
817 A-1.37
B-4.9
C-1.2
1.12
797.5
818 A-1.28
B-4.9
C-1.2
1.11
786.5
819 A-1.28
B-4.9
C-18.6
1.17
824.4
820 A-1.19
B-4.15
C-22.2
1.26
897.5
821 A-1.36
B-4.9
C-2.2
1.15
801.5
822 A-1.28
B-4.14
C-2.2
1.11
796.5
823 A-1.37
B-7.2
C-2.2
0.87
807.5
824 A-1.8
B-7.2
C-1.4
0.80
754.5
825 A-1.28
B-7.2
C-1.4
0.81
770.5
826 A-1.22
B-7.2
C-1.4
0.83
781.5
827 A-1.28
B-1.19
C-23.1
1.13
879.5
828 A-1.35
B-4.15
C-18.4
1.26
787.5
829 A-1.37
B-4.9
C-2.2
1.19
811.5
851 A-1.19
B-1.19
C-20.5
1.09
881.4
852 A-1.8
B-1.23
C-8.2
1.11
862.4
853 A-1.1
B-1.23
C-8.2
1.21
887.4
854 A-1.28
B-1.18
C-18.1
1.14
854.4
855 A-1.8
B-1.18
C-27.2
1.13
826.4
856 A-1.28
B-1.18
C-27.2
1.14
842.4
857 A-1.19
B-1.18
C-2.16
1.13
817.4
858 A-1.8
B-1.18
C-27.1
1.19
832.5
859 A-1.19
B-1.18
C-24.1
1.17
891.4
860 A-1.1
B-4.16
C-1.4
1.12
760.4
861 A-1.19
B-1.18
C-25.1
1.02
844.4
862 A-1.24
B-4.16
C-1.4
1.07
761.4
863 A-1.19
B-1.18
C-2.17
1.08
787.4
864 A-1.19
B-1.18
C-20.2
1.07
869.4
865 A-1.1
B-4.15
C-29.1
1.30
801.5
866 A-1.8
B-4.15
C-29.1
1.20
776.4
867 A-1.19
B-1.18
C-22.4
1.17
949.5
868 A-1.28
B-1.18
C-22.4
1.15
938.4
869 A-1.8
B-4.17
C-2.2
1.08
776.4
870 A-1.24
B-4.17
C-2.2
1.13
802.4
871 A-1.38
B-1.18
C-22.4
1.19
948.5
872 A-1.36
B-1.14
C-1.2
1.00
769.4
873 A-1.1
B-4.15
C-18.10
1.31
815.5
874 A-1.8
B-4.15
C-29.2
1.20
824.4
875 A-1.1
B-4.15
C-29.2
1.29
849.5
876 A-1.8
B-4.15
C-18.10
1.22
790.4
877 A-1.28
B-4.15
C-18.9
1.07
808.4
878 A-1.28
B-4.15
C-18.10
1.23
806.4
879 A-1.19
B-4.9
C-25.1
1.10
882.4
880 A-1.28
B-4.9
C-25.1
1.08
871.4
881 A-1.19
B-1.18
C-20.4
1.16
885.5
882 A-1.19
B-1.18
C-26.1
1.06
890.4
883 A-1.19
B-1.18
C-20.3
1.18
897.5
884 A-1.28
B-1.18
C-20.3
1.16
886.4
885 A-1.19
B-1.19
C-26.2
1.11
947.4
886 A-1.19
B-1.19
C-25.2
1.23
908.4
887 A-1.19
B-1.19
C-22.5
1.14
962.4
888 A-1.37
B-4.14
C-2.2
1.07
807.4
889 A-1.19
B-7.2
C-22.2
0.92
917.4
890 A-1.37
B-7.2
C-22.2
0.92
917.4
891 A-1.40
B-4.9
C-22.1
1.06
964.39
892 A-1.39
B-4.9
C-22.1
1.07
964.4
893 A-1.37
B-4.9
C-18.6
1.12
835.4
894 A-1.8
B-4.9
C-18.9
1.09
816.4
895 A-1.28
B-4.9
C-18.9
1.10
832.4
896 A-1.37
B-4.9
C-18.9
1.12
843.4
897 A-1.28
B-4.15
C-22.2
1.17
886.4
898 A-1.28
B-7.2
C-22.2
0.91
906.4
899 A-1.28
B-4.18
C-2.2
1.08
800.4
900 A-1.19
B-7.2
C-1.2
0.78
793.4
901 A-1.28
B-7.2
C-1.2
0.76
782.4
902 A-1.37
B-4.15
C-22.2
1.18
897.4
903 A-1.41
B-4.15
C-22.2
1.21
906.4
904 A-1.41
B-7.2
C-1.2
0.80
802.4
905 A-1.19
B-7.2
C-22.1
0.84
944.4
906 A-1.28
B-7.2
C-22.1
0.83
933.4
907 A-1.37
B-7.2
C-22.1
0.84
944.4
908 A-1.44
B-4.9
C-22.2
1.08
931.4
909 A-1.28
B-4.14
C-22.2
1.16
906.4
910 A-1.24
B-4.15
C-18.9
1.10
818.4
911 A-1.36
B-4.9
C-1.2
1.02
787.4
912 A-1.28
B-4.7
C-2.2
0.97
782.4
913 A-1.28
B-7.2
C-18.9
0.83
828.4
914 A-1.36
B-7.2
C-18.9
0.80
829.4
915 A-1.37
B-7.2
C-18.9
0.83
839.5
916 A-1.36
B-4.9
C-22.1
1.08
938.4
917 A-1.36
B-7.2
C-22.1
0.82
934.4
918 A-1.36
B-7.2
C-22.2
0.89
907.4
919 A-1.36
B-4.15
C-22.2
1.15
887.4
920 A-1.36
B-4.14
C-2.2
1.02
797.4
921 A-1.37
B-7.2
C-22.3
0.86
899.4
922 A-1.36
B-4.9
C-5.4
1.10
837.4
923 A-1.37
B-4.14
C-22.2
1.17
917.4
924 A-1.37
B-4.9
C-22.2
1.21
921.4
925 A-1.42
B-4.9
C-22.2
1.28
911.3
926 A-1.28
B-4.9
C-2.4
1.06
830.4
927 A-1.36
B-4.14
C-22.2
1.14
907.4
928* A-1.37
B-4.14
C-2.2
1.06
807.4
929 A-1.36
B-4.9
C-18.9
1.08
833.4
930 A-1.36
B-1.19
C-2.2
1.09
801.4
931 A-1.28
B-7.2
C-18.6
0.82
820.4
932 A-1.36
B-7.2
C-18.6
0.80
821.4
933 A-1.37
B-7.2
C-18.6
0.84
831.4
934 A-1.36
B-4.9
C-22.2
1.18
911.3
935 A-1.19
B-4.14
C-22.2
1.18
917.4
936 A-1.22
B-4.14
C-22.2
1.19
917.4
937 A-1.41
B-4.9
C-22.2
1.24
930.4
938 A-1.36
B-7.2
C-2.15
0.84
839.4
939* A-1.36
B-7.2
C-2.15
0.82
839.4
940* A-1.36
B-4.9
C-2.15
1.11
843.3
941 A-1.36
B-4.9
C-2.15
1.13
843.3
942 A-1.36
B-4.15
C-2.15
1.10
819.4
943 A-1.39
B-4.15
C-22.2
1.16
913.4
944 A-1.43
B-4.9
C-22.2
1.23
893.3
945 A-1.46
B-4.15
C-22.2
1.21
904.4
946 A-1.8
B-4.9
C-18.6
1.10
808.4
947 A-1.36
B-4.9
C-18.6
1.08
825.4
948 A-1.28
B-1.18
C-22.2
1.13
872.4
949 A-1.36
B-1.18
C-22.2
1.11
873.4
950 A-1.19
B-7.2
C-2.15
0.87
849.4
951 A-1.22
B-7.2
C-2.15
0.88
849.4
952 A-1.22
B-7.2
C-5.4
0.85
843.4
953 A-1.28
B-7.2
C-5.4
0.83
832.4
954 A-1.36
B-7.2
C-5.4
0.81
833.4
955 A-1.37
B-7.2
C-5.4
0.84
843.4
956 A-1.24
B-7.2
C-2.15
0.89
848.4
957 A-1.28
B-7.2
C-2.15
0.86
838.4
958 A-1.18
B-7.2
C-2.15
0.90
848.4
959 A-1.37
B-7.2
C-2.15
0.87
849.4
960 A-1.46
B-7.2
C-2.15
0.90
856.4
961 A-1.45
B-4.15
C-22.2
1.12
913.4
962 A-1.45
B-4.9
C-22.2
1.14
937.4
963 A-1.46
B-4.9
C-1.2
1.10
804.4
964 A-1.22
B-4.9
C-22.2
1.23
921.4
965 A-1.8
B-4.9
C-22.2
1.19
894.4
966 A-1.39
B-4.9
C-22.2
1.17
937.4
967 A-1.46
B-4.9
C-18.6
1.15
842.3
968 A-1.46
B-4.15
C-18.6
1.12
818.4
969 A-1.46
B-4.9
C-5.4
1.17
854.3
970 A-1.46
B-7.2
C-18.6
0.86
838.4
971 A-1.36
B-4.9
C-25.3
1.18
899.4
972 A-1.28
B-4.9
C-25.3
1.20
898.4
973 A-1.46
B-4.9
C-2.2
1.16
818.4
974 A-1.28
B-2.5
C-2.15
1.09
828.4
975 A-1.36
B-4.14
C-2.15
1.08
839.4
example A B C t R [min] LC-MS method H MS- data m/z [M+H] +
223 A-1.14 B-1.16 C-1.1 1.13 758.6
224 A-1.1 B-1.16 C-1.1 1.15 744.7
225 A-1.12 B-1.16 C-1.1 1.21 758.7
226 A-1.6 B-1.16 C-1.1 1.11 772.5
227 A-1.25 B-1.16 C-1.1 1.27 742.6
228 A-1.14 B-2.13 C-1.1 1.14 744.5
229 A-1.14 B-1.3 C-1.1 1.17 728.6
230 A-1.1 B-1.3 C-1.1 1.20 714.7
231 A-1.1 B-2.13 C-1.1 1.17 730.7
232 A-1.1 B-1.22 C-1.1 1.16 730.7
233 A-1.1 B-1.4 C-1.1 1.19 714.7
234 A-1.14 B-1.9 C-1.1 1.16 732.5
235 A-1.14 B-1.2 C-1.1 1.15 728.5
236 A-1.14 B-1.12 C-1.1 1.22 764.7
237 A-1.1 B-1.8 C-1.1 1.22 732.7 [MH] -
238 A-1.1 B-1.12 C-1.1 1.25 750.6
239 A-1.25 B-1.5 C-1.1 1.24 728.6
240 A-1.1 B-2.4 C-1.1 1.13 706.6
241 A-1.1 B-2.3 C-1.1 1.13 721.6
242 A-1.14 B-5.1 C-10.19 1.42 843.8
243 A-1.1 B-5.1 C-10.19 1.45 829.7
244 A-1.23 B-5.1 C-10.19 1.44 832.9
245 A-1.2 B-2.13 C-1.1 1.21 756.7
246 A-1.14 B-1.2 C-10.19 1.46 824.7
247 A-1.1 B-1.2 C-10.19 1.49 810.7
248 A-1.14 B-2.13 C-10.19 1.44 840.8
249 A-1.1 B-2.13 C-10.19 1.47 826.8
250 A-1.14 B-1.12 C-10.19 1.51 860.7
251 A-1.1 B-1.12 C-10.19 1.53 846.7
252 A-1.25 B-3.1 C-1.1 1.04 699.5
253 A-1.14 B-1.8 C-10.19 1.49 844.6
254 A-1.1 B-1.8 C-10.19 1.51 828.8 [MH] -
255 A-1.14 B-1.1 C-10.19 1.42 870.7
256 A-1.1 B-1.1 C-10.19 1.44 856.9
257 A-1.14 B-1.5 C-10.23 1.24 784.6
258 A-1.1 B-1.5 C-10.23 1.26 770.7
259 A-1.4 B-1.5 C-2.1 1.22 820.5
260 A-1.5 B-1.5 C-2.1 1.22 812.7
261 A-1.2 B-3.1 C-10.19 1.31 823.7
262 A-1.3 B-3.1 C-10.19 1.26 809.7
263 A-1.14 B-1.5 C-10.24 1.28 798.8
264 A-1.1 B-1.5 C-10.24 1.29 784.8
265 A-1.14 B-3.2 C-10.19 1.36 811.7
266 A-1.1 B-3.2 C-10.19 1.39 797.7
267 A-1.14 B-1.13 C-10.19 1.49 860.7
268 A-1.1 B-1.13 C-10.19 1.51 846.7
269 A-1.14 B-1.13 C-1.1 1.20 764.7
270 A-1.14 B-1.10 C-10.19 1.16 825.8
271 A-1.1 B-1.10 C-10.19 1.18 811.7
272 A-1.14 B-1.1 C-10.24 1.27 828.7
273 A-1.1 B-1.1 C-10.24 1.30 814.6
274 A-1.14 B-1.5 C-10.26 1.38 838.7
275 A-1.2 B-1.1 C-10.19 1.47 882.9
276 A-1.3 B-1.1 C-10.19 1.44 868.8
277 A-1.1 B-2.1 C-1.1 1.14 718.6
278 A-1.14 B-2.1 C-1.1 1.11 732.6
279 A-1.14 B-2.2 C-1.1 1.15 746.7 [MH] -
280 A-1.1 B-1.17 C-2.2 1.30 784.6
281 A-1.14 B-1.18 C-10.19 1.37 841.7
282 A-1.1 B-1.18 C-10.19 1.39 827.8
283 A-1.6 B-1.17 C-2.2 1.27 812.8
284 A-1.14 B-1.13 C-10.2 1.37 874.8
285 A-1.14 B-1.13 C-10.4 1.42 888.8
286 A-1.14 B-1.13 C-10.1 1.39 874.8
287 A-1.14 B-1.13 C-10.3 1.44 888.8
288 A-1.14 B-1.13 C-10.14 1.38 888.8
289 A-1.14 B-1.13 C-10.15 1.43 902.8
290 A-1.14 B-1.13 C-10.16 1.54 886.8
291 A-1.14 B-1.13 C-10.17 1.58 900.9
292 A-1.14 B-1.13 C-10.18 1.50 872.7
293 A-1.1 B-1.13 C-10.2 1.40 860.7
294 A-1.1 B-1.13 C-10.4 1.45 874.7
295 A-1.1 B-1.13 C-10.1 1.42 860.7
296 A-1.1 B-1.13 C-10.3 1.47 874.7
297 A-1.1 B-1.13 C-4.10 1.35 848.7
298 A-1.1 B-1.13 C-10.14 1.41 874.8
299 A-1.1 B-1.13 C-10.15 1.46 888.9
300 A-1.1 B-1.13 C-10.16 1.57 872.8
301 A-1.1 B-1.13 C-10.17 1.60 886.9
302 A-1.1 B-1.13 C-10.18 1.53 858.7
303 A-1.1 B-1.13 C-10.19 1.51 846.8
304 A-1.14 B-1.5 C-4.10 1.24 842.7
305 A-1.14 B-1.5 C-10.20 1.26 828.7
306 A-1.14 B-1.5 C-10.21 1.24 828.6
307 A-1.14 B-1.5 C-10.1 1.32 854.8
308 A-1.14 B-1.5 C-10.2 1.30 854.8
309 A-1.14 B-1.5 C-10.4 1.35 868.7
310 A-1.1 B-1.5 C-4.10 1.27 828.7
311 A-1.1 B-1.5 C-10.20 1.28 814.7
312 A-1.1 B-1.5 C-10.21 1.26 814.7
313 A-1.1 B-1.5 C-10.1 1.35 840.7
314 A-1.1 B-1.5 C-10.4 1.38 854.7
315 A-1.1 B-1.14 C-10.19 1.43 847.8
316 A-1.23 B-1.14 C-10.19 1.43 850.8
317 A-1.1 B-4.1 C-1.1 1.23 784.6
318 A-1.14 B-1.14 C-1.1 1.10 765.5
319 A-1.1 B-1.14 C-1.1 1.12 751.6
320 A-1.23 B-1.14 C-1.1 1.12 754.6
321 A-1.14 B-4.2 C-1.1 1.09 758.6
322 A-1.14 B-4.3 C-1.1 1.09 760.5
323 A-1.1 B-4.2 C-1.1 1.12 744.6
324 A-1.1 B-4.3 C-1.1 1.11 746.6
325 A-1.15 B-1.13 C-2.1 1.25 822.7
326 A-1.14 B-1.13 C-2.1 1.23 806.7
327 A-1.16 B-1.13 C-2.1 1.21 803.7
328 A-1.15 B-2.7 C-2.2 1.04 824.8
329 A-1.14 B-2.7 C-2.2 1.01 808.6
330 A-1.14 B-1.13 C-4.4 1.26 874.7
331 A-1.14 B-1.13 C-4.5 1.38 888.8
332 A-1.14 B-1.13 C-4.6 1.27 848.8
333 A-1.14 B-1.13 C-4.7 1.27 862.7
334 A-1.14 B-1.13 C-4.8 1.29 932.8
335 A-1.14 B-1.13 C-4.2 1.35 850.7
336 A-1.14 B-1.13 C-4.11 1.29 862.7
337 A-1.14 B-1.13 C-10.5 1.33 860.6
338 A-1.14 B-1.13 C-10.6 1.35 860.7
339 A-1.14 B-1.13 C-4.12 1.38 842.8
340 A-1.14 B-1.13 C-10.7 1.29 846.8
341 A-1.14 B-1.13 C-10.26 1.45 858.8
342 A-1.1 B-2.6 C-2.8 1.19 781.6
343 A-1.1 B-2.6 C-2.2 1.22 781.7
344 A-1.8 B-1.14 C-10.19 1.32 822.7
345 A-1.14 B-4.2 C-10.19 1.41 854.7
346 A-1.1 B-4.2 C-10.19 1.43 840.7
347 A-1.23 B-4.2 C-10.19 1.43 843.7
348 A-1.1 B-2.7 C-3.7 0.96 835.8
349 A-1.14 B-1.20 C-1.1 1.12 783.5
350 A-1.1 B-1.20 C-1.1 1.14 769.6
351 A-1.1 B-2.15 C-2.2 1.22 795.6
352 A-1.1 B-2.5 C-3.3 0.78 838.8
353 A-1.1 B-2.7 C-3.3 0.68 837.7
354 A-1.1 B-1.13 C-6.3 0.97 849.7
355 A-1.1 B-1.13 C-3.5 0.97 845.7
356 A-1.1 B-1.13 C-3.7 1.246 831.8
357* A-1.1 B-1.13 C-3.7 1.17 831.7
358 A-1.14 B-1.13 C-10.8 1.29 860.8
359 A-1.14 B-1.13 C-10.9 1.28 860.7
360 A-1.14 B-1.13 C-10.10 1.34 874.8
361 A-1.14 B-1.13 C-10.11 1.34 874.8
362 A-1.14 B-1.13 C-10.12 1.33 862.8
363 A-1.14 B-1.13 C-10.13 1.33 862.8
364 A-1.1 B-2.7 C-3.4 0.82 851.7
365 A-1.1 B-1.14 C-2.2 1.27 791.8
366 A-1.1 B-1.14 C-2.8 1.24 791.7
367 A-1.8 B-1.14 C-2.2 1.15 766.6
368 A-1.15 B-2.15 C-2.2 1.22 825.7
369 A-1.1 B-1.13 C-7.1 1.44 965.7
370 A-1.11 B-1.13 C-2.1 1.23 809.6
371 A-1.10 B-1.13 C-2.1 1.29 828.7
372 A-1.1 B-1.14 C-3.4 0.97 848.7
373* A-1.1 B-1.14 C-3.4 0.95 848.7
374 A-1.1 B-1.14 C-3.3 0.84 834.6
375 A-1.8 B-1.14 C-3.3 0.74 809.7
376 A-1.1 B-1.13 C-1.3 1.34 788.6
377 A-1.15 B-2.9 C-2.2 0.94 838.8
378 A-1.9 B-1.13 C-2.1 1.16 Method I 842.52
379 A-1.14 B-2.5 C-10.19 1.38 865.8
380 A-1.1 B-2.5 C-10.19 1.41 851.7
381 A-1.23 B-2.5 C-10.19 1.41 854.7
382 A-1.14 B-1.20 C-10.19 1.42 879.8
383 A-1.1 B-1.20 C-10.19 1.44 865.7
384 A-1.23 B-1.20 C-10.19 1.44 868.8
385 A-1.1 B-1.13 C-1.2 1.30 776.6
386 A-1.1 B-1.13 C-2.7 1.31 762.6
387 A-1.7 B-1.13 C-2.1 1.26 829.8
388* A-1.1 B-1.14 C-3.7 1.14 832.7
389 A-1.1 B-1.14 C-3.7 1.13 832.7
390* A-1.1 B-1.14 C-3.5 0.93 846.8
391 A-1.1 B-1.14 C-3.5 0.89 846.7
392* A-1.14 B-1.14 C-3.7 1.13 846.8
393 A-1.14 B-1.14 C-3.7 1.13 846.8
394* A-1.14 B-1.14 C-3.5 0.91 860.8
395 A-1.14 B-1.14 C-3.5 0.88 860.8
396 A-1.1 B-1.13 C-6.4 1.34 834.8
397 A-1.12 B-1.13 C-2.1 1.31 806.8
398 A-1.10 B-1.14 C-3.7 1.20 868.8
399* A-1.10 B-1.14 C-3.7 1.18 868.7
400 A-1.12 B-1.14 C-3.7 1.22 846.8
401* A-1.12 B-1.14 C-3.7 1.20 846.8
402 A-1.8 B-1.14 C-3.7 1.01 805.8 [MH] -
403* A-1.8 B-1.14 C-3.7 1.03 807.7
404 A-1.11 B-1.14 C-3.7 1.14 849.8
405* A-1.11 B-1.14 C-3.7 1.16 849.8
406 A-1.1 B-2.8 C-2.2 1.27 795.8
407 A-1.1 B-2.8 C-2.1 1.13 797.6
408 A-1.14 B-4.4 C-1.1 1.20 794.6
409 A-1.1 B-4.4 C-1.1 1.22 780.6
410 A-1.8 B-2.5 C-10.19 1.230 826.8
411 A-1.8 B-1.20 C-10.19 1.34 840.8
412 A-1.1 B-1.14 C-2.1 1.16 793.6
413* A-1.1 B-1.14 C-2.1 1.16 793.6
414 A-1.10 B-1.14 C-6.3 0.94 886.7
415 A-1.11 B-1.14 C-6.3 0.87 867.7
416 A-1.1 B-1.13 C-6.2 0.90 835.6
417 A-1.1 B-2.5 C-3.7 1.09 836.6
418 A-1.12 B-2.5 C-3.7 1.15 850.7
419 A-1.10 B-2.5 C-3.7 1.14 872.7
420 A-1.11 B-2.5 C-3.7 1.07 853.6
421 A-1.6 B-2.5 C-3.7 1.07 864.8
422 A-1.26 B-2.5 C-10.19 1.46 885.8
423 A-1.1 B-6.2 C-2.2 1.25 794.6
424 A-1.1 B-6.2 C-2.1 1.13 796.7
425 A-1.1 B-2.5 C-3.6 0.81 850.7
426 A-1.10 B-2.5 C-3.6 0.86 886.7
427 A-1.12 B-2.5 C-3.6 0.85 864.7
428 A-1.7 B-2.5 C-3.6 0.82 887.8
429 A-1.8 B-6.2 C-2.2 1.13 769.6
430 A-1.14 B-2.10 C-1.1 1.11 754.7
431 A-1.1 B-1.13 C-12.1 1.35 822.7
432 A-1.8 B-1.14 C-11.1 1.16 778.7
433 A-1.1 B-1.14 C-1.2 1.21 777.6
434 A-1.8 B-1.14 C-1.2 1.08 752.7
435 A-1.8 B-2.5 C-2.6 1.06 798.7
436 A-1.8 B-2.5 C-2.5 1.19 796.6
437* A-1.8 B-2.5 C-2.5 1.16 796.8
438 A-1.1 B-1.18 C-1.2 1.13 757.6
439 A-1.1 B-1.20 C-1.2 1.23 795.7
440 A-1.8 B-1.20 C-1.2 1.09 770.6
441 A-1.1 B-4.7 C-1.1 1.01 751.7
442 A-1.1 B-2.10 C-1.2 1.19 766.6
443 A-1.8 B-1.20 C-2.2 1.17 784.7
444 A-1.8 B-4.5 C-2.2 0.83 730.6
445 A-1.8 B-1.14 C-10.20 1.13 810.6
446 A-1.8 B-1.14 C-10.12 1.13 824.7
447 A-1.1 B-4.6 C-1.2 1.18 768.6
448 A-1.8 B-2.10 C-1.2 1.06 741.6
449 A-1.1 B-2.10 C-1.1 1.12 740.5
450 A-1.1 B-2.11 C-1.1 1.17 742.6
451 A-1.1 B-1.13 C-6.1 0.89 849.7
452 A-1.8 B-1.13 C-6.1 0.78 824.7
453 A-1.17 B-1.14 C-1.2 1.21 814.8
454 A-1.7 B-1.14 C-1.2 1.21 814.6
455 A-1.8 B-4.6 C-2.2 1.13 757.6
456 A-1.1 B-4.6 C-2.2 1.25 782.6
457 A-1.1 B-1.13 C-13.1 1.33 820.7
458 A-1.8 B-1.14 C-7.1 1.25 941.6
459 A-1.1 B-1.14 C-3.1 0.82 806.8
460 A-1.1 B-4.7 C-1.2 1.09 777.7
461 A-1.17 B-1.14 C-2.2 1.27 828.7
462 A-1.17 B-1.14 C-2.8 1.24 828.7
463 A-1.7 B-1.14 C-2.2 1.28 828.8
464 A-1.7 B-1.14 C-2.8 1.24 828.6
465 A-1.1 B-7.1 C-1.1 0.82 751.6
466 A-1.17 B-1.18 C-2.2 1.21 808.7
467 A-1.17 B-1.18 C-2.8 1.17 808.6
468 A-1.7 B-1.18 C-2.2 1.21 808.7
469 A-1.1 B-2.10 C-2.2 1.25 780.6
470 A-1.8 B-2.10 C-2.2 1.12 755.6
471 A-1.1 B-4.8 C-1.2 0.89 777.7
472 A-1.7 B-4.7 C-2.2 1.16 828.8
473 A-1.7 B-4.7 C-2.8 1.13 828.6
474 A-1.8 B-4.7 C-2.2 1.02 766.7
475 A-1.8 B-1.13 C-9.1 1.15 907.7
476 A-1.24 B-1.14 C-1.2 1.14 778.7
477 A-1.8 B-1.18 C-2.2 1.09 746.7
478 A-1.20 B-1.18 C-2.2 1.24 777.7
479 A-1.8 B-1.13 C-9.2 1.19 937.7
480 A-1.8 B-1.19 C-2.2 1.19 784.7
481 A-1.7 B-1.19 C-2.2 1.32 846.7
482 A-1.20 B-2.5 C-2.2 1.26 801.6
483 A-1.19 B-1.18 C-2.2 1.12 773.6
484 A-1.20 B-2.10 C-2.2 1.28 786.7
485 A-1.20 B-2.7 C-2.2 1.06 800.6
486 A-1.19 B-4.7 C-2.2 1.07 793.8
487 A-1.8 B-1.23 C-2.2 1.12 766.7
488 A-1.1 B-2.12 C-1.2 1.15 757.6
489 A-1.19 B-1.19 C-2.1 1.12 813.7
490 A-1.20 B-6.2 C-2.2 1.28 800.6
491 A-1.20 B-4.6 C-2.2 1.28 788.6
492 A-1.7 B-1.13 C-2.4 1.32 857.8
493 A-1.7 B-1.14 C-2.4 1.23 858.7
494 A-1.1 B-7.1 C-1.2 0.91 777.7
495 A-1.8 B-1.14 C-5.1 1.24 828.6
496 A-1.21 B-1.14 C-1.2 1.18 825.8
497 A-1.18 B-1.20 C-2.8 1.20 810.6
498 A-1.19 B-1.20 C-2.2 1.20 811.6
499 A-1.24 B-1.20 C-2.2 1.22 810.6
500 A-1.24 B-1.20 C-2.8 1.18 810.6
501 A-1.22 B-1.20 C-2.2 1.22 811.7
502 A-1.27 B-1.14 C-1.2 1.15 825.7
503 A-1.1 B-1.14 C-5.2 1.21 779.7
504 A-1.18 B-4.7 C-2.2 1.11 792.8
505 A-1.22 B-4.7 C-2.2 1.07 793.6
506 A-1.8 B-1.14 C-14.1 1.20 780.8
507 A-1.1 B-4.9 C-1.1 1.14 769.5
508 A-1.8 B-1.13 C-5.3 1.22 765.7
509 A-1.1 B-1.14 C-8.1 1.36 868.7
510 A-1.8 B-1.14 C-8.1 1.26 843.8
511 A-1.22 B-1.18 C-2.2 1.14 773.7
512 A-1.18 B-1.18 C-2.2 1.16 772.7
513 A-1.1 B-4.10 C-1.1 1.07 731.6
514 A-1.24 B-4.7 C-2.2 1.09 792.7
515 A-1.22 B-4.11 C-2.2 1.21 773.7
516 A-1.19 B-4.11 C-2.2 1.19 773.7
517 A-1.24 B-2.12 C-2.2 1.16 772.7
518 A-1.18 B-2.12 C-2.2 1.18 772.6
519 A-1.24 B-1.19 C-1.2 1.18 796.6
520 A-1.19 B-1.19 C-2.8 1.18 811.7
521 A-1.22 B-1.19 C-2.8 1.20 811.7
522 A-1.7 B-1.20 C-2.2 1.29 846.7
523 A-1.24 B-1.18 C-2.2 1.15 772.7
524 A-1.24 B-1.19 C-8.1 1.34 887.7
525 A-1.22 B-1.19 C-8.1 1.33 888.7
526 A-1.18 B-4.11 C-2.2 1.22 772.7
527 A-1.8 B-1.26 C-2.2 1.23 800.6
528 A-1.1 B-1.26 C-2.2 1.36 823.9 [MH] -
529 A-1.22 B-2.12 C-2.2 1.16 773.7
530 A-1.1 B-2.16 C-1.1 1.20 751.6
531 A-1.1 B-5.3 C-1.1 1.19 754.7
532 A-1.24 B-5.3 C-1.1 1.11 755.6
533 A-1.28 B-4.12 C-2.2 1.01 Method I 776.7
534 A-1.8 B-1.27 C-2.2 1.14 784.6
535 A-1.1 B-1.27 C-2.2 1.07 Method B 809.26
536 A-1.1 B-2.5 C-8.1 1.32 872.7
537 A-1.1 B-1.19 C-2.3 1.15 795.6
538 A-1.1 B-1.18 C-8.1 1.30 848.8
539 A-1.19 B-1.19 C-18.1 1.34 903.8
540 A-1.19 B-1.19 C-18.1 1.30 903.8
541 A-1.19 B-4.9 C-2.2 1.21 811.6
542 A-1.8 B-1.18 C-8.1 1.20 823.7
543 A-1.24 B-4.7 C-1.2 1.01 778.6
544 A-1.19 B-4.7 C-1.2 0.99 779.7
545 A-1.24 B-4.9 C-1.2 1.16 796.6
546 A-1.19 B-4.9 C-1.2 1.14 797.6
547 A-1.8 B-1.14 C-18.3 1.19 768.6
548 A-1.8 B-1.14 C-18.4 1.25 782.6
549* A-1.1 B-1.18 C-8.1 1.30 848.8
550* A-1.8 B-1.18 C-8.1 1.19 823.8
551 A-1.1 B-5.3 C-1.2 1.25 780.8
552 A-1.24 B-5.3 C-1.2 1.19 781.7
553 A-1.19 B-5.3 C-1.2 1.17 782.7
554 A-1.22 B-5.3 C-1.2 1.17 782.6
555 A-1.1 B-2.16 C-1.2 1.28 777.6
556 A-1.24 B-2.16 C-1.2 1.21 778.7
557 A-1.19 B-1.18 C-18.1 1.20 865.8
558 A-1.19 B-1.18 C-18.1 1.24 865.7
559 A-1.31 B-1.14 C-2.2 1.29 820.6
560 A-1.31 B-1.19 C-2.2 1.33 838.6
561 A-1.19 B-5.3 C-1.1 1.09 756.6
562 A-1.22 B-5.3 C-1.1 1.10 756.6
563 A-1.19 B-1.27 C-2.2 1.17 811.6
564 A-1.8 B-1.14 C-2.14 1.26 846.6
565 A-1.18 B-4.12 C-2.2 1.21 786.6
566 A-1.8 B-1.14 C-21.1 1.09 784.6
567 A-1.19 B-4.12 C-2.2 1.17 787.6
568 A-1.31 B-4.12 C-2.2 1.28 814.7
569 A-1.1 B-1.18 C-2.10 1.24 819.6
570 A-1.8 B-1.18 C-3.4 0.80 803.7
571 A-1.19 B-1.18 C-20.1 1.26 905.8
572* A-1.1 B-1.14 C-1.4 1.19 765.7
573 A-1.8 B-1.14 C-1.4 1.09 740.7
574 A-1.24 B-1.14 C-1.4 1.15 766.7
575 A-1.1 B-5.3 C-1.4 1.25 768.7
576 A-1.8 B-5.3 C-1.4 1.12 743.7
577* A-1.19 B-1.18 C-20.1 1.22 905.7
578 A-1.8 B-1.14 C-18.2 1.27 860.7
579* A-1.8 B-1.14 C-18.2 1.23 860.7
580 A-1.28 B-4.12 C-2.13 1.24 802.6
581 A-1.28 B-4.13 C-2.2 1.15 779.6
582 A-1.28 B-1.18 C-10.19 1.30 818.7
583 A-1.14 B-1.4 C-1.1 1.16 728.6
584 A-1.1 B-2.13 C-2.3 1.16 756.7
585 A-1.14 B-1.11 C-10.19 1.41 870.7
586 A-1.1 B-1.11 C-10.19 1.44 856.7
587 A-1.1 B-2.13 C-2.2 1.30 770.6
588 A-1.1 B-2.13 C-2.1 1.17 772.6
589 A-1.14 B-3.1 C-10.19 1.24 811.6
590 A-1.1 B-3.1 C-10.19 1.26 797.7
591 A-1.1 B-1.5 C-2.2 1.25 770.6
592 A-1.3 B-3.1 C-2.8 1.04 753.7
593 A-1.3 B-3.1 C-2.2 1.05 753.7
594 A-1.6 B-3.1 C-2.2 1.03 769.7
595 A-1.1 B-1.13 C-1.1 1.22 750.6
596 A-1.2 B-1.11 C-10.19 1.48 882.8
597 A-1.3 B-1.11 C-10.19 1.43 868.8
598 A-1.1 B-2.5 C-1.1 1.08 755.5
599 A-1.2 B-1.13 C-10.19 1.54 872.9
600 A-1.3 B-1.13 C-10.19 1.51 856.8 [MH] -
601 A-1.1 B-1.1 C-2.8 1.24 800.8
602 A-1.1 B-1.1 C-2.2 1.26 800.7
603 A-1.1 B-1.13 C-2.2 1.37 790.8
604 A-1.1 B-1.13 C-2.8 1.34 790.8
605 A-1.1 B-1.5 C-3.2 0.79 799.8
606 A-1.8 B-1.13 C-2.8 1.22 765.7
607 A-1.8 B-1.13 C-2.2 1.24 765.6
608 A-1.8 B-1.13 C-2.1 1.13 767.6
609 A-1.8 B-1.1 C-2.2 1.14 775.6
610 A-1.14 B-1.14 C-10.19 1.41 861.7
611 A-1.1 B-1.5 C-3.3 0.81 813.8
612 A-1.1 B-1.5 C-3.4 0.95 827.7
613 A-1.15 B-1.13 C-3.4 1.05 877.8
614 A-1.1 B-2.5 C-2.2 1.23 795.6
615 A-1.1 B-2.5 C-2.8 1.20 795.8
616 A-1.14 B-5.2 C-1.1 1.15 780.5
617 A-1.8 B-1.13 C-3.4 0.94 822.7
618 A-1.15 B-1.13 C-3.3 0.92 863.8
619 A-1.1 B-2.5 C-3.4 0.95 852.8
620 A-1.8 B-2.5 C-3.4 0.84 827.8
621* A-1.8 B-2.5 C-3.4 0.83 827.8
622 A-1.8 B-1.14 C-3.4 0.86 823.7
623 A-1.8 B-1.13 C-3.3 0.82 808.7
624 A-1.1 B-6.1 C-2.1 1.12 797.6
625 A-1.10 B-2.5 C-2.1 1.15 833.7
626 A-1.14 B-1.13 C-10.25 1.39 868.8
627 A-1.6 B-1.20 C-2.1 1.15 839.7
628 A-1.1 B-2.5 C-1.2 1.17 781.7
629 A-1.8 B-6.1 C-2.2 1.14 770.7
630 A-1.8 B-6.1 C-2.5 1.21 796.6
631* A-1.8 B-6.1 C-2.5 1.18 796.6
632 A-1.8 B-2.5 C-2.2 1.10 770.6
633 A-1.8 B-1.13 C-2.4 1.19 795.7
634 A-1.20 B-6.1 C-2.2 1.28 801.7
635 A-1.20 B-6.1 C-2.8 1.25 801.7
636 A-1.20 B-1.19 C-2.2 1.34 815.7
637 A-1.19 B-1.19 C-2.2 1.23 811.7
638 A-1.18 B-1.20 C-2.2 1.23 810.6
639 A-1.18 B-1.19 C-2.2 1.26 810.7
640 A-1.24 B-1.19 C-2.2 1.25 810.7
641 A-1.22 B-1.19 C-2.2 1.24 811.8
642 A-1.24 B-1.14 C-2.2 1.20 792.6
643 A-1.18 B-1.19 C-2.1 1.15 812.6
644 A-1.24 B-1.19 C-2.1 1.13 812.6
645 A-1.22 B-1.19 C-2.1 1.13 813.7
646 A-1.22 B-1.14 C-14.1 1.25 807.7
647 A-1.1 B-4.11 C-1.1 1.14 731.5
648 A-1.24 B-4.11 C-1.2 1.14 758.7
649 A-1.19 B-4.11 C-1.2 1.12 759.7
650 A-1.1 B-4.11 C-1.2 1.21 757.6
651 A-1.7 B-1.21 C-2.2 1.28 795.7
652 A-1.24 B-4.11 C-2.2 1.21 772.7
653 A-1.7 B-4.3 C-2.2 1.26 823.7
654 A-1.8 B-1.13 C-1.2 1.18 751.7
655 A-1.24 B-4.9 C-2.2 1.23 810.6
656 A-1.22 B-4.12 C-2.2 1.19 787.6
657 A-1.22 B-4.13 C-2.2 1.19 790.7
658 A-1.24 B-4.12 C-2.2 1.19 786.6
659 A-1.24 B-4.13 C-2.2 1.19 789.7
660 A-1.24 B-1.27 C-2.2 1.19 810.8
661 A-1.24 B-1.18 C-18.1 1.22 864.8
662 A-1.24 B-1.18 C-18.1 1.26 864.7
663 A-1.24 B-1.18 C-2.9 1.12 808.6
664 A-1.18 B-4.13 C-2.2 1.21 789.7
665 A-1.30 B-1.19 C-2.2 1.22 810.8
666 A-1.19 B-4.13 C-2.2 1.17 790.7
667 A-1.31 B-4.12 C-2.8 1.25 814.7
668 A-1.24 B-1.18 C-2.13 1.23 798.7
669 A-1.24 B-1.18 C-2.13 1.18 798.8
670 epimer 1 A-1.24 B-1.18 C-19.1 1.23 848.8
671 epimer 2 A-1.24 B-1.18 C-19.1 1.26 848.8
672 epimer 3 A-1.24 B-1.18 C-19.1 1.28 848.7
673 epimer 4 A-1.24 B-1.18 C-19.1 1.30 848.7
674 epimer 1 A-1.24 B-1.14 C-19.1 1.27 868.7
675 epimer 2 A-1.24 B-1.14 C-19.1 1.31 868.7
676 epimer 3 A-1.24 B-1.14 C-19.1 1.33 868.7
677 epimer 4 A-1.24 B-1.14 C-19.1 1.35 868.7
678 A-1.8 B-1.18 C-2.11 1.15 794.6
679 A-1.8 B-1.18 C-2.10 1.14 794.6
680 A-1.1 B-1.14 C-1.4 1.21 765.7
681 A-1.19 B-1.18 C-2.12 1.19 809.6
682 A-1.18 B-1.18 C-18.1 1.27 864.7
683 A-1.8 B-4.12 C-2.13 1.22 786.6
684 A-1.28 B-4.12 C-2.13 1.20 802.7
685 A-1.30 B-4.13 C-2.2 1.16 789.6
686 A-1.28 B-1.14 C-1.2 1.09 768.6
687 A-1.14 B-2.14 C-1.1 1.13 714.7
688 A-1.6 B-2.14 C-1.1 1.12 728.7
768 A-1.1 B-1.18 C-1.4 1.12 745.5
769 A-1.28 B-4.9 C-2.2 1.18 800.5
770 A-1.28 B-4.9 C-2.8 1.14 800.4
771 A-1.28 B-1.18 C-1.4 1.02 736.4
772 A-1.28 B-4.15 C-1.4 1.07 750.5
773 A-1.8 B-4.15 C-18.2 1.11 748.5
774 A-1.1 B-4.15 C-18.2 1.23 773.5
775 A-1.8 B-4.15 C-18.6 1.13 784.5
776 A-1.28 B-1.18 C-2.15 1.14 804.4
777 A-1.24 B-4.9 C-2.8 1.18 810.5
778 A-1.38 B-4.9 C-2.2 1.22 810.5
779 A-1.38 B-4.9 C-2.8 1.18 810.5
780 A-1.22 B-4.9 C-2.2 1.22 811.5
781 A-1.18 B-4.9 C-2.2 1.23 810.5
782 A-1.19 B-1.18 C-22.1 1.11 910.5
783 A-1.28 B-1.18 C-22.1 1.09 899.5
784 A-1.28 B-4.15 C-18.2 1.12 764.5
785 A-1.28 B-4.15 C-18.6 1.14 800.5
786 A-1.28 B-4.9 C-1.4 1.11 774.4
787 A-1.38 B-4.9 C-1.4 1.15 784.5
788 A-1.1 B-2.17 C-1.4 0.88 754.5
789 A-1.28 B-2.17 C-1.4 0.80 745.5
790 A-1.24 B-2.17 C-1.4 0.83 755.5
791 A-1.28 B-4.15 C-2.15 1.19 818.4
792* A-1.28 B-4.15 C-2.15 1.17 818.4
793 A-1.19 B-4.9 C-2.8 1.16 811.5
794 A-1.19 B-4.9 C-22.1 1.19 948.5
795 A-1.28 B-4.9 C-22.1 1.17 937.5
796 A-1.28 B-7.2 C-2.2 0.86 796.5
797 A-1.24 B-4.9 C-1.4 1.16 784.5
798 A-1.18 B-4.9 C-1.4 1.17 784.5
799 A-1.19 B-4.9 C-1.4 1.13 785.5
800 A-1.22 B-4.9 C-1.4 1.15 785.4
801 A-1.19 B-4.9 C-18.6 1.20 835.5
802* A-1.19 B-4.9 C-18.6 1.17 835.5
803 A-1.19 B-4.9 C-18.2 1.18 799.4
804 A-1.37 B-4.9 C-22.1 1.18 948.5
805 A-1.30 B-4.9 C-2.2 1.19 810.3
806 A-1.37 B-4.15 C-2.15 1.21 829.5
807 A-1.8 B-4.9 C-22.1 1.16 921.5
808 A-1.22 B-4.9 C-22.1 1.20 948.5
809 A-1.28 B-1.19 C-22.2 1.28 910.4
810* A-1.28 B-1.19 C-22.2 1.25 910.4
811 A-1.19 B-1.19 C-22.2 1.31 921.5
812* A-1.19 B-1.19 C-22.2 1.28 921.5
813 A-1.19 B-1.19 C-22.1 1.20 948.5
814* A-1.19 B-1.19 C-22.1 1.18 948.5
815 A-1.28 B-1.19 C-22.1 1.18 937.5
816* A-1.28 B-1.19 C-22.1 1.16 937.5
817 A-1.37 B-4.9 C-1.2 1.12 797.5
818 A-1.28 B-4.9 C-1.2 1.11 786.5
819 A-1.28 B-4.9 C-18.6 1.17 824.4
820 A-1.19 B-4.15 C-22.2 1.26 897.5
821 A-1.36 B-4.9 C-2.2 1.15 801.5
822 A-1.28 B-4.14 C-2.2 1.11 796.5
823 A-1.37 B-7.2 C-2.2 0.87 807.5
824 A-1.8 B-7.2 C-1.4 0.80 754.5
825 A-1.28 B-7.2 C-1.4 0.81 770.5
826 A-1.22 B-7.2 C-1.4 0.83 781.5
827 A-1.28 B-1.19 C-23.1 1.13 879.5
828 A-1.35 B-4.15 C-18.4 1.26 787.5
829 A-1.37 B-4.9 C-2.2 1.19 811.5
851 A-1.19 B-1.19 C-20.5 1.09 881.4
852 A-1.8 B-1.23 C-8.2 1.11 862.4
853 A-1.1 B-1.23 C-8.2 1.21 887.4
854 A-1.28 B-1.18 C-18.1 1.14 854.4
855 A-1.8 B-1.18 C-27.2 1.13 826.4
856 A-1.28 B-1.18 C-27.2 1.14 842.4
857 A-1.19 B-1.18 C-2.16 1.13 817.4
858 A-1.8 B-1.18 C-27.1 1.19 832.5
859 A-1.19 B-1.18 C-24.1 1.17 891.4
860 A-1.1 B-4.16 C-1.4 1.12 760.4
861 A-1.19 B-1.18 C-25.1 1.02 844.4
862 A-1.24 B-4.16 C-1.4 1.07 761.4
863 A-1.19 B-1.18 C-2.17 1.08 787.4
864 A-1.19 B-1.18 C-20.2 1.07 869.4
865 A-1.1 B-4.15 C-29.1 1.30 801.5
866 A-1.8 B-4.15 C-29.1 1.20 776.4
867 A-1.19 B-1.18 C-22.4 1.17 949.5
868 A-1.28 B-1.18 C-22.4 1.15 938.4
869 A-1.8 B-4.17 C-2.2 1.08 776.4
870 A-1.24 B-4.17 C-2.2 1.13 802.4
871 A-1.38 B-1.18 C-22.4 1.19 948.5
872 A-1.36 B-1.14 C-1.2 1.00 769.4
873 A-1.1 B-4.15 C-18.10 1.31 815.5
874 A-1.8 B-4.15 C-29.2 1.20 824.4
875 A-1.1 B-4.15 C-29.2 1.29 849.5
876 A-1.8 B-4.15 C-18.10 1.22 790.4
877 A-1.28 B-4.15 C-18.9 1.07 808.4
878 A-1.28 B-4.15 C-18.10 1.23 806.4
879 A-1.19 B-4.9 C-25.1 1.10 882.4
880 A-1.28 B-4.9 C-25.1 1.08 871.4
881 A-1.19 B-1.18 C-20.4 1.16 885.5
882 A-1.19 B-1.18 C-26.1 1.06 890.4
883 A-1.19 B-1.18 C-20.3 1.18 897.5
884 A-1.28 B-1.18 C-20.3 1.16 886.4
885 A-1.19 B-1.19 C-26.2 1.11 947.4
886 A-1.19 B-1.19 C-25.2 1.23 908.4
887 A-1.19 B-1.19 C-22.5 1.14 962.4
888 A-1.37 B-4.14 C-2.2 1.07 807.4
889 A-1.19 B-7.2 C-22.2 0.92 917.4
890 A-1.37 B-7.2 C-22.2 0.92 917.4
891 A-1.40 B-4.9 C-22.1 1.06 964.39
892 A-1.39 B-4.9 C-22.1 1.07 964.4
893 A-1.37 B-4.9 C-18.6 1.12 835.4
894 A-1.8 B-4.9 C-18.9 1.09 816.4
895 A-1.28 B-4.9 C-18.9 1.10 832.4
896 A-1.37 B-4.9 C-18.9 1.12 843.4
897 A-1.28 B-4.15 C-22.2 1.17 886.4
898 A-1.28 B-7.2 C-22.2 0.91 906.4
899 A-1.28 B-4.18 C-2.2 1.08 800.4
900 A-1.19 B-7.2 C-1.2 0.78 793.4
901 A-1.28 B-7.2 C-1.2 0.76 782.4
902 A-1.37 B-4.15 C-22.2 1.18 897.4
903 A-1.41 B-4.15 C-22.2 1.21 906.4
904 A-1.41 B-7.2 C-1.2 0.80 802.4
905 A-1.19 B-7.2 C-22.1 0.84 944.4
906 A-1.28 B-7.2 C-22.1 0.83 933.4
907 A-1.37 B-7.2 C-22.1 0.84 944.4
908 A-1.44 B-4.9 C-22.2 1.08 931.4
909 A-1.28 B-4.14 C-22.2 1.16 906.4
910 A-1.24 B-4.15 C-18.9 1.10 818.4
911 A-1.36 B-4.9 C-1.2 1.02 787.4
912 A-1.28 B-4.7 C-2.2 0.97 782.4
913 A-1.28 B-7.2 C-18.9 0.83 828.4
914 A-1.36 B-7.2 C-18.9 0.80 829.4
915 A-1.37 B-7.2 C-18.9 0.83 839.5
916 A-1.36 B-4.9 C-22.1 1.08 938.4
917 A-1.36 B-7.2 C-22.1 0.82 934.4
918 A-1.36 B-7.2 C-22.2 0.89 907.4
919 A-1.36 B-4.15 C-22.2 1.15 887.4
920 A-1.36 B-4.14 C-2.2 1.02 797.4
921 A-1.37 B-7.2 C-22.3 0.86 899.4
922 A-1.36 B-4.9 C-5.4 1.10 837.4
923 A-1.37 B-4.14 C-22.2 1.17 917.4
924 A-1.37 B-4.9 C-22.2 1.21 921.4
925 A-1.42 B-4.9 C-22.2 1.28 911.3
926 A-1.28 B-4.9 C-2.4 1.06 830.4
927 A-1.36 B-4.14 C-22.2 1.14 907.4
928* A-1.37 B-4.14 C-2.2 1.06 807.4
929 A-1.36 B-4.9 C-18.9 1.08 833.4
930 A-1.36 B-1.19 C-2.2 1.09 801.4
931 A-1.28 B-7.2 C-18.6 0.82 820.4
932 A-1.36 B-7.2 C-18.6 0.80 821.4
933 A-1.37 B-7.2 C-18.6 0.84 831.4
934 A-1.36 B-4.9 C-22.2 1.18 911.3
935 A-1.19 B-4.14 C-22.2 1.18 917.4
936 A-1.22 B-4.14 C-22.2 1.19 917.4
937 A-1.41 B-4.9 C-22.2 1.24 930.4
938 A-1.36 B-7.2 C-2.15 0.84 839.4
939* A-1.36 B-7.2 C-2.15 0.82 839.4
940* A-1.36 B-4.9 C-2.15 1.11 843.3
941 A-1.36 B-4.9 C-2.15 1.13 843.3
942 A-1.36 B-4.15 C-2.15 1.10 819.4
943 A-1.39 B-4.15 C-22.2 1.16 913.4
944 A-1.43 B-4.9 C-22.2 1.23 893.3
945 A-1.46 B-4.15 C-22.2 1.21 904.4
946 A-1.8 B-4.9 C-18.6 1.10 808.4
947 A-1.36 B-4.9 C-18.6 1.08 825.4
948 A-1.28 B-1.18 C-22.2 1.13 872.4
949 A-1.36 B-1.18 C-22.2 1.11 873.4
950 A-1.19 B-7.2 C-2.15 0.87 849.4
951 A-1.22 B-7.2 C-2.15 0.88 849.4
952 A-1.22 B-7.2 C-5.4 0.85 843.4
953 A-1.28 B-7.2 C-5.4 0.83 832.4
954 A-1.36 B-7.2 C-5.4 0.81 833.4
955 A-1.37 B-7.2 C-5.4 0.84 843.4
956 A-1.24 B-7.2 C-2.15 0.89 848.4
957 A-1.28 B-7.2 C-2.15 0.86 838.4
958 A-1.18 B-7.2 C-2.15 0.90 848.4
959 A-1.37 B-7.2 C-2.15 0.87 849.4
960 A-1.46 B-7.2 C-2.15 0.90 856.4
961 A-1.45 B-4.15 C-22.2 1.12 913.4
962 A-1.45 B-4.9 C-22.2 1.14 937.4
963 A-1.46 B-4.9 C-1.2 1.10 804.4
964 A-1.22 B-4.9 C-22.2 1.23 921.4
965 A-1.8 B-4.9 C-22.2 1.19 894.4
966 A-1.39 B-4.9 C-22.2 1.17 937.4
967 A-1.46 B-4.9 C-18.6 1.15 842.3
968 A-1.46 B-4.15 C-18.6 1.12 818.4
969 A-1.46 B-4.9 C-5.4 1.17 854.3
970 A-1.46 B-7.2 C-18.6 0.86 838.4
971 A-1.36 B-4.9 C-25.3 1.18 899.4
972 A-1.28 B-4.9 C-25.3 1.20 898.4
973 A-1.46 B-4.9 C-2.2 1.16 818.4
974 A-1.28 B-2.5 C-2.15 1.09 828.4
975 A-1.36 B-4.14 C-2.15 1.08 839.4
下表MC-3中列舉類似於對應通用方法3 (
GM-3) (參見實例689)，由對應建構嵌段A、B、D1及D2製備之通式(I)化合物。
表MC-3 (GM-3)
實例 A B D1 D2 t
R[min]
LC-MS 方法H MS- 資料m/z [M+H]
+
690 A-1.8
B-1.19
D1-3.0
Boc-N-甲基-L-白胺酸
1.18
784.6
691 A-1.19
B-1.19
D1-3.0
Boc-N-甲基-L-白胺酸
1.22
811.7
692 A-1.22
B-1.19
D1-3.0
Boc-N-甲基-L-白胺酸
1.23
811.6
693 A-1.19
B-1.19
D1-4.1
Boc-N-甲基-L-白胺酸
1.41
853.8
694 A-1.19
B-1.19
D1-4.1
Boc-N-甲基-L-白胺酸
1.36
853.8
695* A-1.8
B-1.14
D1-4.2
Boc-N-甲基-L-白胺酸
1.28
866.8
696 A-1.22
B-1.19
D1-4.5
Boc-N-甲基-L-白胺酸
1.45
867.8
697 A-1.24
B-1.19
D1-4.5
Boc-N-甲基-L-白胺酸
1.45
866.8
698 A-1.8
B-1.14
D1-4.2
Boc-N-甲基-L-白胺酸
1.32
866.7
699 A-1.8
B-1.14
D1-4.6
Boc-N-甲基-L-白胺酸
1.15
790.7
GM-4 Listed in Table MC-3 below are compounds of general formula (I) prepared from corresponding building blocks A, B, D1 and D2 analogously to the corresponding General Method 3 ( GM-3 ) (see Example 689). Form MC-3 (GM-3) example A B D1 D2 t R [min] LC-MS method H MS- data m/z [M+H] +
690 A-1.8 B-1.19 D1-3.0 Boc-N-methyl-L-leucine 1.18 784.6
691 A-1.19 B-1.19 D1-3.0 Boc-N-methyl-L-leucine 1.22 811.7
692 A-1.22 B-1.19 D1-3.0 Boc-N-methyl-L-leucine 1.23 811.6
693 A-1.19 B-1.19 D1-4.1 Boc-N-methyl-L-leucine 1.41 853.8
694 A-1.19 B-1.19 D1-4.1 Boc-N-methyl-L-leucine 1.36 853.8
695* A-1.8 B-1.14 D1-4.2 Boc-N-methyl-L-leucine 1.28 866.8
696 A-1.22 B-1.19 D1-4.5 Boc-N-methyl-L-leucine 1.45 867.8
697 A-1.24 B-1.19 D1-4.5 Boc-N-methyl-L-leucine 1.45 866.8
698 A-1.8 B-1.14 D1-4.2 Boc-N-methyl-L-leucine 1.32 866.7
699 A-1.8 B-1.14 D1-4.6 Boc-N-methyl-L-leucine 1.15 790.7
GM-4
下表MC-4中列舉類似於對應通用方法4 (
GM-4) (視保護基策略而定，參見實例700或實例976)，由對應建構嵌段A、B及C製備之通式(I)化合物。
表MC-4 (GM-4)
實例 A B C t
R[min]
LC-MS 方法H MS- 資料m/z [M+H]
+
701 A-2.3
B-1.24
C-16.1
1.26
847.8
702 A-2.4
B-酸-6
C-16.8
1.19
844.8
703 A-2.4
B-1.25
C-16.6
1.22
880.7
704 A-2.4
B-酸-6
C-16.2
1.21
858.6
705 A-2.4
B-酸- 6
C-16.3
1.21
858.8
706 A-2.4
B-酸-6
C-16.9
1.23
838.6
707 A-2.4
B-酸-6
C-16.9
1.26
838.8
708 A-2.4
B-酸-6
C-17.4
1.17
780.8
709 A-2.4
B-酸-6
C-17.2
1.38
822.7
710 A-2.4
B-酸-6
C-17.3
1.27
794.6
711 A-2.4
B-酸-6
C-17.5
1.16
802.6
712 A-2.2
B-酸-5
C-16.3
1.38
896.8
976 A-1.22
B-酸-8
C-18.9
1.14
843.4
977 A-1.28
B-酸-9
C-28.1
1.07
872.4
978 A-1.28
B-酸-9
C-28.2
1.00
887.4
979 A-1.28
B-酸-9
C-18.7
1.12
790.4
980 A-1.28
B-酸-9
C-18.8
1.20
804.4
The general formula (I ) compounds. Form MC-4 (GM-4) example A B C t R [min] LC-MS method H MS- data m/z [M+H] +
701 A-2.3 B-1.24 C-16.1 1.26 847.8
702 A-2.4 B-acid-6 C-16.8 1.19 844.8
703 A-2.4 B-1.25 C-16.6 1.22 880.7
704 A-2.4 B-acid-6 C-16.2 1.21 858.6
705 A-2.4 B-acid-6 C-16.3 1.21 858.8
706 A-2.4 B-acid-6 C-16.9 1.23 838.6
707 A-2.4 B-acid-6 C-16.9 1.26 838.8
708 A-2.4 B-acid-6 C-17.4 1.17 780.8
709 A-2.4 B-acid-6 C-17.2 1.38 822.7
710 A-2.4 B-acid-6 C-17.3 1.27 794.6
711 A-2.4 B-acid-6 C-17.5 1.16 802.6
712 A-2.2 B-acid-5 C-16.3 1.38 896.8
976 A-1.22 B-acid-8 C-18.9 1.14 843.4
977 A-1.28 B-acid-9 C-28.1 1.07 872.4
978 A-1.28 B-acid-9 C-28.2 1.00 887.4
979 A-1.28 B-acid-9 C-18.7 1.12 790.4
980 A-1.28 B-acid-9 C-18.8 1.20 804.4
下表MC-5中列舉類似於對應通用方法
GM-5(參見實例713)、
GM-6(參見實例722)、
GM-7(參見實例724)、
GM-8(參見實例725)或
GM-9(參見實例761)，由對應建構嵌段製備之通式(I)化合物。
表 MC-5 (GM-5 至 GM-9) 實例 GM A B C D1 D2 t
R[min]
LC-MS 方法H MS- 資料m/z [M+H]
+
714 GM-5
A-2.4
B-酸-5
D1-1.1
D2-3.1
1.34
845.8
715 GM-5
A-2.3
B-酸-5
D1-1.1
D2-3.1
1.43
870.8
716 GM-5
A-2.4
B-酸-5
D1-1.1
D2-3.1
1.32
845.7
717 GM-5
A-2.3
B-酸-5
D1-1.2
D2-3.1
1.44
836.8
718 由
實例 717以副產物形式分離
1.20
780.7
719 GM-5
A-2.4
B-酸-5
D1-1.2
D2-3.1
1.33
811.7
720 由
實例 719以副產物形式分離
1.06
755.6
721 GM-6
A-1.8
B-1.19
C-17.3
1.31
812.6
723* GM-6
A-1.8
B-1.19
C-17.1
1.27
834.7
726 GM-8
A-1.1
B-1.13
C-7.1
0.87
791.8
727 GM-8
A-1.8
B-1.14
C-7.1
0.70
767.6
728 由
實例 422以副產物形式分離
1.32
865.7
762 GM-9
B-2.5
C-1.2
1.14
784.6
763 GM-9
B-1.14
C-1.2
1.22
829.8
764 GM-9
B-1.14
C-1.2
1.17
793.7
Listed in the following table MC-5 is similar to the corresponding general method GM-5 (seeing example 713), GM-6 (seeing example 722), GM-7 (seeing example 724), GM-8 (seeing example 725) or GM- 9 (see Example 761), a compound of general formula (I) prepared from the corresponding building blocks. Form MC-5 (GM-5 to GM-9) example GM A B C D1 D2 t R [min] LC-MS method H MS- data m/z [M+H] +
714 GM-5 A-2.4 B-acid-5 D1-1.1 D2-3.1 1.34 845.8
715 GM-5 A-2.3 B-acid-5 D1-1.1 D2-3.1 1.43 870.8
716 GM-5 A-2.4 B-acid-5 D1-1.1 D2-3.1 1.32 845.7
717 GM-5 A-2.3 B-acid-5 D1-1.2 D2-3.1 1.44 836.8
718 Isolated as a by-product from Example 717 1.20 780.7
719 GM-5 A-2.4 B-acid-5 D1-1.2 D2-3.1 1.33 811.7
720 Isolated as a by-product from Example 719 1.06 755.6
721 GM-6 A-1.8 B-1.19 C-17.3 1.31 812.6
723* GM-6 A-1.8 B-1.19 C-17.1 1.27 834.7
726 GM-8 A-1.1 B-1.13 C-7.1 0.87 791.8
727 GM-8 A-1.8 B-1.14 C-7.1 0.70 767.6
728 Isolated as a by-product from Example 422 1.32 865.7
762 GM-9 B-2.5 C-1.2 1.14 784.6
763 GM-9 B-1.14 C-1.2 1.22 829.8
764 GM-9 B-1.14 C-1.2 1.17 793.7
後期修飾(Post Modification；PM)Post Modification (Post Modification; PM)
PM-1：磺醯胺形成PM-1: sulfonamide formation
實例729：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-
N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(苯基磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1
H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺 向
實例 726(40 mg，0.0506 mmol)及TEA (0.0213 mL，0.152 mmol)於DCM (0.5 mL)中之室溫溶液中添加苯磺醯氯(0.04 mL，0.15 mmol)，且在室溫攪拌混合物隔夜。濃縮混合物，且將殘餘物溶解於MeCN/DMF中且藉由製備型HPLC (鹼性)直接純化，得到呈白色固體狀之標題化合物(18 mg，38%)。LC-MS B：t
R= 1.14 min；[M+H]
+= 931.45。
Example 729: (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl- N- (3-methoxyphenethyl)-21-methyl-5,16,20,23 -Tetraoxo-3-(phenylsulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecyl Hydrogen-1 H -naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-metha Amide To a room temperature solution of Example 726 (40 mg, 0.0506 mmol) and TEA (0.0213 mL, 0.152 mmol) in DCM (0.5 mL) was added benzenesulfonyl chloride (0.04 mL, 0.15 mmol), and The mixture was stirred overnight. The mixture was concentrated, and the residue was dissolved in MeCN/DMF and directly purified by preparative HPLC (basic) to afford the title compound (18 mg, 38%) as a white solid. LC-MS B: tR = 1.14 min; [M+H] + = 931.45.
PM-2：醯胺偶合PM-2: Amide Coupling
實例750：(4aR,7R,18S,22S)-3-乙醯基-7-苯甲基-22-異丁基-
N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1
H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺 向
實例 726(40 mg，0.0506 mmol)、DIPEA (20 μL，0.126 mmol)及乙酸(1.15 eq)於DMF (0.5 mL)中之室溫溶液中添加(H)ATU (22.2 mg，0.0582 mmol)。在室溫攪拌反應混合物1 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之標題化合物(28 mg，66%)。LC-MS B：t
R= 1.03 min；[M+H]
+= 833.41。
Example 750: (4aR,7R,18S,22S)-3-Acetyl-7-benzyl-22-isobutyl- N- (3-methoxyphenethyl)-21-methyl-5 ,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1 H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18- carboxamide To a room temperature solution of 726 (40 mg, 0.0506 mmol), DIPEA (20 μL, 0.126 mmol) and acetic acid (1.15 eq) in DMF (0.5 mL) was added (H)ATU (22.2 mg, 0.0582 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by preparative HPLC (basic) to afford the title compound (28 mg, 66%) as a white solid. LC-MS B: tR = 1.03 min; [M+H] + = 833.41.
PM-3A：胺基甲酸酯形成PM-3A: carbamate formation
實例754：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸甲酯 向
實例 726(30 mg，0.0379 mmol)及TEA (16 μL，0.114 mmol)於DCM (0.5 mL)中之室溫溶液中添加氯甲酸甲酯(大約6 μL，0.0759 mmol)，且在室溫攪拌反應混合物1.5 h。反應混合物用DMF稀釋且藉由製備型HPLC (鹼性)直接純化，得到呈白色固體狀之標題化合物(22 mg，69%)。LC-MS B：t
R= 1.08 min；[M+H]
+= 849.44。
Example 754: (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)carbamoyl)-21-methyl-5 ,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H- Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14] tetraazacycloheptadecene-3-methyl carboxylate to Example 726 (30 mg, 0.0379 mmol) and TEA (16 μL, 0.114 mmol) in DCM (0.5 mL) at room temperature was added methyl chloroformate (about 6 μL, 0.0759 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with DMF and purified directly by preparative HPLC (basic) to afford the title compound (22 mg, 69%) as a white solid. LC-MS B: tR = 1.08 min; [M+H] + = 849.44.
PM-3B：胺基甲酸酯形成PM-3B: carbamate formation
實例756：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸四氫-2
H-哌喃-4-基酯 向
N,
N'-二丁二醯亞胺基碳酸酯(24.5 mg，0.091 mmol)及TEA (26 μL，0.182 mmol)於MeCN (0.4 mL)中之室溫懸浮液中添加四氫-2
H-哌喃-4-醇(6 μL，0.0607 mmol)。在室溫攪拌反應混合物隔夜，接著向反應混合物中添加
實例 726(40 mg，0.0506 mmol)於MeCN (0.4 mL)中之溶液，且在室溫攪拌反應混合物3 h。混合物用MeCN稀釋且藉由製備型HPLC (鹼性)直接純化，得到呈白色固體狀之標題化合物(28 mg，61%)。LC-MS B：t
R= 1.10 min；[M+H]
+= 919.53。
Example 756: (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)carbamoyl)-21-methyl-5 ,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H- Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylic acid tetrahydro-2 H -pyran-4-yl ester was suspended in MeCN (0.4 mL) in N , N' -disuccinimidyl carbonate (24.5 mg, 0.091 mmol) and TEA (26 μL, 0.182 mmol) at room temperature Tetrahydro- 2H -pyran-4-ol (6 μL, 0.0607 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight, then a solution of Example 726 (40 mg, 0.0506 mmol) in MeCN (0.4 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with MeCN and directly purified by preparative HPLC (basic) to afford the title compound (28 mg, 61%) as a white solid. LC-MS B: tR = 1.10 min; [M+H] + = 919.53.
PM-4：Boc保護的磺醯脒(Sulfonimidamide)PM-4: Sulfonimidamide protected by Boc
實例757：(((4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3
H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-基)(側氧基)(苯基)-l6-硫烷亞基)胺基甲酸三級丁酯
步驟 1 ：向三級丁醇(31 mL，327 mmol)及AcOH (20 mL，350 mmol)之0℃溶液中逐滴添加10% NaOCl (250 mL，413 mmol) (略微放熱)。在0℃攪拌所得乳液10 min，接著將其轉移至分液漏斗。丟棄水層，且其餘的黃色液體用水(2×)洗滌，接著經乾燥(CaCl
2)，過濾，得到呈黃色非黏稠油狀之次氯酸三級丁酯(8.5 g，21%)。
Example 757: (((4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)aminoformyl)-21-methyl -5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro- 3 H -naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecen-3-yl)( Pendantoxy)(phenyl)-l6-sulfanylidene)carbamate tertiary butyl ester Step 1 : Add tertiary butanol (31 mL, 327 mmol) and AcOH (20 mL, 350 mmol) at 0°C To the solution was added 10% NaOCl (250 mL, 413 mmol) dropwise (slightly exothermic). The resulting emulsion was stirred at 0 °C for 10 min before being transferred to a separatory funnel. The aqueous layer was discarded, and the remaining yellow liquid was washed with water (2×), then dried (CaCl 2 ), filtered to give ter-butyl hypochlorite (8.5 g, 21%) as a yellow non-viscous oil.
步驟 2 ：向苯亞磺醯胺(100 mg，0.673 mmol)於THF (1.5 mL)中之0℃溶液中逐滴添加雙(三甲基矽基)醯胺鋰溶液(1.0 M於THF中，1.35 mL，1.35 mmol)。在0℃攪拌棕色渾濁混合物1 h，接著逐滴添加二碳酸二三級丁酯(0.156 mL，0.673 mmol)於THF (0.5 mL)中之溶液。移除冰浴，且在室溫攪拌溶液15 min。向反應混合物中添加水(10 mL)及DCM (100 mL)。分離各層，且水層用DCM (2 × 75 mL)萃取。經合併之有機層用鹽水(50 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由FC (用15%至55% EtOAc/庚烷溶離，在EtOAc/庚烷3:7中R
f= 0.24)純化，得到呈無色油狀之(苯基亞磺醯基)胺基甲酸三級丁酯(140 mg，86%)。LC-MS B：t
R= 0.78 min；[M+H]
+= 241.97。
Step 2 : To a solution of phenylsulfinamide (100 mg, 0.673 mmol) in THF (1.5 mL) at 0 °C was added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.35 mL, 1.35 mmol). The brown cloudy mixture was stirred at 0 °C for 1 h, then a solution of di-tert-butyldicarbonate (0.156 mL, 0.673 mmol) in THF (0.5 mL) was added dropwise. The ice bath was removed, and the solution was stirred at room temperature for 15 min. Water (10 mL) and DCM (100 mL) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with DCM (2 x 75 mL). The combined org. layers were washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated. Purification by FC (elution with 15% to 55% EtOAc/heptane, Rf = 0.24 in EtOAc/heptane 3:7) gave (phenylsulfinyl)carbamate tris as a colorless oil Grade butyl ester (140 mg, 86%). LC-MS B: tR = 0.78 min; [M+H] + = 241.97.
步驟 3 ：向(苯基亞磺醯基)胺基甲酸三級丁酯(54.9 mg 0.228 mmol)於DCM (3 mL)中之0℃溶液中添加新鮮製備之次氯酸三級丁酯(41.2 mg，0.379 mmol)。在0℃攪拌所得混合物30 min，接著在0℃逐滴添加
實例 726(150 mg，0.19 mmol)及DIPEA(0.0974 mL，0.569 mmol)於DCM (5 mL)中之室溫溶液。移除冰浴，且在室溫攪拌反應混合物30 min。向反應物中添加水(10 mL)及DCM (50 mL)，且分離各層。水層用DCM (2 × 35 mL)萃取，且經合併之有機層用鹽水(10 mL)洗滌，經乾燥(MgSO
4)，過濾且濃縮。藉由製備型HPLC (鹼性)純化，得到呈白色固體狀之
實例 757(70 mg，36%)。LC-MS B：t
R= 1.19 min；[M+H]
+= 1030.28。
Step 3 : To a 0°C solution of tert-butyl (phenylsulfinyl)carbamate (54.9 mg 0.228 mmol) in DCM (3 mL) was added freshly prepared tert-butyl hypochlorite (41.2 mg, 0.379 mmol). The resulting mixture was stirred at 0 °C for 30 min, then a room temperature solution of Example 726 (150 mg, 0.19 mmol) and DIPEA (0.0974 mL, 0.569 mmol) in DCM (5 mL) was added dropwise at 0 °C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. Water (10 mL) and DCM (50 mL) were added to the reaction, and the layers were separated. The aqueous layer was extracted with DCM (2 x 35 mL), and the combined org. layers were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated. Purification by preparative HPLC (basic) afforded Example 757 (70 mg, 36%) as a white solid. LC-MS B: tR = 1.19 min; [M+H] + = 1030.28.
PM-5：磺醯脒PM-5: Sulfonamide
實例758：(4aR,7R,18S,22S)-7-苯甲基-22-異丁基-
N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(苯基磺亞胺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1
H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺 向
實例 757(30 mg，0.029 mmol)於MeCN (0.5 mL)中之室溫溶液中添加三甲基碘矽烷(9 μL，0.058 mmol)，且在室溫攪拌反應混合物5 min。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之標題化合物(44 mg，81%)。LC-MS B：t
R= 1.08/1.09 min；[M+H]
+= 930.64。
Example 758: (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl- N- (3-methoxyphenethyl)-21-methyl-5,16,20,23 -Tetra-oxo-3-(phenylsulfonimide)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23- Hexadecahydro-1 H -naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18 - Formamide To a room temperature solution of Example 757 (30 mg, 0.029 mmol) in MeCN (0.5 mL) was added iodotrimethylsilane (9 μL, 0.058 mmol) and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by preparative HPLC (basic) to afford the title compound (44 mg, 81%) as a white solid. LC-MS B: tR = 1.08/1.09 min; [M+H] + = 930.64.
PM-6：腈形成PM-6: Nitrile formation
實例759：(4aR,7R,18S,22S)-7-苯甲基-N-(3-氰基苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺 在140℃加熱
實例 378(20 mg，0.02 mmol)及CuCN (9 mg，0.1 mmol)於吡啶(0.5 mL)中之混合物72 h。藉由製備型HPLC (鹼性)直接純化反應混合物，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 1.05 min；[M+H]
+= 787.28。
Example 759: (4aR,7R,18S,22S)-7-Benzyl-N-(3-cyanophenethyl)-22-isobutyl-21-methyl-5,16,20,23- Four-side oxy-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][ 1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide heated at 140°C Example 378 (20 mg, 0.02 mmol) and CuCN (9 mg, 0.1 mmol) in pyridine (0.5 mL) for 72 h. The reaction mixture was directly purified by preparative HPLC (basic) to afford the title compound as a white solid. LC-MS B: tR = 1.05 min; [M+H] + = 787.28.
PM-7：
N-氧化物形成
PM-7: N -oxide formation
實例760：(9S,13S,19aR,22R)-22-苯甲基-13-異丁基-9-((3-甲氧基苯乙基)胺甲醯基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16
H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉2-氧化物 向
實例 365(30 mg，0.04 mmol)於DCM (0.5 mL)中之0℃溶液中添加mCPBA (11 mg，0.05 mmol)，且將反應混合物升溫至室溫並攪拌4 h。反應混合物用DCM稀釋且用Na
2S
2O
3飽和水溶液淬滅。分離各層，且水相用DCM (2×)再萃取。經合併之有機萃取物用鹽水洗滌，經Na
2SO
4乾燥，過濾且真空蒸發。藉由製備型HPLC (酸性)純化粗產物，得到呈白色固體狀之標題化合物。LC-MS B：t
R= 1.03 min；[M+H]
+= 807.36。
Example 760: (9S, 13S, 19aR, 22R)-22-benzyl-13-isobutyl-9-((3-methoxyphenethyl)carbamoyl)-12-methyl-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16 H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline 2-oxide To a 0 °C solution of Example 365 (30 mg, 0.04 mmol) in DCM (0.5 mL) was added mCPBA (11 mg, 0.05 mmol), and the reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was diluted with DCM and quenched with saturated aqueous Na2S2O3 . The layers were separated, and the aqueous phase was re-extracted with DCM (2x). The combined org. extracts were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (acidic) to afford the title compound as a white solid. LC-MS B: tR = 1.03 min; [M+H] + = 807.36.
下表MC-6中列舉使用上文所描述之後期修飾方法(PM)中之一者，使用對應起始材料製備之式(I)化合物。條件可略微變化。
表 MC-6 ： 實例 PM SM-A ( 實例 ) SM-B t
R[min]
LC-MS 方法H MS- 資料m/z [M+H]
+
730 PM-1
實例726 SCl-20 0.90
982.8
731 PM-1
實例726 SCl-13 1.24
869.7
732 PM-1
實例726 SCl-6 1.45
1015.7
733 PM-1
實例726 SCl-14 1.27
913.7
734 PM-1
實例726 SCl-17 1.28
939.8
735 PM-1
實例726 SCl-16 0.89
926.8
736 PM-1
實例726 SCl-11 1.37
945.8
737 PM-1
實例726 SCl-10 1.24
988.8
738 PM-1
實例726 SCl-12 1.36
994.8 [M-H]
-
739 PM-1
實例726 SCl-5 1.37
961.8
740 PM-1
實例726 SCl-7 1.37
979.8
741 PM-1
實例726 SCl-9 1.37
1002.8
742 PM-1
實例726 SCl-2 1.27
930.8 [M-H]
-
743 PM-1
實例726 SCl-15 1.30
927.8
744 PM-1
實例726 SCl-8 1.31
962.7
745 PM-1
實例726 SCl-19 0.98
968.8
746 PM-1
實例726 SCl-18 1.28
953.8
747 PM-1
實例726 SCl-3 1.28
932.7
748 PM-1
實例727 SCl-9 1.19
978.8
749 PM-1
實例727 SCl-6 1.28
991.7
751 PM-2
實例726 異戊酸
1.32
875.8
752 PM-2
實例726 3-甲氧基丙酸
1.21
877.8
753 PM-2
實例726 吡𠯤甲酸
1.20
897.8
755 PM-3A
實例726 氯甲酸乙酯
1.30
863.8
981 PM-7
實例809
1.15
926.3
982 PM-7
實例909
1.11
922.4
983 PM-7
實例934
1.10
927.3
Table MC-6 below lists the compounds of formula (I) prepared using one of the post-modification methods (PM) described above, using the corresponding starting materials. Conditions may vary slightly. Table MC-6 : example PM SM-A ( example ) SM-B t R [min] LC-MS method H MS- data m/z [M+H] +
730 PM-1 Instance 726 SCl-20 0.90 982.8
731 PM-1 Instance 726 SCl-13 1.24 869.7
732 PM-1 Instance 726 SCl-6 1.45 1015.7
733 PM-1 Instance 726 SCl-14 1.27 913.7
734 PM-1 Instance 726 SCl-17 1.28 939.8
735 PM-1 Instance 726 SCl-16 0.89 926.8
736 PM-1 Instance 726 SCl-11 1.37 945.8
737 PM-1 Instance 726 SCl-10 1.24 988.8
738 PM-1 Instance 726 SCl-12 1.36 994.8 [MH] -
739 PM-1 Instance 726 SCl-5 1.37 961.8
740 PM-1 Instance 726 SCl-7 1.37 979.8
741 PM-1 Instance 726 SCl-9 1.37 1002.8
742 PM-1 Instance 726 SCl-2 1.27 930.8 [MH] -
743 PM-1 Instance 726 SCl-15 1.30 927.8
744 PM-1 Instance 726 SCl-8 1.31 962.7
745 PM-1 Instance 726 SCl-19 0.98 968.8
746 PM-1 Instance 726 SCl-18 1.28 953.8
747 PM-1 Instance 726 SCl-3 1.28 932.7
748 PM-1 Instance 727 SCl-9 1.19 978.8
749 PM-1 Instance 727 SCl-6 1.28 991.7
751 PM-2 Instance 726 Isovaleric acid 1.32 875.8
752 PM-2 Instance 726 3-methoxypropionic acid 1.21 877.8
753 PM-2 Instance 726 picoic acid 1.20 897.8
755 PM-3A Instance 726 Ethyl chloroformate 1.30 863.8
981 PM-7 Instance 809 1.15 926.3
982 PM-7 Instance 909 1.11 922.4
983 PM-7 Instance 934 1.10 927.3
下文實例之表中列舉根據上文所描述之方法製備之實例式(I)化合物。化合物名稱中未提及之立體中心處之組態為未知的，然而僅存在一種差向異構物。
實例之表
實例 式(I) 化合物
1 (7R,13S,17RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-11-(3,3-二甲基丁基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
2 (7R,13S,17S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-11-(2-環己基乙基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
3 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-6-基)乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
4 (3R,9S,13S)-N-(2-(苯并呋喃-6-基)乙基)-3-苯甲基-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
5 (7R,13S,17RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-13-異丁基-14-甲基-9,12,15,19-四側氧基-11-苯乙基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
6 (7R,13S,17RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-11-(3-(苯甲氧基)丙基)-13-異丁基-14-甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
7 (7R,13S,17S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-13-(環丁基甲基)-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
8 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-7,10-二甲基-N-(2-(4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁 𠯤-7-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
9 (3R,9S,13RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-(環丙基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
10 (3R,9S,13RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-(環戊基甲基)-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
11 (3R,9S,13RS)-3-苯甲基-N-(2-(𠳭唍-6-基)乙基)-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
12 (3R,9S,13RS)-3-苯甲基-7-(2-環己基乙基)-N-(2-(3,4-二氫-2H-苯并[b][1,4]二㗁呯-7-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
13 (3R,9S,13RS)-3-苯甲基-7-(2-環己基乙基)-N-(2-(1,3-二氫異苯并呋喃-5-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
14 (3R,9S,13RS)-N-(2-(苯并呋喃-6-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
15 (3R,9S,13RS)-3-苯甲基-7-(2-環己基乙基)-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
16 (3R,9S,13RS)-N-(2-(苯并[d]㗁唑-2-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
17 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
18 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-(2-(吡𠯤-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
19 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-(2-(嘧啶-4-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
20 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-(2-(嘧啶-5-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
21 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(3-(二氟甲氧基)丙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
22 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(2-(2-甲氧基乙氧基)乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
23 (8RS,12S,18aR,21R)-21-苯甲基-12-異丁基-5,11-二甲基-N-(2-(4-甲基噻唑-2-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
24 (8RS,12S,18aR,21R)-21-苯甲基-12-異丁基-5,11-二甲基-N-(2-(5-甲基噻唑-2-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
25 (8RS,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(4-甲氧基苯乙基)-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
26 (8RS,12S,18aR,21R)-21-苯甲基-N-(3-(二氟甲氧基)苯乙基)-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
27 (8RS,12S,18aR,21R)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-N-苯乙基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
28 (8RS,12S,18aR,21R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
29 (8S,12S,18aR,21R)-21-苯甲基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
30 (8S,12S,18aR,21R)-N-(2-(苯并[d]異㗁唑-3-基)乙基)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
31 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
32 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(-8-甲氧基𠳭唍-3-基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
33 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(2-(3-甲氧基苯氧基)乙基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
34 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(2-(4-甲氧基苯氧基)乙基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
35 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(2-(7-甲氧基-2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
36 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(7-氯-5-甲基-2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
37 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(7-氯-2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
38 (4aR,7R,18S,22S)-N-(2-(苯并[d]異㗁唑-3-基)乙基)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
39 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
40 (4aR,7R,18S,22S)-7-苯甲基-N-(4-氰基苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
41 (4aR,7R,18S,22S)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
42 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
43 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(3,5-二甲基異㗁唑-4-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
44 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(5-乙基-1,2,4-㗁二唑-3-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
45 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
46 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(2-異丙基噻唑-4-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
47 (9S,13S,19aR,22R)-22-苯甲基-N-(4-乙基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
48 (9S,13S,19aR,22R)-22-苯甲基-N-(4-(三級丁基)苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
49 (9S,13S,19aR,22R)-22-苯甲基-N-(4-溴苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
50 (9S,13S,19aR,22R)-22-苯甲基-N-(2-氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
51 (9S,13S,19aR,22R)-22-苯甲基-N-(3-氯苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
52 (9S,13S,19aR,22R)-22-苯甲基-N-(3-溴苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
53 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
54 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
55 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
56 (9S,13S,19aR,22R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤並[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
57 (9S,13S,19aR,22R)-22-苯甲基-N-(3,5-二甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
58 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-苯乙基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
59 (9S,13S,19aR,22R)-22-苯甲基-N-(2-氟-4-甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
60 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(4-甲基苯乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
61 (9S,13S,19aR,22R)-22-苯甲基-N-(3,4-二甲基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
62 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(3-甲基苯乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
63 (9S,13S,19aR,22R)-22-苯甲基-N-(2,4-二甲基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
64 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-甲基苯乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
65 (9S,13S,19aR,22R)-22-苯甲基-N-(2,3-二甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
66 (9S,13S,19aR,22R)-22-苯甲基-N-(3-氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
67 (9S,13S,19aR,22R)-22-苯甲基-N-(4-氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
68 (9S,13S,19aR,22R)-22-苯甲基-N-(2,6-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
69 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-苯基-1,2,4-㗁二唑-5-基)乙基)-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
70 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(4,5-二甲基異㗁唑-3-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
71 (9S,13S,19aR,22R)-22-苯甲基-N-(3,5-二甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
72 (9S,13S,19aR,22R)-22-苯甲基-N-(2,6-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
73 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2,4,6-三氟苯乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
74 (9S,13S,19aR,22R)-22-苯甲基-N-(2,6-二氟-4-甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
75 (9S,13S,19aR,22R)-22-苯甲基-N-(3,4-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
76 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-苯基-1,2,4-㗁二唑-5-基)乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
77 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-苯乙基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
78 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(5-甲基-1,2,4-㗁二唑-3-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
79 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-乙基-1,2,4-㗁二唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
80 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
81 (9S,13S,19aR,22R)-22-苯甲基-N-(2,3-二甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
82 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(5-甲基異㗁唑-4-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
83 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(1-甲基-1H-吡唑-4-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
84 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(4-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
85 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-(三級丁基)-1,2,4-㗁二唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
86 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-(3,5-二甲基苯基)-1,2,4-㗁二唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
87 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-(2-(三氟甲氧基)苯基)-1,2,4-㗁二唑-5-基)乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
88 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(5-(2-(三氟甲氧基)苯基)-4H-1,2,4-三唑-3-基)乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
89 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-(三級丁基)異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
90 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(5-(三級丁基)異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
91 (9S,13S,19aR,22R)-22-苯甲基-N-(4-氟-3-甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
92 (9S,13S,19aR,22R)-22-苯甲基-N-(2-氟-5-甲基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
93 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基-4-(2H-1,2,3-三唑-2-基)苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
94 (9S,13S,19aR,22R)-22-苯甲基-N-(2,4-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
95 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(4-甲氧基-3-甲基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
96 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(3-甲基苯乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
97 (9S,13S,19aR,22R)-22-苯甲基-N-(2,3-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
98 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(5-甲基異㗁唑-3-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
99 (9S,13S,19aR,22R)-22-苯甲基-N-(4-溴-2,6-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
100 (9S,13S,19aR,22R)-22-苯甲基-N-(3-氟-4-甲氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
101 (7R,13S,17S)-7-苯甲基-N-(2-(3,4-二氫-2H-苯并[b][1,4]二㗁呯-7-基)乙基)-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
102 (9S,13S,19aR,22R)-22-苯甲基-N-(2,6-二氟-3-甲基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
103 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(異噻唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
104 (9S,13S,19aR,22R)-22-苯甲基-N-(2-氟-6-甲基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
105 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
106 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
107 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-(三級丁基)異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
108 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-苯乙基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
109 (3'S,7'S,13'R)-13'-苯甲基-N-(3,5-二甲氧基苯乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
110 (3'S,7'S,13'R)-13'-苯甲基-N-(2,6-二氟苯乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
111 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(4-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
112 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(3-甲基苯乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
113 (3'S,7'S,13'R)-13'-苯甲基-N-(3,4-二氟苯乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
114 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-乙基-1,2,4-㗁二唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
115 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
116 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-(三級丁基)-1,2,4-㗁二唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
117 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(2-(5-甲基異㗁唑-3-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
118 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
119 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-(三級丁基)異㗁唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
120 (3'S,7'S,13'R)-13'-苯甲基-N-(3,5-二氟苯乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
121 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
122 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(4-(嘧啶-2-基)苯乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
123 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(3-(嘧啶-2-基)苯乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
124 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(1-環丙基-1H-吡唑-4-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
125 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(3-甲基-4-(2H-1,2,3-三唑-2-基)苯乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
126 (9S,13S,19aR,22R)-22-苯甲基-N-(3,5-二氟苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
127 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
128 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丁基-1,2,4-㗁二唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
129 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(1,4-二甲基-1H-吡唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
130 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(3-(3-甲氧基苯基)-1,2,4-㗁二唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
131 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
132 (3'S,7'S,13'R)-13'-苯甲基-N-(2,6-二氟苯乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
133 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(4-(吡𠯤-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
134 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(3-(吡𠯤-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
135 (3'S,7'S,13'R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
136 (3'S,7'S,13'R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
137 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(4-(嘧啶-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
138 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(3-(嘧啶-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
139 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(1-環丙基-1H-吡唑-4-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
140 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
141 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(2-(5-甲基異㗁唑-3-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
142 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
143 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(2-(1-甲基-1H-吡唑-4-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
144 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
145 (3'S,7'S,13'R)-13'-苯甲基-N-(2,2-二氟-2-苯基乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
146 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基-1,2,4-㗁二唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
147 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
148 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-7-基)乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
149 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
150 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(3-(二氟甲氧基)苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
151 (7R,13S,17RS)-7-苯甲基-N-(2,3-二甲氧基苯乙基)-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
152 (3R,9S,13RS)-3-苯甲基-N-(2-(2,3-二氫苯并呋喃-5-基)乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
153 (7R,13S,17S)-7-苯甲基-13-異丁基-N-(4-甲氧基苯乙基)-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
154 (7R,13S,17S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-13-異丁基-14-甲基-9,12,15,19-四側氧基-11-(2-(四氫-2H-哌喃-4-基)乙基)-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
155 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(2-((RS)-四氫-2H-哌喃-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
156 (3R,9S,13RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-17,18-二甲氧基-7-(3-甲氧基-3-甲基丁基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
157 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-((RS)-2-(5,5-二甲基四氫-2H-哌喃-2-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
158 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(2-(2-甲氧基吡啶-4-基)乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
159 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
160 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
161 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-N-(2-(2,3,4,5-四氫苯并[b]㗁呯-8-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
162 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
163 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
164 (3RS,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
165 (3RS,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
166 (3'S,7'S,13'R)-13'-苯甲基-N-((1-(3,4-二甲氧基苯基)環丙基)甲基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
167 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(3-(甲基磺醯基)苯乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
168 (3'S,7'S,13'R)-13'-苯甲基-N-(3-氰基苯乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
169 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(3-(三氟甲基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
170 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(4-(N-𠰌啉基)苯乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
171 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-N-(2-(5-異丙基-1,2,4-㗁二唑-3-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
172 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(4-環丙基-1H-吡唑-1-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
173 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(4-溴-1H-吡唑-1-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
174 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(2-(4-(3-甲氧基丙基)-1H-吡唑-1-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
175 (3'S,7'S,13'R)-13'-苯甲基-N-(2,2-二氟-2-(3-甲氧基苯基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
176 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(1-環丙基-1H-吡唑-4-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
177 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
178 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-N-(2-(3-(三氟甲基)-1,2,4-㗁二唑-5-基)乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
179 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(4-環丙基-1H-吡唑-1-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
180 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
181 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-N-(4-(嘧啶-2-基)苯乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
182 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-N-(2-(3-苯基-1,2,4-㗁二唑-5-基)乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
183 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-N-苯乙基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
184 (7S,11S,17aR,20R)-20-苯甲基-N-(4-溴苯乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
185 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-N-(4-甲氧基苯乙基)-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
186 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-N-(3-甲基苯乙基)-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
187 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
188 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(2-(4-甲氧基-1H-吡唑-1-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
189 (7S,11S,17aR,20R)-20-苯甲基-N-(3-乙炔基苯乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
190 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
191 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-(二氟甲基)異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
192 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-7,10-二甲基-N-(4-甲基苯乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
193 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-N-(4-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
194 (3R,9S,13S)-3-苯甲基-N-(3-乙氧基苯乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
195 (3R,9S,13S)-3-苯甲基-9-異丁基-17,18-二甲氧基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
196 (3R,9S,13S)-3-苯甲基-N-(2-氟苯乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
197 (3R,9S,13S)-3-苯甲基-N-(4-(二甲基胺基)苯乙基)-9-異丁基-17,18-二甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
198 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
199 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
200 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(3-(甲氧基-d3)苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
201 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(3-乙氧基苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
202 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-N-(4-甲基苯乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
203 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(4-(二甲基胺基)苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
204 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-氟苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
205 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(3,5-二甲氧基苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
206 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-(2-(噻吩-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
207 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(2-(5-甲氧基吡啶-2-基)乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
208 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(呋喃-2-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
209 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(3,5-二甲基-1H-吡唑-1-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
210 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(3-甲氧基丙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
211 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-苯乙基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
212 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-N-(2-((RS)-四氫-2H-哌喃-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
213 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-((RS)-2,3-二氫苯并[b][1,4]二氧雜環己烯-2-基)乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
214 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
215 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(4-乙基苯乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
216 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(5-甲氧基戊基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
217 (3R,9S,13S)-N-(4-(1H-吡唑-1-基)苯乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
218 (3R,9S,13S)-N-(4-胺基-3-甲氧基苯乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
219 (3R,9S,13RS)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(4-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
220 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(2-(6-甲氧基吡啶-2-基)乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
221 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
222 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
223 (7R,13S,17S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
224 (7R,13S,17S)-7-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
225 (7R,13S,17S)-7-苯甲基-N-(3-乙氧基苯乙基)-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
226 (7R,13S,17S)-7-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
227 (7R,13S,17S)-7-苯甲基-N-(4-乙基苯乙基)-13-異丁基-11,14-二甲基-9,12,15,19-四側氧基-6,7,8,9,10,11,12,13,14,15,16,17,18,19-十四氫-[1,3]二氧[4',5':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
228 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-17-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
229 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10,17-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
230 (3R,9S,13S)-3-苯甲基-9-異丁基-N-(3-甲氧基苯乙基)-7,10,17-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
231 (3R,9S,13S)-3-苯甲基-9-異丁基-17-甲氧基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
232 (3R,9S,13S)-3-苯甲基-9-異丁基-18-甲氧基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
233 (3R,9S,13S)-3-苯甲基-9-異丁基-N-(3-甲氧基苯乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
234 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-17-氟-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
235 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10,16-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
236 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫萘并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
237 (3R,9S,13S)-3-苯甲基-17-氯-9-異丁基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
238 (3R,9S,13S)-3-苯甲基-9-異丁基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫萘并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
239 (3R,9S,13S)-3-苯甲基-N-(4-乙基苯乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
240 (6R,12S,16S)-6-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-10,13-二甲基-8,11,14,18-四側氧基-5,6,7,8,9,10,11,12,13,14,15,16,17,18-十四氫噻吩并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-16-甲醯胺
241 (6R,12S,16S)-6-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-2,10,13-三甲基-8,11,14,18-四側氧基-5,6,7,8,9,10,11,12,13,14,15,16,17,18-十四氫噻唑并[5,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-16-甲醯胺
242 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-(甲氧基-d3)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
243 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-(甲氧基-d3)-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
244 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-(甲氧基-d3)-N-(3-(甲氧基-d3)苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
245 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-7-基)乙基)-9-異丁基-17-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
246 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-10,16-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
247 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10,16-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
248 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-17-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
249 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-17-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
250 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫萘并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
251 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫萘并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
252 (3R,9S,13S)-3-苯甲基-N-(4-乙基苯乙基)-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
253 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-17-氯-7-(2-環己基乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
254 (3R,9S,13S)-3-苯甲基-17-氯-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
255 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
256 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16,18-二甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
257 (3R,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
258 (3R,13S)-3-苯甲基-7-(2-環己基乙基)-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
259 (7S,11S,20R,22aR)-20-苯甲基-N-(4-溴苯乙基)-7-異丁基-14-甲氧基-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫苯并[p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
260 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14-甲氧基-8-甲基-6,9,13,22-四側氧基-N-(2-(2,3,4,5-四氫苯并[b]㗁呯-8-基)乙基)-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫苯并[p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
261 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-7-基)乙基)-7-(2-環己基乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
262 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
263 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-16-甲氧基-9,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
264 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-16-甲氧基-N-(3-甲氧基苯乙基)-9,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
265 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
266 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
267 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
268 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
269 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
270 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-10,18-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
271 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10,18-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
272 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-16,18-二甲氧基-9,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
273 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-16,18-二甲氧基-N-(3-甲氧基苯乙基)-9,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
274 (3R,9S,13RS)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-(環丙基甲基)-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
275 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-7-基)乙基)-7-(2-環己基乙基)-9-異丁基-16,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
276 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-9-異丁基-16,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
277 (3R,9S,13S)-3-苯甲基-16-氟-9-異丁基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
278 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-16-氟-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
279 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-16-氯-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
280 (7S,11S,20R,22aR)-20-苯甲基-14-乙氧基-7-異丁基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
281 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
282 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
283 (7S,11S,20R,22aR)-20-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-14-乙氧基-7-異丁基-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
284 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環戊基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
285 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環己基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
286 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環戊基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
287 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環己基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
288 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環戊基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((SR)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
289 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環己基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((SR)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
290 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-7-(環戊基甲基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
291 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-7-(環己基甲基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
292 (3RS,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丁基甲基)-9-(2-環己基乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
293 (3RS,7S,13R)-13-苯甲基-7-(環戊基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
294 (3RS,7S,13R)-13-苯甲基-7-(環己基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
295 (3RS,7S,13R)-13-苯甲基-7-(環戊基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
296 (3RS,7S,13R)-13-苯甲基-7-(環己基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
297 (3RS,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(2-((SR)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
298 (3RS,7S,13R)-13-苯甲基-7-(環戊基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(2-((SR)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
299 (3RS,7S,13R)-13-苯甲基-7-(環己基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-9-(2-((SR)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
300 (3RS,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-(環戊基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
301 (3RS,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-(環己基甲基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
302 (3RS,7S,13R)-13-苯甲基-7-(環丁基甲基)-9-(2-環己基乙基)-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
303 (3RS,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
304 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(2-((RS)-四氫-2H-哌喃-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
305 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
306 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
307 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-(環戊基甲基)-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
308 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-(環戊基甲基)-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
309 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-(環己基甲基)-16-甲氧基-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
310 (3R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-7-(2-((RS)-四氫-2H-哌喃-2-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
311 (3R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
312 (3R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
313 (3R,9S,13S)-3-苯甲基-9-(環戊基甲基)-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-7-(((R)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
314 (3R,9S,13S)-3-苯甲基-9-(環己基甲基)-16-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-7-(((S)-四氫-2H-哌喃-2-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
315 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
316 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-N-(3-(甲氧基-d3)苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
317 (3R,9S,13S)-3-苯甲基-9-異丁基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-16-(三氟甲氧基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
318 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
319 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
320 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-(甲氧基-d3)苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
321 (8R,14S,18S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-8-苯甲基-14-異丁基-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
322 (8R,14S,18S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-8-苯甲基-14-異丁基-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-2,2-d2-18-甲醯胺
323 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
324 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-2,2-d2-18-甲醯胺
325 (4aR,7R,18S,22S)-7-苯甲基-N-(3,5-二甲氧基苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
326 (4aR,7R,18S,22S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
327 (4aR,7R,18S,22S)-N-(2-(苯并[d]㗁唑-2-基)乙基)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
328 (8S,12S,18aR,21R)-21-苯甲基-N-(3,5-二甲氧基苯乙基)-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
329 (8S,12S,18aR,21R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-21-苯甲基-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
330 (3S,7S,13R)-9-(2-(7-氧雜雙環[2.2.1]庚-2-基)乙基)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
331 (3S,7S,13R)-9-(2-(5-氧雜螺[3.4]辛-6-基)乙基)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
332 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(2-(四氫呋喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
333 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(2-(四氫-2H-哌喃-3-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
334 (3S,7S,13R)-9-(2-(2,9-二氧雜螺[5.5]十一烷-3-基)乙基)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
335 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-(三級丁氧基)乙基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
336 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-9-(2-(3-甲氧基環丁基)乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
337 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丁基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((S)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
338 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丁基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
339 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-6-甲基-1,5,8,11-四側氧基-7-(丙-2-炔-1-基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
340 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丙基甲基)-6-甲基-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
341 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-7-(環丙基甲基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
342 (8S,12S,18aS,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-11-甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
343 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-11-甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
344 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
345 (8R,14S,18S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-15-甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
346 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-N-(3-甲氧基苯乙基)-15-甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
347 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-N-(3-(甲氧基-d3)苯乙基)-15-甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
348 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-12-異丁基-N-(3-甲氧基苯乙基)-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
349 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-18-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
350 (3S,7S,13R)-13-苯甲基-18-氟-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
351 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[5',4':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
352 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-17-異丙基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
353 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-17-異丙基-N-(3-甲氧基苯乙基)-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
354 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-3-(2-甲氧基乙基)-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
355 (4aR,7R,18S,22S)-7-苯甲基-3-環丁基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
356 (4aR,7R,18S,22S)-7-苯甲基-3-環丙基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
357 (4aS,7R,18S,22S)-7-苯甲基-3-環丙基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
358 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丙基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((S)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
359 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丙基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((R)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
360 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丁基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((S)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
361 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-(環丁基甲基)-6-甲基-1,5,8,11-四側氧基-9-(2-((R)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
362 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(2-((S)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
363 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(2-((R)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
364 (8S,12S,18aR,21R)-21-苯甲基-12,17-二異丁基-N-(3-甲氧基苯乙基)-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
365 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
366 (9S,13S,19aS,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
367 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
368 (8S,12S,18aR,21R)-21-苯甲基-N-(3,5-二甲氧基苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[5',4':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
369 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸2,2,2-三氯乙酯
370 (4aR,7R,18S,22S)-7-苯甲基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
371 (4aR,7R,18S,22S)-7-苯甲基-N-(3-(二氟甲氧基)苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
372 (9S,13S,19aR,22R)-22-苯甲基-13,18-二異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
373 (9S,13S,19aS,22R)-22-苯甲基-13,18-二異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
374 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-18-異丙基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
375 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-18-異丙基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
376 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十四氫-1H-萘并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
377 (8S,12S,18aR,21R)-21-苯甲基-N-(3,5-二甲氧基苯乙基)-12-異丁基-4,5,11-三甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
378 (4aR,7R,18S,22S)-7-苯甲基-N-(3-溴苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
379 (8R,14S,18S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-2,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
380 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-N-(3-甲氧基苯乙基)-2,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
381 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-N-(3-(甲氧基-d3)苯乙基)-2,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
382 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-18-氟-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
383 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-18-氟-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
384 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-18-氟-7-異丁基-N-(3-(甲氧基-d3)苯乙基)-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
385 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
386 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6'-甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
387 (4aR,7R,18S,22S)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-7-苯甲基-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
388 (9S,13S,19aS,22R)-22-苯甲基-18-環丙基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
389 (9S,13S,19aR,22R)-22-苯甲基-18-環丙基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
390 (9S,13S,19aS,22R)-22-苯甲基-18-環丁基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
391 (9S,13S,19aR,22R)-22-苯甲基-18-環丁基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
392 (9S,13S,19aS,22R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-22-苯甲基-18-環丙基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
393 (9S,13S,19aR,22R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-22-苯甲基-18-環丙基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
394 (9S,13S,19aS,22R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-22-苯甲基-18-環丁基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
395 (9S,13S,19aR,22R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-22-苯甲基-18-環丁基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
396 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-9'-(3-甲氧基丙基)-6'-甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
397 (4aR,7R,18S,22S)-7-苯甲基-N-(3-乙氧基苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
398 (9S,13S,19aR,22R)-22-苯甲基-18-環丙基-N-(3-(二氟甲氧基)苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
399 (9S,13S,19aS,22R)-22-苯甲基-18-環丙基-N-(3-(二氟甲氧基)苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
400 (9S,13S,19aR,22R)-22-苯甲基-18-環丙基-N-(3-乙氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
401 (9S,13S,19aS,22R)-22-苯甲基-18-環丙基-N-(3-乙氧基苯乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
402 (9S,13S,19aR,22R)-22-苯甲基-18-環丙基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
403 (9S,13S,19aS,22R)-22-苯甲基-18-環丙基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
404 (9S,13S,19aR,22R)-22-苯甲基-18-環丙基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
405 (9S,13S,19aS,22R)-22-苯甲基-18-環丙基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
406 (7S,11S,21R,23aR)-21-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-8,16-二甲基-6,9,13,23-四側氧基-1,3,4,6,7,8,9,10,11,12,13,20,21,22,23,23a-十六氫-2H-㗁唑并[5',4':4,5]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
407 (7S,11S,21R,23aR)-21-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-8,16-二甲基-6,9,13,23-四側氧基-1,3,4,6,7,8,9,10,11,12,13,20,21,22,23,23a-十六氫-[1,4]㗁 𠯤并[3,4-f]㗁唑并[5',4':4,5]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
408 (8R,14S,18S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-8-苯甲基-2,2-二氟-14-異丁基-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
409 (8R,14S,18S)-8-苯甲基-2,2-二氟-14-異丁基-N-(3-甲氧基苯乙基)-12,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫-[1,3]二氧[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
410 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-14-異丁基-2,15-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
411 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-18-氟-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
412 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
413 (9S,13S,19aS,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
414 (9S,13S,19aR,22R)-22-苯甲基-N-(3-(二氟甲氧基)苯乙基)-13-異丁基-18-(2-甲氧基乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
415 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-13-異丁基-18-(2-甲氧基乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
416 (4aR,7R,18S,22S)-7-苯甲基-3-(2-羥基乙基)-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
417 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
418 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-N-(3-乙氧基苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
419 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-N-(3-(二氟甲氧基)苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
420 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-N-(2-(5,6-二氫-4H-環戊[d]噻唑-2-基)乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
421 (8S,12S,18aR,21R)-21-苯甲基-17-環丙基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
422 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-N-(3-(1,1-二氟乙基)苯乙基)-14-異丁基-2,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
423 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-3,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-3H,15H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-e]吲唑-8-甲醯胺
424 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-3,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22-十六氫-3H-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-e]吲唑-8-甲醯胺
425 (8S,12S,18aR,21R)-21-苯甲基-17-(環丙基甲基)-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
426 (8S,12S,18aR,21R)-21-苯甲基-17-(環丙基甲基)-N-(3-(二氟甲氧基)苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
427 (8S,12S,18aR,21R)-21-苯甲基-17-(環丙基甲基)-N-(3-乙氧基苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
428 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-21-苯甲基-17-(環丙基甲基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
429 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-3,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-3H,15H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-e]吲唑-8-甲醯胺
430 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
431 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-9-(3-甲氧基丙基)-6,10-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
432 (3'S,7'S,13'R)-13'-苯甲基-7'-(環戊基甲基)-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
433 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
434 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
435 (8S,12S,18aR,21R)-21-苯甲基-12-(環戊基甲基)-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22-十六氫-[1,4]㗁 𠯤并[3,4-f]㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
436 (8S,12S,18aR,21R)-21-苯甲基-12-(環戊基甲基)-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
437 (8S,12S,18aS,21R)-21-苯甲基-12-(環戊基甲基)-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
438 (3'R,9'S,13'S)-3'-苯甲基-9'-異丁基-16'-甲氧基-N-(3-甲氧基苯乙基)-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
439 (3'S,7'S,13'R)-13'-苯甲基-18'-氟-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
440 (3'S,7'S,13'R)-13'-苯甲基-18'-氟-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
441 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
442 (3'R,9'S,13'S)-3'-苯甲基-9'-異丁基-N-(3-甲氧基苯乙基)-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
443 (9S,13S,19aR,22R)-22-苯甲基-3-氟-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
444 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4,10-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
445 (3S,7S,13R)-13-苯甲基-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-9-(((R)-四氫-2H-哌喃-2-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
446 (3S,7S,13R)-13-苯甲基-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-9-(2-((S)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
447 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-12,15-二甲基-10,13,16,20-四側氧基-2,3,7,8,9,10,13,14,15,16,17,18,19,20-十四氫-12H-螺[苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11,1'-環丙烷]-18-甲醯胺
448 (3'R,9'S,13'S)-3'-苯甲基-9'-異丁基-7',10'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
449 (3R,9S,13S)-3-苯甲基-9-異丁基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
450 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14,19,20-十六氫苯并呋喃并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
451 (4aR,7R,18S,22S)-7-苯甲基-3-(3-羥基丙基)-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
452 (4aR,7R,18S,22S)-7-苯甲基-3-(3-羥基丙基)-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
453 (3'S,7'S,13'R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
454 (3'S,7'S,13'R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
455 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-11-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十八氫-15H-苯并呋喃并[7,6-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
456 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-11-甲基-6,10,13,19-四側氧基-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十八氫-15H-苯并呋喃并[7,6-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
457 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-9'-(2-甲氧基乙基)-N-(3-甲氧基苯乙基)-6'-甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
458 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-9-((2-(3-甲基異㗁唑-5-基)乙基)胺甲醯基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-18H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-18-甲酸2,2,2-三氯乙酯
459 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12,18-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
460 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
461 (9S,13S,19aR,22R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
462 (9S,13S,19aS,22R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
463 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
464 (9S,13S,19aS,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
465 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
466 (7S,11S,17aR,20R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
467 (7S,11S,17aS,20R)-N-(3-(2H-1,2,3-三唑-2-基)苯乙基)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
468 (7S,11S,17aR,20R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
469 (7S,11S,22R,24aR)-22-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,24-四側氧基-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-十六氫-2H-吡啶并[2,1-f]吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
470 (7S,11S,22R,24aR)-22-苯甲基-7-異丁基-8-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,9,13,24-四側氧基-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-十六氫-2H-吡啶并[2,1-f]吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
471 (9'R,15'S,19'S)-9'-苯甲基-15'-異丁基-N-(3-甲氧基苯乙基)-13',16'-二甲基-11',14',17',21'-四側氧基-8',9',10',11',14',15',16',17',18',19',20',21'-十二氫-13'H-螺[環丙烷-1,12'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-h]喹啉]-19'-甲醯胺
472 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
473 (9S,13S,19aS,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
474 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
475 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-3-(吡啶-3-基磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
476 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
477 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
478 (7S,11S,17aR,20R)-20-苯甲基-N-(2,6-二氟苯乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
479 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-3-((5-甲氧基吡啶-3-基)磺醯基)-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
480 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
481 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
482 (8S,12S,18aR,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
483 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
484 (7S,11S,22R,24aR)-22-苯甲基-N-(2,6-二氟苯乙基)-7-異丁基-8-甲基-6,9,13,24-四側氧基-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-十六氫-2H-吡啶并[2,1-f]吡啶并[2',1':2,3]咪唑并[4,5-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
485 (8S,12S,18aR,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-5,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-5H,15H-咪唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
486 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
487 (9S,13S,19aR,22S)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
488 (3'R,9'S,13'S)-3'-苯甲基-9'-異丁基-17'-甲氧基-N-(3-甲氧基苯乙基)-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
489 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
490 (8S,12S,18aR,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-3,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-3H,15H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-e]吲唑-8-甲醯胺
491 (8S,12S,18aR,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-11-甲基-6,10,13,19-四側氧基-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十八氫-15H-苯并呋喃并[7,6-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
492 (1r,3S,3'S,7'S,13'R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-7'-異丁基-3-甲氧基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
493 (1r,3S,3'S,7'S,13'R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-13'-苯甲基-7'-異丁基-3-甲氧基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
494 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
495 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-1,2',3,3',4',5',6',7',8',9',11',12',13',14'-十四氫-1'H-螺[茚-2,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
496 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(4-(嘧啶-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
497 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
498 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
499 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
500 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
501 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
502 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-N-(3-(嘧啶-2-基)苯乙基)-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
503 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9,10,10-四甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
504 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
505 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
506 (9S,13S,19aR,22R)-22-苯甲基-12-乙基-13-異丁基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
507 (3S,7S,13R)-13-苯甲基-20-氟-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
508 (3S,7S,10R,13R)-13-苯甲基-10-環丙基-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
509 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
510 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
511 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
512 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
513 (3R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
514 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
515 (7S,11S,17aRS,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:4',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
516 (7S,11S,17aRS,20R)-20-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:4',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
517 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:2',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
518 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:2',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
519 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
520 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
521 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
522 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-22-苯甲基-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
523 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
524 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
525 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
526 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:4',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
527 (9S,13S,19aR,22R)-22-苯甲基-5-氯-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
528 (9S,13S,19aR,22R)-22-苯甲基-5-氯-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
529 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:2',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
530 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]異喹啉-3-甲醯胺
531 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
532 (8R,14S,18S)-8-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
533 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
534 (9S,13S,19aR,22R)-22-苯甲基-6-氟-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
535 (9S,13S,19aR,22R)-22-苯甲基-6-氟-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
536 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-17-苯基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
537 (73S,4R,9S,13S)-4-苯甲基-16-氟-9-異丁基-N-(3-甲氧基苯乙基)-10-甲基-6,8,11,15-四側氧基-2-氧雜-5,10,14-三氮雜-1(3,4)-喹啉-7(3,1)-吡咯啶環十五烷-13-甲醯胺
538 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-2-苯基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-吡𠯤并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
539 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-((4,4-二氟環己基)甲基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
540 (3S,7S,10S,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-((4,4-二氟環己基)甲基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
541 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
542 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14-甲氧基-8-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,9,13,22-四側氧基-2-苯基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-吡𠯤并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
543 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
544 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
545 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
546 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
547 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-10-異丙基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
548 (3S,7S,10R,13R)-13-苯甲基-7,10-二異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
549 (7S,11S,20R,22aS)-20-苯甲基-7-異丁基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-2-苯基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-吡𠯤并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
550 (7S,11S,20R,22aS)-20-苯甲基-7-異丁基-14-甲氧基-8-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,9,13,22-四側氧基-2-苯基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-吡𠯤并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
551 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,13,14,15,16,17,18,19,20-十二氫-12H-螺[苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11,1'-環丙烷]-18-甲醯胺
552 (8R,14S,18S)-8-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,13,14,15,16,17,18,19,20-十二氫-12H-螺[苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11,1'-環丙烷]-18-甲醯胺
553 (8R,14S,18S)-8-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,13,14,15,16,17,18,19,20-十二氫-12H-螺[苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11,1'-環丙烷]-18-甲醯胺
554 (8R,14S,18S)-8-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,13,14,15,16,17,18,19,20-十二氫-12H-螺[苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11,1'-環丙烷]-18-甲醯胺
555 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(3-甲氧基苯乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]異喹啉]-3'-甲醯胺
556 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]異喹啉]-3'-甲醯胺
557 (3R,6S,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
558 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
559 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
560 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
561 (8R,14S,18S)-8-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
562 (8R,14S,18S)-8-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-14-異丁基-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
563 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-6-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
564 (3S,7S,10R,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
565 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
566 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-10-(2-甲氧基乙基)-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
567 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
568 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
569 (7S,11S,19bRS,22R)-22-苯甲基-11-異丁基-4-甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,9,12,20-四側氧基-5,6,7,8,9,10,11,12,15,19b,20,21,22,23-十四氫-14H-吡啶并[3',4':16,17][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[6,7-a]異喹啉-7-甲醯胺
570 (7S,11S,20R,22aR)-20-苯甲基-2,7-二異丁基-14-甲氧基-8-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-吡𠯤并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
571 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-6-(2-(3-苯基-1,2,4-㗁二唑-5-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
572 (3S,7S,10S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
573 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-6,9,10-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
574 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
575 (8R,11RS,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-2,11,12,15-四甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
576 (8R,11RS,14S,18S)-8-苯甲基-14-異丁基-2,11,12,15-四甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫苯并呋喃并[7,6-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
577 (3R,6S,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-6-(2-(3-苯基-1,2,4-㗁二唑-5-基)乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
578 (3S,7S,10R,13R)-13-苯甲基-10-(2-(苯甲氧基)乙基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
579 (3S,7S,10S,13R)-13-苯甲基-10-(2-(苯甲氧基)乙基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
580 (7'S,11'S,17a'R,20'R)-20'-苯甲基-11'-異丁基-4'-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2',10'-二甲基-5',9',12',18'-四側氧基-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-十六氫螺[環丙烷-1,16'-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-7'-甲醯胺
581 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-4-(甲氧基-d3)-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
582 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
583 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
584 (13S,4R,10S,14S)-4-苯甲基-14-異丁基-74-甲氧基-N-(3-甲氧基苯乙基)-13-甲基-2,8,12,15-四側氧基-6-氧雜-3,9,13-三氮雜-1(3,1)-吡咯啶-7(1,2)-苯環十五烷-10-甲醯胺
585 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
586 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-17,18-二甲氧基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
587 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-15-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
588 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-15-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫苯并[p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
589 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
590 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-9-異丁基-N-(3-甲氧基苯乙基)-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
591 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
592 (7S,11S,17aS,20R)-20-苯甲基-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-11-異丁基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
593 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-11-異丁基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
594 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-11-異丁基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
595 (3S,7S,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
596 (3R,9S,13S)-3-苯甲基-N-(2-(𠳭唍-7-基)乙基)-7-(2-環己基乙基)-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
597 (3R,9S,13S)-3-苯甲基-7-(2-環己基乙基)-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-9-異丁基-17,18-二甲氧基-10-甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
598 (8R,14S,18S)-8-苯甲基-14-異丁基-N-(3-甲氧基苯乙基)-2,12,15-三甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
599 (3S,7S,13R)-13-苯甲基-N-(2-(𠳭唍-7-基)乙基)-9-(2-環己基乙基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
600 (3S,7S,13R)-13-苯甲基-9-(2-環己基乙基)-N-(2-(2,3-二氫苯并呋喃-6-基)乙基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
601 (7S,11S,20R,22aS)-20-苯甲基-7-異丁基-14,16-二甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
602 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14,16-二甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
603 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
604 (4aS,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
605 (7S,11S,20R,22aR)-20-苯甲基-2-乙基-7-異丁基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
606 (4aS,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
607 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
608 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
609 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-14,16-二甲氧基-8-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
610 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(2-環己基乙基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
611 (7S,11S,20R,22aR)-20-苯甲基-7-異丁基-2-異丙基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
612 (7S,11S,20R,22aR)-20-苯甲基-2,7-二異丁基-14-甲氧基-N-(3-甲氧基苯乙基)-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
613 (4aR,7R,18S,22S)-7-苯甲基-N-(3,5-二甲氧基苯乙基)-3,22-二異丁基-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
614 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
615 (8S,12S,18aS,21R)-21-苯甲基-12-異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
616 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-16-(二氟甲氧基)-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
617 (4aR,7R,18S,22S)-7-苯甲基-3,22-二異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
618 (4aR,7R,18S,22S)-7-苯甲基-N-(3,5-二甲氧基苯乙基)-22-異丁基-3-異丙基-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
619 (8S,12S,18aR,21R)-21-苯甲基-12,17-二異丁基-N-(3-甲氧基苯乙基)-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
620 (8S,12S,18aR,21R)-21-苯甲基-12,17-二異丁基-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
621 (8S,12S,18aS,21R)-21-苯甲基-12,17-二異丁基-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
622 (9S,13S,19aR,22R)-22-苯甲基-13,18-二異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
623 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-3-異丙基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
624 (4aRS,7R,17S,21S)-7-苯甲基-21-異丁基-N-(3-甲氧基苯乙基)-12,20-二甲基-5,15,19,22-四側氧基-1,2,4,4a,5,6,7,8,15,16,17,18,19,20,21,22-十六氫異㗁唑并[4',5':5,6]苯并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-17-甲醯胺
625 (8S,12S,18aR,21R)-21-苯甲基-N-(3-(二氟甲氧基)苯乙基)-12-異丁基-4,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22-十六氫-[1,4]㗁 𠯤并[3,4-f]㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
626 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-7-異丁基-6-甲基-1,5,8,11-四側氧基-9-(3-苯基丙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
627 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
628 (8'R,14'S,18'S)-8'-苯甲基-14'-異丁基-N-(3-甲氧基苯乙基)-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺
629 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-3,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-異㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
630 (8S,12S,18aR,21R)-21-苯甲基-12-(環戊基甲基)-3,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-異㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
631 (8S,12S,18aS,21R)-21-苯甲基-12-(環戊基甲基)-3,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-異㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
632 (8S,12S,18aR,21R)-21-苯甲基-12-異丁基-4,11-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
633 (1r,3S,3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-3-甲氧基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
634 (8S,12S,18aR,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-3,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-異㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
635 (8S,12S,18aS,21R)-21-苯甲基-N-(2,6-二氟苯乙基)-12-異丁基-3,11-二甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-異㗁唑并[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-8-甲醯胺
636 (9S,13S,19aR,22R)-22-苯甲基-N-(2,6-二氟苯乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
637 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
638 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-3-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
639 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
640 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
641 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
642 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
643 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
644 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
645 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-十六氫-[1,4]㗁 𠯤并[3',4':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
646 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-12-乙基-13-異丁基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
647 (3R,9S,13S)-3-苯甲基-9-異丁基-17-甲氧基-N-(3-甲氧基苯乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
648 (3'R,9'S,13'S)-3'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-9'-異丁基-17'-甲氧基-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
649 (3'R,9'S,13'S)-3'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9'-異丁基-17'-甲氧基-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
650 (3'R,9'S,13'S)-3'-苯甲基-9'-異丁基-17'-甲氧基-N-(3-甲氧基苯乙基)-7',10'-二甲基-5',8',11',15'-四側氧基-2',3',4',5',8',9',10',11',12',13',14',15'-十二氫-7'H-螺[環丙烷-1,6'-吡啶并[4,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-13'-甲醯胺
651 (7S,11S,20R,22aR)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-20-苯甲基-14-氟-7-異丁基-8-甲基-6,9,13,22-四側氧基-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-十六氫-2H-苯并[p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-11-甲醯胺
652 (7S,11S,17aRS,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-3-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:4',3'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
653 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-三唑-2-基)苯乙基)-21-苯甲基-12-異丁基-11-甲基-6,10,13,19-四側氧基-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-十六氫-15H-[1,3]二氧[4',5':5,6]苯并[1,2-p]吡啶并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-4,4-d2-8-甲醯胺
654 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-3'-甲醯胺
655 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
656 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
657 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-11-異丁基-4-(甲氧基-d3)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
658 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
659 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-(甲氧基-d3)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
660 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-6-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
661 (3R,6S,9S,13S)-3-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
662 (3R,6R,9S,13S)-3-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
663 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-16,16-二氟-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
664 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-11-異丁基-4-(甲氧基-d3)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
665 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
666 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-11-異丁基-4-(甲氧基-d3)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
667 (7S,11S,17aS,20R)-20-苯甲基-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-N-(2-(3-(三氟甲基)異㗁唑-5-基)乙基)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
668 (7'S,11'S,17a'R,20'R)-20'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11'-異丁基-4'-甲氧基-10'-甲基-5',9',12',18'-四側氧基-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-十六氫螺[環丙烷-1,16'-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-7'-甲醯胺
669 (7'S,11'S,17a'S,20'R)-20'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11'-異丁基-4'-甲氧基-10'-甲基-5',9',12',18'-四側氧基-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-十六氫螺[環丙烷-1,16'-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-7'-甲醯胺
670 (7S,11S,17aS,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-16-苯基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
671 (7S,11S,17aS,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-16-苯基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
672 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-16-苯基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
673 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-16-苯基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
674 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
675 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
676 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
677 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-18-苯基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
678 (7S,11S,19aR,22R)-22-苯甲基-11-異丁基-4-甲氧基-10-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,9,12,20-四側氧基-5,6,7,8,9,10,11,12,19,19a,20,21,22,23-十四氫-14H-吡啶并[3',4':16,17][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[7,6-b]異喹啉-7-甲醯胺
679 (7S,11S,19bR,22R)-22-苯甲基-11-異丁基-4-甲氧基-10-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,9,12,20-四側氧基-5,6,7,8,9,10,11,12,15,19b,20,21,22,23-十四氫-14H-吡啶并[3',4':16,17][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[6,7-a]異喹啉-7-甲醯胺
680 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
681 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-6-苯基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
682 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
683 (7'S,11'S,17a'R,20'R)-20'-苯甲基-11'-異丁基-4'-甲氧基-2',10'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5',9',12',18'-四側氧基-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-十六氫螺[環丙烷-1,16'-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-7'-甲醯胺
684 (7'S,11'S,17a'S,20'R)-20'-苯甲基-11'-異丁基-4'-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2',10'-二甲基-5',9',12',18'-四側氧基-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-十六氫螺[環丙烷-1,16'-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-7'-甲醯胺
685 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)-11-異丁基-4-(甲氧基-d3)-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
686 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
687 (3R,9S,13S)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-3-苯甲基-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
688 (3R,9S,13S)-3-苯甲基-N-(2-(2,3-二氫苯并[b][1,4]二氧雜環己烯-6-基)乙基)-9-異丁基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫苯并[p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
689 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
690 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
691 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
692 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
693 (3S,7S,10R,13R)-13-苯甲基-10-(環戊基甲基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
694 (3S,7S,10S,13R)-13-苯甲基-10-(環戊基甲基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
695 (3S,7S,10S,13R)-13-苯甲基-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-10-(萘-1-基甲基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
696 (3S,7S,10R,13R)-13-苯甲基-10-(環己基甲基)-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
697 (3S,7S,10R,13R)-13-苯甲基-10-(環己基甲基)-N-(2-(3-環丙基異㗁唑-5-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
698 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-10-(萘-1-基甲基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
699 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
700 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(((S)-𠳭唍-3-基)甲基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
701 (3S,7S,13R)-9-(2-環己基乙基)-7-異丁基-N-(3-甲氧基苯乙基)-6-甲基-1,5,8,11-四側氧基-13-(吡啶-2-基甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
702 (3S,7S,13R)-13-苯甲基-9-((2,3-二氫苯并呋喃-2-基)甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
703 (3S,7S,13R)-13-(苯并[b]噻吩-3-基甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-9-(2-((S)-四氫-2H-哌喃-2-基)乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
704 (3S,7S,13R)-13-苯甲基-9-(((S)-𠳭唍-3-基)甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
705 (3S,7S,13R)-13-苯甲基-9-(((R)-𠳭唍-3-基)甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
706 (3S,7S,13R)-13-苯甲基-9-(((R)-6,6-二甲基四氫-2H-哌喃-2-基)甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
707 (3S,7S,13R)-13-苯甲基-9-(((S)-6,6-二甲基四氫-2H-哌喃-2-基)甲基)-7-異丁基-6-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
708 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環戊烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
709 (3S,7S,10R,13R)-13-苯甲基-10-(環己基甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
710 (3S,7S,10R,13R)-13-苯甲基-10-環戊基-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
711 (3'S,7'S,13'R)-13'-苯甲基-3,3-二氟-7'-異丁基-6',9'-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
712 (3S,7S,13R)-N-(2-(苯并[d][1,3]二氧呃-5-基)乙基)-13-苯甲基-9-(((R)-𠳭唍-3-基)甲基)-7-異丁基-6-甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
713 (3S,7S,10R,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
714 (3S,7S,10R,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
715 (3S,7S,10S,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
716 (3S,7S,10S,13R)-13-苯甲基-10-((苯甲氧基)甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
717 (3S,7S,10RS,13R)-13-苯甲基-10-(三級丁氧基甲基)-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
718 (3S,7S,10RS,13R)-13-苯甲基-10-(羥基甲基)-7-異丁基-N-(3-甲氧基苯乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
719 (3S,7S,10RS,13R)-13-苯甲基-10-(三級丁氧基甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
720 (3S,7S,10RS,13R)-13-苯甲基-10-(羥基甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫萘并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
721 (3S,7S,10R,13R)-13-苯甲基-10-環戊基-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
722 (3S,7S,10R,13R)-10,13-二苯甲基-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
723 (3S,7S,10S,13R)-10,13-二苯甲基-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
724 (3R,6RS,9S,13S)-3-苯甲基-6-((苯甲氧基)甲基)-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
725 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-21-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
726 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
727 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
728 (8R,14S,18S)-8-苯甲基-12-(2-環己基乙基)-N-(3-((RS)-1-羥基乙基)苯乙基)-14-異丁基-2,15-二甲基-10,13,16,20-四側氧基-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
729 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(苯基磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
730 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-3-((3-(N-𠰌啉基)丙基)磺醯基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
731 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-3-(甲基磺醯基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
732 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-((3-(三氟甲氧基)苯基)磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
733 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-3-((2-甲氧基乙基)磺醯基)-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
734 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-((四氫-2H-哌喃-4-基)磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
735 (4aR,7R,18S,22S)-7-苯甲基-3-((2-(二甲基胺基)乙基)磺醯基)-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
736 (4aR,7R,18S,22S)-7-苯甲基-3-(苯甲基磺醯基)-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
737 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-((2-側氧基-2,3-二氫苯并[d]㗁唑-5-基)磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
738 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-((喹啉-8-基甲基)磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
739 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-3-((3-甲氧基苯基)磺醯基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
740 (4aR,7R,18S,22S)-7-苯甲基-3-((2-氟-5-甲氧基苯基)磺醯基)-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
741 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-3-((4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁 𠯤-7-基)磺醯基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
742 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(吡啶-3-基磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
743 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-3-((3-甲氧基丙基)磺醯基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
744 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-3-((5-甲氧基吡啶-3-基)磺醯基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
745 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-3-((2-(N-𠰌啉基)乙基)磺醯基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
746 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(((四氫-2H-哌喃-4-基)甲基)磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
747 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(吡啶-2-基磺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
748 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-18-((4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁 𠯤-7-基)磺醯基)-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
749 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-18-((3-(三氟甲氧基)苯基)磺醯基)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
750 (4aR,7R,18S,22S)-3-乙醯基-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
751 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-3-(3-甲基丁醯基)-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
752 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-3-(3-甲氧基丙醯基)-21-甲基-5,16,20,23-四側氧基-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
753 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(吡𠯤-2-羰基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
754 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸甲酯
755 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸乙酯
756 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲酸四氫-2H-哌喃-4-基酯
757 (((4aR,7R,18S,22S)-7-苯甲基-22-異丁基-18-((3-甲氧基苯乙基)胺甲醯基)-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-3H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-基)(側氧基)(苯基)-l6-硫烷亞基)胺基甲酸三級丁酯
758 (4aR,7R,18S,22S)-7-苯甲基-22-異丁基-N-(3-甲氧基苯乙基)-21-甲基-5,16,20,23-四側氧基-3-(苯基磺亞胺醯基)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫-1H-萘并[1,2-p]吡𠯤并[2,1-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
759 (4aR,7R,18S,22S)-7-苯甲基-N-(3-氰基苯乙基)-22-異丁基-21-甲基-5,16,20,23-四側氧基-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-十六氫萘并[1,2-p][1,4]㗁 𠯤并[3,4-f][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
760 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-9-((3-甲氧基苯乙基)胺甲醯基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉2-氧化物
761 (8'R,14'S,18'S)-8'-苯甲基-14'-異丁基-2',12',15'-三甲基-10',13',16',20'-四側氧基-N-(2-(3-苯基異㗁唑-5-基)乙基)-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺
762 (8'R,14'S,18'S)-8'-苯甲基-14'-異丁基-N-(2-(3-異丙基異㗁唑-5-基)乙基)-2',12',15'-三甲基-10',13',16',20'-四側氧基-7',8',9',10',13',14',15',16',17',18',19',20'-十二氫-12'H-螺[環丙烷-1,11'-㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯]-18'-甲醯胺
763 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-苯甲基-1,2,4-㗁二唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
764 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-(環丙基甲基)-1,2,4-㗁二唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
765 (3R,6R,9S,13S)-3-苯甲基-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-9-異丁基-16-甲氧基-6,7,10-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
766 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
767 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
768 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-6,7,10-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
769 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
770 (9S,13S,19aS,22R)-22-苯甲基-5-氟-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
771 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,7,10-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
772 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,7,10,18-四甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
773 (3R,6R,9S,13S)-3-苯甲基-6-乙基-9-異丁基-16-甲氧基-7,10,18-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
774 (3R,6R,9S,13S)-3-苯甲基-6-乙基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
775 (3R,6R,9S,13S)-3-苯甲基-6-(2,2-二氟乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
776 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-6-(2,2,2-三氟乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
777 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
778 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
779 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
780 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
781 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
782 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-6-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
783 (3R,6R,9S,13S)-3-苯甲基-6-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
784 (3R,6R,9S,13S)-3-苯甲基-6-乙基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
785 (3R,6R,9S,13S)-3-苯甲基-6-(2,2-二氟乙基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
786 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
787 (3S,7S,10R,13R)-13-苯甲基-N-(2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)-20-氟-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
788 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(3-甲氧基苯乙基)-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫咪唑并[1',2':1,6]吡啶并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
789 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫咪唑并[1',2':1,6]吡啶并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
790 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫咪唑并[1',2':1,6]吡啶并[2,3-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-3-甲醯胺
791 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-(2,2,2-三氟乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
792 (3R,6S,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-(2,2,2-三氟乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
793 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
794 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
795 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
796 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-5,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-9-甲醯胺
797 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-20-氟-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
798 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-20-氟-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
799 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
800 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20-氟-7-異丁基-6,9,10-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
801 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-(2,2-二氟乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
802 (3S,7S,10S,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-(2,2-二氟乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
803 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-乙基-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
804 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
805 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(2-環丙基-2H-1,2,3-三唑-4-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
806 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-(2,2,2-三氟乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
807 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
808 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
809 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
810 (3S,7S,10S,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
811 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
812 (3S,7S,10S,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
813 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
814 (3S,7S,10S,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
815 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
816 (3S,7S,10S,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
817 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-20'-氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
818 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
819 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
820 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
821 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
822 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
823 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-13-異丁基-5,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-9-甲醯胺
824 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-6,9,10,20-四甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
825 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,10,20-四甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
826 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-7-異丁基-6,9,10,20-四甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
827 (3S,7S,10R,13R)-13-苯甲基-10-((3,3-二氟吡咯啶-1-基)甲基)-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
828 (3R,6R,9S,13S)-3-苯甲基-N-((S)-2-羥基-2-苯基乙基)-6,9-二異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
829 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-5-氟-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
830 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(2-(1-(2-甲氧基乙基)-1H-吡唑-4-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
831 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)-2,2-二氟乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
832 (7S,11S,17aR,20R)-N-(2-(2H-苯并[d][1,2,3]三唑-2-基)乙基)-20-苯甲基-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
833 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
834 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(4-乙炔基-5-甲基-2H-1,2,3-三唑-2-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
835 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
836 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(4-氰基-2H-1,2,3-三唑-2-基)乙基)-11-異丁基-4-甲氧基-2,10-二甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
837 (3S,7S,10R,13R)-13-苯甲基-N-(2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
838 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-3,3,20'-三氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
839 (3'S,7'S,13'R)-13'-苯甲基-3,3,20'-三氟-7'-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
840 (3S,7S,10R,13R)-N-(2-(2H-苯并[d][1,2,3]三唑-2-基)乙基)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
841 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-3,3,20'-三氟-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
842 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-N-((S)-2-羥基-2-苯基乙基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
843 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(6-甲氧基吡啶-3-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
844 (3S,7S,10R,13R)-N-(2-([1,2,4]三唑并[1,5-a]嘧啶-2-基)乙基)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
845 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(3-甲氧基丙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
846 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-N-(3-(三氟甲氧基)丙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
847 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(5-甲氧基吡啶-2-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
848 (3R,6R,9S,13S)-3-苯甲基-N-((S)-2-羥基-2-苯基乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
849 (3R,6R,9S,13S)-3-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
850 (7S,11S,17aR,20R)-20-苯甲基-N-(3-(二氟甲氧基)丙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
851 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-10-(2-(3-甲基-1,2,4-㗁二唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
852 (9S,13S,19aR,22R)-22-苯甲基-18-(5-氟吡啶-2-基)-13-異丁基-12-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤並[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
853 (9S,13S,19aR,22R)-22-苯甲基-18-(5-氟吡啶-2-基)-13-異丁基-N-(3-甲氧基苯乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡𠯤并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
854 (3R,6R,9S,13S)-3-苯甲基-6-((4,4-二氟環己基)甲基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
855 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-7,10-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-6-(2-苯氧基乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
856 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-6-(2-苯氧基乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
857 (3R,6R,9S,13S)-3-苯甲基-6-(環丁氧基甲基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
858 (3R,6R,9S,13S)-3-苯甲基-6-(2-(環己氧基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
859 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-6-((3-苯基-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
860 (7S,11S,14R,17R)-17-苯甲基-11-異丁基-4-甲氧基-N-(3-甲氧基苯乙基)-2,10,13,14-四甲基-5,9,12,15-四側氧基-5,6,7,8,9,10,11,12,13,14,15,16,17,18-十四氫嘧啶并[5,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
861 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-6-((3-甲氧基異㗁唑-5-基)甲基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
862 (7S,11S,14R,17R)-17-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-4-甲氧基-2,10,13,14-四甲基-5,9,12,15-四側氧基-5,6,7,8,9,10,11,12,13,14,15,16,17,18-十四氫嘧啶并[5,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
863 (7S,11S,18aR,21R)-21-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-11-異丁基-4-甲氧基-10-甲基-5,9,12,19-四側氧基-5,6,7,8,9,10,11,12,14,15,16,17,18,18a,19,20,21,22-十八氫氮呯并[2,1-f]吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
864 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-6-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
865 (3R,6R,9S,13S)-3-苯甲基-6-(三級丁基)-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
866 (3R,6R,9S,13S)-3-苯甲基-6-(三級丁基)-9-異丁基-16-甲氧基-7,10,18-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
867 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-6-((3-(4-(2-甲氧基乙基)苯基)-1,2,4-㗁二唑-5-基)甲基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
868 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-6-((3-(4-(2-甲氧基乙基)苯基)-1,2,4-㗁二唑-5-基)甲基)-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
869 (7S,11S,17aR,20R)-20-苯甲基-11-異丁基-2,4-二甲氧基-10-甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
870 (7S,11S,17aR,20R)-20-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-11-異丁基-2,4-二甲氧基-10-甲基-5,9,12,18-四側氧基-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-十六氫-14H-二吡啶并[2,1-f:3',4'-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-7-甲醯胺
871 (3R,6R,9S,13S)-3-苯甲基-N-(2-(4-環丙基-2H-1,2,3-三唑-2-基)乙基)-9-異丁基-16-甲氧基-6-((3-(4-(2-甲氧基乙基)苯基)-1,2,4-㗁二唑-5-基)甲基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
872 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉]-3'-甲醯胺
873 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-7,10,18-三甲基-6-新戊基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
874 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-7,10,18-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-5,8,11,15-四側氧基-6-苯乙基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
875 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(3-甲氧基苯乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-苯乙基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
876 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-7,10,18-三甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-6-新戊基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
877 (3R,6R,9S,13S)-3-苯甲基-6-(2-乙氧基乙基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
878 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-6-新戊基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
879 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-10-((3-甲氧基異㗁唑-5-基)甲基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
880 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-10-((3-甲氧基異㗁唑-5-基)甲基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
881 (3R,6R,9S,13S)-3-苯甲基-6-(2-(3-(三級丁基)-1,2,4-㗁二唑-5-基)乙基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
882 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-6-((4-苯基-1H-1,2,3-三唑-1-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
883 (3R,6R,9S,13S)-3-苯甲基-6-(2-(3-環戊基-1,2,4-㗁二唑-5-基)乙基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-9-異丁基-16-甲氧基-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
884 (3R,6R,9S,13S)-3-苯甲基-6-(2-(3-環戊基-1,2,4-㗁二唑-5-基)乙基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
885 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-10-((4-(5-氟吡啶-2-基)-1H-1,2,3-三唑-1-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
886 (3S,7S,10R,13R)-13-苯甲基-10-((3-(三級丁基)異㗁唑-5-基)甲基)-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
887 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-20-氟-10-(2-(3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)乙基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-3-甲醯胺
888 (9S,13S,19aR,22R)-22-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-13-異丁基-2,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
889 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
890 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
891 (3S,7S,10R,13R)-13-苯甲基-N-((S)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
892 (3S,7S,10R,13R)-13-苯甲基-N-((R)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
893 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-(2,2-二氟乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
894 (3S,7S,10R,13R)-13-苯甲基-10-(2-乙氧基乙基)-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
895 (3S,7S,10R,13R)-13-苯甲基-10-(2-乙氧基乙基)-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
896 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-(2-乙氧基乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
897 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
898 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
899 (9S,13S,19aR,22S)-22-苯甲基-5-氟-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
900 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7'-異丁基-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
901 (3'S,7'S,13'R)-13'-苯甲基-7'-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
902 (3R,6R,9S,13S)-3-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
903 (3R,6R,9S,13S)-N-(2-(2H-苯并[d][1,2,3]三唑-2-基)乙基)-3-苯甲基-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
904 (3'S,7'S,13'R)-N-(2-(2H-苯并[d][1,2,3]三唑-2-基)乙基)-13'-苯甲基-7'-異丁基-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
905 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
906 (3S,7S,10R,13R)-13-苯甲基-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
907 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
908 (3S,7S,10R,13R)-N-(2-([1,2,4]三唑并[1,5-a]嘧啶-2-基)乙基)-13-苯甲基-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
909 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
910 (3R,6R,9S,13S)-3-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-6-(2-乙氧基乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
911 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
912 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
913 (3S,7S,10R,13R)-13-苯甲基-10-(2-乙氧基乙基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
914 (3S,7S,10R,13R)-13-苯甲基-10-(2-乙氧基乙基)-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
915 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-(2-乙氧基乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
916 (3S,7S,10R,13R)-13-苯甲基-20-氟-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
917 (3S,7S,10R,13R)-13-苯甲基-10-((3-(5-氟吡啶-2-基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
918 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
919 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
920 (9S,13S,19aR,22R)-22-苯甲基-13-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-2,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
921 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-((3-(二氟甲基)-1,2,4-㗁二唑-5-基)甲基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
922 (3'S,7'S,13'R)-13'-苯甲基-3,3,20'-三氟-7'-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
923 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-7-異丁基-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
924 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
925 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-N-(3-(三氟甲氧基)丙基)-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
926 (1r,3S,3'S,7'S,13'R)-13'-苯甲基-20'-氟-7'-異丁基-3-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
927 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
928 (9S,13S,19aS,22R)-22-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-13-異丁基-2,12-二甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
929 (3S,7S,10R,13R)-13-苯甲基-10-(2-乙氧基乙基)-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
930 (9S,13S,19aR,22R)-22-苯甲基-5-氟-13-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉-9-甲醯胺
931 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
932 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
933 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-10-(2,2-二氟乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
934 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
935 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7-異丁基-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
936 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-7-異丁基-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
937 (3S,7S,10R,13R)-N-(2-(2H-苯并[d][1,2,3]三唑-2-基)乙基)-13-苯甲基-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
938 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
939 (3S,7S,10S,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
940 (3S,7S,10S,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
941 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
942 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-(2,2,2-三氟乙基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
943 (3R,6R,9S,13S)-3-苯甲基-N-((R)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
944 (3S,7S,10R,13R)-13-苯甲基-N-(3-(二氟甲氧基)丙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
945 (3R,6R,9S,13S)-3-苯甲基-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
946 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
947 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
948 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
949 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-7,10-二甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
950 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-1,2,4-㗁二唑-3-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
951 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
952 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-3,3-二氟-7'-異丁基-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
953 (3'S,7'S,13'R)-13'-苯甲基-3,3-二氟-7'-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
954 (3'S,7'S,13'R)-13'-苯甲基-3,3-二氟-7'-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
955 (3'S,7'S,13'R)-13'-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-3,3-二氟-7'-異丁基-6',9',20'-三甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉]-3'-甲醯胺
956 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基異㗁唑-5-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
957 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
958 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基異㗁唑-3-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
959 (3S,7S,10R,13R)-13-苯甲基-N-(2-(5-環丙基-2H-四唑-2-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
960 (3S,7S,10R,13R)-13-苯甲基-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
961 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(1-(2-甲氧基乙基)-1H-吡唑-4-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-6-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
962 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-N-(2-(1-(2-甲氧基乙基)-1H-吡唑-4-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
963 (3'S,7'S,13'R)-13'-苯甲基-20'-氟-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丙烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
964 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
965 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-6,9-二甲基-N-(2-(3-甲基異㗁唑-5-基)乙基)-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
966 (3S,7S,10R,13R)-13-苯甲基-N-((R)-2-(3-環丙基-1,2,4-㗁二唑-5-基)-2-羥基乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
967 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-20-氟-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
968 (3R,6R,9S,13S)-3-苯甲基-6-(2,2-二氟乙基)-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-9-異丁基-16-甲氧基-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
969 (3'S,7'S,13'R)-13'-苯甲基-3,3,20'-三氟-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-7'-異丁基-6',9'-二甲基-1',5',8',11'-四側氧基-2',3',4',5',6',7',8',9',11',12',13',14'-十二氫-1'H-螺[環丁烷-1,10'-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉]-3'-甲醯胺
970 (3S,7S,10R,13R)-13-苯甲基-10-(2,2-二氟乙基)-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-7-異丁基-6,9,20-三甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]異喹啉-3-甲醯胺
971 (3S,7S,10R,13R)-13-苯甲基-10-((5-(三級丁基)-1,2,4-㗁二唑-3-基)甲基)-20-氟-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
972 (3S,7S,10R,13R)-13-苯甲基-10-((5-(三級丁基)-1,2,4-㗁二唑-3-基)甲基)-20-氟-7-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
973 (9S,13S,19aR,22R)-22-苯甲基-5-氟-N-(2-(4-氟-3-甲氧基異㗁唑-5-基)乙基)-13-異丁基-12-甲基-7,11,14,20-四側氧基-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-十六氫-16H-吡啶并[2',1':6,7][1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-9-甲醯胺
974 (8R,11RS,14S,18S)-8-苯甲基-14-異丁基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-2,12,15-三甲基-10,13,16,20-四側氧基-11-(2,2,2-三氟乙基)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-十四氫㗁唑并[4',5':5,6]苯并[1,2-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-18-甲醯胺
975 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-N-(2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)-6,9,17-三甲基-1,5,8,11-四側氧基-10-(2,2,2-三氟乙基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
976 (3S,7S,10R,13R)-13-苯甲基-N-(2-(3-環丙基-1,2,4-㗁二唑-5-基)乙基)-10-(2-乙氧基乙基)-20-氟-7-異丁基-6,9-二甲基-1,5,8,11-四側氧基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉-3-甲醯胺
977 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-6-(2-((5-甲基吡𠯤-2-基)氧基)乙基)-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
978 (3R,6R,9S,13S)-3-苯甲基-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-6-(2-((2-甲氧基吡啶-4-基)氧基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
979 (3R,6R,9S,13S)-3-苯甲基-6-(環丙基甲基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
980 (3R,6R,9S,13S)-3-苯甲基-6-(環丁基甲基)-9-異丁基-16-甲氧基-N-(2-(3-甲氧基異㗁唑-5-基)乙基)-7,10,18-三甲基-5,8,11,15-四側氧基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氫吡啶并[3,4-p][1]氧雜[4,7,10,14]四氮雜環十七碳烯-13-甲醯胺
981 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-3-((2-(3-甲氧基異㗁唑-5-基)乙基)胺甲醯基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[17,16-c]喹啉17-氧化物
982 (3S,7S,10R,13R)-13-苯甲基-7-異丁基-3-((2-(3-甲氧基異㗁唑-5-基)乙基)胺甲醯基)-6,9,17-三甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉18-氧化物
983 (3S,7S,10R,13R)-13-苯甲基-20-氟-7-異丁基-3-((2-(3-甲氧基-1,2,4-㗁二唑-5-基)乙基)胺甲醯基)-6,9-二甲基-1,5,8,11-四側氧基-10-((3-(三氟甲基)-1,2,4-㗁二唑-5-基)甲基)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氫-[1]氧雜[4,7,10,14]四氮雜環十七碳烯并[16,17-f]喹啉18-氧化物
表3：實例1至764之化合物之結構
example Compound of formula (I)
1 (7R,13S,17RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-11-(3,3-di Methylbutyl)-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15, 16,17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-17-formamide
2 (7R,13S,17S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-11-(2-cyclohexylethyl Base)-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15,16,17 ,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-17-carboxamide
3 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭唍-6-yl)ethyl)-9-isobutyl-17,18-dimethoxy-7,10- Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
4 (3R,9S,13S)-N-(2-(benzofuran-6-yl)ethyl)-3-benzyl-9-isobutyl-17,18-dimethoxy-7,10 -Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
5 (7R,13S,17RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-13-isobutyl-14- Methyl-9,12,15,19-tetraoxo-11-phenethyl-6,7,8,9,10,11,12,13,14,15,16,17,18,19- Tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-17-carboxamide
6 (7R,13S,17RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-11-(3-(benzyl Oxy)propyl)-13-isobutyl-14-methyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15 ,16,17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7, 10,14] tetraazacycloheptadecene-17-carboxamide
7 (7R,13S,17S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-13-(cyclobutylmethyl)- 11,14-Dimethyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15,16,17,18,19-ten Tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycle seventeen Carbene-17-formamide
8 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-7,10-dimethyl-N-(2-(4-methyl-3, 4-dihydro-2H-benzo[b][1,4]㗁𠯤-7-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6 ,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 13-Formamide
9 (3R,9S,13RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-(cyclopropylmethyl)-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6, 7,8,9,10,11,12,13,14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
10 (3R,9S,13RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-(cyclopentylmethyl)-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6, 7,8,9,10,11,12,13,14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
11 (3R,9S,13RS)-3-Benzyl-N-(2-(𠳭唍-6-yl)ethyl)-7-(2-cyclohexylethyl)-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
12 (3R,9S,13RS)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(3,4-dihydro-2H-benzo[b][1,4] Two 㗁呯-7-yl)ethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5, 6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene -13-Formamide
13 (3R,9S,13RS)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(1,3-dihydroisobenzofuran-5-yl)ethyl)- 9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11, 12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
14 (3R,9S,13RS)-N-(2-(benzofuran-6-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16 -Methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
15 (3R,9S,13RS)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-9 -Isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
16 (3R,9S,13RS)-N-(2-(Benzo[d]oxazol-2-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl)-9-iso Butyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
17 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-5,11-dimethyl-6,10,13,19 -Tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H-imidazo[4 ',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 8-formamide
18 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-(2-(pyr-2-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
19 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-(2-(pyrimidin-4-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-deca Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
20 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-(2-(pyrimidin-5-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-deca Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
twenty one (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(3-(difluoromethoxy)propyl)-9-isobutyl-16-methyl Oxy-10-methyl-5,8,11,15-tetra-oxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
twenty two (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(2-(2-methoxyethoxy Base) ethyl) -10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14, 15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
twenty three (8RS,12S,18aR,21R)-21-Benzyl-12-isobutyl-5,11-dimethyl-N-(2-(4-methylthiazol-2-yl)ethyl)- 6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H ,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraaze Heterocyclic heptadecen-8-carboxamide
twenty four (8RS,12S,18aR,21R)-21-Benzyl-12-isobutyl-5,11-dimethyl-N-(2-(5-methylthiazol-2-yl)ethyl)- 6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H ,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraaze Heterocyclic heptadecen-8-carboxamide
25 (8RS,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(4-methoxyphenethyl)-5,11-dimethyl-6,10,13,19 -Tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H-imidazo[4 ',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 8-formamide
26 (8RS,12S,18aR,21R)-21-Benzyl-N-(3-(difluoromethoxy)phenethyl)-12-isobutyl-5,11-dimethyl-6,10 ,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H- imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-8-carboxamide
27 (8RS,12S,18aR,21R)-21-Benzyl-12-isobutyl-5,11-dimethyl-6,10,13,19-tetraoxo-N-phenylethyl-6 ,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-Hexadecahydro-5H,15H-imidazo[4',5':5, 6] Benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
28 (8RS,12S,18aR,21R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-21-benzyl-12-isobutyl-5, 11-Dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-5H,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7, 10,14] tetraazacycloheptadecene-8-carboxamide
29 (8S,12S,18aR,21R)-21-Benzyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl)-12-isobutyl Base-5,11-dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20 ,21,22-Hexadecahydro-5H,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-8-carboxamide
30 (8S,12S,18aR,21R)-N-(2-(Benzo[d]isoxazol-3-yl)ethyl)-21-benzyl-12-isobutyl-5,11-di Methyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-16 Hydrogen-5H,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-8-carboxamide
31 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-21-benzyl-12-isobutyl-5, 11-Dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-5H,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7, 10,14] tetraazacycloheptadecene-8-carboxamide
32 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(-8-methoxy-3-yl)-21-methyl-5,16,20, 23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p ][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
33 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(2-(3-methoxyphenoxy)ethyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2 -p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
34 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(2-(4-methoxyphenoxy)ethyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2 -p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
35 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(2-(7-methoxy-2,3-dihydrobenzo[b][1,4] Dioxin-6-yl)ethyl)-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16 ,17,18,19,20,21,22,23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]Oxa[4, 7,10,14] Tetraazacyclohexadecene-18-carboxamide
36 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(7-chloro-5-methyl-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexen-6-yl)ethyl)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7, 8,16,17,18,19,20,21,22,23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa [4,7,10,14]Tetraazacycloheptadecene-18-carboxamide
37 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxine-6 -yl)ethyl)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17 ,18,19,20,21,22,23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]Oxa[4,7, 10,14] tetraazacycloheptadecene-18-carboxamide
38 (4aR,7R,18S,22S)-N-(2-(Benzo[d]isoxazol-3-yl)ethyl)-7-benzyl-22-isobutyl-21-methyl- 5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho [1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
39 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethane Base)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19 ,20,21,22,23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14] tetraazacycloheptadecene-18-carboxamide
40 (4aR,7R,18S,22S)-7-Benzyl-N-(4-cyanophenethyl)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo base-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][1,4 ]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
41 (4aR,7R,18S,22S)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-7-benzyl-22-isobutyl-21- Methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-16 Hydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18- Formamide
42 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-22-isobutyl-21-methyl -5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphthalene And[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl amine
43 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-22-isobutyl-21-methyl Group-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro Naphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-metha Amide
44 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(5-ethyl-1,2,4-oxadiazol-3-yl)ethyl)-22-isobutyl -21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23 -Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene -18-formamide
45 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-22-isobutyl Base-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22, 23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecane En-18-carboxamide
46 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(2-isopropylthiazol-4-yl)ethyl)-12-methyl-7, 11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1, 4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9 - formamide
47 (9S,13S,19aR,22R)-22-Benzyl-N-(4-ethylphenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo Base-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3', 4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
48 (9S,13S,19aR,22R)-22-Benzyl-N-(4-(tertiary butyl)phenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 [3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
49 (9S,13S,19aR,22R)-22-Benzyl-N-(4-bromophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
50 (9S,13S,19aR,22R)-22-Benzyl-N-(2-fluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
51 (9S,13S,19aR,22R)-22-Benzyl-N-(3-chlorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
52 (9S,13S,19aR,22R)-22-Benzyl-N-(3-bromophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
53 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethane Base)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a ,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacycle Heptadeceno[17,16-c]quinoline-9-formamide
54 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-13-isobutyl-12-methyl -7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro- [1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16-c]quinone Phenyl-9-formamide
55 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-16 Hydrogen-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
56 (9S,13S,19aR,22R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-16 Hydrogen-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
57 (9S,13S,19aR,22R)-22-Benzyl-N-(3,5-dimethoxyphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 [3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
58 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-phenethyl-7,8, 9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7 ][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
59 (9S,13S,19aR,22R)-22-Benzyl-N-(2-fluoro-4-methoxyphenethyl)-13-isobutyl-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 And[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
60 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(4-methylphenethyl)-7,11,14,20-tetraoxo Base-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3', 4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
61 (9S,13S,19aR,22R)-22-Benzyl-N-(3,4-dimethylphenethyl)-13-isobutyl-12-methyl-7,11,14,20- Four-sided oxy-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[ 3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
62 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(3-methylphenethyl)-7,11,14,20-tetraoxo Base-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3', 4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
63 (9S,13S,19aR,22R)-22-Benzyl-N-(2,4-dimethylphenethyl)-13-isobutyl-12-methyl-7,11,14,20- Four-sided oxy-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[ 3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
64 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-methylphenethyl)-7,11,14,20-tetraoxo Base-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3', 4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
65 (9S,13S,19aR,22R)-22-Benzyl-N-(2,3-dimethoxyphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 [3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
66 (9S,13S,19aR,22R)-22-Benzyl-N-(3-fluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
67 (9S,13S,19aR,22R)-22-Benzyl-N-(4-fluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo -7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤 and [3',4 ':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
68 (9S,13S,19aR,22R)-22-Benzyl-N-(2,6-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Side oxygen-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3 ',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
69 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2-(3-phenyl -1,2,4-oxadiazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23 -Hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecene[17, 16-c] quinoline-9-formamide
70 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(4,5-dimethylisoxazol-3-yl)ethyl)-22-isobutyl-21-methyl Group-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro Naphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-metha Amide
71 (9S,13S,19aR,22R)-22-Benzyl-N-(3,5-dimethoxyphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2', 1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
72 (9S,13S,19aR,22R)-22-Benzyl-N-(2,6-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1' :6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
73 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2,4,6-tri Fluorophenethyl)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-Hexadecahydro-16H-pyrido[2', 1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
74 (9S,13S,19aR,22R)-22-Benzyl-N-(2,6-difluoro-4-methoxyphenethyl)-13-isobutyl-12-methyl-7,11 ,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
75 (9S,13S,19aR,22R)-22-Benzyl-N-(3,4-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1' :6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
76 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2-(3-phenyl -1,2,4-oxadiazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23 -Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
77 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-phenethyl-7,8, 9,10,11,12,13,14,17,18,19,19a,20,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1] Oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
78 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(5-methyl-1,2,4-oxadiazole-3- Base) ethyl) -7,11,14,20-tetra-oxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23 -Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
79 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-ethyl-1,2,4-oxadiazol-3-yl)ethyl)-13-isobutyl -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23 -Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
80 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
81 (9S,13S,19aR,22R)-22-Benzyl-N-(2,3-dimethoxyphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2', 1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
82 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(5-methylisoxazol-4-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formyl amine
83 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)ethyl) -7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro- 16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9- Formamide
84 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(4-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1': 6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
85 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-(tertiary butyl)-1,2,4-oxadiazol-3-yl)ethyl)-13 -Isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21 ,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17, 16-c] quinoline-9-formamide
86 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-(3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl) Ethyl)-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19, 19a,20,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeca Ekeno[17,16-c]quinoline-9-carboxamide
87 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2-(3-(2 -(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,17,18, 19,19a,20,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclodeca Heptaceno[17,16-c]quinoline-9-carboxamide
88 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2-(5-(2 -(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)ethyl)-7,8,9,10,11,12,13,14,17,18 ,19,19a,20,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclo Heptadeceno[17,16-c]quinoline-9-formamide
89 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-(tertiary butyl)isoxazol-3-yl)ethyl)-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
90 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(5-(tertiary butyl)isoxazol-3-yl)ethyl)-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
91 (9S,13S,19aR,22R)-22-Benzyl-N-(4-fluoro-3-methoxyphenethyl)-13-isobutyl-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
92 (9S,13S,19aR,22R)-22-Benzyl-N-(2-fluoro-5-methylphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2', 1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
93 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(3-methoxy-4-(2H-1,2,3-triazol-2-yl)benzene Ethyl)-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21, 22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16 -c] quinoline-9-formamide
94 (9S,13S,19aR,22R)-22-Benzyl-N-(2,4-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1' :6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
95 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(4-methoxy-3-methylphenethyl)-12-methyl-7,11,14 ,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2 ',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
96 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(3-methylphenethyl)-7,11,14,20-tetraoxo group-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6 ,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
97 (9S,13S,19aR,22R)-22-Benzyl-N-(2,3-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1' :6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
98 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(5-methylisoxazol-3-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formyl amine
99 (9S,13S,19aR,22R)-22-Benzyl-N-(4-bromo-2,6-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14 ,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2 ',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
100 (9S,13S,19aR,22R)-22-Benzyl-N-(3-fluoro-4-methoxyphenethyl)-13-isobutyl-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
101 (7R,13S,17S)-7-Benzyl-N-(2-(3,4-dihydro-2H-benzo[b][1,4]dioxane-7-yl)ethyl) -13-isobutyl-11,14-dimethyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15,16, 17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14 ]tetraazacyclohexadecene-17-carboxamide
102 (9S,13S,19aR,22R)-22-Benzyl-N-(2,6-difluoro-3-methylphenethyl)-13-isobutyl-12-methyl-7,11, 14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[ 2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
103 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(isothiazol-5-yl)ethyl)-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
104 (9S,13S,19aR,22R)-22-Benzyl-N-(2-fluoro-6-methylphenethyl)-13-isobutyl-12-methyl-7,11,14,20 -Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2', 1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
105 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-methan Amide
106 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-13-isobutyl-12-methyl- [ 1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
107 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-(tertiary butyl)isoxazol-3-yl)ethyl)-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-16 Hydrogen-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
108 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-Dimethyl-1',5',8',11'-Tetraoxo -N-Phenylethyl-2',3',4',5',6',7',8',9',11',12',13',14'-dodecahydro-1'H -Spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formyl amine
109 (3'S,7'S,13'R)-13'-Benzyl-N-(3,5-dimethoxyphenethyl)-7'-isobutyl-6',9'-dimethyl- 1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13', 14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16-c ]quinoline]-3'-formamide
110 (3'S,7'S,13'R)-13'-Benzyl-N-(2,6-difluorophenethyl)-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinonePhenyl]-3'-formamide
111 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(4-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline ]-3'-formamide
112 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(3-methylphenethyl)-1',5 ',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-ten Dihydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline] -3'-formamide
113 (3'S,7'S,13'R)-13'-Benzyl-N-(3,4-difluorophenethyl)-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinonePhenyl]-3'-formamide
114 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-ethyl-1,2,4-oxadiazol-3-yl)ethyl)-7'-iso Butyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaze Heterocyclic heptadeceno[17,16-c]quinoline]-3'-formamide
115 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
116 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-(tertiary butyl)-1,2,4-oxadiazol-3-yl)ethyl)- 7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7 ',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
117 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(2-(5-methylisoxazole-3- Base) ethyl) -1', 5', 8', 11'-tetraoxo-2', 3', 4', 5', 6', 7', 8', 9', 11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene [17,16-c]quinoline]-3'-formamide
118 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropylisozazol-3-yl)ethyl)-7'-isobutyl-6', 9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]quinoline]-3'-formamide
119 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-(tertiary butyl)isozazol-3-yl)ethyl)-7'-isobutyl- 6',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclodecaHeptaceno[17,16-c]quinoline]-3'-formamide
120 (3'S,7'S,13'R)-13'-Benzyl-N-(3,5-difluorophenethyl)-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinonePhenyl]-3'-formamide
121 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
122 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(4-(pyrimidine-2- Base) phenethyl) -7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
123 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(3-(pyrimidine-2- Base) phenethyl) -7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
124 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)ethyl)-13-isobutyl-12-methyl Group-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro -16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9 - formamide
125 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(3-methyl-4-(2H-1,2,3-triazole-2 -yl)phenethyl)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22 ,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16- c] quinoline-9-formamide
126 (9S,13S,19aR,22R)-22-Benzyl-N-(3,5-difluorophenethyl)-13-isobutyl-12-methyl-7,11,14,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1' :6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formamide
127 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
128 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)ethyl)-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
129 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(1,4-dimethyl-1H-pyrazol-3-yl)ethyl)-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
130 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(3-(3-methoxyphenyl)-1,2,4-oxadiazole- 5-yl)ethyl)-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a, 20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclodeca Heptaceno[17,16-c]quinoline-9-carboxamide
131 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl Group-1',5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13 ',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c]quinoline]-3'-formamide
132 (3'S,7'S,13'R)-13'-Benzyl-N-(2,6-difluorophenethyl)-20'-fluoro-7'-isobutyl-6',9'-di Methyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12', 13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17, 16-c]quinoline]-3'-formamide
133 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetra-oxo-N-(4-(pyr-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]quinoline]-3'-formamide
134 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetra-oxo-N-(3-(pyr-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]quinoline]-3'-formamide
135 (3'S,7'S,13'R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-20'-fluoro-7'-Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
136 (3'S,7'S,13'R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-20'-fluoro-7'-Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
137 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetra-oxo-N-(4-(pyrimidin-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16-c]quinoline]-3'-formamide
138 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetra-oxo-N-(3-(pyrimidin-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16-c]quinoline]-3'-formamide
139 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)ethyl)-20'-fluoro-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
140 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20'- Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
141 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(5-methyliso (Zazol-3-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9 ',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacycle Heptadeceno[17,16-c]quinoline]-3'-formamide
142 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-20'-fluoro-7'-isobutyl Base-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline]-3'-formamide
143 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(1-methyl- 1H-pyrazol-4-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaze Heterocyclic heptadeceno[17,16-c]quinoline]-3'-formamide
144 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20'- Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
145 (3'S,7'S,13'R)-13'-Benzyl-N-(2,2-difluoro-2-phenylethyl)-7'-isobutyl-6',9'-dimethyl Group-1',5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13 ',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c]quinoline]-3'-formamide
146 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6', 7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
147 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methyliso (Zazol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9 ',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacycle Heptadeceno[17,16-c]quinoline]-3'-formamide
148 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭-7-yl)ethyl)-9-isobutyl-17,18-dimethoxy-7,10- Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
149 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzo[b][1,4]dioxa Cyclohexen-6-yl)ethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5, 6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene -13-Formamide
150 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(3-(difluoromethoxy)phenethyl)-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
151 (7R,13S,17RS)-7-Benzyl-N-(2,3-dimethoxyphenethyl)-13-isobutyl-11,14-dimethyl-9,12,15, 19-tetraoxo-6,7,8,9,10,11,12,13,14,15,16,17,18,19-tetrahydro-[1,3]dioxo[4', 5':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxamide
152 (3R,9S,13RS)-3-Benzyl-N-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-9-isobutyl-17,18-dimethyl Oxy-7,10-dimethyl-5,8,11,15-tetra-oxo-2,3,4,5,6,7,8,9,10,11,12,13,14, 15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
153 (7R,13S,17S)-7-Benzyl-13-isobutyl-N-(4-methoxyphenethyl)-11,14-dimethyl-9,12,15,19-tetra Side oxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5': 4,5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxamide
154 (7R,13S,17S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-13-isobutyl-14- Methyl-9,12,15,19-tetraoxo-11-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-6,7,8,9,10,11, 12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxamide
155 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-17, 18-Dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-(2-((RS)-tetrahydro-2H-pyran-2-yl)ethyl) -2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14 ]tetraazacyclohexadecene-13-carboxamide
156 (3R,9S,13RS)-N-(2-(benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-17, 18-dimethoxy-7-(3-methoxy-3-methylbutyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5, 6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene -13-Formamide
157 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-((RS)-2-(5,5-dimethyltetrahydro-2H-pyran- 2-yl)ethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7, 8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-methan Amide
158 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(2-(2-methoxypyridine- 4-yl)ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13, 14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
159 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-17, 18-Dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-13-carboxamide
160 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-17, 18-Dimethoxy-10-methyl-5,8,11,15-tetraoxo-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-13-carboxamide
161 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-7,10-dimethyl-5,8,11,15-tetraoxo- N-(2-(2,3,4,5-tetrahydrobenzo[b]oxan-8-yl)ethyl)-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
162 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-3-formamide
163 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-3-formamide
164 (3RS,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetraoxo -9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13 ,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
165 (3RS,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetraoxo -9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13 ,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
166 (3'S,7'S,13'R)-13'-Benzyl-N-((1-(3,4-dimethoxyphenyl)cyclopropyl)methyl)-20'-fluoro-7'-Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]Tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
167 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(3-(methylsulfonyl )Phenylethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene [17,16-c]quinoline]-3'-formamide
168 (3'S,7'S,13'R)-13'-Benzyl-N-(3-cyanophenethyl)-20'-fluoro-7'-isobutyl-6',9'-dimethyl -1',5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16- c] Quinoline] -3'-formamide
169 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-Tetrafluorooxy-N-(3-(trifluoromethyl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
170 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(4-(N-𠰌linyl )Phenylethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene [17,16-c]quinoline]-3'-formamide
171 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(5-isopropyl-1,2,4-oxadiazole-3- Base) ethyl) -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
172 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(4-cyclopropyl-1H-pyrazol-1-yl)ethyl)-20'-fluoro-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
173 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-20'-fluoro-7'-isobutyl Base-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline]-3'-formamide
174 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(2-(4-(3-methoxypropyl)-1H-pyridine Azol-1-yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6 ',7',8',9',11',12',13',14'-dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7 ,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
175 (3'S,7'S,13'R)-13'-Benzyl-N-(2,2-difluoro-2-(3-methoxyphenyl)ethyl)-7'-isobutyl-6 ',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9', 11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacycloheptadeca Carbaeno[17,16-c]quinoline]-3'-formamide
176 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)ethyl)-11-isobutyl-4-methyl Oxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20 ,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 7-formamide
177 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-N-(2 -(3-(Trifluoromethyl)isozazol-5-yl)ethyl)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
178 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-N-(2 -(3-(Trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)-5,6,7,8,9,10,11,12,15,16,17 ,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-7-carboxamide
179 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(4-cyclopropyl-1H-pyrazol-1-yl)ethyl)-11-isobutyl-4-methyl Oxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20 ,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 7-formamide
180 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,9, 12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido [2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
181 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-N-(4 -(pyrimidin-2-yl)phenethyl)-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H -Dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
182 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-N-(2 -(3-Phenyl-1,2,4-oxadiazol-5-yl)ethyl)-5,6,7,8,9,10,11,12,15,16,17,17a,18 ,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-7-carboxamide
183 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-N-phenylethyl Base-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f: 3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecen-7-carboxamide
184 (7S,11S,17aR,20R)-20-Benzyl-N-(4-bromophenethyl)-11-isobutyl-4-methoxy-10-methyl-5,9,12, 18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2 ,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
185 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-N-(4-methoxyphenethyl)-10-methyl-5,9, 12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido [2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
186 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-N-(3-methylphenethyl)-5,9,12 ,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[ 2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
187 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)-11-iso Butyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a ,18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraaza cycloheptadecene-7-carboxamide
188 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(2-(4-methoxy-1H-pyrazol-1-yl) Ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
189 (7S,11S,17aR,20R)-20-Benzyl-N-(3-ethynylphenethyl)-11-isobutyl-4-methoxy-10-methyl-5,9,12 ,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[ 2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
190 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl)-11-isobutyl Base-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
191 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-(difluoromethyl)isoxazol-5-yl)ethyl)-11-isobutyl-4- Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
192 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-7,10-dimethyl-N-(4-methylphenethyl)-5 ,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
193 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-N-(4-methoxyphenethyl)-7,10-dimethyl- 5,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
194 (3R,9S,13S)-3-Benzyl-N-(3-ethoxyphenethyl)-9-isobutyl-17,18-dimethoxy-7,10-dimethyl- 5,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
195 (3R,9S,13S)-3-Benzyl-9-isobutyl-17,18-dimethoxy-N-(3-methoxyphenethyl)-7,10-dimethyl- 5,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
196 (3R,9S,13S)-3-Benzyl-N-(2-fluorophenethyl)-9-isobutyl-17,18-dimethoxy-7,10-dimethyl-5, 8,11,15-Tetrahydrobenzo[p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
197 (3R,9S,13S)-3-Benzyl-N-(4-(dimethylamino)phenethyl)-9-isobutyl-17,18-dimethoxy-7,10- Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
198 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
199 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)- 10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
200 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(3-(methoxy-d3)benzene Ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
201 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(3-ethoxyphenethyl)-9-isobutyl-16-methoxy- 10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
202 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-N-(4-methylbenzene Ethyl)-5,8,11,15-Tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
203 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(4-(dimethylamino)phenethyl)-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
204 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-fluorophenethyl)-9-isobutyl-16-methoxy-10- Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[ p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
205 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(3,5-dimethoxyphenethyl)-9-isobutyl-16-methyl Oxy-10-methyl-5,8,11,15-tetra-oxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
206 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-(2-(thiophen-2-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-deca Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
207 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(2-(5-methoxypyridine- 2-yl)ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13, 14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
208 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(furan-2-yl)ethyl)-9-isobutyl-16-methyl Oxy-10-methyl-5,8,11,15-tetra-oxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
209 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl )-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
210 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(3-methoxypropyl)-10 -Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
211 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-phenethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
212 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15- Four-sided oxy-N-(2-((RS)-tetrahydro-2H-pyran-2-yl)ethyl)-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
213 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-((RS)-2,3-dihydrobenzo[b][1,4 ]Dioxin-2-yl)ethyl)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-13-carboxamide
214 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-10-methyl-N-(2-(3- Methylisozol-5-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
215 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(4-ethylphenethyl)-9-isobutyl-16-methoxy-10 -Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
216 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(5-methoxypentyl)-10 -Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo [p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
217 (3R,9S,13S)-N-(4-(1H-pyrazol-1-yl)phenethyl)-3-benzyl-7-(2-cyclohexylethyl)-9-isobutyl -16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14 ,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
218 (3R,9S,13S)-N-(4-Amino-3-methoxyphenethyl)-3-benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16 -Methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
219 (3R,9S,13RS)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(4-methoxyphenethyl)- 10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
220 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(2-(6-methoxypyridine- 2-yl)ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13, 14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
221 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetra-oxo-N-(2-(3-(three Fluoromethyl)isozazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-16 Hydrogen-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
222 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][1, 4] 㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
223 (7R,13S,17S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-13-isobutyl-11, 14-Dimethyl-9,12,15,19-Tetrahydrooxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetrahydro -[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -17-Formamide
224 (7R,13S,17S)-7-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-11,14-dimethyl-9,12,15,19-tetra Side oxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5': 4,5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxamide
225 (7R,13S,17S)-7-Benzyl-N-(3-ethoxyphenethyl)-13-isobutyl-11,14-dimethyl-9,12,15,19-tetra Side oxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5': 4,5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-carboxamide
226 (7R,13S,17S)-7-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl) -13-isobutyl-11,14-dimethyl-9,12,15,19-tetraoxo-6,7,8,9,10,11,12,13,14,15,16, 17,18,19-tetrahydro-[1,3]dioxo[4',5':4,5]benzo[1,2-p][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-17-carboxamide
227 (7R,13S,17S)-7-Benzyl-N-(4-ethylphenethyl)-13-isobutyl-11,14-dimethyl-9,12,15,19-tetra Oxy-6,7,8,9,10,11,12,13,14,15,16,17,18,19-Tetradetrahydro-[1,3]dioxo[4',5':4 ,5]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-17-formamide
228 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-17- Methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14 ,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
229 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10,17-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
230 (3R,9S,13S)-3-Benzyl-9-isobutyl-N-(3-methoxyphenethyl)-7,10,17-trimethyl-5,8,11,15 -Tetrahydrobenzo[p][1]oxa[4, 7,10,14] Tetraazacyclohexadecene-13-carboxamide
231 (3R,9S,13S)-3-Benzyl-9-isobutyl-17-methoxy-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8 ,11,15-Tetrahydrobenzo[p][1]Oxygen Hetero[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
232 (3R,9S,13S)-3-Benzyl-9-isobutyl-18-methoxy-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8 ,11,15-Tetrahydrobenzo[p][1]Oxygen Hetero[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
233 (3R,9S,13S)-3-Benzyl-9-isobutyl-N-(3-methoxyphenethyl)-7,10,18-trimethyl-5,8,11,15 -Tetrahydrobenzo[p][1]oxa[4, 7,10,14] Tetraazacyclohexadecene-13-carboxamide
234 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-17-fluoro-9-isobutyl Base-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
235 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10,16-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
236 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10-Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydro Naphtho[2,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
237 (3R,9S,13S)-3-Benzyl-17-chloro-9-isobutyl-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8,11 ,15-Tetrahydrobenzo[p][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-13-carboxamide
238 (3R,9S,13S)-3-Benzyl-9-isobutyl-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8,11,15-tetra Side oxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydronaphtho[2,3-p][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-13-carboxamide
239 (3R,9S,13S)-3-Benzyl-N-(4-ethylphenethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8, 11,15-Tetrahydrobenzo[p][1]oxa [4,7,10,14]tetraazacyclohexadecene-13-carboxamide
240 (6R,12S,16S)-6-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-10,13-dimethyl-8,11,14,18-tetra Pendant oxygen-5,6,7,8,9,10,11,12,13,14,15,16,17,18-tetrahydrothieno[2,3-p][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-16-carboxamide
241 (6R,12S,16S)-6-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-2,10,13-trimethyl-8,11,14,18 -Tetrahydrothiazolo[5,4-p][1]Oxygen Hetero[4,7,10,14]tetraazacyclohexadecene-16-carboxamide
242 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-16-(methoxy-d3)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8 ,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-formyl amine
243 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-(methoxy-d3)-N-(3-methoxybenzene Ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15- Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
244 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-(methoxy-d3)-N-(3-(methoxy -d3) phenethyl) -10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13, 14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
245 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭-7-yl)ethyl)-9-isobutyl-17-methoxy-7,10-dimethyl -5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
246 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-10,16-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11, 12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
247 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10,16-dimethyl Base-5,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p ][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
248 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-17-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
249 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-17-methoxy-N-(3-methoxyphenethyl)- 10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
250 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl base)-9-isobutyl-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-tetrahydronaphtho[2,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
251 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10-methyl-5 ,8,11,15-Tetrahydronaphtho[2,3- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
252 (3R,9S,13S)-3-Benzyl-N-(4-ethylphenethyl)-9-isobutyl-7,10-dimethyl-5,8,11,15-tetra Oxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4 ,7,10,14] Tetraazacyclohexadecene-13-carboxamide
253 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-17-chloro-7-(2 -Cyclohexylethyl)-9-isobutyl-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
254 (3R,9S,13S)-3-Benzyl-17-chloro-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10- Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[ p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
255 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-16,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
256 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16,18-dimethoxy-N-(3-methoxyphenylethyl) Base)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
257 (3R,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl) -16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14 ,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
258 (3R,13S)-3-Benzyl-7-(2-cyclohexylethyl)-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,8 ,11,15-Tetrahydrobenzo[p][1]Oxygen Hetero[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
259 (7S,11S,20R,22aR)-20-Benzyl-N-(4-bromophenethyl)-7-isobutyl-14-methoxy-8-methyl-6,9,13, 22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydrobenzo[p][1, 4] 㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-formamide
260 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14-methoxy-8-methyl-6,9,13,22-tetraoxo-N-(2 -(2,3,4,5-Tetrahydrobenzo[b]㗁呯-8-yl)ethyl)-1,3,4,6,7,8,9,10,11,12,13, 19,20,21,22,22a-Hexadecahydrobenzo[p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraaza cycloheptadecene-11-carboxamide
261 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭唍-7-yl)ethyl)-7-(2-cyclohexylethyl)-9-isobutyl-10- Methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[ 3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
262 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-9 -isobutyl-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 - Tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
263 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-16-methoxy-9,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11, 12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
264 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-16-methoxy-N-(3-methoxyphenethyl)-9,10-dimethyl Base-5,8,11,15-tetrahydrooxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p ][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
265 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl base)-9-isobutyl-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-tetrahydropyrido[4,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
266 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10-methyl-5 ,8,11,15-Tetrahydropyrido[4,3- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
267 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base) -7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
268 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1 ,5,8,11-Tetrahydronaphtho[1,2- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
269 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6, 9-Dimethyl-1,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro Naphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
270 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-10,18-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11, 12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
271 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10,18-dimethyl Base-5,8,11,15-Tetrahydropyrido-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetrahydropyrido[3 ,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
272 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-16,18-dimethoxy-9,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
273 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-16,18-dimethoxy-N-(3-methoxyphenethyl)-9,10 -Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzene And[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
274 (3R,9S,13RS)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-(cyclopropylmethyl)-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8 ,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-formyl amine
275 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭唍-7-yl)ethyl)-7-(2-cyclohexylethyl)-9-isobutyl-16, 18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14 ,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
276 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-9 -Isobutyl-16,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
277 (3R,9S,13S)-3-Benzyl-16-fluoro-9-isobutyl-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8,11 ,15-Tetrahydrobenzo[p][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-13-carboxamide
278 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-16-fluoro-9-isobutyl Base-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
279 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-16-chloro-9-isobutyl Base-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 -Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
280 (7S,11S,20R,22aR)-20-Benzyl-14-ethoxy-7-isobutyl-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H-benzo[ p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
281 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-16-methoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-formyl amine
282 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)- 10-methyl-5,8,11,15-tetrahydropyridine-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyridine And[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
283 (7S,11S,20R,22aR)-20-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethane Base)-14-ethoxy-7-isobutyl-8-methyl-6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11 ,12,13,19,20,21,22,22a-Hexadecahydro-2H-benzo[p]pyrido[2,1-f][1]oxa[4,7,10,14]tetra Azacyclohexadecene-11-carboxamide
284 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopentylmethyl )-6-methyl-1,5,8,11-tetraoxo-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-3-carboxamide
285 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclohexylmethyl) -6-methyl-1,5,8,11-tetraoxo-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4 ,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraaza Cycloheptadecene-3-carboxamide
286 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopentylmethyl )-6-methyl-1,5,8,11-tetrahydrooxy-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-3-carboxamide
287 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclohexylmethyl) -6-Methyl-1,5,8,11-tetraoxo-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4 ,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraaza Cycloheptadecene-3-carboxamide
288 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopentylmethyl )-6-methyl-1,5,8,11-tetraoxo-9-(2-((SR)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2, 3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-3-carboxamide
289 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclohexylmethyl) -6-Methyl-1,5,8,11-tetraoxo-9-(2-((SR)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3 ,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]four Azacyclohexadecene-3-carboxamide
290 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base)-7-(cyclopentylmethyl)-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
291 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base)-7-(cyclohexylmethyl)-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
292 (3RS,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclobutylmethyl)- 9-(2-cyclohexylethyl)-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
293 (3RS,7S,13R)-13-Benzyl-7-(cyclopentylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11- Four-sided oxy-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
294 (3RS,7S,13R)-13-Benzyl-7-(cyclohexylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetra Oxy-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
295 (3RS,7S,13R)-13-Benzyl-7-(cyclopentylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11- Four-sided oxy-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
296 (3RS,7S,13R)-13-Benzyl-7-(cyclohexylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetra Oxy-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
297 (3RS,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetraoxo -9-(2-((SR)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
298 (3RS,7S,13R)-13-Benzyl-7-(cyclopentylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11- Tetraoxo-9-(2-((SR)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
299 (3RS,7S,13R)-13-Benzyl-7-(cyclohexylmethyl)-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11-tetra Oxy-9-(2-((SR)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
300 (3RS,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-(cyclopentylmethyl)-N-(3-methoxyphenethyl)-6- Methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[ 1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
301 (3RS,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-(cyclohexylmethyl)-N-(3-methoxyphenethyl)-6-methyl Base-1,5,8,11-tetrahydronaphtho-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1 ,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
302 (3RS,7S,13R)-13-Benzyl-7-(cyclobutylmethyl)-9-(2-cyclohexylethyl)-N-(3-methoxyphenethyl)-6-methyl -1,5,8,11-Tetrahydronaphtho[1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1, 2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
303 (3RS,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1 ,5,8,11-Tetrahydronaphtho[1,2- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
304 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-7-(2-((RS)-tetrahydro-2H-pyran-2-yl)ethyl)-2, 3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-13-carboxamide
305 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-7-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-13-carboxamide
306 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-16- Methoxy-10-methyl-5,8,11,15-tetraoxo-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-13-carboxamide
307 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-(cyclopentylmethyl )-16-methoxy-10-methyl-5,8,11,15-tetraoxo-7-(((R)-tetrahydro-2H-pyran-2-yl)methyl)- 2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14] tetraazacycloheptadecene-13-carboxamide
308 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-(cyclopentylmethyl )-16-methoxy-10-methyl-5,8,11,15-tetraoxo-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)- 2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14] tetraazacycloheptadecene-13-carboxamide
309 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-(cyclohexylmethyl) -16-Methoxy-10-methyl-5,8,11,15-tetraoxo-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-13-carboxamide
310 (3R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,8,11, 15-Tetrahydrooxy-7-(2-((RS)-tetrahydro-2H-pyran-2-yl)ethyl)-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
311 (3R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,8,11, 15-Tetrahydrooxy-7-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
312 (3R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,8,11, 15-tetraoxo-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
313 (3R,9S,13S)-3-Benzyl-9-(cyclopentylmethyl)-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5, 8,11,15-tetraoxo-7-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9 ,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
314 (3R,9S,13S)-3-Benzyl-9-(cyclohexylmethyl)-16-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,8 ,11,15-Tetrahydrooxy-7-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
315 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
316 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-isobutyl-N-(3-(methoxy-d3)phenethyl)-6- Methyl-1,5,8,11-Tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1 ]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
317 (3R,9S,13S)-3-Benzyl-9-isobutyl-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8,11,15-tetra Oxy-16-(trifluoromethoxy)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydrobenzo[p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
318 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6, 9-Dimethyl-1,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro -[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
319 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14] Tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
320 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-(methoxy-d3)phenethyl)-6,9-dimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
321 (8R,14S,18S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-8-benzyl-14-isobutyl-12, 15-Dimethyl-10,13,16,20-Tetrahydrooxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetrahydro -[1,3]dioxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -18-Formamide
322 (8R,14S,18S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-8-benzyl-14-isobutyl-12, 15-Dimethyl-10,13,16,20-Tetrahydrooxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetrahydro -[1,3]dioxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -2,2-d2-18-formamide
323 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-12,15-dimethyl-10,13,16,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetrahydro-[1,3]dioxo[4',5': 5,6]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
324 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-12,15-dimethyl-10,13,16,20-tetra Pendant oxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetrahydro-[1,3]dioxo[4',5': 5,6]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-2,2-d2-18-carboxamide
325 (4aR,7R,18S,22S)-7-Benzyl-N-(3,5-dimethoxyphenethyl)-22-isobutyl-21-methyl-5,16,20,23 -Tetrahydrooxy-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p] [1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
326 (4aR,7R,18S,22S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-7-benzyl-22-isobutyl- 21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23- Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 18-formamide
327 (4aR,7R,18S,22S)-N-(2-(Benzo[d]oxazol-2-yl)ethyl)-7-benzyl-22-isobutyl-21-methyl-5 ,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[ 1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
328 (8S,12S,18aR,21R)-21-Benzyl-N-(3,5-dimethoxyphenethyl)-12-isobutyl-5,11-dimethyl-6,10, 13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H-imidazole And[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohepta Carbene-8-formamide
329 (8S,12S,18aR,21R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-21-benzyl-12-isobutyl- 5,11-Dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21 ,22-Hexadecahydro-5H,15H-imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4, 7,10,14] Tetraazacyclohexadecene-8-carboxamide
330 (3S,7S,13R)-9-(2-(7-Oxabicyclo[2.2.1]hept-2-yl)ethyl)-N-(2-(benzo[d][1,3] Dioxo-5-yl)ethyl)-13-benzyl-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-3-carboxamide
331 (3S,7S,13R)-9-(2-(5-Oxaspiro[3.4]oct-6-yl)ethyl)-N-(2-(benzo[d][1,3]dioxyl Er-5-yl)ethyl)-13-benzyl-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradecahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-3-formamide
332 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(2-(tetrahydrofuran-2-yl)ethyl)-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
333 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(2-(tetrahydro-2H-pyran-3-yl)ethyl)-1,2,3,4,5,6, 7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -3-Formamide
334 (3S,7S,13R)-9-(2-(2,9-Dioxaspiro[5.5]undec-3-yl)ethyl)-N-(2-(benzo[d][1 ,3]Dioxo-5-yl)ethyl)-13-benzyl-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3 ,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]four Azacyclohexadecene-3-carboxamide
335 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-(tertiary Butoxy)ethyl)-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
336 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-9- (2-(3-methoxycyclobutyl)ethyl)-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3- Formamide
337 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclobutylmethyl)- 6-methyl-1,5,8,11-tetraoxo-9-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-3-carboxamide
338 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclobutylmethyl)- 6-Methyl-1,5,8,11-tetraoxo-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-3-carboxamide
339 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base)-6-methyl-1,5,8,11-tetraoxo-7-(prop-2-yn-1-yl)-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3- Formamide
340 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopropylmethyl )-6-methyl-1,5,8,11-tetrahydrooxy-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-3-carboxamide
341 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base)-7-(cyclopropylmethyl)-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
342 (8S,12S,18aS,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-11-methyl-6,10,13,19-tetra Oxy-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-oxazolo[4',5' :5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-formyl amine
343 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-11-methyl-6,10,13,19-tetra Oxy-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-oxazolo[4',5' :5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-formyl amine
344 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-7-isobutyl-6-methyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-ten Tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
345 (8R,14S,18S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-8-benzyl-12-(2-cyclohexylethyl Base)-14-isobutyl-15-methyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18 ,19,20-tetrahydro-[1,3]dioxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-18-carboxamide
346 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-14-isobutyl-N-(3-methoxyphenethyl)-15-methyl-10 ,13,16,20-Tetradetrahydro-[1,3]di Oxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
347 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-14-isobutyl-N-(3-(methoxy-d3)phenethyl)-15- Methyl-10,13,16,20-Tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetradetrahydro-[1 ,3]Dioxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18- Formamide
348 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-12-isobutyl-N-(3-methoxyphenethyl)-5,11-dimethyl-6 ,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H, 15H-imidazo[4',5':5,6]benzo[1,2-p]pyrhazo[2,1-f][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecen-8-carboxamide
349 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-18-fluoro-7-isobutyl Base-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14 -Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
350 (3S,7S,13R)-13-Benzyl-18-fluoro-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
351 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6,10,13,19 -Tetrahydro-15H-oxazolo[5',4':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8 - formamide
352 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-17-isopropyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6 ,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-㗁Azolo[4',5':5,6]benzo[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10,14]tetraazepine Cycloheptadecene-8-carboxamide
353 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-17-isopropyl-N-(3-methoxyphenethyl)-5,11-dimethyl-6 ,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H, 15H-imidazo[4',5':5,6]benzo[1,2-p]pyrhazo[2,1-f][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecen-8-carboxamide
354 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-3-(2-methoxyethyl)-N-(3-methoxyphenethyl)-21-methyl Group-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro -1H-Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
355 (4aR,7R,18S,22S)-7-Benzyl-3-cyclobutyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16, 20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
356 (4aR,7R,18S,22S)-7-Benzyl-3-cyclopropyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16, 20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
357 (4aS,7R,18S,22S)-7-Benzyl-3-cyclopropyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16, 20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
358 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopropylmethyl )-6-methyl-1,5,8,11-tetraoxo-9-(2-((S)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2, 3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-3-carboxamide
359 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclopropylmethyl )-6-methyl-1,5,8,11-tetraoxo-9-(2-((R)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2, 3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-3-carboxamide
360 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclobutylmethyl)- 6-methyl-1,5,8,11-tetraoxo-9-(2-((S)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-3-carboxamide
361 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-(cyclobutylmethyl)- 6-methyl-1,5,8,11-tetraoxo-9-(2-((R)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-3-carboxamide
362 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(2-((S)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-3-carboxamide
363 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(2-((R)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-3-carboxamide
364 (8S,12S,18aR,21R)-21-Benzyl-12,17-diisobutyl-N-(3-methoxyphenethyl)-5,11-dimethyl-6,10, 13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H-imidazole And[4',5':5,6]benzo[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-8-carboxamide
365 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1': 6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
366 (9S,13S,19aS,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1': 6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
367 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formyl amine
368 (8S,12S,18aR,21R)-21-Benzyl-N-(3,5-dimethoxyphenethyl)-12-isobutyl-4,11-dimethyl-6,10, 13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-oxazolo [5',4':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadeca En-8-carboxamide
369 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)aminoformyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphtho[ 1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylic acid 2,2,2-trichloro ethyl ester
370 (4aR,7R,18S,22S)-7-Benzyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl)-22-isobutyl Base-21-methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22, 23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecane En-18-carboxamide
371 (4aR,7R,18S,22S)-7-Benzyl-N-(3-(difluoromethoxy)phenethyl)-22-isobutyl-21-methyl-5,16,20, 23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p ][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
372 (9S,13S,19aR,22R)-22-Benzyl-13,18-diisobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20 -Tetrahydro-16H-pyroxy[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
373 (9S,13S,19aS,22R)-22-Benzyl-13,18-diisobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20 -Tetrahydro-16H-pyroxy[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
374 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-18-isopropyl-N-(3-methoxyphenethyl)-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
375 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-18-isopropyl-12-methyl-N-(2-(3-methylisoxazol-5-yl ) Ethyl) -7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
376 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-4,4a,5,6,7,8,16,17,18,19,20,21,22,23-tetradetrahydro-1H-naphtho[1,2-p]pyrido[2 ,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
377 (8S,12S,18aR,21R)-21-Benzyl-N-(3,5-dimethoxyphenethyl)-12-isobutyl-4,5,11-trimethyl-6, 10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H -imidazo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-8-carboxamide
378 (4aR,7R,18S,22S)-7-Benzyl-N-(3-bromophenethyl)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo -1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-Hexadecahydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
379 (8R,14S,18S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-8-benzyl-12-(2-cyclohexylethyl Base)-14-isobutyl-2,15-dimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16, 17,18,19,20-Tetradetrahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-18-carboxamide
380 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-14-isobutyl-N-(3-methoxyphenethyl)-2,15-dimethyl Base-10,13,16,20-tetrahydrooxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetrahydro-oxazolo[ 4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
381 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-14-isobutyl-N-(3-(methoxy-d3)phenethyl)-2, 15-Dimethyl-10,13,16,20-Tetrahydrooxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-Tetrahydro Zazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl amine
382 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base)-18-fluoro-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formyl amine
383 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-18-fluoro-7-isobutyl-N-(3-methoxyphenethyl)-6- Methyl-1,5,8,11-Tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1 ]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
384 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-18-fluoro-7-isobutyl-N-(3-(methoxy-d3)phenethyl )-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-fourteen Hydrogen-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
385 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-naphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene] -3'-formamide
386 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6'-methyl-1',5',8 ',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro- 1'H-spiro[cyclopropane-1,10'-naphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-3'- Formamide
387 (4aR,7R,18S,22S)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-7-benzyl-22-isobutyl-21- Methyl-5,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-16 Hydronaphtho[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18- Formamide
388 (9S,13S,19aS,22R)-22-Benzyl-18-cyclopropyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
389 (9S,13S,19aR,22R)-22-Benzyl-18-cyclopropyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
390 (9S,13S,19aS,22R)-22-Benzyl-18-cyclobutyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
391 (9S,13S,19aR,22R)-22-Benzyl-18-cyclobutyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
392 (9S,13S,19aS,22R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-22-benzyl-18-cyclopropyl- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 17,16-c]quinoline-9-formamide
393 (9S,13S,19aR,22R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-22-benzyl-18-cyclopropyl- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 17,16-c]quinoline-9-formamide
394 (9S,13S,19aS,22R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-22-benzyl-18-cyclobutyl- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 17,16-c]quinoline-9-formamide
395 (9S,13S,19aR,22R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-22-benzyl-18-cyclobutyl- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 17,16-c]quinoline-9-formamide
396 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-9'-(3-methoxypropyl)- 6'-methyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-naphtho[1,2-p][1]oxa[4,7,10,14] Tetraazacyclohexadecene]-3'-formamide
397 (4aR,7R,18S,22S)-7-Benzyl-N-(3-ethoxyphenethyl)-22-isobutyl-21-methyl-5,16,20,23-tetra Oxy-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][1, 4] 㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
398 (9S,13S,19aR,22R)-22-Benzyl-18-cyclopropyl-N-(3-(difluoromethoxy)phenethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9- Formamide
399 (9S,13S,19aS,22R)-22-Benzyl-18-cyclopropyl-N-(3-(difluoromethoxy)phenethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9- Formamide
400 (9S,13S,19aR,22R)-22-Benzyl-18-cyclopropyl-N-(3-ethoxyphenethyl)-13-isobutyl-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
401 (9S,13S,19aS,22R)-22-Benzyl-18-cyclopropyl-N-(3-ethoxyphenethyl)-13-isobutyl-12-methyl-7,11, 14,20-Tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyridine [2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
402 (9S,13S,19aR,22R)-22-Benzyl-18-cyclopropyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl ) Ethyl) -7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
403 (9S,13S,19aS,22R)-22-Benzyl-18-cyclopropyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl ) Ethyl) -7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] Quinoline-9-formamide
404 (9S,13S,19aR,22R)-22-Benzyl-18-cyclopropyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl )-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a, 20,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecene And[17,16-c]quinoline-9-formamide
405 (9S,13S,19aS,22R)-22-Benzyl-18-cyclopropyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl )-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a, 20,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecene And[17,16-c]quinoline-9-formamide
406 (7S,11S,21R,23aR)-21-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-8,16-dimethyl-6,9,13,23 -Tetraoxo-1,3,4,6,7,8,9,10,11,12,13,20,21,22,23,23a-Hexadecahydro-2H-oxazolo[5',4':4,5]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11 - formamide
407 (7S,11S,21R,23aR)-21-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-8,16-dimethyl-6,9,13,23 -Tetraoxo-1,3,4,6,7,8,9,10,11,12,13,20,21,22,23,23a-Hexadecahydro-[1,4]㗁𠯤 [3,4-f]oxazolo[5',4':4,5]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycle seventeen Carbene-11-formamide
408 (8R,14S,18S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-8-benzyl-2,2-difluoro-14 -isobutyl-12,15-dimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18, 19,20-Tetradetrahydro-[1,3]dioxo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-18-carboxamide
409 (8R,14S,18S)-8-Benzyl-2,2-difluoro-14-isobutyl-N-(3-methoxyphenethyl)-12,15-dimethyl-10, 13,16,20-Tetrahydro-[1,3]dioxo [4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
410 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-14-isobutyl-2,15-dimethyl-N-(2-(3-methyliso (Zazol-5-yl)ethyl)-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19, 20-Tetradetrahydroazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -18-formamide
411 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-18-fluoro-7-isobutyl-6-methyl-N-(2-(3-methyl Isoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13 ,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
412 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
413 (9S,13S,19aS,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
414 (9S,13S,19aR,22R)-22-Benzyl-N-(3-(difluoromethoxy)phenethyl)-13-isobutyl-18-(2-methoxyethyl) -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23 -Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
415 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl)-13-isobutyl Base-18-(2-methoxyethyl)-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17, 18,19,19a,20,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadeceno[17,16-c]quinoline-9-carboxamide
416 (4aR,7R,18S,22S)-7-Benzyl-3-(2-hydroxyethyl)-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl- 5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
417 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-12-isobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6 ,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-㗁Azolo[4',5':5,6]benzo[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10,14]tetraazepine Cycloheptadecene-8-carboxamide
418 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-N-(3-ethoxyphenethyl)-12-isobutyl-4,11-dimethyl-6 ,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-㗁Azolo[4',5':5,6]benzo[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10,14]tetraazepine Cycloheptadecene-8-carboxamide
419 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-N-(3-(difluoromethoxy)phenethyl)-12-isobutyl-4,11-di Methyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-16 Hydrogen-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-8-carboxamide
420 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-N-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethyl )-12-isobutyl-4,11-dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18 ,18a,19,20,21,22-Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyroxylo[2,1-f] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
421 (8S,12S,18aR,21R)-21-Benzyl-17-cyclopropyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxine -6-yl)ethyl)-12-isobutyl-4,11-dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12, 13,16,17,18,18a,19,20,21,22-Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazole [2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
422 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-N-(3-(1,1-difluoroethyl)phenethyl)-14-isobutyl -2,15-Dimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20- tetradetrahydroazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18 - formamide
423 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-3,11-dimethyl-6,10,13,19 -Tetra-oxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-3H,15H-pyrido[2 ',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-e]indazole-8-carboxamide
424 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-3,11-dimethyl-6,10,13,19 -Tetraoxo-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22-Hexadecahydro-3H-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-e]indazole-8-formyl amine
425 (8S,12S,18aR,21R)-21-Benzyl-17-(cyclopropylmethyl)-12-isobutyl-N-(3-methoxyphenethyl)-4,11-di Methyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-16 Hydrogen-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-8-carboxamide
426 (8S,12S,18aR,21R)-21-Benzyl-17-(cyclopropylmethyl)-N-(3-(difluoromethoxy)phenethyl)-12-isobutyl-4 ,11-Dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21, 22-Hexadexahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7 ,10,14] tetraazacycloheptadecene-8-carboxamide
427 (8S,12S,18aR,21R)-21-Benzyl-17-(cyclopropylmethyl)-N-(3-ethoxyphenethyl)-12-isobutyl-4,11-di Methyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-16 Hydrogen-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-8-carboxamide
428 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-21-benzyl-17-(cyclopropylmethyl )-12-isobutyl-4,11-dimethyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18 ,18a,19,20,21,22-Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyroxylo[2,1-f] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
429 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-3,11-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro -3H,15H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-e]indazole -8-formamide
430 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10-Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydro Pyrido[2',1':2,3]imidazo[4,5-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
431 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-9-(3-methoxypropyl)-6,10 -Dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphthalene And[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
432 (3'S,7'S,13'R)-13'-Benzyl-7'-(cyclopentylmethyl)-6',9'-dimethyl-N-(2-(3-Methyliso㗁Azol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclodecaHeptaceno[17,16-c]quinoline]-3'-formamide
433 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline ]-3'-formamide
434 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -1', 5', 8', 11'-tetraoxo-2', 3', 4', 5', 6', 7', 8', 9', 11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene [17,16-c]quinoline]-3'-formamide
435 (8S,12S,18aR,21R)-21-Benzyl-12-(cyclopentylmethyl)-4,11-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22 -Hexadecahydro-[1,4]㗁𠯤[3,4-f]oxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4 ,7,10,14] Tetraazacyclohexadecene-8-carboxamide
436 (8S,12S,18aR,21R)-21-Benzyl-12-(cyclopentylmethyl)-4,11-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-8-formamide
437 (8S,12S,18aS,21R)-21-Benzyl-12-(cyclopentylmethyl)-4,11-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-8-formamide
438 (3'R,9'S,13'S)-3'-Benzyl-9'-isobutyl-16'-methoxy-N-(3-methoxyphenethyl)-7',10'- Dimethyl-5',8',11',15'-tetraoxo-2',3',4',5',8',9',10',11',12',13',14',15'-Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[3,4-p][1]oxa[4,7,10,14]tetraaze Heterocyclic heptadecene]-13'-formamide
439 (3'S,7'S,13'R)-13'-Benzyl-18'-fluoro-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl Group-1',5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13 ',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c]quinoline]-3'-formamide
440 (3'S,7'S,13'R)-13'-Benzyl-18'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methyliso (Zazol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9 ',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacycle Heptadeceno[17,16-c]quinoline]-3'-formamide
441 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14] Tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
442 (3'R,9'S,13'S)-3'-Benzyl-9'-isobutyl-N-(3-methoxyphenethyl)-7',10'-dimethyl-5', 8',11',15'-tetraoxo-2',3',4',5',8',9',10',11',12',13',14',15'- Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[2',1':2,3]imidazo[4,5-p][1]oxa[4,7, 10,14]tetraazacyclohexadecene]-13'-formamide
443 (9S,13S,19aR,22R)-22-Benzyl-3-fluoro-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl Base)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
444 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4,10-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro -14H-Dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
445 (3S,7S,13R)-13-Benzyl-7-isobutyl-6-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5 ,8,11-tetraoxo-9-(((R)-tetrahydro-2H-pyran-2-yl)methyl)-1,2,3,4,5,6,7,8, 9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3 - formamide
446 (3S,7S,13R)-13-Benzyl-7-isobutyl-6-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5 ,8,11-tetraoxo-9-(2-((S)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2,3,4,5,6,7, 8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -3-Formamide
447 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-12,15-dimethyl-10,13,16,20-tetra Pendant oxy-2,3,7,8,9,10,13,14,15,16,17,18,19,20-tetrahydro-12H-spiro[benzofuro[7,6-p ][1]oxa[4,7,10,14]tetraazacyclohexadecene-11,1'-cyclopropane]-18-formamide
448 (3'R,9'S,13'S)-3'-Benzyl-9'-isobutyl-7',10'-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -5', 8', 11', 15'-tetraoxo-2', 3', 4', 5', 8', 9', 10', 11', 12', 13',14',15'-Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[2',1':2,3]imidazo[4,5-p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene]-13'-formamide
449 (3R,9S,13S)-3-Benzyl-9-isobutyl-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8,11,15-tetra Pendantoxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetrahydropyrido[2',1':2,3]imidazo [4,5-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
450 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Pendant oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14,19,20-hexadecahydrobenzofuro[4,5-p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
451 (4aR,7R,18S,22S)-7-Benzyl-3-(3-hydroxypropyl)-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl- 5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
452 (4aR,7R,18S,22S)-7-Benzyl-3-(3-hydroxypropyl)-22-isobutyl-21-methyl-N-(2-(3-methylisoxazole -5-yl)ethyl)-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21, 22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadeca En-18-carboxamide
453 (3'S,7'S,13'R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-7'-isobutyl- 6',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclodecaHeptaceno[17,16-c]quinoline]-3'-formamide
454 (3'S,7'S,13'R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-7'-isobutyl- 6',9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclodecaHeptaceno[17,16-c]quinoline]-3'-formamide
455 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-11-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-6 ,10,13,19-tetraoxo-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-eighteen Hydrogen-15H-benzofuro[7,6-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-methan Amide
456 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-11-methyl-6,10,13,19-tetra Oxy-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-octahydro-15H-benzofuro[ 7,6-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
457 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-9'-(2-methoxyethyl)-N-(3-methoxyphenethyl)- 6'-methyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-naphtho[1,2-p][1]oxa[4,7,10,14] Tetraazacyclohexadecene]-3'-formamide
458 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-9-((2-(3-methylisoxazol-5-yl)ethyl)amine Formyl)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23- Hexadecahydro-18H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c] 2,2,2-trichloroethyl quinoline-18-carboxylate
459 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12,18-dimethyl-7,11,14,20 -Tetrahydro-16H-pyroxy[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
460 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline ]-3'-formamide
461 (9S,13S,19aR,22R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
462 (9S,13S,19aS,22R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
463 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
464 (9S,13S,19aS,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
465 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14] Tetraazacyclohexadeceno[16,17-f]isoquinoline-3-carboxamide
466 (7S,11S,17aR,20R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-20-benzyl-11-isobutyl-4- Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
467 (7S,11S,17aS,20R)-N-(3-(2H-1,2,3-triazol-2-yl)phenethyl)-20-benzyl-11-isobutyl-4- Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
468 (7S,11S,17aR,20R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-20-benzyl-11-isobutyl-4- Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
469 (7S,11S,22R,24aR)-22-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-8-methyl-6,9,13,24-tetra Oxy-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-Hexadecahydro-2H-pyrido[2,1-f] Pyrido[2',1':2,3]imidazo[4,5-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
470 (7S,11S,22R,24aR)-22-Benzyl-7-isobutyl-8-methyl-N-(2-(3-methylisozol-5-yl)ethyl)-6 ,9,13,24-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-hexadecahydro-2H- Pyrido[2,1-f]pyrido[2',1':2,3]imidazo[4,5-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-11-carboxamide
471 (9'R,15'S,19'S)-9'-Benzyl-15'-isobutyl-N-(3-methoxyphenethyl)-13',16'-dimethyl-11', 14',17',21'-Tetraoxo-8',9',10',11',14',15',16',17',18',19',20',21'- Dodecahydro-13'H-spiro[cyclopropane-1,12'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-h]quinoline ]-19'-formamide
472 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline- 9-formamide
473 (9S,13S,19aS,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-13-isobutyl-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline- 9-formamide
474 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-9-formyl amine
475 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-5 ,16,20,23-tetraoxo-3-(pyridin-3-ylsulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20 ,21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacycle Heptadecene-18-carboxamide
476 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7'-isobutyl-6', 9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]quinoline]-3'-formamide
477 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-10-methyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21- Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-methan Amide
478 (7S,11S,17aR,20R)-20-Benzyl-N-(2,6-difluorophenethyl)-11-isobutyl-4-methoxy-10-methyl-5,9 ,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyridine And[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
479 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-3-((5-methoxypyridin-3-yl)sulfonyl)-21-methyl-N-( 2-(3-Methylisozol-5-yl)ethyl)-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16, 17,18,19,20,21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-18-formamide
480 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl Base)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
481 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-5-fluoro-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
482 (8S,12S,18aR,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-4,11-dimethyl-6,10,13, 19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-oxazolo[4 ',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 8-formamide
483 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-11-isobutyl Base-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
484 (7S,11S,22R,24aR)-22-Benzyl-N-(2,6-difluorophenethyl)-7-isobutyl-8-methyl-6,9,13,24-tetra Oxy-1,3,4,6,7,8,9,10,11,12,13,21,22,23,24,24a-Hexadecahydro-2H-pyrido[2,1-f ]pyrido[2',1':2,3]imidazo[4,5-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-formyl amine
485 (8S,12S,18aR,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-5,11-dimethyl-6,10,13, 19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-5H,15H-imidazo[ 4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene -8-formamide
486 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f ]quinoline-9-formamide
487 (9S,13S,19aR,22S)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formyl amine
488 (3'R,9'S,13'S)-3'-Benzyl-9'-isobutyl-17'-methoxy-N-(3-methoxyphenethyl)-7',10'- Dimethyl-5',8',11',15'-tetraoxo-2',3',4',5',8',9',10',11',12',13',14',15'-Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[2,3-p][1]oxa[4,7,10,14]tetraaze Heterocyclic heptadecene]-13'-formamide
489 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20, 21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecane Ekeno[17,16-c]quinoline-9-carboxamide
490 (8S,12S,18aR,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-3,11-dimethyl-6,10,13, 19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-3H,15H-pyrido[ 2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-e]indazole-8-carboxamide
491 (8S,12S,18aR,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-11-methyl-6,10,13,19-tetra Oxy-3,4,6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-octadechydro-15H-benzofuro [7,6-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8-carboxamide
492 (1r,3S,3'S,7'S,13'R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-7'- Isobutyl-3-methoxy-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6 ',7',8',9',11',12',13',14'-dodecahydro-1'H-spiro[cyclobutane-1,10'-naphtho[1,2-p ][1]oxa[4,7,10,14]tetraazacyclohexadecene]-3'-formamide
493 (1r,3S,3'S,7'S,13'R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-13'-benzyl-7'- Isobutyl-3-methoxy-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6 ',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4, 7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
494 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinone Phenyl]-3'-formamide
495 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl)-1',5',8',11'-tetra-oxo-1,2',3,3',4',5',6',7',8',9',11',12',13',14'-Tetradetrahydro-1'H-spiro[indene-2,10'-[1]oxa[4,7,10,14]tetraazacycle seventeen Carbaeno[17,16-c]quinoline]-3'-formamide
496 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-Dimethyl-1',5',8',11'-Tetraoxo -N-(4-(pyrimidin-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16- c] Quinoline] -3'-formamide
497 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-3-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
498 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-3-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
499 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-3-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
500 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-3-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
501 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-3-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
502 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-Dimethyl-1',5',8',11'-Tetraoxo -N-(3-(pyrimidin-2-yl)phenethyl)-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16- c] Quinoline] -3'-formamide
503 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9,10,10-tetramethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
504 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-9-methan Amide
505 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f ]quinoline-9-formamide
506 (9S,13S,19aR,22R)-22-Benzyl-12-ethyl-13-isobutyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-formyl amine
507 (3S,7S,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
508 (3S,7S,10R,13R)-13-Benzyl-10-cyclopropyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-ten Tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
509 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14,20-four sides Oxy-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrro[ 2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
510 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinone Phenyl-9-formamide
511 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-11-isobutyl Base-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
512 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
513 (3R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8 ,11,15-Tetrahydropyrido[3,2-p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
514 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-9-methan Amide
515 (7S,11S,17aRS,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-11-isobutyl Base-3-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:4',3'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
516 (7S,11S,17aRS,20R)-20-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-11-isobutyl Base-3-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:4',3'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
517 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-3-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:2',3'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
518 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-11-isobutyl-3-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:2',3'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
519 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20'-fluoro-7'-isobutyl Base-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline]-3'-formamide
520 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
521 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
522 (9S,13S,19aR,22R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-22-benzyl-3-fluoro-13-isobutyl Base-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
523 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
524 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21, 22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17, 16-c] quinoline-9-formamide
525 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19 ,19a,20,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclodeca Heptaceno[17,16-c]quinoline-9-carboxamide
526 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-11-isobutyl-3-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:4',3'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
527 (9S,13S,19aR,22R)-22-Benzyl-5-chloro-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl Base)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
528 (9S,13S,19aR,22R)-22-Benzyl-5-chloro-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
529 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-11-isobutyl Base-3-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:2',3'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
530 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14] Tetraazacyclohexadeceno[17,16-c]isoquinoline-3-carboxamide
531 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-2,12,15-trimethyl-10,13,16,20 -Tetrahydrobenzofuro[7,6-p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
532 (8R,14S,18S)-8-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-14-isobutyl-2,12,15-tri Methyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetrahydrobenzofuran And[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
533 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-N-(2-(3-methoxyisoxazol-5-yl)ethyl) -2,10-Dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
534 (9S,13S,19aR,22R)-22-Benzyl-6-fluoro-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl Base)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
535 (9S,13S,19aR,22R)-22-Benzyl-6-fluoro-13-isobutyl-N-(3-methoxyphenethyl)-12-methyl-7,11,14, 20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
536 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6,10,13,19 -Tetra-oxo-17-phenyl-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-㗁Azolo[4',5':5,6]benzo[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10,14]tetraazacycle Heptadecene-8-carboxamide
537 (73S,4R,9S,13S)-4-Benzyl-16-fluoro-9-isobutyl-N-(3-methoxyphenethyl)-10-methyl-6,8,11, 15-tetraoxo-2-oxa-5,10,14-triaza-1(3,4)-quinoline-7(3,1)-pyrrolidinecyclopentadecane-13-formyl amine
538 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-2-phenyl-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro- 2H-pyrido[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
539 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(( 4,4-difluorocyclohexyl)methyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[ 17,16-c]quinoline-3-formamide
540 (3S,7S,10S,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(( 4,4-difluorocyclohexyl)methyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[ 17,16-c]quinoline-3-formamide
541 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16 ,17-f]quinoline-9-formamide
542 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14-methoxy-8-methyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-6,9,13,22-tetra-oxo-2-phenyl-1,3,4,6,7,8,9,10,11,12,13,19,20,21 ,22,22a-Hexadecahydro-2H-pyrido[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohepta Carbene-11-formamide
543 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7'-isobutyl-6', 9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[16,17-f]quinoline]-3'-formamide
544 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[16,17-f]quinoline]-3'-formamide
545 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20'-fluoro-7'-isobutyl Base-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]quinoline]-3'-formamide
546 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20'- Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
547 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-10-isopropyl-6,9-dimethyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-ten Tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
548 (3S,7S,10R,13R)-13-Benzyl-7,10-diisobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl )Ethyl)-1,5,8,11-Tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro- [1] Oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
549 (7S,11S,20R,22aS)-20-Benzyl-7-isobutyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-2-phenyl-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro- 2H-pyrido[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
550 (7S,11S,20R,22aS)-20-Benzyl-7-isobutyl-14-methoxy-8-methyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-6,9,13,22-tetra-oxo-2-phenyl-1,3,4,6,7,8,9,10,11,12,13,19,20,21 ,22,22a-Hexadecahydro-2H-pyrido[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohepta Carbene-11-formamide
551 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-2,12,15-trimethyl-10,13,16,20 -Tetraoxo-7,8,9,10,13,14,15,16,17,18,19,20-dodecahydro-12H-spiro[benzofuro[7,6-p][ 1]Oxa[4,7,10,14]tetraazacyclohexadecene-11,1'-cyclopropane]-18-formamide
552 (8R,14S,18S)-8-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-14-isobutyl-2,12,15-tri Methyl-10,13,16,20-tetraoxo-7,8,9,10,13,14,15,16,17,18,19,20-dodecahydro-12H-spiro[benzo Furo[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11,1'-cyclopropane]-18-carboxamide
553 (8R,14S,18S)-8-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-14-isobutyl- 2,12,15-trimethyl-10,13,16,20-tetraoxo-7,8,9,10,13,14,15,16,17,18,19,20-dodecahydro -12H-spiro[benzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11,1'-cyclopropane]-18- Formamide
554 (8R,14S,18S)-8-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-14-isobutyl- 2,12,15-trimethyl-10,13,16,20-tetraoxo-7,8,9,10,13,14,15,16,17,18,19,20-dodecahydro -12H-spiro[benzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-11,1'-cyclopropane]-18- Formamide
555 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(3-methoxyphenethyl)-6',9'-dimethyl-1', 5',8',11'-Tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'- Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]isoquinone Phenyl]-3'-formamide
556 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7'-isobutyl-6', 9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]isoquinoline]-3'-formamide
557 (3R,6S,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(( 4,4-difluorocyclohexyl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-13-carboxamide
558 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(( 4,4-difluorocyclohexyl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-13-carboxamide
559 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-7,11,14,20-tetra-oxo-N-(2-(3-(three Fluoromethyl)isozazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
560 (9S,13S,19aR,22R)-22-benzyl-5-fluoro-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-N-(2-( 3-(trifluoromethyl)isozazol-5-yl)ethyl)-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
561 (8R,14S,18S)-8-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-14-isobutyl- 2,12,15-trimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20 - Tetrahydrobenzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
562 (8R,14S,18S)-8-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-14-isobutyl- 2,12,15-trimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20 - Tetrahydrobenzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
563 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-6-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
564 (3S,7S,10R,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl-6,9-dimethyl-N-(2-(3 -Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
565 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-11-isobutyl-4-methoxy -2,10-Dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
566 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-10-(2-methoxyethyl)-6,9-dimethyl-N-(2-(3- Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
567 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-11-isobutyl Base-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17 ,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-7-carboxamide
568 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-N -(2-(3-(Trifluoromethyl)isozazol-5-yl)ethyl)-5,6,7,8,9,10,11,12,15,16,17,17a,18 ,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-7-carboxamide
569 (7S,11S,19bRS,22R)-22-Benzyl-11-isobutyl-4-methoxy-N-(3-methoxyphenethyl)-10-methyl-5,9, 12,20-Tetrahydro-14H-pyrido[3',4 ':16,17][1]oxa[4,7,10,14]tetraazacyclohexadeceno[6,7-a]isoquinoline-7-carboxamide
570 (7S,11S,20R,22aR)-20-Benzyl-2,7-diisobutyl-14-methoxy-8-methyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22 ,22a-Hexadecahydro-2H-pyrido[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -11-formamide
571 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-6-(2-(3-phenyl-1,2,4-oxadiazole- 5-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
572 (3S,7S,10S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9,10-trimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
573 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-6,9,10-trimethyl-N-(2-(3-methylisoxazol-5-yl) Ethyl)-1,5,8,11-Tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[ 1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
574 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,10 -Trimethyl-1,5,8,11-Tetradecyloxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro- [1] Oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
575 (8R,11RS,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-2,11,12,15-tetramethyl-10,13 ,16,20-Tetrahydrobenzofuro[7,6- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
576 (8R,11RS,14S,18S)-8-Benzyl-14-isobutyl-2,11,12,15-tetramethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -10,13,16,20-tetrahydrooxy-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetrahydro Benzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
577 (3R,6S,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-6-(2-(3-phenyl-1,2,4-oxadiazole- 5-yl)ethyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1 ]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
578 (3S,7S,10R,13R)-13-Benzyl-10-(2-(benzyloxy)ethyl)-7-isobutyl-6,9-dimethyl-N-(2- (3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
579 (3S,7S,10S,13R)-13-Benzyl-10-(2-(benzyloxy)ethyl)-7-isobutyl-6,9-dimethyl-N-(2- (3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
580 (7'S,11'S,17a'R,20'R)-20'-Benzyl-11'-isobutyl-4'-methoxy-N-(2-(3-methoxyisoxazole- 5-yl)ethyl)-2',10'-dimethyl-5',9',12',18'-tetraoxo-5',6',7',8',9', 10',11',12',14',15',17',17a',18',19',20',21'-hexadecahydrospiro[cyclopropane-1,16'-dipyrido[ 2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-7'-formamide
581 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-4-(methoxy-d3)-N-(2-(3-methoxyisoxazol-5-yl )ethyl)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
582 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-16-methoxy-N-(2-(3-methoxyiso Azol-5-yl)ethyl)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12, 13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
583 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
584 (13S,4R,10S,14S)-4-Benzyl-14-isobutyl-74-methoxy-N-(3-methoxyphenethyl)-13-methyl-2,8, 12,15-tetraoxo-6-oxa-3,9,13-triaza-1(3,1)-pyrrolidine-7(1,2)-phenylcyclopentadecane-10-metha Amide
585 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl Base)-9-isobutyl-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
586 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-17,18-dimethoxy-N-(3-methoxyphenylethyl) Base)-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-ten Tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
587 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-15-methoxy-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H-benzo[ p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
588 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-15-methoxy-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydrobenzo[p][ 1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-formamide
589 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-7-(2-cyclohexylethyl base)-9-isobutyl-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
590 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-9-isobutyl-N-(3-methoxyphenethyl)-10-methyl-5 ,8,11,15-Tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
591 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl-6,9, 13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H-benzo[ p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
592 (7S,11S,17aS,20R)-20-Benzyl-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-11-isobutyl-10-methyl -5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro- 14H-Dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
593 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-11-isobutyl-10-methyl -5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro- 14H-Dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
594 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethane base)-11-isobutyl-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a ,18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraaza cycloheptadecene-7-carboxamide
595 (3S,7S,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1,5,8,11-tetra Pendant oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[ 4,7,10,14] tetraazacycloheptadecene-3-carboxamide
596 (3R,9S,13S)-3-Benzyl-N-(2-(𠳭唍-7-yl)ethyl)-7-(2-cyclohexylethyl)-9-isobutyl-17, 18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14 ,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
597 (3R,9S,13S)-3-Benzyl-7-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-9 -Isobutyl-17,18-dimethoxy-10-methyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
598 (8R,14S,18S)-8-Benzyl-14-isobutyl-N-(3-methoxyphenethyl)-2,12,15-trimethyl-10,13,16,20 -Tetrahydrooxazolo[4',5':5,6 ]Benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
599 (3S,7S,13R)-13-Benzyl-N-(2-(𠳭唍-7-yl)ethyl)-9-(2-cyclohexylethyl)-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[ 1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
600 (3S,7S,13R)-13-Benzyl-9-(2-cyclohexylethyl)-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)-7 -Isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14 - Tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
601 (7S,11S,20R,22aS)-20-Benzyl-7-isobutyl-14,16-dimethoxy-N-(3-methoxyphenethyl)-8-methyl-6 ,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H- Benzo[p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
602 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14,16-dimethoxy-N-(3-methoxyphenethyl)-8-methyl-6 ,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H- Benzo[p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
603 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[1,2-p] Pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
604 (4aS,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[1,2-p] Pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
605 (7S,11S,20R,22aR)-20-Benzyl-2-ethyl-7-isobutyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl -6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro- 2H-Benzo[p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
606 (4aS,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-N-(2-(3-methylisozol-5-yl)ethyl)-5 ,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H- Naphtho[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
607 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-5 ,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H- Naphtho[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
608 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-5 ,16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[ 1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
609 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-14,16-dimethoxy-8-methyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22 ,22a-Hexadecahydro-2H-benzo[p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-formyl amine
610 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(2-cyclohexylethyl Base) -7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
611 (7S,11S,20R,22aR)-20-Benzyl-7-isobutyl-2-isopropyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl Group-6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro -2H-Benzo[p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
612 (7S,11S,20R,22aR)-20-Benzyl-2,7-diisobutyl-14-methoxy-N-(3-methoxyphenethyl)-8-methyl-6 ,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22,22a-hexadecahydro-2H- Benzo[p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
613 (4aR,7R,18S,22S)-7-Benzyl-N-(3,5-dimethoxyphenethyl)-3,22-diisobutyl-21-methyl-5,16, 20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
614 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6,10,13,19 -Tetrahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8 - formamide
615 (8S,12S,18aS,21R)-21-Benzyl-12-isobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6,10,13,19 -Tetrahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-8 - formamide
616 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-16-(difluoromethoxy )-9-isobutyl-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
617 (4aR,7R,18S,22S)-7-Benzyl-3,22-diisobutyl-21-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro -1H-Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
618 (4aR,7R,18S,22S)-7-Benzyl-N-(3,5-dimethoxyphenethyl)-22-isobutyl-3-isopropyl-21-methyl-5 ,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H- Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
619 (8S,12S,18aR,21R)-21-Benzyl-12,17-diisobutyl-N-(3-methoxyphenethyl)-4,11-dimethyl-6,10, 13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro-15H-oxazolo [4',5':5,6]benzo[1,2-p]pyrazo[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-8-formamide
620 (8S,12S,18aR,21R)-21-Benzyl-12,17-diisobutyl-4,11-dimethyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22- Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-8-formamide
621 (8S,12S,18aS,21R)-21-Benzyl-12,17-diisobutyl-4,11-dimethyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22- Hexadecahydro-15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrazolo[2,1-f][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-8-formamide
622 (9S,13S,19aR,22R)-22-Benzyl-13,18-diisobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro -16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline- 9-formamide
623 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-3-isopropyl-21-methyl-N-(2-(3-methylisoxazol-5-yl )ethyl)-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23- Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18- Formamide
624 (4aRS,7R,17S,21S)-7-Benzyl-21-isobutyl-N-(3-methoxyphenethyl)-12,20-dimethyl-5,15,19,22 -Tetraoxo-1,2,4,4a,5,6,7,8,15,16,17,18,19,20,21,22-Hexadecahydroisozozolo[4',5 ':5,6]benzo[1,2-p][1,4]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacycle seventeen Carbene-17-formamide
625 (8S,12S,18aR,21R)-21-Benzyl-N-(3-(difluoromethoxy)phenethyl)-12-isobutyl-4,11-dimethyl-6,10 ,13,19-tetraoxo-6,7,8,9,10,11,12,13,15,16,18,18a,19,20,21,22-hexadecahydro-[1,4 ]㗁𠯤[3,4-f]㗁azolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadecene-8-carboxamide
626 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-7-isobutyl-6- Methyl-1,5,8,11-tetraoxo-9-(3-phenylpropyl)-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
627 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethane Base)-3-fluoro-13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17 ,19,19a,20,21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14] Tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
628 (8'R,14'S,18'S)-8'-Benzyl-14'-isobutyl-N-(3-methoxyphenethyl)-2',12',15'-trimethyl- 10',13',16',20'-Tetraoxo-7',8',9',10',13',14',15',16',17',18',19', 20'-Dodecahydro-12'H-spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2-p][1]oxa[ 4,7,10,14]tetraazacyclohexadecene]-18'-formamide
629 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-3,11-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro -15H-Isoxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14] tetraazacycloheptadecene-8-carboxamide
630 (8S,12S,18aR,21R)-21-Benzyl-12-(cyclopentylmethyl)-3,11-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-15H-isozozolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7, 10,14] tetraazacycloheptadecene-8-carboxamide
631 (8S,12S,18aS,21R)-21-Benzyl-12-(cyclopentylmethyl)-3,11-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22 -Hexadecahydro-15H-isozozolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7, 10,14] tetraazacycloheptadecene-8-carboxamide
632 (8S,12S,18aR,21R)-21-Benzyl-12-isobutyl-4,11-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-hexadecahydro -15H-oxazolo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetra Azacyclohexadecene-8-carboxamide
633 (1r,3S,3'S,7'S,13'R)-13'-benzyl-7'-isobutyl-3-methoxy-6',9'-dimethyl-N-(2-( 3-Methylisozol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-naphtho[1,2-p][1]Oxa[4,7,10,14]tetraazacyclohexadecene]-3'-formamide
634 (8S,12S,18aR,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-3,11-dimethyl-6,10,13, [ 4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene -8-Formamide
635 (8S,12S,18aS,21R)-21-Benzyl-N-(2,6-difluorophenethyl)-12-isobutyl-3,11-dimethyl-6,10,13, [ 4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene -8-Formamide
636 (9S,13S,19aR,22R)-22-Benzyl-N-(2,6-difluorophenethyl)-5-fluoro-13-isobutyl-12-methyl-7,11,14 ,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[2 ',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
637 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
638 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-3-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
639 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
640 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
641 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
642 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-methan Amide
643 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-ten Hexahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16- c] quinoline-9-formamide
644 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20,21,22,23-ten Hexahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16- c] quinoline-9-formamide
645 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,16,17,19,19a,20, 21,22,23-hexadecahydro-[1,4]㗁𠯤[3',4':6,7][1]oxa[4,7,10,14]tetraazacyclohexadecane Ekeno[17,16-c]quinoline-9-carboxamide
646 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-12-ethyl -13-isobutyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22, 23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c ]quinoline-9-formamide
647 (3R,9S,13S)-3-Benzyl-9-isobutyl-17-methoxy-N-(3-methoxyphenethyl)-7,10-dimethyl-5,8 ,11,15-Tetrahydropyrido[4,3-p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
648 (3'R,9'S,13'S)-3'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-9'-isobutyl-17'- Methoxy-7',10'-dimethyl-5',8',11',15'-tetraoxo-2',3',4',5',8',9',10 ',11',12',13',14',15'-Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[4,3-p][1]oxa[ 4,7,10,14]tetraazacyclohexadecene]-13'-formamide
649 (3'R,9'S,13'S)-3'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9'- Isobutyl-17'-methoxy-7',10'-dimethyl-5',8',11',15'-tetraoxo-2',3',4',5', 8',9',10',11',12',13',14',15'-dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[4,3-p ][1]oxa[4,7,10,14]tetraazacyclohexadecene]-13'-formamide
650 (3'R,9'S,13'S)-3'-Benzyl-9'-isobutyl-17'-methoxy-N-(3-methoxyphenethyl)-7',10'- Dimethyl-5',8',11',15'-tetraoxo-2',3',4',5',8',9',10',11',12',13',14',15'-Dodecahydro-7'H-spiro[cyclopropane-1,6'-pyrido[4,3-p][1]oxa[4,7,10,14]tetraaze Heterocyclic heptadecene]-13'-formamide
651 (7S,11S,20R,22aR)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-20-benzyl-14-fluoro-7-isobutyl Base-8-methyl-6,9,13,22-tetraoxo-1,3,4,6,7,8,9,10,11,12,13,19,20,21,22, 22a-Hexadecahydro-2H-benzo[p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-11-carboxamide
652 (7S,11S,17aRS,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-3-methoxy -10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21 -Hexadecahydro-14H-dipyrido[2,1-f:4',3'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7- Formamide
653 (8S,12S,18aR,21R)-N-(4-(2H-1,2,3-triazol-2-yl)phenethyl)-21-benzyl-12-isobutyl-11- Methyl-6,10,13,19-tetraoxo-6,7,8,9,10,11,12,13,16,17,18,18a,19,20,21,22-16 Hydrogen-15H-[1,3]dioxo[4',5':5,6]benzo[1,2-p]pyrido[2,1-f][1]oxa[4,7, 10,14] Tetraazacyclohexadecene-4,4-d2-8-formamide
654 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -1', 5', 8', 11'-tetraoxo-2', 3', 4', 5', 6', 7', 8', 9', 11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-naphtho[1,2-p][1]oxa[4,7,10,14] Tetraazacyclohexadecene]-3'-formamide
655 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
656 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-11-isobutyl Base-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17 ,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-7-carboxamide
657 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-11-isobutyl Base-4-(methoxy-d3)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15 ,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-7-formamide
658 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -2,10-Dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
659 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-(methoxy Base-d3)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
660 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-6-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
661 (3R,6S,9S,13S)-3-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-6-((4,4-difluorocyclo Hexyl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
662 (3R,6R,9S,13S)-3-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-6-((4,4-difluorocyclo Hexyl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
663 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-16,16-difluoro-11-isobutyl Base-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
664 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-11-isobutyl-4-(methoxy Base-d3)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
665 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)-5-fluoro -13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20 ,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 17,16-c]quinoline-9-formamide
666 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-11-isobutyl Base-4-(methoxy-d3)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15 ,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-7-formamide
667 (7S,11S,17aS,20R)-20-Benzyl-11-isobutyl-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-N -(2-(3-(Trifluoromethyl)isozazol-5-yl)ethyl)-5,6,7,8,9,10,11,12,15,16,17,17a,18 ,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-7-carboxamide
668 (7'S,11'S,17a'R,20'R)-20'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11'-isobutyl -4'-methoxy-10'-methyl-5',9',12',18'-tetraoxo-5',6',7',8',9',10',11 ',12',14',15',17',17a',18',19',20',21'-hexadehydrospiro[cyclopropane-1,16'-dipyrido[2,1- f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-7'-formamide
669 (7'S,11'S,17a'S,20'R)-20'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11'-isobutyl-4 '-Methoxy-10'-methyl-5',9',12',18'-tetraoxo-5',6',7',8',9',10',11', 12',14',15',17',17a',18',19',20',21'-hexadecahydrospiro[cyclopropane-1,16'-dipyrido[2,1-f: 3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-7'-formamide
670 (7S,11S,17aS,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-16-phenyl-5,6,7,8,9,10,11,12,15,16,17,17a,18, 19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-7-formamide
671 (7S,11S,17aS,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-16-phenyl-5,6,7,8,9,10,11,12,15,16,17,17a,18, 19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-7-formamide
672 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-16-phenyl-5,6,7,8,9,10,11,12,15,16,17,17a,18, 19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-7-formamide
673 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -10-methyl-5,9,12,18-tetraoxo-16-phenyl-5,6,7,8,9,10,11,12,15,16,17,17a,18, 19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-7-formamide
674 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quino Phenyl-9-formamide
675 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quino Phenyl-9-formamide
676 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quino Phenyl-9-formamide
677 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-13-isobutyl-12-methyl- 7,11,14,20-tetraoxo-18-phenyl-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quino Phenyl-9-formamide
678 (7S,11S,19aR,22R)-22-Benzyl-11-isobutyl-4-methoxy-10-methyl-N-(2-(3-methylisoxazol-5-yl )Ethyl)-5,9,12,20-tetraoxo-5,6,7,8,9,10,11,12,19,19a,20,21,22,23-tetradecylhydro- 14H-pyrido[3',4':16,17][1]oxa[4,7,10,14]tetraazacyclohexadeceno[7,6-b]isoquinoline-7 - formamide
679 (7S,11S,19bR,22R)-22-Benzyl-11-isobutyl-4-methoxy-10-methyl-N-(2-(3-methylisoxazol-5-yl )Ethyl)-5,9,12,20-Tetraoxo-5,6,7,8,9,10,11,12,15,19b,20,21,22,23-Tetradetrahydro- 14H-pyrido[3',4':16,17][1]oxa[4,7,10,14]tetraazacyclohexadeceno[6,7-a]isoquinoline-7 - formamide
680 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9,10-trimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
681 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-6-phenyl-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-metha Amide
682 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-6-((4,4-difluorocyclo Hexyl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
683 (7'S,11'S,17a'R,20'R)-20'-Benzyl-11'-isobutyl-4'-methoxy-2',10'-dimethyl-N-(2- (3-Methylisozol-5-yl)ethyl)-5',9',12',18'-tetraoxo-5',6',7',8',9',10 ',11',12',14',15',17',17a',18',19',20',21'-hexadehydrospiro[cyclopropane-1,16'-dipyrido[2 ,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-7'-formamide
684 (7'S,11'S,17a'S,20'R)-20'-Benzyl-11'-isobutyl-4'-methoxy-N-(2-(3-methoxyisoxazole-5- Base) ethyl) -2',10'-dimethyl-5',9',12',18'-tetraoxo-5',6',7',8',9',10',11',12',14',15',17',17a',18',19',20',21'-hexadecahydrospiro[cyclopropane-1,16'-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-7'-formamide
685 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)-11-iso Butyl-4-(methoxy-d3)-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12, 15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7, 10,14] tetraazacycloheptadecene-7-carboxamide
686 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6', 9'-Dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceneAnd[17,16-c]quinoline]-3'-formamide
687 (3R,9S,13S)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-3-benzyl-9-isobutyl-7, 10-Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydro Benzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
688 (3R,9S,13S)-3-Benzyl-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl) -9-isobutyl-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12, 13,14,15-Tetradetrahydrobenzo[p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
689 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20'-fluoro-7'-isobutyl Base-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazepine Heterocyclic heptadeceno[17,16-c]quinoline]-3'-formamide
690 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methyliso (Zazol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9 ',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazepine Cycloheptadeceno[17,16-c]quinoline]-3'-formamide
691 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20'- Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
692 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20'- Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
693 (3S,7S,10R,13R)-13-Benzyl-10-(cyclopentylmethyl)-N-(2-(5-cyclopropyl-1,2,4-oxadiazole-3- Base) ethyl) -20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7 ,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinone Phenyl-3-carboxamide
694 (3S,7S,10S,13R)-13-Benzyl-10-(cyclopentylmethyl)-N-(2-(5-cyclopropyl-1,2,4-oxadiazole-3- Base) ethyl) -20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7 ,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinone Phenyl-3-carboxamide
695 (3S,7S,10S,13R)-13-Benzyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-10-(naphthalene-1-ylmethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
696 (3S,7S,10R,13R)-13-Benzyl-10-(cyclohexylmethyl)-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl )ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7, 8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -3-Formamide
697 (3S,7S,10R,13R)-13-Benzyl-10-(cyclohexylmethyl)-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20- Fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
698 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl )-10-(naphthalene-1-ylmethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
699 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3 -Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
700 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(((S)- 𠳭唍-3-yl)methyl)-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3- Formamide
701 (3S,7S,13R)-9-(2-Cyclohexylethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6-methyl-1,5,8,11 -Tetrahydrooxy-13-(pyridin-2-ylmethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphthalene And[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
702 (3S,7S,13R)-13-Benzyl-9-((2,3-dihydrobenzofuran-2-yl)methyl)-7-isobutyl-6-methyl-N-( 2-(3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-methan Amide
703 (3S,7S,13R)-13-(Benzo[b]thiophen-3-ylmethyl)-7-isobutyl-6-methyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-1,5,8,11-tetraoxo-9-(2-((S)-tetrahydro-2H-pyran-2-yl)ethyl)-1,2 ,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeca Ekeno[17,16-c]quinoline-3-carboxamide
704 (3S,7S,13R)-13-Benzyl-9-(((S)-𠳭唍-3-yl)methyl)-7-isobutyl-6-methyl-N-(2-( 3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
705 (3S,7S,13R)-13-Benzyl-9-(((R)-𠳭唍-3-yl)methyl)-7-isobutyl-6-methyl-N-(2-( 3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
706 (3S,7S,13R)-13-Benzyl-9-(((R)-6,6-Dimethyltetrahydro-2H-pyran-2-yl)methyl)-7-isobutyl -6-Methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5 ,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c] quinoline-3-formamide
707 (3S,7S,13R)-13-Benzyl-9-(((S)-6,6-Dimethyltetrahydro-2H-pyran-2-yl)methyl)-7-isobutyl -6-Methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5 ,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c] quinoline-3-formamide
708 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -1', 5', 8', 11'-tetraoxo-2', 3', 4', 5', 6', 7', 8', 9', 11', 12',13',14'-Dodecahydro-1'H-spiro[cyclopentane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadecene And[17,16-c]quinoline]-3'-formamide
709 (3S,7S,10R,13R)-13-Benzyl-10-(cyclohexylmethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3-methyliso (Zazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13, 14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
710 (3S,7S,10R,13R)-13-Benzyl-10-cyclopentyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-ten Tetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
711 (3'S,7'S,13'R)-13'-Benzyl-3,3-difluoro-7'-isobutyl-6',9'-dimethyl-N-(2-(3-methyl Isoxazol-5-yl)ethyl)-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraAzacyclohexadeceno[17,16-c]quinoline]-3'-formamide
712 (3S,7S,13R)-N-(2-(Benzo[d][1,3]dioxer-5-yl)ethyl)-13-benzyl-9-(((R)- 𠳭唍-3-yl)methyl)-7-isobutyl-6-methyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3- Formamide
713 (3S,7S,10R,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl-N-(3-methoxyphenethyl)-6, 9-Dimethyl-1,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro Naphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
714 (3S,7S,10R,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl-6,9-dimethyl-N-(2-(3 -Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
715 (3S,7S,10S,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl-N-(3-methoxyphenethyl)-6, 9-Dimethyl-1,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro Naphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
716 (3S,7S,10S,13R)-13-Benzyl-10-((benzyloxy)methyl)-7-isobutyl-6,9-dimethyl-N-(2-(3 -Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11, 12,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
717 (3S,7S,10RS,13R)-13-Benzyl-10-(tertiary butoxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9 -Dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphthalene And[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
718 (3S,7S,10RS,13R)-13-Benzyl-10-(hydroxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl -1,5,8,11-Tetrahydronaphtho[1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydronaphtho[1, 2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
719 (3S,7S,10RS,13R)-13-Benzyl-10-(tertiary butoxymethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3- Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
720 (3S,7S,10RS,13R)-13-Benzyl-10-(hydroxymethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3-methyliso Azol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14 - Tetrahydronaphtho[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
721 (3S,7S,10R,13R)-13-Benzyl-10-cyclopentyl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methyl Isoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13 ,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
722 (3S,7S,10R,13R)-10,13-Benzhydryl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazole -5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
723 (3S,7S,10S,13R)-10,13-Benzhydryl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazole -5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
724 (3R,6RS,9S,13S)-3-Benzyl-6-((benzyloxy)methyl)-N-(2-(3-cyclopropyl-1,2,4-oxadiazole -5-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5, 6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclo Heptadecene-13-carboxamide
725 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-21-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-5 ,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H- Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
726 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[1,2-p] Pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
727 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H- Pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-methan Amide
728 (8R,14S,18S)-8-Benzyl-12-(2-cyclohexylethyl)-N-(3-((RS)-1-hydroxyethyl)phenethyl)-14-isobutyl Base-2,15-dimethyl-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20 -Tetradetrahydroazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 18-formamide
729 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(phenylsulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
730 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-3-((3-(N-𠰌 Linyl)propyl)sulfonyl)-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
731 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-3-(methylsulfonyl)- 5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
732 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-((3-(trifluoromethoxy)phenyl)sulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
733 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-3-((2-methoxyethyl)sulfonyl)-N-(3-methoxyphenethyl )-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22, 23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 18-formamide
734 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-((tetrahydro-2H-pyran-4-yl)sulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
735 (4aR,7R,18S,22S)-7-Benzyl-3-((2-(dimethylamino)ethyl)sulfonyl)-22-isobutyl-N-(3-methoxy phenylethyl)-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
736 (4aR,7R,18S,22S)-7-Benzyl-3-(phenylmethylsulfonyl)-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl -5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro- 1H-Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
737 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-((2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)sulfonyl)-2,3,4,4a,5,6,7, 8,16,17,18,19,20,21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrazo[2,1-f][1]oxa[4 ,7,10,14] tetraazacycloheptadecene-18-carboxamide
738 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-((quinolin-8-ylmethyl)sulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22 ,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene -18-formamide
739 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-3-((3-methoxyphenyl)sulfonyl )-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22, 23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 18-formamide
740 (4aR,7R,18S,22S)-7-Benzyl-3-((2-fluoro-5-methoxyphenyl)sulfonyl)-22-isobutyl-N-(3-methoxy phenylethyl)-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
741 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-3-((4-methyl-3 ,4-dihydro-2H-benzo[b][1,4]㗁𠯤-7-yl)sulfonyl)-5,16,20,23-tetraoxo-2,3,4,4a ,5,6,7,8,16,17,18,19,20,21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrazo[2,1-f] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
742 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(pyridin-3-ylsulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecyl Hydrogen-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl amine
743 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-3-((3-methoxypropyl)sulfonyl )-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22, 23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene- 18-formamide
744 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-3-((5-methoxypyridin-3-yl) Sulfonyl)-21-methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21 ,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrhazo[2,1-f][1]oxa[4,7,10,14]tetraazacyclohepta Carbene-18-formamide
745 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-3-((2-(N-𠰌 Linyl)ethyl)sulfonyl)-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20, 21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-18-carboxamide
746 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)-2,3,4,4a,5,6,7,8,16,17,18, 19,20,21,22,23-Hexadecahydro-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetra Azacyclohexadecene-18-carboxamide
747 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(pyridin-2-ylsulfonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecyl Hydrogen-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl amine
748 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-18-((4-methyl-3,4-dihydro-2H-benzo[b] [1,4]㗁𠯤-7-yl)sulfonyl)-N-(2-(3-methylisozol-5-yl)ethyl)-7,11,14,20-tetraoxo Group-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrro[2',1': 6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-9-carboxamide
749 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-12-methyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-7 ,11,14,20-tetraoxo-18-((3-(trifluoromethoxy)phenyl)sulfonyl)-7,8,9,10,11,12,13,14,17 ,18,19,19a,20,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline-9-carboxamide
750 (4aR,7R,18S,22S)-3-Acetyl-7-benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16, 20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
751 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-3-(3-methylbutyryl)- 5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-1H -Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
752 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-3-(3-methoxypropionyl)-21- Methyl-5,16,20,23-tetraoxo-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-16 Hydrogen-1H-naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formyl amine
753 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(pyridine-2-carbonyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro- 1H-Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
754 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)aminoformyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphtho[ Methyl 1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylate
755 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)aminoformyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylate ethyl ester
756 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-18-((3-methoxyphenethyl)aminoformyl)-21-methyl-5,16, 20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphtho[ 1,2-p]pyrido[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxylic acid tetrahydro-2H-pyran- 4-yl ester
757 (((4aR,7R,18S,22S)-7-benzyl-22-isobutyl-18-((3-methoxyphenethyl)carbamoyl)-21-methyl-5, 16,20,23-tetraoxo-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro-3H-naphthalene And[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecen-3-yl)(side oxy) (Phenyl)-l6-sulfanylidene)carbamate tertiary butyl ester
758 (4aR,7R,18S,22S)-7-Benzyl-22-isobutyl-N-(3-methoxyphenethyl)-21-methyl-5,16,20,23-tetra Oxy-3-(phenylsulfoniminoyl)-2,3,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydro -1H-Naphtho[1,2-p]pyrro[2,1-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-carboxamide
759 (4aR,7R,18S,22S)-7-Benzyl-N-(3-cyanophenethyl)-22-isobutyl-21-methyl-5,16,20,23-tetraoxo base-1,2,4,4a,5,6,7,8,16,17,18,19,20,21,22,23-hexadecahydronaphtho[1,2-p][1,4 ]㗁𠯤[3,4-f][1]oxa[4,7,10,14]tetraazacyclohexadecene-18-formamide
760 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-9-((3-methoxyphenethyl)aminoformyl)-12-methyl-7,11, 14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H-pyrido[ 2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline 2-oxide
761 (8'R,14'S,18'S)-8'-Benzyl-14'-isobutyl-2',12',15'-trimethyl-10',13',16',20'-tetra Pendant oxy-N-(2-(3-phenylisoxazol-5-yl)ethyl)-7',8',9',10',13',14',15',16', 17',18',19',20'-Dodecahydro-12'H-spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2 -p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-formamide
762 (8'R,14'S,18'S)-8'-Benzyl-14'-isobutyl-N-(2-(3-isopropylisozazol-5-yl)ethyl)-2', 12',15'-trimethyl-10',13',16',20'-quadoxy-7',8',9',10',13',14',15',16',17',18',19',20'-Dodecahydro-12'H-spiro[cyclopropane-1,11'-oxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacyclohexadecene]-18'-formamide
763 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-Benzyl-1,2,4-oxadiazol-5-yl)ethyl)-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
764 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)ethyl) -7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6', 7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
765 (3R,6R,9S,13S)-3-Benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-9-isobutyl-16 -Methoxy-6,7,10-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12, 13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
766 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-11-isobutyl-4 -Methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a, 18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacycle Heptadecene-7-carboxamide
767 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-11-isobutyl-4 -Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19 ,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-7-carboxamide
768 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-6,7,10-trimethyl -5,8,11,15-Tetrahydropyrido-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetrahydropyrido[3, 4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
769 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
770 (9S,13S,19aS,22R)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
771 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -6,7,10-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14, 15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
772 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -6,7,10,18-tetramethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13, 14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
773 (3R,6R,9S,13S)-3-Benzyl-6-ethyl-9-isobutyl-16-methoxy-7,10,18-trimethyl-N-(2-(3 -Methylisozol-5-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12, 13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
774 (3R,6R,9S,13S)-3-Benzyl-6-ethyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-7,10, 18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydro Pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
775 (3R,6R,9S,13S)-3-Benzyl-6-(2,2-difluoroethyl)-9-isobutyl-16-methoxy-7,10,18-trimethyl -N-(2-(3-Methylisoxazol-5-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
776 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10-Dimethyl-5,8,11,15-tetraoxo-6-(2,2,2-trifluoroethyl)-2,3,4,5,6,7,8 ,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 13-Formamide
777 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
778 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-5-fluoro -13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20 ,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 16,17-f]quinoline-9-formamide
779 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-5-fluoro -13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20 ,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 16,17-f]quinoline-9-formamide
780 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16 ,17-f]quinoline-9-formamide
781 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-5-fluoro-13-isobutyl-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
782 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(( 3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-9-isobutyl-16-methoxy-7,10-dimethyl -5,8,11,15-Tetrahydropyrido-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetrahydropyrido[3, 4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
783 (3R,6R,9S,13S)-3-Benzyl-6-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl) -9-isobutyl-16-methoxy-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-7,10-dimethyl-5,8,11, 15-Tetrahydropyrido[3,4-p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
784 (3R,6R,9S,13S)-3-Benzyl-6-ethyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisoxazole-5- Base) ethyl) -7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
785 (3R,6R,9S,13S)-3-Benzyl-6-(2,2-difluoroethyl)-9-isobutyl-16-methoxy-N-(2-(3-methyl Oxyisozol-5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8 ,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 13-Formamide
786 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6 ,9,10-Trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
787 (3S,7S,10R,13R)-13-Benzyl-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-20-fluoro -7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
788 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(3-methoxyphenethyl)-6,9,10-trimethyl-1,5,8 ,11-Tetrahydro-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydroimidazo[1',2':1, 6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
789 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10 -Trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydroimidazole And[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
790 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,10 -Trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydroimidazole And[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-3-carboxamide
791 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10,18-trimethyl-5,8,11,15-tetraoxo-6-(2,2,2-trifluoroethyl)-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
792 (3R,6S,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10,18-trimethyl-5,8,11,15-tetraoxo-6-(2,2,2-trifluoroethyl)-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
793 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-5-fluoro- 13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16 ,17-f]quinoline-9-formamide
794 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
795 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11- Four-side oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14 ]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
796 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-5,12-di Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline -9-formamide
797 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20-fluoro-7-isobutyl-6 ,9,10-Trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
798 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-20-fluoro-7-isobutyl-6 ,9,10-Trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
799 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
800 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20-fluoro- 7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11 ,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
801 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2 ,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Quinoline-3-formamide
802 (3S,7S,10S,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2 ,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Quinoline-3-formamide
803 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-ethyl -20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-methan Amide
804 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-10-((3 -(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl-1,5,8, 11-Tetrahydro-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
805 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethyl)-5-fluoro -13-isobutyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20 ,21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[ 16,17-f]quinoline-9-formamide
806 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-9-isobutyl-16-methyl Oxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-(2,2,2-trifluoroethyl)-2,3,4,5,6 ,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-13-carboxamide
807 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14] Tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
808 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20-fluoro- 10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
809 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6 ,9-Dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline-3-carboxamide
810 (3S,7S,10S,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6 ,9-Dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline-3-carboxamide
811 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole- 5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
812 (3S,7S,10S,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole- 5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
813 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
814 (3S,7S,10S,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
815 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11- Four-side oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14 ]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
816 (3S,7S,10S,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11- Four-side oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14 ]tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
817 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20'-fluoro-7'- Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[16,17-f]quinoline]-3'-formamide
818 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl )-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8', 9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]quinoline]-3'-formamide
819 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy Isoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9 ,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3- Formamide
820 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4- (Odiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
821 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- Base) ethyl) -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16 ,17-f]quinoline-9-formamide
822 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12-di Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline- 9-formamide
823 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-13-isobutyl-5,12 -Dimethyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]iso Quinoline-9-formamide
824 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-6,9,10,20-tetramethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -1,5,8,11-tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro -[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-carboxamide
825 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10 ,20-Tetramethyl-1,5,8,11-Tetramethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradecine Hydrogen-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-carboxamide
826 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl Base-6,9,10,20-Tetramethyl-1,5,8,11-Tetramethyl-1,2,3,4,5,6,7,8,9,10,11,12 ,13,14-Tetradecylhydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-carboxamide
827 (3S,7S,10R,13R)-13-Benzyl-10-((3,3-difluoropyrrolidin-1-yl)methyl)-20-fluoro-7-isobutyl-N-( 2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5 ,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[17,16 -c] quinoline-3-formamide
828 (3R,6R,9S,13S)-3-Benzyl-N-((S)-2-hydroxy-2-phenylethyl)-6,9-diisobutyl-16-methoxy- 7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 - Tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
829 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-5-fluoro-13-isobutyl -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23 -Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f] Quinoline-9-formamide
830 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(2-(1-(2-methoxyethyl)-1H-pyridine Azol-4-yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6 ',7',8',9',11',12',13',14'-dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7 ,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
831 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,2-difluoroethyl Base)-11-isobutyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15 ,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-7-formamide
832 (7S,11S,17aR,20R)-N-(2-(2H-Benzo[d][1,2,3]triazol-2-yl)ethyl)-20-benzyl-11-iso Butyl-4-methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a ,18,19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraaza cycloheptadecene-7-carboxamide
833 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-11-isobutyl-4-methyl Oxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20 ,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 7-formamide
834 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(4-ethynyl-5-methyl-2H-1,2,3-triazol-2-yl)ethyl) -11-isobutyl-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12, 15,16,17,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7, 10,14] tetraazacycloheptadecene-7-carboxamide
835 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-11-isobutyl-4-methyl Oxy-2,10-dimethyl-5,9,12,18-tetra-oxo-5,6,7,8,9,10,11,12,15,16,17,17a,18, 19,20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadeca Carbene-7-formamide
836 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(4-cyano-2H-1,2,3-triazol-2-yl)ethyl)-11-isobutyl Base-4-methoxy-2,10-dimethyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17 ,17a,18,19,20,21-hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetra Azacyclohexadecene-7-carboxamide
837 (3S,7S,10R,13R)-13-Benzyl-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-20-fluoro -10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl- 1,5,8,11-Tetrahydro-[1]oxa [4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
838 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-3,3,20'-tri Fluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
839 (3'S,7'S,13'R)-13'-Benzyl-3,3,20'-trifluoro-7'-isobutyl-N-(2-(3-methoxyisoxazole-5 -yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7 ',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
840 (3S,7S,10R,13R)-N-(2-(2H-Benzo[d][1,2,3]triazol-2-yl)ethyl)-13-benzyl-20-fluoro -10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl- 1,5,8,11-Tetrahydro-[1]oxa [4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
841 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-3,3 ,20'-trifluoro-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4', 5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxy Hetero[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline]-3'-formamide
842 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )Methyl)-N-((S)-2-Hydroxy-2-phenylethyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline-3-carboxamide
843 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(6-methoxypyridin-3-yl)ethyl)-6,9-dimethyl-1,5,8,11-four sides Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline-3-carboxamide
844 (3S,7S,10R,13R)-N-(2-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethyl)-13-benzyl-20 -Fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9-dimethyl Group-1,5,8,11-Tetrahydrooxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1] Oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
845 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(3-methoxypropyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[ 17,16-c]quinoline-3-formamide
846 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-N-(3-(trifluoromethoxy)propyl)-1, 2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacycle seventeen Carbaeno[17,16-c]quinoline-3-carboxamide
847 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(5-methoxypyridin-2-yl)ethyl)-6,9-dimethyl-1,5,8,11-four sides Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline-3-carboxamide
848 (3R,6R,9S,13S)-3-Benzyl-N-((S)-2-hydroxy-2-phenylethyl)-9-isobutyl-16-methoxy-7,10 ,18-Trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl) -2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7 ,10,14] tetraazacycloheptadecene-13-carboxamide
849 (3R,6R,9S,13S)-3-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4- (Odiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
850 (7S,11S,17aR,20R)-20-Benzyl-N-(3-(difluoromethoxy)propyl)-11-isobutyl-4-methoxy-10-methyl-5 ,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20,21-hexadecahydro-14H- Dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
851 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 7-isobutyl-6,9-dimethyl-10-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-1,5,8,11 -Tetrahydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[17,16-c]quinoline-3-formamide
852 (9S,13S,19aR,22R)-22-Benzyl-18-(5-fluoropyridin-2-yl)-13-isobutyl-12-methyl-N-(2-(3-methyl Isoxazol-5-yl)ethyl)-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20 ,21,22,23-Hexadecahydro-16H-pyrro[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno [17,16-c]quinoline-9-formamide
853 (9S,13S,19aR,22R)-22-Benzyl-18-(5-fluoropyridin-2-yl)-13-isobutyl-N-(3-methoxyphenethyl)-12- Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-16 Hydrogen-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline -9-formamide
854 (3R,6R,9S,13S)-3-Benzyl-6-((4,4-difluorocyclohexyl)methyl)-9-isobutyl-16-methoxy-N-(2- (3-methoxyisoxazol-5-yl)ethyl)-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7 ,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadeca En-13-carboxamide
855 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-7,10-dimethyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-5,8,11,15-tetraoxo-6-(2-phenoxyethyl)-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-formyl amine
856 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10-Dimethyl-5,8,11,15-tetraoxo-6-(2-phenoxyethyl)-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-metha Amide
857 (3R,6R,9S,13S)-3-Benzyl-6-(cyclobutoxymethyl)-N-(2-(5-cyclopropyl-1,2,4-oxadiazole-3 -yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6, 7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadeca Carbene-13-formamide
858 (3R,6R,9S,13S)-3-Benzyl-6-(2-(cyclohexyloxy)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl -N-(2-(3-Methylisoxazol-5-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
859 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-6-((3-phenyl-1,2,4-oxadiazole-5- base)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxy Hetero[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
860 (7S,11S,14R,17R)-17-Benzyl-11-isobutyl-4-methoxy-N-(3-methoxyphenethyl)-2,10,13,14-tetra Methyl-5,9,12,15-tetraoxo-5,6,7,8,9,10,11,12,13,14,15,16,17,18-tetrahydropyrimido[ 5,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
861 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-6-((3-methoxyisoxazol-5-yl)methyl)-7,10-dimethyl-5,8,11,15-four-side oxy- 2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7, 10,14] Tetraazacyclohexadecene-13-carboxamide
862 (7S,11S,14R,17R)-17-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-4-methoxy -2,10,13,14-Tetramethyl-5,9,12,15-Tetramethyl-5,6,7,8,9,10,11,12,13,14,15,16, 17,18-tetrahydropyrimido[5,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-7-carboxamide
863 (7S,11S,18aR,21R)-21-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-11-isobutyl Base-4-methoxy-10-methyl-5,9,12,19-tetraoxo-5,6,7,8,9,10,11,12,14,15,16,17, 18,18a,19,20,21,22-Octahydroazepine[2,1-f]pyrido[3,4-p][1]oxa[4,7,10,14]tetraaza Heterocyclic heptadecene-7-carboxamide
864 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(2 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8, 11,15-Tetrahydropyrido[3,4-p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
865 (3R,6R,9S,13S)-3-Benzyl-6-(tertiary butyl)-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)- 7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15 - Tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
866 (3R,6R,9S,13S)-3-Benzyl-6-(tertiary butyl)-9-isobutyl-16-methoxy-7,10,18-trimethyl-N-( 2-(3-Methylisozol-5-yl)ethyl)-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
867 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-6-((3-(4-(2-methoxyethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-7, 10-Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydro Pyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
868 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-6-((3-(4-(2-methoxyethyl)phenyl)- 1,2,4-oxadiazol-5-yl)methyl)-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-7,10-dimethyl-5 ,8,11,15-Tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
869 (7S,11S,17aR,20R)-20-Benzyl-11-isobutyl-2,4-dimethoxy-10-methyl-N-(2-(3-methylisoxazole- 5-yl)ethyl)-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19,20 ,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene- 7-formamide
870 (7S,11S,17aR,20R)-20-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-11-isobutyl-2,4-di Methoxy-10-methyl-5,9,12,18-tetraoxo-5,6,7,8,9,10,11,12,15,16,17,17a,18,19, 20,21-Hexadecahydro-14H-dipyrido[2,1-f:3',4'-p][1]oxa[4,7,10,14]tetraazacyclohexadecene -7-formamide
871 (3R,6R,9S,13S)-3-Benzyl-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-9-iso Butyl-16-methoxy-6-((3-(4-(2-methoxyethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-7 ,10-Dimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecyl Hydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
872 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl) Ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8 ',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[17,16-c]quinoline]-3'-formamide
873 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-7,10,18-trimethyl -6-Neopentyl-5,8,11,15-Tetradecyloxy-2,3,4,5,6,7,8,9,10,11,12,13,14,15-Tetradecyl Hydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
874 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-7,10,18-trimethyl-N-(2-(3-methyliso Azol-5-yl)ethyl)-5,8,11,15-tetraoxo-6-phenethyl-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
875 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(3-methoxyphenethyl)-7,10,18-trimethyl -5,8,11,15-tetraoxo-6-phenethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecyl Hydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
876 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-7,10,18-trimethyl-N-(2-(3-methyliso Azol-5-yl)ethyl)-6-neopentyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
877 (3R,6R,9S,13S)-3-Benzyl-6-(2-ethoxyethyl)-9-isobutyl-16-methoxy-N-(2-(3-methoxy Isoxazol-5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
878 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10,18-trimethyl-6-neopentyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10,11, 12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
879 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 7-isobutyl-10-((3-methoxyisoxazol-5-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1, 2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacycle seventeen Carbaeno[16,17-f]quinoline-3-carboxamide
880 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-10 -((3-methoxyisoxazol-5-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5 ,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17 -f] quinoline-3-formamide
881 (3R,6R,9S,13S)-3-Benzyl-6-(2-(3-(tertiary butyl)-1,2,4-oxadiazol-5-yl)ethyl)-N -(2-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5 ,8,11,15-Tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
882 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl Base-16-methoxy-7,10-dimethyl-5,8,11,15-tetraoxo-6-((4-phenyl-1H-1,2,3-triazole-1 -yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
883 (3R,6R,9S,13S)-3-Benzyl-6-(2-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)ethyl)-N-(2 -(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9-isobutyl-16-methoxy-7,10-dimethyl-5,8, 11,15-Tetrahydropyrido[3,4-p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
884 (3R,6R,9S,13S)-3-Benzyl-6-(2-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)ethyl)-9-isobutyl Base-16-methoxy-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-7,10-dimethyl-5,8,11,15-tetraoxo Base-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4, 7,10,14] Tetraazacyclohexadecene-13-carboxamide
885 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 10-((4-(5-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-7-isobutyl-6,9-dimethyl- 1,5,8,11-Tetrahydro-[1]oxa [4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
886 (3S,7S,10R,13R)-13-Benzyl-10-((3-(tertiary butyl)isoxazol-5-yl)methyl)-N-(2-(5-cyclopropane Base-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[17,16-c]quinoline-3-carboxamide
887 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-20-fluoro- 10-(2-(3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl-6,9-dimethyl -1,5,8,11-Tetrahydro-[1]Oxygen-1,2,3,4,5,6,7,8,9,10,11,12,13,14 Hetero[4,7,10,14]tetraazacyclohexadeceno[17,16-c]quinoline-3-carboxamide
888 (9S,13S,19aR,22R)-22-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-13-isobutyl-2,12 -Dimethyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quino Phenyl-9-formamide
889 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7-isobutyl Base-6,9,20-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5- Base) methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formamide
890 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-7-isobutyl-6,9 ,20-Trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]isoquinoline-3-carboxamide
891 (3S,7S,10R,13R)-13-Benzyl-N-((S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxy Ethyl)-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6 ,9-Dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecine Hydrogen-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
892 (3S,7S,10R,13R)-13-Benzyl-N-((R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxy Ethyl)-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6 ,9-Dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecine Hydrogen-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
893 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoro Ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline- 3-Formamide
894 (3S,7S,10R,13R)-13-Benzyl-10-(2-ethoxyethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2 -(3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formyl amine
895 (3S,7S,10R,13R)-13-Benzyl-10-(2-ethoxyethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxyiso (Zazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-methan Amide
896 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2-ethoxyethyl Base)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8, 9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3 - formamide
897 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl )methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa [4,7,10,14]tetraazacyclohexadecene-13-carboxamide
898 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20 -Trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-1 ,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclodeca Heptaceno[16,17-f]isoquinoline-3-carboxamide
899 (9S,13S,19aR,22S)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-12 -Methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-ten Hexahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline -9-formamide
900 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7'- Isobutyl-6',9',20'-trimethyl-1',5',8',11'-tetra-oxo-2',3',4',5',6',7 ',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
901 (3'S,7'S,13'R)-13'-Benzyl-7'-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6', 9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclodecaHeptaceno[16,17-f]isoquinoline]-3'-formamide
902 (3R,6R,9S,13S)-3-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-9-isobutyl-16-methyl Oxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazole-5 -yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
903 (3R,6R,9S,13S)-N-(2-(2H-Benzo[d][1,2,3]triazol-2-yl)ethyl)-3-benzyl-9-iso Butyl-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4 -(oxadiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4 -p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
904 (3'S,7'S,13'R)-N-(2-(2H-Benzo[d][1,2,3]triazol-2-yl)ethyl)-13'-benzyl-7'-Isobutyl-6',9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
905 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(( 3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9,20-trimethyl-1,5 ,8,11-Tetrahydro-[1]oxa[4, 7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formamide
906 (3S,7S,10R,13R)-13-Benzyl-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl) -7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetra Oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetra Azacyclohexadeceno[16,17-f]isoquinoline-3-carboxamide
907 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-((3-(5- Fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11- Four-side oxy-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14 ]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formamide
908 (3S,7S,10R,13R)-N-(2-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethyl)-13-benzyl-20 -Fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetrafluorooxy-10-((3-(trifluoromethyl)-1,2,4-㗁Oxadiazol-5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4 ,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
909 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,17 -Trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-1 ,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclodeca Heptaceno[16,17-f]quinoline-3-carboxamide
910 (3R,6R,9S,13S)-3-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-6-(2-ethoxyethyl) -9-isobutyl-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8, 9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13 - formamide
911 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-7'-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole -5-yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
912 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-12-methyl- 7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23-hexadecahydro-16H -pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-9-methan Amide
913 (3S,7S,10R,13R)-13-Benzyl-10-(2-ethoxyethyl)-7-isobutyl-N-(2-(3-methoxyisoxazole-5 -yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10, 11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formyl amine
914 (3S,7S,10R,13R)-13-Benzyl-10-(2-ethoxyethyl)-7-isobutyl-N-(2-(3-methoxy-1,2, 4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7 ,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17-f]iso Quinoline-3-formamide
915 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2-ethoxyethyl Base) -7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3- Formamide
916 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl )methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1 ,5,8,11-Tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetrahydro-[1]oxa[ 4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
917 (3S,7S,10R,13R)-13-Benzyl-10-((3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl) -7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5 ,8,11-Tetrahydro-[1]oxa[4, 7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formamide
918 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-6,9,20-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5- Base) methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]isoquinoline-3-formamide
919 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxy-1,2,4-oxadiazole- 5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4- (Odiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4- p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
920 (9S,13S,19aR,22R)-22-Benzyl-13-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-2,12-Dimethyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21 ,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16, 17-f] quinoline-9-formamide
921 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-((3-(difluoro Methyl)-1,2,4-oxadiazol-5-yl)methyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]isoquinoline-3-carboxamide
922 (3'S,7'S,13'R)-13'-Benzyl-3,3,20'-trifluoro-7'-isobutyl-N-(2-(3-methoxy-1,2, 4-oxadiazol-5-yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4', 5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxy Hetero[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
923 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-7-isobutyl-6,9 ,17-Trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]quinoline-3-carboxamide
924 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl -6,9-Dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methanol base)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14]four Azacyclohexadeceno[16,17-f]quinoline-3-carboxamide
925 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-N-( 3-(trifluoromethoxy)propyl)-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[ 16,17-f]quinoline-3-formamide
926 (1r,3S,3'S,7'S,13'R)-13'-benzyl-20'-fluoro-7'-isobutyl-3-methoxy-N-(2-(3-methoxy Isoxazol-5-yl)ethyl)-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
927 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-6,9,17-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5- Base) methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
928 (9S,13S,19aS,22R)-22-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-13-isobutyl-2,12 -Dimethyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22,23- Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quino Phenyl-9-formamide
929 (3S,7S,10R,13R)-13-Benzyl-10-(2-ethoxyethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy- 1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6 ,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17-f ]quinoline-3-formamide
930 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-13-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- Base) ethyl) -12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20, 21,22,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[17 ,16-c]quinoline-9-formamide
931 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxyisoxazole- 5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10 ,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3-metha Amide
932 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxy-1,2 ,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6, 7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17-f] Isoquinoline-3-carboxamide
933 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoro Ethyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9 ,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3 - formamide
934 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- Base) ethyl) -6,9-dimethyl-1,5,8,11-tetrafluorooxy-10-((3-(trifluoromethyl)-1,2,4-oxadiazole- 5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
935 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7-isobutyl Base-6,9,17-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5- Base) methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
936 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl Base-6,9,17-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5- Base) methyl) -1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10, 14] Tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
937 (3S,7S,10R,13R)-N-(2-(2H-Benzo[d][1,2,3]triazol-2-yl)ethyl)-13-benzyl-20-fluoro -7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole -5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydro-[1]oxa[4,7 ,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
938 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-6,9,20-trimethyl-1,5,8,11-tetrafluorooxy-10-(2,2,2-trifluoroethyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Isoquinoline-3-formamide
939 (3S,7S,10S,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-6,9,20-trimethyl-1,5,8,11-tetrafluorooxy-10-(2,2,2-trifluoroethyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Isoquinoline-3-formamide
940 (3S,7S,10S,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- Base) ethyl) -6,9-dimethyl-1,5,8,11-tetrafluorooxy-10-(2,2,2-trifluoroethyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16, 17-f] quinoline-3-formamide
941 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- Base) ethyl) -6,9-dimethyl-1,5,8,11-tetrafluorooxy-10-(2,2,2-trifluoroethyl)-1,2,3,4, 5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16, 17-f] quinoline-3-formamide
942 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxy-1,2,4-oxadiazole- 5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetrafluorooxy-6-(2,2,2-trifluoroethyl)-2,3, 4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14] tetraazacycloheptadecene-13-carboxamide
943 (3R,6R,9S,13S)-3-Benzyl-N-((R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxy Ethyl)-9-isobutyl-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl )-1,2,4-oxadiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-fourteen Hydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
944 (3S,7S,10R,13R)-13-Benzyl-N-(3-(difluoromethoxy)propyl)-20-fluoro-7-isobutyl-6,9-dimethyl- 1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3, 4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[ 16,17-f]quinoline-3-formamide
945 (3R,6R,9S,13S)-3-Benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-9-isobutyl-16 -Methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazole -5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][ 1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
946 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-N-( 2-(3-Methylisozol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-methan Amide
947 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy -1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Quinoline-3-formamide
948 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10-Dimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl base)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4 ,7,10,14] Tetraazacyclohexadecene-13-carboxamide
949 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxy-1,2,4-oxadiazole- 5-yl)ethyl)-7,10-dimethyl-5,8,11,15-tetrafluorooxy-6-((3-(trifluoromethyl)-1,2,4-㗁di Azol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p] [1] Oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
950 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7-isobutyl Base-6,9,20-trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Isoquinoline-3-formamide
951 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl Base-6,9,20-trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Isoquinoline-3-formamide
952 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-3,3 -Difluoro-7'-isobutyl-6',9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4', 5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxy Hetero[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
953 (3'S,7'S,13'R)-13'-Benzyl-3,3-difluoro-7'-isobutyl-N-(2-(3-methoxyisoxazol-5-yl) Ethyl)-6',9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7 ',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
954 (3'S,7'S,13'R)-13'-Benzyl-3,3-difluoro-7'-isobutyl-N-(2-(3-methoxy-1,2,4-㗁Oxadiazol-5-yl)ethyl)-6',9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4', 5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxy Hetero[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
955 (3'S,7'S,13'R)-13'-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-3,3-difluoro-7 '-Isobutyl-6',9',20'-trimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline]-3'-formamide
956 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20 -Trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9 ,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3 - formamide
957 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20 -Trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9 ,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3 - formamide
958 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-7-isobutyl-6,9,20 -Trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9 ,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline-3 - formamide
959 (3S,7S,10R,13R)-13-Benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-7-isobutyl-6,9 ,20-trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline -3-Formamide
960 (3S,7S,10R,13R)-13-Benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6 ,9,20-Trimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7 ,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17-f]iso Quinoline-3-formamide
961 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(1-(2-methoxyethyl)-1H-pyrazole -4-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)-1,2,4 -(oxadiazol-5-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4 -p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
962 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-N-(2-(1-(2-methoxyethyl)-1H-pyrazole-4 -yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole -5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetrahydro-[1]oxa[4,7 ,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
963 (3'S,7'S,13'R)-13'-Benzyl-20'-fluoro-N-(2-(4-fluoro-3-methoxyisozazol-5-yl)ethyl)-7 '-Isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5',6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclopropane-1,10'-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
964 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20-fluoro- 7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole- 5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
965 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazole-5- Base) ethyl) -1,5,8,11-tetrafluorooxy-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)- 1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacycle Heptadeceno[16,17-f]quinoline-3-carboxamide
966 (3S,7S,10R,13R)-13-Benzyl-N-((R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-hydroxy Ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1, 2,4-oxadiazol-5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1 ]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-carboxamide
967 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-20-fluoro-N-(2-(4-fluoro-3-methoxyiso Azol-5-yl)ethyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7 ,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinone Phenyl-3-carboxamide
968 (3R,6R,9S,13S)-3-Benzyl-6-(2,2-difluoroethyl)-N-(2-(4-fluoro-3-methoxyisoxazole-5- Base) ethyl) -9-isobutyl-16-methoxy-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6 ,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclodeca Heptacene-13-carboxamide
969 (3'S,7'S,13'R)-13'-Benzyl-3,3,20'-trifluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl) Ethyl)-7'-isobutyl-6',9'-dimethyl-1',5',8',11'-tetraoxo-2',3',4',5', 6',7',8',9',11',12',13',14'-Dodecahydro-1'H-spiro[cyclobutane-1,10'-[1]oxa[4 ,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline]-3'-formamide
970 (3S,7S,10R,13R)-13-Benzyl-10-(2,2-difluoroethyl)-N-(2-(4-fluoro-3-methoxyisoxazole-5- Base) ethyl) -7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8 ,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17-f]isoquinoline -3-Formamide
971 (3S,7S,10R,13R)-13-Benzyl-10-((5-(tertiary butyl)-1,2,4-oxadiazol-3-yl)methyl)-20-fluoro -7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8 ,11-Tetrahydro-[1]oxa[4,7, 10,14]tetraazacyclohexadeceno[16,17-f]quinoline-3-formamide
972 (3S,7S,10R,13R)-13-Benzyl-10-((5-(tertiary butyl)-1,2,4-oxadiazol-3-yl)methyl)-20-fluoro -7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo -1,2,3,4,5,6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraaza Cycloheptadeceno[16,17-f]quinoline-3-carboxamide
973 (9S,13S,19aR,22R)-22-Benzyl-5-fluoro-N-(2-(4-fluoro-3-methoxyisozazol-5-yl)ethyl)-13-iso Butyl-12-methyl-7,11,14,20-tetraoxo-7,8,9,10,11,12,13,14,17,18,19,19a,20,21,22 ,23-Hexadecahydro-16H-pyrido[2',1':6,7][1]oxa[4,7,10,14]tetraazacyclohexadeceno[16,17- f] quinoline-9-formamide
974 (8R,11RS,14S,18S)-8-Benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15 -Trimethyl-10,13,16,20-tetrafluorooxy-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15 ,16,17,18,19,20-tetrahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14 ] Tetraazacyclohexadecene-18-carboxamide
975 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl )-6,9,17-trimethyl-1,5,8,11-tetrafluorooxy-10-(2,2,2-trifluoroethyl)-1,2,3,4,5, 6,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17- f] Quinoline-3-formamide
976 (3S,7S,10R,13R)-13-Benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-10-(2 -Ethoxyethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6 ,7,8,9,10,11,12,13,14-Tetradetrahydro-[1]oxa[4,7,10,14]tetraazacyclohexadecene[16,17-f ]quinoline-3-formamide
977 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -7,10,18-Trimethyl-6-(2-((5-methylpyr-2-yl)oxy)ethyl)-5,8,11,15-tetraoxo-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-13-formamide
978 (3R,6R,9S,13S)-3-Benzyl-9-isobutyl-16-methoxy-N-(2-(3-methoxyisozazol-5-yl)ethyl) -6-(2-((2-methoxypyridin-4-yl)oxy)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10 ,14] Tetraazacycloheptadecene-13-formamide
979 (3R,6R,9S,13S)-3-Benzyl-6-(cyclopropylmethyl)-9-isobutyl-16-methoxy-N-(2-(3-methoxyiso (Zazol-5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-metha Amide
980 (3R,6R,9S,13S)-3-Benzyl-6-(cyclobutylmethyl)-9-isobutyl-16-methoxy-N-(2-(3-methoxyisoxazole -5-yl)ethyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetrahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacyclohexadecene-13-carboxamide
981 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-3-((2-(3-methoxyisoxazol-5-yl)ethyl)amine Formyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazole-5 -yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxa[4,7,10 ,14]tetraazacyclohexadeceno[17,16-c]quinoline 17-oxide
982 (3S,7S,10R,13R)-13-Benzyl-7-isobutyl-3-((2-(3-methoxyisoxazol-5-yl)ethyl)aminoformyl) -6,9,17-trimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl )Methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecylhydro-[1]oxa[4,7,10,14 ]tetraazacyclohexadeceno[16,17-f]quinoline 18-oxide
983 (3S,7S,10R,13R)-13-Benzyl-20-fluoro-7-isobutyl-3-((2-(3-methoxy-1,2,4-oxadiazole-5 -yl)ethyl)aminoformyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)-1,2, 4-oxadiazol-5-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradetrahydro-[1]oxy Hetero[4,7,10,14]tetraazacyclohexadeceno[16,17-f]quinoline 18-oxide
Table 3: Structures of compounds of Examples 1 to 764
在以上表3、表4及表5中，結構中指示為「abs」之立體源或不對稱中心表示如所描繪之呈各別鏡像異構性富集之絕對(
R)-或(
S)
-組態的該立體源或不對稱中心。結構中指示為「&1」之立體源或不對稱中心表示呈各別(
RS)-組態之該立體源或不對稱中心，亦即包含各別鏡像異構性富集之(
R)-組態或鏡像異構性富集之(
S)
-組態或在此類中心處之差向異構物之任何混合物。
In Table 3, Table 4 and Table 5 above, a stereogenic source or asymmetric center indicated as "abs" in a structure represents an absolute ( R )- or ( S ) enriched in the respective enantiomerically as depicted. - The stereo source or asymmetry center of the configuration. A stereogenic source or asymmetric center indicated as "&1" in a structure indicates the stereogenic source or asymmetric center in its respective ( RS )-configuration, i.e. the ( R )-group comprising the respective enantiomerically enriched or enantiomerically enriched ( S ) -configuration or any mixture of epimers at such centers.
II.生物分析 可進一步表徵本發明化合物：關於其整體藥物動力學及藥理學特性，使用此項技術中熟知之習知分析，例如關於其在不同物種(諸如大鼠或狗)中之生物利用度；或針對其關於藥物安全性及/或毒理學特性之特性，使用此項技術中熟知之習知分析，例如關於細胞色素P450酶抑制及時間依賴性抑制、孕烷X受體(pregnane X receptor；PXR)活化、麩胱甘肽結合或光毒性行為。
II. Bioassays The compounds of the invention can be further characterized: with respect to their overall pharmacokinetic and pharmacological properties, using conventional assays well known in the art, for example with respect to their bioavailability in different species such as rats or dogs or for its characterization with respect to drug safety and/or toxicological properties, using conventional assays well known in the art, such as for cytochrome P450 enzyme inhibition and time-dependent inhibition, pregnane X receptor (pregnane X receptor) X receptor; PXR) activation, glutathione binding or phototoxic behavior.
生物活體外分析biological in vitro analysis
化合物EC
50及E
max值之評估 根據以下實驗方法測定式(I)化合物對於CFTR之校正劑活性。該方法量測隔夜化合物培育對於重組U2OS細胞株(DiscoveRx，#93-0987C3)中之F508del-CFTR細胞表面表現之影響。此細胞株經工程改造以共表現(i)用Prolink (PK)(PK =短β-半乳糖片段)標記之人類F508del-CFTR及(ii)定位於質膜之剩餘物β-半乳糖酶(酶受體；EA)。與增加質膜處之PK標記之F508del-CFTR之化合物一起培育將導致EA片段互補而形成功能性β-半乳糖酶，其藉由化學螢光反應定量。
Evaluation of Compound EC50 and Emax Values The calibrator activity of the compounds of formula (I) towards CFTR was determined according to the following experimental method. This method measures the effect of overnight compound incubation on the cell surface expression of F508del-CFTR in a recombinant U2OS cell line (DiscoveRx, #93-0987C3). This cell line was engineered to co-express (i) human F508del-CFTR tagged with Prolink (PK) (PK = short β-galactose fragment) and (ii) the plasma membrane localized remnant β-galactosidase ( Enzyme receptor; EA). Incubation with compounds that increase the PK-tagged F508del-CFTR at the plasma membrane will result in complementation of the EA fragment to form a functional β-galactosidase, which is quantified by chemiluminescent reaction.
簡言之，以3500個細胞/孔將細胞接種至384孔低容積培養盤(Corning，#3826)中之20 µl完全培養基(Mc Coy's 5a (#36600-021，Gibco) + 10% FBS Gibco + 青黴素/鏈黴素)中。在培育箱中培育細胞5 h，之後添加5 µl/孔之化合物稀釋系列(於完全培養基中之5×工作儲備液)。分析中之最終DMSO濃度為0.25%。將細胞與化合物一起在培育箱中在37℃、5% CO
2下共培育16 h。次日，在室溫於暗處培育細胞培養盤2 h。接著，添加10 µl每孔之快速偵測試劑(DiscoverX，#93-0247)，在室溫於暗處另外培育培養盤30 min，且量測化學發光。使用呈上部平線區之化合物固有最大功效產生濃度反應曲線，且根據此等CRC，測定化合物固有EC
50值。計算相對於校正劑魯瑪卡托之E
max之化合物特定E
max值(E
maxlumacaftor = 100%)。
Briefly, cells were plated at 3500 cells/well in 20 µl complete medium (Mc Coy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin/streptomycin). Cells were incubated in the incubator for 5 h, after which 5 µl/well of the compound dilution series (5× working stock in complete medium) was added. The final DMSO concentration in the assay was 0.25%. The cells were co-incubated with the compounds for 16 h in an incubator at 37°C, 5% CO 2 . The next day, the cell culture plates were incubated for 2 h at room temperature in the dark. Next, 10 µl per well of Rapid Detection Reagent (DiscoverX, #93-0247) was added, the plates were incubated for an additional 30 min at room temperature in the dark, and chemiluminescence was measured. Concentration response curves were generated using the compound's intrinsic maximal potency in the upper flat region, and from these CRCs, compound intrinsic EC50 values were determined. Compound-specific Emax values were calculated relative to the Emax of the calibrator lumacaftor ( Emax lumacaftor = 100%).
所計算之IC
50值可視日常分析效能而波動。此類波動為熟習此項技術者已知。來自若干量測之EC
50值以幾何平均值給出。所計算之E
max值可視日常分析效能而波動。此類波動為熟習此項技術者已知。來自若干量測之E
max值以算術平均值給出。
The calculated IC50 values may fluctuate depending on the performance of routine assays. Such fluctuations are known to those skilled in the art. EC50 values from several measurements are given as geometric means. The calculated E max value may fluctuate depending on daily analytical performance. Such fluctuations are known to those skilled in the art. E max values from several measurements are given as arithmetic mean.
參考文獻 Elborn JS. (2016) Cystic fibrosis. Lancet 388:2519-2531。Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991) Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 354: 526-8。
生物資料之表：
實例 EC
50 [nmol/l] Emax [%]
1
56
105
2
110
150
3
816
151
4
673
195
5
369
109
6
420
112
7
398
118
8
887
210
9
360
130
10
82
123
11
182
132
12
270
184
13
268
153
14
160
185
15
187
240
16
269
137
17
466
180
18
388
117
19
743
125
20
721
102
21
350
108
22
600
104
23
991
115
24
823
131
25
547
142
26
299
111
27
474
114
28
603
106
29
439
140
30
275
113
31
463
111
32
318
146
33
255
141
34
260
121
35
262
109
36
306
120
37
122
205
38
299
191
39
415
450
40
897
147
41
280
215
42
353
419
43
862
137
44
571
247
45
682
324
46
679
137
47
213
247
48
409
151
49
347
136
50
558
256
51
352
187
52
348
176
53
596
404
54
558
373
55
945
245
56
764
256
57
414
315
58
759
175
59
772
237
60
662
228
61
421
202
62
809
222
63
418
250
64
441
143
65
647
282
66
587
169
67
615
236
68
448
331
69
454
262
70
754
202
71
338
326
72
142
335
73
214
253
74
128
271
75
255
191
76
196
283
77
231
237
78
544
277
79
327
296
80
170
308
81
233
232
82
598
246
83
731
309
84
274
299
85
260
244
86
314
157
87
162
190
88
230
112
89
132
262
90
364
129
91
466
210
92
289
256
93
777
189
94
257
201
95
250
178
96
425
206
97
146
285
98
311
326
99
205
254
100
184
273
101
201
163
102
225
332
103
499
256
104
211
204
105
173
351
106
864
308
107
794
257
108
581
222
109
231
321
110
478
261
111
392
242
112
817
200
113
369
158
114
924
220
115
380
250
116
554
253
117
776
237
118
329
265
119
328
248
120
331
212
121
615
354
122
324
292
123
873
280
124
382
347
125
271
229
126
261
230
127
107
311
128
190
292
129
406
264
130
1000
264
131
127
320
132
110
313
133
149
213
134
506
150
135
177
255
136
270
271
137
254
311
138
538
292
139
463
381
140
142
318
141
313
331
142
194
381
143
922
320
144
211
327
145
309
107
146
247
318
147
270
339
148
811
198
149
191
259
150
151
130
151
759
106
152
668
133
153
460
115
154
398
102
155
260
144
156
647
123
157
395
121
158
315
169
159
385
100
160
224
116
161
250
137
162
472
132
163
377
185
164
519
167
165
287
149
166
624
111
167
822
238
168
338
193
169
334
170
170
329
267
171
144
301
172
324
213
173
455
212
174
954
194
175
229
179
176
821
245
177
647
248
178
680
237
179
731
251
180
388
257
181
718
251
182
406
270
183
621
237
184
410
205
185
379
275
186
644
209
187
645
267
188
586
275
189
453
270
190
334
310
191
474
295
192
316
107
193
521
118
194
613
178
195
889
202
196
425
106
197
579
132
198
195
243
199
230
214
200
210
270
201
222
109
202
187
160
203
183
134
204
198
173
205
175
229
206
272
164
207
317
138
208
277
188
209
392
118
210
352
108
211
309
146
212
292
130
213
292
100
214
292
221
215
214
172
216
420
102
217
202
135
218
353
143
219
206
182
220
258
103
221
833
229
222
216
249
223
388
141
224
340
144
225
191
110
226
520
213
227
290
103
228
460
190
229
279
117
230
482
103
231
592
173
232
526
105
233
610
92
234
471
110
235
825
117
236
435
126
237
300
128
238
375
153
239
514
142
240
1260
77
241
1660
92
242
177
232
243
181
232
244
177
239
245
260
174
246
140
105
247
146
111
248
106
191
249
116
175
250
86
160
251
83
159
252
888
111
253
88
136
254
102
152
255
183
299
256
147
319
257
249
116
258
424
117
259
428
136
260
783
243
261
327
215
262
339
231
263
448
140
264
442
117
265
266
106
266
357
136
267
107
275
268
100
273
269
350
251
270
423
172
271
266
185
272
374
176
273
365
169
274
288
186
275
148
333
276
91
333
277
830
134
278
709
167
279
643
112
280
297
188
281
110
361
282
114
360
283
272
231
284
337
136
285
239
118
286
177
144
287
207
154
288
147
175
289
186
160
290
188
260
291
109
210
292
114
191
293
340
137
294
265
138
295
202
174
296
158
144
297
193
225
298
220
186
299
109
136
300
103
210
301
112
202
302
106
193
303
180
275
304
581
193
305
533
123
306
923
139
307
423
113
308
469
103
309
456
113
310
788
202
311
454
127
312
727
111
313
313
119
314
469
111
315
115
349
316
55
343
317
661
89
318
679
295
319
574
296
320
363
297
321
816
266
322
504
197
323
742
258
324
666
247
325
187
237
326
276
273
327
461
225
328
987
228
329
796
198
330
418
138
331
121
240
332
309
183
333
345
182
334
323
232
335
270
262
336
207
212
337
452
116
338
292
173
339
195
237
340
278
139
341
144
237
342
464
128
343
332
270
344
126
284
345
95
268
346
106
282
347
131
282
348
340
155
349
597
258
350
546
299
351
756
127
352
297
262
353
513
177
354
231
321
355
87
307
356
167
353
357
475
124
358
411
171
359
318
144
360
184
224
361
264
183
362
153
247
363
252
230
364
264
201
365
398
387
366
265
172
367
249
321
368
918
147
369
107
243
370
388
229
371
226
180
372
72
360
373
200
149
374
102
333
375
461
316
376
156
284
377
704
111
378
45
138
379
76
312
380
65
325
381
68
322
382
44
264
383
65
317
384
54
282
385
191
326
386
393
149
387
342
215
388
310
163
389
115
320
390
269
188
391
70
319
392
327
144
393
118
314
394
262
151
395
110
316
396
241
190
397
262
207
398
125
280
399
506
146
400
164
292
401
559
189
402
305
314
403
550
179
404
157
254
405
343
171
406
409
173
407
684
123
408
241
134
409
214
144
410
129
269
411
138
250
412
377
291
413
557
129
414
372
251
415
840
274
416
526
345
417
437
343
418
276
259
419
358
243
420
437
231
421
391
320
422
192
193
423
278
239
424
831
235
425
348
364
426
269
217
427
248
274
428
614
218
429
606
224
430
964
194
431
208
281
432
474
413
433
167
344
434
664
327
435
895
119
436
458
300
437
844
159
438
474
422
439
253
345
440
788
296
441
815
326
442
443
154
443
316
275
444
1050
199
445
958
194
446
900
248
447
447
220
448
961
109
449
543
165
450
379
107
451
257
307
452
886
292
453
417
251
454
234
236
455
677
211
456
250
185
457
326
144
458
209
238
459
726
390
460
310
398
461
444
262
462
345
130
463
278
269
464
319
109
465
800
387
466
548
328
467
936
152
468
504
361
469
381
110
470
662
169
471
981
278
472
284
239
473
585
119
474
478
359
475
992
314
476
333
344
477
754
327
478
168
337
479
480
253
480
201
276
481
448
225
482
414
247
483
517
311
484
251
117
485
238
204
486
201
303
487
1340
147
488
910
270
489
625
273
490
222
181
491
209
178
492
305
168
493
687
253
494
260
295
495
296
207
496
523
317
497
535
171
498
198
313
499
189
321
500
553
199
501
198
308
502
752
295
503
772
137
504
149
298
505
229
330
506
318
211
507
469
337
508
382
378
509
75
327
510
108
256
511
624
314
512
300
316
513
815
169
514
170
304
515
518
140
516
494
155
517
986
222
518
655
189
519
184
332
520
345
155
521
433
191
522
204
237
523
483
352
524
60
339
525
56
288
526
394
167
527
151
318
528
321
337
529
947
206
530
334
353
531
265
336
532
397
375
533
221
352
534
273
394
535
407
424
536
175
358
537
384
294
538
80
340
539
95
391
540
269
256
541
185
357
542
368
334
543
785
399
544
774
398
545
349
385
546
350
411
547
281
330
548
106
326
549
166
167
550
687
129
551
222
317
552
413
358
553
287
304
554
324
310
555
219
309
556
327
322
557
594
253
558
167
355
559
155
236
560
114
249
561
437
215
562
444
282
563
125
330
564
49
298
565
338
254
566
703
278
567
384
307
568
391
238
569
108
270
570
374
323
571
47
347
572
701
200
573
423
306
574
308
319
575
411
273
576
523
268
577
600
268
578
53
319
579
399
131
580
198
319
581
300
303
582
116
279
583
339
90
584
575
156
585
176
168
586
221
165
587
414
106
588
650
102
589
298
160
590
362
201
591
341
259
592
881
119
593
614
190
594
810
171
595
332
233
596
167
195
597
168
211
598
759
312
599
151
299
600
97
286
601
589
138
602
286
299
603
205
301
604
354
103
605
637
257
606
521
150
607
121
283
608
804
267
609
574
320
610
89
311
611
344
251
612
148
298
613
82
312
614
484
317
615
465
170
616
581
92
617
75
318
618
80
309
619
155
322
620
316
266
621
339
288
622
199
296
623
248
349
624
921
171
625
781
186
626
163
253
627
786
395
628
363
355
629
521
215
630
261
175
631
898
133
632
927
326
633
652
316
634
173
178
635
404
112
636
91
276
637
106
300
638
182
297
639
173
305
640
132
339
641
87
305
642
168
366
643
220
270
644
277
270
645
289
211
646
158
201
647
820
182
648
748
159
649
908
149
650
596
214
651
375
127
652
593
155
653
332
140
654
290
330
655
150
318
656
357
327
657
347
291
658
283
300
659
359
325
660
91
358
661
421
247
662
124
297
663
801
210
664
231
291
665
119
323
666
484
311
667
764
149
668
160
330
669
856
230
670
353
167
671
235
179
672
103
312
673
67
314
674
262
133
675
194
159
676
62
267
677
37
283
678
355
296
679
869
277
680
448
340
681
447
313
682
110
351
683
362
262
684
986
235
685
500
234
686
436
332
687
794
107
688
458
104
689
245
390
690
478
401
691
201
364
692
104
301
693
40
401
694
241
213
695
201
237
696
14
252
697
27
306
698
199
313
699
299
338
700
188
186
701
165
268
702
295
162
703
316
167
704
398
156
705
305
193
706
707
162
707
502
305
708
874
195
709
47
284
710
149
280
711
778
301
712
187
211
713
31
432
714
36
410
715
64
283
716
144
313
717
69
348
718
359
272
719
124
313
720
881
244
721
142
328
722
101
347
723
512
160
724
93
345
725
1370
200
726
624
234
727
5050
138
728
235
232
729
100
258
730
593
248
731
381
248
732
64
239
733
349
235
734
299
325
735
314
176
736
153
286
737
665
298
738
110
256
739
101
297
740
111
280
741
116
294
742
214
246
743
207
217
744
178
239
745
693
206
746
211
213
747
234
213
748
529
295
749
153
301
750
784
267
751
217
213
752
706
200
753
430
264
754
219
279
755
168
270
756
311
252
757
145
280
758
334
266
759
296
131
760
723
333
761
676
202
762
929
333
763
264
181
764
374
315
765
300
323
766
154
393
767
212
390
768
497
292
769
140
346
770
1001
228
771
597
299
772
514
343
773
841
339
774
751
345
775
875
359
776
325
360
777
875
216
778
141
302
779
811
213
780
116
280
781
124
296
782
859
439
783
889
410
784
311
391
785
210
365
786
156
337
787
190
323
788
549
344
789
675
358
790
650
350
791
80
345
792
628
261
793
235
105
794
83
354
795
141
384
796
156
321
797
399
308
798
197
324
799
258
335
800
266
352
801
149
330
802
723
200
803
248
355
804
115
360
805
191
276
806
233
394
807
206
358
808
116
399
809
10
391
810
161
285
811
19
333
812
127
280
813
110
346
814
631
242
815
128
413
816
741
286
817
420
375
818
385
359
819
276
431
820
49
461
821
200
392
822
131
363
823
241
366
824
674
354
825
353
388
826
283
340
827
54
379
828
299
317
829
142
320
830 1040
310
831 491
231
832 518
367
833 615
411
834 240
300
835 363
326
836 967
257
837 198
358
838 118
358
839 123
336
840 128
363
841 120
271
842 495
305
843 114
368
844 1040
356
845 453
308
846 165
261
847 186
340
848 225
364
849 46
465
850 1150
224
851 148
310
852 163
249
853 92
322
854 136
326
855 80
341
856 35
357
857 407
337
858 95
308
859 36
342
860 578
288
861 722
384
862 921
335
863 587
326
864 617
385
865 103
356
866 337
324
867 31
413
868 18
397
869 358
305
870 201
316
871 32
378
872 535
318
873 41
336
874 66
332
875 21
333
876 113
317
877 186
361
878 27
336
879 63
360
880 59
359
881 309
337
882 473
367
883 111
344
884 96
385
885 78
328
886 15
359
887 111
340
888 170
410
889 34
403
890 34
409
891 1490
402
892 467
442
893 216
394
894 339
431
895 136
409
896 188
427
897 32
454
898 22
440
899 819
294
900 831
374
901 736
390
902 55
453
903 51
414
904 722
365
905 311
415
906 294
433
907 425
454
908 94
401
909 17
430
910 477
423
911 531
341
912 272
332
913 294
390
914 368
358
915 334
361
916 196
470
917 487
398
918 42
462
919 104
443
920 175
380
921 231
393
922 302
396
923 26
500
924 33
409
925 92
286
926 759
416
927 27
492
928 971
247
929 306
513
930 142
460
931 298
507
932 373
491
933 399
485
934 37
528
935 24
496
936 26
469
937 59
460
938 245
498
939 737
288
940 673
298
941 135
459
942 194
460
943 240
471
944 77
336
945 33
502
946 447
404
947 281
458
948 61
501
949 113
518
950 201
464
951 165
405
952 339
438
953 268
394
954 382
383
955 381
394
956 508
412
957 192
451
958 338
439
959 222
413
960 85
507
961 353
453
962 103
453
963 267
447
964 21
418
965 32
453
966 82
404
967 92
472
968 226
478
969 142
452
970 109
463
971 163
482
972 128
436
973 117
446
974 703
440
975 119
497
976 179
348
977 281
410
978 129
457
979 209
394
980 53
435
981 133
448
982 236
530
983 270
506
References Elborn JS. (2016) Cystic fibrosis. Lancet 388:2519-2531. Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991) Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 354: 526 -8.
Biological data table:
example EC50 [nmol/l] Emax [%]
1 56 105
2 110 150
3 816 151
4 673 195
5 369 109
6 420 112
7 398 118
8 887 210
9 360 130
10 82 123
11 182 132
12 270 184
13 268 153
14 160 185
15 187 240
16 269 137
17 466 180
18 388 117
19 743 125
20 721 102
twenty one 350 108
twenty two 600 104
twenty three 991 115
twenty four 823 131
25 547 142
26 299 111
27 474 114
28 603 106
29 439 140
30 275 113
31 463 111
32 318 146
33 255 141
34 260 121
35 262 109
36 306 120
37 122 205
38 299 191
39 415 450
40 897 147
41 280 215
42 353 419
43 862 137
44 571 247
45 682 324
46 679 137
47 213 247
48 409 151
49 347 136
50 558 256
51 352 187
52 348 176
53 596 404
54 558 373
55 945 245
56 764 256
57 414 315
58 759 175
59 772 237
60 662 228
61 421 202
62 809 222
63 418 250
64 441 143
65 647 282
66 587 169
67 615 236
68 448 331
69 454 262
70 754 202
71 338 326
72 142 335
73 214 253
74 128 271
75 255 191
76 196 283
77 231 237
78 544 277
79 327 296
80 170 308
81 233 232
82 598 246
83 731 309
84 274 299
85 260 244
86 314 157
87 162 190
88 230 112
89 132 262
90 364 129
91 466 210
92 289 256
93 777 189
94 257 201
95 250 178
96 425 206
97 146 285
98 311 326
99 205 254
100 184 273
101 201 163
102 225 332
103 499 256
104 211 204
105 173 351
106 864 308
107 794 257
108 581 222
109 231 321
110 478 261
111 392 242
112 817 200
113 369 158
114 924 220
115 380 250
116 554 253
117 776 237
118 329 265
119 328 248
120 331 212
121 615 354
122 324 292
123 873 280
124 382 347
125 271 229
126 261 230
127 107 311
128 190 292
129 406 264
130 1000 264
131 127 320
132 110 313
133 149 213
134 506 150
135 177 255
136 270 271
137 254 311
138 538 292
139 463 381
140 142 318
141 313 331
142 194 381
143 922 320
144 211 327
145 309 107
146 247 318
147 270 339
148 811 198
149 191 259
150 151 130
151 759 106
152 668 133
153 460 115
154 398 102
155 260 144
156 647 123
157 395 121
158 315 169
159 385 100
160 224 116
161 250 137
162 472 132
163 377 185
164 519 167
165 287 149
166 624 111
167 822 238
168 338 193
169 334 170
170 329 267
171 144 301
172 324 213
173 455 212
174 954 194
175 229 179
176 821 245
177 647 248
178 680 237
179 731 251
180 388 257
181 718 251
182 406 270
183 621 237
184 410 205
185 379 275
186 644 209
187 645 267
188 586 275
189 453 270
190 334 310
191 474 295
192 316 107
193 521 118
194 613 178
195 889 202
196 425 106
197 579 132
198 195 243
199 230 214
200 210 270
201 222 109
202 187 160
203 183 134
204 198 173
205 175 229
206 272 164
207 317 138
208 277 188
209 392 118
210 352 108
211 309 146
212 292 130
213 292 100
214 292 221
215 214 172
216 420 102
217 202 135
218 353 143
219 206 182
220 258 103
221 833 229
222 216 249
223 388 141
224 340 144
225 191 110
226 520 213
227 290 103
228 460 190
229 279 117
230 482 103
231 592 173
232 526 105
233 610 92
234 471 110
235 825 117
236 435 126
237 300 128
238 375 153
239 514 142
240 1260 77
241 1660 92
242 177 232
243 181 232
244 177 239
245 260 174
246 140 105
247 146 111
248 106 191
249 116 175
250 86 160
251 83 159
252 888 111
253 88 136
254 102 152
255 183 299
256 147 319
257 249 116
258 424 117
259 428 136
260 783 243
261 327 215
262 339 231
263 448 140
264 442 117
265 266 106
266 357 136
267 107 275
268 100 273
269 350 251
270 423 172
271 266 185
272 374 176
273 365 169
274 288 186
275 148 333
276 91 333
277 830 134
278 709 167
279 643 112
280 297 188
281 110 361
282 114 360
283 272 231
284 337 136
285 239 118
286 177 144
287 207 154
288 147 175
289 186 160
290 188 260
291 109 210
292 114 191
293 340 137
294 265 138
295 202 174
296 158 144
297 193 225
298 220 186
299 109 136
300 103 210
301 112 202
302 106 193
303 180 275
304 581 193
305 533 123
306 923 139
307 423 113
308 469 103
309 456 113
310 788 202
311 454 127
312 727 111
313 313 119
314 469 111
315 115 349
316 55 343
317 661 89
318 679 295
319 574 296
320 363 297
321 816 266
322 504 197
323 742 258
324 666 247
325 187 237
326 276 273
327 461 225
328 987 228
329 796 198
330 418 138
331 121 240
332 309 183
333 345 182
334 323 232
335 270 262
336 207 212
337 452 116
338 292 173
339 195 237
340 278 139
341 144 237
342 464 128
343 332 270
344 126 284
345 95 268
346 106 282
347 131 282
348 340 155
349 597 258
350 546 299
351 756 127
352 297 262
353 513 177
354 231 321
355 87 307
356 167 353
357 475 124
358 411 171
359 318 144
360 184 224
361 264 183
362 153 247
363 252 230
364 264 201
365 398 387
366 265 172
367 249 321
368 918 147
369 107 243
370 388 229
371 226 180
372 72 360
373 200 149
374 102 333
375 461 316
376 156 284
377 704 111
378 45 138
379 76 312
380 65 325
381 68 322
382 44 264
383 65 317
384 54 282
385 191 326
386 393 149
387 342 215
388 310 163
389 115 320
390 269 188
391 70 319
392 327 144
393 118 314
394 262 151
395 110 316
396 241 190
397 262 207
398 125 280
399 506 146
400 164 292
401 559 189
402 305 314
403 550 179
404 157 254
405 343 171
406 409 173
407 684 123
408 241 134
409 214 144
410 129 269
411 138 250
412 377 291
413 557 129
414 372 251
415 840 274
416 526 345
417 437 343
418 276 259
419 358 243
420 437 231
421 391 320
422 192 193
423 278 239
424 831 235
425 348 364
426 269 217
427 248 274
428 614 218
429 606 224
430 964 194
431 208 281
432 474 413
433 167 344
434 664 327
435 895 119
436 458 300
437 844 159
438 474 422
439 253 345
440 788 296
441 815 326
442 443 154
443 316 275
444 1050 199
445 958 194
446 900 248
447 447 220
448 961 109
449 543 165
450 379 107
451 257 307
452 886 292
453 417 251
454 234 236
455 677 211
456 250 185
457 326 144
458 209 238
459 726 390
460 310 398
461 444 262
462 345 130
463 278 269
464 319 109
465 800 387
466 548 328
467 936 152
468 504 361
469 381 110
470 662 169
471 981 278
472 284 239
473 585 119
474 478 359
475 992 314
476 333 344
477 754 327
478 168 337
479 480 253
480 201 276
481 448 225
482 414 247
483 517 311
484 251 117
485 238 204
486 201 303
487 1340 147
488 910 270
489 625 273
490 222 181
491 209 178
492 305 168
493 687 253
494 260 295
495 296 207
496 523 317
497 535 171
498 198 313
499 189 321
500 553 199
501 198 308
502 752 295
503 772 137
504 149 298
505 229 330
506 318 211
507 469 337
508 382 378
509 75 327
510 108 256
511 624 314
512 300 316
513 815 169
514 170 304
515 518 140
516 494 155
517 986 222
518 655 189
519 184 332
520 345 155
521 433 191
522 204 237
523 483 352
524 60 339
525 56 288
526 394 167
527 151 318
528 321 337
529 947 206
530 334 353
531 265 336
532 397 375
533 221 352
534 273 394
535 407 424
536 175 358
537 384 294
538 80 340
539 95 391
540 269 256
541 185 357
542 368 334
543 785 399
544 774 398
545 349 385
546 350 411
547 281 330
548 106 326
549 166 167
550 687 129
551 222 317
552 413 358
553 287 304
554 324 310
555 219 309
556 327 322
557 594 253
558 167 355
559 155 236
560 114 249
561 437 215
562 444 282
563 125 330
564 49 298
565 338 254
566 703 278
567 384 307
568 391 238
569 108 270
570 374 323
571 47 347
572 701 200
573 423 306
574 308 319
575 411 273
576 523 268
577 600 268
578 53 319
579 399 131
580 198 319
581 300 303
582 116 279
583 339 90
584 575 156
585 176 168
586 221 165
587 414 106
588 650 102
589 298 160
590 362 201
591 341 259
592 881 119
593 614 190
594 810 171
595 332 233
596 167 195
597 168 211
598 759 312
599 151 299
600 97 286
601 589 138
602 286 299
603 205 301
604 354 103
605 637 257
606 521 150
607 121 283
608 804 267
609 574 320
610 89 311
611 344 251
612 148 298
613 82 312
614 484 317
615 465 170
616 581 92
617 75 318
618 80 309
619 155 322
620 316 266
621 339 288
622 199 296
623 248 349
624 921 171
625 781 186
626 163 253
627 786 395
628 363 355
629 521 215
630 261 175
631 898 133
632 927 326
633 652 316
634 173 178
635 404 112
636 91 276
637 106 300
638 182 297
639 173 305
640 132 339
641 87 305
642 168 366
643 220 270
644 277 270
645 289 211
646 158 201
647 820 182
648 748 159
649 908 149
650 596 214
651 375 127
652 593 155
653 332 140
654 290 330
655 150 318
656 357 327
657 347 291
658 283 300
659 359 325
660 91 358
661 421 247
662 124 297
663 801 210
664 231 291
665 119 323
666 484 311
667 764 149
668 160 330
669 856 230
670 353 167
671 235 179
672 103 312
673 67 314
674 262 133
675 194 159
676 62 267
677 37 283
678 355 296
679 869 277
680 448 340
681 447 313
682 110 351
683 362 262
684 986 235
685 500 234
686 436 332
687 794 107
688 458 104
689 245 390
690 478 401
691 201 364
692 104 301
693 40 401
694 241 213
695 201 237
696 14 252
697 27 306
698 199 313
699 299 338
700 188 186
701 165 268
702 295 162
703 316 167
704 398 156
705 305 193
706 707 162
707 502 305
708 874 195
709 47 284
710 149 280
711 778 301
712 187 211
713 31 432
714 36 410
715 64 283
716 144 313
717 69 348
718 359 272
719 124 313
720 881 244
721 142 328
722 101 347
723 512 160
724 93 345
725 1370 200
726 624 234
727 5050 138
728 235 232
729 100 258
730 593 248
731 381 248
732 64 239
733 349 235
734 299 325
735 314 176
736 153 286
737 665 298
738 110 256
739 101 297
740 111 280
741 116 294
742 214 246
743 207 217
744 178 239
745 693 206
746 211 213
747 234 213
748 529 295
749 153 301
750 784 267
751 217 213
752 706 200
753 430 264
754 219 279
755 168 270
756 311 252
757 145 280
758 334 266
759 296 131
760 723 333
761 676 202
762 929 333
763 264 181
764 374 315
765 300 323
766 154 393
767 212 390
768 497 292
769 140 346
770 1001 228
771 597 299
772 514 343
773 841 339
774 751 345
775 875 359
776 325 360
777 875 216
778 141 302
779 811 213
780 116 280
781 124 296
782 859 439
783 889 410
784 311 391
785 210 365
786 156 337
787 190 323
788 549 344
789 675 358
790 650 350
791 80 345
792 628 261
793 235 105
794 83 354
795 141 384
796 156 321
797 399 308
798 197 324
799 258 335
800 266 352
801 149 330
802 723 200
803 248 355
804 115 360
805 191 276
806 233 394
807 206 358
808 116 399
809 10 391
810 161 285
811 19 333
812 127 280
813 110 346
814 631 242
815 128 413
816 741 286
817 420 375
818 385 359
819 276 431
820 49 461
821 200 392
822 131 363
823 241 366
824 674 354
825 353 388
826 283 340
827 54 379
828 299 317
829 142 320
830 1040 310
831 491 231
832 518 367
833 615 411
834 240 300
835 363 326
836 967 257
837 198 358
838 118 358
839 123 336
840 128 363
841 120 271
842 495 305
843 114 368
844 1040 356
845 453 308
846 165 261
847 186 340
848 225 364
849 46 465
850 1150 224
851 148 310
852 163 249
853 92 322
854 136 326
855 80 341
856 35 357
857 407 337
858 95 308
859 36 342
860 578 288
861 722 384
862 921 335
863 587 326
864 617 385
865 103 356
866 337 324
867 31 413
868 18 397
869 358 305
870 201 316
871 32 378
872 535 318
873 41 336
874 66 332
875 twenty one 333
876 113 317
877 186 361
878 27 336
879 63 360
880 59 359
881 309 337
882 473 367
883 111 344
884 96 385
885 78 328
886 15 359
887 111 340
888 170 410
889 34 403
890 34 409
891 1490 402
892 467 442
893 216 394
894 339 431
895 136 409
896 188 427
897 32 454
898 twenty two 440
899 819 294
900 831 374
901 736 390
902 55 453
903 51 414
904 722 365
905 311 415
906 294 433
907 425 454
908 94 401
909 17 430
910 477 423
911 531 341
912 272 332
913 294 390
914 368 358
915 334 361
916 196 470
917 487 398
918 42 462
919 104 443
920 175 380
921 231 393
922 302 396
923 26 500
924 33 409
925 92 286
926 759 416
927 27 492
928 971 247
929 306 513
930 142 460
931 298 507
932 373 491
933 399 485
934 37 528
935 twenty four 496
936 26 469
937 59 460
938 245 498
939 737 288
940 673 298
941 135 459
942 194 460
943 240 471
944 77 336
945 33 502
946 447 404
947 281 458
948 61 501
949 113 518
950 201 464
951 165 405
952 339 438
953 268 394
954 382 383
955 381 394
956 508 412
957 192 451
958 338 439
959 222 413
960 85 507
961 353 453
962 103 453
963 267 447
964 twenty one 418
965 32 453
966 82 404
967 92 472
968 226 478
969 142 452
970 109 463
971 163 482
972 128 436
973 117 446
974 703 440
975 119 497
976 179 348
977 281 410
978 129 457
979 209 394
980 53 435
981 133 448
982 236 530
983 270 506
參考化合物 1：
阿比西丁 (Apicidin)係購自Sigma-Aldrich且在上文DiscoveRx分析中在相同條件下評估；化合物顯示EC
50：＞20000 nmol/l。
Reference compound 1 : Apicidin was purchased from Sigma-Aldrich and evaluated in the above DiscoveRx assay under the same conditions; compound showed EC50 : >20000 nmol/l.
