TWI429450B - 丙型肝炎病毒蛋白酶抑制劑 - Google Patents
丙型肝炎病毒蛋白酶抑制劑 Download PDFInfo
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- TWI429450B TWI429450B TW98131053A TW98131053A TWI429450B TW I429450 B TWI429450 B TW I429450B TW 98131053 A TW98131053 A TW 98131053A TW 98131053 A TW98131053 A TW 98131053A TW I429450 B TWI429450 B TW I429450B
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- Prior art keywords
- compound
- aryl
- heteroaryl
- alkyl
- heterocycloalkyl
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- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 293
- 125000003118 aryl group Chemical group 0.000 claims description 79
- 125000001072 heteroaryl group Chemical group 0.000 claims description 77
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 59
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- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係有關於丙型肝炎病毒蛋白酶抑制劑。
丙型肝炎病毒(HCV)是一種(+)有義的單鏈RNA病毒((+)-sense single-stranded RNA)，也是主要引起非甲型、非乙型肝炎的致病因數。HCV感染是威脅人類健康的問題。例如參見WO 05/007681；WO 89/04669；EP 381216；Alberti等人的J. Hepatology,31(增刊1),17-24(1999)；Alter,J. Hepatology,31(增刊1),88-91(1999)；以及Lavanchy,J. Viral肝炎,6,35-47(1999)。
由HCV感染引起的肝炎因為病毒快速突變和避開固有的免疫反應而很難治療。目前僅有的抗-HCV治療劑是幹擾素-α，幹擾素-α/病毒唑組合，以及PEG化的(pegylated)幹擾素-α。但是，發現幹擾素-α或幹擾素-α/病毒唑組合的持續響應率<50%，而且病人會很大程度地受到這些治療劑的副反應影響。例如參見Walker,DDT,4,518-529(1999);Weiland,FEMS Microbial. Rev.,14,279-288(1994)；以及WO 02/18369。因此，人們仍然需要開發更有效、更易接受的抗HCV藥物。
病毒複製所需的HCV蛋白酶包含約3000個氨基酸。它包括核殼體蛋白(C)、包膜蛋白(E1和E2)、以及一些非結構蛋白(NS2,NS3,NS4a,NS5a和NS5b)。
NS3蛋白具有絲氨酸蛋白酶活性，被認為是病毒複製和感染所必需。這一點通過黃熱病毒NS3蛋白酶的變異降低病毒感染性、以及HCV NS3蛋白酶活性位點的變異完全抑制了黑猩猩模型中的HCV感染這些現象得以證明。例如參見Chamber等人的Proc. Natl. Acad. Sci. USA 87,8898-8902(1990)以及Rice等人的J. Virol. 74(4) 2046-51(2000)。另外，發現所述HCV NS3蛋白酶能夠在NS3/NS4a,NS4a/NS4b,NS4b/NS5a,NS5a/NS5b連接點促進蛋白質水解。因此認為HCV NS3絲氨酸蛋白酶對於病毒複製過程中四種病毒蛋白質的產生有關。例如參見US 2003/0207861。因此，所述HCV NS3蛋白酶是用來治療HCV感染的一個吸引人的靶標。可能的NS3 HCV蛋白酶抑制劑可以在以下文獻中找到：WO 02/18369,WO 00/09558,WO 00/09543,WO 99/64442,WO 99/07733,WO 99/07734,WO 99/50230,WO 98/46630,WO 98/17679,WO 97/43310,US 5,990,276,Dunsdon等人的,Biorg. Med. Chem. Lett. 10,1571-1579(2000)；Llinas-Brunet等人的Biorg. Med. Chem. Lett. 10,2267-2270(2000)；以及S. LaPlante等人的Biorg. Med. Chem. Lett. 10,2271-2274(2000)。
本發明是基於以下出人意料的發現，即某些大環化合物能夠阻斷NS3-4A蛋白酶活性，降低HCV RNA水準，抑制對其他抑制劑耐受的HCV蛋白酶突變體，並且在血循環中的半衰期延長。
在一個方面，本發明涉及下面式(I)的化合物：
其中，R1
是-H、-OH、C1-6
烷基、C1-6
烷氧基、C3-10
環烷基、C1-10
雜環烷基、芳基、雜芳基、-Z-R或-NH-Z-R；其中R是H，或者是選自以下的部分：C1-6
烷基、C3-10
環烷基、C1-10
雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、芳基或雜芳基；Z是-C(O)-、-C(O) O-、-C(O) C(O) O-、-C(O) C(O) NH-、-C(O) NR’-、-OC(S)-、-C(S) NR’-或-C(NH) O-，R，是H、C1-6
烷基、C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基；R2
是H，或者是選自以下的部分：C1-6
烷基、C3-10
環烷基、C1-10
雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、芳基或雜芳基；A是N或CH；U是-O-、-NH-、-NH(CO)-、-NHS(O)-或-NHSO2
-；W是-(CH2
)m
-、-NH(CH2
)n
-、-(CH2
)n
NH-、-O(CH2
)n
-、-(CH2
)n
O-、-S(CH2
)n
-、-(CH2
)n
S-、-S(O)-、-SO(CH2
)n
-、-(CH2
)n
S(O)-、-SO2
(CH2
)n
-或-(CH2
)n
SO2
-，m是1,2或3，n是0,1或2；X是-O-、-S-、-NH-或-OCH2
-；Y是或，其中，V和T各自獨立地是-CH-或-N-；A1
和A2
各自獨立地是選自以下的部分：C4-10
環烷基、C1-10
雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、芳基或雜芳基，或者任選與C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基稠合；且Ri
是H、鹵素、硝基、氰基或氨基，或者是選自以下的部分：C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、C3-10
環烷基、C1-10
雜環烷基、芳基和雜芳基，所述C1-6
烷基、C1-6
烷氧基、C2-6
烯基和C2-6
炔基各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基，C3-10
環烷基、C1-10
雜環烷基、芳基和雜芳基各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基，或者任選與C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基稠合；是單鍵或雙鍵。
變量U,W,X和Z指定的基團是二價基團。上面所示的各基團的取向與變量在該結構式中所示的取向相同。以變量U指定-NHSO-基團為例，如該結構式所示，是插在C=O和R2
之間。該-NHS(O)-基團的N原子與C=O相連，S原子與R2
相連。另一個例子是變量Z指定的-C(O) O-插在NH和R之間(即，-NH-Z-R)。-C(O) O-中的C原子與NH相連，O原子與R相連。
參見式(I)，化合物的亞組特徵為，R1
是-NH-Z-R，其中，Z是-C(O)-、-C(O) O-、-C(O) C(O) O-或-C(O) C(O) NH-；R2
是或；X是O；A是CH；W是-CH2
CH2
-、-OCH2
-、-SCH2
-或-SOCH2
-；U是-NHSO2
-；是雙鍵；或者Y是，其中的T是CH或N；Ri
是任選被鹵素、氨基、C1-6
烷基或C1-6
烷氧基取代的苯基或噻唑基(thioazolyl)；Rii
,Riii
,Riv
,和Rv
各自獨立地是H、鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基或C2-6
炔基，或者是選自以下的部分：C3-10
環烷基、C1-10
雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、芳基或雜芳基，或者任選與C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基稠合。R1
的例子是-NH-C(O) O-t-Bu、-NH-C(O) O-環戊基和-NH-C(O)-呋喃基。
該化合物的另一個亞組特徵如下，Y是
其中，Ri
,Rii
,Riii
,Riv
,Rv
和Rvi
各自獨立地是H、鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基、環烷基、雜環烷基、芳基和雜芳基各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6
烷基、C1-6
烷氧基、C2-6
烯基、C2-6
炔基、芳基或雜芳基；並任選與C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基稠合。
在上面的化合物中，Ri
可以是例如以下：
其中，n為1或2。
本發明化合物還具有的特徵是，是單鍵，R2
是，或R1
是-H、-OH、C1-6烷基、C1-6
烷氧基、C3-10
環烷基、C1-10
雜環烷基、芳基或雜芳基，或-Z-R。
術語“烷基”表示飽和的直鏈或支鏈烴基部分，如-CH3
或-CH(CH3
)2
。術語“烷氧基”表示-O-(C1-6
烷基)基團。術語“烯基”表示包含至少一個雙鍵的直鏈或支鏈烴基部分，例如-CH=CH-CH3
。術語“炔基”表示包含至少一個三鍵的直鏈或支鏈烴基部分，例如-C≡C-CH3
。術語“環烷基”表示飽和環狀烴基部分，例如環己基。術語“環烯基”表示包含至少一個雙鍵的非芳族的環狀烴基部分。術語“雜環烷基”表示具有至少一個環雜原子(如N,O或S)的飽和環狀部分，例如4-四氫吡喃基。術語“雜環烯基”表示具有至少一個環雜原子(如N,O或S)和至少一個環雙鍵的非芳族的環狀部分，例如吡喃基。術語“芳基”表示具有一個或多個芳族環的烴基部分。芳基部分的例子包括：苯基(Ph)、亞苯基、萘基、亞萘基、芘基、蒽基和菲基。術語“雜芳基”表示包含一個或多個具有至少一個雜原子(例如N,O或S)的芳環的部分。雜芳基部分的例子包括呋喃基、亞呋喃基、芴基、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、異喹啉基和吲哚基。術語“氨基”表示-NH2
、-NH-(C1-6
烷基)或-N(C1-6
烷基)2
的基團。
除非另外特別指出，本文所述的烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基和雜芳基包括取代的和未取代的部分。環烷基、環烯基、雜環烷基、雜環烯基、芳基和雜芳基上可能的取代基包括但不限於：C1
-C10
烷基、C2
-C10
烯基、C2
-C10
炔基、C3
-C20
環烷基、C3
-C20
環烯基、C1
-C20
雜環烷基、C1
-C20
雜環烯基、C1
-C10
烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、氨基、C1
-C10
烷基氨基、C1
-C20
二烷基氨基、芳基氨基、二芳基氨基、C1
-C10
烷基氨磺醯基、芳基氨磺醯基、C1
-C10
烷基亞氨基、芳基亞氨基、C1
-C10
烷基磺基亞氨基、芳基磺基亞氨基、羥基、鹵素、硫代、C1
-C10
烷硫基、芳硫基、C1
-C10
烷基磺醯基、芳基磺醯基、醯基氨基、氨基醯基、氨基硫代醯基、脒基、胍基、脲基、氰基、硝基、亞硝基、疊氮基、醯基、硫代醯基、醯氧基、羧基和羧酸酯基。另一方面，烷基，烯基或炔基上的取代基包括上述所有取代基，但是C1
-C10
烷基除外。環烷基、環烯基、雜環烷基、雜環烯基、芳基和雜芳基還可以相互稠合。
下面列出了本發明的281種示例性的化合物。
另一方面，本發明涉及一種治療HCV感染的方法，該方法包括給予需要的病人有效量的上面式(I)的化合物。
又一方面，本發明涉及一種用來治療HCV感染的藥物組合物。該組合物包含有效量的至少一種式(I)的化合物和藥學上可接受的載體。可以包含HCV生命週期中除HCV NS3蛋白酶以外的靶標的抑制劑，如NS5B聚合酶,NS5A,NS4B或p7。
這類抑制劑的例子包括但不限於：N-[3-(1-環丁基甲基-4-羥基-2-氧代-1,2-二氫-喹啉-3-基)-1,1-二氧代-1,4-二氫-116-苯並[1,2,4]噻二嗪-7-基]-甲磺醯胺(WO04041818)，反-1,2-二-4-[(苯基乙醯基-吡咯烷-2-(S)-羰基)氨基]-苯基乙烯(WO0401413)和1-氨基金剛烷(Amentadine,Griffin,2004,J. Gen. Virol. 85:p451)。藥物組合物還可包含免疫調節劑或第二抗病毒劑。免疫調節劑指能介導免疫應答的活性試劑。免疫調節劑的例子包括但不限於，Nov-205(諾瓦勒斯治療劑公司(Novelos Therapeutics Inc.),WO02076490)和IMO-2125(伊達拉藥物公司(Idera Pharmaceuticals Inc.),WO05001055)。抗病毒劑指能殺滅病毒或抑制病毒複製的活性試劑。抗病毒劑的例子包括但不限於：病毒唑、利巴米定(ribamidin)、幹擾素-α,Peg化幹擾素以及HCV蛋白酶抑制劑，例如2-(2-{2-環己基-2-[(吡嗪-2-羰基)-氨基]-乙醯基氨基}-3,3-二甲基-丁醯基)-八氫-環戊[c]吡咯-1-羧酸(1-環丙基氨基草醯基-丁基)-醯胺(Telaprevir,頂尖藥物公司(Vertex Pharmaceuticals Inc.),WO02018369),3-[2-(3-叔丁基-脲基)-3,3-二甲基-丁醯基]-6,6-二甲基-3-氮雜二環[3.1.0]己烷-2-羧酸(2-氨基甲醯基-1-環丁基甲基-2-氧代-乙基)-醯胺(Boceprevir,先靈堡研究機構(Schering-Plough Research Institute),WO03062265)和4-氟-1,3-二氫-異吲哚-2-羧酸14-叔丁氧基羰基氨基-4-環丙磺醯基氨基羰基-2,15-二氧代-3,16-二氮雜三環[14.3,0.04,6]十九碳-7-烯-18-基酯(ITMN-191,InterMune Inc.,US2005/0267018)。
該組合物在治療HCV感染或者製造用於該治療的藥物中的應用也屬於本發明範圍之內。
下面對本發明的一個或多個實施方式進行了詳細描述。由說明書和申請專利範圍可以顯而易見地看出本發明的其它特徵、目標和優點。
本發明的化合物可以通過本領域眾所周知的方法由可商購的原料製備。例如，可以通過下面的歷程1所示的路徑合成本發明的化合物：
如歷程1所示，多環化合物(i
)首先與N-(叔丁氧基羰基)-L-脯氨酸(ii
)偶聯，然後進行甲基化，形成中間體(iii
)。中間體(iii
)進行去保護反應，除去N-丁氧基羰基，形成N-遊離化合物(iv
)，其與羧酸(v
)偶聯，形成中間體(vi
)。通過水解中間體(vi
)，得到酸(vii
)，該酸與胺化合物(viii
)偶聯，制得具有兩個烯基端基的吡咯烷化合物(ix
)。中間體(ix
)在格拉布催化劑存在下進行烯烴置換反應，獲得所需的大環化合物(x
)。大環類似物(xi
)的雙鍵可以在Pd-C存在下進一步氫化，獲得飽和-大環化合物(xi
)。
以下歷程2和3顯示兩種本發明化合物的備選合成路線。
上述方法還包括在歷程1-3中具體描述的步驟之前或之後進行的步驟，以添加或去除合適的保護基團，最終能夠合成所需的化合物。此外，不同合成步驟可以以備選的順序或次序進行，以獲得所需的化合物。用於合成式(I)可應用的化合物的合成化學轉化和保護基團方法(保護和去保護)是本領域已知的，包括例如以下文獻所述的那些：R.Larock,Comprehensive Organic Transformations(綜合有機轉化)
,VCH出版社(1989);T.W. Greene和P.G.M. Wuts,Protective Groupsin Organic Synthesis(有機合成中的保護基團)
，第二版，約翰威力和薩孫出版社(John Wiley and Sons)(1991);L. Fieser和M. Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(有機合成中的費氏和費氏試劑)
，約翰威力和薩孫出版社(1994)；以及L. Paquette著的Encyclopedia of Reagents for Organic Synthesis(用於有機合成的試劑全書)
，約翰威力和薩孫出版社(1995)，以及其隨後的版本。
下面實施例1-281詳細描述了化合物1-281的實際製備方式。
本文所述的化合物包含非芳族的雙鍵和不對稱中心。因此，所述化合物可以是多種外消旋體和外消旋混合物，簡單對映體，單獨非對映體，非對映體混合物，互變異構體，以及順-異構體或反-異構體形式。可以預期所有這些異構體形式。例如，上面所示結構式(I)的化合物可以具有以下立體化學構型(II)：
上述化合物包括化合物本身，如果適用，包括其鹽，前藥和溶劑化物。例如鹽可由陰離子和結構式(I)的化合物上的正電荷基團(如氨基)形成。合適的陰離子包括：氯離子、溴離子、硫酸根離子、硝酸根離子、磷酸根離子、檸檬酸根離子、甲磺酸根離子、三氟乙酸根離子、乙酸根離子、蘋果酸根離子、甲苯磺酸根離子、酒石酸根離子、富馬酸根離子、谷氨酸根離子、葡糖醛酸根離子、乳酸根離子、戊二酸根離子和馬來酸根離子。類似地，鹽也可以由陽離子和結構式(I)的化合物上的負電荷基團(如羧酸根)形成。合適的陽離子包括鈉離子、鉀離子、鎂離子、鈣離子和銨陽離子，如四甲基銨離子。結構式(I)的化合物還包括含季氮原子的那些鹽。前藥的例子包括酯類和其他藥學上可接受的衍生物，這些前藥在給予病人後能夠提供結構式(I)的活性化合物。溶劑化物指在結構式(I)的活性化合物和藥學上可接受的溶劑之間形成的配合物。藥學上可接受的溶劑的例子包括水，乙醇，異丙醇，乙酸乙酯，乙酸和乙醇胺。
本發明範圍之內的一種治療HCV感染的方法是通過給予病人有效量的一種或多種結構式(I)的化合物。術語“治療的”或“治療”表示給予感染了HCV、表現出感染HCV的症狀、或者易受HCV感染的對象所述化合物，以獲得治療效果，例如治癒、緩解、改變、影響、改善或防止HCV感染、感染HCV的症狀、或者易受HCV感染的傾向。術語“有效量”表示使得被治療的對象獲得治療效果所需的本發明活性化合物的量。本領域技術人員應當認識到，有效劑量可根據所治療的疾病種類、給藥途徑、所用賦形劑、以及可能並行採用的其它治療而改變。
本發明的化合物可以以有效水準長時間保留在血循環中。因此，這些化合物可以每天一次給予有效量以提供治療效果。
為了實施本發明的方法，包含一種或多種本發明化合物的組合物可以胃腸外給藥、口服給藥、鼻內給藥、直腸給藥、局部給藥或含服。術語“胃腸外”表示皮下注射，皮內注射，靜脈注射，肌內注射，關節內注射，動脈內注射，滑膜內注射，胸骨內注射，鞘內注射，傷口注射或顱內注射，以及任何合適的注射技術。
無菌可注射組合物可以是位於無毒的胃腸外可接受的稀釋劑或溶劑中的溶液或懸浮液，例如在1,3-丁二醇中的溶液。可採用的可接受的媒介物和溶劑為甘露醇，水，林格溶液和等滲氯化鈉溶液。另外，通常使用非揮發性油作為溶劑或懸浮介質(例如合成的單甘油酯或二甘油酯)。脂肪酸，例如油酸及其甘油酯衍生物可用來製備可注射製劑，例如可使用藥學上可接受的天然油類，例如橄欖油或蓖麻油，特別是它們的聚氧基乙烯化形式。這些油溶液或懸浮液還可包含長鏈醇稀釋劑或懸浮劑，羧甲基纖維素或類似的分散劑。其它常用的表面活性劑，例如吐溫(Tween)或司盤(Span)或通常用於生產藥學上可接受的固體、液體或者其它劑型的其它類似的乳化劑或生物利用度促進劑，也可用來配製藥物組合物。
用於口服給藥的組合物可以是任何可以接受的口服劑型，包括膠囊、片劑、乳液和水懸浮液、分散體和溶液。對於片劑，常用的載體包括乳糖和玉米澱粉。通常還可加入潤滑劑，例如硬脂酸鎂。對於膠囊形式的口服給藥，可用的稀釋劑包括乳糖和乾燥的玉米澱粉。當水懸浮液或乳液口服給藥時，可以將活性成分懸浮或溶解在與乳化劑或懸浮劑合併的油相中。如果需要，可以加入某些甜味劑、香料或著色劑。
可以根據藥物製劑領域眾所周知的技術製備鼻噴霧劑或吸入組合物。例如，可使用苄醇或其它合適的防腐劑、提高生物利用度的吸收促進劑、氟代烴、和/或本領域已知的其它增溶劑或分散劑，將這樣的組合物製成在鹽水中的溶液。
包含一種或多種本發明的活性化合物的組合物還可以成栓劑的形式，用於直腸給藥。
所述藥物組合物中的載體必須是“可以接受”的，即與組合物的活性成分相容(優選能夠使活性成分穩定化)，且不會對被治療的對象造成不利影響。可以將一種或多種增溶劑作為用來遞送本發明的活性化合物的藥物賦形劑。其它載體的例子包括膠體氧化矽、硬脂酸鎂、纖維素、月桂基硫酸鈉和D＆C#10黃。
本發明的化合物可以與第二抗HCV試劑一起用來治療HCV，這些第二抗HCV試劑包括例如在HCV生命週期中除HCV NS3蛋白酶以外的靶標的抑制劑、免疫調節劑和其他抗病毒試劑。本發明的化合物和第二抗HCV試劑可以同時施用給藥或在不同時間給藥。對於同時給藥，可以將兩種試劑混合形成單一藥丸，或者單獨製成藥丸。兩種試劑各自以一定的量服用，使得它們的總量為熟練技術人員認可的治療HCV的有效量。
可以通過體外試驗(參見實施例282和283)初步篩選上述本發明化合物在治療HCV感染方面的效力，然後通過動物試驗和臨床試驗確定。其他方法對本領域的普通技術人員而言也是顯而易見的。
下面的實施例僅僅是說明性的，並不以任何方式對說明書的其它部分構成限制。我們相信，本領域的技術人員基於本文的描述，無需另外的工作便可最完整程度地利用本發明。本文引用的所有出版物的全文全部以引用的方式納入本文作為參考。
實施例1：
合成{4-環丙磺醯基氨基羰基-2,15-二氧代-18-[2-(4-三氟甲基-苯基)-苯並[4,5]呋喃並[3,2-d]嘧啶-4-基氧基]-3,16-二氮雜三環[14.3.0.04,6]十九烷-14-基}-氨基甲酸環戊酯(化合物1)
化合物I-3首先由可商購的1-叔丁氧基羰基氨基-2-乙烯基-環丙烷羧酸乙酯通過以下所示路線製備：
向1-叔丁氧基羰基氨基-2-乙烯基-環丙烷羧酸乙酯(0.34克，1.3毫摩爾)在THF(5毫升)和甲醇(5毫升)的溶液中加入LiOH(0.13克，5.3毫摩爾)水的懸浮液。室溫攪拌過夜後，用10% HCl(2毫升)使反應猝滅，真空下去除溶劑。產生的固體粉末用水(10毫升)洗滌，得到化合物I-1(0.27克，90%)。MS m/z 249.9(M+
+23)；1
H NMR(CDCl3
)δ10.35(brs,1H),5.84-5.71(m,1H),5.29(d,J=17.4Hz,1H),5.12(d,J=10.2Hz,1H),2.23-2.14(m,1H),1.87-1.65(m,1H),1.58-1.41(m,1H),1.43(s,9H)。
於室溫攪拌化合物I-1(0.52克，2.3毫摩爾)、2-(1H-7-氮雜苯並三唑-1-基)-1,1,3,3-四甲基脲陽離子(uronium)六氟-磷酸鹽甲銨(methanaminium)(HATU,1.74克，4.6毫摩爾)和4-二甲基氨基吡啶(1.39克，11.6毫摩爾)在CH2
Cl2
(40毫升)中的溶液，隨後在15分鐘內緩慢加入環丙烷磺醯胺(0.57克，4.7毫摩爾)、二異丙基乙胺(1.81毫升，14.0毫摩爾)和1,8-二氮雜二環[5,4,0]十一碳-7-烯(1.80克，11.7毫摩爾)。於室溫攪拌反應混合物過夜之後，真空下去除溶劑。殘餘物通過矽膠柱色譜純化，得到化合物I-2(0.51克，66%)。MS m/z 353.1(M+
+23)；1
H NMR(CDCl3
)δ9.75(brs,1H),5.64-5.51(m,1H),5.30(d,J=17.4H),5.16(d,J=10.2Hz,1H),2.95-2.89(m,1H),2.19-2.10(m,1H),1.93-1.88(m,1H),1.47(s,9H),1.46-1.38(m,1H),1.32-1.23(m,2H),1.15-1.00(m,2H)。
在室溫下向化合物I-2
(0.50克，1.5毫摩爾)在MeOH(8毫升)中的溶液加入SOCl2
(0.26克，2.2毫摩爾)。反應混合物回流1小時之後，真空除去MeOH和SOCl2
。殘餘物用戊烷磨碎，過濾得到米白色固體中間體I-3
(0.32克，91%)。MS m/z(M+
+1)；1
H NMR(CD3
COD)δ5.77-5.65(m,1H),5.43(d,J=17.4Hz,1H),5.32(d,J=10.2Hz,1H),3.06-2.97(m,1H),2.45(dd,J=17.4Hz,J=7.8,1H),2.16(dd,J=8.0Hz,J=7.8Hz,1H),1.75(dd,J=10.1Hz,J=7.8Hz,1H),1.32-0.86(m,4H)。
化合物1通過以下路線製備：
於0℃攪拌3-氨基-苯並呋喃-2-羧酸醯胺(1.00克，5.7毫摩爾)和吡啶(1毫升，12.26毫摩爾)在THF(25毫升)中的溶液10分鐘。向形成的溶液中緩慢加入4-三氟甲基-苯甲醯氯(1.48克，7.1毫摩爾)。然後將溫度升高至室溫，攪拌混合物12小時。減壓下除去溶劑之後，收集形成的固體，用水洗滌，空氣乾燥後得到I-4(1.92克，96.0%)。MS:m/z 349.0(M+
+1)。
I-4(1.92克，5.5毫摩爾)和2N NaOH(13毫升)在EtOH(25毫升)的懸浮液於85℃加熱12小時。冷卻之後，將混合物酸化，然後除去EtOH。收集形成的固體，過濾，用水洗滌，乾燥後獲得I-5(1.71克，95.0%)。MS m/z 331(M+
+1)。
將I-5(1.71克，5.2毫摩爾)和過量磷醯氯(POCl3
)的溶液回流2小時。冷卻並且完全濃縮之後，混合物用二氯甲烷和10%氫氧化鈉萃取。有機層用MgSO4
乾燥，濃縮，用CH2
Cl2
和正己烷結晶，得到化合物I-6(1.49克，82%)。MS m/z 348.8,350.9(M+
+1)；1
H NMR(CDCl3
)δ8.70(d,2H),8.34(d,1H),7.82-7.75(m,4H),7.57(ddd,1H)。
0℃，向Boc-反-4-羥基-L-脯氨酸(0.53克，2.3毫摩爾)在DMSO(25毫升)的懸浮液中加入t-BuOK(0.82克，5.1毫摩爾)。使該混合物溫熱至室溫並攪拌1小時後，與10℃緩慢加入化合物I-6(0.81克，2.3毫摩爾)。繼續攪拌過夜。加入碘甲烷(1.02克，6.9毫摩爾)，室溫下再攪拌反應混合物30分鐘。反應混合物用10% HCl水溶液中和至pH為6-7，並用二氯甲烷進行萃取。有機層用MgSO4
乾燥，真空蒸發，並通過矽膠柱層析純化，得到化合物I-7(1.12克，86%)。MS m/z 557.8(M+
+1)；1
H NMR(CDCl3
)δ8.63(d,2H),8.28(d,1H),7.80-7.74(m,2H),7.70(d,2H),7.51(ddd,1H)。
室溫，向化合物I-7(1.13克，2.0毫摩爾)在MeOH(20毫升)溶液中加入SOCl2
(1.21克，9.8毫摩爾。將反應混合物回流1小時，除去MeOH和SOCl2
。殘餘物用戊烷研碎。將懸浮液過濾，得到為米白色固體的化合物I-8(0.87克，95%)。MS m/z 458.1(M+
+1)。
室溫，向HATU(1.12克，3.0毫摩爾)、1-羥基苯並三唑(HOBT，0.41克，3.0毫摩爾)、I-8(0.86克，1.9毫摩爾)和2-叔丁氧基羰基氨基-壬-8-烯酸(1.21克，1.9毫摩爾)在CH2
Cl2
(40毫升)的溶液中加入N-甲基嗎啉(NMM,1.02克，9.9毫摩爾)。攪拌過夜後，該化合物真空條件下濃縮。殘餘物通過矽膠柱色譜純化，得到化合物I-9(1.03克，73%)。MS m/z 711.3(M+
+1)。
室溫，向化合物I-9(1.01克，1.4毫摩爾)在THF(20毫升)的溶液中加入0.5M LiOH(5.7毫升，2.9毫摩爾)。攪拌過夜後，反應混合物用10% HCl進行中和至pH<7，並與真空進行濃縮。形成的殘餘物過濾並用水洗滌，得到化合物I-10(0.91克，92%)。MS:m/z 697.3(M+
+1)。
室溫，將NMM(0.12克，1.2毫摩爾)加入到化合物I-3(0.28克，0.4毫摩爾)、HATU(0.31克，0.8毫摩爾)、HOBT(0.08克，0.6毫摩爾)和化合物I-10(0.09克，0.4毫摩爾)在CH2
Cl2
(10毫升)的溶液中。攪拌過夜後，反應混合物在真空條件下濃縮。殘餘物通過矽膠柱色譜純化，得到化合物I-11(0.10克，85%)。MS m/z 921.3(M+
+1)；1
H NMR(CDCl3
) δ10.24(s,1H),8.61(d,2H),8.26(d,1H),7.77(d,2H),7.73-7.64(m,2H),7.54-7.47(m,1H),7.11(s,1H),6.19(d,1H),5.88-5.70(m,2H),5.38-5.25(m,2H),5.16(d,1H),5.00-4.90(m,2H),4.60(dd,1H),4.88-4.34(m,2H),4.18-4.10(m,1H),2.98-2.89(m,1H),2.68(dd,2H),2.18-1.96(m,6H),1.50-1.32(m,7H),1.28(s,9H),1.09-1.25(m,2H)。
室溫，在N2
氣氛下向化合物I-11(0.10克，0.11毫摩爾)在CH2
Cl2
(10毫升)的溶液中加入霍維達-格拉布(Hoveyda-Grubbs)二代(35毫克，0.056毫摩爾)。然後，於40℃攪拌反應混合物24小時，進行易位環化(metathesis cyclization)。將反應猝滅，反應混合物通過柱層析純化，得到化合物1-12(30毫克，31%)。MS:m/z 893.3(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),8.59(d,2H),8.21(d,1H),7.77(d,2H),7.69-7.57(m,2H),7.46(dd,1H),7.20(s,1H),6.12(s,1H),5.69(q,IH),5.12(d,1H),4.97(dd,1H),4.81-4.68(m,2H),4.28-4.07(m,2H),2.96-2.49(m,3H),2.30(q,1H),1.96-1.12(m,14H),1.08(s,9H),0.96-0.82(m,2H)。
室溫，在N2
氣氛下向化合物1-12(30毫克，0.034毫摩爾)在MeOH(10毫升)的溶液中加入5% Pd-C(5毫克)。然後，在室溫、壓力60psi，氫氣氛下攪拌反應混合物4小時。將反應混合物過濾並通過柱層，析純化，得到化合物1(16.5毫克，55%)。MS:m/z 895.3(M+
+1)；1
H NMR(CDCl3
)δ10.79(s,1H),8.57(d,2H),8.21(d,1H),7.75(d,2H),7.64(m,2H),7.46(d,1H),7.11(s,1H),6.11(s,1H),5.29(d,1H),4.72(m,2H),4.38(m,2H),4.12(m,1H),3.02-2.58(m,3H),1.98-0.86(m,29H)。
實施例2-141：化合物2-141的合成
化合物2-141各自按照與實施例1所述類似的方式製備。
化合物2:MS:m/z 883.3(M+
+1)；1
H NMR(CDCl3
) δ10.51(s,1H),8.53(d,2H),8.16(d,1H),7.73(d,2H),7.62(m,2H),7.22(m,2H),6.07(s,1H),5.23(d,1H),4.77(dd,1H),4.49(d,1H),4.35(m,1H),4.13(m,1H),3.02-2.57(m,3H),1.99-0.91(m,30H)。
化合物3:MS:m/z 823.2(M+
+1)；1
H NMR(CDCl3
) δ10.38(s,1H),8.53(d,2H),8.16(d,1H),7.73(d,2H),7.61(m,2H),7.41(m,2H),6.13(m,2H),5.69(q,1H),4.98(dd,1H),4.78(m,1H),4.55(m,1H),4.42(m,1H),4.19(m,1H),2.89(m,1H),2.78(m,2H),2.52(m,1H),2.23(q,1H),1.96-0.84(m,15H),1.90(s,3H)。
化合物4:MS:m/z 882.3(M+
+1)；1
H NMR(CDCl3
) δ10.47(s,1H),8.64(d,1H),8.52(m,3H),7.70(d,2H),7.44(dd,1H),6.07(s,1H),5.63(q,1H),5.01-4.73(m,3H),4.07-4.01(m,2H),2.90-2.22(m,4H),1.97-1.09(m,17H),0.94(s,9H),0.90-0.88(m,1H)。
化合物5:MS:m/z 840.2(M+
+1)；1
H NMR(CDCl3
) δ10.42(s,1H),8.64-8.47(m,4H),7.80(d,2H),7.50-7.27(m,2H),6.15(s,1H),5.69(q,1H),5.23(d,1H),5.02(dd,1H),4.84(dd,1H),4.53(d,1H),4.25-4.11(m,2H),3.32(s,3H),2.93-2.15(m,4H),1.92-0.83(m,16H)。
化合物6:MS:m/z 824.2(M+
+1)；1
H NMR(CDCl3
)δ10.48(s,1H),8.63(d,1H),8.62-8.48(m,3H),7.78(d,2H),7.44-7.40(m,1H),6.16-6.14(m,2H),5.73(q,1H),5.04(dd,1H),4.85(dd,1H),4.55(s,1H),4.51(s,1H),4.15(d,1H),2.93-2.89(m,2H),2.77-2.22(m,3H),1.95-1.85(m,1H),1.79(s,3H),1.76-0.83(m,15H)。
化合物7:Ms:m/z 839.2(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),8.46(d,2H),8.15(d,1H),7.71(d,2H),7.62-7.37(m,3H),7.16(s,1H),6.08(s,1H),5.71(q,1H),5.25(d,1H),4.96(dd,1H),4.75(dd,1H),4.44(d,1H),4.35-4.09(m,2H),3.34(s,3H),2.96-2.71(m,2H),2.57(brs,1H),2.28(q,1H),2.08-0.87(m,16H)。
化合物8:Ms:m/z 849.3(M+
+1)；1
H NMR(CDCl3
)δ10.54(s,1H),8.45(d,2H),8.06(d,1H),7.71(d,2H),7.57(m,3H),7.35(s,1H),6.28(d,1H),6.04(s,1H),5.71(q,1H),4.96(dd,1H),4.67(dd,1H),4.47(d,1H),4.45(brs,1H),4.11(m,1H),2.92-2.45(m,4H),2.32(q,1H),1.96-0.84(m,20H)。
化合物9:Ms:m/z 880.3(M+
+1)；1
H NMR(CDCl3
)δ10.45(s,1H),8.40(d,2H),8.14(s,1H),7.97(d,1H),7.64(d,2H),7.48-7.41(m,2H),7.25-7.20(m,1H),5.96(s,1H),5.63(q,1H),4.92-4.86(m,2H),4.77(d,1H),4.44(s,1H),4.20(dd,1H),4.03(dd,1H),2.90-2.84(m,2H),2.80-2.63(m,1H),2.38-2.32(m,1H),1.98-1.02(m,15H),0.91(s,9H),0.90-.086(m,1H)。
化合物10:MS:m/z 911.2(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.54(d,2H),7.87-7.80(m,1H),7.71(d,2H),7.56(dd,1H),7.33-7.20(m,1H),6.88(s,1H),6.13(s,1H),5.65(q,1H),5.07-4.94(m,2H),4.69(dd,1H),4.57(d,1H),4.43-4.38(m,1H),4.24-4.01(m,2H),2.91-2.80(m,2H),2.74(s,3H),2.65-2.63(m,1H),2.60-2.41(m,1H),2.22(q,1H),1.98-0.86(m,20H)。
化合物11:MS:m/z 907.3(M+
+1)。
化合物12:MS:m/z 923.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.57(d,2H),8.06(d,1H),7.76(d,2H),7.51(s,1H),7.14-6.93(m,2H),6.13(s,1H),5.80-5.60(m,1H),5.31(d,1H),4.97-4.83(m,2H),4.79(dd,1H),4.64-4.04(m,3H),3.88(s,3H),2.94-2.43(m,3H),2.36-0.86(m,25H)。
化合物13:MS:m/z 852.3(M+
+1)；1
H NMR(CDCl3
)δ10.68(s,1H),8.38(d,2H),7.95(d,1H),7.72-7.58(m,3H),7.47(d,2H),7.24-7.19(m,1H),6.01(s,1H),5.69(q,1H),4.94(dd,1H),4.78(dd,1H),4.70(d,1H),4.46(d,1H),4.22-3.98(m,2H),2.97-2.80(m,2H),2.57(s,6H),2.67-2.41(m,1H),2.23(q,1H),1.85-0.84(m,16H)。
化合物14:MS:m/z 766.2(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.62(m,2H),8.24(m,1H),7.77(d,2H),7.67(m,2H),7.48(m,1H),6.90(s,1H),6.18(s,1H),5.72(q,1H),4.98(dd,1H),4.65(dd,1H),4.24(m,1H),4.05(m,1H),2.92(m,1H),2.76(m,2H),2.58-2.28(m,4H),1.94-1.05(m,13H),0.97-0.86(m,2H)。
化合物15:MS:m/z 893.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.88(s,1H),8.68(d,1H),8.26(d,1H),7.80-7.65(m,4H),7.35-7.26(m,1H),6.98(d,1H),6.20(d,1H),5.71(q,1H),5.18(d,1H),5.00(dd,1H),4.77(dd,1H),4.64(d,1H),4.46(s,1H),4.25(dd,1H),4.15(dd,1H),2.92-2.28(m,4H),2.17-0.82(m,24H)。
化合物16:MS:m/z 877.3(M+
+1)；1
H NMR(CDCl3
)δ10.40(s,1H),8.45(d,2H),8.04(d,1H),7.62(d,2H),7.58-7.50(m,2H),7.44(s,1H),7.35(dd,1H),6.02(s,1H),5.95(d,1H),5.63(q,1H),4.81(dd,1H),4.70(dd,1H),4.49(d,1H),4.42-4.38(m,1H),4.04(dd,1H),2.90-2.20(m,6H),1.96-0.83(m,23H)。
化合物17:Ms:m/z 907.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.73(s,1H),8.62(d,1H),7.96(s,1H),7.71(d,1H),7.64(dd,1H),7.59-7.25(m,3H),6.11(s,1H),5.62(q,1H),5.21(d,1H),4.99(dd,1H),4.79(dd,1H),4.61(d,1H),4.52(s,1H),4.25-4.10(m,2H),2.95-2.51(m,3H),2.47(s,3H),2.31(q,1H),2.03-0.91(m,24H)。
化合物18:Ms:m/z 767.2(M+
+1)；1
H NMR(CDCl3
)δ10.38(s,1H),8.49(d,2H),8.15(d,1H),7.77(d,2H),7.64-7.58(m,2H),7.41-7.32(m,1H),7.29(s,1H),6.08(s,1H),5.78(q,1H),5.08(dd,1H),4.66(dd,1H),4.42(d,1H),4.09-4.06(m,1H),3.85-3.62(m,4H),2.93-2.45(m,4H),2.04-0.87(m,13H)。
化合物19:MS:m/z 899.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.51(d,2H),7.80(dd,1H),7.70(d,2H),7.51-7.42(m,1H),7.37-7.23(m,1H),6.97(s,1H),6.06(s,1H),5.63(q,1H),4.96-4.85(m,2H),4.75-4.63(m,2H),4.09-4.02(m,2H),2.93-2.43(m,4H),2.21(q,1H),1.96-0.76(m,24H)。
化合物20:MS:m/z 895.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.43(d,2H),7.81(s,1H),7.67(d,2H),7.51(s,1H),7.35-7.28(m,2H),5.92(s,1H),5.57(q,1H),5.19(d,1H),4.88-4.61(m,3H),4.14-4.00(m,2H),2.83-2.41(m,4H),2.38(s,3H),2.24(q,1H),1.96-1.16(m,15H),1.05(s,9H),0,97-0.78(m,1H)。
化合物21:MS:m/z 923.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.50(d,2H),7.67(d,2H),7.59(s,1H),7.41(d,1H),7.34(s,1H),7.16(d,1H),6.06(s,1H),5.64(q,1H),5.23(d,1H),4.94(dd,1H),4.87(dd,1H),4.58-4.42(m,2H),4.30-4.02(m,2H),3.84(s,3H),2.88-2.44(m,4H),2.21(q,1H),1.84-0.78(m,23H)。
化合物22:MS:m/z 752.2(M+
+1)；1
H NMR(CDCl3
)δ10.76(s,1H),8.61(d,2H),8.25(m,1H),7.79(d,2H),7.67(d,2H),7.52(m,1H),6.70(s,1H),6.19(s,1H),5.69(q,1H),5.08(m,1H),4.65(dd,1H),4.23(dd,1H),4.02(m,1H),3.05-1.98(m,7H),1.96-0.82(m,13H)。
化合物23:MS:m/z 907.3(M+
+1)；1
H NMR(CDCl3
)δ10.40(s,1H),8.56(d,2H),8.08(d,1H),7.73(d,2H),7.29(s,1H),7.26-7.20(m,2H),6.13(s,1H),5.71(q,1H),5.22(d,1H),4.95(dd,1H),4.82-4.73(m,1H),4.63-4.51(m,1H),4.33-4.06(m,2H),2.96-2.51(m,4H),2.53(s,3H),2.24(q,1H),1.96-0.94(m,24H)。
化合物24:MS:m/z 916.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.48(d,2H),8.08(s,1H),7.68(d,2H),7.50-7.37(m,3H),6.01(s,1H),5.59(q,1H),5.13(d,1H),4.83(dd,1H),4.74-4.63(m,2H),4.15(dd,1H),4.05(d,1H),2.94-2.41(m,4H),2.21(q,1H),1.89-1.14(m,14H),1.03(s,9H),0.96-0.85(m,1H)。
化合物25:MS:m/z 923.3(M+
+1)。
化合物26:MS:m/z 923.3(M+
+1)；1
H NMR(CDCl3
)δ1035(s,1H),8.50(d,2H),7.69(d,2H),7.52(dd,1H),7.40(s,1H),7.12(d,1H),6.75(d,1H),6.05(s,1H),5.63(q,1H),5.27(d,1H),4.97-4.83(m,1H),4.75(dd,1H),4.42(brs,1H),4.28-4.08(m,2H),4.08(s,3H),2.91-2.38(m,4H),2.23(q,1H),1.96-0.82(m,24H)。
化合物27:MS:m/z 894.3(M+
+1)；1
H NMR(CDCl3
)δ10.38(s,1H),8.47(d,2H),8.08(d,1H),7.62(d,2H),7.58-7.54(m,2H),7.40-7.33(m,1H),7.31(s,1H),6.07(s,1H),5.63(q,1H),4.95(dd,1H),4.83(d,1H),4.87(dd,1H),4.58(d,1H),4.31-4.19(m,1H),4.09(dd,1H),3.40-3.32(m,4H),3.01-2.41(m,8H),2.19(q,1H),1.92-0.83(m,15H)。
化合物28:MS:m/z 878.3(M+
+1)；1
H NMR(CDCl3
)δ10.56(s,1H),8.41(d,2H),8.02(d,1H),7.74(s,1H),7.68(d,2H),7.53-7.47(m,2H),7.35-7.32(m,1H),6.01(s,1H),5.62(q,1H),4.90(dd,1H),4.78(dd,1H),4.59-4.43(m,2H),4.35-4.25(m,1H),4.05(dd,1H),3.61-3.49(m,1H),3.01-2.45(m,8H),2.21(q,1H),1.85-0.83(m,18H)。
化合物29:MS:m/z 909.3(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),8.53(4,2H),8.16(d,1H),7.67(d,2H),7.64-7.43(m,4H),6.03(s,1H),5.61(q,1H),5.22-5.19(m,1H),4.87(dd,1H),4.66(dd,1H),4.57(d,1H),4.19-4.01(m,3H),3.71-3.42(m,4H),3.19-2.97(m,2H),2.91-2.43(m,4H),2.20(q,1H),1.95-0.81(m,17H)。
化合物30:MS:m/z 906.3(M+
+1)；1
H NMR(CDCl3
)δ10.18(s,1H),8.62(d,2H),8.25(d,1H),7.78(d,2H),7.70-7.61(m,2H),7.55-7.46(m,1H),7.01(1H),6.18(1H),5.71(q,1H),5.12(d,1H),5.02(dd,1H),4.77(dd,1H),4.64(d,1H),4.53-4.43(1H),4.31-4.18(m,2H),,2.83-2.44(m,3H),2.28(q,1H),1.95-1.22(m,23H),0.83(s,3H)。
化合物31:MS:m/z 907.3(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),8.57(d,2H),8.05(d,1H),7.77(d,2H),7.42-7.26(m,3H),6.15(s,1H),5.69(q,1H),5.29(d,1H),4.96(dd,1H),4.78(dd,1H),4.63-4.56(m,1H),4.40-4.13(m,3H),2.91-2.64(m,3H),2.62(s,3H),2.56-2.22(m,2H),1.89-0.96(m,23H)。
化合物32:MS:m/z 895.2(M+
+1)；1
H NMR(CDCl3
)δ10.45(s,1H),8.60(d,2H),8.22(d,1H),7.55(d,2H),7.67-7.60(m,2H),7.45(dd,1H),7.20(s,1H),6.12(s,1H),5.65(q,1H),5.13(d,1H),4.97(dd,1H),4.81-4.71(m,2H),4.14-4.10(m,2H),2.82-2.45(m,3H),2.27(q,1H),1.97-1.21(m,14H),1.08(s,9H),0.89-0.80(m,4H)。
化合物33:MS:m/z 853.3(M+
+1)；1
H NMR(CDCl3
)δ10.22(s,1H),8.58(s,1H),8.48(d,2H),8.08(d,1H),7.57(d,2H),7.53-7.44(m,2H),7.39-7.26(m,1H),6.05(s,1H),5.65(q,1H),5.21(d,1H),4.95(dd,1H),4.82(dd,1H),4.40(d,1H),4.21-4.03(m,2H),3.27(s,3H),2.81-2.40(m,3H),2.22(q,1H),1.95-1.20(m,15H),0.81(s,3H)。
化合物34:MS:m/z 923.3(M+
+1)；1
H NMR(CDCl3
)δ10.17(s,1H),8.61(d,2H),8.25(d,1H),7.80(d,2H),7.65-7.50(m,2H),7.41(dd,1H),6.97(s,1H),6.18(s,1H),5.72(q,1H),5,15(d,1H),5.05(dd,1H),4.77(dd,1H),4.65(d,1H),4.29-4.10(m,2H),3.78-3.52(m,2H),3.23-3.03(m,2H),2.79-2.85(m,2H),2.56(brs,1H),2.27(q,1H),1.98-1.19(m,20H),0.88(s,3H)。
化合物35:MS:m/z 894.2(M+
+1)；1
H NMR(CDCl3
)δ10.45(s,1H),8.47(d,2H),8.12(s,1H),8.05(d,1H),7.70(d,2H),7.53-7.46(m,2H),7.31-7.22(m,1H),6.03(s,1H),5.70(q,1H),5.03-4.84(m,4H),4.24(d,1H),2.95-2.47(m,3H),2.38(q,1H),1.94-1.11(m,25H),0.85(s,3H)。
化合物36:MS:m/z 889.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.47(d,2H),8.07(d,1H),7.65(d,2H),7.57(s,1H),7.55-7.42(m,2H),7.38-7.27(m,2H),6.82(d,1H),6.62(d,1H),5.63(dd,1H),6.15(s,1H),5.63(q,1H),4.92(dd,1H),4.74-4.59(m,2H),4.42(d,1H),4.17(dd,1H),2.79-2.42(m,3H),2.23(q,1H),1.95-1.05(m,15H),0.76(s,3H)。
化合物37:MS:m/z 837.3(M+
+1)；1
H NMR(CDCl3
)δ10.16(s,1H),8,48(d,2H),8.11(d,1H),7.69(d,2H),7.58(d,2H),7.36(dd,1H),7.17(s,1H),6.15(s,1H),6.04(d,1H),5.64(q,1H),4.94(dd,1H),4.67(dd,1H),4.47(dd,1H),4.41(d,1H),4.12(dd,1H),2.78-2.68(m,1H),2.43(brs,1H),2.22(q,1H),1.98-1.64(m,7H),1.53-1.11(m,12H),0.78(s,3H)。
化合物38:MS:m/z 863.3(M+
+1)；1
H NMR(CDCl3
)δ10.52(s,1H),8.38(d,2H),7.92(d,1H),7.88(s,1H),7.65(d,2H),7.58-7.52(m,2H),7.35-7.21(m,1H),6.19(d,1H),5.92(s,1H),5.71(q,1H),5.01(dd,1H),4.81(dd,1H),4.62(d,1H),4.37(brs,1H),4.11-4.01(m,1H),2.98-2.87(m,1H),2.74-2.52(m,2H),2.33(q,1H),1.98-1.19(m,16H),0.88(s,3H),0.68-0.41(m,4H)。
化合物39:MS:m/z 908.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.48(d,2H),8.15(d,1H),7.67(d,2H),7.57-7.46(m,2H),7.39-7.35(m,2H),6.07(s,1H),5.62(q,1H),4.98-4.86(m,2H),4.77(dd,1H),4.58(d,1H),4.02(dd,1H),3.38-3.24(m,4H),2.99-2.81(m,4H),2.82-2.42(m,3H),2.19(q,1H),1.88-1.04(m,15H),0.92-0.72(m,4H)。
化合物40:MS:m/z 866.3(M+
+1)；1
H NMR(CDCl3
)δ10.51(s,1H),8.37(d,2H),7.91(d,1H),7.69(s,1H),7.61(d,2H),7.53-7.42(m,2H),7.23-7.14(m,1H),6.01(s,1H),5.67(q,1H),4.94(dd,1H),4.72(dd,1H),4.61(d,1H),4.43(d,1H),4.30-4.02(m,2H),2.94-2.60(m,3H),2.57(s,6H),2.20(q,1H),1.80-1.15(m,15H),0.77(s,3H)。
化合物41:MS:m/z 892.3(M+
+1)；1
H NMR(CDCl3
)δ10.40(s,1H),8,51(d,2H),8.16(d,1H),7.85(d,2H),7.65(s,1H),7.58(d,1H),7.41-7.37(m,1H),6.14(s,1H),5.59(q,1H),4.99(dd,1H),4.80(dd,1H),4.62(d,1H),4.57(d,1H),4.45-4.37(m,1H),4.17(dd,1H),3.75-3.65(m,2H),3.60-3.48(m,2H),2.80-2.45(m,3H),2.24(q,1H),1.89-1.41(m,20H),0.8(s,3H)。
化合物42:MS:m/z 907.3(M+
+1)；1
H NMR(CDCl3
)δ10.20(s,1H),8.43(d,2H),8.10(d,1H),7.65(d,2H),7.60-7.55(m,2H),7.39-7.35(m,1H),7.25(s,1H),6.05(s,1H),5.98(d,1H),5.66(q,1H),4.93(dd,1H),4.72(dd,1H),4.52-4.42(m,2H),4.08(dd,1H),3.78-3.60(m,2H),3.21-3.11(m,2H),3.81-2.43(br,3H),2.19-2.05(m,2H),1.85-1.09(m,19H),0.77(s,3H)。
化合物43:Ms:m/z 890.3(M+
+1)；1
H NMR(CDCl3
)δ10.16(s,1H),8.55(d,2H),8.21(d,1H),8.14(s,1H),7.68(d,2H),7.58-7.41(m,4H),7.21(s,1H),6.40(s,1H),6.18(s,1H),5.63(q,1H),4.95(dd,1H),4.78-4.62(m,2H),4.44(d,1H),4.16(dd,1H),2.69-2.44(m,3H),2.24(q,1H),1.98-1.15(m,15H),0.79(s,3H)。
化合物44:MS:m/z 879.3(M+
+1)；1
H NMR(CDCl3
)δ10.22(s,1H),8.59(d,2H),8.22(d,1H),7.76(d,2H),7.75-7.60(m,2H),7.48-7.42(m,1H),7.17(s,1H),6.20(s,1H),6.16(d,1H),5.71(q,1H),5.02(dd,1H),4.77(dd,1H),4.60-4.52(m,2H),4.20(dd,1H),2.79-2.45(m,3H),2.21(q,1H),1.96-1.07(m,15H),1.03(s,9H),0.82(s,3H)。
化合物45:MS:m/z 933.3(M+
+1)；1
H NMR(CDCl3
)δ10.22(s,1H),8.56(d,2H),8.19(d,1H),7.88(d,2H),7.69-7.42(m,3H),7.19(s,1H),6.81-6.62(m,4H),6.11(s,1H),5.68(q,1H),5.00(dd,1H),4.77(dd,1H),4.55(d,2H),4.41-4.12(m,2H),2.82-2.42(m,3H),2.28(q,1H),2.01-1.11(m,15H),0.83(s,1H)。
化合物46:MS:m/z 891.3(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.35(d,2H),7.94(d,1H),7.66(s,1H),7.62(d,2H),7.54-7.46(m,2H),7.22(dd,1H),5.93-5.84(m,2H),5.61(q,1H),4.92(dd,1H),4.87(dd,1H),4.58(d,1H),4.41-4.36(m,1H),4.04(dd,1H),2.82-2.75(m,1H),2.65-2.50(m,2H),2.24(q,1H),1.80-1.00(m,24H),0.81(s,3H)。
化合物47:MS:m/z 867.3(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),8.54(d,2H),8.18(d,1H),7.86(d,1H),7.66(d,2H),7.61(m,2H),7.46(m,2H),6.13(s,1H),5.67(q,1H),4.94(dd,1H),4.77(m,1H),4.61(m,1H),4.40(d,1H),4.20(m,1H),3.72(s,3H),2.91(m,1H),2.72-2.39(m,3H),2.25(q,1H),1.96-0.82(m,15H)。
化合物48:MS:m/z 908.2(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.44(d,1H),8.23(d,1H),7.67(m,3H),7.52(m,1H),7.07(s,1H),6.04(s,1.H),5.68(q,1H),5.12(d,1H),4.98(dd,1H),4.79-4.68(m,2H),4.34(s,1H),4.20(dd,1H),4.00(m,1H),2.95(s,3H),2.93(m,1H),2.72(m,2H),2.52(m,1H),2.26(q,1H),1.94-0.82(23H)。
化合物49:MS:m/z 920.2(M+
+1)。
化合物50:MS:m/z 806.2(M+
+1)；1
H NMR(CDCl3
)δ10.47(s,1H),8.77-8.53(m,2H),8.19(d,1H),8.13(d,1H),7.73(s,1H),7.53-7.30(m,2H),7.26-7.18(m,1H),6.07(s,1H),5.70-5.40(m,2H),4.98-4.61(m,2H),4.40-4.03(m,3H),3.47(s,3H),2.95-2.90(m,1H),2.87-2.50(m,3H),2.20(dd,1H),2.10-1.86(m,3H),1.61-1.08(m,11H),0.96(m,1H)。
化合物51:MS:m/z 822.3,824.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.69-8.44(m,3H),8.34(d,2H),7.65(s,1H),7.42-7.30(m,3H),6.04(s,1H),5.70-5.45(m,2H),4.91-4.63(m,2H),4.35-4.03(m,3H),3.42(s,3H),2.84(s,1H),2.72-2.50(m,3H),2.22(dd,1H),2.19(m,3H),1.54-0.78(m,11H)。
化合物52:MS:m/z 774.2(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.65-8.58(m,1H),8.46(d,1H),8.18(d,1H),8.06(d,1H),7.46-7.38(m,3H),7.19-7.11(m,1H),6.13(s,1H),6.04(d,1H),5.66(dd,1H),5.27-5.08(m,1H),5.07-4.67(m,2H),4.52-4.39(m,2H),4.13-4.09(m,1H),3.62-3.60(m,1H),2.95-2.10(m,4H),1.98(s,3H),1.90-0.81(m,14H)。
化合物53:MS:m/z 825.3(M+
+1)。
化合物54:MS:m/z 805.3,807.3(M+
+1)；1
H NMR(CDCl3
)δ10.46(s,1H),8.28-8.19(m,1H),7.98(s,1H),7.88-7.85(m,1H),7.63-7.39(m,6H),6.07(s,1H),5.67-5.46(m,2H),4.96-4.79(m,2H),4.41-4.09(m,3H),3.37(s,3H),2.97-0.88(m,20H)。
化合物55:MS:m/z 789.2(M+
+1)；1
H NMR(CDCl3
)δ10.61(s,1H),8.49(s,1H),8.39-8.24(m,2H),8.05-7.94(m,2H),7.56-7.04(m,5H),5.90(s,1H),5.47(br,1H),4.93-4.69(br,2H),4.40-4.07(m,3H),3.46(s,1H),3.23(s,3H),2.91-2.07(m,11H),1.99-1.54(m,4H),1.32-0.81(m,5H)。
化合物56:MS:m/z 839.3,843.3(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),8.24(d,1H),7.89(d,1H),7.63(d,1H),7.56(s,1H),7.52-7.40(m,2H),7.14(brs,1H),6.08(s,1H),5.69(q,1H),5.30(brs,1H),4.97(dd,1H),4.74(dd,1H),4.46(d,1H),4.40-4.22(m,1H),4.13-4.08(m,1H),3.36(s,3H),2.99-2.05(m,5H),1.90-1.10(m,15H),0.99-0.88(m,1H)。
化合物57:MS:m/z 827.2(M+
+1)；1
H NMR(CDCl3
)δ10.17(s,1H),8.42(d,2H),7.84(d,1H),7.49-7.41(m,4H),7.28(m,1H),7.13(brs,1H),6.16(s,1H),5.63(q,1H),4.95(m,1H),4.70(dd,1H),4.63(m,1H),4.31-4.11(m,2H),2.97-2.70(m,3H),2.50-1.06(m,17H),0.91(m,1H)。
化合物58:MS:m/z 803.3(M+
+1)。
化合物59:Ms:m/z 789.2(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),8.53-8.41(m,3H),7.81(d,1H),7.59-7.42(m,4H),7.26(m,1H),7.18(s,1H),6.17(s,1H),5.17(q,1H),5.28(dd,1H),4.95(dd,1H),4.75(m,1H),4.43(d,1H),4.38-4.04(m,2H),3.40(s,3H),2.96-2.67(m,3H),2.60-2.41(m,1H),2.37-2.22(m,1H),1.99-0.85(m,14H)。
化合物60:MS:m/z 773.2(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.46(d,2H),7.88-7.84(m,1H),7.60-7.50(m,4H),7.35-7.17(m,1H),6.20(s,1H),6.08(d,1H),5.72(q,1H),4.98(dd,1H),4.72(dd,1H),4.56(m,1H),4.41(d,1H),4.21(m,1H),2.94-2.90(m,1H),2.80-2.77(m,1H),2.55-2.52(m,1H),2.23(q,1H),1.98-1.90(m,1H),1.84(s,3H),1.80-0.80(m,16H)。
化合物61:MS:m/z 845.3(M+
+1)；1
H NMR(CDCl3
)δ10.41(s,1H),8.34(d,2H),7.84(d,1H),7.53-7.44(m,1H),7.40-7.33(m,3H),7.19(s,1H),6.14(s,1H),5.71(q,1H),5.15(d,1H),4.98(dd,1H),4.89-4.80(m,2H),4.25-4.19(m,2H),2.95-2.90(m,1H),2.88-2.42(m,3H),2.44(s,3H),2.29(m,1H),1.98-1.20(m,14H),1.11(s,9H),1.00-0.87(1H)。
化合物62:MS:m/z 841.2(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.35(d,2H),7.89(d,1H),7.60-7.57(m,1H),7.33(d,2H),7.17(d,1H),7.05(s,1H),6.22(s,1H),5.68(q,1H),4.97(dd,1H),4.77-4.64(m,2H),4.33-4.17(m,2H),2.93-2.74(m,3H),2.44(s,3H),2.21(m,1H),1.95-0.91(m,17H)。
化合物63:MS:m/z 903.3；905.3(M+
+1)；1
H NMR(CDCl3
)δ10.18(s,1H),8.45(d,2H),8.23(d,1H),7.64(m,2H),7.49(d,3H),7.01(s,1H),6.17(s,1H),5.72(q,1H),5.13(d,1H),4.99(dd,1H),4.77(dd,1H),4.58(d,1H),4.53(brs,1H),4.27(m,1H),4.14(m,1H),2.83-2.44(m,3H),2.27(q,1H),1.95-1.22(m,23H),0.83(s,3H)。
化合物64:MS:m/z 787.3(M+
+1)；1
H NMR(CDCl3
)δ10.45(s,1H),8.25(d,2H),7.75(d,1H),7.67(s,1H),7.53-7.52(m,1H),7.26(d,2H),6.29(d,1H),6.19(s,1H),5.67(q,1H),4.94(dd,1H),4.75(dd,1H),4.52(brs,1H),4.42(d,1H),4.10-4.18(m,1H),2.89-2.50(m,3H),2.43(s,3H),2.35-2.20(m,1H),1.98-1.85(m,1H),1.82(s,3H),1.62-0.81(m,16H)。
化合物65:MS:m/z 803.2(M+
+1)；1
H NMR(CDCl3
)δ10.46(s,1H),8.30(d,1H),8.17(d,2H),7.63(d,1H),7.55(s,1H),7.45-7.41(m,1H),7.25-7.20(m,2H),5.97(s,1H),5.65-5.59(m,1H),5.36(d,1H),4.91-4.87(m,1H),4.73(dd,1H),4.37-4.05(m,3H),3.30(s,3H),2.84-2.47(m,3H),2.38(s,3H),2.40-2.16(m,1H),1.90-0.87(m,16H)。
化合物66:MS:m/z 871.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.19-8.02(m,2H),7.93(s,1H),7.67(s,1H),7.47-7.26(m,3H),6.05(s,1H),5.62(q,1H),5.34(d,1H),4.96-4.42(m,4H),4.36-4.10(m,2H),2.95-2.90(m,1H),2.77(s,3H),2.76-2.48(m,3H),2.35(s,3H),2.30-0.87(m,24H)。
化合物67:MS:m/z 875.3(M+
+1)。
化合物68:TG-2379:MS:m/z 871.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.34(d,2H),7.85(d,1H),7.73(s,1H),7.54-7.46(m,1H),7.38-7.22(m,3H),6.12(s,1H),5.65(q,1H),5.35(d,1H),4.93(dd,1H),4.78(dd,1H),4.62-4.50(m,2H),4.32-4.08(m,2H),2.81-2.42(m,3H),2.40(s,3H),2.26(q,1H),1.93-1.11(m,23H),0.80(s,3H)。
化合物69:MS:m/z 861.3(M+
+1)。
化合物70:MS:m/z 857.2(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.09(s,H),8.05(s,1H),7.96(dd,1H),7.58(dd,1H),7.47-7.19(m,3H),7.06(d,1H),6.21(s,1H),5.69(q,1H),4.95(dd,1H),4.81-4.60(m,2H),4.35-4.17(m,2H),3.94(s,3H),2.92-2.41(m,3H),2.23(q,1H),1.92-0.82(m,17H)。
化合物71:MS:m/z 819.2(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.01-7.81(m,3H),7.71(d,1H),7.34-7.22(m,3H),6.96(d,1H),6.01(s,1H),5.61(q,1H),5.27(dd,1H),4.90(dd,1H),4.69(dd,1H),4.38(d,1H),4.22-4.03(m,2H),3.87(s,3H),3.28(s,3H),2.86-2.42(m,3H),2.20(q,1H),1.97-0.88(m,16H)。
化合物72:MS:m/z 861.3(M+
+1)；1
H NMR(CDCl3
)δ10.38(s,1H),8.10-7.98(m,2H),7.86(d,1H),7.54-7.22(m,3H),7.20(s,1H),7.06(d,1H),6.10(s,1H),5.70(q,1H),5.29(d,1H),4.97(dd,1H),4.79-4.67(m,2H),4.18-4.04(m,2H),3.94(s,3H),2.95-2.57(m,3H),2.28(q,1H),1.91-0.87(m,25H)。
化合物73:Ms:m/z 803.2(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.12-8.96(m,2H),7.85(d,1H),7.56-7.26(m,4H),7.05(d,1H),6.19-6.15(m,2H),5.71(q,1H),4.96(dd,1H),4.74(s,1H),4.53-4.42(m,2H),4.19(d,1H),3.93(s,3H),2.91-2.20(m,4H),2.10-0.82(m,19H)。
化合物74:MS:m/z 861.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.39(d,2H),7.81(d,1H),7.50-7.26(m,3H),7.00(d,2H),6.05(s,1H),5.65(q,1H),5.21(d,1H),4.95(dd,1H),4.84(dd,1H),4.68(d,1H),4.21-4.07(m,2H),3.90(s,3H),2.90-2.45(m,4H),2.22(q,1H),1.98-1.20(m,14H),1.13(s,9H),0.99-0.84(m,1H)。
化合物75:MS:m/z 887.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.38(d,2H),7.82(d,1H),7.61(s,1H),7.59-7.43(m,1H),7.35-7.20(m,1H),7.01(d,2H),6.07(s,1H),5.68(q,1H),5.42(d,1H),4.98(dd,1H),4.75(dd,1H),4.58(s,1H),4.38-4.13(m,3H),3.88(s,3H),2.86(br,2H),2.59-2.11(m,2H),1.96-1.20(m,22H),0.92-0.78(m,4H)。
化合物76:Ms:m/z 903.3,905.3(M+
+1)。
化合物77:MS:m/z 887.3(M+
+1)。
化合物78:MS:m/z 883.4(M+
+1)；1
H NMR(CDCl3
)δ10.19(s,1H),8.46(d,2H),8.25(d,1H),7.62(m,2H),7.46(m,1H),7.04(d,2H),6.96(s,1H),6.19(s,1H),5.73(q,1H),5.15(d,1H),5.02(dd,1H),4.77(m,1H),4.58(m,2H),4.30(m,1H),4.15(m,3H),2.79(m,2H),2.54(m,1H),2.26(q,1H),1.92-0.83(m,26H),0.83(s,3H)。
化合物79:MS:m/z 869.4(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.44(d,2H),8.24(d,1H),7.60(m,2H),7.44(m,1H),7.04(s,1H),7.00(d,2H),6.16(s,1H),5.71(q,1H),5.21(d,1H),4.97(dd,1H),4.74(m,1H),4.57(m,2H),4.30(m,1H),4.15(m,3H),2.91(m,1H),2.75(m,2H),2.56(m,1H),2.26(q,1H),1.92-0.83(m,26H)。
化合物80:MS:m/z 883.4(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.43(d,2H),8.23(d,1H),7.61-7.39(m,4H),7.03(d,2H),6.18(s,1H),5.71(q,1H),5.30(d,1H),4.96(dd,1H),4.79-4.57(m,4H),4.41-4.22(m,1H),4.15-4.08(m,1H),2.96-2.67(m,3H),2.57-2.42(m,1H),2.25(q,1H),1.98-0.87(m,29H)。
化合物81:MS:m/z 897.4(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.42(d,2H),8.21(d,1H),7.57-7.25(m,4H),7.02(d,2H),6.14(s,1H),5.67-5.64(m,1H),5.40(d,1H),5.03-4.93(m,1H),4.79-4.54(m,4H),4.39-4.12(m,2H),2.77-2.72(m,2H),2.54(br,1H),2.26(q,1H),2.03-1.24(m,29H),0.80(s,3H)。
化合物82:MS:m/z 915.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.38(d,2H),7.74(d,1H),7.57-7.24(m,3H),7.27(d,2H),6.14(s,1H),5.66(q,1H),5.32(d,1H),4.98(dd,1H),4.76(dd,1H),4.71-4.48(m,3H),4.39-4.08(m,2H),2.85-2.42(m,3H),2.31(q,1H),2.03-1.24(m,29H),0.80(s,3H)。
化合物83:MS:m/z 901.2(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.46(d,2H),7.82(d,1H),7.54(dd,1H),7.42(s,1H),7.32(m,1H),6.98(d,2H),6.14(s,1H),5.65(q,1H),5.33(d,1H),4.97(dd,1H),4.76(dd,1H),4.71-4.50(m,3H),4.41-4.08(m,2H),2.93-2.42(m,4H),2.31(q,1H),2.03-0.80(m,29H)。
化合物84:MS:m/z 885.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.42(d,2H),8.23(d,1H),7.58(m,2H),7.44(dd,1H),7.22(s,1H),7,01(d,2H),6.17(s,1H),5.67(q,1H),5.16(d,1H),4.98(dd,1H),4.75(dd,1H),4.62(m,2H),4.38-4.08(m,2H),2.80-2.42(m,3H),2.32(q,1H),1.96-1.20(m,21H),1.13(s,9H),0.81(m,3H)。
化合物85:MS:m/z 923.2(M+
+1)。
化合物86:MS:m/z 883.2(M+
+1)；1
H NMR(CDCl3
)δ10.41(s,1H),8.19(d,1H),8.06(d,1H),7.95(s,1H),7.61-7.41(m,4H),6.92(d,1H),6.12(s,1H),6.04(s,2H),5.67(q,1H),5.35(d,1H),4.97(dd,1H),4.77(dd,1H),4.58(d,1H),4.36-4.11(m,2H),2.85-2.43(m,3H),2.27(q,1H),1.98-1.21(m,24H),0.81(s,3H)。
化合物87:MS:m/z 869.2(M+
+1)；1
H NMR(CDCl3
) δ10.36(s,1H),8.17(d,1H),7.97(d,1H),7.88(s,1H),7.58-7.32(m,4H),6.85(d,1H),6.02(s,1H),5.98(s,2H),5.59(q,1H),5.37(d,1H),4.87(d,1H),4.68(dd,1H),4.52-4.02(m,3H),2.90-2.38(m,4H),2.23(q,1H),1.91-0.88(m,24H)。
化合物88:MS:m/z 868.5(M+
+1)。
化合物89:MS:m/z 882.5(M+
+1)。
化合物90:MS:m/z 910.3(M+
+1)；1
H NMR(CDCL3
) δ10.32(s,1H),8.34(d,2H),8.22(d,1H),7.61-7.43(m,3H),7.44(dd,1H),6.76(d,2H),6.14(s,1H),5.62(q,1H),5.39(d,1H),4.96(dd,1H),4.72(dd,1H),4.63(brs,1H),4.55(d,1H),4.41-4.04(m,2H),3.42(q,4H),2.80-2.42(m,3H),2.32(q,1H),1.98-1.17(m,29H),0.83(s,3H)。
化合物91:MS:m/z 896.3(M+
+1)；1
H NMR(CDCl3
) δ10.46(s,1H),8.33(d,2H),8.21(d,1H),7.62-7.43(m,3H),7.43(dd,1H),6.77(d,2H),6.13(s,1H),5.65(q,1H),5.39(d,1H),4.93(dd,1H),4.73(dd,1H),4.64(brs,1H),4.53(d,1H),4.43-4.05(m,2H),3.43(q,4H),2.94-2.42(m,4H),2.29(q,1H),2.14-0.83(m,29H)。
化合物92:MS:m/z 901.4,903.4(M+
+1)；1
H NMR(CDCl3
) δ10.40(s,1H),8.36(d,2H),8.23(s,1H),7.58-7.26(m,5H),6.15(s,1H),5.65(q,1H),5.19(d,1H),4.96(dd,1H),4.77(dd,1H),4.62-4.52(m,2H),4.33-4.08(m,2H),3.01-2.42(m,5H),2.25(q,1H),1.96-0.89(m,29H)。
化合物93:MS:m/z 915.4,917.4(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),8.38(d,2H),8.22(s,1H),7.59-7.34(m,5H),6.13(s,1H),5.70(q,1H),5.29(d,1H),4.98(dd,1H),4.78(dd,1H),4.62-4.55(m,2H),4.35-4.08(m,2H),3.04-2.96(m,1H),2.80-2.43(m,3H),2.25(q,1H),1.97-1.20(m,29H),0.81(s,3H)。
化合物94:MS:m/z 867.4(M+
+1)。
化合物95:MS:m/z 881.3(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.41(d,2H),8.22(d,1H),7.63-7.21(m,4H),7.20(d,2H),6.16(s,1H),5.65(q,1H),5.38(d,1H),4.94(dd,1H),4.80(dd,1H),4.65-4.56(m,2H),4.38-4.12(m,2H),3.08-2.92(m,1H),2.83-2.67(m,2H),2.59-2.41(m,1H),2.25(q,1H),1.98-1.08(,m,28H),0.95-0.86(m,4H)。
化合物96:MS:m/z 881.4(M+
+1)；1
H NMR(CDCl3
)δ10.47(s,1H),8.40(d,2H),8.23(d,IH),7.76(s,1H),7.62-7.41(m,5H),6.13(s,1H),5.65(q,1H),5.33(d,1H),5.03-4.87(m,2H),4.78(dd,1H),4.57(d,1H),4.38-4.04(m,2H),2.95-2.43(m,4H),2.21(q,1H),2.01-1.37(m,20H),1.33(s,9H),1.21-0.86(m,3H)。
化合物97:MS:m/z 895.4(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.40(d,2H),8.23(d,1H),7.59-7.43(m,5H),6.98(d,1H),6.16(s,1H),5.65(q,1H),5.41(d,1H),4,98(dd,1H),4.79(q,1H),4.62-4.52(m,1H),4.36-4.09(m,3H),2.75(brs,2H),2.59-2.56(m,1H),2.28(q,1H),1.91-1.18(m,31H),0.89-0.78(m,4H)。
化合物98:MS:m/z 869.4(M+
+1)；1
H NMR(CDCl3
)δ10.41(s,1H),8.42(d,2H),8.23(d,1H),7.62-7.43(m,5H),7.44(dd,1H),6.17(s,1H),5.64(q,1H),5.17(d,1H),4.97(dd,1H),4.77-4.63(m,2H),4.21-4.10(m,2H),2.94-2.55(m,4H),2.27(q,1H),1.891.15(m,23H),1.10(s,9H),0.98-0.87(m,1H)。
化合物99:MS:m/z 925.4(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.37(d,2H),8.03(d,1H),7.50(d,2H),7.48(s,1H),7.01-6.92(m,2H),6.13(s,1H),5.65(q,1H),5.39(d,1H),4.98(dd,1H),4.88(dd,1H),4.64(s,1H),4.53(d,1H),4.41-4.23(m,1H),4.19-4.11(m,1H),3.88(s,3H),2.78-2.42(m,3H),2.26(q,1H),2.04-1.18(m,31H),0.89-0.78(m,4H)。
化合物100:MS:m/z 925.4(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.35(d,2H),7.77(d,1H),7.48(d,2H),7.38-7.22(m,1H),7.04-6.81(m,2H),6.16(s,1H),5.68(q,1H),5.21(d,1H),4.99(dd,1H),4.78(dd,1H),4.57(d,1H),4.22-4.03(m,3H),4.00(s,3H),2.80-2.43(m,3H),2.31(q,1H),1.96-1.20(m,31H),0.95-0.78(m,4H)。
化合物101:MS:m/z 827.3(M+
+1)。
化合物102:MS:m/z 897.4(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.39(d,2H),8.20(d,1H),7.59-7.37(m,5H),7.14(s,1H),6.04(s,1H),5.61(q,1H),5.21(d,1H),4.87(dd,1H),4.77(dd,1H),4.57(d,1H),4.19-4.07(m,4H),3.67-3.42(m,2H),3.17-2.40(m,6H),2.20(q,1H),1.93-0.78(m,27H)。
化合物103:MS:m/z 866.3(M+
+1)；1
H NMR(CDCl3
) δ10.45(s,1H),8.31(d,2H),8.12(d,1H),7.51-7.42(m,5H),7.32-7.25(m,1H),6.09(s,1H),5.61(q,1H),4.90(dd,1H),4.81(dd,1H),4.59(d,1H),4.50-4.36(m,2H),4.13(dd,1H),3.69-3.27(m,3H),3.10(brs,4H),2.90-2.41(m,4H),2.19(q,1H),1.98-0.78(m,25H)。
化合物104:MS:m/z 811.3(M+
+1)；1
H NMR(CDCl3
) δ10.38(s,1H),8.38(d,2H),8.19(d,1H),7.60-7.31(m,5H),7.32-7.25(m,1H),6.15(s,1H),5.65(q,1H),4.88(dd,1H),4.70(dd,1H),4.57(dd,1H),4.40(d,1H),4.21-4.05(m,2H),2.95-2.41(m,4H),2.22(q,1H),2.01(s,3H),1.98-0.79(m,24H)。
化合物105:MS:m/z 868.4(M+
+1)；1
H NMR(CDCl3
) δ10.57(s,1H),8.37(d,2H),8.15(d,1H),8.09(s,1H),7.58-7.51(m,4H),7.27(dd,1H),6.09(s,1H),5.61(q,1H),4.98-4.79(m,4H),4.44(s,1H),4.10(dd,1H),3.79-3.68(m,2H),2.92-2.45(m,4H),2.24(q,1H),1.98-0.88(m,32H)。
化合物106:MS:m/z 882.4(M+
+1)；1
H NMR(CDCl3
) δ10.37(s,1H),8.35(d,2H),8.16(d,1H),7.56-7.48(m,2H),7.42(d,2H),7.36-7.33(m,1H),7.30(s,1H),6.09(s,1H),5.63(q,1H),4.97-4.86(m,2H),4.76(dd,1H),4.58(d,1H),4.28-4.11(m,2H),3.39-3.25(m,4H),3.01-2.82(m,5H),2.75-2.44(m,2H),2.16(q,1H),1.95-0.76(m,25H)。
化合物107:MS:m/z 863.3(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.33(d,2H),8.32(d,1H),7.59-7.40(m,6H),7.37(s,1H),6.81(d,1H),6.65(d,1H),6.25(s,1H),6.13(s,1H),5.62(q,1H),4.87(dd,1H),4.69-4.52(m,2H),4.42(d,1H),4.18(dd,1H),2.95-2.40(m,4H),2.24-0.78(m,25H)。
化合物108:MS:m/z 840.4(M+
+1)；1
H NMR(CDCl3
)δ10.67(s,1H),8.32(d,2H),8.19(d,1H),7.77(s,1H),7.58-7.44(m,4H),7.34-7.25(m,1H),6.14(s,1H),5.77(q,1H),4.98(dd,1H),4.78-4.71(m,2H),4.44(d,1H),4.29(brs,1H),4.11-4.05(m,1H),2.96-2.72(m,2H),2.64(s,6H),2.41(br,1H),2.20(q,1H),1.96-0.78(m,25H)。
化合物109:MS:m/z 837.4(M+
+1)；1
H NMR(CDCl3
)δ10.49(s,1H),8.35-8.25(m,3H),7.71(s,1H),7.55-7.41(m,4H),7.26(s,1H),6.19(d,1H),6.01(s,1H),5.63(q,1H),4.88(dd,1H),4.71(brs,1H),4.56(d,1H),4.39(brs,1H),4.06(d,1H),2.81-2.45(m,4H),2.23(q,1H),1.99-1.64(m,4H),1.58-0.77(m,21H),0.51(brs,4H)。
化合物110:MS:m/z 865.4(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),8.29(d,2H),8.15(d,1H),7.56-7.42(m,5H),7.36-7.24(m,1H),6.05(s,1H),5.98(d,1H),5.64(q,1H),4.87(dd,1H),4.69(dd,1H),4.55(d,1H),4.42(dd,1H),4.04(dd,1H),2.81-2.05(m,5H),1.95-1.71(m,4H),1.57-0.76(m,29H)。
化合物111:MS:m/z 881.4(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.33(d,2H),8.30(s,1H),7.58-7.41(m,4H),7.39(dd,1H),7.22(s,1H),6.10(s,1H),5.98(d,1H),5.62(q,1H),4.91(dd,1H),4.68(dd,1H),4.46-4.40(m,2H),4.05(dd,1H),3.79-3.62(m,2H),3.21-3.09(m,2H),2.88-2.40(m,3H),2.22-1.72(m,6H),1.47-0.78(m,25H)。
化合物112:MS:m/z 864.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.38(d,2H),8.23(d,1H),8.09(s,1H),7.57-7.45(m,5H),7.41(dd,1H),7.28(s,1H),6.42(s,1H),6.15(s,1H),5.62(q,1H),4.86(dd,1H),4.75-4.66(m,2H),4.49(d,1H),4.17(dd,1H),2.83-2.43(m,3H),2.25(q,1H),1.99-0.78(m,25H)。
化合物113:MS:m/z 853.4(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.36(d,2H),8.30(d,1H),7.62-7.46(m,4H),7.41-7.36(m,1H),7.17(s,1H),6.19(s,1H),6.17(d,1H),5.68(q,1H),4.92(dd,1H),4.73(dd,1H),4.58-4.43(m,2H),4.19(dd,1H),2.89-2.43(m,3H),2.22(q,1H),1.99-1.82(m,6H),1.59-0.83(m,28H)。
化合物114:MS:m/z 907.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.39(d,2H),8.21(d,1H),7.56(dd,1H),7.48(d,2H),7.40(dd,1H),7.24(s,1H),7.18(d,2H),7.03(d,2H),6.92(s,1H),6.06(s,1H),5.74(d,1H),5.61(q,1H),4.87(dd,1H),4.70(dd,1H),4.42(d,1H),4.31(dd,1H),4.08(dd,1H),2.84-2.79(m,1H),2.65-2.43(m,2H),2.23(q,1H),1.88-1.62(m,6H),1.49-0.78(m,19H)。
化合物115:MS:m/z 895.4(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.40(d,2H),8.01(s,1H),7.55(d,2H),7.46-7.32(m,3H),6.13(s,1H),5.61(q,1H),5.32(brs,1H),5.01-4.87(m,1H),4.89(dd,1H),4.62-4.55(m,2H),4.34-4.08(m,2H),2.94-2.55(m,4H),2.50(s,3H),2.23(q,1H),1.95-1.10(m,32H)。
化合物116:MS:m/z 909.4(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.40(d,2H),8.01(s,1H),7.55(d,2H),7.47-7.26(m,3H),6.14(s,1H),5.69(q,1H),5.37(d,1H),4.99(dd,1H),4.78(dd,1H),4.60(d,1H),4.40-4.05(m,3H),2.80-2.51(m,3H),2.50(s,3H),2.29(q,1H),1.98-1.12(m,32H),0.82(s,3H)。
化合物117:MS:m/z 855.2(M+
+1)；1
H NMR(CDCl3
)δ10.08(s,1H),8.22(d,2H),8.03(d,2H),7.44-7.18(m,3H),7.26-7.17(m,1H),7.13(d,1H),6.12(s,1H),5.65(q,1H),4.89(dd,1H),4.77(dd,1H),4.49(d,1H),4.42-4.36(m,1H),4.13(dd,1H),3.16(s,1H),2.84-2.46(m,4H),2.16(q,1H),1.95-0.77(m,31H)。
化合物118:MS:m/z 895.4(M+
+1)。
化合物119:MS:m/z 895.4(M+
+1)。
化合物120:MS:m/z 840.2(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.38(d,2H),8.20(d,1H),8.00(d,1H),7.61-7.54(m,2H),7.50(d,2H),7.41-7.35(m,1H),7.15(s,1H),6.72(d,1H),6.10(d,1H),5.63(q,1H),5.27(d,1H),4.89(dd,1H),4.68(dd,1H),4.51-4.42(m,2H),4.12(dd,1H),2.84-2.43(m,4H),2.22(q,1H),1.98-0.84(m,24H)。
化合物121:MS:m/z 829.3(M+
+1)。
化合物122:MS:m/z 833.3(M+
+1)。
化合物123:MS:m/z 821.3(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),7.90(dd,1H),7.60(s,1H),7.27(dd,1H),7.32-7.20(m,2H),6.91(s,1H),6.53(dd,1H),6.03(s,1H),5.64(q,1H),4.98-4.89(m,2H),4.71-4.58(m,2H),4.14-4.03(m,2H),2.86-2.80(m,1H),2.67-2.40(m,2H),2.22(q,1H),1.98-1.10(m,15H),1.05(s,9H),0.98-0.82(m,1H)。
化合物124:MS:m/z 779.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),7.93(dd,1H),7.70(s,1H),7.65-7.55(dd,1H),7.41-7.26(m,2H),7.04(s,1H),6.61(s,1H),6.15(s,1H),5.72(q,1H),5.37(d,1H),5.01-4.91(m,1H),4.77(dd,1H),4.46(d,1H),4.37-4.09(m,2H),3.36(s,3H),2.92-2.53(m,3H),2.23(q,1H),1.99-0.86(m,16H)。
化合物125:MS:m/z 817.2(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),7.98(d,1H),7.66(s,1H),7.60(dd,1H),7.40-7.09(m,3H),6.11(s,1H),6.60(s,1H),6.17(s,1H),5.72(q,1H),4.99(dd,1H),4.76-4.67(m,2H),4.31-4.18(m,2H),2.91-2.75(m,2H),2.45(br,1H),2.22-0.84(m,17H)。
化合物126:MS:m/z 763.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),7.81(dd,1H),7.60(s,1H),7.52(dd,1H),7.35-7.18(m,3H),6.52(d,1H),6.13-6.01(m,2H),5.61(q,1H),4.83(dd,1H),4.62(dd,1H),4.45(dd,1H),4.38(d,1H),4.17(dd,1H),2.85-2.79(m,1H),2.67(d,1H),2.41(m,1H),2.21-0.84(m,20H)。
化合物127:MS:m/z 821.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.15(s,1H),7.79(d,1H),7.45-7.42(m,3H),7.35-7.25(m,1H),7.01(s,1H),5.89(s,1H),5.54(q,1H),5.19(d,1H),4.85(dd,1H),4.67(dd,1H),4.54(d,1H),4.20(dd,1H),4.04(d,1H),2.91-2.44(m,3H),2.24(q,1H),2.01-1.11(m,15H),1.06(s,9H),0.83-0.78(m,1H)。
化合物128:MS:m/z 833.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.07(d,1H),7.56-7.22(m,5H),6.89(d,1H),5.96(s,1H),5.57-5.49(m,1H),5.21-5.17(m,1H),4.96-4.83(m,1H),4.72(dd,1H),4.67(d,1H),4.18-4.03(m,2H),2.90-2.79(m,1H),2.69(s,3H),2.64-2.46(m,2H),2.22(q,1H),1.97-1.04(m,15H),1.04(s,9H),0.96-0.87(m,1H)。
化合物129:MS:m/z 836.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),7.88(d,1H),7.53-7.50(m,1H),7.49(dd,1H),7.19(s,1H),6.65(s,1H),6.04(s,1H),5.70-5.50(m,1H),5.12-4.48(m,4H),4.19-3.98(m,2H),2.95-2.58(m,3H),2.48(s,3H),2.32-2.12(m,1H),1.97-1.18(m,15H),1.00(s,9H),0.98-0.86(m,1H)。
化合物130:MS:m/z 832.2(M+
+1)；1
H NMR(CDCl3
)δ10.20(s,1H),7.84(dd,1H),7.52(dd,1H),7.39(,1H),7.38-7.26(m,2H),6.62(s,1H),6.05(s,1H),5.60(q,1H),4.83(dd,1H),4.67(dd,1H),4.55(dd,1H),4.36(d,1H),4.08(dd,1H),2.81-2.50(m,3H),2.48(s,3H),2.45-2.37(m,1H),2.18(q,1H),1.99-0.87(m,15H)。
化合物131:MS:m/z 888.3(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.23(d,1H),7.41(s,1H),7.30(m,2H),7.11(s,1H),6.16(s,1H),5.68(q,1H),5.23(d,1H),4.98(dd,1H),4.75(brs,1H),4.54(d,1H),4.36-4.11(m,3H),3.39-3.27(m,1H),2.96-2.63(m,3H),2.54(s,3H),2.25(q,1H),1.89-0.93(m,30H)。
化合物132:MS:m/z 888.3(M+
+1)；1
H NMR(CDCl3
)δ10.24(s,1H),8.37(d,1H),7.74-7.51(m,2H),7.48-7.42(m,1H),7.22(s,1H),7.12(s,1H),6.17(s,1H),5.70(q,1H),5.28(d,1H),4.99(dd,1H),4.76(dd,1H),4.58(d,1H),4.52(brs,1H),4.35-4.16(m,2H),3.40-3.35(m,1H),2.79-2.43(m,3H),2.25(q,1H),1.95-1.23(m,29H),0.87-0.76(m,3H)。
化合物133:MS:m/z 887.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.59(s,1H),8.22(d,1H),7.81(d,1H),7.58-7.42(m,3H),6.95-6.89(m,2H),6.09(s,1H),5.68(q,1H),5.32(d,1H),4.99(m,1H),4.74(m,1H),4.54(d,1H),4.39-4.22(m,1H),4.14-4.11(m,1H),2.90(m,1H),2.78(m,2H),2.55(m,1H),2.27(q,1H),1.90-1.10(m,21H),1.45(s,9H),0.94-0.83(m,2H)。
化合物134:MS:m/z 901.3(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.8.51(s,1H),8.23(d,1H),7.81(d,1H),7.59-7.43(m,3H),7.13(s,1H),6.90(d,1H),6.09(s,1H),5.68(q,1H),5.22(d,1H),4.99(dd,1H),4.76(m,1H),4.55(d,1H),4.39-4.22(m,1H),4.14-4.11(m,1H),2.78(m,2H),2.55(m,1H),2.27(q,1H),1.90-0.83(m,23H),1.46(s,9H)。
化合物135:MS:m/z 888.3(M+
+1)。
化合物136:MS:m/z 902.3(M+
+1)。
化合物137:MS:m/z 899.4(M+
+1)。
化合物138:MS:m/z 885.3(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.17(d,1H),7.58(m,2H),7.42-7.33(m,2H),6.63(m,1H),6.07(s,1H),5.67(q,1H),5.29(d,1H),4.97(dd,1H),4.77(m,1H),4.57(m,1H),4.42-4.03(m,3H),2.89(m,1H),2.75(m,5H),2.52(m,1H),2.27(q,1H),1.91-0.82(m,32H)。
化合物139:MS:m/z 803.3(M+
+1)。
化合物140:MS:m/z 817.3(M+
+1)。
化合物141:MS:m/z 831.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.05(s,1H),7.56-7.48(m,3H),6.06(s,1H),5.62(q,1H),5.15(dd,1H),4.91(dd,1H),4.75(dd,1H),4.59(d,1H),4.35-4.02(m,3H),2.96-2.88(m,1H),2.74-2.65(m,2H),2.53(s,3H),2.24(q,1H),1.96-0.89(m,24H)。
實施例142和143：
合成[4-環丙磺醯基氨基羰基-2,15-二氧代-18-(2-苯基-苯並[4,5]呋喃並[3,2-b]吡啶-4-基氧基)-3,16-二氮雜三環[14.3.0.04,6]十九碳-7-烯-14-基]-氨基甲酸叔丁酯(化合物142)和[4-環丙磺醯基氨基羰基-2,15-二氧代-18-(2-苯基-苯並[4,5]呋喃並[3,2-b]吡啶-4-基氧基)-3,16-二氮雜三環[14.3.0.04,6]十九碳-7-烯-14-基]-氨基甲酸環戊酯(化合物143)
化合物142和143通過以下合成路線製備：
向2-羥基苄腈(30克，251.6毫摩爾)在乙基甲基酮(320毫升)的溶液中加入碳酸鉀(69.6克，755.5毫摩爾)。於室溫攪拌30分鐘之後，在形成的混合物中加入氯丙酮(34.95克，377.8毫摩爾)，然後於100℃加熱該溶液過夜。最後，減壓下除去反應溶劑，形成的固體用水和乙醚洗滌後得到I-13(31克，產率：70.3%)。MS:m/z 176.0(M+
+1)；1
H NMR(CDCl3
)δ7.59(d,1H),7.46(dd,1H),7.41(d,1H),7.24(dd,1H),2.50(s,3H)。
於5-10℃，在恒定攪拌下，向2-乙醯基-3-氨基苯並呋喃I-13(2.17克，12.38毫摩爾)和苯甲醛(1.31克，12.38毫摩爾)的乙醇(30毫升)溶液中逐滴加入氫氧化鈉水溶液(70%,5毫升)。攪拌過夜之後，亮黃色固體的粗產物懸浮在該反應溶液中。過濾固體，收集，並用乙醇重結晶，獲得絲狀針形物I-14(2.7克，90%)。MS:m/z 264.0(M+
+1)；1
H NMR(CDCl3
)δ7.83(d,1H),7.71(dd,2H),7.64(d,1H),7.62(d,1H),7.58-7.39(m,5H),7.29-7.24(m,1H),5.83(m,2H)。
將中間體I-14(1.32克，5.0毫摩爾)懸浮於乙酸酐(10毫升)中，並在熱水浴中攪拌。攪拌過夜後，將反應混合物倒入冰-水中。分離並收集懸浮的粗產物，然後用乙醇重結晶，得到I-15(1.52g,90%)。MS:m/z 306.0(M+
+1)；1
H NMR(CDCl3
)δ8.58(d,1H),7.91(d,1H),7.72(m,3H),7.54-7.44(m,5H),7.34-7.7.28(m,1H),2.35(s,3H)。
將中間體I-15(1.22克，4.0毫摩爾)在CHCl3
(20毫升)的溶液緩慢滴加到溴(0.72g 4.5毫摩爾)在CHCl3
(15毫升)的溶液中。攪拌過夜後，該反應混合物用冰水驟冷。將懸浮的固體分離、收集和用乙醇/H2
O重結晶，獲得I-16(1.12克，60%)。MS:m/z 465.9(M+
+1)；1
H NMR(CDCl3
)δ10.22(brs,1H),8.63(d,1H),7.61-7.25(m,8H),5.92(d,1H),5.62(d,1H),2.37(s,3H)。
向I-16(0.93克，2.0毫摩爾)在丙酮(25毫升)的溶液中加入無水乙酸鉀(0.2克，2.0毫摩爾)。攪拌過夜後，將反應混合物倒入冷水中。將懸浮的固體分離、收集和用乙醇重結晶，得到單溴化物-化合物I-17(0.46克，60%)。MS:m/z 385.9(M+
+1)；1
H NMR(CDCl3
)δ10.50(brs,1H),8.54(d,1H),8.48(s,1H),7.93(m,2H),7.56-7.46(m,5H),7.36-7.31(m,1H),2.35(s,3H)。
化合物I-17(0.35克，1.0毫摩爾)在乙酸(5毫升)和正磷酸(5毫升)中回流5小時。將反應混合物冷卻至室溫，倒入冰水中再攪拌30分鐘。將懸浮的固體分離、收集和用DMF重結晶，得到1-18(0.2克，80%)。MS:m/z 262.0(M+
+1)。
I-18(1.0克，3.8毫摩爾)和磷醯氯(POCl3
)(10毫升)的溶液回流2小時。將該溶液冷卻和完全濃縮之後，產生的殘餘物用10%氫氧化鈉猝滅，用二氯甲烷(20毫升x 3)萃取。收集有機層，用硫酸鈉乾燥，並濃縮。粗產物用CH2
Cl2
和正己烷重結晶，獲得I-19(0.7克，75%)。MS:m/z 279.9(M+
+1)；1
H NMR(CDCl3
)δ8.45(d,1H),8.09(d,2H),7.84(s,1H),7.71-7.64(m,2H),7.56-7.47(m,4H)。
於0℃向Boc-反-4-羥基-L-脯氨酸(0.53克，2.3毫摩爾)在DMSO(10毫升)的懸浮液中加入t
-BuONa(0.49克，5.08毫摩爾)。加熱至室溫並攪拌1小時後，於10℃緩慢加入中間體I-19(0.64克，2.3毫摩爾)。攪拌該反應混合物4小時，然後用10% HCl水溶液猝滅至pH為6-7。過濾粗固體，用水洗滌，真空乾燥，得到I-20(0.94g,86.3%)。MS:m/z 475.1(M+
+1)；1
H NMR(CDCl3
)δ8.27(d,1H),7.97(m,2H),7.86-7.76(m,3H),7.66-7.44(m,4H),5.81(s,1H),4.47(m,1H),4.03-3.89(m,2H),2.81(m,1H),2.50(q,1H)。
室溫，向I-20(1.1克，2.3毫摩爾)的MeOH(20毫升)溶液中加入SOCl2
(1.17克，9.9毫摩爾)。回流1小時後，真空去除反應溶劑，得到粗化合物I-21，該混合物無需進一步純化即可用於下一步驟。MS:m/z 389.1(M+
+1)。
室溫，向I-21(0.78g,2.0毫摩爾)、2-(1H-7-氮雜苯並三唑-1-基)-1,1,3,3-四甲基脲陽離子六氟-磷酸鹽甲銨(HATU,1.12克，3.0毫摩爾)、N-羥基苯並三唑(HOBT,0.4克，3.0毫摩爾)和2-叔丁氧基羰基氨基-壬-8-烯酸(1.19克，5.2毫摩爾)的CH2
Cl2
(20毫升)溶液中加入NMM(1.0克，9.9毫摩爾)。攪拌混合物過夜之後，真空濃縮。殘餘物通過矽膠柱色譜純化，得到化合物I-22(1.02克，80.7%)。MS:m/z 642.3(M+
+1)；1
H NMR(CDCl3
)δ8.24(d,1H),8.05(d,2H),7.58(m,2H),7.56-7.41(m,4H),7.28(d,1H),5.83-5.76(q,1H),5.71(s,1H),5.24(d,1H),5.01-4.82(m,2H),4.76(dd,1H),4.75-4.34(m,2H),4.03(m,1H),3.77(s,3H),2.78(m,1H),2.36(q,1H),2.01(m,2H),1.75(m,1H),1.54(m,1H),1.42(m,6H),1.31(s,9H)。
室溫，向I-22(1.0克，1.6毫摩爾)在THF(20毫升)的溶液中加入0.5M LiOH(5.7毫升，2.9毫摩爾)。反應混合物攪拌過夜之後，用10% HCl酸化至pH<7，並真空濃縮，得到固體產物，將固體產物過濾並用水洗滌，得到I-23。MS:m/z 628.1(M+
+1)；1
H NMR(CDCl3
)δ8.34(brs,1H),8.04(d,2H),7.62(m,2H),7.60-7.41(m,4H),7.28(m,2H),5.81-5.72(q,1H),5.70(s,1H),5.29(d,1H),5.00-4.87(m,3H),4.48(m,2H),4.01(m,1H),2.77(m,2H),1.98(m,2H),1.72(m,1H),1.61(m,1H),1.44(m,6H),1.33(s,9H)。
室溫，將NMM(0.12克，1.2毫摩爾)加入到化合物I-23(0.26克，0.41毫摩爾)、HATU(0.31克，0.81毫摩爾)、HOBT(0.084克，0.61毫摩爾)和環丙烷磺酸(1-氨基-2-乙烯基-環丙烷羰基)-醯胺(0.094克，0.41毫摩爾)在CH2
Cl2
(10毫升)的溶液中。攪拌反應混合物過夜之後，真空濃縮。殘餘物通過矽膠柱色譜純化，得到化合物I-24(0.15g,45%)。MS:m/z 804.3(M+
+1)；1
H NMR(CDCl3
)δ10.22(s,1H),8.35(d,1H),8.01(d,2H),7.59(d,2H),7.48-7.30(m,5H),7.04(s,1H),5.78(m,3H),5.35(d,1H),5.23(d,1H),5.15(d,1H),4.93(m,2H),4.53(dd,1H),4.41-4.30(m,2H),4.05(m,1H),2.91(m,1H),2.61(m,2H),2.14(dd,1H),2.04(m,3H),1.91-1.52(m,3H),1.45-1.22(18H),1.21(m,2H)。
室溫，在N2
下向化合物I-24(100毫克，0.12毫摩爾)在CH2
Cl2
的溶液中加入霍維達-格拉布第二代催化劑(35毫克，0.056毫摩爾)，然後加熱該反應混合物至40℃並攪拌24小時。將反應混合物濃縮並通過柱純化，得到化合物142(30毫克，31%)。MS:m/z 812.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.28(d,1H),8.04(d,2H),7.61-7.41(m,7H),7.00(s,1H),5.69(m,2H),5.19(d,1H),4.97(dd,1H),4.67(m,2H),4.31(m,1H),4.05(m,1H),2.89(m,1H),2.70(m,2H),2.55(m,1H),2.29(q,1H),1.89-1.11(m,13H),1.19(s,9H),0.97-0.86(m,2H)。
室溫，向化合物142(0.1克,0.14毫摩爾)在CH2
Cl2
(5毫升)的溶液中加入過量4N HCl在二噁烷(2毫升)中的溶液。攪拌4小時後，蒸發去除HCl、二噁烷和CH2
Cl2
，得到粗化合物I-25，該粗化合物無需進一步純化即可用於下一步驟。MS:m/z 712.3(M+
+1)。
將I-25溶解於乙腈(2毫升)中，然後加入飽和NaHCO3
(1毫升)。攪拌反應混合物10分鐘。室溫在反應混合物中加入氯甲酸環戊酯(0.02克，0.15毫摩爾)。再攪拌2小時之後，反應混合物用飽和NaHCO3
猝滅，用CH2
Cl2
萃取。殘餘物通過矽膠柱色譜純化，得到化合物143(0.1克，87%)。MS:m/z 824.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.29(d,1H),8.07(d,2H),7.62-7.32(m,7H),7.00(s,1H),5.75(s,1H),5.70(q,1H),5.22(d,1H),4.99(dd,1H),4.75(m,2H),4.56(d,1H),4.32(m,1H),4.05(m,1H),2.89(m,1H),2.70(m,2H),2.52(m,1H),2.29(q,1H),1.91-0.85(m,23H)。
實施例144-253：化合物144-253的合成
化合物144-253各自按照與實施例142和143中所述類似的方式製備。
化合物144:MS:m/z 7887.3(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.40(s,1H),8.21(d,1H),8.08(dd,1H),7.56-7.11(m,7H),6.80(s,1H),5.63(m,2H),4.93(m,1H),4.79(m,1H),4.31(m,2H),4.05(m,1H),3.45(s,3H),2.87(m,1H),2.70(m,2H),2.52(m,1H),2.25(q,1H),1.91-0.84(m,15H)。
化合物145:MS:m/z 872.3(M+
+1)。
化合物146:MS:m/z 770.3(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),8.25(d,1H),8.00(d,2H),7.56-7.25(m,7H),6.66(s,1H),5.69(m,2H),5.45(d,1H),4.95(dd,1H),4.70(m,1H),4.40-4.28(m,2H),4.05(m,1H),3.52(s,3H),2.88(m,1H),2.70(m,2H),2.51(m,1H),2.30(q,1H),1.87-1.09(m,13H),0.97-0.84(m,2H)。
化合物147:MS:m/z 697.2(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.24(d,1H),8.04(d,2H),7.56-7.31(m,8H),5.63(m,2H),4.97(dd,1H),4.63(m,1H),4.09(m,1H),3.96(m,1H),2.84(m,1H),2.62(m,2H),2.6-2.03(m,4H),1.95-0.84(m,15H)。
化合物148:MS:m/z 872.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.09(dd,1H),7.69(d,1H),7.48-7.14(m,7H),5.71(m,2H),5.31(d,1H),4.98(dd,1H),4.74(m,1H),4.55(d,1H),4.36(m,1H),4.05(m,2H),3.96(s,3H),2.89(m,1H),2.68(m,2H),2.52(m,1H),2.28(q,1H),2.00-0.88(m,23H)。
化合物149:MS:m/z 818.2(M+
+1)。
化合物150:MS:m/z 802.2(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.08(dd,1H),7.68(d,1H),7.49(d,1H),7.39-7,13(m,6H),6.10(d,1H),5.72(m,2H),4.95(dd,1H),4.63(m,2H),4.17(d,1H),4.06(m,1H),3.92(s,3H),2.89(m,1H),2.69(m,2H),2.46(m,1H),2.26(q,1H),1.94-0.86(m,15H),1.91(s,3H)。
化合物151:MS:m/z 854.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.27(d,1H),8.03(d,2H),7.59(m,3H),7.45(dd,1H),7.01(d,2H),6.88(m,1H),5.74(m,2H),5.19(d,1H),4.96(m,2H),4.75(s,1H),4.53(d,1H),4.32(m,1H),4.04(m,1H),3.87(s,3H),2.89(m,1H),2.69(m,2H),2.46(m,1H),2.27(q,1H),1.90-1.12(m,21H),0.92-0.87(m,2H)。
化合物152:MS:m/z 842.3(M+
+1)。
化合物153:MS:m/z 854.3(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.58(s,1H),8.43(m,1H),7.85(d,1H),7.59(m,2H),7.37(m,3H),7.12(dd,1H),7.01(d,1H),5.65(m,2H),5.31(d,1H),4.94(dd,1H),4.72(m,2H),4.53(d,1H),4.37(m,1H),4.07(m,1H),3.87(s,3H),2.88(m,1H),2.66(m,2H),2.50(m,1H),2.28(q,1H),1.88-0.82(m,23H)。
化合物154:MS:m/z 854.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.50(s,1H),8.29(d,1H),7.63(s,1H),7.56(m,3H),7.43(m,2H),7.28(m,1H),7.11(s,1H),6.98(dd,1H),
5.74(s,1H),5.69(q,1H),5.29(d,1H),4.94(dd,1H),4.73(m,1H),4.57(d,1H),4.34(m,1H),4.04(m,1H),3.92(s,3H),2.88(m,1H),2.68(m,2H),2.51(m,1H),2.29(q,1H),1.87-0.84(m,23H)。
化合物155:Ms:m/z 842.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.28(d,1H),7.85(d,1H),7.57(m,2H),7.40(m,3H),7.14(dd,1H),7.01(d,2H),5.68(q,1H),5.58(s,1H),5.19(d,1H),4.92(dd,1H),4.67(m,2H),4.33(m,1H),4.03(m,1H),3.87(s,3H),2.89(m,1H),2.68(m,2H),2.54(m,1H),2.28(q,1H),1.90-1.11(m,13H),1.21(s,9H),0.97-0.87(m,2H)。
化合物156:MS:m/z 854.3(M+
+1)；1
H NMR(CDCl3
)δ10.24(s,1H),8.59(s,1H),8.04(m,2H),7.84(d,1H),7.49-7.28(m,4H),7.08(d,1H),6.91(s,1H),5.72(s,1H),5.68(q,1H),5.21(d,1H),4.97(dd,1H),4.71-4.67(m,2H),4.56(d,1H),4.36(m,1H),4.05(s,3H),4.04(m,1H),2.90(m,1H),2.69(m,2H),2.54(m,1H),2.31(q,1H),1.96-1.06(m,21H),0.95-0.83(m,2H)。
化合物157:MS:m/z 838.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.59(s,1H),8.27(d,1H),7.92(d,2H),7.57(m,2H),7.44(m,1H),7.26-7.17(m,3H),5.68(s,1H),5.64(q,1H),5.37(d,1H),4.96(m,1H),4.76(m,1H),4.67(m,1H),4.56(d,1H),4.36(m,1H),4.04(m,1H),2.89(m,1H),2.69(m,2H),2.53(m,1H),2.40(s,3H),2.31(q,1H),1.94-1.07(m,21H),0.95-0.83(m,2H)。
化合物158:MS:m/z 842.3(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.26(d,1H),8.05(m,2H),7.58(m,2H),7.43(m,1H),7.25-7.19(m,4H),5.72(s,1H),5.68(q,1H),5.35(d,1H),4.96(dd,1H),4.75-4.69(m,2H),4.56(d,1H),4.36(m,1H),4.04(m,1H),2.87(m,1H),2.67(m,2H),2.50(m,1H),2.28(q,1H),1.91-1.07(m,21H),0.97-0.84(m,2H)。
化合物159:MS:m/z 872.3(M+
+1)。
化合物160:MS:m/z 872.1(M+
+1)；1
H NMR(CDCl3
)δ10.48(s,1H),8.02(m,2H),7.68(d,1H),7.47(d,1H),7.23-7.17(m,4H),5.74(m,2H),5.68(q,1H),5.23(d,1H),4.97(dd,1H),4.76(s,1H),4.67(m,1H),4.54(d,1H),4.33(m,1H),4.04(m,1H),3.93(s,3H),2.89(m,1H),2.67(m,2H),2.52(m,1H),2.27(q,1H),1.92-1.06(m,21H),0.97-0.84(m,2H)。
化合物161:MS:m/z 860.2(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.01(m,2H),7.67(d,1H),7.47(d,1H),7.29-7.16(m,5H),5.68(m,2H),5.23(d,1H),4.95(dd,1H),4.69-4.63(m,2H),4.31(m,1H),4.04(m,1H),3.92(s,3H),2.88(m,1H),2.67(m,2H),2.54(m,1H),2.27(q,1H),1.92-0.83(m,15H),1.20(s,9H)。
化合物162:MS:m/z 856.1(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.03(m,2H),7.66(d,1H),7.48(d,1H),7.32(s,1H),7.29-7.15(m,5H),5.73(m,2H),4.92(dd,1H),4.69(m,2H),4.31(d,1H),4.06(m,1H),3.91(s,3H),2.85(m,1H),2.68(m,2H),2.44(m,1H),2.20(q,1H),1.93-0.83(m,15H)。
化合物163：MS：m/z 854.2(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.60(s,1H),8.01(m,2H),7.68(d,1H),7.46(m,4H),7.15(m,2H),5.71(s,1H),5.68(q,1H),5.37(d,1H),4.96(dd,1H),4.67(s,1H),4.64(m,1H),4.55(d,1H),4.36(m,1H),4.03(m,1H),3.93(s,3H),2.88(m,1H),2.68(m,2H),2.52(m,1H),2.28(q,1H),1.94-1.07(m,21H),0.97-0.84(m,2H)。
化合物164:MS:m/z 830.4(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.25(d,1H),8.04(m,2H),7.57(m,2H),7.42(m,1H),7.25-7.14(m,4H),5.68(m,2H),5.25(d,1H),4.92(dd,1H),4.66(m,2H),4.32(m,1H),4.05(m,1H),2.87(m,1H),2.68(m,2H),2.55(m,1H),2.28(q,1H),1.91-1.06(m,13H),1.20(s,9H),0.97-0.84(m,2H)。
化合物165:MS:m/z 868.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.53(s,1H),8.13(d,1H),7.91(m,2H),7.58(m,1H),7.19(m,1H),7.00(m,3H),5.72(s,1H),5.68(q,1H),5.28(d,1H),4.95(dd,1H),4.79(s,1H),4.68(m,1H),4.53(d,1H),4.37(m,1H),4.05(m,1H),3.91(s,3H),2.88(m,1H),2.66(m,2H),2.50(m,1H),2.40(s,3H),2.25(q,1H),1.90-1.06(m,21H),0.97-0.83(m,2H)。
化合物166:MS:m/z 868.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.59(s,1H),7.98(m,2H),7.71(s,1H),7.46(d,1H),7.27(m,2H),7.15(m,2H),5.71(s,1H),5.68(q,1H),5.29(d,1H),4.94(dd,1H),4.78(s,1H),4.67(m,1H),4.54(d,1H),4.36(m,1H),4.04(m,1H),3.93(s,3H),2.88(m,1H),2.68(m,2H),2.53(m,1H),2.40(s,3H),2.28(q,1H),1.92-1.08(m,21H),0.97-0.83(m,2H)。
化合物167:MS:m/z 872.4(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.51(s,1H),8.08(d,1H),8.01(m,2H),7.15(d,2H),7.04(m,3H),5.73(s,1H),5.69(q,1H),5.30(d,1H),4.95(dd,1H),4.79(s,1H),4.65(m,1H),4.53(d,1H),4.37(m,1H),4.04(m,1H),3.91(s,3H),2.88(m,1H),2.66(m,2H),2.50(m,1H),2.28(q,1H),1.90-1.05(m,21H),0.97-0.83(m,2H)。
化合物168:MS:m/z 826.4(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.28(d,1H),7.94(d,2H),7.56(m,2H),7.42(m,1H),7.28(m,3H),7.03(s,1H),5.68(m,2H),5.21(d,1H),4.94(dd,1H),4.67(m,2H),4.32(m,1H),4.05(m,1H),2.89(m,1H),2.68(m,2H),2.55(m,1H),2.55(s,3H),2.35(q,1H),1.94-1.07(m,13H),1.20(s,9H),0.97-0.84(m,2H)。
化合物169:MS:m/z 858.3,859.3(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),8.58(s,1H),8.24(d,1H),8.00(d,2H),7.57(m,2H),7.45(m,3H),7.25(s,1H),5.71(s,1H),5.66(q,1H),5.41(d,1H),4.96(dd,1H),4.75(m,2H),4.55(d,1H),4.35(m,1H),4.04(m,1H),2.87(m,1H),2.69(m,2H),2.57(m,1H),2.28(q,1H),1.92-0.83(m,23H)。
化合物170:MS:m/z 772.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.22(d,1H),8.00(m,2H),7.59(m,2H),7.41(m,1H),7.20-7.10(m,4H),6.12(d,1H),5.72(m,2H),4.96(dd,1H),4.64(m,1H),4.55(m,1H),4.40(d,1H),4.01(m,1H),2.88(m,1H),2.66(m,2H),2.50(m,1H),2.26(q,1H),1.92-1.05(m,13H),1.91(s,3H),0.97-0.85(m,2H)。
化合物171:MS:m/z 768.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.26(d,1H),7.93(d,2H),7.57(m,2H),7.42(m,1H),7.27(m,4H),6.16(d,1H),5.69(m,2H),4.94(dd,1H),4.67(m,1H),4.57(m,1H),4.40(d,1H),4.05(m,1H),2.89(m,1H),2.68(m,2H),2.51(m,1H),2.39(s,3H),2.30(q,1H),1.94-1.05(m,13H),1.92(s,3H),0.97-0.84(m,2H)。
化合物172:MS:m/z 788.2(M+
+1)；1
H NMR(CDCl3
)δ10.32(s,1H),8.22(d,1H),8.01(m,2H),7.57(m,2H),7.42(m,1H),7.22-7.11(m,4H),5.72(m,2H),5.39(d,1H),4.96(dd,1H),4.71(m,1H),4.39(m,2H),4.04(m,1H),3.54(s,3H),2.89(m,1H),2.71(m,2H),2.54(m,1H),2.25(q,1H),1.91-1.06(m,13H),0.93-0.83(m,2H)。
化合物173:MS:m/z 822.2(M+
+1)；1
H NMR(CDCl3
)δ10.15(s,1H),8.27(d,1H),7.91(d,2H),7.59(m,2H),7.44(m,1H),7.27(m,3H),7.15(d,1H),7.07(s,1H),5.75(s,1H),5.69(q,1H),4.91(dd,1H),4.68(m,2H),4.32(d,1H),4.06(m,1H),2.89(m,1H),2.68(m,2H),2.41(m,1H),2.39(s,3H),2.21(q,1H),1.96-1.08(m,13H),0.96-0.83(m,2H)。
化合物174:MS:m/z 826.2(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.22(d,1H),8.02(m,2H),7.59(m,2H),7.41(m,1H),7.24-7.13(m,5H),5.73(s,1H),5.67(q,1H),4.89(dd,1H),4.72(m,2H),4.31(d,1H),4.05(m,1H),2.87(m,1H),2.69(m,2H),2.47(m,1H),2.24(q,1H),1.93-1.04(m,13H),0.93-0.82(m,2H)。
化合物175:MS:m/z 842.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.58(s,1H),8.26(d,1H),8.10(dd,1H),7.61-7.14(m,7H),6.91(s,1H),5.67(m,2H),5.38(d,1H),4.96(dd,1H),4.70(m,1H),4.56(d,1H),4.36(m,1H),4.06(m,1H),2.88(m,1H),2.69(m,2H),2.51(m,1H),2.28(q,1H),1.87-0.88(m,23H)。
化合物176:MS:m/z 844.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.00(m,3H),7.42(4,1H),7.37(d,1H),7.19(m,3H),6.98(s,1H),5.68(m,2H),5.19(d,1H),4.96(dd,1H),4.66(m,2H),4.30(m,1H),4.04(m,1H),2.89(m,1H),2.67(m,2H),2.52(s,3H),2.51(m,1H),2.26(q,1H),1.94-1.05(m,13H),1.20(s,9H),0.98-0.83(m,2H)。
化合物177:MS:m/z 840.2(M+
+1)；1
H NMR(CDCl3
)δ10.25(s,1H),8.00(m,3H),7.42(d,1H),7.35-7.11(m,6H),5.73(s,1H),5.69(q,1H),4.93(dd,1H),4.66(m,2H),4.32(d,1H),4.04(m,1H),2.89(m,1H),2.70(m,2H),2.51(s,3H),2.48(m,1H),2.23(q,1H),1.95-1.04(m,13H),0.96-0.82(m,2H)。
化合物178:MS:m/z 784.2(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.27(d,1H),7.92(d,2H),7.55(m,2H),7.41(m,1H),7.27(m,4H),5.70(m,2H),5.45(d,1H),4.95(dd,1H),4.67(m,1H),4.36(m,2H),4.06(m,1H),3.49(s,3H),2.89(m,1H),2.69(m,2H),2.51(m,1H),2.39(s,3H),2.26(q,1H),1.96-1.06(m,13H),0.97-0.83(m,2H)。
化合物179:MS:m/z 856.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),7.92(d,2H),7.69(d,1H),7.44(d,1H),7.29(d,2H),7.15(s,1H),7.05(dd,1H),6.97(s,1H),5.68(m,2H),5.22(d,1H),4.95(dd,1H),4.62(m,2H),4.30(m,1H),4.03(m,1H),3.93(s,3H),2.87(m,1H),2.66(m,2H),2.54(m,1H),2.41(s,3H),,2.29(q,1H),1.94-0.82(m,15H),1.21(s,9H)。
化合物180:Ms:m/z 814.3(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),7.92(d,2H),7.63(d,1H),7.42(d,1H),7.33-7.21(m,4H),7.10(dd,1H),5.66(m,2H),5.41(d,1H),4.94(dd,1H),4.65(m,1H),4.37(m,2H),4.03(m,1H),3.91(s,3H),3.50(s,3H),2.87(m,1H),2.66(m,2H),2.51(m,1H),2.41(s,3H),2.25(q,1H),1.94-1.07(m,13H),0.93-0.83(m,2H)。
化合物181:Ms:m/z 852.2(M+
+1)；1
H NMR(CDCl3
)δ10.19(s,1H),7.91(d,2H),7.71(d,1H),7.48(d,1H),7.30-7.15(m,5H),7.13(dd,1H),5.66(s,1H),5.64(q,1H),4.94(dd,1H),4.65(m,2H),4.30(d,1H),4.03(m,1H),3.93(s,3H),2.84(m,1H),2.67(m,2H),2.46(m,1H),2.40(s,3H),2.22(q,1H),1.95-0.84(m,15H)。
化合物182:MS:m/z 798.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),7.92(d,2H),7.72(d,1H),7.43(d,1H),7.39(s,1H),7.21(m,3H),7.11(dd,1H),6.18(d,1H),5.70(q,1H),5.64(s,1H),4.94(dd,1H),4.66(dd,1H),4.56(m,1H),4.39(d,1H),4.02(m,1H),3.93(s,3H),2.84(m,1H),2.68(m,2H),2.47(m,1H),2.39(s,3H),2.25(q,1H),1.95-0.83(m,15H),1.91(s,3H)。
化合物183:MS:m/z 802.2(M+
+1)；1
H NMR(CDCl3
)δ10.39(s,1H),7.96(m,3H),7.44(m,2H),7.35(m,1H),7.14(m,3H),5.66(m,2H),5.41(d,1H),4.92(dd,1H),4.61(m,1H),4.30(m,2H),4.00(m,1H),3.50(s,3H),2.89(m,1H),2.72(m,2H),2.51(s,3H),2.50(m,1H),2.26(q,1H),1.93-1.06(m,13H),0.97-0.83(m,2H)。
化合物184:MS:m/z 786.2(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),7.96(m,3H),7.42(m,2H),7.32(m,1H),7.15(m,3H),6.12(d,1H),5.69(q,1H),5.65(s,1H),4.94(dd,1H),4.64(m,1H),4.54(m,1H),4.38(d,1H),3.98(m,1H),2.88(m,1H),2.71(m,2H),2.50(m,1H),2.49(s,3H),2.27(q,1H),1.92-0.82(m,15H),1.91(s,3H)。
化合物185:MS:m/z 812.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),7.96(m,3H),7.41(d,1H),7.36(d,1H),7.25(m,1H),7.10(m,3H),6.19(d,1H),5.71(q,1H),5.64(s,1H),4.95(dd,1H),4.66(m,1H),4.48(m,2H),3.99(m,1H),2.89(m,1H),2.70(m,2H),2.51(m,1H),2.50(s,3H),2.27(q,1H),1.91-1.10(m,14H),0.97-0.80(m,2H),0.80-0.68(m,4H)。
化合物186:MS:m/z 856.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.00(m,3H),7.42(d,1H),7.37(d,1H),7.25-7.13(m,3H),7.04(s,1H),5.72(s,1H),5.69(q,1H),5.23(d,1H),4.97(dd,1H),4.77(s,1H),4.67(m,1H),4.55(d,1H),4.35(m,1H),4.04(m,1H),2.89(m,1H),2.68(m,2H),2.52(s,3H),2.51(m,1H),2.25(q,1H),1.93-1.06(m,21H),0.97-0.83(m,2H)。
化合物187:MS:m/z 830.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.01(d,2H),7.93(d,1H),7.50(m,4H),7.29(m,2H),7.07(s,1H),5.67(m,2H),5.19(d,1H),4.94(dd,1H),4.67(m,2H),4.30(m,1H),4.04(m,1H),2.89(m,1H),2.69(m,2H),2.52(m,1H),2.28(q,1H),1.94-1.05(m,13H),1.19(s,9H),0.97-0.84(m,2H)。
化合物188:MS:m/z 842.2(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),8.02(d,2H),7.93(d,1H),7.52(m,4H),7.32(s,1H),7.26(m,1H),7.08(s,1H),5.68(s,1H),5.66(q,1H),5.22(d,1H),4.92(dd,1H),4.71(m,2H),4.57(d,1H),4.33(m,1H),4.05(m,1H),2.89(m,1H),2.68(m,2H),2.53(m,1H),2.28(q,1H),1.95-0.83(m,23H)。
化合物189:MS:m/z 882.4(M+
+1)。
化合物190:MS:m/z 884.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),7.96(m,3H),7.54(m,1H),7.36-7.26(m,5H),5.70(m,2H),5.27(d,1H),4.95(dd,1H),4.74(m,1H),4.53(d,1H),4.32(m,1H),4.05(m,2H),2.95(m,2H),2.69(m,2H),2.52(m,1H),2.28(q,1H),1.94-0.83(m,23H),1.29(d,6H)。
化合物191:MS:m/z 898.2(M+
+1)。
化合物192:MS:m/z 880.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.28(d,1H),7.95(d,2H),7.50(m,4H),7.42(dd,1H),7.27(s,1H),7.21(s,1H),5.68(s,1H),5.65(q,1H),5.35(d,1H),4.94(dd,1H),4.72(m,2H),4.57(d,1H),4.35(m,1H),4.04(m,1H),2.88(m,1H),2.68(m,2H),2.53(m,1H),2.28(q,1H),1.93-1.05(m,21H),1.36(s,9H),0.97-0.82(m,2H)。
化合物193:MS:m/z 894.2(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.28(d,1H),7.95(d,2H),7.52(m,4H),7.41(dd,1H),7.34(s,1H),7.26(s,1H),5.70(s,1H),5.65(q,1H),5.41(d,1H),4.95(dd,1H),4.75(m,2H),4.57(d,1H),4.36(m,1H),4.05(m,1H),2.70(m,2H),2.50(m,1H),2,29(q,1H),1.93-0.82(m,23H),1.46(s,3H),1.36(s,9H)。
化合物194:MS:m/z 857.3(M+
+1)。
化合物195:MS:m/z 857.3(M+
+1)。
化合物196:MS:m/z 784.3(M+
+1)；1
H NMR(CDCl3
)δ10.20(s,1H),8.27(d,1H),7.88(d,1H),7.57(m,2H),7.39(m,3H),7.13(dd,1H),7.01(d,2H),6.14(d,1H),5.68(q,1H),5.62(s,1H),4.97(dd,1H),4.64(m,2H),4.41(d,1H),4.07(m,1H),3.87(s,3H),2.87(m,1H),2.67(m,2H),2.45(m,1H),2.25(q,1H),1.93-0.85(m,15H),1.92(s,3H)。
化合物197:MS:m/z 856.3(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.03(s,1H),8.00(d,2H),7.45(d,1H),7.35(d,1H),7.16(m,2H),7.00(d,2H),5.71(s,1H),5.69(q,1H),5.23(d,1H),4.95(dd,1H),4.62(m,2H),4.30(m,1H),4.03(m,1H),3.86(s,3H),2.88(m,1H),2.66(m,2H),2.51(s,3H),2.50(m,1H),2.31(q,1H),1.91-0.82(m,15H),1.22(s,9H)。
化合物198:MS:m/z 784.2(M+
+1)。
化合物199:MS:m/z 798.3(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),7.96(m,3H),7.58(s,1H),7.43(d,1H),7.32(d,1H),7.16(s,1H),6.97(d,2H),6.24(d,1H),5.69(q,1H),5.64(s,1H),4.96(dd,1H),4.66(m,1H),4.55(m,1H),4.40(d,1H),4.02(m,1H),3.84(s,3H),2.87(m,1H),2.68(m,2H),2.49(s,3H),2.50(m,1H),2.28(q,1H),1.91-0.83(m,15H),1.91(s,3H)。
化合物200:MS:m/z 852.2(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.03(s,1H),7.96(d,2H),7.52(s,1H),7.45(d,1H),7.34(d,1H),7.23(s,1H),6.98(d,2H),5.67(s,1H),5.64(q,1H),5.21(m,1H),4.93(dd,1H),4.67(m,2H),4.30(d,1H),4.04(m,1H),3.85(s,3H),2.87(m,1H),2.66-2.40(m,3H),2.51(s,3H),2.22(q,1H),1.95-0.82(m,15H)。
化合物201:MS:m/z 814.3(M+
+1)；1
H NMR(CDCl3
)δ10.41(s,1H),7.98(m,3H),7.60(s,1H),7.43(d,1H),7.33(d,1H),7.16(s,1H),6.98(d,2H),5.64(m,2H),5.29(m,2H),4.93(dd,1H),4.69(m,1H),4.36(m,1H),4.01(m,1H),3.84(s,3H),3.42(s,3H),2.87(m,1H),2.66(m,2H),2.50(m,1H),2.49(s,3H),2.25(q,1H),1.94-0.82(m,15H)。
化合物202:MS:m/z 838.2(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.26(d,1H),8.00(d,2H),7.60(m,2H),7.44(m,2H),7.23(m,2H),7.01(d,2H),5.73(s,1H),5.67(q,1H),4.94(dd,1H),4.68(m,2H),4.32(d,1H),4.07(m,1H),3.86(s,3H),2.86(m,1H),2.67(m,2H),2.41(m,1H),2.23(q,1H),1.94-1.08(m,13H),0.94-0.87(m,2H)。
化合物203:MS:m/z 842.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.28(d,1H),7.63(s,1H),7.57(m,3H),7.42(m,2H),7.25(m,1H),7.08(s,1H),6.97(dd,1H),5.71(m,2H),5.22(d,1H),4.92(dd,1H),4.64(m,2H),4.31(m,1H),4.00(m,1H),3.91(s,3H),2.89(m,1H),2.69(m,2H),2.55(m,1H),2.29(q,1H),1.85-0.83(m,15H),1.19(s,9H)。
化合物204:MS:m/z 784.2(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.26(d,1H),7.62(s,1H),7.58(m,3H),7.41(m,2H),7.25(m,2H),6.96(dd,1H),6.13(d,1H),5.71(q,1H),5.68(s,1H),4.95(dd,1H),4.63(t,1H),4.59(m,1H),4.41(d,1H),4.04(m,1H),3.90(s,3H),2.88(m,1H),2.71(m,2H),2.52(m,1H),2.29(q,1H),1.92-1.1.05(m,13H),1.91(s,3H),0.97-0.84(m,2H)。
化合物205:MS:m/z 801.3(M+
+1)；1
H NMR(CDCl3
) δ10.34(s,1H),8.25(d,1H),7.61(s,1H),7.57(m,3H),7.39-7.25(m,4H),6.93(dd,1H),5.70(m,2H),5.44(d,1H),4.94(dd,1H),4.70(m,1H),4.39(d,1H),4.32(m,1H),4.03(m,1H),3.90(s,3H),3.48(s,3H),2.88(m,1H),2.70(m,2H),2.52(m,1H),2.26(q,1H),1.89-0.82(m,15H)。
化合物206:MS:m/z 838.2(M+
+1)；1
H NMR(CDCl3
)δ10.19(s,1H),8.27(d,1H),7.62(s,1H),7.58(m,3H),7.41(m,2H),7.25(m,3H),6.97(dd,1H),5.71(s,1H),5.63(q,1H),4.92(dd,1H),4.64(m,2H),4.33(d,1H),4.05(m,1H),3.90(s,3H),2.88(m,1H),2.69(m,2H),2.46(m,1H),2.23(q,1H),1.94-1.1.03(m,13H),0.95-0.84(m,2H)。
化合物207:MS:m/z 800.2(M+
+1)；1
H NMR(CDCl3
)δ10.24(s,1H),8.27(d,1H),7.86(d,1H),7.55(m,2H),7.42(m,3H),7.12(m,2H),7.00(d,1H),5.68(q,1H),5.62(s,1H),5.47(d,1H),4.92(dd,1H),4.68(m,1H),4.40(m,2H),4.04(m,1H),3.87(s,3H),3.50(s,3H),2.89(m,1H),2.68(m,2H),2.50(m,1H),2.25(q,1H),1.91-1.03(m,13H),0.98-0.82(m,2H)。
化合物208:MS:m/z 838.2(M+
+1)；1
H NMR(CDCl3
)δ10.19(s,1H),8.27(d,1H),7.82(d,1H),7.57(m,2H),7.39(m,5H),7.12(dd,1H),7.02(d,1H),5.63(q,1H),5.60(s,1H),4.90(dd,1H),4.70(m,2H),4.32(d,1H),4.03(m,1H),3.85(s,3H),2.86(m,1H),2.71-2.52(m,2H),2.39(m,1H),2.20(q,1H),1.94-0.84(m,15H)。
化合物209:MS:m/z 896.4(M+
+1)；1
H NMR(CDCl3
)δ10.20(s,1H),8.31(d,1H),7.99(d,2H),7.58(m,2H),7.42(m,1H),7.30-7.22(m,2H),7.01(d,2H),5.68(s,1H),5.66(q,1H),5.37(d,1H),4.96(dd,1H),4.78-4.51(m,4H),4.37(m,1H),4.06(m,1H),2.69(m,2H),2.51(m,1H),2.28(q,1H),1.94-0.83(m,23H),1.46(s,3H),1.37(d,6H)。
化合物210:MS:m/z 882.4(M+
+1)；1
H NMR(CDCl3
)δ10.24(s,1H),8.27(d,1H),7.98(d,2H),7.58(m,2H),7.42(m,1H),7.24(m,1H),7.01(d,2H),6.89(s,1H),5.68(s,1H),5.66(q,1H),5.22(d,1H),4.97(dd,1H),4.78-4.52(m,4H),4.36(m,1H),4.04(m,1H),2.88(m,1H),2.68(m,2H),2.54(m,1H),2.29(q,1H),1.94-1.05(m,21H),1.37(d,6H),0.97-0.83(m,2H)。
化合物211:MS:m/z 922.2(M+
+1)；1
H NMR(CDCl3
)δ10.13(s,1H),8.26(d,1H),8.10(d,2H),7.59(m,2H),7.42(m,1H),7.35-7.25(m,3H),7.03(s,1H),5.77(s,1H),5.66(q,1H),5.20(d,1H),4.99(dd,1H),4.71(m,2H),4.56(d,1H),4.35(m,1H),4.03(m,1H),2.70(m,2H),2.50(m,1H),2.29(q,1H),1.90-0.84(m,23H),0.85(s,3H)。
化合物212:MS:m/z 892.4(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.59(s,1H),8.25(d,1H),8.18(d,2H),7.73(d,2H),7.58(m,2H),7.45(m,1H),7.34(s,1H),5.74(s,1H),5.68(q,1H),5.39(d,1H),4.94(dd,1H),4.72(m,2H),4.55(d,1H),4.31(m,1H),4.04(m,1H),2.86(m,1H),2.67(m,2H),2.49(m,1H),2.26(q,1H),1.91-1.05(m,23H)。
化合物213:MS:m/z 880.4(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.26(d,1H),8.16(d,2H),7.74(d,2H),7.59(m,2H),7.45(m,1H),7.30(m,2H),5.71(s,1H),5.66(q,1H),5.25(d,1H),4.95(dd,1H),4.71(m,1H),4.65(d,1H),4.28(m,1H),4.03(m,1H),2.87(m,1H),2.70(m,2H),2.51(m,1H),2.27(q,1H),1.92-1.06(m,13H),1.19(s,9H),0.97-0.82(m,2H)。
化合物214:MS:m/z 780.2(M+
+1)。
化合物215:MS:m/z 822.2(M+
+1)。
化合物216:MS:m/z 910.3(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.15(d,2H),7.75(d,2H),7.61(s,1H),7.47(d,1H),7.25-7.15(m,3H),5.72(s,1H),5.68(q,1H),5.18(d,1H),4.98(dd,1H),4.67(m,2H),4.28(m,1H),4.04(m,1H),3.93(s,3H),2.89(m,1H),2.69(m,2H),2.52(m,1H),2.28(q,1H),1.91-0.85(m,15H),1.20(s,9H)。
化合物217:MS:m/z 922.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.17(m,3H),7.74(d,2H),7.26(m,1H),7.17(s,1H),7.02(m,2H),5.77(s,1H),5.69(q,1H),5.20(d,1H),4.96(dd,1H),4.77(s,1H),4.69(m,1H),4.54(d,1H),4.33(m,1H),4.04(m,1H),3.92(s,3H),2.89(m,1H),2.71(m,2H),2.52(m,1H),2.28(q,1H),1.90-1.05(m,21H),0.97-0.83(m,2H)。
化合物218:MS:m/z 892.4(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.35(s,1H),8.28(d,1H),8.24(d,1H),7.59(m,4H),7.44(m,1H),7.33(s,1H),7.15(s,1H),5.80(s,1H),5.67(q,1H),5.27(d,1H),4.95(dd,1H),4.70(m,2H),4.58(d,1H),4.30(m,1H),4.06(m,1H),2.88(m,1H),2.70(m,2H),2.54(m,1H),2.28(q,1H),1.92-0.83(m,23H)。
化合物219:MS:m/z 880.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.34(s,1H),8.28(d,1H),8.20(d,1H),7.60(m,4H),7.45(m,1H),7.29(s,1H),7.13(s,1H),5.77(s,1H),5.67(q,1H),5.19(m,1H),4.94(dd,1H),4.67(m,2H),4.26(m,1H),4.05(m,1H),2.88(m,1H),2.71(m,2H),2.53(m,1H),2.29(q,1H),1.90-0.83(m,15H),1.18(s,9H)。
化合物220:MS:m/z 892.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.39(d,1H),8.06(d,2H),7.88(s,1H),7.71(d,1H),7.45(m,3H),7.36(s,1H),7.18(s,1H),5.68(s,1H),5.65(q,1H),5.33(d,1H),4.93(dd,1H),4.72(m,2H),4.67(d,1H),4.36(m,1H),4.05(m,1H),2.88(m,1H),2.70(m,2H),2.53(m,1H),2.28(q,1H),1.92-0.84(m,23H)。
化合物221:MS:m/z 880.4(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.39(d,1H),8.04(d,2H),7.87(s,1H),7.69(d,1H),7.48(m,3H),7.33(s,1H),7.25(s,1H),5.67(m,2H),5.21(d,1H),4.94(dd,1H),4.68(m,2H),4.30(m,1H),4.04(m,1H),2.88(m,1H),2.69(m,2H),2.52(m,1H),2.28(q,1H),1.93-0.84(m,15H),1.17(s,9H)。
化合物222:MS:m/z 814.3(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),8.46(s,1H),8.27(d,1H),7.47(m,3H),7.41(m,1H),7.33(s,1H),7.16(d,1H),7.05(s,1H),6.56(d,1H),5.69(m,2H),5.24(d,1H),4.95(dd,1H),4.66(m,1H),4.58(d,1H),4.38(m,1H),4.05(m,1H),2.89(m,1H),2.70(m,2H),2.34(m,1H),2.29(q,1H),1.90-1.06(m,21H),0.96-0.83(m,2H)。
化合物223:MS:m/z 802.2(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.28(d,1H),7.54(m,3H),7.42(m,1H),7.29(s,1H),7.20(d,1H),7.08(s,1H),6.56(d,1H),5.66(m,2H),5.15(d,1H),4.95(dd,1H),4.69(m,2H),4.30(m,1H),4.05(m,1H),2.89(m,1H),2.68(m,2H),2.35(m,1H),2.29(q,1H),1.89-1.04(m,13H),1.19(s,9H),0.97-0.83(m,2H)。
化合物224:MS:m/z 848.2(M+
+1)；1
H NMR(CDCl3
)δ10.30(s,1H),8.08(d,1H),7.58(d,1H),7,39(d,1H),7.14(s,1H),7.12-6.95(m,4H),5.70(m,2H),5.20(d,1H),4.95(dd,1H),4.66(m,1H),4.59(d,1H),4.33(m,1H),4.03(m,1H),3.91(s,3H),2.90(m,1H),2.66(m,2H),2.52(m,1H),2.28(q,1H),1.89-1.06(m,13H),1.24(s,9H),0.94-0.83(m,2H)。
化合物225:MS:m/z 760.2(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),8.25(d,1H),7.55(m,3H),7.40(m,1H),7.27(m,2H),7.16(d,1H),6.54(d,1H),5.66(m,2H),5.42(d,1H),4.94(dd,1H),4.67(m,1H),4.46(d,1H),4.35(m,1H),4.04(m,1H),3.50(s,3H),2.89(m,1H),2.66(m,2H),2.33(n),1H),2.26(q,1H),1.92-0.83(m,15H)。
化合物226:MS:m/z 798.2(M+
+1)；1
H NMR(CDCl3
)δ10.20(s,1H),8.25(d,1H),7.55(m,3H),7.41(m,1H),7.27(m,3H),7.16(d,1H),6.56(d,1H),5.66(m,2H),4.94(dd,1H),4.67(m,2H),4.35(d,1H),4.05(m,1H),2.88(m,1H),2.66(m,2H),2.43(m,1H),2.26(q,1H),1.96-0.83(m,15H)。
化合物227:MS:m/z 744.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.21(d,1H),7.55(m,3H),7.39(m,1H),7.33-7.25(m,2H),7.12(d,1H),6.56(d,1H),6.16(d,1H),5.66(q,1H),5.62(s,1H),4.94(dd,1H),4.62(m,1H),4.59(m,1H),4.41(d,1H),4.06(m,1H),2.87(m,1H),2.68(m,2H),2.50(m,1H),2.26(q,1H),1.95-0.83(m,15H),1.90(s,3H)。
化合物228:MS:m/z 857.3(M+
+1)。
化合物229:MS:m/z 830.3(M+
+1)；1
H NMR(CDCl3
)δ10.25(s,1H),8.26(d,1H),7.59(m,2H),7.43(m,2H),7.25(m,2H),7.19(m,1H),7.06(m,1H),5.76(s,1H),5.72(q,1H),5.18(m,1H),4.97(dd,1H),4.68(m,2H),4.56(d,1H),4.30(m,1H),4.04(m,1H),2.90(m,1H),2.70(m,2H),2.39(m,1H),2.27(q,1H),1.90-0.80(m,23H)。
化合物230:MS:m/z 860.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.10(d,1H),7.58(d,1H),7.39(d,1H),7.18(s,1H),7.09-6.97(m,4H),5.72(s,1H),5.68(q,1H),5.24(d,1H),4.95(dd,1H),4.80(s,1H),4.65(m,1H),4.54(d,1H),4.32(m,1H),4.03(m,1H),3.91(s,3H),2.94(m,1H),2.68(m,2H),2.54(m,1H),2.28(q,1H),1.90-1.05(m,21H),0.95-0.84(m,2H)。
化合物231:MS:m/z 848.2(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),7.64(d,1H),7.60(d,1H),7.48(d,1H),7.40(d,1H),7.20(s,1H),7.15(m,2H),6.88(s,1H),5.65(m,2H),5.10(d,1H),4.96(dd,1H),4.63(m,2H),4.31(m,1H),4.04(m,1H),3.94(s,3H),2.86(m,1H),2.68(m,2H),2.56(m,1H),2.29(q,1H),1.94-0.83(m,15H),1.22(s,9H)。
化合物232:MS:m/z 836.2(M+
+1)；1
H NMR(CDCl3
)δ10.29(s,1H),7.89(dd,1H),7.60(d,1H),7.50(dd,1H),7.40(d,1H),7.22(m,2H),7.10(m,1H),7.00(s,1H),5.68(m,2H),5.18(d,1H),4.95(dd,1H),4.66(m,2H),4.29(m,1H),4.04(m,1H),2.88(m,1H),2.67(m,2H),2.53(m,1H),2.26(q,1H),1.92-0.83(m,15H),1.20(s,9H)。
化合物233:MS:m/z 806.2(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.05(d,1H),7.59(d,1H),7.38(m,2H),7.14-6.97(m,4H),5.70(m,2H),5.64(d,1H),4.96(dd,1H),4.65(m,1H),4.58(m,2H),4.04(m,1H),3.90(s,3H),3.58(s,3H),2.89(m,1H),2.68(m,2H),2.53(m,1H),2.25(q,1H),1.88-0.82(m,15H)。
化合物234:MS:m/z 860.2(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),7.63(d,1H),7.60(d,1H),7.45(d,1H),7.40(d,1H),7.20(m,2H),7.10(m,2H),5.69(s,1H),5.67(q,1H),5.30(d,1H),4.94(dd,1H),4.78(s,1H),4.64(m,1H),4.55(d,1H),4.36(m,1H),4.04(m,1H),3.94(s,3H),2.89(m,1H),2.68(m,2H),2.53(m,1H),2.26(q,1H),1.93-1.04(m,21H),0.97-0.82(m,2H)。
化合物235:MS:m/z 844.2(M+
+1)；1
H NMR(CDCl3
)δ10.24(s,1H),8.04(d,1H),7.58(d,1H),7.39(d,1H),7.31(m,2H),7.18(s,1H),7.08(m,3H),5.70(s,1H),5.67(q,1H),4.86(dd,1H),4.64(m,2H),4.26(d,1H),4.02(m,1H),3.90(s,3H),2.84(m,1H),2.65(m,2H),2.44(m,1H),2.20(q,1H),1.91-0.83(m,15H)。
化合物236:MS:m/z 832.2(M+
+1)；1
H NMR(CDCl3
)δ10.27(s,1H),8.22(d,1H),7.58(m,2H),7.44(m,1H),7.29(m,1H),7.10(s,1H),6.94(d,1H),6.90(s,1H),5.69(m,2H),5.18(d,1H),4.93(dd,1H),4.67(m,2H),4.28(m,1H),4.05(m,1H),2.85(m,1H),2.68(m,2H),2.55(s,3H),2.54(m,1H),2.28(q,1H),1.91-0.83(m,15H),1.19(s,9H)。
化合物237:MS:m/z 844.3(M+
+1)；1
H NMR(CDCl3
)δ10.23(s,1H),8.22(d,1H),7.58(m,2H),7.40(m,1H),7.29(m,2H),6.96(d,1H),6.84(s,1H),5.69(s,1H),5.66(q,1H),5.20(d,1H),4.94(dd,1H),4.73(s,1H),4.67(m,1H),4.58(d,1H),4.35(m,1H),4.05(m,1H),2.89(m,1H),2.68(m,2H),2.56(s,3H),2.54(m,1H),2.26(q,1H),1.91-0.83(m,23H)。
化合物238:MS:m/z 844.3(M+
+1)；1
H NMR(CDCl3
)δ10.26(s,1H),8.22(d,1H),7.55(m,2H),7.43(m,2H),7.18(m,1H),6.93(s,1H),6.75(s,1H),5.70(m,2H),5.21(d,1H),4.94(dd,1H),4.78(s,1H),4.63(m,1H),4.53(d,1H),4.35(m,1H),4.05(m,1H),2.89(m,1H),2.67(m,2H),2.53(s,3H),2.52(m,1H),2.26(q,1H),1.92-1.04(m,21H),0.95-0.83(m,2H)。
化合物239:MS:m/z 790.2(M+
+1)；1
H NMR(CDCl3
)δ10.34(s,1H),8.20(d,1H),7.54(m,2H),7.38(m,2H),7.28(s,1H),7.14(s,1H),6.73(s,1H),5.68(m,2H),5.43(d,1H),4.94(dd,1H),4.65(m,1H),4.39(m,2H),4.04(m,1H),3.58(s,3H),2.89(m,1H),2.68(m,2H),2.51(s,3H),2.50(m,1H),2.28(q,1H),1.93-1.06(m,13H),0.94-0.82(m,2H)。
化合物240:MS:m/z 828.2(M+
+1)；1
H NMR(CDCl3
)δ10.18(s,1H),8.22(d,1H),7.56(m,2H),7.40(m,2H),7.20(s,2H),7.08(s,1H),6.76(d,1H),5.71(s,1H),5.66(q,1H),4.94(dd,1H),4.66(m,2H),4.29(d,1H),4.04(m,1H),2.88(m,1H),2.65(m,2H),2.53(s,3H),2.45(m,1H),2.23(q,1H),1.96-1.05(m,13H),0.95-0.83(m,2H)。
化合物241:MS:m/z 778.1(M+
+1)；1
H NMR(CDCl3
)δ10.38(s,1H),7.89(dd,1H),7.58(d,2H),7.44(dd,1H),7.35(d,1H),7.24(m,2H),7.05(m,1H),6.18(d,1H),5.71(q,1H),5.62(s,1H),4.95(dd,1H),4.63(m,1H),4.50(m,1H),4.40(d,1H),4.00(m,1H),2.88(m,1H),2.66(m,2H),2.53(m,1H),2.22(q,1H),1.96-0.82(m,15H),1.91(s,3H)。
化合物242:MS:m/z 846.4(M+
+1)。
化合物243:MS:m/z 858.3(M+
+1)；1
H NMR(CDCl3
)δ10.28(s,1H),8.24(d,1H),7.57(m,2H),7.42(m,2H),7.19(s,1H),7.08(s,1H),6.79(d,1H),5.66(m,2H),5.24(d,1H),4.96(m,1H),4.78(s,1H),4.67(m,1H),4.55(d,1H),4.35(m,1H),4.03(m,1H),2.85(m,3H),2.67(m,2H),2.53(m,1H),2.28(q,1H),1.94-0.84(m,26H)。
化合物244:MS:m/z 872.3(M+
+1)；1
H NMR(CDCl3
)δ10.13(s,1H),8.24(d,1H),7.53(m,2H),7.41(m,2H),7.19(s,1H),6.99(s,1H),6.79(d,1H),5.69(m,2H),5.23(d,1H),4.98(dd,1H),4.77(s,1H),4.65(m,1H),4.55(d,1H),4.35(m,1H),4.04(m,1H),2.87(q,2H),2.68(m,2H),2.53(m,1H),2.29(q,1H),1.94-0.84(m,26H),0.83(s,3H)。
化合物245:MS:m/z 831.2(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.26(d,1H),7.90(d,2H),7.58(m,2H),7.46(d,2H),7.00(s,1H),5.69(m,2H),5.09(d,1H),4.99(dd,1H),4.62(m,3H),4.27(m,1H),4.05(m,1H),2.89(m,1H),2.70(m,2H),2.56(m,1H),2.29(q,1H),1.94-0.84(m,23H)。
化合物246:MS:m/z 761.4(M+
+1)；1
H NMR(CDCl3
)δ10.21(s,1H),8.17(d,1H),7.80(d,3H),7.56(m,2H),7.41(d,2H),6.58(s,1H),5.61(m,2H),5.21(d,1H),4.65(m,2H),4.24(m,1H),4.05(m,1H),2.89(m,1H),2.70(m,2H),2.56-2.21(m,2H),1.94-0.84(m,15H),1.87(s,3H)。
化合物247:MS:m/z 803.4(M+
+1)。
化合物248:MS:m/z 845.3(M+
+1)。
化合物249:MS:m/z 917.2(M+
+1)；1
H NMR(CDCl3
)δ10.22(s,1H),8.08(d,1H),7.78(s,1H),7.40(s,1H),7.06(s,1H),6.97(m,2H),5.64(m,2H),5.32(d,1H),4.94(dd,1H),4.70(m,2H),4.54(d,1H),4.34(dd,1H),4.08(m,1H),3.83(s,3H),3.18(m,1H),2.73-2.43(m,2H),2.33(q,1H),2.15-1.20(m,30H),0.83(s,3H)。
化合物250:MS:m/z 905.4(M+
+1)。
化合物251:MS:m/z 901.3(M+
+1)。
化合物252:MS:m/z 917.4(M+
+1)。
化合物253:MS:m/z 903.3(M+
+1)。
實施例254：合成[4-環丙磺醯基氨基羰基-18-(2-氟-苯並[4,5]呋喃並[3,2-b]喹啉-11-基氧基)-2,15-二氧代-3,16-二氮雜三環[14.3.0.04,6]十九烷-14-基]-氨基甲酸環戊酯(化合物254)
化合物254通過以下合成路線製備。
0℃，向Boc-反-4-羥基-L-脯氨酸(0.53克，2.30毫摩爾)在DMSO(10毫升)的溶液中加入t
-BuONa(0.49克，5.08毫摩爾)。溫熱至室溫並再攪拌1小時後，於10℃緩慢加入中間體I-26(0.62克，2.31毫摩爾)。攪拌該反應混合物4小時，然後用10% HCl水溶液猝滅至pH為6-7。過濾粗懸浮固體，用水洗滌，真空乾燥，得到I-27(0.92克，86%)。MS:m/z 467.1(M+
+1)。
5℃，向I-27(0.90克，1.93毫摩爾)、HATU(58.9克，1.55毫摩爾)、HOBt(7.0克，0.52毫摩爾)和NMM(38.3克，3.86毫摩爾)在CH2
Cl2
(10毫升)的溶液中滴加環丙烷磺酸(1-氨基-2-乙烯基-環丙烷羰基)-醯胺(54.0克，2.03毫摩爾)和NMM(0.19克，1.93毫摩爾)溶解於CH2
Cl2
的混合物。溫熱至室溫並再攪拌16小時後，將反應混合物過濾，濃縮和通過矽膠柱層析純化，獲得粗產物I-28(0.89克，產率80%)。MS:m/z 679.1(M+
+1)。
室溫，将化合物I-28(1.20克，1.77毫摩爾)溶解於MeOH(18毫升)，然後利用冰浴冷卻該溶液。在反應混合物中逐滴加入亞硫醯氯(0.39毫升，5.30毫摩爾)。移去冰浴之後，反應混合物在65℃加熱1小時。將形成的溶液冷卻至40℃，過濾，用冷MeOH和醚洗滌，獲得淺黃色粉末，以得到白色粉末的I-29，該化合物無需進一步純化即可用於下一反應步驟。MS:m/z 579.1(M+
+1)。
5℃，向2-環戊氧基羰基氨基-壬-8-烯酸(0.87克，2.34毫摩爾)、HATU(1.16克，3.05毫摩爾)和HOBt(0.14克，1.02毫摩爾)在CH2
Cl2
(10毫升)的溶液中滴加溶解於DMF(10毫升)的I-29(1.18克，2.03毫摩爾)和NMM(0.49克，4.87毫摩爾)的混合物。溫熱至室溫並再攪拌16小時之後，加入10% HCl(1毫升)，將反應混合物濃縮。將殘餘物冷卻至5℃，用5% HCl(水溶液)(10毫升x 2)和NaHCO3
(水溶液)(10毫升x 2)順序洗滌，得到淺黃色固體。將該固體溶解於MeOH(10毫升)，並通過緩慢加入少量醚進一步沉澱，獲得I-30(1.51克，產率88%)。MS:m/z 844.3(M+
+1)。
通過氮氣鼓泡將化合物I-30(0.50克，0.59毫摩爾)在CH2
Cl2
(120毫升)中的溶液脫氣1小時。加入第二代霍維達-格拉布催化劑(48毫克，0.076毫摩爾)，然後反應混合物於40℃加熱16小時。由HPLC指示反應完成後，將反應混合物冷卻至30℃，濃縮並通過矽膠柱層析純化，得到產物I-31(0.30克，產率62%)。MS:m/z 816.3(M+
+1)；1
H NMR(CDCl3
)δ10.33(s,1H),8.30(d,1H),8.11(dd,1H),7.88(dd,1H),7.67-7.56(m,2H),7.46(dd,1H),7.43-7.30(m,2H),6.12(s,1H),5.64(q,1H),5.22(d,1H),4.92(dd,1H),4.77(d,1H),4.66(dd,1H),4.32-4.22(m,1H),4.04(dd,1H),2.93-2.46(m,3H),2.31(q,1H),1.92-0.80(m,25H)。
室溫N2
氣氛下，向化合物I-31(50毫克，0.061毫摩爾)在MeOH(10毫升)的溶液中加入5% Pd-C(5毫克)。然後，在氫氣氣氛，60psi壓力和室溫條件下攪拌反應混合物4小時。將反應混合物過濾並通過柱層析純化，得到化合物254(27.6毫克，55%)。MS:m/z 818.3(M+
+1)；1
H NMR(CDCl3
)δ10.50(s,1H),8.28(d,1H),8.13(dd,1H),7.80(dd,1H),7.65-7.57(m,2H),7.45(dd,1H),7.39-7.30(m,2H),6.11(s,1H),5.25(d,1H),4.96(brs,1H),4.68(dd,1H),4.60(d,1H),4.37(dd,1H),4.14(dd,1H),3.02-2.57(m,3H),1.92-0.80(m,29H)。
化合物255-281各自按照與實施例254中所述類似的方式製備。
化合物255:MS:m/z 764.2(M+
+1)；1
H NMR(CDCl3
)δ10.47(s,1H),7.88-7.84(m,3H),7.70(s,1H),7.56(dd,1H),7.37(m,1H),7.18(m,1H),6.20(d,1H),5.97(s,1H),5.64(q,1H),4.94(dd,1H),4.68(m,1H),4.61(d,1H),4.44(m,1H),4.02(m,1H),2.85(m,2H),2.70(m,1H),2.58(m,1H),2.25(q,1H),1.92(s,3H),1.90-1.03(m,15H)。
化合物256:MS:m/z 815.6(M+
+1)；1
H NMR(CDCl3
)δ10.31(s,1H),8.32(d,1H),8.25(m,1H),7.81(dd,1H),7.64(m,2H),7.46(dd,1H),7.23-7.1.2(m,2H),6.20(s,1H),5.66(q,1H),5.16(d,1H),4.98(dd,1H),4.75-4.64(m,3H),4.31(m,1H),4.08(m,1H),2.88(m,1H),2.78(m,2H),2.55(m,1H),2.29(q,1H),1.92-0.84(m,23H)。
化合物257:MS:m/z 804.1(M+
+1)；1
H NMR(CDCl3
)δ10.52(s,1H),8.29(d,1H),8.03-7.97(m,2H),7.82(dd,1H),7.63-7.42(m,3H),7.21(m,1H),5.97(s,1H),5.60(q,1H),5.44(d,1H),4.85(dd,1H),4.66(m,2H),4.29(m,1H),4.02(m,1H),3.88-3.62(m,2H),2.87-2.58(m,5H),2.33(q,1H),1.90-0.78(m,15H),0.97(s,6H)。
化合物258:MS:m/z 806.1(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.28(d,1H),8.07(m,1H),7.84(s,1H),7.62(m,3H),7.44(m,2H),7.18(m,1H),6.06(s,1H),5.67(q,1H),4.96(dd,1H),4.80(d,1H),4.60(m,1H),4.41(m,1H),4.10(m,2H),3.66(m,1H),3.39(m,2H),3.22(s,3H),2.91-2.58(m,4H),2.20(q,1H),1.90-0.86(m,15H)。
化合物259:MS:m/z 788.1(M+
+1)；1
H NMR(CDCl3
)δ10.51(s,1H),8.28(d,1H),7.94(m,1H),7.86(s,1H),7.64(d,1H),7.60-7.43(m,4H),7.16(m,1H),6.00(s,1H),5.85(m,1H),5.62(m,2H),5.30-5.19(m,2H),4.93(dd,1H),4.66(m,1H),4.58-4.36(m,3H),4.02(m,1H),2.87-2.56(m,4H),2.26(q,1H),1.86-0.86(m,15H)。
化合物260:MS:m/z 762.2(M+
+1)；1
H NMR(CDCl3
)δ10.63(s,1H),8.26(d,1H),8.10(s,1H),7.88(d,1H),7.67-7.44(m,4H),6.84(s,1H),5.89(s,1H),5.68(q,1H),5.38(d,1H),4.97(dd,1H),4.76(m,1H),4.58(d,1H),4.21(m,1H),3.96(m,1H),3.66(s,3H),2.91-2.60(m,4H),2.25(q,1H),1.89-0.89(m,15H)。
化合物261:MS:m/z 704.2(M+
+1)；1
H NMR(CD3
OD)δ9.26(s,1H),8.47(d,1H),8.26(m,1H),8.15(dd,1H),7.97-7.82(m,3H),7.66(m,1H),6.54(s,1H),5.74(q,1H),5.13(dd,1H),4.60(d,1H),4.35(m,2H),3.72-3.58(m,2H),2.97-2.81(m,3H),2.51(m,1H),2.33(q,1H),1.99-1.06(m,15H)。
化合物262:MS:m/z 818.3(M+
+1)；1
H NMR(CDCl3
)δ10.42(s,1H),8.30(d,1H),8.12(m,1H),7.86(m,1H),7.49-7.33(m,5H),6.10(s,1H),5.66(m,2H),5.08-4.66(m,4H),4.28(m,1H),4.03(m,1H),3.86-3.58(m,4H),2.86-2.57(m,4H),2.34(q,1H),2.03-0.87(m,17H)。
化合物263:MS:m/z 780.2(M+
+1)；1
H NMR(CDCl3
)δ10.60(s,1H),8.04-7.92(m,3H),7.78(m,1H),7.56(dd,1H),7.38(m,1H),6.94(m,1H),5.89(s,1H),5.67(q,1H),5.40(d,1H),4.95(dd,1H),4.76(m,1H),4.57(d,1H),4.20(m,1H),3.97(m,1H),3.64(s,3H),2.94-2.63(m,4H),2.23(q,1H),1.88-1.09(m,15H)。
化合物264:MS:m/z 931.3(M+
+1)；1
H NMR(CDCl3
)δ10.43(s,1H),8.30(d,1H),8.10(m,1H),7.86(d,1H),7.62-7.34(m,5H),6.08(s,1H),5.60(q,1H),5.38(s,1H),4.90-4.62(m,4H),4.26(m,1H),4.03(m,1H),3.64(m,2H),3.15(m,2H),2.85-2.55(m,4H),2.33(q,1H),1.83-0.86(m,19H),1.44(s,9H)。
化合物265:MS:m/z 780.2(M+
+1)；1
H NMR(CDCl3
)δ10.45(s,1H),8.29(d,1H),8.05(m,1H),7.78(d,1H),7.63-7.25(m,4H),6.04(m,2H),5.63(q,1H),4.91(dd,1H),4.72-4.63(m,3H),4.43-4.32(m,2H),4.02(m,1H),3.78-3.58(m,1H),2.85-2.35(m,6H),2.03-0.86(m,15H)。
化合物266:MS:m/z 776.3(M+
+1)；1
H NMR(CDCl3
)δ10.56(s,1H),8.24(d,1H),8.00(s,1H),7.87-7.79(m,2H),7.61-7.42(m,4H),7.06(m,1H),5.93(s,1H),5.61(q,1H),5.44(m,1H),4.91(dd,1H),4.68(m,1H),4.25-3.96(m,4H),2.86-2.57(m,4H),2.29(q,1H),1.81-0.88(m,18H)。化合物267:MS:m/z 812.2(M+
+1)；1
H NMR(CDCl3
)δ10.47(s,1H),8.27(d,1H),7.90(m,1H),7.81(m,2H),7.76-7.43(m,4H),7.17(m,1H),6.03-5.85(m,2H),5.61(q,1H),4.88(dd,1H),4.72-4.61(m,2H),4.25-3.98(m,4H),2.86-2.58(m,4H),2.30(q,1H),1.84-0.88(m,15H)。
化合物268:MS:m/z 832.2(M+
+1)；1
H NMR(CDCl3
)δ10.50(s,1H),8.35-8.29(m,1H),8.15-8.01(m,1H),7.84-7.32(m,5H),7.13-7.03(m,1H),6.10(s,1H),5.54(m,1H),5.36(d,1H),5.05-4.83(m,2H),4.74-4.65(m,1H),4.36(m,1H),4.14-4.05(m,1H),2.88-2.51(m,4H),2.12-0.88(m,24H)。
化合物269:MS:m/z 834.3(M+
+1)。
化合物270:MS:m/z 792.2(M+
+1)。
化合物271:MS:m/z 822.2(M++1)；1
H NMR(CDCl3
)δ10.38(s,1H),8.09(m,1H),7.99(dd,1H),7.83(dd,1H),7.58(dd,1H),7.41-7.25(m,3H),6.15(s,1H),5.59(q,1H),5.16(d,1H),4.89(dd,1H),4.78-4.67(m,2H),4.25(m,1H),4.07(m,1H),2.77-2.70(m,3H),2.57(m,1H),2.30(q,1H),1.90-0.82(m,15H),1.23(s,9H)。
化合物272:MS:m/z 822.2(M+
+1)；1
H NMR(CDCl3
)δ10.37(s,1H),8.10(m,1H),7.98(dd,1H),7.83(dd,1H),7.58(dd,1H),7.42-7.27(m,2H),7.19(s,1H),6.16(s,1H),5.62(q,1H),5.11(d,1H),4.92(dd,1H),4.78-4.67(m,2H),4.24(m,1H),4.07(m,1H),2.86-2.77(m,3H),2.56(m,1H),2.32(q,1H),1.90-0.82(m,15H),1.23(s,9H)。
化合物273:MS:m/z 850.3,852.3(M+
+1)。
化合物274:MS:m/z 834.2(M+
+1)；1
H NMR(CDCl3
)δ10.43(s,1H),8.08(m,1H),7.95(dd,1H),7.91(dd,1H),7.56(dd,1H),7.50(s,1H),7.37-7.31(m,2H),6.05(s,1H),5.58(q,1H),5.39(d,1H),4.72-4.67(m,4H),4.27(m,1H),4.03(m,1H),2.89-2.67(m,3H),2.55(m,1H),2.29(q,1H),1.90-0.87(m,23H)。
化合物275:MS:m/z 780.2(M+
+1)；1
H NMR(CDCl3
)δ10.61(s,1H),8.06-7.92(m,3H),7.75(m,1H),7.55(dd,1H),7.39(m,1H),6.90(m,1H),5.89(s,1H),5.66(q,1H),5.44(d,1H),4.94(dd,1H),4.77(m,1H),4.58(d,1H),4.20(m,1H),3.96(m,1H),3.65(s,3H),2.93-2.67(m,4H),2.24(q,1H),1.87-1.09(m,15H)。
化合物276:MS:m/z 818.1(M+
+1)；1
H NMR(CDCl3
)δ10.35(s,1H),8.05(m,1H),7.96(dd,1H),7.75(dd,1H),7.57-7.52(m,2H),7.39-7.32(m,3H),6.06(s,1H),5.60(q,1H),4.85-4.73(m,2H),4.55-4.48(m,2H),4.06(m,1H),2.83(m,2H),2.69(m,1H),2.50(m,1H),2.23(q,1H),1.85-1.05(m,15H)。
化合物277:MS:m/z 856.3(M+
+1)。
化合物278:MS:m/z 764.2(M+
+1)；1
H NMR(CDCl3
)δ10.49(s,1H),7.94-7.82(m,3H),7.72(s,1H),7.55(dd,1H),7.38(m,1H),7.17(m,1H),6.21(d,1H),5.99(s,1H),5.62(q,1H),4.94(dd,1H),4.68(m,1H),4.61(d,1H),4.45(m,1H),4.02(m,1H),2.85(m,2H),2.71(m,1H),2.56(m,1H),2.27(q,1H),1.92(s,3H),1.90-1.03(m,15H)。
化合物279:MS:m/z 834.3(M+
+1)；1
H NMR(CDCl3
)δ10.43(s,1H),8.05(m,1H),7.96(dd,1H),7.91(dd,1H),7.55(dd,1H),7.48(s,1H),7.37-7.32(m,2H),6.05(s,1H),5.57(q,1H),5.39(d,1H),4.79-4.67(m,4H),4.28(m,1H),4.03(m,1H),2.87-2.67(m,3H),2.54(m,1H),2.29(q,1H),1.90-0.87(m,23H)。
化合物280:MS:m/z 818.2(M+
+1)；1
H NMR(CDCl3
)δ10.36(s,1H),8.02(m,1H),7.94(dd,1H),7.71(dd,1H),7.60(s,1H),7.54-7.51(dd,1H),7.42(d,1H),7.36-7.30(m,2H),6.03(s,1H),5.60(q,1H),4.86-4.72(m,2H),4.56-4.48(m,2H),4.05(m,1H),2.84(m,2H),2.68(m,1H),2.48(m,1H),2.23(q,1H),1.88-1.05(m,15H)。
化合物281按照與實施例1中所述類似的方式製備：化合物281:MS:m/z 901.2(M+
+1)；1
H NMR(CDCl3
)δ10.25(s,1H),8.48(d,1H),7.59(dd,1H),7.39(d,1H),7.32(dd,1H),7.15(s,1H),7.04(s,1H),6.14(s,1H),5.69(ddd,1H),5.04(m,2H),4.72(m,1H),4.56(m,2H),4.24-4.15(m,2H),3.97(s,3H),3.34(tt,1H),2.55(m,1H),2.24-2.26(m,1H),2.01-0.69(m,34H)。
蛋白質的表達和純化
將含有編碼N-末端His6
-標簽的NS4A(21-32)
-GSGS-NS3(3-181)
基因的質粒轉化入諾瓦金公司(Novagen)的大腸桿菌(E. coli
)菌株BL21(DE3) pLysS中來過度表達蛋白質。37℃，在200毫升含有卡那黴素和氯黴素的Lauria-Bertani(LB)培養基中過夜培養轉化的BL21(DE3) pLysS單菌落。將細菌培養液轉移至迪菲科公司(Difco)的6升含抗生素的LB培養基中，22℃振盪培育。600nm吸光度達到0.6後，在22℃用1mM異丙基-1-硫代-β-D-吡喃半乳糖苷(IPTG)誘導培養物5小時。然後離心(4℃，6,000×g，15分鐘)收集培養物。將細胞糰粒重懸在150毫升緩衝液A(50mM HEPES，pH 7.4，0.3M NaCl，0.1%(w/v) CHAPS，10mM咪唑，10%(v/v)甘油)中。使混合物流過在30psi操作的微流化儀(Microfluidizer)四次使之分散，然後離心(4℃，58,250×g，30分鐘)除去細胞碎片。在有10mM咪唑存在下，用法瑪西亞公司(Pharmacia)的GradiFrac系統將含His6
-標簽蛋白的細胞裂解液以3毫升/分鐘加載到25毫升恰根公司(Qiagen)的Ni-NTA柱上。用10個柱體積的裂解緩衝液洗滌柱。用8個柱體積的補加了300mM咪唑的緩衝液A洗脫結合的NS4A(21-32)
-GSGS-NS3(3-181)
。通過用緩衝液B(50mM HEPES，pH 7.4，0.1%(w/v)CHAPS，10%(v/v)甘油，5mM二硫蘇糖醇(DTT)和1M NaCl)平衡的Q-瓊脂糖柱進一步純化合並的諸組分。收集含NS4A(21-32)
-GSGS-NS3(3-181)
的洗脫液，利用用緩衝液C(50mM HEPES，pH 7.4，0.1%(w/v)CHAPS，5mM DTT，10%(v/v)甘油)預平衡的聚丙烯醯胺葡聚糖(sephacryl)-75柱(16×100cm，法瑪西亞公司)以流速5毫升/分鐘通過尺寸排阻層析進一步純化。冷凍純化的蛋白質，保存於-80℃備用。
製備含50mM Tris,pH 7.4,100mM NaCl,20%甘油,0.012% CHAPS,10mM DTT,5μM底物Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-Ψ-[COOAla]-Ser-Lys(DABCYL)-NH2
(RET S1,ANASPEC)和10μM測試化合物的溶液。在96孔板的各孔中加入80微升的所述溶液。加入20μL用含有50mM Tris緩衝液，pH 7.4，100mM NaCl，20%甘油和0.012% CHAPS的緩衝液配製的10nM NS3/4A蛋白酶開始反應。NS3/4A蛋白酶的終濃度是2nM，低於底物RET S1的Km。
30℃培育試驗溶液30分鐘。然後加入100μL 1%TFA終止反應。將200μL等份試樣轉移至安捷侖公司(Agilent)的96-孔板的各孔中。
採用下述的反相HPLC分析反應產物。HPLC系統包括：Agilent 1100，脫氣柱G1379A，二元泵G1312A，自動進樣器G1367A，柱恒溫室G1316A，二極管陣列檢測器G1315B，柱：Agilent，ZORBAX Eclipse XDB-C18，4.6mm，5μm，P/N 993967-902，柱恒溫器：室溫，注射體積：100μL；溶劑A=HPLC級水+0.09% TFA，溶劑B=HPLC級乙腈+0.09% TFA。HPLC總的運行時間為7.6分鐘，包括4分鐘線性梯度從25到50%溶劑B，50%溶劑B保持30秒，梯度從50到25%溶劑B再保持30秒。用25%溶劑B再次平衡柱2.6分鐘，然後注射下一樣品。根據HPLC結果計算各測試化合物的IC50
值(觀察到50% NS3/4A活性受抑制時的濃度)。
在上述抑制試驗中測試了化合物1-281。結果顯示，274個化合物的IC50
低於20nM，7個化合物的IC50
在20-100nM範圍。
此外，發現某些本發明的化合物出乎意料地能以有效方式抑制耐受一種或多種其他HCV藥物的HCV蛋白酶突變體。
在含10%胎牛血清(FBS)、1.0毫克/毫升G418和適當補充劑的DMEM(培養基A)中培養含HCV複製子的細胞。
在第1天，用胰蛋白酶/EDTA混合物處理複製子細胞單層，移取該細胞單層，用培養基A稀釋至終濃度48,000細胞/毫升。將該溶液(1毫升)接種于24-孔組織培養平板的各孔中，37℃，5% CO2
氣氛下，在組織培育箱中培養過夜。
在第2天，用含10%FBS和適當補充劑的DMEM(培養基B)順序稀釋測試化合物(用100%DMSO配製)。在所有系列稀釋中，DMSO的終濃度維持在0.2%。
除去複製子細胞單層上的培養基，然後加入將含各種濃度化合物的培養基B。將不含化合物的培養基B加入其它孔作為無化合物的對照。
37℃，5% CO2
氣氛下，在組織培育箱中將細胞與化合物或0.2% DMSO在培養基B中培育72小時。然後，除去培養基，用PBS洗滌複製子細胞單層一次。將RNA提取試劑(例如，Rneasy試劑盒的試劑或TRIZOL試劑)立即加入細胞以避免RNA降解。按照生產商的使用說明書的改進方法提取總RNA以改善提取效率和一致性。最後，洗脫包含HCV複製子RNA的細胞總RNA，保存在-80℃以待進一步加工。
用兩套特異性引物實施TaqMan實時RT-PCR定量測定試驗：一套用於HCV，另一套ACTB(β-肌動蛋白)。將總RNA加入PCR反應，從而在同一PCR孔中定量測定HCV和ACTB RNA。根據各孔中ACTB RNA的水準對實驗失敗作標記並捨棄。根據同一PCR板中獲得的標準曲線計算各孔中的HCV RNA水準。利用DMSO或無化合物對照作為0%抑制來計算化合物處理所致的HCV RNA水準的抑制百分比。根據任何給定化合物的滴定曲線計算EC50
(HCV RNA水準達到50%抑制時的濃度)。
在HCV複製子細胞試驗中測試了化合物1-281。結果顯示，274個化合物的EC50
值低於20nM，7個化合物的EC50
值在20-100nM之間。
試驗前一天，雄性Sprague-Dawley大鼠(300-400克)在戊巴比妥麻醉下頸靜脈外科移植聚乙烯插管用於血液採樣。任意飲水禁食過夜，然後在第二天通過口服強飼(PO)給予測試化合物。給藥後48小時收集一系列的大鼠血液樣品，並在離心後回收肝素化血漿。提取血漿中的測試化合物，並通過液相色譜-質譜(LC-MS/MS)分析進行測定。
標準藥物代謝動力學參數採用WinNonlin(版本4.0,Pharsight,CA,USA)通過非房室分析進行評價。血漿中測試化合物的濃度相對於時間的曲線中最大的點標注為C最大
。表觀最終相消除(t 1/2
)按ln(2)/λz
計算，其中λz
是消除速率常數。自給藥時間點至無窮的(AUC(0-inf)
)濃度-時間曲線下面積按照線性梯形規則計算。
某些本發明的化合物顯示延長的半衰期和大的AUC值。
說明書中所揭示的所有特徵可以以任意的組合方式結合。說明書中所揭示的各種特徵可以被起到相同、等價或類似目的的特徵代替。因此，除非另外說明，所揭示的各種特徵僅僅是一系列等價或類似特徵的一個例子。
通過以上說明，本領域技術人員可以很容易地確定本發明的主要特徵，同時可以在不背離本發明的精神和範圍的前提下，對本發明進行各種改變和改良，以使其適用於各種應用和條件。因此，其他的實施方式也在所附申請專利範圍之內。
Claims (20)
- 一種以下結構式的化合物：
- 如申請專利範圍第1項所述的化合物，其特徵在於，X是O。
- 如申請專利範圍第1項所述的化合物，其特徵在於，A是CH，W是-CH2 CH2 -、-OCH2 -、-SCH2 -或-SOCH2 -。
- 如申請專利範圍第1項所述的化合物，其特徵在於，U是-NHSO2 -。
- 如申請專利範圍第1-4項中任一項所述的化合物，其特徵在於，Y是，其中，T是CH或N，且Ri ,Rii ,Riii ,Riv 和Rv 各自獨立地是H、鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基或C2-6 炔基，或者是選自以下的部分：C3-10 環烷基、C1-10 雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基、C2-6 炔基、芳基或雜芳基，或者任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合。
- 一種以下結構式的化合物：
- 如申請專利範圍第6項所述的化合物，其特徵在於，X是O。
- 如申請專利範圍第6項所述的化合物，其特徵在於，W是-CH2 CH2 -、-OCH2 -、-SCH2 -或-SOCH2 -；是雙鍵。
- 如申請專利範圍第6項所述的化合物，其特徵在於，U是-NHSO2 -。
- 如申請專利範圍第6-9項中任一項所述的化合物，其特徵在於，Y是，其中，T是CH或N，且Ri ,Rii ,Riii , Riv 和Rv 各自獨立地是H、鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基或C2-6 炔基，或者是選自以下的部分：C3-10 環烷基、C1-10 雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基、C2-6 炔基、芳基或雜芳基，或與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合。
- 一種以下結構式的化合物：
- 如申請專利範圍第11項所述的化合物，其特徵在於，X是O。
- 如申請專利範圍第11項所述的化合物，其特徵在於，A是CH；W是-CH2 CH2 -、-OCH2 -、-SCH2 -或-SOCH2 -；是雙鍵。
- 如申請專利範圍第11項所述的化合物，其特徵在於，U是-NHSO2 -。
- 如申請專利範圍第11-14項中任一項所述的化合物，其特徵在於，Y是，其中，T是CH或N，且Ri ,Rii ,Riii ,Riv 和Rv 各自獨立地是H、鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基或C2-6 炔基，或者是選自以下的部分：C3-10 環烷基、C1-10 雜環烷基、芳基和雜芳基，它們各自任選被以下取代基單取代、二取代或三取代：鹵素、硝基、氰基、氨基、C1-6 烷基、C1-6 烷氧基、C2-6 烯基、C2-6 炔基、芳基或雜芳基，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合。
- 一種化合物，其中所述化合物是以下化合物中的一種：
- 一種藥物組合物，其包含申請專利範圍第1-16項中任一項所述的化合物以及藥學上可接受的載體。
- 一種如申請專利範圍第1-16項中任一項所述的化合物在製備藥物中的用途，所述藥物是用於治療丙型肝炎病毒感染。
- 如申請專利範圍第18項所述的用途，其特徵在於，所述化合物通過口服給予需要治療的對象。
- 如申請專利範圍第18或19項所述的用途，其特徵在於，所述化合物一天給予一次。
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