TWI429450B - Hcv protease inhibitors - Google Patents

Hcv protease inhibitors Download PDF

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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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compound
aryl
heteroaryl
alkyl
heterocycloalkyl
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TW201109028A (en
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Chen Fu Liu
Kuang Yuan Lee
Pei Chin Cheng
Yo Chin Liu
Pin Lo
Kuo Feng Tseng
Chih Ming Chen
Chi Hsin Richard King
Chu Chung Lin
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Taigen Biotechnology Co Ltd
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丙型肝炎病毒蛋白酶抑制劑Hepatitis C virus protease inhibitor

本發明係有關於丙型肝炎病毒蛋白酶抑制劑。The present invention relates to hepatitis C virus protease inhibitors.

發明背景Background of the invention

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)。Hepatitis C virus (HCV) is a (+) sense single-stranded RNA ((+)-sense single-stranded RNA) and is a causative factor that primarily causes non-A, non-B hepatitis. HCV infection is a problem that threatens human health. See, for example, WO 05/007681; WO 89/04669; EP 381216; Alberti et al, J. Hepatology, 31 (Supp. 1), 17-24 (1999); Alter, J. Hepatology, 31 (Supp. 1), 88- 91 (1999); and Lavanchy, J. Viral Hepatitis, 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。Hepatitis caused by HCV infection is difficult to treat because of rapid mutation of the virus and avoidance of an innate immune response. The only anti-HCV therapeutics currently available are interferon-alpha, interferon-alpha/ribavirin combinations, and pegylated interferon-alpha. However, the sustained response rate of the interferon-α or interferon-α/ribavirin combination was found to be <50%, and the patient was largely affected by the side effects of these therapeutic agents. See, for example, Walker, DDT, 4, 518-529 (1999); Weiland, FEMS Microbial. Rev., 14, 279-288 (1994); and WO 02/18369. Therefore, there is still a need to develop more effective and acceptable anti-HCV drugs.

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)。The HCV protease required for viral replication contains approximately 3000 amino acids. It includes nucleocapsid protein (C), envelope proteins (E1 and E2), and some non-structural proteins (NS2, NS3, NS4a, NS5a and 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)。The NS3 protein has serine protease activity and is considered essential for viral replication and infection. This is evidenced by the fact that the mutation of the yellow fever virus NS3 protease reduces viral infectivity and that the variation of the active site of the HCV NS3 protease completely inhibits HCV infection in the chimpanzee model. See, for example, Chamber et al., Proc. Natl. Acad. Sci. USA 87, 8898-8902 (1990) and Rice et al, J. Virol. 74(4) 2046-51 (2000). In addition, the HCV NS3 protease was found to promote proteolysis at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a, NS5a/NS5b junctions. Therefore, HCV NS3 serine protease is thought to be involved in the production of four viral proteins during viral replication. See, for example, US 2003/0207861. Thus, the HCV NS3 protease is an attractive target for the treatment of HCV infection. Possible NS3 HCV protease inhibitors can be found in 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 et al, Biorg. Med. Chem. Lett. 10, 1571-1579 (2000); Bilin. Med. Chem of Llinas-Brunet et al. Lett. 10, 2267-2270 (2000); and S. LaPlante et al., Biorg. Med. Chem. Lett. 10, 2271-2274 (2000).

發明概要Summary of invention

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。The present invention is based on the surprising discovery that certain macrocyclic compounds are capable of blocking NS3-4A protease activity, reducing HCV RNA levels, inhibiting HCV protease mutants that are tolerant to other inhibitors, and prolonging the half-life in the blood circulation.

在一個方面，本發明涉及下面式(I)的化合物：In one aspect, the invention relates to compounds of formula (I) below:

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。Wherein R 1 is -H, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, -ZR or -NH-ZR; wherein R is H or a moiety selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl And each of them is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl, aryl or heteroaryl; Z is -C(O)-, -C(O) O-, -C(O) C(O) O-, -C(O) C (O) NH-, -C(O) NR'-, -OC(S)-, -C(S) NR'- or -C(NH) O-, R, is H, C 1-6 alkyl , C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; R 2 is H, or is selected from the group consisting of C 1-6 alkyl, C 3-10 ring An alkyl group, a C 1-10 heterocycloalkyl group, an aryl group and a heteroaryl group, each of which is optionally mono-, di- or tri-substituted with a halogen, a nitro group, a cyano group, an amino group, a C 1-6 group; Alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl; A is N or CH; U is -O-, -NH-, -NH (CO)-, -NHS(O)- or -NHSO 2 -; W is -(CH 2 ) m -, -NH(CH 2 ) n -, -(CH 2 ) n NH-, -O(CH 2 ) n -, -(CH 2 ) n O-, -S(CH 2 ) n -, -(CH 2 ) n S-, -S(O)-, -SO(CH 2 ) n -, -(CH 2 ) n S(O)-, -SO 2 (CH 2 ) n -or-(CH 2 ) n SO 2 -, m is 1, 2 or 3, n is 0, 1 or 2; X is -O-, -S-, -NH- or -OCH 2 -; Y is or Wherein V and T are each independently -CH- or -N-; and A 1 and A 2 are each independently a moiety selected from the group consisting of C 4-10 cycloalkyl, C 1-10 heterocycloalkyl, Aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; And R i is H, halogen, nitro, cyano or amino, or is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl And C 2-6 alkynyl are each optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, C 3-10 cycloalkyl, C 1-10 heterocyclic The alkyl, aryl and heteroaryl groups are each optionally substituted by the following substituents Substituted, disubstituted or trisubstituted by: halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, or optionally fused to C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl ; It is a single button or a double button.

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。The groups designated by the variables U, W, X and Z are divalent groups. The orientation of each group shown above is the same as the orientation shown in the formula. U specifies the variable -NHSO- group, for example, as shown in the structural formula, is interposed between the C = O and R 2. The N atom of the -NHS(O)- group is bonded to C=O, and the S atom is bonded to R 2 . Another example is the -C(O)O-specified by the variable Z interposed between NH and R (ie, -NH-ZR). The C atom in -C(O) O- is bonded to NH, and the O atom is bonded to R.

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。Referring to formula (I), the subgroup of the compound is characterized in that R 1 is -NH-ZR, wherein Z is -C(O)-, -C(O) O-, -C(O) C(O) O -or-C(O) C(O) NH-; R 2 is or ; X is O; A is CH; W is -CH 2 CH 2 -, - OCH 2 -, - SCH 2 - or -SOCH 2 -; U is -NHSO 2 -; Is a double bond; or Y is Wherein T is CH or N; R i is phenyl or thioazolyl optionally substituted by halogen, amino, C 1-6 alkyl or C 1-6 alkoxy; R ii , R iii , R iv , and R v are each independently H, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl Or a moiety selected from the group consisting of C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by the following substituents: Halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl is fused. Examples of R 1 are -NH-C(O)Ot-Bu, -NH-C(O)O-cyclopentyl and -NH-C(O)-furanyl.

該化合物的另一個亞組特徵如下，Y是Another subgroup characteristic of the compound is as follows, Y is

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。Wherein R i , R ii , R iii , R iv , R v and R vi are each independently H, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, cycloalkyl, heterocycloalkyl, aryl and The heteroaryl groups are each optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl a C 2-6 alkynyl group, an aryl group or a heteroaryl group; and optionally fused to a C 3-10 cycloalkyl group, a C 1-10 heterocycloalkyl group, an aryl group or a heteroaryl group.

在上面的化合物中，Ri 可以是例如以下：In the above compounds, R i may be, for example, the following:

其中，n為1或2。Where n is 1 or 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。The compounds of the invention also have the feature that Is a single button, R 2 is Or R 1 is -H, -OH, C1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, or -ZR.

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。The term "alkyl" means a saturated straight or branched chain hydrocarbon moieties, such as -CH 3 or -CH (CH 3) 2. The term "alkoxy" denotes an -O-(C 1-6 alkyl) group. The term "alkenyl" denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one double bond, such as -CH = CH-CH 3. The term "alkynyl" denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one triple bond, such as -C≡C-CH 3. The term "cycloalkyl" denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "cycloalkenyl" denotes a non-aromatic cyclic hydrocarbyl moiety comprising at least one double bond. The term "heterocycloalkyl" denotes a saturated cyclic moiety having at least one ring heteroatom such as N, O or S, for example 4-tetrahydropyranyl. The term "heterocyclenyl" denotes a non-aromatic cyclic moiety having at least one ring heteroatom (such as N, O or S) and at least one ring double bond, such as a pyranyl group. The term "aryl" denotes a hydrocarbyl moiety having one or more aromatic rings. Examples of the aryl moiety include phenyl (Ph), phenylene, naphthyl, naphthylene, anthracenyl, fluorenyl and phenanthryl. The term "heteroaryl" denotes a moiety comprising one or more aromatic rings having at least one heteroatom (eg, N, O or S). Examples of the heteroaryl moiety include furyl, furanyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquine Alkyl and anthracenyl. The term "amino" denotes a group of -NH 2 , -NH-(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 .

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。Unless otherwise specified, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups as described herein include both substituted and unsubstituted moieties. . Possible substituents on cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups include, but are not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, C 1 -C 20 dialkylamino, arylamino, diarylamino , C 1 -C 10 alkylsulfamoyl, arylsulfamoyl, C 1 -C 10 alkylimino, arylimino, C 1 -C 10 alkylsulfoimino, aryl sulfonate Amino, hydroxy, halogen, thio, C 1 -C 10 alkylthio, arylthio, C 1 -C 10 alkylsulfonyl, arylsulfonyl, decylamino, aminoguanidino, amino Thiomethyl, fluorenyl, fluorenyl, ureido, cyano, nitro, nitroso, azide, sulfhydryl, thiodecyl, decyloxy, carboxy and carboxylate groups. On the other hand, the substituent on the alkyl group, the alkenyl group or the alkynyl group includes all of the above substituents, except for the C 1 -C 10 alkyl group. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be fused to each other.

下面列出了本發明的281種示例性的化合物。The 281 exemplary compounds of the invention are listed below.

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。In another aspect, the invention relates to a method of treating an HCV infection, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) above.

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。In still another aspect, the invention relates to a pharmaceutical composition for treating an HCV infection. The composition comprises an effective amount of at least one compound of formula (I) and a pharmaceutically acceptable carrier. Inhibitors of targets other than HCV NS3 protease in the HCV life cycle, such as NS5B polymerase, NS5A, NS4B or p7, may be included.

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)。Examples of such inhibitors include, but are not limited to, N-[3-(1-cyclobutylmethyl-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-1,1 -dioxo-1,4-dihydro-116-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (WO04041818), trans-1,2-di-4- [(Phenylethyl-pyrrolidine-2-(S)-carbonyl)amino]-phenylethene (WO0401413) and 1-aminoadamantane (Amentadine, Griffin, 2004, J. Gen. Virol. 85: p451 ). The pharmaceutical composition may also comprise an immunomodulatory agent or a second antiviral agent. An immunomodulatory agent is an active agent that mediates an immune response. Examples of immunomodulators include, but are not limited to, Nov-205 (Novelos Therapeutics Inc., WO02076490) and IMO-2125 (Idera Pharmaceuticals Inc., WO05001055). An antiviral agent refers to an active agent that kills a virus or inhibits viral replication. Examples of antiviral agents include, but are not limited to, ribavirin, ribamidin, interferon-[alpha], Pegylated interferon, and HCV protease inhibitors, such as 2-(2-{2-cyclohexyl-2- [(Pyrazin-2-carbonyl)-amino]-ethoxymethylamino}-3,3-dimethyl-butanyl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid (1-cyclopropyl) Alanine-butyl- decylamine (Telaprevir, Vertex Pharmaceuticals Inc., WO02018369), 3-[2-(3-tert-butyl-ureido)-3,3-dimethyl -Butyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-B Benthoamine (Boceprevir, Schering-Plough Research Institute, WO03062265) and 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl Amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3,0.04,6]dodecyl-7-en-18-yl ester (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。The use of the composition in the treatment of HCV infection or in the manufacture of a medicament for use in such a treatment is also within the scope of the invention.

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。One or more embodiments of the invention are described in detail below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims.

較佳實施例之詳細說明Detailed description of the preferred embodiment

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：The compounds of the present invention can be prepared from commercially available starting materials by methods well known in the art. For example, the compounds of the invention can be synthesized by the route shown in Scheme 1 below:

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 )。As shown in Scheme 1, the polycyclic compound ( i ) is first coupled with N-(tert-butoxycarbonyl)-L-proline ( ii ) and then methylated to form intermediate ( iii ). The intermediate ( iii ) is subjected to a deprotection reaction to remove the N-butoxycarbonyl group to form an N-free compound ( iv ) which is coupled with a carboxylic acid ( v ) to form an intermediate ( vi ). By hydrolyzing the intermediate ( vi ), an acid ( vii ) is obtained which is coupled with an amine compound ( viii ) to obtain a pyrrolidine compound ( ix ) having two alkenyl end groups. The intermediate ( ix ) is subjected to an olefin displacement reaction in the presence of a groucher catalyst to obtain the desired macrocyclic compound ( x ). The double bond of the macrocyclic analog ( xi ) can be further hydrogenated in the presence of Pd-C to obtain a saturated-macrocyclic compound ( 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。The following Schemes 2 and 3 show alternative synthetic routes for the two compounds of the invention.

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。The above methods also include procedures performed before or after the steps specifically described in Schemes 1-3 to add or remove suitable protecting groups to ultimately synthesize the desired compound. Furthermore, different synthetic steps can be performed in an alternate order or order to obtain the desired compound. Synthetic chemical transformation and protecting group methods (protection and deprotection) for the synthesis of compounds of formula (I) are known in the art and include, for example, those described in the literature: R. Larock, Comprehensive Organic Transformations ( Integrated Organic Transformation) , VCH Press (1989); TW Greene and PGM Wuts, Protective Groupsin Organic Synthesis , Second Edition, John Wiley and Sons ( 1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Power and Sasun Press (1994); and Encyclopedia of L. Paquette Reagents for Organic Synthesis (Reagents for Organic Synthesis) , John Power and Sasun Press (1995), and subsequent editions.

下面實施例1-281詳細描述了化合物1-281的實際製備方式。The actual preparation of the compound 1-281 is described in detail in the following Examples 1-181.

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)：The compounds described herein contain non-aromatic double bonds and asymmetric centers. Thus, the compound may be a plurality of racemates and racemic mixtures, simple enantiomers, individual diastereomers, diastereomeric mixtures, tautomers, and cis-isomers or anti-isoforms. The form of the body. All of these isomeric forms are contemplated. For example, the compound of formula (I) shown above may have the following stereochemical configuration (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。The above compounds include the compound itself, if applicable, including its salts, prodrugs and solvates. For example, a salt can be formed from an anion and a positively charged group (e.g., an amino group) on a compound of formula (I). Suitable anions include: chloride, bromide, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetate, malate, tosylate , tartarate ion, fumarate ion, glutamate ion, glucuronide ion, lactate ion, glutarate ion and maleate ion. Similarly, salts can also be formed from cations and negatively charged groups (e.g., carboxylates) on compounds of formula (I). Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. The compounds of formula (I) also include those containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives which, upon administration to a patient, provide the active compound of formula (I). Solvate refers to a complex formed between the active compound of formula (I) and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid and ethanolamine.

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。One method of treating HCV infection within the scope of the present invention is by administering to a patient an effective amount of one or more compounds of formula (I). The term "therapeutic" or "treating" means administering a compound to a subject infected with HCV, exhibiting symptoms of HCV infection, or susceptible to HCV infection, to achieve a therapeutic effect, such as curing, alleviating, altering, affecting, ameliorating or preventing. HCV infection, symptoms of HCV infection, or a tendency to be susceptible to HCV infection. The term "effective amount" means the amount of active compound of the invention required to achieve a therapeutic effect in a subject being treated. One skilled in the art will recognize that the effective dosage will vary depending upon the type of disease being treated, the route of administration, the excipients employed, and other treatments that may be employed in parallel.

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。The compounds of the invention may remain in the blood circulation for an extended period of time at an effective level. Thus, these compounds can be administered in an effective amount once a day to provide a therapeutic effect.

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。For carrying out the methods of the invention, compositions comprising one or more compounds of the invention may be administered parenterally, orally, intranasally, rectally, topically or subcutaneously. The term "parenteral" means subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, wound or intracranial, and any Suitable injection techniques.

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。The sterile injectable compositions may be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, non-volatile oils are generally employed as a solvent or suspending medium (for example, synthetic mono or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, can be used in the preparation of injectable preparations, for example, pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or suspending agent, carboxymethyl cellulose or a similar dispersing agent. Other commonly used surfactants, such as Tween or Span, or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, may also be used. To formulate a pharmaceutical composition.

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。Compositions for oral administration can be any acceptable oral dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. For tablets, commonly used carriers include lactose and corn starch. A lubricant such as magnesium stearate can also usually be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When the aqueous suspension or emulsion is administered orally, the active ingredient may be suspended or dissolved in the oil phase in association with an emulsifier or suspension. Some sweeteners, perfumes or colorants can be added if desired.

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。Nasal sprays or inhalation compositions can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such compositions can be formulated in saline using benzyl alcohol or other suitable preservatives, absorption enhancers that enhance bioavailability, fluorohydrocarbons, and/or other solubilizing or dispersing agents known in the art. Solution in.

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。Compositions comprising one or more of the active compounds of the invention may also be in the form of a suppository for rectal administration.

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。The carrier in the pharmaceutical composition must be "acceptable", i.e., compatible with the active ingredients of the composition (preferably capable of stabilizing the active ingredient) without adversely affecting the subject being treated. One or more solubilizing agents can be used as pharmaceutical excipients for the delivery of the active compounds of the invention. Examples of other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C #10 yellow.

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。The compounds of the invention may be used in combination with a second anti-HCV agent to treat HCV, including, for example, inhibitors, immunomodulators and other antiviral agents in addition to the HCV NS3 protease during the HCV life cycle. The compound of the invention and the second anti-HCV agent can be administered simultaneously or at different times. For simultaneous administration, the two agents can be combined to form a single pill or separately made into pills. Each of the two agents is administered in an amount such that the total amount thereof is an effective amount for the treatment of HCV recognized by the skilled artisan.

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。The efficacy of the above compounds of the invention in the treatment of HCV infection can be initially screened by in vitro assays (see Examples 282 and 283) and then determined by animal and clinical trials. Other methods will also be apparent to those of ordinary skill in the art.

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。The following examples are merely illustrative and are not intended to limit the other parts of the specification in any way. It is believed that one skilled in the art, based on the description herein, may utilize the invention in its fullest extent without additional work. The entire disclosures of all publications cited herein are hereby incorporated by reference in their entirety.

實施例1：Example 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)Synthesis of {4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furan[3,2 -d]pyrimidin-4-yloxy]-3,16-diazatricyclo[14.3.0.04,6]nonadecane-14-yl}-carbamic acid cyclopentyl ester (compound 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：Compound I-3 was first prepared from the commercially available ethyl 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylate by the following route:

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)。To a solution of ethyl 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylate (0.34 g, 1.3 mmol) in THF (5 mL) 5.3 mmol of water suspension. After stirring overnight at room temperature, the reaction was quenched with EtOAc (EtOAc) The resulting solid powder was washed with water (10 ml) to afford Compound I-1 (0.27 g, 90%). MS m/z 249.9 (M + +23); 1 H NMR (CDCl 3 ) δ 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J = 17.4 Hz, 1H), 5.12 (d, J = 10.2 Hz, 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***-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)。Stir compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea cation at room temperature ( Uronium) hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol) and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH 2 Cl 2 (40 mL) Then, cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 ml, 14.0 mmol) and 1,8-diazabicyclo[5,4 were slowly added over 15 minutes. , 0] undec-7-ene (1.80 g, 11.7 mmol). After stirring the reaction mixture at room temperature overnight, the solvent was removed in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS m / z 353.1 (M + + 23); 1 H NMR (CDCl 3 ) δ 9.75 (brs, 1H), 5.64 - 5.51 (m, 1H), 5.30 (d, J = 17.4H), 5.16 (d) , J = 10.2 Hz, 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)。To compound I-2 (0.50 g, 1.5 mmol) in MeOH (8 mL) was added SOCl 2 (0.26 g, 2.2 mmol) at room temperature. After the reaction mixture was refluxed for 1 hour, MeOH and SOCl 2 were removed in vacuo. The residue was pulverized with pentane and filtered to give an off-white solid intermediate I-3 (0.32 g, 91%). MS m/z (M + +1); 1 H NMR (CD 3 COD) δ 5.77-5.65 (m, 1H), 5.43 (d, J = 17.4 Hz, 1H), 5.32 (d, J = 10.2 Hz) , 1H), 3.06-2.97 (m, 1H), 2.45 (dd, J = 17.4 Hz, J = 7.8, 1H), 2.16 (dd, J = 8.0 Hz, J = 7.8 Hz, 1H), 1.75 (dd, J = 10.1 Hz, J = 7.8 Hz, 1H), 1.32 - 0.86 (m, 4H).

化合物1通過以下路線製備：Compound 1 was prepared by the following route:

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)。A solution of 3-amino-benzofuran-2-carboxylic acid decylamine (1.00 g, 5.7 mmol) and pyridine (1 mL, 12.26 mmol) in THF (25 mL) was stirred for 10 min. To the resulting solution was slowly added 4-trifluoromethyl-benzylguanidinium chloride (1.48 g, 7.1 mmol). The temperature was then raised to room temperature and the mixture was stirred for 12 hours. After removing the solvent under reduced pressure, the formed solid was collected, washed with water, and evaporated to dryness. 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)。A suspension of I-4 (1.92 g, 5.5 mmol) and 2N NaOH (13 mL) in EtOH (25 mL). After cooling, the mixture was acidified and then EtOH was removed. The solid which formed was collected, filtered, washed with water and dried to give I-5 (1.71 g, 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)。The I-5 (1.71 g, 5.2 mmol) and excess phosphorus acyl chloride (POCl 3) was refluxed for 2 hours. After cooling and complete concentration, the mixture was extracted with dichloromethane and 10% sodium hydroxide. The organic layer was dried with MgSO 4, concentrated, diluted with CH 2 Cl 2 and n-hexane to give Compound I-6 (1.49 g, 82%). MS m / z 348.8, 350.9 (M + +1); 1 H NMR (CDCl 3 ) δ 8.70 (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)。To a suspension of Boc-trans-4-hydroxy-L-valine (0.53 g, 2.3 mmol) in DMSO (25 mL) was added t-BuOK (0.82 g, 5.1 mmol). After warming the mixture to room temperature and stirring for 1 hour, compound I-6 (0.81 g, 2.3 mmol) was slowly added at 10 °C. Continue stirring overnight. Methyl iodide (1.02 g, 6.9 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with a 10% aqueous HCl solution to pH 6-7 and extracted with dichloromethane. The organic layer was dried with MgSO 4, evaporated in vacuo and purified by silica gel column chromatography to give compound I-7 (1.12 g, 86%). MS m/z 557.8 (M + +1); 1 H NMR (CDCl 3 ) δ 8.63 (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)。To a solution of Compound I-7 (1.13 g, 2.0 mmol) in MeOH was added a solution of SOCl (20 is mL) 2 (1.21 g, 9.8 mmoles. The reaction mixture was refluxed for 1 hour, remove MeOH and SOCl 2. The residue was the suspension was filtered and triturated with pentane to give white solid compound I-8 (0.87 g of, 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***(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)。Room temperature, to HATU (1.12 g, 3.0 mmol), 1-hydroxybenzotriazole (HOBT, 0.41 g, 3.0 mmol), I-8 (0.86 g, 1.9 mmol) and 2-tert-butoxy amino carbonyl - non-8-enoic acid (1.21 g, 1.9 mmol) was added a solution of methyl N- CH 2 Cl 2 (40 ml) morpholine (NMM, 1.02 g, 9.9 mmol). After stirring overnight, the compound was concentrated under vacuum. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 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)。To a solution of Compound I-9 (1.01 g, 1.4 mmol) in THF (20 mL) After stirring overnight, the reaction mixture was neutralized with 10% HCl to pH <7 and concentrated with vacuo. The resulting residue was filtered and washed with water tolululu 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)。NMM (0.12 g, 1.2 mmol) was added to compound I-3 (0.28 g, 0.4 mmol), HATU (0.31 g, 0.8 mmol), HOBT (0.08 g, 0.6 mmol) and Compound I -10 (0.09 g, 0.4 mmol) in a solution of CH 2 Cl 2 (10 ml). After stirring overnight, the reaction mixture was concentrated under vacuum. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS m / z 921.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.24 (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)。At room temperature, under an atmosphere of N 2 to compound I-11 (0.10 g, 0.11 mmol) in a solution of CH 2 Cl 2 (10 mL)加入霍维达- Grubbs (Hoveyda-Grubbs) II (35 mg, 0.056 Millimoles). Then, the reaction mixture was stirred at 40 ° C for 24 hours to carry out metathesis cyclization. The reaction was quenched and the reaction mixture was purified mpjjjjjjj MS: m/z 893.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.39 (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)。At room temperature, under an atmosphere of N 2 1-12 (30 mg, 0.034 mmol) was added to compound 5% Pd-C (5 mg) in MeOH (10 mL) solution. Then, the reaction mixture was stirred at room temperature under a pressure of 60 psi for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered and purified by column chromatography eluting to afford compound 1 (16.5 mg, 55%). MS: m/z 895.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.79 (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Example 2-141: Synthesis of Compound 2-141

化合物2-141各自按照與實施例1所述類似的方式製備。Compounds 2-141 were each prepared in a similar manner to that described in Example 1.

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)。Compound 2: MS: m/z 883.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.51 (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)。Compound 3: MS: m / z 823.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 4: MS: m / z 882.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 5: MS: m/z 840.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 6: MS: m/z 824.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.48 (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)。Compound 7: Ms: m/z 839.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.39 (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)。Compound 8: Ms: m/z 849.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.54 (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)。Compound 9: Ms: m/z 880.3 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 10: MS: m/z 911.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 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)。Compound 12: MS: m/z 923.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 13: MS: m/z 852.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.68 (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)。Compound 14: MS: m/z 766.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 15: MS: m/z 893.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 16: MS: m/z 877.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.40 (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)。Compound 17: Ms: m/z 907.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 18: Ms: m/z 767.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 19: MS: m/z 899.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 20: MS: m/z 895.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 21: MS: m/z 923.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 22: MS: m/z 752.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.76 (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)。Compound 23: MS: m / z 907.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 24: MS: m/z 916.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 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)。Compound 26: MS: m/z 923.3 (M + +1); 1 H NMR (CDCl 3 ) δ 1035 (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)。Compound 27: MS: m/z 894.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 28: MS: m/z 878.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.56 (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)。Compound 29: MS: m/z 909.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.27 (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)。Compound 30: MS: m/z 906.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.18 (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)。Compound 31: MS: m/z 907.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.39 (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)。Compound 32: MS: m/z 895.2 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 33: MS: m/z 853.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.22 (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)。Compound 34: MS: m/z 923.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.17 (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)。Compound 35: MS: m/z 894.2 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 36: MS: m/z 889.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 37: MS: m/z 837.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.16 (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)。Compound 38: MS: m/z 863.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.52 (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)。Compound 39: MS: m / z 908.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 40: MS: m / z 866.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 41: MS: m/z 892.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.40 (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)。Compound 42: MS: m/z 907.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.20 (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)。Compound 43: Ms: m/z 890.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.16 (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)。Compound 44: MS: m/z 879.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.22 (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)。Compound 45: MS: m/z 933.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.22 (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)。Compound 46: MS: m/z 891.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (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)。Compound 47: MS: m/z 867.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.35 (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)。Compound 48: MS: m / z 908.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 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)。Compound 50: MS: m/z 806.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.47 (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. 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)。Compound 51: MS: m/z 822.3, 824.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 52: MS: m/z 774.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 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)。Compound 54: MS: m/z 805.3, 807.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.46 (s, 1H), 8.28-8.19 (m, 1H), 7.78 (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)。Compound 55: MS: m/z 789.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.61 (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)。Compound 56: MS: m/z 839.3, 843.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.27 (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)。Compound 57: MS: m/z 827.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.17 (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)。Compound 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)。Compound 59: Ms: m/z 789.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.39 (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)。Compound 60: MS: m/z 773.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 61: MS: m/z 845.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.41 (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)。Compound 62: MS: m/z 841.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.21. (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)。Compound 63: MS: m/z 903.3; 905.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.18 (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)。Compound 64: MS: m/z 787.3 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 65: MS: m/z 803.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.46 (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)。Compound 66: MS: m/z 871.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 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)。Compound 68: TG-2379: MS: m/z 871.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 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)。Compound 70: MS: m/z 857.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 71: MS: m/z 819.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 72: MS: m/z 861.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 73: Ms: m/z 803.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 74: MS: m/z 861.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 75: MS: m/z 887.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 76: Ms: m/z 903.3, 905.3 (M + +1).

化合物77:MS:m/z 887.3(M+ +1)。Compound 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)。Compound 78: MS: m / z 883.4 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 79: MS: m/z 869.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 80: MS: m/z 883.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 81: MS: m/z 897.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (s, 1H), 8.42 (d, 2H), 8.21 (d, 1H), 7.57-7. 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)。Compound 82: MS: m/z 915.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (s, 1H), 8.38 (d, 2H), 7.74 (d, 1H), 7.57-7. 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)。Compound 83: MS: m / z 901.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 84: MS: m/z 885.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 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)。Compound 86: MS: m/z 883.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.41 (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)。Compound 87: MS: m/z 869.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 88: MS: m/z 868.5 (M + +1).

化合物89:MS:m/z 882.5(M+ +1)。Compound 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)。Compound 90: MS: m/z 910.3 (M + +1); 1 H NMR (CDCL 3 ) δ 10.32 (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)。Compound 91: MS: m / z 896.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 92: MS: m / z 901.4,903.4 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 93: MS: m/z 915.4, 917.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.27 (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)。Compound 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)。Compound 95: MS: m/z 881.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 96: MS: m/z 881.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.47 (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)。Compound 97: MS: m/z 895.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 98: MS: m/z 869.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.41 (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)。Compound 99: MS: m/z 925.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 100: MS: m / z 925.4 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 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)。Compound 102: MS: m/z 897.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (s, 1H), 8.39 (d, 2H), 8.20 (d, 1H), 7.59-7. 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)。Compound 103: MS: m/z 866.3 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 104: MS: m/z 811.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 105: MS: m/z 868.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.57 (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)。Compound 106: MS: m/z 882.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 107: MS: m/z 863.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (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)。Compound 108: MS: m/z 840.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.67 (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)。Compound 109: MS: m/z 837.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.49 (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)。Compound 110: MS: m/z 865.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.39 (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)。Compound 111: MS: m/z 881.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 112: MS: m/z 864.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 113: MS: m/z 853.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (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)。Compound 114: MS: m/z 907.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 115: MS: m/z 895.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 116: MS: m/z 940 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 117: MS: m/z 855.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.08 (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)。Compound 118: MS: m/z 895.4 (M + +1).

化合物119:MS:m/z 895.4(M+ +1)。Compound 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)。Compound 120: MS: m/z 840.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 121: MS: m/z 829.3 (M + +1).

化合物122:MS:m/z 833.3(M+ +1)。Compound 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)。Compound 123: MS: m/z 821.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.27 (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)。Compound 124: MS: m/z 779.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 125: MS: m/z 817.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (s, 1H), 7.78 (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)。Compound 126: MS: m/z 763.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 127: MS: m/z 821.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 128: MS: m/z 833.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 129: MS: m/z 836.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (s, 1H), 7.78 (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)。Compound 130: MS: m/z 832.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.20 (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)。Compound 131: MS: m/z 888.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 132: MS: m/z 888.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.24 (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)。Compound 133: MS: m/z 887.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 134: MS: m / z 901.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 135: MS: m/z 888.3 (M + +1).

化合物136:MS:m/z 902.3(M+ +1)。Compound 136: MS: m / z 902.3 (M + +1).

化合物137:MS:m/z 899.4(M+ +1)。Compound 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)。Compound 138: MS: m/z 885.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 139: MS: m/z 803.3 (M + +1).

化合物140:MS:m/z 817.3(M+ +1)。Compound 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)。Compound 141: MS: m / z 831.3 (M + +1); 1 H NMR (CDCl 3) 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：Examples 142 and 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)Synthesis of 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-(2-phenyl-benzo[4,5]furo[3,2-b]pyridin-4-yloxy -3,16-diazatricyclo[14.3.0.04,6]dodecyl-7-en-14-yl]-carbamic acid tert-butyl ester (compound 142) and [4-cyclopropanesulfonyl) Aminocarbonyl-2,15-dioxo-18-(2-phenyl-benzo[4,5]furo[3,2-b]pyridin-4-yloxy)-3,16-diaza Heterotricyclo[14.3.0.04,6]dodecyl-7-en-14-yl]-carbamic acid cyclopentyl ester (compound 143)

化合物142和143通過以下合成路線製備：Compounds 142 and 143 were prepared by the following synthetic route:

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***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)。Potassium carbonate (69.6 g, 755.5 mmol) was added to a solution of 2-hydroxybenzonitrile (30 g, 251.6 mmol) in ethyl methyl ketone (320 ml). After stirring at room temperature for 30 minutes, chloroacetone (34.95 g, 377.8 mmol) was added to the resulting mixture, which was then heated at 100 ° C overnight. Finally, the reaction solvent was removed under reduced pressure, and the obtained solid was washed with water and diethyl ether to afford I-13 (31 g, yield: 70.3%). MS: m/z 176.0 (M + +1); 1 H NMR (CDCl 3 ) δ 7.59 (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)。Ethyl 2-acetamido-3-aminobenzofuran I-13 (2.17 g, 12.38 mmol) and benzaldehyde (1.31 g, 12.38 mmol) at 5-10 ° C under constant stirring (30) Aqueous sodium hydroxide (70%, 5 mL) was added dropwise to the solution. After stirring overnight, the crude product of a bright yellow solid was suspended in the reaction solution. The solid was filtered, collected, and recrystallized from ethanol to give a filamentous needle I-14 (2.7 g, 90%). MS: m/z 264.0 (M + +1); 1 H NMR (CDCl 3 ) δ 7.83 (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)。Intermediate I-14 (1.32 g, 5.0 mmol) was suspended in acetic acid (10 mL) and stirred in a hot water bath. After stirring overnight, the reaction mixture was poured into ice-water. The suspended crude product was separated and collected, then recrystallized from ethanol to afford I-15 (l. MS: m/z 306.0 (M + +1); 1 H NMR (CDCl 3 ) δ 8.58 (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)。Intermediate I-15 (1.22 g, 4.0 mmol) in CHCl 3 solution (20 ml) was slowly added dropwise bromine (0.72g 4.5 mmol) in CHCl 3 (15 mL). After stirring overnight, the reaction mixture was quenched with ice water. The suspended solid was separated, collected and washed with ethanol / H 2 O and recrystallized to give I-16 (1.12 g, 60%). MS: m/z 465.9 (M + +1); 1 H NMR (CDCl 3 ) δ 10.22 (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)。Anhydrous potassium acetate (0.2 g, 2.0 mmol) was added to a solution of I-16 (0.93 g, 2.0 mmol) in acetone (25 mL). After stirring overnight, the reaction mixture was poured into cold water. The suspended solid was isolated, collected and recrystallized from ethanol to afford monobromide-compound I-17 (0.46 g, 60%). MS: m/z 385.9 (M + +1); 1 H NMR (CDCl 3 ) δ 10.50 (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)。Compound I-17 (0.35 g, 1.0 mmol) was refluxed in EtOAc (5 mL)EtOAc. The reaction mixture was cooled to room temperature, poured into ice water and stirred for 30 min. The suspended solids were separated, collected and recrystallized from DMF to afford 1-18 (0.2 g, 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)。I-18 (1.0 g, 3.8 mmol) and phosphorous acyl chloride (POCl 3) (10 ml) was refluxed for 2 hours. After the solution was cooled and concentrated, the residue was purified eluting with EtOAc (EtOAc) The organic layer was collected, dried over sodium sulfate and concentrated. The crude product was recrystallized from n-hexane 2 Cl 2 and CH, to obtain I-19 (0.7 g, 75%). MS: m/z 279.9 (M + +1); 1 H NMR (CDCl 3 ) δ 8.45 (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)。To a suspension of Boc-trans-4-hydroxy-L-valine (0.53 g, 2.3 mmol) in DMSO (10 mL) was added t- BuONa (0.49 g, 5.08 mmol). After heating to room temperature and stirring for 1 hour, intermediate I-19 (0.64 g, 2.3 mmol) was slowly added at 10 °C. The reaction mixture was stirred for 4 hours and then quenched with 10% aqueous HCl to pH 6-7. The crude solid was filtered, washed with water and dried thenjjjjjj MS: m/z 475.1 (M + +1); 1 H NMR (CDCl 3 ) δ 8.27 (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)。To a solution of I-20 (1.1 g, 2.3 mmol) in MeOH (20 mL) was added a solution of SOCl 2 (1.17 g, 9.9 mmol). After refluxing for 1 h, the solvent was evaporated in vacuo to afford crude compound I-21. 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***-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***(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)。To room temperature, to I-21 (0.78 g, 2.0 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea cation hexafluoro -Methylammonium phosphate (HATU, 1.12 g, 3.0 mmol), N-hydroxybenzotriazole (HOBT, 0.4 g, 3.0 mmol) and 2-tert-butoxycarbonylamino-indole-8-enoic acid ( 1.19 g, 5.2 mmol) in CH 2 Cl 2 (20 ml) was added NMM (1.0 g, 9.9 mmol). After the mixture was stirred overnight, it was concentrated in vacuo. The residue was purified by silica gel column chromatography toield of compound I-22 (1.02 g, 80.7%). MS: m/z 642.3 (M + +1); 1 H NMR (CDCl 3 ) δ 8.24 (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)。To a solution of I-22 (1.0 g, 1.6 mmol) in THF (20 mL). After the reaction mixture was stirred with EtOAc EtOAc EtOAc EtOAc. MS: m/z 628.1 (M + +1); 1 H NMR (CDCl 3 ) δ 8.34 (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)。NMM (0.12 g, 1.2 mmol) was added to compound I-23 (0.26 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), HOBT (0.084 g, 0.61 mmol) and cyclopropane at room temperature acid (1-amino-2-vinyl - cyclopropanecarbonyl) - Amides (0.094 g, 0.41 mmol) in a solution of CH 2 Cl 2 (10 ml). After the reaction mixture was stirred overnight, concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS: m/z 804.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.22 (s, 1H), 8.35 (d, 1H), 8.1 (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)。To the solution of compound I-24 (100 mg, 0.12 mmol) in CH 2 Cl 2 was added Hovida-Grubb 2nd generation catalyst (35 mg, 0.056 mmol) at room temperature under N 2 , then the reaction was heated The mixture was brought to 40 ° C and stirred for 24 hours. The reaction mixture was concentrated and purified by column to afford compound 142 (30 mg, 31%). MS: m/z 812.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (s, 1H), 8.28 (d, 1H), 8.04 (d, 2H), 7.71-7.41 (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)。At room temperature, 142 (0.1 g, 0.14 mmol) was added to an excess of the compound 4N HCl solution in dioxane (2 mL) in a solution of CH 2 Cl 2 (5 mL). After stirring for 4 hours, evaporated to remove HCl, dioxane and CH 2 Cl 2, to give crude Compound I-25, the crude compound was used without further purification in the next step. 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)。The I-25 was dissolved in acetonitrile (2 ml), then saturated NaHCO 3 (1 mL). The reaction mixture was stirred for 10 minutes. Cyclopentyl chloroformate (0.02 g, 0.15 mmol) was added to the reaction mixture at room temperature. After stirring for 2 hours, the reaction mixture was quenched with saturated NaHCO 3, extracted with CH 2 Cl. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS: m/z 824.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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Examples 144-253: Synthesis of Compound 144-253

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。Compounds 144-253 were each prepared in a similar manner as described in Examples 142 and 143.

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)。Compound 144: MS: m/z 7887.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 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)。Compound 146: MS: m/z 770.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.35 (s, 1H), 8.25 (d, 1H), 8.00 (d, 2H), 7.56-7. 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)。Compound 147: MS: m/z 697.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 148: MS: m/z 872.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (s, 1H), 8.09 (dd, 1H), 7.69 (d, 1H), 7.48-7. 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)。Compound 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)。Compound 150: MS: m / z 802.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 151: MS: m/z 854.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 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)。Compound 153: MS: m/z 854.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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),Compound 154: MS: m/z 854.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。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)。Compound 155: Ms: m/z 842.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 156: MS: m/z 854.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.24 (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)。Compound 157: MS: m/z 838.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 158: MS: m / z 842.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 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)。Compound 160: MS: m/z 872.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.48 (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)。Compound 161: MS: m/z 860.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (s, 1H), 8.1 (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)。Compound 162: MS: m/z 856.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 163: MS: m/z 854.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 164: MS: m / z 830.4 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 165: MS: m/z 868.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 166: MS: m/z 868.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (s, 1H), 8.59 (s, 1H), 7.78 (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)。Compound 167: MS: m/z 872.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 168: MS: m/z 826.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 169: MS: m/z 858.3, 859.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.35 (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)。Compound 170: MS: m/z 772.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 171: MS: m/z 768.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 172: MS: m/z 788.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.32 (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)。Compound 173: MS: m/z 822.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.15 (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)。Compound 174: MS: m/z 826.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.21. (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)。Compound 175: MS: m/z 842.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 176: MS: m/z 844.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 177: MS: m/z 840.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.25 (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)。Compound 178: MS: m/z 784.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 179: MS: m/z 856.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 180: Ms: m / z 814.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 181: Ms: m/z 852.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.19 (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)。Compound 182: MS: m/z 798.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。Compound 183: MS: m / z 802.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 184: MS: m/z 786.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 185: MS: m / z 812.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 186: MS: m/z 856.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 187: MS: m/z 303. (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (s, 1H), 8.1 (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)。Compound 188: MS: m / z 842.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 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)。Compound 190: MS: m/z 884.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 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)。Compound 192: MS: m/z 880.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 193: MS: m/z 495 (m + +1); 1 H NMR (CDCl 3 ) δ 10.21. (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)。Compound 194: MS: m/z 857.3 (M + +1).

化合物195:MS:m/z 857.3(M+ +1)。Compound 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)。Compound 196: MS: m/z 784.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.20 (s, 1H), 8.27 (d, 1H), 7.78 (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)。Compound 197: MS: m/z 856.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (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)。Compound 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)。Compound 199: MS: m/z 798.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (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)。Compound 200: MS: m / z 852.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 201: MS: m/z 814.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.41 (s, 1H), 7.78 (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)。Compound 202: MS: m/z 838.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 203: MS: m/z 842.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 204: MS: m/z 784.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 205: MS: m / z 801.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 206: MS: m/z 838.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.19 (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)。Compound 207: MS: m / z 800.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 208: MS: m/z 838.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.19 (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)。Compound 209: MS: m/z 896.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.20 (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)。Compound 210: MS: m/z 882.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.24 (s, 1H), 8.27 (d, 1H), 7.78 (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)。Compound 211: MS: m/z 922.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.13 (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)。Compound 212: MS: m/z 892.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 213: MS: m/z 880.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 214: MS: m/z 780.2 (M + +1).

化合物215:MS:m/z 822.2(M+ +1)。Compound 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)。Compound 216: MS: m/z 910.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 217: MS: m/z 922.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 218: MS: m/z 892.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 219: MS: m/z 880.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 220: MS: m / z 892.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 221: MS: m/z 880.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 222: MS: m/z 814.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.29 (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)。Compound 223: MS: m / z 802.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 224: MS: m/z 848.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.30 (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)。Compound 225: MS: m/z 760.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.35 (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)。Compound 226: MS: m / z 798.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 227: MS: m/z 744.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 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)。Compound 229: MS: m/z 830.3 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 230: MS: m/z 860.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 231: MS: m/z 848.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 232: MS: m / z 836.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 233: MS: m / z 806.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 234: MS: m/z 860.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 235: MS: m/z 844.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.24 (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)。Compound 236: MS: m/z 372 (m + +1); 1 H NMR (CDCl 3 ) δ 10.27 (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)。Compound 237: MS: m/z 844.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.23 (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)。Compound 238: MS: m/z 844.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.26 (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)。Compound 239: MS: m/z 790.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.34 (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)。Compound 240: MS: m/z 828.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.18 (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)。Compound 241: MS: m/z 778.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 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)。Compound 243: MS: m/z 858.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.28 (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)。Compound 244: MS: m/z 872.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.13 (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)。Compound 245: MS: m / z 831.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 246: MS: m/z 761.4 (M + +1); 1 H NMR (CDCl 3 ) δ 10.21. (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)。Compound 247: MS: m/z 803.4 (M + +1).

化合物248:MS:m/z 845.3(M+ +1)。Compound 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)。Compound 249: MS: m / z 917.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 250: MS: m/z 905.4 (M + +1).

化合物251:MS:m/z 901.3(M+ +1)。Compound 251: MS: m / z 901.3 (M + +1).

化合物252:MS:m/z 917.4(M+ +1)。Compound 252: MS: m/z 917.4 (M + +1).

化合物253:MS:m/z 903.3(M+ +1)。Compound 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)Example 254: Synthesis of [4-cyclopropanesulfonylaminocarbonyl-18-(2-fluoro-benzo[4,5]furo[3,2-b]quinolin-11-yloxy)-2 ,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadecane-14-yl]-carbamic acid cyclopentyl ester (compound 254)

化合物254通過以下合成路線製備。Compound 254 was prepared by the following synthetic route.

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)。To a solution of Boc-trans-4-hydroxy-L-proline (0.53 g, 2.30 mmol) in DMSO (10 mL) was added t- BuONa (0.49 g, 5.08 mmol). After warming to room temperature and stirring for an additional 1 hour, intermediate I-26 (0.62 g, 2.31 mmol) was slowly added at 10 °C. The reaction mixture was stirred for 4 hours and then quenched with 10% aqueous HCl to pH 6-7. The crude suspension solid was filtered, washed with water and dried mjjjjjjj 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)。5 ° C, to I-27 (0.90 g, 1.93 mmol), HATU (58.9 g, 1.55 mmol), HOBt (7.0 g, 0.52 mmol) and NMM (38.3 g, 3.86 mmol) in CH 2 Cl 2 (10 ml) was added dropwise to a solution of (1-amino-2-vinyl-cyclopropanecarbonyl)-decylamine (54.0 g, 2.03 mmol) and NMM (0.19 g, 1.93 mmol). A mixture of CH 2 Cl 2 . The mixture was warmed to rt. 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)。Compound I-28 (1.20 g, 1.77 mmol) was dissolved in MeOH (18 mL). Thionium chloride (0.39 ml, 5.30 mmol) was added dropwise to the reaction mixture. After removing the ice bath, the reaction mixture was heated at 65 ° C for 1 hour. The resulting solution was cooled to 40 &lt;0&gt;C, filtered, washed with cold MeOH and ether to afford pale white powder. 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)。5 ℃, 2- cyclopentyloxycarbonyl group - non-8-enoic acid (0.87 g, 2.34 mmol), HATU (1.16 g, 3.05 mmol) and HOBt (0.14 g, 1.02 mmol) in CH 2 solution of cl 2 (10 ml) was added dropwise dissolved in DMF (10 mL) was (1.18 g, 2.03 mmol) and NMM (0.49 g, 4.87 mmol) of I-29. After warming to room temperature and stirring for additional 16 hours, 10% HCl (1 mL) was then evaporated. The residue was cooled to 5 ℃, with 5% HCl (aq) (10 mL x 2) and NaHCO 3 (aq) (10 mL x 2) and washed sequentially, to give a pale yellow solid. The solid was dissolved in MeOH (10 mL). 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)。By nitrogen bubbling Compound I-30 (0.50 g, 0.59 mmol) in degassed CH 2 Cl 2 (120 mL) for 1 hour. A second generation Hovda-Grubb catalyst (48 mg, 0.076 mmol) was added and the reaction mixture was heated at 40 °C for 16 hours. After the completion of the reaction was indicated by HPLC, the reaction mixture was cooled to 30 ° C, concentrated and purified by silica gel column chromatography to afford product I-31 (0.30 g, yield 62%). MS: m/z 816.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.33 (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)。At room temperature under an atmosphere of N 2, a solution of compound I-31 (50 mg, 0.061 mmol) was added 5% Pd-C (5 mg) in MeOH (10 mL) solution. Then, the reaction mixture was stirred under a hydrogen atmosphere at a pressure of 60 psi and room temperature for 4 hours. The reaction mixture was filtered and purified by EtOAc EtOAc EtOAc MS: m/z 818.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.50 (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).

實施例255-281：化合物255-281的合成Examples 255-281: Synthesis of Compound 255-281

化合物255-281各自按照與實施例254中所述類似的方式製備。Compounds 255-281 were each prepared in a similar manner as described in Example 254.

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)。Compound 255: MS: m/z 764.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.47 (s, 1H), 7.78-7.84 (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)。Compound 256: MS: m/z 815.6 (M + +1); 1 H NMR (CDCl 3 ) δ 10.31 (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)。Compound 257: MS: m / z 804.1 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 258: MS: m/z 806.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 259: MS: m/z 788.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.51 (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)。Compound 260: MS: m/z 762.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.63 (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)。Compound 261: MS: m/z 704.2 (M + +1); 1 H NMR (CD 3 OD) δ 9.26 (s, 1H), 8.47 (d, 1H), 8.26 (m, 1H), 8. , 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)。Compound 262: MS: m/z 818.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.42 (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)。Compound 263: MS: m / z 780.2 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 264: MS: m/z 931.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.43 (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)。Compound 265: MS: m/z 780.2 (M + +1); 1 H NMR (CDCl 3 ) 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)。Compound 266: MS: m/z 776.3 (M + +1); 1 H NMR (CDCl 3 ) δ 10.56 (s, 1H), 8.24 (d, 1H), 8.00 (s, 1H), 7.87-7. 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). Compound 267: MS: m/z 812.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.47 (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)。Compound 268: MS: m/z 832.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.50 (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)。Compound 269: MS: m/z 834.3 (M + +1).

化合物270:MS:m/z 792.2(M+ +1)。Compound 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)。Compound 271: MS: m/z 822.2 (M++1); 1 H NMR (CDCl 3 ) δ 10.38 (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)。Compound 272: MS: m/z 822.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.37 (s, 1H), 8.10 (m, 1H), 7.78 (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)。Compound 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)。Compound 274: MS: m/z 834.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.43 (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)。Compound 275: MS: m/z 780.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.61 (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)。Compound 276: MS: m/z 818.1 (M + +1); 1 H NMR (CDCl 3 ) δ 10.35 (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)。Compound 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)。Compound 278: MS: m/z 764.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.49 (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)。Compound 279: MS: m / z 834.3 (M + +1); 1 H NMR (CDCl 3) 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)。Compound 280: MS: m/z 818.2 (M + +1); 1 H NMR (CDCl 3 ) δ 10.36 (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)。Compound 281 was prepared according to the Example 1 a similar manner: Compound 281: MS: m / z 901.2 (M + +1); 1 H NMR (CDCl 3) 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).

實施例282：NS3/4A蛋白酶的抑制Example 282: Inhibition of NS3/4A protease

蛋白質的表達和純化Protein expression and purification

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。The plasmid containing the NS4A (21-32) -GSGS-NS3 (3-181) gene encoding the N-terminal His 6 -tag was transformed into E. coli strain BL21 (DE3) from Novagen. ) pLysS is used to overexpress proteins. Transformed BL21(DE3) pLysS single colonies were grown overnight in 200 ml of Lauria-Bertani (LB) medium containing kanamycin and chloramphenicol at 37 °C. The bacterial culture was transferred to 6 liters of antibiotic-containing LB medium of Difco (Difco) and incubated at 22 ° C with shaking. After the absorbance at 600 nm reached 0.6, the culture was induced with 1 mM isopropyl-1-thio-β-D-galactopyranoside (IPTG) at 22 ° C for 5 hours. The culture was then collected by centrifugation (4 ° C, 6,000 x g, 15 minutes). The cell pellet was resuspended in 150 ml of buffer A (50 mM HEPES, pH 7.4, 0.3 M NaCl, 0.1% (w/v) CHAPS, 10 mM imidazole, 10% (v/v) glycerol). The mixture was passed through a Microfluidizer operated at 30 psi for four times to disperse, and then centrifuged (4 ° C, 58, 250 × g, 30 minutes) to remove cell debris. There 10mM imidazole in the presence of usage Marcia Company (Pharmacia) containing the GradiFrac system His 6 - tagged protein cell lysate of 3 ml / min 25 ml loaded onto QIAGEN (Qiagen) a Ni-NTA column. The column was washed with 10 column volumes of lysis buffer. Bound NS4A (21-32) -GSGS-NS3 ( 3-181 ) was eluted with 8 column volumes of buffer A supplemented with 300 mM imidazole. Q-Sepharose column equilibrated by buffer B (50 mM HEPES, pH 7.4, 0.1% (w/v) CHAPS, 10% (v/v) glycerol, 5 mM dithiothreitol (DTT) and 1 M NaCl) The combined components were further purified. The eluate containing NS4A (21-32) -GSGS-NS3 (3-181) was collected using buffer C (50 mM HEPES, pH 7.4, 0.1% (w/v) CHAPS, 5 mM DTT, 10% (v /v) Glycerol) A pre-equilibrated polyphthyl dextran-75 column (16 x 100 cm, Pharmacia) was further purified by size exclusion chromatography at a flow rate of 5 ml/min. The purified protein was frozen and stored at -80 ° C until use.

HPLC微孔測試HPLC micropore test

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。Preparation containing 50 mM Tris, pH 7.4, 100 mM NaCl, 20% glycerol, 0.012% CHAPS, 10 mM DTT, 5 μM substrate Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-Ψ-[COOAla]-Ser- A solution of Lys (DABCYL)-NH 2 (RET S1, ANASPEC) and 10 μM test compound. 80 microliters of the solution was added to each well of a 96-well plate. The reaction was initiated by the addition of 20 μL of 10 nM NS3/4A protease formulated with a buffer containing 50 mM Tris buffer, pH 7.4, 100 mM NaCl, 20% glycerol and 0.012% CHAPS. The final concentration of the NS3/4A protease is 2 nM, which is lower than the Km of the substrate RET S1.

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。The test solution was incubated at 30 ° C for 30 minutes. The reaction was then stopped by the addition of 100 μL of 1% TFA. A 200 [mu]L aliquot was transferred to each well of a 96-well plate from Agilent.

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)。The reaction product was analyzed by reverse phase HPLC as described below. The HPLC system consisted of: Agilent 1100, degassing column G1379A, binary pump G1312A, autosampler G1367A, column thermostat G1316A, diode array detector G1315B, column: Agilent, ZORBAX Eclipse XDB-C18, 4.6 mm, 5 μm, P /N 993967-902, column thermostat: room temperature, injection volume: 100 μL; solvent A = HPLC grade water + 0.09% TFA, solvent B = HPLC grade acetonitrile + 0.09% TFA. The total HPLC run time was 7.6 minutes, including a 4 minute linear gradient from 25 to 50% solvent B, 50% solvent B for 30 seconds, and a gradient from 50 to 25% solvent B for another 30 seconds. The column was again equilibrated with 25% solvent B for 2.6 minutes and then the next sample was injected. The IC 50 value of each test compound was calculated from the HPLC results (concentration at which 50% of NS3/4A activity was observed to be inhibited was observed).

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。Compound 1-281 was tested in the above inhibition test. The results showed that 274 compounds had an IC 50 of less than 20 nM and 7 compounds had an IC 50 in the range of 20-100 nM.

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。Furthermore, it has been found that certain compounds of the invention unexpectedly inhibit HCV protease mutants that are resistant to one or more other HCV drugs in an effective manner.

實施例283：HCV複製子細胞試驗方案Example 283: HCV Replicon Cell Test Protocol

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。The cells containing the HCV replicon were cultured in DMEM (medium A) containing 10% fetal bovine serum (FBS), 1.0 mg/ml G418 and appropriate supplements.

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。On day 1, the replicon cell monolayer was treated with a trypsin/EDTA mixture, the cell monolayer was removed and diluted with medium A to a final concentration of 48,000 cells/ml. This solution (1 ml) was inoculated into each well of a 24-well tissue culture plate, and cultured in a tissue incubator at 37 ° C under a 5% CO 2 atmosphere overnight.

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%。On day 2, test compounds (prepared with 100% DMSO) were serially diluted with DMEM (medium B) containing 10% FBS and appropriate supplements. The final concentration of DMSO was maintained at 0.2% in all serial dilutions.

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。The medium on the monolayer of the replicon cell is removed, and then the medium B containing various concentrations of the compound is added. Medium B containing no compound was added to the other wells as a control without compound.

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。Cells were incubated with compound or 0.2% DMSO in medium B for 72 hours in a tissue incubator at 37 ° C under 5% CO 2 atmosphere. Then, the medium was removed, and the replicon cell monolayer was washed once with PBS. RNA extraction reagents (eg, reagents from the Rneasy kit or TRIZOL reagent) are immediately added to the cells to avoid RNA degradation. Total RNA was extracted according to the manufacturer's instructions for improvement to improve extraction efficiency and consistency. Finally, total cellular RNA containing HCV replicon RNA was eluted and stored at -80 °C for further processing.

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)。Implement TaqMan with two specific primers Real-time RT-PCR quantitative assays: one for HCV and the other for ACTB (β-actin). Total RNA was added to the PCR reaction to quantify HCV and ACTB RNA in the same PCR well. The experimental failure was marked and discarded based on the level of ACTB RNA in each well. The level of HCV RNA in each well was calculated from the standard curve obtained in the same PCR plate. The percent inhibition of HCV RNA levels due to compound treatment was calculated using DMSO or no compound control as 0% inhibition. EC 50 is calculated according to the titration curve of any given compound (HCV RNA level of 50% inhibition concentration).

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。Compound 1-281 was tested in the HCV replicon cell assay. The results show, EC 274 values below 50 compounds of 50 values between 20-100 nM EC 20nM, 7 of compounds.

實施例284：藥物代謝動力學研究Example 284: Pharmacokinetic Study

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。One day prior to the test, male Sprague-Dawley rats (300-400 g) underwent a jugular vein grafted polyethylene cannula under pentobarbital anesthesia for blood sampling. Any drinking water was fasted overnight and then the test compound was administered by oral gavage (PO) the next day. A series of rat blood samples were collected 48 hours after administration, and heparinized plasma was recovered after centrifugation. Test compounds in plasma were extracted and assayed by liquid chromatography-mass spectrometry (LC-MS/MS) analysis.

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。Standard pharmacokinetic parameters were evaluated by non-compartmental analysis using WinNonlin (version 4.0, Pharsight, CA, USA). Test compound concentration in plasma versus time curve of the largest maximum point labeled C. The apparent final phase elimination ( t 1/2 ) is calculated as ln(2) / λ z , where λ z is the elimination rate constant. The area under the concentration-time curve from the time point of administration to infinity (AUC (0-inf) ) was calculated according to the linear trapezoidal rule.

某些本發明的化合物顯示延長的半衰期和大的AUC值。Certain compounds of the invention exhibit extended half-lives and large AUC values.

其他實施方式Other embodiments

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。All of the features disclosed in the specification can be combined in any combination. The various features disclosed in the specification can be replaced by features that serve the same, equivalent or similar purpose. Accordingly, the various features disclosed are only one example of a series of equivalent or similar features, unless otherwise indicated.

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。From the above description, those skilled in the art can easily determine the main features of the present invention, and various modifications and improvements can be made to the various applications and without departing from the spirit and scope of the invention. condition. Accordingly, other embodiments are also within the scope of the appended claims.

Claims (20)

一種以下結構式的化合物： 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)-、-NHSO-或-NHSO2 -；W是-(CH2 )m -、-NH(CH2 )n -、-(CH2 )n NH-、-O(CH2 )n -、 -(CH2 )n O-、-S(CH2 )n -、-(CH2 )n S-、-SO-、-SO(CH2 )n -、-(CH2 )n SO-、-SO2 (CH2 )n -或-(CH2 )n SO2 -，m為1,2或3，n為0,1或2；X為-O-、-S-、或-NH-；和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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合；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，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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合。A compound of the formula: Wherein R 1 is -H, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl or -NH-ZR; wherein R is H or a moiety selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, Each is optionally mono-, di- or tri-substituted with a halogen: nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, aryl or heteroaryl; Z is -C(O)-, -C(O)O-, -C(O)C(O)O-, -C(O)C(O) NH-, -C(O)NR'-, -OC(S)-, -C(S)NR'- or -C(NH)O-, R' is H, C 1-6 alkyl, C 3 a -10 cycloalkyl group, a C 1-10 heterocycloalkyl group, an aryl group or a heteroaryl group; R 2 is H or a moiety selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, each of which is optionally mono-, di- or tri-substituted with halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl; A is N or CH; U is -O-, -NH-, -NH(CO) -, - NHSO- or -NHSO 2 -; W is - (CH 2) m - -NH (CH 2) n -, - (CH 2) n NH -, - O (CH 2) n -, - (CH 2) n O -, - S (CH 2) n -, - (CH 2) n S-, -SO-, -SO(CH 2 ) n -, -(CH 2 ) n SO-, -SO 2 (CH 2 ) n - or -(CH 2 ) n SO 2 -, m is 1, 2 or 3, n is 0, 1 or 2; X is -O-, -S-, or -NH-; and Y is or Wherein V and T are each independently -CH- or -N-; and A 1 and A 2 are each independently a moiety selected from the group consisting of C 4-10 cycloalkyl, C 1-10 heterocycloalkyl, Aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; R i is H, halogen, nitro, cyano or amino, or is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkyne , C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2 Each of the -6 alkynyl groups is optionally mono-, di-, or tri-substituted with a halogen: nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl , aryl and heteroaryl are each optionally substituted by the following substituents Disubstituted or trisubstituted by: halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl An alkyl group, a C 1-10 heterocycloalkyl group, an aryl group or a heteroaryl group, or optionally fused to a C 3-10 cycloalkyl group, a C 1-10 heterocycloalkyl group, an aryl group or a heteroaryl group. 如申請專利範圍第1項所述的化合物，其特徵在於，X是O。 The compound of claim 1, wherein X is 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 -。The compound according to item 1 of the scope of the patent application, wherein, A is CH, W is -CH 2 CH 2 -, - OCH 2 -, - SCH 2 - or -SOCH 2 -. 如申請專利範圍第1項所述的化合物，其特徵在於，U是-NHSO2 -。The compound of claim 1, wherein U is -NHSO 2 -. 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。The compound of any one of claims 1-4, wherein Y is Wherein T is CH or N, and R i , R ii , R iii , R iv and R v are each independently H, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1- a 6 alkoxy group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, or a moiety selected from the group consisting of C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl , each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to a C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl group. 一種以下結構式的化合物： 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、雜芳基或-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CH或N；U是-O-、-NH-、-NH(CO)-、-NHSO-或-NHSO2 -；W是-(CH2 )m -、-NH(CH2 )n -、-(CH2 )n NH-、-O(CH2 )n -、-(CH2 )n O-、-S(CH2 )n -、-(CH2 )n S-、-SO-、-SO(CH2 )n -、-(CH2 )n SO-、-SO2 (CH2 )n -或-(CH2 )n SO2 -，m是1,2或3，n是0,1或2；X是-O-、-S-、或-NH-；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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合；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，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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合；和是單鍵或雙鍵。A compound of the formula: Wherein R 1 is -H, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl or -ZR; wherein R is H or a moiety selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, each of which is Monosubstituted, disubstituted, or trisubstituted by the following substituents: halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 - 6 alkynyl, aryl or heteroaryl; Z is -C(O)-, -C(O)O-, -C(O)C(O)O-, -C(O)C(O)NH -, -C(O)NR'-, -OC(S)-, -C(S)NR'- or -C(NH)O-, R' is H, C 1-6 alkyl, C 3- 10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; R 2 is H, or is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl; A is CH or N; U is -O-, -NH-, -NH(CO)- , -NHSO- or -NHSO 2 -; W is - (CH 2) m - -NH (CH 2) n -, - (CH 2) n NH -, - O (CH 2) n -, - (CH 2) n O -, - S (CH 2) n -, - (CH 2) n S-, -SO-, -SO(CH 2 ) n -, -(CH 2 ) n SO-, -SO 2 (CH 2 ) n - or -(CH 2 ) n SO 2 -, m is 1, 2 or 3, n is 0, 1 or 2; X is -O-, -S-, or -NH-; Y is or Wherein V and T are each independently -CH- or -N-; and A 1 and A 2 are each independently a moiety selected from the group consisting of C 4-10 cycloalkyl, C 1-10 heterocycloalkyl, Aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; R i is H, halogen, nitro, cyano or amino, or is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkyne , C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2 Each of the -6 alkynyl groups is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 olefin , C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, Each of the aryl and heteroaryl groups is optionally monosubstituted by the following substituents, Disubstituted or trisubstituted: halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring alkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, or optionally with C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or fused heteroaryl; and It is a single button or a double button. 如申請專利範圍第6項所述的化合物，其特徵在於，X是O。 The compound of claim 6, wherein X is 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。The compound according to item 6 of the scope of the patent application, wherein, W is -CH 2 CH 2 -, - OCH 2 -, - SCH 2 - or -SOCH 2 -; It is a double bond. 如申請專利範圍第6項所述的化合物，其特徵在於，U是-NHSO2 -。The compound of claim 6, wherein U is -NHSO 2 -. 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。The compound of any one of claims 6-9, wherein Y is Wherein T is CH or N, and R i , R ii , R iii , R iv and R v are each independently H, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1- a 6 alkoxy group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, or a moiety selected from the group consisting of C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl , each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or fused to a C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl group. 一種以下結構式的化合物： 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；A是N或CH； U是-O-、-NH-、-NH(CO)-、-NHSO-或-NHSO2 -；W是-(CH2 )m -、-NH(CH2 )n -、-(CH2 )n NH-、-O(CH2 )n -、-(CH2 )n O-、-S(CH2 )n -、-(CH2 )n S-、-SO-、-SO(CH2 )n -、-(CH2 )n SO-、-SO2 (CH2 )n -或-(CH2 )n SO2 -，m是1,2或3，n是0,1或2；X是-O-、-S-、或-NH-；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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合；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，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，或任選與C3-10 環烷基、C1-10 雜環烷基、芳基或雜芳基稠合；和是單鍵或雙鍵。A compound of the formula: Wherein R 1 is -H, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, -ZR or -NH-ZR; wherein R is H or a moiety selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl And each of them is optionally monosubstituted, disubstituted, or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 olefin , C 2-6 alkynyl, aryl or heteroaryl; Z is -C(O)-, -C(O)O-, -C(O)C(O)O-, -C(O) C(O)NH-, -C(O)NR'-, -OC(S)-, -C(S)NR'- or -C(NH)O-, R' is H, C 1-6 alkane , C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; A is N or CH; U is -O-, -NH-, -NH(CO)-, - NHSO- or -NHSO 2 -; W is -(CH 2 ) m -, -NH(CH 2 ) n -, -(CH 2 ) n NH-, -O(CH 2 ) n -, -(CH 2 ) n O-, -S(CH 2 ) n -, -(CH 2 ) n S-, -SO-, -SO(CH 2 ) n -, -(CH 2 ) n SO-, -SO 2 (CH 2 n - or -(CH 2 ) n SO 2 -, m is 1, 2 or 3, n is 0, 1 or 2; X is -O-, -S-, or -NH-; Y is or Wherein V and T are each independently -CH- or -N-; and A 1 and A 2 are each independently a moiety selected from the group consisting of C 4-10 cycloalkyl, C 1-10 heterocycloalkyl, Aryl and heteroaryl, each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; R i is H, halogen, nitro, cyano or amino, or is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkyne , C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2 Each of the -6 alkynyl groups is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 olefin , C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, Each of the aryl and heteroaryl groups is optionally monosubstituted by the following substituents, Or trisubstituted by: halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl a C 1-10 heterocycloalkyl, aryl or heteroaryl group, or optionally fused to a C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; It is a single button or a double button. 如申請專利範圍第11項所述的化合物，其特徵在於，X是O。 The compound of claim 11, wherein X is 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。The compound according to item 11 of the scope of the patent application, wherein, A is CH; W is -CH 2 CH 2 -, - OCH 2 -, - SCH 2 - or -SOCH 2 -; It is a double bond. 如申請專利範圍第11項所述的化合物，其特徵在於，U是-NHSO2 -。The compound of claim 11, wherein U is -NHSO 2 -. 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。The compound of any one of claims 11-14, wherein Y is Wherein T is CH or N, and R i , R ii , R iii , R iv and R v are each independently H, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1- a 6 alkoxy group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, or a moiety selected from the group consisting of C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl and heteroaryl , each of which is optionally monosubstituted, disubstituted or trisubstituted by halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl, or optionally fused to a C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl group. 一種化合物，其中所述化合物是以下化合物中的一種： A compound wherein the compound is one of the following compounds: 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。 A pharmaceutical composition comprising the compound of any one of claims 1 to 16 and a pharmaceutically acceptable carrier. 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。 A use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for the treatment of a hepatitis C virus infection. 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。 The use according to claim 18, wherein the compound is administered orally to a subject in need of treatment. 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。The use according to claim 18 or 19, wherein the compound is administered once a day.
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