CN110423265A - A kind of preparation method and purposes of cyclic peptide TRF2 inhibitor - Google Patents

A kind of preparation method and purposes of cyclic peptide TRF2 inhibitor Download PDF

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CN110423265A
CN110423265A CN201910265325.5A CN201910265325A CN110423265A CN 110423265 A CN110423265 A CN 110423265A CN 201910265325 A CN201910265325 A CN 201910265325A CN 110423265 A CN110423265 A CN 110423265A
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oxos
dioxa
pyrroles
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孙海鹰
董瑶
郭天玥
陈夏
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China Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to the preparation methods of the cyclic peptide compound (I) of a kind of interaction for blocking telomere binding protein TRF2 and other albumen, and decapeptide C-terminal pentapeptide end two amino acid side chain is connected using chemical method, construct cyclic peptide to control its conformation；The hydrophobic effect that substitution simulates itself and TRF2 is carried out to N-terminal pentapeptide with non-peptide micromolecular, has designed and synthesized a kind of cyclic peptide compound (I), the invention further relates to its medical applications as TRF2 inhibitor.

Description

A kind of preparation method and purposes of cyclic peptide TRF2 inhibitor
Technical field
The present invention relates to the peptidomimetic micromoleculars of a kind of interaction for blocking telomere binding protein TRF2 and other albumen Compound and their preparation method and purposes.
Background technique
Shelterin is the albumen composition that telomerase is formed by six telomere binding proteins, and major function is to protect End of chromosome is protected, avoids it from being identified as DNA break by DNA repair mechanism and end of chromosome is prevented to be coupled.TRF2 is The important component of Shelterin is keeping two 3 ' end DNA of important feature required for Telomere Stability single-stranded and T- It plays an important role in the formation of Loop.In addition, TRF2 also plays an important role in DNA damage reparation.TRF2 can be with telomere Double-stranded DNA, which combines, simultaneously recruits many other albumen on telomere, its function be mainly these albumen for being recruited by it come It realizes.TRFH structural domain is an important structural domain in TRF2, much by TRF2 recruit albumen be by with TRF2 TRFH structural domain in conjunction with and be recruited, therefore research and develop block TRF2 TRFH structural domain and other protein bound small molecule chemical combination Object is significant in the research of the Biological mechanism of action of TRF2 and other telomere binding proteins.
We disclose a kind of peptidomimetic class TRF2 inhibitor in the present invention, this kind of compound can be used for TRF2 and other ends The protein-bonded Biological mechanism of action research of grain, and it is possibly used for the new drug development using telomere binding protein as target spot.
Summary of the invention
The invention discloses quasi- peptides shown in formula I, formula (I) compound is had the following structure:
Wherein L is-(CH2)6-10, wherein one or more methylene can replace by oxygen atom；X is-CH2Or-CH2CH2-； R1Selected from amide groups, arbitrarily the aryl replaced, the heterocyclic aryl arbitrarily replaced；R2For C1-C6Alkyl, naphthenic base or substituted Naphthenic base, one or more hydrogen atoms can be replaced by hydroxyl, amino, alkoxy, alkylamino, alkane sulfydryl in above-mentioned group；R3 For C1-C8Alkyl, arbitrarily replace alkyl, naphthenic base, substituted naphthenic base；R4And R5For C1-C8Alkyl, arbitrarily replace Alkyl, naphthenic base, the naphthenic base arbitrarily replaced, alkoxy, alkylamino, alkane sulfydryl, the aryl arbitrarily replaced, arbitrarily replace it is miscellaneous Aryl.
The structure of the further preferred Formula II of compound in the present invention:
Wherein L is-(CH2)6-10, wherein one or more methylene can replace by oxygen atom；R1For C1-C6Alkyl, ring Alkyl or substituted naphthenic base, one or more hydrogen atoms can be taken by hydroxyl, amino, alkoxy, alkylamino in above-mentioned group Generation；R2For C1-C8Alkyl, arbitrarily replace alkyl, naphthenic base, substituted naphthenic base；R3For C1-C8Alkyl, any replace Alkyl, naphthenic base, the naphthenic base arbitrarily replaced, the aryl arbitrarily replaced, the heteroaryl arbitrarily replaced；R4For-OR5Or it is selected from Hydrogen, alkyl, the alkyl arbitrarily replaced, naphthenic base, the naphthenic base arbitrarily replaced；R5For C1-C8Alkyl, arbitrarily replace alkyl, Naphthenic base, the naphthenic base arbitrarily replaced, the aryl arbitrarily replaced, the heteroaryl arbitrarily replaced.
Compound in Formulas I synthesizes with the following method:
Specifically includes the following steps:
The condensation of amino acid derivativges 1 and 2 prepares dipeptidase derivant 3；
Tripeptide derivative 4 is prepared with amino acid derivativges condensation after 3 deprotection bases；
Tetrapeptide derivative 5 is prepared with amino acid derivativges condensation after 4 deprotection bases；
Tetrapeptide derivative 6 is prepared with amino acid derivativges condensation after 5 protecting groups；
6, which cross olefin metathesis reaction cyclization, obtains cyclic peptide intermediate 7；
Double bond and deprotection base in reduction 7 prepare intermediate 8；
8 with replace benzoic acid, and in case of need deprotection base obtain Formulas I representative compound 9；
P is protecting group in structure above, is selected from Boc, Cbz or Fmoc as needed.
Part of compounds structure representated by formula (I) and Formula II and name are as follows:
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-1)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isopropoxybenzoyl amino) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-2)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-3)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-4)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-5)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- phenylpropyl alcohol oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-6)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzene ethoxybenzo amino) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-7)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- hexamethylene methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-8)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isobutoxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-9)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- (2- menaphthyl) oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-10)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isoamoxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-11)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- benzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-12)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent methylbenzyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-13)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- methylbenzyloxy benzoyl-amidos) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-14)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to methylbenzyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-15)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- m-chloro benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-16)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-17)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- bromo-benzyloxy benzoyl-amidos) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-18)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-19)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-20)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-21)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- (1- naphthalene methoxyl group) benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-22)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- (2- naphthalene methoxyl group) benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-23)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent bromo-benzyloxy benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-24)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-25)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- methylbenzyloxy benzoyl-amidos) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-26)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-27)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-28)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- hexamethylene methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-29)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- positive hexyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-30)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-31)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- hexichol propoxyl group benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-32)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isoamoxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-33)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isobutoxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-34)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isopropoxybenzoyl amino) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-35)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclobutoxy group benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-36)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopentyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-37)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopropyl methoxybenzoyl base amino) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-38)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hexamethylene methoxybenzoyl base amino) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-39)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- positive hexyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-40)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hydroxybenzoylamino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-41)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-42)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethoxybenzo amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-43)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethylamino oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-44)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- the third amino oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-45)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- fourth amino oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-46)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (penta amino oxygroup benzoyl-amido of 3- benzyloxy -5-) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-47)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- second carboxyl oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-48)；
Embodiment
Method 1-- condensation reaction:
The amine or ammonium salt of the acid of 1eq and 1eq are dissolved in DMF or methylene chloride, under stiring in 0 degree of addition 1.1eq EDC or HBTU, 1.1eq HOBt and 3.5eq DIEA.Reaction solution stirs to TLC after being warmed to room temperature and shows fully reacting.Under decompression After most of solvent is evaporated off, the hydrochloric acid of residue 1N, water phase ethyl acetate or methylene chloride are extracted three times, extract liquor It is respectively washed once after merging with saturated sodium bicarbonate solution and saturated sodium chloride solution, mistake after organic phase anhydrous sodium sulfate drying Filter, concentration, crude product obtain condensation product with column chromatographic purifying.
The removing of universal synthesis method 2-Boc protecting group:
Method 1: the substrate with Boc protecting group is dissolved in methylene chloride, and trifluoracetic acid is added in room temperature under stiring, Trifluoroacetic dosage is determined according to response situation, and after TLC shows fully reacting, solvent and excessive trifluoracetic acid is evaporated off, Residue diluted with water is neutralized to neutrality with saturated sodium bicarbonate solution, is extracted three times with ethyl acetate or methylene chloride, organic Mutually merge, washed once with saturated sodium chloride solution, organic phase is following with being directly used in after anhydrous sodium sulfate drying, filtering, concentration Reaction.
Method 2: the substrate with Boc protecting group is dissolved in methanol, and the HCl of 4N is added at room temperature in Isosorbide-5-Nitrae-dioxy six Solution in ring, reaction solution is stirred show fully reacting to TLC after solvent is evaporated off, obtained hydrochloride is directly used in following anti- It answers.
The removing of universal synthesis method 3-Cbz:
Substrate with Cbz is dissolved in methanol, the air in reaction flask is added in reaction solution after being replaced with nitrogen 10% Pd-C reacts under hydrogen to TLC and shows fully reacting.After filtering out catalyst, filtrate is concentrated, and resulting crude product is direct For following reaction.
The removing of universal synthesis method 4-Fmoc protecting group:
Substrate with Fmoc protecting group is dissolved in methylene chloride, isometric piperidines is added at room temperature, stirring is extremely TLC shows fully reacting.After reaction solution concentration crude product be used directly for following reaction or it is necessary in the case where use Column chromatographic purifying.
Olefin metathesis reaction:
Cyclization precursor is dissolved in methylene chloride or 1, in 2- dichloroethanes, Grubbs catalyst is added in reaction solution.Instead It answers liquid to be back to TLC under nitrogen protection and shows fully reacting, crude product is evaporated off after solvent with column chromatographic purifying and obtains cyclization product (compound 7).1H NMR (300MHz, CDCl3) δ 7.80-7.60 (m, 1H), 7.55-7.20 (m, 2H), 5.95-5.70 (m, 3H), 5.30-5.02 (m, 5H), 4.80-4.55 (m, 3H), 4.30 (m, 1H), 4.15-3.40 (m, 10H), 3.10 (brs, 3H), 2.95 (brs, 3H), 2.20-1.80 (m, 4H), 1.65-120 (m, 15H), 0.90-0.80 (m, 6H)；ESI-MS m/z calc' D for C33H57N6O9 [M+H]+681.41, found 681.55.
The hydrogenation of double bond and deprotection base:
Substrate with double bond is dissolved in methanol, the air in reaction flask is added in reaction solution after being replaced with nitrogen 10% Pd-C reacts under hydrogen to TLC and shows fully reacting.After filtering out catalyst, filtrate concentration, crude product is directly used in down The reaction in face.
The synthesis of Partial key amino acid derivativges
The preparation of N-Boc-O- allyl-serine
S- serine (1) is dissolved in dioxane: water=1: in 1 mixed solution, sequentially adding 1eq NaOH, 2eq NaHCO3、1.1eq Boc2O is stirred overnight at room temperature, and is acid, EA extraction, saturated salt solution with 3N hydrochloric acid tune PH after fully reacting It washes once, anhydrous sodium sulfate is dry, and concentration obtains S-N-Boc- serine crude product.S-N-Boc- serine crude product is dissolved in suitable It measures in DMF, 3.1eq 60%NaH is slowly added portionwise at 0 DEG C.After reaction solution stirs 30min at 0 DEG C, it is slowly added dropwise The DMF solution of 1.05eq 3- bromopropene, finishes, and reaction solution is slowly increased to be stirred at room temperature 3h and uses 3N after TLC detects fully reacting Hydrochloric acid tune PH is washed to acidity, EA extraction, organic phase with saturated common salt, and anhydrous sodium sulfate is dry, and concentration obtains S-N-Boc-O- Allyl-serine, yield are about 68%.
The preparation of S-N-Boc-O- allyl-serine-N, N- dimethylformamide
S-N-Boc-O- allyl-serine is dissolved in appropriate DMF, under the conditions of 0 DEG C, 1.1eq HBTU, 1.5eq is added 1.2eq dimethylamine hydrochloride is slowly added portionwise in HOBT, 3eq DIEA, mentions to room temperature reaction 4-5h, TLC detection fully reacting, It is diluted with water, is extracted with ethyl acetate three times, organic phase uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturation after merging respectively Salt washing, anhydrous sodium sulfate is dry, and concentration, post separation obtains S-N-Boc-O- allyl-serine-N, N- dimethylformamide, Yield is about 81%.
The preparation of S-2-Cbz- amino -3- alanine
The N-Cbz S- asparagine protected is dissolved in water: acetonitrile: ethyl acetate=1: in 2: 2 mixed solution, at 0 DEG C Under conditions of, 1.5eq iodobenzene diethylester is added, is slowly increased to that 5h is stirred at room temperature, after TLC detects fully reacting, suction filtered through kieselguhr, Filter cake is washed 3 times with a small amount of EA, dry, obtains S-2-Cbz- amino -3- alanine crude product, yield is about 62%.
The preparation of S-2-Cbz- amino -3-Boc- alanine
S-2-Cbz- amino -3- alanine is dissolved in dioxane: water=1: in 1 mixed solution, being sequentially added 1eqNaOH、2eq NaHCO3、1.1eq Boc2O is stirred overnight at room temperature, and after fully reacting, it is extra to be removed with petroleum ether extraction Boc2Water phase 3N hydrochloric acid tune PH is 5 after O, is extracted with ethyl acetate three times, merges organic phase, saturated common salt washing is primary, nothing Aqueous sodium persulfate is dry, and concentration obtains S-2-Cbz- amino -3-Boc- alanine, yield is about 85%.
Final product synthetic route according to shown in [0008] utilizes universal synthesis method shown in [0068]-[0079] to close At.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-1):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.20- 7.05 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.10-4.95 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 10H), 3.35 (s, 3H), 3.20-3.15 (brs, 3H), 2.95-2.85 (brs, 3H), 2.30-1.40 (m, 11H), 1.40- 1.05 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C34H53N6O9[M+H]+ 689.38 found 689.50.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isopropoxybenzoyl amino) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-2):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.20- 7.05 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.10-4.95 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 11H), 3.20-3.15 (brs, 3H), 2.95-2.85 (brs, 3H), 2.30-1.40 (m, 11H), 1.40-1.05 (m, 9H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C36H57N6O9[M+H]+717.41 found 717.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-3):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 9H), 7.20- (7.05 m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.20 (brs, 2H), 5.10-4.95 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 10H), 3.20-3.15 (brs, 3H), 2.95-2.85 (brs, 3H), 2.30-1.40 (m, 11H), 1.40-1.05 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C40H57N6O9[M+ H]+765.41 found 765.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-4):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.15-6.95 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 4.90-4.85 (m, 1H), 4.75-4.25 (m, 4H), 4.05- 3.40 (m, 12H), 3.10-3.04 (brs, 3H), 2.85-2.75 (brs, 3H), 2.30-1.40 (m, 12H), 1.40-1.05 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H), 0.51 (m, 2H), 0.30 (m, 2H)；ESI-MS m/z calc'd for C37H57N6O9[M+H]+729.41 found 729.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-5):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.15- 7.02 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.05-4.94 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 11H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.40 (m, 19H), 1.40-1.05 (brd, J= 7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C38H59N6O9[M+H]+743.43, found 743.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- phenylpropyl alcohol oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-6):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.30- 7.05 (m, 7H), 6.45 (brd, J=6.5Hz, 1H), 5.05-4.94 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 12H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.85-2.78 (m, 2H), 2.40-1.40 (m, 13H), 1.40-1.05 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C42H61N6O9[M+ H]+793.44 found 793.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzene ethoxybenzo amino) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-7):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.05 (m, 11H), 6.45 (brd, J=6.5Hz, 1H), 5.05-4.94 (m, 1H), 4.85-4.40 (m, 4H), 4.05-3.40 (m, 12H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.85-2.78 (m, 2H), 2.40-1.40 (m, 11H), 1.40-1.05 (brd, J= 7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C41H59N6O9[M+H]+779.43, fbund 779.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- hexamethylene methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-8):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.20-7.05 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.05-4.94 (m, 1H), 4.85-4.40 (m, 4H), 4.05- 3.40 (m, 12H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.40 (m, 18H), 1.40-1.05 (m, 7H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C40H63N6O9[M+H]+771.46 found 771.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isobutoxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-9):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.20- 7.05 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.05-4.94 (m, 1H), 4.85-4.45 (m, 4H), 4.05-3.40 (m, 12H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.40 (m, 12H), 1.35 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 12H)；ESI-MS m/z calc'd for C37H59N6O9[M+H]+731.43 found 745.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- (2- menaphthyl) oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-10):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.05 (m, 13H), 6.50 (brd, J=6.5Hz, 1H), 5.10 (brs, 1H), 5.02-4.95 (m, 1H), 4.82-4.45 (m, 4H), 3.95- 3.40 (m, 10H), 3.20-3.05 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.45 (m, 11H), 1.35 (brd, J= 7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C44H58N6O9[M+H]+815.43, found 815.60
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isoamoxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-11):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48-7.30 (m, 4H), 7.20-7.05 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 5.01-4.84 (m, 1H), 4.80-4.45 (m, 4H), 3.95- 3.40 (m, 12H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.40 (m, 14H), 1.35 (brd, J= 7.2Hz, 3H), 1.05-0.80 (m, 12H)；ESI-MS m/z calc'd for C38H61N6O9[M+H]+745.44, found 745.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- benzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-12):1H NMR (300MHz, CDCl3) δ 7.66 (brd, J=6.5Hz, 1H), 7.51 (m, 1H), 7.48- 7.29 (m, 10H), 7.21 (m, 1H), 7.14-7.04 (m, 2H), 6.78 (m, 1H), 6.75 (m, 1H), 5.08 (brs, 4H), 4.94 (m, 1H), 4.87-4.65 (m, 3H), 4.54 (m, 1H), 3.86-3.32 (m, 10H), 3.11 (brs, 3H), 2.94 (brs, 3H), 2.23-1.48 (m, 11H), 1.40 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H) .ESI-MS m/z calc ' d for C47H63N6O10[M+H]+871.46 found 871.54.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent methylbenzyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-13):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.54 (m, 1H), 7.49 (m, 1H), 7.47-7.36 (m, 2H), 7.33-7.15 (m, 7H), 7.15-7.07 (m, 2H), 6.81-6.70 (m, 2H), 5.07 (m, 4H), 4.94 (m, 1H), 4.87-4.74 (m, 1H), 4.74-4.67 (m, 1H), 4.67-4.62 (m, 1H), 4.53 (m, 1H), 3.99- 3.74 (m, 3H), 3.73-3.48 (m, 5H), 3.39 (m, 2H), 3.18-3.05 (m, 3H), 3.04-2.89 (m, 3H), 2.39 (m, 6H), 2.11-1.96 (m, 2H), 1.95-1.78 (m, 3H), 1.76-1.60 (m, 3H), 1.55 (m, 2H), 1.35 (d, J= 6.8Hz, 3H), 1.04-0.88 (m, 7H) .ESI-MS m/z calc ' d for C49H66N6O10[M+Na]+922.1, found 922.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- methylbenzyloxy benzoyl-amidos) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-14):1H NMR (300MHz, CDCl3) δ 7.63 (m, 1H), 7.52 (m, 1H), 7.32 (m, 4H), 7.20 (m, 5H), 7.08 (m, 2H), 6.80-6.65 (m, 2H), 5.05 (m, 4H), 4.95 (m, 1H), 4.80 (m, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.62-4.48 (m, 1H), 3.97-3.79 (m, 2H), 3.77-3.49 (m, 5H), 3.50-3.30 (m, 2H), 3.09 (m, 3H), 3.04-2.89 (m, 3H), 2.38 (s, 6H), 2.33-2.23 (m, 1H), 2.09-1.93 (m, 2H), 1.85 (m, 3H), 1.76-1.60 (m, 3H), 1.60-1.44 (m, 2H), 1.36 (m, 3H), 1.04-0.81 (m, 7H) .ESI-MS m/z calc’d for C49H66N6O10[M+Na]+922.1 found 922.5.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to methylbenzyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-15):1H NMR (300MHz, CDCl3) δ 7.63 (m, 1H), 7.52 (m, 1H), 7.32 (m, 4H), 7.20 (m, 5H), 7.08 (m, 2H), 6.80-6.65 (m, 2H), 5.05 (m, 4H), 4.95 (m, 1H), 4.80 (m, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.62-4.48 (m, 1H), 3.97-3.79 (m, 2H), 3.77-3.49 (m, 5H), 3.50-3.30 (m, 2H), 3.09 (m, 3H), 3.04-2.89 (m, 3H), 2.38 (s, 6H), 2.33-2.23 (m, 1H), 2.09-1.93 (m, 2H), (1.85 m, 3H), 1.76-1.60 (m, 3H), 1.60-1.44 (m, 2H), 1.36 (m, 3H), 1.04-0.81 (m, 7H) .ESI-MS m/z calc’d for C49H66N6O10[M+Na]+922.1 found 922.5.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- m-chloro benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-16):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.50 (m, 1H), 7.47-7.42 (m, 2H), 7.40-7.30 (m, 5H), 7.26-7.20 (m, 1H), 7.09 (m, 2H), 6.77-6.68 (m, 2H), 5.18-5.01 (m, 4H), 4.96 (m, 1H), 4.80 (m, 1H), 4.74-4.61 (m, 2H), 4.59-4.46 (m, 1H), 3.99-3.91 (m, 1H), 3.84 (m, 1H), 3.74-3.48 (m, 5H), 3.47-3.35 (m, 2H), 3.12 (m, 3H), 2.95 (m, 3H), 2.36-2.21 (m, 1H), 2.10-1.95 (m, 1H), 1.94-1.80 (m, 3H), 1.79-1.63 (m, 3H), 1.56 (m, 2H), 1.34 (m, 3H), 1.05-0.86 (m, 6H) .ESI-MS m/z calc ' d for C47H60Cl2N6O10[M+Na]+962.9 found 963.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-17):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.48 (m, 1H), 7.43-7.30 (m, 8H), 7.21 (m, 1H), 7.12-7.02 (m, 2H), 6.77-6.64 (m, 2H), 5.11-5.01 (m, 4H), 4.96 (m, 1H), 4.80 (m, 1H), 4.74-4.61 (m, 2H), 4.59-4.47 (m, 1H), 3.96-3.79 (m, 3H), 3.73-3.48 (m, 5H), 3.47-3.36 (m, 2H), 3.12 (m, 3H), 2.95 (m, 3H), 2.30 (m, 1H), 1.99 (m, 1H), 1.93-1.79 (m, 3H), 1.78-1.62 (m, 3H), 1.62-1.49 (m, 2H), 1.34 (m, 3H), 0.95 (m, 6H) .ESI-MS m/z calc ' d for C47H60Cl2N6O10[M+Na]+962.9 found 963.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- bromo-benzyloxy benzoyl-amidos) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-18):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.65-7.58 (m, 2H), 7.54- 7.44 (m, 3H), 7.41-7.33 (m, 2H), 7.34-7.21 (m, 4H), 7.13-7.06 (m, 2H), 6.73 (m, 2H), 5.19- 5.01 (m, 4H), 5.00-4.90 (m, 1H), 4.85-4.77 (m, 1H), 4.77-4.60 (m, 2H), 4.53 (m, 1H), 4.02- 3.89 (m, 2H), 3.87-3.77 (m, 1H), 3.59 (m, 5H), 3.48-3.35 (m, 2H), 3.17-3.05 (m, 3H), 3.05- 2.90 (m, 3H), 2.36-2.22 (m, 1H), 2.06-1.92 (m, 2H), 1.90-1.78 (m, 3H), 1.77-1.63 (m, 3H), 1.62-1.50 (m, 2H), 1.34 (m, 3H), 1.02-0.91 (m, 6H) .ESI-MS m/z calc ' d for C47H60Br2N6O10 [M+Na]+1051.8, found 1051.9.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to bromo-benzyloxy benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-19):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.58-7.43 (m, 5H), 7.36- 7.27 (m, 4H), 7.21 (m, 1H), 7.13-7.05 (m, 2H), 6.79-6.66 (m, 2H), 5.11-5.00 (m, 4H), 4.99- 4.90 (m, 1H), 4.80 (m, 1H), 4.69 (m, 2H), 4.60-4.47 (m, 1H), 3.94 (m, 1H), 3.90-3.78 (m, 1H), 3.74-3.48 (m, 5H), 3.48-3.36 (m, 2H), 3.12 (m, 3H), 2.96 (m, 3H), 2.36-2.22 (m, 1H), 2.07- 1.94 (m, 1H), 1.93-1.79 (m, 3H), 1.79-1.61 (m, 3H), 1.61-1.49 (m, 2H), 1.34 (m, 3H), 1.04- 0.87 (m, 6H) .ESI-MS m/z calc ' d for C47H60Cl2N6O10[M+Na]+962.9 found 963.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-20):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.50 (m, 1H), 7.42-7.31 (m, 2H), 7.27-7.12 (m, 5H), 7.09 (m, 2H), 7.08-6.98 (m, 2H), 6.78-6.68 (m, 2H), 5.14-5.02 (m, 4H), 4.96 (m, 1H), 4.86-4.76 (m, 1H), 4.67 (m, 2H), 4.54 (m, 1H), 3.99-3.76 (m, 2H), 3.74- 3.48 (m, 5H), 3.47-3.36 (m, 2H), 3.12 (m, 3H), 2.95 (m, 3H), 2.34-1.97 (m, 3H), 1.80-1.97 (m, 3H), 1.80-1.62 (m, 3H), 1.62-1.46 (m, 2H), 1.43-1.30 (m, 3H), 1.02-0.87 (m, 6H) .ESI-MS m/ z calc’d for C47H60F2N6O10[M+Na]+940.0 found 940.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-21):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.49 (m, 1H), 7.47-7.32 (m, 4H), 7.22 (m, 1H), 7.16-7.01 (m, 6H), 6.79-6.69 (m, 2H), 5.12-5.01 (m, 4H), 5.01-4.90 (m, 1H), 4.86-4.76 (m, 1H), 4.75-4.62 (m, 2H), 4.60-4.47 (m, 1H), 3.97-3.79 (m, 3H), 3.73-3.48 (m, 5H), 3.43 (m, 2H), 3.17-3.04 (m, 3H), 2.96 (m, 3H), 2.36-2.23 (m, 1H), 2.05-1.96 (m, 1H), 1.94-1.80 (m, 3H), 1.79-1.62 (m, 3H), 1.61-1.47 (m, 2H), 1.34 (d, J=6.8Hz, 3H), 1.05-0.88 (m, 6H) .ESI-MS m/z calc ' d for C47H60F2N6O10[M+Na]+940.0 found 940.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis--(1- naphthalene methoxybenzoyl base amino) -15- isobutyls Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-22):1H NMR (300MHz, CDCl3) δ 7.95-7.75 (m, 8H), 7.67 (m, 1H), 7.60- 7.44 (m, 7H), 7.22-7.12 (m, 2H), 6.86 (m, 1H), 6.74 (m, 1H), 5.33-5.17 (m, 4H), 5.02-4.90 (m, 1H), 4.82 (m, 1H), 4.69 (m, 2H), 4.55 (m, 1H), 3.97 (m, 1H), 3.90-3.79 (m, 1H), 3.75-3.47 (m, 6H), 3.47-3.36 (m, 2H), 3.11 (m, 3H), 2.95 (m, 3H), 2.34-2.24 (m, 1H), 2.01-1.94 (m, 1H), 1.92-1.78 (m, 3H), 1.76-1.63 (m, 3H), 1.62-1.49 (m, 2H), 1.36 (s, 3H), 1.04-0.91 (m, 6H) .ESI-MS m/z calc’d for C55H66N6O10[M+Na]+994.1 found 994.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis--(2- naphthalene methoxybenzoyl base amino) -15- isobutyls Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-23):1H NMR (300MHz, CDCl3) δ 8.20-8.00 (m, 2H), 7.99-7.81 (m, 4H), 7.75-7.42 (m, 9H), 7.38-7.15 (m, 4H), 7.03-6.85 (m, 1H), 6.77 (m, 1H), 5.67-5.33 (m, 4H), 5.01-4.92 (m, 1H), 4.85 (m, 1H), 4.74-4.65 (m, 1H), 4.63 (m, 1H), 4.58-4.45 (m, 1H), 4.02- 3.90 (m, 1H), 3.85 (m, 1H), 3.76-3.47 (m, 5H), 3.47-3.34 (m, 2H), 3.07 (m, 3H), 2.94 (d, J= 18.2Hz, 3H), 2.19-1.99 (m, 2H), 1.97-1.80 (m, 3H), 1.71 (m, 3H), 1.62-1.50 (m, 2H), 1.44- 1.32 (m, 3H), 0.93 (m, 6H) .ESI-MS m/z calc ' d for C55H66N6O10[M+Na]+994.1 found 994.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent bromo-benzyloxy benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-24):1H NMR (300MHz, CDCl3) δ 7.67 (m, 1H), 7.63-7.47 (m, 5H), 7.41- 7.31 (m, 2H), 7.26-7.16 (m, 3H), 7.15-7.10 (m, 2H), 6.81-6.70 (m, 2H), 5.23-5.12 (m, 4H), 4.96 (m, 1H), 4.89-4.76 (m, 1H), 4.76-4.62 (m, 2H), 4.62-4.47 (m, 1H), 3.98-3.79 (m, 2H), 3.74-3.51 (m, 5H), 3.50-3.32 (m, 2H), 3.17-3.03 (m, 3H), 2.99 (m, 3H), 2.36-2.22 (m, 1H), 2.04 (m, 1H), 1.94-1.81 (m, 3H), 1.77-1.63 (m, 3H), 1.61-1.50 (m, 2H), 1.35 (d, J=6.8Hz, 3H), 0.96 (m, 6H) .ESI-MS m/z calc ' d for C47H60Br2N6O10[M+Na]+1051.8, found 1051.9.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-25):1H NMR (300MHz, CDCl3) δ 7.72-7.65 (m, 1H), 7.61-7.47 (m, 4H), 7.45-7.35 (m, 3H), 7.35-7.20 (m, 7H), 7.17-7.08 (m, 2H), 6.86-6.71 (m, 2H), 5.27-5.12 (m, 5H), 5.02-4.92 (m, 1H), 4.90-4.76 (m, 1H), 4.77-4.60 (m, 2H), 4.62-4.45 (m, 1H), 3.99-3.78 (m, 2H), 3.76-3.49 (m, 5H), 3.48-3.31 (m, 2H), 3.20-3.04 (m, 3H), 3.03-2.84 (m, 3H), 2.35- 2.24 (m, 1H), 2.09-1.98 (m, 1H), 1.97-1.79 (m, 3H), 1.77-1.60 (m, 3H), 1.60-1.46 (m, 2H), 1.35 (d, J=6.7Hz, 3H), 1.02-0.90 (m, 6H) .ESI-MS m/z calc ' d for C47H60Cl2N6O10[M+Na]+ 962.9 found 963.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- meta-methoxy benzyloxybenzoyl amino) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-26):1H NMR (300MHz, CDCl3) δ 7.70-7.59 (m, 1H), 7.55-7.43 (m, 1H), 7.37-7.29 (m, 2H), 7.26-7.18 (m, 1H), 7.15-7.06 (m, 2H), 7.06-6.95 (m, 3H), 6.93-6.85 (m, 2H), 6.81-6.70 (m, 2H), 5.19-5.02 (m, 4H), 5.01-4.89 (m, 1H), 4.86-4.77 (m, 1H), 4.76-4.61 (m, 2H), 4.53 (m, 1H), 3.99-3.89 (m, 1H), 3.89-3.77 (m, 6H), 3.76-3.48 (m, 5H), 3.49-3.33 (m, 2H), 3.17-3.05 (m, 3H), 3.04-2.90 (m, 3H), 2.34-2.22 (m, 1H), 2.07-1.96 (m, 1H), 1.93- 1.78 (m, 3H), 1.76-1.61 (m, 3H), 1.61-1.48 (m, 2H), 1.34 (d, J=6.8Hz, 3H), 1.04-0.89 (m, 6H).ESI-MS m/z calc’d for C49H66N6O12[M+Na]+954.1 found 954.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent fluorine benzyloxybenzoyl amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-27):1H NMR (300MHz, CDCl3) δ 7.77-7.61 (m, 1H), 7.63-7.43 (m, 3H), 7.33 (tdd, J=13.9,11.6,6.4Hz, 4H), 7.16 (m, 5H), 6.93-6.69 (m, 2H), 5.30-5.06 (m, 3H), 5.04-4.92 (m, 1H), 4.87-4.76 (m, 1H), 4.75-4.60 (m, 1H), 4.51 (m, 1H), 3.98-3.78 (m, 2H), 3.77-3.51 (m, 5H), 3.49-3.33 (m, 2H), 3.20-3.04 (m, 3H), 3.04-2.89 (m, 3H), 2.36-2.22 (m, 1H), 2.09-2.00 (m, 1H), 1.98-1.81 (m, 3H), 1.80-1.63 (m, 3H), 1.62-1.49 (m, 2H), 1.46-1.33 (m, 3H), 1.06-0.87 (m, 6H) .ESI-MS m/z calc ' d for C47H60F2N6O10[M+Na]+940.0, found 940.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-28):1H NMR (300MHz, CDCl3) δ 7.77-7.59 (m, 1H), 7.38 (m, 1H), 7.17 (m, 1H), 6.94-6.80 (m, 2H), 6.52 (m, 1H), 5.04-4.90 (m, 1H), 4.90-4.70 (m, 3H), 4.69-4.50 (m, 2H), 4.50-4.42 (m, 1H), 3.98 (m, 1H), 3.91-3.81 (m, 1H), 3.81-3.69 (m, 1H), 3.70-3.44 (m, 5H), 3.43-3.28 (m, 1H), 3.17-3.04 (m, 2H), 3.02-2.87 (m, 3H), 2.30 (m, 1H), 2.00-1.71 (m, 17H), 1.69-1.53 (m, 8H), 1.34 (m ,=3H), 0.98-0.83 (m, 6H) .ESI-MS m/z calc ' d for C43H66N6O10[M+Na]+840.0 found 840.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- hexamethylene methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-29):1H NMR (300MHz, CDCl3) δ 7.77-7.59 (m, 1H), 7.38 (m, 1H), 7.17 (m, 1H), 6.94-6.80 (m, 2H), 6.52 (m, 1H), 5.04-4.90 (m, 1H), 4.90-4.70 (m, 3H), 4.69-4.50 (m, 2H), 4.50-4.42 (m, 1H), 3.98 (m, 1H), 3.91-3.81 (m, 1H), 3.81-3.69 (m, 1H), 3.70-3.44 (m, 5H), 3.43-3.28 (m, 1H), 3.17-3.04 (m, 2H), 3.02-2.87 (m, 3H), 2.30 (m, 1H), 2.00-1.71 (m, 17H), 1.69-1.53 (m, 8H), 1.34 (m ,=3H), 0.98-0.83 (m, 6H) .ESI-MS m/z calc ' d for C43H66N6O10[M+Na]+840.0 found 840.2.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- positive hexyloxy benzoyl-amido) -15- isobutyl group .N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-30):1H NMR (300MHz, CDCl3) δ 7.74-7.64 (m, 1H), 7.48-7.39 (m, 1H), 7.24-7.19 (m, 2H), 6.93 (m, 2H), 6.68 (m, 1H), 6.63-6.55 (m, 1H), 5.03-4.93 (m, 1H), 4.88- 4.77 (m, 1H), 4.74-4.59 (m, 2H), 4.55-4.43 (m, 1H), 4.00-3.86 (m, 2H), 3.83-3.74 (m, 6H), 3.70-3.50 (m, 5H), 3.45 (m, 2H), 3.18-3.06 (m, 3H), 3.01-2.90 (m, 3H), 1.92-1.67 (m, 23H), 1.65-1.52 (m, 4H), 1.38-1.23 (m, 17H), 1.07 (m, 3H), 0.99-0.90 (m, 6H) .ESI-MS m/z calc ' d for C47H74N6O10[M+Na]+906.1 found 906.3.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-31):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.48 (brd, J= 6.4Hz, 1H), 7.20 (brd, J=6.5Hz, 1H), 6.95-6.90 (m, 2H), 6.45 (brd, J=6.5Hz, 1H), 6.65- 6.60 (m, 1H), 5.01-4.84 (m, 1H), 4.80-4.60 (m, 3H), 4.60-4.45 (m, 1H), 3.95-3.75 (m, 7H), 3.65-3.30 (m, 7H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.40-1.40 (m, 12H), 1.35 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H), 0.70-0.55 (m, 4H), 0.40-0.30 (m, 4H) .ESI-MS m/z calc’d for C41H63N6O10[M+H]+799.45.44 found 799.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- hexichol propoxyl group benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-32):1H NMR (300MHz, CDCl3) δ 7.68 (d, J=7.2Hz, 1H), 7.48 (d, J=6.9Hz, 1H), 7.34-7.26 (m, 6H), 7.25-7.15 (m, 8H), 6.95 (dd, J=5.7,2.3Hz, 2H), 6.75 (d, J=8.5Hz, 1H), 6.58 (dt, J=4.2,2.1Hz, 1H), 4.96 (ddd, J=7.6,6.1,3.1Hz, 1H), 4.86-4.75 (m, 1H), 4.74-4.62 (m, 2H), 4.60-4.48 (m, 1H), 4.00 (t, J=6.2Hz, 5H), 3.93-3.79 (m, 2H), 3.73-3.50 (m, 5H), 3.50-3.36 (m, 2H), 3.16-3.04 (m, 3H), 2.95 (d, J=14.3Hz, 3H), 2.82 (t, J=7.6Hz, 5H), 2.38-2.25 (m, 1H), 2.17-1.98 (m, 7H), 1.96-1.79 (m, 4H), 1.79-1.64 (m, 3H), 1.62-1.46 (m, 3H), 1.35 (d, J=6.8Hz, 3H), 1.02-0.91 (m, 6H)
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isoamoxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-33):1H NMR (300MHz, CDCl3) δ 7.71 (brd, J=6.5Hz, 1H), 7.60-7.48 (m, 1H), 7.48-7.30 (m, 5H), 7.25-7.20 (brd, J=6.5Hz, 1H), 7.10-7.05 (m, 1H), 7.01-6.94 (m, 1H), 6.85-6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 4.10-3.30 (m, 12H), 3.17-3.04 (brs, 3H), 3.02-2.80 (brs, 3H), 2.30-1.45 (m, 14H), 1.40 (brd, J=7.2Hz, 3H), 1.10-0.70 (m, 12H) .ESI-MS m/z calc ' d for C45H67N6O10[M+H]+ 851.48 fourd 851.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isobutoxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-34):1H NMR (300MHz, CDCl3) δ 7.71 (brd, J=6.5Hz, 1H), 7.60-7.49 (m, 1H), 7.48-7.30 (m, 5H), 7.30-7.20 (m, 1H), 7.09-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.85- 6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 4.05-3.30 (m, 12H), 3.17-3.04 (brs, 3H), 2.97-2.85 (brs, 3H), 2.30-1.45 (m, 12H), 1.40 (brd, J=7.2Hz, 3H), 1.10-0.70 (m, 12H) .ESI-MS m/z calc ' d for C44H65N6O10[M+H]+837.47 found 837.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isopropoxybenzoyl amino) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-35):1H NMR (300MHz, CDCl3) δ 7.71 (brd, J=6.5Hz, 1H), 7.58-7.49 (m, 1H), 7.48-7.25 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.09-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.80-6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.34 (m, 11H), 3.17-3.04 (brs, 3H), 2.97-2.85 (brs, 3H), 2.36-1.45 (m, 11H), 1.40-1.25 (m, 9H), 0.95-0.70 (m, 6H) .ESI-MS m/z calc ' d for C43H63N6O10[M+H]+823.46 found 823.67.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclobutoxy group benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-36):1H NMR (300MHz, CDCl3) δ 7.71 (brd, J=6.5Hz, 1H), 7.58-7.49 (m, 1H), 7.48-7.30 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.10-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.70-6.60 (m, 1H), 6.60-6.55 (m, 1H), 5.13-5.02 (brs, 2H), 4.95-4.84 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.34 (m, 11H), 3.17-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.36-1.45 (m, 17H), 1.35 (brd, J=7.2Hz, 3H), 0.95-0.70 (m, 6H) .ESI-MS m/z calc ' d for C44H63N6O10[M+H]+ 835.45 found 835.58.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopentyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-37):1H NMR (300MHz, CDCl3) δ 7.75-7.60 (m, 1H), 7.58-7.49 (m, 1H), 7.48-7.30 (m, 5H), 7.24 (brd, J=6.5Hz, 1H), 7.10-6.99 (m, 1H), 6.98-6.94 (m, 1H), 6.70- 6.60 (m, 1H), 6.60-6.55 (m, 1H), 5.13-5.02 (brs, 2H), 4.95-4.84 (m, 1H), 4.79-4.49 (m, 4H), 4.35-4.30 (m, 1H), 3.95-3.34 (m, 10H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.30- 1.40 (m, 19H), 1.35 (brd, J=7.2Hz, 3H), 0.95-0.70 (m, 6H) .ESI-MS m/z calc ' d for C45H65N6O10[M+H]+849.47 found 849.60.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopropyl methoxybenzoyl base amino) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-38):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.58-7.30 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.10-7.02 (m, 1H), 6.98-6.94 (m, 1H), 6.50-6.30 (m, 2H), 5.15-5.02 (brs, 2H), 4.95-4.84 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.75 (m, 5H), 3.65-3.30 (m, 7H), 3.20-3.04 (brs, 3H), 3.04-2.85 (brs, 3H), 2.35-1.40 (m, 12H), 1.35 (brd, J= 7.2Hz, 3H), 0.95-0.80 (m, 6H), 0.70-0.55 (m, 2H), 0.40-0.30 (m, 2H) .ESI-MS m/z calc ' d for C44H63N6O10[M+H]+835.45 found 835.61.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hexamethylene methoxybenzoyl base amino) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-39):1H NMR (300MHz, CDCl3) δ 7.66 (m, 1H), 7.56-7.31 (m, 7H), 7.19 (m, 1H), 7.11-7.01 (m, 1H), 7.01-6.91 (m, 1H), 6.68 (m, 2H), 5.16-5.02 (m, 2H), 4.96 (m, 1H), 4.81 (m, 1H), 4.68 (m, 2H), 4.57 (m, 1H), 3.99-3.84 (m, 3H), 3.78 (m, 3H), 3.74-3.51 (m, 5H), 3.51-3.39 (m, 2H), 3.19-3.06 (m, 3H), 3.06-2.90 (m, 3H), 2.33 (m, 1H), 2.07-1.88 (m, 5H), 1.87-1.68 (m, 9H), 1.66-1.49 (m, 4H), 1.36m, 5H), 1.17-1.02 (m, 4H), 1.03-0.83 (m, 6H).
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- positive hexyloxy benzoyl-amido) -15- isobutyl Base-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine of [1,17] dioxa [4,7,10,13] 21-ring -3- formamide (I-40):1H NMR (300MHz, CDCl3) δ 7.67 (d, J=7.1Hz, 1H), 7.54-7.31 (m, 7H), 7.21 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 6.77-6.59 (m, 2H), 5.15-5.05 (m, 2H), 4.95 (m, 1H), 4.87-4.77 (m, 1H), 4.76-4.63 (m, 2H), 4.62-4.47 (m, 1H), 4.03-3.90 (m, 4H), 3.89-3.78 (m, 1H), 3.76-3.50 (m, 6H), 3.43 (m, 2H), 3.18-3.05 (m, 3H), 2.97 (m, 3H), 2.32 (m, 1H), 2.04 (m, 1H), 1.98-1.84 (m, 3H), 1.84-1.64 (m, 6H), 1.63-1.53 (m, 2H), 1.53-1.42 (m, 3H), 1.41- 1.25 (m, 9H), 1.02-0.89 (m, 10H)
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hydroxybenzoylamino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-41):1H NMR (300MHz, CDC13) δ 7.70 (brd, J=6.5Hz, 1H), 7.55-7.45 (m, 1H), 7.48-7.25 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.09-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.80-6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.34 (m, 13H), 3.15-3.05 (brs, 3H), 2.95-2.83 (brs, 3H), 2.35-1.45 (m, 11H), 0.95-0.70 (m, 6H)
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-42):1H NMR (300MHz, CDC13) δ 7.71 (brd, J=6.5Hz, 1H), 7.55-7.45 (m, 1H), 7.48-7.25 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.09-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.80-6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.34 (m, 13H), 3.15-3.05 (brs, 3H), 2.95-2.83 (brs, 3H), 2.35-1.45 (m, 11H), 1.40-1.25 (brd, J =7.2Hz, 3H), 0.95-0.70 (m, 6H) .ESI-MS m/z calc ' d for C41H59N6O10[M+H]+795.42, found 795.61.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethoxybenzo amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-43):1H NMR (300MHz, CDCl3) δ 7.70 (brd, J=6.5Hz, 1H), 7.55-7.45 (m, 1H), 7.48-7.25 (m, 5H), 7.20 (brd, J=6.5Hz, 1H), 7.09-7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.80-6.60 (m, 2H), 5.13-5.02 (brs, 2H), 4.95-4.85 (m, 1H), 4.79-4.49 (m, 4H), 3.95-3.30 (m, 12H), 3.15-3.05 (brs, 3H), 2.95-2.83 (brs, 3H), 2.35-1.45 (m, 11H), 1.40-1.20 (m, 6H), 0.95-0.80 (m, 6H) .ESI-MS m/z calc ' d for C42H61N6O10[M+H]+809.44 found 809.65.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethylamino oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-44):1H NMR (300MHz, CD3OD) δ 7.50-7.45 (m, 2H), 7.45-7.30 (m, 3H), 7.25 (m, 1H), 7.16 (m, 1H), 6.60 (m, 1H), 5.20 (brs, 2H), 5.02 (m, 1H), 4.80-4.35 (m, 4H), 4.30-4.20 (m, 2H), 4.02 (m, 1H), 3.75-3.45 (m, 9H), 3.35-3.30 (m, 2H), 3.20 (brs, 3H), 2.95 (brs, 3H), 2.25-1.55 (m, 11H), 1.40-1.30 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc’d for C42H62N7O10[M+H]+824.45 found 824.7.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- the third amino oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-45): ESI-MS m/z calc ' d for C43H64N7O10[M+H]+838.46, found 838.7.
(3S, 12S, 15S, 18S, 23aS, E) -12- (penta amino oxygroup benzoyl-amido of 3- benzyloxy -5-) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-47): ESI-MS m/z calc ' d for C45H68N7O10[M+H]+866.50, found 866.8.
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- second carboxyl oxygroup benzoyl-amido) -15- is different Butyl-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four nitrogen of [1,17] dioxa [4,7,10,13] Miscellaneous 21-ring -3- formamide (I-48):1H NMR (300MHz, CD3OD) δ 7.50-7.45 (m, 2H), 7.45-7.30 (m, 3H), 7.25 (m, 1H), 7.16 (m, 1H), 6.60 (m, 1H), 5.20-5.15 (m, 4H), 5.02 (m, 1H), 4.80-4.35 (m, 4H), 3.98 (m, 1H), 3.80-3.40 (m, 7H), 3.35-3.30 (m, 2H), 3.20 (brs, 3H), 2.95 (brs, 3H), 2.25-1.55 (m, 11H), 1.40-1.30 (brd, J=7.2Hz, 3H), 1.05-0.80 (m, 6H)；ESI-MS m/z calc'd for C44H59N6O12[M+H]+839.41, found 839.7.
Ki of the compound in conjunction with the TRFH structural domain of TRF2 measures (ACS according to the method delivered Med.Chem.Lett.2018,9 (5), 507-511)

Claims (6)

1. the compound or its pharmaceutically acceptable salt of a kind of logical formula (I):
Wherein L is-(CH2)6-10, wherein one or more methylene can replace by oxygen atom；X is-CH2Or-CH2CH2-； R1Selected from amide groups, arbitrarily the aryl replaced, the heterocyclic aryl arbitrarily replaced；R2For C1-C6Alkyl, naphthenic base or substituted Naphthenic base, one or more hydrogen atoms can be replaced by hydroxyl, amino, alkoxy, alkylamino, alkane sulfydryl in above-mentioned group；R3 For C1-C8Alkyl, arbitrarily replace alkyl, naphthenic base, substituted naphthenic base；R4And R5For C1-C8Alkyl, arbitrarily replace Alkyl, naphthenic base, the naphthenic base arbitrarily replaced, alkoxy, alkylamino, alkane sulfydryl, the aryl arbitrarily replaced, arbitrarily replace it is miscellaneous Aryl.
2. the structure of the further preferred Formula II of compound in the present invention:
Wherein L is-(CH2)6-10, wherein one or more methylene can replace by oxygen atom；R1For C1-C6Alkyl, cycloalkanes Base or substituted naphthenic base, one or more hydrogen atoms can be replaced by hydroxyl, amino, alkoxy, alkylamino in above-mentioned group； R2For C1-C8Alkyl, arbitrarily replace alkyl, naphthenic base, substituted naphthenic base；R3For C1-C8Alkyl, the alkane that arbitrarily replaces Base, naphthenic base, the naphthenic base arbitrarily replaced, the aryl arbitrarily replaced, the heteroaryl arbitrarily replaced；R4For-OR5Or it is selected from hydrogen, alkane Base, the alkyl arbitrarily replaced, naphthenic base, the naphthenic base arbitrarily replaced；R5For C1-C8Alkyl, the alkyl, the cycloalkanes that arbitrarily replace Base, the naphthenic base arbitrarily replaced, the aryl arbitrarily replaced, the heteroaryl arbitrarily replaced.
3. part of compounds representated by formula (I) and Formula II is as follows:
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-1)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isopropoxybenzoyl amino) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-2)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-3)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-4)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-5)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- phenylpropyl alcohol oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-6)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzene ethoxybenzo amino) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-7)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- hexamethylene methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-8)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isobutoxy benzoyl-amido) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-9)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- (2- menaphthyl) oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-10)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- isoamoxy benzoyl-amido) -15- isobutyl group-N, N, 18- front three Base -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- first of [1,17] dioxa [4,7,10,13] Amide (I-11)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- benzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- tri- Methyl-1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring -3- of [1,17] dioxa [4,7,10,13] Formamide (I-12)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent methylbenzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-13)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- methylbenzyloxy benzoyl-amidos) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-14)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to methylbenzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-15)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- m-chloro benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-16)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-17)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- bromo-benzyloxy benzoyl-amidos) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-18)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-19)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- fluorine benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-20)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- to fluorine benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-21)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- (1- naphthalene methoxyl group) benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-22)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- (2- naphthalene methoxyl group) benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-23)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent bromo-benzyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-24)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent benzyl chloride oxygroup benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-25)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- methylbenzyloxy benzoyl-amidos) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-26)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- adjacent fluorine benzyloxybenzoyl amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-27)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-28)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- hexamethylene methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-29)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- positive hexyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-30)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- bis- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-31)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3,5- hexichol propoxyl group benzoyl-amido) -15- isobutyl group-N, N, 18- Trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21-ring of [1,17] dioxa [4,7,10,13] - 3- formamide (I-32)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isoamoxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-33)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isobutoxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-34)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- isopropoxybenzoyl amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-35)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclobutoxy group benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-36)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopentyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-37)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- cyclopropyl methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-38)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hexamethylene methoxybenzoyl base amino) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-39)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- positive hexyloxy benzoyl-amido) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 20 of [1,17] dioxa [4,7,10,13] One ring -3- formamide (I-40)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- hydroxybenzoylamino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-41)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- methoxybenzoyl base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-42)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethoxybenzo amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine 21 of [1,17] dioxa [4,7,10,13] Ring -3- formamide (I-43)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- ethylamino oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-44)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- the third amino oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-45)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- fourth amino oxygroup benzoyl-amido) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-46)；
(3S, 12S, 15S, 18S, 23aS, E) -12- (penta amino oxygroup benzoyl-amido of 3- benzyloxy -5-) -15- isobutyl group - N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously four azepine two of [1,17] dioxa [4,7,10,13] 11 ring -3- formamides (I-47)；(3S, 12S, 15S, 18S, 23aS, E) -12- (3- benzyloxy -5- second carboxyl oxygroup benzoyl Base amino) -15- isobutyl group-N, N, 18- trimethyl -1,13,16,19- tetra- oxos-pyrroles [2,1-f] simultaneously [1,17] dioxa [4,7,10,13] four azepine 21-ring -3- formamide (I-48).
4. the compound in Formulas I synthesizes with the following method:
5. specifically includes the following steps: the condensation of amino acid derivativges 1 and 2 prepares dipeptidase derivant 3；After 3 deprotection bases with ammonia Base acid derivative condensation prepares tripeptide derivative 4；Tetrapeptide derivative 5 is prepared with amino acid derivativges condensation after 4 deprotection bases； Tetrapeptide derivative 6 is prepared with amino acid derivativges condensation after 5 protecting groups；6, which cross olefin metathesis reaction cyclization, obtains among cyclic peptide Body 7；Double bond and deprotection base in reduction 7 prepare intermediate 8；8 with the benzoic acid that replaces, and in case of need Deprotection base obtains the compound 9 of Formulas I representative.
6. being existed according to compound of formula I described in claim any one or its pharmaceutically acceptable salt as TRF2 inhibitor Purposes in terms for the treatment of cancer.
CN201910265325.5A 2019-04-03 2019-04-03 A kind of preparation method and purposes of cyclic peptide TRF2 inhibitor Pending CN110423265A (en)

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CN112142683A (en) * 2020-09-01 2020-12-29 成都大学 Aza-eleven-membered ring compound, preparation method and application thereof, and medicine containing compound
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN111518166A (en) * 2020-05-20 2020-08-11 中国药科大学 Peptide-like compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
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CN112142683A (en) * 2020-09-01 2020-12-29 成都大学 Aza-eleven-membered ring compound, preparation method and application thereof, and medicine containing compound
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