CN109715167A - Regulator of amino 1,2- and the 1,3- diol compound that lipid replaces as TLR2 dimerization - Google Patents

Regulator of amino 1,2- and the 1,3- diol compound that lipid replaces as TLR2 dimerization Download PDF

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CN109715167A
CN109715167A CN201780048372.3A CN201780048372A CN109715167A CN 109715167 A CN109715167 A CN 109715167A CN 201780048372 A CN201780048372 A CN 201780048372A CN 109715167 A CN109715167 A CN 109715167A
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alkyl
propyl
amino
bis
tetradecyloxyaniline
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W·赖斯德罗
S·R·纳塔拉
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Neuropore Therapies Inc
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Neuropore Therapies Inc
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract

The present invention relates to the amino 1 that lipid replaces, 2- and 1,3- diol compound, pharmaceutical composition comprising these compounds, and these compounds are for treating inflammatory disease and certain the nervous system diseases related with inflammatory signals conductive process, the including but not limited to treatment method or the purposes in drug of the protein of false folding.

Description

Tune of amino 1,2- and the 1,3- diol compound that lipid replaces as TLR2 dimerization Save agent
Cross reference to related applications
This application claims the priority for the U.S. Provisional Application 62/370,637 that August in 2016 is submitted on the 3rd, full text passes through Reference is included in herein.
Technical field
The present invention relates to the amino 1 that lipid replaces, 2- and 1,3- diol compound, the pharmaceutical compositions comprising these compounds Object and these compounds are for treating inflammatory disease and certain nervous system diseases related with inflammatory signals conductive process Disease, the including but not limited to treatment method or the purposes in drug of the protein of false folding.
Background
Toll-like receptor (TLR) is outpost's receptor of immune system.When these receptors are when cell surface is activated, they Start the recruitment of an adaptin family containing TIR structural domain, the cascade of these protein induction signals eventually leads to cell class Type specificity inflammatory reaction leads to proinflammatory mediation son such as IL1, the raising of IL6, IL8 and TNF α.It is expressed on mammalian cell Different TLR receptors in, TLR2 and TLR1 or TLR6 form heterodimer, to start inflammation with ligand derived from various microorganisms Reaction.Have in various bacterium ligands lipopolysaccharides (LPS), acylated lipopeptid, lipopolysaccharide, peptide glycan, porin, glycosyl-phosphatidyl- Colloidal sol anchor and other bacterial cell wall components, such as the lipoteichoicacid (LTA) from streptococcus pneumonia.It is micro- in addition to TLR2 Outside bioactivation, it was found that the abnormal aggregation of the oligomeric protein (such as alpha-synapse nucleoprotein (aSyn)) of neuron release can be in nerve Similar inflammatory reaction, including Parkinson's disease (PD) are induced in the animal model of degenerative disease, dementia with Lewy body, multisystem is withered Contract (MSA) and Alzheimer disease (AD).See, for example, Kim etc., Nat.Commun.2013,4,1562.
TLR2 allows to distinguish various recognition modes by the ability that heterodimer inducement signal conducts, this, which allows to design, has The ligand of specific suppression mode.Kajava etc., J.Biol.Chem.2010,285,6227.Mainly with particular pathologies agonist (such as the pathogenic alpha-synapse nucleoprotein of oligomerization) competition, but do not influence to participate in bacterium or virus infection pro-inflammatory signals conduction its Therefore the inhibitor of his ligand can be used as potential therapeutic agent.Described herein is directly as TLR2 and its heterodimeric protein The compound of the inhibitor of interaction, not as the delivery vectors of other therapeutic agents, (such as the liposome of activating agent is passed It send, or as delivering and the targeting agent of the covalently bound therapeutic agent molecules of the polar head of lipid composition).
The function of Toll-like receptor is related with various protein foldings, protein dimerization and inflammatory process and is related to all Such as following related disease: Alzheimer disease (Gambuzza, M. etc., the Toll-like receptor in Alzheimer disease: see by acology Point (" Toll-like receptors in Alzheimer ' s disease:a therapeutic perspective) ", CNS Neurol.Disord.Durg Targets 2014,13 (9), 1542-58), Parkinson's disease and the Parkinson with dementia Sick (Parkinson ' s disease and Parkinson ' s disease with dementia) (Beraud, D. etc. are wrong The alpha-synapse nucleoprotein and Toll-like receptor accidentally folded: for the therapy target (" Misfolded α-synuclein of Parkinson's disease And Toll-like receptors:therapuetic targets for Parkinson's disease "), Parkinsonism Relat.Disord.2012,18 (supplements 1), S17-20), frontotemporal dementia, dementia with Lewy body (lewy body Disease), multi-system atrophy (Vieira, B. etc., the neuroinflamation in multi-system atrophy: to the reaction of alpha-synuclein aggregation and Reason (" Neuroinflammation in multiple system atrophy:Response to and cause of A-synuclein aggregation) ", Front.Cell Neurosci.2015,9,437), amyotrophic lateral sclerosis (Casula, M. etc., Toll-like receptor signal transduction (" the Toll-like receptor in amyotrophic lateral sclerosis myeloid tissue Signaling in amyotrophic lateral sclerosis spinal cord tissue) ", Neuroscience 2011,179,233-43), Huntington disease (Kalathur, R.K.R. etc., Huntington's disease and its treatment target gene: is ground based on HD Study carefully global functional profile (" Huntington ' the s disease and its therapeutic target in intercrossed data library genes:a global functional profile based on the HD Research Crossroads Database "), BMC Neurology 2012,12,47), inflammatory disease, asthma and chronic obstructive pulmonary disease (COPD) (Zuo, L. etc., in asthma and COPD Toll-like receptor molecular regulation (" Molecular regulation of Toll-like Receptors in asthma and COPD "), Front.Physiol.2016,6,312), chronic peptic ulcer (Smith, S., helicobacter pylori infections and it is immune in Toll-like receptor effect (" Roll of Toll-like Receptors in Helicobacter pylori infection and immunity "), World J.Gastrointe St.Pathophysiol.2014,5 (3), 133-146), (Harding, C.V. etc., antigen of mycobacterium tuberculosis present tuberculosis It adjusts: effect (" the Regulation of antigen presentation by Mycobacterium of Toll-like receptor Tuberculosis:a role for Toll-like receptors "), Nat.Rev.Microbiol.2010,8 (4), 296-307), rheumatoid arthritis (Huang, Q.-Q. etc., the effect " Roll of the Toll-like receptor in rheumatoid arthritis Of Toll like receptors in rheumatoid arthritis "), Curr.Rheumatol.Rep.2009,11 (5), 357-364), (Zhang, Q. etc. are with or without Toll-like receptor approach in the chronic nasosinusitis of nasal polyp to chronic nasosinusitis Differential expression (" the Differential expression of Toll-like receptor pathway genes of gene In chronic rhinosinusitis with or without nasal polyps "), Acta Otolaryngol.2013,133 (2), 165-173), hepatitis (including hepatitis B and hepatitis C) (Zhang, E. etc., Toll (" Toll-like receptor is infected in innate immune response control hepatitis type B virus (HBV) that sample receptor (TLR) mediates (TLR)-mediated innate immune responses in control of hepatitis B virus(HBV) Infection "), Med.Microbiol.Immunol.2015,204 (1), 11-20；Howell, J. etc., hepatitis C infection In Toll-like receptor: influence (" the Toll-like receptors in hepatitis C to pathogenesis and treatment Infection:implications for pathogenesis and treatment "), J.Gastroenterol.Hepatol.2013,28 (5), 766-776), gout, lupus, psoriasis, psoriatic arthritis (Santegoets, K.C.M. etc., the Toll-like receptor in rheumatic disease: we are to resist mistake to have paid high cost ? (" Toll-like receptors in rheumatic diseases:are we paying a high price for Our defense against bugs? "), FEBS Letters 2011,585 (23), 3660-3666), vasculitis, laryngitis, (engagement of Chen, X. etc., the T4 sample receptor 2 in CD4 (+) T cell promote the local immunity of tuberculous pleurisy patient to pleurisy React (" Engagement of Toll-like receptor2on CD4 (+) T cells facilitates local Immune responses in patients with tuberculous pleurisy "), J.Infect.Dis.2009, 200 (3), 399-408), eczema (Miller, L.S., Toll-like receptor (" the Toll-like receptors in skin Skin "), Adv.Dermatol.2008,24,71-87), gastritis (Schmausser, B. etc., Toll-like receptor TLR4, TLR5 and Influence of the TLR9 to stomach cancer cell: mean with helicobacter pylori interact (" Toll-like receptors TLR4, TLR5and TLR9on gastric carcinoma cells:an implication for interaction with Helicobacter pylori "), Int.J.Med.Microbiol.2005,295 (3), 179-85), vasculitis (Song, G.G. etc., Toll-like receptor polymorphism and vasculitis neurological susceptibility: confluence analysis and systematic review (" Toll-like receptor polymorphisms and vasculitis susceptibility:meta-analysis and systematic Review "), Mol.Biol.Rep.2013,40 (2), 1315-23), laryngitis (King, S.N. etc., it is white thin in acute vocal cord injury Characterization (" the Characterization of the Leukocyte Response in Acute Vocal Fold of born of the same parents' response Injury "), PLoS One, 2015；10 (10): e0139260), allergic reaction (Gangloff, S.C. etc., in anaphylactia Toll-like receptor and immune response (" Toll-like receptors and immune response in allergic Disease "), Clin.Rev.Allergy Immunol.2004,26 (2), 115-25), multiple sclerosis (Miranda- Hernandez, S. etc., effect (" Role of toll-like receptors in of the Toll-like receptor in multiple sclerosis Multiple sclerosis "), Am.J.Clin.Exp.Immunol.2013,2 (1), 75-93), Crohn disease (Cario, E., the Toll-like receptor in inflammatory bowel disease: (" Toll-like receptors in inflammatory bowel after 10 years Diseases:A decade later "), Inflamm.Bowel Dis.2010,16 (9), 1583-1597) and it is traumatic Cerebral injury (Hua, F. etc., the genome spectrum of Toll-like receptor approach in traumatic brain injury mouse: the effect of exogenous progesterone (“Genomic profile of Toll-like receptor pathways in traumatically brain- Injured mice:effect of exogenous progesterone "), J.Neuroinflammation 2011,8, 42)。
Amino acid is discussed, the patent publications of cation and other modified lipids include: U.S. Patent Publication 2015/ 0030670,2005/0113345,2005/0175682,2011/0091525,2011/0152 251 and 2015/0065414；PCT Open WO2002/0729068, WO2005/039504, WO2009/129385, WO2011/062955, WO2013/030678 and WO2013/135359；And United States Patent (USP) 7,803,397,8,609,663 and 8,936,942.Other publications include: Long, E.M. etc., the subclass of acylated Anti-inflammatory mediator occupies Toll-like receptor 2 to inhibit by peroxisome proliferation-activated receptors Neutrophil recruitment (" A subclass of acylated anti-inflammatory mediators usurp Toll-like receptor 2to inhibit neutrophil recruitment through peroxisome Proliferator-activated receptor "), PNAS 2011,103 (39), 16357-16362；Kang, J.Y. etc., Lipopeptid mode (" Recognition of Lipopeptide is identified by 6 heterodimer of Toll-like receptor 2-Toll sample receptor Patterns by Toll-like Receptor 2-Toll-like Receptor 6Heterodimer "), Immunity2009,31(6),873-884；Kajava, A.V. etc., hydrogen bond network control ligand positioning on the surface TLR2 and thin Born of the same parents' signal transduction (" A Network of Hydrogen Bonds on the Surface of TLR2Controls Ligand Positioning and Cell Signaling "), J.Biol.Chem.2010,285,6227-6234；Medel, I. etc., VB-201, a kind of oxidized phospholipids small molecule, the innate cells for inhibiting CD14- and Toll-like receptor -2 to rely on activate and inhibit artery Atherosis (" VB-201, an oxidized phospholipid small molecule, inhibits CD14-and Toll-like receptor-2-dependent innate cell activation and constrains Atherosclerosis "), Clin.Exp.Immunol.2014,175 (1), 126-37；Kadl, A. etc., by Toll-like receptor 2 Inflammation (" the Oxidized phospholipid-induced inflammation is of the oxidized phospholipids induction of mediation Mediated by Toll-like receptor2 "), Free Radic.Biol.Med.2011,51 (10), 1903-9.
This document describes the amino 1 that lipid replaces, 2- and 1,3- diol compound is combined as TLR2 heterodimer Antagonist has efficient and selectivity.
Summary of the invention
In one aspect, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salts:
In formula
R1It is H ,-CO2-C1-8Alkyl ,-CO2-CHRaAryl ,-CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) Aryl ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)-CHRaHeteroaryl ,-CHRaAryl ,-CHRaHeteroaryl ,- SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl；
Wherein RaIt is H or C1-15Alkyl；
RbIt is H or-C1-5Alkyl-NReRf；
Wherein ReIt is H or C1-4Alkyl, RfIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
RcIt is H or C1-4Alkyl, RdIt is H, C1-4Alkyl or-CO2C1-4Alkyl；And
Each aryl or heteroaryl are optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4 Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl ,-OC1-4Alkyl-aryl-group or-CO2C1-4Alkyl；
R2It is H or C1-4Alkyl；
R3aIt is H ,-C6-14Alkyl ,-CHRgAryl ,-CHRgHeteroaryl ,-CHRgHeterocyclylalkyl ,-C1-4Alkyl-NRhRi,– C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk；
RgIt is H or C1-4Alkyl；
RhIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
RiIt is H, C1-4Alkyl or-C (=NH)-NHRm；
Wherein RmIt is H ,-SO2Aryl or-CO2C1-4Alkyl；
RjIt is H or C1-4Alkyl；
RkIt is H or C1-4Alkyl；
Wherein each aryl, heteroaryl and Heterocyclylalkyl are optionally replaced by following group :-OH, C1-4Alkyl ,-CO2C1-4 Alkyl, phenyl or benzyloxy；
Or R2And R3aAtom connected to them is formed together C2-4Alkylidene；
R3bIt is H；Or R3aAnd R3bCarbon atom connected to them is formed together 4- to 7- membered heterocycloalkyl, optionally By C1-4Alkyl or-CO2C1-4Alkyl replaces；
R4It is H or C1-4Alkyl；
R5It is C8-16Alkyl or C8-16Alkenyl；
R6It is C8-16Alkyl or C8-16Alkenyl；
M is 0 or 1；
N is 0 or 1；
P is 0 or 1；
Wherein at least one in n and p is 1.
On the other hand, the present invention relates to the compound of formula (II) or its pharmaceutically acceptable salts:
In formula
R21It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R22It is H or C1-4Alkyl；
R24It is H or C1-4Alkyl；
R25It is C8-16Alkyl or C8-16Alkenyl；
R26It is C8-16Alkyl or C8-16Alkenyl；
N2 is 0 or 1；
P2 is 0 or 1；
Wherein at least one in n2 and p2 is 1.
On the other hand, the present invention relates to the compound of formula (III) or its pharmaceutically acceptable salts:
In formula
R31It is phenyl or bicyclic heteroaryl；
R32It is H or C1-4Alkyl；
R33It is C1-4Alkyl-NRxRy；
Wherein RxIt is H, C1-4Alkyl or-CO2-C1-4Alkyl；
RyIt is H or C1-4Alkyl；
R34It is H or C1-4Alkyl；
R35It is C14-18Alkyl or C14-18Alkenyl.
On the other hand, the present invention relates to the compound of formula (IV) or its pharmaceutically acceptable salts:
In formula
G1It is N or CH；
R41It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R41’It is not present or H or C1-4Alkyl；Wherein work as R41’It is H or C1-4When alkyl, with R41’The nitrogen of connection has positive electricity Lotus；
R42It is H or C1-4Alkyl；
R43It is-OC1-18Alkyl ,-OC1-18Alkenyl ,-C1-18Alkyl or-C1-18Alkenyl is respectively optionally taken by following group Generation :-OH ,-OC1-4Alkyl ,-C (O) OH ,-C (O) OC1-4Alkyl ,-C (O) NHR4bOr aryl；
R44It is-OC4-18Alkyl or-OC4-18Alkenyl is respectively optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O)OH、–C(O)OC1-4Alkyl ,-C (O) NHR4cOr aryl；
Wherein R4bAnd R4cIt is H or C each independently1-4Alkyl.
On the other hand, the present invention relates to the compound of formula (V) or its pharmaceutically acceptable salts:
In formula
G2It is key ,-CH2-、–CH2NH- or-CH2NHCH2-；
G3It is-C (O)-or-CH2-；
R51It is H, C1-4Alkyl ,-CO2C1-4Alkyl, heterocycle or-C1-4Alkyl-NR5aR5b；Wherein R5aIt is H or C1-4Alkyl, R5bIt is H, C1-4Alkyl or-CO2C1-4Alkyl；And
R52It is H or C1-4Alkyl；
Or R51And R52Carbon connected to them is formed together optionally by-CO2C1-4Alkyl-substituted Heterocyclylalkyl；
R53It is H or C1-4Alkyl；
O is 0 or 1；
R is 0 or 1；
S is 0 or 1；
R54It is C8-18Alkyl or C8-18Alkenyl；And
R55It is C8-18Alkyl or C8-18Alkenyl.
On the other hand, the present invention relates to the compound of formula (VI) or its pharmaceutically acceptable salts:
In formula
R61It is H ,-CO2-C1-8Alkyl ,-CO2-CHR6aAryl ,-CO2-CHR6aHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHR6b-NR6cR6d,-C(O)-CHR6aHeteroaryl ,-CHR6aAryl ,-CHR6aIt is miscellaneous Aryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl；
Wherein R6aIt is H or C1-15Alkyl；
R6bIt is H or-C1-5Alkyl-NR6eR6f；
R6cIt is H or C1-4Alkyl；
R6dIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
R6eIt is H or C1-4Alkyl；
R6fIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
Each aryl or heteroaryl are optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4 Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl or-OC1-4Alkyl-aryl-group；
R62It is H or C1-4Alkyl；
R66It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R67It is H, C1-4Alkyl or-C (=NH)-NHR6m；
Wherein R6mIt is H ,-SO2Aryl or-CO2C1-4Alkyl；
R63It is H or C1-4Alkyl；
R64Be H or-OH,
Or R64It is-C1-18Alkyl ,-C1-18Alkenyl ,-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or- OC1-4Alkyl replaces；
R65It is H or-C4-8Naphthenic base,
Or R65It is-C1-18Alkyl ,-C1-18Alkenyl ,-OC1-12Alkyl or-OC1-12Alkenyl, respectively optionally by-OH or- OC1-4Alkyl replaces；And
T is 0 or 1.
In some embodiments, formula (I), (II), (III), (IV), the compound of (V) or (VI) are to be selected to retouch herein It states or the compound of those of example substance.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes at least one formula (I) Compound or its pharmaceutically acceptable salt.On the other hand, the present invention relates to a kind of pharmaceutical composition, the medicine groups Close the compound or its pharmaceutically acceptable salt that object includes at least one formula (II).On the other hand, the present invention relates to one Kind pharmaceutical composition, described pharmaceutical composition include the compound or its pharmaceutically acceptable salt of at least one formula (III).? On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes the compound of at least one formula (IV) Or its pharmaceutically acceptable salt.On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes The compound or its pharmaceutically acceptable salt of at least one formula (V).On the other hand, the present invention relates to a kind of pharmaceutical compositions Object, described pharmaceutical composition include the compound or its pharmaceutically acceptable salt of at least one formula (VI).On the other hand, The present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition include compound at least one arbitrary table 1-6 or its Pharmaceutically acceptable salt.Pharmaceutical composition according to the present invention can further include pharmaceutically acceptable excipient.This Invention further relates to the compound or its pharmaceutically acceptable salt of the formula (I) as drug.The invention further relates to be used as drug The compound or its pharmaceutically acceptable salt of formula (II).The invention further relates to be used as drug formula (III) compound or its Pharmaceutically acceptable salt.The invention further relates to the compounds or its pharmaceutically acceptable salt of the formula (IV) for being used as drug.This Invention further relates to the compound or its pharmaceutically acceptable salt of the formula (V) as drug.The invention further relates to be used as drug Formula (VI) compound or its pharmaceutically acceptable salt.The invention further relates to be used as drug any table 1-6 in compound or Its pharmaceutically acceptable salt.
On the other hand, the present invention relates to the methods for treating disease related with TLR2 heterodimerization or illness, including give Need a effective amount of at least one formula (I) of the object of this treatment, (II), (III), (IV), the compound of (V) or (VI), or Compound or any aforementioned pharmaceutically acceptable salt in any table 1-6.On the other hand, this document describes for treat with The compound or composition of the related disease of TLR2 heterodimerization or illness.
On the other hand, the present invention relates to the methods for treating disease related with TLR2 heterodimerization or medical condition, including It gives and needs a effective amount of at least one formula (I) of the object of this treatment, (II), (III), (IV), the chemical combination of (V) or (VI) Compound or any aforementioned pharmaceutically acceptable salt in object, or any table 1-6.The invention further relates to formula (I), (II), (III), (IV), the compound or any aforementioned pharmaceutically acceptable in the compound of (V) or (VI), or any table 1-6 Salt is preparing the application in the drug for treating the disease and medical condition.
On the other hand, the present invention relates to the heterodimerizations of TLR2 in interference cell, or adjust, and prevention slows down, reverses or press down The method of TLR2 heterodimerization in cell processed, including make cell and a effective amount of at least one formula (I), (II), (III), (IV), , or the compound in any table 1-6 or any salt above-mentioned and/or at least one of the invention (V) or the compound of (VI) Pharmaceutical composition is in contact, wherein the contact is external, in vitro or internal contact.
Other embodiments of the invention, feature can be readily appreciated that from following detailed description and practice of the invention And advantage.
For simplicity, the content (including patent) for the publication quoted in the specification is totally incorporated herein by reference.
Detailed description of the invention
Before further describing the invention, it should be appreciated that the present invention is not limited to the specific embodiments, because they It certainly may variation.It should also be understood that the purpose of terms used herein is only description specific embodiment, it is not used to be construed as limiting, Because the scope of the present invention only by as a whole specification or the appended claims limited.
Unless otherwise indicated, all scientific and technical terminologies used herein are understood with one skilled in the art of the present invention Common meaning it is identical.All reference is incorporated into full for all patents referred to herein, application, published application and other publications Herein.If determined described in the patent for defining and being totally incorporated herein by reference described in this section, application and other publications Justice is opposite or inconsistent, then the definition prior to being totally incorporated herein by reference is defined described in this section.
Herein and the appended claims used in singular "one", "an" and it is " described " include plural number instruction Object, unless the context is clearly stated.It should also be noted that claims can be formulated as excluding any optional element.Equally, This explanation application makees reference claim element and relatively uses this kind of removing property term, such as " only ", " only ", or makes With the antecedent basis of " negative " limitation.
Terms used herein "comprising", " containing " and " comprising " are opened with it, infinite meaning uses.
To provide conciser description, term " about " is not used before some quantitative expressions herein.It should be understood that either No clearly to use term " about ", each content herein indicates the numerical value actually given, and it is also represented by based on ability The approximation for the given numerical value that domain ordinary skill can rationally infer, including due to experiment and/or measuring condition generate it is this kind of The equivalent value and approximation of given numerical value.No matter when as a percentage when yield, this kind of yield is indicated in specific chemistry Measuring entity quality and same entity than under the conditions of for calculating yield can be obtained the maximum amount of ratio.Percents Concentration indicate quality ratio, unless otherwise indicated.
Unless otherwise defined, the meaning of all technical and scientific terms as used herein with it is of the art general Being generally understood for logical technical staff is consistent.Although can also be used and similar or equivalent any method described herein and material implementation Or the test present invention, but preferred method and material is described below.All publications being mentioned above are incorporated by reference this Text, it is associated with cited publication come these methods of disclosure and description and/or material.
Unless otherwise indicated, the methods and techniques of embodiment of the present invention generally follow conventional method well known in the art into Row and as described in several general or bibliography particularly, the bibliography is quoted through this specification and discussion. See, e.g., Loudon, Organic Chemistry (" organic chemistry "), fourth edition；New York: Oxford University Press (Oxford University Press), 2002,360-361,1084-1085 page；Smith and March, March's (" numb ruler is advanced to organise Advanced Organic Chemistry:Reactions, Mechanisms, and Structure Learn: reaction, mechanism and structure "), the 5th edition, Wei Li scientific company (Wiley-Interscience), 2001.
Herein for naming the nomenclature of motif compound to illustrate in the embodiments herein.The nomenclature is usually using city The ChemBioDraw Ultra software 14.0 editions sold obtains.
It should be understood that for clarity, some features of the invention described in the content of individual each embodiment are also It may be incorporated in single embodiment and provide.Conversely, in the content of single embodiment Short Description it is of the invention Each feature can also be provided separately or be provided in the form of any suitable sub-portfolio.With the chemical group represented by changeable-shaped All combinations of relevant embodiment are specific in the scope of the invention and by being disclosed herein, just as independent and bright herein Really it is open each and each combination so that such combination comprising itself for stable compound compound (that is, separable, characterization With the compound of detection biological activity).In addition, describing the institute of chemical group listed in the embodiment of such changeable-shaped There is sub-portfolio to be also specifically included in the scope of the invention and by being disclosed herein, just as individually and clearly disclosing chemical group herein Each of and each such sub-portfolio.
Representative embodiments
Formula (I)
In some embodiments of formula (I), R1It is H ,-CO2-C1-8Alkyl ,-CO2-CHRaAryl ,-CO2-CHRaIt is miscellaneous Aryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)-CHRaHeteroaryl ,- CHRaAryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl；Wherein RaIt is H or C1-15Alkane Base；RbIt is H or-C1-5Alkyl-NReRf；Wherein ReIt is H or C1-4Alkyl, RfIt is H, C1-4Alkyl or-CO2C1-4Alkyl；RcBe H or C1-4Alkyl, RdIt is H, C1-4Alkyl or-CO2C1-4Alkyl；And each aryl or heteroaryl are optionally replaced by some groups: halogen Element, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl or-OC1-4Alkyl-aryl-group.
In some embodiments of formula (I), R1It is H ,-CO2-C1-8Alkyl ,-CO2-CHRaAryl ,-CO2-CHRaIt is miscellaneous Aryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)-CHRaHeteroaryl ,- CHRaAryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.In some embodiments, R1 It is H ,-CO2-CHRaAryl ,-CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRaHeteroaryl ,-CHRaAryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.? In some embodiments, R1It is H.In other embodiments, R1It is-CO2-C1-8Alkyl.In other embodiments, R1Be- CO2-CHRaAryl or-CO2-CHRaHeteroaryl.In other embodiments, R1It is-C (O)-C1-4Alkyl ,-C (O) aryl, Or-C (O)-heteroaryl.In other embodiments, R1It is-C (O)-CHRb-NRcRd.In other embodiments, R1It is-C (O)-CHRaHeteroaryl.In other embodiments, R1It is-CHRaAryl or-CHRaHeteroaryl.In other embodiments In, R1It is-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.In some embodiments, R1Aryl is phenyl.At it In his embodiment, R1Aryl is fluorenyl (fluorenyl).In some embodiments, R1Heteroaryl is bicyclic heteroaryl.In other realities It applies in mode, R1Heteroaryl is indyl, benzofuranyl, benzothienyl, benzoxazolyl or benzothiazolyl.At other In embodiment, R1Heteroaryl is indyl.In some embodiments, R1Aryl or heteroaryl are unsubstituted.In other realities It applies in mode, R1Aryl or heteroaryl are independently selected by one or more from substituent group below and replace: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl and-OC1-4Alkyl-aryl-group.In other embodiments In, R1Aryl or heteroaryl are independently selected by one or more from substituent group below and replace: halogen, C1-4Alkyl, C1-4Fluothane Base ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl ,-OC1-4Alkyl-aryl-group and-CO2C1-4Alkyl.In some implementations In mode, R1Aryl or heteroaryl are replaced by following group: methyl, fluorine, phenyl or benzyloxy.In some embodiments, R1 Aryl or heteroaryl are replaced by following group: methyl, fluorine, phenyl, benzyloxy or tert-butoxycarbonyl.
In some embodiments, R1It is-CO2-CH2Fluorenyl, acetyl group or benzyloxycarbonyl group.In some embodiments, R1It is tert-butoxycarbonyl.In some embodiments, R1It is substituted or unsubstituted benzyl.In some embodiments, R1It is The benzyl replaced by halogen or phenyl.
In some embodiments, RaIt is H.In other embodiments, RaIt is C1-15Alkyl.In other embodiments, RaIt is C10-15Alkyl.
In some embodiments, RbIt is H.In some embodiments, RbIt is-C1-5Alkyl-NReRf.In some implementations In mode, ReIt is H.In other embodiments, ReIt is C1-4Alkyl.In some embodiments, RfIt is H.In some embodiment party In formula, RfIt is C1-4Alkyl.In other embodiments, RfIt is-CO2C1-4Alkyl.
In some embodiments, RcIt is H.In some embodiments, RcIt is C1-4Alkyl.In some embodiments, RdIt is H.In other embodiments, RdIt is C1-4Alkyl.In other embodiments, RdIt is-CO2C1-4Alkyl.
In some embodiments, R2It is H.In other embodiments, R2It is C1-4Alkyl.
In some embodiments, R1And R2It is all hydrogen.
In some embodiments, R3aIt is H.In other embodiments, R3aIt is-C6-14Alkyl.In other embodiments In, R3aIt is-CHRgAryl ,-CHRgHeteroaryl or-CHRgHeterocyclylalkyl.In some embodiments, R3aAryl is benzene Base.In some embodiments, R3aHeteroaryl is pyrrole radicals, imidazole radicals, indyl or benzimidazolyl.In other embodiments In, R3aHeteroaryl is pyrrole radicals or indyl.In other embodiments, R3aHeterocyclylalkyl is monocyclic heterocycloalkyl.Some In embodiment, R3aHeterocyclylalkyl is pyrrolidinyl or piperazinyl.In some embodiments, R3aAryl, heteroaryl and heterocycle Alkyl is unsubstituted.In other embodiments, R3aAryl, heteroaryl and Heterocyclylalkyl are replaced by following group :-OH, C1-4 Alkyl or-CO2C1-4Alkyl.In other embodiments, R3aAryl and heteroaryl are optionally replaced by phenyl or benzyloxy.
In some embodiments, R3aIt is-C1-4Alkyl-NRhRi.In other embodiments, R3aIt is-C1-4Alkyl- CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk。
In some embodiments, RgIt is H.In other embodiments, RgIt is C1-4Alkyl.
In some embodiments, RhIt is H.In other embodiments, RhIt is C1-4Alkyl.In other embodiments, RhIt is-CO2C1-4Alkyl.
In some embodiments, RiIt is H.In other embodiments, RiIt is C1-4Alkyl.In other embodiments, RiIt is-C (=NH)-NHRm。
In some embodiments, RmIt is H.In some embodiments, RmIt is-SO2Phenyl.In other embodiments, RmIt is-CO2C1-4Alkyl.
In some embodiments, RjIt is H.In some embodiments, RjIt is C1-4Alkyl.In some embodiments, RkIt is H.In some embodiments, RkIt is C1-4Alkyl.
In some embodiments, R2And R3aIt is formed together C2-4Alkylidene.In some embodiments, R2And R3aTogether Form C3Alkylidene.
In some embodiments, R3bIt is H.In some embodiments, R3aAnd R3bCarbon atom one connected to them It rises and forms 4- to 7- membered heterocycloalkyl, optionally by C1-4Alkyl or-CO2C1-4Alkyl replaces.In some embodiments, described Heterocyclylalkyl is pyrrolidines or piperazine.
In some embodiments, R3aIt is substituted or unsubstituted-CH2Phenyl.In some embodiments, R3aBe by - the CH that benzyloxy, hydroxyl or phenyl replace2Phenyl.In some embodiments, R3aIt is-CH2Imidazole radicals, optionally by uncle Butoxy carbonyl replaces.In some embodiments, R3aIt is-CH2Indyl.In some embodiments, R3aIt is-CH2Piperazine Pyridine is optionally replaced by tert-butoxycarbonyl.In some embodiments, R3aIt is butylamine, is optionally taken by tert-butoxycarbonyl Generation.In some embodiments, R3aIt is propylamine, is optionally replaced by guanidine radicals, wherein the guanidine radicals optionally replaces.Some In embodiment, R3aIt is carboxyethyl, is optionally replaced by tert-butyl.In some embodiments, R3aIt is carboxymethyl, optionally Replaced by tert-butyl.In some embodiments, R3aAnd R3bIt is all hydrogen.
In some embodiments, R4It is H.In some embodiments, R4It is C1-4Alkyl.
In some embodiments, R5And R6It is C each independently8-16Alkyl or C8-16Alkenyl.In some embodiments In, R5And R6It is C each independently8-16Alkyl.In some embodiments, R5And R6It is identical.In other embodiments, R5With R6It is different.In some embodiments, R5And R6It is the hydrocarbon of straight chain.In some embodiments, R5And R6Individually C14Alkyl.
In some embodiments, m is 0.In other embodiments, m is 1.In some embodiments, n is 0.? In some embodiments, n is 1.In some embodiments, p is 0.In other embodiments, p is 1.In some embodiment party In formula, n is that 1 and p is 0.In other embodiments, it is 1 that n, which is 0 and p,.
In some embodiments, R5And R6It is C each independently13-16Alkyl or C13-16Alkenyl.In some embodiments In, R5And R6It is C each independently8-11Alkyl, C13-16Alkyl, C8-11Alkenyl or C13-16Alkenyl.In some embodiments, R5 And R6It is C each independently8-11Alkyl, C13-16Alkyl, C8-11Alkenyl or C13-16Alkenyl, and R1It is H ,-CO2-C1-8Alkyl ,- CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)- CHRaHeteroaryl ,-CHRaAryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.Some In embodiment, R5And R6It is C each independently8-11Alkyl, C13-16Alkyl, C8-11Alkenyl or C13-16Alkenyl, and R3aIt is H、–C6-14Alkyl ,-CHRgAryl ,-CHRgHeterocyclylalkyl ,-C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4 Alkyl-CONRjRk.In some embodiments, R5And R6It is C each independently14Alkyl or C14Alkenyl.In some embodiments In, R5And R6It is C each independently16Alkyl or C16Alkenyl.
In some embodiments, R1It is-CO2-C1-8Alkyl or-C (O)-CHRb-NRcRd, and R3aIt is-C6-14Alkyl ,- CHRgAryl ,-CHRgHeteroaryl ,-CHRgHeterocyclylalkyl ,-C1-4Alkyl-NRhRi,–C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkane Base-CO2Or-C H,1-4Alkyl-CONRjRk.In some embodiments, R1It is-CO2-C1-8Alkyl, m are 1.In some embodiment party In formula, R1It is-CO2-C1-8Alkyl, R2It is C1-4Alkyl.
In other embodiments, formula (I) compound is selected from the compound of table 1:
Table 1
And its pharmaceutically acceptable salt.
In some embodiments, compound is not the compound of table 1X.
Table 1X.
And its pharmaceutically acceptable salt.
Formula (II)
In some embodiments of formula (II), R21It is H.In other embodiments, R21It is C1-4Alkyl.In other realities It applies in mode, R21It is-CO2C1-4Alkyl.In other embodiments, R21It is H or-CO2Tert-butyl.In some embodiments In, R22It is H.In other embodiments, R22It is C1-4Alkyl.In some embodiments, R24It is H.In other embodiments In, R24It is C1-4Alkyl.
In some embodiments, R25And R26It is C each independently8-16Alkyl or C8-16Alkenyl.In some embodiments In, R25And R26It is C each independently8-16Alkyl.In some embodiments, R25And R26It is identical.In other embodiments In, R25And R26It is different.In some embodiments, R25And R26It is straight-chain hydrocarbons.In some embodiments, R25And R26Respectively C naturally14Alkyl.
In some embodiments, n2 is 0.In some embodiments, n2 is 1.In some embodiments, p2 is 0. In other embodiments, p2 is 1.In some embodiments, it is 0 that n2, which is 1 and p2,.In other embodiments, n2 be 0 and P2 is 1.
In other embodiments, formula (II) compound is selected from the compound of table 2:
Table 2
And its pharmaceutically acceptable salt.
Formula (III)
In some embodiments of formula (III), R31It is phenyl or bicyclic heteroaryl.In some embodiments, R31It is Phenyl.In some embodiments, R31It is bicyclic heteroaryl.In some embodiments, the R31Heteroaryl be pyrrole radicals, Imidazole radicals, furyl or thienyl.
In some embodiments, R32It is H.In other embodiments, R32It is C1-4Alkyl.
In some embodiments, R33It is C1-4Alkyl-NRxRy.In some embodiments, RxIt is H.In some embodiment party In formula, RxIt is C1-4Alkyl.In some embodiments, RxIt is-CO2-C1-4Alkyl.In some embodiments, RyIt is H.At it In his embodiment, RyIt is C1-4Alkyl.In some embodiments, RxAnd RyIt is all H.In some embodiments, RxBe- CO2Tert-butyl, RyIt is H.
In some embodiments, R34It is H.In some embodiments, R34It is C1-4Alkyl.
In some embodiments, R35It is C14-18Alkyl.In some embodiments, R35It is C14-18Alkenyl.In some realities It applies in mode, the C14-18Alkenyl has a double bond.In some embodiments, the C14-18Alkenyl is cis- with one Double bond.
In other embodiments, formula (III) compound is selected from the compound of table 3:
Table 3
And its pharmaceutically acceptable salt.
Formula (IV)
In some embodiments of formula (IV), compound be formula ((IVa), (IVb) or (IVc):
Wherein G1,R41,R41’,R42,R43And R44Such as the definition of formula (IV)；
Or its pharmaceutically acceptable salt.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), G1It is N.In other embodiments, G1 It is CH.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), R41It is H.In some embodiments, R41It is C1-4Alkyl.In some embodiments, R41It is-CO2C1-4Alkyl.In some embodiments, R41’It is not present.At it In his embodiment, R41’It is H or C1-4Alkyl, wherein with R41’The nitrogen of connection has positive charge.In some embodiments, R41’ It is H.In other embodiments, R41’It is C1-4Alkyl.In some embodiments, R41It is H, methyl or tert-butoxycarbonyl.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), R42It is H.In other embodiments, R42It is C1-4Alkyl, such as methyl.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), R43It is-OC1-18Alkyl or-OC1-18Alkene Base is respectively optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O) OH ,-C (O) OC1-4Alkyl ,-C (O) NHR4bOr virtue Base.In some embodiments, R43It is-C1-18Alkyl or-C1-18Alkenyl is respectively optionally replaced by following group :-OH ,- OC1-4Alkyl ,-C (O) OH ,-C (O) OC1-4Alkyl ,-C (O) NHR4bOr aryl.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), R44It is-OC4-18Alkyl, optionally by with Lower group replaces :-OH ,-OC1-4Alkyl ,-C (O) OH ,-C (O) OC1-4Alkyl ,-C (O) NH2、–C(O)NHC1-4Alkyl or virtue Base.In other embodiments, R44It is-OC4-18Alkenyl is optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O) OH、–C(O)OC1-4Alkyl ,-C (O) NH2、–C(O)NHC1-4Alkyl or aryl.
In some embodiments of formula (IV), (IVa), (IVb) or (IVc), R43It is-OC1-18Alkyl, R44It is-OC4-18 Alkyl.In some embodiments, R43It is-OC1-18Alkenyl and R44It is-OC4-18Alkenyl.In some embodiments, R43Be- OC13-18Alkyl, R44It is-OC13-18Alkyl.In some embodiments, R43It is-OC13-18Alkenyl and R44It is-OC13-18Alkenyl.? In some embodiments, R43It is-OC1-12Alkyl, R44It is-OC4-12Alkyl.In some embodiments, R43It is-OC1-12Alkenyl And R44It is-OC4-12Alkenyl, wherein R43And R44Respectively optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O) OC1-4 Alkyl ,-C (O) NH2、–C(O)NHC1-4Alkyl or aryl.In some embodiments, R43And R44Individually-OC7Alkyl.? In some embodiments, R43And R44Individually-OC14Alkyl or-OC14Alkenyl.In some embodiments, R43And R44Respectively It is-OC16Alkyl or-OC16Alkenyl.In some embodiments, R43And R44Individually-OC18Alkyl or-OC18Alkenyl.
In other embodiments, compound is selected from the compound of table 4:
Table 4
And its pharmaceutically acceptable salt.
Formula (V)
In some embodiments of formula (V), G2It is key.In some embodiments, G2It is-CH2-.In some embodiment party In formula, G2It is-CH2NH-.In other embodiments, G2It is-CH2NHCH2-。
In some embodiments, G3It is-C (O)-.In other embodiments, G3It is-CH2-。
In some embodiments, R51It is H.In some embodiments, R51It is C1-4Alkyl.In some embodiments In, R51It is-CO2C1-4Alkyl.In some embodiments, R51Heterocycle, for example, pyrrolidinyl, tetrahydrofuran base, piperidyl, Piperazinyl or morpholinyl.In other embodiments, R51It is-C1-4Alkyl-NR5aR5b；Wherein R5aIt is H or C1-4Alkyl, R5bIt is H、C1-4Alkyl or-CO2C1-4Alkyl.
In some embodiments, R52It is H.In other embodiments, R52It is C1-4Alkyl.
In some embodiments, R51And R52Carbon connected to them is formed together Heterocyclylalkyl；The wherein heterocycle Alkyl is optionally by-CO2C1-4Alkyl replaces.In some embodiments, R51And R52Carbon connected to them is formed together miscellaneous Naphthenic base；Wherein the Heterocyclylalkyl is optionally replaced by tert-butoxycarbonyl.In some embodiments, R51And R52With it The carbon that is connected be formed together piperidyl, optionally by-CO2C1-4Alkyl replaces, such as is replaced by tert-butoxycarbonyl.
In some embodiments, R53It is H.In other embodiments, R53It is C1-4Alkyl.
In some embodiments, o is 0.In some embodiments, o is 1.In some embodiments, r is 0.? In some embodiments, r is 1.In some embodiments, s is 0.In some embodiments, s is 1.
In some embodiments, it is 1 that r, which is 1 and s,.In some embodiments, it is 0 that r, which is 1 and s,.In some embodiment party In formula, r is that 0 and s is 1.In some embodiments, G2It is key, r is that 1, s is 0.In some embodiments, G2It is key, r is 1, s is 0, R51And R52Carbon connected to them is formed together Heterocyclylalkyl；Wherein the Heterocyclylalkyl is optionally by-CO2C1-4 Alkyl replaces.In some embodiments, G2It is-CH2, r is that 1, s is 0.In some embodiments, G2It is-CH2, r is 1, S is 0, R51And R52Carbon connected to them is formed together Heterocyclylalkyl；Wherein the Heterocyclylalkyl is optionally by-CO2C1-4Alkane Base replaces.In some embodiments, G2It is-CH2NH-, r are that 1, s is 0.In some embodiments, G2It is-CH2NH-, r are 1, s is 0, R51And R52Carbon connected to them is formed together Heterocyclylalkyl；Wherein the Heterocyclylalkyl is optionally by-CO2C1-4 Alkyl replaces.In some embodiments, G2It is-CH2NHCH2, r is that 1, s is 0.In some embodiments, G2Be- CH2NHCH2, r is that 1, s is 0, R51And R52Carbon connected to them is formed together Heterocyclylalkyl；Wherein the Heterocyclylalkyl is appointed Selection of land is by-CO2C1-4Alkyl replaces.In some embodiments, G2It is-CH2NHCH2, r is that 1, s is 0.In some embodiments In, G2It is-CH2Or-CH2NH-, r are that 1, s is 0, R51It is heterocycle.In some embodiments, R51It is heterocycle, R52It is H.
In some embodiments, R53It is H.In some embodiments, R53It is C1-4Alkyl.
In some embodiments, R54It is C8-18Alkyl.In some embodiments, R54It is C8-18Alkenyl.In some realities It applies in mode, R55It is C8-18Alkyl.In some embodiments, R55It is C8-18Alkenyl.In some embodiments, R54And R55 It is C each independently8-18Alkyl or C8-18Alkenyl.In some embodiments, R54And R55It is C each independently8-18Alkyl.? In some embodiments, R54And R55It is C each independently8-18Alkenyl.In some embodiments, R54And R55It is identical.? In other embodiments, R54And R55It is different.In some embodiments, R54And R55It is straight-chain hydrocarbons.In some embodiments In, R54And R55Individually C14Alkyl.In some embodiments, R54And R55Individually C14Alkenyl.In some embodiments, R54And R55Individually C16Alkyl or C16Alkenyl.In some embodiments, R54And R55Individually C18Alkyl or C18Alkenyl.
In other embodiments, formula (V) compound is selected from the compound of table 5:
Table 5
And its pharmaceutically acceptable salt.
Formula (VI)
In some embodiments of formula (VI), R61It is H.In some embodiments, R61It is-CO2-C1-8Alkyl.One In a little embodiments, R61It is-CO2-CHR6aAryl or-CO2-CHR6aHeteroaryl, wherein R6aIt is H or C1-15Alkyl, the virtue Base or heteroaryl are optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluothane Base ,-CN, phenyl or-OC1-4Alkyl-aryl-group.In some embodiments, R61It is-C (O)-C1-4Alkyl.In some embodiment party In formula, R61It is-C (O) aryl or-C (O)-heteroaryl, is respectively optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluorine Alkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl or-OC1-4Alkyl-aryl-group.In some embodiments, R61 It is-C (O)-CHR6b-NR6cR6d, wherein R6bIt is H or-C1-5Alkyl-NR6eR6f；R6eIt is H or C1-4Alkyl, R6fIt is H, C1-4Alkyl, Or-CO2C1-4Alkyl；R6cIt is H or C1-4Alkyl, R6dIt is H, C1-4Alkyl or-CO2C1-4Alkyl.In some embodiments, R61 It is-C (O)-CHR6aHeteroaryl ,-CHR6aAryl or-CHR6aHeteroaryl, wherein R6aIt is H or C1-15Alkyl, aryl or heteroaryl Base is respectively optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,- CN, phenyl or-OC1-4Alkyl-aryl-group.In some embodiments, R61It is-SO2-C1-4Alkyl ,-SO2Aryl or-SO2It is miscellaneous Aryl.In some embodiments, R61It is-CHR6aAryl, wherein R6aIt is H or C1-15Alkyl, the aryl optionally by with Lower group replaces: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl or-OC1-4 Alkyl-aryl-group.In some embodiments, R61It is-CHR6aHeteroaryl, wherein R6aIt is H or C1-15Alkyl, the heteroaryl are appointed Selection of land is replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl, Or-OC1-4Alkyl-aryl-group.In some embodiments, R61It is-CH2Phenyl.In some embodiments, R61It is-CH2Naphthalene Base.
In some embodiments, R62It is H.In some embodiments, R62It is C1-4Alkyl.
In some embodiments, R61It is-CHR6aAryl or-CHR6aHeteroaryl, wherein R6aIt is H or C1-15Alkyl, virtue Base or heteroaryl are respectively optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4 Fluoroalkyl ,-CN, phenyl or-OC1-4Alkyl-aryl-group；And R62It is H or methyl.In some embodiments, R61It is-CH2Phenyl Or-CH2Naphthalene；And R62It is H.
In some embodiments, R66It is H.In some embodiments, R66It is C1-4Alkyl.In other embodiments In, R66It is-CO2C1-4Alkyl.In some embodiments, R67It is H.In some embodiments, R67It is C1-4Alkyl.One In a little embodiments, R67It is-C (=NH)-NHR6m, wherein R6mIt is H ,-SO2Aryl or-CO2C1-4Alkyl.In some embodiment party In formula, R66It is-CO2C1-4Alkyl, R67It is H.In some embodiments, R66It is H and R67It is C1-4Alkyl or-C (=NH)- NHR6m, wherein R6mIt is H ,-SO2Aryl or-CO2C1-4Alkyl.In some embodiments, R66And R67It is all H.
In some embodiments, R63It is H.In some embodiments, R63It is C1-4Alkyl.In some embodiments In, R62And R63It is all H.In other embodiments, R62And R63In one be H, the other is C1-4Alkyl.
In some embodiments, R64It is H.In some embodiments, R64It is-OH.In some embodiments, R64 It is-C1-18Alkyl or-C1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces.In some embodiments, R64Be- OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces.In some embodiments, R65It is H. In some embodiments, R65It is-C4-8Naphthenic base.In some embodiments, R65It is-C1-18Alkyl or-C1-18Alkenyl, respectively From optionally by-OH or-OC1-4Alkyl replaces.In some embodiments, R65It is-OC1-18Alkyl or-OC1-18Alkenyl, respectively Optionally by-OH or-OC1-4Alkyl replaces.
In some embodiments, R64It is-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkane Base replaces；And R65It is-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces.In some implementations In mode, R64And R65Individually-OC18Alkenyl.In some embodiments, R64It is-C1-18Alkyl or-C1-18Alkenyl, optionally By-OH or-OC1-4Alkyl replaces；And R65It is H.In some embodiments, R65It is-OC1-18Alkyl or-OC1-18Alkenyl, optionally Ground is by-OH or-OC1-4Alkyl replaces；And R64It is H.In some embodiments, R65It is-C4-8Naphthenic base, R64It is H.
In some embodiments, t is 0.In some embodiments, t is 1.In some embodiments, t is 0 and R65 It is-C4-8Naphthenic base.In some embodiments, t is 1；R64It is-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH Or-OC1-4Alkyl replaces；And R65It is-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces. In some embodiments, t is 1 and R64And R65Individually-OC18Alkenyl.In some embodiments, t is 1；R64It is-C1-18 Alkyl or-C1-18Alkenyl, optionally by-OH or-OC1-4Alkyl replaces；And R65It is H.In some embodiments, t is 1；R65 It is-OC1-18Alkyl or-OC1-18Alkenyl, optionally by-OH or-OC1-4Alkyl replaces；And R64It is H.In some embodiments, T is 0, R65It is-C4-8Naphthenic base, and R64It is H.
In other embodiments, formula (VI) compound is selected from the compound of table 6:
Table 6
And its pharmaceutically acceptable salt.
Any formula given herein or compound, such as formula (I), (II), (III), (IV), (V) or (VI) or table 1-6 Compound, it is intended to indicate the compound and certain variations or form with structure shown in structural formula.Specifically, it provides herein The compound of any formula can have asymmetric center, therefore exist in the form of different enantiomer or diastereomer.It is generalized All optical isomers and stereoisomer and their mixtures in any proportion for closing object, are considered as in general formula In the range of.Therefore, any formula given herein is intended to indicate that the racemic modification of any ratio, one or more mapping bodily forms Formula, one or more diastereomer forms, one or more resistances turn isomeric form and their mixture.When the change of table 1-6 When conjunction object is depicted as having specific three-dimensional chemical configuration, any substitution spatial chemistry structure of compound is also provided herein The mixture of the stereoisomer of any ratio of type and compound.Any compound of table 1-6 is intended to indicate that any ratio Racemic modification, one or more enantiomeric forms, one or more diastereomer forms, one or more resistances turn isomery shape Formula and their mixture.In addition, certain structures can be with geometric isomer (that is, cis and trans isomer), tautomerism Body or resistance rotation isomers exist.In addition, any formula given herein is intended to indicate that the hydrate of these compounds, solvate And amorphous form and their mixture, even if these forms are not explicitly listed.In some embodiments, solvent It is water and solvate is hydrate.
Chemistry definition
Term " alkyl " refers to the linear or branched alkyl group group on main chain with 1 to 12 carbon atom.Alkyl group Example include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl (tBu), amyl, Group in isopentyl, tertiary pentyl, hexyl, isohesyl and ordinary skill, and introduction provided herein is considered phase When in any previous embodiment.
Term " alkenyl " refers to one or more double bonds and with the linear chain or branched chain alkyl of 2 to 12 carbon atoms. The example of alkenyl includes vinyl, allyl and butyl- 3- alkene -1- base.The term is interior including cis and trans isomer and its mixed Close object.
Term " alkylidene " refers to the bivalent group as alkane group.Alkylidene can be linear chain or branched chain divalent alkane Base."C1-4Alkylidene " refers to the alkylidene with 1 to 4 carbon atom.
Term " aryl " refer to single ring (phenyl) or multiple fused rings (such as naphthalene, anthryl or indanyl) 6 to The monovalent aromatic carbocyclic group of 14 carbon atoms, wherein fused rings are optional armaticity, as long as aryl and precursor structure Tie point is the atom by aromatic ring." aryl " includes the group of such as phenyl and fluorenyl as herein defined.
Term " fluoroalkyl " refers to the alkyl as defined above replaced by one or more fluoro substituents.The example of fluoroalkyl Including but not limited to: methyl fluoride, difluoromethyl, trifluoromethyl, fluoro ethyl, bis-fluoro ethyls and trifluoroethyl.
Term " heteroaryl " refer to monocycle, condensed-bicyclic or fused polycycle aromatic heterocycle (ring structure contain selected from carbon original The annular atom of son and at most four hetero atoms (being selected from nitrogen, oxygen and sulphur)), each heterocycle contains 3 to 12 annular atoms.Heteroaryl base The demonstrative example of group includes following entity (in the form of appropriate coupling part):
Term " Heterocyclylalkyl " refers to saturation or part unsaturated group, with monocycle or multi-fused rings (including condensed, bridge The loop system of company or loop coil), and there is 3-20 annular atom, including 1-10 hetero atom.These annular atoms are selected from: carbon, nitrogen, sulphur Or oxygen.In some embodiments, the nitrogen of heterocycle and/or sulphur atom are optionally aoxidized to provide N- oxide ,-S (O)-or-SO2Part.The demonstrative example of heterocyclic group includes following entity (in the form of appropriate coupling part):
Term " halogen " refers to chlorine, fluorine, bromine or iodine." halogenated " expression chloro, fluoro, bromo or the iodo of term.
Term " oxo " refers to ketonic oxygen.For example, being cyclopentanone by the cyclopenta of oxo.
Those skilled in the art will recognize that it is listed above or shown in type be not exhaustive, it is fixed that these also may be selected Other types within the scope of the term of justice.
" substituted " the expression special groups of term or part are with one or more substituent groups.Term is " unsubstituted " to be indicated Special groups are without substituent group." what is optionally replaced " indicates that special groups are unsubstituted or are replaced by one or more to term Base replaces.In term, " substituted " in the case where being used for description scheme system, replaces any chemical combination being frequently experienced in system Valence allows position.
Any formula described herein is intended to indicate that the compound and certain variants or form of the structural formula.For example, herein The formula provided is intended to include racemic form or one or more enantiomerisms, diastereo-isomerism or geometric isomer or it is mixed Close object.In addition, any formula given herein still means that the hydrate of this compound, solvate or polymorph or it is mixed Close object.
Any chemical formula given herein is also intended to the unlabelled form and isotope labelled form of representation compound. The compound of isotope labelling has gives structure described in chemical formula herein, the difference is that one or more atom quilts The atom for having selectable atomic mass or mass number replaces.Can mix the isotope of the compounds of this invention example include hydrogen, Carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine isotope, respectively for example2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F 、36Cl and125I.The compound of this kind of isotope labelling can be used for being metabolized research (it is preferable to use14C), Reaction kinetics research (make With for example2H or3H) including detection or imaging technique (such as positron emission tomography art (PET) or single photon emission calculate body Layer Imaging (SPECT)) drug or substrate tissue distribution assays or in the radiation treatment of patient.Specifically,18F Or11The compound of C flag is particularly preferred for PET or SPECT research.It can be such as Brooks, D.J., " ositron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development (the positron emission tomography art in medicine for central nervous system exploitation Tomography art is calculated with single photon emission) " NeuroRx 2005,2 (2), 226-236 and bibliography cited herein institute It states and carries out PET and SPECT research.In addition, (i.e. with heavy isotope such as deuterium2H) replace can provide because metabolic stability it is higher (such as Prolonged half-life in vivo or dose requirements reduce) and certain treatment advantages of generation.Compound isotopically labelled of the invention and Its prodrug can usually be prepared by carrying out method disclosed in following scheme or embodiment and preparation, and the method is with being easy to The isotope labeling reagent of acquisition replaces nonisotopic labels reagent.
Herein to a kind of substituent group in use, nomenclature " Ci-j" (wherein j > i) expression independently realize from i to j Each carbon atom number purpose embodiment of the present invention of (including i and j).For example, term C1-3It independently indicates to contain a carbon Atom (C1) embodiment, containing there are two carbon atom (C2) embodiment and containing there are three carbon atom (C3) embodiment.
It is mentioned in this article any disubstituted including a variety of connection possibilities, wherein allowing more than one possibility Property.For example, disubstituted-A-B- (wherein A ≠ B) indicates that A is connected to the first substitution atom and B is connected to second and takes herein For the disubstituted of atom, also illustrate that A is connected to the second substitution atom and B is connected to the disubstituted of the first substitution atom.
The invention also includes formula (I), (II), (III), (IV), (V) or (VI) compound represented or any table 1-6 The pharmaceutically acceptable salt of compound, preferably those described above and specific compound shown in this article, and including The pharmaceutical compositions of the salt, and the method using the salt.
" pharmaceutically acceptable salt " is intended to indicate that the free acid of compound illustrated herein or the salt of alkali, do not have toxicity, It can biologically tolerate or biologically be suitable for being administered to object.Usually referring to, S.M.Berge etc., " Pharmaceutical Salts (" pharmaceutical salts ") " J.Pharm.Sci., 1977,66,1-19.It is preferred pharmaceutically acceptable Salt be pharmaceutically effectively and be adapted for contact with object tissue without those of excessive toxicity, stimulation or allergic reaction.This Compound described in text can have the group of enough acidity, the group of alkalinity enough or two kinds of functional group or every type One or more of type, and therefore pharmaceutically may be used with a variety of inorganic or organic base and inorganic and organic acid reaction with being formed The salt of receiving.
The example of pharmaceutically acceptable salt includes sulfate, pyrosulfate, disulfate, sulphite, bisulfite Salt, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetic acid Salt, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalic acid Salt, malonate, succinate, suberate, sebacate, fumarate, maleate, 1,4- acetylenedicarboxylic acid salt, 1,6- Hexyndioic acid salt, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy Yl benzoic acid salt, phthalate, sulfonate, methyl sulfonate, propyl sulfonic acid salt, benzene sulfonate, xylenesulfonate, Naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt, phenyl acetate salt, phenylpropionic acid salt, phenylbutyrate, citrate, lactate, γ - Hydroxybutyric acid salt, glycollate, tartrate and mandelate.The list of other suitable pharmaceutically acceptable salts is found in Remington's Pharmaceutical Sciences (" Remington pharmaceutical science "), the 17th edition, Pennsylvania Yi Si The Mack Publishing Company (Mack Publishing Company) to pause, 1985.
The compound or any table 1- represented for the formula (I), (II), (III), (IV), (V) or (VI) containing basic nitrogen 6 compound, can prepare pharmaceutically acceptable salt by any proper method adoptable in this field, for example, using acid at Free alkali is managed, such as using inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid) or is used Organic acid (such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, amber Amber acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic, salicylic acid, oleic acid, palmitinic acid, lauric acid, pyranoside Sour (such as glucuronic acid or galacturonic acid), 'alpha '-hydroxy acids (such as mandelic acid, citric acid or tartaric acid), amino acid (such as asparagus fern Propylhomoserin or glutamic acid), aromatic acid (such as benzoic acid, Aspirin, naphthoic acid or cinnamic acid), sulfonic acid (such as dodecane Base sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid or ethanesulfonic acid)) or any compatible acid blend (as described herein in the examples) with And it is considered as other acid and its mixture of equivalent or acceptable substituent in any ordinary skill.
The invention further relates to formula (I), (II), (III), (IV), (V) or (VI) compound represented or any table 1-6 The pharmaceutically acceptable prodrug of compound, and the treatment method using the pharmaceutically acceptable prodrug.Term " prodrug " The precursor for indicating specified compound, after being administered to object its pass through in vivo chemistry or physiology course (such as solvolysis or Digestion) or generate compound (such as prodrug, which is placed under physiological pH, makes it be converted into formula compound) in physiological conditions." medicine The prodrug that acceptable prodrug on " refers to no toxicity, can biologically tolerate and biologically is suitable for being administered to object.Choosing The exemplary steps for selecting and preparing appropriate prodrug derivant are described in such as " Design of Prodrugs (" prodrug design ") ", H.Bundgaard is compiled, Ai Er Swail publishing house (Elsevier), and 1985.
The invention further relates to formula (I), (II), (III), (IV), (V) or (VI) compound represented or any table 1-6 The usage of the pharmaceutically acceptable pharmaceutical active metabolite and the metabolin of compound in the methods of the invention." drug is living Property metabolin " indicate formula (I), (II), (III), (IV), the compound that (V) or (VI) are represented or any table 1-6 compound or The pharmaceutical activity metabolite of the salt of any of the above-described compound in vivo.Known in the art or adoptable routine techniques can be used Determine the prodrug and active metabolite of compound.See, for example, Bertolini etc., J.Med.Chem.1997,40,2011- 2016；Shan etc., J.Pharm.Sci.1997,86 (7), 765-767；Bagshawe,Drug Dev.Res.1995,34,220- 230；Bodor,Adv.Drug Res.1984,13,255-331；(" prodrug is set Bundgaard, Design of Prodrugs Meter ") (Ai Er Swail publishing house (Elsevier Press), 1985)；And Larsen, Design and Application Of Prodrugs (" prodrug design and application "), Drug Design and Development (" drug design and development ") (Krogsgaard-Larsen etc. is compiled, and is breathed out Wood Academic Press Inc (Harwood Academic Publishers), 1991).
Pharmaceutical composition
For therapeutic purposes, the pharmaceutical composition including compound described herein, which may also include, one or more can pharmaceutically be connect The excipient received.The substance that pharmaceutically acceptable excipient refers to no toxicity and biologically is suitable for being administered to object.It is this kind of Excipient promotes the administration process of compound described herein and compatible with active constituent.The example of pharmaceutically acceptable excipient Including stabilizer, lubricant, surfactant, diluent, antioxidant, binder, colorant, swelling agent, emulsifier or tune Taste agent.In a preferred embodiment, pharmaceutical composition according to the present invention is aseptic composite.Those skilled in the art can be used Member is known or the complex technique preparation pharmaceutical composition that can be used.
The present invention also relates to aseptic composites, and the country and the composition of local code of the composition are determined including meeting.
According to the conventional method for being used for the preparation of a variety of dosage forms in this field, pharmaceutical composition described herein and compound can match Solution, emulsion, suspension or the dispersing agent or pill that are made as in appropriate drug solvent or carrier, tablet, pastille, suppository, Wafer, sugar-coat agent, granule, powder agent, powder agent used for reconstruction or the capsule together with solid carriers.Drug of the invention Composition can be administered by suitable route of delivery, such as oral, parenterally, rectum, nose, part or ocular route, or it is logical Cross inhalation.Preferably, the composition is formulated as administered intravenously or orally.
For oral administration, the compound of the present invention can (such as tablet or capsule) or solution, emulsion in solid form Or the form of suspension provides.To prepare Orally administered composition, the compound of the present invention can be prepared to form such as daily about 0.01 To the dosage of about 50mg/kg or daily about 0.05 to about 20mg/kg or daily about 0.1 to about 10mg/kg.Other dosage include Daily about 0.1mg to 1g, daily about 1mg to about 10mg, daily about 10mg to about 50mg, daily about 50mg to about 250mg or every Its about 250mg to 1g.Oral tablet may include and compatible pharmaceutically acceptable excipient (such as diluent, disintegrating agent, bonding Agent, lubricant, sweetener, flavoring agent, colorant and preservative) mixing active constituent.Suitable inert filler includes carbonic acid Sodium and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorb Sugar alcohol etc..Exemplary fluids oral vehicle includes ethyl alcohol, glycerol, water etc..Starch, polyvinylpyrrolidone (PVP), starch second Alkyd sodium, microcrystalline cellulose and alginic acid are exemplary disintegrating agents.Bonding agent may include starch and gelatin.If it does, lubrication Agent can be magnesium stearate, stearic acid or talcum.If desired, certain material (such as glycerin monostearate or two can be used Tristerin) coating tablet is with the absorption in delaying stomach and intestine road, or uses enteric coating peridium.
Capsule for oral administration includes hard and Perle.To prepare hard gelatin capsule, can by active constituent with Solid, semisolid or liquid diluent mixing.Perle can be by by active constituent and water, oil (such as peanut oil or olive Olive oil), atoleine, the mixture of the list of short chain fatty acids and two glyceride, polyethylene glycol 400 or mixed with propylene glycol mode Preparation.
Liquid for oral administration can be the form of suspension, solution, emulsion or syrup, or can be and face The dry products rebuild with preceding water or other suitable carriers.This kind of liquid composition is optional to include: pharmaceutically acceptable tax Shape agent, as suspending agent (such as D-sorbite, methylcellulose, mosanom, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, Aluminium stearate gel etc.)；Non-aqueous supporting agent, such as oily (such as apricot kernel oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water；It is anti- Rotten agent (such as methyl p-hydroxybenzoate or propylparaben or sorbic acid)；Wetting agent (such as lecithin)；And (such as Fruit needs) flavoring agent or colorant.
Composition of the invention can be formulated as suppository for rectally.For parenterally using (including intravenous, muscle In interior, peritonaeum, intranasal or subcutaneous route), reagent of the invention can be buffered to suitable pH with aseptic aqueous solution agent or suspension It is provided with isotonicity or in the form of parenteral acceptable oil.Suitable aqueous carrier includes Ringer's solution and isotonic Sodium chloride.This kind of form can be unit dosage form (such as ampoule or disposable injection device), multiple dose form (such as can be from The middle medicine bottle for taking out suitable dose) or solid form or the pre-concentration liquid that can be used for preparing injectable formulation.At several minutes to number In it time, the range of exemplary infusion dosage is the g/kg/ minutes reagents mixed with drug-carrier of about 1 to 1000 μ.
For intranasal, sucking or oral administration, usable for example also the spray formulation comprising suitable carrier gives this hair Bright pharmaceutical composition.
For local use, the compound of the present invention is preferably formulated as emulsifiable paste or ointment or suitable for the class of local administration Like carrier.For local administration, the compound of the present invention can be mixed with drug-carrier, concentration is the pact that drug accounts for carrier 0.1% to about 10%.Another mode for giving reagent of the invention is using patch formulation to achieve the effect that transdermal delivery.
Terms used herein " treatment " or " processing " are for obtaining beneficial or desired result (including clinical effectiveness) Method.For purposes of the present invention, beneficial or desired result includes but is not limited to: reducing the serious of disease, symptom or illness Degree or the deterioration for inhibiting disease, symptom or illness, the degree and/or prevention and illness phase of mitigation symptom and/or mitigation symptom The deterioration of the symptom of pass prevents the development of disease, symptom or illness, alleviates disease, symptom or illness, cause disease, illness or Resolution of symptoms (in terms of the severity of symptom or frequency), or stop the symptom of disease or illness.Beneficial or desired result It can also slow down, the carry out process of prevention or reverse disease or illness.For example, beneficial effect may include slowing down Parkinson's disease from morning 3) stage phase is (for example, prodromic phase or stage 1,2 or arrive the progress in late stage (for example, stage 4 or 5), or in prodromic phase Or early stage prevents Parkinson's disease.
The development expression of " delaying " disease or illness used herein is postponed, hinders, slows down, slows down, stablizes and/or is dragged Prolong the development of the disease or illness.Delay the time span that can have different, this depends on the medical history of disease and/or to be treated Individual.As it is known by the man skilled in the art, in fact, sufficiently or significantly delaying to cover prevention (described in not developing into For the individual of disease or illness).For example, the method (for example, in forerunner's individual) of " delaying " Parkinson's disease development is one Kind reduces disease within given time compared with without using this method and develops probability and/or reduce within given time The method of disease degree.
Term " object " refers to the mammalian subject for needing the treatment, such as people." object " can be people, or can be Cat, dog, ox, rat, mouse, horse or other domestic mammals.
Exemplary diseases characterized by protein aggregation include: Alzheimer's disease, Parkinson's disease, and volume temporo is silly It stays, dementia with Lewy body (lewy body disease), dull-witted Parkinson's disease, multi-system atrophy, amyotrophic lateral sclerosis and Huntington disease, and Inflammation disease, such as asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcer, pulmonary tuberculosis, rheumatoid arthritis, slowly Property nasosinusitis, hepatitis (such as hepatitis B or hepatitis C), gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriasis Arthritis, vasculitis, laryngitis, allergic reaction, multiple sclerosis, Crohn disease, traumatic brain injury, CIDP (chronic inflammation Property Demyelinating Polyneuropathy), atopic dermatitis, acne vulgaris, brandy nose, non-alcoholic fatty liver disease, non-alcoholic Steatohepatitis, corneal wound, cornea disorder, this special Graves disease (juvenile macular degeneration), age-related macular degeneration lose Mass formed by blood stasis, diabetic keratopathy wound, herpes simplex virus and antimycotic, antibacterium, antiviral and antitumor disease or illness.
In one aspect, the compound of the present invention and the selectively targeted TLR2 albumen dimer of pharmaceutical composition.Therefore, this A little compounds and pharmaceutical composition can be used for preventing, reverse, slowing down or inhibiting TLR2 protein and other native protein ligands Dimerization, and in the method for the invention for treat or as this class dimerization caused by nerve related to this dimerization And inflammatory disease.In a preferred embodiment, treatment method targeting Parkinson's disease, Alzheimer's disease, lewy body disease are more System atrophy, atopic dermatitis, traumatic brain injury or multiple sclerosis.The compound of the present invention, composition and method are also used In illeffects of the mitigation secondary to protein dimerization and/or false folding, such as Neuronal cell death.
In some respects, the compound of the present invention, composition and method are for inhibiting TLR2 dimerization.In alternative aspect, The compound of the present invention, composition and method are used to inhibit the dimerization of TLR2 and TLR1 or TLR6 or both.
In inhibition method of the invention, " effective quantity " refers to the progress or inverse that is enough to reduce, slow down TLR2 dimerization Turn the amount of TLR2 dimerization.It can be measured by amount of the conventional method of analysis as described below to dimerization.This adjusting It is useful, including external test in a variety of environment.In these methods, cell is preferably nerve cell or HEK or THP is thin Born of the same parents.
In treatment method according to the present invention, " effective quantity " refers to be controlled needed for being enough to make to need the object acquisition of this kind for the treatment of Treat the amount or dosage of benefit.The effective quantity or dosage of the compound of the present invention can by conventional method (as modeling, dosage escalation or Clinical test) determine, wherein consider conventional factors, for example, the mode or approach of administration or drug delivery, reagent medicine for power It learns, the judgement of the severity of infection and process, the health status of object, the state of an illness and weight and attending physician.Exemplary dose The range of amount is daily every Kilogram subject weight about 1ug to 2mg active agent, preferably from about 0.05 to 100mg/kg/ days or about 1 To 35mg/kg/ days or about 0.1 to 10mg/kg/ days.In other embodiments, the range of exemplary dose is about 1mg to about 1g/ days, or about 1-500,1-250,1-100,1-50,50-500 or 250-500mg/ days.Accumulated dose can be single or separated Dosage device (such as BID, TID, QID) is given.
Once the disease of patient improves, can regulating dosage be used for preventative or maintenance therapy.For example, the agent of administration Amount or frequency or both, which can change to be down to symptom, keeps the required level for treating or preventing effect.Certainly, if symptom Mitigate to proper level, can stop treating.But when any symptom recurs, patient can require the interval in long-term basis to control It treats.Patient may also need the long-term treatment on the basis of long time-histories.
Pharmaceutical composition
The compound of the present invention can join with one or more other active constituents in the treatment of neurodegenerative disease With for pharmaceutical composition or method.Other other active constituents for cancer applications include other cancer therapeutic agents or Mitigate the medicament of the adverse reaction of cancer chemotherapeutic agents.This kind of combination can be used for increasing effect, improve other diseases symptom, subtract Few one or more side effects reduce required the compounds of this invention dosage.Other active constituent can with the present inventionization It closes and is given in the separated pharmaceutical composition of object, or can be included in single drug composition together with the compounds of this invention. Other active constituent can while giving the compounds of this invention, before or after give.
Composite reagent comprising other active constituent is known to those or to be found to effectively treat as described herein Disease, obstacle, illness and symptom ingredient, including it is active to another target relevant to the disease, obstacle or symptom Those of, such as, but not limited to: the compound for a) solving protein Misfolding (such as reduces these protein to generate, improve it The drug for removing or changing its aggregation and/or propagating)；B) treat the disease symptoms compound (such as dopamine substitution treat Method)；And c) by complementary mechanisms as neuroprotective agent drug (such as target those of autophagy drug, it is anti-oxidant Those of drug and pass through those of other machining functions drug (such as adenine A2A antagonist)).
For example, composition and preparation of the invention and treatment method may also include other drugs or drug, such as Nerve caused by TLR2 dimerization is related or TLR2 dimerization or inflammatory disease (such as Parkinson's disease, A Erci are alleviated in treatment Sea silent sick (AD), lewy body disease (LBD) and multi-system atrophy (MSA) or related symptoms or illness) other activating agent.Example Such as, pharmaceutical composition of the invention may also include one or more activating agents, and treatment method may also include and give effective quantity One or more activating agents.In some embodiments, activating agent in addition can be antibiotic (such as antibacterial or antibacterial Peptide or protein matter, such as effectively antagonize those of Gram-positive or negative bacteria), fluid, cell factor, immunomodulator, Anti-inflammatory agent, complement activator are (as included collagen spline structure domain or fibrinogen spline structure domain (such as fiber gel albumen (ficolin)), the peptide or protein matter of carbohydrate binding domain etc.) and combinations thereof.Other activating agent includes for being somebody's turn to do Those of composition and method, including dopamine therapy medicine, catechol-O- transmethylase (COMT) inhibitor, monoamine Oxidase inhibitor, cognitive enhancer (such as acetylcholinesterase inhibitor or Memantine hydrochloride), adenine 2A receptor antagonist, β- Secretase inhibitors or inhibitors of gamma-secretase.In certain embodiments, at least one compound of the invention can be in drug With one or more drug combinations in composition or treatment method, the drug is selected from: Tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), galanthamine (Reminyl), eserine, neostigmine, Icopezil (Icopezil) (CP-118954,5,7- dihydro -3- [2- [l- (phenyl methyl) -4- piperidyl] ethyl] -6H- pyrrolo--[4, 5-f-]-l, 2- benzo isoxazole -6- ketone maleate), ER-127528 (4- [(the fluoro- l- indone of 5,6- dimethoxy -2-) -2- Base] methyl-l- (3- luorobenzyl) piperidine hydrochlorate), Zha Napuqi (zanapezil) (TAK-147；3- [l- (phenyl methyl) piperazine Pyridine -4- base]-l- (2,3,4,5- tetrahydro-lH-l- benzo-aza -8- base)-l- propane fumarate), Metrifonate (Metrifonate)(T-588；(-)-R-. α .- [[2- (dimethylamino) ethyoxyl] methyl] benzo [b] thiophene -5- methanol Hydrochloride), FK-960 (N- (4- acetyl-l- piperazinyl)-is to fluorobenzamide hydrate), TCH-346 (N- methyl-N-2- third Acyl biphenyl simultaneously [b, f] oxa-- 10- methylamine), SDZ-220-581 ((S)-α .- amino -5- ((phosphonomethyl))-[l, l'- connection Phenyl] -3- propionic acid), Memantine hydrochloride (Namenda/Exiba) and 1,3,3,5,5- pentamethylcyclohexane-l- amine (Neramexane), Flurbiprofen (tarenflurbil) (Flurizan), 3- amino propane sulfonic acid (tramiprosate) (Alzhemed), nioform (clioquinol), PBT-2 (8- hydroxy quinolone derivative), l- (2- (2- naphthalene) ethyl)- 4- (3- trifluoromethyl)-l, 2,3,6- tetrahydropyridine, huperzine A, posatirelin (posatirelin), Leuprorelin (leuprolide) or derivatives thereof, isopropyl Crane (ispronicline), (3- aminopropyl) (normal-butyl) phosphinic acids (SGS- 742), N- methyl -5- (3- (5- isopropoxypyrid base)) the amyl- 2- amine (ispronicline) of -4-, 1- decyl ammonium (1- Decanaminium), N- (2- hydroxyl -3- sulfopropyl)-N- methyl-N-octyl -, inner salt (zt-1), salicylate (salt), A Si Woods, A Mobilin, benorylate, choline salicylate magnesium, Diflunisal, Fa Xiaming, gaultherolin, magnesium salicylate, Shuan Shui Poplar ester, Diclofenac, Aceclofenac, acemetacin, Bromfenac, Etodolac, Indomethacin, Nabumetone, sulindac, Tuo Mei Spit of fland, brufen, Carprofen, fenbufen, fenoprofen, Flurbiprofen, Ketoprofen, ketorolac, loxoprofen, naproxen, thiophene Lip river Fragrant acid, suprofen, mefenamic acid, meclofenamic acid, bute, apazone, analgin, Oxyphenbutazone, Sulfinpyrazone, pyrrole sieve former times Health, Lornoxicam, Meloxicam, tenoxicam, celecoxib, 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl, Luo Meikao former times cloth, SC 69124, rofecoxib, Valdecoxib, aulin, aryl alkanoic acid, 2- arylpropionic acid (profens), N- aryl-anthranilic acid (fenamic acid), pyrazoles Alkane derivatives, former times health class, cox 2 inhibitor, sulfonanilide (sulphonanilides), essential fatty acid and Frankie Minoza (Minozac) (two hydrochloride hydrate of 2- (4- (4- methyl -6- phenyl pyridazine -3- base) piperazine-l- base) pyrimidine) or combinations thereof object.
Application method
The compound and pharmaceutical composition of this paper can be used to treat or prevent the disease or illness of individual.In some embodiment party In formula, the method for the treatment of disease relevant to TLR2 heterodimerization or illness is provided, including the individual giving construction to needs (I), the compound or any aforementioned of (II), (III), (IV), (V) or (VI) is represented compound or table 1,2,3,4,5 or 6 The pharmaceutically acceptable salt of compound.In some embodiments, treatment disease relevant to TLR2 heterodimerisation is provided The method of disease or illness, including give a effective amount of at least one chemical entities as described herein of subject.
In some embodiments, it provides containing one or more formulas (I), (II), (III), (IV), (V) or (VI) The combination of the pharmaceutically acceptable salt of the compound or any aforesaid compound of the compound or table 1,2,3,4,5 or 6 of representative Object, for treating disease related with TLR2 heterodimerization or illness.In some embodiments, it provides containing at least one The composition of chemical entities as described herein, for treating disease relevant to TLR2 heterodimerization or illness.
The compound or table 1,2,3,4,5 or 6 of formula (I), (II), (III), (IV), (V) or (VI) representative is also provided herein Compound or its pharmaceutically acceptable salt in preparation for treating the medicine of disease relevant to TLR2 heterodimerization or illness Purposes in object.In some embodiments, at least one chemical entities as described herein are provided to prepare for treating Purposes in the drug of disease relevant to TLR2 heterodimerization or illness.
In some embodiments, the disease or illness are selected from: Alzheimer's disease, Parkinson's disease, and volume temporo is silly Slow-witted, dementia with Lewy body (lewy body disease), Parkinson's disease is with dull-witted, multi-system atrophy, amyotrophic lateral sclerosis, Huntington disease, inflammation Property disease, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcer, pulmonary tuberculosis, rheumatoid arthritis, chronic nose Sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, blood Guan Yan, laryngitis, allergic reaction, multiple sclerosis, Crohn disease and traumatic brain injury.
The heterodimerization of TLR2 in interference cell is additionally provided, or adjusts, prevent, slow down, reverse or inhibits in cell The method of TLR2 heterodimerization, be related to making cell and a effective amount of at least one formula (I), (II), (III), (IV), (V) or (VI) compound or its pharmaceutically acceptable salt of the compound or table 1,2,3,4,5 or 6 that represent are in contact.In some implementations In mode, the heterodimerization for interfering TLR2 in cell is provided, or adjust, prevent, slow down, reverse or inhibit in cell The method of TLR2 heterodimerization is related to that cell is made to be in contact with a effective amount of at least one chemical entities as described herein.
The compound represented containing one or more formulas (I), (II), (III), (IV), (V) or (VI) is also provided herein Or the composition of the pharmaceutically acceptable salt of the compound or any aforesaid compound of table 1,2,3,4,5 or 6, for interfering The heterodimerization of TLR2 in cell, or adjust, prevent, slow down, reverse or inhibit the TLR2 heterodimerization in cell.In some realities It applies in scheme, provides the composition containing at least one chemical entities as described herein, be used to interfere TLR2 in cell Heterodimerization, or adjust, prevent, slow down, reverse or inhibit the TLR2 heterodimerization in cell.
Be also provided herein at least one chemical entities as described herein, for example, formula (I), (II), (III), (IV), (V) or (VI) represent compound table 1,2,3,4,5 or 6 compound or any aforesaid compound it is pharmaceutically acceptable Salt is preparing the heterodimerization for interfering TLR2, or the purposes TLR2 in the drug for adjusting, prevent, slow down, reversing or inhibiting Purposes in the drug of heterodimerization.
Kit
Additionally provide product and kit comprising any compound provided herein or pharmaceutical composition.Product may include Container with label.Suitable container includes such as bottle, bottle and test tube.Container can be by a variety of materials such as glass or plastics It is made.Container can accommodate pharmaceutical composition provided herein.Label on container may indicate that pharmaceutical composition for prevent, Illness as described herein is treated or inhibited, and also can indicate that the guidance used in vivo or in vitro.
In one aspect, there is provided herein the kits and operation instructions that contain compound or composition described herein. Kit may include the specification for treating disease relevant to TLR2 heterodimerization or illness in the individual of needs.Examination Agent box can be in addition (quiet containing any material or equipment that can be used for giving compound or composition, such as bottle, syringe or IV Arteries and veins injection) bag.Kit also may include aseptic packaging.
General synthetic method
The compounds of this invention can be prepared by many methods of following general description, more specifically, can be below Embodiment in prepare (such as the scheme provided in following example).In following procedure description, when in discribed general formula In in use, symbol should be understood to mean above with respect to this paper general formula description those of group.
When needing to obtain the specific enantiomeric of compound, any conjunction for separating or splitting enantiomer is can be used in this Suitable conventional method is completed from corresponding mixture of enantiomers.Thus, for example, diastereoisomer derivative can be by right The reaction of body mixture (such as racemic modification) and suitable chipal compounds is reflected to prepare.It may then pass through any convenient Method separates diastereoisomer, such as by crystallizing and recycling required enantiomter.It, can in another method for splitting To use chiral hplc to separate racemate.Or, if it is desired, it can be by making in one of the method Specific enantiomter is obtained with suitable chiral intermediate.
If necessary to obtain the specific isomers of compound or in other ways purify reaction product, chromatography, recrystallization It can also be used together with intermediate or final product with other conventional separation methods.
Also contemplate the solvate or its pharmaceutically acceptable salt of compound provided herein.Containing of solvate Metering or non-stoichiometric solvent are learned, and is usually formed in crystallization process.Hydrate is formed when solvent is water, or is worked as Alcohol adduct is formed when solvent is alcohol.
In some embodiments, the compound of formula (I) can be synthesized according to scheme 1.
Scheme 1
Wherein R1、R2、R3a、R3b、R4、R5、R6, m, n and p such as formula (I) or its any variant as described herein definition；PG It is blocking group, X is halogen.
In some embodiments, the compound of formula (II) can be synthesized according to scheme 2.
Scheme 2
Wherein R21、R22、R24、R25、R26, n2 and p2 such as formula (II) or its any variant as described herein definition；PG is Blocking group, X are halogens.
In some embodiments, the compound of formula (III) can be synthesized according to scheme 3.
Scheme 3
Wherein R31、R32、R33、R34And R35Such as the definition of formula (III) or its any variant as described herein.
In some embodiments, the compound of formula (IV) can be synthesized according to scheme 4.
Scheme 4
Wherein R41、R41’、R42、R43、R44And G1Such as the definition of formula (IV) or its any variant as described herein.
In some embodiments, the compound of formula (V) can be synthesized according to scheme 5.
Scheme 5
Wherein R51、R52、R53、R54、R55、G2、G3, o, r and s such as formula (V) or its any variant as described herein definition； And R56It is H or OH.
In some embodiments, the compound of formula (VI) can be synthesized according to scheme 6.
Scheme 6
Wherein R61、R62、R63、R64、R65、R66、R67With the definition of t such as formula (VI) or its any variant as described herein.
Chemical synthesis
It can be used for the Exemplary chemical entity of the method for the present invention referring now to following specific embodiment description.This field Technical staff should be understood that obtain multiple compounds herein, can suitably be selected starting material, thus by suitable The reaction scheme of local with or without protection is using final required substituent group to generate required product.Alternatively, may It needs or wants the use on final required substituting group position to carry by reaction scheme and can be taken by required in due course For the proper group of base substitution.In addition, those skilled in the art will appreciate that the conversion shown in following scheme can arbitrarily with The compatible sequence of specific side group function carries out.It is respectively reacted described in general scheme preferably at about 0 DEG C to organic solvent used Reflux temperature under carry out.The compound of isotope labelling described herein is prepared according to process described below, uses appropriate label Starting material.This kind of material can usually be bought from the market supply quotient of the chemical reagent of radio-labeled.
Embodiment
Following embodiment is for explanation but the unrestricted present invention.Those skilled in the art will appreciate that can be suitable by selecting Starting material and reagent modify following synthetic reaction and scheme to obtain formula (I), (II), (III), (IV), (V) or (VI) Other compounds.Use above-mentioned conventional method prepare compound.
Embodiment 1:((2S) -3- (4- (benzyloxy) phenyl) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- Oxo propyl- 2- yl) t-butyl carbamate
Bis- (tetradecyloxyaniline) propyl of step 1:(2,3-) t-butyl carbamate.In 50mL sealing cover vial, Successively use 1- bromo-tetradecane (10.71mL, 36mmol), sodium hydroxide (50% aqueous solution；6.0mL) and 4-butyl ammonium hydrogen sulfate (1.02g, 3.0mmol) handles (2,3- dihydroxypropyl) t-butyl carbamate (1.15g, 6.0mmol) at toluene (6.0mL) In mixture.Bottle is sealed and heats simultaneously vigorous stirring overnight at 65 DEG C.Mixture is cooled to room temperature (rt) to be used in combination Toluene (2 × 25mL) extraction.Combined organic layer is washed with water, with sodium sulphate drying and is evaporated.Gained colourless liquid is led to Cross silica gel column chromatography (hexane-ethylacetate (0-25%)) purifying, obtain title compound, be colourless liquid (1.52g, 44% yield).1H NMR (500MHz, chloroform-d) δ 4.88 (s, 1H), 3.57 (dt, J=9.3,6.7Hz, 1H), 3.52-3.29 (m, 7H), 3.17 (dt, J=12.1,5.7Hz, 1H), 1.63-1.48 (m, 5H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C36H73NO4Theoretical value 585；Measured value 585.
Bis- (tetradecyloxyaniline) propane -1- amine of step 2:2,3-.By (bis- (tetradecyloxyaniline) propyl of 2,3-) carbamic acid The tert-butyl ester (1.50g, 2.57mmol) is dissolved in tetrahydrofuran (10mL), and with HCl processing, (4N is in dioxanes；10mL), institute Mixture is obtained to be stirred at room temperature 5 hours.Mixture is concentrated, is then concentrated again twice with 1:1 dichloromethane-ether.It will obtain Solid freeze-drying, obtain title compound, be white powder (100% yield).1HNMR (500MHz, chloroform-d) δ 8.29 (s, 3H),4.00–3.63(m,2H),3.63–3.27(m,7H),3.24(s,1H),3.11(s,1H),1.75–1.43(m,4H), 1.26 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C31H65NO2Theoretical value 485；Measured value 485.
Step 3: in 30mL sealing cover vial, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates of 2,3- (260mg, It 0.5mmol) is suspended in 1:2 sodium bicarbonate/dioxanes saturated aqueous solution (21mL), with Boc-L-Tyr (O-Bn)-OSu (234mg, 0.5mmol) processing, and obtained mixture is stirred at room temperature overnight.Mixture water and salt water are diluted, And it is extracted with ethyl acetate (2 × 25mL).Combined organic layer is dry with sodium sulphate, and evaporate.By residue silicagel column It purifies (hexane-ethylacetate (0-100%)), obtains the title compound (205mg, 49% yield) of white solid.1H NMR (500MHz, chloroform-d) δ 7.39 (dt, J=14.8,7.6Hz, 4H), 7.32 (t, J=7.1Hz, 1H), 7.18-7.06 (m, 2H), 6.90 (d, J=8.4Hz, 2H), 6.12 (d, J=21.0Hz, 1H), 5.03 (d, J=2.0Hz, 2H), 4.25 (s, 1H), 3.47 (tdd, J=10.9,6.6,3.3Hz, 2H), 3.43-3.27 (m, 6H), 3.23 (dt, J=12.8,5.6Hz, 1H), 2.98 (q, J=12.9,12.0Hz, 2H), 1.50 (dq, J=14.7,6.7Hz, 4H), 1.41 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C52H88N2O6, theoretical value 860；Measured value 860.
Embodiment 2:(2S) -2- amino -3- (4- (benzyloxy) phenyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionyl Amine hydrochlorate
According to 1 step 2 of embodiment, by ((2S) -3- (4- (benzyloxy) phenyl) -1- ((2,3- bis- (tetradecyloxyanilines) third Base) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (167.5mg, 0.2mmol) prepares title compound, it obtains greyish white Color solid (150mg, 100% yield).1H NMR(500MHz,DMSO-d6) δ 8.35 (dt, J=11.5,5.8Hz, 1H), 8.17 (s, 3H), 7.53-7.24 (m, 6H), 7.15 (d, J=8.2Hz, 2H), 7.03-6.87 (m, 2H), 5.06 (d, J=3.0Hz, 2H), 3.95 (t, J=7.1Hz, 1H), 3.81-3.68 (m, 1H), 3.69-3.59 (m, 1H), 3.44 (t, J=6.5Hz, 1H), 3.32 (m, 3H), 3.13 (dd, J=10.6,5.9Hz, 1H), 3.04 (dt, J=13.5,5.2Hz, 1H), 2.94 (tt, J= 13.0,6.9Hz, 2H), 2.01-1.67 (m, 1H), 1.44 (dq, J=12.0,6.5Hz, 4H), 1.34-1.06 (m, 44H), 0.85 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C47H80N2O4, theoretical value 738；Measured value 738.
Embodiment 3:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxygen For propyl- 2- yl) t-butyl carbamate
According to 1 step 3 of embodiment, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and live The Boc-L-Trp-OSu (201mg, 0.5mmol) of change prepares title compound, obtains colloidal solid (265mg, 69% yield).1H NMR (500MHz, chloroform-d) δ 8.05 (s, 1H), 7.66 (dd, J=8.0,3.9Hz, 1H), 7.34 (dd, J=8.2, 1.8Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.12 (t, J=7.5Hz, 1H), 7.06 (d, J=2.3Hz, 1H), 6.06 (d, J=25.0Hz, 1H), 5.13 (s, 1H), 4.41 (s, 1H), 3.39 (dt, J=9.3,6.7Hz, 2H), 3.34-3.20 (m, 5H), 3.16 (dd, J=14.1,8.2Hz, 3H), 1.66-1.45 (m, 4H), 1.42 (s, 9H), 1.25 (s, 44H), 0.88 (t, J= 6.8Hz,6H)；ESI-MS m/z[M+H]+C47H83N3O5, theoretical value 771；Measured value 771.
Embodiment 4:(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- indol-3-yl) propionamide Hydrochloride
According to embodiment 1, by ((2S) -1- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -3- (1H- indoles - 3- yl) -1- oxo propyl- 2- yl) t-butyl carbamate (154mg, 0.2mmol) prepares title compound, obtain colloidal solid (100% yield).1H NMR(500MHz,DMSO-d6) δ 11.02 (s, 1H), 8.49 (t, J=6.0Hz, 1H), 8.23-8.04 (m, 3H), 7.65 (d, J=7.9Hz, 1H), 7.35 (d, J=8.1Hz, 1H), 7.20 (d, J=2.2Hz, 1H), 7.08 (ddd, J =8.1,6.9,1.1Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 3.98 (d, J=6.5Hz, 1H), 3.78-3.50 (m, 6H), 3.48-3.36 (m, 2H), 3.24-2.96 (m, 3H), 1.54-1.31 (m, 4H), 1.34-1.12 (m, 44H), 0.85 (t, J= 6.8Hz,6H)；ESI-MS m/z[M+H]+C42H75N3O3, theoretical value 671；Measured value 671.
Embodiment 5:(2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidines -1- carboxylic acid tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-L-Pro-OSu (156mg, 0.5mmol) prepares title compound, obtains colourless liquid (252mg, 74% yield).1H NMR (500MHz, chloroform-d) δ 4.39-4.12 (d, 1H), 3.56 (m, 1H), 3.52-3.35 (m, 7H), 3.32 (s, 1H), 2.08 (t, J=19.9Hz, 2H), 1.99-1.78 (m, 2H), 1.67-1.50 (m, 6H), 1.45 (s, 11H), 1.25 (s, 42H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+Na]+C41H80N2O5, theoretical value 704；Measured value 704.
Embodiment 6:(2S)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- carboxamide hydrochloride
According to embodiment 1, by (2S) -2- ((2,3- bis- (tetradecyloxyaniline) propyl) carbamyl) pyrrolidines -1- Carboxylic acid tert-butyl ester (136.2mg, 0.2mmol) prepares title compound, obtains white solid (100% yield).1H NMR (500MHz,DMSO-d6) δ 9.26 (s, 1H), 8.46 (s, 1H), 4.14 (dd, J=10.2,3.9Hz, 1H), 3.79-3.69 (m, 3H),3.68–3.57(m,2H),3.56–3.34(m,4H),3.28–3.14(m,2H),1.93–1.80(m,3H),1.53–1.39 (m, 4H), 1.24 (s, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C36H72N2O3, theoretical value 582；It is real Measured value 582.
Embodiment 7:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (4- hydroxy phenyl) -1- oxo Propyl- 2- yl) t-butyl carbamate
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc (tertbutyloxycarbonyl)-L-Tyr-OSu (189mg, 0.5mmol) prepares title compound, obtain white solid (163mg, 44% yield).1H NMR (500MHz, chloroform-d) δ 7.10-7.00 (m, 2H), 6.80-6.65 (m, 2H), 6.16 (d, J= 18.5Hz, 1H), 5.25 (s, 1H), 5.01 (s, 1H), 4.25 (s, 1H), 3.56-3.28 (m, 8H), 3.23 (d, J=14.3Hz, 1H), 2.97 (s, 2H), 1.51 (dp, J=13.8,7.0,6.6Hz, 4H), 1.41 (s, 9H), 1.25 (s, 44H), 0.88 (t, J =6.9Hz, 6H)；ESI-MS m/z[M+H]+C45H82N2O6, theoretical value 748；Measured value 748.
Embodiment 8:(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (4- hydroxy phenyl) propionyl amine salt Hydrochlorate
According to embodiment 1, by ((2S) -1- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -3- (4- hydroxy benzenes Base) -1- oxo propyl- 2- yl) t-butyl carbamate (149.5mg, 0.2mmol) prepares title compound, obtain white solid (100% yield).1H NMR(500MHz,DMSO-d6) δ 9.35 (s, 1H), 8.39 (dt, J=11.2,5.4Hz, 1H), 8.15 (s, 3H), 7.15-6.90 (m, 2H), 6.81-6.53 (m, 2H), 3.91 (t, J=6.8Hz, 1H), 3.45 (t, J=6.5Hz, 1H), 3.40-3.11 (m, 7H), 3.06 (dt, J=13.6,5.4Hz, 1H), 2.91 (m, J=7.4,7.0Hz, 1H), 2.85 (ddd, J=13.8,7.1,3.7Hz, 1H), 1.54-1.36 (m, 4H), 1.23 (d, J=3.1Hz, 44H), 0.85 (t, J= 6.8Hz,6H)；ESI-MS m/z[M+H]+C40H74N2O4, theoretical value 648；Measured value 648.
Embodiment 9: tert-butyl ((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- bis- Base) diamino acid (9H- fluorenes -9- base) methyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Nα-Fmoc-Nε- Boc-L-Lys-OSu (283mg, 0.5mmol) prepares title compound, and obtaining white solid, (152mg, 33% produces Rate).1H NMR (500MHz, chloroform-d) δ 7.76 (d, J=7.6Hz, 2H), 7.59 (d, J=7.4Hz, 2H), 7.40 (t, J= 7.5Hz, 2H), 7.31 (t, J=7.5Hz, 2H), 6.33 (s, 1H), 5.49 (s, 1H), 4.59 (s, 1H), 4.43-4.31 (m, 2H), 4.21 (t, J=7.0Hz, 1H), 4.11 (d, J=6.9Hz, 1H), 3.69-3.23 (m, 9H), 3.19-2.95 (m, 2H), 1.85 (s, 1H), 1.61 (s, 2H), 1.52 (dq, J=14.0,6.4,5.7Hz, 4H), 1.43 (s, 9H), 1.25 (q, J=6.8, 5.5Hz, 47H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C57H95N3O7, theoretical value 935；Measured value 935.
Embodiment 10:((2S) -6- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo hex- 2- yl) Carbamic acid (9H- fluorenes -9- base) methyl ester hydrochloride
According to embodiment 1, by tert-butyl ((5S) -6- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -6- oxo Hex- 1,5- diyl) diamino acid (9H- fluorenes -9- base) methyl ester (94mg, 0.1mmol) prepares title compound, obtain white Solid (100% yield).1H NMR(500MHz,DMSO-d6) δ 7.89 (d, J=7.5Hz, 2H), 7.84-7.74 (m, 4H), 7.71 (t, J=7.8Hz, 2H), 7.50 (dd, J=8.4,3.6Hz, 1H), 7.41 (t, J=7.4Hz, 2H), 7.32 (t, J= 7.4Hz, 2H), 4.32-4.12 (m, 3H), 3.95 (tt, J=9.3,5.3Hz, 1H), 3.42 (qd, J=6.9,2.9Hz, 3H), 3.34 (s, 4H), 3.11 (ddt, J=34.7,13.1,6.5Hz, 2H), 2.74 (s, 2H), 1.61 (d, J=9.6Hz, 1H), 1.57-1.47 (m, 3H), 1.46-1.34 (m, 4H), 1.21 (s, J=4.8Hz, 46H), 0.84 (t, J=6.9Hz, 6H)；ESI- MS m/z[M+H]+C52H87N3O5, theoretical value 835；Measured value 835.
Embodiment 11:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxygen For propyl- 2- yl) carbamic acid (9H- fluorenes -9- base) methyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Fmoc-L-Trp-OSu (262mg, 0.5mmol) prepares title compound, obtains white solid (185mg, 42% yield).1H NMR (500MHz, chloroform-d) δ 8.05 (d, J=3.0Hz, 1H), 7.76 (d, J=7.6Hz, 2H), 7.70 (s, 1H), 7.55 (t, J=8.2Hz, 2H), 7.45-7.33 (m, 3H), 7.30 (td, J=7.5,3.1Hz, 2H), 7.17 (dt, J=30.1,7.5Hz, 2H), 7.08-7.00 (m, 1H), 5.99 (d, J=22.3Hz, 1H), 5.52 (s, 1H), 4.54-4.27 (m, 3H), 4.20 (t, J =7.1Hz, 1H), 3.51-3.21 (m, 6H), 3.21-3.07 (m, 3H), 1.46 (q, J=6.7Hz, 2H), 1.37 (q, J= 7.0Hz, 2H), 1.33-1.06 (m, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C57H85N3O5, theoretical Value 915；Measured value 915.
Embodiment 12:((2R) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxygen For propyl- 2- yl) t-butyl carbamate
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-D-Trp-OSu (262mg, 0.5mmol) prepares title compound, obtains white solid (175mg, 46% yield).1H NMR (500MHz, chloroform-d) δ 8.06 (s, 1H), 7.66 (dd, J=8.0,3.9Hz, 1H), 7.34 (dd, J=8.2,1.9Hz, 1H), 7.23-7.16 (m, 1H), 7.12 (t, J=7.4Hz, 1H), 7.06 (d, J=2.3Hz, 1H), 6.06 (d, J=24.9Hz, 1H), 5.13 (s, 1H), 4.41 (s, 1H), 3.47-3.04 (m, 11H), 1.48 (q, J=6.6Hz, 2H), 1.42 (s, 11H), 1.26 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C47H83N3O5, theoretical value 771；Measured value 771.
Embodiment 13:(2R) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- indol-3-yl) propionyl Amine hydrochlorate
According to embodiment 1, by ((2R) -1- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -3- (1H- indoles - 3- yl) -1- oxo propyl- 2- yl) t-butyl carbamate (154mg, 0.2mmol) prepares title compound, obtain colloidal solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.42 (s, 3H), 8.01 (s, 1H), 7.26 (s, 3H), 7.17-6.71 (m, 2H), 4.55-4.04 (m, 1H), 3.33 (s, 11H), 1.45 (d, J=20.1Hz, 4H), 1.24 (t, J=6.9Hz, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C42H75N3O3, theoretical value 671；Measured value 671.
Embodiment 14:(4S) -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -4- ((tert-butoxycarbonyl) ammonia Base) -5- oxopentanoate
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260 mg, 0.5mmol) of 2,3- and Boc-L-Glu (OtBu)-OSu (200 mg, 0.5 mmol) prepares title compound, and obtaining white solid, (230 mg, 60% produces Rate).1H NMR (500 MHz, chloroform-d) δ 6.51 (t, J=5.4 Hz, 1H), 5.26 (s, 1H), 4.09 (s, 1H), 3.62- 3.21 (m, 9H), 2.39 (dtd, J=16.7,7.3,2.6 Hz, 1H), 2.28 (dt, J=16.5,7.0 Hz, 1H), 2.08 (dtd, J=14.1,7.1,4.9 Hz, 1H), 1.96-1.78 (m, 1H), 1.56 (d, J=8.2 Hz, 4H), 1.44 (d, J= 6.8 Hz, 18H), 1.26 (s, 44H), 0.88 (t, J=6.9 Hz, 6H)；ESI-MS m/z[M+Na]+C45H88N2O7, theoretical value 792；Measured value 792.
Embodiment 15:(4S) -4- amino -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- oxopentanoic acid hydrochloric acid Salt
According to embodiment 1, by (4S) -5- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -4- ((tert-butoxy Carbonyl) amino) -5- oxopentanoate (154 mg, 0.2 mmol) prepares title compound, obtain white solid (100% Yield).1H NMR (500 MHz, chloroform-d) δ 8.48-7.93 (m, 4H), 4.01-3.13 (m, 9H), 2.65 (s, 2H), 1.87 (dddd, J=18.6,15.0,10.6,5.6 Hz, 2H), 1.72 (ddd, J=14.6,10.8,6.4 Hz, 1H), 1.54 (s, 4H), 1.25 (s, 44H), 0.88 (t, J=6.8 Hz, 6H)；ESI-MS m/z[M+H]+C36H72N2O5, theoretical value 614；Actual measurement Value 614.
Embodiment 16:(2R) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidines -1- carboxylic acid tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-D-Pro-OSu (156mg, 0.5mmol) prepares title compound, obtains white solid (275mg, 81% yield).1H NMR (500MHz, chloroform-d) δ 4.45-4.10 (m, 1H), 3.67-3.16 (m, 12H), 2.47-2.00 (m, 2H), 1.86 (s, 2H), 1.54 (q, J=6.9Hz, 4H), 1.46 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z [M+H]+C41H80N2O5, theoretical value 682；Measured value 682.
Embodiment 17:(2R)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- carboxamide hydrochloride
According to embodiment 1, by (2R) -2- ((2,3- bis- (tetradecyloxyaniline) propyl) carbamyl) pyrrolidines -1- Carboxylic acid tert-butyl ester (204mg, 0.3mmol) prepares title compound, obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 11.37 (s, 1H), 7.62 (d, J=97.3Hz, 2H), 3.94-3.21 (m, 11H), 2.63-2.42 (m, 1H), 2.22-1.95 (m, 2H), 1.95-1.61 (m, 2H), 1.62-1.45 (m, 4H), 1.25 (s, 44H), 0.87 (t, J= 6.8Hz,6H)；ESI-MS m/z[M+H]+C36H72N2O3, theoretical value 582；Measured value 582.
Embodiment 18:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((4- aminomethyl phenyl) sulfonamido) acetamide
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and first Benzenesulfonyl-Gly-OSu (163mg, 0.5mmol) prepares title compound, obtains white solid (115mg, 33% yield).1H NMR (500MHz, chloroform-d) δ 7.87-7.68 (m, 2H), 7.31 (d, J=8.0Hz, 2H), 6.50 (t, J=5.6Hz, 1H), 5.14 (t, J=5.9Hz, 1H), 3.66-3.13 (m, 11H), 2.43 (s, 3H), 1.56 (tt, J=11.3,7.1Hz, 4H), 1.26 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C40H74N2O5S, theoretical value 718；Measured value 718。
Embodiment 19:4- ((2S) -3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -2- ((tert-butoxycarbonyl) ammonia Base) -3- oxopropyl) -1H- imidazoles -1- carboxylic acid tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-L-His (Boc)-OSu (226mg, 0.5mmol) prepares title compound, obtains white solid (245mg, 60% yield).1H NMR (500MHz, chloroform-d) δ 8.01 (t, J=1.7Hz, 1H), 7.17 (d, J=1.9Hz, 1H), 6.89 (s, 1H), 6.11 (s, 1H), 4.43 (s, 1H), 3.61-3.15 (m, 9H), 3.09 (s, 1H), 2.94 (dd, J=14.9,5.5Hz, 1H), 1.60 (s, 9H), 1.53 (q, J=7.1Hz, 4H), 1.44 (s, 9H), 1.34-1.16 (m, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI- MS m/z[M+Na]+C47H88N4O7, theoretical value 844；Measured value 844.
Embodiment 20:(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- imidazol-4 yl) propionyl Amine dihydrochloride
According to embodiment 1, by 4- ((2S) -3- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -2- ((tertiary fourth oxygen Base carbonyl) amino) -3- oxopropyl) -1H- imidazoles -1- carboxylic acid tert-butyl ester (164mg, 0.2mmol) prepares title compound, it obtains To white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.89 (s, 1H), 8.21 (s, 4H), 7.62 (s, 1H), (4.70 d, J=41.4Hz, 1H), 3.87-3.18 (m, 9H), 2.61-2.15 (m, 2H), 1.72-1.45 (m, 4H), 1.24 (d, J =7.3Hz, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C37H72N4O3, theoretical value 622；Measured value 622。
Embodiment 21:(3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- oxopropyl) t-butyl carbamate
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc- β-Ala-OSu (143mg, 0.5mmol) prepares title compound, obtains white solid (255mg, 78% yield).1H NMR (500MHz, chloroform-d) δ 5.97 (t, J=5.6Hz, 1H), 5.21 (s, 1H), 3.68-3.35 (m, 10H), 3.30 (dt, J =13.7,5.2Hz, 1H), 2.37 (t, J=6.0Hz, 2H), 1.63-1.47 (m, 4H), 1.43 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C39H78N2O5, theoretical value 678；Measured value 678.
Embodiment 22:3- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide hydrochloride
According to embodiment 1, by (3- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -3- oxopropyl) amino first Tert-butyl acrylate (196.5mg, 0.3mmol) prepares title compound, obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.43 (s, 3H), 6.54 (s, 1H), 3.60-3.19 (m, 11H), 2.76 (s, 2H), 1.96 (s, 2H), (1.55 t, J=6.6Hz, 4H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+Theoretical value C34H70N2O3,556；Measured value 556.
Embodiment 23:(3S) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- ((tert-butoxycarbonyl) ammonia Base) -4- ketobutyric acid the tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-L-Asp (OtBu)-OSu (193mg, 0.5mmol) prepares title compound, and obtaining white solid, (160mg, 42% produces Rate).1H NMR (500MHz, chloroform-d) δ 6.79 (q, J=5.2Hz, 1H), 5.63 (d, J=8.6Hz, 1H), 4.43 (s, 1H), 3.63-3.21 (m, 9H), 2.89 (dd, J=16.9,4.7Hz, 1H), 2.59 (dd, J=16.9,6.1Hz, 1H), 1.56 (td, J =14.2,12.7,5.7Hz, 4H), 1.44 (d, J=5.1Hz, 18H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)； ESI-MS m/z[M+Na]+C44H86N2O7, theoretical value 778；Measured value 778.
Embodiment 24:(3S) -3- amino -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -4- ketobutyric acid hydrochloric acid Salt
According to embodiment 1, by (3S) -4- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -3- ((tert-butoxy Carbonyl) amino) -4- ketobutyric acid the tert-butyl ester (151mg, 0.2mmol) prepares title compound, and obtaining white solid, (100% produces Rate).1H NMR (499MHz, chloroform-d) δ 8.09 (d, J=111.7Hz, 4H), 3.92-3.20 (m, 10H), 3.08 (s, 2H), 1.55 (s, 4H), 1.26 (s, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C35H70N2O5, theoretical value 600；Measured value 600.
Embodiment 25:(2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -2- oxoethyl) (methyl) carbamic acid The tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-Sar-OSu (Sar=N- methylglycine；143mg, 0.5mmol) title compound is prepared, obtain white solid (220mg, 67% yield).1H NMR (500MHz, chloroform-d) δ 6.41 (s, 1H), 3.87 (s, 2H), 3.66-3.20 (m, 9H), 2.92 (s, 3H), 1.55 (td, J=7.2,3.7Hz, 4H), 1.46 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C39H78N2O5, theoretical value 678；Measured value 678.
Embodiment 26:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (methylamino) acetamide hydrochloride
According to embodiment 1, by (2- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -2- oxoethyl) (methyl) T-butyl carbamate (196.5mg, 0.3mmol) prepares title compound, obtains white solid (100% yield).1H NMR (499MHz, chloroform-d) δ 9.42 (s, 2H), 7.45 (d, J=12.9Hz, 1H), 3.88 (s, 2H), 3.72-3.19 (m, 9H), 2.82 (s, 3H), 1.54 (q, J=6.8Hz, 4H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+ H]+C34H70N2O3, theoretical value 556；Measured value 556.
Embodiment 27:(3S) -3- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -4- ((bis- (tetradecane oxygen of 2,3- Base) propyl) amino) -4- ketobutyric acid the tert-butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Fmoc-L-Asp (OtBu)-OSu (254mg, 0.5mmol) prepares title compound, and obtaining white solid, (280mg, 64% produces Rate).1H NMR (499MHz, chloroform-d) δ 7.76 (d, J=7.6Hz, 2H), 7.58 (d, J=7.5Hz, 2H), 7.40 (t, J= 7.5Hz, 2H), 7.31 (t, J=7.5Hz, 2H), 6.89-6.64 (m, 1H), 5.96 (d, J=8.4Hz, 1H), 4.50 (s, 1H), 4.40 (tt, J=18.4,9.0Hz, 2H), 4.22 (t, J=7.2Hz, 1H), 3.62-3.22 (m, 9H), 2.92 (dd, J= 17.0,4.4Hz 1H), 2.61 (dd, J=17.1,6.6Hz, 1H), 1.67-1.49 (m, 4H), 1.45 (s, 9H), 1.25 (q, J =7.3,5.2Hz, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C54H88N2O7, theoretical value 878；Actual measurement Value 878.
Embodiment 28:(3S) -3- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -4- ((bis- (tetradecane oxygen of 2,3- Base) propyl) amino) -4- ketobutyric acid
According to embodiment 1, by (3S) -3- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino), ((2,3- is bis- by -4- (tetradecyloxyaniline) propyl) amino) -4- ketobutyric acid the tert-butyl ester (175.4mg, 0.2mmol) prepares title compound, obtain ash White solid (100% yield).1H NMR (499MHz, chloroform-d) δ 7.76 (dd, J=7.6,3.0Hz, 2H), 7.58 (d, J= 7.3Hz 2H), 7.40 (td, J=7.5,2.5Hz, 2H), 7.31 (td, J=7.5,2.4Hz, 2H), 6.85 (dd, J=38.1, 6.0Hz, 1H), 5.96 (d, J=8.9Hz, 1H), 4.66-4.28 (m, 3H), 4.21 (q, J=7.1Hz, 1H), 3.77 (q, J= 4.7,3.8Hz, 2H), 3.64 (dt, J=7.4,5.0Hz, 2H), 3.58-3.19 (m, 6H), 3.15-2.81 (m, 1H), 2.82- 2.48 (m, 1H), 1.53 (p, J=6.7Hz, 4H), 1.38-1.11 (m, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/ z[M-H]+C50H80N2O7, theoretical value 820；Measured value 820.
Embodiment 29:(4S) -4- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -5- ((bis- (tetradecane oxygen of 2,3- Base) propyl) amino) -5- oxopentanoate
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Fmoc-L-Glu (OtBu)-OSu (261mg, 0.5mmol) prepares title compound, and obtaining white solid, (265mg, 60% produces Rate).1H NMR (499MHz, chloroform-d) δ 7.76 (d, J=7.5Hz, 2H), 7.59 (d, J=7.5Hz, 2H), 7.40 (t, J= 7.5Hz, 2H), 7.31 (t, J=7.4Hz, 2H), 6.54 (s, 1H), 5.74 (s, 1H), 4.52-4.27 (m, 2H), 4.21 (t, J =7.2Hz, 2H), 3.71-3.13 (m, 9H), 2.43 (d, J=16.7Hz, 1H), 2.35-2.19 (m, 1H), 2.09 (dd, J= 14.3,7.0Hz, 1H), 1.93 (dd, J=14.7,7.4Hz, 1H), 1.65-1.49 (m, 4H), 1.46 (s, 9H), 1.25 (q, J =7.5,5.7Hz, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C55H90N2O7, theoretical value 914；Actual measurement Value 914.
Embodiment 30:(4S) -4- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -5- ((bis- (tetradecane oxygen of 2,3- Base) propyl) amino) -5- oxopentanoic acid
According to embodiment 1, by (4S) -4- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino), ((2,3- is bis- by -5- (tetradecyloxyaniline) propyl) amino) -5- oxopentanoate (178mg, 0.2mmol) prepares title compound, it obtains greyish white Color solid (100% yield).1H NMR (500MHz, chloroform-d) δ 7.75 (t, J=6.3Hz, 2H), 7.59 (t, J=7.3Hz, 2H), 7.39 (t, J=7.1Hz, 2H), 7.34-7.27 (m, 2H), 6.76 (s, 1H), 5.82 (d, J=8.3Hz, 1H), 4.47- 4.24 (m, 3H), 4.20 (q, J=7.1Hz, 1H), 3.59-3.16 (m, 9H), 2.59-2.46 (m, 1H), 2.45-2.28 (m, 1H), 2.14 (s, 1H), 2.05-1.82 (m, 1H), 1.52 (h, J=6.5Hz, 4H), 1.24 (q, J=6.7,5.4Hz, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C51H82N2O7, theoretical value 858；Measured value 858.
Embodiment 31:((5R) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- diyl) two Carbamic acid benzyl tertiary butyl ester
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Nα- Z-Nε- Boc-D-Lys-OSu (237mg, 0.5mmol) prepares title compound, obtains white solid (280mg, 66% yield).1H NMR (499MHz, chloroform-d) δ 7.44-7.29 (m, 5H), 6.36 (d, J=6.7Hz, 1H), 5.43 (s, 1H), 5.10 (d, J =3.5Hz, 2H), 4.57 (s, 1H), 4.11 (d, J=6.9Hz, 1H), 3.65-3.18 (m, 9H), 3.09 (d, J=7.0Hz, 2H), 1.97-1.74 (m, 1H), 1.73-1.59 (m, 2H), 1.54 (q, J=6.7Hz, 4H), 1.50-1.31 (m, 3H), 1.42 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C50H91N3O7, theoretical value 869；It is real Measured value 869.
Embodiment 32:((2R) -6- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo hex- 2- yl) Carbamic acid benzyl ester hydrochloride
According to embodiment 1, by ((5R) -6- ((2,3- bis- (tetradecyloxyaniline) propyl) amino) -6- oxo hex- 1, 5- diyl) diamino acid benzyl tertiary butyl ester (169mg, 0.2mmol) prepares title compound, obtain white solid (100% Yield).1H NMR (500MHz, chloroform-d) δ 8.21 (s, 3H), 7.41-7.29 (m, 5H), 7.17 (s, 1H), 6.09 (s, 1H), 5.07(s,2H),4.24(s,1H),3.59–3.20(m,9H),2.93(m,2H),2.15(s,3H),1.74(m,3H),1.53 (t, J=6.8Hz, 4H), 1.24 (d, J=3.5Hz, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+ C45H83N3O5, theoretical value 747；Measured value 747.
Embodiment 33:((2R) -3- ([1,1 '-xenyl] -4- base) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) ammonia Base) -1- oxo propyl- 2- yl) t-butyl carbamate
In 30mL sealing cover vial, with HATU (2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea Hexafluorophosphate) (285mg, 0.75mmol) and diisopropylethylamine (174 μ L, 1.0mmol) processing Boc-4-Phe-D- phenyl- Solution of the Ala-OH (171mg, 0.5mmol) in DMF (5mL).It is stirred at room temperature after five minutes, 2 is added into reaction flask, Bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 3-, close the lid, and stirring continues 5 hours at room temperature. Mixture water (10mL) and salt water (10mL) are diluted, extracted with ethyl acetate (2 × 25mL), and combined organic layer is used Sodium sulphate is dried and concentrated.Residue purifies (hexane-ethylacetate (0-100%)) on a silica gel column, obtains title compound, For white solid (172mg, 43% yield).1H NMR (500MHz, chloroform-d) δ 7.60-7.49 (m, 4H), 7.42 (t, J= 7.5Hz, 2H), 7.33 (t, J=7.4Hz, 1H), 7.28 (dd, J=8.7,2.6Hz, 2H), 6.15 (d, J=30.8Hz, 1H), 5.04 (d, J=21.2Hz, 1H), 4.34 (s, 1H), 3.80 (dt, J=9.5,6.5Hz, 1H), 3.56-3.18 (m, 8H), 3.10 (dq, J=8.1,5.0,4.2Hz, 2H), 1.49 (dq, J=14.5,6.9Hz, 4H), 1.41 (d, J=1.4Hz, 9H), 1.35- 1.09 (m, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C51H86N2O5, theoretical value 830；Measured value 830。
Embodiment 34:(2R) -3- ([1,1 '-xenyl] -4- base) -2- amino-N- (bis- (tetradecyloxyanilines) third of 2,3- Base) propionamide hydrochloride
According to embodiment 1, by ((2R) -3- ([1,1 '-xenyl] -4- base) -1- ((2,3- bis- (tetradecyloxyanilines) Propyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (162mg, 0.2mmol) prepares title compound, obtain solid (100% yield).1H NMR(500MHz,DMSO-d6) δ 8.41 (dt, J=14.0,5.8Hz, 1H), 8.26 (s, 3H), 7.70- 7.55 (m, 4H), 7.45 (t, J=7.6Hz, 2H), 7.35 (dd, J=11.5,7.7Hz, 3H), 4.08 (d, J=34.4Hz, 1H), 3.81-3.56 (m, 1H), 3.52-3.16 (m, 7H), 3.14-2.87 (m, 3H), 1.40 (ddd, J=28.0,13.0, 6.6Hz, 4H), 1.32-1.02 (m, 44H), 0.85 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C46H78N2O3, theoretical Value 708；Measured value 708.
Embodiment 35:((2S) -3- ([1,1 '-xenyl] -4- base) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) ammonia Base) -1- oxo propyl- 2- yl) t-butyl carbamate
According to embodiment 33, by Boc-4-Phe-L- phenyl Ala-OH (171mg, 0.5mmol) and 2,3- bis- (14 Alkoxy) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, and obtaining white solid, (225mg, 56% produces Rate).1H NMR (500MHz, chloroform-d) δ 7.54 (dd, J=16.5,7.8Hz, 4H), 7.42 (t, J=7.5Hz, 2H), 7.33 (t, J=7.4Hz, 1H), 7.28 (dd, J=8.7,2.5Hz, 2H), 6.15 (d, J=30.9Hz, 1H), 5.04 (d, J= 20.8Hz, 1H), 4.34 (s, 1H), 3.57-3.17 (m, 9H), 3.17-2.95 (m, 2H), 1.49 (dd, J=13.1,7.5Hz, 4H), 1.41 (s, 9H), 1.36-1.15 (m, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+Na]+ C51H86N2O5, theoretical value 830；Measured value 830.
Embodiment 36:(2S) -3- ([1,1 '-xenyl] -4- base) -2- amino-N- (bis- (tetradecyloxyanilines) third of 2,3- Base) propionamide hydrochloride
According to embodiment 1, by ((2S) -3- ([1,1 '-xenyl] -4- base) -1- ((2,3- bis- (tetradecyloxyanilines) Propyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (162mg, 0.2mmol) prepares title compound, obtain white Solid (100% yield).1H NMR(500MHz,DMSO-d6) δ 8.41 (dd, J=13.0,6.5Hz, 1H), 8.26 (s, 3H), 7.64 (t, J=7.0Hz, 4H), 7.45 (t, J=7.6Hz, 2H), 7.35 (dd, J=11.2,7.7Hz, 3H), 4.05 (s, 1H), 3.67 (m, 1H), 3.58-3.15 (m, 7H), 3.15-2.84 (m, 3H), 1.56-1.32 (m, 4H), 1.21 (d, J=8.9Hz, 44H), 0.85 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C46H78N2O3, theoretical value 708；Measured value 708.
Embodiment 37:((5S) -6- ((2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidines -1- Base) -6- oxo hex- 1,5- diyl) diamino acid di tert butyl carbonate
According to embodiment 33, by Boc-L-Lys- (Boc)-L-Pro-OH (222mg, 0.5mmol) and 2,3- bis- (ten Tetraalkoxy) propane -1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtain colloidal solid (220mg, 48% Yield).1H NMR (500MHz, chloroform-d) δ 6.74-6.64 (t, J=5.6Hz, 1H), 5.38-5.24 (m, 1H), 4.92 (s, 1H), 4.55-4.37 (m, 2H), 3.77-3.61 (m, 1H), 3.61-3.19 (m, 10H), 3.10 (d, J=8.4Hz, 2H), 2.34-2.17 (m, 1H), 2.12 (m, 1H), 2.00-1.87 (m, 2H), 1.80-1.64 (m, 1H), 1.55 (tdd, J=12.7, 9.4,5.5Hz, 6H), 1.43 (d, J=1.5Hz, 18H), 1.25 (s, 48H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z [M+Na]+C52H100N4O8, theoretical value 932；Measured value 932.
Embodiment 38:(2S) -1- (L- lysyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- formamide Dihydrochloride
According to embodiment 1, by ((5S) -6- ((2S) -2- ((2,3- bis- (tetradecyloxyaniline) propyl) carbamyl) Pyrrolidin-1-yl) -6- oxo hex- 1,5- diyl) diamino acid di tert butyl carbonate (182mg, 0.2mmol) prepares title compound Object obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.33 (s, 3H), 7.93 (s, 3H), 4.74 (s, 1H), 4.45 (s, 1H), 4.00-3.31 (m, 10H), 3.04 (d, J=51.0Hz, 2H), 2.47 (s, 2H), 1.93 (q, J= 51.8,39.5Hz, 4H), 1.61-1.45 (m, 4H), 1.25 (s, 48H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+ H]+C42H84N4O4, theoretical value 710；Measured value 710.
Embodiment 39:(2- ((2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidin-1-yl) -2- Oxoethyl) t-butyl carbamate
According to embodiment 33, by Boc-Gly-L-Pro-OH (136mg, 0.5mmol) and 2, the bis- (tetradecane oxygen of 3- Base) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtain white solid (185mg, 50% yield).1H NMR (500MHz, chloroform-d) δ 6.87 (dt, J=16.5,5.3Hz, 1H), 5.40 (s, 1H), 4.51 (d, J=8.1Hz, 1H), 4.08-3.80 (m, 2H), 3.79-3.12 (m, 11H), 2.34 (ddt, J=12.5,5.8,2.9Hz, 1H), 2.18-2.06 (m, 1H), 2.00 (ddt, J=12.6,6.8,3.6Hz, 1H), 1.90 (dddd, J=17.7,12.9,8.0,2.3Hz, 1H), 1.65 (s, 1H), 1.55 (td, J=7.2,3.8Hz, 4H), 1.45 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)； ESI-MS m/z[M+Na]+C43H83N3O6, theoretical value 761；Measured value 761.
Embodiment 40:(2S)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -1- glycyl pyrrolidines -2- formamide hydrochloric acid Salt
According to embodiment 1, by (2- ((2S) -2- ((2,3- bis- (tetradecyloxyaniline) propyl) carbamyl) pyrroles Alkane -1- base) -2- oxoethyl) t-butyl carbamate (148mg, 0.2mmol) prepares title compound, obtain white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.01 (d, J=193.1Hz, 3H), 4.57 (s, 1H), 4.01 (s, 1H),3.83–3.04(m,11H),2.52(s,1H),2.35–1.76(m,3H),1.53(s,4H),1.25(s,44H),0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C38H75N3O4, theoretical value 639；Measured value 639.
Embodiment 41:3- (2- (5- (benzyloxy) -1H- indol-3-yl) acetylamino)-N- (bis- (tetradecane oxygen of 2,3- Base) propyl) propionamide
According to embodiment 33, by 2- (5- (benzyloxy) -1H- indol-3-yl) acetic acid (80mg, 0.283mmol) and 3- amino-N- (2,3- bis- (tetradecyloxyaniline) propyl) propionamide hydrochloride (167mg, 0.283mmol) prepares title compound, Obtain brown solid (192mg, 83% yield).1H NMR (499MHz, chloroform-d) δ 8.26 (d, J=2.3Hz, 1H), 7.47 (d, J=7.1Hz, 2H), 7.38 (t, J=7.6Hz, 2H), 7.33-7.27 (m, 1H), 7.12 (d, J=2.3Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 6.94 (dd, J=8.8,2.4Hz, 1H), 6.53 (s, 1H), 6.24 (s, 1H), 6.11 (s, 1H), 5.09 (s, 2H), 3.77-3.61 (m, 2H), 3.48-3.31 (m, 9H), 3.16 (qd, J=7.4,4.4Hz, 3H), 2.33 (dd, J =7.0,5.1Hz, 2H), 1.53 (q, J=7.3Hz, 4H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/ z[M+Na]+C51H83N3O5, theoretical value 841；Measured value 841.
Embodiment 42:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (3- tosyl Base guanidine radicals) amyl- 2- yl) carbamic acid (9H- fluorenes -9- base) methyl ester
According to embodiment 33, by Nα-Fmoc-L-Arg-Nw- Tos-OH (275mg, 0.5mmol) and 2,3- bis- (14 Alkoxy) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, and obtaining colloidal solid, (182mg, 36% produces Rate).1H NMR (500MHz, chloroform-d) δ 7.75 (dd, J=7.8,4.5Hz, 4H), 7.57 (dd, J=7.5,3.4Hz, 2H), 7.38 (t, J=7.5Hz, 2H), 7.26 (m, 2H), 7.20 (d, J=8.1Hz, 2H), 6.76 (s, 1H), 6.44 (s, 2H), 5.82 (s, 1H), 4.47-4.26 (m, 2H), 4.16 (dd, J=15.3,8.3Hz, 1H), 3.73-3.15 (m, 7H), 3.00 (d, J= 9.6Hz, 3H), 2.35 (s, 3H), 2.04 (m, 2H), 1.68-1.41 (m, 4H), 1.36-1.10 (m, 46H), 0.88 (td, J= 7.0,1.6Hz,6H)；ESI-MS m/z[M+Na]+C59H93N5O7S, theoretical value 1039；Measured value 1039.
Embodiment 43:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (bis- (tertiary fourths of 1,3- Oxygroup)) guanidine radicals) amyl- 2- yl) carbamic acid (9H- fluorenes -9- base) methyl ester
According to embodiment 33, by Nα-Fmoc-L-Arg-(Boc)2- OH (298mg, 0.5mmol) and 2,3- bis- (14 Alkoxy) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, and obtaining colloidal solid, (105mg, 20% produces Rate).1H NMR (500MHz, chloroform-d) δ 10.72 (s, 1H), 7.76 (dd, J=7.6,4.5Hz, 2H), 7.70-7.54 (m, 2H), 7.46-7.36 (m, 2H), 7.31 (dd, J=8.3,6.6Hz, 2H), 6.59 (s, 1H), 6.08-5.85 (m, 1H), 5.63 (s,1H),4.62–4.18(m,5H),3.89–3.18(m,8H),3.00(s,2H),2.54(s,1H),2.04–1.84(m,1H), 1.78-1.56 (m, 4H), 1.51 (d, J=8.9Hz, 18H), 1.35-1.07 (m, 44H), 0.88 (td, J=7.0,1.4Hz, 6H)；ESI-MS m/z[M+H]+C62H103N5O9, theoretical value 1063；Measured value 1063.
Embodiment 44:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) amyl- 2- yl of -5- guanidine radicals -1- oxo) Carbamic acid (9H- fluorenes -9- base) methyl ester dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 43 (53mg, 0.05mmol), obtains colloidal solid (100% yield).1H NMR (500MHz, chloroform-d) δ 7.83-7.67 (m, 2H), 7.61 (s, 2H), 7.44-7.32 (m, 2H), 7.29 (d, J=7.3Hz, 2H), 4.33 (d, J=19.7Hz, 3H), 4.21 (dt, J=17.1,8.5Hz, 1H), 3.90-3.15 (m, 11H), 2.13-1.64 (m, 2H), 1.57-1.39 (m, 6H), 1.25 (s, 44H), 0.87 (t, J=6.8Hz, 6H)；ESI- MS m/z[M+H]+C52H87N5O5, theoretical value 963；Measured value 963.
Embodiment 45:((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (3- tosyl Base guanidine radicals) amyl- 2- yl) t-butyl carbamate
According to embodiment 33, N is preparedα-Boc-L-Arg-(Nw- Tos)-OH (214mg, 0.5mmol) and 2,3- it is bis- (tetradecyloxyaniline) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) obtains colloidal liquid (310mg, 69% yield).1H NMR (499MHz, chloroform-d) δ 7.75 (d, J=8.0Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 6.76 (s, 1H), 6.40 (s, 2H), 5.32 (d, J=30.0Hz, 1H), 4.11 (q, J=8.1,7.6Hz, 1H), 3.72-3.14 (m, 9H), 3.00 (d, J= 8.1Hz, 2H), 2.38 (s, 3H), 1.98 (s, 2H), 1.54 (qd, J=13.5,7.6,6.7Hz, 6H), 1.41 (s, 9H), 1.24 (s, 44H), 0.87 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+Na]+C49H91N5O7S, theoretical value 917；Measured value 917.
Embodiment 46:(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -5- (3- tosyl guanidine radicals) Valeryl amine hydrochlorate
According to embodiment 1, title compound is prepared by embodiment 45 (179mg, 0.2mmol), it is solid to obtain lightpink Body (100% yield).1H NMR (500MHz, chloroform-d) δ 8.69 (s, 1H), 8.26 (d, J=52.4Hz, 3H), 8.03 (s, 1H), 7.88 (d, J=7.8Hz, 2H), 7.64 (s, 1H), 7.35 (d, J=7.9Hz, 2H), 4.29 (s, 1H), 3.86-3.19 (m, 11H), 2.42 (s, 3H), 2.06 (s, 2H), 1.88 (s, 2H), 1.51 (d, J=8.6Hz, 4H), 1.24 (dd, J=7.9, 4.8Hz 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C44H83N5O5S, theoretical value 795；Measured value 795.
Embodiment 47:((2S) -4- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1,4- dioxo butyl- 2- yl) t-butyl carbamate
According to embodiment 1, by bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-L-Asp-OSu (165mg, 0.5mmol) prepares title compound, obtains white solid (200mg, 57% yield).1H NMR (500MHz, chloroform-d) δ 3.61 (dt, J=9.3,6.6Hz, 1H), 3.54-3.26 (m, 9H), 2.98-2.64 (m, 2H), 1.73-1.49 (m, 7H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H).
Embodiment 48:((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- diyl) two Carbamic acid di tert butyl carbonate
According to embodiment 1, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- and Boc-L-Lys (Boc)-OSu (222mg, 0.5mmol) prepares title compound, obtains white solid (180mg, 44% yield).1H NMR (500MHz, chloroform-d) δ 6.38 (s, 1H), 5.08 (s, 1H), 4.58 (s, 1H), 4.03 (s, 1H), 3.68-3.19 (m, 9H), 3.10 (d, J=7.4Hz, 2H), 1.83 (dq, J=13.6,7.3Hz, 1H), 1.65-1.46 (m, 7H), 1.44 (s, 18H), 1.37 (q, J=7.7Hz, 2H), 1.26 (s, 46H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+ C47H93N3O7, theoretical value 835；Measured value 835.
Embodiment 49:(2S) -2,6- diamino-N-(bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 48 (162mg, 0.2mmol), obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.26 (s, 3H), 8.01 (s, 3H), 4.41 (s, 1H), 3.83-3.24 (m,10H),3.15(s,2H),2.55(s,2H),2.05(s,1H),1.98–1.64(m,3H),1.54(s,4H),1.26(s, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C37H77N3O3, theoretical value 613；Measured value 613.
Embodiment 50:((5S) -5- acetylaminohydroxyphenylarsonic acid 6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo oneself Base) t-butyl carbamate
According to embodiment 33, by NαAcetyl group-Nε- Boc-L- lysine (144mg, 0.5mmol) and 2,3- bis- (ten Tetraalkoxy) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtain the title compound of pale solid Object (152mg, 40% yield).1H NMR (500MHz, chloroform-d) δ 6.34 (d, J=16.1Hz, 1H), 6.26 (s, 1H), 4.60 (s, 1H), 4.35 (dt, J=8.2,6.2Hz, 1H), 3.65-3.19 (m, 9H), 3.09 (d, J=7.4Hz, 2H), 2.01 (s, 3H), 1.90-1.71 (m, 1H), 1.63 (dt, J=15.1,7.5Hz, 1H), 1.51 (m, 6H), 1.44 (s, 9H), 1.25 (s, 46H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C44H87N3O6, theoretical value 777；Measured value 777.
Embodiment 51:(2S) -2- acetylaminohydroxyphenylarsonic acid 6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide hydrochloric acid Salt
According to embodiment 1, title compound is prepared by embodiment 50 (151mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 8.26 (s, 3H), 7.96 (s, 1H), 4.57 (s, 1H), 3.70- 3.24 (m, 10H), 3.09 (d, J=11.8Hz, 2H), 2.23 (d, J=41.2Hz, 3H), 1.97-1.71 (m, 5H), 1.54 (t, J=7.1Hz, 5H), 1.25 (s, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C39H79N3O4, theoretical value 655；Measured value 655.
Embodiment 52:4- (2- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -3- ((2,3- bis- (tetradecyloxyanilines) Propyl) amino) -3- oxopropyl) piperidines -1- carboxylic acid tert-butyl ester
According to embodiment 33, by Nα- Fmoc- β-(1-Boc- piperidin-4-yl)-DL-Alanine (247mg, 0.5mmol) and bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- prepare title compound, obtain glue The title compound (130mg, 27% yield) of shape solid.1H NMR (500MHz, chloroform-d) δ 7.77 (d, J=7.5Hz, 2H), 7.57 (d, J=7.2Hz, 2H), 7.40 (td, J=7.5,2.0Hz, 2H), 7.31 (t, J=7.5Hz, 2H), 6.31 (d, J= 17.7Hz, 1H), 5.24 (d, J=8.4Hz, 1H), 4.56-4.30 (m, 2H), 4.26-3.95 (m, 4H), 3.71-3.15 (m, 9H), 2.66 (d, J=12.3Hz, 2H), 1.74 (s, 1H), 1.66-1.50 (m, 7H), 1.45 (s, 9H), 1.25 (d, J= 4.6Hz, 45H), 1.12 (dd, J=33.9,12.7Hz, 2H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+Na]+ C59H97N3O7, theoretical value 983；Measured value 983.
Embodiment 53:(1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -3- (piperidin-4-yl) propyl- 2- Base) carbamic acid (9H- fluorenes -9- base) methyl ester hydrochloride
According to embodiment 1, title compound is prepared by embodiment 52 (96mg, 0.1mmol), obtains brown solid (100% yield).1H NMR (499MHz, chloroform-d) δ 9.43 (s, 1H), 9.13 (s, 1H), 7.75 (d, J=7.5Hz, 2H), 7.58 (d, J=7.2Hz, 2H), 7.40 (t, J=7.5Hz, 2H), 7.34-7.28 (m, 2H), 6.80 (s, 1H), 5.64 (s, 1H), 4.55-4.29 (m, 2H), 4.20 (q, J=10.1,6.8Hz, 2H), 3.58-3.13 (m, 13H), 2.83 (s, 2H), 2.14-1.59 (m, 2H), 1.57-1.42 (m, 5H), 1.35-1.13 (m, 46H), 0.87 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C54H89N3O5, theoretical value 861；Measured value 861.
Embodiment 54:4- (((benzyloxy) carbonyl) amino) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) Piperidines -1- carboxylic acid tert-butyl ester
According to embodiment 33, by Cbz-Pip (Boc)-OH (189mg, 0.5mmol) and 2,3- bis- (tetradecyloxyanilines) Propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtain colloidal solid title compound (160mg, 38% yield).1H NMR (500MHz, chloroform-d) δ 7.34 (q, J=7.3,6.8Hz, 5H), 6.88 (s, 1H), 5.08 (s, 2H), 4.88 (s, 1H), 3.83 (d, J=13.5Hz, 2H), 3.61-3.20 (m, 9H), 3.06 (ddd, J=14.0,10.6, 3.1Hz,2H),2.17–1.83(m,4H),1.64–1.45(m,4H),1.45(s,9H),1.35–1.13(m,44H),0.88(t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C50H89N3O7, theoretical value 867；Measured value 867.
Embodiment 55:(4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) piperidin-4-yl) carbamic acid benzyl Ester hydrochloride
According to embodiment 1, title compound is prepared by embodiment 54 (85mg, 0.1mmol), obtains brown solid (100% yield).1H NMR (499MHz, chloroform-d) δ 9.40 (s, 1H), 9.23 (d, J=59.5Hz, 1H), 7.41-7.28 (m, 5H), 6.99 (d, J=17.6Hz, 1H), 6.00 (s, 1H), 5.07 (d, J=2.1Hz, 2H), 3.58-3.11 (m, 11H), 2.47 (d, J=13.5Hz, 2H), 2.33-1.90 (m, 4H), 1.52 (m, 4H), 1.25 (d, J=4.7Hz, 44H), 0.88 (t, J =6.8Hz, 6H)；ESI-MS m/z[M+H]+C45H81N3O5, theoretical value 745；Measured value 745.
Embodiment 56:((5S) -5- (([1,1 '-xenyl] -4- ylmethyl) amino) -6- ((bis- (tetradecane oxygen of 2,3- Base) propyl) amino) -6- oxo-hexyl) t-butyl carbamate
Step 1:N2- ([1,1'- xenyl] -4- ylmethyl)-N6- (tert-butoxycarbonyl)-L-lysine methyl esters.It will [1,1 '-xenyl] -4- formaldehyde (546mg, 3.0mmol) and N6- (tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride The mixture of (890mg, 3.0mmol) in THF (50mL) is with NaBH (OAc)3(763mg, 3.6mmol) processing, and will reaction Mixture is stirred at room temperature overnight.By reaction mixture saturation K2CO3Aqueous solution (25mL) is handled and is stirred for 30 minutes. Separating obtained layer, water layer are extracted with EtOAc (2x 50mL).Combined organic layer is washed with brine, is dried over sodium sulfate, Evaporation, and purified using silica gel column chromatography (hexane-EtOAc (0-100%)), title compound is obtained, is colourless liquid (520mg)。1H NMR (500MHz, chloroform-d) δ 7.70-7.48 (m, 4H), 7.48-7.30 (m, 5H), 4.51 (s, 1H), 3.85 (d, J=13.0Hz, 1H), 3.73 (s, 3H), 3.67 (d, J=13.0Hz, 1H), 3.29 (t, J=6.6Hz, 1H), 3.10 (t, J =6.5Hz, 2H), 1.67 (m, 2H), 1.54-1.35 (m, 13H).ESI-MS m/z[M+H]+C25H34N2O4, theoretical value 427；It is real Measured value 427.
Step 2:N2- ([1,1 '-xenyl] -4- ylmethyl)-N6- (tert-butoxycarbonyl)-L-lysine.To N2- ([1,1'- xenyl] -4- ylmethyl)-N6- (tert-butoxycarbonyl)-L-lysine methyl esters (427mg, 1.0mmol) THF- Water (3.0mL) solution of LiOH (96mg, 4.0mmol) is added in MeOH (6mL) solution.After being stirred at room temperature 4 hours, pass through Saturation KHSO is added4Aqueous solution (10mL) neutralizes mixture.Form precipitating, be collected by vacuum filtration, it is dry, and without into The purifying of one step is used for next step.1H NMR(500MHz,DMSO-d6) δ 7.62 (dd, J=25.5,7.8Hz, 4H), 7.52- 7.28 (m, 5H), 6.73 (s, 1H), 3.80 (d, J=13.6Hz, 1H), 3.62 (d, J=14.0Hz, 1H), 2.87 (d, J= 6.6Hz,2H),2.79(s,1H),1.47(m,2H),1.36(s,13H)；ESI-MS m/z[M+H]+C24H32N2O4, theoretical value 413；Measured value 413.
Step 3. is according to embodiment 33, by N2- ([1,1 '-xenyl] -4- ylmethyl)-N6- (tert-butoxy carbonyl Base)-L-lysine (206mg, 0.5mmol) and bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- Title compound is prepared, the title compound (285mg, 65% yield) of colloidal solid is obtained.1H NMR (500MHz, chloroform-d) δ7.66–7.52(m,4H),7.51–7.30(m,6H),4.67(s,1H),3.98(s,2H),3.74–3.21(m,8H),3.06 (ddt, J=20.2,13.2,6.3Hz, 2H), 1.83 (d, J=52.7Hz, 2H), 1.63-1.40 (m, 6H), 1.35 (s, 9H), 1.30-1.13 (m, 46H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C55H95N3O5, theoretical value 879；Actual measurement Value 879.
Embodiment 57:(2S) -2- (([1,1 '-xenyl] -4- ylmethyl) amino) -6- amino-N- (2,3- bis- (14 Alkoxy) propyl) caproamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 56 (176mg, 0.2mmol), obtains brown solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.81 (s, 1H), 8.36 (s, 1H), 7.95 (s, 3H), 7.67-7.26 (m,9H),4.33(s,2H),4.09(m,1H),3.74–3.16(m,9H),3.13–2.89(m,2H),2.08(s,2H),1.81 (s, 2H), 1.63-1.39 (m, 6H), 1.38-1.01 (m, 44H), 0.87 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+ C50H87N3O3, theoretical value 779；Measured value 779.
Embodiment 58:((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- ((4- luorobenzyl) amino) -6- Oxo-hexyl) t-butyl carbamate
According to embodiment 33, by N6(tert-butoxycarbonyl)-N2(4- luorobenzyl)-L-lysine (176mg, 0.5mmol) (according to embodiment 56 synthesize) and bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates of 2,3- (260mg, Title compound 0.5mmol) is prepared, the title compound (225mg, 55% yield) of colloidal solid is obtained.1H NMR (500MHz, chloroform-d) δ 7.40 (dd, J=8.2,5.2Hz, 2H), 7.21 (s, 1H), 7.05 (t, J=8.6Hz, 2H), 4.69 (s,1H),4.03–3.81(m,2H),3.75–3.20(m,10H),3.06(m,2H),1.84(m,2H),1.62–1.48(m, 4H), 1.48-1.41 (m, 2H), 1.37 (s, 9H), 1.25 (d, J=5.1Hz, 46H), 0.88 (t, J=6.8Hz, 6H)；ESI- MS m/z[M+H]+C49H90FN3O5, theoretical value 821；Measured value 821.
Embodiment 59:(2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((4- luorobenzyl) amino) oneself Carboxamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 58 (164mg, 0.2mmol), obtains brown solid (100% yield).1H NMR (499MHz, chloroform-d) δ 9.82 (s, 1H), 8.79 (s, 1H), 8.07 (s, 3H), 7.56 (s, 2H), 7.04 (t, J=8.4Hz, 2H), 4.24-3.74 (m, 5H), 3.71-3.14 (m, 9H), 2.97 (s, 2H), 2.22-1.92 (m, 2H), 1.78 (s, 2H), 1.62-1.41 (m, 6H), 1.40-1.08 (m, 44H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C44H82FN3O3, theoretical value 721；Measured value 721.
Embodiment 60:((5S) -5- (benzylamino) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo oneself Base) t-butyl carbamate
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) (being synthesized by following with method identical in embodiment 56) and bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates of 2,3- (260mg, Title compound 0.5mmol) is prepared, the title compound (168mg, 42% yield) of colloidal solid is obtained.1H NMR (500MHz, chloroform-d) δ 7.51-7.27 (m, 6H), 4.67 (s, 1H), 3.93 (s, 2H), 3.77-3.20 (m, 9H), 3.05 (qd, J=14.0,6.6Hz, 2H), 1.81 (m, 2H), 1.54 (dt, J=14.4,7.4Hz, 4H), 1.48-1.41 (m, 2H), 1.37 (s, 9H), 1.25 (br s, 46H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C49H91N3O5, theoretical value 803；Measured value 803.
Embodiment 61:(2S) -6- amino -2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide two Hydrochloride
According to embodiment 1, title compound is prepared by embodiment 60 (160mg, 0.2mmol), obtains brown solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.80 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 7.95 (s, 3H), 7.53 (d, J=5.7Hz, 2H), 7.32 (d, J=6.8Hz, 3H), 4.05 (s, 3H), 3.67-3.03 (m, 9H), 3.03- 2.86 (m, 2H), 2.02 (d, J=36.0Hz, 2H), 1.77 (s, 2H), 1.52 (p, J=7.0Hz, 6H), 1.35-1.08 (m, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C44H83N3O3, theoretical value 703；Measured value 703.
Embodiment 62:((5R) -5- (benzylamino) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo oneself Base) t-butyl carbamate
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-D-Lys (168mg, 0.5mmol) Bis- (tetradecyloxyaniline) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) the preparation marks of (being synthesized according to embodiment 56) and 2,3- Compound is inscribed, the title compound (185mg, 46% yield) of colloidal solid is obtained.1H NMR (500MHz, chloroform-d) δ 7.58- 7.30(m,5H),7.21(s,1H),4.71(s,1H),4.09–3.86(m,2H),3.79–3.23(m,10H),3.16–2.97 (m, 2H), 2.04-1.67 (m, 2H), 1.54 (ddd, J=14.0,9.2,5.2Hz, 4H), 1.44 (t, J=6.5Hz, 2H), 1.35 (s, 9H), 1.25 (d, J=5.3Hz, 46H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+H]+C49H91N3O5, Theoretical value 803；Measured value 803.
Embodiment 63:((2R) -6- amino -2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide two Hydrochloride
According to embodiment 1, title compound is prepared by embodiment 62 (160mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.75 (s, 1H), 8.61 (s, 1H), 7.96 (m, 3H), 7.50 (d, J =34.3Hz, 2H), 7.34 (s, 3H), 3.91-3.20 (m, 3H), 3.19-2.88 (m, 11H), 2.37-1.69 (m, 4H), 1.54 (s, 6H), 1.41-1.05 (m, 44H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C44H83N3O3, theoretical value 703；Measured value 703.
Embodiment 64:((is cis-) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) cyclohexyl) carbamic acid The tert-butyl ester
According to embodiment 33, by (cis-) -4- ((tert-butoxycarbonyl) amino) hexamethylene -1- carboxylic acid (122mg, 0.5mmol) and bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- prepare title compound, obtain white Color solid (220mg, 62% yield).1H NMR (500MHz, chloroform-d) δ 6.00 (t, J=5.6Hz, 1H), 4.70 (s, 1H), 3.71 (d, J=20.6Hz, 1H), 3.63-3.36 (m, 8H), 3.29 (dt, J=13.6,5.2Hz, 1H), 2.16 (dt, J= 9.0,4.5Hz, 1H), 1.80-1.49 (m, 12H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)； ESI-MS m/z[M+Na]+C43H84N2O5, theoretical value 732；Measured value 732.
Embodiment 65:(is cis-) -4- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) hexamethylene -1- formamide hydrochloric acid Salt
According to embodiment 1, by ((cis-) -4- ((2,3- bis- (tetradecyloxyaniline) propyl) carbamyl) cyclohexyl) T-butyl carbamate (142mg, 0.2mmol) prepares title compound, obtains white solid (100% yield).1H NMR (499MHz, chloroform-d) δ 8.43 (s, 3H), 6.60 (s, 1H), 3.69-3.35 (m, 9H), 3.29 (s, 1H), 2.39-1.87 (m, 5H), 1.78 (d, J=21.5Hz, 4H), 1.54 (q, J=6.9Hz, 4H), 1.25 (s, 44H), 0.88 (t, J=6.9Hz, 6H)； ESI-MS m/z[M+H]+C38H76N2O3, theoretical value 610；Measured value 610.
Embodiment 66:((is trans-) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) cyclohexyl) carbamic acid The tert-butyl ester
According to embodiment 33, by (trans-) -4- ((tert-butoxycarbonyl) amino) hexamethylene -1- carboxylic acid (122mg, 0.5mmol) and bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- prepare title compound, obtain white Color solid (190mg, 54% yield).1H NMR (500MHz, chloroform-d) δ 5.95 (t, J=5.4Hz, 1H), 4.35 (s, 1H), 3.65-3.33 (m, 9H), 3.28 (dt, J=13.4,5.2Hz, 1H), 2.14-1.84 (m, 5H), 1.62-1.48 (m, 6H), 1.44 (s, 9H), 1.26 (s, 44H), 1.10 (qd, J=12.8,3.5Hz, 2H), 0.88 (t, J=6.9Hz, 6H)；ESI-MS m/z[M+Na]+C43H84N2O5, theoretical value 732；Measured value 732.
Embodiment 67:(is trans-) -4- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) hexamethylene -1- formamide hydrochloric acid Salt
According to embodiment 1, white solid (100% yield) is obtained by embodiment 66 (142mg, 0.2mmol).1H NMR (500MHz, chloroform-d) δ 8.38 (s, 3H), 5.97 (s, 1H), 3.64-3.02 (m, 11H), 2.18 (d, J=85.5Hz, 5H), 1.55 (s, 7H), 1.26 (s, 45H), 0.88 (t, J=6.8Hz, 6H)；ESI-MS m/z[M+H]+C38H76N2O3, theoretical Value 610；Measured value 610.
Embodiment 68:(6- (18-9- alkene-1- base amino)-6- oxo hex- 1,5- diyl) (R, Z)-diamino acid benzyl Base tertiary butyl ester
According to embodiment 1, by oleyl amine (70%) (191mg, 0.5mmol) and Nα-Z-Nε-Boc-D-Lys-OSu (237mg, 0.5mmol) prepares title compound, obtains white solid (225mg, 71% yield).1H NMR (500MHz, chlorine Imitative-d) δ 7.45-7.29 (m, 5H), 6.05 (s, 1H), 5.43 (s, 1H), 5.40-5.28 (m, 2H), 5.10 (d, J=2.4Hz, 2H), 4.57 (s, 1H), 4.07 (q, J=7.3Hz, 1H), 3.22 (q, J=6.8Hz, 2H), 3.09 (d, J=6.8Hz, 2H), 2.10-1.89 (m, 4H), 1.85 (dtd, J=13.5,7.9,5.3Hz, 1H), 1.64 (q, J=7.8Hz, 2H), 1.57-1.47 (m, 4H), 1.42 (s, 9H), 1.34-1.10 (m, 26H), 0.88 (t, J=6.8Hz, 3H)；ESI-MS m/z[M+Na]+ C37H63N3O5, theoretical value 653；Measured value 653.
Embodiment 69:(R, Z)-(6- amino-1- (18-9- alkene-1- base amino)-1- oxo hex- 2- yl) carbamic acid Benzyl ester hydrochloride
According to embodiment 1, title compound is prepared by embodiment 68 (126mg, 0.2mmol), obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.12 (s, 3H), 7.75 (s, 1H), 7.30 (m, 5H), 6.35 (s, 1H),5.43–5.22(m,2H),5.06(s,2H),4.31(s,1H),3.89–3.44(m,2H),3.19(s,2H),2.97(s, 2H), 2.11-1.87 (m, 2H), 1.75 (d, J=44.9Hz, 4H), 1.48 (s, 4H), 1.26 (q, J=9.6,8.4Hz, 24H), 0.88 (t, J=6.8Hz, 3H)；ESI-MS m/z[M+H]+C32H55N3O3, theoretical value 531；Measured value 531.
Embodiment 70:(6- oxo -6- (myristyl amino) hex- 1,5- diyl) (R)-diamino acid benzyl tert-butyl Ester
According to embodiment 1, by tetradecylamine (112mg, 0.5mmol) and Nα-Z-Nε-Boc-D-Lys-OSu (237mg, 0.5mmol) prepares title compound, obtains white solid (248mg, 86% yield).1H NMR (500MHz, chlorine Imitative-d) δ 7.45-7.29 (m, 5H), 6.04 (s, 1H), 5.43 (s, 1H), 5.10 (d, J=2.4Hz, 2H), 4.57 (s, 1H), 4.10 (dd, J=23.2,7.1Hz, 1H), 3.22 (q, J=6.8Hz, 2H), 3.09 (d, J=6.8Hz, 2H), 1.85 (dtd, J =13.5,7.9,5.3Hz, 1H), 1.71-1.55 (m, 1H), 1.54-1.45 (m, 2H), 1.42 (s, 9H), 1.37 (q, J= 7.6Hz, 2H), 1.25 (s, 24H), 0.88 (t, J=6.9Hz, 3H)；ESI-MS m/z[M+Na]+C33H57N3O5, theoretical value 599；Measured value 599.
Embodiment 71:(R)-(6- amino -1- oxo -1- (myristyl amino) hex- 2- yl) carbamic acid benzyl ester salt Hydrochlorate
According to embodiment 1, title compound is prepared by embodiment 70 (115mg, 0.2mmol), obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.24 (s, 3H), 7.40-7.29 (m, 6H), 6.02 (d, J=8.1Hz, 1H), 5.05 (s, 2H), 4.28 (s, 1H), 3.19 (d, J=11.6Hz, 2H), 2.98 (s, 2H), 2.09-1.58 (m, 4H), 1.48 (s, 2H), 1.36-1.16 (m, 24H), 0.88 (t, J=6.9Hz, 3H)；ESI-MS m/z[M+H]+C28H49N3O3, theoretical Value 477；Measured value 477.
Embodiment 72:3- ((((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl oxygroup) -3,16- two Oxa- -5,12- diaza melissane -10- base) amino) methyl) -1H- indoles -1- carboxylic acid tert-butyl ester
Step 1:(S) -3- (((6- ((tert-butoxycarbonyl) amino) -1- methoxyl group -1- oxo hex- 2- yl) amino) first Base) -1H- indoles -1- carboxylic acid tert-butyl ester.By 3- formoxyl -1H- indoles -1- carboxylic acid tert-butyl ester (736mg, 3.0mmol) and N6- Mixture NaBH of (the tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (890mg, 3.0mmol) in THF (50mL) (OAc)3(763mg, 3.6mmol) processing, and reaction mixture is stirred at room temperature overnight.Reaction mixture is saturated K2CO3Aqueous solution (25mL) is handled and is stirred for 30 minutes.Separating obtained layer, water layer are extracted with EtOAc (2x 50mL).It will close And organic layer be washed with brine, be dried over sodium sulfate, evaporate, and use silica gel column chromatography (hexane-EtOAc (0- 100%) it) purifies, obtains title compound, be colourless liquid (1,325mg).ESI-MS m/z[M+H]+C26H39N3O6, theoretical Value 490；Measured value 490.
Step 2:N6(tert-butoxycarbonyl)-N2((1- (tert-butoxycarbonyl) -1H- indol-3-yl) methyl)-L- relies Propylhomoserin.To N2([1,1'- xenyl] -4- ylmethyl)-N6(tert-butoxycarbonyl)-L-lysine methyl esters (1225mg, Water (8.0mL) solution of LiOH (180mg, 7.5mmol) is added in 1:1THF-MeOH (15mL) solution 2.5mmol).In room After lower stirring 4 hours of temperature, KHSO is saturated by being added4Aqueous solution (20mL) neutralizes mixture.Precipitating is formed, vacuum filter is passed through Separation, and with EtOAc (2 × 50mL) aqueous layer extracted and evaporate.Then it purifies on a silica gel column, with methylene chloride-methanol (0- 10%) it is used as eluant, eluent, obtains required product (680mg).ESI-MS m/z[M+H]+C25H37N3O6, theoretical value 476；Measured value 476。
Step 3: according to embodiment 33, by N6(tert-butoxycarbonyl)-N2((1- (tert-butoxycarbonyl) -1H- Yin Diindyl -3- base) methyl)-L-lysine (238mg, 0.5mmol) and bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates of 2,3- (260mg, 0.5mmol) prepares title compound, obtains the title compound (235mg, 50% yield) of colloidal solid.1H NMR (500MHz, chloroform-d) δ 8.18 (d, J=8.3Hz, 1H), 7.82 (s, 1H), 7.67 (t, J=6.4Hz, 1H), 7.32 (dt, J =30.8,7.6Hz, 2H), 7.08 (d, J=35.6Hz, 1H), 5.92 (s, 1H), 4.72 (s, 1H), 4.25 (m, 2H), 3.79- 3.20(m,12H),3.17–2.90(m,2H),1.92–1.80(m,1H),1.53(m,6H),1.47–1.36(m,2H),1.33– 1.04 (m, 66H), 0.87 (d, J=7.0Hz, 6H).ESI-MS m/z[M+H]+C56H100N4O7, theoretical value 942；Measured value 942.
Embodiment 73:(2S) -2- (((1H- indol-3-yl) methyl) amino) -6- amino-N- (bis- (tetradecane oxygen of 2,3- Base) propyl) caproamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 72 (188mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.40 (s, 1H), 8.46 (br s, 2H) 8.32-7.35 (m, 3H), 7.07 (d, J=20.4Hz, 1H), 5.99 (s, 1H), 5.05-3.95 (m, 2H), 3.95-3.14 (m, 6H), 2.86 (m, 2H), 1.77-1.33 (m, 6H), 1.40-1.02 (m, 48H), 0.88 (td, J=6.8,4.3Hz, 6H).ESI-MS m/z[M+H]+ C46H84N4O3, theoretical value 742；Measured value 742.
Embodiment 74:3- (2- (((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl oxygroup) -3,16- Dioxa -5,12- diaza melissane -10- base) amino) -2- oxoethyl) the tertiary fourth of -5- methoxyl group -1H- indoles -1- carboxylic acid Ester
Step 1:N6(tert-butoxycarbonyl)-N2(2- (5- methoxyl group -1H- indol-3-yl) acetyl group)-L-lysine Methyl esters
According to embodiment 33, by 2- (5- methoxyl group -1H- indol-3-yl) acetic acid (616mg, 3.0mmol) and N6- (tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (890mg, 3.0mmol) prepares title compound, obtains colloidal solid Title compound (680mg, 51% yield).ESI-MS m/z[M+H]+C23H33N3O6, theoretical value 448；Measured value 448.
Step 2:(S) -3- (2- ((6- ((tert-butoxycarbonyl) amino) -1- methoxyl group -1- oxo hex- 2- yl) amino) - 2- oxoethyl) -5- methoxyl group -1H- indoles -1- carboxylic acid tert-butyl ester.By N6(tert-butoxycarbonyl)-N2(2- (5- methoxyl group- 1H- indol-3-yl) acetyl group)-L-lysine methyl esters (1119mg, 2.5mmol) is dissolved in methylene chloride (20mL), it is added Di-tert-butyl dicarbonate (818mg, 3.75mmol), by N, N- dimethyl aminopyridine (DMAP) (55mg, 0.25mmol) is added In mixture, and reaction solution is continued to stirring 2 hours at room temperature.After confirming that product is formed by TLC, from reaction mixture Middle evaporating volatile substances, and purifying on silica gel column chromatography use hexane to hexane-EtOAc (0-100%) as eluant, eluent.It closes And pure product fractions and evaporate, required product is obtained, is colloidal liquid (1342mg, 98% yield).ESI-MS m/z[M+H]+ C28H41N3O8, theoretical value 548；Measured value 548.
Step 3:N6(tert-butoxycarbonyl)-N2(2- (1- (tert-butoxycarbonyl) -5- methoxyl group -1H- indol-3-yl) Acetyl group)-L-lysine.According to 72 step 2 of embodiment, by (S) -3- (2- ((6- ((tert-butoxy carbonyl of above-mentioned acquisition Base) amino) -1- methoxyl group -1- oxo hex- 2- yl) amino) -2- oxoethyl) the tertiary fourth of -5- methoxyl group -1H- indoles -1- carboxylic acid Ester (1370mg, 2.5mmol) and LiOH (180mg, 7.5mmol) prepare title compound, obtain the title compound of colloidal solid Object (850mg, 64% yield).ESI-MS m/z[M+H]+C27H39N3O8, theoretical value 534；Measured value 534.
Step 4: according to embodiment 33, by N6(tert-butoxycarbonyl)-N2(2- (1- (tert-butoxycarbonyl) -5- Methoxyl group -1H- indol-3-yl) acetyl group)-L-lysine (267mg, 0.5mmol) and bis- (tetradecyloxyaniline) the propyl- 1- of 2,3- Amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtains title compound (232mg, 46% production of white solid Rate).1H NMR (500MHz, chloroform-d) δ 8.02 (s, 1H), 7.64-7.46 (m, 1H), 7.05-6.85 (m, 2H), 6.27 (d, J =18.3Hz, 1H), 5.93 (s, 1H), 4.57 (s, 1H), 4.36 (q, J=7.0Hz, 1H), 3.83 (s, 3H), 3.71-3.34 (m, 10H), 3.29 (dt, J=12.5,5.1Hz, 2H), 2.97 (d, J=21.8Hz, 2H), 1.66 (s, 9H), 1.55 (h, J= 7.9,7.4Hz, 9H), 1.43 (s, 9H), 1.26 (br s, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+ C58H102N4O9, theoretical value 1000；Measured value 1000.
Embodiment 75:(2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (2- (5- methoxyl group -1H- Yin Diindyl -3- base) acetylamino) hexanoyl amine hydrochlorate
According to embodiment 1, title compound is prepared by embodiment 74 (200mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 7.98 (s, 4H), 7.51 (m, 1H), 7.15-6.95 (m, 1H), 6.95–6.68(m,1H),6.00(s,1H),4.51(s,1H),3.95–3.62(m,5H),3.60–3.11(m,12H),1.81– 1.43 (m, 10H), 1.25 (br s, 44H), 0.88 (td, J=6.9,2.9Hz, 6H).ESI-MS m/z[M+H]+C48H86N4O5, Theoretical value 800；Measured value 800.
Embodiment 76:5- (benzyloxy) -3- (2- (((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl Oxygroup) -3,16- dioxa -5,12- diaza melissane -10- base) amino) -2- oxoethyl) -1H- indoles -1- carboxylic acid uncle Butyl ester
According to embodiment 33, by N2(2- (5- (benzyloxy) -1- (tert-butoxycarbonyl) -1H- indol-3-yl) second Acyl group)-N6(tert-butoxycarbonyl)-L-lysine (synthesizes) (305mg, 0.5mmol) according to embodiment 74 and 2,3- is bis- (tetradecyloxyaniline) propyl- 1- amine hydrochlorate (260mg, 0.5mmol) prepares title compound, obtains the title compound of white solid Object (310mg, 58% yield).1H NMR (500MHz, chloroform-d) δ 8.03 (s, 1H), 7.53 (s, 1H), 7.46 (d, J= 7.6Hz, 2H), 7.38 (dd, J=8.5,6.6Hz, 2H), 7.31 (dd, J=8.6,6.1Hz, 1H), 7.13-6.90 (m, 2H), 6.27 (d, J=14.2Hz, 2H), 5.09 (s, 2H), 4.51 (s, 1H), 4.35 (q, J=7.0Hz, 1H), 3.60-3.09 (m, 9H), 2.96 (s, 2H), 1.67 (s, 9H), 1.53 (tq, J=13.8,7.3Hz, 6H), 1.42 (s, 9H), 1.26 (br s, 48H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C64H106N4O9, theoretical value 1076；Measured value 1076.
Embodiment 77:(2S) -6- amino -2- (2- (5- (benzyloxy) -1H- indol-3-yl) acetylamino)-N- (2,3- Bis- (tetradecyloxyaniline) propyl) hexanoyl amine hydrochlorate
According to embodiment 1, title compound is prepared by embodiment 76 (215mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 8.03 (m, 3H), 7.83-7.51 (m, 1H), 7.49-6.73 (m, 11H), 5.06 (d, J=15.3Hz, 2H), 4.48 (s, 1H), 3.88-3.58 (m, 3H), 3.58-3.09 (m, 8H), 2.81 (m, 2H), 1.61-1.38 (m, 6H), 1.26 (br s, 48H), 0.88 (t, J=6.6Hz, 6H).ESI-MS m/z[M+H]+ C54H90N4O5, theoretical value 876；Measured value 876.
Embodiment 78:((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- ((naphthalene -2- ylmethyl) ammonia Base) -6- oxo-hexyl) t-butyl carbamate
According to embodiment 33, by N6(tert-butoxycarbonyl)-N2(naphthalene -2- ylmethyl)-L-lysine is (according to reality Apply synthesis described in example 56) (194mg, 0.5mmol) and bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates of 2,3- (260mg, Title compound 0.5mmol) is prepared, the title compound (315mg, 74% yield) of pale solid is obtained.1H NMR (500MHz, chloroform-d) δ 8.05-7.73 (m, 4H), 7.58-7.45 (m, 3H), 7.23 (s, 1H), 4.67 (s, 1H), 4.32- 3.99(m,2H),3.74(m,1H),3.65–3.21(m,8H),3.19–2.89(m,2H),1.87(br s,2H),1.53(dq,J =11.8,6.5,6.0Hz, 4H), 1.47-1.04 (m, 57H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+ C53H93N3O5, theoretical value 853；Measured value 853.
Embodiment 79:(2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((naphthalene -2- ylmethyl) amino) Caproamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 78 (171mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (499MHz, chloroform-d) δ 9.58 (s, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.69 (m, 6H),7.35(s,2H),4.45–3.88(m,3H),3.42(s,10H),2.89(s,1H),2.20–1.83(m,2H),1.84– 1.59 (m, 2H), 1.49 (s, 6H), 1.37-1.02 (br s, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+ C48H85N3O3, theoretical value 753；Measured value 753.
Embodiment 80:4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperazine -1- carboxylic acid Ester
According to embodiment 33, by 3- (4- (tert-butoxycarbonyl) piperazine -1- base) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains white solid Title compound (285mg, 74% yield).1H NMR (500MHz, chloroform-d) δ 7.46 (d, J=2.6Hz, 1H), 7.30 (t, J =7.9Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 7.09 (d, J=8.2Hz, 1H), 6.69 (t, J=5.3Hz, 1H), 3.74 (dt, J=13.5,5.4Hz, 1H), 3.67-3.34 (m, 12H), 3.21 (t, J=5.2Hz, 4H), 1.57 (m, 4H), 1.49 (s, 9H), 1.41-1.11 (m, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C47H85N3O5, theoretical value 773； Measured value 773.
Embodiment 81:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (piperazine -1- base) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 80 (155mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 10.09 (s, 2H), 8.15 (s, 1H), 8.03-7.38 (m, 2H), 3.92-3.00 (m, 16H), 1.56 (s, 4H), 1.25 (br s, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+ H]+C42H77N3O3Theoretical value, 673；Measured value 673.
Embodiment 82:4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperidines -1- carboxylic acid Ester
According to embodiment 33, by 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains white solid Title compound (280mg, 73% yield).1H NMR (500MHz, chloroform-d) δ 7.67 (d, J=1.9Hz, 1H), 7.53 (dt, J=7.2,1.8Hz, 1H), 7.41-7.29 (m, 2H), 6.69 (t, J=5.4Hz, 1H), 4.26 (d, J=13.5Hz, 2H), 3.75 (dt, J=13.7,5.4Hz, 1H), 3.66-3.26 (m, 8H), 2.92-2.59 (m, 3H), 1.83 (d, J=12.7Hz, 2H), 1.66 (td, J=12.6,4.3Hz, 2H), 1.57 (m, 4H), 1.49 (s, 9H), 1.40-1.06 (m, 48H), 0.88 (t, J =6.9Hz, 6H).ESI-MS m/z[M+H]+C48H86N2O5, theoretical value 772；Measured value 772.
Embodiment 83:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 82 (154mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.73 (br d, Hz, 2H), 7.72 (s, 1H), 7.54 (d, J= 7.0Hz, 1H), 7.39 (d, J=8.3Hz, 2H), 6.74 (s, 1H), 3.98-3.30 (m, 11H), 3.04 (s, 2H), 2.85 (s, 1H), 2.26 (s, 2H), 2.07 (d, J=12.9Hz, 2H), 1.76 (s, 4H), 1.57 (m, 4H), 1.26 (br s, 46H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C43H78N2O3, theoretical value 672；Measured value 672.
Embodiment 84:4- (2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperazine -1- carboxylic acid Ester
According to embodiment 33, by 2- (4- (tert-butoxycarbonyl) piperazine -1- base) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains colourless liquid Title compound (325mg, 84% yield).1H NMR (500MHz, chloroform-d) δ 9.58 (s, 1H), 8.15 (dd, J=7.9, 1.7Hz, 1H), 7.42 (td, J=7.7,1.8Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 4.12 (q, J=7.1Hz, 1H), 3.88-3.31 (m, 12H), 2.94 (t, J=5.2Hz, 4H), 1.55 (m, 4H), 1.49 (s, 9H), 1.35-1.09 (m, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C47H85N3O5, theoretical value 773； Measured value 773.
Embodiment 85:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperazine -1- base) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 84 (155mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 10.41 (s, 2H), 7.96 (d, J=7.7Hz, 1H), 7.56 (dd, J =19.1,11.8Hz, 2H), 7.38 (t, J=7.4Hz, 1H), 3.97-3.23 (m, 21H), 1.55 (m, 4H), 1.36-1.07 (m, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C42H77N3O3, theoretical value 673；Measured value 673.
Embodiment 86:4- (2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperidines -1- carboxylic acid Ester
According to embodiment 33, by 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains white solid Title compound (315mg, 81% yield).1H NMR (500MHz, chloroform-d) δ 7.38 (td, J=7.6,1.4Hz, 1H), 7.34-7.28 (m, 2H), 7.21 (t, J=7.3Hz, 1H), 6.31 (t, J=5.6Hz, 1H), 4.39-4.13 (m, 2H), 3.77 (ddd, J=13.7,6.3,4.6Hz, 1H), 3.68-3.36 (m, 8H), 3.17 (tt, J=12.1,3.5Hz, 1H), 2.80 (td, J=13.0,2.6Hz, 2H), 1.83 (dd, J=13.3,3.3Hz, 2H), 1.70-1.51 (m, 6H), 1.48 (s, 9H), 1.26 (br s, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C48H86N2O5, theoretical value 772；Measured value 772.
Embodiment 87:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperidin-4-yl) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 86 (154mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.63 (br d, 2H), 7.52-7.40 (m, 2H), 7.36 (d, J= 7.5Hz, 1H), 7.24 (d, J=7.5Hz, 1H), 6.42 (t, J=5.5Hz, 1H), 3.88-3.21 (m, 11H), 3.01 (m, 2H), 2.33-2.14 (m, 2H), 2.16-1.98 (m, 2H), 1.55 (m, 4H), 1.25 (br s, 44H), 0.88 (t, J= 6.8Hz,6H)。ESI-MS m/z[M+H]+C43H78N2O3, theoretical value 672；Measured value 672.
Embodiment 88:4- (4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperazine -1- carboxylic acid Ester
According to embodiment 33, by 4- (4- (tert-butoxycarbonyl) piperazine -1- base) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains light pink solid Title compound (310mg, 80% yield).1H NMR (500MHz, chloroform-d) δ 7.81-7.57 (m, 2H), 6.93 (d, J= 8.5Hz, 2H), 6.61 (t, J=5.5Hz, 1H), 3.73 (dt, J=13.7,5.4Hz, 1H), 3.65-3.36 (m, 12H), 3.25 (t, J=5.2Hz, 4H), 1.57 (m, 4H), 1.49 (s, 9H), 1.38-1.14 (m, 44H), 0.88 (t, J=6.9Hz, 6H). ESI-MS m/z[M+H]+C47H85N3O5, theoretical value 773；Measured value 773.
Embodiment 89:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- (piperazine -1- base) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 88 (155mg, 0.2mmol), obtains brown solid (100% yield).1H NMR (500MHz, chloroform-d) δ 10.08 (s, 2H), 7.79 (s, 2H), 6.86 (s, 1H), 4.04-3.21 (m, 11H), 2.52 (s, 6H), 1.56 (q, J=6.9Hz, 4H), 1.25 (br s, 44H), 0.88 (t, J=6.9Hz, 6H). ESI-MS m/z[M+H]+C42H77N3O3, theoretical value 673；Measured value 673.
Embodiment 90:4- (4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperidines -1- carboxylic acid Ester
According to embodiment 33, by 4- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains white solid Title compound (325mg, 84% yield).1H NMR (500MHz, chloroform-d) δ 7.71 (d, J=8.1Hz, 2H), 7.25 (d, J =8.0Hz, 2H), 6.71 (t, J=5.5Hz, 1H), 4.25 (d, J=13.1Hz, 2H), 3.75 (dt, J=13.7,5.4Hz, 1H), 3.67-3.29 (m, 8H), 2.80 (t, J=12.9Hz, 2H), 2.69 (t, J=12.1,3.6Hz, 1H), 1.90-1.74 (m, 2H), 1.70-1.52 (m, 6H), 1.48 (s, 9H), 1.41-1.16 (m, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C48H86N2O5, theoretical value 772；Measured value 772.
Embodiment 91:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- (piperidin-4-yl) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 90 (154mg, 0.2mmol), obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.73 (br d, 2H), 7.73 (d, J=7.5Hz, 2H), 7.30 (d, J =7.7Hz, 2H), 6.72 (t, J=5.4Hz, 1H), 3.97-3.29 (m, 11H), 3.03 (s, 2H), 2.83 (s, 1H), 2.25 (s, 2H), 2.06 (d, J=13.1Hz, 2H), 1.70 (s, 4H), 1.56 (m, 4H), 1.37-1.10 (m, 44H), 0.87 (t, J= 6.8Hz,6H)。ESI-MS m/z[M+H]+C43H78N2O3, theoretical value 672；Measured value 672.
Embodiment 92:4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) -1,1- lupetidine - 1-- iodide
It will be suspended in DMF (3.0mL) according to title compound prepared by embodiment 83 (336mg, 0.5mmol), and to K is added in mixture2CO3(207mg, 1.5mmol) and methyl iodide (62 μ L, 1.0mmol).Then it is heated 2 hours at 60 DEG C. It (is monitored after the completion by TLC-5%MeOH- methylene chloride), evaporating volatile substances are simultaneously extracted using the aqueous solution of chloroform (2 × 25mL) It takes.Obtained organic layer sodium sulphate is dry and evaporates.Then it is completely dried under freeze-drying to remove remaining DMF, obtains institute Product is needed, is white solid (295mg, 71% yield).1H NMR (500MHz, chloroform-d) δ 7.87 (d, J=1.9Hz, 1H), 7.57 (dt, J=7.6,1.5Hz, 1H), 7.45-7.33 (m, 2H), 7.08 (s, 1H), 4.15-3.91 (m, 2H), 3.83 (d, J =12.6Hz, 2H), 3.71-3.51 (m, 9H), 3.48-3.33 (m, 5H), 3.22 (m, 1H), 2.24 (q, J=13.2Hz, 2H), 2.13 (d, J=14.8Hz, 2H), 1.98 (s, 3H), 1.56 (h, J=6.8,6.0Hz, 4H), 1.43-1.12 (m, 47H), 0.87 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C45H83N2O3, theoretical value 701；Measured value 701.
Embodiment 93:N- (bis- (oxygroup in the heptan) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt
Bis- (oxygroup in the heptan) propyl of step 1:(2,3-) t-butyl carbamate.At room temperature by NaOH aqueous solution (50%, 15mL) and Bu4NI (2.76g, 7.5mmol) be added stirring (2,3- dihydroxypropyl) t-butyl carbamate (3g, 15mmol) and in toluene (30mL) solution of 1- heptyl bromide (7.5ml, 45mmol).After being vigorously stirred 6 hours at 50-60 DEG C, make Reaction mixture reaches environment temperature, and ethyl acetate and water is added.Organic phase is washed with brine and dries (Na2SO4).It uses The hexane solution of 10-20% ethyl acetate obtains required product (3.0g, 52%) by column chromatography eluting residue.ESI- MS m/z[M+H]+C22H45NO4, theoretical value 388；Measured value 388.
Bis- (oxygroup in heptan) the propyl- 1- amine hydrochlorates of step 2:2,3-.Product obtained in above-mentioned steps 1 is dissolved in methanol In (10mL), methanol HCl (20mL) is added and is stirred at room temperature for 3 hours.Then solvent is evaporated to dryness, obtains institute Need product (100% yield).ESI-MS m/z[M+H]+C17H37NO2, theoretical value 288；Measured value 288.
Step 3:4- (3- ((bis- (oxygroup in the heptan) propyl of 2,3-) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester
3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (500mg, 1.637mmol) is dissolved in methylene chloride In (5.0mL).Addition 2,3- bis- (oxygroup in heptan) propyl- 1- amine .HCl (478mg, 1.637mmol) and HBTU (620mg, 1.637mmol) and by reaction mixture stir 10 minutes.DIPEA (0.84ml, 6.548mmol) is added and is stirred at room temperature 3 Hour.It removes solvent and is purified by silica gel column chromatography, with the hexanes of 15% ethyl acetate, obtain required product (550mg, 58% yield).ESI-MS m/z[M+H]+C34H58N2O5, theoretical value 575；Measured value 575.
Step 4: compound obtained in step 3 (230mg, 4.0mmol) being dissolved in methanol (3.0mL), methanol is added HCl (10mL) is stirred at room temperature 3 hours, and solvent is evaporated under reduced pressure to doing, obtains required product (100% yield).1H NMR (300MHz,DMSO-d6)δppm:9.3-9.2(br s,1H),9.0(br s,1H),8.6-8.4(s,1H),7.8-7.3(m, 4H),3.6-3.2(m,11H),3.1-2.8(m,3H),2.0-1.8(m,4H),1.6-1.3(m,4H),1.3-1.0(m,16H), 0.87(m,6H).ESI-MS m/z[M+H]+C29H50N2O3, theoretical value 475；Measured value 475.
Embodiment 94:N- (bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloric acid Salt
Step 1:4- (3- ((bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) carbamyl) phenyl) piperidines -1- carboxylic acid The tert-butyl ester.3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (500mg, 1.637mmol) is dissolved in methylene chloride In (5.0mL).Then bis- (5- methoxypentyloxy) the propyl- 1- amine .HCl (476mg, 1.637mmol) of 2,3- are added (according to implementation The preparation of 93 the method for example) and HBTU (620mg, 1.637mmol), and reaction mixture is stirred 10 minutes.DIPEA is added It (n,N-diisopropylethylamine) (0.84ml, 6.548mmol) and is stirred at room temperature 3 hours.It removes solvent and passes through silicagel column Chromatography purifying, with the hexanes of 25% ethyl acetate, obtains required product (500mg, 53% yield).ESI-MS m/z[M+H]+C32H54N2O7, theoretical value 579；Measured value 579.
Step 2: by the compound obtained in step 1 (232mg, 4.0mmol) dissolution in methyl alcohol (3.0mL), being added Methanol HCl (10mL) is simultaneously stirred at room temperature 3 hours, and solvent is evaporated under reduced pressure to dry.Obtain required product (100% yield).1H NMR(300MHz,DMSO-d6)δppm:9.3(br s,1H),9.2-9.0(br s,1H),8.6-8.4(s,1H),7.8-7.3 (m,4H),3.6-3.3(m,13H),3.2(m,8H),3.1-2.8(m,3H),2.0-1.8(m,4H),1.6-1.3(m,8H), 1.3-1.2(m,4H).ESI-MS m/z[M+H]+C27H46N2O5, theoretical value 479；Measured value 479.
Embodiment 95:N- (3- (benzyloxy) -2- (dodecyloxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloric acid Salt
Step 1:(3- (benzyloxy) -2- (dodecyloxy) propyl) t-butyl carbamate.To the 3- (benzyloxy of stirring Base) 2- hydroxypropylamino t-butyl formate (3.0g, 16mmol) and 1- bromo-dodecane (7.98g, 48mmol) toluene 50%NaOH aqueous solution (9.0mL) and Bu are added in (15mL) solution4NI (2.95g, 8mmol), gained mixture is heated to It 50-60 DEG C and is vigorously stirred at such a temperature 6 hours.After the completion, mixture is cooled to environment temperature and with ethyl acetate and Water process.Organic phase is concentrated, and is purified by silica gel column chromatography, with the hexanes of 5-20% ethyl acetate, is obtained To required brown liquid.ESI-MS m/z[M+H]+C27H47NO4, theoretical value 450；Measured value 450.
Step 2:3- (benzyloxy) -2- (dodecyloxy) propyl- 1- amine hydrochlorate.Change obtained in step 1 to stirring It closes in methanol (5mL) solution of object (3g) and methanol HCl (10mL) is added, and continue stirring 1 hour at room temperature.After the completion, will Mixture concentration, obtains required product, is colourless liquid (100% yield).ESI-MS m/z[M+H]+C22H39NO2, theoretical value 350；Measured value 350.
Step 3:4- (3- ((3- (benzyloxy) -2- (dodecyloxy) propyl) carbamyl) phenyl) piperidines -1- carboxylic acid The tert-butyl ester.According to embodiment 93, by 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (1.76g, 5.76mmol) Title compound is prepared with 3- (benzyloxy) -2- (dodecyloxy) propane -1- amine hydrochlorate (2.0g, 5.76mmol), is obtained The title compound (2.1g, 57% yield) of colourless liquid.ESI-MS m/z[M+H]+C39H60N2O5, theoretical value 637；Measured value 637。
Step 4: according to embodiment 1, the product (64mg, 0.1mmol) obtained by above-mentioned steps 3 prepares title compound Object obtains pale solid (100% yield).ESI-MS m/z[M+H]+C34H52N2O3, theoretical value 537；Measured value 537.
Embodiment 96:5- (2- (dodecyloxy) -3- (3- (piperidin-4-yl) benzamido) propoxyl group) methyl valerate Hydrochloride
Step 1:4- (3- ((2- (dodecyloxy) -3- hydroxypropyl) carbamyl) phenyl) tertiary fourth of piperidines -1- carboxylic acid Ester.Under nitrogen, to 4- (3- ((3- (benzyloxy) -2- (dodecyloxy) propyl) carbamyl) phenyl) piperidines -1- of stirring 10%Pd/C (200mg) is added portionwise in methanol (20mL) solution of carboxylic acid tert-butyl ester (2.0g, 3.14mmol), it then will reaction Mixture stirs 18 hours at Hydrogen Vapor Pressure (10-15psi).After the completion, mixture is filtered and is concentrated by Celite pad, Crude product is obtained, is colourless liquid, is directly used in next step.ESI-MS m/z[M+H]+C32H54N2O5, theoretical value 547；Measured value 547.
Step 2:4- (3- ((2- (dodecyloxy) -3- ((5- methoxyl group -5- oxopentyl) oxygroup) propyl) carbamyl Base) phenyl) piperidines -1- carboxylic acid tert-butyl ester.To 4- (3- (2- (dodecyloxy) -3- hydroxypropyl carbamyl) benzene of stirring Base) piperidines -1- carboxylic acid tert-butyl ester (1.2g, 2.19mmol) and 5- bromo pentane acid A ester (1.37g, 6.59mmol) toluene (10mL) 50%NaOH aqueous solution (4.0mL) and Bu are added in mixture4NI (400mg, 0.001mol), and gained reaction mixture is added Heat is vigorously stirred 1 hour at such a temperature to 50-60 DEG C.After the completion, reaction mixture is cooled to environment temperature and uses second Acetoacetic ester and water process.Organic phase is concentrated, is purified with silica gel column chromatography, with the hexanes of 5-30% ethyl acetate, Required product is obtained, is colourless liquid.ESI-MS m/z[M+H]+C38H64N2O7, theoretical value 661；Measured value 661.
Step 3: according to embodiment 1, the product (264mg, 0.4mmol) obtained by above-mentioned steps 2 prepares titled Object is closed, colorless gum solid (100% yield) is obtained.1H NMR(300MHz,DMSO-d6):δ8.62-8.41(s,1H), 7.74-7.65(s,2H),7.45-7.31(m,2H),3.66(s,3H),3.63-3.31(m,10H),2.96-2.71(m,4H), 2.31-2.19(m,2H),2.03-1.83(m,5H),1.58-1.32(m,7H),1.31-1.24(m,18H),0.85-0.83(t, J=5.7Hz, 3H).ESI-MS m/z[M+H]+C33H56N2O5, theoretical value 561；Measured value 561.
Embodiment 97:5- (2- (dodecyloxy) -3- (3- (piperidin-4-yl) benzamido) propoxyl group) pentanoic acid hydrochloride Salt
Step 1:5- (3- (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzamido) -2- (dodecyloxy) third Oxygroup) valeric acid.Under inert atmosphere, at room temperature to the 4- of stirring (3- ((2- (dodecyloxy) -3- ((5- methoxyl group -5- oxo Amyl) oxygroup) propyl) carbamyl) phenyl) and piperidines -1- carboxylic acid tert-butyl ester (1.15g) methanol (5mL) solution in slowly plus Enter 2M LiOH.H2O solution (10mL) continues stirring 18 hours.Reaction mixture is concentrated to dryness.Crude product with water is diluted And it is washed with isopropyl ether.Gained water phase is acidified to pH 2 using 2N HCl and is extracted with ethyl acetate.By the organic layer of collection It is concentrated and is purified by silica gel column chromatography, with 5-10% ethanol/methylene gradient elution, obtain required product, be colourless Liquid (900mg, 82%).ESI-MS m/z[M+H]+C37H62N2O7, theoretical value 647；Measured value 647.
Step 2: being slowly added into methylene chloride (4mL) solution for the product (500mg) that the above-mentioned steps 1 of stirring obtain Isosorbide-5-Nitrae-dioxanes (10mL) solution of 4N HCl, and continue stirring 30 minutes at room temperature.Concentration gained reaction mixture, obtains Required product, for pale solid (100% yield).1H NMR(300MHz,DMSO-d6):δ12.0(s,1H),8.5(br s, 1H),8.62-8.51(m,2H),7.71(s,2H),7.43-7.36(m,2H),3.58-3.45(m,11H),3.16-2.91(m, 3H),2.31-2.19(m,2H),1.91-1.82(m,4H),1.51-1.62(m,6H),1.22-1.03(m,18H),0.85- 0.83 (t, J=5.7Hz, 3H).ESI-MS m/z[M+H]+C32H54N2O5, theoretical value 547；Measured value 547.
Embodiment 98:N- (2- (dodecyloxy) -3- ((5- (methylamino) -5- oxopentyl) oxygroup) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt
Step 1:4- (3- (2- (dodecyloxy) -3- (5- (methylamino)-oxo-pentyloxy) propyl carbamyl) benzene Base) piperidines -1- carboxylic acid tert-butyl ester.To the 5- (3- (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzamido)-of stirring 2- (dodecyloxy) propoxyl group) valeric acid (250mg, 0.38mmol) DMF (5mL) solution in be added DIPEA (0.656mL, 3.8mmol) and HBTU (230mg, 0.608mmol) and it is stirred at room temperature 30 minutes.Then, by MeNH2.HCl(60mg, It 0.874mmol) is added in reaction mixture and continues stirring 18 hours at room temperature.Reaction mixture ethyl acetate is dilute It releases, with saturation NaHCO3Solution, saturation NH4Cl solution, water and aqueous salt solu-tion.The organic phase of collection is dry, it is concentrated and leads to The purifying of parlkaline silica gel column chromatography, with 5% ethanol/methylene gradient elution, isolates required pure products, is yellow liquid Body (220mg, 88%).ESI-MS m/z[M+H]+C38H65N3O6, theoretical value 661；Measured value 661.
Step 2: HCl is added into methylene chloride (2mL) solution for the product (220mg) that the above-mentioned steps 1 of stirring obtain 1,4- dioxanes (5mL) solution and be stirred at room temperature 30 minutes.Concentration gained reaction mixture, obtains required product, is Viscous oily matter (100% yield).1H NMR(300MHz,DMSO-d6):δ8.91(br s,1H),8.67(br s,1H), 8.54(s,1H),7.67(s,2H),7.37-7.35(m,2H),3.58-3.41(m,11H),3.16-2.91(m,3H),2.92- 2.71(m,3H),2.31-2.19(m,2H),1.91-1.82(m,4H)1.61-1.32(m,6H),1.22-1.03(m,18H), 0.85-0.83 (t, J=5.7Hz, 3H).ESI-MS m/z[M+H]+C33H57N3O4, theoretical value 561；Measured value 561.
Embodiment 99:N- (3- ((5- amino-5-oxo amyl) oxygroup) -2- (dodecyloxy) propyl) -3- (piperidines - 4- yl) benzamide hydrochloride salt
Step 1:4- (3- ((3- ((5- amino-5-oxo amyl) oxygroup) -2- (dodecyloxy) propyl) carbamyl) Phenyl) piperidines -1- carboxylic acid tert-butyl ester.According to embodiment 98, by 5- (3- (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) Benzamido) -2- (dodecyloxy) propoxyl group) valeric acid (250mg, 0.38mmol) and NH4Cl(46.75mg, Required product 0.874mmo) is obtained, is yellow liquid (220mg, 88%).ESI-MS m/z[M+H]+C37H63N3O6, theoretical value 647；Measured value 647.
Step 2: HCl is added into methylene chloride (2mL) solution for the product (220mg) that the above-mentioned steps 1 of stirring obtain 1,4- dioxanes (5mL) solution and minute is stirred at room temperature.Concentration gained reaction mixture, obtains required product, is viscous Property grease (100% yield).1H NMR(300MHz,DMSO-d6):):δ8.91(br s,1H),8.67(br s,1H), 8.54(s,1H),7.67(s,2H),7.37-7.35(m,2H),7.13(s,1H),6.85(s,1H),3.75-3.41(m,11H), 3.16-2.91(m,3H),2.31-2.19(m,2H),1.91-1.82(m,4H),1.62-1.45(m,6H),1.22-1.03(m, 19H), 0.85-0.83 (t, J=5.8Hz, 3H).ESI-MS m/z[M+H]+C32H55N3O4, theoretical value 547；Measured value 547.
Embodiment 100:N- (3- (octyloxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt
Step 1:4- (3- ((3- (octyloxy) propyl) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester.According to implementation Described in example 33, by 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) and 3- (octyloxy) third Alkane -1- amine (112mg, 0.5mmol) prepares title compound, obtain colorless gum liquid title compound (226mg, 95% Yield).ESI-MS m/z[M+H]+C28H46N2O4, theoretical value 475；Measured value 475.
Step 2: according to embodiment 1, title compound is prepared by the product (95mg, 0.2mmol) of above-mentioned steps 1, Obtain white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.67 (br d, 2H), 7.55 (d, J=6.9Hz, 1H), 7.45-7.32 (m, 3H), 7.14 (s, 1H), 3.83-3.50 (m, 6H), 3.44 (t, J=6.6Hz, 2H), 3.10 (d, J= 49.3Hz, 2H), 2.85 (s, 1H), 2.26 (s, 2H), 2.13-1.97 (m, 2H), 1.85 (m, 4H), 1.57 (q, J=6.9Hz, 2H),1.34–1.15(m,8H),0.95–0.70(m,3H)。ESI-MS m/z[M+H]+C23H38N2O2, theoretical value 375；Measured value 375。
Embodiment 101:3- (piperidin-4-yl)-N- myristyl benzamide hydrochloride salt
Step 1:4- (3- (myristyl carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester.According to embodiment 33, By 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) and the tetradecane -1- amine (107mg, Title compound 0.5mmol) is prepared, the title compound (210mg, 84% yield) of gummy white solid is obtained.ESI-MS m/ z[M+H]+Theoretical value C31H52N2O3,501；Measured value 501.
Step 2: according to embodiment 1, title compound being prepared by the product (100mg, 0.2mmol) of step 1, is obtained White solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.69 (br d, 2H), 7.67 (s, 1H), 7.61 (t, J= 4.3Hz, 1H), 7.39 (d, J=4.6Hz, 2H), 6.24 (s, 1H), 3.65 (d, J=10.8Hz, 2H), 3.43 (q, J=9.3, 8.2Hz, 2H), 3.04 (s, 2H), 2.85 (s, 1H), 2.26 (d, J=12.8Hz, 2H), 2.07 (d, J=13.2Hz, 2H), 1.80 (s, 2H), 1.70-1.53 (m, 2H), 1.44-1.11 (m, 20H), 0.88 (t, J=6.9Hz, 3H).ESI-MS m/z[M+ H]+C26H44N2O, theoretical value 401；Measured value 401.
Embodiment 102:N- (3- (2- methoxy ethoxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt
Step 1:4- (3- ((3- (2- methoxy ethoxy) propyl) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester. According to embodiment 33, by 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) and 3- (2- Methoxy ethoxy) propyl- 1- amine (67mg, 0.5mmol) prepares title compound, obtain the title compound of colourless liquid (158mg, 75% yield).ESI-MS m/z[M+H]+C23H36N2O5, theoretical value 421；Measured value 421.
Step 2: according to embodiment 1, title compound is prepared by the product (84mg, 0.2mmol) of above-mentioned steps 1, Obtain colourless liquid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.44 (s, 1H), 9.17 (s, 1H), 7.71 (m, 2H), 7.61 (d, J=6.9Hz, 1H), 7.37 (d, J=7.7Hz, 2H), 3.94-3.42 (m, 10H), 3.29 (s, 3H), 3.08 (d, J=16.1Hz, 2H), 2.87 (s, 1H), 2.22 (t, J=8.5Hz, 2H), 2.06 (q, J=13.8,11.3Hz, 2H), 1.92 (d, J=5.7Hz, 2H).ESI-MS m/z[M+H]+C18H28N2O3, theoretical value 321；Measured value 321.
Embodiment 103:N- (3- ethyoxyl -2- hydroxypropyl) -3- (piperidin-4-yl) benzamide hydrochloride salt
Step 1:4- (3- ((3- ethyoxyl -2- hydroxypropyl) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester.According to Described in embodiment 33, by 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) and 1- amino -3- Ethyoxyl propan-2-ol (60mg, 0.5mmol) prepares title compound, obtain colourless liquid title compound (165mg, 75% Yield).ESI-MS m/z[M+H]+C22H34N2O5, theoretical value 407；Measured value 407.
Step 2: according to embodiment 1, title compound is prepared by the product (81mg, 0.2mmol) of above-mentioned steps 1, Obtain colourless liquid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.69 (s, 1H), 9.37 (s, 1H), 7.77 (s, 1H), 7.68 (d, J=6.5Hz, 1H), 7.39 (d, J=6.4Hz, 2H), 7.07 (m, 1H), 4.03 (s, 1H), 3.42-3.80 (m, 10H), 2.69 (m, 1H), 2.55 (s, 29H), 2.36-2.17 (m, 2H), 2.15-1.97 (m, 2H), 1.21 (t, J= 7.0Hz,3H)。ESI-MS m/z[M+H]+C17H26N2O3, theoretical value 307；Measured value 307.
Embodiment 104:4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) tertiary fourth of -4- Phenylpiperidine -1- carboxylic acid Ester
According to embodiment 33, by 1- (tert-butoxycarbonyl) -4- Phenylpiperidine -4- carboxylic acid (153mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains colourless liquid Title compound (315mg, 81% yield).1H NMR (500MHz, chloroform-d) δ 7.35 (d, J=4.3Hz, 3H), 7.29- 7.22 (m, 2H), 5.74 (t, J=5.5Hz, 1H), 3.60 (t, J=8.5Hz, 2H), 3.55-3.02 (m, 11H), 2.47-2.25 (m, 2H), 2.02 (m, 2H), 1.48 (s, 2H), 1.45 (s, 9H), 1.42-1.35 (m, 2H), 1.27 (d, J=4.3Hz, 44H), 0.89 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C48H86N2O5, theoretical value 772；Measured value 772.
Embodiment 105:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- Phenylpiperidine -4- carboxamide hydrochloride
According to embodiment 1, by embodiment 103 (154mg, 0.2mmol), white solid (100% yield) is obtained.1H NMR (500MHz, chloroform-d) δ 9.62 (s, 2H), 7.52-7.27 (m, 5H), 5.77 (d, J=5.5Hz, 1H), 3.87-3.60 (m, 1H), 3.51 (d, J=13.0Hz, 2H), 3.42 (m, 7H), 2.55 (s, 2H), 2.39 (s, 2H), 1.66 (s, 4H), 1.55- 1.08 (m, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C43H78N2O3, theoretical value 672；Measured value 672.
Embodiment 106:3- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- phenylpropionyl amine hydrochlorate
Step 1:(3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- oxo -2- phenyl propyl) carbamic acid uncle Butyl ester.According to embodiment 33, by 3- ((tert-butoxycarbonyl) amino) -2- phenylpropionic acid (133mg, 0.5mmol) and 2, Bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 3- prepare title compound, obtain the title of colourless liquid Compound (310mg, 85% yield).1H NMR (500MHz, chloroform-d) δ 7.27 (m, 5H), 5.83 (t, J=5.8Hz, 1H), 5.17(s,1H),3.83–2.99(m,12H),1.70–1.45(m,4H),1.42(s,9H),1.27(br s,44H),0.89(t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C45H82N2O5, theoretical value 732；Measured value 732.
Step 2: according to embodiment 1, title compound is prepared by the product (146mg, 0.2mmol) of above-mentioned steps 1, Obtain white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 8.71 (s, 3H), 7.35 (q, J=10.5, 8.7Hz, 3H), 7.26 (s, 2H), 5.96 (d, J=26.3Hz, 1H), 4.18 (s, 1H), 3.63-3.03 (m, 9H), 1.71 (s, 2H), 1.40 (dd, J=14.3,7.1Hz, 4H), 1.26 (br s, 44H), 0.88 (t, J=6.8Hz, 6H).ESI-MS m/z[M +H]+C40H74N2O3, theoretical value 632；Measured value 632.
Embodiment 107:3- benzyl -3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) tertiary fourth of piperidines -1- carboxylic acid Ester
According to embodiment 33, by 3- benzyl -1- (tert-butoxycarbonyl) piperidines -3- carboxylic acid (170mg, 0.5mmol) Title compound is prepared with bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of 2,3-, obtains colourless liquid Title compound (273mg, 70% yield).1H NMR (500MHz, chloroform-d) δ 7.25-7.16 (m, 3H), 7.14-7.06 (m, 2H),4.03(m,1H),3.65–3.21(m,6H),3.19–2.73(m,4H),2.62(m,2H),1.73–1.47(m,4H), 1.43 (s, 9H), 1.26 (s, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C49H88N2O5, theoretical value 786；Measured value 786.
Embodiment 108:3- benzyl-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) piperidines -3- carboxamide hydrochloride
According to embodiment 1, title compound is prepared by embodiment 107 (157mg, 0.2mmol), obtains white solid (100% yield).1H NMR (500MHz, chloroform-d) δ 11.69 (s, 1H), 7.32-7.27 (m, 4H), 7.09 (t, J= 9.2Hz, 2H), 6.65 (d, J=19.4Hz, 1H), 3.94-3.22 (m, 12H), 2.98 (t, J=13.0Hz, 1H), 2.77 (d, J =13.9Hz, 2H), 1.94 (m, 3H), 1.69 (m, 2H), 1.58-1.46 (m, 4H), 1.42-1.14 (m, 44H), 0.88 (t, J =6.9Hz, 6H).ESI-MS m/z[M+H]+C44H80N2O3, theoretical value 686；Measured value 686.
Embodiment 109:2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperidin-4-yl) acetamide Hydrochloride
Step 1:4- (1- (benzylamino) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -2- oxoethyl) piperazine Pyridine -1- carboxylic acid tert-butyl ester.According to embodiment 33, by 2- (benzylamino) -2- (1- (tert-butoxycarbonyl) piperidin-4-yl) Acetic acid (174mg, 0.5mmol) and bis- (tetradecyloxyaniline) propane -1- amine hydrochlorates (260mg, 0.5mmol) of 2,3- prepare title Compound obtains the title compound (262mg, 64% yield) of light yellow liquid.ESI-MS m/z[M+H]+C50H91N3O5, reason By value 815；Measured value 815.
Step 2: according to embodiment 1, title compound is prepared by the product (163mg, 0.2mmol) of above-mentioned steps 1, Obtain light yellow solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.96 (d, J=72.6Hz, 1H), 8.95 (d, J =94.9Hz, 3H), 8.37 (s, 1H), 7.60 (s, 2H), 7.32 (s, 3H), 4.16 (s, 3H), 3.76-3.27 (m, 12H), 3.03 (d, J=75.6Hz, 5H), 2.51 (s, 1H), 2.27 (s, 1H), 1.90 (s, 2H), 1.52 (s, 4H), 1.24 (t, J= 10.2Hz, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C45H83N3O3, theoretical value 715；Measured value 715.
Embodiment 110:4- ((benzylamino) methyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) piperidines -4- formamide Hydrochloride
Step 1:4- ((benzylamino) methyl) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) piperidines -1- Carboxylic acid tert-butyl ester.According to embodiment 33, by 4- ((benzylamino) methyl) -1- (tert-butoxycarbonyl) piperidines -4- carboxylic acid Bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (260mg, 0.5mmol) of (174mg, 0.5mmol) and 2,3- prepare title compound Object obtains the title compound (215mg, 53% yield) of yellow liquid.ESI-MS m/z[M+H]+C50H91N3O5, theoretical value 815；Measured value 815.
Step 2: according to embodiment 1, title compound is prepared by the product (163mg, 0.2mmol) of above-mentioned steps 1, Obtain yellow liquid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.82-8.66 (m, 4H), 7.62 (m, 2H), 7.36 (m,3H),6.03(s,1H),4.32(m,2H),3.98–2.77(m,14H),2.57–2.04(m,4H),1.54(m,4H),1.25 (br s, 44H), 0.88 (td, J=7.0,2.0Hz, 6H).ESI-MS m/z[M+H]+C45H83N3O3, theoretical value 715；Measured value 715。
Bis- (tetradecyloxyaniline) the propyl- 1- amine of embodiment 111:N- benzyl -2,3-
In 50mL round-bottomed flask, by bis- (tetradecyloxyaniline) the propyl- 1- amine hydrochlorates (520mg, 1.0mmol) of 2,3- and benzene Formaldehyde (127mg, 1.2mmol) is dissolved in THF (15mL), then, NaBH (OAc) is added portionwise into reaction mixture3 (414,2.0mmol), and stirring was continued at room temperature overnight.Then with saturation NaHCO3Solution neutralizes, and is extracted into acetic acid second In ester (2 × 50mL).Combined organic phase is washed with brine, with sodium sulphate drying and is evaporated.Then, on silica gel column chromatography Purifying, uses methylene chloride-MeOH (0-10%) as eluant, eluent.Merge evaporation pure product fractions, obtain required product, is colourless Liquid (225mg, 39% yield).1H NMR (500MHz, chloroform-d) δ 7.51-7.28 (m, 7H), 3.62 (ddd, J=11.2, 8.1,5.4Hz, 2H), 3.54-3.32 (m, 6H), 2.77 (qd, J=12.2,5.7Hz, 2H), 1.55 (m, 4H), 1.38-1.20 (m, 44H), 0.88 (t, J=6.9Hz, 6H).ESI-MS m/z[M+H]+C38H71NO2, theoretical value 575；Measured value 575.
Bis- (tetradecyloxyaniline) the propyl- 1- ammonium-iodide of embodiment 112:N- benzyl-N, N- dimethyl -2,3-
According to embodiment 92, title compound is prepared by embodiment 110 (175mg, 0.305mmol), is obtained pale yellow Color solid (178mg, 80%).1H NMR (500MHz, chloroform-d) δ 7.68 (dd, J=7.0,1.8Hz, 2H), 7.59-7.37 (m, 3H), 5.19-4.86 (m, 2H), 4.19 (dq, J=10.0,3.3,2.8Hz, 1H), 4.01 (dd, J=13.8,2.2Hz, 1H), 3.80-3.45 (m, 5H), 3.43-3.26 (m, 8H), 1.74-1.47 (m, 4H), 1.25 (br s, 44H), 0.88 (t, J= 6.8Hz,6H)。ESI-MS m/z[M+H]+C40H76INO2, theoretical value 731；Measured value 731.
Embodiment 113:4- (3- ((bis- (((Z)-ten four -8- alkene -1- base) oxygroup) propyl of 2,3-) carbamyl) phenyl) Piperidines -1- carboxylic acid tert-butyl ester
To stirring 4- (3- (2,3- dihydroxypropyl carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester (500mg, 50% saturation NaOH solution 1.322mmol) and in toluene (15mL) mixture of oleoyl bromine (2.2g, 7.936mmol) is added (4.0mL) and Bu4NI (2.95g, 0.661mmol), by gained reaction mixture be heated to 50-60 DEG C and at such a temperature acutely Stirring 6 hours.Pass through the completion of TLC monitoring reaction.At room temperature by reaction mixture ethyl acetate (2 × 20ml) and water (10ml) processing.Combined organic phase is concentrated, and is purified by silica gel column chromatography, with the hexane solution of 5-20% ethyl acetate Gradient elution obtains pure required product, is colorless gel (450mg, 54%) .ESI-MS m/z [M+H]+C48H82N2O5, reason By value 768；Measured value 768.
Embodiment 114:N- (bis- (((Z)-ten four -8- alkene -1- base) oxygroup) propyl of 2,3-) -3- (piperidin-4-yl) benzene first Amide hydrochloride
Methanol HCl (10mL) and at room temperature is added into methanol (5ml) solution of the embodiment 113 (550mg) of stirring Continue stirring 1 hour.Reaction is monitored by TLC to complete, and mixture, and the thick production obtained by preparative HPLC purifying is concentrated Object obtains required target product (N- (2,3- bis- ((Z)-ten four -8- alkenyl oxygroup) propyl) -3- (piperidin-4-yl) benzoyl Amine hydrochlorate is colourless pasty solid (230mg, 48%)1H NMR (300MHz, DMSO-d6): δ 7.70 (d, J=5.7Hz, 2H),7.43-7.35(m,2H)),5.36-5.26(m,4H),3.56-3.26(m,16H),3.01-2.89(m,3H),1.97- (1.93 m, 12H), 1.44-1.41 (m, 5H), 1.41-1.2 (m, 23H), 0.845 (t, J=6.0,7.2Hz, 6H).ESI-MS m/z[M+H]+C43H74N2O3, theoretical value 668；Measured value 668.
Embodiment 115:4- (3- ((bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl of 2,3-) ammonia first Aminosulfonylphenyl) piperidines -1- carboxylic acid tert-butyl ester
According to embodiment 33, by 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (153mg, 0.5mmol) With bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propane -1- amine hydrochlorate (313mg, the 0.5mmol) (roots of 2,3- According to embodiment 1 using oleoyl bromine prepare) prepare title compound, obtain colorless oil title compound (325mg, 74% Yield).1H NMR (499MHz, chloroform-d) δ 7.68 (d, J=1.9Hz, 1H), 7.53 (dt, J=7.1,1.8Hz, 1H), 7.42-7.29 (m, 2H), 6.72 (t, J=5.5Hz, 1H), 5.63-5.05 (m, 8H), 4.25 (s, 2H), 3.83-3.33 (m, 10H),2.88–2.56(m,7H),2.20–1.93(m,9H),1.92–1.73(m,2H),1.72–1.51(m,6H),1.48(s, 9H), 1.40-1.17 (m, 26H), 0.89 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C56H94N2O5, theoretical value 876； Measured value 876.
Embodiment 116:N- (bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl of 2,3-) -3- (piperidines - 4- yl) benzamide hydrochloride salt
According to embodiment 1, title compound is prepared by embodiment 115 (175mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.69 (br d, 2H), 7.73 (s, 1H), 7.54 (d, J=7.0Hz, 1H), 7.39 (d, J=8.2Hz, 2H), 6.77 (d, J=6.0Hz, 1H), 5.55-5.13 (m, 8H), 3.90-3.30 (m, 9H), 3.04 (s, 2H), 2.77 (t, J=6.7Hz, 6H), 2.26 (s, 2H), 2.15-1.92 (m, 10H), 1.77 (s, 4H), 1.56 (q, J=7.2Hz, 4H), 1.44-1.12 (m, 28H), 0.88 (t, J=6.7Hz, 6H).ESI-MS m/z[M+H]+C51H86N2O3, reason By value 776；Measured value 776.
Embodiment 117:((5R) -5- (benzylamino) -6- ((bis- (((9Z, 12Z)-ten eight -9,12- diene -1- of 2,3- Base) oxygroup) propyl) amino) -6- oxo-hexyl) t-butyl carbamate
According to embodiment 33, by N2- benzyl-N6- (tert-butoxycarbonyl)-D-Lys (168mg, 0.5mmol) With bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl- 1- amine hydrochlorate (313mg, the 0.5mmol) preparations of 2,3- Title compound obtains the title compound (410mg, 90% yield) of colorless oil.1H NMR (500MHz, chloroform-d) δ 7.45 (d, J=5.6Hz, 2H), 7.43-7.32 (m, 3H), 7.13-6.92 (m, 1H), 5.48-5.20 (m, 8H), 4.82 (s, 1H), 4.24 (d, J=12.9Hz, 1H), 4.16-3.99 (m, 3H), 3.84-3.69 (m, 1H), 3.69-3.27 (m, 7H), 3.18–2.94(m,3H),2.79(s,6H),2.13–1.80(m,8H),1.66–1.41(m,5H),1.40–1.16(m,44H), 0.89 (t, J=6.8Hz, 6H).ESI-MS m/z[M+H]+C57H99N3O5, theoretical value 907；Measured value 907.
Embodiment 118:(2R) -6- amino -2- (benzylamino)-N- (bis- (((9Z, 12Z)-ten eight -9,12- two of 2,3- Alkene -1- base) oxygroup) propyl) caproamide dihydrochloride
According to embodiment 1, title compound is prepared by embodiment 117 (181mg, 0.2mmol), it is solid to obtain canescence Body (100% yield).1H NMR (500MHz, chloroform-d) δ 9.65 (s, 1H), 8.51 (s, 1H), 7.76 (s, 3H), 7.52 (s, 2H), 7.33 (s, 3H), 5.34 (m, 8H), 4.19 (m, 8H), 3.49 (m, 9H), 2.90 (m, 2H), 2.76 (dt, J=6.6, 4.3Hz, 4H), 2.04 (q, J=8.0,7.6Hz, 8H), 1.77 (s, 1H), 1.53 (s, 5H), 1.30 (br s, 32H), 0.88 (t, J=6.7Hz, 6H).ESI-MS m/z[M+H]+C52H91N3O3, theoretical value 807；Measured value 807.
Embodiment 119:(S) -6- amino -2- (benzylamino)-N- myristyl caproamide dihydrochloride
Step 1:(S)-(5- (benzylamino) -6- oxo -6- (myristyl amino) hexyl) t-butyl carbamate.Root According to described in embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and the tetradecane -1- Amine (107mg, 0.5mmol) prepares title compound, obtains the title compound (155mg, 58% yield) of colloidal solid.ESI- MS m/z[M+H]+C32H57N3O3, theoretical value 532；Measured value 532.
Step 2: according to embodiment 1, title compound is prepared by the product (106mg, 0.2mmol) of above-mentioned steps 1, Obtain pale solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.19 (s, 1H), 8.30 (s, 1H), 7.78 (s, 1H),7.40(m,5H),4.19(s,1H),4.00(s,2H),3.36–3.10(m,1H),3.07–2.80(m,3H),1.97(s, 2H), 1.70 (m, 2H), 1.46 (s, 3H), 1.25 (d, J=8.6Hz, 26H), 0.88 (td, J=6.9,3.5Hz, 3H).ESI- MS m/z[M+H]+C27H49N3O, theoretical value 432；Measured value 432.
Embodiment 120:(S) -6- amino -2- (benzylamino)-N- decyl caproamide dihydrochloride
Step 1:(S)-(5- (benzylamino) -6- (Decylamino) -6- oxo-hexyl) t-butyl carbamate.According to reality It applies described in example 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and decyl- 1- amine (79mg, Title compound 0.5mmol) is prepared, semisolid title compound (158mg, 66% yield) is obtained.ESI-MS m/z[M+H]+ C28H49N3O3, theoretical value 476；Measured value 476.
Step 2: according to embodiment 1, title compound being prepared by the product (97mg, 0.2mmol) of step 1, is obtained Pale solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.30 (s, 1H), 8.39 (s, 1H), 7.42 (m, 7H), 4.10 (m, 3H), 3.52-2.63 (m, 4H), 1.88 (m, 5H), 1.47 (s, 4H), 1.26 (br s, 14H), 0.87 (t, J= 6.9Hz,3H)。ESI-MS m/z[M+H]+C23H41N3O, theoretical value 376；Measured value 376.
Embodiment 121:(S) -6- amino -2- (benzylamino)-N- (3- ethoxycarbonyl propyl) caproamide dihydrochloride
Step 1:(S)-(5- (benzylamino) -6- ((3- ethoxycarbonyl propyl) amino) -6- oxo-hexyl) carbamic acid uncle Butyl ester.According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and 3- Ethoxy-c -1- amine (52mg, 0.5mmol) prepares title compound, and obtaining semisolid title compound, (153mg, 73% produces Rate).ESI-MS m/z[M+H]+C23H39N3O4, theoretical value 422；Measured value 422.
Step 2: according to embodiment 1, title compound being prepared by the product (84mg, 0.2mmol) of step 1, is obtained Colloidal solid (100% yield).1H NMR (500MHz, chloroform-d) δ 7.86-7.31 (m, 8H), 3.68-3.54 (m, 3H), 3.50(m,3H),3.25(s,5H),2.04(m,2H),1.81(m,2H),1.52-1.00(m,7H)。ESI-MS m/z[M+H]+ C18H31N3O2, theoretical value 322；Measured value 322.
Embodiment 122:(S) -6- amino -2- (benzylamino)-N- (3- (octyloxy) propyl) caproamide dihydrochloride
Step 1:(S)-(5- (benzylamino) -6- ((3- (octyloxy) propyl) amino) -6- oxo-hexyl) carbamic acid The tert-butyl ester.According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and 3 3- (octyloxy) propyl- 1- amine (112mg, 0.5mmol) prepares title compound, obtain semisolid title compound (172mg, 68% yield).ESI-MS m/z[M+H]+C29H51N3O4, theoretical value 506；Measured value 506.
Step 2: according to embodiment 1, title compound being prepared by the product (101mg, 0.2mmol) of step 1, is obtained Colloidal solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.34 (s, 1H), 8.42 (s, 1H), 7.42 (m, 7H), 4.10(m,3H),3.40(s,5H),2.97(m,3H),2.04(m,2H),1.75(s,3H),1.52(s,3H),1.33–1.10 (m, 12H), 0.87 (t, J=6.7Hz, 3H).ESI-MS m/z[M+H]+C24H43N3O2, theoretical value 406；Measured value 406.
Embodiment 123:(S) -6- amino-N- (2- cyclohexyl-ethyl) -2- ((naphthalene -2- ylmethyl) amino) caproamide disalt Hydrochlorate
Step 1:(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo-hexyl) ammonia Base t-butyl formate.According to embodiment 33, by N6- (tert-butoxycarbonyl)-N2- (naphthalene -2- ylmethyl)-L-lysine (193mg, 0.5mmol) and 2- cyclohexyl second -1- amine (82mg, 0.5mmol) prepare title compound, obtain semisolid title Compound (182mg, 73% yield).ESI-MS m/z[M+H]+C30H45N3O3, theoretical value 496；Measured value 496.
Step 2: according to embodiment 1, title compound is prepared by the product (100mg, 0.2mmol) of above-mentioned steps 1, Obtain pale solid (100% yield).1H NMR (500MHz, chloroform-d) δ 9.53 (s, 1H), 8.52 (s, 1H), 7.62 (m, 10H),4.09(m,5H),2.93(m,2H),2.21–0.51(m,19H)。ESI-MS m/z[M+H]+C25H37N3O, theoretical value 396；Measured value 396.
Embodiment 124:(S) -6- Amino-N-methyl -2- ((naphthalene -2- ylmethyl) amino) caproamide dihydrochloride
Step 1:(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo-hexyl) ammonia Base t-butyl formate.According to embodiment 33, by N6- (tert-butoxycarbonyl)-N2- (naphthalene -2- ylmethyl)-L-lysine (193mg, 0.5mmol) and methylamine hydrochloride (34mg, 0.5mmol) prepare title compound, obtain semisolid title compound Object (156mg, 78% yield).ESI-MS m/z[M+H]+C23H33N3O3, theoretical value 400；Measured value 400.
Step 2: according to embodiment 1, the product (80mg, 0.2mmol) obtained by above-mentioned steps 1 prepares title compound Object obtains canescence colloidal solid (100% yield).1H NMR(500MHz,DMSO-d6)δ9.85(s,1H),9.35(s,1H), 8.63 (q, J=4.7Hz, 1H), 8.14-7.80 (m, 7H), 7.79-7.39 (m, 3H), 4.22 (q, J=13.1Hz, 2H), 3.88–3.36(m,1H),2.79–2.70(m,2H),2.50(s,3H),2.10–1.06(m,6H)。ESI-MS m/z[M+H]+ C18H25N3O, theoretical value 300；Measured value 300.
Embodiment 125:(2S) two hydrochloric acid of -6- amino -2- (benzylamino)-N- (bis- (oxygroup in the heptan) propyl of 2,3-) caproamide Salt
Step 1:((5S) -5- (benzylamino) -6- ((bis- (oxygroup in the heptan) propyl of 2,3-) amino) -6- oxo-hexyl) amino T-butyl formate.According to 93 step 3 of embodiment, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (400mg, 1.19mmol) and bis- (oxygroup in the heptan) propane -1- amine (347mg, 1.19mmol) of 2,3- prepare title compound, obtain semisolid Title compound (370mg, 51% yield).ESI-MS m/z[M+H]+C35H63N3O5, theoretical value 606；Measured value 606.
Step 2: above compound being dissolved in methanol (2mL), is added methanol HCl (10mL), it is small to stir 3 at room temperature When, solvent is concentrated under vacuum to dry, obtains title compound (100% yield).1H NMR(300MHz,DMSO-d6)d ppm:10.0(br s,1H),9.4-9.2(br s,1H),8.8-8.6(s,1H),8.0(s,3H),7.6-7.3(m,5H),4.0 (s,2H),3.8-3.6(s,1H),3.6-3.2(m,10H),3.2(m,1H),2.8-2.6(m,2H),2.0-1.7(m,2H), 1.6-1.4(m,4H),1.4-1.0(m,18H),0.8(m,6H)。ESI-MS m/z[M+H]+C30H55N3O3, theoretical value 506；It is real Measured value 506.
Embodiment 126:(2S) -6- amino -2- (benzylamino)-N- (bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) Caproamide dihydrochloride
Step 1:((5S) -5- (benzylamino) -6- ((bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) amino) -6- Oxo-hexyl) t-butyl carbamate.According to 93 step 3 of embodiment, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine Bis- (5- methoxypentyloxy) the propyl- 1- amine .HCl (476mg, 1.637mmol) of (400mg, 1.19mmol) and 2,3- prepare title Compound obtains semisolid title compound (400mg, 55% yield).ESI-MS m/z[M+H]+C33H59N3O7, theoretical value 610；Measured value 610.
Step 2: above compound being dissolved in methanol (2mL), methanol HCl (10mL) is added and is stirred at room temperature 3 Hour, solvent is concentrated under vacuum to dry, obtains title compound (100% yield).1H NMR(300MHz,DMSO-d6)d ppm:10.0-9.8(br s,1H),9.3(br s,1H),8.7(s,1H),8.0(s,3H),7.6-7.3(m,5H),4.0(s, 2H),3.8-3.7(s,1H),3.6-3.3(m,11H),3.0(s,6H),2.8-2.6(m,2H),2.0-1.7(m,2H),1.6- 1.3(m,18H)。ESI-MS m/z[M+H]+C28H51N3O5, theoretical value 510；Measured value 510.
Embodiment 127:(S)-(5- (benzylamino) -6- oxo -6- (myristyl amino) hexyl) tertiary fourth of carbamic acid Ester
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and The tetradecane -1- amine (107mg, 0.5mmol) prepares title compound, obtain colloidal solid title compound (155mg, 58% Yield).ESI-MS m/z[M+H]+C32H57N3O3, theoretical value 532；Measured value 532.
Embodiment 128:(S)-(5- (benzylamino) -6- (Decylamino) -6- oxo-hexyl) t-butyl carbamate
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and Decyl- 1- amine (79mg, 0.5mmol) prepares title compound, obtains semisolid title compound (158mg, 66% yield). ESI-MS m/z[M+H]+C28H49N3O3, theoretical value 476；Measured value 476.
Embodiment 129:(S)-(5- (benzylamino) -6- ((3- ethoxycarbonyl propyl) amino) -6- oxo-hexyl) amino first Tert-butyl acrylate
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and 3- ethoxy-c -1- amine (52mg, 0.5mmol) prepares title compound, obtain semisolid title compound (153mg, 73% Yield).ESI-MS m/z[M+H]+C23H39N3O4, theoretical value 422；Measured value 422.
Embodiment 130:(S)-(5- (benzylamino) -6- ((3- (octyloxy) propyl) amino) -6- oxo-hexyl) amino T-butyl formate
According to embodiment 33, by N2Benzyl-N6(tert-butoxycarbonyl)-L-lysine (168mg, 0.5mmol) and 3 3- (octyloxy) propyl- 1- amine (112mg, 0.5mmol) prepares title compound, obtains semisolid title compound (172mg, 68% yield).ESI-MS m/z[M+H]+C29H51N3O4, theoretical value 506；Measured value 506.
Embodiment 131:(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo oneself Base) t-butyl carbamate
According to embodiment 33, by N6- (tert-butoxycarbonyl)-N2- (naphthalene -2- ylmethyl)-L-lysine (193mg, 0.5mmol) and 2- cyclohexyl second -1- amine (82mg, 0.5mmol) prepares title compound, obtains semisolid title compound (182mg, 73% yield).ESI-MS m/z[M+H]+C30H45N3O3, theoretical value 496；Measured value 496.
Embodiment 132:(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo oneself Base) t-butyl carbamate
According to embodiment 33, by N6- (tert-butoxycarbonyl)-N2- (naphthalene -2- ylmethyl)-L-lysine (193mg, 0.5mmol) and methylamine hydrochloride (34mg, 0.5mmol) prepares title compound, obtains semisolid title compound (156mg, 78% yield).ESI-MS m/z[M+H]+C23H33N3O3, theoretical value 400；Measured value 400.
Embodiment 133:(2S) -6- amino-N- (3- ethyoxyl -2- hydroxypropyl) -2- ((naphthalene -2- ylmethyl) amino) oneself Carboxamide dihydrochloride
Step 1:((5S) -6- ((3- ethyoxyl -2- hydroxypropyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxygen For hexyl) t-butyl carbamate.According to embodiment 33, by N6(tert-butoxycarbonyl)-N2(naphthalene -2- ylmethyl)-L- Lysine (according to embodiment 56 synthesize) (194mg, 0.5mmol) and 1- amino -3- ethyoxyl propan-2-ol (60mg, Title compound 0.5mmol) is prepared, the title compound (173mg, 71% yield) of yellow liquid is obtained.ESI-MS m/z[M+ H]+C27H41N3O5, theoretical value 488；Measured value 488.
Step 2: according to 1 step 2 of embodiment, the product obtained by above-mentioned steps 1 (98mg, 0.2mmol) prepares titled Object is closed, yellow liquid (100% yield) is obtained.1H NMR(500MHz,DMSO-d6)δ9.76(s,1H),9.34(s,1H),8.63 (s,1H),8.12–7.78(m,8H),7.76–7.38(m,3H),4.21(s,2H),4.05–3.62(m,3H),3.53–3.22 (m, 6H), 3.09 (td, J=13.8,7.1Hz, 1H), 2.04-1.68 (m, 2H), 1.56 (q, J=7.7Hz, 2H), 1.35 (s, 2H), 1.12 (dd, J=7.4,6.5Hz, 3H).ESI-MS m/z[M+H]+C22H33N3O3, theoretical value 388；Measured value 388.
Embodiment 134:(S) -6- amino -2- (benzylamino)-N- (2- (oxygroup in heptan) ethyl) caproamide dihydrochloride
Step 1:(S)-(5- (benzylamino) -6- ((2- (oxygroup in heptan) ethyl) amino) -6- oxo-hexyl) carbamic acid The tert-butyl ester.According to 93 step 3 of embodiment, by (S) -2- (benzylamino) -6- (tertbutyloxycarbonylamino) caproic acid (400mg, 1.19mmol) and 2- (oxygroup in heptan) ethamine (189mg, 1.19mmol) prepares title compound, obtains semisolid title compound Object (380mg, 67% yield).ESI-MS m/z[M+H]+C27H47N3O4, theoretical value 478；Measured value 478.
Step 2: above compound being dissolved in methanol (2mL), is added methanol HCl (10mL), it is small to be stirred at room temperature 3 When, evaporation solvent obtains title compound (100% yield) to doing.1H NMR(300MHz,DMSO-d6)δ10.0(br s, 1H),9.3(br s,1H),8.8(s,1H),8.1(s,2H),7.6-7.3(m,5H),4.0(s,2H),3.7(s,1H),3.5- 3.2(m,6H),2.8-2.6(m,2H),1.9-1.4(m,8H),1.4-1.0(m,8H),0.9-0.7(m,3H)。ESI-MS m/z [M+H]+C22H39N3O2, theoretical value 378；Measured value 378.
Embodiment 135:(2S) -6- amino -2- (benzylamino)-N- (2- (oxygroup in heptan) -3- methoxy-propyl) caproamide Dihydrochloride
Step 1:((5S) -5- (benzylamino) -6- ((2- (oxygroup in heptan) -3- methoxy-propyl) amino) -6- oxo oneself Base) t-butyl carbamate.According to 93 step 3 of embodiment, by (S) -2- (benzylamino) -6- (tertbutyloxycarbonylamino) oneself Sour (400mg, 1.19mmol) and 2- (oxygroup in heptan) 3- methoxy propane -1- amine hydrochlorate (241mg, 1.19mmol) prepare title Compound obtains semisolid title compound (350mg, 56% yield).ESI-MS m/z[M+H]+C29H51N3O5, theoretical value 522；Measured value 522.
Step 2: above compound being dissolved in methanol (2mL), is added methanol HCl (10mL), it is small to be stirred at room temperature 3 When, evaporation solvent obtains title compound (100% yield) to doing.1H NMR(300MHz,DMSO-d6)δ9.7(br s,1H), 9.3(br s,1H),8.7(s,1H),8.0-7.8(s,2H),7.6-7.3(m,5H),4.0(s,2H),3.8-3.6(s,1H), 3.5-3.2(m,8H),2.8-2.6(m,3H),2.9-2.7(m,2H),1.6-1.4(m,4H),1.4-1.1(m,12H),0.9- 0.7(m,3H)。ESI-MS m/z[M+H]+C24H43N3O3, theoretical value 422；Measured value 422.
It can be used and similar method those of is described herein prepares following compound.
Embodiment 136:N- (1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) the amino) -1- oxo tetradecane -2- base) -5- Fluoro- 1H- indoles -3- formamide
Embodiment 137:N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((1- (the fluoro- 1H- indol-3-yl of 5-) tetradecane Base) amino) acetamide
Embodiment 138:3- ((1- (1H- indol-3-yl) myristyl) amino)-N- (bis- (tetradecyloxyanilines) third of 2,3- Base) propionamide
Embodiment 139:2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- guanidine radicals propionamide
Using with similar method those of be described herein prepare title compound by bis- (octadecane epoxide) the propyl- 2- amine of 1,3- Object.
Embodiment 140:2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- (1H- imidazoles -5- base) propionamide
Embodiment 141:2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- (1H- indoles -2- base) propionamide
Embodiment 142:2,5- diamino-N-(bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) pentanamide
Embodiment 143:2,6- diamino-N-(bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) caproamide
Biological Examples 1: the preparation that liposome is formed
8 milligrams of embodiments 13 are dissolved in 1 milliliter of chloroform.Gained colourless transparent solution is filled using Bueche rotovap It sets and is evaporated under 40 DEG C of decompressions.
Uniform nearly transparent coating is obtained on glass wall, and the 1X PBS buffer solution of 1mL pH7.3 is inwardly added.It will Reaction flask is vortexed 3 minutes, obtains the cloudy suspension of liposome.Then reaction flask is immersed in ultra sonic bath 3 minutes, then with 5 Second interval repeats probe sonication 5 times.Then translucent solution is repeated to squeeze out 10 times by 100nm molecular filter, and will be several Clear solution storage is at 4 DEG C.The scattering of differential light is carried out to the solution using Wyatt (dynapro) device, is put down as the result is shown Equal partial size is 120nm, the coefficient of dispersion 0.15.
This method, which can be used for preparing, has other nonactive lipids (such as commercially those of sale (Avantis polar lipid Matter)) mixture Liposomal formulation.
Biological Examples 2: in vitro test
The trigalloyl of two acylated lipoprotein (Pam2CSK4, TLR2/6 agonists) and synthesis of synthesis is obtained from InvivoGen Change lipoprotein (Pam3CSK4, TLR1/2 agonist), and be dissolved in the concentration in the water of endotoxin-free to 1mg/mL, is vortexed straight To being completely dissolved, and stored at -20 DEG C with aliquot.TNF α is obtained from Thermo Fischer Scient Inc. (Thermo Fisher Scientific), and it is used as the counter-selection choosing to the specificity of TLR signal transduction.It is dissolved in the water of endotoxin-free to concentration For 0.2mg/ml, and -20 DEG C are stored in aliquot.Before cell is added, the ligand of the dissolution of equal portions is vortexed in short-term, Then it is diluted to 25ng/mL Pam2CSK4,1000ng/mL Pam3CSK4 or TNF α in the medium.It is surveyed every time for determining Surely the agonist EC run50Final upper concentration be 5ng/mL (Pam2CSK4) or 200ng/mL (Pam3CSK4 or TNF α).
By test compound fresh lysate in the 3-10mM stock solution in 50%DMSO/50%EtOH, and in water-bath It is ultrasonically treated 5-10 minutes in ultrasonoscope.Serial dilutions are prepared in 50%DMSO/50%EtOH, then in the medium Dilution.The ultimate density that the ultimate density of DMSO used in measurement is 0.5%, EtOH is 0.5%.
HEK-Blue hTLR2 reporter cell (hero company (InvivoGen)) is to stablize expression people TLR2 gene and NF κ B The HEK-293 cell of secretion embryonic alkaline phosphatase (SEAP) the report construct in promoter site downstream.According to manufacturer Scheme, using contain 1X GlutaMax (Gibco), 10% heat-inactivated fetal calf serum (Gibco), Pen-Strep (50U/mL Penicillin, 50 μ g/mL streptomysins, Gibco), 100 μ g/mL Normocin (InvivoGen) and selective antibiotic, 1x HEK-Blue selects the Da Shi of (InvivoGen) to improve Yi Shi culture medium (DMEM；Gibco)) culture HEK-Blue hTLR2 report Road molecule.The Quanti-Blue reagent (InvivoGen) for the alkaline phosphatase that is used to detect and quantitatively secrete is dissolved in In the water of 100mL endotoxin-free, it is warmed to 37 DEG C and is kept for 30 minutes, then filtered using 0.2 μm of film.
HEK-Blue hTLR2 antagonistic effect
On day 1, every kind of test chemical compound diluted liquid of 50 μ L is duplicate or each of 96 orifice plates are added in vehicle Control Then 150 μ L HEK-Blue hTLR2 cell suspending liquids (1 × 10 are added in Kong Zhong5A cells/well) and in 37 DEG C/5%CO2Temperature It educates 2 hours.Then, by the approximate EC of 50 every kind of agonists of μ L (Pam2CSK4, Pam3CSK4 or TNF α)50Concentration be added to containing It tests in the hole of compound or vehicle Control.By cell in 37 DEG C/5%CO2It is lower to be incubated for 18 hours.For measuring operation every time, Untreated HEK-Blue hTLR2 cell is handled with the agonist of serial dilution to determine the EC accordingly run50Value.
On day 2, alkaline phosphatase (SEAP) activity of secretion is detected in cell culture supernatant.In short It, collects 20 μ L from each hole and is transferred to 96 orifice plates.Then, 200 μ L Quanti-Blue detection examination is added into each hole Agent.Plate is incubated at room temperature 15 minutes, and SEAP activity is assessed at 655nm by spectrophotometer OD reading.Table 7 is shown Compound is to Pam2CSK4, the activity of Pam3CSK4 and TNF α.Compound indicates the activity of Pam2CSK4 and Pam3CSK4 Subtract the IC of the response of the cell handled after background signal with agonist50Value.IC of the compound of embodiment 93 to TNF α50For 10μM.Every other compound is as shown in table 7 to the activity of TNF α, IC50Value≤30 μM are expressed as (+), IC50> 30 μM of expressions of value For (-).
Table 7:

Claims (79)

1. a kind of compound of formula (I):
Wherein
R1It is H ,-CO2-C1-8Alkyl ,-CO2-CHRaAryl ,-CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) virtue Base ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)-CHRaHeteroaryl ,-CHRaAryl ,-CHRaHeteroaryl ,- SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl；
Wherein RaIt is H or C1-15Alkyl；
RbIt is H or-C1-5Alkyl-NReRf；
Wherein ReIt is H or C1-4Alkyl, RfIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
RcIt is H or C1-4Alkyl, RdIt is H, C1-4Alkyl or-CO2C1-4Alkyl；And
Each aryl or heteroaryl are respectively optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4 Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl ,-OC1-4Alkyl-aryl-group or-CO2C1-4Alkyl；
R2It is H or C1-4Alkyl；
R3aIt is H ,-C6-14Alkyl ,-CHRgAryl ,-CHRgHeteroaryl ,-CHRgHeterocyclylalkyl ,-C1-4Alkyl-NRhRi,–C1-4 Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk；
RgIt is H or C1-4Alkyl；
RhIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
RiIt is H, C1-4Alkyl or-C (=NH)-NHRm；
Wherein RmIt is H ,-SO2Aryl or-CO2C1-4Alkyl；
RjIt is H or C1-4Alkyl；And
RkIt is H or C1-4Alkyl；
And wherein each aryl, heteroaryl and Heterocyclylalkyl are respectively optionally replaced by following group :-OH, C1-4Alkyl ,- CO2C1-4Alkyl, phenyl or benzyloxy；
Or R2And R3aAtom connected to them is formed together C2-4Alkylidene；
R3bIt is H；Or R3aAnd R3bCarbon atom connected to them is formed together 4- to 7- membered heterocycloalkyl, optionally by C1-4Alkane Base or-CO2C1-4Alkyl replaces；
R4It is H or C1-4Alkyl；
R5It is C8-16Alkyl or C8-16Alkenyl；
R6It is C8-16Alkyl or C8-16Alkenyl；
M is 0 or 1；
N is 0 or 1；And
P is 0 or 1；
Wherein at least one in n and p is 1；
Or its pharmaceutically acceptable salt；
On condition that the compound is not the compound or its pharmaceutically acceptable salt of table 1x.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R1It is H ,-CO2-C1-8Alkyl ,-CO2- CHRaAryl ,-CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRb- NRcRd,-C(O)-CHRaHeteroaryl ,-CHRaAryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2It is miscellaneous Aryl；Or H；Or-CO2-C1-8Alkyl；Or-CO2-CHRaAryl or-CO2-CHRaHeteroaryl；Or-C (O)-C1-4 Alkyl ,-C (O) aryl or-C (O)-heteroaryl；Or-C (O)-CHRb-NRcRd；Or-C (O)-CHRaHeteroaryl；Or- CHRaAryl or-CHRaHeteroaryl；Or-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R1It is H ,-CO2-CHRaAryl ,- CO2-CHRaHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRaHeteroaryl ,-CHRa- Aryl ,-CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.
4. compound as claimed in any one of claims 1-3 or its pharmaceutically acceptable salt, wherein the R1Aryl is benzene Base；Or the R1Aryl is fluorenyl；Or the R1Heteroaryl is bicyclic heteroaryl；Or the R1Heteroaryl is indyl, benzo furan It mutters base, benzothienyl, benzoxazolyl or benzothiazolyl；Or the R1Heteroaryl is indyl.
5. such as compound of any of claims 1-4 or its pharmaceutically acceptable salt, wherein the R1Aryl is miscellaneous Aryl is unsubstituted；Or the R1Aryl or heteroaryl are independently selected by one or more from substituent group below and replace: halogen Element, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl and-OC1-4Alkyl-aryl-group；Or institute State R1Aryl or heteroaryl are replaced by following substituent group: methyl, fluorine, phenyl, benzyloxy or tert-butoxycarbonyl.
6. compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, wherein R1It is-CO2-CH2- Fluorenyl, acetyl group or benzyloxycarbonyl group；Or R1It is tert-butoxycarbonyl；Or R1It is substituted or unsubstituted benzyl；Or R1It is by halogen The benzyl that element or phenyl replace.
7. such as compound of any of claims 1-6 or its pharmaceutically acceptable salt, wherein RaIt is H；Or RaIt is C1-15Alkyl；Or RaIt is C10-15Alkyl.
8. such as compound of any of claims 1-7 or its pharmaceutically acceptable salt, wherein RbIt is H；Or RbBe- C1-5Alkyl-NReRf。
9. such as compound of any of claims 1-8 or its pharmaceutically acceptable salt, wherein ReIt is H；Or ReIt is C1-4Alkyl.
10. compound as claimed in any one of claims 1-9 wherein or its pharmaceutically acceptable salt, wherein RfIt is H；Or RfIt is C1-4Alkyl；Or RfIt is-CO2C1-4Alkyl.
11. such as compound of any of claims 1-10 or its pharmaceutically acceptable salt, wherein RcIt is H；Or RcIt is C1-4Alkyl.
12. such as compound of any of claims 1-11 or its pharmaceutically acceptable salt, wherein RdIt is H；Or RdIt is C1-4Alkyl；Or RdIt is-CO2C1-4Alkyl.
13. such as compound of any of claims 1-12 or its pharmaceutically acceptable salt, wherein R2It is H；Or R2It is C1-4Alkyl.
14. such as compound of any of claims 1-13 or its pharmaceutically acceptable salt, wherein R1And R2All it is Hydrogen.
15. compound or its pharmaceutically acceptable salt as described in any one of claim 1-14, wherein R3aIt is H；Or R3a It is-C6-14Alkyl；Or R3aIt is-CHRgAryl ,-CHRgHeteroaryl or-CHRgHeterocyclylalkyl；Or R3aIt is-C1-4Alkyl- NRhRi；Or R3aIt is-C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk.In some embodiments In, R3aIt is substituted or unsubstituted-CH2Phenyl；Or R3aIt is that-CH is replaced by benzyloxy, hydroxyl or phenyl2Phenyl；Or R3a It is-CH2Imidazole radicals is optionally replaced by tert-butoxycarbonyl；Or R3aIt is-CH2Indyl；Or R3aIt is-CH2Piperidines, optionally Ground is replaced by tert-butoxycarbonyl；Or R3aIt is butylamine, is optionally replaced by tert-butoxycarbonyl；Or R3aPropylamine, optionally by Guanidine radicals replaces, wherein the guanidine radicals is optionally substituted；Or R3aIt is carboxyethyl, is optionally replaced by tert-butyl；Or R3aIt is carboxylic first Base is optionally replaced by tert-butyl.
16. compound or its pharmaceutically acceptable salt as described in any one of claim 1-15, wherein the R3aAryl It is phenyl；Or the R3aHeteroaryl is pyrrole radicals, imidazole radicals, indyl or benzimidazolyl；Or the R3aHeteroaryl is pyrrole Cough up base or indyl；Or the R3aHeterocyclylalkyl is monocyclic heterocycloalkyl；Or the R3aHeterocyclylalkyl is pyrrolidinyl or piperazine Base；Or the R3aAryl, heteroaryl and Heterocyclylalkyl are unsubstituted；Or the R3aAryl, heteroaryl and Heterocyclylalkyl quilt- OH、C1-4Alkyl or-CO2C1-4Alkyl replaces；Or the R3aAryl and heteroaryl are optionally replaced by phenyl or benzyloxy.
17. compound or its pharmaceutically acceptable salt as described in any one of claim 1-16, wherein RgIt is H；Or RgIt is C1-4Alkyl.
18. compound or its pharmaceutically acceptable salt as described in any one of claim 1-17, wherein RhIt is H；Or RhIt is C1-4Alkyl；Or RhIt is-CO2C1-4Alkyl.
19. compound or its pharmaceutically acceptable salt as described in any one of claim 1-18, wherein RiIt is H；Or RiIt is C1-4Alkyl；Or RiIt is-C (=NH)-NHRm。
20. compound or its pharmaceutically acceptable salt as described in any one of claim 1-19, wherein RmIt is H；Or Rm It is-SO2Phenyl；Or RmIt is-CO2C1-4Alkyl.
21. compound or its pharmaceutically acceptable salt as described in any one of claim 1-20, wherein RjIt is H；Or RjIt is C1-4Alkyl.
22. compound or its pharmaceutically acceptable salt as described in any one of claim 1-21, wherein RkIt is H；Or RkIt is C1-4Alkyl.
23. compound or its pharmaceutically acceptable salt as described in any one of claim 1-22, wherein R2And R3aTogether Form C2-4Alkylidene；Or R2And R3aIt is formed together C3Alkylidene.
24. compound or its pharmaceutically acceptable salt as described in any one of claim 1-23, wherein R3bIt is H；Or R3a And R3bCarbon atom connected to them is formed together 4- to 7- membered heterocycloalkyl, optionally by C1-4Alkyl or-CO2C1-4Alkyl Replace.
25. compound or its pharmaceutically acceptable salt as described in any one of claim 1-24, wherein R3aAnd R3bAll it is Hydrogen.
26. compound or its pharmaceutically acceptable salt as described in any one of claim 1-25, wherein R4It is H；Or R4It is C1-4Alkyl.
27. compound or its pharmaceutically acceptable salt as described in any one of claim 1-26, wherein R5And R6Respectively solely It is on the spot C8-16Alkyl or C8-16Alkenyl；Or R5And R6It is C each independently8-16Alkyl；Or R5And R6It is identical；Or R5And R6 It is different；Or R5And R6It is straight-chain hydrocarbons；Or R5And R6Individually C14Alkyl.
28. compound or its pharmaceutically acceptable salt as described in any one of claim 1-27, wherein R5And R6Respectively solely It is on the spot C13-16Alkyl or C13-16Alkenyl.
29. compound or its pharmaceutically acceptable salt as described in any one of claim 1-27, wherein R5And R6Respectively solely It is on the spot C8-11Alkyl, C13-16Alkyl, C8-11Alkenyl or C13-16Alkenyl.
30. compound as claimed in claim 29, wherein R1It is H ,-CO2-C1-8Alkyl ,-CO2-CHRaHeteroaryl ,-C (O)- C1-4Alkyl ,-C (O) aryl ,-C (O)-heteroaryl ,-C (O)-CHRb-NRcRd,-C(O)-CHRaHeteroaryl ,-CHRaAryl ,- CHRaHeteroaryl ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl.
31. the compound as described in claim 29 or 30, wherein R3aIt is H ,-C6-14Alkyl ,-CHRgAryl ,-CHRgHeterocycle Alkyl ,-C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk。
32. compound or its pharmaceutically acceptable salt as described in any one of claim 1-27, wherein R5And R6Respectively solely It is on the spot C14Alkyl or C14Alkenyl.
33. compound or its pharmaceutically acceptable salt as described in any one of claim 1-32, wherein m is 0；Or m is 1。
34. compound or its pharmaceutically acceptable salt as described in any one of claim 1-33, wherein n is 0；Or n is 1。
35. compound or its pharmaceutically acceptable salt as described in any one of claim 1-34, wherein p is 0；Or p is 1。
36. compound or its pharmaceutically acceptable salt as described in any one of claim 1-35, it is 0 that wherein n, which is 1 and p,； Or it is 1 that n, which is 0 and p,.
37. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R1It is-CO2-C1-8Alkyl or-C (O)-CHRb-NRcRd, and R3aIt is-C6-14Alkyl ,-CHRgAryl ,-CHRgHeteroaryl ,-CHRgHeterocyclylalkyl ,-C1-4Alkyl- NRhRi,–C1-4Alkyl-CO2C1-4Alkyl ,-C1-4Alkyl-CO2Or-C H,1-4Alkyl-CONRjRk。
38. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R1It is-CO2-C1-8Alkyl, m are 1.
39. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R1It is-CO2-C1-8Alkyl, R2It is C1-4Alkyl.
40. a kind of compound selected from the group below:
((2S) -3- (4- (benzyloxy) phenyl) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo propyl- 2- yl) T-butyl carbamate；
(2S) -2- amino -3- (4- (benzyloxy) phenyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxo propyl- 2- yl) ammonia Base t-butyl formate；
(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- indol-3-yl) propionamide；
(2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidines -1- carboxylate tert-butyl ester；
(2S)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- formamide；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (4- hydroxy phenyl) -1- oxo propyl- 2- yl) amino T-butyl formate；
(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (4- hydroxy phenyl) propionamide；
((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- diyl) diamino acid (9H- Fluorenes -9- base) methyl tertbutyl ester；
((2S) -6- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo hex- 2- yl) carbamic acid (9H- Fluorenes -9- base) methyl ester；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxo propyl- 2- yl) ammonia Base formic acid (9H- fluorenes -9- base) methyl ester；
((2R) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- (1H- indol-3-yl) -1- oxo propyl- 2- yl) ammonia Base t-butyl formate；
(2R) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- indol-3-yl) propionamide；
(4S) -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -4- ((tert-butoxycarbonyl) amino) -5- oxopentanoic acid uncle Butyl ester；
(4S) -4- amino -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- oxopentanoic acid；
(2R) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidines -1- carboxylic acid tert-butyl ester；
(2R)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- formamide；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((4- aminomethyl phenyl) sulfonamido) acetamide；
4- ((2S) -3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -2- ((tert-butoxycarbonyl) amino) -3- oxo third Base) -1H- imidazoles -1- carboxylic acid tert-butyl ester；
(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (1H- imidazol-4 yl) propionamide；
(3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- oxopropyl) t-butyl carbamate；
3- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
(3S) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- ((tert-butoxycarbonyl) amino) -4- ketobutyric acid uncle Butyl ester；
(3S) -3- amino -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -4- ketobutyric acid；
(2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -2- oxoethyl) (methyl) t-butyl carbamate；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (methylamino) acetamide；
(3S) -3- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) - The 4- ketobutyric acid tert-butyl ester；
(3S) -3- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) - 4- ketobutyric acid；
(4S) -4- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) - 5- oxopentanoate；
(4S) -4- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -5- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) - 5- oxopentanoic acid；
((5R) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- diyl) diamino acid benzyl uncle Butyl ester；
((2R) -6- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo hex- 2- yl) carbamic acid benzyl Ester；
((2R) -3- ([1,1 '-xenyl] -4- base) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo propyl- 2- Base) t-butyl carbamate；
(2R) -3- ([1,1 '-xenyl] -4- base) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
((2S) -3- ([1,1 '-xenyl] -4- base) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo propyl- 2- Base) t-butyl carbamate；
(2S) -3- ([1,1 '-xenyl] -4- base) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
((5S) -6- ((2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidin-1-yl) -6- oxo hex- 1,5- diyl) diamino acid di tert butyl carbonate ester；
(2S) -1- (L- lysyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) pyrrolidines -2- formamide；
(2- ((2S) -2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) pyrrolidin-1-yl) -2- oxoethyl) amino T-butyl formate；
(2S)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -1- glycyl pyrrolidines -2- formamide；
3- (2- (5- (benzyloxy) -1H- indol-3-yl) acetylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (3- tosyl guanidine radicals) amyl- 2- Base) carbamic acid (9H- fluorenes -9- base) methyl ester；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (1,3- bis- (tert-butoxies)) guanidine radicals) Amyl- 2- yl) carbamic acid (9H- fluorenes -9- base) methyl ester；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) the amyl- 2- yl of -5- guanidine radicals -1- oxo) carbamic acid (9H- Fluorenes -9- base) methyl ester；
((2S) -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -5- (3- tosyl guanidine radicals) amyl- 2- Base) t-butyl carbamate；
(2S) -2- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -5- (3- tosyl guanidine radicals) pentanamide；
((2S) -4- amino -1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1,4- dioxo butyl- 2- yl) carbamic acid The tert-butyl ester；
The tertiary fourth of ((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo hex- 1,5- diyl) diamino acid two Ester；
(2S) -2,6- diamino-N-(bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide；
((5S) -5- acetylaminohydroxyphenylarsonic acid 6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo-hexyl) tertiary fourth of carbamic acid Ester；
(2S) -2- acetylaminohydroxyphenylarsonic acid 6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide；
4- (2- ((((9H- fluorenes -9- base) methoxyl group) carbonyl) amino) -3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -3- Oxopropyl) piperidines -1- carboxylic acid tert-butyl ester；
(1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -1- oxo -3- (piperidin-4-yl) propyl- 2- yl) carbamic acid (9H- fluorenes -9- base) methyl ester hydrochloride；
4- (((benzyloxy) carbonyl) amino) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) piperidines -1- carboxylic acid uncle Butyl ester；
(4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) piperidin-4-yl) carbamic acid benzyl ester；
((5S) -5- (([1,1 '-xenyl] -4- ylmethyl) amino) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) - 6- oxo-hexyl) t-butyl carbamate；
(2S) -2- (([1,1 '-xenyl] -4- ylmethyl) amino) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) oneself Amide；
((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- ((4- luorobenzyl) amino) -6- oxo-hexyl) amino T-butyl formate；
(2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((4- luorobenzyl) amino) caproamide；
((5S) -5- (benzylamino) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo-hexyl) carbamic acid uncle Butyl ester；
(2S) -6- amino -2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide；
((5R) -5- (benzylamino) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -6- oxo-hexyl) carbamic acid uncle Butyl ester；
((2R) -6- amino -2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide；
3- ((((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl oxygroup) -3,16- dioxa -5,12- phenodiazine Miscellaneous melissane -10- base) amino) methyl) -1H- indoles -1- carboxylic acid tert-butyl ester；
(2S) -2- (((1H- indol-3-yl) methyl) amino) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) caproamide Dihydrochloride；
3- (2- (((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl oxygroup) -3,16- dioxa -5,12- two Azepine melissane -10- base) amino) -2- oxoethyl) -5- methoxyl group -1H- indoles -1- carboxylic acid tert-butyl ester；
(2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (2- (5- methoxyl group -1H- indol-3-yl) acetyl ammonia Base) hexanoyl amine hydrochlorate；
5- (benzyloxy) -3- (2- (((10S) -2,2- dimethyl -4,11- dioxo -14- (myristyl oxygroup) -3,16- two Oxa- -5,12- diaza melissane -10- base) amino) -2- oxoethyl) -1H- indoles -1- carboxylic acid tert-butyl ester；
(2S) -6- amino -2- (2- (5- (benzyloxy) -1H- indol-3-yl) acetylamino)-N- (2,3- bis- (tetradecyloxyanilines) Propyl) hexanoyl amine hydrochlorate；
((5S) -6- ((bis- (tetradecyloxyaniline) propyl of 2,3-) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo-hexyl) T-butyl carbamate；
Two hydrochloric acid of (2S) -6- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((naphthalene -2- ylmethyl) amino) caproamide Salt；
N- (1- ((bis- (tetradecyloxyaniline) propyl of 2,3-) the amino) -1- oxo tetradecane -2- base) fluoro- 1H- indoles -3- first of -5- Amide；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- ((1- (the fluoro- 1H- indol-3-yl of 5-) myristyl) amino) acetamide；
3- ((1- (1H- indol-3-yl) myristyl) amino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) propionamide；
2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- guanidine radicals propionamide；
2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- (1H- imidazoles -5- base) propionamide；
2- amino-N- (bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) -3- (1H- indoles -2- base) propionamide；
2,5- diamino-N-(bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) pentanamide；With
2,6- diamino-N-(bis- (octadecane epoxide) the propyl- 2- yls of 1,3-) caproamide,
And its pharmaceutically acceptable salt.
41. a kind of compound of formula (IV):
Wherein
G1It is N or CH；
R41It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R41’It is not present or H or C1-4Alkyl；Wherein work as R41’It is H or C1-4When alkyl, with R41’The nitrogen of connection has positive charge；
R42It is H or C1-4Alkyl；
R43It is-OC1-18Alkyl ,-OC1-18Alkenyl ,-C1-18Alkyl or-C1-18Alkenyl is respectively optionally replaced by following group :- OH、-OC1-4Alkyl ,-C (O) OH ,-C (O) OC1-4Alkyl ,-C (O) NHR4bOr aryl；And
R44It is-OC4-18Alkyl or-OC4-18Alkenyl is each optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O) OC1-4Alkyl ,-C (O) NHR4cOr aryl；
Wherein R4bAnd R4cIt is H or C each independently1-4Alkyl；
Or its pharmaceutically acceptable salt.
42. compound as claimed in claim 41 or its pharmaceutically acceptable salt, wherein G1It is N.
43. compound as claimed in claim 41 or its pharmaceutically acceptable salt, wherein G1It is CH.
44. compound or its pharmaceutically acceptable salt as described in any one of claim 41-43, wherein R41It is H, methyl Or tert-butoxycarbonyl.
45. compound or its pharmaceutically acceptable salt as described in any one of claim 41-44, wherein R41’It is not present.
46. compound or its pharmaceutically acceptable salt as described in any one of claim 41-45, wherein R42It is H.
47. compound or its pharmaceutically acceptable salt as described in any one of claim 41-46, wherein R43It is OC1-18 Alkyl ,-OC1-18Alkenyl ,-C1-18Alkyl or-C1-18Alkenyl, wherein the alkyl or alkenyl is optionally by-OH or-OC1-4Alkyl Replace.
48. compound or its pharmaceutically acceptable salt as described in any one of claim 41-47, wherein R44It is OC4-18 Alkyl or-OC4-18Alkenyl, wherein the alkyl or alkenyl is optionally replaced by following group :-OH ,-OC1-4Alkyl ,-C (O) OC1-4Alkyl ,-C (O) NH2,–C(O)NHC1-4Alkyl or phenyl.
49. a kind of compound selected from the group below:
4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperazine -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (piperazine -1- base) benzamide hydrochloride salt；
4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt；
4- (2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperazine -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperazine -1- base) benzamide hydrochloride salt；
4- (2- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperidin-4-yl) benzamide hydrochloride salt；
4- (4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperazine -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- (piperazine -1- base) benzamide hydrochloride salt；
4- (4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) piperidines -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- (piperidin-4-yl) benzamide hydrochloride salt；
4- (3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) phenyl) -1,1- lupetidine -1-- iodide；
N- (bis- (oxygroup in the heptan) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt；
N- (bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt；
N- (3- (benzyloxy) -2- (dodecyloxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt；
5- (2- (dodecyloxy) -3- (3- (piperidin-4-yl) benzamido) propoxyl group) methyl valerate hydrochloride；
5- (2- (dodecyloxy) -3- (3- (piperidin-4-yl) benzamido) propoxyl group) valerate hydrochlorate；
N- (2- (dodecyloxy) -3- ((5- (methylamino) -5- oxopentyl) oxygroup) propyl) -3- (piperidin-4-yl) benzene Carboxamide hydrochloride；
N- (3- ((5- amino-5-oxo amyl) oxygroup) -2- (dodecyloxy) propyl) -3- (piperidin-4-yl) benzamide Hydrochloride；
N- (3- (octyloxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt；
3- (piperidin-4-yl)-N- myristyl benzamide hydrochloride salt；
N- (3- (2- methoxy ethoxy) propyl) -3- (piperidin-4-yl) benzamide hydrochloride salt；
N- (3- ethyoxyl -2- hydroxypropyl) -3- (piperidin-4-yl) benzamide hydrochloride salt；
4- (3- ((bis- (((Z)-ten four -8- alkene -1- base) oxygroup) propyl of 2,3-) carbamyl) phenyl) tertiary fourth of piperidines -1- carboxylic acid Ester；
N- (bis- (((Z)-ten four -8- alkene -1- base) oxygroup) propyl of 2,3-) -3- (piperidin-4-yl) benzamide hydrochloride salt；
4- (3- ((bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl of 2,3-) Carbamoylphenyl) piperidines - 1- carboxylic acid tert-butyl ester；With
N- (bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl of 2,3-) -3- (piperidin-4-yl) benzamide Hydrochloride,
Or its pharmaceutically acceptable salt.
50. a kind of compound of formula (V):
Wherein
G2It is key ,-CH2-、–CH2NH- or-CH2NHCH2-；
G3It is-C (O)-or-CH2-；
R51It is H, C1-4Alkyl ,-CO2C1-4Alkyl, heterocycle or-C1-4Alkyl-NR5aR5b；Wherein R5aIt is H or C1-4Alkyl, R5bIt is H、C1-4Alkyl or-CO2C1-4Alkyl；And
R52It is H or C1-4Alkyl；
Or R51And R52Carbon connected to them is formed together optionally by-CO2C1-4Alkyl-substituted Heterocyclylalkyl；
R53It is H or C1-4Alkyl；
O is 0 or 1；
R is 0 or 1；
S is 0 or 1；
R54It is C8-18Alkyl or C8-18Alkenyl；And
R55It is C8-18Alkyl or C8-18Alkenyl；
Or its pharmaceutically acceptable salt.
51. compound as claimed in claim 50 or its pharmaceutically acceptable salt, wherein G2It is key.
52. compound as claimed in claim 50 or its pharmaceutically acceptable salt, wherein G2It is-CH2-。
53. compound as claimed in claim 50 or its pharmaceutically acceptable salt, wherein G2It is-- CH2NH- or- CH2NHCH2-。
54. compound or its pharmaceutically acceptable salt as described in any one of claim 50-53, wherein G3It is-C (O)-.
55. compound or its pharmaceutically acceptable salt as described in any one of claim 50-53, wherein G3It is-CH2-。
56. compound or its pharmaceutically acceptable salt as described in any one of claim 50-55, wherein R51Be H or- C1-4Alkyl-NR5aR5b；Wherein R5aIt is H or C1-4Alkyl, R5bIt is H, C1-4Alkyl or-CO2C1-4Alkyl.
57. compound or its pharmaceutically acceptable salt as described in any one of claim 50-56, wherein R52It is H.
58. compound or its pharmaceutically acceptable salt as described in any one of claim 50-55, wherein R51And R52With it The carbon that is connected be formed together Heterocyclylalkyl；Wherein the Heterocyclylalkyl is optionally replaced by tert-butoxycarbonyl.
59. compound or its pharmaceutically acceptable salt as described in any one of claim 50-55, wherein R51And R52With it The carbon that is connected be formed together piperidyl, optionally by-CO2C1-4Alkyl replaces.
60. a kind of compound selected from the group below:
4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) -4- Phenylpiperidine -1- carboxylic acid tert-butyl ester；
N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -4- Phenylpiperidine -4- carboxamide hydrochloride；
3- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- phenylpropionyl amine hydrochlorate；
3- benzyl -3- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) piperidines -1- carboxylic acid tert-butyl ester；
3- benzyl-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) piperidines -3- carboxamide hydrochloride；
2- (benzylamino)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) -2- (piperidin-4-yl) acetamide hydrochloride；
4- ((benzylamino) methyl)-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) piperidines -4- carboxamide hydrochloride；
Bis- (tetradecyloxyaniline) propane -1- amine of N- benzyl -2,3-；With
Bis- (tetradecyloxyaniline) propane -1- ammonium-iodide of N- benzyl-N, N- dimethyl -2,3-,
Or its pharmaceutically acceptable salt.
61. a kind of compound of formula (VI):
Wherein
R61It is H ,-CO2-C1-8Alkyl ,-CO2-CHR6aAryl ,-CO2-CHR6aHeteroaryl ,-C (O)-C1-4Alkyl ,-C (O) virtue Base ,-C (O)-heteroaryl ,-C (O)-CHR6b-NR6cR6d,-C(O)-CHR6aHeteroaryl ,-CHR6aAryl ,-CHR6aHeteroaryl Base ,-SO2-C1-4Alkyl ,-SO2Aryl or-SO2Heteroaryl；
Wherein R6aIt is H or C1-15Alkyl；
R6bIt is H or-C1-5Alkyl-NR6eR6f；
R6cIt is H or C1-4Alkyl；
R6dIt is H, C1-4Alkyl or-CO2C1-4Alkyl；
R6eIt is H or C1-4Alkyl；
R6fIt is H, C1-4Alkyl or-CO2C1-4Alkyl；And
Each aryl or heteroaryl are respectively optionally replaced by following group: halogen, C1-4Alkyl, C1-4Fluoroalkyl ,-OH ,-OC1-4 Alkyl ,-OC1-4Fluoroalkyl ,-CN, phenyl or-OC1-4Alkyl-aryl-group；
R62It is H or C1-4Alkyl；
R66It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R67It is H, C1-4Alkyl or-C (=NH)-NHR6m；
Wherein R6mIt is H ,-SO2Aryl or-CO2C1-4Alkyl；
R63It is H or C1-4Alkyl；
R64It is H or-OH,
Or R64It is-C1-18Alkyl ,-C1-18Alkenyl ,-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4 Alkyl replaces；
R65It is H or-C4-8Naphthenic base,
Or R65It is-C1-18Alkyl ,-C1-18Alkenyl ,-OC1-12Alkyl or-OC1-12Alkenyl, respectively optionally by-OH or-OC1-4 Alkyl replaces；And
T is 0 or 1；
Or its pharmaceutically acceptable salt.
62. compound as claimed in claim 61 or its pharmaceutically acceptable salt, wherein R61It is-CH2Phenyl or-CH2Naphthalene Base.
63. compound or its pharmaceutically acceptable salt as described in claim 61 or 62, wherein R62It is H.
64. compound or its pharmaceutically acceptable salt as described in any one of claim 61-63, wherein R66Be H or- CO2C1-4Alkyl.
65. compound or its pharmaceutically acceptable salt as described in any one of claim 61-64, wherein R66And R67All it is H。
66. compound or its pharmaceutically acceptable salt as described in any one of claim 61-65, wherein R63It is H or first Base.
67. compound or its pharmaceutically acceptable salt as described in any one of claim 61-66, wherein R64Be H or- OH。
68. compound or its pharmaceutically acceptable salt as described in any one of claim 61-66, wherein R64It is-C1-18 Alkyl ,-C1-18Alkenyl ,-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces.
69. compound or its pharmaceutically acceptable salt as described in any one of claim 61-68, wherein R65Be H or- C4-8Naphthenic base.
70. compound or its pharmaceutically acceptable salt as described in any one of claim 61-68, wherein R65It is-C1-18 Alkyl ,-C1-18Alkenyl ,-OC1-18Alkyl or-OC1-18Alkenyl, respectively optionally by-OH or-OC1-4Alkyl replaces.
71. a kind of compound selected from the group below:
((5R) -5- (benzylamino) -6- ((bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroup) propyl of 2,3-) ammonia Base) -6- oxo-hexyl) t-butyl carbamate；
(2R) -6- amino -2- (benzylamino)-N- (bis- (((9Z, 12Z)-ten eight -9,12- diene -1- base) oxygroups) third of 2,3- Base) caproamide dihydrochloride；
(S) -6- amino -2- (benzylamino)-N- myristyl caproamide dihydrochloride；
(S) -6- amino -2- (benzylamino)-N- decyl caproamide dihydrochloride；
(S) -6- amino -2- (benzylamino)-N- (3- ethoxycarbonyl propyl) caproamide dihydrochloride；
(S) -6- amino -2- (benzylamino)-N- (3- (octyloxy) propyl) caproamide dihydrochloride；
(S) -6- amino-N- (2- cyclohexyl-ethyl) -2- ((naphthalene -2- ylmethyl) amino) caproamide dihydrochloride；
(S) -6- Amino-N-methyl -2- ((naphthalene -2- ylmethyl) amino) caproamide dihydrochloride；
(2S) -6- amino -2- (benzylamino)-N- (bis- (oxygroup in the heptan) propyl of 2,3-) caproamide dihydrochloride；
Two hydrochloric acid of (2S) -6- amino -2- (benzylamino)-N- (bis- ((5- methoxypentyl) oxygroup) propyl of 2,3-) caproamide Salt；
(S)-(5- (benzylamino) -6- oxo -6- (myristyl amino) hexyl) t-butyl carbamate；
(S)-(5- (benzylamino) -6- (Decylamino) -6- oxo-hexyl) t-butyl carbamate；
(S)-(5- (benzylamino) -6- ((3- ethoxycarbonyl propyl) amino) -6- oxo-hexyl) t-butyl carbamate；
(S)-(5- (benzylamino) -6- ((3- (octyloxy) propyl) amino) -6- oxo-hexyl) t-butyl carbamate；
(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo-hexyl) the tertiary fourth of carbamic acid Ester；
(S)-(6- ((2- cyclohexyl-ethyl) amino) -5- ((naphthalene -2- ylmethyl) amino) -6- oxo-hexyl) the tertiary fourth of carbamic acid Ester；
(2S) -6- amino-N- (3- ethyoxyl -2- hydroxypropyl) -2- ((naphthalene -2- ylmethyl) amino) caproamide dihydrochloride；
(S) -6- amino -2- (benzylamino)-N- (2- (oxygroup in heptan) ethyl) caproamide dihydrochloride；With
(2S) -6- amino -2- (benzylamino)-N- (2- (oxygroup in heptan) -3- methoxy-propyl) caproamide dihydrochloride,
Or its pharmaceutically acceptable salt.
72. a kind of compound of formula (II):
Wherein
R21It is H, C1-4Alkyl or-CO2C1-4Alkyl；
R22It is H or C1-4Alkyl；
R24It is H or C1-4Alkyl；
R25It is C8-16Alkyl or C8-16Alkenyl；
R26It is C8-16Alkyl or C8-16Alkenyl；
N2 is 0 or 1；And
P2 is 0 or 1；
Wherein at least one in n2 and p2 is 1；
Or its pharmaceutically acceptable salt.
73. a kind of compound selected from the group below:
((cis-) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) cyclohexyl) t-butyl carbamate；
(cis-) -4- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) hexamethylene -1- formamide；
((trans-) -4- ((bis- (tetradecyloxyaniline) propyl of 2,3-) carbamyl) cyclohexyl) t-butyl carbamate；With
(trans-) -4- amino-N- (bis- (tetradecyloxyaniline) propyl of 2,3-) hexamethylene -1- formamide；
And its pharmaceutically acceptable salt.
74. a kind of compound of formula (III):
Wherein
R31It is phenyl or bicyclic heteroaryl；
R32It is H or C1-4Alkyl；
R33It is C1-4Alkyl-NRxRy；
Wherein RxIt is H, C1-4Alkyl or-CO2-C1-4Alkyl；With
RyIt is H or C1-4Alkyl；
R34It is H or C1-4Alkyl；And
R35It is C14-18Alkyl or C14-18Alkenyl；
Or its pharmaceutically acceptable salt.
75. a kind of compound selected from the group below:
(6- (18-9- alkene-1- base amino)-6- oxo hex- 1,5- diyl) (R, Z)-diamino acid benzyl tertiary butyl ester；
(R, Z)-(6- amino-1- (18-9- alkene-1- base amino)-1- oxo hex- 2- yl) carbamic acid benzyl ester；
(6- oxo -6- (myristyl amino) hex- 1,5- diyl) (R)-diamino acid benzyl tertiary butyl ester；With
(R)-(6- amino -1- oxo -1- (myristyl amino) hex- 2- yl) carbamic acid benzyl ester；
And its pharmaceutically acceptable salt.
76. a kind of pharmaceutical composition, it includes at least one compound as described in any one of claim 1-75 or its medicines Acceptable salt on optionally also includes pharmaceutically acceptable excipient.
77. a kind of method for treating disease relevant to TLR2 heterodimerization or illness, the method includes controlling to needs are this kind of The object for the treatment of is given a effective amount of at least one compound as described in any one of claim 1-75 or its and can pharmaceutically be connect The salt received.
78. the method stated such as claim 77, wherein the disease or illness are selected from the group: Alzheimer's disease, Parkinson Family name's disease, frontotemporal dementia, dementia with Lewy body (lewy body disease), dull-witted Parkinson's disease, multi-system atrophy, amyotrophic lateral sclerosis are prosperous The court of a feudal ruler disease, inflammation disease, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcer, pulmonary tuberculosis, rheumatoid joint Inflammation, chronic nasosinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriasis Arthritis, vasculitis, laryngitis, allergic reaction, multiple sclerosis, Crohn disease, traumatic brain injury, CIDP (chronic inflammation Property Demyelinating Polyneuropathy), atopic dermatitis, acne vulgaris, brandy nose, non-alcoholic fatty liver disease, non-alcoholic Steatohepatitis, corneal wound, cornea disorder, this special Graves disease (juvenile macular degeneration), age-related macular degeneration lose Mass formed by blood stasis, diabetic keratopathy wound, herpes simplex virus and antimycotic, antibacterium, antiviral and antitumor disease or illness.
79. the heterodimerization of TLR2 in a kind of interference cell, or adjust, prevent, slow down, reverse or inhibit TLR2 different two in cell The method of dimerization, including make cell and a effective amount of at least one compound as described in any one of claim 1-75 or its Salt and/or at least one pharmaceutical composition as described in claim 76 are in contact, wherein the contact be it is external, it is in vitro or In vivo.
CN201780048372.3A 2016-08-03 2017-08-01 Regulator of amino 1,2- and the 1,3- diol compound that lipid replaces as TLR2 dimerization Pending CN109715167A (en)

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