CN101198583A

CN101198583A - Compounds which inhibit beta-secretase activity and methods of use

Info

Publication number: CN101198583A
Application number: CNA2006800207195A
Authority: CN
Inventors: A·K·高希; N·库马拉古鲁巴兰; 刘春峰; T·德瓦萨穆德拉姆; 雷晖; L·斯旺森; S·安卡拉; J·唐; G·比尔塞尔
Original assignee: Oklahoma Medical Research Foundation; University of Illinois; Purdue Research Foundation; CoMentis Inc
Current assignee: Oklahoma Medical Research Foundation; University of Illinois; Purdue Research Foundation; CoMentis Inc
Priority date: 2005-04-08
Filing date: 2006-04-10
Publication date: 2008-06-11
Also published as: ZA200709236B

Abstract

The present invention provides novel beta-secretase inhibitors of the general formula (I), where the variables A<1>, A<2>, L<1>, L<2>, L<3>, R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and R<7> are as defined in the claims, a method for their use in treating Alzheimer's disease, and methods for their use in reducing memapsin 2 catalytic activity.

Description

Suppress active compound of beta-secretase (SECRETASE) and using method thereof

The cross reference of related application

The application requires to reach in the rights and interests of the U.S. Patent application 60/717,541 of submission on September 14th, 2005 in the U.S. Patent application 60/669,541 that on April 8th, 2005 submitted to, the whole separately reference that is incorporated herein as all purposes of these applications.

About under the research or exploitation subsidized in federal government

The statement of the right of the invention of carrying out

Support, under fund AG-18933 that gives by NIH and AI-38189, carried out the present invention by government.Government has some right among the present invention.

Background of invention

Alzheimer's disease is a kind of people's carrying out property mental deterioration, especially causes lethe, entanglement and disorientation.Alzheimer's disease accounts for the major part of senile dementia, is adult's main causes of death (Natl.Vital Stat.Rep.49:1-87 (2001), the instruction integral body of the document is incorporated herein for Anderson, R.N.).On histology, the brain of suffering from the people of alzheimer's disease is characterized as mainly by amyloid beta in the brain (A β) and gathers in the caused cell neuroneme distortion and have senile plaque, and these senile plaques are by the particulate state with amyloid core or threadly have a liking for banking group and formed.A β accumulate in this disease generation and the development in bringing into play effect (Selkoe, DJ., Nature 399:23-31 (1999)), it is the proteolytic fragments of amyloid precursor protein (APP).APP at first generates A β (Lin, people such as X., Proc.Natl.Acad.Sci.USA 97:1456-1460 (2000) by beta-secretase (also being called memapsin 2) cutting and then by the gamma-secretase cutting; De Stropper, people such as B., Nature 397:387-390 (1998)).

Need exploitation to be used for the treatment of the active compound and the method for alzheimer's disease.The present invention has realized these and other needs.

Summary of the invention

The invention provides new beta-secretase inhibitor and using method thereof, comprise the method for the treatment of alzheimer's disease.

On the one hand, the invention provides beta-secretase inhibitor compound with (I) formula:

In formula (I), R ¹Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted C ₃-C ₂₀Alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y.

R ⁵Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ²And R ³Be independently halogen ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y.

R ⁴Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y.

R ⁶And R ⁷Be-S (O) independently ₂R ¹¹,-C (O) R ¹²,-NR ⁸R ⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y.

Symbol n represents 0 to 2 integer.

R ⁸Be-C (O) R independently ¹³,-S (O) ₂R ¹⁴, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ⁹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.

R ¹⁰Be-C (O) R independently ¹³, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ¹¹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.If n is 2, then R ¹¹Choose wantonly and be-NR ¹⁵R ¹⁶If n is 1 or 2, then R ¹¹Not hydrogen.

R ¹²Be independently-NR ¹⁸R ¹⁹,-OR ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ¹³Be independently-OR ¹⁹,-NR ¹⁸R ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ¹⁴Be independently-NR ¹⁸R ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

R ¹⁸And R ¹⁹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.

R ¹⁵And R ¹⁶Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.

L ¹And L ³Be independently valence link ,-NR ¹⁷-,-S (O) _q-, replacement or unsubstituted alkylidene group or replacement or unsubstituted assorted alkylidene group.L ²Be replace or unsubstituted alkylidene group ,-NR ¹⁷-,-S (O) _q-or replacement or unsubstituted assorted alkylidene group.

R ¹⁷Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.

Symbol q represents 0 to 2 integer.

A ¹And A ²Be to replace or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.Y is a carrier part.

L ⁴Be valence link ,-OP (OH) ₂O-,-C (O) OR ²⁰-,-C (O) NHR ²¹-,-S (O) ₂NHR ²²-, replacement or unsubstituted alkylidene group, replacement or unsubstituted assorted alkylidene group or peptidyl connect base.

R ²⁰, R ²¹And R ²²Be replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.

In another aspect of this invention, beta-secretase inhibitor compound of the present invention can be used for respectively with respect to do not have beta-secretase inhibitor in the presence of reduce memapsin 2 catalytic activitys, reduce the beta-secretase site hydrolysis of memapsin 2 substrates and/or reduce the method that amyloid beta gathers for the amount gathered of memapsin 2 catalytic activitys, the hydrolysis of beta-secretase site and amyloid beta.

On the other hand, the invention provides the pharmaceutical composition of the combination that comprises memapsin 2 beta-secretase inhibitor compounds of the present invention or memapsin 2 beta-secretase inhibitor compounds and pharmaceutically acceptable carrier.

In another aspect of this invention, the beta-secretase inhibitor compound of the present invention hydrolysis of beta-secretase site and/or the amyloid beta that can be used for the treatment of with beta-secretase activity, beta amyloid precursor protein gathers diseases associated or illness.Usually, treat mammiferous disease or illness.In exemplary, this disease is an alzheimer's disease.

Detailed Description Of The Invention

Shortenings and definition

Shortenings used herein has its conventional sense in the chemistry and biology field.Chemical structure that this paper proposes and chemical formula make up according to the standard rule of known chemical valence in the chemical field.

When the substituting group group was illustrated by the chemical formula of its routine of writing from left to right, they comprised the substituting group that chemically is equal to that is produced by writing this structure from right to left equally, for example-and CH ₂O-is equal to-OCH ₂-.

Term " alkyl " itself or as other substituent a part of expression straight chain (promptly not having branch) or side chain or the combination of the two, these chains can be saturated fully, single or polynary undersaturated and can comprise divalence and multivalence group, and having specified carbonatoms (is C ₁-C ₁₀Represent 1 to 10 carbon), other has except the explanation.The example of stable hydrocarbon group includes but not limited to for example following group: the homologue and the isomer of methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, (cyclohexyl) methyl, homologue and isomer such as n-pentyl, n-hexyl, n-heptyl, n-octyl etc.Unsaturated alkyl is to have one or more pair of key or triple-linked alkyl.The example of unsaturated alkyl includes but not limited to vinyl, 2-propenyl, butenyl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1, the 4-pentadienyl), ethynyl, 1-and 3-proyl, 3-butynyl and more high-grade homologue and isomer.Alkoxyl group is to connect the base (O-) alkyl that is connected with the remainder of molecule by oxygen.

Term " alkylidene group " itself or as other substituent a part of expression by alkyl deutero-divalent group, such as but not limited to-CH ₂CH ₂CH ₂CH ₂-, this term also comprises hereinafter as " assorted alkylidene group " described those groups.Usually, alkyl (or alkylidene group) can have 1 to 24 carbon atom, preferably has 10 or those groups of carbon atom still less in the present invention." low alkyl group " or " low-grade alkylidene " is to have 8 or the still less short-chain alkyl or the alkylidene group of carbon atom usually.

Term " assorted alkyl " itself or represent to comprise that at least one carbon atom and at least one are selected from the heteroatoms of O, N, P, Si and S and nitrogen and sulphur atom can be chosen wantonly oxidized and nitrogen heteroatom can be chosen wantonly by quaternised stable straight or branched or cyclic hydrocarbon group wherein during with other term combination, perhaps their combination, other has except the explanation.Heteroatoms O, N, P and S and Si can be positioned at any interior location of assorted alkyl or be positioned at the position that alkyl is connected with the remainder of molecule.Example includes but not limited to-CH ₂-CH ₂-O-CH ₃,-CH ₂-CH ₂-NH-CH ₃,-CH ₂-CH ₂-N (CH ₃)-CH ₃,-CH ₂-S-CH ₂-CH ₃,-CH ₂-CH ₂,-S (O)-CH ₃,-CH ₂-CH ₂-S (O) ₂-CH ₃,-CH=CH-O-CH ₃,-Si (CH ₃) ₃,-CH ₂-CH=N-OCH ₃,-CH=CH-N (CH ₃)-CH ₃, O-CH ₃,-O-CH ₂-CH ₃With-CN.Maximum 2 heteroatomss can be adjacent, for example-and CH ₂-NH-OCH ₃With-CH ₂-O-Si (CH ₃) ₃Similarly, term " assorted alkylidene group " itself or as other substituent part expression by assorted alkyl deutero-divalent group, such as but not limited to-CH ₂-CH ₂-S-CH ₂-CH ₂-and-CH ₂-S-CH ₂-CH ₂-NH-CH ₂-.For assorted alkylidene group, heteroatoms can also occupy an one or both ends (for example alkylidene group oxygen base, alkylenedioxy group, alkylidene amino, alkylidene group diamino etc.) of two chain ends.In addition, for alkylidene group and assorted alkylidene group linking group, linking group does not position by the direction that the structural formula of linking group is write.For example, formula-C (O) ₂R '-both represented-C (O) ₂R '-, expression-R ' C (O) again ₂-.As mentioned above, assorted as used herein alkyl comprises those groups that are connected with the remainder of molecule by heteroatoms, for example-C (O) R ' ,-C (O) NR ' ,-NR ' R " ,-OR ' ,-SR ' and/or-SO ₂R '.When describing " assorted alkyl ", describing specific assorted alkyl as-NR ' R then " when waiting, should be appreciated that the assorted alkyl of term with-NR ' R " is not unnecessary or mutually exclusive.Or rather, describing specific assorted alkyl can be clearer.Therefore, term " assorted alkyl " should not be construed as in this article get rid of specific assorted alkyl, for example-NR ' R " etc.

Term " cycloalkyl " and " Heterocyclylalkyl " itself or represent the annular form of " alkyl " and " alkyl of mixing " during with the combination of other term respectively, other has except the explanation.In addition, for Heterocyclylalkyl, heteroatoms can also occupy the position that heterocycle is connected with the remainder of molecule.The example of cycloalkyl includes but not limited to cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, suberyl etc.The example of Heterocyclylalkyl includes but not limited to 1-(1,2,5,6-tetrahydro pyridyl), piperidino, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetramethylene sulfide-2-base, tetramethylene sulfide-3-base, 1-piperazinyl, 2-piperazinyl etc.

Term " halogeno-group " or " halogen " itself or as other substituent a part of expression fluorine, chlorine, bromine or iodine atom, other has except the explanation.In addition, term also is intended to comprise single haloalkyl and multi-haloalkyl as " haloalkyl ".For example, term " halo (C ₁-C ₄) alkyl " be intended to include but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl etc.

The polynary undersaturated aromatic hydrocarbons substituting group of term " aryl " expression, described aromatic hydrocarbons substituting group can be monocycles or condense together or covalently bound many rings (preferred 1 to 3 ring) that other has except the explanation.Term " heteroaryl " refers to contain 1 to 4 heteroatomic aromatic yl group (or ring) that is selected from N, O and S, and wherein nitrogen and sulphur atom are optional oxidized and nitrogen-atoms is optional by quaternized.Heteroaryl can be connected with the remainder of molecule by carbon or heteroatoms.The limiting examples of aryl and heteroaryl comprises phenyl, the 1-naphthyl, the 2-naphthyl, the 4-xenyl, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 3-pyrazolyl, the 2-imidazolyl, the 4-imidazolyl, pyrazinyl, 2- azoles base, 4- azoles base, 2-phenyl-4- azoles base, 5- azoles base, the different  azoles of 3-base, the different  azoles of 4-base, the different  azoles of 5-base, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl-, the 5-indyl, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.Each aryl of above indication and the substituting group of heteroaryl ring system are selected from following acceptable substituting group.

For briefly, when term " aryl " and other term are used in combination (for example aryloxy, aryl sulphur oxygen base (arylthioxy), arylalkyl), this term had both comprised aryl rings as defined above, comprised heteroaryl ring as defined above again.Thereby, term " arylalkyl " is intended to comprise those groups (for example benzyl, styroyl, pyridylmethyl etc.) that aryl wherein is connected with alkyl, and described alkyl comprises those alkyl (for example Phenoxymethyl, 2-pyridyloxy methyl, 3-(1-naphthyloxy) propyl group etc.) that carbon atom (for example methylene radical) has wherein been replaced by for example Sauerstoffatom.

Term " oxo base " expression is by two keys and carbon atom bonded oxygen as used herein.

Term " alkyl sulphonyl " expression has formula-S (O as used herein ₂The part of)-R ', wherein R ' is an alkyl as defined above.R ' can have the carbon (" C for example of given number ₁-C ₄Alkyl sulphonyl ").

Above term (for example " alkyl ", " assorted alkyl ", " aryl " and " heteroaryl ") is intended to comprise the replacement of described group separately and does not replace form.The preferred substituted of all types of groups provides hereinafter.

The substituting group of alkyl and assorted alkyl (comprising those groups that are commonly referred to alkylidene group, alkenyl, assorted alkylidene group, heterochain thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl) can be one or more various groups, and described group is selected from but is not limited to :-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R  ,-OC (O) R ' ,-C (O) R ' ,-CO ₂R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R  ,-NR " C (O) ₂R ' ,-NR-C (NR ' R " R )=NR  ' ,-NR-C (NR ' R ")=NR  ,-S (O) R ' ,-S (O) ₂R ' ,-S (O) ₂NR ' R " ,-NRSO ₂R ' ,-CN and-NO ₂, its number is 0 to (2m '+1), wherein m ' is the sum of carbon atom in the described group.R ', R ", R  and R  ' preferably refer to hydrogen, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl (for example aryl that is replaced by 1-3 halogen), replacement or unsubstituted alkyl, alkoxyl group or thio alkoxy or arylalkyl separately independently.When compound of the present invention comprises an above R group, each R group is independently selected, as each R ', R ", R  and R  ' group, if there are these groups more than." when being connected with same nitrogen-atoms, they can form 4,5,6 or 7 yuan of rings with the nitrogen-atoms combination as R ' and R.For example ,-NR ' R " is intended to include but not limited to 1-pyrrolidyl and 4-morpholinyl.To substituent discussion, it will be appreciated by those skilled in the art that term " alkyl " is intended to comprise following group by above: comprise with group but not the group of hydrogen group bonded carbon atom, for example haloalkyl (for example-CF ₃With-CH ₂CF ₃) and acyl group (for example-C (O) CH ₃,-C (O) CF ₃,-C (O) CH ₂OCH ₃Deng).

With similar to the described substituting group of alkyl, the substituting group of aryl and heteroaryl has multiple and for example is selected from the following group that number is 0 overall number of stating a price to the aromatic ring system: halogen ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R  ,-OC (O) R ' ,-C (O) R ' ,-CO ₂R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R  ,-NR " C (O) ₂R ' ,-NR-C (NR ' R " R )=NR  ' ,-NR-C (NR ' R ")=NR  ,-S (O) R ' ,-S (O) ₂R ' ,-S (O) ₂NR ' R " ,-NRSO ₂R ' ,-CN and-NO ₂,-R ' ,-N ₃,-CH (Ph) ₂, fluorine (C ₁-C ₄) alkoxyl group and fluorine (C ₁-C ₄) alkyl; Wherein R ', R ", R  and R  ' preferably be independently selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl.When compound of the present invention comprises an above R group, each R group is independently selected, as each R ', R ", R  and R  ' group, if there are these groups more than.

Can choose the formula of formation-T-C (O)-(CRR ') wantonly for two in the substituting group on aryl rings or the heteroaryl ring adjacent atom _qThe ring of-U-, wherein T and U be independently-NR-,-O-,-CRR '-or singly-bound, q is 0 to 3 integer.Perhaps, two in the substituting group on aryl rings or the heteroaryl ring adjacent atom can choose (the CH by formula-A-wantonly ₂) _rThe substituting group of-B-is replaced, wherein A and B be independently-CRR '-,-O-,-NR-,-S-,-S (O)-,-S (O) ₂-,-S (O) ₂NR '-or singly-bound, r is 1 to 4 integer.So in the singly-bound of the new ring that forms can choose wantonly by two keys and replace.Perhaps, two in the substituting group on aryl rings or the heteroaryl ring adjacent atom can choose wantonly by formula-(CRR ') _s-X '-(C " R ) _d-substituting group replace, wherein s and d are 0 to 3 integer independently, X ' is-O-,-NR '-,-S-,-S (O)-,-S (O) ₂-or-S (O) ₂NR '.Substituent R, R ', R " and R " preferably are independently selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl.

Term " heteroatoms " or " ring hetero atom " are intended to comprise oxygen (O), nitrogen (N), sulphur (S), phosphorus (P) and silicon (Si) as used herein.

" substituting group " expression is selected from the group with the lower section as used herein:

(A)-OH ,-NH ₂,-SH ,-CN ,-CF ₃,-NO ₂, oxo base, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) be selected from alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that following substituting group replaces by at least one:

(i) the oxo base ,-OH ,-NH ₂,-SH ,-CN ,-CF ₃,-NO ₂, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) be selected from alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that following substituting group replaces by at least one:

(a) the oxo base ,-OH ,-NH ₂,-SH ,-CN ,-CF ₃,-NO ₂, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) be selected from alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl or the heteroaryl that following substituting group replaces by at least one: the oxo base ,-OH ,-NH ₂,-SH ,-CN ,-CF ₃,-NO ₂, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl and unsubstituted heteroaryl.

As used herein " size limited substituting group " or " the substituting group group that size is limited " expression be selected from above to " substituting group " described all substituent groups, wherein, replace or unsubstituted alkyl each replace naturally or unsubstituted C ₁-C ₂₀Alkyl replaces or unsubstituted assorted alkyl respectively replaces or unsubstituted 2 to 20 yuan of assorted alkyl naturally, and each replaces replacement or unsubstituted cycloalkyl or unsubstituted C naturally ₄-C ₈Cycloalkyl replaces or unsubstituted Heterocyclylalkyl respectively replaces or unsubstituted 4 to 8 yuan of Heterocyclylalkyls naturally.

As used herein " rudimentary substituting group " or " rudimentary substituting group group " expression be selected from above to " substituting group " described all substituent groups, wherein, replace or unsubstituted alkyl each replace naturally or unsubstituted C ₁-C ₈Alkyl replaces or unsubstituted assorted alkyl respectively replaces or unsubstituted 2 to 8 yuan of assorted alkyl naturally, and each replaces replacement or unsubstituted cycloalkyl or unsubstituted C naturally ₅-C ₇Cycloalkyl replaces or unsubstituted Heterocyclylalkyl respectively replaces or unsubstituted 5 to 7 yuan of Heterocyclylalkyls naturally.

Term " pharmacologically acceptable salt " is intended to comprise the salt with the active compound of nontoxic relatively acid or alkali preparation, and this depends on the concrete substituting group of finding on compound as herein described.When compound of the present invention contains relative tart functional group, can obtain base addition salt by separately or in suitable inert solvent the neutral form of these compounds is contacted with the required alkali of capacity.The example of pharmaceutically acceptable base addition salt comprises sodium salt, sylvite, calcium salt, ammonium salt, organic hydrogen base salt or magnesium salts or similar salt.When compound of the present invention contains alkaline relatively functional group, can obtain acid salt by separately or in suitable inert solvent the neutral form of these compounds is contacted with the required acid of capacity.The example of pharmaceutically acceptable acid additive salt comprises by mineral acid and relative nontoxic those salt of organic acid deutero-, the salt of described mineral acid for example has hydrochloride, hydrobromate, nitrate, carbonate, supercarbonate, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, vitriol, hydrosulfate, hydriodate or phosphite etc., and described organic acid for example has acetate, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, fumaric acid, lactic acid, amygdalic acid, phthalandione, Phenylsulfonic acid, tosic acid, Citric Acid, tartrate, methylsulfonic acid etc.Comprise that also amino acid salts such as arginic acid salt etc. and organic acid salt such as glucuronate or galacturonic acid (galactunoric acid) salt etc. is (for example referring to people such as Berge, " Pharmaceutical Salts ", Journal OF Pharmaceutical Science, 1977,66,1-19).Some specific compound of the present invention not only contains basic functionality but also contain acidic functionality, and these functional groups allow compound to be converted into alkali or acid salt.

Therefore, compound of the present invention can be used as salt, for example exists with the salt of pharmaceutically acceptable acid.The present invention includes these salt.The example of these salt comprise hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, acetate, citrate, fumarate, tartrate (for example (+)-tartrate, (-)-tartrate or the mixture of the two, comprise racemic mixture), succinate, benzoate and with the salt of amino acid such as L-glutamic acid.Can prepare these salt by method known to those skilled in the art.

The neutral form of compound preferably regenerates by making salt also separate parent compound according to a conventional method with alkali or acid contact.The parent form of compound is in some physical properties, for example be different from various salt forms on the solubleness in polar solvent.

Except salt form, the present invention also provides the compound of prodrug forms.The prodrug of compound as herein described is those compounds that are easy to provide through chemical transformation compound of the present invention under physiological condition.In addition, can also in the environment prodrug be converted into compound of the present invention in vitro by chemistry or biochemical method.For example, when prodrug being placed the transdermal patch storage storehouse of containing suitable enzyme or chemical reagent, this prodrug can slowly be converted into compound of the present invention.

Some compound of the present invention can and comprise the solvation form of hydrated form and exists with the non-solvent form.Usually, the solvation form is equivalent to the non-solvent form, and is included in the scope of the present invention.Some compound of the present invention can be with polymorph or amorphous forms and is existed.Usually, for the purposes that the present invention considered, all physical form all are equivalent, and are intended to comprise within the scope of the invention.

Some compound of the present invention has unsymmetrical carbon (rotophore) or two key; Racemoid, diastereomer, tautomer, geometrical isomer and independent isomer are included in the scope of the present invention.Compound of the present invention does not comprise known in the art very unstable so that can not synthesize and/or isolating those compounds.

Compound of the present invention can also contain the atom isotope of non-natural ratio at the atom place of one or more these compounds of formation.For example, can with radio isotope such as tritium ( ³H), iodine-125 ( ¹²⁵I) or carbon-14 ( ¹⁴C) compound is carried out radio-labeling.All isotopic variations of compound of the present invention (no matter whether being radioactivity) all are included in the scope of the present invention.

" hydrophobic " group is to reduce the solubleness of compound in octane or the group of the solubleness of increase compound in octane.The example of hydrophobic grouping comprises aliphatic group, aryl and aralkyl.

Term " natural amino acid " refers to following 23 kinds of natural amino acids known in the art (preceding 3 letter abbreviations by them are represented) as used herein: Ala, Arg, Asn, Asp, Cys, Cys-Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.Term " amino acid whose side chain " is the substituting group on the natural amino acid alpha-carbon as used herein.

Term " alpha-non-natural amino acid " refers to formula NH ₂-C (R ₃₂) ₂The compound of-COOH, wherein R ₃₂Be any pendant moiety well known by persons skilled in the art independently of one another; The example of alpha-non-natural amino acid includes but not limited to: oxyproline, high proline(Pro), 4-amino-phenylalanine, nor-leucine, Cyclohexylalanine, α-An Jiyidingsuan, N-methyl-L-Ala, N-methyl-glycine, N-methyl-L-glutamic acid, tertiary butyl glycine, butyrine, tertiary butyl L-Ala, ornithine, α-An Jiyidingsuan, 2-aminoidan-2-formic acid etc. and their derivative, and especially when the nitrogen in the amine when coverlet or dialkyl group.

The peptide substituting group is the sequence of the natural or alpha-non-natural amino acid that links together by amido linkage, and this amido linkage forms by the α-carboxylic acid reaction that makes amino acid whose α-amine and adjacent amino acid.The preferred peptide sequence only comprises natural amino acid.In one embodiment, the peptide substituting group is the sequence of about 6 natural amino acids.In another embodiment, the peptide substituting group is the sequence of 2 natural amino acids.In another embodiment, the peptide substituting group is 1 natural amino acid.

" transition state isostere " or " isostere " are to comprise oxyethylamine linking group-CH (OH)-CH as used herein ₂The compound of-NH-.This isostere also is called " oxyethylamine isostere " in this article.The oxyethylamine linking group can find between a pair of natural or alpha-non-natural amino acid of peptide.The oxyethylamine group is the isostere of the transition state of amido linkage hydrolysis.

" memapsin 2 " refer to by NCBI (" the NCBI ") protein that accession number NP_036236 identified (being sometimes referred to as " β-site APP-nickase 1 " or " BACE-1 ") as used herein, comprise homologue, isoform and subdomain (also being called beta-secretase) that it keeps proteolytic activity.The sequence of active memapsin 2 protein and protein fragments (and nucleotide coding sequence) is differentiated before in common pendent U. S. application numbers 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454) and is disclosed and goes through, the whole separately reference that is incorporated herein as all purposes of these applications." memapsin 2 protein " represent the fragment of memapsin 2 protein or its maintenance proteolytic activity of total length as used herein.

" memapsin 1 " refers to comprise homologue, isoform and subdomain that it keeps proteolytic activity by NCBI (" the NCBI ") protein that accession number NP_036237 identified (being sometimes referred to as " β-site APP-nickase 2 " or " BACE-2 ") and/or those (the whole references that are incorporated herein as all purposes of these applications) of before being disclosed and having gone through in common pendent U. S. application numbers 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454) as used herein.

" cathepsin D " refers to comprise homologue, isoform and subdomain that it keeps proteolytic activity by NCBI (" NCBI ") protein that accession number NP_036236 identified (being sometimes referred to as " β-site APP-nickase 1 " or " BACE-1 ") and/or the protein identified by enzymatic structure database (Enzyme Structure Database) subclass EC3.4.23.5. as used herein.

" beta-secretase site " is the aminoacid sequence by active memapsin 2 or the cutting of its active fragments.Special beta-secretase site before also was suggested and went through (the whole reference that is incorporated herein as all purposes of these applications) in common pendent U. S. application numbers 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454), and comprised that Sweden's type mutant nucleotide sequence (Swedish mutation sequence) and natural beta amyloid precursor protein cut sequence.Therefore, can measure the ability that beta-secretase inhibitor reduces substrate such as beta amyloid precursor protein, beta amyloid precursor protein analogue or the site hydrolysis of the segmental beta-secretase of beta amyloid precursor protein.

" beta-secretase inhibitor " refers to can reduce for the activity when not having inhibitor the compound of the proteolytic activity of memapsin 2.

Term is represented one (kind) or a plurality of (kinds) as used herein.In addition, the group of phrase " quilt ... replace " expression indication can be by the one or more replacements in any or all appointment substituting groups as used herein.For example, when group such as alkyl or heteroaryl " by unsubstituted C ₁-C ₂₀Alkyl or unsubstituted 2 to 20 yuan of assorted alkyl replace " time, this group can contain one or more unsubstituted C ₁-C ₂₀Alkyl and/or one or more unsubstituted 2 to 20 yuan of assorted alkyl.

" significant quantity " of compound of the present invention is the amount that obtains its intended purposes effectively.When term " significant quantity " was used for the treatment of in curee's (for example Mammals, people etc.) the context of method, this term was treatment significant quantity (i.e. the amount that described disease or morbid state are obtained to treat effective result effectively)." treatment " comprises prevention and improves specific disease or morbid state, and cure diseases in some cases.

I. beta-secretase inhibitor

On the one hand, the invention provides the compound of inhibition (promptly reducing) beta-secretase (memapsin 2) catalytic activity.These compounds can be called " compound of the present invention ", " beta-secretase inhibitor compound " or " memapsin 2 beta-secretase inhibitors " in this article.Aspect this, compound has formula (I) structure:

R ⁶And R ⁷Be-S (O) independently ₂R ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y.

Symbol n represents 0 to 2 integer.

Symbol q represents 0 to 2 integer.

In some embodiments, L ³Be unsubstituted C ₁-C ₅(C for example ₁-C ₃) alkylidene group.L ³Can also be unsubstituted 2 to 5 yuan of assorted alkylidene groups.In other embodiments, L ³Be-(CH ₂) _e-S-.Symbol e represents 0 to 10 integer.In some embodiments, e is 1.

In some embodiments, R ¹Be hydrogen, halogen ,-NR ⁸R ⁹,-OR ¹⁰Or-S (O) _nR ¹¹In other embodiments, R ¹Be hydrogen ,-NR ⁹S (O) _nR ¹⁴,-OR ¹⁰Or-S (O) _nR ¹¹R ¹Can also be hydrogen or-NR ⁹S (O) _nR ¹⁴

R ⁵, R ⁸, R ⁹, R ¹⁰And R ¹¹Can be hydrogen, replacement or unsubstituted C independently ₁-C ₂₀Alkyl, replacement or unsubstituted 2 to 20 yuan of assorted alkyl, replacement or unsubstituted C ₅-C ₇Cycloalkyl, replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryls or-L ⁴-Y.

In some embodiments of formula (I), replace or each R naturally of unsubstituted alkylidene group ²³-replace or unsubstituted C ₁-C ₂₀Alkylidene group replaces or each R naturally of unsubstituted assorted alkylidene group ²³-replace or unsubstituted 2 to 20 yuan of assorted alkylidene groups, replace or each R naturally of unsubstituted alkyl ²³-replace or unsubstituted C ₁-C ₂₀Alkyl replaces or each R naturally of unsubstituted assorted alkyl ²³-replace or unsubstituted 2 to 20 yuan of assorted alkyl, replace or each R naturally of unsubstituted cycloalkyl ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl replaces or each R naturally of unsubstituted Heterocyclylalkyl ²³-replace or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, replace or each R naturally of unsubstituted heteroaryl ²⁴-replace or unsubstituted heteroaryl, replace or each R naturally of unsubstituted aryl ²⁴-replace or unsubstituted aryl.

R ²³Be independently oxo base, halogen ,-CN ,-CF ₃,-OCF ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl.

R ²⁴Be independently halogen ,-CN ,-CF ₃,-OCF ₃,-OCH ₃, OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl.

Symbol t is 0 to 2 integer independently.

R ²⁷, R ²⁸And R ²⁹Be hydrogen, R independently ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl.If t is 1 or 2, then R ²⁷Not hydrogen.

R ²⁵Be independently oxo base, halogen ,-CN ,-OH ,-CF ₃,-OCF ₃,-OCH ₃, unsubstituted C ₁-C ₂₀Alkyl, unsubstituted 2 to 20 yuan of assorted alkyl, unsubstituted C ₅-C ₇Cycloalkyl, unsubstituted 5 to 7 yuan of Heterocyclylalkyls, unsubstituted aryl or unsubstituted heteroaryls.R ²⁶Be independently halogen ,-CN ,-OH ,-CF ₃,-OCF ₃,-OCH ₃, unsubstituted C ₁-C ₂₀Alkyl, unsubstituted 2 to 20 yuan of assorted alkyl, unsubstituted C ₅-C ₇Cycloalkyl, unsubstituted 5 to 7 yuan of Heterocyclylalkyls, unsubstituted aryl or unsubstituted heteroaryls.

In some embodiments, A ¹And/or A ²Be R independently ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.

In other embodiments, R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And/or R ¹²Be hydrogen, R independently ²³-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²³-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And/or R ¹²Can be to replace or unsubstituted C ₁-C ₂₀Alkyl or replacement or unsubstituted Heterocyclylalkyl.R ², R ³, R ⁴, R ⁸, R ⁹, R ¹⁰, R ¹¹And/or R ¹²Can also be unsubstituted C ₁-C ₂₀Alkyl.R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And/or R ¹²Can also be unsubstituted C ₁-C ₅Alkyl.

R ⁴, R ⁶And/or R ⁷Can be hydrogen, R independently ²³-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²³-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.R ⁴, R ⁶And/or R ⁷Can also be hydrogen or unsubstituted C independently ₁-C ₂₀Alkyl.In some embodiments, R ⁴, R ⁶And/or R ⁷Be hydrogen or unsubstituted C independently ₁-C ₅Alkyl.

R ²⁷, R ²⁸And R ²⁹Can be hydrogen, R independently ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl.R ²³Can be independently oxo base, halogen ,-CN ,-CF ₃,-OCF ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl.R ²⁴Can be independently halogen ,-CN ,-CF ₃,-OCF ₃,-OCH ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl.

In some embodiments, R ²And R ³Can be hydrogen, halogen or unsubstituted C independently ₁-C ₂₀Alkyl.

R ⁵Can be R ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.R ⁵Can also be R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.In some embodiments, R ⁵Be R ²⁴-replace or unsubstituted aryl.In some relevant embodiments, R ²⁴Be halogen ,-CN ,-OH ,-CF ₃, unsubstituted C ₁-C ₂₀Alkyl or unsubstituted alkoxyl group (C for example ₁-C ₂₀Alkoxyl group).R ⁵Can also be halogenophenyl (for example difluorophenyl) or phenyl.In some relevant embodiments, L ₃Be unsubstituted C ₁-C ₅(C for example ₁-C ₃) alkylidene group.

In some embodiments, R ⁵Be selected from and replace or unsubstituted tetrahydrofuran base, replacement or unsubstituted THP trtrahydropyranyl and replacement or unsubstituted pyridine ylmethyl.In some relevant embodiments, L ³Be unsubstituted C ₁-C ₅Alkyl.In other relevant embodiment, L ₃It is methylene radical.

In some embodiments, R ⁵Be R ²⁴-replace or unsubstituted aryl or R ²⁴-replace or unsubstituted heteroaryl (for example replacing or unsubstituted thiazolyl, replacement or unsubstituted  azoles base, replacement or unsubstituted imidazolyl or replacement or unsubstituted pyrazolyl).In some embodiments, R ⁵Be R ²⁴-replace or unsubstituted phenyl (halogenophenyl for example, as 3,5-difluorophenyl) or R ²⁴-replace or unsubstituted thiazolyl.In another relevant embodiment, L ³It is methylene radical.

In some embodiments, R ⁵Be selected from and replace or unsubstituted phenyl; replace or unsubstituted pyrazolyl; replace or unsubstituted furyl; replace or unsubstituted imidazolyl; replace or unsubstituted different  azoles base; replace or unsubstituted  di azoly; replace or unsubstituted  azoles base; replace or unsubstituted pyrryl; replace or the unsubstituted pyridine base; replace or unsubstituted pyrimidyl; replace or unsubstituted pyridazinyl; replace or unsubstituted thiazolyl; replace or unsubstituted triazolyl; replace or unsubstituted thienyl; replace or unsubstituted dihydro-thiophene and pyrazolyl; replace or unsubstituted thianaphthenyl; replace or unsubstituted carbazyl; replace or unsubstituted benzimidazolyl-; replace or unsubstituted benzothienyl; replace or unsubstituted benzofuryl; replace or unsubstituted indyl; replace or the unsubstituted quinolines base; replace or unsubstituted benzotriazole base; replace or unsubstituted benzothiazolyl; replace or unsubstituted benzoxazol base; replace or unsubstituted benzimidazolyl-; replace or unsubstituted isoquinolyl; replace or unsubstituted pseudoindoyl; replace or unsubstituted acridyl; replace or unsubstituted benzoisazolyl (benzisoxa  azoles base); replace or unsubstituted T10; replace or unsubstituted pyrazinyl; replace or unsubstituted tetrahydrofuran base; replace or unsubstituted pyrrolinyl; replace or unsubstituted pyrrolidyl; replace or unsubstituted morpholinyl; replace or unsubstituted indyl; replace or unsubstituted diaza  base; replace or unsubstituted azepine  base; replace or unsubstituted thia  base or replacement or unsubstituted oxa- base.

A ¹And A ²Can be to replace or unsubstituted C independently ₅-C ₇Cycloalkyl, replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.A ¹And/or A ²Can also be to replace or unsubstituted aryl (for example phenyl) or replacement or unsubstituted heteroaryl (for example pyridyl) independently.

In some embodiments, A ¹And A ²Be to replace or unsubstituted phenyl independently; replace or unsubstituted pyrazolyl; replace or unsubstituted furyl; replace or unsubstituted imidazolyl; replace or unsubstituted different  azoles base; replace or unsubstituted  di azoly; replace or unsubstituted  azoles base; replace or unsubstituted pyrryl; replace or the unsubstituted pyridine base; replace or unsubstituted pyrimidyl; replace or unsubstituted pyridazinyl; replace or unsubstituted thiazolyl; replace or unsubstituted triazolyl; replace or unsubstituted thienyl; replace or unsubstituted dihydro-thiophene and pyrazolyl; replace or unsubstituted thianaphthenyl; replace or unsubstituted carbazyl; replace or unsubstituted benzimidazolyl-; replace or unsubstituted benzothienyl; replace or unsubstituted benzofuryl; replace or unsubstituted indyl; replace or the unsubstituted quinolines base; replace or unsubstituted benzotriazole base; replace or unsubstituted benzothiazolyl; replace or unsubstituted benzoxazol base; replace or unsubstituted benzimidazolyl-; replace or unsubstituted isoquinolyl; replace or unsubstituted pseudoindoyl; replace or unsubstituted acridyl; replace or unsubstituted benzoisazolyl (benzisoxa  azoles base); replace or unsubstituted T10; replace or unsubstituted pyrazinyl; replace or unsubstituted tetrahydrofuran base; replace or unsubstituted pyrrolinyl; replace or unsubstituted pyrrolidyl; replace or unsubstituted morpholinyl; replace or unsubstituted indyl; replace or unsubstituted diaza  base; replace or unsubstituted azepine  base; replace or unsubstituted thia  base; replace or unsubstituted piperidyl or replacement or unsubstituted oxa- base.

In some embodiments, L ³And L ¹Be valence link, unsubstituted alkylidene group or unsubstituted assorted alkylidene group independently.In other embodiments, L ³And L ¹Be valence link, unsubstituted C independently ₁-C ₂₀Alkylidene group or unsubstituted 2 to 20 yuan of assorted alkylidene groups.L ³And L ¹Can also be valence link, unsubstituted C independently ₁-C ₅Alkylidene group or unsubstituted 2 to 5 yuan of assorted alkylidene groups.L ³Can also be C ₁-C ₅Alkylidene group.L ¹Can be the unsubstituted C of side chain ₁-C ₅Alkylidene group.

In some embodiments, L ²Be unsubstituted C ₁-C ₂₀Alkylidene group or unsubstituted 2 to 20 yuan of assorted alkylidene groups.In other embodiments, L ²Be unsubstituted C ₁-C ₅Alkylidene group or unsubstituted 2 to 5 yuan of assorted alkylidene groups.L ²Can be unsubstituted C ₁-C ₅Alkylidene group.L ²Can be the unsubstituted C of side chain ₁-C ₅Alkylidene group.L ²It can also be methylene radical.In some relevant embodiments, A ²Be to replace or unsubstituted heteroaryl (for example pyridyl) or replacement or unsubstituted aryl (for example phenyl).In some relevant embodiments, A ¹Be to replace or unsubstituted heteroaryl (for example pyridyl) or replacement or unsubstituted aryl (for example phenyl).

In some embodiments, work as R ¹Be-NR ⁸R ⁹And R ⁸Be-S (O) ₂R ¹⁴The time, R then ⁶Be hydrogen.R ⁷Can be to replace or unsubstituted alkyl.R ⁷Can be unsubstituted C ₁-C ₅Alkyl.R ²And R ³Can all be hydrogen.Therefore, in some embodiments, R ¹Be-NR ⁸R ⁹, R ⁸Be-S (O) ₂R ¹⁴, R ⁶Be hydrogen, R ⁷Be unsubstituted C ₁-C ₅Alkyl, and R ²And R ³Be hydrogen.

In some embodiments, work as R ¹When being hydrogen, R then ⁶Not hydrogen.In some relevant embodiments, R ⁶Be to replace or unsubstituted alkyl.In some relevant embodiments, R ⁶Be unsubstituted C ₁-C ₅Alkyl.In some relevant embodiments, R ⁶Be to replace or unsubstituted C ₃-C ₆Cycloalkyl.In some relevant embodiments, R ⁶Be to replace or unsubstituted cyclopropyl.In some relevant embodiments, R ⁷Be hydrogen.In some relevant embodiments, R ²And R ³Be hydrogen.

In some embodiments, R ¹Be hydrogen.R ², R ³And R ⁴Can be hydrogen.A ¹Can be to replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.In some relevant embodiments, A ¹Be to replace or unsubstituted heteroaryl (for example replacing or unsubstituted thiazolyl (thioazolyl), replacement or unsubstituted  azoles base, replacement or unsubstituted imidazolyl or replacement or unsubstituted pyrazolyl).A ²Can be to replace or unsubstituted aryl or heteroaryl.A ²Can also be to replace or unsubstituted phenyl or replacement or unsubstituted pyridine base.R ⁶Can be replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl (for example unsubstituted (C ₁-C ₆) alkyl or unsubstituted (C ₃-C ₆) cycloalkyl).L ¹It can be unsubstituted methylene radical.L ²It can be unsubstituted methylene radical.In some relevant embodiments, R ⁶Be methyl or cyclopropyl, R ⁷Be hydrogen, L ¹Be unsubstituted methylene radical, and L ²It is unsubstituted methylene radical.L ³It can be unsubstituted methylene radical.R ⁵Can be to replace or unsubstituted phenyl.In some relevant embodiments, A ¹Be to replace or unsubstituted 2-thiazolyl (for example unsubstituted 2-thiazolyl or be substituted or unsubstituted alkyl, one or more unsubstituted (C for example ₁-C ₅) the 2-thiazolyl that replaces of alkyl).For example, A ¹Can be 2-(4-methylthiazol base).A ²Can be to replace or unsubstituted 3-pyridyl or replacement or unsubstituted phenyl (for example phenyl of a 3-(pyridyl that 5-replaces) or a position replacement).In some embodiments, the phenyl of a 3-(pyridyl that 5-replaces) and a position replacement is substituted or unsubstituted alkyl (for example unsubstituted C ₁-C ₅Alkyl or C ₁-C ₅Haloalkyl) replaces.The some or all of embodiments of each substituting group definition can make up and form suitable subgenus in this section.Therefore, in some embodiments, R ¹, R ², R ³And R ⁴Be hydrogen, A ¹Be to replace or unsubstituted 2-thiazolyl A ²Be to replace or unsubstituted 3-pyridyl or replacement or unsubstituted phenyl R ⁶Be unsubstituted (C ₁-C ₆) alkyl or unsubstituted (C ₃-C ₆) cycloalkyl, R ⁷Be hydrogen, and L ¹, L ²And L ³It is unsubstituted methylene radical.

In some embodiments, R ¹Be-NR ⁹S (O) _nR ¹⁴R ⁶Can be hydrogen.A ¹Can be to replace or unsubstituted phenyl.A ²Can be to replace or unsubstituted phenyl or replacement or unsubstituted pyridine base.In some relevant embodiments, n is 2, R ⁹Be unsubstituted (C ₁-C ₅) alkyl (for example methyl), and R ¹⁴Be unsubstituted (C ₁-C ₅) alkyl (for example methyl).L ²It can be unsubstituted methylene radical.L ¹It can be the methyl methylene radical.R ², R ³And R ⁴Can be hydrogen.The some or all of embodiments of each substituting group definition can make up and form suitable subgenus in this section.Therefore, in some embodiments, R ¹Be-NR ⁹S (O) _nR ¹⁴, R ⁶Be hydrogen, A ¹Be to replace or unsubstituted phenyl A ²Be to replace or unsubstituted phenyl or replacement or unsubstituted pyridine base, n is 2, R ⁹Be unsubstituted (C ₁-C ₅) alkyl (for example methyl), R ¹⁴Be unsubstituted (C ₁-C ₅) alkyl (for example methyl), L ²Be unsubstituted methylene radical, L ¹Be the methyl methylene radical, and R ², R ³And R ⁴Be hydrogen.

In some embodiments, the beta-secretase inhibitor compound has formula (II) structure:

In formula (II), L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, A ¹And A ²Define in the discussion of formula (I) as mentioned.

In some embodiments, the beta-secretase inhibitor compound has formula (III) structure:

In formula (III), L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, A ¹And A ²Define in the discussion of formula (I) as mentioned.

In another embodiment, the beta-secretase inhibitor compound has formula (IV) structure:

In formula (II), L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ²³, A ¹And A ²Define in the discussion of formula (I) as mentioned.In some embodiments, R ²³Be unsubstituted C ₁-C ₅Alkyl.

In another embodiment, the beta-secretase inhibitor compound has the formula V structure:

In formula V, L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ²³, A ¹And A ²Define in the discussion of formula (I) as mentioned.In some embodiments, R ²³Be unsubstituted C ₁-C ₅Alkyl.

In another embodiment, the beta-secretase inhibitor compound has formula (VI) structure:

In formula (VI), L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ²³, A ¹And A ²Define in the discussion of formula (I) as mentioned.In some embodiments, R ²³Be unsubstituted C ₁-C ₅Alkyl.

In another embodiment, the beta-secretase inhibitor compound has formula (VII) structure:

In formula (VII), L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ²³, A ¹And A ²Define in the discussion of formula (I) as mentioned.In some embodiments, R ²³Be unsubstituted C ₁-C ₅Alkyl.

In some embodiments, the group in the replacement described in the compound of formula (I)-(VII) more than is replaced by at least one substituting group group separately.More particularly, in some embodiments, replaced by at least one substituting group group separately at the alkyl of the replacement described in the compound of formula (I)-(VII), the assorted alkyl of replacement, the cycloalkyl of replacement, the Heterocyclylalkyl of replacement, the aryl of replacement, the heteroaryl of replacement, the alkylidene group of replacement or the assorted alkylidene group of replacement more than.In other embodiments, at least one or all these group is replaced by the limited substituting group group of at least one size.Perhaps, at least one or all these group is replaced by at least one rudimentary substituting group group.

In other embodiment of the compound of formula (I)-(VII), replace or unsubstituted alkyl each replace naturally or unsubstituted C ₁-C ₂₀Alkyl replaces or unsubstituted assorted alkyl respectively replaces or unsubstituted 2 to 20 yuan of assorted alkyl naturally, and each replaces replacement or unsubstituted cycloalkyl or unsubstituted C naturally ₄-C ₈Cycloalkyl replaces or unsubstituted Heterocyclylalkyl respectively replaces or unsubstituted 4 to 8 yuan of Heterocyclylalkyls naturally, and each replaces replacement or unsubstituted alkylidene group or unsubstituted C naturally ₁-C ₂₀Alkylidene group, and replacement or unsubstituted assorted alkylidene group each replace naturally or unsubstituted 2 to 20 yuan of assorted alkylidene groups.

Perhaps, replacement or unsubstituted alkyl respectively replace or unsubstituted C naturally ₁-C ₈Alkyl replaces or unsubstituted assorted alkyl respectively replaces or unsubstituted 2 to 8 yuan of assorted alkyl naturally, and each replaces replacement or unsubstituted cycloalkyl or unsubstituted C naturally ₅-C ₇Cycloalkyl replaces or unsubstituted Heterocyclylalkyl respectively replaces or unsubstituted 5 to 7 yuan of Heterocyclylalkyls naturally, and each replaces replacement or unsubstituted alkylidene group or unsubstituted C naturally ₁-C ₈Alkylidene group, and replacement or unsubstituted assorted alkylidene group each replace naturally or unsubstituted 2 to 8 yuan of assorted alkylidene groups.

In some embodiments, compound of the present invention comprises the compound of any one or all tables 1.In some embodiments, compound of the present invention comprises the compound of any one or all following examples 4.

A. carrier part

In common pendent U. S. application numbers 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454) (these applications are incorporated herein the reference as all purposes), the isostere beta-secretase inhibitor that has and do not have carrier part demonstrates the generation (Hsiao that reduces A β effectively in the tg2576 mouse of Sweden's type sudden change of expressing human amyloid precursor protein, K. wait the people, Science 274,99-102 (1996)).Therefore, one skilled in the art will know that compound of the present invention can be used with the form that has or do not have carrier part.Carrier part can be connected with the position of any suitable on the compound of the present invention.

" carrier part " refers to strengthen compound and passes chemical part hemato encephalic barrier (BBB) ability, that covalently or non-covalently be connected with beta-secretase inhibitor compound of the present invention as used herein.Beta-secretase inhibitor of the present invention can pass through covalent interaction (for example peptide bond) or be connected or combination with carrier part by noncovalent interaction (for example ionic linkage, hydrogen bond, Van der Waals force).

Hemato encephalic barrier is the permeability barrier that is present between outer liquid of brain inner cell and the capillary vessel intracavity blood.This barrier is derived from the textural difference between the capillary vessel of finding in the interior capillary vessel of brain and other tissue.The most significant difference is the tight connection between endotheliocyte in the textural difference of brain capillary vessel.Outer capillary endothelial cell strides endothelium resistance (3-33ohms/cm with being positioned at brain ²) compare, these special tight connections can produce the very high endothelium resistance (1500-2000ohms/cm that strides ²), thereby reduced observed parietal cell diffusion (Brightman in other organ based on water-based liquid, M., Bradbury MWB (editor), Physiology and Pharmacology of the blood-brainbarrier. experimental pharmacology handbook (Handbook of experimental pharmacology) 103, Springer-Verlag, Berlin, (1992); Lo, people such as E.H., Brain Res.Rev., 38:140-148, (2001)).Therefore, in some embodiments, compound of the present invention and carrier part (in following formula, representing) covalent attachment with symbol Y.

The carrier part of any suitable can be used for the present invention.The useful carrier part for example comprises lipophilic carriers part, enzyme substrates carrier part, peptidyl carrier part and nanoparticulate carriers part.Carrier part can also comprise the oligose unit or pass through other molecule that phosphoric acid ester bond or fat-ester bond or other hydrolyzable key are connected with compound that these keys can be by the Glycosylase in lysosome and the endosome, Phosphoric acid esterase, esterase, lipase or the cutting of other lytic enzyme.Carrier part can contain guanidine, amino or imidazoles functional group.

1. lipophilic carriers part

The lipophilic carriers part can increase total lipotropy of compound, helps to pass BBB thus.Can use any suitable method known in the art to come quantitative lipotropy.For example, can measure partition ratio (log P between the hot alcohol and water _O/w), represent lipophilic degree thus.In some embodiments, the log P that partly has of lipophilic carriers _O/wBe 1.5-2.5.Lipophilic carriers partly is that this area is extensively known, for example at Lambert, and D.M., Eur JPharm Sci., 11:S15-27 goes through in (2000).Be used to increase by two glyceryl ester, lipid acid and the phosphatide that the lipophilic exemplary lipophilic carriers of compound partly comprises modification and unmodified.

Oxidations of some lipophilic carriers part experience enzyme mediation after passing BBB produce the impermeable form of hydrophilic film of carrier part, its still be hunted down behind BBB (people such as Bodor, PharmacolTher 76:1-27 (1997); People such as Bodor, American Chemical Society, Washington, DC 317-337 page or leaf (1995); People such as Chen, J Med Chem 41:3773-3781 (1998); People such as Wu, J Pharm Pharmacol 54:945-950 (2002)).The exemplary lipophilic carriers of the oxidation of experience enzyme mediation partly comprises 1,4-dihydro trigonelline people such as (, J Med Chem, 32:622-625 (1989)) Palomino; Successfully be used for testosterone and zidovudine are transported the alkyl phosphonates carrier part (Somogyi, people such as G., Int J Pharm, 166:15-26 (1998)) that passes hemato encephalic barrier; With the lipotropy dihydropyridine carrier part that becomes ion pyridine  salt through oxydasis (people such as Bodor, Science, 214 (18): 1370-1372 (1981)).

2. peptidyl carrier part

The peptidyl carrier part is to be used to help the compound transhipment to pass the part of partly or entirely being made up of peptide (comprising polypeptide, protein, antibody and antibody fragment) of BBB (people such as Wu, J Clin Invest100:1804-1812 (1997); U.S. Patent number 4,801,575; People such as Pardridge, Adv DrugDeliv Rev, 36:299-321 (1999)).

The peptidyl carrier part can with corresponding part or receptor target in specific peptide movement system, acceptor or the ligand interaction of the endotheliocyte of BBB.The unitransport system can comprise the transhipment (Application No. 20040110928) of carrier mediated or the receptor-mediated BBB of passing.The exemplary peptides base carrier partly comprises: Regular Insulin (people such as Pardridge, Nat Rev Drug Discov, 1:131-139 (2002)); Less peptide, for example enkephalin, throtropin releasing hormone, arginine-vassopressin (Bergley, J Pharm Pharmacol, 48:136-146 (1996); People such as Banks, Peptides, 13:1289-1294 (1992); People such as Han, AAPS Pharm.Si, 2:E6 (2000)); Chimeric peptide, for example those that describe among the WO-A-89/10134; Amino acid derivative, for example those disclosed in the Application No. 20030216589; Trans-activating factor peptide (tat peptide) (Schwarze, people such as S.R., Science 285:1569-1572 (1999)); Poly arginine peptide (Wender, people such as P.A., Proc.Natl.Acad.Sci.USA 97:13003-13008 (2000)); Insulin-like growth factor-i; RhIGF-1-2; Transferrins,iron complexes; Leptin; Low-density lipoprotein (Pardridge, Nat.Rev.DrugDiscov.1:131-139 (2002); People such as Colma, Pharm.Res.17:266-274 (2000); Pardridge, Endocrine Rev, 7:314-330 (1986); People such as Golden, J Clin Invest, 99:14-18 (1997); People such as Bickel, Adv.Drug Deliv.Rev.46 (1-3): 247-79 (2001)); And Prostatropin (bFGF) (Application No. 20040102369).

Common pendent Application No. 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454) disclose: the burnt micro-image of the copolymerization of the cell of hatching with the isostere beta-secretase inhibitor that is combined with the fluorescence trans-activating factor demonstrates intracellular uneven distribution.Some high fluorescence intensities are presented in endosome and the intracellular cystic structures of lysosome.This shows that the trans-activating factor carrier part may have been modified by proteolytic enzyme in lysosome or endosome, thereby produces the inhibitor that can not leave lysosome or endosome chamber.Lysosome and endosome contain the multiple protein enzyme, comprise lytic enzyme, for example cathepsin A, B, C, D, H and L.In these enzymes some are endopeptidases, for example cathepsin D and H.Other enzyme is an exopeptidase, for example cathepsin A and C, and cathepsin B had both had endopeptidase activity, had the exopeptidase activity again.Thereby the specific enough extensive hydrolysis trans-activating factor peptide of these proteolytic enzyme is away from inhibitor compound, and hydrolysis carrier peptides thus is away from the isostere inhibitor.Therefore, show that trans-activating factor and other carrier peptides can be used in particular for the isostere inhibitor is passed to lysosome and endosome specifically.When being applied to Mammals by the mechanism such as injection, the penetrable cell of bonded compound also penetrates into lysosome and the inside of endosome.Then, the proteolytic enzyme in lysosome and the endosome can stop the trans-activating factor hydrolysis from lysosome and endosome and escape thus.

Carrier peptides can be a trans-activating factor or can be by other basic peptide of the proteolytic enzyme of lysosome and endosome institute hydrolysis, for example widow-L-arginine.Can assemble the responsive specificity peptide bond of proteolytic enzyme cutting, promote that thus carrier compound removes from inhibitor lysosome or endosome.For example, dipeptides Phe-Phe, Phe-Leu, Phe-Tyr and other can be organized proteolytic enzyme D cutting.

In one embodiment, the peptidyl carrier molecule comprises Cationic functional groups such as trans-activating factor-peptide (Schwarze, S.R. wait the people, Science 285:1569-1572 (1999)) or 9 arginine residues (Wender, P.A. wait the people, Proc.Natl.Acad.Sci.USA 97:13003-13008 (2000)).Useful Cationic functional groups for example comprises guanidine, amino and imidazoles functional group.Therefore, Cationic functional groups also comprises the side chain of amino acid side chain such as Methionin, arginine and histidine residues.In some embodiments, the peptidyl carrier molecule can comprise 1-10 Cationic functional groups.When compound of the present invention and carrier part in conjunction with or when being connected, the gained binding substances can be called " carrier peptides-inhibitor " binding substances or " CPI " in this article.The CPI binding substances can be applied to vitro samples or Mammals, thus serves as compound of the present invention and enters vitro samples or mammiferous intracellular transport vehicle.Carrier part and CPI binding substances can strengthen compound of the present invention and pass cell and hemato encephalic barrier effectively and suppress memapsin 2 cutting APP, generate the ability of A β subsequently.

The transcytosis (AME) of absorption mediation provides the peptidyl carrier part can pass the machine-processed for choosing of BBB.The difference of the transcytosis of AME and other form is, it is by interacting with the electrostatic interaction of anionic site or with the specificity of saccharide residue and being mediated that carrier part and chamber plasma membrane initial combines.C-end structure and the alkaline picked-up of measuring by AME by carrier part.Exemplary adsorptivity peptidyl carrier part comprises peptide and protein (cationic protein) and some lectins (glycoprotein is conjugated protein) with alkaline iso-electric point.Referring to: Tamai, people such as I., J.Pharmacol.Exp.Ther.280:410-415 (1997); Kumagai, people such as A.K., J.Biol.Chem.262:15214-15219 (1987).

The peptidyl carrier part also comprises the antibody carrier part.Antibody carrier partly is to comprise antibody or its segmental carrier part.Usually, antibody or antibody fragment are monoclonal antibodies or derived from monoclonal antibody.Antibody carrier part and cell receptor or the translocator of expressing on the surface, chamber of brain capillary endothelial cell combine (Application No. 20040101904).Exemplary antibody or its fragment comprise the MAb 83-14 (people such as Pardridge with insulin human's receptors bind, Pharm Res.12:807-816 (1995)), anti-Transferrins,iron complexes antibody (Li, J.Y. wait the people, Protein Engineering 12:787-796 (1999)) and simulate the monoclonal antibody of endogenous protein or peptide that the known BBB of passing as above is discussed.

3. nanoparticulate carriers part

Nanoparticulate carriers partly is that diameter or length are usually less than 1 micron solid colloid carrier.Compound can be wrapped, absorption or covalently bound on nanoparticulate carriers surface partly.The nanoparticulate carriers part has been successfully used to multiple compound is delivered to brain, these compounds comprise six peptide dalagrin (ICI154129 N,N-bisallyl-Tyr-Gly-Gly-), Loperamide, tubocerarine and Dx (people such as Ambikanandan, J.Pharm Pharmaceut Sci 6 (2): 252-273 (2003)).Except helping to be transported to inside and outside the brain, the non-ionic type sanitising agent such as the Tween-80 that can be used to wrap up nanoparticle can also be used for suppressing the outflow pump.Zordan-Nudo, people such as T., Cancer Res, 53:5994-6000 (1993).The exemplary materials that is used to prepare the nanoparticulate carriers part comprises Polyalkylcyanoacrylanano (PACA) (people such as Bertling, Biotechnol.Appl.Biochem.13:390-405 (1991)), paracyanogen base butyl acrylate (PBCA) (people such as Chavany, Pharm.Res.9:441-449 (1992)), have and be absorbed into the surface and with the paracyanogen base butyl acrylate (Kreuter of the peptide-drug mixture of Polysorbate 80 parcel, J. wait the people, Brain Res, 674:171-174 (1995); Kreuter, J., Adv Drug Deliv Rev, 47:65-81, (2001); Kreuter, J., Curr Med Chem, 2:241-249 (2002)), Polyisohexylcyanoacrylate (PIHCA) (people such as Chavany, Pharm.Res.11:1370-1378 (1994)), Polyhexyl cyanoacrylate (PHCA) (people such as Zobel, Antisense Nucleic Acid Drug Dev.7:483-493 (1997)) and the polybutylcyanoacrylate of Pegylation (Pilar, people such as C., Pharm Res18 (8): 1157-1166 (2001)).

4. connection base section

Connecting base section can be used for carrier part is connected with beta-secretase inhibitor of the present invention.For example, the connection base molecule that can adopt polymer technology (for example Pegylation) and introduce long spacerarm stops sterically hindered (Yoshikawa, people such as T., J PharmacolExp Ther, 263:897-903,1992) between compound and carrier.Connecting base section can cut maybe and can not cut.

The connection base molecule that can cut comprises the part that can cut.But the cutting part of any suitable can be used for the present invention, for example comprises phosphoric acid ester, ester, disulphide etc.The part that can cut also comprises can be by those parts of biological enzyme such as peptase, Glycosylase, Phosphoric acid esterase, esterase, lipase or the cutting of other lytic enzyme.When the biological activity of carrier part interfering compound, the connection base molecule that can cut is particularly useful.The basic molecule of exemplary cut connection comprises N-succinimido-3-2-pyridyl disulfide group propionic salt (SPDP) or N-hydroxy-succinamide (NHS).

The connection base molecule that can not cut be participate in carrier part and compound by common to the stable key of coenocorrelation and enzyme be connected those.When carrier part not during the biological activity of interfering compound, the connection base molecule that general use can not be cut.The exemplary connection base molecule that can not cut comprises that the hydrazides of the acid amides (for example N-hydroxy-succinamide polyoxyethylene glycol (NHS-PEG)) of thioether (for example-maleimide amino benzoyl N-hydroxy-succinamide ester (MBS)), acid amides (for example N-hydroxy-succinamide (NHS-XX-)), expansion and expansion is connected (for example hydrazides-PEG-vitamin H-), avidin-vitamin H and PEG connection basic (people such as Ambikanandan, J.Pharm Pharmaceut Sci 6 (2): 252-273 (2003); Pardridge, Adv Drug Deliv Rev, 36:299-321 (1999); U.S. Patent number 6,287,792).

II. exemplary synthetic

By the synthetic compound of the present invention of the suitable combination of common well-known synthetic method.The technology that can be used for synthetic compound of the present invention was both apparent for various equivalent modifications, was easy to again reach.Below discuss and be suggested some that is used for illustrating the several different methods that can be used for synthetic compound of the present invention.But this discussion is not to be intended to limit reaction range or the reaction sequence that can be used for preparing compound of the present invention.

Schema 1

In schema 1,2 and 3, L ¹, L ², L ³, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, A ¹And A ²As defined above.Synthesizing in following examples part of some 1s and 2s compound has detailed description.1s is handled with triethylamine and methylsulfonyl chloride, handle with sodiumazide then, carry out the palladium reduction reaction then, obtain the ring 2s that methylamine replaces.Form isophthaloyl amine 4s by between protected m-phthalic acid 3s of part and methylamine 2s, forming amido linkage.At last, produce alkylating acid amides 5s by the alkylated reaction that uses alkylogen to carry out the sodium hydride mediation.

Schema 2

Perhaps, compound 5s can prepare according to the order in the schema 2, wherein makes aldehyde 6s and amine that suits and sodium cyanoborohydride carry out the reductive amination reaction, obtains amine 7s.Then,, carry out the ester hydrolysis then, obtain alkylating acid amides 5s amine 7s and 3s coupling.

Schema 3

Epoxide 8s is handled with suitable amine, obtain amino alcohol 9s.Remove the Boc blocking group with acid, with fragment 5s coupling (schema 1), produce final inhibitor 10s then.

III. the activity of beta-secretase inhibitor

In order to develop useful beta-secretase inhibitor, can selectivity reduce the candidate inhibitor of memapsin 2 catalytic activitys in external discriminating, can measure it subsequently and reduce the ability that A β generates.Those methods that can adopt methods known in the art and/or this paper to propose are measured the activity of inhibitor compound.

Can use biological activity memapsin 2 (reorganization or naturally occurring) to differentiate and measure the compound that reduces memapsin 2 catalytic activitys.Memapsin 2 can find in the n cell of in-vitro separation, perhaps can be by coexpression or expression in cell.Can use multiple methods known in the art to measure the reduction of memapsin 2 catalytic activitys in the presence of inhibitor for the activity when not having inhibitor.

For example, can measure compound causes peptide in the presence of memapsin 2 beta-secretase site hydrolysis can be tested the ability that reduces of geodetic.These data can for example be expressed as K _i, apparent K _i, Vi/Vo or suppress percentage.K _iBe to show that compound suppresses the inhibition equilibrium constant of the ability of given enzyme (for example memapsin 2, memapsin 1 and/or cathepsin D).K _iNumerical value is more little, shows that compound of the present invention is high more to the avidity of enzyme.K _iValue is irrelevant with substrate, can be by apparent K _iTransform.

In the presence of substrate, measure apparent K according to the technology (for example referring to Bieth, J., Bayer-Symposium V: proteinase inhibitor, 463-469 page or leaf, Springer-Verlag, Berlin (1994)) of establishing _iApparent K _iStandard error be error from the non-linear regression of Vi/Vo data, the well-known technology of these Vi/Vo The data (for example referring to Bieth, J., Bayer-Symposium V: proteinase inhibitor, the 463-469 page or leaf, Springer-Verlag, Berlin (1994); Ermolieff, people such as J., Biochemistry 39:12450-12456 (2000), the instruction integral body of these documents is incorporated herein by reference) measure down at the different concns (for example about 10nM is to about 1000nM) of compound of the present invention.Vi/Vo has described the ratio (people such as Ermolieff, Biochemistry 40:12450-12456 (2000)) of the enzyme substrates initial conversion speed that is caused by enzyme when not having (Vo) or (Vi) inhibitor is arranged.The Vi/Vo value is 1.0 to show that compound does not have inhibitory enzyme.The Vi/Vo value shows that less than 1.0 compound of the present invention has suppressed the activity of enzyme.

Can behind the compound of the beta-secretase site hydrolysis that reduces peptide in the presence of the memapsin 2, can further measure the ability that these compounds selectivity for other enzyme suppresses memapsin 2 when identifying.Usually, other enzyme is a peptidohydrolase, for example memapsin 1 or cathepsin D.Can use bioactive enzyme (reorganization or naturally occurring) to measure the compound that reduces cathepsin D's catalytic activity or memapsin 1 catalytic activity.The catalytic activity of cathepsin D or memapsin 1 can find in the n cell of in-vitro separation, perhaps can be by coexpression or expression in cell.Can use assay method in the external or body of standard, for example well-known in the art or as other described those assay methods of this paper measure the restraining effect of compound of the present invention.

For example, can measure selectivity by the degree that the degree of measuring and same compound suppresses the beta-secretase site of memapsin 1 and/or cathepsin D's cutting peptide substrate is compared memapsin 2 hydrolysis substrate peptides.Can be used for measuring memapsin 2 active exemplary peptide substrates and comprise APP and derivative thereof, for example FS-2 (Bachem Americas, torrance, CA).The active exemplary peptide substrate that can be used for measuring memapsin 1 and cathepsin D for example comprises: the peptide that comprises sequence ELDLAVEFWHDR.These data can for example be expressed as K _i, apparent K _i, Vi/Vo or suppress percentage, and can describe with respect to the catalytic activity of memapsin 1 or cathepsin D and the opinion on public affairs compound to the restraining effect of memapsin 2 catalytic activitys.For example, if the K of the reaction between inhibitor compound of the present invention and memapsin 1 or the cathepsin D _iBe 1000 and inhibitor compound of the present invention and memapsin 2 between the K of reaction _iBe 100, then inhibitor compound is to memapsin 1 inhibiting 10 times to the active restraining effect of the beta-secretase of memapsin 2.

Can reduce (perhaps additionally by tested geodetic for showing the beta-secretase site hydrolysis that in the presence of memapsin 2, causes peptide, the compound of the ability selectivity to the effect of memapsin 2) can be measured them and cause the amount of amyloid beta (A β) or generate the ability that can tested geodetic reduces in cell model or animal model.For example, after measured the isostere inhibitor of memapsin 2 reduce the ability that A β generates in institute's culturing cell (common pendent U. S. application number 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454)).In brief, inhibitor can be joined with the nucleotide construction thing of coding people APP Sweden type mutant (perhaps London type (London) sudden change or double mutant) and if necessary in the culture with the cell (for example human embryo kidney (HEK) (HEK293) cell, HeLa cell, Chinese hamster ovary cell or neuroblastoma are the M17 cell) of the nucleotide construction thing stable transfection of the people memapsin 2 that encodes.By A β being carried out immunoprecipitation, carry out the SDS-gel electrophoresis then, the amount of the A β that generated when having with the unrestraint agent is detected and quantitatively.

Except cell cultures, the inhibitor that animal model also can be used to measure memapsin 2 reduces the ability that A β generates.For example, can (Science 274 for Hsiao, people such as K., and 99-102 (1996) carries out peritoneal injection to the animal (for example tg2576 mouse) of the Sweden type sudden change of expressing human amyloid precursor protein with inhibitor.Then, can collect blood plasma and by catching ELISA (BioSourceInternational, Camarillo CA) measure A β level.

Can use with inhibitor bonded fluorescent marker and by the Laser Scanning Confocal Microscope video picture and determine inhibitor existing in the organ of animal model or in CC (common pendent U. S. application number 20040121947 and international application no PCT/USO2/34324 (publication number WO03/039454)).

The sample that is obtained by Mammals can be liquid sample, for example blood plasma or serum sample, perhaps can be tissue sample, for example biosy of brain tissue sample.Can use standard technique (for example Western blotting and ELISA assay method) to measure the amount of amyloid beta or the minimizing that amyloid beta generates.

In following examples part, provided the other example of the assay method of differentiating memapsin 2-beta-secretase inhibitor.Active other method of measuring the active of memapsin 2, memapsin 1 and cathepsin D and reducing the material of these enzymic activitys is known in the art.The selection of suitable measuring method is fully within those skilled in the art's limit of power.

IV. pharmaceutical composition

On the other hand, the invention provides the pharmaceutical composition of the combination that comprises beta-secretase inhibitor compound of the present invention or beta-secretase inhibitor compound and pharmaceutically acceptable carrier.This pharmaceutical composition comprises optically active isomer, diastereomer or the pharmacologically acceptable salt of inhibitor disclosed herein.For example, in some embodiments, this pharmaceutical composition comprises compound of the present invention and as the citrate of pharmacologically acceptable salt.Beta-secretase inhibitor included in this pharmaceutical composition can be covalently bound with carrier part as mentioned above.Perhaps, included beta-secretase inhibitor is not covalently bound with carrier part in this pharmaceutical composition.

" be suitable for medicinal carrier " as used herein and refer to drug excipient, for example be suitable in the intestines or outer pharmaceutically acceptable, physiologically-acceptable organic or the inorganic carrier material of using and can not carrying out adverse reaction of gi tract with compound of the present invention (extract).Suitable pharmaceutically acceptable carrier comprises water, salts solution (for example Ringer's solution), alcohol, oil, gelatin and carbohydrate such as lactose, amylose starch or starch, fatty acid ester, Walocel MT 20.000PV and polyvinylpyrrolidine.Can be with the sterilization of these preparations, and if necessary can with can not mix with auxiliary substance such as lubricant, sanitas, stablizer, wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer reagent, tinting material and/or the aromatoising substance etc. that compound of the present invention carries out adverse reaction.

Compound of the present invention can be used separately or can be applied to the patient jointly.Use jointly and be intended to comprise that alone or in combination (more than one compounds) comes simultaneously or administered compound successively.Therefore, when needing, preparation can also make up with other active substance (for example reducing the material of metabolic degradation).

A. preparation

Beta-secretase inhibitor of the present invention can be with multiple oral, gi tract outer and topical formulations prepare and use.Therefore, compound of the present invention can be used by injection (for example in intravenously, intramuscular, intracutaneous, subcutaneous, the duodenum or peritoneal injection).In addition, compound as herein described can also be used by sucking (in nose).In addition, compound of the present invention can also transdermal administration.Can also envision, multiple route of administration (for example intramuscular, oral, transdermal) can be used to use compound of the present invention.Therefore, the present invention also provides the pharmaceutical composition that comprises pharmaceutically useful carrier or vehicle and one or more compounds of the present invention.

For by compound pharmaceutical composition of the present invention, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials that can also be used as thinner, correctives, tackiness agent, sanitas, tablet disintegrant or become capsule material.

In powder, carrier is the solid that segments with the active ingredient blended that segments.In tablet, active ingredient mixed with the carrier with essential bond property with suitable ratio and be compressed into required shape and size.

Powder and tablet preferably contain 5% to 70% active compound.Suitable carrier is magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Terms " formulation " is intended to comprise active compound and the preparation that becomes capsule material as carrier, the capsule that this carrier can provide the active ingredient suppressed by vector that wherein has or do not have other carrier to surround, thus carrier is linked together with it.Similarly, comprise cachet and lozenge.Tablet, powder, capsule, pill, cachet and lozenge can be as being suitable for Orally administered solid dosage.

In order to prepare suppository, at first, with the active ingredient homodisperse therein, for example pass through to stir with the mixture melt of low melt wax, for example glycerin fatty acid ester or theobroma oil.Then the uniform mixture of fusing is poured in the mould of suitable size, made its cooling, solidify therefrom.

Liquid absorption member comprises solution, suspensoid and emulsion, for example water or water/propylene glycol solution agent.Inject outward for gi tract, liquid preparation can be mixed with the solution in the water-based polyglycol solution.

When using outside needs or the expectation gi tract, the suitable especially mixture of The compounds of this invention is injectable sterile solution, preferred oiliness or aqueous solution, and suspension, emulsion or implant, comprises suppository.Especially, the carrier used outward of gi tract comprises D/W, salt solution, pure water, ethanol, glycerine, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymer etc.Ampulla is a unitary dose easily.Compound of the present invention can also be joined in the liposome or by transdermal pump or patch and use.Be applicable to that medicinal mixture of the present invention is that those skilled in the art are well-known, they for example pharmaceutical science (Pharmaceutical Sciences) (the 17th edition, Mack publishing company, Easton, PA) and among the WO 96/05309 description is arranged, the instruction of the two is incorporated herein by reference.

The aqueous solution that is suitable for orally using can be prepared by the following method: active ingredient is soluble in water, take the circumstances into consideration to add suitable tinting material, correctives, stablizer and thickening material.The aqueous suspension that is suitable for orally using can be prepared by the following method: with the active ingredient of segmentation be dispersed in contain cohesive material such as natural or synthetic is gummy, in the water of resin, methylcellulose gum, Xylo-Mucine and other well-known suspending agent.

Also comprise and be used for facing with the solid form preparation that before changes Orally administered liquid form preparation into.This class I liquid I form comprises solution, suspension and emulsion.Except active ingredient, this class preparation can also contain tinting material, correctives, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent etc.

Pharmaceutical preparation is unit dosage preferably.In this form, preparation is subdivided into the unitary dose of the active ingredient that contains sufficient quantity.Unit dosage can be a packaged preparation, and packing contains the preparation of fractional dose, and described packaged preparation for example is packaged tablet, capsule and the powder in bottle or ampoule.In addition, unit dosage can also be capsule, tablet, cachet or a lozenge itself, and perhaps it can be any these formulations of the suitable number of packaged form.

According to the concrete application and the usefulness of active ingredient, in the unit dose formulations amount of active ingredient at 0.1mg to 10000mg, be more typically 1.0mg to 1000mg, be generally most between the 10mg to 500mg and change or regulate.If necessary, composition can also contain other compatible therapeutical agent.

Some compounds may have limited water solubility, therefore, may need tensio-active agent or other suitable solubility promoter in composition.Described solubility promoter comprises: Polysorbate 20,60 and 80; Pluronic gram F-68, F-84 and P-103; Cyclodextrin; Polyoxyethylene (35) Viscotrol C; Or other material well known by persons skilled in the art.This class solubility promoter adopts with about 0.01% level to about 2% weight usually.

May need viscosity that viscosity is higher than the simple aqueous solution with the variability that reduces dispersible preparation, reduce suspensoid or emulsion preparations component physical sepn and/or improve preparation in addition.This class viscosity makes up combination and other material well known by persons skilled in the art that agent (building agents) for example comprises polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose gum, Vltra tears, Natvosol, carboxymethyl cellulose, hydroxypropylcellulose, chondroitin sulfate and salt thereof, hyaluronic acid and salt thereof, above-mentioned substance.These materials adopt with about 0.01% level to about 2% weight usually.The acceptable amount of above adjuvant is easy to be determined by those skilled in the art arbitrarily.

Composition of the present invention can also comprise the component that slow release and/or comfort are provided.This class component comprises the pharmaceutical carrier material of high-molecular weight negatively charged ion plan mucus (mucomimetic) polymkeric substance, gelling polysaccharide and segmentation.These components are at United States Patent (USP) 4,911, more detailed discussion are arranged in 920,5,403,841,5,212,162 and 4,861,760.The full content integral body of these patents is incorporated herein the reference as all purposes.

B. effective dose

Comprise that by pharmaceutical composition provided by the invention activeconstituents is with the treatment significant quantity, promptly be contained in wherein composition with the amount that obtains its intended purposes (above definition) effectively.To especially depend on the illness of being treated to the effective actual amount of application-specific.For example, when using in the method for treatment alzheimer's disease, this based composition will contain the activeconstituents of the amount that obtains required result (for example reducing the active or minimizing amyloid beta generation of beta-secretase) effectively.Determining of the treatment significant quantity of The compounds of this invention is complete within those skilled in the art's limit of power, can consider that especially the detailed disclosure of this paper is determined.

Being applied to mammiferous dosage and frequency (list or multiple doses) can change according to multiple factor, and described factor comprises: cause memapsin 2 active increase or disease, Mammals that amyloid beta gathers increase whether suffer from other disease with and route of administration; Recipient's size, age, sex, health, body weight, weight index and diet; The complication of the nature and extent of the symptom of the disease for the treatment of (for example alzheimer's disease), the kind of co-therapy, the disease for the treatment of or other and healthy relevant problem.Other treatment plan or material can be united use with the method and the compound of applicant's invention.Adjusting and the control of determining dosage (for example frequency and time length) are complete within those skilled in the art's limit of power.

For any compound as herein described, the treatment significant quantity can be determined by the cell cultures assay method at first.Aimed concn will be those concentration that can reduce the active compound of memapsin 2 catalytic activitys, as adopt described herein or methods known in the art are measured.

As known in the art, the treatment significant quantity that is used for the people can also be determined by animal model.For example, can prepare the dosage that is used for the people has been found that in the effective concentration of animal with acquisition.The dosage that is used for the people can suppress and regulate dosage up or down to regulate by monitoring memapsin 2 as mentioned above.According to aforesaid method and as known in the art other method regulate dosage in the people, to obtain maximum efficiency fully within the limit of power of those of ordinary skill.

Dosage can change according to patient's needs and the compound that is adopted.In the context of the present invention, the dosage that is applied to the patient should be enough to produce in time useful treatment response in the patient.The size of dosage also will be determined by existence, the nature and extent of any adverse side effect.Particular case is determined that appropriate dosage is within doctor's technical scope.Usually, use smaller dose begin treatment less than the compound optimal dose.After this, increase dosage up to obtaining the best use of in these cases with less amount.In one embodiment of the invention, dosage range is 0.001% to 10%w/v.In another embodiment, dosage range is 0.1% to 5%w/v.

Dosage and interval can be regulated separately, so that the level to the effective institute of the specific clinical indication administered compound of being treated to be provided.The treatment plan that this will provide the seriousness with individual disease condition to match.

Utilize instruction provided herein, can design the effective preventative or therapeutic treatment scheme that can not cause remarkable toxicity and treat the shown clinical symptom of particular patient completely effectively.This design should comprise by the toxicity character of the existence of the usefulness of consideration such as compound, relative bioavailability, weight in patients, adverse side effect and seriousness, preferred method of application and selected species carefully selects active compound.

C. toxicity

The toxicity of specific compound and the ratio between the curative effect are its therapeutic indexs, and this ratio can be expressed as LD ₅₀(amount that causes the compound of 50% colony death) and ED ₅₀Ratio between (to the amount of 50% colony's compounds effective).Preferably demonstrate the compound of high therapeutic index.Can be used to prepare the dosage range that is used for the people by cell cultures assay method and/or the resulting therapeutic index data of zooscopy.The dosage of these compounds is preferably comprising ED ₅₀And in the very little or nontoxic plasma concentration scope of toxicity.Dosage can change in this scope, and this depends on formulation that is adopted and the route of administration of being utilized.For example referring to people such as Fingl, the pharmacological basis of treatment (THE PHARMACOLOGICALBASIS OF THERAPEUTICS), the 1st chapter, page 1,1975.Can consider patient's illness and wherein use the ad hoc approach of compound to select definite preparation, route of administration and dosage by individual doctor.

V. reduce the method for memapsin 2 catalytic activitys

In exemplary, provide the method that reduces memapsin 2 catalytic activitys.This method comprises makes memapsin 2 protein contact with the beta-secretase inhibitor compound of the present invention of significant quantity.Memapsin 2 can contact in the adapt circumstance arbitrarily.With respect to for the active amount that does not have in the presence of the beta-secretase inhibitor, memapsin 2 catalytic activitys are lowered.

In another exemplary, provide and used inhibitor of the present invention to come selectivity to reduce the method for memapsin 2 catalytic activitys.Selectivity reduces the activity of memapsin 2 and represent that memapsin 2 not only is lowered for the activity when not having inhibitor, and with because caused active reduction of the inhibitor effect of other peptidohydrolase of antagonism compared, memapsin 2 is to be lowered largely.For example, as mentioned above, the reduction of enzymic activity can be to suppress constant (K _i) expression.When the inhibitor selectivity reduces memapsin 2 activity, the K of reaction between inhibitor compound of the present invention and the memapsin 2 _iLess than the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _i

In exemplary, the K of reaction between inhibitor compound of the present invention and the memapsin 2 _iThan the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _iAt least low 2 times.In another exemplary, the K of reaction between inhibitor compound of the present invention and the memapsin 2 _iThan the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _iAt least low 10 times.In another exemplary, the K of reaction between inhibitor compound of the present invention and the memapsin 2 _iThan the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _iAt least low 100 times.In another exemplary, the K of reaction between inhibitor compound of the present invention and the memapsin 2 _iThan the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _iAt least low 1000 times.In another exemplary, the K that reacts between inhibitor compound of the present invention and the memapsin2 _iThan the K that reacts between inhibitor compound of the present invention and other peptidohydrolase _iAt least low 10000 times.

In some relevant embodiments, to compare with memapsin 1, inhibitor optionally reduces the activity of memapsin 2.In other relevant embodiment, to compare with cathepsin D, inhibitor optionally reduces the activity of memapsin 2.

Therefore, the invention provides selectivity and reduce memapsin 2 active methods.This method comprises makes memapsin 2 protein contact with the beta-secretase inhibitor compound of the present invention of significant quantity.In relevant embodiment, this method is included under the existence of memapsin 1 memapsin 2 is contacted with beta-secretase inhibitor.In the related embodiment for choosing, this method is included under the existence of cathepsin D memapsin 2 is contacted with the beta-secretase inhibitor of significant quantity.In another relevant embodiment, this method is included under the existence of cathepsin D and memapsin 1 memapsin 2 is contacted with the beta-secretase inhibitor of significant quantity.

The activity of beta-secretase is measured in the hydrolysis in beta-secretase site that in some embodiments, can be by measuring the beta-secretase substrate.Therefore, the invention still further relates to by making memapsin 2 protein contact the method for the beta-secretase site hydrolysis that reduces the beta-secretase substrate with beta-secretase inhibitor compound of the present invention.In some embodiments, for the amount of hydrolysis when not having inhibitor, the hydrolysis in beta-secretase site is reduced.In other embodiments, compare with the hydrolysis that is caused by memapsin 1 and/or cathepsin D, hydrolysis is optionally reduced.Therefore, provide for memapsin 1 and/or cathepsin D selectivity to reduce the method for the beta-secretase site hydrolysis of beta amyloid precursor protein in the sample.This method comprises makes memapsin 2 protein contact with beta-secretase inhibitor compound of the present invention.

In another embodiment, the present invention relates to by making memapsin 2 contact the method that reduces the amount of amyloid beta in the sample with the beta-secretase inhibitor compound of the present invention of significant quantity.For the amount of amyloid beta in the sample when not having inhibitor, the amount of amyloid beta is reduced in the sample.Therefore, gathering thus of amyloid beta is reduced.

Memapsin 2 can be touched in the sample of any adapt circumstance or any suitable.For example, memapsin 2 can external, in cell or in Mammals, be touched.Usually, the outer solution of selective body is so that make component not disturb the enzymic activity of memapsin 2 (for example aqueous solution) basically.In some embodiments, external solution comprises biological sample, for example the Mammals sample.Exemplary Mammals sample comprises blood plasma or serum sample and tissue sample, for example biosy of brain tissue sample.Can select suitable cell or cell sample arbitrarily, memapsin 2 is contacted with inhibitor.Cell can contain foregoing endogenous memapsin 2 or reorganization memapsin 2 (common pendent U. S. application number 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454)).Exemplary cells comprises that human embryo kidney (HEK) (HEK293) cell, HeLa cell, Chinese hamster ovary cell or neuroblastoma are M17 cell Hela cell, 293 cells.In exemplary, compound administration of the present invention is in the hydrolysis of Mammals (for example mouse, rabbit or people) with the beta-secretase site of inhibition beta amyloid precursor protein.

VI. treat the method for alzheimer's disease

Therefore, in some embodiments, the invention provides the method for treatment alzheimer's disease in Mammals, this method comprises that the beta-secretase inhibitor of the present invention with significant quantity is applied to mammiferous step.Mammals with inhibitor for treating can be people primates, non-human primates and/or non-human mammal (for example rodents, dog class).In one embodiment, reduce the beta-secretase activity compound of the present invention of (suppressing memapsin 1 and memapsin 2 catalytic activitys) to administration.In another embodiment, reduce the compound of memapsin 2 catalytic activitys for the administration selectivity.In relevant embodiment, compound has minimum influence or not influence to the catalytic activity that reduces memapsin 1.Therefore, the present invention also provides the method for treatment alzheimer's disease in its curee of needs, and this method comprises to the curee uses the beta-secretase inhibitor compound.In exemplary, the beta-secretase inhibitor compound is the part of pharmaceutical preparation, and is as indicated above.

Inhibitor compound of the present invention can be used for the treatment of and active diseases associated of beta-secretase or illness, and these inhibitor compounds can stop, reverse or weaken the development of disease or illness, particularly alzheimer's disease.Except the compound that reduces memapsin 2 catalytic activitys, the compound that selectivity reduces memapsin 2 catalytic activitys also can be used for treatment and memapsin 2 catalytic activity diseases associated or illness or biological procedures, rather than is used for the treatment of and memapsin 2 catalytic activitys and the equal diseases associated of other peptidohydrolase (for example cathepsin D or memapsin 1) or illness or biological procedures.

For example, memapsin 1 and memapsin 2 all cut amyloid precursor protein (APP) to form amyloid beta (this paper also is called A β or amyloid beta) in the beta-secretase site.Therefore, memapsin 1 and memapsin 2 all have beta-secretase activity (Hussain, people such as I., J.Biol.Chem.276:23322-23328 (2001)).But the beta-secretase activity of memapsin 1 significantly is lower than the beta-secretase activity of memapsin 2 (Hussain, people such as I., J.Biol. Chem.276:23322-23328 (2001)).Memapsin 2 is arranged in brain and pancreas and other tissue (Lin, X. wait the people, Proc.Natl.Acad Sci.USA 97:1456-1460 (2000)), and memapsin 1 preferentially is arranged in placenta (Lin, X. wait the people, Proc.Natl.Acad Sci. USA97:1456-1460 (2000)).Alzheimer's disease is with relevant in the brain inner accumulated by the caused A β of beta-secretase (this paper also is called memapsin 2, ASP2 and BACE) cutting APP.Therefore, adopt that for memapsin 1 catalytic activity selectivity suppresses that the method for compound of memapsin 2 catalytic activitys is 2 diseases related at treatment and memapsin, can be important in for example alzheimer's disease.Selectivity inhibition memapsin 2 catalytic activitys become compound of the present invention and are applicable to the drug candidate for the treatment of alzheimer's disease.

A. use the method for beta-secretase inhibitor to CNS

Can inhibitor compound of the present invention be applied to CNS by invasive or noninvasive method.The Noninvasive application process comprises does not need to use machinery or physical method just can break through those methods of hemato encephalic barrier integrity.Usually, noninvasive method comprise use immunoliposome, hemato encephalic barrier division (blood-brain barrier disruption, BBBD) or the sense of smell passage.

Immunoliposome is to have the antibody that is connected with surface of liposome or a liposome of antibody fragment, and the acceptor or the translocator of expressing on described antibody or antibody fragment and the brain capillary endothelial cell combine.The exemplary immunization liposome has made up polymkeric substance (for example Pegylation) technology and chimeric peptide technology.For example, beta-secretase inhibitor can be wrapping to and contain PEG ²⁰⁰⁰In the individual layer lipid vesicle of derivative, described PEG ²⁰⁰⁰Derivative contains reaction active groups at an end, is used for being connected with antibody or its segmental complementary interaction active group.The complementary interaction active group is well-known in the art, for example comprise amine and activatory carboxylic acid, thiol and maleimide etc. (people such as Ambikanandan, J.PharmPharmaceut Sci 6 (2): 252-273 (2003); People such as Huwyler, Proc.Natl.Acad.Sci.USA, 93:14164-14169 (1996); With people such as Huwyler, J Pharmcol Exp Ther.282:1541-1546 (1997); And U.S. Patent number 6,372,250).

The hemato encephalic barrier division is that the close-connected integrity that comprises between the endotheliocyte of hemato encephalic barrier is temporarily lost.Usually, compound is used by injection between whole body or carotid artery and temporary hemato encephalic barrier division uniting of (BBBD).Can be used for causing that the exemplary material of BBBD comprises: solvent, for example dimethyl sulfoxide (DMSO) (DMSO); Ethanol (EtOH); Metal (for example aluminium); The X-radiation; Inducing of pathological conditions (for example hypertension, hypercarbia, hypoxemia or local asphyxia); Antineoplastic agent (for example VP-16, cis-platinum, hydroxyurea, Ro 2-9757 and Etoposide); Or systemic administration convulsivant pentetrazole (metrazol) and anticonvulsive drug Sodital (people such as Ambikanandan, J Pharm Pharmaceut Sci 6 (2): 252-273 (2003)) simultaneously; Vasoactive leukotrienes (people such as Black, J Neurosurg, 81 (5): 745-751 (1994)); Infusion bradykinin, histamine or synthetic bradykinin analogue RMP-7 in the carotid artery (people such as Miller, Science 297:1116-1118 (2002); People such as Matsukado, Neurosurgery39:125-133 (1996); People such as Abbott, Mol Med Today 2:106-113 (1996); People such as Emerich, Clin Pharmacokinet 40:105-123 (2001)); Unidasa (Application No. 20030215432, people such as Kreil, Protein Sci., 4 (9): 1666-1669 (1995)); And injection inertia hypertonic solution, for example N.F,USP MANNITOL or pectinose (Neuwelt between carotid artery, E.A. wait the people, NeuweltEA (editor), Implications of the Blood Brain Barrier and its Manipulation:Clinical Aspects. the 2nd volume, Plenum press, New York, (1989); People such as Neuwelt, J NuclMed, 35:1831-1841 (1994); People such as Neuwelt, Pediatr Neurosurg 21:16-22 (1994); People such as Kroll, Neurosurg, 42:1083-1099 (1998); Rapoport, Cell Mol Neurobiol20:217-230 (2000); With people such as Doran, Neurosurg 36:965-970 (1995)).

It is to be delivered to the olifactory nerve on nasal meatus top 1/3rd in the compound intranasal that the sense of smell passage is used.After transmitting in the intranasal, compound transmits along sensation olifactory nerve unit backward, the significant concentration of generation in celiolymph (CSF) and olfactory bulb (people such as Thorne, Brain Res, 692 (1-2): 278-282 (1995); People such as Thorne, Clin Pharmacokinet 40:907-946 (2001); Illum, Drug DiscovToday 7:1184-1189 (2002); United States Patent (USP) 6,180,603; United States Patent (USP) 6,313,093; With Application No. 20030215398).

The invasive application process is to comprise usually by machinery or physical method the hemato encephalic barrier physical property is broken through to import into compound among the CSF or directly to import those methods in the brain essence into.The invasive application process can comprise usually implants compound injection or operation.

In injecting method, the use syringe needle comes physical property to break through BBB and compound is directly delivered among the CSF.Exemplary injecting method comprises in the ventricle, in the sheath or use in the waist marrow, and can comprise by the storage storehouse of health outside and come infusion compound (people such as Krewson, Brain Res 680:196-206 (1995); People such as Harbaugh, Neurosurg.23 (6): 693-698 (1988); People such as Huang, J Neurooncol 45:9-17 (1999); People such as Bobo, Proc Natl Acad Sci USA 91:2076-2082 (1994); People such as Neuwalt, Neurosurg.38 (4): 1129-1145 (1996)).

In the operation implantation, compound is directly placed brain essence.The exemplary procedure implantation can comprise with compound join the polyanhydride wafer that directly places matter between brain (people such as Brem, Sci Med 3 (4): 1-11 (1996); People such as Brem, J Control Release 74:63-67 (2001)).

VII. crystalline composites

On the other hand, the invention provides the crystalline composites that contains memapsin 2 protein and beta-secretase inhibitor of the present invention.Can be used for memapsin 2 protein (for example memapsin 2 protein fragments, transmembrane protein etc.) with isostere compound formation cocrystallization and before went through (common pendent U. S. application number 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454)).These memapsin 2 protein can be used for forming crystalline composites with beta-secretase inhibitor of the present invention equally.

Can adopt the technology described in common pendent U. S. application numbers 20040121947 and the international application no PCT/USO2/34324 (publication number WO 03/039454) to form crystalline composites.In brief, produce the nucleotide construction thing of coded protein, it (is for example expressed in the intestinal bacteria (E.coli), carry out purifying, with compound crystal of the present invention at host cell, for example mammalian host cell (for example Hela cell, 293 cells) or bacterial host cell.The diffraction resolution limit of crystallization of protein can for example be measured by X-ray diffraction or neutron diffraction technology.

In exemplary, the X-ray diffraction resolution limit that crystallization of protein can have is not higher than about 4.0 Δs.The X-ray diffraction resolution limit that crystallization of protein can also have is not higher than about 4.0 Δs, about 3.5 Δs, about 3.0 Δs, about 2.5 Δs, about 2.0 Δs, about 1.5 Δs, about 1.0 Δs or about 0.5 Δ.In some embodiments, the crystallization of protein X-ray diffraction resolution limit that can also have is not higher than about 2 Δs.The diffraction resolution limit of crystallization of protein can adopt standard X-ray diffraction technology to measure.

In other exemplary, the beta-secretase inhibitor of crystalline composites is at S ₃' binding pocket, S ₄' binding pocket and/or S ₄The binding pocket place links to each other with described protein.S ₃', S ₄' and S ₄Binding pocket goes through in common pendent U. S. application numbers 20040121947 and international application no PCT/USO2/34324 (publication number WO 03/039454).

Term that this paper has adopted and statement can be used as description but not are limited, and be not be intended to use these terms and statement get rid of shown in and coordinator or its part of described feature, can know that various accommodations are possible in desired scope of the present invention.In addition, any one of any embodiment of the present invention or a plurality of feature can not deviate from scope of the present invention with any one or the combination of a plurality of further feature of arbitrarily other embodiment of the present invention.For example, the feature of beta-secretase inhibitor of the present invention can be applicable to treat the method and/or the pharmaceutical composition as herein described of morbid state equally.All publications that this paper quotes, patent and patent application integral body are incorporated herein the reference as all purposes.

VIII. embodiment

Following examples only are used for the illustrative purpose but not are intended to limit the scope of the invention.

Embodiment 1: the preparation of selected B-Secretase inhibitors compound

Synthesizing of embodiment 1.1:3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester

In-78 ℃ will be in THF methylthiazol (1.0g, 10.1mmol) with n-BuLi (1.6M 7.56mL) handled 30 minutes, dropwise add DMF (1.4mL, 18.2mmol).The gained reaction mixture is warmed to room temperature.After raw material disappears (passing through TLC), reaction mixture is cooled to 0 ℃ once more, and adding LAH (0.69g, 18.5mmol).This mixture is warmed to room temperature, stirred 1 hour, reactant NH ₄The cancellation of the Cl aqueous solution is diluted with EtOAc.Separate organic solution,, use Na with EtOAc extraction 2 times ₂SO ₄Drying concentrates.With the resistates purified by flash chromatography, obtain the corresponding alcohol of light yellow oily.

¹H-NMR：(300MHz，CDCl ₃)，δ：6.89(s，1H)；4.95(s，2H)；2.48(s，3H).

(0.57g, 4.4mmol) (0.42mL 5.4mmol) handles with triethyl ethamine with methylsulfonyl chloride with methylthiazol methyl alcohol in methylene dichloride in 0 ℃.The gained mixture was stirred 20 minutes, use NH then ₄The cancellation of the Cl aqueous solution.Evaporating solvent from organic layer carries out flash chromatography with resistates, obtains the corresponding methanesulfonates of buttery.Then with methanesulfonates (0.25g 1.2mmol) is dissolved among the DMF, add sodiumazide (0.62g, 9.6mmol).This mixture heating up was refluxed 2 hours, and NH is used in cooling then ₄The Cl solution washing.Evaporating solvent from organic layer obtains corresponding trinitride.(0.14g 0.91mmol) is dissolved in the ethyl acetate, adds Pd (OH) with trinitride ₂(0.07g), under atmosphere of hydrogen, this suspension was stirred 5 hours.This suspension is filtered by Celite.Evaporating solvent carries out flash chromatography with resistates, obtains the corresponding methylthiazol methylamine of yellow oily.

¹H-NMR：(300MHz，CDCl ₃)，δ：6.74(m，1H)；4.09(m，2H)；2.37(s，3H).

With m-phthalic acid one methyl esters (0.054g, 0.30mmol) with EDCI (0.064g, 0.33mmol), HOBt (0.046g, 0.34mmol), DIPEA (0.07mL, 0.4mmol) and the methylthiazol methylamine (0.046g 0.36mmol) handles.Under argon gas, the gained mixture was stirred 15 hours water cancellation then in room temperature.Layering is with water layer CHCl ₃(2 * 20mL) extractions.With the organic layer Na that merges ₂SO ₄Drying under reduced pressure concentrates.Gained oily matter is dissolved among the THF (5mL), to wherein adding 3mL1.0N LiOH (aqueous solution).The gained mixture was stirred 1.5 hours rapidly.Remove volatile matter by rotary evaporation, with obtained aqueous solution CHCl ₃(* 3) extraction.Use then 1N HCl (aqueous solution) with this acidified aqueous solution to pH1, use CHCl ₃(* 3) extraction.With the organic layer Na that merges ₂SO ₄Drying under reduced pressure concentrates, and obtains corresponding m-phthalic acid.With this product (0.042g 0.11mmol) is dissolved among the DMF, with NaH (0.015g, 0.62mmol) and MeI (0.04mL, 0.64mmol) processing, stirring is spent the night.Remove volatile matter by rotary evaporation, gained solution with 1N LiOH dilution, is used CHCl ₃(* 3) extraction.Use then 1N HCl (aqueous solution) with this acidified aqueous solution to pH1, use CHCl ₃(* 3) extraction.With the organic layer Na that merges ₂SO ₄Drying under reduced pressure concentrates, and obtains N-methyl-N-(4-methyl-thiazol-2-yl methyl)-phthalamic acid.

¹H-NMR：(300MHz，CDCl ₃)，δ：8.16(m，2H)，7.70(m，1H)，7.51(m，1H)，6.91(s，1H)，5.05(s，1.5H)，4.75(s，0.5H)，3.2-3.0(m，3H)，2.46(s，3H).

To (1-Oxyranyle-2-styroyl) t-butyl carbamate that stirs (0.5g, 1.9mmol) add in the solution in iPrOH the 3-methoxybenzylamine (0.28mL, 2.1mmol).This mixture heating up backflow is spent the night, and volatile matter is under reduced pressure removed in cooling then.Resistates is carried out flash chromatography, obtain solid-state corresponding amino alcohol.

¹H NMR(300MHz，CDCl ₃)：δ7.35-7.17(m，6H)，6.93-6.78(m，3H)，4.65(d，1H)，3.90-3.7(m，5H)，3.51(m，1H)，3.15-2.65(m，6H)，1.34(s，9H).

To stir 3-hydroxyl-4-(3-methoxybenzyl amino)-(0.032g 0.079mmol) adds TFA in the solution in methylene dichloride to 1-phenyl fourth-2-aminocarbamic acid tert-butyl ester.The gained mixture was stirred 1 hour, under reduced pressure remove volatile matter then.This amine is dissolved in the methylene dichloride, handle with DIPEA, it is joined N-methyl-N-(4-methyl-thiazol-2-yl methyl)-phthalamic acid (0.021g, 0.071mmol), EDCI (0.015g, 0.078mmol) and HOBt (0.011g is 0.081mmol) in the solution in methylene dichloride.In room temperature the stirring of gained mixture is spent the night, wash with water then, use Na ₂SO ₄Drying is under reduced pressure removed volatile matter.Resistates is carried out flash chromatography, obtain target molecule.

¹H NMR(300MHz，CDCl ₃)：δ7.8-7.M(m，11H)，6.94-6.76(m，4H)，4.95(s，1.5H)，4.63(s，0.5H)，4.38(m，1H)，3.90-3.64(m，5H)，3.18-2.74(m，9H)，2.44(s，3H).

Synthesizing of embodiment 1.2:N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine

By in the 2-propyl alcohol, under refluxad one step of ring-opening reaction of (1-Oxyranyle-2-styroyl)-t-butyl carbamate and 3-methoxybenzylamine obtains 3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester.By being used in CH ₂Cl ₂Or the TFA among the methyl alcohol HCl handles; with Boc group deprotection; obtain 3-amino-1-(3-methoxybenzyl amino)-4-phenyl fourth-2-alcohol, in the presence of N-ethyl-N '-(dimethylaminopropyl) carbodiimide hydrochloride (EDC), I-hydroxybenzotriazole hydrate and diisopropylethylamine, at DMF and CH ₂Cl ₂Mixture in itself and 3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) phenylformic acid are directly carried out the peptide linked reaction, obtain N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine.

By in methylene dichloride, handling with methylsulfonyl chloride and pyridine with the amino dimethyl isophthalate methylsulfonylization of 5-.Under the NaH/DMF condition, carry out the N-alkylation then, obtain 5-(N-methyl methanesulfonamido) dimethyl isophthalate with methyl-iodide.5-(N-methyl methanesulfonamido) dimethyl isophthalate is carried out selective hydrolysis, carry out the coupling of EDC/HOBT/DIPEA mediation then with the Alpha-Methyl benzylamine, obtain 3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) methyl benzoate.In the presence of THF/MeOH, use the 1N NaOH aqueous solution to carry out the ester hydrolysis, obtain pure 3-(N-methyl methanesulfonamido)-5-(the 1-styroyl carbamyl) phenylformic acid of white solid state.

With (1-Oxyranyle-2-styroyl)-t-butyl carbamate (131.6mg that stirs, 0.5mmol), 3-methoxyl group-benzylamine (0.25mL, 2mmol) vlil in 3mL 2-propyl alcohol is 12 hours, obtains 4-(3-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester.Evaporating solvent passes through the silica gel flash column chromatography (at CHCl with crude product ₃In 5-10%MeOH) purifying, obtain colourless 4 solid-state (154mg, productive rates 77%).

In room temperature to the amino dimethyl isophthalate of the 5-that stirs (2.09g, 10mmol) add in the solution in methylene dichloride (30mL) pyridine (2.43mL, 30mmol).(0.86mL 11mmol), spends the night the stirring of gained mixture in room temperature to add methylsulfonyl chloride in 0 ℃.Then this reaction mixture is under reduced pressure concentrated, add ethyl acetate (50mL).The gained white depositions is filtered, use hexane wash, obtain the sulphonamide (2.715g, productive rate 95%) of white solid state.

In room temperature in the suspension of the NaH that stirs (0.24g, 10mmol is 60%, in oil suspension) in 10mLDMF, add above sulphonamide (1.435g, 5mmol), add then methyl iodide (0.62mL, 10mmol).After 5 hours, with reactant H ₂O (25mL) cancellation.Then reaction mixture is extracted with EtOAc, use H ₂O further washing passes through anhydrous Na to remove excessive DMF ₂SO ₄Drying concentrates.With the crude product hexane wash that obtains thus, obtain 5-(the N-methyl methanesulfonamido) dimethyl isophthalate (1.37g, productive rate 91%) of white solid state.

(0.842g 2.8mmol) is dissolved in THF: MeOH (1: 1) (8mL) and H with 5-(N-methyl methanesulfonamido) dimethyl isophthalate ₂Among the O (3mL).Add solid state N aOH (0.112g, 2.8mmol), in stirring at room 18 hours.Reaction mixture is under reduced pressure concentrated.With saturated NaHCO ₃(10mL) solution joins in this reaction mixture, with toluene extraction (to remove＜10% unreacted raw material).The aqueous solution with rare HCl (10%) acidifying, with the EtOAc extraction, is passed through anhydrous Na ₂SO ₄Dry.Evaporating solvent, drying under reduced pressure, (75%, 0.598g), it is not purified to be used for further reaction to obtain 3-(methoxycarbonyl)-5-(N-methylmethane-5-ylsulfonylamino) phenylformic acid of white solid state.

In room temperature to 3-(methoxycarbonyl)-5-(N-methylmethane-5-ylsulfonylamino) phenylformic acid that stirs (0.215g, 0.75mmol), EDC (0.172g, 0.9mmol), (0.122g, 0.9mmol0 is at DMF/CH for HOBt ₂Cl ₂(1: (0.1mL 0.75mmol), adds diisopropylethylamine (0.5mL) then to add the Alpha-Methyl benzylamine in the solution 5mL).In room temperature reaction mixture was stirred 16 hours.Add entry then, this reaction mixture is extracted with EtOAc.Organic layer is passed through Na ₂SO ₄Drying concentrates.The crude product that obtains is thus passed through the silica gel flash column chromatography (at CHCl ₃In 3%MeOH) purifying, obtain corresponding amide 10 (0.343g), it is dissolved in THF: MeOH (1: 1) (6mL) and H ₂Among the O (2mL).Add solid state N aOH (80mg, 2.0mmol), in stirring at room 6 hours.Reaction mixture is under reduced pressure concentrated.With saturated NaHCO ₃(10mL) solution joins in this reaction mixture, with toluene extraction (to remove organic impurity).Aqueous reaction mixture with rare HCl (10%) acidifying, with the EtOAc extraction, is passed through anhydrous Na ₂SO ₄Dry.Evaporating solvent, drying under reduced pressure obtains 3-(N-methylmethane-5-ylsulfonylamino)-5-((1-styroyl) carbamyl) phenylformic acid (0.198g, 60%) of white solid state.

In room temperature to 3-hydroxyl-4-(3-methoxybenzyl amino)-(40mg is 0.1mmol) at CH for 1-phenyl fourth-2-aminocarbamic acid tert-butyl ester ₂Cl ₂Add TFA (0.5mL) in the solution (1mL).In room temperature reaction mixture was stirred 30 minutes.Afterwards, mixture is under reduced pressure concentrated, be dissolved in CH ₂Cl ₂(1mL), stir with diisopropylethylamine (0.2mL).With this mixture join stirring 3-(N-methylmethane-5-ylsulfonylamino)-5-((1-styroyl) carbamyl) phenylformic acid (37.6mg, 0.1mmol), EDC (24mg, 0.125mmol), (16.9mg is 0.125mmol) at DMF/CH for HOBt ₂Cl ₂(1: in the solution 2mL).In room temperature this reaction mixture was stirred 19 hours.Add entry then, this reaction mixture is extracted with EtOAc.Organic layer is passed through Na ₂SO ₄Drying concentrates.With the crude product N that obtains thus ¹-(4-(3-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methylmethane-5-ylsulfonylamino)-N ³-(1-styroyl) isophthaloyl amine passes through the silica gel flash column chromatography (at CHCl ₃In 10%MeOH) purifying, obtain the target molecule (22.3mg, 34%) of white solid state.

¹H NMR(500MHz，CDCl ₃)：δ1.58(3H，d)，2.72(3H，s)，2.74-2.83(4H，m)，3.22(3H，s)，3.69-3.83(6H，m)，4.29-4.33(1H，m)，5.26(1H，q)，6.78(1H，dd)，6.85-6.86(2H，m)，7.13-7.37(12H，m)，7.76(1H，s)，7.89(2H，s)，8.11(1H，s).

Embodiment 2: selected precursor compound synthetic

Following synthetic precursor compound can be used for preparing the method for compound of the present invention provided herein.The guidance that is provided among the above exemplary synthetic and embodiment 1 is provided, and those skilled in the art will know immediately, can prepare following precursor compound by using to synthesize below the well-known technology modification, to obtain multiple inhibitor compound.

Embodiment 2.1:1-(pyridin-3-yl) ethamine:

In room temperature disposable adding ammonium acetate (1.03mol) in the solution of 3-acetylpyridine (82.6mmol) in methyl alcohol (200mL).After 20 minutes, (57.8mmol) joins in this mixture with sodium cyanoborohydride with the mixture stirring.Stir after 1 day, 6M hydrochloric acid is joined in the reaction mixture.Gained solution is washed with ether, with potassium hydroxide water is alkalized to PH=10 then.With the amine chloroform extraction that discharges, the organic extract liquid that merges is passed through anhydrous sodium sulfate drying.Under reduced pressure, obtain the thick amine of colorless oil, it is further purified by under reduced pressure distilling except that after desolvating.

¹H NMR(300MHz，CDCl ₃)，δ：8.552(d，1H)，8.453(dd，1H)，7.678(m，1H)，7.206-7.261(m，1H)，4.148(q，1H)，1.378(d，3H).

Above method also is used to prepare following compound:

1-(3-p-methoxy-phenyl) ethamine:

¹H NMR(300MHz，CDCl ₃)，δ：7.274-7.219(m，1H)，6.941-6.905(m，2H)，6.796-6.757(m，1H)，4.090(q，1H)，3.811(s，3H)，1.382(d，3H).

1-(3-fluorophenyl) ethamine:

¹H NMR(300MHz，CDCl ₃)，δ：7.297-7.224(m，1H)，7.105-7.032(m，2H)，6.903-6.862(m，1H)，4.100(q，1H)，1.352(d，3H).

The different  azoles of embodiment 2.2:(3-methyl-5-yl) the methyl carbamic acid tert-butyl ester

321mg (2.27mmol) 2-(the different  azoles of 3-methyl-5-yl) acetate, 0.5mL (2.32mmol) diphenyl phosphoryl azide (DPPA) and 0.35mL (2.51mmol) the triethylamine solution in the 30mL distillation trimethyl carbinol was refluxed 13.5 hours.With this solution concentration, thick resistates is dissolved among the EtOAc.With organic layer with 1N HCl (3 * 10mL) and saturated NaHCO ₃Solution (3 * 10mL) washings.Organic layer by dried over sodium sulfate, is filtered, concentrate.By fast silica gel chromatogram method (28%EtOAc/ hexane) purifying, obtain the faint yellow solid-state protected amine of 50mg (productive rate 10%).

Embodiment 2.3:(3-(methoxymethyl) phenyl) methylamine

The method that use is found in below with reference to document is with 1, and 3-phenylene dimethanol is converted into (3-(methoxymethyl) phenyl) methyl alcohol: Liu, Xuan; Zheng, Qi-Huang; Fei, Xiangshu; Wang, Ji-Quan; Ohannesian, David W.; Erickson, Leonard C.; Stone, K.Lee; Hutchins, Gary D.; Bioorg.Med.Chem.Lett.2003,13,641-644.According to standard reaction, comprise and form trinitride with DPPA and reduction is a target molecule with (3-(methoxymethyl) phenyl) methanol conversion.

Embodiment 2.4:3-kharophen benzylamino t-butyl formate

In 0 ℃ of 3-aminobenzyl t-butyl carbamate (Hah, Jung-Mi to stirring; Martasek, Pavel; Roman, Linda J.; Silverman, Richard B.; J.Med.Chem.; 2003,46,1661-1669) (287mg is 1.29mmol) at CH ₂Cl ₂Add Et in the solution (10mL) ₃N (0.27mL, 2.0mmol) and Acetyl Chloride 98Min. (0.10mL 1.4mmol), slowly is warmed to room temperature with gained solution.After stirring 4 hours in addition, with the saturated NH of reactant ₄The cancellation of the Cl aqueous solution.Layering is with water layer CH ₂Cl ₂(2 * 20mL) extractions with organic layer water, the salt water washing that merges, are used Na ₂SO ₄Drying under reduced pressure concentrates.Remaining oily matter by column chromatography (60%EtOAc in hexane) purifying, is obtained ethanamide (123.1mg, 36%).

Embodiment 2.5:3-(methylamino) benzylamino t-butyl formate

According to standard reductive amination condition, use formaldehyde and sodium cyanoborohydride 3-aminobenzyl t-butyl carbamate is converted into target molecule.

Embodiment 2.6:5-fluorine m-phthalic acid

Criticize adding 13.8g (87.3mmol) KMnO to the solution mid-score of the 1.9g of gentle reflux (15.3mmol) 5-fluoro-m-xylene in about 13.5mL pyridine and about 9.5mL water ₄After mixture refluxed about 7 hours, add S-WAT with the excessive KMnO of cancellation ₄Warm mixture is filtered, add 1N HCl to pH=3.Filtrate is washed with EtOAc, saturated with NaCl, with (80mL CHCl ₃: 10mL MeOH: 10mL H ₂The extraction agent extraction of mixture O) 3-4 time.The extraction liquid that merges is passed through dried over sodium sulfate, filter, concentrate, obtain the faint yellow solid-state diacid of about 400mg (productive rate 14%).

Embodiment 2.7:5-(benzyloxy) nicotinic acid methyl ester

Under Ar in 60 ℃ with 818mg (5.34mmol) 5-hydroxy niacin, 1.70g (12.3mmol) K ₂CO ₃And the mixture heating up of 1.0mL (8.41mmol) cylite in 25mL DMF 16 hours.This mixture is filtered by cotton, resistates is dissolved in CHCl ₃In.With the organic layer water (2 * 30mL), salt solution (30mL) washing, pass through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method purifying, obtain the orange buttery benzylic ether of 363mg (productive rate 28%).

Embodiment 2.8:(5-(benzyloxy) pyridin-3-yl) methyl alcohol

In the solution of 363mg (1.49mmol) 5-(benzyloxy) nicotinic acid methyl ester in 10mL THF that stirs, add 141mg (3.71mmol) LiAlH in 0 ℃ ₄Remove ice bath, after 55 minutes, add 20.5mgLiAlH ₄After 40 minutes, by continuous adding 160 μ L H ₂O, the 160 μ L 15%NaOH aqueous solution and 480 μ L salt solution cancellation reactants.By fast silica gel chromatogram method (2mL MeOH/100mLCHCl ₃) purifying, obtain 250mg (productive rate 78%) alcohol (yellow oil).

Embodiment 2.9:3-(azido methyl)-5-(benzyloxy) pyridine

In 250mg (1.17mmol) (5-(benzyloxy) pyridin-3-yl) solution of methyl alcohol in 8mL toluene that stirs, add 310 μ L (1.44mmol) DPPA.This mixture is cooled to 0 ℃, adds 210 μ L (1.44mmol) 1,8-diazabicylo [5.4.0]-11 carbon-7-alkene (DBU).Remove ice bath, when being warmed to room temperature, continue to stir.After about 20 hours, solution is diluted with EtOAc, adding 1N HCl to pH is 7 to 8.With the organic layer water (2 * 15mL) and salt solution (15mL) washing, pass through Na ₂SO ₄Dry.After filtering and concentrating, crude product by fast silica gel chromatogram method (56-60%EtOAc/ hexane) purifying, is obtained the trinitride of 181mg (productive rate 65%) colorless oil.

Embodiment 2.10:(5-(benzyloxy) pyridin-3-yl) methylamine

In 181mg 3-(the azido methyl)-solution of 5-(benzyloxy) pyridine in 6mL THF that stirs, add 80.6mg (2.12mmol) LiAlH in 0 ℃ ₄Remove ice bath, when being warmed to room temperature, continue to stir.After 30 minutes, by continuous adding 160 μ L H ₂O, 160 μ L, the 15% NaOH aqueous solution and 480 μ L salt solution cancellation reactants.Mixture is filtered by Celite, concentrate.Crude product is used for next reaction without being further purified.

Embodiment 2.11:(5-picoline-3-yl) methyl alcohol

In the solution of 233mg (1.70mmol) the 5-methylnicotinic acid that stirs (universal method according to 5-fluoro-m-phthalic acid is synthetic) in 30mL THF, add 181mg (4.76mmol) LiAlH in 0 ℃ ₄After 25 minutes, by continuous adding 180 μ L H ₂O, the 180 μ L 15%NaOH aqueous solution and 540 μ L salt solution cancellation reactants.Mixture is filtered by Celite, concentrate, obtain slightly alcohol of 87mg, it is used for next reaction without being further purified.

Embodiment 2.12:(5-picoline-3-yl) methylamine

According to as mentioned to the described universal method of nicotinic acid benzylic ether derivative, synthesized precursor compound by corresponding alcohol.

Embodiment 2.13:(5-methoxypyridine-3-yl) methylamine

According to as mentioned to the described universal method of nicotinic acid benzylic ether derivative, synthesized precursor compound by the hydroxy niacin ester.

Embodiment 2.14:4-fluoro-m-phthalic acid

According to the described method of 5-fluoro-m-phthalic acid, synthesized precursor compound by 2-fluoro-5-tolyl acid.

Embodiment 2.15:4-methyl-m-phthalic acid

According to the described method of 5-fluoro-m-phthalic acid, by 2, the 5-mesitylenic acid has synthesized precursor compound.

Embodiment 2.16:1-(4-methylthiazol-2-yl) the ethyl carbamic acid tert-butyl ester

With BOC-L-Ala-thioamides (1.39g, 6.81mmoles), monochloroacetone (0.65mL, 8.18mmoles) and lime carbonate (1.0g, mixture 10.22mmoles) refluxed 4 hours in ethanol (25mL).This reactant is cooled to room temperature, with the saturated NaHCO of 20mL ₃Aqueous solution cancellation.Vapourisation under reduced pressure ethanol is with ethyl acetate (2 * 30mL) extractions.The organic layer that merges is passed through Na ₂SO ₄Drying concentrates.Resistates is carried out silica gel chromatography (20% ethyl acetate/80% hexane), obtain 48% required product.

Embodiment 2.17:4-((1H-benzo [d] imidazoles-2-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester

With 1-(oxyethane-2-yl)-2-styroyl t-butyl carbamate (185mg, 0.7mmoles), (1H-benzo [d] imidazoles-2-yl) methylamine dihydrochloride (232mg, 1.01mmoles) and HunigShi alkali (0.49mL, 2.8mmoles) solution in iPrOH (6mL) refluxed 12 hours.This reactant is cooled to room temperature, and the vapourisation under reduced pressure solvent carries out chromatography (5%MeOH/95%CHCl ₃), obtain the required product of 175mg (61%).

Embodiment 2.18:N1-(3-hydroxyl-4-((1-isobutyl-piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine dihydrochloride

In 80 ℃ will the 1-in the Virahol (20mL) (oxyethane-2-yl)-N-((oxo boryl) methylene radical)-2-phenyl-ethyl amine (1.61mmol, 424mg) and 4-(aminomethyl) piperidines-1-benzyl formate (1.94mmol, 480mg) heated overnight.Evaporating solvent by purified by flash chromatography, obtains 4-((2-hydroxyl-3-((oxo boryl) methene amido)-4-phenyl butyl amino) methyl) piperidines-1-benzyl formate (880mg).

¹H NMR(300MHz，CDCl ₃)，δ：7.363-7.174(m，10H)，5.118(s，2H)，4.767(br，1H)，4.187(m，2H)，3.786(m，1H)，3.458(m，1H)，3.023-2.671(m，6H)，2.484(d，J＝6.6Hz，2 H)，1.733(m，2H)，1.600(m，1H)，1.347(s，9H)，1.13(m，2H).

(1.04mmol 530mg) joined among the TFA (7.6mL) 4-((2-hydroxyl-3-((oxo boryl) methene amido)-4-phenyl butyl amino) methyl) piperidines-1-benzyl formate that will be in methylene dichloride, in stirring at room 40 minutes.Evaporating solvent.Resistates is dissolved in the methylene dichloride, and (4.14mmol 0.72mL), stirred 30 minutes to add diisopropylethylamine.Then with acid (1.04mmol, 390mg) and bop reagent (1.14mmol 504mg) joins in the flask.Evaporating solvent is spent the night in the stirring of gained mixture.Resistates is dissolved in the chloroform water and salt water washing.At last yellow residue is passed through purified by flash chromatography, obtain product (320mg).

¹HNMR(300MHz，CDCl ₃)，δ：7.992(s，1H)，7.865(m，1H)，7.715(s，1H)，7.383-7.106(m，15H)，5.241(m，1H)，5.093(s，2H)，4.291(m，1H)，4.146(m，2H)，3.843(m，1H)，3.232(s，3H)，3.065(m，1H)，2.962-2.626(m，7H)，2.779(s，3H)，1.714(m，3H)，1.579(d，J＝6.9Hz，3H)，1.120(m，2H).

With above compound (318mg 0.413mmol) is dissolved in the anhydrous methanol, be dissolved in then triethylamine (0.2mL, excessive) and coke tert-butyl acrylate (108.3mg, 0.5mmol) in.The stirring of gained mixture is spent the night.Evaporating solvent is dissolved in resistates in the methyl alcohol then, uses Pd (OH) under 1atm ₂Hydrogenation.After the filtration, evaporating solvent by purified by flash chromatography, obtains product (215mg) with resistates.

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：8.227-7.802(m，3H)，7.365-7.059(m，10H)，5.214(m，1H)，4.308(br，1H)，3.885(m，1H)，3.467(m，1H)，3.293-2.879(m，6H)，3.211(s，3H)，2.805-2.668(m，3H)，2.782(s，3H)，1.717(m，3H)，1.562(d，J＝6.9Hz，3H)，1.386(s，9H)，1.174(m，2H).

(50mg 0.068mmol) joins in the isobutyric aldehyde (0.1mL, excessive), stirs 15 minutes, adds NaBCNH then will to be dissolved in amine in methyl alcohol/acetonitrile (5/1) ₃(12.8mg 0.2mmol), continues to stir 30 minutes.5 acetate are joined in this reaction mixture, continue to stir and spend the night.Evaporating solvent.Then white solid is dissolved in the chloroform, uses NaHCO ₃The aqueous solution, salt water washing are filtered, and use anhydrous Na ₂SO ₄Dry.The gained resistates by purified by flash chromatography, is obtained product (40mg).

¹H NMR(300MHz，CDCl ₃)，δ：8.014(s，1H)，7.902(s，1H)，7.798(s，1H)，7.372-7.087(m，10H)，5.261(m，1H)，4.340(m，1H)，3.870(m，1H)，3.420-3.207(m，3H)，3.282(s，3H)，3.103-2.890(m，4H)，2.841(s，3H)，2.610(m，3H)，2.132(m，2H)，1.935-1.774(m，3H)，1.569(d，J＝6.9Hz，3H)，1.422(s，9H)，1.302(m，2H)，0.979(d，J＝6.6Hz，3H)，

Above compound is dissolved in the 4M HCl two  alkane solution, stirred 1 hour.Evaporating solvent reclaims N1-(3-hydroxyl-4-((1-isobutyl-piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl sulfonamido)-N3-(1-styroyl) the isophthaloyl amine dihydrochloride that obtains white solid state.

Embodiment 2.19:3-(sec.-propyl ((4-methylthiazol-2-yl) methyl) carbamyl) methyl benzoate

Under Ar with Et ₃N (1, catalysis) joins m-phthalic acid one methyl esters (0.294mmol, 1.0 equivalents) of stirring at 2mL SOCl ₂In suspension in.In 90 ℃ this mixture heating up was refluxed 2 hours.Reactant is cooled to room temperature, solvent removed in vacuo.Resistates is placed under the Ar atmosphere, be dissolved in the anhydrous CH of 2mL ₂Cl ₂In.Under Ar with gained solution with being dissolved in the anhydrous CH of 1mL ₂Cl ₂In N-((4-methylthiazol-2-yl) methyl) third-2-amine (0.294mmol, 1.0 equivalents are made by the reductive amination of 4-methylthiazol-2-formaldehyde and Isopropylamine) solution-treated.In stirring at room after 30 minutes, with reactant ET ₃N (0.294mmol, 1 equivalent) handles., after 30 minutes reactant is poured in the separating funnel in stirring at room, used saturated NaHCO ₃Na is passed through in (* 1), water (* 3), salt solution (* 1) washing ₂SO ₄Dry.By removing by filter inorganics, solvent removed in vacuo obtains crude product (productive rate 93%).

The different  azoles of embodiment 2.20:(3-methyl-5-yl) the methyl carbamic acid tert-butyl ester

321mg (2.27mmol) 2-(the different  azoles of 3-methyl-5-yl) acetate, 0.5mL (2.32mmol) diphenyl phosphoryl azide (DPPA) and 0.35mL (2.51mmol) the triethylamine solution in the 30mL distillation trimethyl carbinol was refluxed 13.5 hours.With this solution concentration, thick resistates is dissolved among the EtOAc.With organic layer with 1N HCl (3 * 10mL) and saturated NaHCO ₃Solution (3 * 10mL) washings.Organic layer by dried over sodium sulfate, is filtered, concentrate.By fast silica gel chromatogram method (28%EtOAc/ hexane) purifying, obtain faint yellow solid-state (the different  azoles of 3-methyl-5-yl) the methyl carbamic acid tert-butyl ester of 50mg (productive rate 10%).

Embodiment 2.21:5-fluorine m-phthalic acid

Criticize adding 13.8g (87.3mmol) KMnO to the solution mid-score of the 1.9g of gentle reflux (15.3mmol) 5-fluoro-m-xylene in about 13.5mL pyridine and about 9.5mL water ₄After mixture refluxed about 7 hours, add S-WAT with the excessive KMnO of cancellation ₄Warm mixture is filtered, add 1N HCl to pH=3.Filtrate is washed with EtOAc, saturated with NaCl, with (80mL CHCl ₃: 10mL MeOH: 10mL H ₂The extraction agent extraction of mixture O) 3-4 time.The extraction liquid that merges is passed through dried over sodium sulfate, filter, concentrate, obtain the faint yellow solid-state 5-fluorine m-phthalic acid of about 400mg (productive rate 14%).

Embodiment 2.22:(5-(benzyloxy) pyridin-3-yl) methylamine

Under Ar in 60 ℃ with 818mg (5.34mmol) 5-hydroxy niacin, 1.70g (12.3mmol) K ₂CO ₃And the mixture heating up of 1.0mL (8.41mmol) cylite in 25mL DMF 16 hours.This mixture is filtered by cotton, resistates is dissolved in CHCl ₃In.With the organic layer water (2 * 30mL), salt solution (30mL) washing, pass through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method purifying, obtain 363mg (productive rate 28%) orange buttery 5-(benzyloxy) nicotinic acid methyl ester.

In the solution of 363mg (1.49mmol) 5-(benzyloxy) nicotinic acid methyl ester in 10mL THF that stirs, add 141mg (3.71mmol) LiAlH in 0 ℃ ₄Remove ice bath, after 55 minutes, add 20.5mgLiAlH ₄After 40 minutes, by continuous adding 160 μ L H ₂O, the 160 μ L 15%NaOH aqueous solution and 480 μ L salt solution cancellation reactants.By fast silica gel chromatogram method (2mL MeOH/100mLCHCl ₃) purifying, obtain 250mg (productive rate 78%) (5-(benzyloxy) pyridin-3-yl) methyl alcohol (yellow oil).

In 250mg (1.17mmol) (5-(benzyloxy) pyridin-3-yl) solution of methyl alcohol in 8mL toluene that stirs, add 310 μ L (1.44mmol) DPPA.This mixture is cooled to 0 ℃, adds 210 μ L (1.44mmol) 1,8-diazabicylo [5.4.0]-11 carbon-7-alkene (DBU).Remove ice bath, when being warmed to room temperature, continue to stir.After about 20 hours, solution is diluted with EtOAc, adding 1N HCl to pH is 7 to 8.With the organic layer water (2 * 15mL) and salt solution (15mL) washing, pass through Na ₂SO ₄Dry.After filtering and concentrating, crude product by fast silica gel chromatogram method (56-60%EtOAc/ hexane) purifying, is obtained 3-(azido methyl)-5-(benzyloxy) pyridine of 181mg (productive rate 65%) colorless oil.

In 181mg 3-(the azido methyl)-solution of 5-(benzyloxy) pyridine in 6mL THF that stirs, add 80.6mg (2.12mmol) LiAlH in 0 ℃ ₄Remove ice bath, when being warmed to room temperature, continue to stir.After 30 minutes, by continuous adding 160 μ LH ₂O, the 160 μ L 15%NaOH aqueous solution and 480 μ L salt solution cancellation reactants.Mixture is filtered by Celite, concentrate, obtain thick (5-(benzyloxy) pyridin-3-yl) methylamine.Crude product is without being further purified use.

Embodiment 2.23:(5-picoline-3-yl) methyl alcohol

In the solution of 233mg (1.70mmol) the 5-methylnicotinic acid that stirs (universal method according to 5-fluoro-m-phthalic acid is synthetic) in 30mL THF, add 181mg (4.76mmol) LiAlH in 0 ℃ ₄After 25 minutes, by continuous adding 180 μ L H ₂O, the 180 μ L 15%NaOH aqueous solution and 540 μ L salt solution cancellation reactants.Mixture is filtered by Celite, concentrate, obtain thick (5-picoline-3-yl) methyl alcohol of 87mg, it is used for next reaction without being further purified.

Embodiment 2.24:1, two (chloromethyl)-2 of 5-, 4-dimethylbenzene

In 90 ℃ with 3mL (24.4mmol) m-xylene, 2.6g (28.5mmol) 1,3,5-three  alkane and 2.6g (19.0mmol) ZnCl ₂Solution heating in 100mL 1.0M HCl (in acetate).After 23 hours, add entry, NaHCO ₃And EtOAc.Layering with organic layer water (3-4 *) and salt water washing, is passed through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (hexane is to the 3%EtOAc/ hexane) purifying, it is colourless solid-state 1 to obtain 2.45g (productive rate 49%), two (chloromethyl)-2 of 5-, 4-dimethylbenzene.

Embodiment 2.25:(5-ethylpyridine-3-yl) methyl alcohol

In the mixture of 1.08g (12.0mmol) CuCN in 20mL THF that stirs, add 24mL EtMgBr (1M is in THF) in-78 ℃.Stir after 20 minutes, be added in 387mg 5-(5-bromopyridine-3-yl) methyl alcohol among the 20mL THF, continue to stir 3 hours in-78 ℃.Make this reaction mixture be warmed to room temperature then, stir about 17 hours adds ammonium hydroxide.This mixture stirred become reddish bluely until color, its placement is spent the night.It is used CHCl ₃Na is passed through in (2 *) extraction ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (2.5%MeOH/CHCl ₃) purifying, obtain (5-ethylpyridine-3-yl) methyl alcohol of 37mg (productive rate 13%) yellow oily.

Embodiment 2.26:5-fluorine nicotinic acid methyl esters

In the solution of 243mg (1.6mmol) 5-amino-nicotinic acid methyl esters in 5mL HF-pyridine that stirs, add 119mg (1.72mmol) NaNO in 0 ℃ ₂In 0 ℃ this mixture was stirred 30 minutes, stirred 1 hour in 50 ℃.This reactant is passed through ice and saturated NaHCO ₃The solution cancellation.With water layer CHCl ₃Na is passed through in extraction ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (1%MeOH/CHCl ₃) purifying, obtain the yellow solid-state 5-fluorine nicotinic acid methyl esters of 139mg (productive rate 56%).

Embodiment 2.27:2-chloro-1-(2,4-two fluoro-5-aminomethyl phenyls) ethyl ketone

In 0 ℃ to stir 2, add 6.3g (47.3mmol) AlCl in the 4-difluoro toluene solution ₃And 3.4mL (42.6mmol) chloroacetyl chloride.In 0 ℃ this mixture stirring after 10 minutes, was stirred 30 minutes in 45 ℃ then.Make this mixture be warmed to room temperature, add the dense HCl of about 16mL, 25mL water and 100mL EtOAc.Separate organic layer, with salt solution and saturated NaHCO ₃Na is passed through in (2 *) washing ₂SO ₄Dry.Solution is filtered, concentrate, obtain the colourless solid-state 2-chloro-1-of 9.0g (2,4-two fluoro-5-aminomethyl phenyls) ethyl ketone, it is without being further purified use.

Embodiment 2.28:5-isopropoxy nicotinic acid methyl ester

In 60 ℃ of solution heating with 677mg (3.28mmol) dicyclohexylcarbodiimide (DCC), 0.3mL (3.92mmol) Virahol and 7.7mg (0.078mmol) CuCl.After 13 hours, add 460mg (3.0mmol) 5-hydroxy niacin methyl esters and 10mL benzene, in 105 ℃ of heating 24.5 hours.This mixture is diluted with chloroform, filter.With the organic layer saturated NaHCO of 15mL ₃, water and salt water washing, pass through Na ₂SO ₄Dry.By fast silica gel chromatogram method (100%CHCl ₃) purifying, obtain the 5-isopropoxy nicotinic acid methyl ester of 274mg (productive rate 47%) yellow oily.

Embodiment 2.29:1-(the different  azoles of 3-methyl-5-yl) ethanol

In 0 ℃ of 5.2mL (84.9mmol) ethylidenehydroxylamine, 6.7mL (85.5mmol) 3-butyne-2-alcohol and 1.2mL (8.6mmol) Et that goes through clockwise stirring in 2 hours 45 minutes ₃N is at 20mL CH ₂Cl ₂In solution in add 275mL NaOCl.Remove ice bath, continue to stir 18 hours in room temperature.Add chloroform, layering.With organic layer CHCl ₃(2 *) and (80mL CHCl ₃: 10mL H ₂O: the extraction agent of mixture 10mL MeOH) (2 *) extraction.The extraction liquid that merges is passed through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (2%MeOH/CHCl ₃) purifying, obtain 1-(the different  azoles of the 3-methyl-5-yl) ethanol of the orange-yellow oily of 2.2g (productive rate 20%).

Embodiment 2.30:(4-methoxypyridine-2-yl) methylamine

In room temperature to 1.2g (9.67mmol) 4-methoxypyridine-N-oxide compound that stirs at 18mLCH ₂Cl ₂In mixture in add 1.6mL (12.0mmol) TMSCN.After 5 minutes, add 0.9mL (9.8mmol) dimethylamino formyl chloride.With this solution stirring 13 hours, add CHCl in room temperature ₃With 20mL 10%K ₂CO ₃With water layer CHCl ₃Extract 3 times, the extraction liquid that merges is passed through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (38-44%EtOAc/ hexane) purifying, obtain the colourless solid-state 4-methoxypyridine formonitrile HCN of 949mg (productive rate 73%).

In the solution of 949mg 4-methoxypyridine formonitrile HCN in 15mL THF that stirs, add about 0.6g LiAlH in 0 ℃ ₄React the very heat release that becomes.Make this mixture be warmed to room temperature, after 40 minutes, add following material continuously: 0.4mL H ₂O, 0.4mL 15%NaOH (aqueous solution) and 1.2mL salt solution.In room temperature this mixture was stirred 75 minutes, filter by Celite then, concentrate, obtain 377mg (4-methoxypyridine-2-yl) methylamine, it is used for next reaction without being further purified.

Embodiment 2.31:5-(dimethylamino) nicotinic acid methyl ester

To 283mg (1.86mmol) the 5-amino-nicotinic acid methyl esters that stirs at 19mL CH ₃CN and 19mL37% formaldehyde are (at H ₂Among the O) in solution in add 353mg (5.62mmol) NaCNBH ₃With 50 acetate.With this solution stirring 18.5 hours, add 40mL EtOAc and the saturated NaHCO of 40mL in room temperature ₃Solution.Layering is with the organic layer saturated NaHCO of 25mL ₃With the water washing of 25mL salt, pass through Na ₂SO ₄Drying is filtered, and concentrates.By fast silica gel chromatogram method (0.5%MeOH/CHCl ₃) purifying, obtain 5-(dimethylamino) nicotinic acid methyl ester of 124mg (productive rate 37%) yellow oily.

Embodiment 2.32:3-(2,2-dimethyl-1-((4-methylthiazol-2-yl) methyl) hydrazine carbonyl) methyl benzoate

In room temperature at CH ₂Cl ₂In 3-(methoxycarbonyl) phenylformic acid (253mg, add in 1.40mmol) EDCI (312mg, 1.64mmol) and HOBT (189mg, 1.40mmol), in stirring at room 20 minutes.In this mixture, add N, the N-dimethylhydrazine, add then DIPEA (404mg, 14.0mmol).In room temperature reaction mixture was stirred 16 hours.Then reaction mixture is diluted water, salt water washing, drying with chloroform.Thick resistates by the column chromatography purifying, is obtained 3-(2,2-dimethylhydrazine carbonyl) methyl benzoate (productive rate 60%).

In 0 ℃ to the sodium hydride in THF (3mL) (16mg, add in 0.68mmol) 3-(2,2-dimethylhydrazine carbonyl) methyl benzoate (100mg, 0.45mmol).After 10 minutes, (103mg 0.54mmol), spends the night the reaction mixture stirring in 3-4 ℃ to add 4-methyl-2-brooethyl thiazole.With reaction mixture MeOH cancellation, dilute with ethyl acetate.With organic layer water, salt water washing, drying.Thick resistates by the column chromatography purifying, is obtained 3-(2,2-dimethyl-1-((4-methylthiazol-2-yl) methyl) hydrazine carbonyl) methyl benzoate (productive rate 70%).

Embodiment 2.33:3-(methyl fluoride) benzylamino t-butyl formate

In-78 ℃ at CH ₂Cl ₂DAST (30mL) (600mg, slowly add in 3.72mmol) pure 3-(hydroxymethyl) benzylamino t-butyl formate (630mg, 2.65mmol).In-78 ℃ reaction mixture was stirred 1 hour, stirred 1 hour in addition in room temperature.Then reaction mixture is used the methyl alcohol cancellation, used the sodium bicarbonate cancellation then.Except that after desolvating, thick resistates is carried out column chromatography, obtain 3-(methyl fluoride) benzylamino t-butyl formate (productive rate 60%).

Embodiment 2.34:(3-isopropyl phenyl) methylamine

(4.3gm, 12mmol) (1.6M, 7.5mL 12mmol), stirred 30 minutes middle adding n-BuLi to the Diethylaminoethyl triphenyl  in THF in 0 ℃.Slowly be added in the 3-ethanoyl benzonitrile among the THF then, this reaction mixture stirred 3 hours in addition in 0 ℃.Then reaction mixture is used the aqueous ammonium chloride solution cancellation, diluted with ethyl acetate.With organic layer water, salt water washing, drying.After thick resistates carried out column purification, obtain 3-(third-1-alkene-2-yl) benzonitrile (productive rate 86%).

(1.2gm, 8.3mmol) the middle 10%Pd/C (120mg) that adds stirred 16 hours under atmosphere of hydrogen to the 3-in ethyl acetate (30mL) (third-1-alkene-2-yl) benzonitrile.Then this reaction mixture is filtered, evaporating solvent obtains the 3-sec.-propyl benzonitrile of quantitative yield.

(1.74gm 45.7mmol), made this reaction mixture reach room temperature, in stirring at room 48 hours slowly to add LAH in 0 ℃ in the 3-sec.-propyl benzonitrile in THF.Reaction mixture is cooled to 0 ℃ then, with the ether dilution, with saturated metabisulfite solution cancellation.Resistates is filtered, and evaporating solvent obtains amine (3-isopropyl phenyl) methylamine of quantitative yield.

Embodiment 2.35:3-(3-methoxyl group-4-aminomethyl phenyl) propane-1-amine

In 0 ℃ to the 3-methoxyl group-methyl 4 methylbenzoate in THF (60mL) (3gm, slowly add in 16.6mmol) LAH (3gm, 66.6mmol)., after 30 minutes reaction mixture is handled as mentioned above in 0 ℃ of other stirring, obtained alcohol (3-methoxyl group-4-aminomethyl phenyl) methyl alcohol of quantitative yield.

(3gm 7.07mmol) joins at CH in 0 ℃ Dess-Martin to be crossed iodine alkane (periodinane) ₂Cl ₂(3-methoxyl group-4-aminomethyl phenyl) methyl alcohol (35mL) (1gm, 6.57mmol) in.After 0.5 hour, remove number of C H in 0 ℃ of stirring ₂Cl ₂, reaction mixture is diluted with ether, with sodium hydrogen carbonate solution, hypo solution and water washing.With the organic layer drying, evaporate, obtain the 3-methoxyl group-4-tolyl aldehyde of quantitative yield.

Make 3-methoxyl group-4-tolyl aldehyde and cyanogen methyl triphenyl phosphorane carry out the Wittig reaction, obtain 3-(3-methoxyl group-4-aminomethyl phenyl) vinyl cyanide (productive rate 77%), use aforesaid method that it further is converted into 3-(3-methoxyl group-4-aminomethyl phenyl) propane-1-amine.

Embodiment 2.36:4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester:

To the 3-bromobenzyl t-butyl carbamate in triethylamine (3mL) (220mg, add in 1mmol) trimethyl silyl acetylene (147mg, 1.5mmol), add then cuprous iodide (8mg, 0.04mmol).Stir after 5 minutes, (35mg 0.05mmol), heats this reaction mixture 18 hours in 90 ℃ to add two (triphenyl phosphine) palladiums (II) of dichloro.Then this reaction mixture is filtered,, wash with water with the ethyl acetate dilution.With the organic layer drying, evaporation by the column chromatography purifying, obtains 3-((trimethyl silyl) ethynyl) benzylamino t-butyl formate (productive rate 67%) with thick resistates.

The Boc-group is removed from 3-((trimethyl silyl) ethynyl) benzylamino t-butyl formate, gained amine is used to open epoxide (S)-1-((S)-oxyethane-2-yl)-2-styroyl t-butyl carbamate, obtains 3-hydroxyl-1-phenyl-4-(3-((trimethyl silyl) ethynyl) benzyl amino) fourth-2-aminocarbamic acid tert-butyl ester (productive rate 60%).

In the 3-hydroxyl-1-phenyl-4-in the mixture of THF (2mL) and MeOH (2mL) (3-((trimethyl silyl) ethynyl) benzyl amino) fourth-2-aminocarbamic acid tert-butyl ester, add 1M K ₂CO ₃(0.25mL), in room temperature this reaction mixture was stirred 18 hours.Remove then and desolvate, thick resistates is dissolved in the ethyl acetate again water, salt water washing, drying.Carry out column purification, obtain 4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-aminocarbamic acid tert-butyl ester (productive rate 85%).

Embodiment 2.37:5-(methylsulfonyl methyl) m-phthalic acid diethyl ester

In 0 ℃ to 5-(hydroxymethyl) m-phthalic acid diethyl ester (2.52gm in THF (30mL), (5.25gm 20mmol), adds thiolactic acid (1.52gm then to add triphenylphosphine 10mmol), 20mmol) and diisopropyl azodiformate (4.04gm, 20mmol).Make reaction mixture reach room temperature then, stirred 2 hours.Remove then and desolvate, crude product is dissolved in minimum CH again ₂Cl ₂In.Under agitation add hexane, discard the gained solid.Filtrate is evaporated to dried, resistates is carried out column purification, obtain 5-(ethanoyl thiomethyl) m-phthalic acid diethyl ester (productive rate 95%).

To 5-(ethanoyl thiomethyl) the m-phthalic acid diethyl ester in THF (10mL) and MeOH (10mL) (1.02gm, add in 3.30mmol) sodium methylate (207mg, 3.63mmol), in stirring at room 2 hours.Add in two batches then methyl-iodide (0.69mL, 10.9mmol).After 4 hours, vacuum is removed THF and MeOH in stirring at room, and this reaction mixture is diluted with ethyl acetate.With organic layer water, salt water washing, drying.Thick resistates is carried out column purification, obtain 5-(methyl thiomethyl) m-phthalic acid diethyl ester (productive rate 55%).

(990mg 4.43mmol) joins at CH with m-CPBA in 0 ℃ ₂Cl ₂S-methyl compound (10mL) (500mg, 1.77mmol) in.Stir after 15 minutes, make reaction mixture reach room temperature, stirred 20 hours.Then with reaction mixture CH ₂Cl ₂Dilution is washed with sodium hydrogen carbonate solution.Thick resistates is carried out column purification, obtain 5-(methylsulfonyl methyl) m-phthalic acid diethyl ester (productive rate 73%).

The inhibition of embodiment 3:memapsin 2 catalytic activitys

Measured their usefulness by the catalytic activity of measuring 2 pairs of fluorogenic substrates of compound inhibition memapsin.Use as the described method of people such as Ermolieff (Biochemistry 39:12450-12456 (2000), the instruction integral body of the document is incorporated herein) and carried out kinetics inhibition experiment.In brief, under pH4,37 ℃ by memapsin 2 enzymes and compound preincubate were tested in 20 minutes.By adding fluorogenic substrate FS-2 (Bachem Americas, torrance, CA) beginning determination of activity.Fluorescent signal increases in time as the hydrolysis rate of peptide substrates and is determined.The inhibitory phase of hydrolysis rate is expressed and is fitted to the model (J.Bieth, " proteinase inhibitor, " Bayer symposium V, 463-469,1974) of the inhibitor of combining closely for the contrast that does not suppress.The results are shown in following table 1.

Table 1

Structure	M2K	CDK	M1K	Cell
Structure	M2K	CDK	M1K	Cell	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++
N1-(1-(2,5-dimethyl  azoles-4-yl) ethyl)-N3-(3-hydroxyl 4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+	+	+	++		+++	+++	+++	+++
	+	+	+	++	N1-((2,5-dimethyl  azoles-4-yl) methyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+	+	+	++
N1-(3-hydroxyl-4-(3-(methoxymethyl) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+	+		+	+	+	++
	+	+	+	+	3-((2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl amino) methyl) methyl benzoate	+	+	+	+++
N1-(3-hydroxyl-1-phenyl-4-(pyridine-2-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+	+	+++		+	+	+	+++
	+++	+	+	+++	N1-(3-hydroxyl-1-phenyl-4-(pyridin-3-yl methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+	++	+++
N1-(4-(3-(benzyloxymethyl) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	+	+++			+++	+	++	+++

N1-(3-hydroxyl-4-(3-(sec.-propyl carbamyl) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+		+	+
	+		+	+	N1-(2-hydroxyl-1-(3-methoxybenzyl amino)-5-methyl oneself-3-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+
N1-(2-hydroxyl-1-(3-methoxybenzyl amino)-5-methyl oneself-3-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+		+			+	+
	+		+		N1-(3-hydroxyl-4-(4-anisole ylsulfonylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+		++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(pyridin-3-yl) ethyl) isophthaloyl amine	+++	+	+	+++		+		++
	+++	+	+	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-(2-p-methoxy-phenyl) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++		+
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+	+++		++		+
	+++	+++	+	+++	N1-(4-(2-(1H-indol-3-yl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine
N1-(3-hydroxyl-1-phenyl-4-((tetrahydrofuran (THF)-2-yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine

N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(pyridin-3-yl) ethyl) isophthaloyl amine	+++			+++
	+++			+++	N1-(1-(hexahydro furyl is [2,3-b] furans-3-yl also) ethyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+
N1-((hexahydro furyl is [2,3-b] furans-3-yl also) methyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	++	++	+	+		+
	++	++	+	+	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(3-methoxy-benzyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+	++
N1-(3-hydroxyl-1-phenyl-4-(1-styroyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++	+		+++	+++	+	++
	+++	+++	++	+	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((the different  azoles of 3-methyl-5-yl) methyl) isophthaloyl amine	+	+++	+	+
N1-(3-hydroxyl-1-phenyl-4-(1-styroyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+	+++	++		+	+++	+	+
	+	+	+++	++	N1-(3-hydroxyl-1-phenyl-4-(pyridine-2-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			+++	+++
N1-(1-(4-fluorophenyl) ethyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+++	+++				+++	+++

N1-(3-hydroxyl-4-(methyl ((4-methylthiazol-2-yl) methyl) amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+
	+	+	+		N1-(3-hydroxyl-1-phenyl-4-(1-phenyl propyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+++	+	++
N1-(3-hydroxyl-1-phenyl-4-(pyridin-4-yl methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+	++	+++		+	+++	+	++
	+++	+	++	+++	N1-(3-hydroxyl-1-phenyl-4-(1-phenyl propyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++
N1-(3-hydroxyl-4-((4-methylthiazol-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++	+	+++		+++	+++	+++	+++
	+++	++	+	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine	+++	+	++	+++
N-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-3-(2-methyl-2-phenyl hydrazine carbonyl)-5-(N-methyl methanesulfonamido) benzamide	+++	+++	+	+++		+++	+	++	+++
	+++	+++	+	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-hydrocinnamyl) isophthaloyl amine	+++	+++	+++	+++
N1-(4-(1-(4-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++		+++	+++	+++	+++

N1-(3-hydroxyl-4-(2-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++	+++
	+++	+++	++	+++	N1-(4-(benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++
N1-(4-(1-(4-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++		+++	+++	+++	+++
	+++	+++	+++	+++	N1-benzyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-nitro-N3-(1-styroyl) isophthaloyl amine	++	+++	+++	+++		+++	+++	+	+++
	++	+++	+++	+++	N1-(3-hydroxyl-1-phenyl-4-(1-styroyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++
N1-(4-(3-(dimethylamino) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+		+++		+++	+++		+++
	+++	+		+++	N1-(3-hydroxyl-1-phenyl-4-(pyrazine-2-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+		+++
N1-(4-((1H-benzo [d] imidazoles-2-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		++		+++	+		+++

N1-(3-hydroxyl-1-phenyl-4-(1-(pyridin-3-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++			+++
	+++			+++	N1-(3-hydroxyl-4-((the different  azoles of 3-methyl-5-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((5-pyridone-3-yl) methyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+	+		+++		+++	+++		+++
	+	+		+++	N1-(4-(3-fluorine benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++	+	+++
N1-(3-hydroxyl-1-phenyl-4-(1-(pyridin-3-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++		+++	++	+	+++
	+++	+++		+++	4-or 6-fluoro-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-(1-styroyl) isophthaloyl amine	+	+++	+	++
4-or 6-fluoro-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-(1-styroyl) isophthaloyl amine	+	+++	++	+++		+	+++	+	++
	+	+++	++	+++	N1-(3-hydroxyl-4-(6-picoline-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	+	++	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(pyridin-3-yl) ethyl) isophthaloyl amine	+	+	+	+		++	+	++	+++
	+	+	+	+	N1-(3-hydroxyl-4-(2-methyl-2-phenyl diazanyl)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	+	+	+

N1-(4-((2,5-dimethyl  azoles-4-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		+	+	++
		+	+	++	N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+++	+++
N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+++	+++		+++	+++	+++	+++
	+++	+++	+++	+++	N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	++	+++
N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+++	+++		+++	+++	++	+++
	+++	+++	+++	+++	N1-(3-hydroxyl-4 ((5-picoline-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++	+++
N1-(3-hydroxyl-4-(2-hydroxyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++		+++	+++	++	+++
	+++	+++	+++	+++	N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++
N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++		+++	+++	+++	+++

N1-(3-hydroxyl-4-(1-(4-methylthiazol-2-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++	+++
	+++	+++	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	++	+	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+			+++	++	+	+++
	+++	+++	+		N1-(3-hydroxyl-4-(1-(4-methylthiazol-2-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++	+	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine	++	+++	+	+++		+++	++	+	+++
	++	+++	+	+++	N1-(4-(3-fluorine benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+++	+	+++
N1-(3-hydroxyl-4-(3-methyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++	+++		+	+++	+	+++
	+++	+++	++	+++	N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-4-or 6-methyl-N1-(1-styroyl) isophthaloyl amine	++	+++	++	++
N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-4-or 6-methyl-N1-(1-styroyl) isophthaloyl amine	+	+++	+	++		++	+++	++	++
	+	+++	+	++	N1-(4-(3-kharophen benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++	+++	+++

N1-(4-(3,5-difluoro benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+	+++
	+++	+++	+	+++	N1-(3-hydroxyl-4-(3-methyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+++	+	+++
5-(N-ethyl methanesulfonamido)-N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-styroyl) isophthaloyl amine	++	+++	+++	+++		+	+++	+	+++
	++	+++	+++	+++	N1-cyclopropyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+
N1-(3-hydroxyl-4-((5-methoxypyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++			+++	+++	+
	+++	+++	++		4-or 6-fluoro-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++
N1-(3-hydroxyl-4-((6-picoline-2-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine						+++	+++	+++
					4-or 6-fluoro-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine
N1-(4-(1-(3-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++

N1-(4-(1-(3-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++
	+++	+++		N1-(3-hydroxyl-4-(3-(methoxymethyl) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-(3-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++			+++	+++
	+++	+++		N1-(3-hydroxyl-4-(3-(methylamino) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		+++
N1-(1-(3-fluorophenyl) ethyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	++				+++
	+++	++		N1-(1-(3-fluorophenyl) ethyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-(4-hydroxyl-3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine					+++	+++
				N1-(3-hydroxyl-1-phenyl-4-(quinoline-3-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(4-(3-benzyl ethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++	+++	+++

N1-(3-hydroxyl-4-((the different  azoles of 3-methyl-5-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+	+
	+++	+	+	N1-(3-hydroxyl-4-(3-sec.-propyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(3-hydroxyl-4-((5-methyl furan-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++	+++	+++
	+++	+++	+++	2-fluoro-N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+++	++
N1-(4-(2-fluoro-3-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+	+++	++
	+++	+++	+++	N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-4-(2-morpholino base ethylamino)-4-oxo butyrylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			++
5-((2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl) (3-methoxy-benzyl) amino)-5-oxopentanoic acid methyl esters			+++				++
			+++	N1-(3-hydroxyl-4-(3-sec.-propyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++
N1-(4-(3-(methyl fluoride) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++	+++	+++

N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-5-(N-methyl methanesulfonamido)-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++
	+++	+++	+++	2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl (3-methoxy-benzyl) t-butyl carbamate
N1-(4-(3-((dimethylamino) methyl) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+	+++
	+++	+	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-4,6-dimethyl-N3-(1-styroyl) isophthaloyl amine	++	+++	+++
N1-(4-((5-ethylpyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		++	+++	+++
	+++	+++	+++	N1-(4-(3-(methyl fluoride) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++
N1-(4-(3-benzyl ethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++		+++	+++	+++
	+++	+++	+++	N1-(4-(2-fluoro-6-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(4-(2-(dimethylamino)-N-(3-methoxy-benzyl) kharophen)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			++		+++	+++	+++

3-(2,2-dimethyl-1-((4-methylthiazol-2-yl) methyl) hydrazine carbonyl)-N-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl) benzamide	+	+	+
	+	+	+	N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-4-oxo-4-(pyridin-3-yl methylamino) butyrylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			+
N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-oxo-5-(pyridin-3-yl methylamino) valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			+				+
			+	N1-(3-hydroxyl-4-(2-morpholino base ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	+	++
N1-(4-(1-cyclohexyl ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		++	+	++
	+++	+++	+++	N1-(3-hydroxyl-4-(3-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	++	+
N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-(2-morpholino base ethylamino)-5-oxo valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			+		+	++	+
			+	N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-(4-methylpiperazine-1-base is amino)-5-oxo valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine			+

N1-(1-cyclohexyl ethyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+++	+++
	+++	+++	+++	N1-(3-hydroxyl-4-((the different  azoles of 5-methyl-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(3-hydroxyl-4-((the different  azoles of 5-methyl-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	++	++	++		+++	+++	+++
	++	++	++	N1-(4-((5-fluorine pyridin-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
4-((2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl amino) methyl) piperidines-1-benzyl formate	+++	+++	++		+++	+++	+++
	+++	+++	++	N1-(3-hydroxyl-4-(4-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(3-hydroxyl-1-phenyl-4-(2-(tetramethyleneimine-1-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+		+++	+++	+++
	+	+	+	N1-(3-hydroxyl-4-(2-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	++
N1-(3-hydroxyl-4-(3-isobutyl-benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++	+++	++

N1-(3-hydroxyl-1-phenyl-4-(2-(piperidines-1-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+
	+	+	+	N1-(3-hydroxyl-1-phenyl-4-(piperidin-4-yl methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+
N1-(3-hydroxyl-1-phenyl-4-(piperidines-3-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+		+	+	+
	+	+	+	N1-(3-hydroxyl-1-phenyl-4-(2-(tetramethyleneimine-1-yl) ethylamino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	+	+
4,6-two fluoro-N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-styroyl) isophthaloyl amine	+	+++	++		+	+	+
	+	+++	++	N1-(3-hydroxyl-4-((1-methyl piperidine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+	+
N1-(3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-oxo-5-(2-(piperidines-1-yl) ethylamino) valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine					+	+	+
				N1-(3-hydroxyl-4-((5-isopropoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++		+++
4-((2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl) (3-methoxy-benzyl) amino)-4-ketobutyric acid 2-(3; two (the benzyloxy)-5-oxos-2 of 4-, 5-dihydrofuran-2-yl)-the 2-hydroxyethyl ester					+++		+++

4-((2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-(1-styroyl carbamyl) benzamido)-4-phenyl butyl) (3-methoxy-benzyl) amino)-4-ketobutyric acid 2-(3; 4-dihydroxyl-5-oxo-2,5-dihydrofuran-2-yl)-the 2-hydroxyethyl ester			++
			++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(4-(methylol)  azoles-2-yl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++	+	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-(1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine	+++	+++	+++		+++	+	+++
	+++	+++	+++	N1-(3-hydroxyl-4-((5-isopropoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++	+++	+++
	+++	+++	+++	N1-(3-hydroxyl-4-(1-(the different  azoles of 3-methyl-5-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		+++
N1-(3-hydroxyl-4-(3-isobutyl-benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++		+++		+++		+++
	+++		+++	N1-(3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrroles-2-yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++		+++

N1-(3-hydroxyl-4-((1-methylpyrrolidin-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	+
	+	+	N1-(3-hydroxyl-4-((1-sec.-propyl tetramethyleneimine-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((4-(methylol)  azoles-2-yl) methyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	++	+		+
	++	+	N1-(3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazol-4 yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++
N1-(4-((1H-imidazol-4 yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	++		+++
	++	++	N1-(3-hydroxyl-4-(3-(3-methoxyl group-4-aminomethyl phenyl) propyl group amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++
N1-(4-((5-ethoxy pyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++	++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(4-methyl  azoles-2-yl) ethyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-((3-methoxyl group cyclohexyl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+	++		+++	+++

N1-(3-hydroxyl-4-((3-methoxyl group cyclohexyl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		++
		++	N1-(4-((5-ethoxy pyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-((5-isobutyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		+++		+++	+++
		+++	N1-(3-hydroxyl-4-((4-methoxypyridine-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		+++
N1-(1-(3, the 5-difluorophenyl)-3-hydroxyl-4-(3-methoxybenzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++			+++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methyl  azoles-2-yl) methyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazoles-2-yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	++	+		+++	+++
	++	+	N1-(1-(3, the 5-difluorophenyl)-3-hydroxyl-4-(3-methoxybenzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		+++
N1-(3-hydroxyl-4-((5-methoxypyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++			+++

N1-(3-hydroxyl-4-((5-picoline-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++
	+++	+++	+++	N1-(3-hydroxyl-4-((1-isobutyl-piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine dihydrochloride		+
N1-(3-hydroxyl-4-((1-(2-methoxy-benzyl) piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine dihydrochloride			+			+
			+	N1-(3-hydroxyl-4-((1-(2-methoxy-benzyl) piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine		++
N1-(3-hydroxyl-4-((3-methyl isophthalic acid H-pyrazoles-5-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+					++
	+			N1-(4-(3,4-dimethoxy benzene ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-(thiazole _ 4-yl) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		+++		+++	+++
	+++		+++	N1-(3-hydroxyl-4-((5-isobutyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-((5-isobutoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++		+++		+++	+++

N1-(3-hydroxyl-4-((1-(3-methoxy-benzyl) piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+		+
	+		+	N1-(3-hydroxyl-4-(2-hydroxyl-1-phenylethyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		+++
N1-(3-hydroxyl-4-(3-hydroxyl-4-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		++		+++		+++
	+++		++	N1-(4-((5-(dimethylamino) pyridin-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	++	+++
N1-(4-((5-ethylpyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++		+++	++	+++
	+++	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine	+++		+++
N1-(4-(benzo [d] [1,3] dioxole-5-ylmethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		+++		+++		+++
	+++		+++	N1-(3-hydroxyl-4-((5-isobutoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++		+++
N1-(3-hydroxyl-1-phenyl-4-(3-(trifluoromethyl) benzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++		+++		+++

N1-(4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++
	+++	+++	N1-(4-(3-(difluoro-methoxy) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++	+++
N1-(4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++		+++	+++	+++
	+++	+++	N1-((2,5-dimethyl  azoles-4-yl) methyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl isophthaloyl amine	+++		+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-(thiazol-2-yl) ethyl) isophthaloyl amine	+++	+++		+++		+++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-sec.-propyl-N3-((4-methylthiazol 2-yl) methyl) isophthaloyl amine	+++		+++
N1-(4-(3-ethoxy benzylidene amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++		+++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-isobutyl--N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++
N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++		+++

N1-(4-(benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+
	+				N1-(4-(3-ethoxy benzylidene amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++
N1-(3-hydroxyl-4-(3-isopropoxy benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++		+++		+++
	+++	+++		+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+
N1-(3-hydroxyl-4-(3-isobutoxy benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++					+
	+++				N1-(3-hydroxyl-4-(2-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+			++
N1-(3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	++	+++		+			++
	+++	+++	++	+++	N1-(3-hydroxyl-1-phenyl-4-(3-(trifluoromethyl) benzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+	+++
N1-ethyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++			+++		+++	+++	+	+++

N1-(4-(3-(difluoro-methoxy) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((2-methylthiazol-4-yl) methyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-(4-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	++		+++	+++
	+	++	N1-(3-hydroxyl-4-(2-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl)-5-nitro isophthaloyl amine	+++	+++		+	++
	+++	+++	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(methylsulfonyl methyl)-N3-(1-styroyl) isophthaloyl amine	+++	+++
N1-((4-ethyl thiophene 4-2-yl) methyl)-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl isophthaloyl amine	+++	+++		+++	+++
	+++	+++	N1-(3-hydroxyl-1-phenyl-4-(3-(trifluoromethoxy) benzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-(1-styroyl) isophthaloyl amine	+++	+++
N1-(3-hydroxyl-4-(4-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+	++		+++	+++

N1-(3-hydroxyl-1-phenyl-4-(3-(trifluoromethoxy) benzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++
	+++	+++	N1-benzyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++
N1-cyclopentyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++			+++
	+++		N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((2-methyl  azoles-4-yl) methyl) isophthaloyl amine	+++
N1-(3-hydroxyl-1-phenyl-4-(1-phenylethyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+			+++
	+		N1-(3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++
N1-cyclohexyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	++			+++
	++		N1-cyclopropyl-N3-(3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+++	+++	+++	+++
N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-(pyrazine-2-ylmethyl) isophthaloyl amine	+			+++	+++	+++	+++

N1-(3-hydroxyl-4-(4-methyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine	+
	+	N1-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-5-(methylsulfonyl methyl)-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine
N1-cyclopropyl-N3-(3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-methoxyl group-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine

In table 1, for the Ki data, Ki is greater than 501nM in "+" expression, and " ++ " expression Ki is 500nm to 301nm, " +++" represent that Ki is less than 300nm.For the IC50 data, IC50 is greater than 5 μ M in "+" expression, and " ++ " expression IC50 is 1 to 5 μ M, " +++" represent that IC50 is less than 1 μ M.In last table 1, once above compound title occurs and comprise for the three-dimensional chemical configuration that selects.

Embodiment 4: appraising datum

N1-((2S, 3R)-3-hydroxyl-4-((4-methylthiazol-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.56(d，3H)，2.36(d，3H)，2.85(s，3H)，2.78-3.00(m，4H)，3.30(s，3H)，3.68-3.78(m，1H)，4.01(s，2H)，4.30-4.40(m，1H)，5.20-5.35(m，1H)，6.80(d，1H)，7.10-7.40(m，10H)，7.79-7.82(m，1H)，7.90-7.92(m，1H)，8.01-8.05(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.68(d，3H)，2.41(d，3H)，2.85(s，3H)，2.70-3.02(m，4H)，3.31(s，3H)，3.75(s，3H)，3.70-3.83(m，2H)，4.30-4.40(m，1H)，5.50-5.60(m，1H)，6.72-6.90(m，3H)，7.10-7.30(m，7H)，7.79-7.82(m，1H)，7.90-7.92(m，1H)，8.05-8.10(m，1H).

N1-((2S, 3R)-4-(benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.56(d，3H)，2.82(s，3H)，2.68-3.02(m，4H)，3.27(s，3H)，3.70-3.85(m，3H)，4.25-4.35(m，1H)，5.20-5.30(m，1H)，7.10-7.40(m，15H)，7.75-7.77(m，1H)，7.86-7.90(m，1H)，8.01-8.03(m，1H).

N1-benzyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：2.84(s，3H)，2.70-3.02(m，4H)，3.30(s，3H)，3.74(s，3H)，3.70-3.83(m，3H)，4.30-4.42(m，1H)，4.58(s，2H)，6.74-6.88(m，2H)，7.10-7.38(m，12H)，7.74-7.78(m，H)，7.90-7.94(m，1H)，8.05-8.10(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-nitro-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H MR(300MHz，CDCl ₃+CD ₃OD)：1.59(d，3H)，2.70-3.02(m，4H)，3.73(s，3H)，3.70-3.85(m，3H)，4.28-4.39(m，1H)，5.20-5.35(m，1H)，6.72-6.88(m，2H)，7.10-7.40(m，12H)，8.42-8.44(m，1H)，8.55-8.57(m，1H)，8.74-8.77(m，1H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(pyrazine-2-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR (300MHz, CDCl ₃+ CD ₃OD): 1.58 (d, 3H), 2.80 (s, 3H), 2.70-3.02 (m, 4H), 3.29 (s, 3H), 3.60-3.72 (m, 1H), 3.85-4.01 (m, 2H), 4.34-4.48 (m, 1H), 5.25-5.40 (m, 1H), and 7.12-7.40 (m, 10H), 7.76-7.80 (m, 1H), 7.93-7.97 (m, 1H), 8.03-8.07 (m, 1H), 8.40-8.42 (m, 1H), and 8.46-8.48 (m, 1H), 8.59-8.61 (m, 1H). fusing point: 75-80 ℃

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(500MHz，CDCl ₃)：δ1.58(3H，d，J＝7.0Hz)，2.72(3H，s)，2.74-2.83(4H，m)，3.22(3H，s)，3.69-3.83(6H，m)，4.29-4.33(1H，m)，5.26(1H，m)，6.78(1H，m)，6.85-6.86(2H，m)，7.13-7.37(12H，m)，7.76(1H，s)，7.89(2H，s)，8.11(1H，s)；mp 77-80℃.

N1-((2S, 3R)-4-((1H-benzo [d] imidazoles-2-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.56(d，3H)，2.81(s，3H)，2.68-2.94(m，4H)，3.24(s，3H)，3.70-3.77(m，1H)，3.90-4.01(m，2H)，4.30-4.40(m，1H)，5.20-5.30(m，1H)，7.05-7.50(m，15H)，7.75-7.77(m，1H)，7.86-7.89(m，1H)，8.03-8.06 (m，1H).

N1-((2S, 3R)-4-((2,5-dimethyl  azoles-4-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.48(d，3H)，2.14(s，3H)，2.24(s，3H)，2.58-2.82(m，4H)，2.78(s，3H)，3.23(s，3H)，3.36(s，2H)，3.60-3.70(m，1H)，4.25-4.32(m，1H)，5.18-5.32(m，1H)，7.05-7.32(m，10H)，7.77-7.81(m，1H)，7.90-7.94(m，1H)，8.06-8.09(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-((S)-1-(4-methylthiazol-2-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR (300MHz, CDCl ₃+ CD ₃OD): 1.45 (d, 3H), 1.55 (d, 3H, J=6.9Hz) 2.37 (d, 3H), 2.74-2.84 (m, 2H), 2.81 (s, 3H), 2.95 (d, 2H), 3.30 (s, 3H), 3.58-3.65 (m, 1H), 4.00-4.12 (m, 1H), 4.30-4.42 (m, 1H), 5.22-5.34 (m, 1H), 6.79 (d, 1H) 7.10-7.32 (m, 10H), 7.74-7.78 (m, 1H), and 7.94-7.96 (m, 1H), 8.02-8.05 (m, 1H). fusing point: 80-87 ℃

N1-((2S, 3R)-3-hydroxyl-4-((R)-1-(4-methylthiazol-2-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR (300MHz, CDCl ₃+ CD ₃OD): 1.43 (d, 3H), 1.54 (d, and 3H) 2.33 (d, 3H), 2.62-2.84 (m, 2H), 2.84 (s, 3H), 2.87 (d, 2H), 3.27 (s, 3H), 3.65-3.75 (m, 1H), 4.00-4.12 (m, 1H), 4.28-4.48 (m, 1H), 5.18-5.32 (m, 1H), 6.76 (d, 1H) 7.05-7.35 (m, 10H), 7.78-7.81 (m, 1H), and 7.87-7.90 (m, 1H), 8.02-8.05 (m, 1H). fusing point: 85-90 ℃

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((S)-1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine:

1H NMR (300MHz, CDCl ₃+ CD ₃OD): 1.61 (d, 3H), 2.34 (s, 3H), 2.68-2.88 (m, 4H), 2.77 (s, 3H), 3.23 (s, 3H), 3.62-3.82 (m, 3H), 3.70 (s, 3H), 4.27-4.38 (m, 1H), and 5.40-5.51 (m, 1H), 6.70-6.87 (m, 4H), 7.05-7.50 (m, 5H), 7.71-7.74 (m, 1H), 7.86-7.89 (m, 1H), 7.98-8.03 (m, 1H). fusing point: 57-61 ℃

5-(N-ethyl methanesulfonamido)-N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR (300MHz, CDCl ₃+ CD ₃OD): 1.06 (t, 3H), 1.58 (d, 3H), 2.68-3.02 (m, 4H), 2.87 (s, 3H), 3.62-3.84 (m, 3H), 3.75 (s, 3H), 4.25-4.36 (m, 1H), 5.20-5.33 (m, 1H), 6.73-6.90 (m, 4H), 7.07-7.42 (m, 10H), 7.66-7.72 (m, 1H), 7.83-7.87 (m, 1H), 8.02-8.06 (m, 1H). fusing point: 110-116 ℃

N1-((2S, 3R)-3-hydroxyl-4-(3-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NHMR(300MHz，CDCl ₃)：1.60(d，3H，J＝7.2 Hz)，2.75(s，3H)，2.77-3.07(m，8H)，3.24(s，3H)，3.74(s，3H)，3.81-3.90(m，1H)，4.28-4.40(m，1H)，5.24-5.76(m，1H)，6.72-6.75(m，3H)，7.12-7.37(m，11H)，7.80-7.91(m，3H)，8.15(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：0.80-0.88(m，4H)，2.45(s，3H)，2.80-2.86(m，2H)，2.92-3.02(m，2H)，3.69-3.86 (m，6H)，4.36-4.44(m，1H)，4.96-5.12(m，2H)，6.79-6.99(m，4H)，7.15-7.26(m，8H)，7.64-7.67(m，1H)，7.82(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.64(d，3H，J＝7.2Hz)，2.33(s，3H)，2.79-3.33(m，7H)，3.29(s，3H)，3.82-3.91(m，3H)，4.24-4.41(m，1H)，5.29-5.42(m，1H)，6.93-7.43(m，14H)，7.83(s，1H)，7.94(s，1H)，8.13(s，1H).

N1-((2S, 3R)-4-(3-fluorine benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.40(s，3H)，2.76-2.81(m，2H)，2.92-3.05(m，5H)，3.71-3.78(m，3H)，4.26-4.42(m，1H)，4.86-4.96(m，2H)，6.88-7.66(m，14H).

¹H NMR(300MHz，CDCl ₃)：2.25(s，3H)，2.38(s，3H)，2.65-2.81(m，2H)，2.92-3.13(m，5H)，3.64-3.88(m，3H)，4.22-4.39(m，1H)，4.89(s，2H)，6.82-7.59(m，14H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((the different  azoles of 3-methyl-5-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.73-7.82(m，1H)，7.64-7.66(m，1H)，7.46-7.59(m，1H)，7.37-7.42(m，1H)，7.16-7.29(m，6H)，7.08-7.11(m，1H)，6.90-6.92(m，2H)，6.80-6.83(m，1H)，6.00-6.14(m，1H)，4.77(m，1.5H)，4.33-4.47(m，1.5H) 3.71-3.89(m，6H)，3.00-3.08(m，5H)，2.81-2.90(m，2H)，2.47(s，1H)，2.30(s，3H)；m.p.46-56℃.

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(pyridine-2-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.50-8.51(m，1H)，8.20(s，1H)，8.10-8.13(m，1H)，8.02(s，1H)，7.88(s，1H)，7.65-7.71(m，1H)，7.15-7.31(m，14H)，5.28-5.38(m，1H)，4.39-4.48(m，1H)，3.64-3.84(m，4H)，3.30(s，3H)，2.81-2.95(m，5H)，2.63-2.69(m，1H)，2.28(s，1H)，1.53(d，3H)；m.p.53-67℃.

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(pyridin-4-yl methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.49-8.51(m，2H)，7.93(s，1H)，7.89(s，1H)，7.75(s，1H)，7.09-7.41(m，13H)，6.87-6.97(m，1H)，5.27-5.36(m，1H)，4.31-4.40(m，1H)，3.75-3.91(m，2H)，3.62-3.70(m，2H)，3.31(d，3H)，2.96-2.98(m，2H)，2.81(s，3H)，2.74-2.76(m，2H)，2.02(s，1H)，1.62(d，3H)；m.p.73-84℃.

N1-((2S, 3R)-3-hydroxyl-4-((the different  azoles of 3-methyl-5-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.05(s，1H)，7.97(s，1H)，7.78(s，1H)，7.20-7.40(m，10H)，7.08-7.18(m，1H)，6.97-7.08(m，1H)，5.98(s，1H)，5.26-5.41(m，1H)，4.33-4.43(m，1H)，3.82-4.01(m，2H)3.61-3.65(m，2H)，3.33(s，3H)，2.99-3.02(m，2H)，2.83(s，3H)，2.75-2.76(m，2H)，2.21(s，3H)，1.70(s，1H)，1.62(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((5-pyridone-3-yl) methyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.15(s，1H)，7.81-7.98 (m，3H)，7.72(s，1H)，7.06-7.27(m，9H)，6.86-6.89(m，2H)，6.79-6.81(m，1H)，4.34-4.46(m，2H)，4.22-4.34(m，2H)，3.95-4.03(m，1H)，3.88-3.91(m，2H)，3.60-3.80(m，4H)，3.21(s，3H)，2.77-2.98(m，7H)，2.27(s，1H)；m.p.100-113.5℃.

4-or 6-fluoro-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.25-8.29(m，1H)，7.78-7.85(m，1H)，6.89-7.37(m，17H)，6.66-6.82(m，1H)，5.28-5.37(m，2H)，4.32-4.44(m，1H)，3.76-3.92(m，5H)，2.95-3.06(m，2H)，2.77-2.95(m，2H)，2.17(s，1H)，1.60(d，3H).

6-or 4-fluoro-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.14-8.16 (m，1H)，7.90-7.98(m，1H)，7.00-7.32(m，13H)，6.75-6.90(m，2H)，6.64-6.74(m，2H)，5.18-5.29(m，2H)，4.26-4.42(m，1H)，3.56-3.88(m，6H)，2.89-3.08(m，2H)，2.65-2.89(m，2H)，2.23(s，1H)，1.53-1.55(d，3H)；m.p.55-67℃.

N1-((2S, 3R)-3-hydroxyl-4-((5-picoline-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.46(s，1H)，8.33-8.36(m 1H)，8.19(s，1H)，8.13(s，1H)，8.04-8.07(m，1H)，7.95-7.97(m，1H)，7.69-7.72(m，1H)，7.1 5-7.44(m，11H)，6.89-6.95(m，1H)，5.30-5.44(m，1H)，4.32-4.41(m，1H)，3.99-4.04(m，1H)，3.57-3.83(m，2H)，3.31(s，3H)，2.94-3.09(m，2H)，2.81(s，3H)，2.61-2.62(m，2H)，2.27(s，3H)，2.03(s，1H)，1.65(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-4-or 6-methyl-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.61-7.63(m，1H)，7.14-7.42(m，15H)，6.88-6.95(m，2H)，6.81-6.85(m，1H)，6.16-6.29(m，1H)，5.28-5.36(m，1H)，4.30-4.43(m，1H)，3.72-3.93(m，5H)，3.02-3.04(m，2H)，2.75-2.95(m，3H)，2.42(s，3H)，1.74(s，1H)，1.60(d，3H)；m.p.64-77℃.

N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-6-or 4-methyl-N1-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.66-7.91(m，1H)，7.49(s，1H)，7.08-7.40(m，13H)，6.87-6.90(m，2H)，6.77-6.83(m，1H)，6.57(s，1H)，6.32(s，1H)，5.25-5.37(m，1H)，4.30-4.43(m，1H)，3.65-3.90(m，5H)，2.95-3.16(m，2H)，2.72-2.95(m，3H)，2.13(s，3H)，2.02(s，1H)，1.60(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-methoxypyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.25(s，1H)，8.09(s，1H)，7.98(s，1H)，7.76-7.82(m，1H)，7.72(s，1H)，7.16-7.44(m，14H)，6.77-6.86(m，1H)，5.30-5.45(m，1H)，4.30-4.42(m，1H)，4.00-4.12(m，1H)，3.73-3.87(m，2H)，3.55-3.73(m，2H)，3.33(s，3H)，2.98-3.03(m，2H)，2.82(s，3H)，2.60-2.69(m，2H)，1.70(s，1H)，1.66(d，3H).

4-or 6-fluoro-N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.06(s，1H)，7.61(s，1H)，7.05-7.28(m，10H)，6.85-7.05(m，2H)，6.78-6.81(m，1H)，4.89-5.02(m，2H)，4.36-4.52(m，1H)，3.69-3.87(m，5H)，3.59-3.69(m，1H)，2.96-3.16(m，5H)，2.72-2.84(m，2H)，2.44(s，3H)，2.04(s，1H).

6-or 4-fluoro-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.61-7.81(m，2H)，7.03-7.45(m，10H)，6.87-6.98(m，2H)，6.77-6.87(m，1H)，4.99(s，2H)，4.32-4.46(m，1H)，3.77-3.98(m，5H)，3.62-3.70(m，1H)，2.96-3.04(m，5H)，2.76-2.93(m，2H)，2.46(s，3H)，1.68(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-((6-picoline-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.28(s，1H)，8.01(m，1H)，7.87(m，1H)，7.52-7.57(m，1H)，7.11-7.29(m，10H)，7.00-7.05 (m，2H)，5.28-5.35(m，1H)，4.40-4.46(m，1H)，3.69-3.75(m，3H)，3.27(s，3H)，2.81-2.93(m，2H)，2.78(s，3H)，2.51-2.69(m，2H)，2.42(s，3H)，1.51(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(2-methyl-2-phenyl diazanyl)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

7.88-7.90(m，1H)，7.84-7.85(m，1H)，7.68-7.69(m，1H)，7.16-7.37(m，12H)，6.76-6.86(m，3H)，5.22-5.28(m，1H)，4.37-4.42(m，1H)，4.11-4.14(m，1H)，3.41-3.43(m，2H)，3.27(s，3H)，3.00-3.14(m，2H)，2.96(s，3H)，2.83(s，3H)，1.60(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(2-hydroxyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.01(s，1H)，7.88(s，1H)，7.72(s，1H)，7.12-7.38(m，11H)，6.97-7.01(m，1H)，6.77-6.81(m，2H)，5.24-5.29(m，1H)，4.30(m，1H)，3.86-4.02(m，3H)，3.23(s，3H)，2.83-2.92(m，4H)，2.78(s，3H)，1.60(d，3H).

N1-((2S, 3R)-4-(3-kharophen benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.27(s，1H)，7.90(s，1H)，7.80(s，1H)，7.50(s，1H)，7.38-7.41(m，3H)，7.11-7.26(m，10H)，5.25-5.30(m，1H)，4.26(m，1H)，3.84(m，1H)，3.64-3.76(m，2H)，3.19(s，3H)，2.75-2.85(m，4H)，2.73(s，3H)，1.98(s，3H)，1.60(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((6-picoline-2-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

7.67-7.70(m，1H)，7.51-7.56(m，2H)，7.35-7.40(m，1H)，7.16-7.25(m，6H)，7.02-7.06(m，2H)，6.88(s，1H)，4.95(s，2H)，4.43-4.48(m，1H)，3.94-4.01(m，2H)，3.79-3.82(m，1H)，2.92-3.10(m，7H)，2.50(s，3H)，2.44(s，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-(methoxymethyl) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.06(s，1H)，7.91-7.93(m，1H)，7.78-7.79(m，1H)，7.15-7.38(m，14H)，5.26-5.31(m，1H)，4.40(s，2H)，4.31-4.36(m，1H)，3.68-3.88(m，3H)，3.34(s，3H)，3.27(s，3H)，2.86-2.89(m，2H)，2.79-2.81(m，2H)，2.77(s，3H)，1.59(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-(methylamino) benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl sulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.31(s，1H)，7.91(s，1H)，7.83(s，1H)，7.37-7.44(m，2H)，7.07-7.25(m，9H)，6.57-6.60(m，2H)，6.47-6.49(m，1H)，5.26-5.31(m，1H)，4.29-4.33(m，1H)，3.95-4.00(m，1H)，3.75-3.89(m，2H)，3.22(s，3H)，2.78-2.82(m，4H)，2.73(s，3H)，2.72(s，3H)，1.64(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(4-hydroxyl-3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.09-8.10(m，1H)，7.84-7.86(m，1H)，7.73-7.74(m，1H)，7.35-7.39(m，2H)，7.09-7.29(m，8H)，6.88(s，1H)，6.72(s，2H)，5.20-5.24(m，1H)，4.16-4.21(m，1H)，3.79-3.93(m，3H)，3.75(s，3H)，3.25(s，3H)，3.09-3.15(m，1H)，2.79-2.93(m，3H)，2.81(s，3H)，1.57(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃)：2.44(s，3H)，2.80(d，2H)，2.98(d，3H)，2.95-3.14(m，2H)，3.77(s，3H)，3.64-3.86(m，3H)，4.33-4.45(m，1H)，4.63(bs，0.6H)，4.95(bs，1.4H)，6.76-6.92(m，4H)，7.13-7.29(m，7H)，7.33-7.40(m，1H)，7.50-7.84(m，3H).

N1-(1-(4-fluorophenyl) ethyl)-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.53(d，3H)，2.77(2s，3Htotal)，2.80-2.91(m，3H)，3.24(2s，3H total)，3.74(2s，3H total)，3.64-3.86(m，3H)，4.27-4.40(m，1H)，5.17-5.29(m，2H)，6.73-6.81(m，1H)，6.82-6.88(m，2H)，6.90-7.02(m，2H)，7.12-8.36(m，9H)，7.72-7.78(m，1H)，7.87-7.96(m，2H)，8.01-8.07(m，1H).

N1-((2S, 3R)-4-(3-fluorine benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.57(d，3H)，2.77(s，3H)，2，72-2.80(m，2H)，2.86-2.93(m，2H)，3.25(s，3H)，3.64-3.72(m，1H)，3.72-3.89(m，2H)，4.29-4.40(m，1H)，5.22-5.33(m，1H)，6.88-7.08(m，4H)，7.12-7.38(m，11H)，7.64(d，1H)，7.74-7.77(m，1H)，7.88-7.92(m，1H)，7.99-8.02(m，1H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((S)-1-phenylethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.103-108 ℃. ¹HNMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.939 (s, 1H), 7.791 (s, 1H), 7.631 (s, 1H), 6.985-7.296 (m, 15H), 5.142 (m, 1H), 4.055 (m, 1H), 3.788 (m, 1 H), 3.674 (m, 1H), 3.176 (s, 3H), 2.969 (m, 1H), 2.785 (s, 3H), 2.785 (m, 1H), 2.567 (m, 2H), 1.488 (d, 3H), 1.371 (d, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((S)-1-phenylethyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

M.p.46-51 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.485 (m, 2H), 7.374 (m, 1H), 7.292 (m, 1H), 6.935-7.123 (m, 10H), 6.803 (s, 3H), 4.782 (s, 1.3H), 4.496 (s, 0.7H), 4.180 (m, 1H), 3.611 (m, 1H), 3.530 (m, 1H), 2.893-2.945 (m, 1H), 2.834 (s 3H), 2.653 (m, 1H), 2.470 (m, 2H), 2.273 (s, 3H), 1.249 (m, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((R)-1-phenylethyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.729(m，2H)，7.516(m，1H)，7.402(m1H)，7.327-7.110(m，10H)，6.861(s，1H)，4.938(br，1.2H)，4.634(br，0.8H)，4.360(m，1H)，3.752-3.635(m，2H)，2.980(s 3H)，2.894-2.557(m，4H)，2.424(s，3H)，1.400(d，J＝6.6Hz，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((S)-1-phenyl propyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

M.p.50-55 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), and δ: 7.304-7.561 (m, 4H), 6.998-7.208 (m, 10H), 6.838 (s, 1H), 4.836 (m, 2H), 4.154 (m, 1H), 3.551 (m, 1H), 3.367 (m, 1H), 2.876-2.998 (m, 1H), 2.876 (s, 3H), 2.730 (m, 1H), 2.493 (m, 1H), 2.328 (s 3H), 1.660-1.775 (m, 1H), 1.536-1.633 (m, 1H), 0.675 (t, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((S)-1-phenyl propyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.74-77 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.916 (m, 1H), 7.826 (m, 1H), 7.660 (m, 1H), 7.050-7.334 (m, 15H), 5.201 (m, 1H), 4.214 (m, 1H), 3.598 (m, 1H), 3.411 (m, 1H), 3.229 (s, 3H), 3.938 (m, 1H), 2.805-2.728 (m, 1H), 2.805 (s 3H), 2.527 (m, 1H), 1.699-1.835 (m, 1H), 1.575-1.672 (m, 1H), 1.523 (d, 3H), 0.710 (t, 3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenyl propyl) isophthaloyl amine:

M.p.92-94 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.969 (m, 1H), 7.814 (m, 1H), 7.693 (m, 1H), and 7.026-7.307 (m, 11H), 6.697-6.815 (m, 3H), 4.913 (m, 1H), 4.212 (m, 1H), 3.625-3.787 (m, 3H), 3.680 (s, 3H), 3.217 (s, 3H), 2.993 (m, 1H), 2.650-2.816 (m, 3H), 2.791 (s, 3H), 1.807-1.912 (m, 2H), 0.891 (t, 3H).

N1-((2S, 3R)-4-((R)-1-(4-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.102-109 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.979 (m, 1H), 7.850 (m, 1H), 7.718 (m, 1H), 7.038-7.348 (m, 12H), 6.889-6.947 (m, 2H), 5.245 (m, 1H), 4.177-4.245 (m, 1H), 3.646-3.748 (m, 2H), 3.259 (s, 3H), 2.830 (s, 3H), and 2.700-3.013 (m, 2H), 2.431-2.648 (m, 2H), 1.546 (d, 3H), 1.357 (d, 3H).

N1-((2S, 3R)-4-((S)-1-(4-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.95-97 ℃. ¹HNMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 7.956 (m, 1H), 7.850 (m, 1H), 7.696 (m, 1H), and 7.066-7.362 (m, 12H), 6.900-6.957 (m, 2H), 5.233 (m, 1H), 4.194-4.261 (m, 1H), 3.625-3.768 (m, 2H), 3.261 (s, 3H), 2.950-3.013 (m, 1H), 2.771-2.849 (m, 1H), 2.830 (s, 3H), 2.497-2.634 (m, 2H), 1.553 (d, 3H), 1.352 (d, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((R)-1-phenylethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.95-99 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 8.013 (m, 1H), 7.873 (m, 1H), 7.754 (m, 1H), 7.078-7.363 (m, 15H), 5.245 (m, 1H), 4.250 (m, 1H), 3.651-3.737 (m, 2H), 3.269 (s, 3H), 2.712-2.883 (m, 2H), 2.488-2.683 (m, 2H), 2.834 (s, 3H), 1.560 (d, 3H), 1.378 (d, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((S)-1-(pyridin-3-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

M.p.67-85 ℃. ¹HNMR (300MHz, CDCl ₃Have a spot of CD ₃OD), and δ: 8.323-8.493 (m, 2H), 8.031 (m, 1H), 7.945 (s, 1H), 7.845-7.881 (m, 1H), and 7.606-7.700 (m, 1H), 7.064-7.363 (m, 10H), 5.241 (m, 1H), 4.232 (m, 1H), 3.790 (m, 1H), 3.636 (m, 1H), 3.263 (s, 3H), 2.946-3.028 (m, 1H), and 2.769-2.867 (m, 1H), 2.834 (s, 3H), and 2.587-2.650 (m, 1H), 2.467-2.520 (m, 1H), 1.555 (d, J=7.2Hz, 3H), 1.379 (d, J=5.3Hz, 3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((R)-1-(pyridin-3-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 8.518 (s, 1H), 8.355-8.334 (m, 2H), 8.065 (s, 1H), 7.890 (m, 1H), 7.678-7.613 (m, 2H), 7.378-7.104 (m, 10H), and 5.305-5.240 (m, 1H), 4.279-4.209 (m, 1H), 3.773-3.706 (m, 1H), 3.648-3.596 (m, 1H), 3.281 (s, 3H), 3.027-2.745 (m, 2H), 2.843 (s, 3H), 2.613-2.560 (m, 1H), 2.472-2.413 (m, 1H), 1.587 (d, 3H), 1.427 (d, 3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-(1-(pyridin-3-yl) ethyl) isophthaloyl amine:

M.p.84-89 ℃. ¹H NMR (300MHz, CDCl ₃Have a spot of CD ₃OD), δ: 8.654 (s, 1H), 8.400-8.249 (m, 3H), 7.969 (d, 1H), 7.838-7.735 (m, 2H), 7.397 (m, 1H), and 7.294-7.087 (m, 6H), 6.903-6.801 (m, 3H), 5.297 (m, 1H), 4.264 (m, 1H), 3.971-3.857 (m, 3H), 3.725 (s, 3H), 3.132-2.836 (m, 4H), 1.654-1.598 (m, 3H).

1-((2S, 3R)-3-hydroxyl-4-(1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-(1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.031(m，1H)，7.933(m，1H)，7.786(m，1H)，7.287-7.117(m，6H)，6.984-6.706(m，7H)，5.257(m，1H)，4.361(m，1H)，3.767(m，6H)，3.608-3.725(m，2H)，3.299(s，3H)，3.2.924(m，1H)，2.842(m，1H)，2.805(m，3H)，2.717-2.567(m，2H)，1.613-1.574(m，3H)，1.442-1.406(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((R)-1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.025-7.919(m，2H)，7.809-7.765 (m，1H)，7.391-7.117(m，11H)，6.942-6.754 (m，3H)，5.359-5.249(m，1H)，4.419-4.301(m，1H)，3.744-3.576(m，2H)，3.762(d，3H)，3.298(s，3H)，2.804(s，3H)，2.936-2.565(m，4H)，1.613(d，1.5H)，1.604(d，1.5H)，1.427-1.393(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((S)-1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

m.p.76-82℃. ¹H NMR(300MHz，CDCl ₃)，δ：8.026-7.922(m，2H)，7.812-7.770(m，1H)，7.401-7.120(m，11H)，6.933-6.756(m，3H)，5.363-5.252(m，1H)，4.420-4.302(m，1H)，3.761-3.581(m，2H)，3.764(d，3H)，3.303(s，3H)，2.806(s，3H)，2.938-2.564(m，4H)，1.629-1.598(m，3H)，1.434-1.401(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((S)-1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.007(m，1H)，7.913(m，1H)，7.780(m，1H)，7.275-7.126(m，6H)，6.972-6.742(m，7H)，5.297-5.195(m，1H)，4.405-4.320(m，1H)，3.951-3.672(m，3H)，3.772(s，3 H)，3.753(s，3H)，3.277(s，3H)，2.920-2.882(m，2H)，2.791(s，5H)，1.580-1.558(m，3H).

N1-((2S, 3R)-4-(3,5-difluoro benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.007(s，1H)，7.945(m，1H)，7.800(m，1H)，7.408-7.141(m，9H)，6.909-6.837(m，2H)，6.748-6.638(m，2H)，5.350-5.256(m，1H)，4.415-4.321(m，1H)，3.832(q，J＝14.1；37.2Hz，2H)，3.704-3.653(m，1H)，3.326(s，3H)，2.990(d，2H)，2.818(s，3H)，2.764-2.728(m，2H)，1.621(d，3H).

N1-((2S, 3R)-4-((R or S)-1-(3-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.021-7.924(m，2H)，7.806-7.773(m，1H)，7.400-7.145(m，10H)，7.101-6.861(m，3H)，6.790(m，1H)，5.355-5.248(m，1H)，4.407-4.302(m，1H)，3.797-3.682(m，1H)，3.630-3.554(m，1H)，3.310(d，3H)，2.960-2.857(m，2H)，2.813(s，3H)，2.707-2.581(m，2H)，1.627-1.597(m，3H)，1.420-1.386(m，3H).

N1-((2S, 3R)-4-((S or R)-1-(3-fluorophenyl) ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

m.p.84-88℃. ¹H NMR(300MHz，CDCl ₃)，δ：8.027-7.926(m，2H)，7.814-7.781(m，1H)，7.407-7.169(m，10H)，7.109-6.866(m，3H)，6.771(m，1H)，5.360-5.260 (m，1H)，4.407-4.302(m，1H)，3.822-3.697(m，1H)，3.640-3.554(m，1H)，3.321(d，3H)，2.965-2.893(m，2H)，2.818(s，3H)，2.675-2.561(m，2H)，1.636-1.607(m，3H)，1.432-1.405(m，3H).

N1-((R or S)-1-(3-fluorophenyl) ethyl)-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.116(m，1H)，7.941(m，1H)，7.806(m，1H)，7.334-7.038(m，10H)，6.979-6.869(m，2H)，6.824-6.768(m，1H)，5.313-5.213(m，1H)，4.390(m，1H)，3.893-3.742(m，3H)，3.764(s，3H)，3.300(s，3H)，2.939(m，2H)，2.803(m，5H)，1.625-1.571(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-sec.-propyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR (300MHz, CDCl ₃) δ 7.69-7.18 (m, 1H), 6.91-6.79 (m, 5H), 4.90 (wide s, 1.3H), 4.64 (wide s, 0.7H) 4.41 (m, 1H), 3.96-3.69 (m, 7H), 3.00 (m, 2H), 2.81 (m, 2H), 2.43 (s, 3H), 1.29-1.16 (m, 7H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-isobutyl--N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR (300MHz, CDCl ₃) δ 7.77-7.22 (m, 11H), 7.15-6.81 (m, 5H) 5.00 (wide s, 1.2H), 4.66 (wide s, 0.7H), 4.40 (m, 1H), 3.88-2.83 (m, 14H), 2.46 (s, 3H), 2.20-1.96 (m, 2H), 0.99-0.70 (m, 7H).

N1-ethyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR (300MHz, CDCl ₃) δ 7.71-7.18 (m, 12H), 7.08-6.79 (m, 5H), 4.96 (wide s, 1.2H), 4.63 (wide s, 0.7H), 4.40 (m, 1H), 3.86-3.30 (m, 8H), 3.02-2.82 (m, 5H), 2.44 (s, 3H), 1.11 (m, 4H).

N1-benzyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.84-7.15(m，17H)，6.91-6.79(m，4H)，4.93-4.55(m，4H)，4.38(m，1H)，3.85-3.68(m，6H)，3.00-2.80(m，5H)，2.43(s，3H).

N1-cyclopentyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR (300MHz, CDCl ₃) δ 7.71-7.19 (m, 12H), 7.06-6.81 (m, 5H), 4.88 (wide s, 2H), 4.41 (m, 1H), 4.03-3.68 (m, 7H), 3.02-2.82 (m, 4H), 2.43 (s, 4H), 1.68-1.38 (m, 8H).

N1-((2S, 3R)-4-(2-fluoro-3-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H-NMR(300MHz，CDCl3)δ7.93(s，1H)，7.83(s，1H)，7.68(s，1H)，7.01-7.29(m，10H)，6.92(m，1H)，6.76-6.81(m，2H)，5.19(m，1H)，4.26(m，1H)，3.71-3.82(m，2H)，3.77(s，3H)，3.59-3.64(m，1H)，3.16(s，3H)，2.63-2.78(m，4H)，2.69(s，3H)，1.49(m，3H).

N1-((2S, 3R)-4-(3-((dimethylamino) methyl) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.10(m，1H)，7.99 (m，1H)，7.96(m，1H)，7.19-7.33(m，2H)，7.03-7.20(m，12H)，5.26(m，1H)，4.88(m，1H)，3.68(m，1H)，3.34-3.51(m，3H)，3.29(s，3H)，3.17(m，1H)，3.00-3.04(m，2H)，2.77-2.87(m，1H)，2.79(s，3H)，2.63-2.70(m，1H)，2.17(s，6H)，1.57(m，3H)

N1-((2S, 3R)-4-(2-fluoro-6-methoxybenzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

7.99(s，1H)，7.90(m，1H)，7.75(m，1H)，7.14-7.37(m，10H)，6.93(m，1H)，6.82-6.85(m，1H)，6.70-6.75(m，1H)，5.27(m，1H)，4.33(m，1H)，3.76-3.82(m，2H)，3.72(s，3H)，3.68-3.71(m，1H)，3.24(s，3H)，2.71-2.87(m，4H)，2.76(s，3H)，1.57(m，3H)

N1-((2S, 3R)-3-hydroxyl-4-(2-morpholino base ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.68(s，1H)，8.04-8.06(m，1H)，8.01(m，1H)，7.52-7.55(m，2H)，7.18-7.35(m，8H)，5.35(m，1H)，4.51(m，1H)，4.04(m，1H)，3.33-3.44(m，4H)，3.28(s，3H)，3.02-3.20(m，4H)，2.88-2.93(m，2H)，2.85(s，3H)，2.52-2.58(m，2H)，2.36(m，2H)，2.23(m，2H)，1.72(m，3H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(2-(tetramethyleneimine-1-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.18(s，1H)，7.95(m，1H)，7.86(m，1H)，7.40-7.43(m，2H)，7.19-7.32(m，8H)，5.31(m，1H)，4.46(m，1H)，3.75(m，1H)，3.31(s，3H)，3.06-3.13(m，1H)，2.94-3.01(m，1H)，2.80-2.89(m，4H)，2.82(s，3H)，2.69-2.71(m，2H)，2.58-2.62(m，4H)，1.74-1.77(m，4H)，1.64(m，3H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(2-(piperidines-1-yl) ethylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.12(s，1H)，7.95(m，1H)，7.86(m，1H)，7.23-7.40(m，10H)，5.31(m，1H)，4.46(m，1H)，3.69(m，1H)，3.31(s，3H)，3.06-3.13(m，1H)，2.91-3.00(m，2H)，2.70-2.88(m，3H)，2.81(s，3H)，2.43-2.48(m，2H)，2.32-2.39(m，4H)，1.62(m，3H)，1.48-1.58(m，4H)，1.39-1.42(m，2H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(2-(tetramethyleneimine-1-yl) ethylamino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

7.72(m，1H)，7.42(m，2H)，7.17-7.29(m，6H)，6.89(s，1H)，4.96(s，2H)，4.42(m，1H)，3.66(m，1H)，2.99-3.12(m，6H)，2.76-2.82(m，4H)，2.60-2.64(m，2H)，2.56(m，4H)，2.44(s，3H)，1.78(s，3H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrroles-2-yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.29(m，1H)， 8.00(m，1H)，7.91(m，1H)，7.47-7.49(m，2H)，7.21-7.34(m，8H)，6.77(m，1H)，6.22(m，1H)，6.10(m，1H)，5.36(m，1H)，5.22(m，2H)，4.43(m，1H)，3.98(m，2H)，3.86(m，1H)，3.45-3.52(m，2H)，3.32(s，3H)，2.79-3.02(m，4H)，2.83(s，3H)，1.69(m，3H)，0.89(m，2H)，0.00(s，9H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazol-4 yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

7.96-7.98(m，2H)，7.75(m，1H)，7.21-7.45(m，11H)，6.90(s，1H)，5.36(m，1H)，5.30(s，2H)，4.31(m，1H)，3.87(m，2H)，3.57(m，1H)，3.48(m，2H)，3.31(s，3H)，3.01(m，2H)，2.83(s，3H)，2.73(m，2H)，1.65(m，3H)，3.90(m，2H)，0.00(s，9H)

N1-((2S, 3R)-4-((1H-imidazol-4 yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.18(s，1H)，7.91(m，1H)，7.79(m，1H)，7.18-7.47(m，11H)，7.03(s，1H)，5.28(m，1H)，4.24(m，1H)，3.91(m，1H)，3.29(s，3H)，3.27-3.33(m，2H)，2.83-3.18(m，4H)，2.87(s，3H)，1.62(m，3H)

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazoles-2-yl) methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.19(s，1H)，8.01(m，1H)，7.84(m，1H)，7.17-7.34(m，10H)，6.94(m，1H)，6.90(m，1H)，5.33(m，1H)，5.25(s，2H)，4.40(m，1H)，3.74-3.94(m，2H)，3.60(m，1H)，3.48-3.55(m，2H)，3.29(s，3H)，2.93-3.00(m，1H)，2.79-2.90(m，3H)，2.81(s，3H)，1.55(m，3H)，0.89-0.95(m，2H)，0.00(s，9H)

N1-((2S, 3R)-3-hydroxyl-4-((3-methyl isophthalic acid H-pyrazoles-5-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

8.22(s，1H)，8.12(m，1H)，8.09(m，1H)，7.16-7.44(m，10H)，5.99(s，1H)，5.38(m，1H)，4.96(m，1H)，3.85(m，1H)，3.53-3.66(m，2H)，3.40(s，3H)，3.30-3.36(m，1H)，3.11-3.22(m，1H)，2.91(s，3H)，2.76-2.98(m，2H)，2.30(s，3H)，1.70(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-methyl furan-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.093(s，1H)，7.946(s，1H)，7.850(s，1H)，7.054-7.37(m，10H)，6.094(m，1H)，5.875(m，1H)，5.343-5.248(m，1H)，4.428-4.334(m，1H)，3.777-3.667(m，3H)，3.286(s，3H)，2.951-2.750(m，4H)，2.789(s，3H)，2.167(s，3H)，1.583(d，J＝7.2Hz，3H).

(2R, 3S)-2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-((R)-1-phenylethyl carbamyl) benzamido)-4-phenyl butyl (3-methoxy-benzyl) t-butyl carbamate:

¹H NMR(300MHz，CDCl ₃)，δ：7.951(m，1H)，7.885(s，1H)，7.771(s，1H)，7.405-7.133(m，11H)，6.768(m，3H)，5.310(m，1H)，4.457-4.298(m，3H)，3.910(m，1H)，3.753(s，3H)，3.431-3.327(m，2H)，3.328(s，3H)，2.972(m，2H)，2.829(s，3H)，1.617(d，J＝6.9Hz，3H)，1.490(s，9H).

N1-((2S, 3R)-4-((S)-1-cyclohexyl ethylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.622(m，1H)，7.956(m，2H)，7.514-7.126(m，10H)，5.307-5.215(m，1H)，4.230(m，1H)，3.849(m，1H)，3.274(s，3H)，3.079-2.812(m，4H)，2.698(m，1H)，1.713(d，J＝6.93Hz，3H)，1.668-1.428(m，3H)，1.690(d，J＝6.6Hz，3H)，1.253-0.862(m，8H).

4-(((2R, 3S)-2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-((R)-1-phenylethyl carbamyl) benzamido)-4-phenyl butyl amino) methyl) piperidines-1-benzyl formate:

¹HNMR(300MHz，CDCl ₃)，δ：8.105(s，1H)，7.901(m，1H)，7.792(m，1H)，7.405-7.139(m，15H)，5.326-5.231(m，1H)，5.108(s，2H)，4.377-4.278(m，1H)，4.202-4.078(m，2H)，3.748(m，1H)，3.256(s，3H)，3.024-3.608(m，6H)，2.777(s，3H)，2.584 (m，2H)，1.711(m，3H)，1.612(d，J＝6.9 Hz，3H)，1.125(m，2H).

N1-((R)-1-cyclohexyl ethyl)-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.023(s，1H)，7.905(s，1H)，7.780(m，1H)，7.274-7.134(m，5H)，6.893-6.772(m，4H)，4.377-4.312(m，1H)，4.050-3.977(m，1H)，3.867-3.712(m，3H)，3.768(s，3H)，3.315(s，3H)，3.014-2.733(m，4H)，2.846(s，3H)，1.802-1.605(m，6H)，1.468-1.369(m，1H)，1.238-0.974(m，4H)，1.188(d，J＝6.6Hz，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(piperidin-4-yl methylamino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：8.226(s，1H)，7.844(s，1H)，7.757(s，1H)，7.384-7.041(m，10H)，5.184(m，1H)，4.268(m，1H)，4.126(m，1H)，3.174(s，3H)，2.778(s，3H)，3.373-2.775(m，10H)，2.118-1.861(m，3H)，1.578(d，J＝6.9Hz，3H)，1.567-1.421(m，2H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(piperidines-3-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.879-7.678(m，3H)，7.528-7.115(m，10H)，5.261-5.142(m，1H)，4.479(m，1H)，3.892(m，1H)，3.324(s，3H)，3.328-2.568(m，10H)，2.875(s，3H)，1.992-1.133(m，3H)，1.560(d，J＝6.6Hz，3H)，1.536-1.362(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-((1-methyl piperidine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.939-7.715(m，3H)，7.528-7.115(m，10H)，5.300-5.203(m，1H)，3.834(m，1H)，3.309(s，3H)，3.052-2.590(m，6H)，2.484-2.267(m，4H)，2.355(s，3H)，2.011-1.762(m，3H)，1.572(br，s，3H)，1.536-1.362(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(((R)-1-methylpyrrolidin-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.961(s，1H)，7.881(m，1H)，7.685(m，1H)，7.401-7.089(m，10H)，5.276(m，1H)，4.398(m，1H)，3.862(m，1H)，3.315(s，3H)，3.280-2.646(m，6H)，2.840(s，3H)，2.278(s，3H)，2.356-2.117(m，3H)，2.019-1.674(m，4H)，1.583(d，J＝6.9Hz，3H).

N1-((2S, 3R)-3-hydroxyl-4-(((R)-1-sec.-propyl tetramethyleneimine-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.945(s，1H)，7.869(s，1H)，7.686(s，1H)，7.390-7.098(m，10H)，5.269(m，1H)，4.403(m，1H)，3.672(m，1H)，3.308(s，3H)，3.056-2.659(m，6H)，2.836(s，3H)，2.447(m，4H)，2.011-1.707(m，4H)，1.576(d，J＝6.9Hz，3H)，0.953(d，J＝6.3Hz，3H)，0.921(d，J＝6.3Hz，3H).

N1-((2S, 3R)-3-hydroxyl-4-((3-methoxyl group cyclohexyl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.273-7.879(m，3H)，7.395-7.061(m，10H)，5.263(m，1H)，4.249(m，1H)，4.029(m，1H)，3.496(m，1H)，3.287-3.178(m，6H)，3.139-2.677(m，6H)，2.771(s，3H)，2.077-1.466(m，12H).

N1-((2S, 3R)-3-hydroxyl-4-((1-isobutyl-piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine dihydrochloride:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：8.272-7.836(br，3H)，7.426-7.032(m，10H)，5.172(br，1H)，4.212(br，1H)，3.882(br，1H)，3.243(br，9H)，2.768(br，7H)，1.955(br，5H)，1.569(br，3H)，1.207(br，2H)，0.959(br，6H).

N1-((2S, 3R)-3-hydroxyl-4-((1-(2-methoxy-benzyl) piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine dihydrochloride:

¹H NMR(300MHz，CDCl ₃)，δ：8.108(m，1H)，7.894(m，1H)，7.778(m，1H)，7.395-7.088(m，12H)，6.933-6.841(m，2H)，5.244(m，1H)，4.279(m，1H)，3.814(m，1H)，3.788(s，3H)，3.642(s，2H)，3.261(s，3H)，3.136-2.513(m，10H)，2.818(s，3H)，2.141(m，2H)，1.690(m，1H)，1.586(d，J＝7.2Hz，3H)，1.370(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-((1-(3-methoxy-benzyl) piperidin-4-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.012(m，1H)，7.872(m，1H)，7.742(m，1H)，7.369-7.081(m，11H)，6.850-6.750(m，3H)，5.245(m，1H)，4.302-4.234(m，1H)，3.764(s，3H)，3.730(m，1H)，3.436(s，2H)，3.256(s，3H)，3.104-2.814(m，6H)，2.816(s，3H)，2.725(m，2H)，2.496(m，2H)，1.932(m，2H)，1.653(m，2H)，1.564(d，J＝6.9Hz，3H)，1.461(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((R)-1-(3-p-methoxy-phenyl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.039(m，1H)，7.887(m，1H)，7.763(m，1H)，7.260-7.092(m，7H)，6.966-6.742(m，6H)，5.226(m，1H)，4.295(m，1H)，3.844-3.716(m，8H)，3.272(s，3H)，3.030-2.714(m，4H)，2.823(s，3H)，1.562(d，J＝6.9Hz，3H).

N1-((2S, 3R)-4-(benzo [d] [1,3] dioxole-5-ylmethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.100(m，1H)，7.901(m，1H)，7.790(m，1H)，7.404-7.108(m，10H)，6.800-6.696(m，3H)，5.896(s，2H)，5.273 (m，1H)，4.316(m，1H)，3.806-3.684(m，3H)，3.280(s，3H)，3.024-2.714(m，4H)，2.815(s，3H)，1.597(d，J＝6.9Hz，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(3-(trifluoromethyl) benzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.038(m，1H)，7.896(m，1H)，7.770(m，1H)，7.565-7.111(m，14H)，5.277 (m，1H)，4.330(m，1H)，3.924-3.722(m，3H)，3.283(s，3H)，2.992-2.761(m，4H)，2.818(s，3H)，1.584(d，J＝6.9Hz，3H).

N1-((2S, 3R)-4-(3-(difluoro-methoxy) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.020(m，1H)，7.888(m，1H)，7.764(m，1H)，7.384-6.975(m，14H)，6.746(s，0.3H)，6.500(s，0.4H)，6.253(s，0.3H)，5.263(m，1H)，4.312(m，1H)，3.861-3.731(m，3H)，3.285(s，3H)，3.021-2.801(m，2H)，2.833(s，3H)，2.761(m，2H)，1.578(d，J＝7.2Hz，3H).

¹H NMR(300MHz，CDCl ₃)，δ：7.987(m，1H)，7.874(m，1H)，7.727(m，1H)，7.378-7.076(m，11H)，6.850-6.721(m，3H)，5.255(m，1H)，4.268(m，1H)，3.744(s，3H)，3.739-3.635(m，2H)，3.272(s，3H)，3.002-2.778(m，2H)，2.832(s，3H)，2.608(m，2H)，1.570(d，J＝6.9Hz，3H)，1.377(d，J＝6.6Hz，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(3-(trifluoromethyl) benzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：7.693-7.368(m，8H)，7.264-7.131(m，5H)，6.884(s，1H)，4.943(br，1.5H)，4.638(br，0.5H)，4.339(m，1H)，3.907-3.711(m，3H)，3.097-2.881(m，5H)，2.784(d，J＝5.2Hz，2H)，2.430(s，3H).

N1-((2S, 3R)-4-(3-(difluoro-methoxy) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：7.693-7.116(m，13H)，6.876(s，1H)，6.753(s，0.28H)，6.507(s，0.44H)，6.261(s，0.28H)，4.93 1(br，1.3H)，4.627(br，0.7H)，4.328(m，1H)，3.827-3.688(m，3H)，3.087-2.859(m，5H)，2.756(d，J＝4.5Hz，2H)，2.417(s，3H).

N1-((2S, 3R)-3-hydroxyl-4-(2-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：7.693-7.098(m，10H)，6.927-6.862(m，4H)，4.926(br，1.3H)，4.623(br，0.7H)，4.262(m，1H)，4.105-3.934(m，3H)，3.827(s，3H)，3.177-2.787(m，5H)，2.414(s，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(3-(trifluoromethoxy) benzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：8.021(m，1H)，7.890 (m，1H)，7.765(m，1H)，7.378-7.072(m，14H)，5.266(m，1H)，4.330(m，1H)，3.860-3.714(m，3H)，3.276(s，3H)，3.001-2.698(m，4H)，2.826(s，3H)，1.569(d，J＝6.6Hz，3H).

N1-((2S, 3R)-3-hydroxyl-4-(4-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：7.673-7.353(m，4H)，7.266-7.112(m，8H)，6.877-6.812(m，3H)，4.924(br，1.4H)，4.620(br，0.6H)，4.292(m，1H)，3.827-3.702(m，3H)，3.751(s，3H)，3.073-2.735(m，7H)，2.410(s，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(3-(trifluoromethoxy) benzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)，δ：7.672-7.505(m，3H)，7.41 1-7.076(m，10H)，6.878(s，1H)，4.930(br，1.3H)，4.627(br，0.7H)，4.320(m，1H)，3.842-3.699(m，3H)，3.083-2.852(m，5H)，3.177-2.787(m，5H)，2.754(d，J＝4.5Hz，2H)，2.416(s，3H).

N1-((2S, 3R)-3-hydroxyl-1-phenyl-4-(quinoline-3-ylmethyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ 8.91-8.92(m，1H)，8.03-8.07 (m，3H)，7.93(s，1H)，7.69-7.75(m，2H)，7.64-7.69(m，1H)，7.50-7.55(m，1H)，7.32-7.41(m，3H)，7.17-7.29(m，9H)，7.04-7.06(m，1H)，5.31-5.38(m，1H)，4.34-4.44(m，1H)，4.13-4.17(d，1H)，3.90-3.95(d，1H)，3.64-3.70(m，1H)，3.30(s，3H)，2.96-2.99(d，2H)，2.72-2.84(m，5H)，1.94(s，1H)，1.62-1.65(d，3H)

N1-((2S, 3R)-3-hydroxyl-4-((the different  azoles of 3-methyl-5-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃) δ7.65-7.83(m，2H)，7.48-7.58(m，1H)，7.39-7.44(m，1H)，7.14-7.29(m，6H)，6.80-6.99(m，2H)，5.99(s，1H)，4.96(s，2H)，4.33-4.45(m，1H)，3.83-3.94(m，2H)，3.62-3.72 (m，1H)，2.94-3.15(m，6H)，2.73-2.85(m，2H)，2.44(s，3H)，2.26(s，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-5-(N-methyl methanesulfonamido)-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.72-7.77(m，2H)，7.63-7.66(d，1H)，7.16-7.32(m，6H)，6.89-6.92(m，4H)，6.79-6.82(m，1H)，4.95(s，2H)，4.32-4.44 (m，1H)，3.78-3.90(m，5H)，3.65-3.75(m，1H)，3.33(s，3H)，3.01-3.18(m，4H)，2.97-2.99(d，2H)，2.76-2.89(m，6H)，2.45(s，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-4,6-dimethyl-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.34-7.36(d，3H)，7.11-7.32(m，7H)，7.04-7.11(m，1H)，7.02(s，1H)，6.92(s，1H)，6.85-6.87(m，2H)，6.77-6.80(m，1H)，6.38-6.51(m，1H)，6.20-6.31(m，1H)，5.18-5.29(m，1H)，4.25-4.37(m，1H)，3.72-3.83 (m，5H)，3.63-3.71(m，1H)，3.03-3.09(m，1H)，2.71-2.80(m，5H)，2.32(s，3H)，2.09(s，3H)，1.54-1.56(d，3H).

N1-((2S, 3R)-4-((5-ethylpyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.48(s，1H)，8.20-8.21(d，1H)，8.13(s，1H)，8.01-8.04(d，1H)，7.97(s，1H)，7.70-7.73(m，1H)，7.41-7.44(m，2H)，7.17-7.36(m，10H)，6.77-6.90(m，1H)，5.33-5.42(m，1H)，4.30-4.42(m，1H)，4.01-4.06(m，1H)，3.65-3.69(d，1H)，3.55-3.63(m，1H)，3.32(s，3H)，3.00-3.02(d，2H)，2.80(s，3H)，2.55-2.62(m，4H)，2.02(s，1H)，1.65-1.67(d，3H)，1.17-1.22(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((the different  azoles of 5-methyl-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.03(s，1H)，7.95(s，1H)，7.82(s，1H)，7.63-7.74(m，1H)，7.15-7.34(m，12H)，6.90-7.00(m，1H)，5.96(s，1H)，5.25-5.35(m，1H)，4.33-4.45(m，1H)，3.77-3.88(m，2H)，3.66-3.74 (m，1H)，3.29(s，3H)，2.84-3.02(m，4H)，2.80(s，3H)，2.38(s，3H)，1.57-1.59(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((the different  azoles of 5-methyl-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ 7.63-7.84(m，2H)，7.52-7.63 (m，1H)，7.40-7.45(m，1H)，7.17-7.30(m，5H)，6.90(s，1H)，6.69-6.86(m，2H)，5.97(s，1H)，4.97(s，2H)，4.34-4.40(m，1H)，3.85(s，2H)，3.61-3.71(m，1H)，2.96-3.16(m，5H)，2.80-2.81(d，2H)，2.45(s，3H)，2.38(s，3H)，1.82(s，1H).

N1-((2S, 3R)-4-((5-fluorine pyridin-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-styroyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.44(s，1H)，8.26-8.27(d，1H)，8.04(s，1H)，7.96(s，1H)，7.74(s，1H)，7.18-7.39(m，14H)，6.81-6.98(m，1H)，5.29-5.40(m，1H)，4.30-4.39(m，1H)，4.00-4.05(d，1H)，3.72-3.76(d，1H)，3.58-3.66(m，1H)，3.32-3.33(m，3H)，2.93-3.09(m，2H)，2.82(s，3H)，2.60-2.71(m，2H)，1.63-1.65(d，3H).

4,6-two fluoro-N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.70-8.73(d，1H)，7.72-7.74(d，1H)，7.36-7.37(d，3H)，7.16-7.33(m，8H)，6.96-6.98(m，2H)，6.73-6.84(m，2H)，6.62-6.66(d，1H)，5.28-5.39(m，1H)，4.36-4.47(m，1H)，3.88-3.95(m，4H)，3.73-3.84(m，2H)，3.64-3.73(m，1H)，2.94-3.12(m，2H)，2.88-2.93(m，1H)，2.75-2.81(m，1H)，2.00(s，1H)，1.57-1.59(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isopropoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.17(s，1H)，8.11(s，1H)，7.68-7.86(m，1H)，7.63-7.66(d，1H)，7.49-7.60(m，1H)，7.38-7.43(m，1H)，7.27-7.15(m，6H)，6.94-7.05(m，1H)，6.89(s，1H)，4.96(s，2H)，4.52-4.63(m，1H)，4.28-4.44(m，1H)，3.75-3.85(m，2H)，3.61-3.74(m，1H)，2.88-3.16(m，6H)，2.80(s 3H)，2.45(s，3H)，1.32-1.34(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isopropoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ 8.23(s，1H)，8.16(s，1H)，8.06-8.07(d，1H)，7.95-8.02(m，1H)，7.74(s，1H)，7.42-7.45(m，2H)，7.17-7.35(m，12H)，7.0-7.10(m，1H)，5.30-5.44(m，1H)，4.48-4.62(m，1H)，4.29-4.40(m，1H)，4.03-4.08(d，1H)，3.62-3.84(m，2H)，3.31(s，3H)，2.93-3.08(m，2H)，2.80(s，3H)，2.65-2.73(m，2H)，1.65-1.67(d，3H)，1.29-1.31(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.49(s，1H)，8.25(s，1H)，8.17(s，1H)，7.93-8.05(m，2H)，7.74(s，1H)，7.42-7.50(m，2H)，7.14-7.35(m，9H)，6.99-7.02(d，1H)，5.32-5.43(m，1H)，4.29-4.41(m，1H)，4.03-4.08(d，1H)，3.60-3.82(m，2H)，3.31(s，3H)，2.98-3.00(d，2H)，2.76-2.94(m，5H)，2.62-2.69(m，2H)，2.03(s，1H)，1.65-1.67(d，3H)，1.20-1.26(m，6).

N1-((2S, 3R)-3-hydroxyl-4-(1-(the different  azoles of 3-methyl-5-yl) ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.14(s，1H)，7.98-7.99(m，1H)，7.73-7.77(m，1H)，7.54-7.57(d，1H)，7.07-7.42(m，11H)，6.85-6.94(m，1H)，5.95(s，1H)，5.27-5.41(m，1H)，4.31-4.45(m，1H)，4.03-4.15(m，1H)，3.89-4.00(m，1H)，3.54-3.65(m，1H)，3.33(s，3H)，2.96-3.04(m，2H)，2.83(s，3H)，2.58-2.77(m，2H)，2.16-2.19(m，3H)，1.61-1.64(m，3H)，1.48-1.54(m，3H).

N1-((2S, 3R)-4-((5-ethoxy pyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.23(s，1H)，8.16(s，1H)，8.04-8.10(m，1H)，7.97-8.04(m，1H)，7.95(s，1H)，7.73(s，1H)，7.42-7.44(m，2H)，7.12-7.33(m，12H)，5.29-5.41(m，1H)，4.28-4.40(m，1H)，3.95-4.08(m，3H)，3.63-3.82(m，2H)，3.28(s，3H)，2.88-3.06(m，2H)，2.79(s，3H)，2.63-2.70(m，2H)，1.64-1.66(d，3H)，1.34-1.39(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-methoxypyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.19(s，1H)，8.14(s，1H)，7.71(s，1H)，7.61-7.64(m，1H)，7.47-7.57(m，1H)，7.35-7.40(m，1H)，7.14-7.26(m，7H)，7.04(s，1H)，6.88(s，1H)，4.96(s，2H)，4.27-4.42(m，1H)，3.74-3.88(m，5H)，3.65-3.74(m，1H)，3.36(s，1H)，2.91-3.15(m，5H)，2.78-2.79(d，2H)，2.44(s，3H).

N1-((2S, 3R)-4-((5-ethoxy pyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.21(s，1H)，8.16(s，1H)，7.71-7.87(m，1H)，7.62-7.71(m，1H)，7.47-7.57(m，1H)，7.30-7.47(m，2H)，7.13-7.30(m，6H)，6.90(s，1H)，4.96(s，2H)，4.28-4.43(m，1H)，4.09-4.02(m，2H)，3.86-3.97(m，2H)，3.69-3.82(m，1H)，2.93-3.16(m，7H)，2.77-2.93(m，2H)，2.45(s，3H)，1.38-1.43(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isobutyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.53(s，1H)，8.28-8.31(m，1H)，8.20(s，1H)，7.94(s，1H)，7.76(s，1H)，7.51(s，1H)，7.40-7.45(m，2H)，7.13-7.29(m，11H)，5.26-5.40(m，1H)，4.18-4.36(m，1H)，4.05-4.18(m，1H)，3.70-3.95(m，2H)，3.27-3.35(m，1H)，3.24(s，3H)，2.76-3.07(m，7H)，2.38-2.40(d，2H)，1.70-1.91(m，2H)，1.64-1.67(d，2H)，0.82-0.84(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-((4-methoxypyridine-2-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.40-8.53(m，1H)，8.20-8.27(m，1H)，8.00(s，1H)，7.84-7.98(m，2H)，7.31-7.45(m，2H)，7.08-7.31(m，12)，6.66-6.75(m，2H)，5.26-5.39(m，1H)，4.36-4.52(m，1H)，3.59-4.04(m，5H)，3.26(s，3H)，2.81-3.30(m，3H)，2.78(s，3H)，2.02(s，1H)，1.59-1.61(d，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-picoline-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.36(s，1H)，8.32(s，1H)，7.72-7.81(m，1H)，7.63-7.66(m，1H)，7.51(s，2H)，7.36-7.41(m，1H)，7.00-7.26(m，6H)，6.88(s，1H)，4.95(s，2H)，4.28-4.42(m，1H)，3.61-3.91(m，4H)，2.89-3.11(m，5H)，2.71-2.89(m，2H)，2.44(s，3H)，2.30(s，3H)，2.02(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isobutyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.38(s，1H)，8.29(s，1H)，7.64-7.82(m，1H)，7.63-7.66(m，1H)，7.49-7.55(m，1H)，7.47(s，1H)，7.36-7.41(m，1H)，7.13-7.26(m，7H)，7.02-7.13(m，1H)，6.88(s，1H)，4.95(s，2H)，3.77-3.88(m，2H)，3.66-3.76(m，1H)，2.91-3.16(m，6H)，2.80-2.81(d，2H)，2.43-2.45(m，5H)，1.77-1.89(m，1H)，0.87-0.89(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isobutoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.20-8.21(d，1H)，8.14(s，1H)，7.69-7.83(m，1H)，7.65-7.67(d，1H)，7.49-7.58(m，1H)，7.37-7.43(m，1H)，7.15-7.27(m，7H)，6.92-7.03(m，1H)，6.89(s，1H)，4.96(s，2H)，4.30-4.45 (m，1H)，3.79-3.93H)，2H)，3.74-3.76(d，2H)，2.93-3.17(m，7H)，2.77-2.87(m，2H)，2.45(s，3H)，2.01-2.17(m，1H)，1.01-1.03(d，6H).

N1-((2S, 3R)-4-((5-(dimethylamino) pyridin-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.35-8.38(d，1H)，8.24(s，1H)，8.01(s，1H)，7.95(s，2H)，7.80-7.86(m，1H)，7.73(s，1H)，7.38-7.45(m，2H)，7.13-7.31(m，11H)，6.88-6.97(m，1H)，5.26-5.44(m，1H)，4.28-4.39(m，1H)，4.17-4.28(m，1H)，3.93-4.06(m，1H)，3.60-3.82(m，3H)，3.26(s，3H)，2.97(s，3H)，2.82-2.91(m，4H)，2.77(s，3H)，1.64-1.66(d，3H).

N1-((2S, 3R)-4-((5-ethylpyridine-3-yl) methylamino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHZ，CDCl ₃)δ8.34-8.37(m，2H)，7.68-7.84(m，1H)，7.59-7.68(m，1H)，7.51(s，2H)，7.36-7.41(m，1H)，7.10-7.27(m 6H)，6.99-7.10(m，1H)，6.88(s，1H)，4.95(s，2H)，4.29-4.43(m，1H)，3.77-3.87(m，2H)，3.63-3.76(m，1H)，2.90-3.16(m，6H)，2.79-2.81(d，2H)，2.58-2.65(m，2H)，2.44(s，3H)，1.19-1.25(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isobutoxy pyridin-3-yl) methylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.24(s，1H)，8.18(s，1H)，8.00-8.13(m，2H)，7.95(s，1H)，7.73(s，1H)，7.42-7.44(m，2H)，7.10-7.36(m，11H)，5.28-5.42(m，1H)4.19-4.39(m，1H)，3.99-4.19(m，1H)，3.62-3.85(m，4H)，3.28(s，3H)，2.88-3.08(m，2H)，2.79-2.84(m，4H)，(2.64-2.76，2H)，1.96-2.12(1H)，1.64-1.67(d，3H)，0.98-1.00(d，6H).

N1-((2S, 3R)-4-(3-ethoxy benzylidene amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.13(s，1H)，7.92(s，1H)，7.81(s，1H)，7.67-7.78(m，1H)，7.38-7.41 (m，2H)，7.11-7.33(m，12H)，6.87-6.93(m，2H)，6.76-6.85(m，1H)，5.24-5.36(m，1H)，4.28-4.39(m，1H)，3.94-4.01(m，2H)，3.76-3.92(m，3H)，3.26(s，3H)，2.78-2.91(m，4H)，2.76(s，3H)，1.61-1.63(d，3H)，1.34-1.38(m，3H).

N1-((2S, 3R)-4-(3-ethoxy benzylidene amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.70-7.86(m，1H)，7.65-7.67(m，1H)，7.48-7.60(m，1H)，7.36-7.41(m，1H)，7.12-7.29(m，8H)，6.84-6.93(m，2H)，6.78-6.82(m，1H)，4.96(s，2H)，4.33-4.45(m，1H)，3.97-4.04(m，2H)，3.77-3.89(m，2H)，3.66-3.79 (m，3H)，2.92-3.16(m，5H)，2.73-2.92(m，2H)，2.44(s，3H)，1.36-1.41(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-isopropoxy benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ.7.71-7.85(m，1H)，7.60-7.71(m，1H)，7.48-7.60(m，1H)，7.36-7.41(m，1H)，7.13-7.29(m，7H)，6.84-6.92(m，3H)，6.77-6.81(m，1H)，4.96(s，2H)，4.48-4.60(m，1H)，4.32-4.44(m，1H)，3.73-3.86(m，2H)，3.68-3.77(m，3H)，2.92-3.16(m，5H)，2.74-2.91(m，2H)，2.44(s，3H)，1.30-1.32(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-(3-isobutoxy benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.75-7.86(m，1H)，7.66-7.69(m，1H)，7.51-7.60 (m，1H)，7.38-7.43(m，1H)，7.15-7.33(m，6H)，6.86-6.94(m，4H)，6.81-6.84(m，1H)，4.97(s，2H)，4.34-4.46(m，1H)，2.82-3.95(m，2H)，3.64-3.78(m，4H)，2.95-3.18(m，5H)，2.75-2.95(m，2H)，2.45(s，3H)，1.99-2.13(m，2H)，1.00-1.02(d，6H).

N1-((2S, 3R)-3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ8.38(s，2H)，7.69-7.84(m，1H)，7.63-7.66 (m，1H)，7.48-7.59(m，1H)，7.39-7.43(m，1H)，7.15-7.29(m，7H)，6.70-6.90(m，2H)，4.96(s，2H)，4.32-4.43(m，1H)，3.77-3.87(m，2H)，3.64-3.74(m，1H)，2.95-3.16(m，6H)，2.85-2.96(m，1H)，2.79-2.80(d，2H)，2.44(s，3H)，1.23-1.26(d，6H).

N1-((2S, 3R)-4-(3-benzyl ethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.18(t，3H，J＝7.2Hz)，1.58(d，3H，J＝6.9Hz)，2.56-2.84(m，9H)，3.21(s，3H)，3.67-3.85(m，3H)，4.29-4.40(m，1H)，5.23-5.32(m，1H)，7.05-7.36(m，14H)，7.79(s，1H)，7.91(s，1H)，8.06(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-sec.-propyl benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.19(s，3H)，1.21(s，3H)，1.59(d，3H，J＝6.6Hz)，2.77-2.94(m，8H)，3.27(s，3H)，3.72-3.88(m，3H)，4.22-4.41(m，1H)，5.26-5.33(m，1H)，7.11-7.39(m，14H)，7.77(s，1H)，7.92(s，1H)，8.07(s，1H).

2-fluoro-2-fluoro-N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.85(s，3H)，2.90-3.18(m，7H)，3.81(s，3H)，3.99-4.60(m，5H)，4.92-5.30(m，3H)，6.86(m，4H)，7.17-7.45(m，7H)，7.45-7.52(m，1H)，7.81-7.83(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-sec.-propyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.21(s，3H)，1.23(s，3H)，2.44(s，3H)，2.75-3.20(m，8H)，3.63-3.86(m，3H)，4.35-4.43(m，1H)，4.92(s，2H)，6.82(s，1H)，7.12-7.25 (m，10H)，7.38-7.42(m，1H)，7.7.46-7.83(m，2H).

N1-((2S, 3R)-4-(3-(methyl fluoride) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.62(d，3H，J＝7.2Hz)，2.80-3.25(m，7H)，3.31(s，3H)，3.64-3.93(m，3H)，4.15-4.39(m，1H)，5.23-5.41(m，3H)，7.16-7.46(m，14H)，7.80(s，1H)，7.93(s，1H)，8.03(s，1H).

N1-((2S, 3R)-4-(3-(methyl fluoride) benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.41(s，3H)，2.78-3.08(m，7H)，3.74-3.85(m，3H)，4.26-4.36(m，1H)，4.93(s，2H)，5.24-5.41(d，2H，J＝47.4Hz)，6.88(s，1H)，7.1 5-7.41(m，10H)，7.53-7.66(m，3H).

N1-((2S, 3R)-4-(3-benzyl ethyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.17-1.22(t，3H，J＝7.8Hz)，2.43(s，3H)，2.57-2.65(q，2H，J＝7.8Hz)，2.75-3.10(m，7H)，3.71-3.83(m，3H)，4.32-4.41(m，1H)，4.95(s，2H)，6.87(s，1H)，7.13-7.23(m，10H)，7.35-7.40(m，1H)，7.63-7.73(m，2H).

3-(2,2-dimethyl-1-((4-methylthiazol-2-yl) methyl) hydrazine carbonyl)-N-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl) benzamide:

¹H NMR(300MHz，CDCl ₃)：2.43(s，3H)，2.72-3.02(m，4H)，3.43(s，6H)，3.46-3.73(m，6H)，4.28-4.38(m，1H)，5.17(s，2H)，6.75-6.88(m，4H)，6.99(s，1H)，7.09-7.26(m，6H)，7.66-7.69(m，1H)，7.99-8.02 (m，1H)，8.17(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.42(s，3H)，2.79-3.16(m，11H)，3.76(s，3H)，3.81-3.90(m，1H)，4.25-4.34(m，1H)，4.93(s，2H)，6.73-6.78(m，3H)，6.88(s，1H)，7.13-7.25(m，7H)，7.42-7.46(m，1H)，7.69-7.72(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(4-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.54(d，3H，J＝7.2Hz)，2.67-2.87(m，11H)，3.17(s，3H)，3.67(s，3H)，3.71-3.78(s，1H)，4.22-4.36(m，1H)，5.13-5.25(m，1H)，6.69-6.71(d，2H，J＝7.4Hz)，6.97-7.33(m，13H)，7.73(s，1H)，7.84(s，1H)，8.10(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(2-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.69(d，3H，J＝7.2Hz)，2.78(s，3H)，2.97-3.31(m，11H)，3.73 9s，3H)，3.89-4.16(m，1H)，4.35-4.43(m，1H)，5.22-5.34(m，1H)，6.76-6.81(m，1H)，7.02-7.25(m，14H)，7.46-7.49(m，1H)，7.95-7.98(m，1H)，8.57(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-isobutyl-benzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：0.79(d，6H，J＝6.2Hz)，1.53(d，3H，J＝7.2Hz)，1.64-1.82(m，1H)，2.34-2.82(m，9H)，3.21(s，3H)，3.67-3.3.82(m，3H)，4.22-4.39(m，1H)，5.12-5.30，m，1H)，6.97-7.30(m，14H)，7.74(s，1H)，7.85(s，1H)，8.00(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((R)-1-(4-methylthiazol-2-yl) ethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.88-1.94(br d，3H)，2.65(s，3H)，2.98-3.36(m，7H)，3.93-4.07(m，6H)，4.30-4.33(m，1H)，4.46-4.54(m，1H)，6.99-7.17(m，3H)，7.33-7.47(m，4H)，7.33-7.47(m，4H)，7.63-7.68(m，1H)，7.89-7.93(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(3-isobutyl-benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：0.9(d，6H，J＝6.2Hz)，1.78-1.92(m，1H)，2.45(s，3H)，2.74-3.16(m，9H)，3.78-3.92(m，3H)，4.30-4.38(m，1H)，4.93(s，2H)，6.84-7.35(m，11H)，7.44-7.59(m，1H)，7.72-7.76(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(3-(3-methoxyl group-4-aminomethyl phenyl) propyl group amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.63(d，3H，J＝.3 Hz)，1.82-2.12(m，6H)，2.34-2.62(m，3H)，2.82-2.94(m，7H)，2.96-3.10(m，2H)，3.82(s，3H)，4.68-4.73(m，1H)，5.21-5.30(m，1H)，6.60(s，1H)，7.26-7.30(m，12H)，8.36-8.38(m，2H)，8.96(s，1H).

N1-((2S, 3R)-1-(3, the 5-difluorophenyl)-3-hydroxyl-4-(3-methoxybenzyl amino) fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.40(s，3H)，2.72-2.85(m，3H)，2.98-3.06(m，4H)，3.67-3.84(m，6H)，4.22-4.28(m，1H)，4.93(s，2H)，6.53-6.77(m，1H)，6.78-7.05(m，6H)，7.24-7.26(m，1H)，7.38-7.43(m，1H)，7.69-7.72(m，2H).

N1-((2S, 3R)-1-(3, the 5-difluorophenyl)-3-hydroxyl-4-(3-methoxybenzyl amino) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.61(d，3H，J＝7.2H)，2.71-2.87(m，7H)，3.31(s，3H)，3.71-3.90(m，6H)，4.25-4.36(m，1H)，5.22-5.33(m，1H)，6.58-6.91(m，7H)，7.18-7.27(m，5H)，7.83(s，1H)，7.94(s，1H)，8.03(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-(thiazole-4-yl) fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.62(d，3H，J＝7.2Hz)，2.65-2.80(m，5H)，3.01-3.05(m，1H)，3.19-3.41(m，4H)，3.71-3.83(m，6H)，4.08-4.34(m，1H)，5.29-5.38(m，1H)，6.76-6.96(m，4H)，7.14-7.25(m，6H)，8.01(s，1H)，8.05(s，1H)，8.18(s，1H)，8.75(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-hydroxyl-4-anisole ethylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.63(d，3H，J＝7.2Hz)，2.60-2.89(m，11H)，3.18(s，3H)，3.64-3.78(m，4H)，4.22-4.34(s，1H)，5.14-5.32(m，1H)，6.51-6.67(m，3H)，7.06-7.38(m，10H)，7.69(s，1H)，7.86(s，1H)，8.10(s，1H).

N1-((2S, 3R)-4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：1.62(d，3H，J＝7.2Hz)，2.74-2.94(m，7H)，3.28(s，1H)，3.30(s，3H)，3.71-3.88(m，3H)，4.32-4.38(m，1H)，5.25-5.34(m，1H)，7.17-7.44(m，14H)，7.80(s，1H)，7.92(s，1H)，8.05(s，1H).

N1-((2S, 3R)-4-(3-ethynyl benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.21(s，3H)，2.54-2.86(m，10H)，3.49-3.61(m，3H)，4.07-4.13(m，1H)，4.72(s，2H)，6.67(s，1H)，6.95-7.22(m，10H0，7.40-7.46(m，3H).

N1-((2S, 3R)-4-(benzyl amino)-3-hydroxyl-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.43(s，3H)，2.80-3.09(m，7H)，3.63-3.87(m，3H)，4.28-4.37(m，1H)，4.94(s，2H)，6.88(s，1H)，7.21-7.70(m，14H).

N1-((2S, 3R)-3-hydroxyl-4-(2-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.40(s，3H)，2.85-3.19(m，11H)，3.66-3.78(m，4H)，4.23-4.32(m，1H)，4.91(s，2H)，6.81-6.87(m，4H)，7.09-7.20(m，7H)，7.39-7.43(m，1H)，7.69-7.72(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(4-anisole ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.41(s，3H)，2.72-3.19(m，11H)，3.75(s，3H)，3.82-3.92(s，1H)，4.59-4.68(m，1H)，4.93(s，1H)，6.79-6.88(m，3H)，7.08-7.27(m，8H)，7.40-7.44(m，1H)，7.69-7.72(m，2H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl)-5-nitro isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.41(s，3H)，2.70-2.98(m，2H)，2.98-3.18(m，5H)，3.70-3.73(m，6H)，4.25-4.30(m，1H)，4.92(s，2H)，6.74-6.89(m，4H)，7.10-7.22(m，6H)，8.03(s，1H)，8.35(s，1H)，8.52(s，1H)

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(methylsulfonyl methyl)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300Mz，CDCl ₃)：1.67(d，3H，J＝7.2Hz)，2.78(s，3H)，2.86-2.97(m，4H)，3.80-3.94(m，6H)，4.20(s，2H)，4.42-4.46(m，1H)，5.30-5.39(m，1H)，6.85-6.96(m，3H)，7.21-7.47(m，11H)，7.78(s，1H)，7.94(s，1H)，8.19(s，1H).

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-4-(2-morpholino base ethylamino)-4-oxo butyrylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.60(d，3H，J＝7.2Hz)，2.34-2.67(m，10H)，2.84(s，3H)，2.96-3.04(m，2H)，3.20-3.36(m，2H)，3.32(s，3H)，3.40-3.49(m，1H)，3.60-3.76(m，5H)，3.76(s，3H)，3.90-4.06(m，1H)，4.32-4.45(m，1H)，4.58-4.64(m.2H)5.26-5.38(m，1H)，6.46-6.68(m，1H)，6.66-6.95(m，4H)，7.10-7.42(m，10H)，7.86-7.89(m，1H)，7.96-7.99(m，1H)，8.04-8.08(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-4-oxo-4-(pyridin-3-yl methylamino) butyrylamino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.48(d，3H，J＝6.6Hz)，2.34-3.32(m，6H)，2.80(s，3H)，3.22(s，3H)，3.76(s，3H)，3.80-4.78(m，8H)，5.20-5.32(m， 1H)，6.64-6.82(m，3H)，7.00-7.36(m，12H)，7.42-8.48(m，6H)

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-oxo-5-(pyridin-3-yl methylamino) valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.60(d，3H，J＝7.2Hz)，1.88-2.20(m，2H)，2.24-2.42(m，4H)，2.80(s，3H)，2.82-3.44(m，3H)，3.26(s，3H)，3.64-3.76(m，1H)，3.76(s，3H)，3.80-4.02(m，1H)，4.20-4.58(m，4H)，5.22-5.36(m，1H)，6.60-6.82(m，4H)，7.06-7.40(m，13H)，7.50-8.41(m，5H).

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-(2-morpholino base ethylamino)-5-oxo valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.59(d，3H，J＝6.6Hz)，1.88-2.00(m，2H)，2.20-2.29(m，4H)，2.31-2.52(m，6H)，2.82(s，3H)，2.92-3.08(m，2H)，3.20-3.38(m，2H)，3.29(s，3H)，3.40-3.60(m，2H)，3.64-3.74(m，4H)，3.76(s，3H)，3.92-4.04(m，1H)，4.28-4.40(m，1H)，4.58-4.64(m.2H)5.23-5.36(m，1H)，6.20-6.35(m，1H)，6.62-6.80(m，4H)，7.10-7.40(m，10H)，7.86-7.89(m，1H)，7.95-7.98(m，1H)，7.98-8.00(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-(4-methylpiperazine-1-base is amino)-5-oxo valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.57(d，3H，J＝6.6Hz)，1.84-2.00(m，2H)，2.24-3.16(m，17H)，2.80(s，3H)，3.26(s，3H)，3.40-3.60(m，2H)，3.74(s，3H)，3.92-4.12(m，1H)，4.20-4.72(m，3H)，5.22-5.38(m，1H)，6.56-6.80(m，3H)，7.02-7.24(m，11H)，7.74-8.22(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-(N-(3-methoxy-benzyl)-5-oxo-5-(2-(piperidines-1-yl) ethylamino) valeryl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃0D)：1.56(d，3H，J＝6.6Hz)，1.84-2.00(m，2H)，2.24-3.16(m，19H)，2.81(s，3H)，3.28(s，3H)，3.40-3.60(m，2H)，3.74(s，3H)，3.92-4.12(m，1H)，4.20-4.72(m，3H)，5.20-5.38(m，1H)，6.56-6.80(m，3H)，7.02-7.24(m，11H)，7.74-8.22(m，3H)

4-(((2R; 3S)-and 2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-((R)-1-phenylethyl carbamyl) benzamido)-4-phenyl butyl) (3-methoxy-benzyl) amino)-4-ketobutyric acid 2-(3; two (the benzyloxy)-5-oxos-2 of 4-, 5-dihydrofuran-2-yl)-2-hydroxyethyl ester:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.56(m，3H)，1.88-2.06(m，2H)，2.24-2.60(m，4H)，2.77(s，3H)，2.90-3.80 (m，2H)，3.25(s，3H)，3.75(s，3H)，3.92-4.68(m，8H)，4.78-5.34(m，5H)，6.60-6.82(m，3H)，7.04-7.42(m，21H)，7.74-8.26(m，3H)

4-(((2R; 3S)-and 2-hydroxyl-3-(3-(N-methyl methanesulfonamido)-5-((R)-1-phenylethyl carbamyl) benzamido)-4-phenyl butyl) (3-methoxy-benzyl) amino)-4-ketobutyric acid 2-(3; 4-dihydroxyl-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethyl ester:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.55(d，3H，J＝6.6Hz)，2.40-3.42(m，9H)，2.83(s，3H)，3.25(s，3H)，3.74(s，3H)，3.90-4.36(m，5H)，4.60-4.74(m，2H)，5.18-5.28(m，1H)，6.60-6.80(m，3H)，7.04-7.39(m，11H)，7.58-8.00(m，3H)

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((R)-1-(4-(hydroxymethyl)  azoles-2-yl) ethyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹HNMR(300MHz，CDCl ₃+CD ₃OD)：1.59(d，3H，J＝7.2Hz)，2.60-3.02(m，4H)，2.83(s，3H)，3.26(s，3H)，3.66-3.82(m，3H)，3.73(s，3H)，4.24-4.36(m，1H)，4.44(s.2H)5.32-5.42(m，1H)，6.74-6.83(m，3H)，7.04-7.24(m，6H)，7.53(s.1H)7.75-7.77(m，1H)，7.92-7.96(m，1H)，8.05-8.08(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-((4-(hydroxymethyl)  azoles-2-yl) methyl)-5-(N-methyl methanesulfonamido) isophthaloyl amine:

¹HNMR(300MHz，CDCl ₃+CD ₃OD)：2.70-3.08(m，4H)，2.84(s，3H)，3.27(s，3H)，3.68-3.85(m，3H)，3.73(s，3H)，4.26-4.35(m，1H)，4.46(s.2H)，4.64(s.2H)，6.74-6.88(m，3H)，7.07-7.24(m，6H)，7.53(s.1H)7.75-7.77(m，1H)，7.93-7.96(m，1H)，8.05-8.08(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-(4-methyl  azoles-2-yl) ethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.63(d，3H，J＝7.2Hz)，2.70-3.04(m，4H)，2.85(s，3H)，3.31(s，3H)，3.74-3.88(m，3H)，3.75(s，3H)，4.32-4.39(m，1H)，5.36-5.44(m，1H)，6.76-6.90(m，3H)，7.12-7.26(m，6H)，7.30-7.32(m.1H)7.83-7.84(m，1H)，7.97-7.99(m，1H)，8.10-8.12(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methyl  azoles-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：2.17(s，3H)，2.74-3.16(m，7H)3.64-3.90(m，3H)，3.78(s，3H)，4.34-4.44(m，1H)，4.77-4.84(m，2H)，6.79-6.96(m，3H)，7.00-7.50(m，7H)，7.50-7.89(m.4H).

N1-((2S, 3R)-3-hydroxyl-4-((R)-2-hydroxyl-1-phenylethyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.58(d，3H，J＝6.6Hz)，2.50-3.04(m，4H)，2.84(s，3H)，3.28(s，3H)，3.62-3.86(m，4H)，4.30-4.38(m，1H)，5.20-5.32(m，1H)，7.04-7.20(m，15H)，7.76-7.78(m，1H)，7.85-7.87(m，1H)，8.05-8.08(m，1H).

N1-((2,5-dimethyl  azoles-4-yl) methyl)-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：2.24-2.60(m，6H)，2.76-3.14(m，7H)3.64-3.88(m，3H)，3.76(s，3H)，4.28-4.36(m，1H)，4.40-4.60(m，2H)，6.79-6.92(m，3H)，7.00-7.50(m，6H)，7.50-7.89(m.4H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-(thiazol-2-yl) ethyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.72(d，3H，J＝6.9Hz)，2.70-3.01(m，4H)，2.84(s，3H)，3.29(s，3H)，3.70-3.89(m，3H)，3.75(s，3H)，4.27-4.36(m，1H)，5.54-5.66(m，1H)，6.76-6.90(m，3H)，7.08-7.30(m，6H)，7.67-7.69(m.1H)7.81-7.83(m，1H)，7.95-7.98(m，1H)，8.10-8.13(m，1H).

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.62(d，3H，J＝7.2Hz)，2.60-3.02(m，4H)，2.82(s，3H)，3.32(s，3H)，3.68-3.78(m，3H)，3.75(s，3H)，4.21-4.33(m，1H)，5.24-5.38(m，1H)，6.74-6.84(m，3H)，7.11-7.40(m，11H)，7.90-7.92(m.1H)7.94-7.96 (m，1H)，8.17-8.19(m，1H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((2-methylthiazol-4-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：2.64(s，3H)，2.76-3.14(m，7H)3.66-3.80(m，3H)，3.78(s，3H)，4.30-4.38(m，1H)，4.68-4.84(m，2H)，6.78-6.93(m，3H)，7.04-7.40(m，7H)，7.44-7.82(m.4H).

N1-((4-ethyl thiazole-2-yl) methyl)-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-methyl isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：1.26(t，3H，J＝7.5Hz)，2.62-3.14(m，9H)3.64-3.82(m，3H)，3.75(s，3H)，4.28-4.36(m，1H)，4.84-5.02(m，2H)，6.78-6.91(m，3H)，7.08-7.426(m，7H)，7.33-7.78(m.4H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((2-methyl  azoles-4-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：2.54(s，3H)，2.74-3.10(m，7H)3.68-3.84(m，3H)，3.75(s，3H)，4.27-4.36(m，1H)，4.48-4.62(m，2H)，6.76-6.90(m，3H)，7.07-7.27(m，7H)，7.36-7.84(m.4H).

N1-((2S, 3R)-3-hydroxyl-4-((S)-1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.670(m，2H)，7.526(m，1H)，7.408(m 1H)，7.237-7.107(m，6H)，6.889-6.739(m，4H)，4.931(br，1.3H)，4.630(br，0.7H)，4.293(m，1H)，3.765(s，3H)，3.783-3.633(m，2H)，3.020-2.858(m，5H)，2.646(m，2H)，2.421(s，3H)，1.398(d，J＝6.6Hz，3H).

N1-((2S, 3R)-3-hydroxyl-4-((R)-1-(3-p-methoxy-phenyl) ethylamino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃+CD ₃OD)，δ：7.732(m，2H)，7.532(m，1H)，7.387(m 1H)，7.277-7.113(m，6H)，7.091-6.746(m，4H)，4.932(br，1.4H)，4.633(br，0.6H)，4.333(m，1H)，3.798-3.681(m，2H)，3.731(s，3H)，2.976(s，3H)，2.846(m，2H)，2.772-2.505(m，2H)，2.421(s，3H)，1.426(d，J＝6.3Hz，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-(pyrazine-2-ylmethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：2.54-3.06 (m，7H)，3.65-3.84(m，6H)，4.25-4.36(m，1H)，4.76-4.92(m，2H)，6.74-6.90(m，3H)，7.08-7.82(m，10H)，8.30-8.71(m.3H).

N1-((2S, 3R)-3-hydroxyl-4-(4-methyl benzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)：2.19(s，3H)，2.40(s，3H)，2.63-2.96(m，7H)，3.61-3.69(m，3H)，4.16-4.22(m，1H)，4.78-4.85(s，2H)，6.78(s，1H)，6.99-7.17(m，10H)，7.25-7.58(m，3H).

N1-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N3-methyl-5-(methylsulfonyl methyl)-N3-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹HNMR(300MHz，CDCl ₃)：2.42(s，3H)，2.62-3.18(m，10H)，3.72-3.83(m，6H)，4.2(s，2H)，4.14-4.20(m，1H)，4.824.90(s，2H)，6.76-6.92(m，4H)，7.21-7.38(m，6H)，7.67-8.18(m，3H).

N1-cyclohexyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃) 7.69-7.15(m，1H)，7.05-6.81(m，5H)，4.93(broad s，2H)，4.40(m，1H)，3.87-3.68(m，6H)，3.49(broad s，1H)，3.03-2.81(m，5H)，2.43(s，4H)，1.72-1.54(m，7H)，1.01-0.86(m，4H).

N1-cyclopropyl-N3-((2S, 3R)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-methoxyl group-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.32-7.16(m，10H)，6.93-6.79(m，4H)，4.98(broad s，2H)，4.37(m，1H)，4.00-3.74(m，9H)，3.10-2.77(m，4H)，2.45(s，3H)，0.58-0.48(m，4H).

N1-((2S, 3S)-3-hydroxyl-4-(3-methoxybenzyl amino)-1-phenyl fourth-2-yl)-5-(N-methyl methanesulfonamido)-N3-((R)-1-phenylethyl) isophthaloyl amine:

1H NMR(300MHz，CDCl ₃+CD ₃OD)：1.62(d，3H，J＝7.2Hz)，2.60-3.02(m，4H)，2.82(s，3H)，3.32(s，3H)，3.68-3.78(m，3H)，3.75(s，3H)，4.21-4.33(m，1H)，5.24-5.38(m，1H)，6.74-6.84(m，3H)，7.11-7.40(m，11H)，7.90-7.92(m.1H)7.94-7.96(m，1H)，8.17-8.19(m，1H).

N1-cyclopropyl-N3-((2S, 3R)-3-hydroxyl-4-((5-isopropyl pyridine-3-yl) methylamino)-1-phenyl fourth-2-yl)-N1-((4-methylthiazol-2-yl) methyl) isophthaloyl amine:

¹H NMR(300MHz，CDCl ₃)δ7.32-7.16(m，10H)，6.93-6.79(m，4H)，4.98(broad s，21-1)，4.37(m，1H)，4.00-3.74(m，9H)，3.10-2.77(m，4H)，2.45(s，3H)，0.58-0.48(m，4H).

The inhibition of embodiment 5:memapsin 1, memapsin 2 and cathepsin D's catalytic activity

With peptide substrate NH ₃-ELDLAVEFWHDR-CO ₂(inhibition test that is used for memapsin 2, memapsin1 and cathepsin D) is dissolved in DMSO with 2mg/ml, dilutes with 1: 100 with the 0.1M sodium acetate, and pH just in time is 4.0 before the test.The inhibitor that will be dissolved among the DMSO dilutes with the 0.1M sodium acetate, and pH is 4.0 (dilutions in 1: 100).To merge at the sodium acetate that the 50ml of the inhibitor solution in pH4 damping fluid aliquots containig and 150ml 0.1M contain 100-200nM memapsin 1, memapsin 2 or cathepsin D.Hatch in advance in 37 ℃, begin proteolysis with the substrate of pH4 damping fluid dilution and test by adding 50ml then, continue to hatch in 37 ℃.Remove aliquots containig with the timed interval, (the Alpha-hydroxy styracin in acetone 20mg/ml) merges, and point sample on stainless steel MALDI sample panel is duplicate immediately with itself and isopyknic MALDI-TOF matrix.Molecular biology resource center has in the school carried out the MALDI-TOF mass spectroscopy on PE Biosystems Voyager DE instrument.This instrument is operated under 25,000 acceleration voltages with the anodal pattern with 150ns delay.In the scope of 650-2000 atomic mass unit, detected ion with mass-to-charge ratio (m/z).By Voyager Data Explorer module analysis data, obtain give the ionic strength data of the quality category of substrate and corresponding product in the mixture.The formation of relative product is calculated as the ratio of strength of signal with the strength of signal summation of product and corresponding substrate of product.Use as drag, obtain the relative product that time per unit forms by the initial nonlinear regression analysis that forms the data of 15% product of expression:

1-e ^-kT，

Wherein k is relative hydrolytic rate constant, and T is time (second).Perhaps, use fluorescence cutting assay method (fluorogenic cleavage assay, Ermolieff, people such as J., Biochemistry, 39:12450-12456 (2000)) to measure relative hydrolysis rate.Initial rate from arbitrary method is expressed for the contrast that does not suppress, by nonlinear fitting is the model (Bieth that combines closely of competitive inhibition, J., Bayer-Symposium V: proteinase inhibitor, the 463-469 page or leaf, Spinger-Varlag, Berlin (1994)) measured the inhibition constant K _i(K that memapsin 2, cathepsin D and memapsin 1 are obtained is represented on M2K, CDK and M1K hurdle respectively to the results are shown in table 1 _iValue).

Embodiment 6: the mensuration of cell A β IC50

In the test cell line that A β generates, measured the usefulness of compound to memapsin 2 catalytic activitys.The compound that successfully passes cytolemma shows that they have inhibition intension body cavity (endosomalcompartment) thereby the ability that middle memapsin 2 catalytic activitys blocking-up A β generates.The Chinese hamster ovary cell of cross expressing the people APP695 with London and Sweden's type sudden change converged with 10% be seeded in the porous plate.With compound be dissolved among the DMSO to concentration near 1mM, be diluted to final concentration near 4 μ M (finally being 0.4%DMSO) with substratum.Compound is carried out serial dilution, at the back cell that was applied in the porous plate in 48 hours of inoculation.At 5%CO ₂, continued to hatch 24 hours under 37 ℃.Remove aliquots containig, use sandwich ELISA (BioSource International) A β ₄₀Content is measured.For contrast is hatched, with A β ₄₀Amount fit to 4-parameter I C with respect to the compound concentrations scope ₅₀Model.The result provides (hurdle that is labeled as " cell ") in last table 1.

Claims

1. the compound that has following formula:

Wherein

R ¹Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted C ₃-C ₂₀Alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y;

R ⁵Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;

R ²And R ³Be independently halogen ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y;

R ⁴Be halogen ,-OH ,-CF ₃,-NO ₂,-NR ⁸R ⁹,-OR ¹⁰,-S (O) _nR ¹¹,-C (O) R ¹², hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y;

R ⁶And R ⁷Be-S (O) independently ₂R ¹¹,-C (O) R ¹²,-NR ⁸R ⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or-L ⁴-Y;

N is 0,1 or 2 independently;

R ⁸Be-C (O) R independently ¹³,-S (O) ₂R ¹⁴, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;

R ⁹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;

R ¹⁰Be-C (O) R independently ¹³, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;

R ¹¹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently, if wherein n is 2, R then ¹¹Choose wantonly and be-NR ¹⁵R ¹⁶And if wherein n is 1 or 2, R then ¹¹Not hydrogen;

R ¹²Be independently-NR ¹⁸R ¹⁹,-OR ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;

R ¹³Be independently-OR ¹⁹,-NR ¹⁸R ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl,

R ¹⁴Be independently-NR ¹⁸R ¹⁹, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein

R ¹⁸And R ¹⁹Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;

R ¹⁵And R ¹⁶Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;

L ¹And L ³Be independently valence link ,-NR ¹⁷-,-S (O) _q-, replacement or unsubstituted alkylidene group or replacement or unsubstituted assorted alkylidene group;

L ²Be replace or unsubstituted alkylidene group ,-NR ¹⁷-,-S (O) _q-or replacement or unsubstituted assorted alkylidene group;

R ¹⁷Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;

Q is 0,1 or 2 independently;

A ¹And A ²Be to replace or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;

Y is a carrier part; And

L ⁴Be valence link ,-OP (OH) ₂O-,-C (O) OR ²⁰-,-C (O) NHR ²¹-,-S (O) ₂NHR ²²-, replacement or unsubstituted alkylidene group, replacement or unsubstituted assorted alkylidene group or peptidyl connect base, wherein

2. the compound of claim 1, wherein R ¹Be hydrogen, halogen ,-NR ⁸R ⁹,-OR ¹⁰Or-S (O) _nR ¹¹

3. the compound of claim 1, wherein R ¹Be hydrogen ,-NR ⁹S (O) _nR ¹⁴,-OR ¹⁰Or-S (O) _nR ¹¹

4. the compound of claim 1, wherein R ¹Be hydrogen or-NR ⁹S (O) _nR ¹⁴

5. the compound of claim 1, wherein R ⁵, R ⁸, R ⁹, R ¹⁰And R ¹¹Be hydrogen, replacement or unsubstituted C independently ₁-C ₂₀Alkyl, replacement or unsubstituted 2 to 20 yuan of assorted alkyl, replacement or unsubstituted C ₅-C ₇Cycloalkyl, replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryls or-L ⁴-Y.

6. the compound of claim 1 wherein replaces or each R naturally of unsubstituted alkylidene group ²³-replace or unsubstituted C ₁-C ₂₀Alkylidene group replaces or each R naturally of unsubstituted assorted alkylidene group ²³-replace or unsubstituted 2 to 20 yuan of assorted alkylidene groups, replace or each R naturally of unsubstituted alkyl ²³-replace or unsubstituted C ₁-C ₂₀Alkyl replaces or each R naturally of unsubstituted assorted alkyl ²³-replace or unsubstituted 2 to 20 yuan of assorted alkyl, replace or each R naturally of unsubstituted cycloalkyl ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl replaces or each R naturally of unsubstituted Heterocyclylalkyl ²³-replace or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, replace or each R naturally of unsubstituted heteroaryl ²⁴-replace or unsubstituted heteroaryl, replace or each R naturally of unsubstituted aryl ²⁴-replace or unsubstituted aryl, wherein

R ²³Be independently oxo base, halogen ,-CN ,-CF ₃,-OCF ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl;

R ²⁴Be independently halogen ,-CN ,-CF ₃,-OCF ₃,-OCH ₃, OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl;

T is 0,1 or 2 independently;

R ²⁷, R ²⁸And R ²⁹Be hydrogen, R independently ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²⁵-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²⁵-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²⁵-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁶-replace or unsubstituted heteroaryl or R ²⁶-replace or unsubstituted aryl, if wherein t is 1 or 2, R then ²⁷Not hydrogen, and wherein

R ²⁵Be independently oxo base, halogen ,-CN ,-OH ,-CF ₃,-OCF ₃,-OCH ₃, unsubstituted C ₁-C ₂₀Alkyl, unsubstituted 2 to 20 yuan of assorted alkyl, unsubstituted C ₅-C ₇Cycloalkyl, unsubstituted 5 to 7 yuan of Heterocyclylalkyls, unsubstituted aryl or unsubstituted heteroaryls, and

R ²⁶Be independently halogen ,-CN ,-OH ,-CF ₃,-OCF ₃,-OCH ₃, unsubstituted C ₁-C ₂₀Alkyl, unsubstituted 2 to 20 yuan of assorted alkyl, unsubstituted C ₅-C ₇Cycloalkyl, unsubstituted 5 to 7 yuan of Heterocyclylalkyls, unsubstituted aryl or unsubstituted heteroaryls.

7. the compound of claim 6, wherein R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Be R independently ²³-replace or unsubstituted C ₁-C ₂₀Alkyl, R ²³-replacement or unsubstituted 2 to 20 yuan of assorted alkyl, R ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.

8. the compound of claim 7, wherein

R ²⁷, R ²⁸And R ²⁹Be hydrogen, R independently ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl;

R ²³Be independently oxo base, halogen ,-CN ,-CF ₃,-OCF ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl; And R ²⁴Be independently halogen ,-CN ,-CF ₃,-OCF ₃,-OCH ₃,-OR ²⁷,-S (O) _tR ²⁷,-OCH ₃,-C (O) R ²⁷,-NR ²⁸R ²⁹,-NR ²⁸C (O) R ²⁷,-C (O) NR ²⁸R ²⁹, R ²⁵-replace or unsubstituted C ₁-C ₂₀Alkyl or R ²⁵-replace or unsubstituted 2 to 20 yuan of assorted alkyl.

9. the compound of claim 6, wherein R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Be to replace or unsubstituted C ₁-C ₂₀Alkyl or replacement or unsubstituted Heterocyclylalkyl.

10. the compound of claim 6, wherein R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Be unsubstituted C ₁-C ₂₀Alkyl.

11. the compound of claim 6, wherein R ², R ³, R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Be unsubstituted C ₁-C ₅Alkyl.

12. the compound of claim 1, wherein R ²And R ³Be hydrogen, halogen or unsubstituted C independently ₁-C ₂₀Alkyl.

13. the compound of claim 6, wherein R ⁵Be R ²³-replace or unsubstituted C ₅-C ₇Cycloalkyl, R ²³-replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.

14. the compound of claim 6, wherein R ⁵Be R ²⁴-replace or unsubstituted heteroaryl or R ²⁴-replace or unsubstituted aryl.

15. the compound of claim 6, wherein R ⁵Be R ²⁴-replace or unsubstituted aryl.

16. the compound of claim 1, wherein R ⁵Be selected from and replace or unsubstituted tetrahydrofuran base, replacement or unsubstituted THP trtrahydropyranyl and replacement or unsubstituted pyridine ylmethyl.

17. the compound of claim 16, wherein L ³Be unsubstituted C ₁-C ₅Alkyl.

18. the compound of claim 17, wherein L ³It is methylene radical.

19. the compound of claim 15, wherein R ²⁴Be halogen ,-CN ,-OH ,-CF ₃, unsubstituted C ₁-C ₂₀Alkyl or unsubstituted alkoxyl group.

20. the compound of claim 19, wherein R ⁵It is difluorophenyl.

21. the compound of claim 15, wherein R ⁵It is phenyl.

22. the compound of claim 21, wherein L ³Be unsubstituted C ₁-C ₃Alkylidene group.

23. the compound of claim 21, wherein L ³Be unsubstituted 2 to 5 yuan of assorted alkylidene groups.

24. the compound of claim 23, wherein L ³Be-(CH ₂) _e-S-, wherein symbol e represents 0 to 10 integer.

25. the compound of claim 24, wherein e is 1.

26. the compound of claim 1, wherein A ¹And A ²Be to replace or unsubstituted C independently ₅-C ₇Cycloalkyl, replacement or unsubstituted 5 to 7 yuan of Heterocyclylalkyls, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.

27. the compound of claim 1, wherein A ²Be to replace or unsubstituted aryl or replacement or unsubstituted heteroaryl.

28. the compound of claim 1, wherein A ¹And A ²Be to replace or unsubstituted phenyl independently; replace or unsubstituted pyrazolyl; replace or unsubstituted furyl; replace or unsubstituted imidazolyl; replace or unsubstituted different  azoles base; replace or unsubstituted  di azoly; replace or unsubstituted  azoles base; replace or unsubstituted pyrryl; replace or the unsubstituted pyridine base; replace or unsubstituted pyrimidyl; replace or unsubstituted pyridazinyl; replace or unsubstituted thiazolyl; replace or unsubstituted triazolyl; replace or unsubstituted thienyl; replace or unsubstituted dihydro-thiophene and pyrazolyl; replace or unsubstituted thianaphthenyl; replace or unsubstituted carbazyl; replace or unsubstituted benzimidazolyl-; replace or unsubstituted benzothienyl; replace or unsubstituted benzofuryl; replace or unsubstituted indyl; replace or the unsubstituted quinolines base; replace or unsubstituted benzotriazole base; replace or unsubstituted benzothiazolyl; replace or unsubstituted benzoxazol base; replace or unsubstituted benzimidazolyl-; replace or unsubstituted isoquinolyl; replace or unsubstituted pseudoindoyl; replace or unsubstituted acridyl; replace or unsubstituted benzoisazolyl (benzisoxa  azoles base); replace or unsubstituted T10; replace or unsubstituted pyrazinyl; replace or unsubstituted tetrahydrofuran base; replace or unsubstituted pyrrolinyl; replace or unsubstituted pyrrolidyl; replace or unsubstituted morpholinyl; replace or unsubstituted indyl; replace or unsubstituted diaza  base; replace or unsubstituted azepine  base; replace or unsubstituted thia  base; replace or unsubstituted piperidyl or replacement or unsubstituted oxa- base.

29. the compound of claim 1, wherein A ²Be to replace or unsubstituted aryl.

30. the compound of claim 1, wherein A ²Be to replace or unsubstituted phenyl.

31. the compound of claim 1, wherein A ²Be to replace or unsubstituted heteroaryl.

32. the compound of claim 1, wherein A ²Be to replace or the unsubstituted pyridine base.

33. the compound of claim 1, wherein L ³And L ¹Be valence link, unsubstituted alkylidene group or unsubstituted assorted alkylidene group independently.

34. the compound of claim 1, wherein L ³And L ¹Be valence link, unsubstituted C independently ₁-C ₂₀Alkylidene group or unsubstituted 2 to 20 yuan of assorted alkylidene groups.

35. the compound of claim 1, wherein L ³And L ¹Be valence link, unsubstituted C independently ₁-C ₅Alkylidene group or unsubstituted 2 to 5 yuan of assorted alkylidene groups.

36. the compound of claim 1, wherein L ³Be C ₁-C ₅Alkylidene group.

37. the compound of claim 1, wherein L ¹Be the unsubstituted C of side chain ₁-C ₅Alkylidene group.

38. the compound of claim 1, wherein L ²Be unsubstituted C ₁-C ₂₀Alkylidene group or unsubstituted 2 to 20 yuan of assorted alkylidene groups.

39. the compound of claim 1, wherein L ²Be unsubstituted C ₁-C ₅Alkylidene group or unsubstituted 2 to 5 yuan of assorted alkylidene groups.

40. the compound of claim 1, wherein L ²Be unsubstituted C ₁-C ₅Alkylidene group.

41. the compound of claim 1, wherein L ²Be the unsubstituted C of side chain ₁-C ₅Alkylidene group.

42. the compound of claim 1, wherein L ²It is methylene radical.

43. the compound of claim 40, wherein A ²Be to replace or unsubstituted heteroaryl or replacement or unsubstituted aryl.

44. the compound of claim 43, wherein A ¹Be to replace or unsubstituted heteroaryl or replacement or unsubstituted aryl.

45. the compound of claim 44, wherein A ²Be to replace or unsubstituted phenyl or replacement or unsubstituted pyridine base.

46. the compound of claim 44, wherein A ¹Be to replace or unsubstituted phenyl or replacement or unsubstituted pyridine base.

47. the compound of claim 45, wherein L ²It is methylene radical.

48. the compound of claim 1, if R wherein ¹Be-NR ⁸R ⁹And R ⁸Be-S (O) ₂R ¹⁴, R then ⁶Be hydrogen.

49. the compound of claim 48, wherein R ⁷Be to replace or unsubstituted alkyl.

50. the compound of claim 48, wherein R ⁷Be unsubstituted C ₁-C ₅Alkyl.

51. the compound of claim 48, wherein R ²And R ³Be hydrogen.

52. the compound of claim 1, if R wherein ¹Be hydrogen, R then ⁶Not hydrogen.

53. the compound of claim 52, wherein R ⁶Be to replace or unsubstituted alkyl.

54. the compound of claim 52, wherein R ⁶Be unsubstituted C ₁-C ₅Alkyl.

55. the compound of claim 52, wherein R ⁶Be to replace or unsubstituted C ₃-C ₆Cycloalkyl.

56. the compound of claim 52, wherein R ⁶Be to replace or unsubstituted cyclopropyl.

57. the compound of claim 54, wherein R ⁷Be hydrogen.

58. the compound of claim 57, wherein R ²And R ³Be hydrogen.

59. the method for treatment alzheimer's disease in its curee of needs, this method comprises the compound of using the claim 1 of significant quantity to the curee of this treatment of needs.

60. reduce the method for memapsin 2 catalytic activitys, this method comprises makes memapsin 2 protein contact with the compound of the claim 1 of significant quantity.

61. the method for claim 60, wherein said memapsin 2 beta-secretases contact in cell.

62. selectivity reduces the method for memapsin 2 catalytic activitys for memapsin 1 catalytic activity, this method is included under the existence of memapsin 1 beta-secretase memapsin 2 protein is contacted with the compound of the claim 1 of significant quantity.

63. selectivity reduces the method for memapsin 2 catalytic activitys for cathepsin D's catalytic activity, this method is included under the existence of cathepsin D memapsin 2 protein is contacted with the compound of the claim 1 of significant quantity.

64. selectivity reduces the method for memapsin 2 catalytic activitys for memapsin 1 catalytic activity and cathepsin D's catalytic activity, this method is included under the existence of memapsin 1 beta-secretase and cathepsin D memapsin 2 protein is contacted with the compound of the claim 1 of significant quantity.