CN101475526A - Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof - Google Patents

Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof Download PDF

Info

Publication number
CN101475526A
CN101475526A CNA2009100098615A CN200910009861A CN101475526A CN 101475526 A CN101475526 A CN 101475526A CN A2009100098615 A CNA2009100098615 A CN A2009100098615A CN 200910009861 A CN200910009861 A CN 200910009861A CN 101475526 A CN101475526 A CN 101475526A
Authority
CN
China
Prior art keywords
amino
alkyl
methyl
dihydro
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2009100098615A
Other languages
Chinese (zh)
Other versions
CN101475526B (en
Inventor
R·J·比迪格
Q·陈
G·W·霍兰德
J·M·卡斯尔
W·李
R·V·马克特
I·L·斯科特
C·吴
E·R·戴克
J·李
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Encysive Pharmaceuticals Inc
Original Assignee
Texas Biotechnology Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/973,142 external-priority patent/US6972296B2/en
Application filed by Texas Biotechnology Corp filed Critical Texas Biotechnology Corp
Publication of CN101475526A publication Critical patent/CN101475526A/en
Application granted granted Critical
Publication of CN101475526B publication Critical patent/CN101475526B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A method for the inhibition of the binding of alpha4beta1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and to the use of such compounds either a above, or in formulations for the control or prevention of diseases states in which alpha4beta1 is involved.

Description

The carboxylic acid derivative of inhibition of integrins and its receptors bind
The application is dividing an application of following application: the applying date: December 29 calendar year 2001; Application number: 01145182.3; Denomination of invention: " carboxylic acid derivative of inhibition of integrins and its receptors bind ".
The application is the U.S. Patent Application Serial Number 09/707 of application on November 6th, 2000,068 part continuation application, U.S. Patent Application Serial Number 09/707,068 is the U.S. Patent Application Serial Number 09/565 of application on May 5th, 2000,920 part continuation application, the application requires the interests of the U.S. Provisional Patent Application sequence number 60/132,971 of application on May 7th, 1999.
Technical field
The present invention relates generally to α 4β 1Integrin and its acceptor be VCAM-1 (vascular cell adhesion molecule-1) and fibronectin bonded restraining effect for example.The invention still further relates to and suppress this bonded compound; The medical active composition that contains this compound; And relate to described compound and aspect above or in control or prevention, relate to α 4β 1The preparation of morbid state in application.
Background technology
When tissue is subjected to microbiological attack or when impaired, white corpuscle plays a major role in inflammatory reaction.One of most important aspect of inflammatory reaction relates to the cell adhesion process.In general, white corpuscle circulates by blood flow.Yet when tissue infection or when impaired, white corpuscle identification is subjected to invasion and attack tissue or damaged tissue, is attached to capillary wall, moves in the tissue of getting involved by capillary vessel.These processes are by the protein family mediation that is called cell adhesion molecule.
There are 3 kinds of main types in white corpuscle: granulocyte, monocyte and lymphocyte.Beta 2 integrin alpha 4β 1(being also referred to as Vla-4-4, VLA-4) is the heterodimer albumen of monocyte, lymphocyte and 2 kinds of hypotype granulocyte eosinophilic granulocytes and basophilic granulocyte surface expression.This albumen plays an important role in cell adhesion by its identification and in conjunction with the ability of capillary vessel inwall endotheliocyte associated protein VCAM-1 and fibronectin.
The capillary vessel surrounding tissue infect or impaired after, endotheliocyte is expressed a series of adhesion molecules, comprises VCAM-1, adhesion molecule is very crucial to infecting essential white corpuscle in conjunction with opposing.Before VCAM-1 or fibronectin, white corpuscle is attached on some adhesion molecule at first, it is flowed slow down and make white corpuscle along activation endothelium " rolling ".Monocyte, lymphocyte, basophilic granulocyte and eosinophilic granulocyte can pass through α then 4β 1Integrin combines with VCAM-1 or fibronectin on the vessel wall securely.Evidence suggests, this interaction also participate in these white corpuscles cross cell walls move in the damaged tissue with and initial rolling process.
Although leucocyte migration helps opposing to infect and the destruction exogenous material to damage location, leucocyte migration can become uncontrollable in many cases, and white corpuscle pours in diseased region, causes extensive tissue injury.Therefore, the compound that can block this process can be used as useful medicine.So exploitation prevents that white corpuscle and VCAM-1 and fibronectin bonded inhibitor from should be useful.
Can be by suppressing α 4β 1The part disease of combined treatment includes but not limited to arteriosclerosis, rheumatoid arthritis, asthma, transformation reactions, multiple sclerosis, lupus, inflammatory bowel, graft-rejection, contact hypersensitivity and type i diabetes.α 4β 1Except seeing the part white corpuscle, also see various cancer cells, comprise leukemia cell, melanoma cells, lymphoma cell and sarcoma cell.Proposed to relate to α 4β 1Cell adhesion may participate in some cancer metastasis.Therefore, α 4β 1Binding inhibitors also can be used for the treatment of the cancer of some type.
United States Patent (USP) the 5th, 510 discloses for No. 332 suppressing α 4β 1Separation and purification with protein bound peptide.WO 95/15973, EP 0 341 915, EP 0 422 938 A1, No. the 5th, 192,746, United States Patent (USP) and WO 96/06108 disclose inhibition bonded peptide.WO 96/22966, WO98/04247 and WO 98/04913 disclose the novel cpd that can be used for suppressing and preventing the pathology of cell adhesion and cell adhesion-mediated.
So one of the object of the invention provides and is α 4β 1The novel cpd of binding inhibitors and the medicinal compositions that comprises this novel cpd.
Summary of the invention
The present invention relates to formula I compound or its pharmacy acceptable salt:
Figure A200910009861D00371
Formula I
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 3-10;
A is selected from O, S, C (R 16) (R 17) and NR 6
E is selected from CH 2, O, S and NR 7
J is selected from O, S and NR 8
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
M is selected from C (R 9) (R 10) and (CH 2) u, wherein u is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
X is selected from CO 2B, PO 3H 2, SO 3H, SO 2NH 2, SO 2NHCOR 12, OPO 3H 2, C (O) NHC (O) R 13, C (O) NHSO 2R 14, hydroxyl, tetrazyl and hydrogen;
W is selected from C, CR 15And N; And
B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16And R 17When occurring, independently be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN ,-NO 2, NH 2,-OH, chain alkynyl amino, carbalkoxy, heterocyclic acyl (heterocycloyl), carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16And R 17For unsubstituted group or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
Wherein working as M is C (R 9) (R 10) time, R 9And R 10Can form a ring together;
Wherein working as A is NR 6With at least one Y be CR 1The time, R 1And R 6Can form a ring together;
Prerequisite be when A be C (R 16) (R 17) time, E is not NR 7
For formula I, preferred compound of the present invention can be that the compound with following group: A is NR 6E is NR 7J is O; M is C (R 9) (R 10); Q is 4 or 5; T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; X is CO 2B; W is C or CR 15R 4Be aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic or heterocyclic radical alkyl; R 6, R 7, R 9, R 10And R 15Independent is hydrogen or low alkyl group.
More particularly, compound of the present invention can be described with Formula Il or its pharmacy acceptable salt
Figure A200910009861D00381
Formula II
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 3-7;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
W is selected from C, CR 15And N;
B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15Independently be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN ,-NO 2,-NH 2,-OH, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
R wherein 9And R 10Can form a ring together;
Wherein working as at least one Y is CR 1The time, R 1And R 6Can form a ring together.
For formula II, preferred compound of the present invention can be that the compound with following group: q is 4 or 5; W is C or CR 15T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; R 4Be aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic or heterocyclic radical alkyl; R 6, R 7, R 9, R 10And R 15Independent is hydrogen or low alkyl group.
More particularly, compound of the present invention can be described with Formula Il I or its pharmacy acceptable salt
Figure A200910009861D00401
Formula III
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 2-5;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; And
R 5, R 6, R 7, R 11And R 18Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
B, R 1, R 2, R 3, R 4, R 9And R 10Independently be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 18For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when at least one Y be CR 1The time, R 1And R 6Can form a ring together.
For formula III, preferred compound of the present invention can be the compound with following group: R 18Be hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkyl heterocyclic, heterocyclic radical alkyl or heterocyclic radical; T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; Y is CR 1And C (R 2) (R 3), and q is 2 or 3.
In formula III, the integral part of described molecule
Figure A200910009861D00421
Can be
Figure A200910009861D00422
With
Figure A200910009861D00423
With and pharmacy acceptable salt,
R wherein 19, R 20, R 21And R 28When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, hydroxyl ,-CO 2H, sulfydryl, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 18Be selected from alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
R 22Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
C is the integer of 0-2;
D is the integer of 0-3;
E is the integer of 0-4; And
I is the integer of 0-2.
In one embodiment, R 18Be aralkyl; R 4Be aryl; T is (CH 2) b, wherein b is 0; L is that wherein n is 0 (CH 2) nAnd B, R 6, R 7, R 9And R 10Independent separately is hydrogen.
More particularly, The compounds of this invention can be described with following formula I V or its pharmacy acceptable salt:
Formula IV
Wherein T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
G is the integer of 0-7;
B, R 4, R 9, R 10And R 23When occurring, independently be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 6, R 7, R 11And R 18Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
Wherein B, R 4, R 6, R 7, R 9, R 10, R 11, R 18And R 23For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R 9And R 10Can form a ring together.
Present preferred compound of the present invention also can be described with following formula V or its pharmacy acceptable salt:
Figure A200910009861D00451
Formula V
Wherein h is the integer of 0-5;
B, R 9, R 10, R 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 27When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl) ,-N (C 1-C 3Alkyl) SO 2(C 1-C 3Alkyl) ,-N (C 1-C 3Alkyl) SO 2(aryl) ,-alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 6, R 7And R 18Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl ,-CF 3, carbalkoxy, heterocyclic acyl, carboxyl ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-PO 3H 2, haloalkyl, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, dibenzyl, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl), sulfonamido, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 6, R 7, R 9, R 10, R 18, R 24, R 25, R 26And R 27For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
R wherein 18And R 24Can form a ring together;
R 24And R 25Can form a ring together;
R 25And R 26Can form a ring together;
And R wherein 9And R 10Can form a ring together.
The preferred compound of present V is the compound with following group: B, R 6, R 7, R 9, R 10, R 24, R 25And R 26Independent separately is hydrogen, and R 18Be substituted aralkyl or unsubstituting aromatic alkyl.
Other preferred compound of the present invention can be described with following formula VI or its pharmacy acceptable salt now:
Formula VI
Wherein Z independently is selected from C (O), N, CR at every turn when occurring 30, C (R 31) (R 32), NR 33, CH, O and S;
Z is the integer of 3-6;
K is the integer of 0-5;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
R 6, R 7, R 11, R 18And R 33Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
B, R 4, R 9, R 10, R 30, R 31And R 32When occurring, independently be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 29When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 4, R 6, R 7, R 9, R 10, R 11, R 18, R 29, R 30, R 31, R 32And R 33For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
When L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together.
The new intermediate of available formula VII and VIII prepares segment bounds I-VI compound,
Formula VII
R wherein 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, sulfydryl, hydroxyl ,-CO 2H, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkylamino ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 18And R 34Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
R wherein 18, R 24, R 25And R 34For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
And R wherein 24And R 25Can form a ring together;
Prerequisite is to work as R 24And R 25In the time of can forming a ring together, formed ring is not a benzene.The preferred compound of present VII is the compound with following group: R 34Be hydrogen; R 18Be aralkyl; And R 24And R 25Independent separately is hydrogen, low alkyl group or R wherein 24And R 25Can form the low alkyl group of a ring together.
Following formula VIII is present preferred new intermediate:
Formula VIII
R wherein 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, sulfydryl, hydroxyl ,-CO 2H, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 34Be selected from alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group; And
R 35When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R wherein 24, R 25, R 34And R 35For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group; And
M is the integer of 0-5.The preferred compound of present VIII is the compound with following group: R 34Be hydrogen; M is the integer of 1-3, and R 35When occurring alkyl, halogen, alkoxyl group, haloalkyl, alkylsulfonyl, hydroxyl or cyano group at every turn.
The preferred compound of present I comprises:
(3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({[2-oxo-1-(phenmethyl)-4-propyl group-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-propyl group-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({6-methyl-2-oxo-1-(phenmethyl)-4-[(phenmethyl) the oxygen base]-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3, the 4-3,5-dimethylphenyl) propionic acid,
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(1,4-oxazine alkane (oxazinan)-4-yl)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxo-4-(propyl group amino)-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) the oxygen base]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(1, the 1-dimethyl ethyl) amino]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-the 3-phenylpropionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[4-methyl tetrahydrochysene-1 (2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3, the 5-3,5-dimethylphenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(methoxyl group) phenyl] propionic acid,
(3S)-and 3-[3, two (methoxyl group) phenyl of 5-]-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino } propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({4-(1-azetanyl)-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl) phenyl) methyl)-1,2-dihydro-3-pyridyl) propionic acid amino carbonyl amino))), (3S)-3-((((1-((2-chlorophenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-((((1-((2-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2-bromo phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2,4 dichloro benzene base) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2-chloro-6-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-((((1-((2-chlorophenyl) methyl)-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-trifluoromethyl) oxygen base) phenyl) propionic acid
(3S)-3-[({[1-[(2-chloro-6-methoxy-benzyl)-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
4-{[3-[({[(1S)-and 2-carboxyl-1-(4-aminomethyl phenyl) ethyl] amino } carbonyl) amino]-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-4-yl] amino } phenylformic acid
(3S)-3-{[({1-[(2-chloro benzyl)-4-[(2,2-dimethyl propylene acyl group) amino]-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[4-{[(tertiary butyl amino) carbonyl] amino }-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-cyano group benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2,3-dihydro-1, own (the benzodioxin)-6-yl of 4-benzo dioxane) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(7-methoxyl group-1,3-benzo dioxane penta-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-oxyethyl group-4-p-methoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 4-Dimethoxyphenyl) propionic acid,
(3S)-and 3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2, the 6-difluorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 5-Dimethoxyphenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-methoxyl group-4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,5-dimethoxy-4 '-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 4-3,5-dimethylphenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-5-ethyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl) benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2, the 6-dimethoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-propoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-(3-butoxy phenyl)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino] propionic acid,
(3S)-3-{[({1-[2-chloro-5-(methyl sulphonyl) benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(2-methoxy ethoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-dipropoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(difluoro-methoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-cyano group benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2-naphthyl) propionic acid and (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-p-methoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2,3-dihydro-1-cumarone-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3,5-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[5-chloro-1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-propoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-the 3-phenylpropionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(trifluoromethoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-5-methoxy-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-6-methyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-6-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(ring propoxy-) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(ring propoxy-methoxyl group) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(cyclo propyl methoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3, the 5-3,5-dimethylphenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(difluoromethyl) the oxygen base] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[(1,1,2,2-tetrafluoro ethyl) the oxygen base] phenyl } propionic acid,
(3S)-the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino-3-(1-ethyl-1H-indoles-5-yl) propionic acid and
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-(diethylamino) phenyl } propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(6-methoxyl group-2-naphthyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid,
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(diethylamino) phenyl] propionic acid, (3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-(1-Methyl-1H-indole-5-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[methyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[methyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[ethyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[ethyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-(1H-indoles-5-yl) propionic acid, and their pharmacy acceptable salt.
The preferred compound of present VII comprises:
5-(2-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-benzyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-benzyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 5-dimethyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 5-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3,5-two (trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-tertiary butyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-bromobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 4-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[4-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(pyridine-2-ylmethyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[4-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 3-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 5-dimethyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-amyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-dichloro benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
7-butyl-5-(2-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methyl-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
7-methyl-5-[4-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
4-(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also]-N, the N-dimethyl benzene sulfonamide,
5-(Yu ylmethyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-3,5,6,7,8,9-six hydrogen [1,3] oxazole is [4,5-c] quinoline-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also]-N, the N-dimethyl benzene sulfonamide,
5-(2, the 6-dimethoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-chloro-2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-5,6,7,8,9,10-six hydrogen-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-[2-(difluoro-methoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
The 7-methyl-5-[(1R)-the 1-styroyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dimethyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
3-ammonia-2-[(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also] benzonitrile,
5-(2-chloro-6-methyl-benzyl)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
2-[(2,4-dioxo-2,3 dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also] benzonitrile,
5-(2-chloro-6-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-cyclopropyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dichloro benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
7-methyl-5-(4-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 5-dimethoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-difluorobenzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-fluoro-6-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methoxy-benzyl)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-chloro-2-luorobenzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-sec.-propyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-fluoro-2-methyl-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
The 7-methyl-5-[(1S)-the 1-phenylethyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-isopropoxide benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-ethanoyl-2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methyl-benzyl)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-ethoxy benzyl)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-propoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-isobutoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-isopropoxide benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-6-(2,2, the 2-trifluoro ethoxy) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-d] pyridazine-2 also, the 4-diketone,
5-[2-chloro-6-(2-methoxy ethoxy) benzyl]-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-ethoxy benzyl)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-ethyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-d] pyridazine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-cyclopropyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-propoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(piperidines-1-base alkylsulfonyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(tetramethyleneimine-1-base alkylsulfonyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-6-(cyclopentyl methoxyl group) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(benzyloxy)-6-benzyl chloride base]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2,3-two chloro-6-ethoxy benzyls)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-[2-chloro-5-(trifluoromethyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone and
5-(2-chloro-5-luorobenzyl)-7-methyl-3, [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone for the 5-dihydro.
Also designed derivative, for example ester, carbamate, aminal (aminal), acid amides, optically active isomer and prodrug.
The invention still further relates to the medicinal compositions that comprises acceptable diluent and at least a The compounds of this invention on the physiology.
The invention still further relates to and suppress α 4β 1Integrin and VCAM-1 bonded method make express alpha under the The compounds of this invention that is included in effective inhibitory amount exists 4β 1The cell of integrin and the cells contacting of expressing VCAM-1.VCAM-1 is found in the surface of vascular endothelial cell, antigen presenting cell or other cell types.α 4β 1Be found in white corpuscle such as monocyte, lymphocyte, granulocyte; Stem cell; Or natural express alpha 4β 1Any other cell surface.
The present invention also provides treatment α 4β 1Integrin is in conjunction with the method for disease states mediated, and this method comprises the The compounds of this invention that gives patient's significant quantity, and this The compounds of this invention is independent compound or is its preparation.
The term that this paper is used alone or in combination " alkyl " is meant C 1-C 12Straight or branched, stable hydrocarbon are removed replacement or the unsubstituted saturated chain base that a hydrogen atom produces, unless there is C term alkyl front x-C yIndicate.The representative instance of alkyl is particularly including methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.
The term that this paper is used alone or in combination " alkenyl " is meant the replacement that contains 2-10 carbon atom or substituted straight chain alkenyl or replace or do not replace branched alkenyl not.This examples of groups includes but not limited to vinyl, E-and Z-pentenyl, decene base etc.
The term that this paper is used alone or in combination " alkynyl group " is meant the replacement that contains 2-10 carbon atom or substituted straight chain alkynyl or replace or replace an alkynyl group not.This examples of groups includes but not limited to ethynyl, proyl, propargyl, butynyl, hexin base, decynyl etc.
" alkyl ", " alkenyl " that term " rudimentary " is modified, the C that " alkynyl group " or " alkoxyl group " is meant particular functionality 1-C 6The unit.For example low alkyl group is meant C 1-C 6Alkyl.
The term that this paper is used alone or in combination " aliphatic acyl " be meant the formula that alkanoic acid, chain-ene carboxylic acid or alkyne carboxylic acid produce: alkyl-C (O)-, alkenyl-C (O)-and alkynyl group-C (O)-group, wherein term " alkyl ", " alkenyl " and " alkynyl group " are with above definition.This aliphatic acyl examples of groups particularly including but be not limited to ethanoyl, propionyl, butyryl radicals, pentanoyl, 4-methylpent acyl group, acryl, crot(on)yl, propioloyl and methyl propioloyl.
Term used herein " cycloalkyl " is meant the aliphatic ring system with 3-10 carbon atom and 1-3 ring, particularly including but be not limited to cyclopropyl, cyclopentyl, cyclohexyl, norborneol alkyl (norbornyl) and adamantyl (adamantyl).Cycloalkyl can not be substituted or independently is selected from 1,2 or 3 following substituting group and replaces: low alkyl group, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, halogen, sulfydryl, nitro, carboxaldehyde radicals, carboxyl, carbalkoxy and formamido-.
" cycloalkyl " comprises cis or trans cycloalkyl.In addition, described substituting group can be positioned at the position or the outer position of bridging bicyclic system.
The term that this paper is used alone or in combination " cycloalkenyl group " is meant the annular carbocyclic ring that contains 4-8 carbon atom and one or more pairs of keys.Such cycloalkenyl group example includes but not limited to cyclopentenyl, cyclohexenyl, cyclopentadienyl etc.
Term used herein " cycloalkylalkyl " is meant the cycloalkyl that is connected with low alkyl group, includes but not limited to cyclohexyl methyl.
Term used herein " halogen " or " halogen " are meant iodine, bromine, chlorine or fluorine.
Term used herein " haloalkyl " is meant the low alkyl group of subsidiary at least one halogenic substituent, for example chloromethyl, fluoro ethyl, trifluoromethyl and pentafluoroethyl group etc.
The term that this paper is used alone or in combination " alkoxyl group " is meant alkyl ether groups, the same definition of term wherein " alkyl ".The example of suitable alkyl ether groups includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
Term used herein " alkoxyalkyl " is meant R y-O-R z, R wherein yBe the low alkyl group of above definition, and R zBe alkylidene group ((CH 2) w-), wherein w is the integer of 1-6.Representative instance comprises methoxymethyl, methoxy ethyl and ethoxyethyl group etc.
The term that this paper is used alone or in combination " alkenyloxy " is meant the group of formula: alkenyl-O-, and prerequisite is that this group is not an enol ether, the same definition of wherein said term " alkenyl ".The example of suitable alkenyloxy includes but not limited to allyloxy, E-and Z-3-methyl-2-propenyloxy group etc.
The term that this paper is used alone or in combination " chain oxy-acetylene " is meant the group of formula: alkynyl group-O-, and prerequisite is that this group can not be-alkynol ether (ynol ether).The example of suitable chain alkynyloxy group includes but not limited to alkynes propoxy-, 2-butyne oxygen base etc.
Term used herein " carboxyl " is meant-C (O) O-.
Term " thio alkoxy " is meant the thioether group of formula: alkyl-S-, and wherein " alkyl " definition is the same.
Term used herein " sulfonamido " is meant-SO 2NH 2
Term used herein " carboxaldehyde radicals " be meant R wherein be hydrogen-C (O) R.
Term used herein " formamido-" or " amide group " are meant wherein R aAnd R bIndependence is hydrogen, alkyl or any other suitable substituent-C (O) NR separately aR b
Term used herein " alkoxyl group alkoxyl group " is meant R CO-R dO-, wherein R CFor defining the same low alkyl group R dBe alkylidene group, wherein alkylidene group is-(CH 2) N '-, wherein n ' is the integer of 1-6.The representative instance of alkoxyl group alkoxyl group comprises methoxymethoxy, oxyethyl group methoxy base, tert.-butoxy methoxyl group etc.
Term used herein " alkylamino " is meant R eNH-, wherein R eBe low alkyl group, for example ethylamino, butyl amino etc.
The term that this paper is used alone or in combination " alkenyl amino " is meant formula: alkenyl-NH-or (alkenyl) 2The group of N-, wherein term " alkenyl " definition is the same, and prerequisite is that this group is not the enamine base.An example of this alkenyl amino group is the allyl amino group.
The term that this paper is used alone or in combination " chain alkynyl amino " is meant formula: alkynyl group-NH-or (alkynyl group) 2The group of N-, wherein term " alkynyl group " definition is the same, and prerequisite is that this group is not an amido.An example of this chain alkynyl amino group is the propargyl amino group.
Term used herein " dialkyl amido " is meant R fR gN-, wherein R fAnd R gIndependently be selected from low alkyl group, for example diethylamino and methyl-propyl amino etc.
Term used herein " carbalkoxy " is meant the previously defined alkoxyl group that is connected with parent molecular moiety by carbonyl.The carbalkoxy example comprises methoxycarbonyl, ethoxy carbonyl and isopropoxy carbonyl etc.
The term that this paper is used alone or in combination " aryl " or " aromatic base " be meant the replacement with about 6-12 carbon atom or do not replace the carbocyclic ring aromatic base, for example phenyl, naphthyl, indenyl, 2,3-dihydro indenyl, Azulene base (azulenyl), fluorenyl and anthryl; Perhaps be meant and contain at least one bridged ring nitrogen, the heterocyclic aromatic base of oxygen or sulphur atom, furyl for example, thienyl, pyridyl, pyrryl oxazolyl, thiazolyl, imidazolyl, pyrazolyl, the 2-pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl, 1,2,3-oxadiazole base, 1,2, the 3-triazolyl, 1,3, the 4-thiadiazolyl group, pyridazinyl, pyrimidyl, pyrazinyl, 1,3, the 5-triazinyl, 1,3,5-trithian base, the indolizine base, indyl, pseudoindoyl, the 3H-indyl, indolinyl, benzo [b] furyl, 2, the 3-dihydro benzo furyl, benzo [b] thienyl, the 1H-indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, the cinnolines base, 2, the 3-phthalazinyl, quinazolyl, quinoxalinyl, 1,8-phenodiazine naphthyl (naphthridinyl), pteridyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, the phenoxy group azine group, pyrazolo [1,5-c] triazinyl etc." aralkyl " and " alkylaryl " uses the term " alkyl " of above-mentioned definition.Ring can be polysubstituted ring.
The term that this paper is used alone or in combination " aralkyl " is meant the alkyl that aryl replaces, wherein the same definition of term " alkyl " and " aryl ".The example of suitable aralkyl includes but not limited to phenmethyl, styroyl, phenyl hexyl, diphenyl methyl, pyridylmethyl, tetrazyl methyl, furyl methyl, imidazolyl methyl, indyl methyl, thienyl propyl group etc.
The term that this paper is used alone or in combination " aralkenyl " is meant the alkenyl that aryl replaces, wherein the same definition of term " aryl " and " alkenyl ".
The term that this paper is used alone or in combination " arylamino " is meant the group of formula: aryl-NH-, wherein " aryl " the same definition.The arylamino examples of groups includes but not limited to phenyl amino, naphthyl amino, 2-, 3-and 4-pyridinylamino etc.
Term used herein " benzyl " is meant C 6H 5-CH 2-.
The term that this paper is used alone or in combination " dibenzyl " is meant formula: the group of aryl-aryl, wherein the same definition of term " aryl ".
The term that this paper is used alone or in combination " thioaryl " is meant the group of formula: aryl-S-, wherein the same definition of term " aryl ".An example of thioaryl is a thio-phenyl.
The term that this paper is used alone or in combination " aroyl " is meant the group of formula: aryl-CO-, wherein the same definition of term " aryl ".The example of suitable aroyl includes but not limited to benzoyl group, 4-halogeno-benzene acyl group, 4-carboxyl benzoyl group, naphthoyl base, pyridyl carbonyl etc.
The term that this paper is used alone or in combination " heterocyclic radical " is meant the non-aromatic ring of 3-to 10-unit that contains at least one bridged ring N, O or S atom.Described heterocycle may optionally be aryl-condensed ring.Described heterocycle also can be chosen wantonly by at least one substituting group and replace, and described substituting group independently is selected from hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl group, aryl, cyano group, carboxyl, carbalkoxy, carboxyalkyl, oxo base, aryl sulfonyl and aryl alkyl amino carbonyl etc.
Term used herein " alkyl heterocyclic " is meant the previously defined alkyl that is connected to parent molecular moiety by heterocyclic radical, includes but not limited to 2-methyl-5-thiazole base, 2-methyl isophthalic acid-pyrryl and 5-ethyl-2-thienyl.
Term used herein " heterocyclic radical alkyl " is meant the previously defined heterocyclic radical that is connected to parent molecular moiety by alkyl, includes but not limited to 2-thienyl methyl, 2-pyridylmethyl and 2-(piperidino) ethyl.
Term used herein " heterocyclic acyl " be meant formula: heterocyclic radical-C (O)-group, wherein the same definition of term " heterocyclic radical ".
Term used herein " aminal " is meant structure: R hC (NR iR j) (NR kR l)-hemiacetal, R wherein h, R i, R j, R kAnd R lIndependent separately is hydrogen, alkyl or any other suitable substituent.
Term used herein " ester " is meant-C (O) R m, R wherein mBe hydrogen, alkyl or any other suitable substituent.
Term used herein " carbamate " is meant based on carboxylamine NH 2The compound of C (O) OH.
Term used herein " optically active isomer " is meant the only different compound of stereochemistry of at least one atom, comprises enantiomorph, diastereomer and racemoid.
Using above-mentioned term means and comprises and replace part and non-replacement part.Replacement can be the replacement of one or more groups, for example alcohols; ethers; the ester class; amides; the sulfone class; sulfide-based; hydroxyl; nitro; cyano group; carboxyl; amine; heteroatoms; low alkyl group; lower alkoxy; lower alkoxycarbonyl; the alkoxyl group alkoxyl group; acyloxy; halogen; trifluoromethoxy; trifluoromethyl; alkyl; aralkyl; alkenyl; alkynyl group; aryl; cyano group; carboxyl; carbalkoxy; carboxyalkyl; cycloalkyl; cycloalkylalkyl; heterocyclic radical; alkyl heterocyclic; the heterocyclic radical alkyl; oxo; any substituting group in any substituting group of aryl sulfonyl and aryl alkyl amino carbonyl or above each section or the substituting group that directly is connected or connects by suitable joint.Joint is generally the short chain of 1-3 atom, comprise any combination-C-,-C (O)-,-NH-,-S-,-S (O)-,-O-,-C (O) O-or-S (O) O-.Ring can be substituted repeatedly.
Term " electrophilic " or " give electronics " are meant that substituting group can or be given electronics with respect to the hydrogen electrophilic if hydrogen is when occupying the same position of this molecule.These terms are well known to those skilled in the art, and J.March exists Advanced Organic Chemistry, to discuss in 1985, the 16-18 pages or leaves, the document is attached to herein by reference.Electron withdrawing group comprises halogen, nitro, carboxyl, low-grade alkenyl, alkynyl of low-grade chain, carboxaldehyde radicals, carboxy and amide groups, aryl, quaternary ammonium group, trifluoromethyl, alkylsulfonyl and aryl low-grade alkane acidyl etc.Donor residues comprises such as following group: hydroxyl, low alkyl group, amino, low-grade alkyl amino, two (low alkyl group) amino, aryloxy, sulfydryl, lower alkylthio, low alkyl group sulfydryl and disulphide etc.One skilled in the art will appreciate that the above substituting group can have to electronics or electrophilic characteristic under the different chemical condition.In addition, the present invention has designed the substituent any combination that is selected from above-mentioned group.
Most preferred electronics or the electron-withdrawing substituent given has halogen; nitro; alkyloyl; carboxaldehyde radicals; aromatic yl silane terephthalamide yl; aryloxy; carboxyl; formamido-; cyano group; alkylsulfonyl; sulfoxide; heterocyclic radical; guanidine; quaternary ammonium group; low-grade alkenyl; alkynyl of low-grade chain; sulfonium salt; hydroxyl; lower alkoxy; low alkyl group; amino; low-grade alkyl amino; two (low alkyl group) amino; amine low alkyl group sulfydryl; mercaptoalkyl; alkylthio; carboxyl low-grade alkyl; alkoxy aryl; alkanoylamino; alkyloyl (low alkyl group) amino; the low alkyl group sulfuryl amino; arlysulfonylamino; alkyl sulphonyl (low alkyl group) amino; aryl sulfonyl (low alkyl group) amino; the lower alkyl formamide base; two (low alkyl group) formamido-; sulfamyl; the low alkyl group sulfamyl; two (low alkyl group) sulfamyl; the low alkyl group alkylsulfonyl; aryl sulfonyl and alkane disulfide group.
Term used herein " composition " comprises that the product of the predetermined component that contains specified amount and the predetermined component of specified amount make up and the direct or indirect any product that obtains.
Term used herein " Mammals " comprises people and other animals.
The ring of Y definition can be monocyclic heterocycles or aromatic ring in formula I, II and III, maybe can be bicyclic ring.
The dotted line that uses in formula I, II, III, IV and VI represents that the key of this position can be singly-bound or two key.If for example Y and/or W are for example N, C or CH of substituting group, then the key between atom Y and the W can be singly-bound or two key.Therefore, the ring of Y definition can be saturated rings or unsaturated ring in the described formula, depends on the selection of W and/or Y.In formula IV and VI, dotted line represents to contain azo-cycle at the optional pair keys that contain of indicating positions.
In described formula, some R group may replace it and associate ring repeatedly.R 19, R 20, R 21, R 23, R 27, R 28, R 29And R 25Can replace separately its associate ring once more than.R for instance 19, when c was 0, the ring that associates was not for replacing the ring that associates, and hydrogen is contained in C-2 position and C-4 position; And for R 23, when g was 0, C-2 to C-5 contained hydrogen in the position.
The suitable substituent of the ring of the aryl in the above-mentioned formula, alkyl, cycloalkyl, heterocyclic radical or Y and W definition, if present, comprise alcohols, amine, heteroatoms or directly connect or aryl, alkoxyl group, alkoxyl group alkoxyl group, alkyl, cycloalkyl or the heterocyclic radical of any combination by suitable joint connection.Joint is generally the short chain of 1-3 atom, comprises C, C=O, the CO of any combination 2, O, N, S, S=O, SO 2, for example ethers, amides, amine, ureas, sulphonamide, sulphonamide class etc.
For example, the R in the above-mentioned formula 1, R 2, R 3, R 5, R 6, R 7And R 8Can independently be (but being not limited to): hydrogen; alkyl; phenyl; thienyl methyl; isobutyl-; normal-butyl; the 2-thienyl methyl; 1; 3-thiazol-2-yl-methyl; benzyl; thienyl; the 3-pyridylmethyl; 3-methyl isophthalic acid-thionaphthene-2-base; allyl group; the 3-methoxy-benzyl; propyl group; the 2-ethoxyethyl group; the cyclopropyl methyl; dibenzylsulfide alkyl (sulfanyl) methyl; benzyl alkylsulfonyl methyl; phenyl sulfane ylmethyl; styroyl sulfane ylmethyl; 3-phenyl propyl sulfane ylmethyl; 4-((2-toluino carbonyl) amino) benzyl; 2-pyridyl ethyl; 2-(1H-indol-3-yl) ethyl; 1H-benzimidazolyl-2 radicals-Ji; the 4-piperidino methyl; 3-hydroxyl-4-methoxy-benzyl; the 4-leptodactyline; the 4-aminobenzyl; the phenyl sulfonyl methyl; 4-(kharophen) phenyl; the 4-p-methoxy-phenyl; the 4-aminophenyl; the 4-chloro-phenyl-; (4-(benzyl alkylsulfonyl) amino) phenyl; (4-(methyl sulphonyl) amino) phenyl; the 2-aminophenyl; the 2-aminomethyl phenyl; sec.-propyl; 2-OXo-1-pyrrolidine base; 3-(methyl sulfane base) propyl group; (propylthio alkyl) methyl; octyl group sulfane ylmethyl; the 3-aminophenyl; 4-((2-toluino carbonyl) amino) phenyl; 2-((methyl-benzyl) amino) benzyl; methyl sulfane base ethyl; hydroxyl; chlorine; fluorine; bromine; urea groups; amino; methylsulfonyl amino; kharophen; ethyl sulfane ylmethyl; 2-benzyl chloride base; the 2-bromobenzyl; the 2-luorobenzyl; 2-chloro-6-luorobenzyl; 2-chloro-4-luorobenzyl; 2; the 4-dichloro benzyl; 2-chloro-6-methoxy-benzyl; 2-cyano group benzyl; 2; the 6-difluorobenzyl; 2-chloro-5-(trifluoromethyl) benzyl; 2-chloro-6-methyl-benzyl; 2, the 6-dimethoxy-benzyl; 2-chloro-5-(methyl sulphonyl) benzyl; 2-chloro-6-cyano group benzyl; 2-chloro-6-ethoxy benzyl; 2-chloro-5-methoxy-benzyl; 2-chloro-5-luorobenzyl; 5-chloro-2-luorobenzyl; ethyl; propyl group; butyl; amyl group; cyclopropyl; tertiary butyl amino; propyl group amino; 4-methyl isophthalic acid-piperazinyl; the 1-azelidinyl; the 4-morpholino; (4-carboxyl phenyl) amino; pivalyl amino; ((tertiary butyl amino) carbonyl) amino; trifluoromethyl; benzyloxy; 2-(2-methoxy ethoxy) oxyethyl group; 2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group and 2-(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group) oxyethyl group.
R in the above-mentioned formula 4Substituting group can be (but being not limited to) 1; 3-benzo dioxane penta-5-base; the 1-naphthyl; thienyl; the 4-isobutoxy phenyl; 2; the 6-3,5-dimethylphenyl; the allyloxy phenyl; 3-bromo-4-p-methoxy-phenyl; the 4-butoxy phenyl; 1-cumarone-2-base; the 2-thienyl methyl; phenyl; methyl sulfane base; phenyl sulfane base; styroyl sulfane base; 4-bromo-2-thienyl; 3-methyl-2-thienyl; the 4-aminomethyl phenyl; 3; 5-two (methoxyl group) phenyl; 4-(methoxyl group) phenyl; the 4-fluorophenyl; 3-(methoxyl group) phenyl; 3; 4; 5-trimethoxy phenyl; 2; 3-dihydro-1-cumarone-5-base; the 3-fluorophenyl; 4-(trifluoromethyl) phenyl; 4-fluoro-3-(trifluoromethyl) phenyl; 4-(1; the 1-dimethyl ethyl) phenyl; 3; the 5-3,5-dimethylphenyl; the 4-hydroxy phenyl; 3; the 4-3,5-dimethylphenyl; 3-methyl-4-(methoxyl group) phenyl; 4-hydroxy-3-methyl phenyl; the 3-aminomethyl phenyl; 2; 3-dihydro-indenes-5-base; the 2-aminomethyl phenyl; 2; 6-two (methoxyl group) phenyl; 2; the 6-dihydroxy phenyl; the 4-chloro-phenyl-; the 3-chloro-phenyl-; 3; the 4-dichlorophenyl; 4-((trifluoromethyl) oxygen base) phenyl; the 4-ethylphenyl; 4-(oxyethyl group) phenyl; methyl; the 2-propyl group; 4; 5-dihydro-1; 3-oxazole-2-base; 3-(trifluoromethyl) phenyl; 4-(trifluoromethoxy) phenyl; 2; 3-dihydro-1; 4-benzo dioxane oneself-the 6-base; 7-methoxyl group-1; 3-benzo dioxane penta-5-base; 3-oxyethyl group-4-p-methoxy-phenyl; 3; the 4-Dimethoxyphenyl; 3; 4-diethoxy phenyl; the 3-ethoxyl phenenyl; 3-methoxyl group-4-aminomethyl phenyl; 3; 5-dimethoxy-4 '-aminomethyl phenyl; 3-propoxy-phenyl; the 3-butoxy phenyl; 3-(2-methoxy ethoxy) phenyl; 3; 4-dipropoxy phenyl; 3-(difluoro-methoxy) phenyl; the 2-naphthyl; the 3-isopropyl phenyl; 1-Methyl-1H-indole-5-base; 2; 3-dihydro-1-cumarone-5-base; 1; 3-diethyl-2-oxo-2; 3-diamino-1H-benzoglyoxaline-5-base; 3-(trifluoromethoxy) phenyl; 1-Methyl-1H-indole-6-base; 3-(ring propoxy-) phenyl; 3-(cyclo propyl methoxy) phenyl; 3-(difluoro-methoxy) phenyl; 3-(1; 1; 2,2-tetrafluoro oxyethyl group) phenyl; 1-ethyl-1H-indoles-5-base; 3-(diethylamino) phenyl; 6-methoxyl group-2-naphthyl; the 3-[(methyl sulphonyl) amino] phenyl; 3-[methyl (methyl sulphonyl) amino] phenyl; 3-[ethyl (methyl sulphonyl) amino] phenyl; 1H-indoles-5-base; 3-fluoro-4-p-methoxy-phenyl and 3-(difluoromethyl) phenyl.
Two R independently 1, R 2, R 3Or R 5Group can be connected to form ring together.
R 4And R 11Can be connected to form ring, for example 1-pyrrolidyl, 1-piperidino-(1-position only), 4-methyl isophthalic acid-piperazinyl, 4-ethanoyl-1-piperazinyl and 4-morpholino etc.
R 9And R 10Can be connected to form ring, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.
The abbreviation of using in subsequent reaction flow process and embodiment has: BOC: tert-butoxycarbonyl; DMF: dimethyl formamide; THF: tetrahydrofuran (THF); DME: glycol dimethyl ether; DMSO: dimethyl sulfoxide (DMSO); The NMM:N-methylmorpholine; DIPEA: diisopropyl ethyl amine; CDI:1,1 '-carbonyl dimidazoles; The TBS:TRIS-buffer saline; Ms: methylsulfonyl; TMEDA:N, N, N ', N '-Tetramethyl Ethylene Diamine; DCE:1, the 2-ethylene dichloride; The NCS:N-chlorosuccinimide; The NBS:N-bromo-succinimide; DPPA: diphenyl phosphoryl azide; DEAD: diethylazodicarboxylate; M-CPBA:3-chlorine peroxybenzoic acid; TFAA: trifluoroacetic anhydride; DCM: methylene dichloride; LHMDS: two (trimethyl silyl) lithium amide; Cbz: benzyloxycarbonyl.Amino acid abbreviations is as follows: the C:L-halfcystine; The D:L-aspartic acid; E:L-L-glutamic acid; G: glycine; The H:L-Histidine; The I:L-Isoleucine; The L:L-leucine; The N:L-l-asparagine; The P:L-proline(Pro); The Q:L-glutamine; The S:L-Serine; The T:L-Threonine; The V:L-Xie Ansuan; The W:L-tryptophane.
Embodiment
Following flow process shows the method embodiment of the compound that can be used for synthetic said structure formula.Following examples are described representative compounds of the present invention in detail.
The method that following flow process 1 explanation embodiment 1 introduces.
Figure A200910009861D00771
Flow process 1
The flow process 2 that embodiment 2 methods are described is as follows.
Figure A200910009861D00781
Flow process 2
The flow process 3 that embodiment 3 methods are described is as follows.
Figure A200910009861D00791
Flow process 3
The flow process 4 that embodiment 4 methods are described is as follows.
Figure A200910009861D00792
Flow process 4
The flow process 5 that embodiment 5 methods are described is as follows.
Figure A200910009861D00801
Flow process 5
The flow process 6 that embodiment 6 methods are described is as follows.
Figure A200910009861D00802
Flow process 6
The flow process 7 that embodiment 7 methods are described is as follows.
Figure A200910009861D00803
Flow process 7
The flow process 8 that embodiment 8 methods are described is as follows.
Figure A200910009861D00811
Flow process 8
The flow process 9 that embodiment 9 methods are described is as follows.
Figure A200910009861D00812
Flow process 9
The flow process 10 that embodiment 10 methods are described is as follows.
Figure A200910009861D00821
Flow process 10
The flow process 11 that embodiment 11 methods are described is as follows.
Figure A200910009861D00822
Flow process 11
The flow process 12 that embodiment 12 methods are described is as follows.
Figure A200910009861D00831
Flow process 12
The flow process 13 that embodiment 13 methods are described is as follows.
Figure A200910009861D00832
Flow process 13
The flow process 14 that embodiment 14 methods are described is as follows.
Figure A200910009861D00841
Flow process 14
The flow process 15 that embodiment 15 methods are described is as follows.
Figure A200910009861D00851
Flow process 15
The flow process 16 that embodiment 16 methods are described is as follows.
Figure A200910009861D00852
Flow process 16
The flow process 17 that embodiment 17 methods are described is as follows.
Figure A200910009861D00861
Flow process 17
The flow process 18 that embodiment 18 methods are described is as follows.
Flow process 18
The flow process 19 that embodiment 19 methods are described is as follows.
Figure A200910009861D00871
Flow process 19
The flow process 20 that embodiment 20 methods are described is as follows.
Flow process 20
The flow process 21 that embodiment 21 methods are described is as follows.
Figure A200910009861D00873
Flow process 21
The flow process 22 that embodiment 22 methods are described is as follows.
Flow process 22
The flow process 23 that embodiment 23 methods are described is as follows.
Figure A200910009861D00882
Flow process 23
The flow process 24 that embodiment 24 methods are described is as follows.
Figure A200910009861D00883
Flow process 24
The flow process 25 that embodiment 25 methods are described is as follows.
Figure A200910009861D00891
Flow process 25
The flow process 26 that embodiment 26 is described is as follows.
Flow process 26
The flow process 27 that embodiment 27 is described is as follows.
Figure A200910009861D00901
Flow process 27
The flow process 28 that embodiment 28 is described is as follows.
Flow process 28
The flow process 29 that embodiment 29 is described is as follows.
Figure A200910009861D00903
Flow process 29
The flow process 30 that embodiment 30 is described is as follows.
Figure A200910009861D00911
Flow process 30
The flow process 31 that embodiment 31 is described is as follows.
Figure A200910009861D00912
Flow process 31
Figure A200910009861D00913
Flow process 32
Figure A200910009861D00921
Flow process 33
Figure A200910009861D00931
Flow process 34
Figure A200910009861D00932
Flow process 35
Figure A200910009861D00941
Flow process 36
Figure A200910009861D00942
Flow process 37
Flow process 38
Figure A200910009861D00952
Flow process 39
Flow process 40
Figure A200910009861D00961
Flow process 41
Figure A200910009861D00962
Flow process 42
Can use the The compounds of this invention of the pharmacy acceptable salt form that produces with mineral acid or organic acid.Term " pharmacy acceptable salt " is meant such salt: be applicable to contact tissue and lower animal tissue and do not have over-drastic toxicity, pungency, transformation reactions etc. in rational medical determination range, and have rational interests/risk ratio.Pharmacy acceptable salt is well known in the art.For example S.M.Berge etc. exists J.Pharmaceutical Sciences, 1977, describe pharmacy acceptable salt among the 66:1 etc. in detail.Described salt can original position make or independently make free alkali functional group and suitable organic acid reaction to make in the last separation of The compounds of this invention and purifying.Typical acid salt includes but not limited to acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectinic acid salt (pectinate), persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecylate.In addition, the group that contains basic nitrogen can be quaternized with following material, for example low alkyl group halogen such as methyl, ethyl, propyl group and Butyryl Chloride, bromine and iodine; Dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl vitriol; Long-chain halogenide such as decyl, dodecyl, tetradecyl and stearyl chloride, bromine and iodine; Aralkyl halogen such as bromotoluene and phenethyl bromide etc.Therefore obtain water-soluble or oil soluble or dispersed product.The example that can be used in the acid that forms pharmaceutically-acceptable acid addition comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid and organic acid such as oxalic acid, toxilic acid, succsinic acid and Citric Acid.
By make the part that contains carboxylic acid and suitable alkali for example pharmaceutically acceptable metallic cation oxyhydroxide, carbonate or supercarbonate reaction or with ammonia or organic primary amine, secondary amine or reactive tertiary amine, in the end separate and the purifying The compounds of this invention during, can the in-situ preparing base addition salt.Pharmacy acceptable salt is including, but not limited to the positively charged ion of basic metal or alkaline-earth metal, for example lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the typical organic amine that is used to form base addition salt comprises quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
The formulation that is used for the topical administration The compounds of this invention comprises pulvis, sprays, paste and inhalation.Described active compound is mixed with the sanitas of pharmaceutically acceptable carrier and any needs, the propellent that buffer reagent maybe may need.Ophthalmic preparation, Eye ointments, pulvis and solution are also considered within the scope of the present invention.
Can change activeconstituents actual dose level in the medicinal compositions of the present invention to obtain the active compound of effective dose, realize the therapeutic action that needs of concrete patient, composition and mode of administration.Selected dosage level depend on particular compound activity, route of administration, sanatory severity and the patient's that treats the state of an illness and previous history.Yet this area routine operation is that the initial dose of described compound is lower than the dosage that needs of realizing the therapeutic interest effect, and increases dosage then gradually up to the therapeutic action that needing to realize.
When being used for above or other when treatment, can use the The compounds of this invention of a kind of following form of treatment significant quantity: respective pure form or (existing under the situation of such form) pharmacy acceptable salt, ester or prodrug form.Perhaps described compound can comprise the medicinal compositions administration of purpose compound and one or more pharmaceutically acceptable vehicle." the treatment significant quantity " of term The compounds of this invention means with suitable interests/risk of being applicable to any therapeutic treatment q.s than sanatory described compound.Yet people know that the total daily dosage of The compounds of this invention and composition is determined through rational medical judgment by the attending doctor.Any concrete patient's concrete treatment effective dose level depends on various factors, comprises the similar factor that the medicine of excretion rate, treatment time length, combined utilization of concrete composition, patient's age, body weight, general health situation, sex and diet, administration time, route of administration and employed particular compound of particular compound activity, use of severity, the use of the illness of being treated and illness or the medicine that uses simultaneously with used particular compound and medical field are known.For example the initial dose of described compound well known in the art is lower than the dosage that needs of realizing the therapeutic interest effect, and increases dosage then gradually up to the therapeutic action that needing to realize.
Administration of human or the total per daily dose of zootic The compounds of this invention can be about 0.0001 to about 1000mg/kg/ day.For oral administration, more preferably dosage can be about 0.001 to about 5mg/kg/ day.If desired, effectively per daily dose can be divided into a plurality of dosed administrations; Therefore unit-dose composition can comprise the divided dose of effective per daily dose or its formation per daily dose.
The present invention also provides the medicinal compositions that comprises the The compounds of this invention of preparing with one or more pharmaceutically acceptable non-toxic carriers.Described medicinal compositions can be formulated as solid or liquid form especially, is used for injection of oral administration or parenteral or rectal administration.
Medicinal compositions of the present invention can by in oral, rectum, parenteral, the brain pond, intravaginal, intraperitoneal, part (as with pulvis, paste or drops), oral cavity cheek film or mouth spray or nose spraying administration of human and other Mammalss.Term used herein " parenteral " refer to comprise vein, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the mode of administration of joint cavity injection and infusion.
On the other hand, the invention provides the medicinal compositions that comprises the thinner that can tolerate on composition of the present invention and the physiology.The present invention includes one or more above-claimed cpds can tolerance on one or more nontoxic physiology or acceptable diluent, carrier, adjuvant or solvent (this paper is generically and collectively referred to as thinner) be mixed with the composition of solid and liquid form, be used for parenteral injection, intranasal administration, be used for oral administration or be used for rectal administration or topical etc.
Described composition also can be by crown inner tubular structure fixed mould (intracoronary stent) (tubular unit of being made up of the fine rule net) or by biological degradation polyalcohol, through the conduit topical administration to target site.Described compound also can with aglucon for example antibodies be used for target administration.
The composition that is applicable to parenteral injection can comprise acceptable aseptic aqueous solution or non-aqueous solution agent, dispersion agent, suspensoid or emulsion on the physiology and be used to copy as the sterile powder of aseptic injectable solution or dispersion liquid.The suitable water-based or the example of non-aqueous carrier, thinner, solvent or solvent comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (for example sweet oil), injection organic ester for example ethyl oleate and their suitable mixture.
These compositions also can comprise adjuvant, for example sanitas, wetting agent, emulsifying agent and dispersion agent.For example following various antiseptic-germicides and anti-mycotic agent can guarantee to prevent action of microorganisms: for example parabens, chlorobutanol, phenol, Sorbic Acid etc.Also may need to comprise isotonic agent for example sugar, sodium-chlor etc.Use to postpone for example aluminum monostearate and the gelatin absorption that can postpone to inject pharmaceutical dosage form of absorption agent.
Except that described active compound, suspensoid can comprise suspension agent, for example ethoxylation isooctadecanol, polyoxyethylene sorbitan ester and polyoxyethylene sorbitol acid anhydride ester, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth or these materials partially.
In some cases, for the effect of prolong drug, need slow down the drug absorption of subcutaneous injection or intramuscularly.This can realize by the crystallization of use poorly water-soluble or the liquid suspension of amorphous substance.The uptake rate of medicine depends on its dissolution rate so, and dissolution rate may depend on crystallographic dimension and crystal type.Perhaps, described medicine dissolution or be suspended in the oily solvent, postpone the absorption that parenteral gives pharmaceutical dosage form.
By making described medicine for example form the microencapsulation skeleton in polylactide-poly-glycollide at biological degradation polyalcohol, the reservoir devices formulation is injected in preparation.According to the ratio of medicine and polymkeric substance and the character of employed concrete polymkeric substance, may command drug release rate.The example of other biological degradation polyalcohol comprises poly-(ortho ester) and poly-(acid anhydrides).Also pharmaceutical pack can be embedded in the liposome or micro emulsion that mates with body tissue preparation reservoir devices injection formulations.
For example by the membrane filtration of detention bacterium or in facing, mix sterilant, can make injection formulations aseptic with preceding available sterilized water or other aseptic injection medium dissolves or dispersive aseptic solid composite.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, pulvis and granule.In such solid dosage, active compound can with at least a pharmaceutically acceptable inert excipient or carrier for example Sodium Citrate or Lin Suanergai and/or following any material mix: a) weighting agent or extender, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting agent, for example glycerine; D) disintegrating agent, for example agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some silicate and yellow soda ash; E) liquid retarding agent, for example paraffin; F) absorption enhancer, for example quaternary ammonium compound; G) wetting agent, for example Stearinsaeure n-Hexadecane alcohol ester and glyceryl monostearate; H) absorption agent, for example kaolin and POLARGEL NF, and i) lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.If be capsule, tablet and pill, described formulation also can comprise buffer reagent.
The vehicle of utilization such as lactose or toffee and high molecular weight polyethylene glycol etc., the solids composition of similar type also can be used as the weighting agent of soft-filled gelatin capsule and hard-filled gelatin capsule.
Available dressing and housing for example other Drug coating of knowing of enteric coating and medicine formulation art prepare tablet, dragee, capsule, pill and granule solid dosage.They can be chosen wantonly and comprise opalizer, and can be such composition: they optional with delayed mode only or preferably discharge described activeconstituents at certain partial enteral.The example of spendable embedding composition comprises polymer material and wax.
Described active compound also can be the microencapsulation form, if suitable, can contain one or more above-mentioned vehicle.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspensoid, syrup and elixir.Except that described active compound, liquid dosage form also can close the conventional inert diluent that uses in capable territory, for example water or other solvent, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1, the fatty acid ester of 3-butyleneglycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl carbinol, polyoxyethylene glycol and sorbitan, and their mixture.
Except that inert diluent, oral compositions also can comprise adjuvant, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, seasonings and flavouring agent.
The composition that is used for rectum or vagina administration is preferably suppository, for example theobroma oil, polyoxyethylene glycol or suppository wax are mixed with described suppository can to make The compounds of this invention and the non-irritating excipient that suits or carrier, described vehicle or carrier at room temperature are solid, but under body temperature liquid, therefore fusion and discharge described active compound in rectum or vaginal canal.
The compounds of this invention also can the liposome form administration.Known in the art, generally prepare liposome with phosphatide or other lipid matter.By being dispersed in list in the water medium-or brilliant liposome that forms of many-layer aqua liquid.Can use on any nontoxic, the physiology that can form liposome and can accept and metabolizable lipid.Except that The compounds of this invention, the present composition of liposome form can comprise stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and the phosphatidylcholine (Yelkin TTS) that uses separately or use together.
The method for preparing liposome is known in the art.Edit referring to for example Prescott, Method in Cell Biology, XIV volume, Academic Press, New York, N.Y. (1976), the 33rd page and following document etc.
Term used herein " pharmaceutically acceptable prodrug " is the prodrug of The compounds of this invention, it is applicable to contact tissue and lower animal tissue and does not have excessive toxicity, pungency, allergic effect reaction etc. in rational medical judgment scope, has corresponding rational interests/risk ratio, and be effective to its intended purpose, and be the zwitterionic form of (under possible situation) The compounds of this invention.For example, by hydrolysis in blood, prodrug of the present invention can be converted into the parent compound of following formula in vivo rapidly.At T.Higuchi and V.Stella, With Make the prodrug of novel drug delivery system, edit in the 14th volume of american chemical association series symposium (A.C.S.Symposium Series) and at Edward B.Roche, In the medicinal design Bioreversible carrier (Bioreversible Carriers in Drug Design), its comprehensive argumentation is arranged among the AmericanPharmaceutical Association and Pergamon Press (1987), described document is attached to herein by reference.
The The compounds of this invention that forms by the different compounds of conversion in the body when giving Mammals is included in the scope of the present invention.
The compounds of this invention can be used as the steric isomer that wherein has asymmetric or chiral centre and exists.According to the substituting group configuration around the chiral carbon atom, these steric isomers are " R " or " S " configuration.The present invention has designed various steric isomers and their mixture.Steric isomer comprises the mixture of enantiomorph and diastereomer and enantiomorph or diastereomer.The available available from the market raw material that contains asymmetric or chiral centre synthesizes or by the preparation racemic mixture, then by resolving racemic mixtures well known to those skilled in the art, prepares the various steric isomers of The compounds of this invention.These method for splitting have for instance: (1) is attached on the chirality assistant agent mixture of enantiomers, separate the non-enantiomer mixture that generates by recrystallization or chromatography, discharge optically pure product or (2) direct optically active enantiomorph mixture that separates on the chirality chromatography column from assistant agent then.
The compounds of this invention can the non-solvent form and is comprised hydrate forms such as the solvation form of semihydrate exists.In general, pharmaceutically acceptable solvent for example the solvation form of water and ethanol etc. right and wrong solvation form is equal to for the object of the invention.
On the other hand, the present invention has designed inhibition α 4β 1Integrin and VCAM-1 bonded method.The inventive method can be used in external or body.According to the inventive method, in the presence of the The compounds of this invention of effective inhibitory amount, make express alpha 4β 1The cellular exposure of integrin is in the cell of expressing VCAM-1.
Express alpha 4β 1The cell of integrin can be natural white corpuscle, mastocyte or in the natural express alpha of cell surface 4β 1Other cell type or with comprising coding for alpha 4β 1The expression vector cells transfected of the polynucleotide of integrin (for example genomic dna or cDNA).In an especially preferred embodiment, α 4β 1Integrin is present in for example surface of monocyte, lymphocyte or granulocyte (for example eosinophilic granulocyte or basophilic granulocyte) of white corpuscle.
The cell of expressing VCAM-1 can be n cell (for example endotheliocyte) or with the expression vector cells transfected of the polynucleotide that comprise the VCAM-1 that encodes.The method that is used to produce the transfectional cell of expressing VCAM-1 is a method well known in the art.
When VCAM-1 is present in cell surface, preferably pass through inflammatory cytokine for example tumor necrosis factor-alpha, interleukin 4 and interleukin-1 ' beta ' abduction delivering VCAM-1.
Work as express alpha 4β 1The cell of integrin and VCAM-1 is in Living organism the time, gives described Living organism with the The compounds of this invention of significant quantity.Described compound is preferably medicinal compositions of the present invention.The inventive method is specially adapted to treatment and migrates to the damaged tissue diseases associated uncontrollably with white corpuscle.Such disease is including, but not limited to asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus erythematosus, inflammatory bowel, graft-rejection, contact hypersensitivity, type i diabetes, leukemia and the cancer of the brain.Preferably by in interior, subcutaneous, the nose of blood vessel, through skin or oral delivery realization administration.
The present invention also provides selectivity to suppress α 4β 1Under existing, the The compounds of this invention that the method for integrin and protein bound, this method are included in effective inhibitory amount make integrin be exposed to described protein.In a preferred embodiment, α 4β 1Integrin is in express alpha 4β 1The n cell of integrin or transformant surface expression.
α 4β 1Integrin bonded protein can be expressed in cell surface or be the extracellular matrix integral part.Particularly preferred protein is fibronectin or Unidasa.
Describe The compounds of this invention hereinafter among the embodiment in detail and suppress the bonded ability.These embodiment are in order to describing the preferred embodiments of the invention and practicality, rather than limit the present invention with it, unless explanation is arranged in accompanying Claim in addition.
Embodiment 1
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (10) synthetic
Step 1:(20.8g 135mmol) is dissolved in the methyl alcohol (270mL), adds palladium on carbon (with 10% palladium dry weight basis, Degussa E101 NE/W type ,～50% water-content, 5.75g, 2.7mmol Pd) with compound 1.Replace atmosphere (between vacuum and balloon hydrogen, switching 5 times) with hydrogen, stir the mixture and spend the night, filter then.Vacuum concentrated filtrate is used the 1:1 hexane: ethyl acetate mixture dissolving resistates, water and saturated NaHCO 3, saturated NaHCO 3Wash with brinish 4:1 mixture.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the compound 2 (12.43g, 74%) into white solid.This material need not purifying and can use.
Step 2:(2.64g 21.3mmol) is dissolved in the methylene dichloride (50mL) and is cooled to 0 ℃ with compound 2.(3.6mL, 25.6mmol) (2.90mL 23.4mmol) handles cold solution continuously with pivalyl ammonia with triethylamine.At room temperature stirred solution is 6 hours, refluxes then and spends the night.Mixture is distributed between the methylene dichloride and the NaOH aqueous solution (2N).With salt water washing organic layer, through MgSO 4Dry also filtration, concentrated filtrate obtains compound 3 (3.33g, 75%).
Step 3:Under dry nitrogen atmosphere, with compound 3 (0.50g 2.4mmol) is dissolved in anhydrous THF, (9.6mL) and TMEDA (1.1mL, 7.2mmol) in.The solution that generates is cooled between-20 ℃ and-10 ℃, drips n-Butyl Lithium (the hexane solution 2.25mL of 1.6M) and tert-butyl lithium (pentane solution of 1.7M, 2.1mL) processing continuously with syringe.After 30 minutes, make bathe temperature go back up to-5 to 0 ℃ and by syringe (0.77mL 9.6mmol) handles with iodoethane.0 ℃ of following stirred solution 2 hours, at room temperature stir then and spend the night.With the methyl alcohol chilled mixture and be concentrated into dried.By filtered through silica gel purifying resistates, use the 3:1 hexane: eluent ethyl acetate, recrystallization obtains compound 4 (0.32g, 56%) from hexane then.
Step 4:(0.32g 1.3mmol) is dissolved in the glacial acetic acid (4.5mL), and (0.65g 3.9mmol) handles with potassiumiodide with compound 4.The mixture that heating generates in being adjusted in 115 ℃ oil bath 1.0 hours.Cooling mixture, dilute with water also uses 2N NaOH and 2N HCl is adjusted to pH6.With chloroform extraction mixture (4 times).With the extracting solution of sodium thiosulfate solution washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains the compound 5 (0.25g, 86%) into white solid.This material need not to be further purified and can use.
Step 5:Under 0 ℃, (0.25g 1.1mmol) is dissolved among the THF (45mL), and (toluene solution of 0.5M 2.7mL) drips processing with two (trimethyl silyl) acid amides potassium solutions with compound 5.(0.16mL 1.2mmol) handles the solution that generates, and makes solution be warmed to ambient temperature overnight with 2-chloro bromotoluene.Mixture is distributed between 2N HCl and the ethyl acetate.With salt water washing organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate is through chromatography (SiO 2, gradient elution 4:1 is converted to the 2:1 hexane: ethyl acetate) purifying resistates obtains compound 6 (0.16g, 41%).
Step 6:(0.16g 0.46mmol) is suspended in 1:1 water: among the dense HCl (4.6mL) with compound 6.Made suspension returning 4 hours, compound dissolution during the backflow.Cooling mixture, dilute with water is used ether extraction.After with excessive saturated sodium bicarbonate solution water layer being adjusted to alkalescence, use the ethyl acetate extraction mixture.United extraction liquid is used the salt water washing, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains compound 7 (0.081g, 67%).
Step 7:With compound 7 (0.080g 0.30mmol) is dissolved in 1,2-ethylene dichloride (1.2mL) and DIPEA (0.115mL, 0.66mmol) in and be cooled to 0 ℃.With phosgene solution (toluene solution of 1.93M, 0.170mL, 0.33mmol) the cold solution of fast processing.After 30 minutes, by syringe add fast compound 8 (0.068g, 0.33mmol) 1,2-dichloroethane solution (0.5mL).The mixture heating up to 55 that generates ℃ 1 hour.Mixture is distributed between methylene dichloride and the 2N HCl.Use saturated NaHCO 3The aqueous solution and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrated filtrate obtains compound 9 (0.110g, 74%).
Step 8:(0.11g 0.22mmol) is dissolved in 2:1 THF:H with compound 9 2Handle among the O (0.88mL) and with 2N NaOH solution (0.33mL).Drip methyl alcohol, up to obtaining homogeneous solution.Stirred the mixture 20 minutes, dilute with water washs with ether then.Behind 2N HCl acidifying water layer, use ethyl acetate extraction.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration.Concentrated filtrate obtains (3S)-3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (10,0.095g, 92%).
Embodiment 2
(3S)-and 3-{[({6-methyl-2-oxo-1-(phenmethyl)-4-[(phenmethyl) the oxygen base]-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (15) synthetic
Step 1:To compound 11 (1.0g, 5.9mmol) and K 2CO 3(2.40g, 17.6mmol) add in the acetone suspension (50mL) bromotoluene (2.31g, 13.5mmol).After backflow is spent the night, the cooling reactant, mixture is distributed in ethyl acetate and saturated NaHCO 3Between.With rare HCl and salt water washing organic layer, through MgSO 4Dry after-filtration, concentrated filtrate obtains compound 12 (1.60g, 80%).
Step 2:With compound 12 (0.30g, 0.86mmol), zinc powder (0.30g, 4.6mmol) and saturated NH 4The Cl aqueous solution (0.30mL) is mixed among the MeOH (18mL).This mixture was stirred 1 hour, add then other zinc powder (0.30g, 4.6mmol).The heterogeneous mixture backflow that generates is spent the night.After filtering the mixture and concentrating under reduced pressure filtrate of heat, resistates is dissolved in the ethyl acetate, uses saturated NaHCO 3The aqueous solution and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate obtains compound 13 (0.18g, 66%).
Step 3:With compound 13 (0.30g, 0.94mmol.) and DIPEA (0.40mL 2.3mmol.) is dissolved in CH 2Cl 2In, mixture is cooled to 0 ℃.In solution, drip the toluene solution of phosgene 1.9M, 0.55mL, 1.0mmol).0 ℃ of following stirred reaction mixture 15 minutes, add compound 8 (0.19g, CH 0.94mmol) then 2Cl 2Solution (2mL).At room temperature the solution stirring that generates is spent the night, be poured into then in the ethyl acetate, use saturated NaHCO 3The aqueous solution, 1N HCl and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate.Through flash chromatography on silica gel method purifying resistates, increase to the hexane of 1:2 with 1:1: eluent ethyl acetate obtains compound 14 (0.33g, 64%).
Step 4:(0.33g, 0.6mmol) solution in THF (6mL) is handled with 2N NaOH (2mL) with compound 14.Add MeOH, up to obtaining uniform solution.At room temperature stirred reaction mixture is 30 minutes, and it is poured into H 2Among the O (50mL).Wash water layer (twice) with ether, use 1N HCl acidifying then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (3S)-3-{[({6-methyl-2-oxo-1-(the phenmethyl)-4-[(phenmethyl into pale solid) the oxygen base]-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (15,0.26g, 90%).Fusing point: 124-126 ℃.
Embodiment 3
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (22) synthetic
Step 1:Under 0 ℃, to compound 11 (10.00g, add in anhydrous DMF solution 58.8mmol) (120mL) NaH (60% mineral oil dispersion liquid, 5.40g, 135mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (12.3g, 76.4mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2The O washed twice.The acidifying water layer also filters the precipitation that generates, and obtains compound 16 (14.7g, 85%).
Step 2:Under dry nitrogen atmosphere, compound 16 will be housed, and (8.00g, flask 28.6mmol) adds POCl with diaphragm of rubber and balloon sealing by syringe in room temperature 3(30.0ml, 322mmol).Remove the nitrogen line of pipes, spend the night, be poured into ice (300ml) then and go up and stirred 30 minutes at 70 ℃ of following stirred reaction mixtures.Extract the mixture that generates with methylene dichloride (300ml), through MgSO 4Anhydrous organic phase after-filtration.Concentrating under reduced pressure filtrate obtains the compound 17 (7.3g, 86%) into dark brown solid.
Step 3:At room temperature, to condenser is equipped with and be equipped with add in the 250ml flask of rubber separator of balloon compound 17 (2.1g, 7.05mmol), methyl alcohol (55ml) and ammonium hydroxide aqueous solution (28-30%, 70.0ml, solution 1.14mol).Reaction mixture is heated to 65 ℃ of reactions 60 hours, only open balloon.Filtering mixt, concentrating under reduced pressure filtrate obtain the compound 18 (1.5g, 76%) into brown solid.
Step 4:At room temperature, to compound 18 (0.3g, add continuously in methanol solution 1.02mmol) (50ml) saturated aqueous ammonium chloride (2ml) and zinc powder (0.30g, 4.6mmol).After at room temperature stirring 30 minutes, (0.30g 4.6mmol) and reaction mixture refluxed spends the night to add other zinc powder.With the reaction mixture heat filtering, concentrating under reduced pressure filtrate.Resistates is distributed between ethyl acetate and the 1N NaOH.Filtering solution is used the ethyl acetate extraction water.Through MgSO 4The dry organic phase that merges is also filtered.Concentrating under reduced pressure filtrate obtains the compound 19 (0.21g, 78%) into brown solid.
Step 5:With compound 19 (0.10g, 0.38mmol), (0.040mL, 0.38mmol) (0.14g, anhydrous DMF solution 0.38mmol) (5mL) are heated to 50 ℃ and spend the night NMM with compound 20.Cooling mixture is also used ethyl acetate (60mL) dilution.With 0.5N NaOH (3x30mL) and salt water washing organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate through flash chromatography on silica gel method purifying resistates, increases to the CHCl of 17:3 with 9:1 3: the MeOH wash-out obtains the compound 21 (0.120g, 65%) into yellow foam thing.
Step 6:(0.120g, THF solution (6mL) 0.25mmol) is handled with 2NNaOH (2mL) with compound 21.Add methyl alcohol, up to obtaining uniform solution.At room temperature stirred reaction mixture was poured into H after 30 minutes 2On the O (50mL).Wash water layer (twice) with ether, use 1N HCl acidifying then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (the 3S)-3-{[({4-amino-1-[(2-chlorophenyl into pale solid) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (22,0.100g, 89%).Fusing point: 145-147 ℃.
Embodiment 4
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(methoxyl group)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Compound 23 under 0 ℃ (adding NaH among the 10.00g, anhydrous DMF solution 64.0mmol) (130mL) (60% mineral oil dispersion liquid, 5.90g, 147mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (13.4g, 83.3mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2O washs (twice).The acidifying water layer filters the precipitation that generates and obtains compound 24 (13.5g, 75%).
Step 2:With compound 24 (1.0g, 3.6mmol), K 2CO 3(0.85g, 6.2mmol) and MeI (1.18g, 8.3mmol) acetone suspension (20mL) reflux and spend the night.Use the ethyl acetate diluted reaction mixture, use saturated NaHCO 3The aqueous solution, 1N HCl and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate obtains compound 25 (0.74g, 70%).
Method according to embodiment 3 describes prepares (3S)-3-[({[1-[(2-chlorophenyls with compound 25) methyl]-4-(methoxyl group)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value: (M+H) +=469.93; Measured value: (M+H) +=470.01.
Embodiment 5
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Under dry nitrogen atmosphere, with compound 3 (0.65g, 3.1mmol) be dissolved in anhydrous THF (12.4mL) and TMEDA (0.90mL, 6mmol) in.The solution that generates is cooled between-15 and-10 ℃ and by syringe drip n-Butyl Lithium (hexane solution of 1.6M, 7.75mL, 12.4mmol).1.5 after hour, in cold solution, add N-fluorobenzene sulfimide (1.07g, THF solution (5mL) 3.4mmol) rapidly by syringe.0 ℃ of following stirred solution 1 hour, at room temperature stirred then 3 hours.The water chilled mixture is also used chloroform extraction (4 times).With organic extracting solution of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate is through purification by chromatography resistates (SiO 2, the plunger gel uses 4:1 to be converted to the 3:1 hexane: ethyl acetate), to obtain compound 26 (0.177g, 25%).
According to the method for describing among the embodiment 1, with compound 26 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value: (M+H) -=458.12; Measured value: (M+H) +=458.01.
Embodiment 6
(3S)-and 4-chloro-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:With compound 3 (0.65g, 3.1mmol) be dissolved in THF (21mL) and TMEDA (1.20mL, 7.75mmol) in, make it be cooled to-15 ℃.With n-Butyl Lithium (hexane solution of 1.6M, 4.8mL, 7.8mmol) treatment soln.Mixture was kept 1 hour between-20 and-10 ℃, be cooled to-78 ℃ then.(0.45g, 3.4mmol), device is under the positive nitrogen gas stream simultaneously to add the solid N-chlorosuccinimide.Making reactant be warmed to room temperature gradually stirs then and spends the night.After the water chilled mixture, with chloroform extraction (4 times).Merge organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate, the recrystallization resistates obtains compound 27 (0.25g, 33%) from hexane.
According to the method for describing among the embodiment 1, with compound 27 preparation (3S)-4-chloro-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.
Embodiment 7
(3S)-and 4-bromo-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Under dry nitrogen atmosphere, with compound 3 (2.00g, 9.6mmol) be dissolved in anhydrous THF (32mL) and TMEDA (2.20mL, 14.4mmol) in.The solution that generates is cooled between-20 and-10 ℃, by syringe drip n-Butyl Lithium (hexane solution of 1.60M, 18.0mL, 28.8mmol).After adding, solution is cooled to-78 ℃, by the syringe dripping bromine (0.49mL, 10.5mmol).Make solution slowly be warmed to ambient temperature overnight, then water quenching and use chloroform extraction.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.The recrystallization resistates obtains the compound 28 (1.32g, 48%) into brown white solid from hexane.
According to the method for describing among the embodiment 1, with compound 28 preparation (3S)-4-bromo-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.
Embodiment 8
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (32) synthetic
Step 1:Compound 24 under room temperature (1.5g, and continuous adding saturated ammonium chloride (1.5mL) and zinc powder in methanol solution 5.3mmol) (50ml) (1.5g, 23mmol).After at room temperature stirring 30 minutes, (1.5g 23mmol), spends the night reaction mixture refluxed to add other zinc powder.The filtered while hot reaction mixture, concentrating under reduced pressure filtrate.Adding HCl (1N) in the resistates that obtains is about 4 up to pH, filters and collects the precipitation that generates, and obtains the compound 29 (0.80g, 57%) into brown solid.
Step 2:With compound 29 (0.26g, 1.0mmol) and CDI (025g, DMF solution (10ml) 1.6mmol) is heated to 70 ℃ and spends the night.After being cooled to room temperature, with ethyl acetate diluted mixture thing, with 1N HCl (3 times) and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the compound 30 (0.14g, 50%) into brown solid.
Step 3:(0.1g, 0.36mmol) (0.082g, anhydrous DMF solution 0.40mmol) (5ml) are heated to 70 ℃ and spend the night with compound 8 with compound 30.Cooling mixture is with the ethyl acetate dilution, with 1N HCl (3 times) and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Through flash chromatography method (SiO 2) the purifying resistates, use 9:1CHCl 3: the MeOH wash-out obtains compound 31 (0.17g, 97%).
Step 4:Handle compound 31 (0.170g, THF solution (3ml) 0.35mmol) with 2N NaOH (1ml).Add methyl alcohol up to obtaining uniform solution.At room temperature stirred reaction mixture is 30 minutes, is poured into H 2Among the O (50ml).Wash water layer (twice) with ether, use 1N HCl acidifying then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (the 3S)-3-{[({1-[(2-chlorophenyl into pale solid) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (32,0.150g, 94%).Fusing point: 113-115 ℃.
Embodiment 9
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:(method according to describing in embodiment 1 makes with compound 28, and 0.20g 0.50mmol) is dissolved in DMF (1.8ml) and the water (0.7ml), uses K with compound 33 3PO 4(0.39g, 1.86mmol) and phenyl-boron dihydroxide (0.113g 0.93mmol) handles.With the mixture deoxidation (between vacuum and nitrogen, switching 5 times) that generates, add then tetrakis triphenylphosphine palladium (O) (8.7mg, 0.050mmol).Ditto make the mixture deoxidation and 90 ℃ of following heated overnight.Cooling mixture, dilute with water is with ethyl acetate extraction (twice).With the extracting solution of salt water washing merging, through MgSO 4Dry back is by filtered through silica gel, concentrating under reduced pressure.Resistates is suspended in 1:1 water: in dense HCl (2ml) and the acetonitrile (0.5ml).Made suspension returning 1 hour, cooling is distributed in ethyl acetate and saturated NaHCO then 3Between the aqueous solution.With salt water washing ethyl acetate layer, through MgSO 4Drying is filtered concentrating under reduced pressure.Through flash chromatography method (SiO 2, the 3:1 hexane/ethyl acetate) and the purifying resistates, obtain compound 34 (0.115g, 94%).This material need not purifying and can use.
According to the method for in embodiment 1, describing, with compound 34 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid. 1H?NMR(400MHz，CD 3OD)：δ?2.25(s，3H)，2.50(m，2H)，4.89(t，J＝5.9Hz，1H)，5.34(s，2H)，6.40(d，J＝7.0Hz，1H)，7.0(d，J＝8.0Hz，2H)，7.10(d，J＝8.0Hz，2H)，7.18(m，1H)，7.28(m，2H)，7.35(m，3H)，7.43(m，1H)，7.49(m，3H)。
Embodiment 10
(3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (43) synthetic
Step 1:(2.00g 18.2mmol) is dissolved in the anhydrous methanol of 30mL with compound 35.To wherein add benzylamine (1.97g, 18.2mmol) and triethylamine (2.0g, 20.0mmol).50 ℃ of following stirred reaction mixtures 3 hours, concentrating under reduced pressure then.Resistates is distributed in H 2O and CH 2Cl 2Between.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains compound 36 (2.3g, 82%).
Step 2:To compound 37 (3.50g, add in ethanol 26.5mmol) (10mL) and pyridine (5mL) solution isovaleric aldehyde (2.8mL, 27mmol) and piperidines (1mL).Reaction mixture be heated to refluxed 3 hours after concentrating under reduced pressure.Resistates is distributed between 2N HCl (15mL) and the ethyl acetate (30mL).Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates through the silica gel chromatography purifying, is used the 2:1 hexane: eluent ethyl acetate obtains compound 38 (3.6g, 67%).
Step 3:(2.5g, 12.48mmol) (2.52g, absolute methanol solution 13.7mmol) (25mL) was heated to vigorous reflux 3 hours, cooling back concentrating under reduced pressure with compound 36 with compound 38.With resistates chromatography on silica gel, use the 2:1 hexane: eluent ethyl acetate obtains compound 39 (2.75g, 69%).
Step 4:To compound 39 (2.5g, CCl 7.9mmol) 4Add in the solution (15mL) NBS (1.4g, 8.0mmoL), K 2CO 3(11.0g, 80.0mmol) and benzoyl peroxide (50mg, 0.20mmol).Reaction mixture is heated to backflow 1 hour, is cooled to room temperature, use H 2Use CH after the O dilution 2Cl 2Extract.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With resistates chromatography on silica gel, use the 3:1 hexane: eluent ethyl acetate obtains compound 40 (0.62g, 25%).
Step 5:With 2N NaOH (5mL) and THF (3mL) handle compound 40 (0.60g, 1.9mmol).The mixture that stirring at room temperature generates 2 hours is with using ethyl acetate extraction after the 2N HCl acidifying.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains compound 41 (560mg, 98%).
Step 6:To compound 41 (0.56g, add in the dry-out benzene solution (10mL) 1.86mmol) diphenylphosphine acylazide thing (0.56g, 2.0mmol) and triethylamine (2.02g, 2.0mmol).Reaction mixture be heated to 90 ℃ 1 hour, add compound 8 (0.39g, 1.9mmol) solution in benzene (2mL) then.Under 90 ℃, reactant restir 1 hour, be cooled to room temperature, with using ethyl acetate extraction after the dilution of 10% aqueous ammonium chloride solution.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With resistates chromatography on silica gel, use the 7:3 ethyl acetate: the hexane wash-out obtains compound 42 (0.38g, 40%).
Step 7:(add 2N NaOH (8mL) among the 0.35g, THF:MeOH 1:1 mixture solution (8mL) 0.7mmol) to compound 42.At room temperature reaction stirred is 3 hours, with extracting with ethyl acetate (20mL) after 2NHCl (10mL) acidifying.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains (3S)-3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (43,250mg, 75%).MS: calculated value: (M+H) +=477.25m/z; Measured value: (M+H) +=477.17m/z.
Embodiment 11
(3S)-and 3-[({[2-methyl-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:(2.3g, 15.5mmol) (3.36g, ethanol solution 15.5mmol) (35mL) refluxed 3 hours and concentrated with compound 44 with compound 36.With resistates chromatography on silica gel, use the 1:1 ethyl acetate: the hexane wash-out obtains compound 45 (1.87g, 55% yield).
According to the method for in embodiment 10, describing, with compound 45 preparation (3S)-3-[({[2-methyl-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid. 1H?NMR(400MHz，CD 3OD)：δ?2.28(s，3H)，2.35(s，3H)，2.57(m，2H)，5.16(m，1H)，5.30(s，2H)，7.13(m，4H)，7.30(m，5H)，8.50(s，1H)。
Embodiment 12
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino }-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:To the compound under 0 ℃ 46 (make according to the method for in embodiment 3, describing, add among the 0.50g, THF solution (10mL) 1.8mmol) NaH (60% mineral oil dispersion liquid, 0.23g, 5.1mmol).Under 0 ℃, stirred the mixture 10 minutes, add then ethyl isocyanate (0.65g, 9.15mmol).At room temperature, mixture is stirred a weekend, with the 1NHCl quenching and use ethyl acetate extraction.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains compound 47 (0.60g).This material need not purifying and can use.
According to the method for in embodiment 3, describing, with compound 47 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino }-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.Fusing point: 128-130 ℃.
Embodiment 13
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Compound 48 under 0 ℃ (adding NaH among the 2.00g, anhydrous DMF solution 9.70mmol) (25mL) (60% mineral oil dispersion liquid, 0.89g, 22mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (2.03g, 12.6mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2O washs (twice).The acidifying water layer filters the precipitation that generates and obtains compound 49 (3.45g).This material need not purifying and can use.
According to the method for in embodiment 8, describing, with compound 49 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.Fusing point: 134-136 ℃.
Embodiment 14
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (56) synthetic
Step 1:In room temperature under dry nitrogen atmosphere, to compound 51 (1.67g, add continuously in the DMF suspension (33mL) 9.81mmol) the 2-chloro-benzylamine (1.30mL, 10.8mmol) and EDCI (2.35g, 12.3mmol).At room temperature the mixture that generates of vigorous stirring is 5 hours, with the ethyl acetate dilution and with 2N HCl, H 2O (three times), saturated NaHCO 3The aqueous solution and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the compound 52 (2.55g, 100%) into light yellow solid.
Step 2:(555mg, 2.17mmol) (738mg, dehydrated alcohol 6.5mmol) (4.3mL) and glacial acetic acid (0.22mL) solution are heated to reflux and spend the night with 3-dimethylamino-methacrolein with compound 52.The mixture that generates is cooled to room temperature, after the ethyl acetate dilution, with 2N HCl (twice), H 2O and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates through the silica gel chromatography purifying, is increased to the 1:1 hexane with 7:3: ethyl acetate, use the 19:19:2 hexane at last: ethyl acetate: methanol-eluted fractions obtains the compound 53 (182mg, 27%) into yellow oil.
Step 3:(add 2N NaOH (1mL) and methyl alcohol (2mL) among the 167mg, THF solution (3mL) 0.55mmol) to compound 53.The mixture that stirring generates 15 minutes is used H 2After the O dilution, use ether extraction.Behind 2N HCl acidifying water layer, use ethyl acetate extraction.Use H 2O and salt water washing ethyl acetate layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains the compound 54 (139mg, 91%) into white solid.
Step 4:In room temperature under dry nitrogen atmosphere, by syringe to compound 54 (175mg, THF 0.63mmol) (6.7mL and DIPEA (and 0.23mL, 1.34mmol) add in the suspension DPPA (0.29mL, 1.34mmol).The mixture that stirring at room temperature generates 15 minutes is heated to then and refluxed 3.5 hours.Make mixture be cooled to room temperature, add compound 8 (278mg, THF solution (6.0mL) 1.34mmol) and THF (0.7mL) washing fluid by sleeve pipe.At room temperature stir the mixture overnight that generates, after the ethyl acetate dilution, with 2N HCl (twice), saturated NaHCO 3The aqueous solution and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates is through the silica gel chromatography purifying, and with 7:3, then with 3:2, use the 1:1 hexane at last: eluent ethyl acetate obtains the compound 55 (60mg, 20%) into water white oil.
Step 5:To compound 55 (60mg, add in the THF solution (3mL) 0.12mmol) 0.192N NaOH (0.65mL, 0.12mmol) and methyl alcohol (2mL).The mixture that stirring at room temperature generates 24 hours is used H then 2The O dilution.Remove organic solvent under the decompression, with the water mixture of ether extraction generation.The water freeze-drying is obtained (3S)-3-{[({1-[(2-chlorophenyl into pale solid) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid sodium salt (56,56mg, 95%).MS:(C 24H 23ClN 3O 4) -Calculated value: 452.14m/z; Measured value: 451.99m/z.
Embodiment 15
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({[2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid (62) synthetic
Step 1:Under dry nitrogen atmosphere, by syringe to the 2-thiophen(e)alcohol (1.015g, CH 8.89mmol) that are cooled to 0 ℃ 2Cl 2(17.8ml) add continuously in the solution triethylamine (2.98ml, 21.4mmol) and methylsulfonyl chloride (0.69ml, 8.9mmol).Stirred down the mixture that generates 15 minutes at 0 ℃, add then the 2-hydroxy-3-nitropyridine (1.496g, 10.7mmol) and 4-dimethylaminopyridine (catalytic amount).Make mixture be warmed to room temperature gradually, stir then and spend the night.With ethyl acetate diluted mixture thing, use 2N HCl, H then 2O, saturated NaHCO 3The aqueous solution and salt water washing.Organic phase is through MgSO 4Dry after-filtration and concentrating under reduced pressure filtrate obtain being yellow wax shape solid 58 (395mg).This material need not purifying and can use.
Step 2:Under dry nitrogen atmosphere, (330mg adds iron powders (154mg, 2.8mmol ,-325 orders) in glacial acetic acid solution 1.40mmol) (6.6ml) to 58 in room temperature.In oil bath under the vigorous stirring, the solution that generates be heated to 60 ℃ 20 minutes.Mixture is cooled to room temperature,, filters through C salt with the ethyl acetate dilution.Use H 2O, saturated NaHCO 3With the salt solution wash filtrate.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates is by filtered through silica gel, and use the 1:1 hexane: ethyl acetate increases to the 1:3 hexane: eluent ethyl acetate obtains 59 (188mg, two steps, 12%) into green solid.
Step 3:Under dry nitrogen atmosphere, by syringe to 59 (111mg, CH 0.54mmol) that are cooled to 0 ℃ 2Cl 2(2.7ml) add continuously N in the solution, the N-diisopropylethylamine (0.23ml, 1.30mmol) photoreactive gas (0.31ml, the toluene solution of 1.9M, 0.59mmol).The mixture that stirring generates under 0 ℃ 15 minutes adds beta-amino ester 60 (167mg, CH 0.70mmol) by sleeve pipe then 2Cl 2Solution (2.7ml) and CH 2Cl 2Washing fluid (1.0ml).Make the mixture of generation be warmed to room temperature, stirred 2 hours,, use 2N HCl, H then with the ethyl acetate dilution 2O, saturated NaHCO 3With the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Through silica gel chromatography purifying resistates, use the 1:1 hexane: eluent ethyl acetate obtains being purple foamy 61 (231mg, 91%).
Step 4:At room temperature, (add NaOH (2ml, the H of 2N among the 227mg, THF solution (6ml) 0.48mmol) to ester 61 2O solution, 4mmol) and methyl alcohol (be enough to obtain settled solution, approximately 2ml).The mixture that stir to generate 15 minutes, dilute with water and use ether extraction then.With HCl (2N) acidifying water, use ethyl acetate extraction then.With salt water washing organic phase, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 62 (191mg, 90%) into white solid. 1H?NMR(400MHz，CD 3SOCD 3)δ?2.63(d，J＝7.3Hz，2H)，4.99(dt，J＝8.4，7.3Hz，1H)，5.30(s，2H)，5.98(m，2H)，6.21(dd，J＝7.5，7.0Hz，1H)，6.78(dd，J＝8.1，1.6Hz，1H)，6.85(d，J＝8.1Hz，1H)，6.88(d，J＝1.6Hz，1H)，6.97(dd，J＝5.1，3.5Hz，1H)，7.17(dd，J＝3.5，1.1Hz，1H)，7.35(dd，J＝7.0，1.8Hz，1H)，7.44(dd，J＝5.1，1.1Hz，1H)，7.67(d，J＝8.4Hz，1H)，7.94(dd，J＝7.5，1.8Hz，1H)，8.40(s，1H)。
Embodiment 16
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridyl] amino } carbonyl) amino] propionic acid (68) synthetic
Step 1:In room temperature under dry nitrogen atmosphere, by syringe to N-α-tert-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1.00g, 2.73mmol) and cesium carbonate (adding methyl iodide among the 1.33g, DMF solution (10ml) 4.1mmol) (0.22ml, 3.3mmol).The mixture that stirring at room temperature generates 18 hours with the ethyl acetate dilution, is used H then 2O, 10%Na 2S 2O 5, saturated NaHCO 3With the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the ester 64 (1.21g) into light yellow oil.This material contains DMF but need not purifying and can use.
Step 2:0 ℃ under dry nitrogen atmosphere, in the methanol solution (10ml) of 64 (the crude product material that the above method of 0.86g makes, 1.94mmol theoretical values), add palladium on carbon (300mg, 10% Pd, Degussa E101 NE/W type, wet, 50% (weight) water).With hydrogen place of nitrogen atmosphere (between the hydrogen that vacuum and balloon are supplied with alternately 5 times) and stirred the mixture under 0 ℃ 30 minutes, (177mg is in flask 1.58mmol) to 2 thiophene carboxaldehyde is housed for direct filtration then.Enriched mixture (in the water-bath at room temperature) is dissolved in the ethylene dichloride (6ml) resistates.In this solution, add sodium triacetoxy borohydride (479mg, 2.26mmol) and stirred the mixture 2 hours, with the ethyl acetate dilution saturated NaHCO in back 3(twice) and the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.By the filtered through silica gel resistates, use the 7:3 hexane: eluent ethyl acetate obtains the lactan 65 (75mg, two steps, 12%) into water white oil.
Step 3:In room temperature under dry nitrogen atmosphere, by syringe to Rubber Diaphragm Seal be equipped with 65 (89mg, add in flask 0.29mmol) HCl (7.2ml, the dioxane solution of 4.0M, 28.8mmol).Remove the nitrogen pin and stir mixture overnight in the sealed flask.Use CH 2Cl 2The diluted mixture thing is used saturated NaHCO then 3Washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the amine 66 (60mg, 100%) into light yellow oil.This material need not purifying and can use.
Step 4:In room temperature under dry nitrogen atmosphere, to beta-amino ester 60 (75mg, CH 0.32mmol) 2Cl 2Adding carbonyl dimidazoles in the solution (0.6ml) (51mg, 0.32mmol).The mixture that stirring at room temperature generates 5 minutes adds amine 66 (60mg, CH 0.29mmol) through sleeve pipe 2Cl 2Solution (0.6ml) and CH 2Cl 2(0.2mL) washing fluid.The mixture that stirring at room temperature generates 3 days is then with the ethyl acetate dilution, with 2N HCl (twice), H 2O, saturated NaHCO 3With the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates is by filtered through silica gel, and use the 1:1 hexane: ethyl acetate increases to the 2:3 hexane: eluent ethyl acetate obtains urea 67 (110mg, 80%).
Step 5:At room temperature, to urea 67 (108mg, add in the THF solution (3ml) 0.23mmol) NaOH (1ml, the 2N aqueous solution, 2mmol) and methyl alcohol (being enough to obtain settled solution, about 2ml).The mixture that stirring generates 15 minutes, dilute with water is used ether extraction then.With HCl (2N) acidifying water, use ethyl acetate extraction afterwards.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 68 (92mg, 90%) into white foam. 1H NMR (400MHz, CD 3SOCD 3) δ 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (the overlapping H of m 2O, 2H), 4.01 (m, 1H), 4.59 (d, J=15.0Hz, 1H), 4.68 (d, J=15.0Hz, 1H), 4.96 (m, 1H), 5.97 (s, 2H), 6.24 (d, J=6.6Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 6.75 (dd, J=8.1,1.5Hz, 1H), 6.82 (d, J=8.1Hz, 1H), 6.85 (d, J=1.5Hz, 1H), 6.97 (dd, J=5.1,3.3Hz, 1H), 7.03 (dd, J=3.3,1.5Hz, 1H), 7.42 (dd, J=5.1,1.5Hz, 1H), 12.06 (br.s, 1H).
Embodiment 17
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienyl methyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propionic acid (74) synthetic
Step 1:Under dry nitrogen atmosphere, by syringe to the N-tert-butoxycarbonyl-L-aspartic acid α-benzyl ester (2.10g that is cooled to-15 ℃ (bathe temperature), 6.5mmol) glycol dimethyl ether solution (15ml) in add continuously 4-methylmorpholine (0.71ml, 6.5mmol) and the chloroformic acid isobutyl (0.84ml, 6.5mmol).The mixture that stirring generates 2 minutes filters then, with glycol dimethyl ether (10ml) washing solid filter cake.Filtrate is cooled to once more-15 ℃ (bathing temperature), adds sodium borohydride (370mg, H 9.7mmol) 2O solution (3ml) immediately adds H 2O (100ml).With ethyl acetate extraction mixture (three times), merge organic layer, with cold (0 ℃) HCl (0.2N), H 2O, saturated NaHCO 3With the salt water washing.Through MgSO 4The dry organic layer that generates filters, and concentrating under reduced pressure filtrate obtains 69 (2.50g) into water white oil.This material contains some unreduced mixed acid anhydrides but need not purifying can use.
Step 2:Under dry nitrogen atmosphere, by syringe to the oxalyl chloride (2.4ml, the CH of 2.0M that are cooled to-65 ℃ 2Cl 2Solution, CH 4.8mmol) 2Cl 2Add methyl sulfoxide (0.55ml, CH 7.8mmol) in the solution (30ml) 2Cl 2Solution (8ml).The mixture that stirring generates under-65 ℃ 15 minutes adds alcohol 69 (1.00g, CH 3.2mmol) through sleeve pipe then 2Cl 2Solution (29ml) and CH 2Cl 2(3ml) washing fluid.Under-65 ℃, stirred the mixture 3 hours, and made it to be warmed to-20 ℃ (bathing temperature) then.(0.96ml 6.9mmol), adds H subsequently to add triethylamine 2O (20ml).Use CH 2Cl 2Extract water layer, through MgSO 4The dry organic phase that merges is filtered.Concentrating under reduced pressure filtrate obtains the aldehyde 70 into white solid.This material need not purifying and can use immediately.
Step 3:In room temperature under dry nitrogen atmosphere, to crude product aldehyde 70 (3.2mmol, theoretical value) and 2-amino methyl thiophene (add among the 402mg, dichloroethane solution 3.35mmol) (13ml) sodium triacetoxy borohydride (959mg, 4.5mmol).At room temperature stir the mixture overnight that generates, with the ethyl acetate dilution, use saturated NaHCO then 3With the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Resistates is used the 1:1 hexane through the silica gel chromatography purifying: eluent ethyl acetate obtains the lactan 71 (220mg, 3 steps, 23%) into white solid.
Step 4:In room temperature under dry nitrogen atmosphere, by syringe to Rubber Diaphragm Seal 71 (220mg, add in dioxane solution 0.74mmol) (1.5ml) HCl (1.5ml, the dioxane solution of 4.0M, 6.0mmol).Remove the nitrogen pin and stir mixture 5 hours in the sealed flask.Use CH 2Cl 2The diluted mixture thing is used saturated NaHCO then 3Washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the amine 72 (129mg, 89%) into light yellow oil.This material need not purifying and can use.
Step 5:In room temperature under dry nitrogen atmosphere, to amine 72 (123mg, CH 0.63mmol) 2Cl 2Adding carbonyl dimidazoles in the solution (1.5ml) (112mg, 0.69mmol).At room temperature stir the mixture 5 minutes of generation and add beta-amino ester 60 (164mg, CH 0.69mmol) through sleeve pipe 2Cl 2Solution (0.8ml) and CH 2Cl 2(0.2ml) washing fluid.At room temperature stir the mixture overnight that generates, then with the ethyl acetate dilution, with 2N HCl (twice), H 2O, saturated NaHCO 3With the salt water washing.Organic phase is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.By the filtered through silica gel resistates, use the 49:1 chloroform: methanol-eluted fractions, obtain urea 73 (230mg, 80%) into water white oil, when leaving standstill, urea 73 slowly solidifies.
Step 6:At room temperature, to urea 73 (230mg, add in the THF solution (3ml) 0.50mmol) NaOH (1ml, the aqueous solution of 2N, 2mmol) and methyl alcohol (1ml).The mixture that stir to generate 1 hour, dilute with water and use ether extraction then.With HCl (2N) acidifying water, use ethyl acetate extraction.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 74 (181mg, 84%) into white foam. 1H?NMR(400MHz，CD 3SOCD 3)δ?1.64(m，1H)，2.30(m，1H)，2.64(m，2H)，3.20(m，2H)，4.17(dd，J＝8.8，8.4Hz，1H)，4.56(s，2H)，4.96(m，1H)，5.97(s，2H)，6.30(d，J＝7.0Hz，1H)，6.58(d，J＝8.8Hz，1H)，6.77(m，1H)，6.80-6.90(m，2H)，6.96-7.04(m，2H)，7.45(dd，J＝5.1，0.7Hz，1H)，12.10(br.s，1H)。
Embodiment 18
(3S)-and 3-[({[5-chloro-2-hydroxyl-3-(phenmethyl) phenyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:To 2-phenmethyl-3-chlorophenol (5.00g, Et 22.9mmol) 2Add KNO in the mixture of O (20mL) and 6N HCl (50mL) continuously 3(2.30g, 22.9mmol) and NaNO 2(20mg, catalysis).The mixture that stirring generates 2 hours, dilute with water is also used ethyl acetate extraction.Water and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains 99 (6.0g, 100%).
Step 2:To 99 (add among the 6.0g, methanol solution 22.8mmol) (360mL) zinc powder (6.0g, 92mmol) and saturated NH 4The Cl aqueous solution (6mL).The heterogeneous mixture backflow that generates is spent the night.After filtering the mixture and concentrating under reduced pressure filtrate of heat, be dissolved in resistates in the ethyl acetate and use saturated NaHCO 3With the salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains compound 100 (2.93g, 55%).
Step 3:Under 0 ℃, to 25 (0.20g, CH 0.96mmol) 2Cl 2Add continuously in the solution DIPEA (0.40mL, 2.4mmol) photoreactive gas (toluene solution of 1.93M, 0.60mL, 1.2mmol).Make the mixture of generation be warmed to room temperature, stirred 20 minutes, and then be cooled to 0 ℃.In this mixture, drip 100 (0.25g, CH 1.1mmol) 2Cl 2Solution.Make the mixture of generation be warmed to ambient temperature overnight, dilute with water is also used CH 2Cl 2Extract.Water and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate, through silica gel chromatography purifying resistates, with 9:1 and increase to the 5:1 hexane: eluent ethyl acetate obtains 101 (60mg, 12%).
According to the method for in embodiment 1, describing, from 101 preparation (3S)-3-[({[5-chloro-2-hydroxyl-3-(phenmethyl) phenyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid. 1H?NMR(400MHz，CD 3SO 2CD 3)δ?2.26(s，3H)，2.58(dd，J＝15.8，6.6Hz，1H)，2.67(dd，J＝15.8，8.4Hz，1H)，3.49(s，2H)，4.88(m，1H)，7.00-7.70(m，13H)，11.95(br.s，1H)。
Embodiment 19
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({ butyl [2,5-dioxo-1-(phenmethyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propionic acid synthetic
Step 1:At room temperature, with N-benzyl maleimide (2.60g, 13.9mmol) and n-butylamine (1.00g, 13.7mmol) THF solution (15mL) stir and spend the night and concentrating under reduced pressure.Through silica gel chromatography purifying resistates, increase to the 2:1 hexane with 4:1: eluent ethyl acetate obtains 102 (3.25g, 90%).
According to the method for in embodiment 1, describing, with 102 preparation (3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({ butyl [2,5-dioxo-1-(phenmethyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propionic acid.MP：80-85℃。
Embodiment 20
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({1-(cyclopentyl-methyl)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid synthetic
Step 1:At 0 ℃ under nitrogen atmosphere, to 2-hydroxy-3-nitropyridine (200mg, CH 1.4mmol) 2Cl 2Add in the solution (14mL) pentamethylene methyl alcohol (178mg, 1.78mmol), add subsequently triphenylphosphine (551mg, 2.1mmol).0 ℃ of following stirred solution 15 minutes and by syringe drip azo-2-carboxylic acid's diethyl ester (366mg, 2.1mmol).Reactant was stirred 1 hour, at room temperature stir then and spend the night.With methyl alcohol (20mL) chilled mixture, wash (twice) with water.Use the dichloromethane extraction water layer, through the organic layer after-filtration of dried over mgso merging.Concentrated filtrate, through silica gel chromatography purifying resistates, use the 1:1 hexane: eluent ethyl acetate obtains 103 (299mg, 96% yields) into yellow solid.
According to the method for in embodiment 1, describing, with 103 preparation (3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({1-(cyclopentyl-methyl)-2-oxos-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid. 1H?NMR(400MHz，CDCl 3)：δ?1.2-1.7(m，8H)，2.34(m，1H)，2.81(dd，J＝，1H)，2.95(dd，J＝，1H)，3.92(d，J＝7.7Hz，2H)，5.30(m，1H)，5.92(m，2H)，6.30(t，J＝7.1Hz，1H)，6.68-7.00(m，5H)，8.33(d，J＝7.7Hz，1H)，8.89(s，1H)。
Embodiment 21
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-{[({3-[(2-thiophenyl methyl) amino] phenyl } amino) carbonyl] amino } propionic acid synthetic
Step 1:To 2 thiophene carboxaldehyde (0.48g, add in dichloromethane solution 4.0mmol) the 3-N-methyl-p-nitroaniline (0.51g, 3.7mmol).Solution concentration is added 1 to dry doubling, 2-ethylene dichloride (16mL).The adding molecular sieve ( , 1.1g), add NaBH (OAc) subsequently 3(1.01g, 4.8mmol).At room temperature stirred solution spends the night, with chloroform dilution and wash with water.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 104 (0.72g, 84%).
Step 2:Under 0 ℃, to 104 (0.30g, CH 1.3mmol) 2Cl 2(5.2mL) and triethylamine (0.215mL, 1.5mmol) add in the solution trifluoroacetic anhydride (0.193mL, 1.4mmol).0 ℃ of following stirred solution 15 minutes, removed ice bath and restir mixture 15 minutes.Use CH 2Cl 2The diluted mixture thing is with 2N HCl, water and salt water washing.Organic layer is through Na 2SO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 105 (0.38g, 100%) into yellow solid.
Step 3:At room temperature, (0.38g, (0.36g 6.5mmol) and at 40 ℃ of following vigorous stirring suspension shows 105 completely consumeds up to TLC to add the Fe powder in ethanol 1.4mmol) (2.6mL) and acetate (2.6mL) solution to 105.Through C salt filtering mixt, wash with chloroform.Dilute filtrate with saturated sodium bicarbonate, through Na 2SO 4Dry chloroform layer after-filtration.Concentrating under reduced pressure filtrate, (gradient 6:1 to 4:1 hexane: ethyl acetate) purifying resistates obtains compound 106 (0.102g, 25%) through silica gel column chromatography.
According to the method for in embodiment 1, describing, with 106 preparation (3S)-3-(1,3-benzo dioxane penta-5-yl)-3-{[({3-[(2-thiophenyl methyl) amino] phenyl } amino) carbonyl] amino } propionic acid. 1H NMR (400MHz, CD 3SO 2CD 3) δ 2.50 (m, the overlapping DMSO of 2H), 4.37 (d, J=5.9Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J=5.8Hz, 1H), 6.16 (m, 1H), 6.59 (d, J=8.8Hz, 1H), 6.78 (m, 3H), 6.85 (dd, J=8.8,7.7Hz, 1H), 6.90 (s, 1H), 6.94 (dd, J=5.2,3.7Hz, 1H), 7.00 (d, J=3.3Hz, 1H), 7.33 (dd, J=5.1,1.1Hz, 1H), 8.5 (s, 1H).
Embodiment 22
3-(1,3-benzo dioxane penta-5-yl)-2,2-two fluoro-3-[({[2-oxo-1-(2-thiophenyl methyl) 1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid synthetic
Step 1:In 15 minutes, to be cooled to-78 ℃ (1S, 2R, 5S)-(+)-methyl (R)-to the toluenesulfinic acid ester (drip among the 3.00g, THF solution (25.5mL) 10.2mmol) two (trimethyl silyl) lithium amides (the THF solution of 1.0M, 15.3mL).The mixture that stirring at room temperature generates 6 hours is cooled to 0 ℃ then.Add rapidly piperonylaldehyde (3.06g, 20.4mmol) and CsF (3.10g, 20.4mmol), at room temperature stirred suspension is 36 hours.Use saturated NH 4Cl quenching reactant is used ethyl acetate extraction.With salt water washing organic layer, through Na 2SO 4Dry after-filtration, concentrating under reduced pressure filtrate.Recrystallization resistates from hexane and methylene dichloride obtains compound 108 (1.36g, 46%).
Step 2:(0.78mL, (2.00g is in THF 30.5mmol) (20.2mL) suspension and refluxed 15 minutes 6.1mmol) to join the Zn powder with the bromo difluoro acetate ethyl ester.Suspension is cooled to 0 ℃, and adding 108 (0.87g, 3.0mmol).Making suspension be warmed to room temperature and stir spends the night.Saturated NH with minimum 4The Cl chilled mixture is used ethyl acetate extraction.Use saturated NaHCO 3The aqueous solution and salt water washing organic layer are through Na 2SO 4Dry after-filtration.Concentrating under reduced pressure filtrate, (gradient 6:1 to 4:1 hexane: ethyl acetate) purifying resistates obtains 109 (0.607g is 61% during 80% conversion) through silica gel column chromatography.
Step 3:Under 0 ℃, to 109 (add among the 0.700g, methanol solution 1.70mmol) (4.3mL) trifluoroacetic acid (0.26mL, 3.4mmol).0 ℃ of following stirred solution 2 hours, be evaporated to driedly then, outside temperature is remained on below 30 ℃.Use the ether dissolution resistates, then with 2N HCl washing (twice).With excessive saturated NaHCO 3The water layer that careful alkalization merges is used ether extraction.Through MgSO 4Dry ether layer after-filtration, concentrating under reduced pressure filtrate obtains 110 (0.326g, 80%).
According to the method for in embodiment 1, describing, with 110 preparation 3-(1,3-benzo dioxane penta-5-yl)-2,2-two fluoro-3-[({[2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid.MS: calculated value (M-H) -=476.07; Measured value (M-H) -=476.00.
Embodiment 23
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-({ [9-oxo-8-(phenmethyl)-2,3,4,5,8,9-six hydrogen-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } amino) propionic acid synthetic
Step 1:Under-20 ℃, (0.74g is 3.6mmol) at THF (14.4mL) and TMEDA (1.60mL to 3 by syringe, 10.8mmol) in solution in drip continuously n-Butyl Lithium (hexane solution of 1.6M, 3.4mL, 5.4mmol) and the tert-butyl lithium (pentane solution of 1.7M, 2.5mL, 4.3mmol).Temperature is warmed between-10 and 0 ℃ and kept 2 hours.Add 1 rapidly in the mixture that generates, (1.75mL 14.7mmol), makes solution be warmed to room temperature and stirred 4 days the 4-dibromobutane.Use CHCl behind the water quenching reactant 3Extract (three times).With the extracting solution of salt water washing merging, through Na 2SO 4Dry after-filtration.Concentrating under reduced pressure filtrate, through silica gel column chromatography purifying resistates, use the 4:1 hexane: eluent ethyl acetate obtains 111 (0.41g, 44%).
According to the method for in embodiment 4, describing, with 111 preparation (3S)-3-(1,3-benzo dioxane penta-5-yl)-3-({ [9-oxo-8-(phenmethyl)-2,3,4,5,8,9-six hydrogen-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } amino) propionic acid.MS: calculated value (M-H) -=488.18; Measured value (M-H) -=488.21.
Embodiment 24
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-hydroxy phenyl) propionic acid synthetic
Step 1:Under 0 ℃ under nitrogen, (make 0.19g, CH 0.39mmol) by syringe to 112 according to the method for in embodiment 15, describing 2Cl 2Add BBr in the solution 3(the CH of 1.0M 2Cl 2Solution, 1.2mL, 1.2mmol).Make mixture be warmed to room temperature gradually, stir then and spend the night.The dilute with water mixture also stirred 30 minutes, used saturated NaHCO 3The aqueous solution further dilutes.Wash organic layer with water, combining water layer with 2N HCl acidifying, is used ethyl acetate extraction (three times) then.Through MgSO 4The dry ethyl acetate layer after-filtration that merges, concentrating under reduced pressure filtrate obtains (3S)-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-hydroxy phenyl) propionic acid (113,120mg, 70%). 1H?NMR(400MHz，CD 3SO 2CD 3)δ?2.95(d，J＝5.2Hz，2H)，5.28(s，2H)，5.35(ddd，J＝9.2，4.8，4.4Hz，1H)，6.33(t，J＝7.1Hz，1H)，6.60(d，J＝8.8Hz，2H)，7.04(m，5H)，7.22(m，3H)，7.37(dd，J＝7.7，1.5Hz，1H)，8.35(dd，J＝7.6，1.5Hz，1H)，8.80(s，1H)。
Embodiment 25
(3S)-3-[({[1-[(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid 119 synthetic
Step 1:((13.2mL 87.5mmol), makes mixture be cooled to-20 ℃ to sodium hydride under dry nitrogen atmosphere to add TMEDA in the 60% mineral oil dispersion liquid of 3.6g, THF suspension (300mL) 90mmol).Dropping propionyl ritalin (9.60mL, 76.5mmol), restir solution 15 minutes.(90mL, the hexane solution of 1.6M 144mmol), stirred the mixture that generates 15 minutes in-20 ℃ to drip n-butyllithium solution.(6.0mL 97mmol), after stirring the mixture 15 minutes, uses hydrochloric acid (2N, 250mL) chilled mixture to add methyl-formiate then fast.With ether (150mL) diluting reaction thing, wash organic layer with water more than 2 times.Combining water layer adds sodium-chlor till saturated.With this mixture of ethyl acetate extraction (3 times).With saturated sodium bicarbonate solution and the former ether layer of water washing.Water washing liquor with excessive hydrochloric acid (2N) acidifying merges extracts (3 times) with the saturated back of sodium-chlor with vinyl acetic monomer.Merge all ethyl acetate extraction liquid and through dried over mgso.The mixture that generates is by thick silica gel vacuum filtration, and the acquisition of concentrating under reduced pressure filtrate is 114 (8.27g, 68%) of light yellow oil.This material need not purifying and can use.
Step 2:With additional funnel under room temperature 114 (3.95g 25.0mmol) in the absolute methanol solution (225mL), drips 2-chlorobenzylamine (4.2g, anhydrous methanol 30mmol) (25mL) solution.Solution was refluxed 2 hours after 45 ℃ of heated overnight.Make reaction mixture be cooled to room temperature and be concentrated into dried.With methylene dichloride dissolving resistates after-filtration.Collect solid, vacuum-drying obtains to be 115 (2.20g, 35%) of light yellow solid.
Step 3:Under room temperature 115 (840mg, add continuously in Glacial acetic acid 3.4mmol) (11mL) suspension Sodium Nitrite (46mg, 0.67mmol), water (0.92mL) and nitric acid (70%, 0.85mL, 13.4mmol).At room temperature the pale yellow solution that generates being stirred the back of spending the night dilutes with methylene dichloride and water.Use the dichloromethane extraction water, merge organic layer, water (3 times) and salt solution wash.Organic layer is through the dried over mgso after-filtration, and concentrating under reduced pressure filtrate obtains to be glassy yellow solid 116 (910mg, 92%).This material need not purifying and can use.
Step 4:In room temperature under dry nitrogen atmosphere, to 116 (910mg, add in DMF 3.1mmol) (10.3mL) solution zinc powder (909mg, 13.9mmol) and Triethylammonium chloride (2340mg, 17.0mmol).Make the mixture heating up to 55 ℃ of generation continue 2 hours, be cooled to room temperature then.In the mixture that generates, add CDI (1002mg, 6.18mmol) solid.There is gas to emit after the adding immediately.With mixture heating up to 80 ℃ 1 hour, be cooled to room temperature, then with methylene dichloride and hydrochloric acid (2N) dilution.The water dichloromethane extraction merges organic layer, water (4 times) and salt water washing.Organic layer is through the dried over mgso after-filtration, and the acquisition of concentrating under reduced pressure filtrate is 117 (920mg) of yellow solid.This material contains a small amount of DMF, can use but need not purifying.
Step 5:Under dry nitrogen atmosphere, (800mg, 21ml THF suspension 3.86mmol) is heated to 55 ℃ and spends the night, and dilutes with vinyl acetic monomer after being cooled to room temperature to make 117 (the thick material of 920mg, 3.1mmol theoretical values) and 8.Mixture usefulness hydrochloric acid (2N) that generates and salt water washing 2 times, organic layer is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, the resistates of acquisition is by the silica gel chromatography purifying, and with the 7:3 hexane: the vinyl acetic monomer wash-out obtains to be light yellow foamy 118 (1098mg, two steps, 71%).
Step 6:At room temperature, to 118 (1091mg, add in THF 2.19mmol) (18mL) solution sodium hydroxide (2N, 6mL) and methyl alcohol (112mL).After stirring the mixture 20 minutes, dilute with water is used ether extraction.Behind hydrochloric acid (2N) acidifying water, extract with vinyl acetic monomer.Water and salt water washing vinyl acetic monomer layer are through the dried over mgso after-filtration.The acquisition of concentrating under reduced pressure filtrate is 119 (3S)-3-[({[1-[(2-benzyl chloride bases of white foam)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (1045mg, quantitatively).MS: calculated value (M-H) -=468.13m/z; Measured value (M-H) -=467.99m/z.
Embodiment 26
(3S)-and 3-[({[4-hydroxyl-2-oxo-1-(pyridine-2-ylmethyl)-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Under room temperature 23 (0.50g, (0.89g 16mmol), stirred the mixture 1.5 hours to add potassium hydroxide powder in the DMSO solution (12.5ml) 3.2mmol).(0.63g 3.8mmol), stirs the mixture and spends the night to be incorporated as solid hydrochloric acid 2-pyrmethyl chloride in the mixture that generates.Add this moment Triethylammonium chloride (3.52g, 25.6mmol) and DMF (5mL), add then zinc powder (1.04g, 16.0mmol).With mixture heating up to 80 ℃ 2 hours, be cooled to room temperature then.(1.00g 6.2mmol), ℃ spends the night the mixture heating up to 80 of generation to add CDI in this mixture.With vinyl acetic monomer and saturated sodium bicarbonate aqueous solution diluted mixture thing.Organic layer is through the dried over mgso after-filtration, concentrating under reduced pressure filtrate.Resistates filters by silicagel pad, uses the 9:1 trichloromethane: methanol-eluted fractions obtains 120 (0.14g, 18%).
The method of introducing according to embodiment 25 prepares (3S)-3-[({[4-hydroxyl-2-oxo-1-(pyridine-2-ylmethyl)-1,2-dihydropyridine-3-yl with 120] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=421.15m/z; Measured value (M-H) -=421.06m/z.
Embodiment 27
(3S)-3-{[({1-[2-chloro-5-(methyl sulphonyl) benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Under dry nitrogen atmosphere, to be cooled to 0 ℃ 121 (method of introducing according to embodiment 4 makes with 23, adding m-CPBA among the 220mg, anhydrous methylene chloride solution (14mL) 0.67mmol) (610mg, 3.6mmol).Make the mixture of generation be warmed to room temperature and stirred 4 hours.Water (50mL) diluting reaction thing is with dichloromethane extraction water (2 times).Merge organic layer through the dried over mgso after-filtration, concentrating under reduced pressure filtrate.Resistates is used the 9:1 trichloromethane by the silica gel chromatography purifying: methanol-eluted fractions obtains to be 122 (219mg, 91% yields) of yellow solid.
The method of introducing according to embodiment 25 prepares (3S)-3-{[({1-[2-chloro-5-(methyl sulphonyl) benzyls with 122]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=532.10m/z; Measured value (M-H) -=531.94m/z.
Embodiment 28
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid synthetic
Step 1:To under dry nitrogen atmosphere, stir 123 (70mg, add in the anhydrous methylene chloride solution (3mL) 0.13mmol) zinc bromide (200mg, 0.82mmol).In 0 ℃ of stirred solution 1 hour.Making reaction mixture be warmed to room temperature and stir spends the night.Add entry (50mL), restir mixture 3 hours this moment.Separate each layer, with dichloromethane extraction water layer (2 times).Merge the organic layer after-filtration through dried over mgso, concentrating under reduced pressure filtrate obtains 124 (3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid (60mg, 95% yield).MS: calculated value (M-H) -=484.13m/z; Measured value (M-H) -=484.00m/z.
Embodiment 29
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:At room temperature the malonyl-dichloro under the dry atmosphere of vigorous stirring (25.0g, 177mmol) and valeronitrile (25.0g, mixture 300.7mmol) 24 hours.In the heterogeneous mixture that generates, add ether (50mL).The collecting precipitation thing, obtaining with the ether washing is 125 hydrochlorides (20.2g, 64%) of white solid.
Step 2: to 125 hydrochlorides (6.10g, add in alcohol suspension 27.2mmol) (100mL) triethylamine (5.8g, 57.3mmol) and palladium on carbon (water-content is about 50%, 3.5g, 1.6mmol Pd for 10% palladium dry weight basis, Degussa E101NE/W type).Replace described atmosphere (between vacuum and balloon hydrogen, switching 5 times) with hydrogen, stir the mixture and spend the night, filter then.Concentrating under reduced pressure filtrate obtains 1262Et 3NHCl (11.0g, 94%).This material need not to be further purified and can use.
Method 1262Et according to embodiment 25 introductions 3NHCl prepares (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=496.16m/z; Measured value (M-H) -=495.94m/z.
Embodiment 30
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:To 2-oxo-cyclopentane carboxylic acid, ethyl ester (3.30g, add in toluene solution 21.1mmol) (45ml) the 4-chlorobenzylamine (2.56mL, 21.1mmol).The mixture backflow of generation is spent the night, remove water by Dean-Stark water trap azeotropic.The concentrating under reduced pressure reaction mixture obtains 127 (5.90,99%) into reddish oil.This material need not purifying and can use.
Step 2: under dry nitrogen atmosphere, be cooled to 0 ℃ 127 (11.0g, 39.3mmol) anhydrous THF (75mL) solution add sodium hydride (60% mineral oil dispersion liquid, 1.73g, 43.2mmol).In 0 ℃ of reaction stirred 10 minutes, add then Acetyl Chloride 98Min. (3.9mL, 55mmol).Make reaction mixture be warmed to room temperature gradually, stir then and spend the night.The mixture that concentrating under reduced pressure generates adds frozen water (200mL) and hydrochloric acid (1N, mixture 200mL) in resistates.(300mL) extracts this mixture with vinyl acetic monomer, and the vinyl acetic monomer layer is through the dried over mgso after-filtration.The acquisition of concentrating under reduced pressure filtrate is 128 (13.4g) of brown oil.This material contains mineral oil, but need not purifying can use.
Step 3: be cooled under dry nitrogen atmosphere by syringe slowly add in 0 ℃ anhydrous THF (50ml) solution of raw product 128 (13.4g, 39.3mmol theoretical value) two (trimethyl silyl) lithium amide (the THF solution of 1.0M, 125mL, 125mmol).Make reaction mixture be warmed to room temperature, stir then and spend the night.The concentrating under reduced pressure mixture is with vinyl acetic monomer/hexane grinding residues and filtration.With hydrochloric acid (1N, 250ml) and water (500ml) wash described solid, obtain 129 (5.48g, 2 steps, 48%) into brown solid.
The method of introducing according to embodiment 25 prepares (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxos-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl with 129] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M+H) +=496.16m/z; Measured value (M+H) +=495.99m/z.
Embodiment 31
(3S)-and 3-[({[4-{[(tertiary butyl amino) carbonyl] amino }-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:Under dry nitrogen atmosphere, be cooled to 0 ℃ 46 (500mg, add in anhydrous THF (10mL) solution 1.79mmol) sodium hydride (60% mineral oil dispersion liquid, 210mg, 5.37mmol), the mixture that stir to generate 20 minutes.(0.31mL 2.68mmol), makes reaction mixture be warmed to room temperature, stirs then 2 days to add tert-butyl isocyanate in this mixture.Behind the water quenching reaction mixture, use ethyl acetate extraction 2 times.Merge organic layer, through the dried over mgso after-filtration, the acquisition of concentrating under reduced pressure filtrate is 130 (660mg, 97%) of brown solid.
The method of introducing according to embodiment 3 prepares (3S)-3-[({[4-{[(tertiary butyl amino with 130) carbonyl] amino }-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=552.20m/z; Measured value (M-H) -=551.89m/z.
The available synthetic method acquisition table 2 of aforesaid method, 3,4 and 5 the compound of being similar to.
Embodiment 32
(3S)-and 3-[({[5-chloro-1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:By syringe under room temperature, dry nitrogen atmosphere 31 (350mg, add in dichloromethane solution 0.72mmol) SULPHURYL CHLORIDE (dichloromethane solution of 1.0M, 0.65mL, 0.65mmol).The mixture that stirring generates under room temperature 1 hour, then described compound is distributed between methylene dichloride and the water.Organic layer with the salt water washing after dried over mgso, concentrating under reduced pressure filtrate.Resistates is by the silica gel chromatography purifying, and with 8:1, use the 1:1 hexane at last with 4:1 then: vinyl acetic monomer carries out wash-out, acquisition 131 (240mg, 64%).
The method of introducing according to embodiment 1 prepares (3S)-3-[({[5-chloro-1-(2-benzyl chloride base)-4-hydroxyl-2-oxos-1,2-dihydropyridine-3-yl with 131] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=488.08; Measured value (M-H) -=487.97.
Embodiment 33
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2 ', 6 '-dimethoxy-1,1 '-xenyl-4-yl) propionic acid synthetic
Step 1:In 30 minutes, to be cooled to-78 ℃, (5.07g in the THF solution (85mL) 24mmol), drips the s-butyl lithium (cyclohexane solution of 1.3M for (R)-(+)-N-benzyl-alpha-methyl-benzyl amine in the dry flask of flame, under the nitrogen atmosphere, 18.0mL, 23.4mmol).In-78 ℃ of restir mixtures 30 minutes, (5.1g, THF solution (20mL) 20mmol) went up to ambient temperature overnight mixture temperature to drip the 4-bromo-cinnamic acid tert-butyl ester then.Add saturated ammonium chloride (about 50mL) quenching reactant, wash organic layer with saturated sodium-chloride, through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates is by the silica gel chromatography purifying, and with hexane, be increased to the 3:1 hexane: vinyl acetic monomer carries out wash-out, obtains 132 (4.33g, 47%) into light yellow oil.
Step 2: under room temperature, dry nitrogen atmosphere 132 (7.4g, 15mmol) and 2,6-dimethoxy benzene ylboronic acid (4.9g, in DME 27mmol) (100mL) solution, add the potassiumphosphate fine powder (8.0g, 37.5mM) and dichloro two (triphenylphosphine) palladium (O) (0.5g, 0.75mmol).Make mixture deoxidation (between vacuum and nitrogen, switching 5 times), be heated to then and refluxed 8 hours.Postcooling mixture again, by
Figure A200910009861D01331
After 521 filtrations, concentrating under reduced pressure filtrate.Resistates is by the silica gel chromatography purifying, and with hexane, increase to the 3:1 hexane: vinyl acetic monomer carries out wash-out acquisition 133 (7.8g, 95% yields).
Step 3: in the 250mL flask 133 (3.39g adds continuously acetic acid (0.5mL) and palladium on carbon (10% Pd dry weight basis, water content is about 50%, Degussa E101 NE/W type, 2.5g, 1.2mmol Pd) in ethanolic soln 6.1mmol) (80mL).Under the balloon nitrogen atmosphere, stirred the mixture 36 hours.By Behind 521 filter reaction mixtures, concentrating under reduced pressure filtrate.With vinyl acetic monomer recrystallization resistates, obtain 134 acetic acid (1.0g, 71%) into white solid.
Synthesize (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1 according to the method that embodiment 25 introduces with 134 acetic acid, 2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2 ', 6 '-dimethoxy-1,1 '-xenyl-4-yl) propionic acid.MS: measured value (M+H) +=592.04; Calculated value (M+H) +=592.19.
Embodiment 34
(3S)-and 3-[({[2-(2-chloro-6-ethoxy benzyl)-5-hydroxyl-6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid synthetic
Step 1:In 10 minutes, the sodium tert-butoxide under room temperature, dry nitrogen atmosphere (65g, add in THF 0.642mol) (1L) solution ethanol (250mL, 5.35mol).In the solution that obtains, add in batches 2-chloro-6-fluorine benzonitrile (100g, 0.642mol).At room temperature stirred reaction mixture is 30 minutes, under reduced pressure is reduced to about 250mL volume then.In the mixture impouring chloroform and water that generate, separate each layer.Water (2 times) and salt water washing organic layer are through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains light yellow solid.With this material of hexane recrystallization, obtain 2-chloro-6-oxyethyl group benzonitrile 135 (101g, 87% yield) into white crystalline solid.
Step 2: the 2-chloro-6-oxyethyl group benzonitrile 135 under room temperature, dry nitrogen atmosphere (the THF solution of adding borane among the 93.2g, THF solution (350mL) 0.513mol) (1.0M, 620mL, 0.62mol).The mixture heating up that generates to refluxing 3 hours, is cooled to room temperature then.In this solution, add entry (250mL) very lentamente, make its releasing hydrogen gas.Again the back in several minutes, add concentrated hydrochloric acid (50mL), make solution be heated to 50 ℃ 2 hours.Be distributed between chloroform and the water after the mixture cooling.Wash water layer 6 times with chloroform.Organic moiety with hydrochloric acid (1M) washing merges abandons this organic layer.In the water layer that merges, add chloroform, add potassium hydroxide then, when water be alkaline (pH〉9) till.Wash water layer 5 times with chloroform again.Merge organic moiety, after water, salt solution wash, through sal epsom and silica gel (2g) drying.Filter this mixture, the acquisition of concentrating under reduced pressure filtrate is the 2-chloro-6-oxyethyl group benzylamine 136 of light yellow oil (60.1g, 64% yield).
Step 3: the 2-chloro-6-oxyethyl group benzylamine 136 under room temperature (7.30g, and Glacial acetic acid 39.3mmol) (50mL) and acetic anhydride (50mL) solution small batch adding Sodium Nitrite (6.00g, 85.7mmol).The mixture that generates in its impouring frozen water, is used ethyl acetate extraction after at room temperature stirring and spending the night.With aqueous sodium hydroxide solution (1N, 2 * 100mL) and salt solution (2 times) washing organic layer.Organic layer is through the dried over sodium sulfate after-filtration, and the acquisition of concentrating under reduced pressure filtrate is 137 (9.00g, 100%) of light yellow solid.
Step 4: under room temperature 137 (9.00g, 39.3mmol) and Tetrabutyl amonium bromide (1.0g, in the THF solution (50ml) 3.1mmol), (2N, 50mL 100mmol), ℃ spend the night this mixture heating up to 45 slowly to add aqueous sodium hydroxide solution.Make reaction mixture be cooled to room temperature, dilute with water extracts with vinyl acetic monomer then.Organic layer salt water washing, through the dried over sodium sulfate after-filtration, concentrating under reduced pressure filtrate obtains 138 (7.08g, 96% yields).
Step 5: 138 (dropping SOCl among the 7.08g, dichloromethane solution 37.9mmol) (55mL) under room temperature, dry nitrogen atmosphere 2(9.0mL, dichloromethane solution 120mmol) (30mL).The mixture that generates at room temperature stirs and spends the night, then in the impouring frozen water.The water layer ethyl acetate extraction, the organic layer of merging washs with aqueous sodium hydroxide solution (1N, 2 times), water (3 times) and salt solution (2 times).Organic layer is through the dried over sodium sulfate after-filtration, and the acquisition of concentrating under reduced pressure filtrate is the 2-chloro-6-ethoxy benzyl chlorine 139 of viscosity brown oil (6.69g, 86% yield).
Step 6: at room temperature stir 2-chloro-6-ethoxy benzyl chlorine 139 (6.90g, 33.7mmol) and hydrazine (21.60g, methanol solution 673mmol) (22mL) 3 hours.Mixture is distributed between methylene dichloride and the water then.Organic layer is through the dried over mgso after-filtration, and concentrating under reduced pressure filtrate obtains 140 (6.18g, 92%).
Step 7: to Pyruvic Acid Ethyl ester (3.85mL, 33.7mmol) and slowly add 140 (6.14g, chloroform solns 30.6mmol) (30mL) in the trichloromethane suspension (65mL) of sal epsom.The mixture that generates at room temperature stirs and spends the night.Filter the mixture that generates, concentrating under reduced pressure filtrate obtains 141 (8.43g, 92%).This material need not purifying and just can be used for next procedure.
Step 8: under dry nitrogen atmosphere, be cooled to 0 ℃ 141 (8.43g, in anhydrous THF solution 28.2mmol) (110mL), disposable adding sodium hydride (60% mineral oil dispersion liquid, 1.88g, 47.1mmol).The mixture that generates stirred 30 minutes in 0 ℃, slowly add then methyl malonyl chloride (6.63g, 47.10mmol).Make mixture be warmed to room temperature, stirring is spent the night, and ethyl acetate extraction (2 times) is used in the careful quenching of water then.Merge organic layer, use the salt water washing, through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains 142 (14.29g).This material need not be further purified and just can be used for next procedure.
Step 9: under dry nitrogen atmosphere, be cooled in 0 ℃ the anhydrous DMF solution (60mL) of raw product 142 (14.29g), and disposable adding sodium hydride (60% mineral oil dispersion liquid, 2.90g, 72.2mmol).This solution is heated to 60 ℃ spends the night, the temperature cooling is descended, then with hexane one oscillates.Separate each layer, in DMF layer impouring frozen water.Add hydrochloric acid (2N) acidifying mixture (pH 1).By filtering the collecting precipitation thing, use vinyl acetic monomer dissolution precipitation thing then.Organic solution is through the dried over mgso after-filtration, and concentrating under reduced pressure filtrate obtains 143 (8.42g, 2 steps, 85% yields).
Step 10: (8.42g, 23.9mmol) (60mL, 5.2N) solution in refluxes and spends the night for Zai diox (100mL) and aqueous hydrochloric acid to make 143.This mixture is cooled to room temperature, behind the dilute with water, with ethyl acetate extraction.Organic layer salt water washing is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates use the 1:1 vinyl acetic monomer by the silica gel chromatography purifying: hexane, use the 9:1 vinyl acetic monomer at last with vinyl acetic monomer then: methyl alcohol carries out wash-out acquisition 144 (2.0g, 28%).
The method that Application Example 25 provides is by 144 preparation (3S)-3-[({[2-(2-chloro-6-ethoxy benzyl)-5-hydroxyl-6-methyl-3-oxos-2,3-dihydrogen dazin-4-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid.MS: measured value (M+H) +=545.05; Calculated value (M+H) +=545.18.
Embodiment 35
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) propionic acid synthetic
Step 1:Under dry nitrogen atmosphere, make sodium hydride (8.00g, 60% mineral oil dispersion liquid, 200mmol) and 145 (8.94g, 66.6mmol) the ice-cold mixture in DMF (250mL) is warmed to room temperature gradually.(16ml 200mmol), at room temperature stirs mixture and to spend the night to add iodoethane in the mixture that generates.Reaction mixture is inclined to ice, use ethyl acetate extraction.Organic layer water and salt water washing are through the dried over sodium sulfate after-filtration.Concentrating under reduced pressure filtrate is with hexane dissolving resistates and filtration.The brown solid that drying under reduced pressure generates obtains 146 (9.00g, 71% yields).This material need not purifying and can use.
Step 2: under room temperature, dry nitrogen atmosphere, stir DMF (3.6g, 49mmol) and POCl 3(9.6mL, mixture 100mmol) 1 hour.The flask that this mixture will be housed then places 45 ℃ of oil baths, and short run adding 146 (7.6g, 40mmol).Oil bath temperature is increased to 70 ℃, stirs the mixture and spend the night, be cooled to room temperature then.The dilute with water mixture is used ethyl acetate extraction then.After organic layer water and the salt water washing, through the dried over sodium sulfate after-filtration.Concentrating under reduced pressure filtrate obtains the 7:3 mixture (6.69g) of 147:146.This material need not purifying and can use.
Step 3: in the ethanolic soln (2.2mL) of the 147:146 of above acquisition mixture (2.2g), add continuously propanedioic acid (1.16g, 11.2mmol), pyridine (0.44mL) and piperidines (0.99mL).The mixture heating up that makes generation is cooled to room temperature then to refluxing 6 hours.Mixture is used ethyl acetate extraction (4 times) then with aqueous sodium hydroxide solution (1N) dilution.To pH 3, filter the suspension that obtains with hydrochloric acid (1N) acidifying water, wash solid with water.Collect white solid, drying under reduced pressure obtains 148 (1.69g, two steps: 49%).
Application Example 33 and 25 methods of introducing are by 148 preparation (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxos-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) propionic acid.MS: measured value (M+H) +=594.05; Calculated value (M+H) +=594.21.
Embodiment 36
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid 153 synthetic
Step 1:Under room temperature, dry nitrogen atmosphere 114 (20.3g, add in absolute methanol solution 129mmol) (430mL) 2-chloro-6-oxyethyl group benzylamine 136 (31.1g, 168mmol).In 45 ℃ of heated solutions 1 hour, reflux then and spend the night.Make reaction mixture be cooled to room temperature and be concentrated into dried.With methylene dichloride dissolving resistates after-filtration.Collect solid, vacuum-drying obtains 149 (14.7g, 39%).
Step 2: under room temperature 149 (11.02g, 37.8mmol) add successively in the Glacial acetic acid suspension (126mL) Sodium Nitrite (522mg, 7.6mmol), water (10.5mL) and nitric acid (70%, 9.6mL, 151.2mmol).The bright yellow solution that obtains at room temperature stirred spend the night, then with methylene dichloride and water dilution.With the dichloromethane extraction water, water (3 times) and salt water washing behind the merging organic layer.Organic layer is through the dried over mgso after-filtration, concentrating under reduced pressure filtrate.With methylene dichloride/vinyl acetic monomer recrystallization resistates, obtain to be glassy yellow solid 150 (10.9g, 85%).
Step 3: under room temperature, dry nitrogen atmosphere 150 (10.9g, in the DMF solution (107mL) 32.2mmol), add zinc powder (9.48g, 145mmol) and Triethylammonium chloride (24.4g, 177mmol).The mixture heating up to 55 that obtains ℃ 1 hour, be cooled to room temperature then.In the mixture that obtains, be incorporated as solid CDI (10.4g, 64.4mmol).In case add CDI, discharge gas immediately.Make mixture heating up to 80 then ℃ 2 hours, make then its be cooled to room temperature and impouring hydrochloric acid (2N, 1L) in.After the suspension that produces stirred 20 minutes, water (1L) dilution was also filtered.Solid is resuspended in after-filtration in the water (1L).The vacuum-drying solid obtains to be 151 (10.78g, 100% yields) of white powder.
Step 4: under dry nitrogen atmosphere, make 151 (10.68g, 31.9mmol) and 8 (8.27g, 39.9mmol) mixture heating up to 55 in DMF (64mL) ℃ is spent the night, be cooled to room temperature after, dilute with vinyl acetic monomer.Mixture with hydrochloric acid (2N), water (4 times) and salt water washing obtain makes organic layer through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, the resistates of generation is used the 7:3 hexane by the silica gel chromatography purifying: the vinyl acetic monomer wash-out obtains to be light yellow foamy 152 (14.2g, 82%).
Step 5: under room temperature 152 (11.60g, in the THF solution (138mL) 21.4mmol), add aqueous sodium hydroxide solution (2N, 46mL) and methyl alcohol (92mL).After stirring the mixture 20 minutes, dilute with water extracts with ether.Behind hydrochloric acid (2N) acidifying water, use ethyl acetate extraction.Vinyl acetic monomer layer water and salt water washing are through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains to be light brown foamy (3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid 153 (10.82,98% yield).MS: calculated value (M-H) -=512.16; Measured value (M-H) -=512.03.
Embodiment 37
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid 156 synthetic
Step 1:With 151 under the dry nitrogen atmosphere (8.40g, 28.8mmol) and 154 (8.2g, DMF mixture (100mL) 35mmol) is heated to 55 ℃ and spends the night, be cooled to room temperature after, dilute with vinyl acetic monomer.With the mixture that hydrochloric acid (2N), water (4 times) and salt water washing produce, organic layer is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates is used the hexane that is increased to 1:1 by 8:2 by the silica gel chromatography purifying: the vinyl acetic monomer wash-out obtains 155 (11.1g, 67% yields).
Step 2: under room temperature 155 (9.12g, add in the THF solution (100mL) 15.9mmol) aqueous sodium hydroxide solution (1N, 88mL) and methyl alcohol (63mL).After stirring the mixture 20 minutes, dilute with water extracts with ether.Discarded this ether layer.With hydrochloric acid (2N) acidifying water, with ether extraction (4 times).Organic layer water and salt water washing are through the dried over mgso after-filtration.The acquisition of concentrating under reduced pressure filtrate is (the 3S)-3-[({[1-of white foam (2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid 156 (8.13g, 93%).MS: calculated value (M+H) +=544.19; Measured value (M+H) +=544.04.
Embodiment 38
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(6-methoxyl group-2-naphthyl) propionic acid 159 synthetic
Step 1:Under dry nitrogen atmosphere, make 151 (110mg, 0.29mmol), 157 (130mg, 0.34mmol) and NMM (0.50mL, 4.5mmol) mixture heating up to 55 in DMF (1.0mL) ℃ is spent the night, be cooled to room temperature after, dilute with vinyl acetic monomer.With the mixture that hydrochloric acid (2N), water (4 times) and salt water washing generate, organic layer is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, the resistates of generation is used the 1:1 hexane by the silica gel chromatography purifying: the vinyl acetic monomer wash-out obtains 158 (130mg, 73% yields).
Step 2: under room temperature 158 (130mg, add in the THF solution (3mL) 0.21mmol) aqueous sodium hydroxide solution (2N, 1mL) and methyl alcohol (2mL).After stirring the mixture 20 minutes, dilute with water extracts with ether.With hydrochloric acid (2N) acidifying water, with ethyl acetate extraction.Vinyl acetic monomer layer water and salt water washing are through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains (3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(6-methoxyl group-2-naphthyl) propionic acid 159 (90mg, 74% yield).MS: measured value (M+H) +=580.07; Calculated value (M+H) +=580.19.
Embodiment 39
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta Ib] pyridin-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid 164 synthetic
Step 1:At room temperature, to 129 (5.30g, add successively in the Glacial acetic acid suspension (64mL) 19.2mmol) Sodium Nitrite (266mg, 3.9mmol), water (5.3mL) and nitric acid (70%, 4.9mL, 77mmol).At room temperature stir the bright yellow solution that obtains and spend the night, also filter in the impouring water then, wash with water.The drying under reduced pressure yellow solid obtains 160 (5.35g, 87%).
Step 2: under room temperature, dry nitrogen atmosphere 160 (5.35g, add in the DMF solution (56mL) 16.7mmol) zinc powder (4.88g, 74.7mmol) and Triethylammonium chloride (12.6g, 91.5mmol).Make the mixture heating up to 55 ℃ 1 hour of acquisition, be cooled to room temperature then.In the mixture that produces, be incorporated as solid CDI (5.41g, 33.4mmol).Discharge gas after the adding immediately.Make mixture heating up to 80 then ℃ 2 hours, be cooled to room temperature then, impouring hydrochloric acid (2N, 500mL) in.The suspension that stirs acquisition is after 20 minutes, and water (500mL) dilution is also filtered.Solid is resuspended in after-filtration in the water (500mL).The vacuum-drying solid obtains to be 161 (5.0g, 95% yields) of white powder.
Step 3: make 161 (6.14g, 19.4mmol) and 162 (5.12g, 20.3mmol) mixture in DMF (90mL) is heated to 80 ℃ and spends the night under dry nitrogen atmosphere, be cooled to room temperature after, dilute with vinyl acetic monomer.With the mixture that hydrochloric acid (2N), water (4 times) and salt water washing produce, organic layer is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates is used the 7:3 hexane by the silica gel chromatography purifying: the vinyl acetic monomer wash-out obtains to be light yellow foamy 163 (8.90g, 81%).
Step 4: under room temperature 163 (8.69g, add in the THF solution (35mL) 15.3mmol) aqueous sodium hydroxide solution (2N, 30mL) and methyl alcohol (30mL).Stir the mixture and spend the night, dilute with water extracts with ether then.With hydrochloric acid (2N) acidifying water, extract with vinyl acetic monomer.Vinyl acetic monomer layer water and salt water washing are through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid 164 (7.50g, 91% yield).MS: measured value (M+H) +=540.09; Calculated value (M+H) +=540.19.
Embodiment 40
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-chloro-3-isopropyl phenyl) propionic acid synthetic
Step 1:By syringe under dry nitrogen atmosphere, be cooled to 0 ℃ 162 (200mg drips SO in the Glacial acetic acid mixture (1.65mL) 0.80mmol) 2Cl 2(1.2mL, Glacial acetic acid mixture (1.0mL) 15mmol).After 30 minutes, make it be warmed to room temperature at 0 ℃ of mixture that stirs generation down.Behind the restir 4 hours, make mixture be cooled to 0 ℃ again, carefully add saturated sodium bicarbonate aqueous solution afterwards and make its quenching.Use the ethyl acetate extraction mixture, organic layer washs with saturated sodium bicarbonate aqueous solution, through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, residue is used the 2:1 hexane by the silica gel chromatography purifying: the vinyl acetic monomer wash-out obtains 165 (148mg, 65%).
Prepare (3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxos-2 according to embodiment 25 and 30 methods of introducing by 165,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-chloro-3-isopropyl phenyl) propionic acid.MS: calculated value (M-H) -=586.15; Measured value (M-H) -=585.92.
Embodiment 41
(3S)-and 3-({ [(1-{[2-chloro-6-tetrahydrochysene-1 (2H)-pyridyl phenyl] methyl }-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl } amino)-3-(4-aminomethyl phenyl) propionic acid synthetic
Step 1:To the 166 (0.35g that are cooled to 0 ℃, 1.06mmol the methods of introducing according to embodiment 34 and 35 make) in the suspension in methyl alcohol (7mL) and water (3.5mL), add Glacial acetic acid (189 μ L successively, 3.2mmol) and Sodium Nitrite (178mg, 2.65mmol).Make mixture slowly be warmed to ambient temperature overnight, then with chloroform and water dilution.Check the pH of water, guarantee that pH is 4-5.Organic layer salt water washing, through the dried over mgso after-filtration, the acquisition of concentrating under reduced pressure filtrate is 167 (0.35g, 92%) of yellow solid.
The method of introducing according to embodiment 25 is by 167 preparation (3S)-3-({ [(1-{[2-chloro-6-tetrahydrochysene-1 (2H)-pyridyl phenyl] methyl }-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl } amino)-3-(4-aminomethyl phenyl) propionic acid.MS: calculated value (M-H) -=551.21; Measured value (M-H) -=551.06.
Embodiment 42
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(difluoromethyl) phenyl] propionic acid synthetic
Step 1:3-bromobenzaldehyde 168 (3.00g under dry nitrogen atmosphere, 16.2mmol) DMF solution (69mL) in add palladium (73mg, 0.32mmol), three adjacent toluene phosphines (197mg, 0.65mmol), ethyl propenoate (2.20mL, 20.3mmol) and triethylamine (4.50mL, 32.4mmol).Make this system deoxidation (switch 5 times) between vacuum and nitrogen, after mixture heating up to 125 ℃ 19 hours, make it be cooled to room temperature.The reactant impouring to water, is used ether extraction then.Organic layer is with hydrochloric acid (4N) and salt water washing, through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate obtains 169 (2.74g, 83%), and this material need not to be further purified and can use.
Step 2: by syringe under dry nitrogen atmosphere, be equipped with 169 (1.00g, add in flask 4.9mmol) (dimethylamino) sulfur trifluoride (0.96mL, 9.8mmol).Behind air blast screen post-heating to 90 ℃ 25 minutes, make it be cooled to room temperature in the mixture that obtains.Mixture with the methylene dichloride dilution produces washs with saturated sodium bicarbonate aqueous solution and water.Organic layer is through the dried over mgso after-filtration, concentrating under reduced pressure filtrate.Resistates is used the 1:5 vinyl acetic monomer by the silica gel chromatography purifying: the hexane wash-out obtains 170 (0.62g, 56%).
Step 3: under dry nitrogen atmosphere to be cooled to-78 ℃ (R)-(+)-N-benzyl-alpha-methylbenzylamine (0.70g, in the THF solution (6.7mL) 3.3mmol), drip s-butyl lithium (4.22mL, the cyclohexane solution of 1.3M, 5.5mmol).After 30 minutes, add 170 (0.62g, THF solution (3.4mL) 2.74mmol) in-78 ℃ of mixtures that stir generation down by syringe.Stirred the mixture 5 hours in-78 ℃, then with THF solution (5mL) chilled mixture of ice ethanol (2mL).Make reaction mixture be warmed to room temperature, with its impouring saturated sodium bicarbonate aqueous solution: in the 1:1 mixture of vinyl acetic monomer.Organic layer water (2 times) and salt water washing are through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates is used the 1:5 vinyl acetic monomer by the silica gel chromatography purifying: the hexane wash-out obtains 171 (1.2g, 100%).This material still contains small amount of impurities, but need not to be further purified and can use.
Step 4: under room temperature, dry nitrogen atmosphere 171 (0.50g, add in ethanolic soln 1.14mmol) (10mL) Pd/C (10% Pd dry weight basis, the water of 50% (weight), DegussaE101 NE/W type, 0.25g) and ice ethanol (0.5mL).Replace dry nitrogen atmosphere (between vacuum and balloon hydrogen, switching 5 times) with hydrogen, make mixture heating up to 35 ℃ 6 hours.Make reactant be cooled to room temperature, pass through then
Figure A200910009861D01431
521 filter plugs filter concentrating under reduced pressure filtrate.Dilute resistates with trichloromethane, wash with saturated sodium bicarbonate aqueous solution.Water layer chloroform extraction (2 times), the organic layer of merging is through the dried over mgso after-filtration.Concentrating under reduced pressure filtrate, resistates is used 1:10 methyl alcohol by the silica gel chromatography purifying: the trichloromethane wash-out obtains 172 (180mg, 67%).
Synthesize (3S)-3-{[({1-[(2-chloro-phenyl-s according to the method that embodiment 25 introduces by 172) methyl]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(difluoromethyl) phenyl] propionic acid.MS: calculated value (M-H) -=504.11; Measured value (M-H) -=503.96.
Embodiment 43
By changing the compound of raw material Application Example 3,4,8,25,26,27,29,30,34,36,39 and synthetic some general formula VII of 41 methods of introducing and general formula VIII.Following table 1 provides the characteristic of institute's synthetic compound.
Table 1
Compound 1H NMR (400MHz)
5-(2-benzyl chloride base)-3,5-dihydro [1,3] (CD 3SO 2CD 3) δ 5.27 (s, 2H), 6.67 (d, J=7.4
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 6.88 (dd, J=7.3,1.4Hz, 1H), 7.27-
Ketone 7.37 (m, 2H), 7.51 (dd, J=7.9,1.5Hz, 1H),
7.65(d，J＝7.4Hz，1H)，12.01(br.s，1H).
5-(2-benzyl chloride base)-6-methyl-3,5-(CD 3SO 2CD 3) δ 2.27 (s, 3H), 5.36 (s, 2H),
Dihydro [1,3] oxazole also [4,5-c] pyrrole 6.60 (d, J=7.3Hz, 1H), 6.63 (s, 1H), 7.27-
Pyridine-2,4-diketone 7.37 (m, 2H), 7.51 (d, J=7.7Hz, 1H), 11.9
(br.s，1H).
5-(2-luorobenzyl)-3,5-diamino [1,3] (CD 3SO 2CD 3) δ 5.26 (s, 2H), 6.65 (d, J=7.3
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 6.88,7.12-7.26 (m, 3H), 7.37 (m,
Ketone 1H), 7.69 (d, J=7.3Hz, 1H), 11.93 (br.s,
1H).
5-(2-chloro-6-luorobenzyl)-3,5-two (CD 3SO 2CD 3) δ 5.30 (s, 2H), 6.56 (d, J=7.3
Hydrogen [1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 7.25 (ddd, J=9.4,8.9,1.1Hz,
2,4-diketone 1H), 7.37 (d, J=8.0Hz, 1H), 7.43 (m, 2H),
11.93(br.s，1H).
5-benzyl-6-methyl-3,5-dihydro (CD 3SO 2CD 3) δ 2.30 (s, 3H), 5.37 (s, 2H),
[1,3] oxazole also [4,5-c] pyridine-6.55 (s, 1H), 7.10 (d, J=7.0Hz, 2H), 7.24-
2,4-diketone 7.36 (m, 3H), 11.88 (br.s, 1H).
5-benzyl-3,5-dihydro [1,3] oxazole (CD 3SO 2CD 3) δ 5.20 (s, 2H), 6.60 (d, J=7.3
And [4,5-c] pyridine-2,4-diketone Hz, 1H), 7.28-7.36 (m, 5H), 7.72 (d, J=7.3
Hz，1H)，11.97(br.s，1H).
5-(2, the 5-dimethyl benzyl)-3,5-two (CDCl 3) δ 2.27 (s, 3H), 2.32 (s, 3H), 5.27 (s,
Ammonia [1,3] oxazole is [4,5-c] pyridine-2H) also, 6.42 (d, J=7.3Hz, 1H) 6.90 (s, 1H),
2,4-diketone 7.09 (m, 3H), 10.68 (brs, 1H).
5-(2-methyl-benzyl)-3,5-dihydro (CDCl 3) δ 2.30 (s, 3H), 5.28 (s, 2H), 6.39 (d, J
[1,3] oxazole also [4,5-c] pyridine-=7.3Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 7.09
2, and the 4-diketone (d, J=7.7Hz, 1H), 7.18-7.28 (m, 3H) 10.91
(br?s，1H).
5-(2, the 4-dichloro benzyl)-3,5-dihydro (CDCl 3) δ 5.33 (s, 2H), 6.47 (d, J=7.3Hz,
[1,3] oxazole is [4,5-c] pyridine-1H) also, 7.29 (m, 1H), 7.38 (d, J=7.3Hz, 1H),
2,4-diketone 7.42-7.48 (m, 2H) 10.77 (br s, 1H).
5-(2-methoxy-benzyl)-3,5-two (CDCl 3) δ 3.87 (s, 1H), 5.24 (s, 2H), 6.36 (d, J
Hydrogen [1,3] oxazole also [4,5-c] pyridine-=7.5Hz, 1H), 6.88 (d, J=8.1Hz, 1H), 6.97
2, the 4-diketone (m, 1H), 7.30 (m, 7.45 (d, J=7.5Hz,
1H)，7.55(m，1H)，10.75(br?s，1H).
5-(2, the 5-difluorobenzyl)-3,5-two (CDCl 3) δ 5.26 (s, 2H), 6.46 (d, J=7.4Hz,
Hydrogen [1,3] oxazole is [4,5-c] pyridine-1H) also, 6.96-7.05 (m, 2H), 7.30-7.37 (m, 1H),
2,4-diketone 7.39 (m, 1H), 10.68 (br.s, H).
5-[2-chloro-5-(methylthio group) benzyl]-(CD 3SO 2CD 3) δ 2.41 (s, 3H), _ 5.24 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.65 (d, J=7.2Hz, 1H), 6.83 (d, J=2.6Hz,
Pyridine-2,4-diketone 1H), 7.25 (dd, J=8.0,2.6Hz, 2,7.45 (d, J=
8.0Hz，1H)，7.62(d，J＝7.2Hz，1H)，12.1
(br.s，1H).
5-(4-luorobenzyl)-3,5-dihydro [1,3] (CD 3SO 2CD 3) δ 5.18 (s, 2H), 6.61 (d, J=7.4
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 7.14-7.2 (m, 2H), 7.35-7.39 (m, 2H),
Ketone 7.74 (d, J=7.3Hz, 1H), 11.96 (br., 1H).
5-(2-chloro-5-methoxy-benzyl)-(CD 3SO 2CD 3) δ 3.69 (s, 3H), 5.22 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.42 (d, J=2.9Hz, 1H), 6.65 (d, J=7.3Hz,
Pyridine-2,4-diketone 1H), 6.94 (dd, J=8.8,2.9Hz, 1H), 7.43 (d, J
＝8.8Hz，1H)，7.62(d，J＝7.3Hz，1H)，12.05
(br.s，1H).
5-[3,5-two (trifluoromethyl) benzyl]-(CD 3SO 2CD 3) δ 5.36 (s, 2H), 6.69 (d, J=7.5
3, the 5-dihydro [1,3] oxazole is [4,5-c] Hz also, 1H), 7.91 (d, J=7.5Hz, 1H), 8.08 (s,
Pyridine-2,4-diketone 3H), 12.04 (br.S, 1H).
5-(4-tertiary butyl benzyl)-3, two (CD 3SO 2CD 3) δ 1.24 (s, 9H), 5.15 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.61 (d, J=7.3Hz, 1H), 7.23 (d, J=8.4Hz,
2,4-diketone 2H), 7.35 (d, J=8.4Hz, 2H), 7.74 (d, J=.3
Hz，12.02(br.s，1H).
5-(3-benzyl chloride base)-3,5-dihydro [1,3] (CD 3SO 2CD 3) δ 5.20 (s, 2H), 6.63 (d, J=7.4
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 7.25 (m, 1H), 7.35-7.39 (m, 3H),
Ketone 7.76 (d, J=7.4Hz,, 11.97 (bt.s, 1H).
5-(4-benzyl chloride base)-3,5-dihydro [1,3] (CD 3SO 2CD 3) δ 5.19 (s, 2H), 6.62 (d, 7.3
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 7.29-7.33 (m, 2H), 7.37-7.42 (m,
Ketone 2H), 7.73 (d, J=7.3Hz,, 11.97 (br.s,
1H).
5-[3-(trifluoromethyl) benzyl]-3,5-n.d.
[1,3] oxazole is [4,5-c] pyrrole also for dihydro
Pyridine-2, the 4-diketone
5-(2-bromobenzyl-)-3,5-dihydro [1,3] (CD 3SO 2CD 3) δ 5.23 (s, 2H), 6.68 (d, 7.4
Oxazole is [4,5-c] pyridine-2 also, 4-two Hz, 1H), 6.79 (m, 1H), 7.26 (m, 1H), 7.34 (m,
Ketone 1H), 7.64 (d, J=7.4Hz, 1,7.68 (m, 1H),
12.02(br，s，1H).
5-(3, the 4-dichloro benzyl)-3,5-dihydro [CD 3SO 2CD 3) δ 5.19 (s, 2H), 6.64 (d, J=7.3
[1,3] oxazole is [4,5-c] pyridine-Hz also, 1,7.29 (m, 1H), 7.61 (m, 2H), 7.77 (d,
2,4-diketone J=7.3Hz, 1H), 11.98 (br.s, 1H).
5-(4-methyl-benzyl)-3,5-dihydro (CD 3SO 2CD 3) δ 2.27 (s, 3H), 5.14 (s, 2H),
[1,3] oxazole also [4,5-c] pyridine-6.59 (d, J=7.5Hz, 1H), 7.14 (d, J=8.2Hz,
2,4-diketone 2H), 7.20 (d, J=8.2Hz, 2H), 7.69 (d, J=7.5
Hz，1H)，11.95(br.s，1H).
5-(2-chloro-6-methoxy-benzyl)-(CD 3SO 2CD 3) δ 3.80 (s, 3H), 5.23 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.48 (d, J=7.4Hz, 1H), 7.05-7.15 (m, 3H),
Pyridine-2,4-diketone 7.42 (m, 1H), 11.95 (br.s, 1H).
5-[4-(trifluoromethyl) benzyl]-3,5-(CD 3SO 2CD 3) δ 5.30 (s, 2H), 6.65 (d, J=7.3
Dihydro [1,3] oxazole is [4,5-c] pyrrole Hz also, 1H), 7.48 (d, J=8.0Hz, 2H), 7.71 (d, J=
Pyridine-2,4-diketone 8.0Hz, 2H), 7.76 (d, J=7.3Hz, 1H), 11.96
(br.s，1H).
5-(3-methyl-benzyl)-3,5-dihydro (CD 3SO 2CD 3) δ 2.27 (s, 3H), 5.15 (s, 2H),
[1,3] oxazole also [4,5-c] pyridine-6.62 (d, J=7.3Hz, 1H), 7.104H), 7.72
2, the 4-diketone (d, J=7.3Hz, 1H), 12.53 (br.s, 1H).
5-(pyridine-2-ylmethyl)-3,5-two (CD 3SO 2CD 3) δ 5.29 (s, 2H), 6.62 (d, J=7.3
Hydrogen [1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 7.22-7.33 (m, 2H), 7.71 (d, J=7.3
2,4-diketone Hz, 1H), 7.79 (m, 1H), 8.50H), 11.96
(br.s，1H).
5-(2-benzyl chloride base)-7-methyl-3,5-(CD 3SO 2CD 3) δ 2.10 (s, 3H), 5.23 (s, 2H),
Dihydro [1,3] oxazole also [4,5-c] pyrrole 6.86 (dd, J=7.7,1.5Hz, 1H), 7.31 (m, 2H),
Pyridine-2,4-diketone 7.50 (m, 2H), 12.01 (br s, 1H).
5-(2, the 4-difluorobenzyl)-3,5-dihydro (CD 3SO 2CD 3) δ 5.21 (s, 2H), 6.63 (d, J=7.3
[1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 7.02-7.07 (m, 1H), 7.20-7.29 (m,
2,4-diketone 2H), 7.65 (d, J=7.3Hz, 1H), 11.97 (br.s,
1H).
5-(2, the 6-difluorobenzyl)-3,5-dihydro (CD 3SO 2CD 3) δ 5.25 (s2H), 6.58J=7.3
[1,3] oxazole is [4,5-c] pyridine-H z also, 1H), 7.02-7.12 (m, 2H) 7.38-7.55 (m,
2,4-diketone 1H), 7.63 (d, J=7.3Hz, 1H), 11.91 (br.s,
1H).
5-[3-(trifluoromethoxy) benzyl]-(CD 3SO 2CD 3) δ 5.24 (s, 2H), 6.64 (d, J=7.3
3, and the 5-dihydro [1,3] oxazole is [4,5-c] Hz also, 1H), 7.22-7.35 (m, 3H), 7.46 (t, J=7.7
Pyridine-2,4-diketone Hz, 1H), 7.78 (d, J=7.3Hz, 1H), 11.99 (br.s,
1H).
5-[4-(trifluoromethoxy) benzyl]-(CD 3SO 2CD 3) δ 5.23 (s, 2H), 6.63 (d, J=7.3
3, and the 5-dihydro [1,3] oxazole is [4,5-c] Hz also, 1H), 7.29-7.45 (m, 4H), 7.76 (d, J=7.3
Pyridine-2,4-diketone Hz, 1H), 11.98 (br.s, 1H).
5-[2-(trifluoromethyl) benzyl]-3,5-(CD 3SO 2CD 3) δ 5.40 (s, 2H), 6.73 (d, J=7.3
Dihydro [1,3] oxazole is [4,5-c] pyrrole Hz also, 1H), 6.81 (d, J=7.5Hz, 1H), 7.51 (t, J=
Pyridine-2,4-diketone 7.5Hz, 1H), 7.61 (t, J=7.5Hz, 1H), 7.70 (d,
J＝7.3Hz，1H)，7.80(d，J＝7.5Hz，1H)，
12.04(br.s，1H).
5-(3-methoxy-benzyl)-3,5-two n.d.
Hydrogen [1,3] oxazole also [4,5-c] pyridine-
2, the 4-diketone
5-(2, the 3-dichloro benzyl)-3,5-dihydro n.d.
[1,3] oxazole also [4,5-c] pyridine-
2, the 4-diketone
5-(3, the 5-dimethyl benzyl)-3,5-two (CD 3SO 2CD 3) δ 2.23 (s, 6H), 5.11 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.61 (d, J=7.3Hz, 1H), 6.91 (m, 3H), 7.69
2, the 4-diketone (d, J=7.3Hz, 1H), 12.00 (br.s, 1H).
5-(2-benzyl chloride base)-7-amyl group-3,5-(CD 3SO 2CD 3) δ 0.86 (t, J=6.2Hz, 3H), 1.27
Dihydro [1,3] oxazole also [4,5-c] pyrrole (m, 6H), 1.65 (t, J=6.7Hz, 2H), 5.24 (s, 2H),
Pyridine-2,4-diketone 6.83 (d, J=6.6Hz, 1H), 7.24-7.34 (m, 2H),
7.48(s，1H)，7.50(d，J＝7.7Hz，1H).12.00
(br.s，1H)。
5-(2, the 4-dichloro benzyl)-7-methyl-(CD 3SO 2CD 3) δ 2.10 (s, 3H), 5.19 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.87 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4,2.2
Pyridine-2,4-diketone Hz, 1H), 7.50 (s, 1H), 7.69 (d, J=2.2Hz,
1H)，12.02(br.s，1H).
5-(2-benzyl chloride base)-7-ethyl-3,5-(CD 3SO 2CD 3) δ 1.17 (t, J=7.5Hz, 3H), 2.50
Dihydro [1,3] oxazole is [4,5-c] pyrrole (m, 2H overlapping DMSO) also, 5.25 (s, 2H),
Pyridine-2,4-diketone 6.84 (m, 1H), 7.30 (m, 2H), 7.49 (m, 2H),
12.02(br.s，1H).
7-butyl-5-(2-benzyl chloride base)-3,5-(CD 3SO 2CD 3) δ 0.87 (t, J=7.3Hz, 3H), 1.28
Dihydro [1,3] oxazole also [4,5-c] pyrrole (m, 4H), 1.54 (t, J=7.1Hz, 2H), 5.24 (s, 2H),
Pyridine-2,4-diketone 6.83 (d, J=6.8Hz, 1H), 7.24-7.34 (m, 2H),
7.48-7.56(m，2H)，12.00(br.s，1H).
5-[2-chloro-5-(trifluoromethyl) benzyl (CD 3SO 2CD 3) δ 5.33 (s, 2H), 6.68 (d, J=7.3
Base]-3, the 5-dihydro [1,3] oxazole and Hz, 1H), 7.35 (s, 1H), 7.69-7.79 (m, 3H),
[4,5-c] pyridine-2,4-diketone 11.96 (br.s, 1H).
5-(2, the 6-dichloro benzyl)-3,5-dihydro (CD 3SO 2CD 3) δ 5.38 (s, 2H), 6.53 (d, J=7.4
[1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 7.07 (d, J=7.7Hz, 1H), 7.45-7.50
2, the 4-diketone (m, 1H), 7.52-7.59 (m, 2H), 11.99 (br.s, 1H)
5-(2-chloro-5-luorobenzyl)-3,5-two (CD 3SO 2CD 3) δ 5.27 (s, 2H), 6.67 (d, J=7.3
Hydrogen [1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 6.72 (dd, J=7.3,3.2Hz, 1H), 7.21-
2, and 4-diketone 7.23 (m, 1H), 7.55-7.59 (m, 1H), 7.65 (d, J=
7.3Hz，1H)，12.00(br.s，1H).
5-(2-chloro-6-methyl-benzyl)-7-first (CDCl 3) δ 2.07 (s, 3H), 2.29 (s, 3H), 5.48 (s,
Base-3, the 5-dihydro [1,3] oxazole and 2H), 6.63 (s, 1H), 7.16 (d, J=7.7Hz, 1H),
[4,5-c] pyridine-2,4-diketone 7.25 (t, J=7.7Hz, 1H), 7.34 (d, J=7.7Hz,
1H)，11.33(br.S，1H).
5-(4-benzyl chloride base)-7-methyl-3,5-(CD 3SO 2CD 3) δ 2.08 (s, 3H), 5.14 (s, 2H),
Dihydro [1,3] oxazole also [4,5-c] pyrrole 7.31 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4Hz,
Pyridine-2,4-diketone 2H), 7.58 (s, 1H), 12.03 (br.s, 1H).
5-(2-benzyl chloride base)-5,6,7,8-tetrahydrochysene-(CD 3SO 2CD 3) δ 2.04 (m, 2H), 2.80 (m, 4H),
2H-cyclopenta [b] [1,3] Evil 5.28 (s, 2H), 6.68 (d, J=7.3Hz, 1H), 7.18-
Azoles also [5,4-d] pyridines-2,4 (3H)-7.34 (m, 2H), 7.51 (d, J=7.7Hz, 1H), 11.92
Diketone (br.s, 1H).
7-methyl-5-[4-(methyl sulphonyl) (CD 3SO 2CD 3) δ 2.11 (s, 3H), 2.58 (s, 3H),
Benzyl]-3, the 5-dihydro [1,3] oxazole and 5.28 (s, 2H), 7.58 (d, J=7.3Hz, 2H), 7.64 (s,
[4,5-c] pyridine-2,4-diketone 1H), 7.91 (d, J=7.3Hz, 2H), 12.06 (br.s,
1H).
5-(4-methoxy-benzyl)-3,5-two (CD 3SO 2CD 3) δ 3.73 (s, 3H), 5.10 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.56 (br.d, J=5.9Hz, 1H), 6.89 (d, J=8.8
2,4-diketone Hz, 2H), 7.27 (d, J=8.8Hz, 2H), 7.67 (br.m,
1H)，12.06(br.s，1H).
5-(2-benzyl chloride base)-7-propyl group-3,5-(CD 3SO 2CD 3) δ 0.88 (t, J=7.4Hz, 3H), 1.57
Dihydro [1,3] oxazole also [4,5-c] pyrrole (m, 2H), 2.46 (m, 2H), 5.24 (s, 2H), 6.84 (d, J
Pyridine-2,4-diketone=6.2Hz, 1H), 7.26-7.38 (m, 2H), 7.48 (s,
1H)，7.50(d，J＝7.7Hz，1H)，12.00(br.s，
1H).
4-[(2,4-dioxo-2,3-dihydro (CD 3SO 2CD 3) δ 2.55 (s, 6H), 5.31 (s, 2H),
[1,3] oxazole also [4,5-c] pyridine-6.67 (d, J=7.3Hz, 1H), 7.43-7.51 (m, 2H),
5 (4H)-yl) methyl]-N, N-diformazan 7.66-7.74 (m, 2H), 7.77 (d, J=7.3Hz, 1H),
Base benzsulfamide 1 2.00 (br.s, 1H).
5-(Yu ylmethyl)-3,5-dihydro (CDCl 3) δ 2.19 (s, 6H), 2.30 (s, 3H), 5.25 (s,
[1,3] oxazole is [4,5-c] pyridine-2H) also, 6.31 (d, J=7.3Hz, 1H), 6.73 (d, J=7.3
2,4-diketone H z, 1H), 6.94 (s, 2H), 11.01 (br.s, 1H).
5-(2-benzyl chloride base)-3,5,6,7,8,9-(CD 3SO 2CD 3) δ 1.64 (m, 4H), 2.50 (m, 4H),
Six hydrogen [1,3] oxazole also [4,5-c] quinoline 5.34 (s, 2H), 6.59 (d, J=8.1Hz, 1H), 7.25-
Quinoline-2,4-diketone 7.34 (m, 2H), 7.51 (d, J=7.7Hz, 1H), 11.92
(br.s，1H).
5-(2-benzyl chloride base)-7-ethyl-6-first (CD 3SO 2CD 3) δ 1,10 (t, J=7.4Hz, 3H), 2.22
The base-3, the 5-dihydro [1,3] oxazole also (s, 3H), 2.56 (m, 2H), 5.40 (s, 2H), 6.58 (d, J
[4,5-c] pyridine-2,4-diketone=7.0Hz, 1H), 7.23-7.34 (m, 2H), 7.52 (d, J=
8.1Hz，1H)，11.92(br.s，1H).
5-[2-(methylthio group) benzyl]-3,5-two (CD 3SO 2CD 3) δ 2.52 (s, 3H), 5.19 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.63 (d, J=7.3Hz, 1H), 6.76 (d, J=7.7Hz,
2,4-diketone 1H), 7.09-7.17 (m, 1H), 7.29-7.37 (m, 2H),
7.55(d，J＝7.3Hz，1H)，11.99(s，1H).
2-[(2,4-dioxo-2,3-dihydro (CD 3SO 2CD 3) δ 2.81 (s, 6H), 5.54 (s, 2H),
[1,3] oxazole also [4,5-c] pyridine-6.71 (d, J=7.3Hz, 1H), 6.81 (d, J=7.3Hz,
5 (4H)-yl) methyl]-N, N-diformazan 1H), 7.49-7.61 (m, 2H), 7.69 (d, J=7.3Hz,
Base benzsulfamide 1H), 7.85 (d, J=7.3Hz, 1H), 12.05 (br.s,
1H).
5-(2, the 6-dimethoxy-benzyl)-3,5-(CD 3SO 2CD 3) δ 3.76 (s, 6H), 5.07 (s, 2H),
Dihydro [1,3] oxazole also [4,5-c] pyrrole 6.43 (d, J=7.7Hz, 1H), 6.73 (d, J=8.4Hz,
Pyridine-2,4-diketone 2H), 7.00 (d, J=7.7Hz, 1H), 7.37 (t, J=8.4
Hz，1H)，11.92(br.s，1H).
5-[2-(trifluoromethoxy) benzyl]-(CD 3SO 2CD 3) δ 5.27 (s, 2H), 6.65 (d, J=7.3
3, the 5-dihydro [1,3] oxazole is [4,5-c] Hz also, 1H), 7.08 (dd, J=7.3,1.4Hz, 1H), 7.30-
Pyridine-2,4-diketone 7.49 (m, 3H), 7.63 (d, J=7.3Hz, 1H), 11.99
(br.s，1H).
5-(2-benzyl chloride base)-6,7-dimethyl-(CD 3SO 2CD 3) δ 2.12 (s, 3H), 2.19 (s, 3H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 5.40 (s, 2H), 6.59 (d, J=6.6Hz, 1H), 7.25-
Pyridine-2,4-diketone 7.34 (m, 2H), 7.52 (d, J=7.7Hz, 1H), 11.91
(br.s，1H).
5-[2-chloro-5-(methyl sulphonyl) benzyl (CD 3SO 2CD 3) δ 3.20 (s, 3H), 5.35 (s, 2H),
Base]-3, the 5-dihydro [1,3] oxazole and 6.70 (d, J=7.3Hz, 1H), 7.55 (m, 1H), 7.69
[4,5-c] pyridine-2, the 4-diketone (m, 1H), 790 (m, 2H), 12.04 (br.s, 1H).
5-(4-chloro-2-methoxy-benzyl)-(CD 3SO 2CD 3) δ 3.86 (s, 3H), 5.09 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.60 (d, J=7.3Hz, 1H), 6.90-6.98 (m, 2H),
Pyridine-2,4-diketone 7.12 (d, J=2.2Hz, 1H), 7.59 (d, J=7.3Hz,
1H)，11.95(br.s，1H).
5-(2-benzyl chloride base)-5,6,7,8,9,10-(CD 3SO 2CD 3) δ 1.34 (m, 2H), 1.56 (m, 2H),
Six hydrogen-2H-cyclopenta 1. 69 (m, 2H), 2.70 (m, 4H), 5.45 (s, 2H), 6.69
[b] [1,3] oxazole also [5,4-d] pyridine (d, J=6.6Hz, 1H), 7.24-7.35 (m, 2H), 7.52
-2,4 (3H)-diketone (d, J=7.7Hz, 1H), 11.91 (br.s, 1H).
5-[2-(difluoro-methoxy) benzyl]-(CD 3SO 2CD 3) δ 5.21 (s, 2H), 6.64 (d, J=7.3
3, the 5-dihydro [1,3] oxazole is [4,5-c] Hz also, 1H), 7.02 (d, J=7.3Hz, 1H), 7.20-7.25
Pyridine-2, the 4-diketone (m, 2H), 7.27 (t, J=74.0Hz, 1H), 7.62 (d, J=
7.3Hz，1H)，12.00(br.s，1H).
The 7-methyl-5-[(1R)-the 1-styroyl]-(CD 3SO 2CD 3) δ 1.72 (d, J=7.3Hz, 3H), 2.07
3, the 5-dihydro [1,3] oxazole also [4,5-c] (s, 3H), 6.27 (q, J=7.3Hz, 1H), 7.27-7.40
Pyridine-2, the 4-diketone (m, 6H), 11.95 (br.s, 1H).
5-(4-benzyl chloride base)-7-propyl group-3,5-(CD 3SO 2CD 3) δ 0.89 (t, J=7.3Hz, 3H), 1.54
Dihydro [1,3] oxazole also [4,5-c] pyrrole (m, 2H), 2.44 (t, J=7.7Hz, 2H), 5.15 (s, 2H),
Pyridine-2,4-diketone 7.30 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz,
2H)，7.57(s，1H)，11.97(br.s，1H).
5-[2-(methyl sulphonyl) benzyl]-(CD 3SO 2CD 3) δ 3.43 (s, 3H), 5.60 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.75 (d, J=7.3Hz, 1H), 7.49-7.61 (m, 2H),
Pyridine-2,4-diketone 7.65-7.70 (m, 2H) 7.89-7.91 (m, 1H), 12.02
(br.s，1H).
5-(2, the 6-dimethyl benzyl)-3,5-two (CD 3SO 2CD 3) δ 2.21 (s, 6H), 5.16 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.47 (d, J=7.3Hz, 1H), 6.80 (d, J=7.3Hz,
2,4-diketone 1H), 7.09-7.22 (m, 3H), 12.00 (br.s, 1H).
3-chloro-2-[(2,4-dioxo-2,3-two (CD 3SO 2CD 3) δ 5.38 (s, 2H), 6.61 (d, 7.4Hz,
Hydrogen [1,3] oxazole is [4,5-c] pyridine-1H) also, 7.55 (t, J=8.0Hz, 1H), 7.62 (d, J=7.4
5 (4H)-yl) methyl] benzonitrile Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.87 (d, J=
8.0Hz，1H)，11.96(br.s，1H).
5-(2-chloro-6-methyl-benzyl)-6,7-(CD 3SO 2CD 3) δ 2.06 (s, 3H), 2.09 (s, 3H),
Dimethyl-3, the 5-dihydro [1,3] oxazole 2.10 (s, 3H), 5.58 (s, 2H), 7.13 (d, J=7.7Hz,
And [4,5-c] pyridine-2,4-diketone 1H), 7.20 (t, J=7.7Hz, 2H), 7.27 (d, J=7.7
Hz，1H)，11.84(br.s，1H).
2-[(2,4-dioxo-2,3-dihydro (CD 3SO 2CD 3) δ 5.40 (s, 2H), 6.70 (d, J=7.4
[1,3] oxazole is [4,5-c] pyridine-Hz also, 1H), 7.11 (d, J=7.7Hz, 1H), 7.50 (t, J=
5 (4H)-yl) methyl] benzonitrile 7.7Hz, 1H), 7.66 (td, J=7.7,1.1Hz, 1H),
7.74(d，J＝7.4Hz，1H)，7.88(dd，J＝7.7，1.1
Hz，1H)，12.01(br.s，1H).
5-(2-chloro-6-methoxy-benzyl)-7-(CD 3SO 2CD 3) δ 2.01 (s, 3H), 3.81 (s, 3H),
Methyl-3, the 5-dihydro [1,3] oxazole and 5.21 (s, 2H), 6.86 (s, 1H), 7.11 (m, 2H), 7.41
[4,5-c] pyridine-2, the 4-diketone (t, J=8.2Hz, 1H), 11.96 (br.s, 1H).
5-[3-(methylthio group) benzyl]-3,5-two (CD 3SO 2CD 3) δ 2.45 (s, 3H), 5.16 (s, 2H),
Hydrogen [1,3] oxazole also [4,5-c] pyridine-6.61 (d, J=7.3Hz, 1H), 7.04 (d, J=7.3Hz,
2,4-diketone 1H), 7.16-7.34 (m, 3H), 7.73 (d, J=7.3Hz,
1H)，11.97(br.s，1H).
5-(2-benzyl chloride base)-7-cyclopropyl-(CD 3SO 2CD 3) δ 0.70 (m, 2H), 0.87 (m, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 1.79 (m, 1H), 5.22 (s, 2H), 6.79 (d, J=7.3
Pyridine-2,4-diketone Hz, 1H), 7.31 (m, 1H), 7.45 (s, 1H), 7.50 (d, J
＝7.7Hz，1H)，12.01(br.s，1H).
5-(3-benzyl chloride base)-7-methyl-3,5-(CD 3SO 2CD 3) δ 2.09 (d, J=1.1Hz, 3H), 5.15
Dihydro [1,3] oxazole also [4,5-c] pyrrole (s, 2H), 7.26 (m, 1H), 7.33-7.41 (m, 3H), 7.59
Pyridine-2, the 4-diketone (q, J=1.1Hz, 1H), 11.97 (br.s, 1H).
5-(2, the 6-dichloro benzyl)-7-methyl-(CD 3SO 2CD 3) δ 2.03 (d, J=1.1Hz, 3H), 5.36
3, the 5-dihydro [1,3] oxazole also [4,5-c] (s, 2H), 6.87 (q, J=1.1Hz, 1H), 7.46 (dd, J=
Pyridine-2,4-diketone 8.8,7.4Hz, 1H), 7.56 (d, J=7.4Hz, 1H),
7.57(d，J＝8.8Hz，1H)，11.99(br.s，1H).
7-methyl-5-(4-methyl-benzyl)-(CD 3SO 2CD 3) δ 2.07 (s, 3H), 2.27 (s, 3H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 5.10 (s, 2H), 7.08-7.23 (m, 4H), 7.52 (s, 1H),
Pyridine-2,4-diketone 11.95 (br.s, 1H).
5-(3, the 5-dimethoxy-benzyl)-7-(CD 3SO 2CD 3) δ 2.09 (s, 3H), 3.71 (s, 6H),
Methyl-3, the 5-dihydro [1,3] oxazole and 5.06 (s, 2H), 6.42 (t, J=2.2Hz, 1H), 6.46 (d,
[4,5-c] pyridine-2,4-diketone J=2.2Hz, 2H), 7.51 (s, 1H), 11.96 (br.s,
1H).
5-(2, the 6-difluorobenzyl)-7-methyl-(CD 3SO 2CD 3) δ 2.09 (d, J=1.1Hz, 3H), 5.21
3, the 5-dihydro [1,3] oxazole also [4,5-c] (s, 2H), 7.04-7.13 (m, 2H), 7.38-7.47 (m, 2H),
Pyridine-2,4-diketone 11.91 (br.s, 1H).
5-[3-(methyl sulphonyl) benzyl]-(CD 3SO 2CD 3) δ 3.20 (s, 3H), 5.31 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.66 (d, J=7.3Hz, 1H), 7.5-7.7 (m, 2H), 7.81
Pyridine-2, the 4-diketone (d, J=7.3Hz, 1H), 7.83-7,96 (m, 2H), 11.99
(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-(CD 3SO 2CD 3) δ 1.25 (t, J=7.0Hz, 3H) .4.05
3, the 5-dihydro [1,3] oxazole also [4,5-c] (q, J=7.0Hz, 2H), 5.25 (s, 2H), 6.49 (d, J=
Pyridine-2,4-diketone 7.3Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 7.10 (d,
J＝8.1Hz，1H)，7.12(d，J＝7.3Hz，1H)，7.37
(dd，J＝8.4，8.1Hz.1H)，11.95(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 1.25 (t, J=7.0Hz, 3H), 2.02
Methyl-3, the 5-dihydro [1,3] oxazole also (s, 3H), 4.04 (q, J=7.0Hz, 2H), 5.23 (s, 2H),
[4,5-c] pyridine-2,4-diketone 6.97 (s, 1H), 7.04 (d, J=8.4Hz, 1H), 7.09 (d,
J＝8.0Hz，1H)，7.36(dd，J＝8.4，8.0Hz，
1H)，11.93(br.s，1H).
5-(2-fluoro-6-methoxy-benzyl)-7-(CD 3SO 2CD 3) δ 2.05 (s, 3H), 3.82 (s, 3H),
Methyl-3, the 5-dihydro [1,3] oxazole and 5.12 (s, 2H), 6.82 (dd, J=9.5,8,4Hz, 1H),
[4,5-c] pyridine-2,4-diketone 6.91 (d, J=8.4Hz, 1H), 7.18 (s, 1H), 7.37
(td，J＝8.4，6.6Hz，1H)，11.89(br.s，1H).
5-(2-chloro-6-methoxy-benzyl)-7-(CD 3SO 2CD 3) δ 0.82 (t, J=7.3Hz, 3H), 1.47
Propyl group-3, the 5-dihydro [1,3] oxazole also (sextet, J=7.3Hz, 2H), 2.38 (t, J=7.3Hz,
[4,5-c] pyridine-2,4-diketone 2H), 3.80 (s, 3H), 5.21 (s, 2H), 6.89 (s, 1H),
7.08-7.13(m，2H)，7.40(t，J＝8.3Hz.1H)，
11.93(br.s，1H).
5-(5-chloro-2-luorobenzyl)-7-methyl-(CD 3SO 2CD 3) δ 2.10 (s, 3H), 5.18 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 7.20 (dd, J=6.6,3.0Hz, 1H), 7.29 (dd, J=
Pyridine-2,4-diketone 9.6,8.8Hz, 1H), 7.42 (ddd, J=8.8,4.4,3.0
Hz，1H)，7.51(s，1H)，11.96(br.s，1H).
5-(2-benzyl chloride base)-7-sec.-propyl-(CD 3SO 2CD 3) δ 1.23 (d, J=7.0Hz, 6H), 2.92
3, the 5-dihydro [1,3] oxazole also [4,5-c] (m, 1H), 5.25 (s, 2H), 6.83 (dd, J=7.4,2.2
Pyridine-2,4-diketone Hz, 1H), 7.27-7.35 (m, 2H), 7.49 (s, 1H), 7.51
(dd，J＝7.3，1.8Hz，1H)，12.01(br.s，1H).
5-(5-fluoro-2-methyl-benzyl)-7-first (CD 3SO 2CD 3) δ 2.10 (d, J=1.1Hz, 3H), 2.30
The base-3, the 5-dihydro [1,3] oxazole also (s, 3H), 5.13 (s, 2H), 6.55 (dd, J=9.9,2.6Hz,
[4,5-c] pyridine-2,4-diketone 1H), 7.01 (td, J=8.4,2.6Hz, 1H), 7.25 (dd, J
＝8.4，5.9Hz，1H)，7.42(q，1.1Hz，1H)，11.99
(br.s，1H).
The 7-methyl-5-[(1S)-1-phenyl second (CD 3SO 2CD 3) δ 1.72 (d, J=7.3Hz, 3H), 2.07
The base]-3, the 5-dihydro [1,3] oxazole also (s, 3H), 6.27 (q, J=7.3Hz, 1H), 7.27-7.40
[4,5-c] pyridine-2, the 4-diketone (m, 6H), 11.95 (br.s, 1H).
5-(2-chloro-5-isopropoxide benzyl)-(CD 3SO 2CD 3) δ 1.20 (d, J=6.0Hz, 6H), 2.11
7-methyl-3, the 5-dihydro [1,3] oxazole (s, 3H), 4.50 (m, 1H), 5.16 (s, 2H), 6.34 (d, J
And [4,5-c] pyridine-2,4-diketone=3.0Hz, 1H), 6.91 (dd, J=8.8,3.0Hz, 1H),
7.38(d，J＝8.8Hz，1H)，7.47(s，1H)，12.01
(br.s，1H).
5-(5-ethanoyl-2-methoxybenzyl (CD 3SO 2CD 3) δ 2.47 (s, 3H), 3.93 (s, 3H),
Base)-3, the 5-dihydro [1,3] oxazole and 5.16 (s, 2H), 6.62 (d, J=7.3Hz, 1H), 7.16 (d,
[4,5-c] pyridine-2,4-diketone J=8.4Hz, 1H), 7.59 (d, J=2.2Hz, 1H), 7.63
(d，J＝7.3Hz，1H)，7.97(dd，J＝8.4，2.2Hz，
1H)，11.96(br.s，1H).
5-(2-benzyl chloride base)-7-methyl-3,5-(CD 3SO 2CD 3) δ 2.29 (s, 3H), 5.39 (s, 2H),
Dihydro [1,3] oxazole also [4,5-d] rattle away 7.00 (d, J=7.4Hz, 1H), 7.26-7.37 (m, 2H),
Piperazine-2,4-diketone 7.51 (d, J=7.7Hz, 1H), 12.80 (br.s, 1H).
5-[2-fluoro-6-(trifluoromethyl) benzyl (CD 3SO 2CD 3) δ 2.04 (s, 3H), 5.33 (s, 2H),
Base]-7-methyl-3,5-dihydro [1,3] 7.05 (s, 1H), 7.51-7.72 (m, 3H), 11.98 (br.s,
Oxazole is [4,5-c] pyridine-2 also, 4-two 1H).
Ketone
5-(2-chloro-6-methyl-benzyl)-(CD 3SO 3CD 3) δ 2.02 (m, 2H), 2.21 (s, 3H),
5,6,7,8-tetrahydrochysene-2H-cyclopentadiene 2.64-2.80 (m, 4H), 5.42 (s, 2H), 7.05-7.33 (m,
And [b] [1,3] oxazole [5,4-d] pyrrole 3H also), 11.81 (br.s, 1H).
Pyridine-2,4 (3H)-diketone
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 1.08 (t, J=7.7Hz, 3H), 1.25
Ethyl-3, the 5-dihydro [1,3] oxazole also (t, J=7.0Hz, 3H), 2.44 (q, J=7.7Hz, 2H),
[4,5-c] pyridine-2,4-diketone 4.05 (q, J=7.0Hz, 2H), 5.23 (s, 2H), 6.99 (s,
1H)，7.05(d，J＝8.4Hz，1H)，7.09(d，J＝8.1
Hz，1H)，7.36(dd，J＝8.4，8.1Hz，1H)，11.93
(br.s，1H).
5-(2-chloro-6-propoxy-benzyl)-7-(CD 3SO 2CD 3) δ 0.88 (t, J=7.3Hz, 3H), 1.66
Methyl-3, the 5-dihydro [1,3] oxazole also (m, 2H), 2.01 (d, J=1.1Hz, 3H), 3.95 (t, J=
[4,5-c] pyridine-2,4-diketone 6.2Hz, 2H), 5.24 (s, 2H), 6.91 (q, J=1.1Hz,
1H)，7.03(d，J＝8.4Hz，1H)，7.10(d，J＝8.1
Hz，1H)，7.37(dd，J＝8.4，8.1Hz，1H)，11.95
(br.s，1H).
5-(2-chloro-6-isobutoxy benzyl)-(CD 3SO 2CD 3) δ 0.89 (d, J=7.0Hz, 6H), 1.95
7-methyl-3, the 5-dihydro [1,3] oxazole (m, 1H), 2.00 (s, 3H), 3.79 (d, J=6.2,2H),
And [4,5-c] pyridine-2,4-diketone 5.25 (s, 2H), 6.85 (s, 1H), 7.06 (d, J=8.4Hz,
1H)，7.11(d，J＝8.1Hz，1H)，7.38(dd，J＝
8.4，8.1Hz，1H)，11.97(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-(CD 3SO 2CD 3) δ 1.10 (t, J=7.0Hz, 3H), 2.06
5,6,7, and 8-tetrahydrochysene-2H-cyclopentadiene (m, 2H), 2.70-2.92 (m, 4H), 3.90 (q, J=7.0
And [b] [1,3] oxazole is [5,4-d] pyrrole Hz also, 2H), 5.33 (s, 2H), 6.93 (d, J=8.4Hz,
Pyridine-2,4 (3H)-diketone 1H), 7.03 (d, J=8.1Hz, 1H), 7.26 (dd, J=
8.4，8.1Hz，1H)，11.75(br.s，1H).
5-(2-chloro-6-isopropoxide benzyl)-(CD 3SO 2CD 3) δ 1.16 (d, J=6.2Hz, 6H), 2.02
7-methyl-3, the 5-dihydro [1,3] oxazole (s, 3H), 4.67 (m, 1H), 5.21 (s, 2H), 6.94 (s,
And [4,5-c] pyridine-2,4-diketone 1H), 7.07 (d, J=8.0Hz, 2H), 7.34 (t, J=8.0
Hz，1H)，11.93(br.s，1H).
5-[2-chloro-6-(2,2,2-trifluoro ethoxy (CD 3SO 2CD 3) δ 2.01 (s, 3H), 4.82 (q, J=8.8
Base) benzyl]-7-methyl-3,5-dihydro Hz, 2H), 5.24 (s, 2H), 6.94 (s, 1H), 7.19 (d, J
[1,3] oxazole also [4,5-c] pyridine-=8.4Hz, 1H), 7.22 (d, J=8.1Hz, 1H), 7.43
2, the 4-diketone (dd, J=8.4,8.1H2,1H), 11.92 (br.s, 1H)
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 1.19 (t, J=7.0Hz, 3H), 2.19
Methyl-3, the 5-dihydro [1,3] oxazole also (s, 3H), 3.99 (q, J=7.0Hz, 2H), 5.41 (s, 2H),
[4,5-d] pyridazine-2,4-diketone 6.98 (d, J=8.4Hz, 1H), 7.05 (d, J=8.0Hz,
1H)，7.30(dd，J＝8.4，8.0Hz，1H)，12.70(br.
s，1H).
5-[2-chloro-6-(2-methoxyl group ethoxy (CD 3SO 2CD 3) δ 2.06 (m, 2H), 2.74-2.90 (m,
Base) benzyl]-5,6,7,8-tetrahydrochysene-2H-4H), 3.20 (s, 3H), 3.47 (t, J=4.4Hz, 2H),
Cyclopenta [b] [1,3] oxazole and 4.01 (t, J=4.4Hz, 2H), 5.33 (s, 2H), 6.98 (d,
[5,4-d] pyridines-2,4 (3H)-diketone J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 7.27
(t，J＝8.0Hz，1H)，(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-(CD 3SO 2CD 3) δ 1.03 (t, J=7.0Hz, 3H), 2.06
6,7-dimethyl-3,5-dihydro [1,3] (s, 3H), 2.22 (s, 3H), 3.84 (q, J=7.0Hz, 2H),
Oxazole is [4,5-c] pyridine-2 also, and 4-2 5.48 (s, 2H).6.92(d，8.4Hz，1H)，7.03(d，J＝
Ketone 8.1Hz, 1H), 7.24 (dd, J=8.4,8.1Hz, 1H),
11.76(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 1.06 (m, 6H), 2.24 (s, 3H),
Ethyl-6-methyl-3, and 5-dihydro [1,3] 2.48-2.56 (m overlapping DMSO, 2H), 3.85
Oxazole is [4,5-c] pyridine-2 also, 4-two (q, J=7.0Hz, 2H), 5.48 (s, 2H), 6.92 (d, 8.4
Ketone Hz, 1H), 7.03 (d, J=8.1Hz, 1H), 7.24 (dd, J
＝8.4，8.1Hz，1H)，11.77(br.s，1H).
5-(2-benzyl chloride base)-7-ethyl-3,5-(CD 3SO 2CD 3) δ 1.18 (t, J=7.5Hz, 3H), 2.70
Dihydro [1,3] oxazole also [4,5-d] rattle away (q, J=7.5Hz, 2H), 5.38 (s, 2H), 7.0-7.6 (m,
Piperazine-2,4-diketone 4H), 12.77 (br.s, 1H).
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 0,82 (t, J=7.3Hz, 3H), 1.24
Propyl group-3, the 5-dihydro [1,3] oxazole also (t, J=7.0Hz, 3H), 1.48 (m, 2H), 2.37 (t, J=
[4,5-c] pyridine-2,4-diketone 7.3Hz, 2H), 4.05 (q, J=7.0Hz, 2H), 5.23 (s,
2H)，6.93(s，1H)，7.05(d，J＝8.4Hz，1H)，
7.09(d，J＝8.1Hz，1H)，7.36(dd，J＝8.4，8.1
Hz，1H)，11.94(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 0.55 (m, 2H), 0.81 (m, 2H),
Cyclopropyl-3, the 5-dihydro [1,3] oxazole 1.26 (t, J=7.0Hz, 3H), 1.72 (m, 1H), 4.05 (q,
And [4,5-c] pyridine-2,4-diketone J=7.0Hz, 2H), 5.22 (s, 2H), 6.95 (s, 1H),
7.05(d，J＝8.4Hz，1H)，7.09(d，J＝8.1Hz，
1H)，7.36(dd，J＝8.4，8.1Hz，1H)，11.93(br.
s，1H).
5-(2-chloro-5-propoxy-benzyl)-7-(CD 3SO 2CD 3) δ 0.92 (t, J=7.3Hz, 3H), 1.66
Methyl-3, the 5-dihydro [1,3] oxazole also (m, 2H), 2.10 (s, 3H), 3.85 (m, 2H), 5.17 (s,
[4,5-c] pyridine-2,4-diketone 2H), 6.41 (d, J=3.3Hz, 1H), 6.91 (dd, J=
8.8，3.3Hz，1H)，7.39(d，J＝8.8Hz，1H)，
7.45(s，1H)，12.00(br.s，1H).
5-(2-chloro-5-methoxy-benzyl)-7-(CD 3SO 2CD 3) δ 2.10 (s, 3H), 3.9 (s, 3H), 5.18
Methyl-3, the 5-dihydro [1,3] oxazole also (s, 2H), 6.42 (d, J=3.0Hz, 1H), 6.93 (dd, J=
[4,5-c] pyridine-2,4-diketone 8.8,3.0Hz, 1H), 7.42 (d, J=8.8Hz, 1H),
7.44(s，1H)，12.00(br.s，1H).
5-(2-chloro-6-ethoxy benzyl)-6-(CD 3SO 2CD 3) δ 1.07 (t, J=7.0Hz, 3H), 2.32
Methyl-3, the 5-dihydro [1,3] oxazole also (s, 3H), 3.87 (q, J=7.0Hz, 2H), 5.42 (s, 2H),
[4,5-c] pyridine-2,4-diketone 6.44 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 7.03 (d,
J＝8.1Hz，1H)，7.24(dd，J＝8.4，8.1Hz，
1H)，11.74(br.s，1H).
5-(2-chloro-5-ethoxy benzyl)-7-(CD 3SO 2CD 3) δ 1.26 (t, J=7.0Hz, 3H), 2.10
Methyl-3, the 5-dihydro [1,3] oxazole also (s, 3H), 3.94 (q, J=7.0Hz, 2H), 5.17 (s, 2H),
[4,5-c] pyridine-2, and 4-diketone 6.38 (d, J=2.9Hz, 1H), 6.91 (dd, J=8.8,2.9
Hz，1H)，7.39(d，J＝8.8Hz，1H)，7.44(s，
1H)，11.99(br.s，1H).
5-[2-chloro-5-(piperidines-1-base sulphonyl (CD 3SO 2CD 3) δ 1.35 (m, 2H), 1.47 (m, 4H),
Base) benzyl]-7-methyl-3,5-dihydro 2.10 (s, 3H), 2.81 (m, 4H), 5.30 (s, 2H), 7.18
[1,3] oxazole also [4,5-c] pyridine-(d, J=2.2Hz, 1H), 7.57 (s, 1H), 7.67 (dd, J=
2,4-diketone 8.4,2.2Hz, 1H), 7.78 (d, J=8.4Hz, 1H),
12.07(br.s，1H).
5-[2-chloro-5-(tetramethyleneimine-1-base sulphur (CD 3SO 2CD 3) δ 1.62 (m, 4H), 2.11 (s, 3H),
Acyl group) benzyl]-7-methyl-3,5-2 3.05 (m, 4H), 5.30 (s, 2H), 7.30 (s, 1H), 7-57
Hydrogen [1,3] oxazole also [4,5-c] pyridine-(s, 1H), 7.75-7.82 (m, 2H), 12.08 (br.s, 1H).
2, the 4-diketone
5-[2-chloro-6-(cyclopentyl methoxyl group) (CD 3SO 2CD 3) δ 1.22 (m, 2H), 1.51 (m, 4H),
Benzyl]-7-methyl-3,5-dihydro 1.68 (m, 2H), 2.00 (s, 3H), 2.20 (m, 1H), 3.89
[1,3] oxazole also [4,5-c] pyridine-(d, J=7.0Hz, 2H), 5.24 (s, 2H), 6.86 (s, 1H),
2,4-diketone 7.07 (d, J=8.4Hz, 1H), 7.11 (d, J=8.1Hz,
1H)，7.37(dd，J＝8.4，8.1Hz，1H)，11.97(dr.
s，1H).
5-[2-(benzyloxy)-6-benzyl chloride base]-(CD 3SO 2CD 3) δ 1.90 (s, 3H), 5.15 (s, 2H),
7-methyl-3, the 5-dihydro [1,3] oxazole 5.25 (s, 2H), 6.84 (s, 1H), 7.13 (d, J=8.1Hz,
And [4,5-c] pyridine-2,4-diketone 1H), 7.19 (d, J=7.7Hz, 1H), 7.30-7.37 (m,
5H)，7.39(dd，J＝8.1，7.7Hz，1H)，11.91(br.
s，1H).
5-(2,3-two chloro-6-ethoxy benzylidene (CD 3SO 2CD 3) δ 1.10 (t, J=7.0Hz, 3H), 2.09
Base)-5,6,7,8-tetrahydrochysene-2H-ring penta (m, 2H) 2.80 (m, 2H), 2.89 (m, 2H), 3.92 (q, J
Diene also [b] [1,3] oxazole also [5,4-=7.0Hz, 2H), 5.33 (s, 2H), 6.98 (d, J=8.8
D] pyridine-2,4 (3H)-diketone Hz, 1H), 7.50 (d, J=8.8Hz, 1H), 11.71 (br.s,
1H).
5-[2-chloro-5-(trifluoromethyl) benzyl (CD 3SO 2CD 3) δ 2.11 (s, 3H), 5.29 (s, 2H),
Base]-7-methyl-3,5-dihydro [1,3] 7.34 (s, 1H), 7.54 (s, 1H), 7.72-7.79 (m, 2H),
Oxazole is [4,5-c] pyridine-2 also, 4-2 12.00 (br.s, 1H).
Ketone
5-(2-chloro-5-luorobenzyl)-7-methyl-(CD 3SO 2CD 3) δ 2.11 (s, 3H), 5.20 (s, 2H),
3, the 5-dihydro [1,3] oxazole also [4,5-c] 6.71 (dd, J=9.4,2.9Hz, 1H), 7.22 (td, J=
Pyridine-2,4-diketone 8.4,2.9Hz, 1H), 7.49 (s, 1H), 7.57 (dd, J=
8.4，5.2Hz，1H)，11.99(br.s，1H).
Embodiment 42
Wherein make 26-amino acid peptide (CDELPQLVTLPHPNLHGPEILDVPST) that comprises fibronectin CS1 sequence and the effectiveness that maleimide activatory ovalbumin link coupled method is used to measure institute's synthetic compound with the terminal Cys of N-.Under 4 ℃, with bovine serum albumin(BSA) (BSA) and in conjunction with the ovalbumin of CS1 with 0.5 μ g/ml TBS (50mM TRIS, pH7.5; 150mM NaCl) was coated on for 96 hole polystyrene plate last 16 hours.After at room temperature plate being washed three times, with the TBS sealing that comprises 3% BSA 4 hours with TBS.Before the test, with binding buffer liquid (TBS; 1mM MgCl 21mM CaCl 21mM MnCl 2) with closure plate washing three times.To be resuspended in binding buffer liquid (10 with the fluorescently-labeled Ramos cell of fluorexon AM 7In the cell/ml), dilute by 1:2 with the same buffer that contains or do not contain compound.Add 100 μ M compounds.In each hole, add cell (2.5 x 10 rapidly 5Cells/well), under 37 ℃, hatched 30 minutes.After binding buffer liquid washing three times,, use photofluorometer quantitative with the adherent cell cracking.The results are shown in Table 2-7.IC 50Be defined as and reach 50% and suppress needed dosage, table 2 and table 4 be the IC with μ M measurement 50IC 50Be worth lowlyer, it is just higher to suppress percentage, and compound stops cell adhesion more effectively.
Table 2
Title IC 50Mass-spectrometric data (m/z)
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3S)-0.2 calculated value (M-H) -=444.12;
2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridyl] amino } measured value (M-H) -=444.08
Carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3S)-15 calculated value (M-H) -=430.11;
2-oxo-1-(2-thienyl methyl) tetrahydro-1 H-pyrrolo-3-yl] measured value (M-H) -=430.06
Amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3R)-2 calculated value (M-H) -=444.12;
2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridyl] amino } measured value (M-H) -=444.05
Carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[2-oxygen 0.9 calculated value (M-H) -=440.09;
Generation-1-(2-thienyl methyl)-1,2-dihydro-3-pyridyl] ammonia measured value (M-H) -=439.98
Base } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-({ [((3S)-0.0003 calculated value (M-H) -=586.23;
2-oxo-1-{4-[(2-toluino carbonyl) amino] benzyl } six measured values (M-H) -=586.17
Hydrogen-3-pyridyl) amino] carbonyl } amino) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[2-oxygen 0.001 calculated value (M-H) -=582.20;
Generation-1-{4-[(2-toluino carbonyl) amino] benzyl }-1,2-two measured values (M-H) -=582.20
Hydrogen-3-pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-({ [((3S)-nd nd
The 1-{4-[(2-methyl-benzyl) amino] benzyl }-2-oxo six hydrogen-pyrrole
The pyridine base) amino] carbonyl } amino) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({ butyl 20 calculated values (M-H) -=496.15;
[2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridyl] measured value (M-H) -=496.10
Amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-[({[(3S)-0.015 calculated value (M-H) -=458.13;
2-oxo-1-(2-thienyl methyl) azepanyl] amino } carbonyl) measured value (M-H) -=458.09
Amino] propionic acid
Table 3
Compound I C 50(nM) mass-spectrometric data
(3S)-3-[({[2-methyl-4-(2-methyl-propyl)-6-10 calculated values (M-H) -=475.23m/z;
Oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] measured value (M-H) -=475.02m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-10 calculated values (M-H) -=476.18m/z;
[({ [2-oxo-1-(phenmethyl)-4-propyl group-1,2-two measured values (M-H) -=475.99m/z
Hydrogen-3-pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-4000 calculated values (M-H) -=488.18m/z;
({ [9-oxo-8-(phenmethyl)-2,3,4,5,8,9-six hydrogen measured values (M-H) -=488.19m/z
-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } ammonia
Base) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-second 10 calculated values (M-H) -=466.15m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=46595m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxygen 4 calculated values (M-H) -=480.17m/z;
Generation-4-propyl group-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=480.00m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-first 5 calculated values (M+H) -=454.15m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M+H) -=454.09m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({6-methyl-2-oxo-1-(phenmethyl)-5 calculated value (M-H) -=524.22m/z;
The 4-[(phenmethyl) oxygen base]-1,2-dihydro-3-pyridyl } measured value (M-H) -=524.02m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2,4-10 calculated values (M-H) -=467.15m/z;
Dimethyl-6-oxo-1,6-dihydro-5-pyrimidyl } ammonia measured value (M-H) -=467.00m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 4-dichlorophenyl) methyl]-4-30 calculated values (M-H) -=486.10m/z;
Methyl-2-oxo-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) -=485.95m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) first 10 calculated values (M-H) -=467.15m/z;
Base]-6-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=467.14m/z
Base } amino) carbonyl] amino }-3-(4-aminomethyl phenyl)
Propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(first 20 calculated values (M-H) -=468.13m/z;
The oxygen base)-and 2-oxo-1,2-dihydro-3-pyridyl] ammonia measured value (M-H) -=467.97m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({4-chloro-1-[(2-chlorophenyl) first 20 calculated values (M-H) -=472.08m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=471.91m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-first 15 calculated values (M-H) -=482.15m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=481.93m/z
Carbonyl] amino }-3-[3-methyl-4-(methoxyl group) benzene
Base] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-first 3 calculated values (M+H) +=470.15m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M+H) +=470.01m/z
Carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-first 10 calculated values (M+H) +=468.17m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M+H) +=468.05m/z
Carbonyl] amino }-3-(3, the 4-3,5-dimethylphenyl) propionic acid
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) first 10 calculated values (M-H) -=453.13m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=453.01m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-fluorine 15 calculated values (M-H) -=456.12m/z;
-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl measured value (M-H) -=455.94m/z
Base] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxygen 20 calculated values (M-H) -=529.16m/z;
Generation-4-(phenyl amino)-1,2-dihydro-3-pyridyl] measured value (M-H) -=529.02m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxygen 15 calculated values (M-H) -=530.16m/z;
Generation-4-(2-pyridinylamino)-1,2-dihydro-3-pyridine measured value (M-H) -=529.99m/z
Base] amino } carbonyl) amino]-3-(4-aminomethyl phenyl)
Propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 10 calculated values (M-H) --=454.11m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=454.05m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxygen 15 calculated values (M-H) -=544.17m/z;
Generation-4-[(2-pyridylmethyl) amino]-1,2-dihydro-measured value (M-H) -=544.03m/z
The 3-pyridyl } amino) carbonyl] amino }-3-(4-methyl
Phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxygen 20 calculated values (M-H) -=544.17m/z;
Generation-4-[(3-pyridylmethyl) amino]-1,2-dihydro-measured value (M-H) -=544.02m/z
The 3-pyridyl } amino) carbonyl] amino }-3-(4-methyl
Phenyl) propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-1 calculated value (M-H) -=523.17m/z;
(1,4-oxazine alkane (oxazinan)-4-yl)-2-oxo-measured value (M-H) -=523.02m/z
1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-
3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxygen 10 calculated values (M-H) -=495.18m/z;
Generation-4-(propyl group amino)-1,2-dihydro-3-pyridyl] measured value (M-H) -=495.04m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-4-first 20 calculated values (M-H) -=436.17m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=435.99m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 6-dichlorophenyl) methyl]-4-20 calculated values (M-H) -=486.10m/z;
Methyl-2-oxo-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) --=485.95m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3R)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-first 300 calculated values (M-H) -=376.11m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=376.00m/z
Carbonyl] amino } butyric acid
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-4-first 10 calculated values (M-H) -=496.09m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=495.87m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[4-methyl-2-oxo-1-(phenmethyl)-30 calculated value (M-H) -=418.17m/z;
1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-measured value (M-H) -=417.96/z
3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 8 calculated values (M-H) -=484.12m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=484.03m/z
Carbonyl] amino }-3-[3-methyl-4-(methoxyl group) benzene
Base] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxygen 10 calculated values (M-H) -=514.15m/z;
Generation-4-phenyl-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=514.00m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({4-bromo-1-[(2-chlorophenyl) first 20 calculated values (M-H) -=516.03m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=51590m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-20 calculated values (M-H) -=484.09m/z;
[(the 1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxygen measured value (M-H) -=484.03m/z
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] ammonia
Base } propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-2 calculated values (M-H) -=556.18m/z;
[(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) oxygen measured value (M-H) -=556.03m/z
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino)
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorinated benzene. base) methyl]-4-hydroxyl 15 calculated values (M-H) -=468.13m/z;
Base-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } measured value (M-H) -=468.05m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-3 calculated values (M-H) -=509.20m/z;
[(1, the 1-dimethyl ethyl) amino]-2-oxo-1,2-two measured values (M-H) -=509.06m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino }-3-(4-
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 10 calculated values (M-H) -=440.10m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=440.04m/z
Carbonyl] amino }-the 3-phenylpropionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[4-3 calculated values (M-H) -=536.20m/z;
Methyl tetrahydrochysene-1 (2H)-pyrazinyl]-2-oxo-1,2-measured value (M-H) -=636.12m/z
Dihydro-3-pyridyl } amino) carbonyl] amino }-3-
(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 5 calculated values (M-H) -=470.11m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=470.05m/z
Carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 20 calculated values (M-H) -=530.13m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=530.05m/z
Carbonyl] amino }-3-[3,4,5-trimethoxy phenyl]
Propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 15 calculated values (M-H) -=46813m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=468.08m/z
Carbonyl] amino }-3-(3, the 5-3,5-dimethylphenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-15 calculated values (M-H) -=534.15m/z;
[(3-methyl-5-isoxazolyl) amino]-2-oxo-measured value (M-H) -=534.01m/z
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-
3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 20 calculated values (M-H) -=454.17m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=454.04m/z
Carbonyl] amino }-3-(3-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 5 calculated values (M-H) -=470.11m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=470.03m/z
Carbonyl] amino }-3-[3-(methoxyl group) phenyl] propionic acid
(3S)-and 3-[3, two (methoxyl group) phenyl of 5-]-3-{[({1-3 calculated values (M-H) -=500.12m/z;
[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-measured value (M-H) -=500.07m/z
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }
Propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 8 calculated values (M-H) -=504.13m/z;
Base-2-oxo-1,2-dihydro-3-quinolyl } amino) measured value (M-H) -=504.06m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 20 calculated values (M-H) -=508.04m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=508.09m/z
Carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] third
Acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-2 calculated values (M-H) -=595.21m/z;
[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) measured value (M-H) -=594.97m/z
Amino]-2-oxo-1,2-dihydro-3-pyridyl } ammonia
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-(1-azetanyl)-1-[(2-chlorinated benzene 5 calculated values (M-H) -=493.16m/z;
Base) methyl]-2-oxo-1,2-dihydro-3-pyridyl } measured value (M-H) -=493.05m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 30 calculated values (M-H) -=45809m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=458.03m/z
Carbonyl] amino }-3-(4-fluorophenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 40 calculated values (M-H) -=458.09m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=458.06m/z
Carbonyl] amino }-3-(3-fluorophenyl) propionic acid
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-2 calculated values (M-H) -=600.21m/z;
(2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) measured value (M-H) -=600.10m/z
The oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-
Pyridyl] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 25 calculated values (M-H) -=508.09m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=508.02m/z
Carbonyl] amino }-3-[4-(trifluoromethyl) phenyl] third
Acid
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl 30 calculated values (M-H) -=438.15m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=438.07m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-4-10 calculated values (M-H) -=472.11m/z;
Hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) -=472.06m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl 400 calculated values (M-H) -=496.16m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=496.11m/z
Carbonyl] amino }-3-[4-(1, the 1-dimethyl ethyl) benzene
Base] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-5-first 70 calculated values (M-H) -=452.14m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl } amino) measured value (M-H) -=451.99m/z
Carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
3-(4-chlorophenyl)-3-{[({1-[(2-chlorophenyl) 30 calculated values (M-H) -=474.06m/z;
Methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=474.07m/z
Base } amino) carbonyl] amino } propionic acid
(3S)-3-[({[2-methyl-6-oxo-1-(phenmethyl)-25 calculated value (M+H) -=498.22m/z;
4-(2-pyridyl)-1,6-dihydro-5-pyrimidyl] ammonia measured value (M+H) -=498.10m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
3-(3-chlorophenyl)-3-{[({1-[(2-chlorophenyl) 30 calculated values (M-H) -=474.06m/z;
Methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=474.03m/z
Base } amino) carbonyl] amino } propionic acid
The 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-40 calculated values (M-H) -=508.02m/z;
Oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] measured value (M-H) -=507.97m/z
Amino }-3-(3, the 4-dichlorophenyl) propionic acid
Table 4
Title IC 50Mass-spectrometric data
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.015 calculated values (M-H) -=452.18m/z;
-[({ [2-oxo-1-(phenmethyl)-3-azepanyl] amino } carbonyl measured value (M-H) -=452.10m/z
Base) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.04 calculated values (M-H) -=477.18m/z;
-[(the 1-[(3-cyano-phenyl) methyl]-2-oxo-3-measured value (M-H) -=477.14m/z
Azepanyl} amino) carbonyl] amino } propionic acid
(3S)-3-(4-aminomethyl phenyl)-3 0.6 calculated values (M-H) -=41011m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=410.00m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.5 calculated values (M-H) -=434.13m/z;
-[({ [2-oxo-1-(phenmethyl)-1,2-dihydro-3-pyridyl] measured value (M-H) -=434.05m/z
Amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 1 calculated values (M-H) -=448.14m/z;
-[(the 1-[(4-aminomethyl phenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=44802m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 3 calculated values (M-H) -=464.14m/z;
-([(1-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1,2-measured value (M-H) -=464.03m/z
Dihydro-3-pyridyl) amino] carbonyl } amino) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 1.5 calculated values (M-H) -=448.15m/z;
-[(the 1-[(3-aminomethyl phenyl) methyl }-2-oxo-1,2-two measured values (M-H) -=448.04m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-and 3-[3, two (methoxyl group) phenyl of 5-]-3-[({[2-oxo-0.7 calculated value (M-H) -=456.12m/z;
1-(2-thiophenyl methyl)-1,2-dihydro-3-pyridyl] ammonia measured value (M-H) -=456.00m/z
Base } carbonyl) amino] propionic acid
(3S)-3-[4-(methoxyl group) phenyl]-3-[({[2-oxo-1-(2-0.8 calculated value (M-H) -=426.11m/z;
The thiophenyl methyl)-1,2-dihydro-3-pyridyl] amino } carbonyl measured value (M-H) -=426.00m/z
Base) amino] propionic acid
(3S)-and 3-[({[2-oxo-1-(2-thiophenyl methyl)-1,2-2 2.5 calculated values (M-H) -=464.09m/z;
Hydrogen-3-pyridyl] amino } carbonyl) amino]-3-[3-(trifluoro measured value (M-H) -=463.99m/z
Methyl) phenyl] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 50 calculated values (M-H) -=419.12m/z;
-[({ [3-(phenoxy group) phenyl] amino } carbonyl) amino] propionic acid measured value (M-H) -=418.97m/z
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 5 calculated values (M-H) -=438.11m/z;
-[(3-[(2-thiophenyl methyl) and amino] phenyl } amino) carbonyl measured value (M-H) -=438.00m/z
Base] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.8 calculated values (M-H) -=468.09m/z;
-[(the 1-[(3-chlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=46801m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.8 calculated values (M-H) -=502.12m/z;
-([(2-oxo-1-{[3-(trifluoromethyl) phenyl] methyl }-measured value (M-H) -=502.03m/z
1,2-dihydro-3-pyridyl) amino] carbonyl } amino) propionic acid
(3S)-3-(4-fluorophenyl)-3 1.6 calculated values (M-H) -=414.09m/z,
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=414.01m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 3 calculated values (M-H) -=468.09m/z;
-[(the 1-[(4-chlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=467.99m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.5 calculated values (M-H) -=464.14m/z;
-([(1-{[2-(methoxyl group) phenyl] methyl }-2-oxo-1,2-measured value (M-H) -=464.04m/z
Dihydro-3-pyridyl) amino] carbonyl } amino) propionic acid
(3S)-and 3-[3-(methoxyl group) phenyl]-3 1.4 calculated values (M-H) -=426.11m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=426.02m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-1 calculated value (M-H) -=396.10m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=396.01m/z
Pyridyl] amino } carbonyl) amino]-the 3-phenylpropionic acid
(3S)-3-0.3 calculated value (M-H) -=486.13m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=485.98m/z
Pyridyl] amino } carbonyl) amino]-3-[3,4,5-three (methoxies
Base) phenyl] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.3 calculated values (M-H) -=468.08m/z;
-[(the 1-[(2-chlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=468.03m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 2 calculated values (M-H) -=452.12m/z;
-[(1-[(4-fluoro phenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=452.00m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
3-(1,3-benzo dioxane penta-5-yl)-2,2-two fluoro-3〉100 calculated values (M-H) -=476.07m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=476.00m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 14 calculated values (M-H) -=478.16m/z;
-[(2-oxo-1-[3-(phenoxy group) propyl group] and-1,2-dihydro-measured value (M-H) -=478.09m/z
The 3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 5 calculated values (M-H) -=502.05m/z;
-[(1-[(3,5-dichlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=501.94m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 6 calculated values (M-H) -=426.16m/z;
-[({ [1-(cyclopentyl-methyl)-2-oxo-1,2-dihydro-3-pyrrole measured value (M-H) -=426.09m/z
The pyridine base] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 15 calculated values (M-H) -=454.09m/z;
-[(2-oxo-1-[2-(2-thiophenyl) ethyl] and-1,2-dihydro measured value (M-H) -=453.99m/z
-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.1 calculated value (M+H) +=440.14m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=440.09m/z
Aminomethyl phenyl) propionic acid
(3S)-3-(2,3-dihydro-1-cumarone-5-yl)-3 0.14 calculated values (M-H) -=438.11m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=437.99m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-3-(3-fluorophenyl)-3 3 calculated values (M-H) -=414.09m/z;
-[({ [2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-measured value (M-H) -=413.99m/z
Pyridyl] amino } carbonyl) amino] propionic acid
(3S)-and 3-[({[2-oxo-1-(2-thiophenyl methyl)-1,2-2 1.5 calculated values (M-H) -=464.09m/z;
Hydrogen-3-pyridyl] amino } carbonyl) amino]-3-[4-(trifluoro measured value (M-H) -=463.99m/z
Methyl) phenyl] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 0.5 calculated values (M-H) -=434.13m/z;
-[({ [6-oxo-1-(phenmethyl)-1,6-dihydro-3-pyridyl] measured value (M-H) -=434.02m/z
Amino } carbonyl) amino] propionic acid
(3S)-3-[4-fluoro-3-(trifluoromethyl) phenyl]-3-[({[2-oxygen 0.35 calculated value (M-H) -=482.08m/z;
Generation-1-(2-thiophenyl methyl)-1,2-dihydro-3-pyridyl] measured value (M-H) -=481.97m/z
Amino } carbonyl) amino] propionic acid
(3S)-3-[4-(1, the 1-dimethyl ethyl) phenyl]-3-[({[2-2 calculated values (M-H) -=452.16m/z;
Oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-pyridine measured value (M-H) -=452.02m/z
Base] amino } carbonyl) amino] propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 70 calculated values (M-H) -=494.19m/z;
-[(butyl [2,5-dioxo-1-(phenmethyl) tetrahydrochysene-1H-measured value (M-H) -=494.12m/z
Pyrroles-3-yl] amino } carbonyl) amino] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.04 calculated value (M+H) +=516.16m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M+H) +=516.02m/z
[3,4,5-trimethoxy phenyl] propionic acid
(3S)-and 3-{[({1-[(2, the 6-dichlorophenyl) methyl]-2-oxo-0.2 calculated value (M+H) +=474.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=474.04m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.2 calculated value (M+H) +=512.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-measured value (M+H) +=512.04m/z
Fluoro-3-(trifluoromethyl) phenyl] propionic acid
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-2-oxo-0.1 calculated value (M-H) -=422.15m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=422.01m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-(4-aminomethyl phenyl)-3-{[({1-[(2-aminomethyl phenyl) 0.1 calculated value (M-H) -=418.18m/z;
Methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl measured value (M-H) -=418.02m/z
Base] amino } propionic acid
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.05 calculated value (M+H) +=48409m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=484.03m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 4-dichlorophenyl) methyl]-2-oxo-0.4 calculated value (M+H) +=474.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=474.05m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.04 calculated value (M-H) -=466.11m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=466.00m/z
(2,3-dihydro-1-cumarone, 5-yl) propionic acid
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3 2 calculated values (M-H) -=468.09m/z;
-[(the 1-[(2-chlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H) -=467.97m/z
Hydrogen-3-pyridyl } amino) carbonyl] amino } propionic acid
(3S)-3-(4-aminomethyl phenyl)-3-({ [(2-oxo-1-{[2-1 calculated value (M+H) +=474.10m/z;
(trifluoromethyl) phenyl] methyl }-1,2-dihydro-3-pyridyl) measured value (M+H) +=474.09m/z
Amino] carbonyl } amino) propionic acid
(3S)-and 3-{[({1-[(2, the 5-dichlorophenyl) methyl]-2-oxo-0.15 calculated value (M+H) +=474.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=474.04m/z
Aminomethyl phenyl) propionic acid
(2R)-and the 2-{[({1-[(2-chlorophenyl) methyl]-2-oxo-50 calculated value (M-H) -=424.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-benzene measured value (M-H) -=423.99m/z
The base propionic acid
(2R)-and the 2-{[({1-[(2-chlorophenyl) methyl]-2-oxo-80 calculated value (M-H) -=410.08m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-2-benzene measured value (M-H) -=409.95m/z
Guanidine-acetic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.1 calculated value (M-H) -=452.14m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=451.96m/z
(3, the 5-3,5-dimethylphenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.1 calculated value (M-H) -=424.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-benzene measured value (M-H) -=424.07m/z
The base propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.1 calculated value (M-H) -=454.11m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-measured value (M-H) -=454.01m/z
(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.1 calculated value (M-H) -=440.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=440.00m/z
Hydroxy phenyl) propionic acid
(3S)-3-([(1-{[3-(methoxyl group) phenyl] methyl }-2-oxygen 0.2 calculated value (M-H) -=434.17m/z;
Generation-1,2-dihydro-3-pyridyl) amino] carbonyl } amino)-3-measured value (M-H) -=434.01m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.08 calculated value (M-H) -=558.09m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=557.87m/z
[3,4,5-trimethoxy phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.09 calculated value (M+H) +=454.15m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M+H) +=454.07m/z
(3, the 4-3,5-dimethylphenyl) propionic acid
(3S)-and 3-[({[5-chloro-2-hydroxyl-3-(phenmethyl) phenyl] ammonia 8 calculated values (M-H) -=437.12m/z;
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid measured value (M-H) -=437.06m/z
(3S)-and 3-(4-aminomethyl phenyl)-3-[({[3-(phenmethyl) phenyl] 10 calculated values (M-H) -=387.17m/z;
Amino } carbonyl) amino] propionic acid measured value (M-H) -=387.00m/z
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.04 calculated value (M-H) -=468.13m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-measured value (M-H) -=468.01m/z
Methyl-4-(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.07 calculated value (M-H) -=454.11m/z;
1,2-diamino-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=454.00m/z
The hydroxy-3-methyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 3-dichlorophenyl) methyl]-2-oxo-0.35 calculated value (M-H) -=472.08m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=471.94m/z
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-([1,1 '-xenyl]-2-ylmethyl)-2-oxygen 2.5 calculated values (M-H) -=480.19m/z;
Generation-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-measured value (M-H) -=480.05m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.2 calculated value (M-H) -=438.12m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3-measured value (M-H) -=438.00m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-3 calculated value (M-H) -=438.12m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(2-measured value (M-H) -=437.99m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-0.3 calculated value (M-H) -=464.13m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=464.03m/z
(2,3-dihydro-1H-indenes-5-yl) propionic acid
(3S)-and the 3-{[({1-[(2-cyano-phenyl) methyl]-2-oxo-0.1 calculated value (M+H) +=431.18m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=431.09m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-[2, two (methoxyl group) phenyl of 6-]-3-{[({1-[(2-6 calculated values (M-H) -=484.14m/z;
Chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=483.96m/z
Base } amino) carbonyl] amino } propionic acid
(3S)-and the 3-{[({1-[(3-hydroxy phenyl) methyl]-2-oxo-0.2 calculated value (M+H) +=420.18m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M+H) +=422.05m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-[({[2-methyl-6-oxo-1-(phenmethyl)-1,6-0.1 calculated value (M-H) -=419.17m/z;
Dihydro-5-pyrimidyl } amino } carbonyl) amino]-3-(4-first measured value (M-H) -=419.03m/z
The base phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-oxo-0.1 calculated value (M-H) -=438.12m/z;
1,4-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=438.10m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-(4-aminomethyl phenyl)-3-{[({1-[(2-nitrophenyl) 1 calculated value (M+H) +=451.17m/z;
Methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl measured value (M+H) +=451.07m/z
Base] amino } propionic acid
(3S)-and 3-(4-aminomethyl phenyl)-3-{[({1-[(4-nitrophenyl) 1 calculated value (M+H) +=451.17m/z;
Methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl measured value (M+H) +=451.09m/z
Base] amino } propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-3 calculated value (M-H) -=456.10m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=456.04m/z
(2, the 6-dihydroxy phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 6-difluorophenyl) methyl]-2-oxo-0.3 calculated value (M-H) -=440.14m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=440.00m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 4-difluorophenyl) methyl]-2-oxo-1.3 calculated value (M-H) -=440.14m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=439.96m/z
Aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 5-difluorophenyl) methyl]-2-oxo-0.8 calculated value (M-H) -=440.14m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=439.96m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-methyl-6-0.09 calculated value (M-H) -=453.13m/z;
Oxo-1,6-dihydro-5-pyrimidyl } amino) carbonyl] ammonia measured value (M-H) -=453.00m/z
Base }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-2-oxo 0.1 calculated value (M-H) -=456.11m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=45594m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-bromo-5-fluorophenyl) methyl]-2-oxo 05 calculated value (M-H) -=500.06m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=499.91m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-2-oxo 0.35 calculated value (M-H) -=456.11m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=455.93m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.2 calculated value (M-H) -=512.08m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-measured value (M-H) -=511.96m/z
Methyl-4-(methoxyl group) phenyl] propionic acid
(3S)-and 3-{[({1-[(3,5-dimethyl-4-isoxazolyl) first 3 calculated values (M-H) -=423.17m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] measured value (M-H) -=423.02m/z
Amino }, 3-(4-aminomethyl phenyl) propionic acid
(3S)-3-(4-aminomethyl phenyl)-3-{[({2-oxo-1-2.5 calculated values (M-H) -=446.21m/z;
[(2,4, the 6-trimethylphenyl) methyl]-1,2-dihydro-3-pyridine measured value (M-H) -=446.08m/z
Base } amino) carbonyl] amino } propionic acid
(3S)-and 3-(4-aminomethyl phenyl)-3-{[({1-[(2-methyl isophthalic acid, 3-1 calculated value (M-H) -=425.13m/z;
Thiazole-4-yl) methyl]-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=424.99m/z
Base } amino) carbonyl] amino } propionic acid
(3S)-3-([(1-{[4-(1, the 1-dimethyl ethyl) phenyl] first 6 calculated values (M-H) -=460.22m/z;
Base }-2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl } measured value (M-H) -=460.07m/z
Amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-[({[1-(1,3-benzoxazole-2-ylmethyl)-2-oxygen〉10 calculated values (M-H) -=445.15m/z;
Generation-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-measured value (M-H) -=445.01m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-([(1-{2-[(2-hydroxy phenyl) amino]-2-oxo〉10 calculated values (M-H) -=463.16m/z;
Ethyl }-2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl measured value (M-H) -=463.06m/z
Base } amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-nitrophenyl) methyl]-2-oxygen 4 calculated values (M-H) -=483.11m/z;
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=483.01m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(5-chloro-2-fluorophenyl) methyl]-2-oxo 2.5 calculated values (M-H) -=456.11m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=456.00m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-amino-6-chloro-phenyl-) methyl]-2-oxygen 2 calculated values (M-H) -=453.13m/z;
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=453.02m/z
(4-aminomethyl phenyl) propionic acid
(3S)-3-([(1-{[2-fluoro-4-(trifluoromethyl) phenyl] first 3 calculated values (M-H) -=490.14m/z;
Base }-2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl } measured value (M-H) -=489.99m/z
Amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(5-chloro-2-thiophenyl) methyl]-2-oxo 1.3 calculated values (M-H) -=444.08m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=443.97m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-bromo-5-nitrophenyl) methyl]-2-oxygen 2 calculated values (M-H) -=527.06m/z;
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=526.95m/z
(4-aminomethyl phenyl) propionic acid
3-(4-chloro-phenyl-)-3-{[({1-[(2-chlorophenyl) methyl]-0.03 calculated value (M-H) -=474.06m/z;
4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl measured value (M-H) -=474.07m/z
Base] amino } propionic acid
(3S)-3-[({[2-methyl-6-oxo-1-(phenmethyl)-4-(2-0.025 calculated value (M+H) +=498.22m/z;
Pyridyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) ammonia measured value (M+H) +=498.10m/z
Base]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(5-amino-2-bromophenyl) methyl]-2-oxygen 0.08 calculated value (M-H) -=497.08m/z;
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=497.02m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2, the 5-3,5-dimethylphenyl) methyl]-2-oxygen 0.15 calculated value (M-H) -=432.19m/z;
Generation-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=432.04m/z
(4-aminomethyl phenyl) propionic acid
3-(3-chlorophenyl)-3-{[({1-[(2-chlorophenyl) first 0.03 calculated value (M-H) -=474.06m/z;
Base]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) -=474.03m/z
Base) carbonyl] amino } propionic acid
The 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo 0.04 calculated value (M-H) -=508.02m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=507.97m/z
(3, the 4-dichlorophenyl) propionic acid
(3S)-3-({ [(1-{[5-(acetylamino)-2-bromobenzene 02 calculated value (M-H) -=539.09m/z;
Base] methyl }-2-oxo-1,2-dihydro-3-pyridyl) amino] measured value (M-H) -=539.02m/z
Carbonyl } amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-bromo-5-[(methyl sulphonyl) and amino] 0.25 calculated value (M-H) -=575.06m/z;
Phenyl } methyl)-2-oxo-1,2-dihydro-3-pyridyl] ammonia measured value (M-H) -=575.01m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
3-(4-chlorophenyl)-3-{[({1-[(2-chlorophenyl) first 0.4 calculated value (M-H) -=458.07m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] measured value (M-H) -=457.96m/z
Amino } propionic acid
3-(3-chlorophenyl)-3-{[({1-[(2-chlorophenyl) first 1 calculated value (M-H) -=458.07m/z;
Base]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] measured value (M-H) -=45793m/z
Amino } propionic acid
The 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-21 calculated values (M-H) -=492.03m/z;
Hydrogen-3-pyridyl } amino) carbonyl] amino }-3-(3,4-dichloro measured value (M-H) -=491.85m/z
Phenyl) propionic acid
(3S)-and 3-{[({1-[(2-bromo-4-chloro-phenyl-) methyl]-2-oxo 1 calculated value (M-H) -=516.03m/z;
-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-measured value (M-H) -=515.91m/z
(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(4-chlorophenyl) methyl]-2-oxo-2 calculated value (M-H) -=438.12m/z;
1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-measured value (M-H) -=437.88m/z
Aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-0.035 calculated value (M-H) -=498.14m/z;
Oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] ammonia measured value (M-H) -=498.05m/z
Base }-3-[2,3-dimethyl-4-(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-0.015 calculated value (M-H) -=524.08m/z;
Oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] ammonia measured value (M-H) -=524.03m/z
Base }-the 3-{4-[(trifluoromethyl) the oxygen base] phenyl } propionic acid
(3R)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(1,4-Evil 0.1 calculated value (M-H) -=489.19m/z;
Piperazine alkane-4-yl)-and 2-oxo-1,2-dihydro-3-pyridyl] ammonia measured value (M-H) -=489.13m/z
Base } carbonyl) amino]-the 5-methylhexanoic acid
(3S)-3-[({[4-hydroxyl-6-methyl-2-oxo-1-(benzene first 0.35 calculated value (M-H) -=434.17m/z;
Base)-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-measured value (M-H) -=434.08m/z
3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-0.030 calculated value (M-H) -=559.14m/z;
[(sulfonyl propyl base) amino]-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) -=559.04m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-0.025 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] ammonia measured value (M-H) -=468.06m/z
Base }-3-(4-ethylphenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-0.02 calculated value (M-H) -=484.13m/z;
Oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] ammonia measured value (M-H) -=484.06m/z
Base }-3-[4-(oxyethyl group) phenyl] propionic acid
(3S)-and 3-[({[4-hydroxyl-2-oxo-1-(phenmethyl)-1,2-0.030 calculated value (M-H) -=420.16m/z;
Dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-first measured value (M-H) -=420.08m/z
The base phenyl) propionic acid
Table 5
Title IC 50(μ M) mass-spectrometric data
(3S)-3-[({[1-(the 3-tertiary butyl-2-methoxybenzyl 2.5 calculated values (M-H) -=490.23m/z;
Base)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=490.11m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-[({[1-(4-luorobenzyl)-2-oxo-1,2-2 calculated values (M-H) -=422.12m/z;
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-measured value (M-H) -=422.00m/z
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.025 calculated value (M-H) -=526.08m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=526.01m/z
Base) amino]-3-[4-fluoro-3-(trifluoromethyl) benzene
Base] propionic acid
(3S)-3-[({[1-(2, the 5-dimethyl benzyl)-4-hydroxyl 0.02 calculated value (M-H) -=448.19m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=448.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(2-methyl-benzyl)-0.02 calculated value (M-H) -=434.17m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=434.05m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-hydroxybenzyl)-2-oxo-0.2 calculated value (M-H) -=420.16m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=420.09m/z
Base]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-[({[1-(3-benzyl chloride base)-2-oxo-1,2-0.5 calculated value (M-H) -=438.12m/z;
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-measured value (M-H) -=438.01m/z
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-0.1 calculated value (M-H) -=468.13m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=468.08m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.035 calculated value (M-H) -=498.14m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=497.94m/z
Base) amino]-3-(4-methoxyl group-3,5-dimethyl benzene
Base) propionic acid
4-{[3-[({[(1S)-2-carboxyl-1-(4-methylbenzene 0.004 calculated value (M-H) -=573.15m/z;
Base) ethyl] amino } carbonyl) amino]-1-(2-chlorine measured value (M-H) -=572.92m/z
Benzyl)-and 2-oxo-1,2-dihydropyridine-4-yl] ammonia
Base } phenylformic acid
(3S)-and 3-{[({1-(2-chlorophenyl)-4-[(2,2-0.01 calculated value (M-H) -=537.19m/z;
The dimethyl propylene acyl group) amino]-2-oxo-1,2-two measured values (M-H) -=536.88m/z
Pyridinium hydroxide-3-yl } amino) carbonyl] amino }-3-
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-methoxy-benzyl)-0.09 calculated value (M-H) -=468.13m/z;
2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl measured value (M-H) -=467.99m/z
Base] amino }-3-(4-aminomethyl phenyl) propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.19 calculated value (M-H) -=378.09m/z;
Oxo-1,2-dihydropyridine-3-yl } amino) carbonyl measured value (M-H) -=378.01m/z
Base] amino } butyric acid
(3S)-and 3-[({[4-{[(tertiary butyl amino) carbonyl] ammonia 0.01 calculated value (M-H) -=552.20m/z;
Base }-1-(2-benzyl chloride base)-2-oxo-1,2-dihydro measured value (M-H) -=551.89m/z
Pyridin-3-yl } amino) carbonyl] amino }-3-(4-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-hydroxybenzyl)-2-0.25 calculated value (M-H) -=454.12m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=454.03m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-cyano group benzyl)-4-hydroxyl-0.009 calculated value (M-H) -=445.15m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=445.01m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2, the 4-dichloro benzyl)-4-hydroxyl-0.06 calculated value (M-H) -=488.08m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.96m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(2-methoxybenzyl 0.08 calculated value (M-H) -=450.17m/z;
Base)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=450.02m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.08 calculated value (M-H) -=498.14m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=497.95m/z
Base) amino]-3-(4-methoxyl group-2,5-dimethyl benzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-hydroxybenzyl)-2-0.1 calculated value (M-H) -=454.12m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=454.05m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(the 3-tertiary butyl-2-hydroxyl benzyl 4 calculated values (M-H) -=476.02m/z;
Base)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=476.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.3 calculated value (M-H) -=454.17m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=454.05m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.015 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.95m/z
Base) amino]-3-(3-ethylphenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.01 calculated value (M-H) -=498.10m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=497.85m/z
Base) amino]-3-(2,3-dihydro-1,4-benzo dioxy
Heterocycle oneself-the 6-yl) propionic acid
(3S)-3-[({[1-(2, the 5-difluorobenzyl)-4-hydroxyl-0.015 calculated value (M-H) -=456.14m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=455.96m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-30 calculated values (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.87m/z
Base) amino]-4-(4-aminomethyl phenyl) butyric acid
(3S)-and 3-[({[1-[2-chloro-5-(methylthio group) benzyl]-0.015 calculated value (M-H) -=500.10m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=499.92m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.005 calculated value (M-H) -=514.10m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=513.86m/z
Base) amino]-3-(7-methoxyl group-1,3-benzo dioxy
Heterocycle penta-5-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.002 calculated value (M-H) -=514.13m/z;
Oxo-1,2-dihydropyridine-3-yl } amino) carbonyl measured value (M-H) -=513.90m/z
Base] amino }-3-(3-oxyethyl group-4-anisole
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.015 calculated value (M-H) -=488.10m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.92m/z
Base) amino]-3-(3-fluoro-4-p-methoxy-phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.002 calculated value (M-H) -=50012m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=500.01m/z
Base) amino]-3-(3, the 4-Dimethoxyphenyl) third
Acid
(3S)-3-[({[1-(4-luorobenzyl)-4-hydroxyl-2-0.022 calculated value (M-H) -=438.18m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=438.00m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-methoxy-benzyl)-2-oxo 0.25 calculated value (M-H) -=434.17m/z;
-1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=433.95m/z
Base]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.05 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.94m/z
Base) amino]-3-(2, the 5-3,5-dimethylphenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-methoxy-benzyl)-0.012 calculated value (M-H) -=484.13m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=484.03m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-and 3-{[({1-[3,5-two (trifluoromethyl) benzyl 0.3 calculated value (M-H) -=556.13m/z;
Base]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=555.95m/z
Base] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(4-tertiary butyl benzyl)-4-hydroxyl 0.03 calculated value (M-H) -=476.22m/z;
-2-oxo-1,2-dihydropyridine-3-yl] amino } measured value (M-H) -=476.05m/z
Carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(3-benzyl chloride base)-4-hydroxyl-2-0.015 calculated value (M-H) -=454.12m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=453.99m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-0.007 calculated value (M-H) -=454.12m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=454.00m/z
Base] amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[3-(3 0.017 calculated values (M-H) -=48814m/z;
Methyl fluoride) benzyl]-1,2-dihydropyridine-3-yl } measured value (M-H) -=487.99m/z
Amino) carbonyl] amino }-3-(4-phenmethyl) propionic acid
(3S)-3-[({[1-(2-bromobenzyl)-4-hydroxyl-2-0.015 calculated value (M-H) -=498.07m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=497.97m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(3, the 4-dichloro benzyl)-4-hydroxyl-0.045 calculated value (M-H) -=488.08m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.96m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(4-methyl-benzyl)-0.025 calculated value (M-H) -=434.17m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=434.05m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-0.003 calculated value (M-H) -=484.13m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=484.02m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[4-(3 0.02 calculated values (M-H) -=488.14m/z;
Methyl fluoride) benzyl]-1,2-dihydropyridine-3-yl } measured value (M-H) -=487.99m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.02 calculated value (M-H) -=524.08m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=523.91m/z
Base) amino]-3-[3 (trifluoromethoxy) phenyl] third
Acid
(3S)-3-[({[4-hydroxyl-1-(3-methyl-benzyl)-0.055 calculated value (M-H) -=434.17m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=433.99m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-2-oxo-1-(pyridine-0.045 calculated value (M-H) -=421.15m/z;
The 2-ylmethyl)-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=421.06m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-0.005 calculated value (M-H) -=468.13m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=467.99m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2, the 4-difluorobenzyl)-4-hydroxyl-0.03 calculated value (M-H) -=456.14m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=456.01m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2, the 6-difluorobenzyl)-4-hydroxyl-0.008 calculated value (M-H) -=456.14m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=456.01m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[3-(3 0.045 calculated values (M-H) -=504.14m/z;
The fluorine methoxyl group) benzyl]-1,2-dihydropyridine-3-measured value (M-H) -=503.98m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[4-(3 0.025 calculated values (M-H) -=504.14m/z;
The fluorine methoxyl group) benzyl]-1,2-dihydropyridine-3-measured value (M-H) -=503.98m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-0.0015 calculated value (M-H) -=530.13m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=529.91m/z
Amino } carbonyl) amino]-3-(3, the 5-dimethoxy
Phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.05 calculated value (M-H) -=430.08m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=429.94m/z
Base) amino]-3-(2-furyl) propionic acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[2-(3 0.02 calculated values (M-H) -=488.14m/z;
Methyl fluoride) benzyl]-1,2-dihydropyridine-3-yl } measured value (M-H) -=487.96m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) third
Acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.15 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.99m/z
Base) amino]-4-(4-aminomethyl phenyl) butyric acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.0008 calculated value (M-H) -=528.15m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=527.96m/z
Base) amino]-3-(3,4-diethoxy phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=484.12m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=483.94m/z
Base) amino]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(3-methoxybenzyl 0.04 calculated value (M-H) -=450.17m/z;
Base)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=450.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2, the 3-dichloro benzyl)-4-hydroxyl-0.13 calculated value (M-H) -=488.08m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.92m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-benzyl-2-oxo-5-(fluoroform 1.5 calculated values (M-H) -=472.15m/z;
Base)-1,2-dihydropyridine-3-yl] amino } carbonyl) measured value (M-H) -=471.89m/z
Amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(3, the 5-dimethyl benzyl)-4-hydroxyl 0.06 calculated value (M-H) -=448.19m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=448.02m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-0.04 calculated value (M-H) -=554.09m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=553.98m/z
Amino } carbonyl) amino]-3-[4-(trifluoro methoxy
Base) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=484.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=483.95m/z
Base) amino]-3-(3-methoxyl group-4-aminomethyl phenyl)
Propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=514.14m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=513.95m/z
Base) amino]-3-(3,5-dimethoxy-4 '-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.04 calculated value (M-H) -=524.20m/z;
Oxo-5-amyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=523.98m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.005 calculated value (M+H)=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M+H) +=467.99m/z
Base) amino]-3-(3, the 4-3,5-dimethylphenyl) propionic acid
(3S)-3-[({[1-(2, the 4-dichloro benzyl)-4-hydroxyl-0.02 calculated value (M-H) -=502.09m/z;
5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=501.89m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
[2-({ [1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-〉 10 calculated values (M-H) -=455.11m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl)-1-measured value (M-H) -=454.97m/z
(4-aminomethyl phenyl) diazanyl] acetate
(3S)-3-[({[1-(2-benzyl chloride base)-5-ethyl-4-0.01 calculated value (M-H) -=482.15m/z;
Hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=482.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-0.05 calculated value (M-H) -=441.09m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=441.00m/z
Base]-3-pyridin-3-yl propionic acid
(3S)-3-[({[5-butyl-1-(2-benzyl chloride base)-4-0.025 calculated value (M-H) -=510.18m/z;
Hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=509.98m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl) benzyl 0.01 calculated value (M-H) -=522.10m/z;
Base]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=521.97m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-0.005 calculated value (M-H) -=484.13m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=484.00m/z
Amino } carbonyl) amino]-3-(3-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2, the 6-dichloro benzyl)-4-hydroxyl-0.013 calculated value (M-H) -=488.08m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.91m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-luorobenzyl)-4-hydroxyl 0.014 calculated value (M-H) -=472.11m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=471.96m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-0.01 calculated value (M-H) -=482.15m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=481.98m/z
The 3-yl] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(4-benzyl chloride base)-4-hydroxyl-5-0.02 calculated value (M-H) -=468.13m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=467.94m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M+H) +=496.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=495.99m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-hydroxy-5-methyl base-1-[4-(first 0.02 calculated value (M-H) -=512.15m/z;
The base alkylsulfonyl) benzyl]-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=511.96m/z
Pyridine-3-yl } amino) carbonyl] amino }-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(4-methoxybenzyl 0.02 calculated value (M-H) -=450.17m/z;
Base)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=449.99m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.02 calculated value (M-H) -=496.16m/z;
Oxo-5-propyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=495.94m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-({ [(1-{4-[(dimethylamino) sulphonyl 0.035 calculated value (M-H) -=527.16m/z;
Base] benzyl }-4-hydroxyl-2-oxo-1,2-dihydro measured value (M-H) -=526.96m/z
Pyridin-3-yl) amino] carbonyl } amino)-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[4-hydroxyl-1-(Yu ylmethyl)-2-0.06 calculated value (M-H) -=462.20m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=462.02m/z
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.02 calculated value (M-H) -=508.16m/z;
Oxo-1,2,5,6,7,8-six hydrogen quinoline-3-yl] ammonia measured value (M-H) -=507.96m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-5-ethyl-4-0.025 calculated value (M-H) -=496.16m/z;
Hydroxyl-6-methyl-2-oxo-1,2-dihydropyridine-measured value (M-H) -=495.96m/z
The 3-yl] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.4 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.85m/z
Base) (methyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-hydroxyl-1-[2-(methylthio group) benzyl 0.02 calculated value (M-H) -=466.14m/z,
Base]-2-oxo-1,2-dihydropyridine-3-yl } ammonia measured value (M-H) -=465.97m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-({ [(1-{2-[(dimethylamino) sulphonyl 0.03 calculated value (M-H) -=527.16m/z;
Base] benzyl }-4-hydroxyl-2-oxo-1,2-dihydro measured value (M-H) -=526.97m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[1-(2, the 6-dimethoxy-benzyl)-4-0.01 calculated value (M-H) -=480.18m/z;
Hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=480.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({4-hydroxyl-2-oxo-1-[2-(3 0.025 calculated values (M-H) -=504.14m/z;
The fluorine methoxyl group) benzyl]-1,2-dihydropyridine-3-measured value (M-H) -=503.96m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.35 calculated value (M-H) -=522.10m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=521.95m/z
Base) amino]-4-[3-(trifluoromethyl) benzyl] butyric acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=498.14m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=497.97m/z
Base) amino]-3-(3-propoxy-phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M+H) +=528.19m/z;
Oxo-1,2-diamino pyridin-3-yl] amino } carbonyl measured value (M+H) +=528.02m/z
Base) amino]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-0.006 calculated value (M-H) -=482.15m/z;
Dimethyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=481.95m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.005 calculated value (M-H) -=570.20m/z;
Oxo-5-propyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=569.98m/z
Base } carbonyl) amino]-3-(3, the 4-diethoxybenzene
Base) propionic acid
(3S)-3-(3-butoxy phenyl)-3-[({[1-(2-0.005 calculated value (M+H) +=514.17m/z;
The benzyl chloride base)-and 4-hydroxyl-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=514.00m/z
Pyridine-3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-{[({1-[2-chloro-5-(methyl sulphonyl) 0.003 calculated value (M-H) -=532.10m/z;
Benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-measured value (M-H) -=531.94m/z
The 3-yl } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.08 calculated value (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=468.03m/z
Base) amino]-4-(2-aminomethyl phenyl) butyric acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=514.14m/z;
Oxo-1,2-dichloropyridine-3-yl] amino } carbonyl measured value (M-H) -=513.95m/z
Base) amino]-3-[3-(2-methoxy ethoxy) benzene
Base] propionic acid
(3S)-3-[({[1-(4-chloro-2-methoxy-benzyl)-0.025 calculated value (M-H) -=484.13m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=483.93m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.003 calculated value (M-H) -=556.18m/z;
Oxo-1,2-diamino pyridin-3-yl] amino } carbonyl measured value (M-H) -=555.94m/z
Base) amino]-3-(3,4-dipropoxy phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.12 calculated value (M-H) -=522.18m/z;
Oxo-2,5,6,7,8,9-six hydrogen-1H-cyclopentadiene measured value (M-H) -=521.98m/z
And [b] pyridin-3-yl] amino } carbonyl) amino]-3-
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-12 calculated values (M-H) -=530.15m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=529.92m/z
Base) amino]-4, the 4-diphenyl butyric acid
(3S)-and 3-{[({1-[2-(difluoro-methoxy) phenyl]-0.075 calculated value (M-H) -=486.15m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } measured value (M-H) -=486.00m/z
Amino) carbonyl] amino }-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-{[({4-hydroxy-5-methyl base-2-oxo-1-4 calculated values (M-H) -=448.19m/z;
[(1R)-and the 1-styroyl]-1,2-dihydropyridine-3-measured value (M-H) -=447.99m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-0.03 calculated value (M-H) -=496.16m/z;
Oxo-5-propyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=495.96m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.05 calculated value (M-H) -=496.16m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=495.98m/z
Base) amino]-3-(3,4-diethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.05 calculated value (M-H) -=476.08m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=475.93m/z
Base) amino]-3-(3, the 5-difluorophenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-0.02 calculated value (M-H) -=490.12m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=489.97m/z
Base]-3-(2-naphthyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-0.025 calculated value (M+H) +=446.11m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M+H) +=446.08m/z
Base]-3-(5-methyl-2-furyl) propionic acid
(3S)-3-[({[1-[2-benzyl chloride base]-4-hydroxyl-2-0.025 calculated value (M-H) -=584.21m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=583.98m/z
Base) amino]-3-(3,4-dibutoxy phenyl) third
Acid
(3S)-3-{[({4-hydroxyl-1-[2-(sulfonyloxy methyl 0.035 calculated value (M+H) +=500.15m/z;
Base) benzyl]-2-oxo-1,2-dihydropyridine-3-measured value (M+H) +=500.01m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-0.2 calculated value (M-H) -=490.12m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=489.91m/z
Base]-3-(1-naphthyl) propionic acid
(3S)-3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-0.03 calculated value (M-H) -=526.17m/z;
Oxo-5-propyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=525.95m/z
Base } carbonyl) amino]-3-(3-ethoxyl phenenyl) third
Acid
(3S)-3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-0.015 calculated value (M-H) -=570.20m/z;
Oxo-5-propyl group-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=569.97m/z
Base } carbonyl) amino]-3-(3, the 4-diethoxybenzene
Base) propionic acid
(3S)-3-[({[1-(2, the 6-dimethyl benzyl)-4-hydroxyl 0.035 calculated value (M-H) -=448.19m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=448.02m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-and 3-[3,5-two (trifluoromethyl) phenyl]-3-0.22 calculated value (M-H) -=576.08m/z;
[({ [1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-measured value (M-H) -=575.91m/z
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia
Base] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.006 calculated value (M-H) -=506.09m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=505.93m/z
Base) amino]-3-[3-(difluoro-methoxy) phenyl] third
Acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-0.225 calculated value (M-H) -=455.11m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=455.09m/z
Base) amino]-4-pyridine-2-base butyric acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-0.0006 calculated value (M-H) -=542.17m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=542.06m/z
Base } carbonyl) amino]-3-(3, the 4-diethoxybenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-0.002 calculated value (M-H) -=499.15m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=498.07m/z
Base } carbonyl) amino]-3-(3-ethoxyl phenenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-0.020 calculated value (M+H) +=500.16
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia m/z; Measured value (M+H) +=500.02
Base } carbonyl) amino]-3-(3-methoxyl group-4-methyl m/z
Phenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-0.030 calculated value (M-H) -=504.13m/z;
2-oxo-1,2 dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=504.04m/z
Base) amino]-3-(2-naphthyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-0.015 calculated value (M-H) -=526.17m/z;
Hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=525.95m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-0.025 calculated value (M-H) -=526.17m/z;
Hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=525.97m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-methoxy
Base-4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-0.004 calculated value (M-H) -=570.20m/z;
Hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=570.00m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3,4-two for 3-
Ethoxyl phenenyl) propionic acid
(3S)-3-[{[1-(2-chloro-6-cyano group benzyl)-4-hydroxyl 0.007 calculated value (M-H) -=479.11m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=478.90m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-0.03 calculated value (M-H) -=496.16m/z;
Hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=495.97m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-0.015 calculated value (M-H) -=512.16m/z;
Dimethyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=51195m/z
Amino } carbonyl) amino]-3-(3-methoxyl group-4-first
The base phenyl) propionic acid
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-0.003 calculated value (M-H) -=556.18m/z;
Dimethyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=555.99m/z
Amino } carbonyl) amino]-3-(3, the 4-diethoxy
Phenyl) propionic acid
Table 6
Title IC 50Mass-spectrometric data (m/z)
(nM)
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-2500 calculated values (M-H) -=504.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=50397m/z
Base) amino]-4-(1-naphthyl) butyric acid
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-30 calculated values (M-H) -=512.16m/z;
Dimethyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=511.99m/z
Amino } carbonyl) amino]-3-(3-ethoxyl phenenyl)
Propionic acid
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-40 calculated values (M-H) -=496.16m/z;
Dimethyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=496.05m/z
Amino } carbonyl) amino]-3-(3, the 4-dimethyl benzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-5 calculated values (M-H) -=498.15m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=497.91m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-2 calculated values (M-H) -=572.18m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=571.96m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3,4-two for 3-
Ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-6 calculated values (M-H) -=528.15m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=527.95m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-methoxy
Base-4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-3 calculated values (M-H) -=528.15m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=527.99m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-15 calculated values (M-H) -=556.09m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=555.97m/z
Base) amino]-3-[3-(1,1,2,2-tetrafluoro oxyethyl group)
Phenyl] propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-700 calculated values (M-H) -=488.08m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=487.96m/z
Base) amino]-4-(2-chloro-phenyl-) butyric acid
(3S)-3-{[({4-hydroxyl-1-[3-(methylthio group) benzyl 20 calculated values (M-H) -=466.14m/z;
Base]-2-oxo-1,2-dihydropyridine-3-yl } ammonia measured value (M-H) -=466.04m/z
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-15 calculated values (M-H) -=482.15m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=482.02m/z
Base } carbonyl) amino]-3-(3, the 4-3,5-dimethylphenyl)
Propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-3 calculated values (M-H) -=512.16m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=512.03m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3,4-two for 3-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-5-cyclopropyl-20 calculated value (M+H) +=496.16m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=496.05m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(4-chloro-phenyl-)-4-hydroxyl-2-50 calculated values (M-H) -=494.15m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=494.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(3-benzyl chloride base)-4-hydroxyl-5-20 calculated values (M-H) -=468.13m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=468.02m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2, the 6-dichloro benzyl)-4-hydroxyl-20 calculated value (M-H) -=502.09m/z;
5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=501.92m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[4-hydroxy-5-methyl base-1-(4-methyl 150 calculated values (M-H) -=448.19m/z;
Benzyl)-and 2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=448.05m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
3-(1-cumarone-2-yl)-3-[({[1-(2-chlorine 140 calculated values (M-H) -=480.10m/z;
Phenyl)-and 4-hydroxyl-2-oxo-1,2-dihydropyridine-measured value (M-H) -=479.96m/z
The 3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-[({[1-(2-oxygen benzyl)-4-hydroxyl-2-3 calculated values (M-H) -=524.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=523.95m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-ethoxyl phenenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-15 calculated value (M-H) -=520.13m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=520.00m/z
Base]-3-(6-methoxyl group-2-naphthyl) propionic acid
(3S)-3-[({[1-(3, the 5-dimethoxy-benzyl)-4-70 calculated values (M-H) -=494.19m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=494.04m/z
The 3-yl] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2, the 6-difluorobenzyl)-4-hydroxyl-25 calculated value (M-H) -=470.15m/z;
5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=470.03m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M+H) +=570.20m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=570.00m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3,4-diethoxy phenyl) propionic acid
(3S)-3-{[({4-hydroxyl-1-[3-(sulfonyloxy methyl 25 calculated values (M-H) -=498.13m/z;
Base) benzyl]-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=498.01m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-3 calculated values (M-H) -=556.19m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=556.02m/z
The 3-yl] amino } carbonyl) amino]-3-(3, the 4-diethyl
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-4 calculated values (M-H) -=512.16m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=512.02m/z
The 3-yl] amino } carbonyl) amino]-3-(3-oxyethyl group
Phenyl) butyric acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-45 calculated values (M-H) -=496.16m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=496.01m/z
The 3-yl] amino } carbonyl) amino]-3-(3, the 4-diformazan
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-25 calculated values (M-H) -=512.16m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M-H) -=511.97m/z
The 3-yl] amino } carbonyl) amino]-3-(the 3-methoxyl group-
The 4-aminomethyl phenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-115 calculated value (M-H) -=458.11m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=457.99m/z
Base]-3-(4,5-dimethyl-4-furyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-160 calculated value (M-H) -=520.13m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=519.97m/z
Base]-3-(4-methoxyl group-1-naphthyl) propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-115 calculated values (M-H) -=468.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=467.98m/z
Base) amino]-the 5-phenylpentanoic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-12 calculated values (M-H) -=534.14m/z;
Oxo-1,2-dihydroquinoline-3-yl] amino } carbonyl measured value (M-H) -=533.94m/z
Base) amino]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-18 calculated values (M+H) +=510.18m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=510.06m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3, the 4-3,5-dimethylphenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-7 calculated values (M+H) +=500.16m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=500.06m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=512.16m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=512.03m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-5-cyclopropyl-14 calculated value (M+H) +=526.17m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=526.01m/z
Amino } carbonyl) amino]-3-(3-ethoxyl phenenyl)
Propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-5-cyclopropyl-6 calculated value (M+H) +=570.20m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=570.04m/z
Amino } carbonyl) amino]-3-(3, the 4-diethoxy
Phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-30 calculated values (M-H) -=506.09m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=505.96m/z
Base) amino]-3-[4-(difluoro-methoxy) phenyl] third
Acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-105 calculated value (M-H) -=491.11m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M-H) -=490.96m/z
Base]-3-quinoline-2-base propionic acid
(3S)-3-[({[1-(2-fluoro-6-methoxy-benzyl)-10 calculated values (M-H) -=482.17m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=482.02m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-15 calculated values (M+H) +=528.19m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M+H) +=528.04m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-7 calculated values (M+H) +=558.20m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M+H) +=558.07m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(5-chloro-2-luorobenzyl)-4-hydroxyl 15 calculated values (M-H) -=486.12m/z;
Base-5-methyl-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=486.00m/z
Base] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-14 calculated values (M-H) -=534.14m/z;
Oxo-1,2-dihydroquinoline-3-yl] amino } carbonyl measured value (M-H) -=533.95m/z
Base) amino]-3-(3-methoxyl group-4-aminomethyl phenyl)
Propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-4 calculated values (M-H) -=578.17m/z;
Oxo-1,2-dihydroquinoline-3-yl] amino } carbonyl measured value (M-H) -=577.99m/z
Base) amino]-3-(3,4-diethoxy phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-25 calculated values (M-H) -=518.15m/z;
Oxo-1,2-dihydroquinoline-3-yl] amino } carbonyl measured value (M-H) -=517.96m/z
Base) amino]-3-(3, the 4-3,5-dimethylphenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-150 calculated values (M+H) +=443.11m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M+H) +=443.03m/z
Base) amino]-3-pyridine-2-base propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M-H) -=498.14m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=498.04m/z
Base) amino]-3-(3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-7 calculated values (M-H) -=528.15m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=528.02m/z
Base) amino]-3-(3,5-diethoxy phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-60 calculated values (M+H) +=498.18m/z;
Sec.-propyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=498.05m/z
Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) third
Acid
(3S)-3-[({[1-(5-fluoro-2-methyl-benzyl)-4-20 calculated values (M+H) +=468.19m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M+H) +=468.07m/z
The 3-yl] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-{[({4-hydroxy-5-methyl base-2-oxo-1-1500 calculated values (M+H) +=450.20m/z;
[(1S)-and the 1-styroyl]-1,2-dihydropyridine-3-measured value (M+H) +=450.07m/z
Base } amino) carbonyl] amino }-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-3 calculated values (M+H) +=602.23m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M+H) +=602.04m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3,4-two for 3-
Ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-isopropoxy benzyl 7 calculated values (M-H) -=526.17m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=526.04m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-15 calculated values (M+H) +=558.20m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M+H) +=558.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-methoxy
Base-4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=544.19m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=544.04m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(5-ethanoyl-2-methoxybenzyl 33 calculated values (M-H) -=492.18m/z;
Base)-and 4-hydroxyl-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=492.04m/z
Base] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-35 calculated value (M-H) -=548.16m/z;
5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=548.01m/z
Amino } carbonyl) amino]-3-(6-methoxyl group-2-naphthalene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methoxy-benzyl)-17 calculated values (M+H) +=542.21m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M+H) +=542.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3,4-two for 3-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M-H) -=493.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=492.95m/z
Base) amino]-3-(1-Methyl-1H-indole-5-yl)
Propionic acid
(3S)-3-[({[2-(2-benzyl chloride base)-5-hydroxyl-6-18 calculated values (M+H) +=471.14m/z;
Methyl-3-oxo-2,3-dihydrogen dazin-4-yl] ammonia measured value (M+H) +=471.00m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-5 calculated values (M-H) -=534.14m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=533.91m/z
Base } carbonyl) amino]-3-(6-methoxyl group-2-naphthyl)
Propionic acid
(3S)-3-[({[2-(2-benzyl chloride base)-5-hydroxyl-6-5 calculated values (M+H) +=501.15m/z;
Methyl-3-oxo-2,3-dihydrogen dazin-4-yl] ammonia measured value (M+H) +=501.01m/z
Base } carbonyl) amino]-3-(3-ethoxyl phenenyl) third
Acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-30 calculated value (M+H) +=448.07m/z;
1,2-dihydropyridine-3-yl] amino } carbonyl) ammonia measured value (M+H) +=447.97m/z
Base]-3-thiophene-2-base propionic acid
(3S)-3-[({[5-chloro-1-(2-benzyl chloride base)-4-hydroxyl 6 calculated values (M-H) -=488.08m/z;
Base-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=487.97m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-(3-butoxy phenyl)-3-[({[1-(2-20 calculated values (M-H) -=552.19m/z;
The benzyl chloride base)-and 4-hydroxyl-2-oxo-2,5,6,7-four measured values (M-H) -=552.01m/z
Hydrogen-1H-cyclopenta [b] pyridin-3-yl] ammonia
Base } carbonyl) amino] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-5 calculated values (M-H) -=524.16m/z;
Oxo-1,2-diamino pyridin-3-yl] amino } carbonyl measured value (M-H) -=524.00m/z
Base) amino]-3-[3-(cyclopentyloxy) phenyl] propionic acid
(3S)-3-[({[2-(2-benzyl chloride base)-5-hydroxyl-6-3 calculated values (M+H) +=545.18m/z;
Methyl-3-oxo-2,3-dihydrogen dazin-4-yl] ammonia measured value (M+H) +=544.98m/z
Base } carbonyl) amino]-3-(3, the 4-diethoxybenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-3 calculated values (M-H) -=507.14m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=506.94m/z
Base } carbonyl) amino]-3-(the 1-Methyl-1H-indole-
The 5-yl) propionic acid
(3S)-3-[({[2-(2-benzyl chloride base)-5-hydroxyl-6-10 calculated values (M+H) +=545.18m/z;
Methyl-3-oxo-2,3-dihydrogen dazin-4-yl] ammonia measured value (M+H) +=545.01m/z
Base } carbonyl) amino]-3-(3, the 5-diethoxybenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-70 calculated values (M-H) -=538.10m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=537.95m/z
Base } carbonyl) amino]-3-[4-(trifluoromethoxy)
Phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-10 calculated values (M-H) -=538.10m/z;
Methyl-2-oxo-1,2-diamino pyridin-3-yl] ammonia measured value (M-H) -=537.95m/z
Base } carbonyl) amino]-3-[3-(trifluoromethoxy)
Phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-4 calculated values (M+H) +=486.14m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=486.04m/z
Base } carbonyl) amino]-3-(4-p-methoxy-phenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-15 calculated values (M-H) -=520.13m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=520.03m/z
Base) amino]-3-(6-methoxyl group-2-naphthyl) propionic acid
(3S)-3-{[({1-[2-fluoro-6-(trifluoromethyl) benzyl 100 calculated values (M-H) -=520.15m/z;
Base]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=519.97m/z
Pyridin-3-yl } amino) carbonyl] amino }-3-(4-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-10 calculated values (M-H) -=522.10m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=521.96m/z
Base } carbonyl) amino]-3-[3-(trifluoromethyl) benzene
Base] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-3 calculated values (M-H) -=484.13m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=48400m/z
Base } carbonyl) amino]-3-(3-p-methoxy-phenyl) third
Acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-20 calculated values (M+H) +=510.18m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=51005m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-4 calculated values (M+H) +=540.19m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=540.10m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M+H) +=540.19m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=540.09m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-3 calculated values (M-H) -=542.17m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=542.00m/z
Base } carbonyl) amino]-3-(3, the 5-diethoxybenzene
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=556.19m/z;
5-ethyl-4-hydroxyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=556.01m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=530.17m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=530.04m/z
Amino } carbonyl) amino]-3-(3-ethoxyl phenenyl)
Propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-15 calculated values (M-H) -=538.17m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=538.03m/z
Base } carbonyl) amino]-3-[3-(cyclopentyloxy) benzene
Base] propionic acid
3-(1,1 '-biphenyl-4-yl)-3-[({[1-(2-benzyl chloride 130 calculated values (M-H) -=530.15m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=529.96m/z
Pyridin-3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-30 calculated values (M+H) +=580.15m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=580.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(2,2, the 2-trifluoro ethoxy) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-15 calculated values (M+H) +=554.13m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=554.00m/z
Base } carbonyl) amino]-3-[3-(2,2,2-trifluoro second
The oxygen base) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-3 calculated values (M+H) +=514.17m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=514.05m/z
Base } carbonyl) amino]-3-(3-isopropyl phenyl)
Propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M+H) +=558.20m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=558.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3-different third for 3-
Oxygen base phenyl) propionic acid
Table 7
Title IC 50Mass-spectrometric data (m/z)
(nM)
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-9 calculated values (M+H) +=500.16m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=500.01m/z
Base } carbonyl) amino]-3-(4-methoxyl group-3-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-10 calculated values (M+H) +=554.21m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=554.06m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=580.19m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=580.07m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(6-methoxy
Base-2-naphthyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-12 calculated values (M+H) +=530.17m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=530.00m/z
Base } carbonyl) amino]-3-(3, the 5-dimethoxy-4 '-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-12 calculated values (M+H) +=554.21m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=554.05m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(3-propoxy-phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-propoxy-benzyl)-10 calculated values (M+H) +=528.19m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=528.06m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-isobutoxy benzyl 22 calculated values (M+H) +=542.21m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M+H) +=542.06m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-15 calculated values (M+H) +=540.19m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=540.07m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-propoxy-phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=540.19m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=540.04m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M+H) +=584.22m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=58405m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-40 calculated values (M+H) +=592.19m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=592.04m/z
Base } carbonyl) amino]-3-(2 ', 6 '-dimethoxy-
1,1 '-biphenyl-4-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-30 calculated values (M+H) +=509.16m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=509.03m/z
Base } carbonyl) amino]-3-(the 1-Methyl-1H-indole-
The 7-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=570.20m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=570.09m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-propoxy-benzyl)-5 calculated values (M+H) +=558.20m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=558.03m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-isobutoxy benzyl 14 calculated values (M+H) +=572.22m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M+H) +=572.05m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(3-second
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-isopropoxy benzyl 7 calculated values (M+H) +=558.20m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M+H) +=558.03m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(3-second
Oxygen base phenyl) propionic acid
(3S)-and 3-{[({1-[2-chloro-6-(2,2,2-trifluoro second 4 calculated values (M+H) +=598.16m/z;
The oxygen base) benzyl]-4-hydroxy-5-methyl base-2-oxo-measured value (M+H) +=597.99m/z
1,2-dihydropyridine-3-yl } amino) carbonyl] ammonia
Base }-3-(3-ethoxyl phenenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-15 calculated value (M+H) +=502.12m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M+H) +=501.98m/z
Base) amino]-3-[4-(methylthio group) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=606.20m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=606.04m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(6-methoxyl group-2-naphthyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-6 calculated values (M+H) +=498.14m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=498.02m/z
Base } carbonyl) amino]-3-(2,3-dihydro-1-benzo
Furans-5-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=553.19m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=553.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(1-methyl
-1H-indoles-5-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=542.17m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=542.06m/z
Pyridine-3-yl] amino } carbonyl) amino]-(2,3-two for 3-
Hydrogen-1-cumarone-5-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=614.22m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=614.11m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(3,5-diethoxy phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-isopropoxy benzyl 4 calculated values (M+H) +=558.20m/z;
Base)-and 4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M+H) +=558.02m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(3-second
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=558.20m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=558.07m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-third oxygen
The base phenyl) butyric acid
(3S)-3-(3-butoxy phenyl)-3-[({[1-(2-4 calculated values (M+H) +=572.22m/z;
Chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-measured value (M+H) +=572.04m/z
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl
Base) amino] propionic acid
(3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxy benzylidene 3 calculated values (M+H) +=564.13m/z;
Base)-and 4-hydroxyl-2-oxo-1,2-dihydropyridine-3-measured value (M+H) +=563.99m/z
Base] amino } carbonyl) amino]-3-(3-phenetole
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=544.19m/z;
4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +=544.06m/z
Amino } carbonyl) amino]-3-(3-isopropoxy benzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-2 calculated values (M+H) +=52416m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=524.03m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(2,3-dihydro-1-cumarone-5-yl) propionic acid
(3S)-3-[({[2-(2-chloro-6-ethoxy benzyl)-7 calculated values (M+H) +=515.19m/z;
5-hydroxyl-6-methyl-3-oxo-2, the 3-dihydro measured value (M+H) of rattling away +=515.05m/z
Piperazine-4-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=584.21m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=584.10m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(3-propoxy-phenyl) propionic acid
(3S)-3-[({[2-(2-chloro-6-ethoxy benzyl)-3 calculated values (M+H) +=545.18m/z;
5-hydroxyl-6-methyl-3-oxo-2, the 3-dihydro measured value (M+H) of rattling away +=545.05m/z
Piperazine-4-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[2-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=559.20m/z;
5-hydroxyl-6-methyl-3-oxo-2, the 3-dihydro measured value (M+H) of rattling away +=559.04m/z
Piperazine-4-yl] amino } carbonyl) amino]-(3-different third for 3-
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-6 calculated values (M+H) +=610.23m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=610.14m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-[3-(cyclopentyloxy) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-7 calculated values (M+H) +=566.21m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=555.09m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(cyclopentyloxy) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=526.17m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=526.07m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-the 3-phenylpropionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-8 calculated values (M+H) +=482.15m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=482.07m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-benzene
The base propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-5 calculated values (M+H) +=512.16m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-measured value (M+H) +=512.03m/z
The 3-yl] amino } carbonyl) amino]-3-(2, the 3-dihydro-
1-cumarone-5-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-4 calculated values (M+H) +=594.21m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=594.05m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(1,3-diethyl-2-indoles-2,3-dihydro-1H-benzene
And imidazoles-5-yl) propionic acid
(3S)-3-[({[1-(2-fluoro-6-ethoxy benzyl)-3 calculated values (M+H) +=568.15m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=568.00m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-[3-(three
Methyl fluoride) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M+H) +=584.14m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=584.01m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-[3-(three
The fluorine methoxyl group) phenyl] propionic acid
(3S)-3-{[({1-[2-chloro-6-(2-methoxyl group ethoxy 6 calculated values (M-H) -=568.18m/z;
Base) benzyl]-4-hydroxyl-2-oxo-2,5,6,7-four measured values (M-H) -=568.03m/z
Hydrogen-1H-cyclopenta [b] pyridin-3-yl } ammonia
Base) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({1-[2-chloro-6-(2-methoxyl group ethoxy 4 calculated values (M-H) -=598.19m/z;
Base) benzyl]-4-hydroxyl-2-oxo-2,5,6,7-four measured values (M-H) -=598.01m/z
Hydrogen-1H-cyclopenta [b] pyridin-3-yl } ammonia
Base) carbonyl] amino }-3-(3-ethoxyl phenenyl) third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-4 calculated values (M+H) +=538.17m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=538.09m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(ring propoxy-) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=556.19m/z;
4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro measured value (M-H) -=556.02m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(3-second
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=526.17nm/z;
4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro measured value (M-H) -=526.02m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=570.20m/z;
5-ethyl-4-hydroxyl-6-methyl-2-oxo-1,2-measured value (M-H) -=570.04m/z
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-
(3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=540.19m/z;
5-ethyl-4-hydroxyl-6-methyl-2-oxo-1,2-measured value (M-H) -=540.05m/z
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-
(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-25 calculated values (M+H) +=562.09m/z;
Methyl-2-oxo-1,2-diamino pyridin-3-yl] ammonia measured value (M+H) +=562.17m/z
Base } carbonyl) amino]-3-(2 '-methoxyl group-1,1 '-Lian
Benzene-4-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=57020m/z;
4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro measured value (M-H) -=570.00m/z
Pyridin-3-yl] amino } carbonyl) amino]-(3-is different for 3-
The propoxy-phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=512.16m/z;
4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydro measured value (M-H) -=512.01m/z
Pyridin-3-yl] amino } carbonyl) amino]-the 3-phenyl
Propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-5 calculated values (M-H) -=584.22m/z;
5-ethyl-4-hydroxyl-6-methyl-2-oxo-1,2-measured value (M-H) -=584.03m/z
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-
(3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M-H) -=526.17m/z;
5-ethyl-4-hydroxyl-6-methyl-2-oxo-1,2-measured value (M-H) -=526.00m/z
Dihydropyridine-3-yl] amino } carbonyl) amino]-3-
Phenylpropionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-6 calculated values (M-H) -=592.19m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=592.00m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(6-ethoxy
Base-2-naphthyl) propionic acid
(3S)-3-[({[2-(2-benzyl chloride base)-6-ethyl-5-22 calculated values (M-H) -=483.14m/z;
Hydroxyl-3-oxo-2,3-dihydrogen dazin-4-yl] ammonia measured value (M-H) -=483.03m/z
Base } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-15 calculated values (M-H) -=536.20m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=535.99m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-isobutyl phenenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-4 calculated values (M+H) +=509.16m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=509.05m/z
Base } carbonyl) amino]-3-(the 1-Methyl-1H-indole-
The 6-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-4 calculated values (M-H) -=55017m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M-H) -=550.01m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-[3-(ring propoxy-) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-15 calculated values (M-H) -=574.17m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=574.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(6-oxyethyl group-2-naphthyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-23 calculated values (M-H) -=526.17m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M-H) -=526.04m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-phenyl third
Acid
(3S)-3-[({[2-(2-chloro-6-ethoxy benzyl)-22 calculated values (M-H) -=584.22m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M-H) -=584.09m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3-different third for 3-
Oxygen base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-20 calculated values (M-H) -=540.19m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M-H) -=540.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-6 calculated values (M-H) -=570.20m/z;
4-hydroxyl-2-oxo-5-propyl group-1,2-dihydro pyrrole measured value (M-H) -=570.04m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxy
The base phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-40 calculated values (M-H) -=530.15m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=530.02m/z
Base) amino]-3-(4 '-methyl isophthalic acid, 1 '-biphenyl-4-
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-4 calculated values (M-H) -=533.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=533.00m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(1-Methyl-1H-indole-5-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=58220m/z;
5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydro measured value (M-H) -=582.07m/z
Pyridin-3-yl] amino } carbonyl) amino]-(3-is different for 3-
The propoxy-phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=538.17m/z;
5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydro measured value (M-H) -=538.06m/z
Pyridin-3-yl] amino } carbonyl) amino]-3-(4-first
The base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-propoxy-benzyl)-6 calculated values (M-H) -=526.17m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=526.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-methoxy-benzyl)-3 calculated values (M-H) -=498.14m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=498.01m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
3-[({[2-(2-chloro-6-ethoxy benzyl)-4-hydroxyl 13 calculated values (M-H) -=548.16m/z;
-5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=548.01m/z
Amino } carbonyl) amino]-3-(2-naphthyl) propionic acid
3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl 8 calculated values (M-H) -=576.12m/z;
-5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M-H) -=576.00m/z
Amino } carbonyl) amino]-3-[4-(sulfonyloxy methyl
Base) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-27 calculated values (M-H) -=560.16m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=560.04m/z
Base) amino]-3-(3 '-oxyethyl group-1,1 '-biphenyl-4-
Base) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-20 calculated values (M-H) -=56419m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M-H) -=564.00m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-[3-(cyclobutoxy group) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-17 calculated values (M-H) -=550.17m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=550.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(cyclobutoxy group) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=556.19m/z;
4-hydroxyl-6-methyl-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=556.05m/z
Pyridine-3-yl] amino } carbonyl) amino]-(3-different third for 3-
Oxygen base phenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-10 calculated value (M-H) -=523.17m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=522.99m/z
Base) amino]-3-(3-tetramethyleneimine-1-base phenyl) third
Acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-22 calculated value (M-H) -=537.19m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=537.08m/z
Base) amino]-3-(3-piperidines-1-base phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-22 calculated values (M-H) -=580.22m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M-H) -=580.04m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-[3-(1-ethyl propoxy-) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-20 calculated values (M-H) -=566.20m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=566.01m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(1-ethyl propoxy-) phenyl] propionic acid
(3S)-3-(4-chloro-3-isopropyl phenyl)-3-23 calculated values (M-H) -=586.15m/z;
[({ [1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-2-measured value (M-H) -=585.92m/z
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta
[b] pyridin-3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-38 calculated values (M-H) -=572.14m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=572.00m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(4-chloro-3-isopropyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-30 calculated values (M-H) -=530.15m/z;
Oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=530.02m/z
Base) amino]-3-(3 '-methyl isophthalic acid, 1 '-biphenyl-4-
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M-H) -=533.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=532.97m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(1-Methyl-1H-indole-6-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-3 calculated values (M-H) -=551.17m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M-H) -=551.02m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(1-methyl
-1H-indoles-6-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-23 calculated values (M-H) -=560.16m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=560.01m/z
Base } carbonyl) amino]-3-(4 '-methoxyl group-1,1 '-Lian
Benzene-4-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-55 calculated values (M+H) +=546.18m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M+H) +=546.11m/z
Base } carbonyl) amino]-3-(2 '-methyl isophthalic acid, 1 '-biphenyl
-4-yl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M-H) -=560.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=560.00m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(6-methoxyl group-2-naphthyl) propionic acid
(3S)-3-(4-chloro-3-ethoxyl phenenyl)-3-25 calculated values (M-H) -=572.14m/z;
[({ [1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-2-measured value (M-H) -=571.94m/z
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta
[b] pyridin-3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-30 calculated values (M-H) -=558.12m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=557.77m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(4-chloro-3-ethoxyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M+H) +=582.24m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=582.10m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-(3-isobutyl phenenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-ethoxy benzyl)-4 calculated values (M+H) +=514.17m/z;
4-hydroxy-5-methyl base-2-oxo-1,2-dihydro pyrrole measured value (M+H) +=514.08m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(4-methyl
Phenyl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-134 calculated value (M+H) +=534.11m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M+H) +=534.07m/z
Base) amino]-3-[4-(methyl sulphonyl) phenyl] third
Acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-225 calculated values (M+H) +=594.09m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=593.98m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(2,4-two chloro-3-ethoxyl phenenyls) propionic acid
(3S)-3-{[({1-[2-chloro-5-(piperidines-1-base sulphur 27 calculated values (M-H) -=615.17m/z;
Acyl group) benzyl]-4-hydroxy-5-methyl base-2-oxo-measured value (M-H) -=615.04m/z
1,2-dihydropyridine-3-yl } amino) carbonyl] ammonia
Base }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({1-[2-chloro-5-(tetramethyleneimine-1-base 15 calculated values (M-H) -=601.15m/z;
Alkylsulfonyl) benzyl]-4-hydroxy-5-methyl base-2-oxygen measured value (M-H) -=601.03m/z
Generation-1,2-dihydropyridine-3-yl } amino) carbonyl]
Amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-2 calculated values (M+H) +=582.20m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=582.10m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-[3-(ring propoxy-) phenyl] propionic acid
(3S)-3-{[({1-[2-chloro-6-(cyclopentyl methoxy 20 calculated values (M-H) -=566.20m/z;
Base) benzyl]-4-hydroxy-5-methyl base-2-oxo-measured value (M-H) -=566.09m/z
1,2-dihydropyridine-3-yl } amino) carbonyl] ammonia
Base }-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-{[({1-[2-(benzyloxy)-6-benzyl chloride 10 calculated values (M-H) -=574.17m/z;
Base]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=574.01m/z
Pyridin-3-yl } amino) carbonyl] amino }-3-(4-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-3 calculated values (M+H) +=604.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=604.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-chloro-4,5-diethoxy phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-500 calculated values (M+H) +=652.14m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=651.98m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(2,4-two chloro-3,5-diethoxy phenyl)
Propionic acid
(3R)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-450 calculated values (M+H) +=63812m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=637.97m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(2,4-two chloro-3,5-diethoxy phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-9 calculated values (M+H) +=552.19m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=552.10m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(cyclo propyl methoxy) phenyl] propionic acid
(3S)-3-[({[1-(2-chloro-6-ethoxy benzyl)-4 calculated values (M+H) +=596.21m/z;
4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles measured value (M+H) +=596.11m/z
Pentadiene is [b] pyridin-3-yl also] amino } carbonyl)
Amino]-3-[3-(cyclo propyl methoxy) phenyl] third
Acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-10 calculated values (M+H) +=566.20m/z;
Hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta measured value (M+H) +=566.12m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-[3-(cyclo propyl methoxy) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-13 calculated values (M-H) -=54416m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=544.00m/z
Base } carbonyl) amino]-(2, the 4-diethoxy is phonetic for 3-
Pyridine-5-yl) propionic acid
(3S)-and 3-[({[1-(2,3-two chloro-6-ethoxy benzylidene 5 calculated values (M-H) -=572.13m/z;
Base)-and 4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=571.97m/z
Cyclopenta [b] pyridin-3-yl] amino } carbonyl
Base) amino]-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[3-(cyclo propyl methoxy) phenyl]-3-7 calculated values (M-H) -=628.16m/z;
[({ [1-(2,3-two chloro-6-ethoxy benzyls)-4-hydroxyl measured value (M-H) -=627.98m/z
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircles penta 2
Alkene is [b] pyridin-3-yl also] amino } carbonyl) amino]
Propionic acid
(3S)-and 3-[({[1-(2,3-two chloro-6-ethoxy benzylidene 3 calculated values (M-H) -=602.15m/z;
Base)-and 4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=601.99m/z
Cyclopenta [b] pyridin-3-yl] amino } carbonyl
Base) amino]-3-(3-ethoxyl phenenyl) propionic acid
(3S)-and 3-[({[1-(2,3-two chloro-6-ethoxy benzylidene 5 calculated values (M-H) -=616.16m/z;
Base)-and 4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=616.01m/z
Cyclopenta [b] pyridin-3-yl] amino } carbonyl
Base) amino]-3-(3-isopropyl phenyl) propionic acid
(3S)-3-({ [[1-(2-benzyl chloride base)-4-methoxyl group-2000 calculated value (M-H) -=482.14m/z;
2-oxo-1,2-dihydropyridine-3-yl] (methyl) ammonia measured value (M-H) -=482.07m/z
Base] carbonyl } amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-15 calculated values (M-H) -=560.16m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=559.98m/z
Base } carbonyl) amino]-3-(2 '-methoxyl group-1,1 '-Lian
Benzene-3-yl) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-20 calculated value (M-H) -=458.11m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=457.99m/z
Base) amino]-3-(5-methyl-2-furyl) propionic acid
3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-43 calculated value (M+H) +=548.13m/z;
5-methyl-2-oxo-1,2-dihydropyridine-3-yl] measured value (M+H) +-=548.07m/z
Amino } carbonyl) amino]-3-[4-(sulfonyloxy methyl
Base) phenyl] propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5 calculated value (M-H) -=470.11m/z;
2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyrrole measured value (M-H) -=469.96m/z
Pyridine-3-yl] amino } carbonyl) amino]-3-(2-furans
Base) propionic acid
3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-4 calculated value (M-H) -=444.10m/z;
2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl measured value (M-H) -=443.91m/z
Base) amino]-3-(2-furyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-18 calculated values (M-H) -=548.12m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=548.00m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[4-(trifluoromethyl) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-5 calculated values (M-H) -=494.15m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=494.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3-aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-10 calculated values (M-H) -=548.12m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=547.99m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
[3-(trifluoromethyl) phenyl] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-9 calculated values (M-H) -=508.16m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M-H) -=508.02m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(3, the 5-3,5-dimethylphenyl) propionic acid
(3S)-and 3-[3,5-two (trifluoromethyl) phenyl]-3-130 calculated values (M-H) -=615.11m/z;
[({ [1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-measured value (M-H) -=615.99m/z
2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyrrole
Pyridine-3-yl] amino } carbonyl) amino] propionic acid
(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl) benzyl 6 calculated values (M-H) -=536.12m/z;
Base]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=535.99m/z
Pyridin-3-yl } amino) carbonyl] amino }-3-(4-
Aminomethyl phenyl) propionic acid
(3S)-3-[({[1-(2-chloro-5-luorobenzyl)-4-hydroxyl 5 calculated values (M-H) -=486.12m/z;
Base-5-methyl-2-oxo-1,2-dihydropyridine-3-measured value (M-H) -=485.97m/z
Base] amino } carbonyl) amino]-3-(4-methylbenzene
Base) propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5-2 calculated values (M-H) -=525.19m/z;
Methyl-2-oxo-1,2-dihydropyridine-3-yl] ammonia measured value (M-H) -=525.00m/z
Base } carbonyl) amino]-3-[3-(diethylamino)
Phenyl] propionic acid
3-(1,1 '-biphenyl-4-yl)-3-[({[1-(2-benzyl chloride 30 calculated values (M-H) -=556.16m/z;
Base)-and 4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=555.99m/z
Cyclopenta [b] pyridin-3-yl] amino } carbonyl
Base) amino] propionic acid
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-8 calculated values (M+H) +=522.17m/z;
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta measured value (M+H) +=522.03m/z
[b] pyridin-3-yl] amino } carbonyl) amino]-3-
(2,3-dihydro-1H-indenes-5-yl) propionic acid
(3S)-3-[({[1-(2-chloro-6-methyl-benzyl)-4-10 calculated values (M+H) +=536.19m/z;
Hydroxyl-2-oxo-2,5,6,7-four ammonia-1H-encircle penta measured value (M+H) +=536.08m/z
Diene is [b] pyridin-3-yl also] amino } carbonyl) ammonia
Base]-3-(2,3-dihydro-1H-indenes-5-yl) propionic acid
The N-{1-[(2-chloro-phenyl-) methyl]-4-hydroxy-5-methyl 6000 calculated values (M+H) +=494.17m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl }-N '-measured value (M+H) +=494.01m/z
[(1S)-1-(4-aminomethyl phenyl)-2-(1H-1,2,3,4-
Tetrazolium-5-yl) ethyl] urea
(3S)-and 3-[1,1 '-xenyl]-3-base-3-{[({1-17 calculated values (M-H) -=556.16m/z;
[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-measured value (M-H) -=556.01m/z
2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyrrole
Pyridine-3-yl } amino) carbonyl] amino } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 13 calculated values (M-H) -=56411m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=564.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-the 3-{4-[(trifluoromethyl) the oxygen base] phenyl } third
Acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 13 calculated values (M-H) -=546.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=545.97m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-the 3-{4-[(difluoromethyl) the oxygen base] phenyl } third
Acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 10 calculated values (M-H) -=564.11m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=563.98m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-the 3-{3-[(trifluoromethyl) the oxygen base] phenyl } third
Acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 5 calculated values (M-H) -=546.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=546.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-the 3-{3-[(difluoromethyl) the oxygen base] phenyl } third
Acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 4 calculated values (M-H) -=596.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=596.02m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-{3-[(1,1,2,2-tetrafluoro ethyl) the oxygen base]
Phenyl } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 11 calculated values (M-H) -=538.17m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=538.04m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[3,5-dimethyl-4-(methoxyl group) phenyl]
Propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 5 calculated values (M+H) +=549.19m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M+H) +=549.02m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(1-ethyl-1H-indoles-5-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 7 calculated values (M-H) -=516.11m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=516.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(3, the 5-difluorophenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 3 calculated values (M-H) -=528.13m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=528.00m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[3-fluoro-4-(methoxyl group) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 17 calculated values (M-H) -=522.18m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=522.04m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(4-propyl group phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 20 calculated values (M-H) -=536.20m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=536.06m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(4-propyl group phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 267 calculated values (M-H) -=468.13m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=468.00m/z
Base } amino) carbonyl] amino }-3-(2-methylbenzene
Base) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 25 calculated values (M+H) +=522.18m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M+H) +=522.04m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(4-cyclopropyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 22 calculated values (M-H) -=505.13m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=504.98m/z
Base } amino) carbonyl] amino }-3-(3-quinolyl)
Propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 22 calculated values (M-H) -=531.14m/z,
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=530.99m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(3-quinolyl) propionic acid
3-([(1-{[2-chloro-6-(oxyethyl group) phenyl] first 8 calculated values (M-H) -=488.12m/z;
Base }-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=487.98m/z
-3-pyridyl) amino] carbonyl } amino)-3-(2-furan
The base of muttering) propionic acid
(3S)-and 3-[2,4-two (oxyethyl group)-5-pyrimidyl]-15 calculated values (M-H) -=570.18m/z;
The 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-measured value (M-H) -=570.14m/z
Oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta
[b] pyridin-3-yl } amino) carbonyl] amino } propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 19 calculated values (M+H) +=536.20m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M+H) +=536.07m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(4-cyclopropyl phenyl) propionic acid
(3R)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 15 calculated values (M-H) -=418.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=418.00m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] amino }
Butyric acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 8 calculated values (M-H) -=508.16m/z;
Base-2-oxo-2,5,6,7-four ammonia-1H-encircle penta 2 measured values (M-H) -=508.06m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(4-ethylphenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 17 calculated values (M-H) -=522.17m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=522.06m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[4-(1-methylethyl) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 30 calculated values (M-H) -=482.14m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=482.00m/z
Base } amino) carbonyl] chloro }-3-(4-ethylbenzene
Base) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 175 calculated values (M-H) -=496.16m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=496.01m/z
Base } amino) carbonyl] amino }-3-[4-(1-methyl
Ethyl) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 6 calculated values (M-H) -=510.14m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=510.00m/z
Base } amino) carbonyl] amino }-3-[4-(encircles third oxygen
Base) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 12 calculated values (M-H) -=496.16m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=495.99m/z
Base } amino) carbonyl] amino }-3-(4-propylbenzene
Base) propionic acid
The 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-5-35 calculated values (M-H) -=494.15m/z;
Methyl-2-oxo-1,2-dihydro-3-pyridyl } ammonia measured value (M-H) -=494.01m/z
Base) carbonyl] amino }-3-(4-cyclopropyl phenyl) third
Acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 18 calculated values (M-H) -=494.15m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=494.02m/z
Base } amino) carbonyl] amino }-3-(2, the 3-dihydro-
1H-indenes-5-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 13 calculated values (M-H) -=597.19m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=597.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(9-ethyl-9H-carbazole-3-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 23 calculated values (M-H) -=571.17m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=570.99m/z
Base } amino) carbonyl] amino }-3-(9-ethyl-9H-
Carbazole-3-yl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 3 calculated values (M-H) -=547.17m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=547.04m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(1-Methyl-1H-indole-5-yl)
Propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 3 calculated values (M-H) -=560.14m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=560.03m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-the 3-{3-[(difluoromethyl) the oxygen base] benzene
Base } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 25 calculated values (M-H) -=574.17m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=574.00m/z
Base } amino) carbonyl] amino }-3-[2-(ethoxy
Base) [1,1 '-xenyl]-4-yl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 20 calculated values (M-H) -=600.19m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=600.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[2-(oxyethyl group) [1,1 '-xenyl]-4-
Base] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 20 calculated values (M-H) -=544.16m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=544.04m/z
Base } amino) carbonyl] amino }-3-(2 '-methyl
[1,1 '-xenyl]-3-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 18 calculated values (M-H) -=544.16m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=544.00m/z
Base } amino) carbonyl] amino }-3-(3 '-methyl
[1,1 '-xenyl]-3-yl) propionic acid
(3S)-3-({ [(1-{[2-chloro-6-tetrahydrochysene-1 (2H)-90 calculated value (M-H) -=551.21m/z;
The pyridyl phenyl] methyl }-4-hydroxy-5-methyl base-measured value (M-H) -=551.06m/z
2-oxo-1,2-dihydro-3-pyridyl) amino] carbonyl
Base } amino)-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 23 calculated values (M-H) -=544.16m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=543.99m/z
Base } amino) carbonyl] amino }-3-(4 '-methyl
[1,1 '-xenyl]-3-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 3 calculated values (M-H) -=551.21m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=551.05m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[3-(diethylamino) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 20 calculated values (M-H) -=504.11m/z;
Base-5-methyl-2-oxo-1,3-dihydro-3-pyridine measured value (M-H) -503.96m/z
Base } amino) carbonyl] amino }-3-[3-(difluoro first
Base) phenyl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 16 calculated values (M-H) -=498.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=498.02m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(3-fluorophenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 9 calculated values (M-H) -=498.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=498.01m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(4-fluorophenyl) propionic acid
The N-{1-[(2-chloro-phenyl-) methyl]-the 4-hydroxy-5-methyl〉10000 calculated values (M-H) -=464.12m/z;
Base-2-oxo-1,2-dihydro-3-pyridyl }-N '-measured value (M-H) -=464.01m/z
[(R)-phenyl (1H-1,2,3,4-tetrazolium-5-yl) first
Base] urea
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 4 calculated values (M-H) -=521.16m/z;
Base]-4-hydroxy-5-methyl base-2-oxo-1,2-dihydro measured value (M-H) -=521.00m/z
-3-pyridyl } amino) carbonyl] amino }-3-(1-
Methyl-1H-indole-5-yl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 10 calculated values (M-H) -=565.14m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=565.04m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-[3-(diethylamino) phenyl]
Propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 4 calculated values (M-H) -=508.16m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=508.03m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(3-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 17 calculated values (M-H) -=494.15m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=49409m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-the 3-phenylpropionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 8 calculated values (M-H) -=496.13m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=495.99m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(3-hydroxy phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 9 calculated values (M-H) -=470.11m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=46998m/z
Base } amino) carbonyl] amino }-3-(3-hydroxybenzene
Base) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 50 calculated values (M-H) -=558.18m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=558.00m/z
Base } amino) carbonyl] amino }-3-(3 ', 5 '-diformazan
Base [1,1 '-xenyl]-3-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 15 calculated values (M-H) -=455.12m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=454.00m/z
Base } amino) carbonyl] amino }-the 3-phenylpropionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 3 calculated values (M-H) -=573.12m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=572.98m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-the 3-{3-[(methyl sulphonyl) amino] phenyl }
Propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 3 calculated values (M-H) -=587.14m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=586.98m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-the 3-{3-[(methyl sulphonyl) amino]
Phenyl } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 4 calculated values (M-H) -=530.13m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=530.03m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-[3-(difluoromethyl) phenyl] propionic acid
(2S, 3S)-the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-1500 calculated values (M-H) -=482.15m/z;
Hydroxy-5-methyl base-2-oxo-1,2-dihydro-3-pyrrole measured value (M-H) -=481.99m/z
The pyridine base } amino) carbonyl] amino }-2-methyl-3-
(4-aminomethyl phenyl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 15 calculated values (M-H) -=522.18m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=522.04m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(4-ethylphenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 3 calculated values (M-H) -=55017m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=550.05m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-(2,2-dimethyl-2,3-dihydro-1-benzo
Furans-5-yl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 3 calculated values (M-H) -=542.15m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=542.00m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-[3-fluoro-4-(methoxyl group) phenyl]
Propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 11 calculated values (M-H) -=578.13m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=578.02m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-the 3-{3-[(trifluoromethyl) the oxygen base] benzene
Base } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 1.6 calculated values (M-H) -=587.14m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=586.99m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-{3-[methyl (methyl sulphonyl) amino]
Phenyl } propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 1.3 calculated values (M-H) -=601.15m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=601.00m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-{3-[methyl (methyl sulphonyl)
Amino] phenyl } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 1 calculated value (M-H) -=601.15m/z;
Base-2-oxo-2,5,6,7-tetrahydrochysene-1H-encircle penta 2 measured values (M-H) -=601.00m/z
Alkene is [b] pyridin-3-yl also } amino) carbonyl] ammonia
Base }-3-{3-[ethyl (methyl sulphonyl) amino]
Phenyl } propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 1 calculated value (M-H) -=615.17m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=615.04m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-{3-[ethyl (methyl sulphonyl)
Amino] phenyl } propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 25 calculated values (M-H) -=548.14m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=547.96m/z
Base } amino) carbonyl] amino }-3-(2 '-fluorine [1,1 '-
Xenyl]-the 3-yl) propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 157 calculated values (M-H) -=598.14m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=597.97m/z
Base } amino) carbonyl] amino }-3-[2 '-(fluoroform
Base) [1,1 '-xenyl]-3-yl] propionic acid
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl 10 calculated values (M-H) -=472.11m/z;
Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H) -=471.98m/z
Base } amino) carbonyl] amino }-3-(2-fluorophenyl)
Propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 2 calculated values (M-H) -=533.16m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=533.01m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(1H-indoles-5-yl) propionic acid
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) first 11 calculated values (M-H) -=530.13m/z;
Base]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-measured value (M-H) -=530.00m/z
Cyclopenta [b] pyridin-3-yl } amino) carbonyl
Base] amino }-3-(3, the 5-difluorophenyl) propionic acid
The reference of all references is attached to herein by reference.
Illustrated the present invention by above explanation and embodiment.Its many change schemes more than are illustrated as non-limiting illustrating, because it will be apparent to those skilled in the art that.Therefore, present invention resides in all interior such change schemes of scope and spirit of appended claim book.
Under the design of the present invention and range of condition that do not depart from the definition of following claims, can formation, operation and the arrangement of the inventive method of this paper introduction be changed.
Sequence table
＜110〉Taxas Biotechnology Corp. (Texas Biotechnology Corporation)
＜120〉carboxylic acid derivative of inhibition of integrins and its receptors bind
<140>01145182.3
<141>2001-12-29
<160>1
<170>PatentIn?Release?#1.0，Version?#1.30
<210>1
<211>26
＜212〉protein
<400>1
Figure A200910009861D02301

Claims (31)

1. the compound of structural formula below a kind or its pharmacy acceptable salt,
Figure A200910009861C00021
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 3-10;
A is selected from O, S, C (R 16) (R 17) and NR 6
E is selected from CH 2, O, S and NR 7
J is selected from O, S and NR 8
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
M is selected from C (R 9) (R 10) and (CH 2) u, wherein u is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
X is selected from CO 2B, PO 3H 2, SO 3H, SO 2NH 2, SO 2NHCOR 12, OPO 3H 2, C (O) NHC (O) R 13, C (O) NHSO 2R 14, hydroxyl, tetrazyl and hydrogen;
W is selected from C, CR 15And N; And
B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16And R 17When occurring, independently be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN ,-NO 2,-NH 2,-OH, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16And R 17For unsubstituted group or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
Wherein working as M is C (R 9) (R 10) time, R 9And R 10Can form a ring together;
And wherein when A be NR 6With at least one Y be CR 1The time, R 1And R 6Can form a ring together;
Prerequisite be when A be C (R 16) (R 17) time, E is not NR 7
2. the compound of claim 1, wherein:
A is NR 6
E is NR 7
J is O;
M is C (R 9) (R 10);
Q is 4 or 5;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
X is CO 2B;
W is C or CR 15
R 4Be selected from aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic and heterocyclic radical alkyl; And
R 6, R 7, R 9, R 10And R 15Independently be selected from hydrogen and low alkyl group.
3. the compound of claim 1, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
4. the compound of structural formula below a kind or its pharmacy acceptable salt,
Figure A200910009861C00041
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 3-7;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
W is selected from C, CR 15And N; And
B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15Independently be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN ,-NO 2,-NH 2,-OH, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when at least one Y be CR 1The time, R 1And R 6Can form a ring together.
5. the compound of claim 4, wherein:
Q is 4 or 5;
W is C or CR 15
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
R 4Be selected from aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic and heterocyclic radical alkyl; And
R 6, R 7, R 9, R 10And R 15Independently be selected from hydrogen and low alkyl group.
6. the compound of claim 4, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
7. the compound of structural formula below a kind or its pharmacy acceptable salt,
Figure A200910009861C00061
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S;
Q is the integer of 2-5;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
R 5, R 6, R 7, R 11And R 18Independently be selected from alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group; And
B, R 1, R 2, R 3, R 4, R 9And R 10Independently be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 18For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when at least one Y be CR 1The time, R 1And R 6Can form a ring together.
8. the compound of claim 7, wherein:
R 18Be selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkyl heterocyclic, heterocyclic radical alkyl and heterocyclic radical;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
Y is selected from CR 1And C (R 2) (R 3); And
Q is 2 or 3.
9. the compound of claim 7, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
10. the compound of claim 7, wherein
Figure A200910009861C00071
Be selected from
Figure A200910009861C00081
With
Figure A200910009861C00082
R wherein 19, R 20, R 21And R 28When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, hydroxyl ,-CO 2H, sulfydryl, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 18Be selected from alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, ammonia and-C (O) NH (benzyl) group;
R 22Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H ,-SH ,-CN, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
C is the integer of 0-2;
D is the integer of 0-3;
E is the integer of 0-4; And
I is the integer of 0-2.
11. the compound of claim 7, wherein:
R 18Be aralkyl;
R 4Be aryl;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
B, R 6, R 7, R 9And R 10Independent separately is hydrogen.
12. the compound of structural formula below a kind or its pharmacy acceptable salt,
Figure A200910009861C00101
Wherein T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
G is the integer of 0-7; And
B, R 4, R 9, R 10And R 23When occurring, independently be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 6, R 7, R 11And R 18Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
Wherein B, R 4, R 6, R 7, R 9, R 10, R 11, R 18And R 23For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R 9And R 10Can form a ring together.
13. the compound of claim 12, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
14. the compound of structural formula below a kind or its pharmacy acceptable salt,
Wherein h is the integer of 0-5;
B, R 9, R 10, R 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 27When occurring, independently be selected from every turn halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl) ,-N (C 1-C 3Alkyl) SO 2(C 1-C 3Alkyl) ,-N (C 1-C 3Alkyl) SO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 6, R 7And R 18Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group; And
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl ,-CF 3, carbalkoxy, heterocyclic acyl, carboxyl ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-PO 3H 2, haloalkyl, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, dibenzyl, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl), sulfonamido, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 6, R 7, R 9, R 10, R 18, R 24, R 25, R 26And R 27For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
R wherein 18And R 24Can form a ring together;
R 24And R 25Can form a ring together;
R 25And R 26Can form a ring together;
And R wherein 9And R 10Can form a ring together.
15. the compound of claim 14, wherein B, R 6, R 7, R 9, R 10, R 24, R 25And R 26Independent separately is hydrogen, and R 18Be substituted aralkyl or unsubstituting aromatic alkyl.
16. the compound of claim 14, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
17. the compound of structural formula below a kind or its pharmacy acceptable salt,
Wherein Z independently is selected from C (O), N, CR at every turn when occurring 30, C (R 31) (R 32), NR 33, CH, O and S;
Z is the integer of 3-6;
K is the integer of O-5;
T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3;
L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1;
R 6, R 7, R 11, R 18And R 23Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
B, R 4, R 9, R 10, R 30, R 31And R 32When occurring, be selected from every turn hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, hydroxyl, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group; And
R 29When occurring, independently be selected from every turn halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, hydroxyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
Wherein B, R 4, R 5, R 6, R 7, R 9, R 10, R 11, R 18, R 29, R 30, R 31, R 32And R 33For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together.
18. the compound of claim 17, it is selected from the derivative of ester, carbamate, aminal, acid amides, optically active isomer and prodrug for it.
19. the compound of claim 17, wherein z is 3 or 4.
20. the compound of structural formula below a kind,
Figure A200910009861C00151
R wherein 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, sulfydryl, hydroxyl ,-CO 2H, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group; And
R 18And R 34Independently be selected from alkyl separately, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl, chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group;
R wherein 18, R 24, R 25And R 34For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group;
And R wherein 24And R 25Can form a ring together;
Prerequisite is to work as R 24And R 25When forming a ring together, formed ring is not a benzene.
21. the compound of claim 20, wherein R 34Be hydrogen; R 18Be aralkyl; And R 24And R 25Independent separately is hydrogen, low alkyl group and R wherein 24And R 25Can form the low alkyl group of a ring together.
22. the compound of the claim 20 of structural formula below a kind,
Figure A200910009861C00171
R wherein 24And R 25Independently be selected from separately hydrogen, halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3, sulfydryl, hydroxyl ,-CO 2H, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R 34Be selected from alkyl, alkenyl, alkynyl group, hydroxyalkyl, aliphatic acyl. chain alkynyl amino, carbalkoxy, heterocyclic acyl,-CH=NOH, haloalkyl, the alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, carbamate groups, aryloxy alkyl, hydrogen and-C (O) NH (benzyl) group; And
R 35When occurring, independently be selected from every turn halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl group, alkenyloxy, chain oxy-acetylene, thio alkoxy, hydroxyalkyl, aliphatic acyl ,-CF 3,-CO 2H, sulfydryl, cyano group, nitro, amino, chain alkynyl amino, carbalkoxy, heterocyclic acyl, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 3Alkyl) ,-NHSO 2(aryl), alkoxyalkyl, alkylamino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl group alkoxyl group, carboxaldehyde radicals, formamido-, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, dibenzyl, thioaryl, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocyclic radical alkyl, alkylsulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), sulfonamido, carbamate groups, aryloxy alkyl and-C (O) NH (benzyl) group;
R wherein 24, R 25, R 34And R 35For substituted radical not or by at least one group of replacing for electronics or electron-withdrawing group; And
M is the integer of 0-5.
23. the compound of claim 22, wherein R 34Be hydrogen; M is the integer of 0-3, and R35 is selected from alkyl, halogen, alkoxyl group, haloalkyl, alkylsulfonyl, hydroxyl and cyano group at every turn when occurring.
24. the compound of claim 20, it is selected from:
5-(2-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-benzyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-benzyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 5-dimethyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 5-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3,5-two (trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-tertiary butyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-bromobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 4-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[4-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(pyridine-2-ylmethyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-difluorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[4-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 3-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 5-dimethyl benzyl)-3,5 dihydros [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-amyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 4-dichloro benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
7-butyl-5-(2-benzyl chloride base)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(trifluoromethyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dichloro benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-luorobenzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methyl-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
7-methyl-5-[4-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
4-(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also]-N, the N-dimethyl benzene sulfonamide,
5-(Yu ylmethyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-3,5,6,7,8,9-six hydrogen [1,3] oxazole is [4,5-c] quinoline-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
2-[(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also]-N, the N-dimethyl benzene sulfonamide,
5-(2, the 6-dimethoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(trifluoromethoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-chloro-2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-5,6,7,8,9,10-six hydrogen-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-[2-(difluoro-methoxy) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
The 7-methyl-5-[(1R)-the 1-styroyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(4-benzyl chloride base)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dimethyl benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
3-chloro-2-[(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also] benzonitrile,
5-(2-chloro-6-methyl-benzyl)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
2-[(2,4-dioxo-2,3-dihydro [1,3] oxazole is [4,5-c] pyridines-5 (4H)-yl) methyl also] benzonitrile,
5-(2-chloro-6-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(methylthio group) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-cyclopropyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-dichloro benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
7-methyl-5-(4-methyl-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(3, the 5-dimethoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2, the 6-difluorobenzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[3-(methyl sulphonyl) benzyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-fluoro-6-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methoxy-benzyl)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-chloro-2-luorobenzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-sec.-propyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-fluoro-2-methyl-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
The 7-methyl-5-[(1S)-the 1-phenylethyl]-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-isopropoxide benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(5-ethanoyl-2-methoxy-benzyl)-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-d] pyridazine-2 also, the 4-diketone,
5-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-methyl-benzyl)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-ethoxy benzyl)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-propoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-isobutoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-isopropoxide benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-6-(2,2, the 2-trifluoro ethoxy) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-d] pyridazine-2 also, the 4-diketone,
5-[2-chloro-6-(2-methoxy ethoxy) benzyl]-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-(2-chloro-6-ethoxy benzyl)-6,7-dimethyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-ethyl-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-benzyl chloride base)-7-ethyl-3, the 5-dihydro [1,3] oxazole is [4,5-d] pyridazine-2 also, the 4-diketone, and 5-(2-chloro-6-ethoxy benzyl)-7-propyl group-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-7-cyclopropyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-propoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-methoxy-benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-6-ethoxy benzyl)-6-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2-chloro-5-ethoxy benzyl)-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(piperidines-1-base alkylsulfonyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-5-(tetramethyleneimine-1-base alkylsulfonyl) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-chloro-6-(cyclopentyl methoxyl group) benzyl]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-[2-(benzyloxy)-6-benzyl chloride base]-7-methyl-3, the 5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone,
5-(2,3-two chloro-6-ethoxy benzyls)-5,6,7,8-tetrahydrochysene-2H-cyclopenta [b] [1,3] oxazole is [5,4-d] pyridines-2,4 (3H)-diketone also,
5-[2-chloro-5-(trifluoromethyl) benzyl]-7-methyl-3,5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, 4-diketone and 5-(2-chloro-5-luorobenzyl)-7-methyl-3,5-dihydro [1,3] oxazole is [4,5-c] pyridine-2 also, the 4-diketone.
25. a compound, it is selected from:
(3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenmethyl)-1,6-dihydro-5-pyrimidyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-(1,3-benzo dioxane penta-5-yl)-3-[({[2-oxo-1-(phenmethyl)-4-propyl group-1,2-dihydro-3-pyridyl] amino } carbonyl) amino] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-propyl group-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({6-methyl-2-oxo-1-(phenmethyl)-4-[(phenmethyl) the oxygen base]-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3, the 4-3,5-dimethylphenyl) propionic acid,
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(1,4-oxazine alkane-4-yl)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxo-4-(propyl group amino)-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) the oxygen base]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-6-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(1, the 1-dimethyl ethyl) amino]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-the 3-phenylpropionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[4-methyl tetrahydrochysene-1 (2H)-piperazinyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3, the 5-3,5-dimethylphenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(3-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(methoxyl group) phenyl] propionic acid,
(3S)-and 3-[3,5-two (methoxyl group) phenyl]-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino } propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({4-(1-azetanyl)-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-pyridyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-(1,3-benzo dioxane penta-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl) phenyl) methyl)-1,2-dihydro-3-pyridyl) propionic acid amino carbonyl amino))), (3S)-3-((((1-((2-chlorophenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propionic acid
(3S)-3-((((1-((2-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2-bromo phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2,4 dichloro benzene base) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-((((1-((2-chloro-6-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-((((1-((2-chlorophenyl) methyl)-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl) amino) carbonyl) amino)-3-(4-trifluoromethyl) oxygen base) phenyl) propionic acid
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
4-{[3-[({[(1S)-and 2-carboxyl-1-(4-aminomethyl phenyl) ethyl] amino } carbonyl) amino]-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-4-yl] amino } phenylformic acid
(3S)-3-{[({1-[(2-chloro benzyl)-4-[(2,2-dimethyl propylene acyl group) amino]-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[4-{[(tertiary butyl amino) carbonyl] amino }-1-(2-benzyl chloride base)-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-cyano group benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino carbonyl) amino]-3-(2,3-dihydro-1,4-benzo dioxane oneself-the 6-yl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(7-methoxyl group-1,3-benzo dioxane penta-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-oxyethyl group-4-p-methoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 4-Dimethoxyphenyl) propionic acid,
(3S)-and 3-[({[1-(4-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2, the 6-difluorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 5-Dimethoxyphenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-methoxyl group-4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,5-dimethoxy-4 '-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-ammonia benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3, the 4-3,5-dimethylphenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-5-ethyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl) benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2, the 6-dimethoxy-benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-propoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionyl
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-5-propyl group-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-(3-butoxy phenyl)-3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino] propionic acid,
(3S)-3-{[({1-[2-chloro-5-(methyl sulphonyl) benzyl]-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(2-methoxy ethoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-dipropoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(difluoro-methoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chlorine ,-6-methyl-benzyl)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-cyano group benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2-naphthyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methoxy-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3,4-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-p-methoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-methyl-benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl-) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(2,3-dihydro-1-cumarone-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3,5-diethoxy phenyl) propionic acid,
(3S)-and 3-[({[5-chloro-1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-propoxy-phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-the 3-phenylpropionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(trifluoromethoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-5-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-5-cyclopropyl-4-hydroxyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-5-methoxy-benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-6-methyl-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(1-Methyl-1H-indole-6-yl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(ring propoxy-) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(cyclo propyl methoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-[3-(cyclo propyl methoxy) phenyl] propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3, the 5-3,5-dimethylphenyl) propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(difluoromethyl) the oxygen base] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[(1,1,2,2-tetrafluoro ethyl) the oxygen base] phenyl } propionic acid,
(3S)-the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino-3-(1-ethyl-1H-indoles-5-yl) propionic acid and
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-[3-(diethylamino) phenyl] propionic acid,
And their pharmacy acceptable salt.
26. (3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid and pharmacy acceptable salt thereof.
27. (3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid and pharmacy acceptable salt thereof.
28. (3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-[3-(diethylamino) phenyl] propionic acid and pharmacy acceptable salt thereof.
29. a compound, it is selected from:
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(3-ethoxyl phenenyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-isopropyl phenyl) propionic acid,
(3S)-and 3-[({[1-(2-chloro-6-ethoxy benzyl)-4-hydroxy-5-methyl base-2-oxo-1,2-dihydropyridine-3-yl] amino } carbonyl) amino]-3-(6-methoxyl group-2-naphthyl) propionic acid,
(3S)-and 3-[({[1-(2-benzyl chloride base)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl] amino } carbonyl) amino]-3-(3-aminomethyl phenyl) propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-(1-Methyl-1H-indole-5-yl) propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-the 3-{3-[(methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[methyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[methyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and the 3-{[({1-[(2-chloro-phenyl-) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-IH-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[ethyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } amino) carbonyl] amino }-3-{3-[ethyl (methyl sulphonyl) amino] phenyl } propionic acid,
(3S)-and 3-{[({1-[(2-chloro-6-aminomethyl phenyl) methyl]-4-hydroxyl-2-oxo-2,5,6,7-tetrahydrochysene-1H-cyclopenta [b] pyridin-3-yl } ammonia, base) carbonyl] amino }-3-(1H-indoles-5-yl) propionic acid,
And their pharmacy acceptable salt.
30. a medicinal compositions, said composition comprises:
The compound of claim 1 and pharmaceutically acceptable carrier.
31. a selectivity suppresses Mammals α 4β 1Integrin bonded method, this method comprise claim 1 compound that gives described Mammals therapeutic dose.
CN2009100098615A 2001-10-09 2001-12-29 Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof Expired - Fee Related CN101475526B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/973,142 US6972296B2 (en) 1999-05-07 2001-10-09 Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US09/973142 2001-10-09

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CNB011451823A Division CN100491353C (en) 2001-10-09 2001-12-29 Carboxylic acid derivative capable of inhibiting combination of integrin and its receptor

Publications (2)

Publication Number Publication Date
CN101475526A true CN101475526A (en) 2009-07-08
CN101475526B CN101475526B (en) 2011-05-25

Family

ID=25520549

Family Applications (2)

Application Number Title Priority Date Filing Date
CNB011451823A Expired - Fee Related CN100491353C (en) 2001-10-09 2001-12-29 Carboxylic acid derivative capable of inhibiting combination of integrin and its receptor
CN2009100098615A Expired - Fee Related CN101475526B (en) 2001-10-09 2001-12-29 Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CNB011451823A Expired - Fee Related CN100491353C (en) 2001-10-09 2001-12-29 Carboxylic acid derivative capable of inhibiting combination of integrin and its receptor

Country Status (7)

Country Link
JP (1) JP4149172B2 (en)
CN (2) CN100491353C (en)
CA (1) CA2366800C (en)
HK (1) HK1135376A1 (en)
PL (1) PL223151B1 (en)
SG (2) SG161741A1 (en)
SI (1) SI21096B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023125182A1 (en) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Propionic acid derivative and medical use thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200505861A (en) * 2002-11-08 2005-02-16 Encysive Pharmaceuticals Inc Combination products with carboxylic acid derivatives that inhibit the binding of integrins to their receptors and other therapeutic compounds
CA2680366C (en) 2007-03-09 2016-06-21 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
CA2677049A1 (en) 2007-08-01 2009-02-05 Sionex Corporation Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
AU2010241742A1 (en) * 2009-04-27 2011-11-17 Elan Pharmaceuticals, Inc. Pyridinone antagonists of alpha-4 integrins
US10875875B2 (en) * 2017-04-26 2020-12-29 Aviara Pharmaceuticals, Inc. Propionic acid derivatives and methods of use thereof
WO2024051819A1 (en) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Propionic acid derivative and use thereof in medicine

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2614189A1 (en) * 1976-04-02 1977-10-20 Hoechst Ag Analgesic, antiinflammatory and antipyretic thiazolyl-urea derivs. - prepd. by reacting an isocyanato-carboxylic acid cpd. with an amino-or hydrazino-thiazole
JP2791156B2 (en) * 1988-08-23 1998-08-27 ザ ヌトラスウィート カンパニー Substituted aryl ureas as intense sweeteners
FR2659653B1 (en) * 1990-03-13 1992-05-22 Rhone Poulenc Sante DERIVATIVES OF UREA, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM.
HUT68769A (en) * 1991-05-07 1995-07-28 Merck & Co Inc FIBRINOGéN RECEPTOR ANTAGONIST COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AS EFFECTIVE SUBSTANCE
KR100257837B1 (en) * 1993-03-31 2000-07-01 윌리암스 로저 에이 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors
US5610296A (en) * 1994-12-05 1997-03-11 G. D. Searle & Co. Process for the preparation of amidino phenyl pyrrolidine beta-alanine urea analogs
SK15592000A3 (en) * 1998-04-16 2001-12-03 Texas Biotechnology Corporation N,n-disubstituted amides that inhibit the binding of integrins to their receptors
EP1176956B1 (en) * 1999-05-07 2008-01-09 Encysive Pharmaceuticals, Inc Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023125182A1 (en) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Propionic acid derivative and medical use thereof

Also Published As

Publication number Publication date
SG107574A1 (en) 2004-12-29
CN100491353C (en) 2009-05-27
CA2366800C (en) 2010-08-10
JP4149172B2 (en) 2008-09-10
PL223151B1 (en) 2016-10-31
CN1412181A (en) 2003-04-23
SG161741A1 (en) 2010-06-29
CN101475526B (en) 2011-05-25
CA2366800A1 (en) 2003-04-10
JP2003119181A (en) 2003-04-23
HK1135376A1 (en) 2010-06-04
SI21096A1 (en) 2003-06-30
SI21096B (en) 2012-05-31
PL356532A1 (en) 2003-04-22

Similar Documents

Publication Publication Date Title
KR100851766B1 (en) Carboxylic acid derivatives that inhibit the binding of integrins to their receptors and pharmaceutical compositions comprising the same
RU2263109C2 (en) DERIVATIVES OF CARBOXYLIC ACIDS (VARIANTS), PHARMACEUTICAL COMPOSITION AND METHOD FO SELECTIVE BINDING α4β1-INTEGRIN IN MAMMAL
CN101646656B (en) Pyrimidine hydrazide compounds as PGDS inhibitors
TWI637951B (en) Heterocyclic amides as kinase inhibitors
CN100360499C (en) Propanoic acid derivatives that inhibit binding of integrins to their receptors
CN101538246B (en) Pyrimidine amide compounds as PGDS inhibitors
CN100376569C (en) Inhibitors of farnesyl protein transferase
CN101842357A (en) Substituted pyrazole derivative
RU2156251C2 (en) Derivatives of imidazopyridines, method of their synthesis, pharmaceutical composition and method of its preparing
CN101155799A (en) Pyrimidine inhibitors of kinases
CN101541751A (en) Quinoline compounds
CN103608332A (en) Pyridin-2-amides useful as CB2 agonists
CN101657430A (en) organic compounds and their uses
CN101624391A (en) Thiophene derivatives as antiviral agents for flavivirus infection
CN101018770A (en) PGD2 receptor antagonists for the treatment of inflammatory diseases
CN101553461A (en) 4-substituted phenoxyphenylacetic acid derivatives
JP2002515400A (en) Certain diarylimidazole derivatives; a new class of NPY-specific ligands
CN101370792A (en) Bi-aryl meta-pyrimidine inhibitors of kinases
CN102639532A (en) Fused triazole amines as P2X7 modulators
CN104736533B (en) Vegfr3 inhibitor
CN100491353C (en) Carboxylic acid derivative capable of inhibiting combination of integrin and its receptor
JP2000517301A (en) Tetrahydroisoquinoline derivatives and their pharmacological uses
WO2022042591A1 (en) Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof
CN103261176B (en) 1,4-oxazepane derivatives
CN101563322A (en) 1H-indole-2-carboxylic acid derivatives useful as PPAR modulators

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1135376

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee

Owner name: ENXI XIFU MEDICINE CORP.

Free format text: FORMER NAME: TAXAS BIOTECHNOLOGY CORP.

CP03 Change of name, title or address

Address after: American Texas

Patentee after: Ensey to bless the drug company

Address before: texas

Patentee before: Texas Biotechnology Corp.

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1135376

Country of ref document: HK

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20110525

Termination date: 20151229

EXPY Termination of patent right or utility model