CN1265669A

CN1265669A - Compounds which inhibit leukocyte adhesion mediated by VLA-4

Info

Publication number: CN1265669A
Application number: CN98807765A
Authority: CN
Inventors: M·S·达普恩; D·B·德雷森; F·S·格兰特; M·A·普雷斯; C·Y·鲁; D·萨兰塔基斯; E·D·索尔塞特
Original assignee: Elan Pharmaceuticals LLC; American Home Products Corp
Current assignee: Wyeth LLC; Elan Pharmaceuticals LLC
Priority date: 1997-07-31
Filing date: 1998-07-31
Publication date: 2000-09-06
Also published as: KR20010022423A; IL133641A0; PL338506A1; CA2290746A1; NO20000451L; EP1001973A1; AU8678698A; HUP0004529A2; NO20000451D0; BR9811569A; HUP0004529A3; WO1999006433A1; JP2001512136A

Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

Inhibition is by the compound of the white corpuscle adhesion of VLA-4 mediation

Related application

The application requires U.S. Provisional Application 60/-,-, right of priority, this provisional application is to be the U.S. Patent application 08/904416 on July 31st, 1997 based on the applying date (i) according to 37 C.F.R. § 1.53 (c) (2), the disclosure thing is introduced the present invention in full with for referencial use.

Background technology of the present invention technical field of the present invention

The present invention relates to suppress white corpuscle and adhere, especially suppress compound by the white corpuscle adhesion of VLA-4 mediation.Reference

Following publication, patent and patent application are to be that representative is introduced the application with for referencial use with its subscript numeral. ¹Hemler and Takada, european patent application disclose No. 330506, publish on August 30th, 1989 ²People such as Elices, " cell " (Cell), 60:577-584 (1990) ³Springer, " nature " (Nature), 346:425-434 (1990) ⁴Osborn, " cell " (Cell), 62:3-6 (1990) ⁵People such as Vedder, " surgery " (Surgery), 106:509 (1989) ⁶People such as Pretolani, " The Journal of Experimental Medicine " (J.Exp.Med.), 180:795 (1994) ⁷People such as Abraham, " Journal of Clinical Investigation " (J.Clin.Invest.), 93:776 (1994) ⁸People such as Mulligan, " IMMUNOLOGY KEY WORDS INDEX (J.Immunology), 150:2407 (1993) ⁹People such as Cybulsky, " science " (Science), 251:788 (1991) ¹⁰People such as Li, " arteriosclerosis and thrombosis " (Arterioscler.Thromb.), 13:197 (1993) ¹¹People such as Sasseville, " American Journal of Pathology " (Am.J.Path.), 144:27 (1994) ¹²People such as Yang, " institute of NAS newspaper " (Proc.Nat.Acad.Science (USA)), 90:10494 (1993) ¹³People such as Burkly, " diabetology " (Diabetes), 43:529 (1994) ¹⁴People such as Baron, " Journal of Clinical Investigation " (J.Clin.Invest.), 93:1700 (1994) ¹⁵People such as Hamann, " IMMUNOLOGY KEY WORDS INDEX (J.Immunology), 152:3238 (1994) ¹⁶People such as Yednock, " nature " (Nature), 356:63 (1992) ¹⁷People such as Baron, " The Journal of Experimental Medicine " (J.Exp.Med.), 177:57 (1993) ¹⁸People such as van Dinther-Janssen, " IMMUNOLOGY KEY WORDS INDEX (J.Immunology), 147:4207 (1991) ¹⁹People such as van Dinther-Janssen, " rheumatosis record event " (Annals.RheumaticDis.), 52:672 (1994) ²⁰People such as Elices, " Journal of Clinical Investigation " (J.Clin.Invest.), 93:405 (1994) ²¹People such as Postigo, " Journal of Clinical Investigation " (J.Clin.Invest.), 89:1445 (1991) ²²People such as Paul, " transplant progress " (Transpl.Proceed.), 25:813 (1993) ²³People such as Okarhara, " cancer research " (Can.Res.), 54:3233 (1994) ²⁴People such as Paavonen, " international journal of cancer " (Int.J.Can), 58:298 (1994) ²⁵People such as Schadendorf, " pathology magazine " (J.Path.), 170:429 (1993) ²⁶People such as Bao, " classification " (Diff.), 52:239 (1993) ²⁷People such as Lauri, " Britain's cancer magazine " (British J.Cancer), 68:862 (1993) ²⁸People such as Kawaguchi, " Japanese cancer research magazine " (Japaness J.Cancer Res.), 83:1304 (1992) ²⁹People such as Kogan, US 5510332, and is open on April 23rd, 1996 ³⁰International patent application discloses WO No. 96/01644

Above-mentioned all publications, patent and patent application are all introduced the present invention with for referencial use in full with same degree, and resembling each publication, patent and patent application is specifically and individually to introduce the present invention with for referencial use in full.Prior art

Hemler and Takada ¹At first identify VLA-4 and (be also referred to as α ₄β ₁Integrin and CD49d/CD29) be a member in the cell surface receptor beta 1 integrin family, it is α chain and β chain that each member in this integrin family is contained two subunits.VLA-4 contains α 4 chains and β 1 chain.Have 9 kinds of beta 1 integrins at least, they all have identical β 1 chain and have different α chains separately.These 9 kinds of acceptors are all in conjunction with different complements, for example fibronectin, ln and the collagen of various cell matrix molecules.For example, VLA-4 combines with fibronectin.VLA-4 is also in conjunction with the non-substrate molecule by endotheliocyte and other cell expressing.These non-substrate molecules comprise the VCAM-1 that is expressed by cytokine activatory Human umbilical vein endothelial cells in culture.Fibronectin and VCAM-1 are due to the different epi-positions of VLA-4 in conjunction with activity, and can both be suppressed independently according to each activity of proof ²

Cell-cell adhesion by VLA-4 and the mediation of other cell surface receptor can cause multiple Inflammatory response.Under injury site or other inflammatory stimulus, the activatory vascular endothelial cell is expressed the molecule with the white corpuscle adhesion.The mechanism part of white corpuscle and endotheliocyte adhesion comprises, the cell surface receptor identification on the white corpuscle and in conjunction with the corresponding cell surface molecule on the endotheliocyte.In case combination, white corpuscle are passed vessel wall at once and are entered injury site and discharge chemical mediator with to anti-infective.If look back the content of immunity system adhesion receptor aspect, can be referring to for example Springer ³And Osborn ⁴

Inflammatory encephalopathic for example experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis is that endothelium/white corpuscle adhesion mechanism causes the example of the ruined central nervous system disorder of healthy cerebral tissue.A large amount of white corpuscles pass the patient's who suffers from these inflammatory diseasess hemato encephalic barrier (BBB).White corpuscle discharges the toxicity medium, and these toxicity media cause tissue injury widely, causes the impaired and paralysis of nerve conduction.

In other tract, the leucocyte migration or the activation that are caused by adhesion mechanism also can cause tissue injury.For example, according to proof, the preliminary damage of heart tissue can enter damaged tissue and causes further damage and further worsen (people such as Vedder owing to white corpuscle behind the myocardial ischemia ⁵).Example by machine-processed other inflammatory diseases that mediates of adhesion comprises asthma ^6-8, Alzheimer's, atherosclerosis ^9-10, the AIDS dementia ¹¹, diabetes ^12-14(comprising acute teenager's disease type diabetes), inflammatory bowel ¹⁵(comprising ulcerative colitis and Crohn disease), multiple sclerosis ^16-17, rheumatoid arthritis ^18-21, tissue transplantation ²², metastases ^23-28, meningitis, encephalitis, apoplexy and other cerebral trauma, ephritis, the retinitis, atopic dermatitis, psoriasis, myocardial ischemia and the mediation of acute white corpuscle the injury of lung that for example in adult respiratory distress syndrome, takes place of injury of lung.

For above-mentioned reasons, the analysis of measuring VLA-4 level in the biological specimen contain VLA-4 can be used for for example diagnosing the disease of VLA-4 mediation.In addition, although the understanding of dialogue cell adhesion has had so many progress, just just propose recently in the prior art with adhesion inhibitors treatment inflammatory encephalopathic and other inflammatory diseases ^29-30The present invention has satisfied these and other demand.

The invention summary

The invention provides can be in conjunction with the compound of VLA-4.This compounds can be used for whether there is VLA-4 in the analyzing samples for example and is used to suppress in pharmaceutical composition being combined with VLA-4's by cell adhesion, for example VCAM-1 of VLA-4 mediation.The compounds of this invention is IC to the binding affinity of VLA-4 ₅₀Be about 150 μ M or 150 μ M following (measuring according to following embodiment 46 described methods), The compounds of this invention is defined by following formula I: R wherein ¹Be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; R ²Be selected from cycloalkenyl group, the heterocyclic radical of cycloalkyl, cycloalkenyl group, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heterocyclic radical, aryl, aryl, the heteroaryl of replacement and the heteroaryl that replaces of replacement, and R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together; R ³Be selected from aryl, the heteroaryl of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heteroaryl, heterocyclic radical and the heterocyclic radical that replaces, the wherein R of replacement ²And R ³And and R ²Bonded nitrogen-atoms and and R ³The bonded carbon atom can form the unsaturated heterocycle base of unsaturated heterocycle base or replacement together; Ar is the aryl of aryl, heteroaryl, replacement or the heteroaryl of replacement, and x is the integer of 1-4; Q is-C (X) NR ⁷-, R wherein ⁷Be selected from hydrogen and alkyl, and X is selected from oxygen and sulphur; R ⁵Be-CH ₂X, wherein X is selected from hydrogen, hydroxyl, amido, alkyl, alkoxyl group, aryloxy, aryl, the aryloxy aryl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the alkyl that replaces, the alkoxyl group that replaces, the aryl that replaces, the aryloxy that replaces, the aryloxy aryl that replaces, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement

Condition is: A.R ⁵Be not-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be-O-Z-NR ⁸R ^{8 '}Or-O-Z-R ¹², R wherein ⁸And R ^{8 '}Be independently selected from alkyl, cycloalkyl, cycloalkyl, the heterocyclic radical of replacement and the heterocyclic radical that replaces of hydrogen, alkyl, replacement respectively, and R ⁸And R ^{8 '}Can be joined together to form the heterocyclic radical of heterocyclic radical or replacement, R ¹²Be selected from the heterocyclic radical of heterocyclic radical and replacement, and Z be selected from-C (O)-and-SO ₂-,

Ar is the aryl of aryl, heteroaryl, replacement or the heteroaryl of replacement,

X is the integer of 1-4; B.R ⁵Be not-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be-NR ¹²C (Z ') NR ⁸R ^{8 '}Or-NR ¹²C (Z) R ¹³, wherein Z ' is selected from oxygen, sulphur and NR ¹², R ¹²Be selected from hydrogen, alkyl and aryl, R ⁸And R ^{8 '}Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement respectively, condition is: when Z ' is oxygen, and R ⁸And R ^{8 '}Have at least one to be alkyl, cycloalkyl, cycloalkyl, the saturated heterocyclyl except that morpholinyl and thio-morpholinyl of replacement or the heterocyclic radical that replaces that replaces, or R ⁸And R ^{8 '}Can be joined together to form the saturated heterocyclyl of saturated heterocyclyl except that morpholinyl or thio-morpholinyl, replacement or have the saturated/unsaturated heterocycle base of the amino of alkoxy carbonyl substituted, another condition is, when Z ' is sulphur, and R ⁸And R ^{8 '}Have at least one not to be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement, R ¹³Be selected from the heterocyclic radical and the saturated heterocyclyl except that morpholinyl or thio-morpholinyl of replacement,

X is the integer of 1-4; C.R⁵Not-ALK-X ' that wherein ALK is by methylene (CH₂-) be connected in the alkyl with 1-10 carbon atom on its carbon atom that connects, X ' is selected from the alkyl-carbonyl-amino of replacement, the alkenyl carbonyl that replaces is amino, the alkynyl group carbonylamino that replaces, the heterocyclic radical carbonylamino, the heterocyclic radical carbonylamino that replaces, acyl group, acyloxy, amino carbonyl oxygen base, acylamino-, oxygen base carbonylamino, alkoxy carbonyl, the alkoxy carbonyl that replaces, aryloxy carbonyl, the aryloxy carbonyl that replaces, cyclo alkoxy carbonyl, the cyclo alkoxy carbonyl that replaces, the heteroaryloxy carbonyl, the heteroaryloxy carbonyl that replaces, the heterocyclic oxy group carbonyl, the heterocyclic oxy group carbonyl that replaces, cycloalkyl, the cycloalkyl that replaces, saturated heterocyclyl, the saturated heterocyclyl that replaces, the alkoxyl that replaces, the alkenyloxy that replaces, the chain oxy-acetylene that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, the alkylthio group that replaces, the alkenyl thio that replaces, the sulfur-based chain acetylene that replaces, amino carbonyl amino, amino thio-carbonyl-amino, guanidine radicals, amidino groups, alkyl amidine, the sulfo-amidino groups, halogen, cyano group, nitro,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-cycloalkyl ,-OS (O)₂The cycloalkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂-replace heterocyclic radical, wherein R is hydrogen or alkyl-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-cycloalkyl ,-NRS (O)₂The cycloalkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-cycloalkyl ,-NRS (O)₂The cycloalkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂The heterocyclic radical that-NR-replaces ,-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂the heterocyclic radical of-replacement, one (alkyl of replacement) amino, two (alkyl of replacement) amino, N, N-(alkyl, the alkyl of replacement) amino, N, N-(aryl, the alkyl of replacement) amino, N, N-(aryl of replacement, the alkyl of replacement) amino, N, N-(heteroaryl, the alkyl of replacement) amino, N, N-(heteroaryl of replacement, the alkyl of replacement) amino, N, N-(heterocyclic radical, the alkyl of replacement) amino, N, N-(heterocyclic radical of replacement, the alkyl of replacement) amino, one and two (heterocyclic radical) amino, one and two (heterocyclic radical of replacement) amino, N, N-(alkyl, heterocyclic radical) amino, N, N-(alkyl, the heterocyclic radical of replacement) amino, N, N-(aryl, heterocyclic radical) amino, N, N-(aryl of replacement, heterocyclic radical) amino, N, N-(aryl, the heterocyclic radical of replacement) amino, N, N-(aryl of replacement, the heterocyclic radical of replacement) amino, N, N-(heteroaryl, heterocyclic radical) amino, N, N-(heteroaryl, the heterocyclic radical of replacement) amino, N, N-(heteroaryl of replacement, heterocyclic radical) amino, and N, N-(heteroaryl of replacement, the heterocyclic radical of replacement) amino, D.R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be selected from: the alkyl-carbonyl-amino that (a) replaces, condition is: have at least a substituting group to be selected from alkoxyl on the substituted alkyl part, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl; (b) its alkoxyl part be selected from carboxyl and-COOR²³The alkoxy aryl that replaces of substituting group, R wherein²³alkyl, cycloalkyl, aryl, heteroaryl or the heterocyclic radical of alkyl, replacement, (c) aryl and heteroaryl, (d)-NR ' R ', wherein R ' is independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: having a R ' at least is the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical or replacement, another condition is: when R ' was the alkyl that replaces, wherein having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、 -NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (e)-alkoxyl-NR " R ", R wherein " and be independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: as R " each replace naturally alkyl the time, having a substituting group at least on the moieties that replaces is to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (f) aryloxy group that replaces and the heteroaryloxy of replacement, condition is, having a substituting group at least on the aryloxy group/heteroaryloxy that replaces is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (g)-alkoxyl saturated heterocyclyl ,-alkoxyl replace saturated heterocyclyl ,-the alkoxyl heterocyclic radical that replaces and-alkoxyl that replaces replaces saturated heterocyclyl, (h)-O-heterocyclic radical and-the O-substituted heterocyclic radical, (i) tetrazole radical, (j)-NR-SO₂-substituted alkyl, wherein R is hydrogen, alkyl or aryl, condition is: having a substituting group on the moieties of this substituted alkyl sulfuryl amino at least is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (k) the alkynyl group sulfuryl amino of the alkenyl sulfuryl amino of alkenyl sulfuryl amino, alkynyl group sulfuryl amino, replacement and replacement, (l) alkoxyl that replaces, condition is: the substituting group on the moieties of described substituted alkoxy does not comprise alkoxyl-NR " R ", the unsaturated heterocycle base, alkoxyl, aryloxy group, heteroaryloxy, aryl, heteroaryl and by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, the aryl/hetaryl that N-dialkyl group urea groups replaces, (m) amidino groups, and by 1-3, be independently selected from the amidino groups that alkynyl group, aryl, heteroaryl and the heterocyclic radical of alkenyl, alkynyl group, the replacement of alkyl, alkenyl, the replacement of alkyl, replacement replace, (n)-C (O) NR R , wherein R is independently selected from respectively hydrogen, alkyl, the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: when one of them R is the unsaturated heterocycle base, aryl, heteroaryl or by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1,2-, two Oxymethylenes, 1,2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, during aryl/hetaryl that N-alkyl urea groups or N, N-dialkyl group urea groups replace, another R is alkyl, the alkyl that replaces (not being the alkyl that the unsaturated heterocycle base replaces), cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, the heterocyclic radical of heterocyclic radical or replacement, (o)-NR²²C(O)-R ¹⁸, R wherein¹⁸Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement, and R²²It is the heterocyclic radical of heteroaryl, heterocyclic radical or replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; (p)-SO₂-aryl ,-SO₂The aryl of-replacement ,-SO₂-heteroaryl ,-SO₂-the heteroaryl that replaces or-SO₂-alkyl; (q)-NR ' C (O) NR¹⁹R ¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be independently selected from respectively the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (r)-NR ' C (O) OR¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (s)-amino carbonyl-(N-formoxyl heterocyclic radical); (t)-alkyl-C (O) NH-heterocyclic radical and-heterocyclic radical that alkyl-C (O) NH-replaces, and E. works as R³While being not H, R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be the alkenyl of replacement or the alkynyl group of replacement, and condition is: partly having a substituting group at least at the alkenyl/alkynyl group that replaces is to be selected from alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: when substituted alkyl replaced, having a substituting group at least on the substituted alkyl part was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl;

And pharmacologically acceptable salt,

And have the following condition of getting rid of following compound: A. works as R ¹And R ²The SO that is connected separately with them ₂Form benzisothiazole ketone heterocyclic, R together with nitrogen-atoms ³Be hydrogen and Q be-during C (O) NH-, R then ⁵It or not benzyl; Work as R with B. ¹Be p-methylphenyl, R ²Be methyl, R ³Be that hydrogen, Q are-C (O) NCH ₃-time, then R ⁵It or not benzyl.

In another embodiment, The compounds of this invention can also provide with the prodrug that changes into (for example hydrolysis, metabolism etc.) above-mentioned formula I compound in vivo.In this class embodiment preferred examples, be the carboxylic acid in the formula I compound to be modified into to change into the carboxylic acid group of (comprising its salt) in vivo.In particularly preferred embodiments, this class prodrug is suc as formula shown in the IA compound:

R wherein ¹Be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; R ²Be selected from cycloalkenyl group, the heterocyclic radical of cycloalkyl, cycloalkenyl group, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heterocyclic radical, aryl, aryl, the heteroaryl of replacement and the heteroaryl that replaces of replacement, and R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together; R ³Be selected from aryl, the heteroaryl of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heteroaryl, heterocyclic radical and the heterocyclic radical that replaces, the wherein R of replacement ²And R ³And and R ²Bonded nitrogen-atoms and and R ³The bonded carbon atom can form the unsaturated heterocycle base of unsaturated heterocycle base or replacement together; Ar is the aryl of aryl, heteroaryl, replacement or the heteroaryl of replacement, and x is the integer of 1-4; R ⁶Be selected from 2, the cycloalkyloxy of the alkoxyl group of 4-dioxo tetrahydrofuran (THF)-3-base (3, the 4-enol), amino, alkoxyl group, replacement, cycloalkyloxy, replacement ,-O-(N-succinimido) ,-the NH-adamantyl ,-O-courage steroid-5-alkene-3-beta-yl, wherein Y is the alkyl, aryl of hydrogen, alkyl, replacement and the aryl-NHOY that replaces, wherein p is the definition of the integer of 1-8 and Y the same-NH (CH ₂) _pCOOY, R wherein ⁹Be selected from-C (O)-aryl and-C (O)-substituted aryl and R ¹⁰Be selected from hydrogen and R wherein ¹¹For alkyl-CH ₂COOR ¹¹-OCH ₂NR ⁹R ¹⁰, and-NHSO ₂Z ", Z wherein " be the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement; Q is-C (X) NR ⁷-, R wherein ⁷Be selected from hydrogen and alkyl, and X is selected from oxygen and sulphur; R ⁵Be-CH ₂X, wherein X is selected from hydrogen, hydroxyl, amido, alkyl, alkoxyl group, aryloxy, aryl, the aryloxy aryl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the alkyl that replaces, the alkoxyl group that replaces, the aryl that replaces, the aryloxy that replaces, the aryloxy aryl that replaces, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement

Condition is: A.R ⁵Be not-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be selected from-O-Z-NR ⁸R ^{8 '}With-O-Z-R ¹², R wherein ⁸And R ^{8 '}Be independently selected from alkyl, cycloalkyl, cycloalkyl, the heterocyclic radical of replacement and the heterocyclic radical that replaces of hydrogen, alkyl, replacement respectively, and R ⁸And R ^{8 '}Can be joined together to form the heterocyclic radical of heterocyclic radical or replacement, R ¹²Be selected from the heterocyclic radical of heterocyclic radical and replacement, and Z be selected from-C (O)-and-SO ₂-,

X is the integer of 1-4; B.R ⁵Be not-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be selected from-NR ¹²C (Z ') NR ⁸R ^{8 '}With-NR ¹²C (Z ') R ¹³, wherein Z ' is selected from oxygen, sulphur and NR ¹², R ¹²Be selected from hydrogen, alkyl and aryl, R ⁸And R ^{8 '}Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement respectively, condition is: when Z ' is oxygen, and R ⁸And R ^{8 '}Have at least one to be cycloalkyl, the saturated heterocyclyl except that morpholinyl and thio-morpholinyl of the alkyl that replaces, cycloalkyl, replacement, the heterocyclic radical of replacement, or R ⁸And R ^{8 '}Can be joined together to form the saturated heterocyclyl of saturated heterocyclyl except that morpholinyl or thio-morpholinyl, replacement or have the saturated/unsaturated heterocycle base of the amino of alkoxy carbonyl substituted, another condition is, when Z ' is sulphur, and R ⁸And R ^{8 '}Have at least one not to be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement, R ¹³Be selected from the heterocyclic radical and the saturated heterocyclyl except that morpholinyl or thio-morpholinyl of replacement,

X is the integer of 1-4; C.R⁵Not-ALK-X ' that wherein ALK is by methylene (CH₂-) be connected in the alkyl with 1-10 carbon atom on its carbon atom that connects, X ' is selected from the alkyl-carbonyl-amino of replacement, the alkenyl carbonyl that replaces is amino, the alkynyl group carbonylamino that replaces, the heterocyclic radical carbonylamino, the heterocyclic radical carbonylamino that replaces, acyl group, acyloxy, amino carbonyl oxygen base, acylamino-, oxygen base carbonylamino, alkoxy carbonyl, the alkoxy carbonyl that replaces, aryloxy carbonyl, the aryloxy carbonyl that replaces, cyclo alkoxy carbonyl, the cyclo alkoxy carbonyl that replaces, the heteroaryloxy carbonyl, the heteroaryloxy carbonyl that replaces, the heterocyclic oxy group carbonyl, the heterocyclic oxy group carbonyl that replaces, cycloalkyl, the cycloalkyl that replaces, saturated heterocyclyl, the saturated heterocyclyl that replaces, the alkoxyl that replaces, the alkenyloxy that replaces, the chain oxy-acetylene that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, the alkylthio group that replaces, the alkenyl thio that replaces, the sulfur-based chain acetylene that replaces, amino carbonyl amino, amino thio-carbonyl-amino, guanidine radicals, amidino groups, alkyl amidine, the sulfo-amidino groups, halogen, cyano group, nitro,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-cycloalkyl ,-OS (O)₂The cycloalkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂-replace heterocyclic radical, wherein R is hydrogen or alkyl-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-cycloalkyl ,-NRS (O)₂The cycloalkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-cycloalkyl ,-NRS (O)₂The cycloalkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂The heterocyclic radical that-NR-replaces ,-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂the heterocyclic radical of-replacement, one (alkyl of replacement) amino, two (alkyl of replacement) amino, N, N-(alkyl, the alkyl of replacement) amino, N, N-(aryl, the alkyl of replacement) amino, N, N-(aryl of replacement, the alkyl of replacement) amino, N, N-(heteroaryl, the alkyl of replacement) amino, N, N-(heteroaryl of replacement, the alkyl of replacement) amino, N, N-(heterocyclic radical, the alkyl of replacement) amino, N, N-(heterocyclic radical of replacement, the alkyl of replacement) amino, one and two (heterocyclic radical) amino, one and two (heterocyclic radical of replacement) amino, N, N-(alkyl, heterocyclic radical) amino, N, N-(alkyl, the heterocyclic radical of replacement) amino, N, N-(aryl, heterocyclic radical) amino, N, N-(aryl of replacement, heterocyclic radical) amino, N, N-(aryl, the heterocyclic radical of replacement) amino, N, N-(aryl of replacement, the heterocyclic radical of replacement) amino, N, N-(heteroaryl, heterocyclic radical) amino, N, N-(heteroaryl, the heterocyclic radical of replacement) amino, N, N-(heteroaryl of replacement, heterocyclic radical) amino, and N, N-(heteroaryl of replacement, the heterocyclic radical of replacement) amino, D.R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be selected from: the alkyl-carbonyl-amino that (a) replaces, condition is: have at least a substituting group to be selected from alkoxyl on the substituted alkyl part, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl; (b) its alkoxyl part be selected from carboxyl and-COOR²³The alkoxy aryl that replaced of substituting group, R wherein²³alkyl, cycloalkyl, aryl, heteroaryl or the heterocyclic radical of alkyl, replacement, (c) aryl and heteroaryl, (d)-NR ' R ', wherein R ' is independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: having a R ' at least is the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical or replacement, another condition is: when R ' was the alkyl that replaces, wherein having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、 -NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (e)-alkoxyl-NR " R ", R wherein " and be independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: as R " each replace naturally alkyl the time, wherein having a substituting group at least on the moieties that replaces is to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (f) aryloxy group that replaces and the heteroaryloxy of replacement, condition is, having a substituting group at least on the aryloxy group/heteroaryloxy that replaces is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (g)-alkoxyl saturated heterocyclyl ,-alkoxyl replace saturated heterocyclyl ,-the alkoxyl heterocyclic radical that replaces and-alkoxyl that replaces replaces saturated heterocyclyl, (h)-O-heterocyclic radical and-the O-substituted heterocyclic radical, (i) tetrazole radical, (j)-NR-SO₂-substituted alkyl, wherein R is hydrogen, alkyl or aryl, condition is: having a substituting group on the moieties of this substituted alkyl sulfuryl amino at least is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (k) the alkynyl group sulfuryl amino of the alkenyl sulfuryl amino of alkenyl sulfuryl amino, alkynyl group sulfuryl amino, replacement and replacement, (1) alkoxyl that replaces, condition is: the substituting group on the moieties of described substituted alkoxy does not comprise alkoxyl-NR " R ", the unsaturated heterocycle base, alkoxyl, aryloxy group, heteroaryloxy, aryl, heteroaryl and by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, the aryl/hetaryl that N-dialkyl group urea groups replaces, (m) amidino groups, and by 1-3, be independently selected from the amidino groups that alkynyl group, aryl, heteroaryl and the heterocyclic radical of alkenyl, alkynyl group, the replacement of alkyl, alkenyl, the replacement of alkyl, replacement replace, (n)-C (O) NR R , wherein R is independently selected from respectively hydrogen, alkyl, the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: when one of them R is the unsaturated heterocycle base, aryl, heteroaryl or by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1,2-, two Oxymethylenes, 1,2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, during aryl/hetaryl that N-alkyl urea groups or N, N-dialkyl group urea groups replace, another R is alkyl, the alkyl that replaces (not being the alkyl that the unsaturated heterocycle base replaces), cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, the heterocyclic radical of heterocyclic radical or replacement, (o)-NR²²C(O)-R ¹⁸, R wherein¹⁸Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement, and R²²It is the heterocyclic radical of heteroaryl, heterocyclic radical or replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; (p)-SO₂-aryl ,-SO₂The aryl of-replacement ,-SO₂-heteroaryl ,-SO₂-the heteroaryl that replaces or-SO₂-alkyl; (q)-NR ' C (O) NR¹⁹R ¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be independently selected from respectively the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (r)-NR ' C (O) OR¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (s)-amino carbonyl-(N-formoxyl heterocyclic radical); (t)-alkyl-C (O) NH-heterocyclic radical and-heterocyclic radical that alkyl-C (O) NH-replaces, and E. works as R³While being not H, R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be the alkenyl of replacement or the alkynyl group of replacement, and condition is: partly having a substituting group at least at the alkenyl/alkynyl group that replaces is to be selected from alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: when substituted alkyl replaced, having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl;

And pharmacologically acceptable salt,

Condition is: A. works as R ¹Be adjacent carboxymethyl phenyl, R ²Be hydrogen, R ³Be hydrogen or methyl, R ⁵Be benzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; B. work as R ¹And R ²-work forming benzisothiazole ketone heterocyclic, R ³Be hydrogen or methyl, R ⁵Be benzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; C. work as R ¹Be p-methylphenyl, R ²Be hydrogen, R ⁵Be benzyl or p-hydroxybenzene, R ³Be-(CH ₂) _sC (O) the O-tertiary butyl, wherein s is 1 or 2, and Q be-during C (O) NH-, R then ⁶Be not-the O-tertiary butyl; D. work as R ¹Be p-methylphenyl, R ²Be methyl, R ⁵Be benzyl, R ³Be-CH (φ) ₂, and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; E. work as R ¹Be p-methylphenyl, R ²Be methyl, R ⁵Be methyl, R ³Be-hydroxymethyl and Q be-during C (O) NH-, R then ⁶Be not-the O-methyl; Work as R with F. ¹Be p-methylphenyl, R ²Be methyl, R ³Be the methyl or the tertiary butyl, R ⁵Be to hydroxybenzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-tertiary butyl.

In above-mentioned formula I and IA compound, R ¹Be preferably selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of alkyl, aryl, the replacement of alkyl, replacement.R ¹More preferably be selected from 4-aminomethyl phenyl, methyl, benzyl, normal-butyl, 4-chloro-phenyl-, 1-naphthyl, 2-naphthyl, 4-p-methoxy-phenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl) phenyl, 2-carboxyl phenyl, 3,5-dichlorophenyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 3,4-Dimethoxyphenyl, 4-(CH ₃C (O) NH) phenyl, 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, sec.-propyl, 3,5-two (trifluoromethyl) phenyl, 4-tert-butyl-phenyl, 4-tert.-butoxy phenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloro pyrazoles-4-base, styroyl, 1-N-Methylimidazole-4-base, 4-bromophenyl, 4-amidino groups phenyl, 4-methyl amidino groups phenyl, 4-[CH ₃C (=NH)] phenyl, 5-chloro-2-thienyl, 2,5-two chloro-4-thienyls, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 4-[H ₂NC (S)] phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidine-2-base, 4-(3 '-dimethylamino positive propoxy) phenyl and 1-methyl-pyrazol-4-yl.

In above-mentioned formula I and IA compound, R ²Be preferably hydrogen, methyl, phenyl, benzyl ,-(CH ₂) ₂-2-thienyl and-(CH ₂) ₂-φ.

In one embodiment, R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together.The heterocyclic radical of preferred heterocyclic radical and replacement comprises the heterocyclic radical with following characteristics or the heterocyclic radical of replacement: it has 5-7 annular atoms, have 2-3 heteroatoms that is selected from nitrogen, oxygen and sulphur and this ring in ring optionally encircles to condense with formation as phenyl ring or cyclohexane ring with another and has 10-14 annular atoms and have the individual heteroatomic annelated heterocycles that is selected from nitrogen, oxygen and sulphur of 2-4 in ring.Concrete preferred R ¹/ R ²Engage examples of groups and comprise benzisothiazole ketone group (saccharin-2-yl).

In above-mentioned formula I and IA compound, R ³Preferably include by methyl, phenyl, benzyl, diphenyl methyl ,-CH ₂CH ₂COOH ,-CH ₂COOH, 2-amido ethyl, isobutyl-, the tertiary butyl ,-CH ₂O-benzyl and methylol replace all isomer that produced.

Q is preferably-C (O) NH-or-C (S) NH-.

R ⁵Be preferably selected from replace the institute produced by following radicals might isomer: benzyl, (N-benzyl imidazole-4-yl) methyl, (pyridine-2-yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, 4-[2-(pyridine-2-yl) ethynyl] benzyl, 4-[2-(3-hydroxy phenyl) ethynyl] benzyl, 4-iodine benzyl, 4-cyano group benzyl, 4-(2-bromobenzene formamido group) benzyl, 4-(pyridin-4-yl-C (O) NH-) benzyl and 4-hydroxybenzyl.

In formula IA compound, R ⁶Be preferably 2,4-dioxo tetrahydrofuran (THF)-3-base (3, the 4-enol), methoxyl group, oxyethyl group, isopropoxy, n-butoxy, tert.-butoxy, cyclopentyloxy, neopentyl oxygen, 2-α-sec.-propyl-4-Beta-methyl cyclohexyloxy, 2-β-sec.-propyl-4-Beta-methyl cyclohexyloxy ,-NH ₂, benzyloxy ,-NHCH ₂COOH ,-NHCH ₂CH ₂COOH ,-the NH-adamantyl ,-NHCH ₂CH ₂COOCH ₂CH ₃,-NHSO ₂-right-CH ₃-φ, R wherein ⁸Be hydrogen, methyl, sec.-propyl or benzyl-NHOR ⁸, O-(N-succinimido) ,-O-courage steroid-5-alkene-3-beta-yl ,-OCH ₂-OC (O) C (CH ₃) ₃, wherein z be 1 or 2 and W be selected from pyridin-3-yl, N-picolyl and N-methyl isophthalic acid, 4-dihydropyridine-3-base-O (CH ₂) _zNHC (O) W ,-NR " C (O)-R ', wherein R ' is aryl, heteroaryl or heterocyclic radical, and R " be hydrogen or-CH ₂C (O) OCH ₂CH ₃

Preferred formula I and IA examples for compounds comprise: N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl) glycyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-phenyl alanyl-D; L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(3-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(4-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-L-β-(2-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl)-D; L-phenyl sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-aspartyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(pyridine-2-yl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(3-hydroxy phenyl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-iodophenylalanine N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-cyano group phenylalanine N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycyl-L-phenylalanine N-(saccharin-2-yl)-D, L-alanyl-L-4-(different nicotinoyl amino) phenylalanine methyl ester

And pharmacologically acceptable salt and wherein a kind of ester are selected from the arbitrary above-mentioned ester cpds that the another kind of ester of methyl esters, ethyl ester, n-propyl, isopropyl ester, positive butyl ester, isobutyl ester, secondary butyl ester and the tert-butyl ester is replaced.

The present invention also provides in biological specimen in conjunction with the method for VLA-4, comprises biological specimen can be contacted under the condition in conjunction with VLA-4 at described compound with above-mentioned formula I or IA compound.

Some above-mentioned formula I and formula IA compound also can be used for alleviating in vivo the inflammation by the VLA-4 mediation.

The present invention also provides pharmaceutical composition, wherein contains one or more the above-mentioned formula I or the IA compound of pharmaceutically acceptable carrier and treatment significant quantity, but gets rid of wherein R ³And R ⁵Be formula I or IA compound derived from L-amino acid or other similar configuration raw material.Perhaps, can use racemic mixture.

Pharmaceutical composition of the present invention can be used for treating the disease by the VLA-4 mediation.This class disease comprises, the injury of lung that for example asthma, Alzheimer's, atherosclerosis, AIDS scab are slow-witted, the injury of lung of diabetes (comprising acute teenager's disease type diabetes), inflammatory bowel (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, encephalitis, apoplexy and other cerebral trauma, ephritis, the retinitis, atopic dermatitis, psoriasis, myocardial ischemia and the mediation of acute white corpuscle for example takes place in adult respiratory distress syndrome.

Correspondingly, the invention provides the method for in the patient, treating, comprise aforementioned pharmaceutical compositions patient's administration by the inflammation of VLA-4 mediation.

Preferred above-mentioned formula I and IA compound are included in down compound listed in the Table I:

Table I

????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????R ²/R ³=L-2,3-indoline-2-base	????-CH ₂-φ	????-OH	????H
????p-CH ₃-φ-	????R ²/R ³=L-1,2,3,4-tetrahydroquinoline-2-base		????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????R ²/R ³=L-2,3-indoline-2-base	????-CH ₂-φ	????-OH	????H

????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????H	????H	????-CH ₂-φ	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????H	????H	????-CH ₂-φ	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????H	????CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H
O-methoxycarbonyl-φ-	????H	????H	????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????H	????CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H
O-methoxycarbonyl-φ-	????H	????H	????-CH ₂-φ	????-OH	????H	O-methoxycarbonyl-φ-	????H	????-CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H
Adjacent sulfonyl-benzoyl imido-2-base		????CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H	O-methoxycarbonyl-φ-	????H	????-CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H
Adjacent sulfonyl-benzoyl imido-2-base		????CH ₃(L isomer)	????-CH ₂-φ	????-OH	????H	???p-CH ₃-φ-	????H	????φ-	????-CH ₂-φ	????-OH	????H
???p-CH ₃-φ-	????-CH ₃	Benzyl (L isomer)	????-CH ₂-φ	????-OH	????H	???p-CH ₃-φ-	????H	????φ-	????-CH ₂-φ	????-OH	????H
???p-CH ₃-φ-	????-CH ₃	Benzyl (L isomer)	????-CH ₂-φ	????-OH	????H	???p-CH ₃-φ-	????H	????L-CH(φ) ₂	????-CH ₂-φ	????-OH	????H

????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????-CH ₃	????L-CH(φ) ₂	????-CH ₂-φ	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	1-N-benzyl imidazole-4-base-CH ₂-	????-OH	????H	????p-CH ₃-φ-	????-CH ₃	????L-CH(φ) ₂	????-CH ₂-φ	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	1-N-benzyl imidazole-4-base-CH ₂-	????-OH	????H	????p-CH ₃-φ-	????-CH ₃	????H	3-pyridyl-CH ₂-	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	4-pyridyl-CH ₂-	????-OH	????H	????p-CH ₃-φ-	????-CH ₃	????H	3-pyridyl-CH ₂-	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	????H	4-pyridyl-CH ₂-	????-OH	????H	????p-CH ₃-φ-	????-CH ₃	????H	2-pyridyl-CH ₂-	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	-φ (L isomer)	????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????-CH ₃	????H	2-pyridyl-CH ₂-	????-OH	????H
????p-CH ₃-φ-	????-CH ₃	-φ (L isomer)	????-CH ₂-φ	????-OH	????H	????p-CH ₃-φ-	????H	????HOOCCH ₂-(L isomer)	????-CH ₂-φ	????-OH	????H

????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????R ²/R ³=L-1,2,3,4-tetrahydroquinoline-2-base		????-CH ₂-φ	??-O-CH ₂-φ	????H
????p-CH ₃-φ-	????R ²/R ³=L-2,3-indoline-2-base		????-CH ₂-φ	??-O-CH ₂-φ	????H	????p-CH ₃-φ-	????R ²/R ³=L-1,2,3,4-tetrahydroquinoline-2-base		????-CH ₂-φ	??-O-CH ₂-φ	????H
????p-CH ₃-φ-	????R ²/R ³=L-2,3-indoline-2-base		????-CH ₂-φ	??-O-CH ₂-φ	????H	????p-CH ₃-φ-	????H	????-CH ₃(L isomer)	????-CH ₂-φ	??-O-CH ₂-φ	????H
????p-CH ₃-φ-	????-CH ₃	????H	????-CH ₂-φ	??-O-CH ₂-φ	????H	????p-CH ₃-φ-	????H	????-CH ₃(L isomer)	????-CH ₂-φ	??-O-CH ₂-φ	????H
????p-CH ₃-φ-	????-CH ₃	????H	????-CH ₂-φ	??-O-CH ₂-φ	????H	????p-CH ₃-φ-	????H	-φ (L isomer)	????-CH ₂-φ	??-OCH ₂CH ₃	????H

????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????-CH ₃	????-CH ₂O-benzyl (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H
????p-CH ₃-φ-	????-CH ₃	????-CH ₂OH (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H	????p-CH ₃-φ-	????-CH ₃	????-CH ₂O-benzyl (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H
????p-CH ₃-φ-	????-CH ₃	????-CH ₂OH (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H	????p-CH ₃-φ-	????H	????-CH(φ) ₂(L isomer)	????-CH ₂-φ	????-O-CH ₂-φ	????H
????p-CH ₃-φ-	????φ	????H	????-CH ₂-φ	????OH	????H	????p-CH ₃-φ-	????H	????-CH(φ) ₂(L isomer)	????-CH ₂-φ	????-O-CH ₂-φ	????H
????p-CH ₃-φ-	????φ	????H	????-CH ₂-φ	????OH	????H	????p-CH ₃-φ-	????-CH ₃	-φ (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H
????p-CH ₃-φ-	????-CH ₃	????H	1-N-benzyl imidazole-4-base-CH ₂-	????-OCH ₃	????H	????p-CH ₃-φ-	????-CH ₃	-φ (L isomer)	????-CH ₂-φ	????-OCH ₂CH ₃	????H

?????R ¹	????R ²	????R ³	?????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷
?????R ¹	????R ²	????R ³	?????R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷	?????p-CH ₃-φ-	????-CH ₃	??-CH ₂OH (L isomer)	1-N-benzyl imidazole-4-yl-CH ₂-	????-OCH ₃	????H
?????p-CH ₃-φ-	????H	φ (L isomer)	????-CH ₂-φ	????-OCH ₂φ	????H	?????p-CH ₃-φ-	????-CH ₃	??-CH ₂OH (L isomer)	1-N-benzyl imidazole-4-yl-CH ₂-	????-OCH ₃	????H
?????p-CH ₃-φ-	????H	φ (L isomer)	????-CH ₂-φ	????-OCH ₂φ	????H	?????p-CH ₃-φ-	????-CH ₃	φ (L isomer)	????-CH ₂-φ	????-OCH ₂φ	????H
?????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OCH ₃	????H	?????p-CH ₃-φ-	????-CH ₃	φ (L isomer)	????-CH ₂-φ	????-OCH ₂φ	????H
?????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OCH ₃	????H	?????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OH	????H
?????p-CH ₃-φ-	????-CH ₃	????H	P-[-C ≡ C-(2-pyridyl)]-benzyl-	????-OH	????H	?????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OH	????H
?????p-CH ₃-φ-	????-CH ₃	????H	P-[-C ≡ C-(2-pyridyl)]-benzyl-	????-OH	????H	?????p-CH ₃-φ-	????-CH ₃	????H	P-[-C ≡ C-(-hydroxy phenyl)]-benzyl-	????-OH	????H

????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷
????R ¹	????R ²	????R ³	????R ⁵	????R ^6＇	????Q＝ ????-C(O)NR ⁷- ????R ⁷	????p-CH ₃-φ-	????-CH ₃	????H	To the iodine benzyl-	????-OH	????H
????p-CH ₃-φ-	????-(CH ₂) ₂-2-thienyl	????H	????-CH ₂-φ	????-OCH ₃	????H	????p-CH ₃-φ-	????-CH ₃	????H	To the iodine benzyl-	????-OH	????H
????p-CH ₃-φ-	????-(CH ₂) ₂-2-thienyl	????H	????-CH ₂-φ	????-OCH ₃	????H	????p-CH ₃-φ-	????-(CH ₂) ₂-2-thienyl	????H	????-CH ₂-φ	????-OH	????H
????φ-CH ₂-	????-CH ₃	???-CH ₂OH (L isomer)	1-N-benzyl imidazole-4-base-CH ₂-	????-OCH ₃	????H	????p-CH ₃-φ-	????-(CH ₂) ₂-2-thienyl	????H	????-CH ₂-φ	????-OH	????H
????φ-CH ₂-	????-CH ₃	???-CH ₂OH (L isomer)	1-N-benzyl imidazole-4-base-CH ₂-	????-OCH ₃	????H	?????p-CH ₃-φ-	????-CH ₂CH ₂φ	????H	1-N-benzyl imidazole-4-base-CH ₂-	????-OCH ₃	????H
?????p-CH ₃-φ-	????-CH ₂CH ₂φ	????H	????-CH ₂-φ	????-OH	????H	?????p-CH ₃-φ-	????-CH ₂CH ₂φ	????H	1-N-benzyl imidazole-4-base-CH ₂-	????-OCH ₃	????H
?????p-CH ₃-φ-	????-CH ₂CH ₂φ	????H	????-CH ₂-φ	????-OH	????H	?????p-CH ₃-φ-	????-CH ₃	????H	To the cyano group benzyl-	????-OH	????H

???R ¹	????R ²	????R ³	??R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷
???R ¹	????R ²	????R ³	??R ⁵	????R ^6′	????Q＝ ????-C(O)NR ⁷- ????R ⁷	???p-CH ₃-φ-	????H	The tertiary butyl	??-CH ₂-φ	????-OH	????H
???R ¹/R ²=benzisothia oxazolone		????-CH ₃	P-(pyridine-4-base-C (O) NH) benzyl-	????-OCH ₃	????H	???p-CH ₃-φ-	????H	The tertiary butyl	??-CH ₂-φ	????-OH	????H

Detailed Description Of The Invention

As mentioned above, the present invention relates to suppress white corpuscle and adhere, especially suppress compound by the white corpuscle adhesion of VLA-4 mediation.Yet, before the present invention is described in further detail, define following term earlier.Definition

Used " alkyl " of this specification sheets refers to the alkyl that preferably has 1-10 carbon atom, more preferably have 1-6 carbon atom.The represented examples of groups of this term has methyl, the tertiary butyl, n-heptyl, octyl group etc.

" alkyl of replacement " refers to preferably have 1-10 carbon atom; and has a substituent alkyl that 1-5 is selected from following radicals: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; thio-carbonyl-amino; acyloxy; amino; amidino groups; alkyl amidine; the sulfo-amidino groups; aminoacyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; the aryloxy aryl; the aryloxy aryl that replaces; cyano group; halogen; hydroxyl; nitro; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; heteroarylthio; the heteroarylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; heteroaryl; the aryl that replaces; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; have by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) substituted alkyl of the amino of having protected; and quilt-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂-the heterocyclic radical that replaces or-S (O) ₂Alkyl/substituted alkyl that NRR replaces, wherein R is a hydrogen or alkyl.

" alkoxyl group " refers to " alkyl-O-", and it comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.

" alkoxyl group of replacement " refers to " alkyl-O-of replacement ".

" acyl group " refer to H-C (O)-; alkyl-C (O)-; alkyl-the C (O) that replaces-; alkenyl-C (O)-; alkenyl-the C (O) that replaces-; alkynyl group-C (O)-; alkynyl group-the C (O) that replaces-; cycloalkyl-C (O)-; cycloalkyl-the C (O) that replaces-; aryl-C (O)-; aryl-the C (O) that replaces-; heteroaryl-C (O)-; heteroaryl-the C (O) that replaces-; heterocyclic radical-C (O)-; with the heterocyclic radical-C (O) that replaces-, alkyl wherein; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; cycloalkyl; the cycloalkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" amido " refers to-C (O) NRR, wherein R is independently selected from hydrogen respectively, alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, and two R can connect and form the heterocycle of heterocycle or replacement, wherein alkyl with nitrogen-atoms, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" thio-carbonyl-amino " refers to-C (O) NRR, wherein R is independently selected from hydrogen respectively, alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, and two R can connect and form the heterocycle of heterocycle or replacement, wherein alkyl with nitrogen-atoms, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" acyloxy " refers to alkyl-C (O) O-, alkyl-C (O) O-that replaces, alkenyl-C (O) O-, alkenyl-C (O) O-that replaces, alkynyl group-C (O) O-, alkynyl group-C (O) O-that replaces, aryl-C (O) O-, aryl-C (O) O-that replaces, cycloalkyl-C (O) O-, cycloalkyl-C (O) O-that replaces, heteroaryl-C (O) O-, heteroaryl-C (O) O-that replaces, heterocyclic radical-C (O) O-, with heterocyclic radical-C (O) O-that replaces, wherein alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" alkenyl " refer to preferably have 2-10 carbon atom, more preferably have 2-6 carbon atom and have at least one preferably at the alkenyl of the alkene unsaturated link(age) of 1-2 position.

" alkenyl of replacement " refers to have 1-5 and is selected from following substituent alkenyl: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; thio-carbonyl-amino; acyloxy; amino; amidino groups; alkyl amidine; the sulfo-amidino groups; aminoacyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; the aryloxy aryl; the aryloxy aryl that replaces; halogen; hydroxyl; cyano group; nitro; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; heteroarylthio; the heteroarylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; have by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) the substituted alkenyl base of the amino of having protected; and quilt-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂-the heterocyclic radical that replaces or-S (O) ₂Alkenyl/substituted alkenyl base that NRR replaces, wherein R is a hydrogen or alkyl.

" alkynyl group " refer to preferably have 2-10 carbon atom, more preferably have 3-6 carbon atom and have at least one preferably at the alkynyl group of the alkynes unsaturated link(age) of 1-2 position.

" alkynyl group of replacement " refers to have 1-5 and is selected from following substituent alkynyl group: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; thio-carbonyl-amino; acyloxy; amino; amidino groups; alkyl amidine; the sulfo-amidino groups; aminoacyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; the aryloxy aryl; the aryloxy aryl that replaces; halogen; hydroxyl; cyano group; nitro; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; heteroarylthio; the heteroarylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; have by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) the replacement alkynyl group of the amino of having protected; and quilt-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂-the heterocyclic radical that replaces or-S (O) ₂Alkynyl group/replacement alkynyl group that NRR replaces, wherein R is a hydrogen or alkyl.

" amidino groups " refers to H ₂NC (=NH)-, term " alkyl amidine " refers to have amidino groups (the alkyl HNC (=NH)-) for example of 1-3 alkyl.

" sulfo-amidino groups " refer to RSC (=NH)-, wherein R is a hydrogen or alkyl.

" aminoacyl "-NRC (O) alkyl; the alkyl that-NRC (O) replaces;-NRC (O) cycloalkyl; the cycloalkyl that-NRC (O) replaces;-NRC (O) alkenyl; the alkenyl that-NRC (O) replaces;-NRC (O) alkynyl group; the alkynyl group that-NRC (O) replaces;-NRC (O) aryl; the aryl that-NRC (O) replaces;-NRC (O) heteroaryl; the heteroaryl that-NRC (O) replaces;-NRC (O) heterocyclic radical; the heterocyclic radical that replaces with-NRC (O); wherein R is a hydrogen or alkyl, and alkyl wherein; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; cycloalkyl; the cycloalkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" aminocarboxyl oxygen base "-NRC (O) O-alkyl, the alkyl that-NRC (O) O-replaces,-NRC (O) O-alkenyl, the alkenyl that-NRC (O) O-replaces,-NRC (O) O-alkynyl group, the alkynyl group that-NRC (O) O-replaces,-NRC (O) O-cycloalkyl, the cycloalkyl that-NRC (O) O-replaces,-NRC (O) O-aryl, the aryl that-NRC (O) O-replaces,-NRC (O) O-heteroaryl, the heteroaryl that-NRC (O) O-replaces,-NRC (O) O-heterocyclic radical, the heterocyclic radical that replaces with-NRC (O) O-, wherein R is a hydrogen or alkyl, and alkyl wherein, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" oxygen base carbonylamino " refers to-OC (O) NH ₂-OC (O) NRR,-OC (O) NR-alkyl, the alkyl that-OC (O) NR-replaces,-OC (O) NR-alkenyl, the alkenyl that-OC (O) NR-replaces,-OC (O) NR-alkynyl group, the alkynyl group that-OC (O) NR-replaces,-OC (O) NR-cycloalkyl, the cycloalkyl that-OC (O) NR-replaces,-OC (O) NR-aryl, the aryl that-OC (O) NR-replaces,-OC (O) NR-heteroaryl, the heteroaryl that-OC (O) NR-replaces,-OC (O) NR-heterocyclic radical, the heterocyclic radical that replaces with-OC (O) NR-, wherein R is a hydrogen, alkyl, or R can be connected to each other and form the heterocycle of heterocycle or replacement with nitrogen-atoms, and alkyl wherein, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" oxygen base thio-carbonyl-amino " refers to-OC (S) NH ₂-OC (S) NRR,-OC (S) NR-alkyl, the alkyl that-OC (S) NR-replaces,-OC (S) NR-alkenyl, the alkenyl that-OC (S) NR-replaces,-OC (S) NR-alkynyl group, the alkynyl group that-OC (S) NR-replaces,-OC (S) NR-cycloalkyl, the cycloalkyl that-OC (S) NR-replaces,-OC (S) NR-aryl, the aryl that-OC (S) NR-replaces,-OC (S) NR-heteroaryl, the heteroaryl that-OC (S) NR-replaces,-OC (S) NR-heterocyclic radical, with-OC (S) NR-heterocyclic radical, wherein R is a hydrogen, alkyl, or R can be connected to each other and form the heterocycle of heterocycle or replacement, wherein alkyl with nitrogen-atoms, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" amino carbonyl amino " refers to-NRC (O) NRR;-NRC (O) NR-alkyl; the alkyl that-NRC (O) NR-replaces;-NRC (O) NR-alkenyl; the alkenyl that-NRC (O) NR-replaces;-NRC (O) NR-alkynyl group; the alkynyl group that-NRC (O) NR-replaces;-NRC (O) NR-aryl; the aryl that-NRC (O) NR-replaces;-NRC (O) NR-cycloalkyl; the cycloalkyl that-NRC (O) NR-replaces;-NRC (O) NR-heteroaryl; the heteroaryl that-NRC (O) NR-replaces;-NRC (O) NR-heterocyclic radical; the heterocyclic radical that replaces with-NRC (O) NR-; and wherein R is a hydrogen respectively independently; alkyl; or R can be connected to each other and form the heterocycle of heterocycle or replacement with nitrogen-atoms; one of them amino also can be by protecting group commonly used (Boc for example; Cbz; formyl radical etc.) protection, wherein alkyl; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; cycloalkyl; the cycloalkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" amino thio-carbonyl-amino " refers to-NRC (S) NRR;-NRC (S) NR-alkyl; the alkyl that-NRC (S) NR-replaces;-NRC (S) NR-alkenyl; the alkenyl that-NRC (S) NR-replaces;-NRC (S) NR-alkynyl group; the alkynyl group that-NRC (S) NR-replaces;-NRC (S) NR-aryl; the aryl that-NRC (S) NR-replaces;-NRC (S) NR-cycloalkyl; the cycloalkyl that-NRC (S) NR-replaces;-NRC (S) NR-heteroaryl; the heteroaryl that-NRC (S) NR-replaces;-NRC (S) NR-heterocyclic radical; with-NRC (S) NR-heterocyclic radical; wherein R is a hydrogen respectively independently; alkyl; or R can be connected to each other and form the heterocycle of heterocycle or replacement with nitrogen-atoms; one of them amino also can be by protecting group commonly used (Boc for example; Cbz; formyl radical etc.) protection, wherein alkyl; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; cycloalkyl; the cycloalkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" aryl " or " Ar " refers to the unsaturated aromatic carbon ring group that formed by 6-14 carbon atom, have monocycle (for example phenyl) or compound fused rings (for example naphthyl or anthryl), wherein institute's condensed ring both can be that aromatic nucleus also can not be aromatic nucleus (for example 2-benzoxazolinone, 2H-1,4-benzoxazine-(4H)-ketone-7-base etc.).Preferred aryl groups comprises phenyl and naphthyl.

The aryl that replaces refers to have 1-3 and is selected from following substituent aryl: hydroxyl; acyl group; amido; thio-carbonyl-amino; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amidino groups; alkyl amidine; the sulfo-amidino groups; amino; aminoacyl; aminocarboxyl oxygen base; amino carbonyl amino; amino thio-carbonyl-amino; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; the carboxyl amido; cyano group; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; heteroarylthio; the heteroarylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; halogen; nitro; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; be positioned on the substituted aryl and by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) protected amino or-S (O) ₂NRR, wherein R is a hydrogen or alkyl.

" aryloxy " refers to aryl-O-, and it comprises for example phenoxy group, naphthyloxy etc.

" aryloxy of replacement " refers to aryl-O-of replacing.

" aryloxy aryl " refers to-aryl-O-aryl.

" the aryloxy aryl of replacement " refers to have the individual substituent aryloxy aryl that is selected from following radicals of 1-3 on any aryl or on two aryl: hydroxyl; acyl group; amido; thio-carbonyl-amino; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amidino groups; alkyl amidine; the sulfo-amidino groups; amino; aminoacyl; aminocarboxyl oxygen base; amino carbonyl amino; amino thio-carbonyl-amino; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; the carboxyl amido; cyano group; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; heteroarylthio; the heteroarylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; halogen; nitro; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; be positioned on the substituted aryl and by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) protected amino or-S (O) ₂NRR, wherein R is a hydrogen or alkyl.

" cycloalkyl " refers to have the monocyclic cyclic alkyl that is made of 3-8 carbon atom, and it comprises for example cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group etc.What get rid of from this definition is complex loop, for example adamantyl etc.

" cycloalkenyl group " refer to have 3-8 carbon atom, one or more unsaturated link(age)s are arranged but be not the ring-type thiazolinyl of aromatic nucleus.

" cycloalkyl of replacement " and " cycloalkenyl group of replacement " refers to preferably have 3-8 carbon atom; 1-5 substituent cycloalkyl and cycloalkenyl group that is selected from following radicals arranged: oxo (=O); sulfo-(=S); alkoxyl group; the alkoxyl group that replaces; acyl group; amido; thio-carbonyl-amino; acyloxy; amino; amidino groups; alkyl amidine; the sulfo-amidino groups; aminoacyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; the aryloxy aryl; the aryloxy aryl that replaces; halogen; hydroxyl; cyano group; nitro; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; heteroarylthio; the heteroarylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; have by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) the replacement alkynyl group of the amino of having protected; and quilt-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂-the heterocyclic radical that replaces or-S (O) ₂Alkynyl group/replacement alkynyl group that NRR replaces, wherein R is a hydrogen or alkyl.

" cycloalkyloxy " refers to-the O-cycloalkyl.

" cycloalkyloxy of replacement " refer to-cycloalkyl that O-replaces.

" guanidine radicals " refer to-NRC (=NR) NRR;-NRC (=NR) NR-alkyl;-NRC (=NR) the alkyl that replaces of NR-;-NRC (=NR) NR-alkenyl;-NRC (=NR) the alkenyl that replaces of NR-;-NRC (=NR) NR-alkynyl group;-NRC (=NR) the alkynyl group that replaces of NR-;-NRC (=NR) NR-aryl;-NRC (=NR) the aryl that replaces of NR-;-NRC (=NR) NR-cycloalkyl;-NRC (=NR) the cycloalkyl that replaces of NR-;-NRC (=NR) NR-heteroaryl;-NRC (=NR) the heteroaryl that replaces of NR-;-NRC (=NR) NR-heterocyclic radical; with-NRC (=NR) the heterocyclic radical that replaces of NR-; wherein R represents hydrogen and alkyl respectively independently; and one of them is amino by protecting group commonly used (Boc for example; Cbz; formyl radical etc.) protection, wherein alkyl; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; cycloalkyl; the cycloalkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the definition of the heterocyclic radical of heterocyclic radical and replacement as described in this manual.

" alkylsulfonyl guanidine radicals " refers to-NRC (=NR) NRSO ₂-alkyl ,-NRC (=NR) NRSO ₂-replace alkyl ,-NRC (=NR) NRSO ₂-alkenyl ,-NRC (=NR) NRSO ₂-replace alkenyl ,-NRC (=NR) NRSO ₂-alkynyl group ,-NRC (=NR) NRSO ₂-replace alkynyl group ,-NRC (=NR) NRSO ₂-aryl ,-NRC (=NR) NRSO ₂-replace aryl ,-NRC (=NR) NRSO ₂-cycloalkyl ,-NRC (=NR) NRSO ₂-replace cycloalkyl ,-NRC (=NR) NRSO ₂-heteroaryl ,-NRC (=NR) NRSO ₂-replace heteroaryl ,-NRC (=NR) NRSO ₂-heterocyclic radical and-NRC (=NR) NRSO ₂The heterocyclic radical of-replacement, wherein R is hydrogen and alkyl independently respectively, and the definition of the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the aryl of the cycloalkyl of the alkynyl group of the alkenyl of the alkyl of alkyl, replacement, alkenyl, replacement, alkynyl group, replacement, cycloalkyl, replacement, aryl, replacement, heteroaryl, replacement as described in this manual.

" halogen " or " halogen " refers to fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.

" heteroaryl " is meant 2-10 carbon atom and 1-4 heteroatomic aromatic carbon cyclic group that is selected from oxygen, nitrogen and sulphur in ring.This class heteroaryl can be monocycle (for example pyridyl or furyl) or compound fused rings (for example indolizine base or benzothienyl).Preferred heterocyclic radical comprises pyridyl, pyrryl, indyl and furyl.

" heteroaryl of replacement " refers to have 1-3 substituent heteroaryl that is selected from following radicals: hydroxyl; acyl group; amido; thio-carbonyl-amino; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amidino groups; alkyl amidine; the sulfo-amidino groups; amino; aminoacyl; aminocarboxyl oxygen base; amino carbonyl amino; amino thio-carbonyl-amino; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; the carboxyl amido; cyano group; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; heteroarylthio; the heteroarylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; halogen; nitro; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; be positioned on the substituted aryl and by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) amino of having protected and-S (O) ₂NRR, wherein R is a hydrogen or alkyl.

" heteroaryloxy " refers to-the O-heteroaryl, " heteroaryloxy of replacement " refer to-and heteroaryl that O-replaces.

" heterocycle " or " heterocyclic radical " refers to have monocycle or compound fused rings, 1-10 carbon atom and 1-4 heteroatomic saturated or unsaturated group that is selected from nitrogen, sulphur or oxygen arranged in ring, wherein in condensing ring system, one or more rings can be aryl or heteroaryl.

" saturated heterocyclyl " is meant does not all have unsaturated link(age) in arbitrary ring (for example carbon-to-carbon unsaturated bond, carbon-nitrogen unsaturated link(age), nitrogen-nitrogen unsaturated link(age) etc.) monocycle or compound fused rings heterocyclic radical.

" unsaturated heterocycle base " is meant unsaturated link(age) in arbitrary ring (for example carbon-to-carbon unsaturated bond, carbon-nitrogen unsaturated link(age), nitrogen-nitrogen unsaturated link(age) etc.) monocycle or compound fused rings nonaromatic heterocycles base.

" heterocyclic radical of replacement " refers to have 1-3 substituent heterocyclic radical that is selected from following radicals: oxo (=O); sulfo-(=S); alkoxyl group; the alkoxyl group that replaces; acyl group; amido; thio-carbonyl-amino; acyloxy; amino; amidino groups; alkyl amidine; the sulfo-amidino groups; aminoacyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; the aryloxy aryl; the aryloxy aryl that replaces; halogen; hydroxyl; cyano group; nitro; carboxyl; carboxyalkyl; the carboxyl substituted alkyl; the carboxyl cycloalkyl; the carboxyl substituted cycloalkyl; the carboxyl aryl; the carboxyl substituted aryl; the carboxyl heteroaryl; the carboxyl substituted heteroaryl; the carboxyl heterocyclic radical; the carboxyl substituted heterocyclic radical; cycloalkyl; the cycloalkyl that replaces; guanidine radicals; the alkylsulfonyl guanidine radicals; thiol; alkylthio; the alkylthio that replaces; arylthio; the arylthio that replaces; cycloalkylthio; the cycloalkylthio that replaces; heteroarylthio; the heteroarylthio that replaces; the heterocycle sulfenyl; the heterocycle sulfenyl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocyclic oxy group; the heterocyclic oxy group that replaces; oxygen base carbonylamino; oxygen base thio-carbonyl-amino;-OS (O) ₂-alkyl ,-OS (O) ₂The alkyl of-replacement ,-OS (O) ₂-aryl ,-OS (O) ₂The aryl of-replacement ,-OS (O) ₂-heteroaryl ,-OS (O) ₂The heteroaryl of-replacement ,-OS (O) ₂-heterocyclic radical ,-OS (O) ₂The heterocyclic radical of-replacement ,-OS (O) ₂-NRR ,-NRS (O) ₂-alkyl ,-NRS (O) ₂The alkyl of-replacement ,-NRS (O) ₂-aryl ,-NRS (O) ₂The aryl of-replacement ,-NRS (O) ₂-heteroaryl ,-NRS (O) ₂The heteroaryl of-replacement ,-NRS (O) ₂-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical of-replacement ,-NRS (O) ₂-NR-alkyl ,-NRS (O) ₂The alkyl that-NR-replaces ,-NRS (O) ₂-NR-aryl ,-NRS (O) ₂The aryl that-NR-replaces ,-NRS (O) ₂-NR-heteroaryl ,-NRS (O) ₂The heteroaryl that-NR-replaces ,-NRS (O) ₂-NR-heterocyclic radical ,-NRS (O) ₂The heterocyclic radical that-NR-replaces; one alkylamino; dialkyl amido; one (alkyl of replacement) amino; two (alkyl of replacement) amino; one arylamino; ammonia diaryl base; one (aryl of replacement) amino; two (aryl of replacement) amino; one heteroaryl amino; two heteroaryl aminos; one (heteroaryl of replacement) amino; two (heteroaryl of replacement) amino; one heterocyclic radical amino; two heterocyclic radical amino; one (heterocyclic radical of replacement) amino; two (heterocyclic radical of replacement) amino; has the alkyl of being selected from; the alkyl that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; heterocyclic radical; the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces; have by blocking group commonly used (Boc for example; Cbz; formyl radical etc.) the replacement alkynyl group of the amino of having protected; and quilt-S (O) ₂-alkyl ,-S (O) ₂The alkyl of-replacement ,-S (O) ₂-alkenyl ,-S (O) ₂The alkenyl of-replacement ,-S (O) ₂-cycloalkyl ,-S (O) ₂The cycloalkyl of-replacement ,-S (O) ₂-aryl ,-S (O) ₂The aryl of-replacement ,-S (O) ₂-heteroaryl ,-S (O) ₂The heteroaryl of-replacement ,-S (O) ₂-heterocyclic radical ,-S (O) ₂-the heterocyclic radical that replaces or-S (O) ₂Alkynyl group/replacement alkynyl group that NRR replaces, wherein R is a hydrogen or alkyl.

The example of heterocycle and heteroaryl includes but not limited to azetidine, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene isoxazole phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, thiomorpholine generation, piperidyl, tetramethyleneimine, tetrahydrofuran base etc.

The monocycle or the compound fused rings heterocyclic radical of the replacement that " saturated heterocyclyl of replacement " is meant does not all have unsaturated link(age) in arbitrary ring (for example carbon-to-carbon unsaturated bond, carbon-nitrogen unsaturated link(age), nitrogen-nitrogen unsaturated link(age) etc.).

" the unsaturated heterocycle base of replacement " is meant unsaturated link(age) in the arbitrary ring monocycle of (for example carbon-to-carbon unsaturated bond, carbon-nitrogen unsaturated link(age), nitrogen-nitrogen unsaturated link(age) etc.) or the non-fragrant substituted heterocyclic radical of compound fused rings.

" heterocyclic oxy group " refers to-the O-heterocyclic radical, " heterocyclic oxy group of replacement " refer to-and heterocyclic radical that O-replaces.

" thiol " refers to-SH.

" alkylthio " refers to-the S-alkyl.

" alkylthio of replacement " refer to-alkyl that S-replaces.

" cycloalkylthio " refers to-the S-cycloalkyl.

" cycloalkylthio of replacement " refer to-cycloalkyl that S-replaces.

" arylthio " refers to-the S-aryl, " arylthio of replacement " refer to-and aryl that S-replaces.

" heteroarylthio " refers to-the S-heteroaryl, " heteroarylthio of replacement " refer to-and heteroaryl that S-replaces.

" heterocycle sulfenyl " refers to-the S-heterocyclic radical, " the heterocycle sulfenyl of replacement " refer to-and heterocyclic radical that S-replaces.

" pharmacologically acceptable salt " is meant the pharmacologically acceptable salt of formula I or IA compound, and described salt is derived by various organic and inorganic gegenions well-known in the art, and described salt comprises for example sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt, tetraalkylammonium salt etc.; When compound contained basic functionality, described salt had inorganic acid salt or organic acid salt, for example hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate etc.Compound

The compounds of this invention can be made with following ordinary method and operation by the raw material that is easy to get.Should be appreciated that when providing general or preferred reaction conditions (being mol ratio, solvent, pressure of temperature of reaction, time, reactant etc.), except as otherwise noted, also can use other reaction conditions.Optimum reaction condition can be with the difference of used concrete reactant or solvent difference, but optimum reaction condition can be determined by the optimization routine method by those skilled in the art.

In addition, it is apparent to those skilled in the art that, may need the GPF (General Protection False group to protect some functional groups to avoid adverse effect.The appropriate protection base of different functional groups and to protect the felicity condition with deprotection be well-known in this area.For example; at T.W.Greene and G.M.Wuts " (protecting group in the organic synthesis " (ProtectingGroups in Organic Synthesis), second edition, Wiley New York; described the kinds of protect base in 1991, the document is introduced the present invention with for referencial use.

In addition, The compounds of this invention contains one or more chiral centres usually.Therefore, if necessary, this compounds can be prepared into or be separated into pure stereoisomers, be independent enantiomorph or diastereomer isomer, or be rich in the mixture of steric isomer.Unless otherwise noted, all these class steric isomers (with the mixture that is rich in steric isomer) all within the scope of the present invention.Available for example optically-active raw material of the pure stereoisomers mixture of steric isomer (or be rich in) or stereoselectivity reactant well-known in the art make.Perhaps, available for example chiral column chromatography, chiral separation agent etc. separate the racemic mixture of this compounds.

In preferred synthetic method, wherein Q is-C (O) NR ⁷Formula I and IA compound be like this preparation: earlier with formula II amino acid

R wherein ²And R ³Definition the same, with the coupling of formula III SULPHURYL CHLORIDE

R ¹-SO ₂-Cl III is R wherein ¹Definition the same, with the acid of production IV N-sulfuryl amino

R wherein ¹-R ³Definition the same.

This reaction is generally by with formula II amino acid and at least 1 equivalent, preferably about 1.1-about 2 normal formula III SULPHURYL CHLORIDE are for example reacted in the methylene dichloride etc. at inert solvent and implemented.This reaction is about 24 hours of about 1-under about-70 ℃-Yue 40 ℃ of temperature generally.The acid that generates between the reaction period to remove is preferably carried out in this reaction in the presence of suitable alkali.Suitable alkali comprises, for example tertiary amine, for example triethylamine, diisopropyl ethyl amine, N-methylmorpholine etc.Perhaps, reaction can be under Schotten-Baumann type condition, carry out as alkali with the aqueous solution of alkali such as sodium hydroxide.After reacting completely, comprise that with ordinary method neutralization, extraction, precipitation, chromatography, filtration etc. are with the N-sulfuryl amino acid IV collection that generates.

The formula II amino acid that uses in above-mentioned reaction is known compound, or the compound that made by conventional synthetic method of available known compound.The amino acid whose example that is applicable to above-mentioned reaction includes but not limited to glycine, 2-tertiary butyl glycine, D, L-phenylglycocoll, L-L-Ala, Alpha-Methyl L-Ala, N-methyl-L-phenylalanine, L-diphenylprop propylhomoserin, sarkosine, D, L-phenyl sarkosine, L-aspartic acid β-tert-butyl ester, L-glutamic acid gamma-tert-butyl ester, L-(O-benzyl) Serine, 1-amino-cyclopropane formic acid, the amino cyclobutane formate of 1-, 1-Aminocyclopentane formic acid (cycloleucine), 1-aminocyclohexane formic acid, L-Serine etc.In above-mentioned reaction, if necessary, for example methyl esters, ethyl ester etc. react with the formula III SULPHURYL CHLORIDE can to use formula II amino acid corresponding carboxylic acid ester.Use conventional reagent and condition then, promptly in inert solvent such as methanol, handle,, generate N-sulfuryl amino acid IV so that hydrolysis of ester group becomes carboxylic acid with alkali metal hydroxide.

Equally, the formula III SULPHURYL CHLORIDE of using in above-mentioned reaction is a known compound, or the compound that made by conventional synthetic method of available known compound.This compounds generally is with corresponding sulfonic acid, i.e. R wherein ¹The same formula R of definition ¹-SO ₃The H compound makes with phosphorus trichloride and phosphorus pentachloride reaction.The reaction of this class generally is performed such: with the phosphorus trichloride of sulfonic acid and about 2-5 molar equivalent and phosphorus pentachloride, without solvent or in inert solvent such as methylene dichloride, under about 0 ℃-Yue 80 ℃ of temperature about 48 hours of the about 1-of reaction, with the acquisition SULPHURYL CHLORIDE.Perhaps, the formula III SULPHURYL CHLORIDE can be by using chlorine (Cl ₂) and water under the popular response condition, handle corresponding mercaptan compound, i.e. R wherein ¹The same formula R of definition ¹-SH compound makes.

The example that is applicable to the SULPHURYL CHLORIDE of this reaction includes but not limited to methylsulfonyl chloride, 2-third SULPHURYL CHLORIDE, 1-fourth SULPHURYL CHLORIDE, benzene sulfonyl chloride, the 1-naphthalic sulfonic chloride, the 2-naphthalic sulfonic chloride, Tosyl chloride, α-toluene sulfonyl chloride, the 4-acetylsulphanilyl chloride, 4-amidino groups benzene sulfonyl chloride, 4-tert.-butylbenzene SULPHURYL CHLORIDE, the 4-bromobenzene sulfonyl chloride, 2-carboxyl benzene sulfonyl chloride, 4-cyano group benzene sulfonyl chloride, 3, the 4-two chloro phenylsulfonyl chloride, 3, the 5-two chloro phenylsulfonyl chloride, 3,4-dimethoxy benzene sulfonyl chloride, 3,5-two (trifluoromethyl) benzene sulfonyl chloride, 4-fluorobenzene SULPHURYL CHLORIDE, 4-anisole SULPHURYL CHLORIDE, 2-methoxycarbonyl benzene sulfonyl chloride, 4-methyl amido benzene sulfonyl chloride, the 4-nitrobenzene sulfonyl chloride, 4-thio acylamino benzene sulfonyl chloride, 4-trifluoromethyl benzene sulfonyl chloride, 4-trifluoromethoxy benzene sulfonyl chloride, 2,4, the 6-trimethylbenzene chloride, 2-phenyl ethyl sulfonyl chloride, 2-thiophene SULPHURYL CHLORIDE, 5-chloro-2-thiophene SULPHURYL CHLORIDE, 2,5-two chloro-4-thiophene SULPHURYL CHLORIDE, 2-thiazole SULPHURYL CHLORIDE, 2-methyl-4-thiazole SULPHURYL CHLORIDE, 1-methyl-4-imidazoles SULPHURYL CHLORIDE, 1-methyl-4-pyrazoles SULPHURYL CHLORIDE, 5-chloro-1,3-dimethyl-4-pyrazoles SULPHURYL CHLORIDE, 3-pyridine SULPHURYL CHLORIDE, 2-pyrimidine sulfonyl chlorine etc.In above-mentioned reaction, if necessary, available sulfonic acid fluoride sulfuryl bromide or sulphonic acid anhydride substitute the N-sulfuryl amino acid of SULPHURYL CHLORIDE with production IV.

R wherein ³The formula IV N-sulfuryl amino acid intermediate that is hydrogen also can prepare like this: with formula V sulphonamide

R ¹-SO ₂-NH-R ²V is R wherein ¹And R ²Definition the same with formula L (R ³) CHCOOR reaction, wherein L is a leavings group, for example chlorine, bromine, iodine, methylsulfonyl, p-toluenesulfonyl etc., R ³Definition the same, and R is a hydrogen or alkyl.This reaction generally is performed such: formula V sulphonamide and at least 1 equivalent, the preferred normal above-mentioned carboxylic acid derivative of 1.1-2 were being reacted about 0.5-about 4 hours in the presence of the suitable alkali such as triethylamine, in inert diluent such as DMF, under about 24 ℃-Yue 37 ℃ of temperature.This reaction also is described in people such as Zuckermann, " American Chemical Society can will " (J.Am.Chem.Soc.), 1992,114, among the 10646-10647.The optimization acid's derivative that is applicable to this reaction is α-chlorine carboxylicesters and α-bromine carboxylicesters, for example bromo-acetic acid tert-butyl etc.When in this reaction, using carboxylicesters, be subsequently with ordinary method with hydrolysis of ester group to obtain the acid of formula IV N-sulfuryl amino.

Then the acid of formula IV intermediate N sulfuryl amino is made formula I compound with formula VI amino acid derivative coupling:

R wherein ⁵-R ⁷Definition the same.This coupled reaction generally with well-known coupler for example carbodiimide, bop reagent (hexafluoro phosphonic acids benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium) etc. carries out.The example of suitable carbonization diimine comprises dicyclohexyl carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) etc.If necessary, also can use with the carbodiimide coupler of polymkeric substance as carrier, it for example comprises at " tetrahedron communication " (Tetrahedron Letters), the couplers of describing in 34 (48), 7685 (1993).In addition, for example N-hydroxy-succinamide, I-hydroxybenzotriazole wait and promote this coupled reaction can to use well-known coupling promotor.

This coupled reaction generally is performed such: with formula IV N-sulfuryl amino acid and about 1-about 2 normal couplers and at least 1 equivalent, preferably about 1-about 1.2 normal formula VI amino acid derivative are at inert diluent for example methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), N, dinethylformamide etc. are middle to react.This reaction is generally about 24 hours of about 0 ℃-Yue 37 ℃ of about 12-.After reacting completely, comprise that with ordinary method neutralization, extraction, precipitation, chromatography, filtration etc. are with the formula I compound collection that generates.

Perhaps, the acid of formula IV N-sulfuryl amino can be changed into acyl halide, then with acyl halide and the coupling of formula VI amino acid derivative with production I compound.Can be by IV N-sulfuryl amino acid and inorganic carboxylic acid halides such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride or preferred and oxalyl chloride be reacted the acyl halide for preparing IV under normal condition.This reaction normally with the inorganic acyl halide of about 1-5 molar equivalent or oxalyl chloride, without solvent or inert solvent for example in methylene dichloride or the tetracol phenixin, under about 0 ℃-Yue 80 ℃ of temperature about 48 hours of about 1-.In this reaction, also can use for example N of catalyzer, dinethylformamide.

Then with the acyl halide of formula IV N-sulfuryl amino acid and at least 1 equivalent, preferably about 1.1-about 1.5 normal formula VI amino acid derivative in inert diluent such as methylene dichloride, reacted about 1-about 24 hours in-70 ℃ approximately-Yue 40 ℃.The acid that generates between the reaction period to remove is preferably carried out in this reaction in the presence of suitable alkali.Suitable alkali comprises, for example tertiary amine, for example triethylamine, diisopropyl ethyl amine, N-methylmorpholine etc.Perhaps, reaction can be under Schotten-Baumann type condition, carry out as alkali with the aqueous solution of alkali such as sodium hydroxide.After reacting completely, comprise that with ordinary method neutralization, extraction, precipitation, chromatography, filtration etc. are with the formula I compound collection that generates.

Perhaps, can come preparation I compound by forming formula VII diamino acid derivative earlier: R wherein ², R ³, R ^5-7Definition the same.Formula VII amino acid derivative can be by easily making formula II amino acid and formula VI amino acid derivative coupling with conventional amino acid coupling technology and coupler such as carbodiimide, bop reagent etc. as stated above.Available then formula III SULPHURYL CHLORIDE is the sulfonation of formula VII diamino acid, and with above-mentioned synthetic method preparation I compound.

The formula VI amino acid derivative that uses in above-mentioned reaction is a known compound, or the compound that made by conventional synthetic method of available known compound.For example, formula VI amino acid derivative can be by (Wisconsin USA) makes with alkylogen or the C-alkylation of substituted alkyl halogen for Aldrich, Milwaukee with commercially available 2-acetyl ammonia diethyl malonate.This reaction generally is performed such: use at least 1 normal sodium ethylate and at least one normal alkylogen or substituted alkyl halogen to handle about 6-12 hour in the ethanol that refluxes 2-acetyl ammonia diethyl malonate.By about 12 hours of the about 6-of reflux in aqueous hydrochloric acid the C-alkylation malonic ester that obtains being gone acetyl, hydrolysis and decarboxylation then, to obtain amino acid, generally is amino acid whose hydrochloride.

The example that is applicable to the formula VI amino acid derivative of above-mentioned reaction includes but not limited to the L-alanine methyl ester, L-Isoleucine methyl esters, L-leucine methyl esters, the L-valine methyl ester, β-tertiary butyl-L-aspartic acid methyl esters, the altheine tert-butyl ester, ε-Boc-L-lysine methyl ester, ε-Cbz-L-lysine methyl ester, γ-tertiary butyl-L-glutamic acid methyl ester, the L-glutaminate tert-butyl ester, L-(N-methyl) Histidine methyl esters, L-(N-benzyl) Histidine methyl esters, the L-methyl methionine, L-(O-benzyl) serine methylester, the L-tryptophan methyl ester, the L-phenylalanine methyl ester, the L-phenylalanine isopropyl ester, L-phenylalanine benzyl ester, L-phenylalanyl amine, N-methyl-L-phenylalanine benzyl ester, 3-carboxyl-D, the L-phenylalanine methyl ester, 4-carboxyl-D, the L-phenylalanine methyl ester, L-4-chlorophenylalanine methyl esters, L-4-(3-dimethylamino propoxy) phenylalanine methyl ester, L-4-iodophenylalanine methyl esters, L-3,4-methylenedioxyphenyl alanine methyl ester, L-3,4-ethylidene dioxy base phenylalanine methyl ester, L-4-oil of mirbane alanine methyl ester, the L-L-Tyrosine methyl ester, D, L-hyperphenylalaninemia methyl esters, L-(O-methyl) L-Tyrosine methyl ester, L-(the O-tertiary butyl) L-Tyrosine methyl ester, L-(O-benzyl) L-Tyrosine methyl ester, L-3,5-diiodotyrosine methyl esters, L-3-iodotyrosine methyl esters, β-(1-naphthyl)-L-alanine methyl ester, β-(2-naphthyl)-L-alanine methyl ester, β-(2-thienyl)-L-alanine methyl ester, β-cyclohexyl-L-alanine methyl ester, β-(2-pyridyl)-L-alanine methyl ester, β-(3-pyridyl)-L-alanine methyl ester, β-(4-pyridyl)-L-alanine methyl ester, β-(2-thiazolyl)-D, the L-alanine methyl ester, β-(1,2,4-triazole-3-yl)-and D, L-alanine methyl ester etc.Certainly, if necessary, also can use other ester or the acid amides of above-claimed cpd.

For the ease of synthetic, generally formula I compound is made the form of ester, i.e. R wherein ⁶It is alkoxyl group of alkoxyl group or replacement etc.If necessary, can adopt normal condition and reagent that ester is hydrolyzed into corresponding carboxylic acid.This hydrolysis reaction generally is performed such: for example lithium hydroxide, sodium hydroxide or potassium hydroxide were handled about 1-about 12 hours with ester in the mixture of inert diluent such as methyl alcohol or methyl alcohol and water, under about 0 ℃-Yue 24 ℃ of temperature with at least 1 normal alkali metal hydroxide.Perhaps, available palladium catalyst for example palladium carbon the benzyl ester is hydrolyzed into carboxylic acid.If necessary, can with conventional coupler and condition the carboxylic acid that obtains be coupled to amine as mentioned above, Beta-alanine ethyl ester for example, azanol such as oxyamine and N-hydroxy-succinamide, the alkoxylamine of alkoxylamine and replacement is O-methyl hydroxylamine and O-benzyl hydroxylamine etc. for example.

It will be obvious to those skilled in the art that before or after above-mentioned coupled reaction available well-known synthetic method is easily modified the functional group on the arbitrary substituting group of formula I compound or derivatize.For example, palladium catalyst for example in the presence of the palladium carbon, the nitro on formula I compound or its intermediate substituting group easily can be reduced by hydrogenation, to obtain corresponding amino.This reaction generally is about 24 hours of about 6-in inert diluent such as methyl alcohol, under about 20 ℃-Yue 50 ℃ of temperature.At R ⁵The compound that has nitro on the substituting group can be by for example making with 4-oil of mirbane alanine derivatives etc. in above-mentioned coupled reaction.

Equally, can platinum catalyst for example in the presence of the platinum oxide, in acid thinner with pyridyl hydrogenation to generate corresponding piperidyl analogue.This reaction generally is performed such: at the about 60psi of about 20psi-, preferably under about 40psi pressure, in the presence of the catalyzer, under about 20 ℃-Yue 50 ℃ of temperature, for example with hydrogen pyridine compounds was handled about 2-about 24 hours in the mixture of methyl alcohol and aqueous hydrochloric acid at acid thinner.By for example in above-mentioned coupled reaction, use β-(2-pyridyl)-, β-(3-pyridyl)-or β-(4-pyridyl)-L-alanine derivatives can easily make compound with pyridyl.

In addition, as the R of formula I compound or its intermediate ⁵When primary amino or secondary amino group are arranged on the substituting group, can be with the amino further derivatize of this class, to obtain for example acid amides, sulphonamide, urea, thiocarbamide, carbamate, secondary amine or tertiary amine etc. before or after above-mentioned coupled reaction.At R ⁵There is the compound of primary amino to make on the substituting group by for example corresponding nitro-compound being reduced as mentioned above.Perhaps, this compounds can make by use the formula VI amino acid derivative derived from Methionin, 4-amino-benzene L-Ala in above-mentioned coupled reaction.

Explanation as an example, available conventional acylating agent and condition will contain substituent formula I compound with primary amino or secondary amino group or its intermediate, R wherein for example ⁵Be the formula I compound of (4-aminophenyl) methyl or its intermediate N-acidylate easily, to obtain corresponding amide.This acylation reaction generally is performed such: at coupler in the presence of for example carbodiimide, bop reagent (hexafluoro phosphonic acids benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium) wait, at inert diluent for example methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), N, in the dinethylformamide etc., under about 0 ℃-Yue 37 ℃ of temperature, usefulness at least 1 equivalent, preferably about 1.1-about 1.2 normal carboxylic acids are about 24 hours of the about 4-of aminocompound processing.Preferred use promotor for example N-hydroxy-succinamide, I-hydroxybenzotriazole wait and promote acylation reaction.The example that is applicable to the carboxylic acid of this acylation reaction includes but not limited to N-tert-butoxycarbonyl glycine, N-tert-butoxycarbonyl-L-phenylalanine, N-tert-butoxycarbonyl-L-aspartic acid benzyl ester, phenylformic acid, the different piperidine carboxylic acid of N-tert-butoxycarbonyl, the different piperidine carboxylic acid of N-methyl, N-tert-butoxycarbonyl piperidine carboxylic acid, N-tert-butoxycarbonyl-L-tetrahydroisoquinoline-3-formic acid, N-(toluene-4-alkylsulfonyl)-L-proline(Pro) etc.

Perhaps, available acyl halide or carboxylic acid anhydride will have formula I compound or its intermediate N acidylate of primary amino or secondary amino group, to generate corresponding amide.This reaction generally is performed such: with aminocompound and at least 1 equivalent, preferably about 1.1-about 1.2 normal acyl halides or carboxylic acid anhydride in inert diluent such as methylene dichloride, in reacting about 1-about 24 hours under-70 ℃-Yue 40 ℃ of temperature approximately.If necessary, can use acylation catalyst such as 4-(N, N-dimethylamino) pyridine to promote acylation reaction.This acylation reaction is preferably carried out in the presence of suitable alkali, to remove the acid that during reaction generates.Suitable alkali comprises, for example tertiary amine, for example triethylamine, diisopropyl ethyl amine, N-methylmorpholine etc.Perhaps, can be under Schotten-Baumann type condition, carry out this reaction with the aqueous solution of alkali such as sodium hydroxide etc.

Be applicable to that the acyl halide of this reaction and the example of carboxylic acid anhydride include but not limited to 2-methyl-prop acyl chlorides, trimethyl-acetyl chloride, phenyllacetyl chloride, Benzoyl chloride, 2-bromo-benzoyl chloride, 2-methyl benzoyl chloride, 2-trifluoromethyl benzoyl chloride, different nicotinoyl chlorine, nicotinoyl chlorine, pyridine formyl chloride, diacetyl oxide, succinyl oxide etc.In this reaction, also can use for example N of urea chloride, N-dimethylcarbamyl chloride, N, N-diethylamino formyl chlorides etc. are to generate urea.Equally, also can use two carbonic ethers for example tert-Butyl dicarbonate to generate carbamate.

In similar fashion, available sulfonic acid halide or sulphonic acid anhydride will have formula I compound or its intermediate N sulfonation of primary amino or secondary amino group, to generate sulphonamide.The sulfonic acid halide and the sulphonic acid anhydride that are applicable to this reaction include but not limited to methylsulfonyl chloride, chloromethane SULPHURYL CHLORIDE, Tosyl chloride, trifluoromethanesulfanhydride anhydride etc.Equally, also can use sulphonamide chlorine for example the dimethylamino sulphonyl with generate sulphamide (for example＞N-SO ₂-N＜).

In addition, primary amino on formula I compound or its intermediate substituting group and secondary amino group can react to generate urea or thiocarbamide respectively with isocyanic ester or isothiocyanic acid ester.This reaction generally is performed such: inert solvent for example in the toluene etc., under about 24 ℃-Yue 37 ℃ of temperature, with at least 1 equivalent, preferably about 1.1-about 1.2 normal isocyanic ester or isothiocyanic acid ester be about 24 hours of the about 12-of aminocompound processing.Isocyanic ester and the commercially available acquisition of isothiocyanic acid ester used in this reaction, perhaps available commercial compound is made by conventional synthetic method.For example, suitable amine and phosgene or thiophosgene reaction can easily be made isocyanic ester and isothiocyanic acid ester.Be applicable to that the isocyanic ester of this reaction and the example of isothiocyanic acid ester include but not limited to ethyl isocyanate, propyl isocyanate, 4-cyano-phenyl isocyanic ester, 3-anisole based isocyanate, 2-styroyl isocyanic ester, sulfo-isocyanide methyl esters, isothiocyanic acid ethyl ester, 2-Phenylethyl mustard oil, 3-phenyl propyl isothiocyanic acid ester, 3-(N, N-diethylamino) propyl dithiocarbamate isocyanic ester, isothiocyanic acid phenyl ester, isothiocyanic acid benzyl ester, 3-pyridylthio isocyanic ester, fluorescent yellow isothiocyanic acid ester (isomer I) etc.

In addition, when formula I compound or its intermediate contained primary amino or secondary amino group, available aldehydes or ketones was with amino reductive alkylation, to generate secondary amino group or uncle's amino.This reaction generally is performed such: with aminocompound and at least 1 equivalent, preferably about 1.1-about 1.5 normal aldehydes or ketones and at least 1 equivalent for example sodium cyanoborohydride is at inert diluent for example in methyl alcohol, tetrahydrofuran (THF), its mixture etc., reacted about 1-about 72 hours under about 0 ℃-Yue 50 ℃ of temperature by the metal hydride reducing agent of the amount of aminocompound.The aldehyde and the ketone that are applicable to this reaction comprises, for example phenyl aldehyde, 4-chlorobenzaldehyde, valeral etc.

In similar fashion, when formula I compound or its intermediate contain the substituting group with hydroxyl, can before or after above-mentioned coupled reaction, hydroxyl further be modified or derivatize, to obtain for example ether, carbamate etc.At R ⁵The compound that has hydroxyl on the substituting group can make by for example use the formula VI amino acid derivative derived from tyrosine etc. in above-mentioned reaction.

As an example, contain substituent formula I compound with hydroxyl or its intermediate, R wherein for example ⁵The formula I compound or its intermediate that are (4-hydroxy phenyl) methyl can easily be alkylated into ether by O-.This O-alkylated reaction generally is performed such: with oxy-compound and suitable alkali metal base or alkaline earth metal alkali for example salt of wormwood in inert diluent such as acetone, 2-butanone etc., react, to generate an alkali metal salt or the alkaline earth salt of hydroxyl.This salt need not separate usually, but on the spot with the alkylogen of at least 1 normal alkylogen or replacement or for example alkyl chloride, alkyl bromide, alkyl iodide, methanesulfonates or p-toluenesulfonic esters reaction of sulphonate, to generate ether.This reaction generally is about 72 hours of about 24-under about 60 ℃-Yue 150 ℃ of temperature.In this reaction, when using alkyl chloride or alkyl bromide, preferably in reaction mixture, add the sodium iodide or the potassiumiodide of catalytic amount.

Be applicable to that the alkylogen of this reaction or the alkylogen of replacement and the example of sulphonate include but not limited to bromo-acetic acid tert-butyl, N-tertiary butyl chloride ethanamide, the 1-bromo ethyl phenenyl, α-bromophenyl ethyl acetate, 2-(N-ethyl-N-phenyl amino) ethyl chloride, 2-(N, the N-diethylamino) ethyl chloride, 2-(N, the N-diisopropylaminoethyl) ethyl chloride, 2-(N, the N-dibenzyl amino) ethyl chloride, 3-(N, N-diethylamino) propyl chloride, 3-(N-benzyl-N-methylamino) propyl chloride, N-(2-chloroethyl) morpholine, 2-(hexamethyleneimino) ethyl chloride, 3-(N methyl piperazine) propyl chloride, 1-(3-chloro-phenyl-)-4-(3-chloropropyl) piperazine, 2-(4-hydroxy-4-phenyl piperidine) ethyl chloride, N-tert-butoxycarbonyl-3-piperidine methyl p-toluenesulfonic esters etc.

Perhaps, can adopt the Mitsunobu reaction with the hydroxyl O-alkylation on formula I compound or its intermediate substituting group.In this reaction, with alcohol for example 3-(N, N-dimethylamino)-1-propyl alcohol etc. in inert diluent such as tetrahydrofuran (THF), under-10 ℃-Yue 5 ℃ of temperature, reacted about 0.25-about 1 hour with about 1.0-about 1.3 normal triphenylphosphines and about 1.0-about 1.3 normal diethylazodicarboxylates.Add for example N-tertiary butyl L-Tyrosine methyl ester of about 1.0-about 1.3 normal oxy-compound then, with reaction mixture about 48 hours of stir about 2-under about 0 ℃-Yue 30 ℃ of temperature, with generation O-alkylate.

In similar fashion, the formula I compound or its intermediate that contain fragrant hydroxyl can react to generate diaryl ether with aryl iodide.This reaction generally is performed such: with suitable alkali for example sodium hydride in inert diluent such as dimethylbenzene, under about-25 ℃-Yue 10 ℃ of temperature, form an alkali metal salt of hydroxyl.Under about 10 ℃-Yue 30 ℃ of temperature, this salt was handled about 0.5-about 2.0 hours with about 1.1-about 1.5 normal cuprous bromide dimethyl thioether title complexs then, then with processing such as about 1.1-about 1.5 normal aryl iodides such as 2-iodo-benzoic acid sodium.Next reaction mixture was heated about 2-about 24 hours at about 70 ℃-Yue 150 ℃, to obtain diaryl ether.

In addition, can with the compound that contains hydroxyl easily derivatize to form carbamate.In a method of this class carbamate of preparation, with formula I oxy-compound or its intermediate and about 1.0-about 1.2 normal 4-chloroformate nitrophenyl esters in inert diluent such as methylene dichloride, in reacting about 0.5-about 2.0 hours under-25 ℃-Yue 0 ℃ of temperature approximately.With excessive, preferably about 2-about 5 normal trialkylamines such as triethylamine are handled the carbonic ether of gained about 0.5-2 hour, then with about 1.0-about 1.5 normal primary amine or secondary amine processing, with the acquisition carbamate.The example that is applicable to the amine of this reaction includes but not limited to piperazine, 1-methylpiperazine, 1-ethanoyl piperazine, morpholine, thiomorpholine, tetramethyleneimine, piperidines etc.

Perhaps, prepare in the method for carbamate at another, the compound that will contain hydroxyl reacted about 2-about 72 hours with about 1.0-about 1.5 normal urea chlorides in inert diluent such as methylene dichloride, under about 25 ℃-Yue 70 ℃ of temperature.This reaction generally is to carry out in the presence of suitable alkali, to remove the acid that during reaction generates.Suitable alkali comprises, for example tertiary amine, for example triethylamine, diisopropyl ethyl amine, N-methylmorpholine etc.In addition, preferably 4-(N, the N-dimethylamino) pyridine of at least 1 equivalent (by the amount of oxy-compound) is added in the reaction mixture to promote reaction.The example of urea chloride comprises, for example dimethylcarbamyl chloride, diethylamino formyl chloride etc.

Equally, when formula I compound or its intermediate contain primary hydroxyl or secondary hydroxyl, this class hydroxyl easily can be changed into leavings group, and with its displacement to generate for example amine, sulfide and fluorochemical.For example, by the hydroxyl nucleophilic displacement of derivatize, the derivative of 4-hydroxyl-L-proline(Pro) can be changed into corresponding 4-amino-L-proline(Pro), 4-thiol-L-proline(Pro) or 4-fluoro-L-proline(Pro).Generally speaking, when using chipal compounds in these reactions, the stereochemistry on the carbon atom that connects the derivatize hydroxyl is inverted usually.

This reaction generally is performed such: handle oxy-compound with at least 1 normal sulfonic acid halide such as Tosyl chloride etc. in pyridine earlier, so that hydroxyl changes into leavings group.This conversion reaction is about 48 hours of about 1-under about 0 ℃-Yue 70 ℃ of temperature usually.Available then sodiumazide is easily replaced the p-toluenesulfonic esters that obtains, for example with p-toluenesulfonic esters and at least 1 normal sodiumazide at inert diluent such as N, the about 1-of reaction is about 12 hours in the mixture of dinethylformamide and water, under about 0 ℃-Yue 37 ℃ of temperature, to generate corresponding triazo-compound.Then can be by for example azido-being reduced, to generate amino (NH with palladium-carbon catalyst hydrogenation ₂) compound.

Equally, available mercaptan easily is replaced as sulfide with p-toluenesulfonic esters.This reaction generally is performed such: with p-toluenesulfonic esters and at least 1 normal mercaptan such as thiophenol at suitable alkali as 1, under 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) exists, at inert diluent such as N, the about 1-of reaction is about 12 hours in the dinethylformamide, under about 0 ℃-Yue 37 ℃ of temperature, to generate sulfide.In addition, in inert diluent such as methylene dichloride, under about 0 ℃-Yue 37 ℃ of temperature, fluoridize morpholine sulphur p-toluenesulfonic esters was handled about 12-about 24 hours, can obtain corresponding fluorine cpd with three.

In addition, can be easily the substituent formula I compound that contains the iodine aryl or its intermediate, R wherein for example will be had ⁵The formula I compound or its intermediate that are (4-iodophenyl) methyl changed into aryl-linking compound before or after above-mentioned coupled reaction.This reaction generally is performed such: palladium catalyst for example in the presence of four (triphenyl phosphine) palladium, in inert diluent such as tetrahydrofuran (THF), under about 24 ℃-Yue 30 ℃ of temperature, handle the iodine aryl compound until reacting completely with about 1.1-about 2 normal iodate aryl zinc such as iodate 2-(methoxycarbonyl) phenyl zinc.This reaction also is described in for example Rieke, and " organic chemistry magazine " is (J.Org.Chem.) in 1991,56,1445.

In some cases, formula I or IA compound or its intermediate can contain the substituting group with one or more sulphur atoms.For example, when the formula II amino acid that uses is during derived from L-thiazolidine-4-formic acid, L-(5, the 5-dimethyl) thiazolidine-4-formic acid, L-parathiazan-3-formic acid etc., can there be sulphur atom in formula I or IA compound or its intermediate in above-mentioned reaction.When having sulphur atom, can be before or after above-mentioned coupled reaction with conventional reagent and reaction conditions with oxidized sulfur atom, to obtain sulfoxide or sulphones.Be suitable for becoming the reagent of sulfoxide compound to comprise sulfide oxidation, for example hydrogen peroxide, 3-chlorine peroxybenzoic acid (MCPBA), sodium periodate etc.This oxidizing reaction generally is performed such: with sulfide and about 0.95-about 1.1 normal oxygenants in inert solvent such as methylene dichloride, in reacting about 1-about 24 hours under-50 ℃-Yue 75 ℃ of temperature approximately.Sulfoxide and reactions such as at least 1 normal oxygenant such as hydrogen peroxide, MCPBA, potassium permanganate in addition by obtaining can further be oxidized to sulfone with sulfoxide.Perhaps, sulfone can be by directly making sulfide and 2 equivalents, preferred excessive oxidant reaction at least.This reaction also is described in March, and " organic chemistry progress " (Advanced OrganicChemistry) the 4th edition, the 1201-1202 page or leaf, Wiley Publisher is in 1992.

As mentioned above, has the R that is not hydrogen ²Substituent formula I compound can use amino acid that formula II N-replaces such as sarkosine, N-methyl-L-phenylalanine etc. to make in above-mentioned coupled reaction.Perhaps, this compounds can by with conventional synthetic method with formula I or IV sulphonamide (R wherein ²Be hydrogen) N-alkylation and making.This N-alkylated reaction generally is performed such: the alkylogen of sulphonamide and at least 1 normal alkylogen of normal, preferred 1.1-2 or replacement was being reacted about 2-about 48 hours in the presence of alkali such as the salt of wormwood, in inert diluent such as acetone, 2-butanone etc., under about 25 ℃-Yue 70 ℃ of temperature.The example that is applicable to the alkylogen of the alkylogen of this reaction or replacement includes but not limited to methyl-iodide etc.

In addition, can be with R wherein ²Be hydrogen and R ¹Be the formula I or the IV sulphonamide intramolecular cyclization of 2-alkoxy carbonyl aryl, to generate 1,2-benzisothiazole-3-ketone derivatives or its analogue.This reaction generally is performed such: in inert diluent such as tetrahydrofuran (THF), under about 0 ℃-Yue 30 ℃ of temperature, with the normal suitable alkali of about 1.0-1.5 such as alkalimetal hydride with about 48 hours of sulphonamide such as N-(2-methoxycarbonyl phenyl sulfonyl) glycine-the about 2-of L-phenylalanine benzyl ester processing; to obtain 1 of cyclisation, 2-benzisothiazole-3-ketone derivatives.

At last, wherein Q is-C (S) NR ⁷Formula I compound can be by in above-mentioned synthetic method, replacing formula II amino acid to make with the thiocarbamoyl acid derivative.This thiocarbamoyl acid derivative can be according to people such as Shalaky at " organic chemistry magazine " (J.Org.Chem.), among the 61:9045-9048 (1996) and people such as Brain at " organic chemistry magazine " (J.Org.Chem.), the method of describing among the 62:3808-3809 (1997) makes, and above-mentioned document is introduced the present invention with for referencial use.Pharmaceutical preparation

When as drug use, formula I and IA compound are normally with the form administration of pharmaceutical composition.These compounds can be to comprise the multiple route of administration administration of oral administration, rectal administration, transdermal administration, subcutaneous administration, intravenous administration, intramuscular administration and intranasal administration.The Injectable composition of these compounds and oral compositions all are that effectively these compositions prepare in the well-known mode of pharmacy field, and contain at least a active compound of the present invention.

The invention still further relates to pharmaceutical composition, wherein said composition contains one or more formulas I and IA compound as active ingredient and pharmaceutically acceptable carrier.In the process of the preparation present composition, normally with active ingredient and mixed with excipients, dilute or with the carrier package of capsule, anther sac, paper or other vessel form with vehicle.When with vehicle during as thinner, it can be solid, semisolid or fluent material, and as vehicle, carrier or the medium of active ingredient.Therefore, said composition can be tablet, pill, pulvis, lozenge, anther sac, cachet, elixir, suspension agent, emulsion, solution, syrup, aerosol (as solid or liquid medium), for example contain ointment, soft hard gelatin capsule, suppository, aseptic parenteral solution and aseptic packaging powder up to the active compound of 10% weight.

In preparation during preparation, may need with active compound with mill before other component is mixed, so that the compound with suitable particle diameter to be provided.If active compound is insoluble basically, need be ground into particle diameter usually less than 200 purpose powder.If active compound is water-soluble basically, generally be by grind with its particle size adjustment to can be in preparation the degree of uniformly distributing basically, for example about 40 orders.

Some examples of suitable vehicle comprise lactose, glucose, sucrose, sorbyl alcohol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, Polyvinylpyrolidone (PVP), Mierocrystalline cellulose, water, syrup and methylcellulose gum.Preparation can also contain: lubricant is talcum powder, Magnesium Stearate and mineral oil for example; Wetting agent; Emulsifying agent and suspension agent; Sanitas is methyl hydroxybenzoate and nipasol for example; Sweeting agent; And seasonings.Can also adopt means known in the art, the present composition is mixed with the formulation that active ingredient energy quick-release, slowly-releasing or delay after patient's administration are discharged.

The present composition is preferably made unit dose formulations, and per unit dosage contains the about 100mg of the 5-that has an appointment, more generally contains the about 30mg active ingredient of the 10-that has an appointment.Term " unit dose formulations " is meant, is suitable for as the in fact discontinuous unit at people or mammiferous unitary dose, and per unit contains the active ingredient of the amount of pre-determining that can produce required curative effect as calculated and suitable drug excipient.

Active compound of the present invention is all effective in very wide dosage range, and normally with medicinal significant quantity administration.Yet, need to understand, the actual dosage of compound should be determined according to the correlation circumstance of the disease that comprises the desire treatment, selected route of administration, particular compound, patient's age, body weight and the reaction of administration, the severity of patient's symptom etc. by the doctor.

In order to prepare solids composition such as tablet, main active ingredient is mixed with drug excipient, contain the solid preformulation composite of the uniform mixture of The compounds of this invention with formation.When to mention these pre-preparation compositions be uniform, this was meant that active ingredient is evenly dispersed in the composition, therefore just was easy to composition is subdivided into formulation such as tablet, pill and the capsule with equivalent effective unit dosage.Then the solid preformulation is subdivided into and contains for example above-mentioned unit dosage of the about 500mg of 0.1-active compound of the present invention.

Can be with tablet of the present invention or coating of pill or compound, to obtain to produce the formulation of slow release effect.For example, dosage and external dose composition in tablet or pill can comprise, wherein the external dose composition is wrapped interior dose components.Available enteric layer separates these two portions, and this enteric layer can prevent disintegration under one's belt, and layer segment intactly enters into duodenum in making, the release of layer segment in perhaps postponing.Have multiple material to can be used for enteric layer or dressing, this class material comprises poly-acid and poly-acid and mixtures of material such as shellac, hexadecanol and rhodia.

Can be used for the liquid dosage form of novel composition oral administration of the present invention or drug administration by injection is comprised the aqueous solution, suitably seasoned syrup, aqeous suspension or oil suspension, seasoning emulsion made from edible oil such as Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil and elixir and the liquid dosage form made from similar pharmaceutical carrier.

Suck or be blown into composition and be included in solution and suspension in pharmaceutically acceptable water solvent or organic solvent or their mixture and powder.This liquid or solid composition can contain suitable pharmaceutically acceptable vehicle, above-mentioned vehicle for example.Preferred through port of said composition or nasal respiration administration are to produce part or systemic effect.Available rare gas element will be in the composition spray in the pharmaceutically acceptable preferred solvent.Can directly from spraying plant, suck spray solution, perhaps can be connected in spraying plant on the face shield or the intermittent positive pressure breathing (IPPB) machine on.Can be preferably with solution, suspension, powder composition per os or nasal administration from the device of delivery formulation in a suitable manner.

Illustrate pharmaceutical composition of the present invention with example of formulations below.

Example of formulations 1

Preparation contains the hard gelatin capsule of following component: group component (mg/ capsule) active ingredient 30.0 starch 305.0 Magnesium Stearates 5.0

Said components mixed and pack in the hard gelatin capsule with the amount of each capsule 340mg.

Example of formulations 2

Prepare tablet with following component: group component (mg/ sheet) active ingredient 25.0 Microcrystalline Celluloses 200.0 silicon dioxide colloids 10.0 stearic acid 5.0

Said components is mixed, and be pressed into the tablet of every heavy 240mg.

Example of formulations 3

Preparation contains the Foradil Aerolizer formoterol fumarate of following component: component % weight active ingredient 5 lactose 95

Activated mixture is mixed with lactose, and mixture is added in the Diskus.

Example of formulations 4

Every of preparation as described below contains the tablet of 30mg active component: group component (mg/ sheet) active component 30.0mg starch 45.0mg microcrystalline cellulose 35.0mg PVP (10% the aqueous solution) 4.0mg sodium carboxymethyl starch 4.5mg dolomol 0.5mg talcum powder 1.0mg is 120mg altogether

Active ingredient, starch and Mierocrystalline cellulose are crossed 20 purpose U.S. sieve, and thorough mixing.The gained powder is mixed with Polyvinylpyrolidone (PVP) solution, cross 16 order U.S. sieve then.The gained particle 50 ℃ of-60 ℃ of dryings, and is crossed 16 order U.S. sieve.Sodium starch glycolate, Magnesium Stearate and talcum powder are crossed 30 order U.S. sieve earlier, be added to then in the particle, after the mixing, compressing tablet on tabletting machine is to obtain the tablet of every heavy 150mg.

Example of formulations 5

Each capsule of preparation as described below contains the capsule of 40mg active ingredient: group component (mg/ capsule) active ingredient 40.0mg starch 109.0mg Magnesium Stearate 1.0mg is 150.0mg altogether

Active ingredient, starch, Magnesium Stearate are mixed, cross 20 order U.S. sieve, pack in the hard gelatin capsule with the amount of each capsule 150mg then.

Example of formulations 6

The every bolt of preparation as described below contains the suppository of 25mg active ingredient: group component active ingredient 25mg saturated fatty acid glyceride adds to 2000mg

Active ingredient is crossed 60 order U.S. sieve, and be suspended in advance in the saturated fatty acid glyceride that melts with required low-grade fever.Then mixture is poured in the suppository mold of 2.0g capacity, and cooling.

Example of formulations 7

The every 5.0ml of preparation as described below contains the suspending agent of 50mg active component: group component active component 50.0mg xanthans 4.0mg sodium carboxymethylcellulose (11%) microcrystalline cellulose (89%) 50.0mg sucrose 1.75g Sodium Benzoate 10.0mg flavor enhancement and the appropriate purified water of pigment add to 5.0ml

Active ingredient, sucrose and xanthan gum are mixed, cross 10 order U.S. sieve, then with the Microcrystalline Cellulose of preparation in advance and the aqueous solution of Xylo-Mucine.With some water Sodium Benzoate, seasonings and pigment are diluted, and under agitation be added in the mixture.Then water is added to volume required.

Example of formulations 8 group components (mg/ capsule) active ingredient 15.0mg starch 407.0mg Magnesium Stearate 3.0mg is 425.0mg altogether

Active ingredient, starch and Magnesium Stearate are mixed, cross 20 order U.S. sieve, and pack in the hard gelatin capsule with the amount of each capsule 560mg.

Example of formulations 9

Press following formulation intravenous injection: group component active ingredient 250.0mg isotonic saline solution 1000ml

Example of formulations 10

Preparation local administration preparation as described below: group component active ingredient 1-10g emulsifying wax 30g Liquid Paraffin 20 white vaseline add to 100g

White vaseline is heated to fusing.Mix Liquid Paraffin and emulsifying wax, and stir until dissolving.Add active ingredient, and continue to stir and disperse fully until it.Then the gained mixture is cooled to curing.

In the methods of the invention, employed another preferred formulation has adopted transdermal delivery device (" patch ").This transdermal administration patch can be used for The compounds of this invention continuous or discontinuous infiltration with manipulated variable.The structure and the application that are used for the transdermal administration patch of delivery of pharmaceutically active agents are well-known in the art.Referring to, for example on June 11st, 1991 disclosed US5023252, the disclosure thing is introduced the present invention with for referencial use.This patch can be made continuously, be pulsed or the form of instant delivery of pharmaceutically active agents.

When hope maybe needs directly or indirectly to be administered to pharmaceutical composition in the brain, can adopt direct technology.Direct technology generally comprises the ventricular system that delivery catheter is inserted into the user, to walk around hemato encephalic barrier.US 5011472 has described a kind of implantable drug delivery system that is used for biologically active agent is delivered to particular anatomical region in the body, and the disclosure thing is introduced the present invention with for referencial use.

Usually the preferred Indirection techniques that adopts generally comprises, and by hydrophilic medicament is changed into fat-soluble medicine composition is made pro-drug.The medicine latent effect generally is by with the hydroxyl on the medicine, carbonyl, sulfate radical and primary amino retardance, so that medicine fat-soluble stronger and can pass hemato encephalic barrier and realize.Perhaps, the hypertonic solution that can temporarily open hemato encephalic barrier by intra-arterial input can strengthen sending of hydrophilic medicament.Practicality

The compounds of this invention is used in the biological specimen in conjunction with VLA-4 (α ₄β ₁Integrin), therefore can be used for, for example analyze the VLA-4 in this class sample.In this analysis, The compounds of this invention can be attached on the carrier, and the VLA-4 sample is added in the carrier.Available ordinary method for example adopts the sandwich ELISA analysis to measure the amount of VLA-4 in the sample.Perhaps, can be in competitive binding analysis the VLA-4 of applying marking, to measure the VLA-4 that exists in the sample.Other suitable analytical procedure is well-known in the art.

In addition, some The compounds of this invention can suppress therefore can be used for the treatment of the disease by the VLA-4 mediation by the white corpuscle of VLA-4 mediation and the adhesion of endotheliocyte in vivo.This class disease comprises the inflammation in the mammalian subject, for example asthma, Alzheimer's, atherosclerosis, the AIDS dementia, diabetes (comprising acute teenager's disease type diabetes), inflammatory bowel (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, encephalitis, apoplexy, with other cerebral trauma, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung that the injury of lung of myocardial ischemia and the mediation of acute white corpuscle for example takes place in adult respiratory distress syndrome.

Can in multiple systems, identify the biological activity of above-mentioned definite The compounds of this invention.For example, compound solid surface can be fixed on, and the adhesion of the cell of expressing VLA-4 can be measured.Adopt this class mode can screen a large amount of compounds.The cell that is suitable for carrying out this evaluation comprises any white corpuscle of known expression VLA-4, for example T cell, B cell, monocyte, eosinophil and basophilic leukocyte.Can use multiple leucocyte cell line, the example comprises Jurkat and U937.

But also the combination of test compounds competitive inhibition VLA-4 and VCAM-1 or VLA-4 with known can be in conjunction with the bonded ability of the antibody of the tagged compound of VLA-4 such as The compounds of this invention or VLA-4.In these are analyzed, VCAM-1 can be fixed on the solid surface.VCAM-1 can also be expressed with as recombination fusion protein, combination can be in immunoassay, measured like this VLA-4 with Ig tail (for example IgG).Perhaps, can use the inoblast of cell, for example activated endothelial cells or the VCAM-1 transfection of expressing VCAM-1.In order to measure the ability of blocking-up adhesion brain endothelial cell, the preferred especially analytical procedure of in the open WO91/05038 of international patent application, describing of using.This application is introduced the present invention in full with for referencial use.

There are many analysis modes to adopt the analysis component of mark.This Mk system can have various ways.Can marker directly or indirectly be coupled on the component that will analyze according to method well-known in the art.Can use multiple marker.Can adopt any method in the several method with the component mark.The most frequently used detection method is to use ³H, ¹²⁵I, ³⁵S, ¹⁴C or ³²The radioautography of the compound of P mark etc.The non-radioactive marker comprises, antibody, fluorophore, chemoluminescence agent, enzyme that can bonding mark and play the paired member's of particular combination part for the part of mark.Will be according to required sensitivity, come selectable marker with the easy degree of compound bonded, required stability and adoptable instrument.

The suitable body inner model of measuring the effectiveness of treatment Inflammatory response comprises that EAE (experimental autoimmune encephalomyelitis) in mouse, rat, cavy or the primate and other depend on the inflammatory model of α-4 integrin.

Can be required bioactive compound-modified with having as required, to obtain desired characteristic, for example pharmacological property of Gai Shaning (for example body internal stability, bioavailability) or the ability that in diagnostic use, is detected.For example, on sulfonamide compounds of the present invention, introduce one or more D-amino acid and can increase the body internal stability usually.Available several different methods is measured stability, for example is determined at the proteic transformation period with between peptase, human plasma or serum incubation period.Disclose multiple protein stability test method (referring to, people's such as Verhoef " European drug metabolism pharmacokinetics magazine " (Eur.J.Drug Metab.Pharmacokinet.) for example, 1990,15 (2): 83-93).

For diagnostic use, the multiple marker of detectable signal that can directly or indirectly provide can be connected on the compound.Therefore, keep biological activity simultaneously, can adopt multiple mode that The compounds of this invention is modified in order to realize multiple final purpose.In addition, can introduce multiple reaction site endways to connect particle, entity substrate, macromole etc.

The compound of mark has in the multiple body or external application.Can use multiple marker, for example radionuclide (for example, radiating gamma-ray radio isotope such as technetium-99 or indium-111), fluorescent substance (for example fluorescein), enzyme, enzyme substrates, enzyme cofactor, enzyme inhibitors, chemiluminescence compound, bioluminescent compound etc.Those of ordinary skills should know that other is suitable for the marker in conjunction with these title complexs, perhaps should adopt normal experiment to determine suitable marker.Adopt is that known standard technique can be these markers in conjunction with getting on to those skilled in the art.

External application comprises diagnostic use, for example can monitor Inflammatory response by the white corpuscle that detects the expression VLA-4 that exists.The compounds of this invention also can be used for separating or these cells of mark.In addition, as mentioned above, The compounds of this invention can be used for identifying the interactional potential inhibitor of VLA-4/VCAM-1.

In order to carry out diagnosing image in vivo, use radio isotope according to well-known technology usually to discern for example inflammation site.Utilize intermediate functional group, radio isotope directly or indirectly can be attached on the peptide.For example, chela and agent such as diethylene triaminepentaacetic acid(DTPA) (DTPA) and ethylene diaminetetraacetic acid (EDTA) and similar molecule have been used to albumen and metal ion radio isotope are combined.

Can be with the paramagnetism isotropic substance with the title complex mark in magnetic resonance image (MRI) or spectrum (ESP), to carry out in-vivo diagnostic, MRI and ESR are known.Usually can use any ordinary method that is used for the viewable diagnostic imaging.Usually can use the emission gamma-rays that is used for photographing imaging or the radio isotope and the paramagnetic coordination of positron usually to carry out MRI.Therefore, compound can be used for monitoring the improvement process of individual interior Inflammatory response.By measure expressing lymphocytic increase or the minimizing of VLA-4, can determine whether purpose is to improve the particular treatment of disease effective.

The cell adhesion that pharmaceutical composition of the present invention can be used for blocking or inhibition is relevant with obstacle with multiple disease.For example, there is multiple inflammatory diseases relevant with integrin or white corpuscle.The disease of available medicine composite for curing of the present invention comprises injury of lung (adult respiratory distress syndrome), asthma, ephritis and the acute and chronic inflammation of for example transplant rejection (for example homograft rejection), Alzheimer's, atherosclerosis, AIDS dementia, diabetes (comprising acute teenager's disease type diabetes), the retinitis, metastases, rheumatoid arthritis, the mediation of acute white corpuscle, comprises atopic dermatitis, psoriasis, myocardial ischemia and inflammatory bowel (comprising Crohn disease and ulcerative colitis).In preferred embodiments, pharmaceutical composition of the present invention is used to treat disease of brain, for example multiple sclerosis (MS), viral meningitis and encephalitis.

Inflammatory bowel is the general name of similar disease ulcerative colitis of two classes and Crohn disease.Crohn disease is spontaneous, chronic, ulcerative inflammation, it is characterized in that, the granuloma Inflammatory response causes all layers of intestines wall all to be demarcated clearly and normally saturating wall.GI arbitrary section, to anus, all possibility is influenced from mouth, but this disease mainly is to influence terminal ileum and/or colon.Ulcerative colitis is that major limitation is in mucous membrane of colon and submucosal Inflammatory response.In the damage of inflammatory bowel, a large amount of white corpuscles and scavenger cell are arranged, and may be that they have caused inflammatory damage.

Asthma is a kind of disease, it is characterized in that, tracheobronchial tree strengthens for the reactivity of the multiple stimulation that increases the weight of the ictal contraction of segmental bronchus.This stimulation causes that multiple inflammatory mediator discharges from the mastocyte of IgE bag quilt, described inflammatory mediator comprises histamine, acidophilia and neutrophilia chemokine, leukotriene, prostaglandin(PG) and platelet activating factor.The release of these factors has replenished basophilic cell, eosinophil and the neutrophil(e) cell who causes inflammatory damage.

Atherosclerosis is a kind of artery disease (for example coronary artery, carotid artery, aorta and an iliac artery disease).Basic property damage, atherosclerosis have constituted the focus patch that increases in the inner membrance, the fibering lid that this patch has lipid core and is covered with.Atherosclerosis jeopardizes artery blood flow and weakens affected artery.Myocardial infarction and cerebral infarction are the main consequences of this disease.Scavenger cell and white corpuscle are replenished to atheroma and are caused inflammation.

Rheumatoid arthritis is a kind of chronic recurrent inflammation, and it mainly causes the damage and the destruction in joint.Rheumatoid arthritis at first influences the little joint of hand and pin usually, but may influence wrist, elbow, ankle and knee afterwards.Sacroiliitis is to cause by synovial fluid cell and by the leukocytic interaction that penetrates in the knuckle synovia lining in the circulation.Referring to, Paul for example, " immunology " be (the 3rd edition, Raven Press, 1993) (Immunology).

Another indication of The compounds of this invention is to treat the organ or the transplant rejection of VLA-4 mediation.Recent years, transplanted tissue and the organ for example efficient of the surgical technic of skin, kidney, liver, heart, lung, pancreas and marrow have had considerable raising.The chances are lacks the gratifying promoting agent induce in the host for the immune compatibility of homotransplant of transplanting or organ for main outstanding problem.When homogeneous variant cell or organ are transplanted when giving host's (being that donor and acceptor are the Different Individual from same species), host immune system may be provided with immunne response (host versus graft disease) to the exotic antigen in the graft, causes transplanted disorganization.CD 8 ⁺Cell, CD 4 cells and monocyte have all participated in transplanted tissue's repulsion.The compounds of this invention in conjunction with α-4 integrin is useful especially for the intravital immunne response of blocking-up isoantigen inductive acceptor, thereby has just prevented that this class cell from participating in destroying transplanted tissue or organ.Referring to, people such as Paul for example, " the international transplanting " (TransplantInternational) 9,420-425 (1996); People such as Georczynski, " immunology " (Immunology) 87,573-580 (1996); People such as Georczynski, " transplantation immunity " (Transplant.Immunol.) 3,55-66 (1995); People such as Yang, " implantology " (Transplantation) 60,71-76 (1995); People such as Anderson, APMIS102,23-27 (1994).

In conjunction with the related application of the The compounds of this invention of VLA-4 be adjusted in " graft versus host disease " (GVHD) in related immunne response.Referring to, people such as Schlegel for example, " IMMUNOLOGY KEY WORDS INDEX (J.Immunology), 155:3856-3865 (1995).GVHD is the potential fatal disease, and it is organized in immunocompetence and transplantedly takes place when giving the allogeneic acceptor.In this case, the immunologically competent cell of donor may be attacked the tissue of acceptor.The target that skin, internal organ epithelium and liver organization are normally attacked, and may be destroyed during GVHD.When immuning tissue was transplanted, for example when carrying out bone marrow transplantation, this disease can cause the consequence of especially severe; But not too serious in other cases GVHD also has report, comprises heart and liver transplantation.Therapeutical agent of the present invention can be used in particular for blocking the activation of donor T-cell, thereby disturbs the ability of the interior target cell of they dissolving hosts.

The Another Application of The compounds of this invention is to suppress metastases.Thereby express several tumour cells of VLA-4 and existing report of compound that can block this cell and endotheliocyte adhesion in conjunction with VLA-4.People such as Steinback, " urology research " (Urol.Res.), 23:175-83 (1995); People such as Orosz, " international journal of cancer " (Int.J.Cancer), 60:867-71 (1995); People such as Freedman, Leuk.Lymphoma 13,47-52 (1994); People such as Okahara, " cancer research " (Cancer Res.), 54:3233-6 (1994).

The Another Application of The compounds of this invention is the treatment multiple sclerosis.Multiple sclerosis is the neural autoimmune disorder of carrying out property, and nearly 250000-350000 population suffers from this disease in the U.S..Multiple sclerosis is considered to because due to the specific autoimmune response of the spacer sleeve of the attack of some of them white corpuscle and initiation destruction myelin-covering nerve fiber.In the animal model of multiple sclerosis, directly the mouse monoclonal antibody of antagonism VLA-4 shows the effect of blocking leukocyte to the endotheliocyte adhesion, has therefore just prevented the inflammation of animal central nervous system and the paralysis that can cause subsequently ¹⁶

Pharmaceutical composition of the present invention is suitable for using in multiple drug delivery system.The appropriate formulation of Shi Yonging is referring to Remington ' s Pharmaceutical Sciences, MacePublishing Company, Philadelphia, PA, the 17th edition (1985) in the present invention.

In order to prolong serum half-life, The compounds of this invention can be incapsulated, join in the chamber of liposome, be prepared into colloid, perhaps can use other routine techniques of the serum half-life that can prolong compound.The multiple method for preparing liposome is arranged, the method for describing among people's such as Szoka U.S. Pat 4235871, US 4501728 and the US 4837028 for example, above-mentioned publication is all introduced the present invention with for referencial use.

The amount of patient's administration is depended on that the purpose of disease, the administration of desire treatment is for example prevented or treatment, patient's body situation, administering mode etc.In treatment is used, composition be be enough to cure or to the symptom of small part cure diseases or its syndromic amount to suffering from patient's administration of disease.The appropriate amount of realizing this purpose is called " treatment significant quantity ".The significant quantity that is used for this purpose will depend on that the disease of treatment and clinicist are according to for example judgement of severity, patient's age, body weight and the general situation of health etc. of inflammation of some other factor.

Composition to patient's administration is the aforementioned pharmaceutical compositions form.Can be with these compositions by conventional sterilising technology sterilization, perhaps sterile filtration.The aqueous solution that obtains can package spare or lyophilize, and this freeze-dried preparation mixes with the aqua sterilisa carrier before administration.The pH of compound formulation is generally 3-11, more preferably 5-9,7-8 most preferably.Should be appreciated that and use some above-mentioned vehicle, carrier or stablizer may cause forming pharmacologically acceptable salt.

The therapeutic dose of The compounds of this invention will with for example treatment at administering mode, patient's the health of special purpose, compound and symptom and prescriber's judgement different and different.For example, for intravenous administration, dosage generally is the about 500 μ g of the about 20 μ g-of every kg body weight, the about 300 μ g of the about 100 μ g-of preferred every kg body weight.For intranasal administration, proper dosage generally is the about 1mg of the about 0.1pg-of every kg body weight.Effective dose can be inferred from dose-response curve external or that the animal model test macro is produced.

Illustrate the present invention below by synthetic and biological Examples, but this not to limit the scope of the invention by any way.Except as otherwise noted, otherwise all temperature all be degree centigrade.

Embodiment

In the following embodiments, following abbreviation has following connotation.If an abbreviation is not defined, then it has its received connotation usually.Aq or aq.=water solution A cOH=acetate bd=wide bimodal bm=wide multiplet bs=wide unimodal Bn=benzyl Boc=N-tert-butoxycarbonyl Boc ₂O=tert-Butyl dicarbonate BOP=hexafluoro phosphonic acids benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium Cbz=carbobenzoxy-(Cbz) CHCl ₃=chloroform CH ₂Cl ₂=methylene dichloride (COCl) ₂=oxalyl chloride d=bimodal dd=double doublet dt=two three peak DBU=1,8-phenodiazine two heterocycles [5.4.0] 11 carbon-7-alkene DCC=1,3-dicyclohexyl carbodiimide DMAP=4-N, N-dimethyl aminopyridine DME=ethylene glycol dimethyl ether DMF=N, dinethylformamide DMSO=methyl-sulphoxide EDC=hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide Et ₃N=triethylamine Et ₂O=ether EtOAc=ethyl acetate EtOH=ethanol eq or eq.=equivalent Fmoc=N-(9-fluorenyl methoxy carbonyl) FmocONSu=N-(9-fluorenyl methoxy carbonyl) succinimide g=gram h=hour H₂O=water HBr=Hydrogen bromide HCl=spirit of salt HOBT=I-hydroxybenzotriazole hydrate hr=hour K ₂CO ₃=salt of wormwood L=rise m=multiplet MeOH=methyl alcohol mg=milligram MgSO ₄=sal epsom mL=milliliter mm=millimeter mM=mmole volumetric concentration mmol=mmole mp=fusing point N=standard NaCl=sodium-chlor Na ₂CO ₃=yellow soda ash NaHCO ₃=sodium bicarbonate NaOEt=sodium ethylate NaOH=sodium hydroxide NH ₄Cl=ammonium chloride NMM=N-methylmorpholine Phe=L-phenylalanine Pro=L-proline(Pro) psi=pound/square inch PtO ₂=platinum dioxide q=quartet quint.=quintet rt=room temperature s=unimodal sat=saturated t=triplet t-BuOH=tert-butyl alcohol TFA=trifluoroacetic acid THF=oxolane TLC or tlc=thin-layered chromatography Ts=p-toluenesulfonyl TsCl=paratoluensulfonyl chloride TsOH=p-methyl benzenesulfonic acid μ L=microlitre

In the following embodiments, all temperature all are degree centigrade (except as otherwise noted).Following method is to be used to prepare pointed in its lower section compound.

Method 1

N-tosylation step

According to Cupps, the method that Boutin and Rapoport (J.Org.Chem.) describe in 1985,50,3972 at " organic chemistry magazine " is with suitable amino acid N-tosylation.

Method 2

The methyl esters preparation process

Amino acid methyl ester is to make according to the method that Brenner and Huber (Helv.Chim.Acta.) describe in 1953,36,1109 at " Switzerland's chemistry journal ".

Method 3

BOP coupling step

Required dipeptides ester be by with suitable N-protected amino acid (1 equivalent) with suitable amino acid ester or aminoguanidine hydrochloride acid esters (1 equivalent), hexafluoro phosphonic acids benzotriazole-(dimethylamino) Phosphonium [BOP] (2.0 equivalent), triethylamine (1.1 equivalent) and DMF reaction make 1-base oxygen base-three.Reaction mixture at room temperature stirred spend the night.By flash chromatography with the crude product purifying, to obtain the dipeptides ester.

Method 4

Step of hydrogenation I

Hydrogenation is that the palladium carbon (10% weight ratio) with 10% spends the night under 30psi pressure in methyl alcohol.With Celite pad mixture is filtered, obtained required aminocompound.

Method 5

Hydrolysing step I

LiOH (or NaOH) (0.95 equivalent) is added to cold (0 ℃) THF/H of suitable ester ₂O (2: 1,5-10mL) in the solution.At 0 ℃, be reflected at temperature maintenance in 1-3 hour complete.Use the ethyl acetate extraction reaction mixture,, obtained required carboxylate salt the water lyophilize.

Method 6

Ester hydrolysing step II

LiOH (1.1 equivalent) is added to cold (0 ℃) THF/H of suitable ester ₂O (2: 1,5-10mL) in the solution.At 0 ℃, be reflected at temperature maintenance in 1-3 hour complete.Reaction mixture is concentrated, residuum is placed water, with aqueous hydrochloric acid with pH regulator to 2-3.Use the ethyl acetate extraction product, merge organic phase, use the salt water washing, use MgSO ₄Drying is filtered and is concentrated, and has obtained desired acid.

Method 7

Ester hydrolysing step III

Suitable ester is dissolved in diox/H ₂O (1: 1) adds the NaOH of 0.9 normal 0.5N.Reaction mixture was stirred 3-16 hour, concentrate then.The residuum that obtains is dissolved in the water, uses ethyl acetate extraction.The water lyophilize, obtained desired carboxylic acid sodium salt.

Method 8

Sulfonylation step I

The amino phenylalanine analogues (11.2mmol) of due care is dissolved in methylene dichloride (25mL) and is cooled to-78 ℃,, drip pyridine (2mL) then to wherein adding required SULPHURYL CHLORIDE (12mmol).The temperature of this solution is risen to room temperature, and stirred 48 hours.This reaction soln is transferred in the 250mL separating funnel that methylene dichloride (100mL) is housed, with hydrochloric acid (50mL * 3), salt solution (50mL) and water (100mL) extraction of 1N.Dry organic phase (MgSO ₄), solvent is concentrated to obtain required product.

Method 9

The reduction amination step

With suitable aldehyde with Tos-Pro-p-NH ₂-Phe reduction amination is performed such: use acetate, nitrilotriacetic base sodium borohydride, methylene dichloride, mixture is merged, at room temperature stir and spend the night.By flash chromatography with the crude product purifying.

Method 10

BOC removes step

At 0 ℃, anhydrous spirit of salt (HCl) gas is fed the methanol solution 15 minutes of suitable Boc-amino acid ester, and reaction mixture was stirred 3 hours.Solution concentration to pulpous state, is dissolved in Et with it ₂O, and concentrate once more.Repeat this step, the solid that obtains dried overnight under high vacuum.

Method 11

Tert-butyl ester hydrolysing step I

The tert-butyl ester is dissolved in CH ₂Cl ₂, and handle with TFA.Be reflected in 1-3 hour fully, afterwards reaction mixture concentrated, the residuum that obtains is dissolved in the water, lyophilize is to obtain desired acid.

Method 12

EDC coupling step I

Suitable aminoguanidine hydrochloride acid esters (1 equivalent), N-methylmorpholine (1.1-2.2 equivalent) and I-hydroxybenzotriazole (2 equivalent) are mixed into the CH of N-(toluene-4-alkylsulfonyl)-L-proline(Pro) (1 equivalent) ₂Cl ₂In the solution (5-20mL), be placed in the ice bath, add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalent).The temperature of reaction mixture is risen to room temperature, and stirring is spent the night.Reaction mixture is poured in the water, used saturated NaHCO successively ₃, salt water washing organic phase, dry (MgSO ₄Or Na ₂SO ₄), filter and concentrate.By column chromatography purifying crude product.

Method 13

EDC coupling Step II

With suitable aminoguanidine hydrochloride acid esters (1 equivalent), Et ₃N (1.1 equivalent) and I-hydroxybenzotriazole (2 equivalent) are mixed in the DMF solution (5-20mL) of suitable N-protected amino acid (1 equivalent), are placed in the ice bath, add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalent).The temperature of reaction mixture is risen to room temperature, and stirring is spent the night.With reaction mixture at EtOAc and H ₂Distribute between the O, use citric acid, the H of 0.2N successively ₂O, saturated NaHCO ₃, and salt water washing organic phase, dry then (MgSO ₄Or Na ₂SO ₄), filter and concentrate.By column chromatography or preparation TLC purifying crude product.

Method 14

The sulfonylation Step II

Suitable SULPHURYL CHLORIDE is dissolved in CH ₂Cl ₂And place ice bath.Add L-Pro-L-Phe-OMe.HCl (1 equivalent) and Et ₃N (1.1 equivalent) rises to room temperature to the temperature of reaction mixture, stirs under nitrogen and spends the night.Reaction mixture is concentrated, residuum at EtOAc and H ₂Distribute between the O, use saturated NaHCO successively ₃, and salt water washing organic phase, dry then (MgSO ₄Or Na ₂SO ₄), filter and concentrate.By column chromatography or preparation TLC purifying crude product.

Method 15

Sulfonylation Step II I

With Et ₃N (5 equivalent) is added to the CH of L-Pro-L-4-(3-dimethylamino propoxy)-Phe-OMe (making with method 10) (1 equivalent) ₂Cl ₂In the solution, add suitable SULPHURYL CHLORIDE (1.1 equivalent) then.The temperature of reaction mixture is risen to room temperature, under nitrogen, stir and spend the night.Reaction mixture is concentrated, be dissolved among the EtOAc, use saturated NaHCO successively ₃Citric acid washing with 0.2N.Use solid NaHCO ₃With the water alkalization, use the EtOAc extraction product.With salt water washing organic phase, dry (MgSO ₄Or Na ₂SO ₄), filter and concentrate.By preparation TLC purifying methyl esters crude product.According to the corresponding acid of describing in the method 7 of step preparation.

Method 16

Step of hydrogenation II

NaOAc (1 equivalent) and 10%Pd/C are added in the methyl alcohol (10-15mL) of azlactone.At 40psi H ₂Down reaction mixture is placed on the hydrogenator.After 8-16 hour, reaction mixture is filtered, filtrate is concentrated, obtained the dehydrogenation methyl dipeptide by Celite pad.This ester is dissolved in diox/H ₂Among the O (5-10mL), add the NaOH (1.05 equivalent) of 0.5N.Stir after 1-3 hour, reaction mixture is concentrated, residuum is dissolved in H ₂Among the O, wash with EtOAc.With aqueous phase as acidified, use the EtOAc extraction product with the HCl of 0.2N.Merge organic phase, and the water washing of usefulness salt (1 * 5mL), dry (MgSO ₄Or Na ₂SO ₄), filter and concentrate, generated acid, product is to be about 1: 1 non-enantiomer mixture.

Method 17

Tert-butyl ester hydrolysing step II

The tert-butyl ester is dissolved in CH ₂Cl ₂(5mL), and handle with TFA (5mL).Be reflected in 1-3 hour fully, afterwards reaction mixture concentrated, soluble in water residuum, and concentrate.Soluble in water again residuum, and lyophilize, required product obtained.

Embodiment 1

Synthesizing of N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine

With N-(toluene-4-alkylsulfonyl)-2S-indoline-2-formic acid (331.2mg; 1.04mmol) and 4-methylmorpholine (3.5 equivalents; 400 μ L), BOP (1.1 equivalents, 506mg) and phenylalanine benzyl ester (1.0 equivalents 444mg) are dissolved among the exsiccant DMF (5mL).Be separated to and be the dipeptides of oily matter.The benzyl ester is dissolved in the EtOH of the 10% palladium carbon that contains catalytic amount: H ₂O (1: 1) (2.5mL) in, and at 50psi H ₂Following hydrogenation.By diatomite filtration, with solvent removed under reduced pressure, be separated to this title compound, be solid, fusing point is 167-170 ℃.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.64(d，1H，J＝8.50Hz)，7.43

(d，2H，J＝8.25Hz)，7.23(m，2H)，7.12-7.00(m，6H)，6.86(m，2H)，

4.82(m，1H)，4.60(m，1H)，3.12(m，3H)，2.62(m，1H)，2.32(s，3H).

¹³C?NMR(75MHz，CD ₃OD)：δ＝174.37，173.24，146.90，142.92，

138.09，136.61，133.74，131.49，130.92，129.90，129.49，129.13，128.22，

127.37,126.78,119.34,65.28,55.44,38.74,34.15,22.03. mass-spectrometric data: (FAB) 465 (M+H).

Embodiment 2 synthetic N-(toluene-4-alkylsulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-benzene

L-Ala

Experimental procedure according to embodiment 1 (20) has made this title compound, is white solid, fusing point=74-78 ℃.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.61(m，3H)，7.24-6.85(m，10H)，

4.65(m，1H)，4.55(m，1H)，4.22(d，1H，J＝10.5Hz)，4.05(d，1H，J＝

10.5Hz)，3.18-2.92(m，4H)，2.34(s，3H).

¹³C?NMR(75MHz，CD ₃OD)：δ＝174.62，173.36，146.96，138.63，

136.89，134.17，131.34，131.03，130.12，129.62，129.25，128.87，128.23，

127.74,57.59,56.83,47.14,38.75,31.72,32.00. mass-spectrometric data: (FAB) 479 (M+H).

Embodiment 3

Synthesizing of N-(toluene-4-alkylsulfonyl) glycyl-L-phenylalanine

(547mg is 2.40mmol) at CH with N-(toluene-4-alkylsulfonyl) glycine ₂Cl ₂Pulp (7mL), and in ice bath, cool off.Add oxalyl chloride (0.30mL), add a DMF then.The temperature of mixture is risen to room temperature, and stirred 1 hour.Remove volatile matter in a vacuum, acyl chlorides is dissolved in CH ₂Cl ₂(8mL), and in ice bath, cool off.(919mg 2.1mmol), adds triethylamine (0.75mL) then to add tosic acid phenylalanine benzyl ester.The temperature of mixture is risen to room temperature lentamente, and stirred 19 hours.Use CH ₂Cl ₂(40mL) with mixture diluted, use successively 1N hydrochloric acid (2 * 10mL), the NaHCO of 1M ₃(15mL) and salt solution (10mL) washing, dry then (MgSO ₄), filter and evaporation in a vacuum.(purifying of 3: 2 hexane/EtOAc) has obtained dipeptides benzyl ester (0.51g, 50%) with the fast silica gel chromatogram method with residuum.This benzyl ester is dissolved among the THF (20mL), adds 10% Pd/C (60mg).With mixture at 15psi H ₂Following hydrogenation 1.5 hours.By Celite pad mixture is filtered, vacuum-evaporation is the residuum MeOH/CHCl that obtains ₃Recrystallization has obtained this title compound, is white solid (304mg, 76%), fusing point=157-161 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃)：δ＝12.8(bs，1H)，8.13(d，1H，J＝8.0Hz)，7.86

(d，1H，J＝6.1Hz)，7.65(d，2H，J＝8.2Hz)，7.35(d，2H，J＝8.2Hz)，

7.29-7.17(5H)，4.49(m，1H)，3.01(dd，1H，J＝5.0，13.7Hz)，3.57(m，

3H)，2.85(dd，1H，J＝8.5，13.7Hz)，2.37(s，3H).

¹³C?NMR(CDCl ₃)：δ＝172.9，167.7，143.0，137.7，137.6，129.9，

129.5,128.6,127.0,53.7,45.3,37.2,21.4. mass-spectrometric data: (FAB) m/e 377 (M+H).

Embodiment 4

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine

Embodiment 21 (180) products (0.62mmol) and 5%Pd-C (10%) are added in the ethanol (40mL), and jolting is 16 hours under 35psi hydrogen.By diatomite reaction mixture is filtered and concentrates.With the crude product crystallization, obtain this title compound with the EtOAc/ hexane, be white solid (190mg, 78.5%), fusing point=128-130 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝7.65(d，2H，J＝8.18Hz)；7.26

(m，7H)；4.84(m，1H)；3.73(q，1H，J＝7.02)；3.58(d，1H，J＝4.28

Hz)；3.20(m，2H)；2.55(s，3H)；2.43(s，3H).

¹³C?NMR(CDCl ₃，300MHz)：δ＝175.23，168.75，144.90，136.50，

133.53，130.57，129.89，129.34，128.17，127.75，54.39，53.84，37.82，

37.18,22.15. mass-spectrometric data: (+FAB) 391 (M+H), 413 (M+Na).

Embodiment 5

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine

Made this title compound according to embodiment 4 (41) described methods.Use Et ₂The O/ hexane has obtained white solid with the crude product crystallization, fusing point=105-108 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝7.72(d，2H，J＝8.06Hz)；7.26

(m，6H)，7.09(d，2H，7.63Hz)；6.84(d，1H，J＝7.69Hz)；5.46(d，1H，

J＝7.70Hz)；4.71(m，1H)；3.77(m，2H)；3.09(m，2H)；2.41(s，3H)；

1.14(d，3H，J＝7.14Hz).

¹³C?NMR(CDCl ₃，300MHz)：δ＝174.60，172.17，144.69，136.79，

136.19，130.47，129.93，129.26，129.20，127.80，127.72，53.94，53.05，

37.74,22.17,19.71. mass-spectrometric data: (+FAB) 391 (M+H), 413 (M+Na).

Embodiment 6

Synthesizing of N-(2-methoxycarbonyl benzenesulfonyl) glycyl-L-phenylalanine

Made this title compound according to embodiment 4 (41) described methods, product is a white solid, fusing point=140-143 ℃.The NMR data are as follows:

¹H?NMR(CD ₃OD，300MHz)：δ＝7.75(m，2H)；7.50(m，2H)；7.02

(m，5H)；4.32(m，1H)；3.74(s，3H)；3.44(d，2H，J＝7.57Hz)；2.91(m，

1H)；2.72(m，1H).

¹³C?NMR(CD ₃OD，300MHz)：δ＝170.66，169.90，140.00，138.73，

134.49，133.15，131.96，131.05，130.95，130.92，130.01，129.96，128.35，

55.79,54.29,46.98,38.08,31.23. mass-spectrometric data: (+FAB) 421 (M+H), 443 (M+Na).

Embodiment 7

Synthesizing of N-(2-methoxycarbonyl benzenesulfonyl)-L-alanyl-L-phenylalanine

Made this title compound according to embodiment 4 (41) described methods, product is glassy semisolid.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝8.02(d，1H，J＝7.14Hz)；7.84

(d，1H，J＝7.15Hz)；7.62(m，2H)；7.20(m，6H)；6.50(d，1H，J＝6.59

Hz)；4.71(m，1H)；3.98(s，3H)；3.87(m，1H)；3.10(m，2H)；1.14(d，

3H，J＝7.14Hz).

¹³C?NMR(CDCl ₃，300MHz)：δ＝175.08，172.26，168.58，138.99，

136.47，133.47，132.58，131.63，130.78，130.51，129.95，129.15，127.65，

54.12,54.01,53.68,37.93,19.23. mass-spectrometric data: (+FAB) 435 (M+H).

The preparation embodiment A

Synthesizing of N-(saccharin-2-yl) glycyl-L-phenylalanine

Triethylamine (4.70mmol) is added in THF (15mL) solution of L-prolyl-L-phenylalanine benzyl ester (4.64mmol), will reacts and at room temperature carry out 30 minutes.Reaction mixture is cooled to 0 ℃, adds 2-(chlorosulfonyl) methyl benzoate (4.64mmol), will react and at room temperature carry out 4 hours.With EtOAc (3 * 50mL) and water (50mL) extractive reaction mixture, merge organic layer, use saturated NaHCO successively ₃(50mL) (MgSO is used in 2 * 50mL) washings with saturated NaCl ₄Drying is filtered, and rotary evaporation, has obtained colorless oil (2.30g, 90%).(the 50%EtOAc/ hexane Rf=0.47) with the crude product purifying, has obtained N-(2-methoxycarbonyl benzenesulfonyl)-L-prolyl-L-phenylalanine benzyl ester, is colorless oil (1.49g, 58%) by silica gel chromatography.

To be cooled to 0 ℃ the sodium hydride among the THF (10mL) (1.47mmol washs, no mineral oil), drip THF (5mL) solution of N-(2-methoxycarbonyl phenyl) alkylsulfonyl-L-prolyl-L-phenylalanine benzyl ester.Stirred 1 hour at 0 ℃ with regard to reaction mixture, then restir 2 hours at room temperature.With EtOAc (3 * 100mL) and hydrochloric acid (50mL) the extractive reaction mixture of 0.2N, merge the EtOAc layer, use the hydrochloric acid (50mL) of 0.2N, saturated NaHCO successively ₃(50mL) with saturated NaCl (2 * 50mL) washings.With organic layer MgSO ₄Drying is filtered and is concentrated, and has obtained colorless oil (0.63g, 91%).(the 50%EtOAc/ hexane Rf=0.42) with the crude product purifying, has obtained N-(benzisothia oxazolone)-L-glycyl-L-phenylalanine benzyl ester by silica gel chromatography; be colorless oil (0.25g; 36%), then with it with 10% palladium carbon hydrogenation in THF, and with mixture at 50psi H ₂Following jolting.By diatomite mixture is filtered and evaporation, obtained this title compound, product is white solid (42mg, 52%), fusing point=201-204 ℃.The NMR data are as follows:

¹H?NMR(CD ₃OD，300MHz)：δ＝7.80(m，4H)；7.01(m，5H)；4.43

(t，1H，J＝5.43Hz)；4.17(d，2H，J＝5.43)；2.99(m，1H)；2.82(m，

1H).

¹³C?NMR(CD ₃OD，300MHz)：δ＝167.94，160.99，139.70，138.87，

137.10，136.46，131.11，129.89，129.01，128.21，126.77，122.87，56.57，

41.57,39.04. mass-spectrometric data: (+FAB) 398 (M+H), 411 (M+Na).

Embodiment 8

Synthesizing of N-(saccharin-2-yl)-L-alanyl-L-phenylalanine

Made this title compound according to the described step of preparation embodiment A (48), product is a white solid, fusing point=190-193 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝7.86?&?6.95(m，9H)；4.66(bs，2H)；

3.18(m，1H)；2.97(m，1H)；1.69(d，3H，J＝6.59).

¹³C?NMR(CDCl ₃，300MHz)：δ＝176.31，169.18，158.14，138.01，

136.68，135.86，129.77，128.81，127.27，127.21，126.13，121.68，112.01，

66.48,54.99,51.80,37.53,14.65. mass-spectrometric data: (+FAB) 403 (M+H), 425 (M+Na).

Embodiment 9

N-(toluene-4-alkylsulfonyl)-D, L-phenyl glycyl-L-phenylalanine synthetic

According to method 1 described step/made N-(toluene-4-alkylsulfonyl) phenylglycocoll with phenylglycocoll.

In DMF, handle N-(toluene-4-alkylsulfonyl) phenylglycocoll-OH and L-Phe-OBn.HCl with BOP and NMM, carry out water treatment and purified by flash chromatography after, obtained N-(toluene-4-alkylsulfonyl) phenylglycocoll-L-Phe-OBn.In THF, handle product with 10% palladium carbon, and with mixture at 50psi H ₂Following jolting.By diatomite filtration, evaporation has obtained this title compound, is solid, fusing point=150-152 ℃ with mixture.The NMR data are as follows:

¹H?NMR(DMSO-d ₆，300MHz)：δ＝2.30(s，3H)，2.70-2.95(m，

2H)，4.13-4.30(m，1H)，5.03-5.20(m，1H)，6.88-7.34(m，12H)，7.55(m，

2H)，8.38-8.67(m，2H).

¹³C?NMR(DMSO-d ₆，75MHz)：δ＝21.3，37.3，53.7，59.6，126.7，

126.8，126.87，126.92，127.4，127.6，128.2，128.26，128.35，128.6，

129.4,129.5,137.2,137.9,138.8,142.5,169.0,172.8. mass-spectrometric data: (FAB+) 453 (M+H).

Embodiment 10

N-(toluene-4-alkylsulfonyl)-N-methyl-L-phenylalanyl-D, L-phenylalanine synthetic

(500mg 2.79mmol) is dissolved in the NaOH solution (6mL) of 1N with N-methyl-L-phenylalanine.Add diox (9mL), add then Tosyl chloride (532mg, 2.79mmol), with mixture vigorous stirring 1 hour.Remove volatile matter in a vacuum, residuum is dissolved in the water (30mL), use Et ₂(2 * 30mL) wash O, use the hcl acidifying of 1N then.Use CHCl ₃(3 * 30mL) extraction mixtures extraction liquid vacuum-evaporation, have obtained N-(toluene-4-alkylsulfonyl)-N-methylbenzene L-Ala, are solid (424mg, 45%).

Employing method 3 described steps are with N-(toluene-4-alkylsulfonyl)-N-methylbenzene L-Ala and L-phenylalanine ethyl ester coupling (400mg, 62%).With NaOH in ethanol with the ethyl ester hydrolysis, made this title compound.Proton and carbon NMR analysis revealed, product is the mixture of diastereomer.The NMR data are as follows:

¹H?NMR(CDCl ₃)：δ＝9.15(bs，1H)，7.38-6.89(14H)，4.82(m，1H)，

4.70(m，1H)，3.31-2.95(3H)，2.81(s，1/2×3H)，2.55(s，1/2×3H)，

2.50(m，1H)，2.37(s，1/2×3H)，2.35(s，1/2×3H).

¹³C?NMR(CDCl ₃)：δ＝175.3，169.6，169.5，143.5，143.4，137.0，

136.9，135.6，135.5，135.3，135.2，129.8，129.7，129.6，129.3，129.2，

129.1，129.0，128.7，128.6，128.5，128.4，127.2，127.1，127.0，126.6，

126.4，124.8，61.2，61.0，53.5，53.4，37.4，37.1，33.9，33.5，29.9，29.6，

21.4. mass-spectrometric data: FAB m/e 481 (M+H).

Embodiment 11

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine

According to method 3 described steps with Boc-L-diphenylprop propylhomoserin and the coupling of L-phenylalanine benzyl ester.By handling the Boc group is sloughed, mixture is evaporated with TFA and phenylmethylether.The gained residuum is dissolved in Et ₂Among the O, and use saturated NaHCO successively ₃With saturated NaCl washing.Use MgSO ₄Dry Et ₂The O layer filters and evaporation, has obtained the dipeptides of deprotection.The ester tosylation of this title compound that will obtain according to method 1 described step.Make this title compound according to method 7 described steps, be solid, fusing point=228-230 ℃.The NMR data are as follows:

¹H?NMR(CD ₃OD，300MHz)：δ＝2.11(s，3H)，2.37-2.46(m，2H)，

3.78(m，1H)，3.99(d，1H，J＝10.8Hz)，4.49(d，1H，J＝10.8Hz)，

6.86-7.04(m，17H)，7.36(d，2H，J＝8.3Hz).

¹³C?NMR(CD ₃OD，75MHz)：δ＝22.0，39.8，56.1，56.3，61.6，

128.09，128.14，128.4，128.7，128.8，129.8，129.9，130.0，130.1，130.3，

131.07,131.11,138.7,140.0,142.2,142.4,144.9,172.3,174.5. mass-spectrometric data: (FAB+) 549 (M+Li).

Embodiment 12

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine

According to method 1 described step, made N-(toluene-4-alkylsulfonyl) sarkosine with sarkosine.Carry out coupling by method 3 described steps.Employing method 7 described steps have made this title compound with the ester hydrolysis, are solid, fusing point=＞200 ℃ (decomposition temperature).The NMR data are as follows:

¹H?NMR(D ₂O，300MHz)：δ＝2.17(s，3H)，2.28(s，3H)，2.71-3.05

(m，2H)，3.31-3.48(dd，2H)，4.34(m，1H)，6.74(s，1H)，6.97-7.16(m，

7H)，7.37(d，2H，J＝8.0Hz)，7.44(s，1H).

¹³C?NMR(D ₂O，75MHz)：δ＝27.7，37.2，43.0，57.3，59.8，61.7，

124.7，134.3，134.6，134.9，135.8，137.0，138.9，143.7，144.2，144.3，

152.0,176.0,184.6. mass-spectrometric data: (FAB+) 493 (M+H).

Embodiment 13

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-β-(3-pyridyl) L-Ala synthetic

With sodium Metal 99.5 (1.40g, 61mmol) be dissolved in contain acetamino diethyl malonate (6.62g, among EtOH 30.5mmol) (100mL), add hydrochloric acid 3-pyrmethyl chloride (5.00g, 30.5mmol).Mixture heating up was refluxed 6 hours.Cooling is then filtered to remove NaCl (washing with EtOH).The solvent vacuum is removed, mixture is dissolved in the saturated sodium bicarbonate aqueous solution (100mL), with EtOAc (3 * 100mL) extractions.Remove and desolvate, by fast silica gel chromatogram method (95: 5 CH ₂Cl ₂/ MeOH) purifying residuum has obtained 2-(3-pyridylmethyl)-2-acetamino diethyl malonate (2.84g, 30%).

2-(3-pyridylmethyl)-2-acetamino diethyl malonate is dissolved in the hydrochloric acid (30mL) of 6N, reflux 19 hours is cooled to room temperature with it then, and hydrochloric acid soln is removed in vacuum-evaporation.Amino acid dihydrochloride intermediate is dissolved in among the saturated MeOH of HCl gas (30mL), and stirred 3.5 hours.Vacuum-evaporation has obtained two hydrochloric acid β-(3-pyridyl) alanine methyl ester (2.235g, 100%) to remove MeOH/HCl.

With N-(toluene-4-alkylsulfonyl) sarkosine and 3-(3-pyridyl) alanine methyl ester coupling, generated N-(toluene-4-alkylsulfonyl) sarcosyl-β-(3-pyridyl) L-Ala (166mg, 17%) according to method 3 described steps.With in NaOH aqueous solution Zai diox/water of 1N with this methyl esters hydrolysis, made this title compound (129mg, 100%).The NMR data are as follows:

¹H?NMR(DMSO-d ₆)：δ＝8.30(m，2H)，7.66(d，2H，J＝8.0Hz)，

7.63(m，1H)，7.51(m，1H)，7.42(d，2H，J＝7.9Hz)，7.20(m，1H)，4.07

(m，1H)，3.56(s，2H)，3.11(dd，1H，J＝4.8，13.2Hz)，2,96(dd，1H，J

＝5.5，13.4Hz)，2.52(s，3H)，2.40(s，3H).

¹³C?NMR(DMSO-d ₆)：δ＝172.7，166.0，150.8，147.3，143.8，137.3，

134.8,134.0,130.2,127.7,123.3,55.3,53.2,36.2,34.9,21.4. mass-spectrometric data: FAB m/e 392 (M+H).

Embodiment 14

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-β-(4-pyridyl) L-Ala synthetic

According to embodiment 13 (107) described methods, but substitute hydrochloric acid 3-pyrmethyl chloride, made this title compound with hydrochloric acid 4-pyrmethyl chloride.The NMR data are as follows:

¹H?NMR(CD ₃OD)：δ＝8.39(d，2H，J＝5.3Hz)，7.68(d，2H，J＝

8.2Hz)，7.41(d，2H，J＝8.0Hz)，7.34(d，2H，J＝5.8Hz)，4.58(m，

1H)，3.70(d，1H，J＝16.6Hz)，3.54(d，1H，J＝16.5Hz)，3.30(dd，1H，

J＝4.9，13.7Hz)，3.07(dd，2H，J＝7.6，13.7Hz)，2.66(s，3H)，2.43(s，

3H).

¹³C?NMR(CD ₃OD)：δ＝176.0，270.2，150.8，150.1，146.1，135.7，

131.5,129.3,127.4,56.4,54.8,39.1,37.6,22.1. mass-spectrometric data: FAB m/e 392 (M+H).

Embodiment 15

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-L-β-(2-pyridyl) L-Ala

With N-(toluene-4-alkylsulfonyl) sarkosine and L-β-(2-pyridyl) alanine methyl ester coupling, obtained N-(toluene-4-alkylsulfonyl) sarcosyl-L-β-(2-pyridyl) alanine methyl ester according to method 3 described steps.With in NaOH aqueous solution Zai diox/water of 1N with this methyl esters hydrolysis, made this title compound.The NMR data are as follows:

¹H?NMR(DMSO-d ₆)：δ＝8.38(m.1H)，7.72(d，1H，J＝7.4Hz)，

7.65(d，2H，J＝8.2Hz)，7.59(m，1H)，7.41(d，2H，J＝8.2Hz)，7.21

(d，1H，J＝7.8Hz)，7.12(m?1H)，4.23(m，1H)，3.50(m，2H)，3.23(dd，

1H，J＝4.8，13.4Hz)，3.01(dd，2H，J＝7.1，13.4Hz)，2.53(s，3H)，

2.40(s，3H).

¹³C?NMR(DMSO-d ₆)：δ＝173.4，165.7，159.7，148.9，243.8，136.1，

134.0,130.2,127.7,124.0,121.4,54.7,53.3,36.1,21.4. mass-spectrometric data: FAB m/e 414 (M+Na).

Embodiment 16

N-(toluene-4-alkylsulfonyl)-D, L-phenyl sarcosyl-L-phenylalanine synthetic

According to method 1 described step, made N-(toluene-4-alkylsulfonyl) phenyl sarkosine with the phenyl sarkosine.Make this title compound with embodiment 9 (65) described methods, be solid, fusing point=78-82 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.41(s，3H)，2.48(s，3H)，2.97-

3.34(m，2H)，4.89(m，1H)，5.63(s，1H)，6.77-6.92(m，3H)，7.13-7.35

(m，10H)，7.66(d，2H，J＝7.5Hz).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.2，32.3，38.0，53.9，64.4，127.8，

128.1，129.1，129.4，129.88，129.95，130.0，130.3，133.9，136.2，136.4，

144.4,169.8,175.2. mass-spectrometric data: (FAB+) 467 (M+H).

The preparation Embodiment B

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-N-methyl-L-phenylalanine

With N-(toluene-4-alkylsulfonyl) sarkosine and N-methyl-L-phenylalanine methyl ester coupling, generated N-(toluene-4-alkylsulfonyl) sarcosyl-N-methylbenzene alanine methyl ester according to method 3 described steps.With LiOH in THF/ water with this methyl esters hydrolysis, made this title compound.Proton and carbon NMR analysis revealed, product are the mixtures that ratio is about 65: 35 amido linkage rotational isomer.The NMR data are as follows:

¹H?NMR(CDCl ₃)：δ＝7.59(d，0.65×2H，J＝7.4Hz)，7.54(d，

0.35×2H，J＝7.3Hz)，7.34-7.18(7H)，5.25(m，0.65H)，5.09(m，

0.35H)，3.93(d，0.65H，J＝14.6Hz)，3.58(d，0.65H，J＝14.6H)，3.41

(m，1H)，3.10(m，1H)，2.97(s，0.65×3H)，2.92(s，0.35×3H)，2.41(s，

3H)，2.39(s，0.65×3H)，2.38(s，0.35×3H).

¹³C?NMR(CDCl ₃)：δ＝173.3，168.1，167.8，143.9，143.8，136.9，

136.8，133.3，129.7，129.1，128.8，128.7，128.6，127.5，127.0，126.8，

59.0,52.8,52.7,35.0,34.7,34.2,33.0,30.1,21.5. mass-spectrometric data: FAB m/e 405 (M+Na).

Embodiment 17

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-aspartyl-L-phenylalanine

With method 3 described steps with Cbz-4-(1, the 1-dimethyl ethyl) aspartic acid and the coupling of the phenylalanine tert-butyl ester.According to method 4 described steps the Cbz group is sloughed.With the ester tosylation of method 1 described step with gained.Made this title compound with method 11 described steps.The NMR data are as follows:

¹H?NMR(CD ₃OD，300MHz)：δ＝2.18(s，3H)，2.18-2.39(m，2H)，

2.68-2.89(m，2H)，3.97(t，1H，J＝5.2Hz)，4.22(t，1H，J＝4.9Hz)，

6.97-7.12(m，7H)，7.45(d，2H，J＝8.2Hz).

¹³C?NMR(CD ₃OD)，75MHz)：δ＝22.1，38.6，38.9，55.1，55.9，

128.5，128.8，130.1，130.9，131.0，131.3，138.3，138.6，139.4，145.5，

172.6. mass-spectrometric data: (FAB+) 435 (M+H).

Embodiment 18

N-(toluene-4-alkylsulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-phenylpropyl alcohol ammonia

Synthesizing of acid benzyl ester

With N-(toluene-4-alkylsulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl) (1 equivalent) and Et ₃N (2.0 equivalent), BOP (1.1 equivalent) and L-phenylalanine benzyl ester HCl salt (1.1 equivalent) are dissolved among the DMF.Be separated to the benzyl ester, be oily matter.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.62(d，2H，J＝8.16Hz)，7.33

(m，5H)，7.23-7.08(m，8H)，6.70(d，2H，J＝8.16Hz)，5.10(q，2H，J＝

11.50Hz)，4.72(m，1H)，4.52(m，1H)，4.18(m，2H)，3.07(m，2H)，2.85

(m，2H)，2.52(m，1H)，2.34(s，3H).

Synthesizing of embodiment 19N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine benzyl ester

Prepare this title compound with the method among the embodiment 18 (173).Be separated to title compound, be oily matter.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.66(d，1H，J＝7.98Hz)，7.42-

6.92(m，16H)，6.66(d，2H，J＝8.50Hz)，5.17(q，2H，J＝10.08Hz)，

4.83(m，1H)，4,58(m，1H)，3.07(m，3H)，2.62(m，1H)，2.32(s，3H).

Embodiment 20

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine benzyl ester

BOP (2.1mmol) and N-methylmorpholine (4.0mmol) are added in DMF (10mL) solution of N-(toluene-4-alkylsulfonyl)-L-L-Ala (2.0mmol).Reaction mixture was at room temperature stirred 45 minutes.Add L-phenylalanine benzyl ester (2.0mmol), reaction mixture was at room temperature stirred 16 hours.Water (100mL) and ether (3 * 50mL) extractive reaction mixtures.Merge organic layer, use successively 0.2N hydrochloric acid (2 * 50mL), saturated NaHCO ₃(50mL) and saturated NaCl (50mL) washing.Use MgSO ₄Dry organic layer filters and concentrates, and has obtained colorless oil (387mg, 40%).With fast silica gel chromatogram method (50% EtOAc/ hexane, Rf=0.61) purifying crude product.With this title compound CHCl ₃/ hexane recrystallization has obtained white solid, fusing point=109-110 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝7.75(d，2H，J＝8.24Hz)；7.26

(m，13H)；5.88(d，1H，J＝7.69Hz)；5.11(q，2H，J＝12.1Hz)；4.76(q，

1H，J＝7.69Hz)；3.85(m，1H)；3.00(d，2H，J＝5.98Hz)；2.37(s，3H)；

1.19(d，3H，J＝7.09Hz).

¹³C?NMR(CDCl ₃，300MHz)：δ＝171.83，171.49，144.30，137.34，

136.12，135.53，130.36，130.00，129.90，129.19，129.12，127.85，127.71，

127.65,67.92,54.07,52.94,38.26,22.13,19.96. mass-spectrometric data: (+FAB) 481 (M+H).

Embodiment 21

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine benzyl ester

Made this title compound according to method 3, with crude product Et ₂The crystallization of O/ hexane has obtained white solid, fusing point=80-82 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝7.64(d，2H，J＝8.24Hz)；7.26

(m，13H)；5.16(q，2H，J＝12.1Hz)；4.92(d?of?t，1H，J＝6.71?&?11.29

Hz)；3.7.70(d，1H，J＝16.48Hz)；3.43(d，1H，J＝16.48Hz)；3.15(m，

2H)；2.56(s，3H)；2.44(s，3H).

¹³C?NMR(CDCl ₃，300MHz)：δ＝171.34，167.88，144.88，135.97，

135.60，133.61，130.56，129.85，129.36，129.22，129.15，128.16，127.84，

67.93,54.51,53.51,38.29,37.15,22.16. mass-spectrometric data: (+FAB) 481 (M+H).

Embodiment 22

N-(toluene-4-alkylsulfonyl)-D, L-phenyl glycyl-L-phenylalanine ethyl ester synthetic

According to method 1 described step, made N-(toluene-4-alkylsulfonyl) phenylglycocoll with phenylglycocoll.Make this title compound according to embodiment 11 (86) described methods, be solid, fusing point=145-147 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝1.12-1.29(m，3H)，2.38(s，3H)，

2.91-3.05(m，2H)，4.04-4.20(m，2H)，4.65-4.81(m，2H)，5.85-5.95(m，

1H)，6.07-6.21(m，1H)，6.65(m，1H)，6.95(m，1H)，7.02-7.33(m，10H)，

7.60(m，2H).

¹³C NMR (CDCl ₃, 75MHz): δ=(the non-mapping that separates by oblique line

Isomer) 14.57/14.70,22.09/22.10,38.1,53.7/54.2,61.00/61.06,

62.26/62.34，127.61/127.76，127.81/127.88，128.06/128.16，

129.06/129.16，129.3，129.6，129.69/129.76，130.06/130.08，135.4，

136.01/136.55，136.94/137.21，144.03/144.13，168.67/169.00，

171.07/171.22. mass-spectrometric data: (+FAB) 481 (M+H).

Embodiment 23N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester

Synthetic

With the hydrochloride of L-(O-benzyl) serine methylester (6.28g, 25.2mmol) with Tosyl chloride (1.1 equivalents, 5.36g) and Et ₃(2.2 equivalents 7.48mL) are dissolved in methylene dichloride (50mL) to N.Reaction mixture was at room temperature stirred 12 hours.Solvent removed under reduced pressure is fallen.Add EtOAc and salt solution, use MgSO ₄Dry organic layer.Isolate required N-(toluene-4-alkylsulfonyl)-L-(O-benzyl) serine methylester, be oily matter, productive rate be 100% (10.04g, 25.5mmol).Then with itself and methyl iodide (1.1 equivalents, 1.88mL) and K ₂CO ₃(1.1 equivalents 4.10g) are dissolved in the anhydrous propanone (50mL) together.This solution backflow is spent the night.Solvent removed under reduced pressure is fallen.Add EtOAc, with salt water washing organic layer.Use MgSO ₄Dry organic layer.Solvent removed under reduced pressure is fallen.Isolated required N-methyl-derivatives, be clarifying oily matter, productive rate be 40% (4.16g, 11mmol).This ester is dissolved in 1: 1 diox of NaOH (1.1 equivalent): in the solution of water (50mL).Isolate the compound of wanting, be solid.

(754mg is 2.07mmol) with phenylalanine ethyl ester hydrochloride (1.1 equivalents, 525mg), Et with N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) Serine ₃N (2.2 equivalents, 636mL) and bop reagent (1.1 equivalents 1.00g) are dissolved in the 30mL dry DMF.Reaction mixture was at room temperature stirred 12 hours.Add EtOAc.Use saturated NaHCO successively ₃, 10% citric acid and salt water washing organic layer.Use MgSO ₄Dry organic layer.After solvent removed under reduced pressure fallen, crude product wash-out (silica gel in chromatographic column; CHCl ₃/ MeOH9: 1).Isolated this title ester, be oily, productive rate is that 60% (664mg 1.23mmol), is the mixture of diastereomer.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.69(d，2H，J＝8.22Hz)，7.27

(m，5H)，7.15(m，5H)，7.04(m，2H)，4.80(m，2H)，4.29(m，4H)，3.76

(m，1H)，3.58(m，1H)，3.19(m，2H)，2.71(s，1.5H)，2.57(s，1.5H)，

2.35(s，3H)，1.27(m，3H).

¹³C?NMR(75MHz，CDCl ₃)：δ＝171.50，168.70，143.98.137.84，

136.44，136.18，129.93，128.98，128.45，128.37，128.25，127.65，73.75，

67.15，66.99，62.17，60.35，59.98，53.93，53.75，38.34，30.95，22.15，

14.69. mass-spectrometric data: (FAB) 539 (M+H).

Embodiment 24

Synthesizing of N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-phenylalanine ethyl ester

(664mg, 1.23mmol) Pearlman ' the s catalyzer with catalytic amount is dissolved among the MeOH (10mL) with embodiment 23 (191) products.Under 5psi pressure, hydrogenation was carried out 2 hours.Solution is passed through diatomite filtration.After reduction vaporization falls solvent, be separated to this title compound, be oily matter with quantitative yield.The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.68(m，2H)，7.30(m，7H)，4.77

(m，1H)，4.46(m，1H)，4.18(m，2H)，3.65(m，1H)，3.47(m，2H)，3.07

(m，2H)，2.78(s，1.5H)，2.54(s，1.5H)，2.42(s，3H)，1.25(m，3H).

¹³C?NMR(75MHz，CDCl ₃)：δ＝171.47，170.31，144.78，136.42，

135.77，130.67，129.88，129.33，127.92，127.80，62.44，60.99，60.81，

54.00,53.77,38.32,32.19,31.96,22.24,14.76. mass-spectrometric data: (FAB) 449 (M+H).

Embodiment 25

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine benzyl ester

According to method 3 described steps with Boc-L-diphenylprop propylhomoserin and the coupling of L-phenylalanine benzyl ester.According to embodiment 11 (86) described methods the Boc group is sloughed.According to the ester tosylation of method 1 described step with gained, obtained this title compound, be solid, fusing point=79-84 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.36(s，3H)，2.77(m，2H)，4.25-

4.39(m，2H)，4.95(d，2H，J＝4.9Hz)，5.19(d，1H，J＝8.0Hz)，6.18

(d，1H，J＝7.8Hz)，6.92(m，2H)，7.08-7.38(m，20H)，7.55(d，2H，J＝

8.4Hz).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.1，38.8，54.1，54.7，60.9，67.7，

127.6，127.70，127.72，128.0，128.7，129.10，129.14，129.3，129.9，

130.2,135.5,136.0,137.0,139.4,140.1,144.2,169.9,170.8. mass-spectrometric data: (FAB+) 633 (M+H).

Embodiment 26 synthetic N-(toluene-4-alkylsulfonyl)-N-methyl D, L-phenyl glycyl-L-phenylalanine second

Ester

With thionyl chloride with N-(toluene-4-alkylsulfonyl) phenylglycocoll esterification in toluene, to generate N-(toluene-4-alkylsulfonyl) phenyl glycine methyl ester.Then with itself and methyl iodide (1.1 equivalents, 1.88mL) and K ₂CO ₃(1.1 equivalents 4.10g) are dissolved in the anhydrous propanone (50mL) together.This solution backflow is spent the night.Solvent removed under reduced pressure is fallen.Add EtOAc, with salt water washing organic layer.Use MgSO ₄Dry organic layer.Reduction vaporization falls solvent.According to of the ester hydrolysis of method 6 described steps, generating N-(toluene-4-alkylsulfonyl)-N-aminomethyl phenyl glycine, with itself and the coupling of L-phenylalanine ethyl ester, obtained this title compound according to method 3 described steps with gained.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝1.27(t，3H)，2.43(s，3H)，2.60(s，

3H)，2.98-3.25(m，2H)，4.21(q，2H)，4.80-4.91(m，1H)，5.68(s，1H)，

6.59(br?d，minor?dia.，1H?with?6.73)6.73(br?d，major?dia.，1H?with

6.59)，6.92-7.02(m，2H)，7.11-7.43(m，10H)，7.69(d，2H).

¹³C NMR (CDCl ₃, 75MHz): δ=(more diastereomer) 14.75,22.16,

32.20，38.38，53.56，62.21，64.43，127.79，128.07，129.07，129.13，

129.27，129.87，129.92，130.04，134.18，136.10，136.32，144.22，169.08，

171.71; (less diastereomer) 14.68,22.16,32.12,38.51,53.97,62.21,

64.22，127.76，128.16，129.07，129.13，129.32，129.87，129.92，130.26，

134.26,136.10,136.52,144.26,169.08,171.71. mass-spectrometric data: (FAB+) 495 (M+H).

Embodiment 27

Synthesizing of N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine methyl esters

Made N-(toluene-4-alkylsulfonyl) sarkosine methyl esters according to method 1 described step with the sarkosine methyl esters.With N-(toluene-4-alkylsulfonyl) sarkosine and (N-benzyl) Histidine methyl esters in the presence of BOP and NMM, coupling in DMF, product carried out water treatment and purified by flash chromatography after, obtained this title compound.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.44(s，3H)，2.76(s，3H)，3.09(m，

2H)，3.44(d，1H，J＝16.4Hz)，3.68(s，3H)，3.83(d，1H，J＝16.5Hz)，

4.80(m，1H)，5.07(s，2H)，6.74(s，1H)，7.14(d，2H，J＝6.0Hz)，7.33

(m，5H)，7.50(s，1H)，7.68(d，2H，J＝8.3Hz)，8.06(br?d，1H，8.1Hz).

¹³C?NMR(CDCl ₃，75MHz)：δ＝14.8，22.1，30.2，37.1，51.4，52.6，

52.9，54.4，61.0，117.8，128.0，128.2，128.8，129.6，130.5，134.0，136.6，

137.8,137.9.144.6,168.2,172.1. mass-spectrometric data: (FAB+) 485 (M+H).

Embodiment 28N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters

Synthetic

(420mg 1.53mmol) is dissolved under the ice bath temperature in the dry DMF (20mL) with N-methyl-N-(toluene-4-alkylsulfonyl)-L-Serine.Add L-(N-benzyl) Histidine methyl ester hydrochloride (1.1 equivalents, 500mg) and Et ₃N (2.2 equivalents, 471mL) and HOBT (1.1 equivalents, 229mg).After 15 minutes, (1.1 equivalents 502mg), at room temperature stir reaction mixture and to spend the night to add EDCI.Add EtOAc, use saturated NaHCO successively ₃, 10% citric acid and salt solution (3 * 50mL) washing organic layers.Use MgSO ₄Dry organic layer falls solvent removed under reduced pressure.Purifying crude product in silica gel chromatographic column is used 1: 3 EtOAc/ hexane, 9: 1 CHCl successively ₃: the MeOH wash-out.Be separated to this title compound, be oily matter, productive rate be 30% (230mg, 0.447mmol).The NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.91(d，1H，J＝7.50Hz)，7.73

(d，2H，J＝8.31Hz)，7.46(s，1H)，7.32(m，5H)，7.15(m，2H)，6.69(s，

1H)，5.04(s，2H)，4.74(m，1H)，4.46(m，1H)，3.71(m，2H)，3.66(s，

3H)，3.06(m，2H)，2.80(s，3H)，2.40(s，3H).

¹³C?NMR(75MHz，CDCl ₃)：δ＝171.98，170.40，144.41，137.93，

136.54，135.976，130.41，129.57，128.88，128.01，117.74，61.42，61.15，

53.07,51.46,32.29,30.09,22.13 (lacking 1 C). and mass-spectrometric data: (FAB) 515 (M+H).

Embodiment 29

N-(toluene-4-alkylsulfonyl)-D, L-phenyl glycyl-L-phenylalanine benzyl ester synthetic

According to method 3 described steps, with N-(toluene-4-alkylsulfonyl)-D, L-phenylglycocoll and the coupling of L-phenylalanine benzyl ester have made this title compound, are solid, fusing point=148-150 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.37(s，3H)，2.91-3.07(m，2H)，

4.70-4.85(m，2H)，5.04(dd，2H)，5.94(br?d，1H)，6.23(br?d，1H)，6.84

(d，2H)，7.00-7.40(m，15H)，7.60(d，2H).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.1，38.1，54.2，61.1，67.9，127.7，

127.8，127.9，128.1，128.2，129.1，129.4，129.6，129.7，129.8，130.0，

135.4,135.8,136.5,137.2,144.1,169.1,170.9. mass-spectrometric data: (FAB+) 543 (M+H).

Embodiment 30 synthetic N-(toluene-4-alkylsulfonyl)-N-methyl D, L-phenyl glycyl-L-phenylalanine benzyl

Ester

According to embodiment 26 (198) described steps, made this title compound, be solid, fusing point=46-49 ℃.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.41(s，3H)，2.54，(s，3H)，2.96-

3.22(m，2H)，4.90(q，1H，J＝3.0Hz)，5.15(dd，2H)，5.65(s，1H)，6.51

(d，1H，J＝6.9Hz)，6.95(d，2H，J＝6.2Hz)，7.04(m，2H)，7.15-7.40

(m，13H)，7.67(d，2H，J＝8.2Hz).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.2，32.1，38.4，53.9，64.3，68.0，

127.8，128.1，129.1，129.2，129.3，129.4，129.8，129.9，130.0，130.1，

130.2,134.2,135.6,136.2,136.5,144.2,169.1,171.4. mass-spectrometric data: (FAB+) 557 (M+H).

Embodiment 31 synthetic N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine first

Ester

Made N-(toluene-4-alkylsulfonyl)-2-thienyl ethamine according to method 1 described step.With this compound and bromo-acetic acid tert-butyl reaction; generated N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) tert-butyl glycinate (according to Zuckermann; Kerr; Kent; with Moos in " American Chemical Society can will " (J.Am.Chem.Soc.); 1992,114, the method for describing among the 10646-10647).According to method 17 described steps with this ester hydrolysis.Made this title compound according to method 13 described steps.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.43(s，3H)，2.85(m，2H)，3.05-

3.22(m，3H)，3.40(m，1H)，3.69(dd，2H)，3.73(s，3H)，4.83(m，1H)，

6.73(d，1H，J＝2.3Hz)，6.90(t，1H，J＝2.4Hz)，6.98(br?d，1H，J＝

6.2Hz)，7.13(d，1H，J＝3.2Hz)，7.17-7.35(m，7H)，7.66(d，2H，J＝

8.0Hz).

Synthesizing of embodiment 32N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine

According to method 7 described steps, made this title compound by the product of embodiment 31 (289), be solid, fusing point＞200 ℃.

Embodiment 33N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-(N-benzyl) Histidine first

Synthesizing of ester

Made this title compound according to embodiment 31 (289) described methods.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.41(s，3H)，2.82(m，2H)，3.02-

3.30(m，3H)，3.46(m，1H)，3.67(s，3H)，3.75(dd，2H)，4.79(m，1H)，

5.00(s，2H)，6.77(s，1H)，7.10-7.35(m，12H)，7.48(s，1H)，7.69(d，2H，

J＝7.3Hz)，7.97(br?d，1H，J＝6.9Hz).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.1，30.2，35.3，51.4，52.6，52.7，

52.9，118.1，127.2，127.9，128.0，128.8，129.2，129.4，129.5，130.5，

135.7,136.6,137.6,137.8,138.5,144.6,168.9,172.0. mass-spectrometric data: (FAB+) 575 (M+H); 597 (M+Na ⁺).

Synthesizing of embodiment 34N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-phenylalanine

Made this title compound according to embodiment 31 (289) and 32 (290) described methods.The NMR data are as follows:

¹H?NMR(CDCl ₃，300MHz)：δ＝2.41(s，3H)，2.56(m，2H)，3.03-

3.37(m，4H)，3.72(dd，2H)，4.84(q，1H，J＝3.4Hz)，7.02(d，2H，J＝

6.1Hz)，7.12-7.34(m，10H)，7.63(d，2H，J＝8.3Hz)，8.78(br?s，1H).

¹³C?NMR(CDCl ₃，75MHz)：δ＝22.1，35.1，37.8，52.6，52.7，53.8，

127.3，127.9，128.0，129.2，129.3，129.4，130.0，130.6，135.2，136.0，

138.1,144.9,169.9,175.0. mass-spectrometric data: (FAB+) 481 (M+H).

Embodiment 35

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-cyano group phenylalanine synthetic

With N-(toluene-4-alkylsulfonyl) sarkosine and the coupling of 4-cyano group phenylalanine methyl ester hydrochloride (according to Wagner; Voight; with Vieweg at Pharmazie 1984; 39; the method of describing among the 226-230); generated N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-cyano group phenylalanine methyl ester.With the NaOH of 0.5N in THF/ water with this methyl esters hydrolysis, made this title compound.The NMR data are as follows:

¹H?NMR(CD ₃OD/CDCl ₃)：δ＝7.69(m，3H)，7.41(m，3H)，4.79(m，

1H)，3.77(d，1H，J＝16.7Hz)，3.55(d，1H，J＝16.5Hz)，3.32(dd，

1H，J＝4.9，14.0Hz)，3.13(dd，1H，J＝8.8，14.0Hz)，2.67(s，3H)，

2.45(s，3H).

¹³C?NMR(CD ₃OD/CDCl ₃)：δ＝174.0，170.6，146.2，144.9，135.5，

134.0,132.2,131.6,129.3,120.4,112.3,54.8,50.4,39.0,37.7,22.4. mass-spectrometric data: FAB m/e 416 (M+H).

Embodiment 36

Synthesizing of N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycyl-L-phenylalanine

According to method 1 described step, made N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycine with L-tertiary butyl glycine.With N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycine and L-phenylalanine ester in the presence of BOP and NMM, coupling in DMF, made the ester of this title compound.It is carried out routine take off the ester processing, obtained this title compound.The NMR data are as follows:

¹H?NMR(CDCl ₃)：δ7.7(d，2H)，7.25(m，5H)，7.0(m，2H)，5.93(d，

1H)，5.57(d，1H)，4.6(m，1H)，3.3(d，1H)，3.0-2.7(d?of?d，2H)，2.35(s，

3H)，0.87(s，9H).

Embodiment 37N-(saccharin-2-yl)-D, L-alanyl-L-4-(different nicotinoyl amino) phenylpropyl alcohol

Synthesizing of propylhomoserin methyl esters

This title compound makes according to method described in the preparation embodiment A.With N-(saccharin-2-yl)-D, L-alanyl-L-p-Aminophenylalanine methyl esters (1 equivalent) and Et ₃N (1.1 equivalent) is dissolved in the methylene dichloride, and (1.1 equivalents, 860mL) reaction is to generate this title compound with different nicotinoyl chlorine.The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400MHz) (1: 1 mixture of diastereomer): δ=

10.43(d，1H)；8.80(m，2H)；8.45?and?8.25(two?m，1H)，8.23(m，1H)；

8.04(m，3H)；7.82(m，2H)；7.65(m，2H)；7.20(m，2H)；4.76(m，1H)；

4.45(m，1H)；3.40?and?3.42(two?s，3H)；3.00(m，2H)，1.65?and?1.70

(two?s，3H).

Zhi Bei other compound is included in down the compound of listing in the Table II according to the method described above.

??????R ¹	????R ²	?????R ³	???????R ⁵	????R ^6＇	????Q＝ ???-C(O)NR ⁷- ????R ⁷	The embodiment numbering.
??????R ¹	????R ²	?????R ³	???????R ⁵	????R ^6＇	????Q＝ ???-C(O)NR ⁷- ????R ⁷	The embodiment numbering.	????p-CH ₃-φ-	????-CH ₃	????L-CH(φ) ₂	????-CH ₂-φ	????-OH	????H	????38
????p-CH ₃-φ-	????φ	????H	????-CH ₂-φ	????OH	????H	????39	????p-CH ₃-φ-	????-CH ₃	????L-CH(φ) ₂	????-CH ₂-φ	????-OH	????H	????38
????p-CH ₃-φ-	????φ	????H	????-CH ₂-φ	????OH	????H	????39	????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OCH ₃	????H	????40
????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OH	????H	????41	????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OCH ₃	????H	????40
????p-CH ₃-φ-	????-CH ₂φ	????H	????-CH ₂-φ	????-OH	????H	????41	????p-CH ₃-φ-	????-CH ₃	????H	P-[-C ≡ C-(2-pyridyl)]-benzyl-	????-OH	????H	????42

??????R ¹	????R ²	??????R ³	??????R ⁵	????R ^6＇	???Q＝ ???-C(O)NR ⁷- ???R ⁷	The embodiment numbering.
??????R ¹	????R ²	??????R ³	??????R ⁵	????R ^6＇	???Q＝ ???-C(O)NR ⁷- ???R ⁷	The embodiment numbering.	????p-CH ₃-φ-	????-CH ₃	??????H	P-[-C ≡ C-(m-hydroxy phenyl)]-benzyl-	????-OH	???H	????43
????p-CH ₃-φ-	????-CH ₃	??????H	???p-iodobenzyl-	????-OH	???H	????44	????p-CH ₃-φ-	????-CH ₃	??????H	P-[-C ≡ C-(m-hydroxy phenyl)]-benzyl-	????-OH	???H	????43
????p-CH ₃-φ-	????-CH ₃	??????H	???p-iodobenzyl-	????-OH	???H	????44	????φ-CH ₂-	????-CH ₃	??????-CH ₂OH ??????(Lisomer)	1-N-phenylimidazole-4-base-CH ₂-	????-OCH ₃	???H	????45

Embodiment 46

Measure the experiment in vitro of test compounds in conjunction with VLA-4

Come the evaluation test compound to α with experiment in vitro ₄β ₁The combination of integrin.In this body, can be used for estimating the level of VCAM-1 in the biological specimen in the experiment in conjunction with the compound of VLA-4 by conventional determining method (for example competitive binding assay).For IC ₅₀, the sensitivity of this experiment is about 1nM.

α ₄β ₁The activity of integrin is by measuring solubility VCAM-1 and expressing high-level α ₄β ₁The interaction of the human T-cell system-Jurkat cell of integrin (for example American type culture collection TIB 152, TIB 153 and CRL 8163) and definite.VCAM-1 is with α ₄β ₁Integrin rely on pattern and cell surface interaction (people such as Yednock, " journal of biological chemistry " (J.Biol.Chem.), 1995,270:28740).

Express recombinant solubility VCAM-1 is with as containing 7 VCAM-1 extracellular domains at the N-end, containing human IgG at the C-end ₁The chimeric fusion protein of CH.Express and this VCAM-1 fusion rotein of purifying according to the described method of above-mentioned Yednock.

According to the described method of top Yednock, growth Jurkat cell in the RPMI 1640 that is supplemented with 10% foetal calf serum, penicillin, Streptomycin sulphate and glutamine.

MnCl with 1.5mM ₂With 5 μ g/mL, 15/7 antibody on ice with Jurkat cell cultures 30 minutes.Mn ^{+ 2}Activated receptor to be strengthening the part combination, and the 15/7th, monoclonal antibody, its identification is activated/α that part occupies ₄β ₁The conformation of integrin, and this molecule is locked in this conformation, VCAM-1/ α just stablized thus ₄β ₁The interaction of integrin.Document referring to people such as above-mentioned Yednock.Other researchist be prepared into the antibody that is similar to 15/7 antibody (people such as Luque, 1996, " journal of biological chemistry " (J.Biol.Chem.), 271:11067), these antibody also can be used for this experiment.

Then with cell with the serial dilution of standard 5-point, concentration is that the test compounds that 66 μ M-0.01 μ M do not wait was at room temperature cultivated 30 minutes.Then 15 μ L solubilities reorganization VCAM-1 fusion rotein is added in the Jurkat cell, and cultivates 30 minutes (referring to people such as top Yednock) on ice.

Then with cell washing twice, be resuspended in the goat F that PE-puts together (ab ') with 1: 200 ratio ₂Anti--mouse IgG Fc (Immunotech, Westbrook, ME) in, cultivated 30 minutes on ice, in the dark.As described in people such as top Yednock,, analyze with standard fluorescence activating cells sorter (" FACS ") with cell washing twice.

IC ₅₀Compound less than about 15 μ M has in conjunction with α ₄β ₁The ability of integrin.

When in this experiment, testing, the IC of the compound among the embodiment 1-45 ₅₀All be 15 μ M or less than 15 μ M.

Embodiment 47

Measure test compounds in conjunction with α ₄β ₁External saturation testing

Following vitro test is to measure compound to show active required blood plasma level in (" the EAE ") model of the experimental autoimmune encephalomyelitis described in the next embodiment or other body inner model.

With the Jurkat cell washing of logarithmic growth, and be resuspended in the standard animal plasma that contains 20 μ g/ml, 15/7 antibody (in a last embodiment, describing).

With the Jurkat cell contain promising acquisition typical curve select with standard 12-serial dilution, concentration is 2 times of dilutions in the standard serum sample of the test compounds that do not wait of 66 μ M-0.01 μ M, perhaps 2 times of dilutions in the plasma sample of gathering from the peripheral blood with the animal of test compounds treatment.

Cell was at room temperature cultivated 30 minutes, with phosphate buffered saline (PBS) (" PBS ") (tested media) washing that contains 2% foetal calf serum and 1mM calcium chloride and 1mM magnesium chloride 2 times, to remove unconjugated 15/7 antibody.

Then cell is placed the goat F (ab ') of phycoerythrin-put together with 1: 200 ratio ₂It is anti--mouse IgG Fc that (Immunotech, Westbrook ME) (for non-specific crosslinking reaction, adsorbed with 5% serum of gathering from test animal this solution) by cultivating altogether, and cultivation 30 minutes in 4 ℃, dark.

, and be resuspended in the identical solution cell washing twice with tested media.Then at " journal of biological chemistry " (J.Biol.Chem.) according to people such as Yednock, 1995, the method for describing among the 270:28740, (" FACS ") analyzes with standard fluorescence activating cells sorter.

Then data are drawn to dosage with fluorescence, for example draw with standard dose-reactive mode.Represent at the resulting dosage level of the flat-top of curve and to obtain to render a service required level in the model in vivo.

This test can be used for being determined as saturated other integrin as with α ₄β ₁The α that integrin is the most close ₉β ₁Integrin (people such as Palmer, 1993, " cytobiology magazine " (J.Cell.Bio.), the blood plasma level that binding site 123:1289) is required.This combination has and can predict by α ₉β ₁Practicality in the body of 6 integrin-mediated inflammation, this inflammation comprises, for example vascular occlusion of the smooth muscle cell proliferation in the tracheae overreaction followed of chronic asthma and obstruction, the atherosclerosis, postangioplasty, fibrosis that ephrosis causes and renal glomerulus form inflammation and the cicatrization that the development of synovial membrane hypertrophy in scar, aortic stenosis, the rheumatoid arthritis and ulcerative colitis and Crohn disease is followed.

Therefore, available CCL188, promptly use coding for alpha ₉The SW 480 of the cDNA transfection of integrin (ATCC # CCL228) (people such as Yokosaki, 1994, " journal of biological chemistry " (J.Biol.Chem.) 269:26691) carries out above-mentioned test, to measure α ₉β ₁The combination of integrin.Can use and express other α and β ₁SW 480 cells of subunit in contrast.

Therefore, on the other hand, the present invention relates in the Mammals diseased individuals, treat by α ₉β ₁The method of the disease that integrin mediated, described method comprise, will treat the The compounds of this invention of significant quantity to described diseased individuals administration.This compound is preferably with the above-mentioned pharmaceutical composition administration of this paper.Effectively per daily dose will depend on the factor that can be judged easily by clinicist situation etc. as age, body weight and the health of diseased individuals.Yet in preferred embodiments, the dosage of The compounds of this invention every day is about 20-500 μ g/kg body weight.Adopt conventional oral preparations, The compounds of this invention shows activity in this model.

Embodiment 48

Interior evaluating

Use standard multiple sclerosis model, experimental autoimmune (or allergy) encephalomyelitis (" EAE ") are measured test compounds alleviates the motor damage in rat or cavy effect.Alleviating of motor damage is owing to due to the blocking-up of the sticking action between white corpuscle and the endotheliocyte, and relevant with the anti-inflammatory activity of test compounds.People such as Keszthelyi in " neurological " (Neurology), 1996, described this model among the 47:1053-1059, and this model can be used for measuring delaying of seizure of disease.

Brain and spinal cord homogenate in isopyknic phosphate buffered saline (PBS) with the Hartley cavy that grows up.In homogenate, add isopyknic Freund's complete adjuvant (100mg Mycobacterium tuberculosis+10mL Freund's incomplete adjuvant).Mixture was circulated about 20 minutes repeatedly through the 20ml syringe and make its emulsification with peristaltic pump.

With isoflurane with female Lewis rat (2-3 month size, 170-220g) or the anesthesia of Hartley cavy, at 3 above-mentioned emulsion of each flank side injection, each 0.1ml.Find motor damage outbreak after about 9 days.

The 8th day, promptly just before symptom takes place, begin to treat with test compounds.With compound by subcutaneous (" SC "), oral (" PO ") or intraperitoneal (" IP ") administration.Dosage is 10mg/kg-200mg/kg, administration 5 days, and the general dosage of SC is 10-100mg/kg, and PO is 10-50mg/kg, and IP is 10-100mg/kg.

Use and postpone the anti-α that symptom takes place ₄β ₁The antibody GC5/3 of integrin (people such as Keszthelyi (Neurology) in " neurological ", 1996,47:1053-1059) in contrast, and with this antibody the 8th day and the dosage subcutaneous injection with 3mg/kg in the 11st day.

Measure the damage of body weight and motor every day.Evaluate the motor degree of injury with following clinical marking standard:

0 does not change

Weak or the paralysis of 1 afterbody

2 hind leg weaknesses

3 back acroparalysia

4 is dying or dead

If with respect to control group, test compounds has postponed the generation of symptom, for example makes above-mentioned clinical marking be no more than 2, or has slowed down weight loss, so just thinks that test compounds has activity.

Embodiment 49

Asthmatic model

By α ₄β ₁6 integrin-mediated inflammation comprises, for example tracheae hyperergy and the obstruction followed of chronic asthma.Describe below and can be used for measuring the asthmatic model that The compounds of this invention is treated effect in the body of asthma.

According to people such as Abraham (J.Clin.Invest.) at " Journal of Clinical Investigation ", people such as 93:776-787 (1994) and Abraham are at " U.S. breathes and circulation maintenance treatment magazine " (Am J.Respir Crit Care Med.), the method that 156:696-703 (1997) describes (the two lists the present invention in for your guidance all in full), The compounds of this invention is mixed with aerosol, gives sheep Ascaris suum antigen hyperirritability with it.The compound that alleviates reaction of early antigen inductive segmental bronchus and/or the reaction of retardance later stage tracheae has the late phase reaction and the tracheae hyperergy (" AHR ") of anti-antigen induction, and is considered in this model activity is arranged.

Use had not only shown the tracheae effect that allergy sheep early stage but also that show segmental bronchus reaction in late period is measured test compounds to the Ascaris suum antigen that sucks.Lignocaine with 2% with the nasal airway local anaesthesia after, balloon catheter is put into the oesophagus bottom by a nostril.Then with the flexible fiber bronchoscope as guiding, give the animal intubate by another nostril with preparing to be placed on endotracheal sebific duct.

Estimate pleura pressure according to Abraham (1994).With can freely make be used to provide aerosol, mass median aerodynamic diameter is that the atomizer for medicine of 3.2 μ m (measuring with the Andersen cascade impactor) is aerosol drug delivery (it is as follows to fill a prescription).This atomizer links to each other with the dosimetry meter that is made of magnetic valve and compressed gas source (20psi).The relief outlet of this sprays directly extends in the plastics T-sheet, and an end of this T-sheet divides with the suction unit of piston respiratory organ and links to each other.When the inhalation cycle of respiratory organ begins, with 1 second kind of magnetic valve activation.Aerosol is with the V of 500mL _TSpeed administration with 200 breaths/min.Only use 0.5% sodium hydrogen carbonate solution in contrast.

In order to estimate bronchial reactivity, can produce cumulative concentration-response curve to carbachol according to Abraham (1994).Can be before treatment beginning, after the treatment beginning and impose antigenic stimulation and carry out the segmental bronchus examination of living tissue after 24 hours.Can carry out the segmental bronchus examination of living tissue according to the described method of Abraham (1994).

Can carry out the interior adhesion experiment of body of pulmonary alveolar macrophage according to the described method of Abraham (1994), and calculate the shared per-cent of adhesive cell.Aerosol formulation

According to following step, the concentration of setup test compound in 0.5% sodium bicarbonate/salt solution (w/v) is sodium bicarbonate/salt solution storing solution: the 100.0mL of the solution of 30.0mg/mL: A. preparation 0.5%

Component	Gram/100.0mL	Final concentration
Component	Gram/100.0mL	Final concentration	Sodium bicarbonate	??????0.5g	???0.5％
Salt solution	Add to 100.0mL in right amount	Add to 100% in right amount	Sodium bicarbonate	??????0.5g	???0.5％

Step:

1. the 0.5g sodium bicarbonate is placed the volumetric flask of 100mL.

2. add about 90.0mL salt solution, ultrasonic until its dissolving.

3. add an amount of salt solution to 100.0mL, and thorough mixing.B. preparing concentration is the test compounds solution of 30.0mg/mL: 10.0mL

Component	Gram/10.0mL	Final concentration
Component	Gram/10.0mL	Final concentration	Test compounds	?????0.300g	????30.0mg/mL
0.5% sodium bicarbonate/salt solution storing solution	Add to 100.0mL in right amount	Add to 100% in right amount	Test compounds	?????0.300g	????30.0mg/mL

Step:

1. the 0.300g test compounds is placed the volumetric flask of 10.0mL.

2. add about 9.7mL 0.5% sodium bicarbonate/salt solution storing solution.

3. ultrasonicly dissolve fully until test compounds.

4. add that an amount of 0.5% sodium bicarbonate/the salt solution storing solution is to 10.0mL, and thorough mixing.Adopt conventional oral preparations, The compounds of this invention shows activity in this model.

Claims

1. formula I compound:

R wherein ¹Be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; R ²Be selected from cycloalkenyl group, the heterocyclic radical of cycloalkyl, cycloalkenyl group, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heterocyclic radical, aryl, aryl, the heteroaryl of replacement and the heteroaryl that replaces of replacement, and R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together; R ³Be selected from aryl, the heteroaryl of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, heteroaryl, heterocyclic radical and the heterocyclic radical that replaces, the wherein R of replacement ²And R ³And and R ²Bonded nitrogen-atoms and and R ³The bonded carbon atom can form the unsaturated heterocycle base of unsaturated heterocycle base or replacement together; Ar is the aryl of aryl, heteroaryl, replacement or the heteroaryl of replacement, and x is the integer of 1-4; Q is-C (X) NR ⁷-, R wherein ⁷Be selected from hydrogen and alkyl, and X is selected from oxygen and sulphur; R ⁵Be-CH ₂X, wherein X is selected from hydrogen, hydroxyl, amido, alkyl, alkoxyl group, aryloxy, aryl, the aryloxy aryl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the alkyl that replaces, the alkoxyl group that replaces, the aryl that replaces, the aryloxy that replaces, the aryloxy aryl that replaces, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement

X is the integer of 1-4; B.R ⁵Be not-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be-NR ¹²C (Z ') NR ⁸R ^{8 '}Or-NR ¹²C (Z ') R ¹³, wherein Z ' is selected from oxygen, sulphur and NR ¹², R ¹²Be selected from hydrogen, alkyl and aryl, R ⁸And R ^{8 '}Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement respectively, condition is: when Z ' is oxygen, and R ⁸And R ^{8 '}Have at least one to be alkyl, cycloalkyl, cycloalkyl, the saturated heterocyclyl except that morpholinyl and thio-morpholinyl of replacement or the heterocyclic radical that replaces that replaces, or R ⁸And R ^{8 '}Can be joined together to form the saturated heterocyclyl of saturated heterocyclyl except that morpholinyl or thio-morpholinyl, replacement or have the saturated/unsaturated heterocycle base of the amino of alkoxy carbonyl substituted, another condition is, when Z ' is sulphur, and R ⁸And R ^{8 '}Have at least one not to be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement, R ¹³Be selected from the heterocyclic radical and the saturated heterocyclyl except that morpholinyl or thio-morpholinyl of replacement,

X is the integer of 1-4; C.R⁵Not-ALK-X ' that wherein ALK is by methylene (CH₂-) be connected in the alkyl with 1-10 carbon atom on its carbon atom that connects, X is selected from the alkyl-carbonyl-amino of replacement, the alkenyl carbonyl that replaces is amino, the alkynyl group carbonylamino that replaces, the heterocyclic radical carbonylamino, the heterocyclic radical carbonylamino that replaces, acyl group, acyloxy, amino carbonyl oxygen base, acylamino-, oxygen base carbonylamino, alkoxy carbonyl, the alkoxy carbonyl that replaces, aryloxy carbonyl, the aryloxy carbonyl that replaces, cyclo alkoxy carbonyl, the cyclo alkoxy carbonyl that replaces, the heteroaryloxy carbonyl, the heteroaryloxy carbonyl that replaces, the heterocyclic oxy group carbonyl, the heterocyclic oxy group carbonyl that replaces, cycloalkyl, the cycloalkyl that replaces, saturated heterocyclyl, the saturated heterocyclyl that replaces, the alkoxyl that replaces, the alkenyloxy that replaces, the chain oxy-acetylene that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, the alkylthio group that replaces, the alkenyl thio that replaces, the sulfur-based chain acetylene that replaces, amino carbonyl amino, amino thio-carbonyl-amino, guanidine radicals, amidino groups, alkyl amidine, the sulfo-amidino groups, halogen, cyano group, nitro,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-cycloalkyl ,-OS (O)₂The cycloalkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂-replace heterocyclic radical, wherein R is hydrogen or alkyl-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-cycloalkyl ,-NRS (O)₂The cycloalkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-cycloalkyl ,-NRS (O)₂The cycloalkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂The heterocyclic radical that-NR-replaces ,-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂the heterocyclic radical of-replacement, one (alkyl of replacement) amino, two (alkyl of replacement) amino, N, N-(alkyl, the alkyl of replacement) amino, N, N-(aryl, the alkyl of replacement) amino, N, N-(aryl of replacement, the alkyl of replacement) amino, N, N-(heteroaryl, the alkyl of replacement) amino, N, N-(heteroaryl of replacement, the alkyl of replacement) amino, N, N-(heterocyclic radical, the alkyl of replacement) amino, N, N-(heterocyclic radical of replacement, the alkyl of replacement) amino, one and two (heterocyclic radical) amino, one and two (heterocyclic radical of replacement) amino, N, N-(alkyl, heterocyclic radical) amino, N, N-(alkyl, the heterocyclic radical of replacement) amino, N, N-(aryl, heterocyclic radical) amino, N, N-(aryl of replacement, heterocyclic radical) amino, N, N-(aryl, the heterocyclic radical of replacement) amino, N, N-(aryl of replacement, the heterocyclic radical of replacement) amino, N, N-(heteroaryl, heterocyclic radical) amino, N, N-(heteroaryl, the heterocyclic radical of replacement) amino, N, N-(heteroaryl of replacement, heterocyclic radical) amino, and N, N-(heteroaryl of replacement, the heterocyclic radical of replacement) amino, D.R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be selected from: the alkyl-carbonyl-amino that (a) replaces, condition is: have at least a substituting group to be selected from alkoxyl on the substituted alkyl part, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl; (b) its alkoxyl part be selected from carboxyl and-COOR²³The alkoxy aryl that replaces of substituting group, R wherein²³alkyl, cycloalkyl, aryl, heteroaryl or the heterocyclic radical of alkyl, replacement, (c) aryl and heteroaryl, (d)-NR ' R ', wherein R ' is independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: having a R ' at least is the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical or replacement, another condition is: when R ' was the alkyl that replaces, wherein having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、 -NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (e)-alkoxyl-NR " R ", R wherein " and be independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: as R " each replace naturally alkyl the time, having a substituting group at least on the moieties that replaces is to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (f) aryloxy group that replaces and the heteroaryloxy of replacement, condition is, having a substituting group at least on the aryloxy group/heteroaryloxy that replaces is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (g)-alkoxyl saturated heterocyclyl ,-alkoxyl replace saturated heterocyclyl ,-the alkoxyl heterocyclic radical that replaces and-alkoxyl that replaces replaces saturated heterocyclyl, (h)-O-heterocyclic radical and-the O-substituted heterocyclic radical, (i) tetrazole radical, (j)-NR-SO₂-substituted alkyl, wherein R is hydrogen, alkyl or aryl, condition is: have at least on the moieties of this substituted alkyl sulfuryl amino-individual substituting group is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (k) the alkynyl group sulfuryl amino of the alkenyl sulfuryl amino of alkenyl sulfuryl amino, alkynyl group sulfuryl amino, replacement and replacement, (l) alkoxyl that replaces, condition is: the substituting group on the moieties of described substituted alkoxy does not comprise alkoxyl-NR " R ", the unsaturated heterocycle base, alkoxyl, aryloxy group, heteroaryloxy, aryl, heteroaryl and by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, the aryl/hetaryl that N-dialkyl group urea groups replaces, (m) amidino groups, and by 1-3, be independently selected from the amidino groups that alkynyl group, aryl, heteroaryl and the heterocyclic radical of alkenyl, alkynyl group, the replacement of alkyl, alkenyl, the replacement of alkyl, replacement replace, (n)-C (O) NR R , wherein R is independently selected from respectively hydrogen, alkyl, the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: when one of them R is the unsaturated heterocycle base, aryl, heteroaryl or by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1,2-, two Oxymethylenes, 1,2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, during aryl/hetaryl that N-alkyl urea groups or N, N-dialkyl group urea groups replace, another R is alkyl, the alkyl that replaces (not being the alkyl that the unsaturated heterocycle base replaces), cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, the heterocyclic radical of heterocyclic radical or replacement, (o)-NR²²C(O)-R ¹⁸, R wherein¹⁸Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement, and R²²It is the heterocyclic radical of heteroaryl, heterocyclic radical or replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; (p)-SO₂-aryl ,-SO₂The aryl of-replacement ,-SO₂-heteroaryl ,-SO₂-the heteroaryl that replaces or-SO₂-alkyl; (q)-NR ' C (O) NR¹⁹R ¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be independently selected from respectively the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (r)-NR ' C (O) OR¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (s)-amino carbonyl-(N-formoxyl heterocyclic radical); (t)-alkyl-C (O) NH-heterocyclic radical and-heterocyclic radical that alkyl-C (O) NH-replaces, and E. works as R³While being not H, R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be the alkenyl of replacement or the alkynyl group of replacement, and condition is: partly having a substituting group at least at the alkenyl/alkynyl group that replaces is to be selected from alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: when substituted alkyl replaced, having a substituting group at least on the substituted alkyl part was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl;

And pharmacologically acceptable salt,

And the condition of getting rid of following compound in addition: A. works as R ¹And R ²The SO that is connected separately with them ₂Form benzisothiazole ketone heterocyclic, R together with nitrogen-atoms ³Be hydrogen and Q be-during C (O) NH-, R then ⁵It or not benzyl; Work as R with B. ¹Be p-methylphenyl, R ²Be methyl, R ³Be that hydrogen, Q are-C (O) NCH ₃-time, then R ⁵It or not benzyl.

2. formula IA compound:

X is the integer of 1-4; C.R⁵Not-ALK-X ' that wherein ALK is by methylene (CH₂-) be connected in the alkyl with 1-10 carbon atom on its carbon atom that connects, X ' is selected from the alkyl-carbonyl-amino of replacement, the alkenyl carbonyl that replaces is amino, the alkynyl group carbonylamino that replaces, the heterocyclic radical carbonylamino, the heterocyclic radical carbonylamino that replaces, acyl group, acyloxy, amino carbonyl oxygen base, acylamino-, oxygen base carbonylamino, alkoxy carbonyl, the alkoxy carbonyl that replaces, aryloxy carbonyl, the aryloxy carbonyl that replaces, cyclo alkoxy carbonyl, the cyclo alkoxy carbonyl that replaces, the heteroaryloxy carbonyl, the heteroaryloxy carbonyl that replaces, the heterocyclic oxy group carbonyl, the heterocyclic oxy group carbonyl that replaces, cycloalkyl, the cycloalkyl that replaces, saturated heterocyclyl, the saturated heterocyclyl that replaces, the alkoxyl that replaces, the alkenyloxy that replaces, the chain oxy-acetylene that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, the alkylthio group that replaces, the alkenyl thio that replaces, the sulfur-based chain acetylene that replaces, amino carbonyl amino, amino thio-carbonyl-amino, guanidine radicals, amidino groups, alkyl amidine, the sulfo-amidino groups, halogen, cyano group, nitro,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-cycloalkyl ,-OS (O)₂The cycloalkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂-replace heterocyclic radical, wherein R is hydrogen or alkyl-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-cycloalkyl ,-NRS (O)₂The cycloalkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-cycloalkyl ,-NRS (O)₂The cycloalkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂The heterocyclic radical that-NR-replaces ,-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂the heterocyclic radical of-replacement, one (alkyl of replacement) amino, two (alkyl of replacement) amino, N, N-(alkyl, the alkyl of replacement) amino, N, N-(aryl, the alkyl of replacement) amino, N, N-(aryl of replacement, the alkyl of replacement) amino, N, N-(heteroaryl, the alkyl of replacement) amino, N, N-(heteroaryl of replacement, the alkyl of replacement) amino, N, N-(heterocyclic radical, the alkyl of replacement) amino, N, N-(heterocyclic radical of replacement, the alkyl of replacement) amino, one and two (heterocyclic radical) amino, one and two (heterocyclic radical of replacement) amino, N, N-(alkyl, heterocyclic radical) amino, N, N-(alkyl, the heterocyclic radical of replacement) amino, N, N-(aryl, heterocyclic radical) amino, N, N-(aryl of replacement, heterocyclic radical) amino, N, N-(aryl, the heterocyclic radical of replacement) amino, N, N-(aryl of replacement, the heterocyclic radical of replacement) amino, N, N-(heteroaryl, heterocyclic radical) amino, N, N-(heteroaryl, the heterocyclic radical of replacement) amino, N, N-(heteroaryl of replacement, heterocyclic radical) amino, and N, N-(heteroaryl of replacement, the heterocyclic radical of replacement) amino, D.R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be selected from: the alkyl-carbonyl-amino that (a) replaces, condition is: have at least a substituting group to be selected from alkoxyl on the substituted alkyl part, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl; (b) its alkoxyl part be selected from carboxyl and-COOR²³The alkoxy aryl that replaces of substituting group, R wherein²³alkyl, cycloalkyl, aryl, heteroaryl or the heterocyclic radical of alkyl, replacement, (c) aryl and heteroaryl, (d)-NR ' R ', wherein R ' is independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: having a R ' at least is the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical or replacement, another condition is: when R ' was the alkyl that replaces, wherein having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、 -NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (e)-alkoxyl-NR " R ", R wherein " and be independently selected from respectively alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: as R " each replace naturally alkyl the time, wherein having a substituting group at least on the moieties that replaces is to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, substituted alkyl with amino of having been protected by commonly used blocking group, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl, (f) aryloxy group that replaces and the heteroaryloxy of replacement, condition is, having a substituting group at least on the aryloxy group/heteroaryloxy that replaces is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (g)-alkoxyl saturated heterocyclyl ,-alkoxyl replace saturated heterocyclyl ,-the alkoxyl heterocyclic radical that replaces and-alkoxyl that replaces replaces saturated heterocyclyl, (h)-O-heterocyclic radical and-the O-substituted heterocyclic radical, (i) tetrazole radical, (j)-NR-SO₂-substituted alkyl, wherein R is hydrogen, alkyl or aryl, condition is: having a substituting group on the moieties of this substituted alkyl sulfuryl amino at least is not halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, N-dialkyl group urea groups, (k) the alkynyl group sulfuryl amino of the alkenyl sulfuryl amino of alkenyl sulfuryl amino, alkynyl group sulfuryl amino, replacement and replacement, (l) alkoxyl that replaces, condition is: the substituting group on the moieties of described substituted alkoxy does not comprise alkoxyl-NR " R ", the unsaturated heterocycle base, alkoxyl, aryloxy group, heteroaryloxy, aryl, heteroaryl and by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1, 2-two Oxymethylenes, 1, 2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, N-alkyl urea groups or N, the aryl/hetaryl that N-dialkyl group urea groups replaces, (m) amidino groups, and by 1-3, be independently selected from the amidino groups that alkynyl group, aryl, heteroaryl and the heterocyclic radical of alkenyl, alkynyl group, the replacement of alkyl, alkenyl, the replacement of alkyl, replacement replace, (n)-C (O) NR R , wherein R is independently selected from respectively hydrogen, alkyl, the alkyl that replaces, cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement, condition is: when one of them R is the unsaturated heterocycle base, aryl, heteroaryl or by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl group, 1,2-, two Oxymethylenes, 1,2-dioxy ethylidene, alkoxyl, alkenyloxy, chain oxy-acetylene, alkyl amino, alkenyl amino, chain alkynyl amino, the alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amino, alkyl sulfonyl-amino, during aryl/hetaryl that N-alkyl urea groups or N, N-dialkyl group urea groups replace, another R is alkyl, the alkyl that replaces (not being the alkyl that the unsaturated heterocycle base replaces), cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl group, the alkynyl group that replaces, the heterocyclic radical of heterocyclic radical or replacement, (o)-NR²²C(O)-R ¹⁸, R wherein¹⁸Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement, and R²²It is the heterocyclic radical of heteroaryl, heterocyclic radical or replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement; (p)-SO₂-aryl ,-SO₂The aryl of-replacement ,-SO₂-heteroaryl ,-SO₂-the heteroaryl that replaces or-SO₂-alkyl; (q)-NR ' C (O) NR¹⁹R ¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be independently selected from respectively the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (r)-NR ' C (O) OR¹⁹, wherein R ' is selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkyl, heteroaryl, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, the replacement of alkyl, replacement, and R¹⁹Be selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement; (s)-amino carbonyl-(N-formoxyl heterocyclic radical); (t)-alkyl-C (O) NH-heterocyclic radical and-heterocyclic radical that alkyl-C (O) NH-replaces, and E. works as R³While being not H, R⁵Be not-(CH₂) _x-Ar-R ^5”, R wherein^5”be the alkenyl of replacement or the alkynyl group of replacement, and condition is: partly having a substituting group at least at the alkenyl/alkynyl group that replaces is to be selected from alkyl, the alkyl that replaces, aryl, the aryl that replaces, cycloalkyl, the cycloalkyl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, with the heterocyclic radical that replaces, condition is: when substituted alkyl replaced, having a substituting group at least on the moieties that replaces was to be selected from alkoxyl, the alkoxyl that replaces, acyl group, acylamino-, thio-carbonyl-amino, acyloxy, alkenyl, amino, amidino groups, alkyl amidine, the sulfo-amidino groups, aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino, amino carbonyl oxygen base, aryloxy group, the aryloxy group that replaces, cyano group, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, the carboxyl substituted alkyl, the carboxyl cycloalkyl, the carboxyl substituted cycloalkyl, the carboxyl aryl, the carboxyl substituted aryl, the carboxyl heteroaryl, the carboxyl substituted heteroaryl, the carboxyl heterocyclic radical, the carboxyl substituted heterocyclic radical, cycloalkyl, the cycloalkyl that replaces, guanidine radicals, the sulfonyl guanidine radicals, the thiol base, alkylthio group, the alkylthio group that replaces, arylthio, the arylthio that replaces, cycloalkylthio, the cycloalkylthio that replaces, heteroarylthio, the heteroarylthio that replaces, the heterocycle sulfenyl, the heterocycle sulfenyl that replaces, heterocyclic radical, the heterocyclic radical that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocyclic oxy group, the heterocyclic oxy group that replaces, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O)₂-alkyl ,-OS (O)₂The alkyl of-replacement ,-OS (O)₂-aryl ,-OS (O)₂The aryl of-replacement ,-OS (O)₂-heteroaryl ,-OS (O)₂The heteroaryl of-replacement ,-OS (O)₂-heterocyclic radical ,-OS (O)₂The heterocyclic radical of-replacement ,-OS (O)₂-NRR、-NRS(O) ₂-alkyl ,-NRS (O)₂The alkyl of-replacement ,-NRS (O)₂-aryl ,-NRS (O)₂The aryl of-replacement ,-NRS (O)₂-heteroaryl ,-NRS (O)₂The heteroaryl of-replacement ,-NRS (O)₂-heterocyclic radical ,-NRS (O)₂The heterocyclic radical of-replacement ,-NRS (O)₂-NR-alkyl ,-NRS (O)₂The alkyl that-NR-replaces ,-NRS (O)₂-NR-aryl ,-NRS (O)₂The aryl that-NR-replaces ,-NRS (O)₂-NR-heteroaryl ,-NRS (O)₂The heteroaryl that-NR-replaces ,-NRS (O)₂-NR-heterocyclic radical ,-NRS (O)₂the heterocyclic radical that-NR-replaces, one alkyl amino, dialkyl amido, one (alkyl of replacement) amino, two (alkyl of replacement) amino, one arylamino, ammonia diaryl base, one (aryl of replacement) amino, two (aryl of replacement) amino, one heteroaryl amino, two heteroaryl aminos, one (heteroaryl of replacement) amino, two (heteroaryl of replacement) amino, one heterocyclic radical is amino, two heterocyclic radicals are amino, one (heterocyclic radical of replacement) amino, two (heterocyclic radical of replacement) amino, has the alkyl of being selected from, the alkyl that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the asymmetric disubstituted amido of the different substituents of the heterocyclic radical that replaces, have by blocking group commonly used (Boc for example, Cbz, the substituted alkyl of the amino of formoxyl etc.) having protected, and quilt-S (O)₂-alkyl ,-S (O)₂The alkyl of-replacement ,-S (O)₂-alkenyl ,-S (O)₂The alkenyl of-replacement ,-S (O)₂-cycloalkyl ,-S (O)₂The cycloalkyl of-replacement ,-S (O)₂-aryl ,-S (O)₂The aryl of-replacement ,-S (O)₂-heteroaryl ,-S (O)₂The heteroaryl of-replacement ,-S (O)₂-heterocyclic radical ,-S (O)₂-the heterocyclic radical that replaces or-S (O)₂Alkyl/substituted alkyl that NRR replaces, wherein R is hydrogen or alkyl;

And pharmacologically acceptable salt,

Condition is: A. works as R ¹Be adjacent carboxymethyl phenyl, R ²Be hydrogen, R ³Be hydrogen or methyl, R ⁵Be benzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; B. work as R ¹And R ²Form benzisothiazole ketone heterocyclic, R together ³Be hydrogen or methyl, R ⁵Be benzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; C. work as R ¹Be p-methylphenyl, R ²Be hydrogen, R ⁵Be benzyl or p-hydroxybenzene, R ³Be-(CH ₂) _sC (O) the O-tertiary butyl, wherein s is 1 or 2, and Q be-during C (O) NH-, R then ⁶Be not-the O-tertiary butyl; D. work as R ¹Be p-methylphenyl, R ²Be methyl, R ⁵Be benzyl, R ³Be-CH (φ) ₂, and Q be-during C (O) NH-, R then ⁶Be not-the O-benzyl; E. work as R ¹Be p-methylphenyl, R ²Be methyl, R ⁵Be methyl, R ³Be-hydroxymethyl and Q be-during C (O) NH-, R then ⁶Be not-the O-methyl; Work as R with F. ¹Be p-methylphenyl, R ²Be methyl, R ³Be the methyl or the tertiary butyl, R ⁵Be to hydroxybenzyl and Q be-during C (O) NH-, R then ⁶Be not-the O-tertiary butyl.

3. claim 1 or 2 compound, wherein R ¹Be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of alkyl, aryl, the replacement of alkyl, replacement.

4. claim 1 or 2 compound, wherein R ¹Be selected from 4-aminomethyl phenyl, methyl, benzyl, normal-butyl, 4-chloro-phenyl-, 1-naphthyl, 2-naphthyl, 4-p-methoxy-phenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl) phenyl, 2-carboxyl phenyl, 3,5-dichlorophenyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 3,4-Dimethoxyphenyl, 4-(CH ₃C (O) NH) phenyl, 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, sec.-propyl, 3,5-two (trifluoromethyl) phenyl, 4-tert-butyl-phenyl, 4-tert.-butoxy phenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloro pyrazoles-4-base, styroyl, 1-N-Methylimidazole-4-base, 4-bromophenyl, 4-amidino groups phenyl, 4-methyl amidino groups phenyl, 4-[CH ₃C (=NH)] phenyl, 5-chloro-2-thienyl, 2,5-two chloro-4-thienyls, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 4-[H ₂NC (S)] phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidine-2-base, 4-(3 '-dimethylamino positive propoxy) phenyl and 1-methyl-pyrazol-4-yl.

5. claim 1 or 2 compound, wherein R ²Be selected from hydrogen, methyl, phenyl, benzyl ,-(CH ₂) ₂-2-thienyl and-(CH ₂) ₂-φ.

6. claim 1 or 2 compound, wherein R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together.

7. claim 1 or 2 compound, wherein R ³Be selected from methyl, phenyl, benzyl, diphenyl methyl ,-CH ₂CH ₂COOH ,-CH ₂COOH, 2-amido ethyl, isobutyl-, the tertiary butyl ,-CH ₂O-benzyl and methylol.

8. claim 1 or 2 compound, wherein R ²And R ³And and R ²Bonded nitrogen-atoms and and R ³The bonded carbon atom can form the unsaturated heterocycle base of unsaturated heterocycle base or replacement together.

9. claim 1 or 2 compound, wherein Q be-C (O) NH-or-C (S) NH-.

10. claim 1 or 2 compound, wherein R ⁵Be selected from benzyl, (N-benzyl imidazole-4-yl) methyl, (pyridine-2-yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, 4-[2-(pyridine-2-yl) ethynyl] benzyl, 4-[2-(3-hydroxy phenyl) ethynyl] benzyl, 4-iodine benzyl, 4-cyano group benzyl, 4-(2-bromobenzene formamido group) benzyl, 4-(pyridin-4-yl-C (O) NH-) benzyl and 4-hydroxybenzyl.

11. the compound of claim 1 or 2, wherein R ⁶Be selected from 2,4-dioxo tetrahydrofuran (THF)-3-base (3, the 4-enol), methoxyl group, oxyethyl group, isopropoxy, n-butoxy, tert.-butoxy, cyclopentyloxy, neopentyl oxygen, 2-α-sec.-propyl-4-Beta-methyl cyclohexyloxy, 2-β-sec.-propyl-4-Beta-methyl cyclohexyloxy ,-NH ₂, benzyloxy ,-NHCH ₂COOH ,-NHCH ₂CH ₂COOH ,-the NH-adamantyl ,-NHCH ₂CH ₂COOCH ₂CH ₃,-NHSO ₂-right-CH ₃-φ, R wherein ⁸Be hydrogen, methyl, sec.-propyl or benzyl-NHOR ⁸, O-(N-succinimido) ,-O-courage steroid-5-alkene-3-beta-yl ,-OCH ₂-OC (O) C (CH ₃) ₃, wherein z be 1 or 2 and W be selected from pyridin-3-yl, N-picolyl and N-methyl isophthalic acid, 4-dihydropyridine-3-base-O (CH ₂) _zNHC (O) W ,-NR " C (O)-R ', wherein R ' is aryl, heteroaryl or heterocyclic radical, and R " be hydrogen or-CH ₂C (O) OCH ₂CH ₃

12. be selected from the compound of following compound: N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl) glycyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-phenyl alanyl-D; L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(3-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(4-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-L-β-(2-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl)-D; L-phenyl sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-aspartyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(pyridine-2-yl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(3-hydroxy phenyl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-iodophenylalanine N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-cyano group phenylalanine N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycyl-L-phenylalanine N-(saccharin-2-yl)-D, L-alanyl-L-4-(different nicotinoyl amino) phenylalanine methyl ester

13. in biological specimen,, comprise biological specimen can be contacted under the condition in conjunction with VLA-4 at described compound with the compound of claim 1 or 2 in conjunction with the method for VLA-4.

14. the method for claim 13, wherein R ¹Be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of alkyl, aryl, the replacement of alkyl, replacement.

15. the method for claim 13, wherein R ¹Be selected from 4-aminomethyl phenyl, methyl, benzyl, normal-butyl, 4-chloro-phenyl-, 1-naphthyl, 2-naphthyl, 4-p-methoxy-phenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl) phenyl, 2-carboxyl phenyl, 3,5-dichlorophenyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 3,4-Dimethoxyphenyl, 4-(CH ₃C (O) NH) phenyl, 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, sec.-propyl, 3,5-two (trifluoromethyl) phenyl, 4-tert-butyl-phenyl, 4-tert.-butoxy phenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloro pyrazoles-4-base, styroyl, 1-N-Methylimidazole-4-base, 4-bromophenyl, 4-amidino groups phenyl, 4-methyl amidino groups phenyl, 4-[CH ₃C (=NH)] phenyl, 5-chloro-2-thienyl, 2,5-two chloro-4-thienyls, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 4-[H ₂NC (S)] phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidine-2-base, 4-(3 '-dimethylamino positive propoxy) phenyl and 1-methyl-pyrazol-4-yl.

16. the method for claim 13, wherein R ²Be selected from hydrogen, methyl, phenyl, benzyl ,-(CH ₂) ₂-2-thienyl and-(CH ₂) ₂-φ.

17. the method for claim 13, wherein R ¹And R ²And and R ²Bonded nitrogen-atoms and and R ¹Bonded SO ₂Base can form the heterocyclic radical of heterocyclic radical or replacement together.

18. the method for claim 13, wherein R ³Be selected from methyl, phenyl, benzyl, diphenyl methyl ,-CH ₂CH ₂COOH ,-CH ₂COOH, 2-amido ethyl, isobutyl-, the tertiary butyl ,-CH ₂O-benzyl and methylol.

19. the method for claim 13, wherein R ²And R ³And and R ²Bonded nitrogen-atoms and and R ³The bonded carbon atom can form the unsaturated heterocycle base of unsaturated heterocycle base or replacement together.

20. the method for claim 13, wherein Q be-C (O) NH-or-C (S) NH-.

21. the method for claim 13, wherein R ⁵Be selected from benzyl, (N-benzyl imidazole-4-yl) methyl, (pyridine-2-yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, 4-[2-(pyridine-2-yl) ethynyl] benzyl, 4-[2-(3-hydroxy phenyl) ethynyl] benzyl, 4-iodine benzyl, 4-cyano group benzyl, 4-(2-bromobenzene formamido group) benzyl, 4-(pyridin-4-yl-C (O) NH-) benzyl and 4-hydroxybenzyl.

22. the method for claim 13, wherein R ⁶Be selected from 2,4-dioxo tetrahydrofuran (THF)-3-base (3, the 4-enol), methoxyl group, oxyethyl group, isopropoxy, n-butoxy, tert.-butoxy, cyclopentyloxy, neopentyl oxygen, 2-α-sec.-propyl-4-Beta-methyl cyclohexyloxy, 2-β-sec.-propyl-4-Beta-methyl cyclohexyloxy ,-NH ₂, benzyloxy ,-NHCH ₂COOH ,-NHCH ₂CH ₂COOH ,-the NH-adamantyl ,-NHCH ₂CH ₂COOCH ₂CH ₃,-NHSO ₂-right-CH ₃-φ, R wherein ⁸Be hydrogen, methyl, sec.-propyl or benzyl-NHOR ⁸, O-(N-succinimido) ,-O-courage steroid-5-alkene-3-beta-yl ,-OCH ₂-OC (O) C (CH ₃) ₃, wherein z be 1 or 2 and W be selected from pyridin-3-yl, N-picolyl and N-methyl isophthalic acid, 4-dihydropyridine-3-base-O (CH ₂) _zNHC (O) W ,-NR " C (O)-R ', wherein R ' is aryl, heteroaryl or heterocyclic radical, and R " be hydrogen or-CH ₂C (O) OCH ₂CH ₃

23. the method for claim 13; wherein said compound is selected from following compound: N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine N-(toluene-4-alkylsulfonyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl) glycyl-L-phenylalanine N-(2-methoxycarbonyl benzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-phenyl alanyl-D; L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-diphenylprop aminoacyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(3-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-β-(4-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl) sarcosyl-L-β-(2-pyridyl) L-Ala N-(toluene-4-alkylsulfonyl)-D; L-phenyl sarcosyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-L-aspartyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-(2S-1; 2; 3; 4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-(2S-indoline-2-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-L-alanyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl)-L-diphenylprop aminoacyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-phenyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine ethyl ester N-(toluene-4-alkylsulfonyl) sarcosyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-methyl D; L-phenyl glycyl-L-phenylalanine benzyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-benzyl glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(pyridine-2-yl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-4-[2-(3-hydroxy phenyl) ethynyl]-D; L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-iodophenylalanine N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine methyl ester N-(toluene-4-alkylsulfonyl)-N-(2-thienyl ethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-(N-benzyl) Histidine methyl esters N-(toluene-4-alkylsulfonyl)-N-(2-phenylethyl) glycyl-L-phenylalanine N-(toluene-4-alkylsulfonyl) sarcosyl-D; L-4-cyano group phenylalanine N-(toluene-4-alkylsulfonyl)-L-tertiary butyl glycyl-L-phenylalanine N-(saccharin-2-yl)-D, L-alanyl-L-4-(different nicotinoyl amino) phenylalanine methyl ester

24. pharmaceutical composition wherein contains pharmaceutically acceptable carrier and one or more claims 1 of treatment significant quantity or 2 compound.

25. treatment is by the method for the inflammation of VLA-4 mediation in mammalian subject, described method comprises that pharmaceutical composition with the claim 24 of treatment significant quantity is to described patient's administration.

26. according to the method for claim 25, wherein said inflammation is selected from asthma, Alzheimer's, atherosclerosis, the AIDS dementia, diabetes (comprising acute teenager's disease type diabetes), inflammatory bowel (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, encephalitis, apoplexy, with other cerebral trauma, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung that the injury of lung of myocardial ischemia and the mediation of acute white corpuscle for example takes place in adult respiratory distress syndrome.