CN1133648C

CN1133648C - Subtsituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4

Info

Publication number: CN1133648C
Application number: CNB988077531A
Authority: CN
Inventors: Ed; E·D·索尔塞特; ��ķ��; C·M·塞姆科; D·萨兰塔基斯; M·A·普雷斯; ¡; L·J·隆巴尔多; A·克雷夫特; A·W·康拉迪; F·S·格兰特; ��ɭ; D·B·德雷森; ն�; M·S·达普恩; R·B·鲍迪; ά; S·阿什维尔
Original assignee: Wyeth LLC; Elan Pharmaceuticals LLC
Current assignee: Wyeth LLC; Elan Pharmaceuticals LLC
Priority date: 1997-07-31
Filing date: 1998-07-30
Publication date: 2004-01-07
Anticipated expiration: 2018-07-30
Also published as: CN1265668A; NO20000450D0; KR20010022411A; AR013384A1; PL338423A1; NO20000450L; HUP0004259A3; BR9812114A; AU8661198A; EP1001972A1; JP2001512134A; WO1999006431A1; NZ502582A; HUP0004259A2; TW534910B; ZA986827B; IL133640A0; CA2290747A1; AU756696B2

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 are also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

The phenylalanine type compound of the replacement of the leukocyte adhesion of inhibition VLA-4 mediation

Related application mutual with reference to clauses and subclauses

The application requires U.S. Provisional Application No.60/,, interests, its according to 37C.F.R. ξ 1.53 (c) (2) (i) from the U.S. Patent application No.08/920394 conversion of on July 31st, 1997 application.

Invention field

The present invention relates to suppress leukocyte adhesion, particularly the compound of the leukocyte adhesion of VLA-4 mediation.

Reference

Publication below above footnote has been quoted among the application, patent and patent application:

¹Hemler and Takada, the open No.330 of Europe patent application, on August 30th, 506,1989 is open

²Elices etc., cell (Cell), 60: 577-584 (1990)

³Springer, nature (Nature), 346: 425-434 (1990)

⁴Osborn etc., cell (Cell), 62: 3-6 (1990)

⁵Vedder etc., surgery (Surgery), 106: 509 (1989)

⁶Pretolani etc., experiment pharmaceutical journal (J.Exp.Med.), 180: 795 (1994)

⁷Abraham etc., Journal of Clinical Investigation (J.Clin.Invest.), 93: 776 (1994)

⁸Mulligan etc., Journal of Immunology (J.Immunology), 150: 2407 (1993)

⁹Cybulsky etc., science (Science), 251: 788 (1991)

¹⁰Li etc., arteriosclerosis, thrombus (Arterioslcer.Thromb.), 13: 197 (1993)

¹¹Sasseville etc., American Journal of Pathology Am.J.Path., 144: 27 (1994)

¹²Yang etc., Proceedings of the National Academy of Sciences (Proc.Nat.Acad.Science) (USA), 90: 10494 (1993)

¹³Burkly etc., diabetes (Diabetes), 43: 529 (1994)

¹⁴Baron etc., Journal of Clinical Investigation (J.Clin.Invest.), 93: 1700 (1994)

¹⁵Hamann etc., Journal of Immunology (J.Immunology), 152: 3238 (1994)

¹⁶Yednock etc., nature (Nature), 356: 63 (1992)

¹⁷Baron etc., experiment pharmaceutical journal (J.Exp.Med.), 177: 57 (1993)

¹⁸Van Dinther-Janssen etc., Journal of Immunology (J.Immunology), 147: 4207 (1991)

¹⁹Van Dinther-Janssen etc., rheumatosis annual Annals.Rheumatic Dis., 52: 672 (1993)

²⁰Elices etc., Journal of Clinical Investigation (J.Clin.Invest.), 93: 405 (1994)

²¹Postigo etc., Journal of Clinical Investigation (J.Clin.Invest.), 89: 1445 (1991)

²²Paul etc. transplant record compilation (Transpl.Proceed.), 25: 813 (1993)

²³Okarhara etc., cancer research (Can.Res.), 54: 3233 (1994)

²⁴Paavonen etc., international journal of cancer (Int.J.Can.), 58: 298 (1994)

²⁵Schadendorf etc., pathology magazine J.Path., 170: 429 (1993)

²⁶Bao etc., Diff., 52: 239 (1993)

²⁷Lauri etc., Britain's cancer magazine (British J.Cancer), 68: 862 (1993)

²⁸Kawaguchi etc., Japanese cancer research magazine (Japanese J.Cancer Res.), 83: 1304 (1992)

²⁹Kogan etc., U.S. patent No.5 announced on April 23rd, 510,332,1996

³⁰The open No.WO96/01644 of international patent application

All above-mentioned these publications, patent and patent application are incorporated by reference here in full, its degree just and each publication, patent and patent application particularly with each to indicate its hereby incorporated by reference the same.

The statement of prior art

VLA-4 (also being referred to as α 4 beta 1 integrins and CD49d/CD29) is at first by Hemler and Takada ¹Be accredited as a member in the cell surface receptor beta 1 integrin family, it contains two subunits separately, a α chain and a β chain.VLA-4 comprises α 4 chains and β 1 chain.Have 9 beta 1 integrins at least, all these 9 beta 1 integrins are shared identical β 1 chain and are had unique α chain separately.These 9 acceptors are all in conjunction with the different complement of various cell matrix molecules, for example fibronectin, ln and collagen protein.For example, VLA-4 is in conjunction with fibronectin.VLA-4 is also in conjunction with the non-substrate molecule of endotheliocyte and other cell expressing.These non-substrate molecules comprise VCAM-1, and it is expressed on cytokine-activated human umbilical vein epithelial cell in culture.The different epi-position of VLA-4 is determining fibronectin and VCAM-1 in conjunction with activity, and each activity shows and suppressed independently ²

The intercellular adhesion of VLA-4 and other cell surface receptor mediation is relevant with a lot of inflammatory reactions.In the site of damage and other inflammatory stimulus, it is adhering molecule that activated blood vessel epithelial cell is expressed for white corpuscle.The epithelial mechanism of leukocyte adhesion partly relates to identification and the combination for corresponding cell surface molecule on the epithelial cell of cell surface receptor on the white corpuscle.Vessel wall entered injured site and discharged chemical mediator and resisted infection in case combination, white corpuscle are just divided a word with a hyphen at the end of a line.About immune adhesion receptor, referring to, for example, Springer ³And Osborn ⁴

Struvite disease of brain, for example experimental autoimmunization encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis are that wherein endothelium/leukocyte adhesion mechanism causes the example to the central nervous system disorder of healthy brain tissue impairment.A large amount of leucocyte migrations are crossed blood-brain-barrier (BBB) in suffering from the patient of these inflammatory diseases.White corpuscle discharges the toxicity medium, causes tissue injury widely, causes nerve conduction and the paralysis damaged.

In other tract, tissue injury is also by causing leucocyte migration or activated adhesive mechanism to take place.For example, the initial injury to heart tissue causes further injury and more complicated (Vedder etc. owing to white corpuscle enters injured tissue behind the discovery myocardial ischemia ⁵).Other inflammatory disease of adhesive mechanism mediation for example comprises asthma ^6-8, presenile dementia, atherosclerosis ^9-10, aids dementia ¹¹, diabetes ^12-14(comprising the diabetes that acute teenager is taken place), enteritis ¹⁵(comprising ulcerative colitis and Crohn disease), multiple sclerosis ^16-17, rheumatoid arthritis ^18-21, tissue transplantation ²², metastases ^23-28, meningitis, brain inflammation, apoplexy and other brain injury, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung of myocardial ischemia and the mediation of acute white corpuscle, for example injury of lung that is taken place in grownup's respiratory distress syndrome.

Find out that from above measuring the test example that contains VLA-4 level in the VLA-4 biological material is useful as the disease for diagnosis VLA-4 mediation.In addition, although the understanding of leukocyte adhesion is had these progress, this area just just relates to the application of adhesion inhibitors in encephalitis and other inflammatory disease recently ^29,30The present invention satisfies these and other needs.

Summary of the invention

The invention provides compound in conjunction with VLA-4.Such compound can be used for VLA-4 in the test samples for example existence and in pharmaceutical composition, make the cell adhesion that is used for suppressing the VLA-4 mediation, for example VCAM-1 and VLA-4's combines.Compound of the present invention has the binding affinity for VLA-4, with IC ₅₀Expression is about 15 μ M or littler (measuring according to the following examples 136), and wherein compound defines by following formula I:

Wherein

R ¹Be selected from alkyl, the alkyl of replacement, aryl, the aryl of replacement, cycloalkyl, the cycloalkyl of replacement, heterocyclic radical, the heterocyclic radical of replacement, the heteroaryl of heteroaryl and replacement;

R ²Be selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group, the cycloalkenyl group of replacement, heterocyclic radical, the heterocyclic radical of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, and R ¹And R ²With bonding R ²Nitrogen-atoms and bonding R ¹SO ₂Group can form the heterocyclic radical of heterocyclic radical or replacement together;

R ³Be selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocyclic radical, the heterocyclic radical of replacement and work as R ²Not with R ¹When forming heterocyclic radical, R ²And R ³With bonding R ²Nitrogen-atoms and bonding R ³Carbon atom can form the heterocyclic radical of heterocyclic radical or replacement together;

R ⁵Be-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be selected from

(a) alkyl-carbonyl-amino of Qu Daiing, prerequisite be on the substituted moieties substituting group at least one be selected from alkoxyl group, the alkoxyl group of replacement; acyl group, acyl amino, thio-carbonyl-amino; acyloxy, alkenyl, amino; amidino groups, alkyl amidine, sulfo-amidino groups; aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino; aminocarboxyl oxygen base, aryloxy, the aryloxy of replacement; cyano group, halogen, hydroxyl; nitro, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; cycloalkyl, the cycloalkyl of replacement, guanidine radicals; the guanidine radicals sulfone, mercaptan, alkylthio; the alkylthio that replaces, thioaryl, the thioaryl of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces, sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces, heteroaryl oxygen base, the heteroaryl oxygen base of replacement; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and described substituted radical is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the substituted alkyl of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(b) alkoxyl group part be selected from carboxyl and wherein R be alkyl, the alkyl of replacement, cycloalkyl, aryl, heteroaryl and heterocyclic radical-alkoxy aryl of the substituting group replacement of COOR;

(c) aryl and heteroaryl;

(d)-and NR ' R ', wherein each R ' is independently selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, cycloalkyl, the cycloalkyl of replacement; the heterocyclic radical of heterocyclic radical and replacement, condition are that at least one R ' is substituted alkyl, cycloalkyl; the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, further prerequisite is when R ' is the alkyl that replaces; at least one substituting group is selected from alkoxyl group on the substituted moieties, the alkoxyl group of replacement, acyl group; acyl amino, thio-carbonyl-amino, acyloxy; the key thiazolinyl, amino, amidino groups; alkyl amidine, sulfo-amidino groups, aminoacyl; amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base; aryloxy, the aryloxy of replacement, cyano group; halogen, hydroxyl, nitro; carboxyl, carboxyalkyl, the alkyl of carboxyl substituted; the carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted, carboxyl aryl; the aryl of carboxyl substituted, carboxyl heteroaryl, the heteroaryl of carboxyl substituted; the carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted, cycloalkyl; the cycloalkyl that replaces, guanidine radicals, guanidine radicals sulfone; mercaptan, alkylthio, the alkylthio of replacement; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces, thio ceteroary, the thio ceteroary of replacement; the sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino; dialkyl amido, one-and two-(alkyl of replacement) amino, one-and two-arylamino; one-and the two-arylamino that replaces; one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces, one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces; the described substituted radical of asymmetric two replacement amine with different substituents is selected from alkyl, the alkyl of replacement, aryl; the aryl that replaces; heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement; with have with GPF (General Protection False group Boc for example; Cbz, the alkyl of the replacement of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(e)-and alkoxyl group-NR " R ", each R wherein " be independently selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement; the heterocyclic radical of heterocyclic radical and replacement, prerequisite are as R " when being the alkyl that replaces, at least one is selected from alkoxyl group the substituting group on the substituted moieties; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkenyl; amino, amidino groups, alkyl amidine; the sulfo-amidino groups, aminoacyl, amino carbonyl amino; amino thio-carbonyl-amino, aminocarboxyl oxygen base, aryloxy; the aryloxy that replaces, cyano group, halogen; hydroxyl, nitro, carboxyl; carboxyalkyl, the alkyl of carboxyl substituted, carboxyl cycloalkyl; the cycloalkyl of carboxyl substituted, carboxyl aryl, the aryl of carboxyl substituted; the carboxyl heteroaryl, the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical; the heterocyclic radical of carboxyl substituted, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, mercaptan; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces; the sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and substituted radical wherein is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the substituted alkyl of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(f) substituted alkenyl or substituted alkynes base, prerequisite be on substituted alkenyl/alkynes base section substituting group at least one be selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, cycloalkyl; the cycloalkyl that replaces, heteroaryl, the heteroaryl of replacement; the heterocyclic radical of heterocyclic radical and replacement, prerequisite are that at least one is selected from alkoxyl group the substituting group on the moieties of this replacement when substituted alkyl replaces; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkenyl amino; amidino groups, alkyl amidine, sulfo-amidino groups; aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino; aminocarboxyl oxygen base, aryloxy, the aryloxy of replacement; cyano group, halogen, hydroxyl; nitro, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; cycloalkyl, the cycloalkyl of replacement, guanidine radicals; the guanidine radicals sulfone, mercaptan, alkylthio; the alkylthio that replaces; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces; thio ceteroary, the thio ceteroary of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and described substituted radical is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the alkyl of the replacement of the amino of protection such as formyl radical, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(g) the heteroaryl oxygen base of aryloxy of Qu Daiing and replacement, prerequisite are that at least one substituting group is not a halogen on substituted aryloxy/heteroaryl oxygen base, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, the alkynes base, 1,2-dioxy base alkylidene group, 1,2-dioxy base ethylidene, alkoxyl group, alkene oxygen base, alkynyloxy group, alkylamino, alkenyl amino, alkynes base amino, alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amido, alkyl sulfonyl-amino, N-alkyl or N, the N-dialkyl ureas;

(h)-alkoxyl group-saturated heterocyclic radical, the heterocyclic radical of-alkoxyl group-saturated-replacement ,-alkoxyl group-heterocyclic radical of replacing and-saturated heterocyclyl of alkoxyl group-replacement of replacing;

(i)-the O-heterocyclic radical and-heterocyclic radical that O-replaces;

(j) tetrazyl;

(k)-NR-SO ₂The alkyl of-replacement, wherein R is a hydrogen, alkyl or aryl, prerequisite is that at least one substituting group is not a halogen on the moieties of substituted alkyl sulfonyl-amino, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynes base, 1,2-dioxy methylene, 1,2-dioxy base ethylidene, alkoxyl group, alkene oxygen base, alkynyloxy group, alkylamino, alkenyl amino, alkynes base amino, alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amido, alkyl sulfonyl-amino, N-alkyl or N, the N-dialkyl ureas;

(1) alkenyl sulfuryl amino, alkynes base sulfuryl amino, the alkynes base sulfuryl amino of the alkenyl sulfuryl amino of replacement and replacement;

(m) alkoxyl group of Qu Daiing, prerequisite are that the substituting group on the moieties of alkoxyl group of described replacement does not comprise alkoxyl group-NR " R ", undersaturated heterocyclic radical, alkyl oxy, aryloxy, heteroaryl oxygen base, aryl, heteroaryl and by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, the alkynes base, 1,2-dioxy methylene, 1,2-dioxy base ethylidene, alkoxyl group, alkene oxygen base, alkynyloxy group, alkylamino, alkenyl amino, alkynes base amino, alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amido, alkyl sulfonyl-amino, N-alkyl or N, the aryl/hetaryl that the N-dialkyl ureas replaces;

(n) amidino groups and be independently selected from alkyl, the alkyl of replacement, alkenyl, the alkenyl of replacement, alkynes base, the alkynes base of replacement, aryl, the amidino groups that the substituting group of heteroaryl and heterocyclic radical replaces by 1-3;

(o)-and C (O) NR R , wherein each R is independently selected from hydrogen, alkyl, the alkyl that replaces, cycloalkyl, the cycloalkyl of replacement, alkenyl, the alkenyl of replacement, alkynes base, the alkynes base that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, prerequisite be when a R be undersaturated heterocyclic radical alkyl, aryl, heteroaryl or by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynes base, 1,2-dioxy methylene, 1,2-dioxy base ethylidene, alkoxyl group, alkene oxygen base, alkynyloxy group, alkylamino, alkenyl amino, alkynes base amino, alkyl-carbonyl oxygen base, acyl group, alkyl-carbonyl-amino, alkoxycarbonyl amido, alkyl sulfonyl-amino, N-alkyl or N, during aryl/hetaryl that the N-dialkyl ureas replaces, another R is an alkyl, the alkyl of replacement (not being the alkyl that undersaturated heterocyclic radical replaces), cycloalkyl, the cycloalkyl that replaces, alkenyl, the alkenyl of replacement, the alkynes base, the alkynes base of replacement and the heterocyclic radical of heterocyclic radical and replacement;

(p)-NR ¹²C (O)-R ⁸, R wherein ⁸Be selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, and R ¹²Be alkyl, the alkyl of replacement, aryl, the aryl of replacement, cycloalkyl, the cycloalkyl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(q)-SO ₂-aryl ,-SO ₂The aryl of-replacement ,-SO ₂-heteroaryl ,-SO ₂-the heteroaryl that replaces or-SO ₂-alkyl;

(r)-NR ' C (O) NR ⁹R ⁹, wherein R ' is selected from alkyl, the alkyl of replacement, aryl, the aryl of replacement, cycloalkyl, the cycloalkyl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, and each R ⁹Be independently selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(s)-NR ' C (O) OR ⁹, wherein R ' is selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, and R ⁹Be selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(t)-aminocarboxyl-(N-formyl radical heterocyclic radical); With

(u)-alkyl-C (O) NH-heterocyclic radical and-heterocyclic radical that alkyl-C (O) NH-replaces;

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

X is the integer of 1-4;

Q is-C (X) NR ⁷-, R wherein ⁷Be selected from hydrogen and alkyl; Be selected from oxygen and sulphur with X;

With its pharmaceutically-acceptable salts.

In another embodiment, compound of the present invention can also be provided as and transform the prodrug that (for example hydrolysis, metabolism etc.) become the compound of top formula I in the body.In the preferred embodiment of such embodiment, the hydroxy-acid group of the compound of formula I is modified to will be converted into the carboxylic acid group of (comprising its salt) in the body.In particularly preferred embodiments, the compounds represented of such prodrug through type IA:

Wherein

R ²Be selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group, the cycloalkenyl group of replacement, heterocyclic radical, the heterocyclic radical of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, and R ¹And R ²With bonding R ²Nitrogen-atoms and bonding R ¹SO ₂Group can form the heterocyclic radical of heterocycle or replacement together;

R ³Be selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocyclic radical, the heterocyclic radical of replacement and work as R ²Not with R ¹When forming heterocyclic radical, R ²And R ³With bonding R ²Nitrogen-atoms and bonding R ³Carbon atom can form the heterocyclic radical of heterocycle or replacement together;

R ⁵Be-(CH ₂) _x-Ar-R ^{5 '}, R wherein ^{5 '}Be selected from

(a) alkyl-carbonyl-amino of Qu Daiing, prerequisite be on the substituted moieties substituting group at least one be selected from alkoxyl group, the alkoxyl group of replacement; acyl group, acyl amino, thio-carbonyl-amino; acyloxy, alkenyl, amino; amidino groups, alkyl amidine, sulfo-amidino groups; aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino; aminocarboxyl oxygen base, aryloxy, the aryloxy of replacement; cyano group, halogen, hydroxyl; nitro, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; cycloalkyl, the cycloalkyl of replacement, guanidine radicals; the guanidine radicals sulfone, mercaptan, alkylthio; the alkylthio that replaces, thioaryl, the thioaryl of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces, sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces, heteroaryl oxygen base, the heteroaryl oxygen base of replacement; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl, an alkylamino, dialkyl amido; one-and two-(alkyl of replacement) amino; one-and two-arylamino, one-and the two-arylamino that replaces, one-and two-heteroaryl amino; one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino, one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine; wherein substituted radical is selected from alkyl; the alkyl that replaces, aryl, the aryl of replacement; heteroaryl; the heteroaryl that replaces, heterocyclic radical and the heterocyclic radical that replaces; with have with GPF (General Protection False group Boc for example; Cbz, the alkyl of the replacement of the amino of protection such as formyl radical, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(c) aryl and heteroaryl;

(d)-and NR ' R ', wherein each R ' is independently selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, cycloalkyl, the cycloalkyl of replacement; the heterocyclic radical of heterocyclic radical and replacement, condition are that at least one R ' is the alkyl that replaces, cycloalkyl; the cycloalkyl that replaces, the heterocyclic radical of heterocyclic radical and replacement, further prerequisite is when R ' is the alkyl that replaces; at least one substituting group is selected from alkoxyl group on the substituted moieties, the alkoxyl group of replacement, acyl group; acyl amino, thio-carbonyl-amino, acyloxy; alkenyl, amino, amidino groups; alkyl amidine, sulfo-amidino groups, aminoacyl; amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base; aryloxy, the aryloxy of replacement, cyano group; halogen, hydroxyl, nitro; carboxyl, carboxyalkyl, the alkyl of carboxyl substituted; the carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted, carboxyl aryl; the aryl of carboxyl substituted, carboxyl heteroaryl, the heteroaryl of carboxyl substituted; the carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted, cycloalkyl; the cycloalkyl that replaces, guanidine radicals, guanidine radicals sulfone; mercaptan, alkylthio, the alkylthio of replacement; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces, thio ceteroary, the thio ceteroary of replacement; the sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl, an alkylamino, dialkyl amido; one-and two-(alkyl of replacement) amino; one-and two-arylamino, one-and the two-arylamino that replaces, one-and two-heteroaryl amino; one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino, one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine; described substituted radical is selected from alkyl; the alkyl that replaces, aryl, the aryl of replacement; heteroaryl; the heteroaryl that replaces, heterocyclic radical and the heterocyclic radical that replaces; with have with GPF (General Protection False group Boc for example; Cbz, the alkyl of the replacement of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(e)-and alkoxyl group-NR " R ", each R wherein " be independently selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement; the heterocyclic radical of heterocyclic radical and replacement, prerequisite are as R " when being the alkyl that replaces, at least one is selected from alkoxyl group the substituting group on the moieties of this replacement; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, amino; alkenyl, amidino groups, alkyl amidine; the sulfo-amidino groups, aminoacyl, amino carbonyl amino; amino thio-carbonyl-amino, aminocarboxyl oxygen base, aryloxy; the aryloxy that replaces, cyano group, halogen; hydroxyl, nitro, carboxyl; carboxyalkyl, the alkyl of carboxyl substituted, carboxyl cycloalkyl; the cycloalkyl of carboxyl substituted, carboxyl aryl, the aryl of carboxyl substituted; the carboxyl heteroaryl, the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical; the heterocyclic radical of carboxyl substituted, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, mercaptan; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces; the sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents group and replaces amine, and described substituted radical is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the alkyl of the replacement of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(f) substituted alkenyl or substituted alkynes base, prerequisite be on substituted alkenyl/alkynes base section substituting group at least one be selected from alkyl, the alkyl of replacement; aryl, the aryl of replacement, cycloalkyl; the cycloalkyl that replaces, heteroaryl, the heteroaryl of replacement; the heterocyclic radical of heterocyclic radical and replacement, prerequisite are that at least one is selected from alkoxyl group the substituting group on the moieties of this replacement when substituted alkyl replaces; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkenyl; amino, amidino groups, alkyl amidine; the sulfo-amidino groups, aminoacyl, amino carbonyl amino; amino thio-carbonyl-amino, aminocarboxyl oxygen base, aryloxy; the aryloxy that replaces, cyano group, halogen; hydroxyl, nitro, carboxyl; carboxyalkyl, the alkyl of carboxyl substituted, carboxyl cycloalkyl; the cycloalkyl of carboxyl substituted, carboxyl aryl, the aryl of carboxyl substituted; the carboxyl heteroaryl, the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical; the heterocyclic radical of carboxyl substituted, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, mercaptan; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces; the sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and described substituting group is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the alkyl of the replacement of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces;

(h)-alkoxyl group-saturated heterocyclyl, the heterocyclic radical of-alkoxyl group-saturated-replacement ,-alkoxyl group-heterocyclic radical of replacing and-the saturated heterocyclic radical of alkoxyl group-replacement of replacing;

(i)-the O-heterocyclic radical and-heterocyclic radical that O-replaces;

(j) tetrazyl;

(p)-NR ¹²C (O)-R ⁸, R wherein ⁸Be selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, R ¹²Be alkyl, the alkyl of replacement, aryl, the aryl of replacement, cycloalkyl, the cycloalkyl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(r)-NR ' C (O) NR ⁹R ⁹, wherein R ' is selected from alkyl, the alkyl of replacement, aryl, the aryl of replacement, cycloalkyl, the cycloalkyl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, each R ⁹Be independently selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(s)-NR ' C (O) OR ⁹, wherein R ' is selected from alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, R ⁹Be selected from hydrogen, alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

(t)-aminocarboxyl-(N-formyl radical heterocyclic radical); With

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

X is the integer of 1-4;

R ⁶Be selected from 2,4-dioxo-tetrahydrofuran (THF)-3-base (3, the 4-enol), amino, alkoxyl group, the alkoxyl group of replacement, cycloalkyloxy, the cycloalkyloxy of replacement ,-O-(N-succinimido),-NH-adamantyl ,-O-courage steroid-5-alkene-3-beta-yl ,-NHOY, wherein Y is a hydrogen, alkyl, the alkyl of replacement, aryl and the aryl that replaces ,-NH (CH ₂) _pCOOY wherein p is that integer and the Y of 1-8 as above defines-OCH ₂NR ⁹R ¹⁰, R wherein ⁹Be selected from-C (O)-aryl and-aryl and the R of C (O)-replacement ¹⁰Be selected from hydrogen and-CH ₂COOR ¹¹, R wherein ¹¹Be alkyl, and NHSO ₂Z, wherein Z is an alkyl, the alkyl of replacement, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement;

With its pharmaceutically-acceptable salts,

Condition is

Work as R ¹Be p-CH ₃-φ-, R ⁶Be methoxyl group, Q is C (O) NH-, and R ²And R ³When being connected to form pyrrolidyl, R then ⁵Not p-[-OCH ₂CH ₂N (C ₂H ₅) ₂]-benzyl-, p-[-OCH ₂CH ₂N (sec.-propyl) ₂]-benzyl-, p-[-OCH ₂CH ₂-1-pyrrolidyl]-benzyl-, p-[-OCH ₂CH ₂-1-(4-pyrimidyl) piperazinyl]-benzyl-, p-[-OCH ₂CH ₂-N-morpholinyl]-benzyl-or p-[-OCH ₂CH ₂-N-piperidyl]-benzyl-.

Preferably, in the above in the compound of formula I and IA, R ¹Be selected from alkyl, the alkyl of replacement, aryl, the aryl of replacement, heterocyclic radical, the heterocyclic radical of replacement, the heteroaryl of heteroaryl and replacement.More preferably, R ¹Be selected from the 4-aminomethyl phenyl, methyl, benzyl, normal-butyl, the 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-p-methoxy-phenyl, phenyl, 2,4, the 6-trimethylphenyl, 2-(methoxycarbonyl) phenyl, 2-carboxyl phenyl, 3,5-dichlorophenyl, the 4-trifluoromethyl, 3, the 4-dichlorophenyl, 3,4-Dimethoxyphenyl, 4-(CH ₃C (O) NH-) phenyl, 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, sec.-propyl, 3,5-two-(trifluoromethyl) phenyl, the 4-tert-butyl-phenyl, 4-tert.-butoxy phenyl, 4-nitrophenyl, the 2-thienyl, 1-N-methyl-3-methyl-5-chloro is for pyrazoles-4-base, styroyl, 1-N-Methylimidazole-4-base, 4-bromophenyl, 4-amidino groups phenyl, 4-methyl amidino groups phenyl, 4-[CH ₃SC (=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-fluoro phenyl, 2-fluoro phenyl, 3-fluoro phenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidine-2-base, 4-(3 '-dimethylamino-positive propoxy)-phenyl and 1-methyl-pyrazol-4-yl.

Preferably, above in the compound of formula I and IA, R ²Be hydrogen, methyl, phenyl, benzyl ,-(CH ₂) ₂-2-thienyl and-(CH ₂) ₂-φ.

In one embodiment, R ¹And R ²With bonding R ²Nitrogen-atoms and bonding R ¹SO ₂Base forms the heterocyclic group of heterocyclic group or replacement together.The heterocyclic group of preferred heterocyclic group and replacement comprises that having 5-7 becomes to have in the annular atoms ring the individual nitrogen that is selected from of 2-3, oxygen and sulphur heteroatomic those, this ring randomly condenses another ring, for example phenyl or cyclohexyl ring are to provide 10-14 to become to have in the annular atoms ring the individual nitrogen, the heteroatomic condensed ring heterocycle of oxygen and sulphur of being selected from of 2-4.Particularly preferred R ¹/ R ²Linking group comprises for example benzisothiazole ketone group (asccharin-2-yl).

In one embodiment, R ²And R ³With bonding R ²Nitrogen-atoms and bonding R ³Carbon atom form 4-6 together and become to have 1-2 in the annular atoms ring and be selected from nitrogen, the heterocyclic radical of oxygen and sulphur or the heterocyclic radical of replacement, this ring randomly is selected from fluorine, methyl, hydroxyl by one to two, amino, phenyl, thio-phenyl, the substituting group of sulfo-benzyl replaces maybe can condense another ring, for example phenyl or cycloalkyl ring are to provide 10-14 to become to have in the annular atoms ring the individual nitrogen, the heteroatomic condensed ring heterocycle of oxygen and sulphur of being selected from of 1-2.Such heterocycle comprises azetidinyl (for example L-azetidinyl), thiazolidyl (for example L-thiazolidyl), piperidyl (for example L-piperidyl), piperazinyl (for example L-piperazinyl), indolinyl (L-2 for example, 3-indoline-2-yl), tetrahydric quinoline group (L-1 for example, 2,3,4-tetrahydroquinoline-2-yl), thio-morpholinyl (for example L-thiomorpholine-3-yl), pyrrolidyl (for example L-pyrrolidyl), for example 4-hydroxyl pyrrolidine base is (for example for the pyrrolidyl that replaces, 4-α-(or β-) hydroxyl-L-pyrrolidyl), 4-fluoro pyrrolidyl (for example, 4-α-(or β-) fluoro-L-pyrrolidyl), 3-phenylpyrrole alkyl (for example, 3-α-(or β-) phenyl-L-pyrrolidyl), 3-thio-phenyl pyrrolidyl (for example, 3-α-(or β-) thio-phenyl-L-pyrrolidyl), 4-amino-pyrroles alkyl (for example, 4-α-(or β-) amino-L-pyrrolidyl), 3-methoxyl group pyrrolidyl (for example, 3-α-(or β-) methoxyl group-L-pyrrolidyl), 4, the 4-alkyl dimethyl pyrrole, the piperazinyl of replacement is the 4-N-Cbz-piperazinyl for example, the thiazolidyl of replacement, for example 5,5-dimethylthiazole alkane pyridine-4-base, 1,1,-dioxo-thiazolidyl (for example, L-1,1-dioxo-thiazolidine-2-yl), 1 of replacement, 1-dioxo-thiazolidyl, L-1 for example, 1-dioxo-5,5-dimethylthiazole alkane-2-base, 1,1-dioxo thio-morpholinyl (for example, L-1,1-dioxo-thiomorpholine-3-yl) or the like.

Preferably, above in the compound of formula I and IA, R ³Comprise by methyl phenyl, benzyl, diphenyl methyl ,-CH ₂CH ₂-COOH ,-CH ₂-COOH, 2-acid amides ethyl, isobutyl-, the tertiary butyl ,-CH ₂O-benzyl and hydroxymethyl replace and all isomer of generation.In addition, in another preferred embodiment, R ³And R ²With bonding R ²Nitrogen-atoms can form the heterocyclic radical of heterocyclic radical or replacement together.

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

R ⁵Be preferably selected from all possible isomers that is replaced by following group and produce: 4-[NH₂CH ₂C (O) NH-] benzyl, 4-[HOOCCH₂CH ₂C (O) NH-] benzyl, 4-[-NHC (O) CH₂NHBoc] benzyl, 4-[-NHC (O) CH (CH₃) NHBoc] benzyl, 4-[-NHC (O) CH (CH₂φ) NHBoc] benzyl, 4-[-NHC (O) CH₂NHC (O) NH-3 '-aminomethyl phenyl] benzyl, 4-[-NHC (O) CH (NHBoc) (CH₂) ₄NHCbz] benzyl, 4-[-NHC (O) CH₂CH(C(O)OCH ₂φ)-NHCbz] benzyl, 4-φ-benzyl, 4-[-NHC (O) CH (CH₂CH ₂CH ₂CH ₂NH ₂) NHBoc] benzyl, 4-[H₂NCH ₂CH ₂CH ₂C (O) NH-] benzyl, 4-(BocHNCH₂CH ₂CH ₂-C (O) NH-) benzyl, 4-[φ CH₂OCH ₂(BocHN) CHC (O) NH-] benzyl, 4-[CH₃NHCH ₂CH ₂CH ₂C (O) NH-] benzyl, 4-[N-methyl piperidine-4-oxygen] benzyl, 4-[CH₃N(Boc)CH ₂CH ₂CH ₂C (O) NH-] benzyl, 4-[φ CH₂OCH ₂(H ₂N) CHC (O) NH-] benzyl, 4-[HO (O) C (Cbz-NH) CHCH₂CH ₂-C (O) NH-] benzyl, 4-[φ CH₂O(O)C(Cbz-NH)CHCH ₂CH ₂-C (O) NH-] benzyl, 4-[HO (O) C (NH₂)CHCH ₂CH ₂-C (O) NH-] benzyl, 4-[CH₃(N-Boc)NCH ₂C (O) NH-] benzyl, 4-[CH₃NHCH ₂C (O) NH-] benzyl, 4-[(CH₃) ₂NCH ₂C (O) NH-] benzyl, 4-[-O-CH (COOH) φ] benzyl, the 4-[2-carboxyl phenyl-]-benzyl, 4-[2-carboxyl aminomethyl phenyl-]-benzyl 4-[φ CH₂OC(O)NHCH ₂CH ₂NH-] benzyl, 4-N[-(SO₂)CH ₃]- CH ₂CH ₂CH ₂N(CH ₃) ₂] benzyl, 4-t-butyl-O (O) CCH₂-O-benzyl NH] benzyl, 4-[N, N-di (4-N, N dimethylamino) benzyl) amino] benzyl, 4-(2-formoxyl-1,2,3,4-tetrahydroisoquinoline-3-base-CH₂NH) benzyl, 4-[-OCH₂CH ₂-1 '-(4 '-pyrimidine radicals) piperazinyl]-benzyl, 4-[-OCH₂CH ₂-(1 '-piperidyl)]-benzyl, 4-[-OCH₂CH ₂-(1 '-pyrrolidinyl)]-benzyl, 4-[-OCH₂CH ₂CH ₂-(1 '-piperidyl)]-benzyl, 4-[(CH₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl, 4-[(CH₃) ₂NCH ₂CH ₂O-] benzyl, 4-[-OCH₂CH ₂CH ₂-(1 '-(4 '-the methyl piperazine base))]-benzyl, 4-[-OCH₂CH ₂CH ₂-4-(3 '-chlorophenyl)-piperazine-1-yl]-benzyl, 4-[-OCH₂CH ₂N(φ)CH ₂CH ₃]-benzyl, 4-[-OCH₂-3 '-(N-Boc)-piperidyl]-benzyl, and 4-[-O-(3-(N-Boc)-piperidyl] benzyl, 3-[-O-(N-methyl piperidine-4-yl)] benzyl, 4-[-O-(N-methyl piperidine-4-yl)] benzyl, 4-[two-isopropylamino-CH₂CH ₂O-]-benzyl, 4-[N-3-methyl butyl-N-trifyl) amino] benzyl, 4-[-OCH₂CH ₂-(N-morpholinyl)]-benzyl, 4-[-OCH₂CH(NHBoc)CH ₂Cyclohexyl]-benzyl, 4-[OCH₂CH ₂-(N-piperidyl)]-benzyl, 4-[-OCH₂CH ₂CH ₂-(4-m-chlorphenyl)-piperazine-1-yl]-benzyl, 4-[-OCH₂CH ₂-(N-homopiperidinyl)-benzyl, 4-[-OCH₂CH ₂N (benzyl)₂]-benzyl, 3-[-OCH₂CH ₂CH ₂N(CH ₃) ₂]-benzyl, 4-[-OCH₂CH ₂N(C ₂H ₅) ₂]-benzyl, 4-[-OCH₂CH ₂CH ₂N(C ₂H ₅) ₂]-benzyl, 4-[-OCH₂CH ₂N(C ₂H ₅) ₂]-benzyl, 4-[-OCH₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl, 4-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl, [cyclopenta acetenyl]-benzyl, 4-[-C ≡ C-φ-4 ' φ]-benzyl, 4-[-C ≡ C-CH₂-O-S(O) ₂-4′-CH ₃-φ]-benzyl, 4-[-C ≡ C-CH₂NHC(O)NH ₂]-benzyl, 4-[-C ≡ C-CH₂-O-(4′-COOCH ₂CH ₃) φ]-benzyl, 4-[-C ≡ C-CH (NH₂)-cyclohexyl]-benzyl, 4-[-C ≡ C-CH₂-O-phenyl]-benzyl, 4-[-C ≡ C-CH₂OCH ₃]-benzyl, 4-[-C ≡ C-CH₂-O-(4′-C(O)OC ₂H ₅) phenyl]-benzyl, 4-[-C ≡ C-CH₂CH(C(O)OCH ₃) ₂]-benzyl, 4-[-C ≡ C-CH₂CH(NHC(O)CH ₃) C (O) OH]-benzyl, 4-[-C ≡ C-CH₂NH-(4,5-dihydro-4-oxo-5-phenyl-oxazoles-2-yl)]-benzyl, 4-[-OCH₂CH ₂CH ₂-(N-morpholino)]-benzyl, 4-[-OCH₂COOH]-benzyl, 4-[-OCH₂The COO-tert-butyl group]-benzyl, 4-[-N (SO₂CH ₃)(CH ₂) ₃-N(CH ₃) ₂]-benzyl, 4-[NHS (O)₂CF ₃]-benzyl, 4-[-C (=NH) NH₂]-benzyl, 4-[-NHSO₂-CH ₂Cl]-benzyl, 4-[-OCH₂C (O) NH-benzyl]-benzyl, 4-[-OCH₂C (O) O-benzyl]-benzyl, 4-[-OCH₂C (O) OH]-benzyl, 4-[-OCH₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl, 4-[-OCH₂C(O)NH ₂]-benzyl, 4-[-OCH₂C (O) the NH tert-butyl group]-benzyl, 4-[-OCH₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl, 4-[-NHSO₂-CH＝CH ₂]-benzyl, 4-[-NHSO₂-CH ₂CH ₂Cl]-benzyl, 4-benzyl-benzyl, 4-[-OCH₂C (O) piperidin-1-yl] benzyl, 4-[-OCH₂C(O)N(CH(CH ₃) ₂) ₂] benzyl, 4-amidino benzyl, 4-acetylamino benzyl, 4-(N-methyl) acetylamino benzyl, 4-(NHC (O) CH₂NHC (O) NH-fluorescin) benzyl, 4-(NHC (O) CH₂CH(NH ₂) COOH, (1-tosyl imidazol-4 yl)-methyl-, [(1-N, N-dimethylamino-sulfonyl)-imidazole radicals-4-yl] methyl-, 4-(N-tosyl-amino) benzyl, and 4-[N-methyl trifluoro acetylamino] phenyl.

In the compound of formula IA, R ⁶Preferably 2,4-dioxo-tetrahydrofuran (THF)-3-base (3, the 4-enol), methoxyl group, oxyethyl group, different-propoxy-, 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, benzyl oxygen base ,-NHCH ₂COOH ,-NHCH ₂CH ₂COOH ,-NH-adamantyl ,-NHCH ₂CH ₂COOCH ₂CH ₃,-NHSO ₂-right-CH ₃-φ ,-NHOR ⁸, R wherein ⁸Be hydrogen, methyl, sec.-propyl or benzyl, O-(N-succinimido) ,-O-courage steroid-5-alkene-3-beta-yl ,-OCH ₂-OC (O) C (CH ₃) ₃,-O (CH ₂) _zNHC (O) W, wherein z be 1 or 2 and W be selected from pyridin-3-yl ,-N-picolyl and N-methyl isophthalic acid, 4-dihydro-pyridin-3-yl ,-NR " C (O)-R ', wherein R ' is an aryl, heteroaryl or heterocycle and R " be hydrogen or-CH ₂C (O) OCH ₂CH ₃

Preferred compound in top formula I and the IA scope for example comprises:

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(carboxyl) propionamido]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-L-alanyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-D-alanyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-D-phenylalanyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[3-(fluorescein) sulfo-urea groups] kharophen }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl glycyl) amino]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[3-(3-aminomethyl phenyl) urea groups] kharophen }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N α-tertbutyloxycarbonyl-N ε-carbobenzoxy-(Cbz)-L-lysyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[γ-(α-benzyl-N α-carbobenzoxy-(Cbz)-L-aspartoyl) amino]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N α-tertbutyloxycarbonyl-L-lysyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[γ-(L-aspartoyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(the amino butyramide of 4-)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-t-butoxycarbonyl amino) butyramide]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-methylamino) butyramide]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-tertbutyloxycarbonyl-N-methylamino) butyramide]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(O-benzyl)-and the L-seryl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[δ-(D, L-glutamy) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl sarcosyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[(N-tertbutyloxycarbonyl sarcosyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(sarcosyl) amino]-the L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(sarcosyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[(sarcosyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N, N-dimethyl glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[N, N-dimethyl glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(α-carboxyl benzyl oxygen base)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(carboxyl) phenyl]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(methoxycarbonyl) phenyl]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[2-(N-benzyloxycarbonyl amino) ethyl] amino }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[2-(N-benzyloxycarbonyl amino) ethyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[3-(N, N-dimethylamino) propyl group]-the N-[trifyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[4-[(tertbutyloxycarbonyl) methoxyl group] benzyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-{N, N-two [4-(N, N-dimethylamino) benzyl] amino }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[(2-formyl radical-1,2,3,4-tetrahydroisoquinoline-3-yl) methyl] amino }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[2-(N, N-dimethylamino) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-dimethylamino) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N-ethyl-N-phenyl amino) oxyethyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-diisopropylaminoethyl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N-t-butoxycarbonyl amino) propoxy-]-the L-phenylalanine methyl ester

N-(thiophene-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(5-chlorothiophene-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-diethylamino) oxyethyl group]-the L-phenylalanine

N-(2,5-dichloro-thiophene-3-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(1-methylpyrazole-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-diethylamino) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine methyl ester

N-(thiazole-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N-methyl-N-benzylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-diethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N-methyl-N-benzylamino) propoxy-]-the L-phenylalanine methyl ester

N-(1-Methylimidazole-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(2-methyl thiazolium diazole-5-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(4-cyano group benzenesulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-(3, the 3-dimethyl) prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(2-azabicyclo [3.2.2]) octane-2-yl) oxyethyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-(thia morpholine-3-carbonyl)-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(2-azabicyclo [3.2.2]) octane-2-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-[2-(cyclopentyl) ethynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-{2-[4-(phenyl) phenyl] ethynyl }-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-[3-(toluene-4-alkylsulfonyl oxygen base) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-[3-(urea groups) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-[3-(4-ethoxycarbonyl propoxy-) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-D, L-phenylalanyl-4-[2-(1-aminocyclohexyl-1-yl) ethynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(phenoxy group) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-[3-(phenoxy group) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(methoxyl group) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-[3-(methoxyl group) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(4-ethoxycarbonyl phenoxy) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-[3-(4-ethoxycarbonyl phenoxy) third-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4,4-two (methoxycarbonyl) fourth-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-[4,4-two (methoxycarbonyl) fourth-1-alkynyl]-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(4-acetyl ammonia-4-carboxyl fourth-1-alkynes)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-(4-acetyl ammonia-4-carboxyl fourth-1-alkynes)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{3-[(4,5-dihydro-4-oxo-5-Ben Ji oxazole-2-yl) amino] third-1-alkynes }-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-4-{3-[(4,5-dihydro-4-oxo-5-Ben Ji oxazole-2-yl) amino] third-1-alkynes }-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(carboxyl) phenoxy group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[4-(pyrimidine-2-base) piperazine-1-yl] oxyethyl group }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(piperidines-1-yl) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(tetramethyleneimine-1-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(piperidines-1-yl) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{3-[4-(3-chloro-phenyl-) piperazine-1-yl] propoxy-}-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(1-tertiary butyloxycarbonyl phenylpiperidines-3-yl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(morpholine-4-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(1-tertiary butyloxycarbonyl phenylpiperidines-3-yl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(piperidines-1-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{3-[4-(3-chloro-phenyl-) piperazine-1-yl] propoxy-}-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(azepan-1-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(azepan-1-yl) oxyethyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(4-methylpiperazine-1-yl) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-[2-(tetramethyleneimine-1-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(4-methylpiperazine-1-yl) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-[2-(morpholine-4-yl) oxyethyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[4-(3-methoxythiophene-2-yl)-4-hydroxy piperidine-1-yl] oxyethyl group }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-(1-methyl piperidine-4-oxygen base)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(1-methyl piperidine-4-oxygen base)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-(1-methyl piperidine-4-oxygen base)-L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-(1,1-dioxo thiomorpholine-3-carbonyl)-4-(1-methyl piperidine-4-oxygen base)-L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-(1,1-dioxo thiomorpholine-3-carbonyl)-4-(1-methyl piperidine-4-oxygen base)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-(1-methyl piperidine-4-oxygen base)-L-phenylalanine

N-(α tosyl group)-L-prolyl-4-(1-methyl piperidine-4-oxygen base)-L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(chloromethane alkylsulfonyl) amino-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(vinylsulfonyl) amino-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-trifyl-N-isobutyl-) amino-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(vinylsulfonyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-benzylamino carbonyl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(benzyloxycarbonyl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(benzyloxycarbonyl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(carboxyl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(carboxyl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(aminocarboxyl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertiary butyl aminocarboxyl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxy piperidine-1-yl) oxyethyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(piperidines-1-base carbonyl) methoxyl group]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[N, N-diisopropylaminoethyl carbonyl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N, N-diisopropylaminoethyl carbonyl) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(amidino groups) phenylalanine

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

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-methyl acetyl ammonia)-L-phenylalanine isopropyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-methyl acetyl ammonia)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-methyl trifluoro acetyl ammonia)-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-methyl piperidine oxygen the base)-phenylalanine tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-L-(4-methyl piperidine oxygen base) phenylalanine tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine and its pharmaceutically-acceptable salts and above-mentioned all ester cpds, one of them ester group is selected from methyl esters by another, ethyl ester; n-propyl, isopropyl ester, positive butyl ester; isobutyl ester, the ester group displacement of the secondary butyl ester and the tert-butyl ester.

The present invention also provides the method in conjunction with VLA-4 in the biological material, comprising described compound therein in conjunction with under the condition of VLA-4 with the compound contact biological material of top formula I or IA.

Some of the compound of top formula I or IA also are used to reduce the inflammation of VLA-4 mediation in the body.

The present invention also provides above one or more that contain pharmaceutical acceptable carrier and treatment significant quantity except R ³And R ⁵The pharmaceutical composition of formula I beyond L-amino acid or other similar configuration initiator are derived or the compound of IA.Perhaps can use racemic mixture.

Pharmaceutical composition of the present invention can be used for treating the disease of VLA-4 mediation.Such disease comprises for example asthma, presenile dementia, atherosclerosis, aids dementia, diabetes (comprising the diabetes that acute teenager is taken place), enteritis (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, brain inflammation, apoplexy and other brain injury, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung of myocardial ischemia and the mediation of acute white corpuscle, for example injury of lung that is taken place in grownup's respiratory distress syndrome.

Therefore, the present invention also provides the method for patient's inflammatory disease of treatment VLA-4 mediation, and this method comprises patient's administration aforementioned pharmaceutical compositions.

Above the compound of preferred formula I and IA comprise those that propose in the following Table I:

Q is-C (O) NH-under all situations

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[NHC(O)CH ₂NHBoc]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-NHC(O)CH ₂NH ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[NHC(O)CH ₂NHBoc]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-NHC(O)CH ₂NH ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-NHC(O)CH ₂CH ₂C (O) OH]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		4-[-NHC(O)CH ^(CH ₃) NHBoc]-benzyl-( ^Be equivalent to the L isomer)	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-NHC(O)CH ₂CH ₂C (O) OH]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring			-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	4-[-NHC(O)CH ^(CH ₃) NHBoc]-benzyl-( ^Be equivalent to the D isomer)	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-(H ₂NCH ₂CH ₂CH ₂C (O) NH) benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-(Boc-HNCH ₂CH ₂CH ₂C (O) NH) benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-(H ₂NCH ₂CH ₂CH ₂C (O) NH) benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-(Boc-HNCH ₂CH ₂CH ₂C (O) NH) benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[CH ₃(Boc)NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[CH ₃(Boc)NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[φCH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[HO(O)C(Cbz-NH)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[φCH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[HO(O)C(Cbz-NH)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[HO(O)C(H ₂N)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[HO(O)C(H ₂N)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)	p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OCH ₂CH ₃	p-CH ₃-φ-		p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OCH ₂CH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)		p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-			p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)		p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH
p-CH ₃-φ-			p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-[-O-CH (COOH) φ]-benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	4-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-]-φ-CH ₂-	-OH
p-CH ₃-φ-	-CH ₃	-CH ₂OH (L isomer)	p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	4-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-]-φ-CH ₂-	-OH
p-CH ₃-φ-	-CH ₃	-CH ₂OH (L isomer)	p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³=5,5-dimethylthiazole alkane-4-base	p-[(CH ₃) ₂NCH ₂CH ₂O]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³=5,5-dimethylthiazole alkane-4-base	p-[(CH ₃) ₂NCH ₂CH ₂O]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂N(φ)CH ₂CH ₃]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[diisopropylaminoethyl-CH ₂CH ₂O-]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂N(φ)CH ₂CH ₃]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[diisopropylaminoethyl-CH ₂CH ₂O-]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH(NHBoc)CH ₂Cyclohexyl]-benzyl	-OCH ₃
The 2-thienyl-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH(NHBoc)CH ₂Cyclohexyl]-benzyl	-OCH ₃
The 2-thienyl-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	5-chloro-2-thienyl-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-	-OH
2,5-two chloro-4-thienyls	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-	-OH
2,5-two chloro-4-thienyls	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	1-N-methyl-4-pyrazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-	-OCH ₃	1-N-methyl-4-pyrazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	m-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
The 2-thiazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	m-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
The 2-thiazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl-	-OCH ₃
1-N-methyl-4-imidazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl-	-OCH ₃
1-N-methyl-4-imidazolyl	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	2-methyl-4-thiadiazolyl group	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
p-CH ₃-φ-	R ₂/R ₃=thiazole-4-base		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	2-methyl-4-thiadiazolyl group	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH
p-CH ₃-φ-	R ₂/R ₃=thiazole-4-base		p-[-OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	p-NC-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)	p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂C(CH ₃) ₂-		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OH	p-NC-φ-		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂C(CH ₃) ₂-		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)	p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OCH ₂CH ₃

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-S-CH ₂-(L-thiomorpholine-3-yl)		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-S-CH ₂-(L-thiomorpholine-3-yl)		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OH
p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	P-(cyclopentyl-C ≡ C-) benzyl	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OH
p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	P-(cyclopentyl-C ≡ C-) benzyl	-OH	p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	P-[-C ≡ C-φ-p-φ]-benzyl-	-OH
p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	p-[-C≡C-CH ₂-O-S(O) ₂-p-CH ₃-φ]-benzyl-	-OH	p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	P-[-C ≡ C-φ-p-φ]-benzyl-	-OH
p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	p-[-C≡C-CH ₂-O-S(O) ₂-p-CH ₃-φ]-benzyl-	-OH	p-CH ₃-φ-	H	-CH ₂-φ (L-isomer)	p-[-C≡C-CH ₂NHC(O)NH ₂]-benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂-3-(N-Boc)-piperidyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-morpholinyl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂-3-(N-Boc)-piperidyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-morpholinyl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂CH ₂(N-piperidyl)]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂CH ₂-1-(4-m-chloro-phenyl-)-piperazinyl]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂CH ₂(N-piperidyl)]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring			-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂CH ₂-(N-homopiperidinyl)-benzyl	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-homopiperidinyl)-benzyl	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂CH ₂-(N-homopiperidinyl)-benzyl	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-homopiperidinyl)-benzyl	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		m-[OCH ₂CH ₂-(1-pyrrolidyl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-	-OCH ₃

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-morpholinyl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-(N-morpholinyl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[-O-(3-(N-Boc)-piperidines]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[-O-(3-(N-Boc)-piperidines]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	M-[O-(N-methyl piperidine-4-yl)]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[O-(N-methyl piperidine-4-yl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	M-[O-(N-methyl piperidine-4-yl)]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[O-(N-methyl piperidine-4-yl)]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-	P-[(1-methyl piperidine-4-yl)-O-]-benzyl-	-OCH ₂CH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-yl)		P-[(1-methyl piperidine-4-yl)-O-]-benzyl-	-OCH ₂CH ₃	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-	P-[(1-methyl piperidine-4-yl)-O-]-benzyl-	-OCH ₂CH ₃

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-yl)	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-yl)		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	p-CH ₃-φ-		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃
p-CH ₃-φ-			P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dioxo thiomorpholine-4-yl)	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH
φ-CH ₃-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	p-CH ₃-φ-		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH
φ-CH ₃-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[NHSO ₂-CF ₃]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[NHSO ₂-CF ₃]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[NHSO ₂-CF ₃]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[NHSO ₂-CF ₃]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[NHSO ₂-CH ₂Cl]-benzyl-	-OCH ₃

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-NHSO ₂-CH＝CH ₂]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[N-3-methyl butyl-N-trifyl) amino] benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[-NHSO ₂-CH＝CH ₂]-benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[N-3-methyl butyl-N-trifyl) amino] benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	The p-[N-vinylsulfonyl) amino] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂C (O) NH-benzyl]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	The p-[N-vinylsulfonyl) amino] benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂C (O) NH-benzyl]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂C (O) O-benzyl]-benzyl-	-OC ₃H
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂C (O) NH-benzyl]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂C (O) O-benzyl]-benzyl-	-OC ₃H
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂C (O) NH-benzyl]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂C (O) OH]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂C(O)NH ₂]-benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	p-[OCH ₂C (O) OH]-benzyl-	-OH

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂C(O)NH ₂]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂C (O) the NH tertiary butyl]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂C(O)NH ₂]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[-OCH ₂C (O) the NH tertiary butyl]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[OCH ₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OH	p-CH ₃-φ-	-CH ₃	H	p-[-C(＝NH)NH ₂]-benzyl-	-OH
p-CH ₃-φ-	-CH ₃	H	p-[-C(O)NH ₂]-benzyl-	-OH	p-CH ₃-φ-	-CH ₃	H	p-[-C(＝NH)NH ₂]-benzyl-	-OH
p-CH ₃-φ-	-CH ₃	H	p-[-C(O)NH ₂]-benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-methyl kharophen) benzyl-	-OCH(CH ₃) ₂

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-(N-methyl kharophen) benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-methyl trifluoro kharophen) benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-(N-methyl kharophen) benzyl-	-OH
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-methyl trifluoro kharophen) benzyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	(1-tosyl group imidazol-4 yl) methyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		1-([N, N dimethylamino alkylsulfonyl]-imidazoles-4-yl) methyl-	-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	(1-tosyl group imidazol-4 yl) methyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring			-OCH ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-(N-tosyl group amino) benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-tosyl group amino) benzyl-	-OH	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-(N-tosyl group amino) benzyl-	-OCH ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-tosyl group amino) benzyl-	-OH	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)	P-(3-N, N-dimethyl propoxy-)-benzyl-	-OC(CH ₃) ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(N-methyl piperidine oxygen base)-benzyl-	-OC(CH ₃) ₃	p-CH ₃-φ-		P-(3-N, N-dimethyl propoxy-)-benzyl-	-OC(CH ₃) ₃

R ¹	R ²	R ³	R ⁵	R ^6′
R ¹	R ²	R ³	R ⁵	R ^6′	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-yl)	P-(N-methyl piperidine oxygen base)-benzyl-	-OC(CH ₃) ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(φ)-benzyl-	-OC(CH ₃) ₃	p-CH ₃-φ-		P-(N-methyl piperidine oxygen base)-benzyl-	-OC(CH ₃) ₃
p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring		P-(φ)-benzyl-	-OC(CH ₃) ₃	p-CH ₃-φ-	R ²/R ³3 carbon atoms (L-pyrrolidyl) of=ring	P-(φ)-benzyl-	-OH

The detailed description of invention

The present invention relates to suppress the particularly compound of the leukocyte adhesion of VLA-4 mediation of leukocyte adhesion.Before describing the present invention in detail, at first define following term. Definition

Alkyl as used herein, that " alkyl " refers to preferably have 1-10 carbon atom and more preferably have 1-6 carbon atom.This term is methyl for example, the tertiary butyl, n-heptyl, octyl group or the like.

" alkyl of replacement " refers to preferably to have 1-10 carbon atom, has 1-5 and is selected from following substituent alkyl: alkoxyl group, the alkoxyl group of replacement; acyl group, acyl amino, thio-carbonyl-amino; acyloxy, amino, amidino groups; alkyl amidine, sulfo-amidino groups, alkylthio amidino groups aminoacyl; amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base; aryl, the aryl of replacement, aryloxy; the aryloxy that replaces, aryloxy aryl, the aryloxy aryl of replacement; cyano group, halogen, hydroxyl; nitro, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; cycloalkyl, the cycloalkyl of replacement, guanidine radicals; the guanidine radicals sulfone, mercaptan, alkylthio; the alkylthio that replaces, thioaryl, the thioaryl of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, thio ceteroary; the thio ceteroary that replaces, sulfo-heterocyclic radical, the sulfo-heterocyclic radical of replacement; heteroaryl; the aryl that replaces, the heteroaryl of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl, an alkylamino, dialkyl amido; one-and two-(alkyl of replacement) amino; one-and two-arylamino, one-and the two-arylamino that replaces, one-and two-heteroaryl amino; one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino, one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine; described substituting group is selected from alkyl; the alkyl that replaces, aryl, the aryl of replacement; heteroaryl; the heteroaryl that replaces, heterocyclic radical and the heterocyclic radical that replaces; with have with GPF (General Protection False group Boc for example; Cbz, the alkyl of the replacement of the amino of formyl radical or the like protection, perhaps alkyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkyl that NRR replaces.

" alkoxyl group " refers to group " 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 or the like.

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

" acyl group " refer to group H-C (O)-, alkyl-C (O)-, the alkyl-C of replacement (O)-; alkenyl-C (O)-, the alkenyl-C of replacement (O)-, alkynes base-C (O)-; alkynes base-the C (O) that replaces-, cycloalkyl-C (O)-, the cycloalkyl-C of replacement (O)-; aryl-C (O)-, the aryl-C of replacement (O)-, heteroaryl-C (O)-; heteroaryl-the C (O) that replaces-, heterocyclic radical-C (O)-, the heterocyclic radical-C of replacement (O)-; alkyl wherein; the alkyl that replaces, alkenyl, the alkenyl of replacement; the alkynes base; the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement; aryl; the aryl that replaces, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement as defined herein.

" acyl amino " refers to group-C (O) NRR, and wherein each R is independently selected from hydrogen, alkyl, the alkyl of replacement; alkenyl, the alkenyl of replacement, alkynes base; the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, heterocyclic radical, the heterocyclic radical of replacement; wherein each R is connected to form the heterocycle of heterocycle or replacement with nitrogen-atoms, alkyl wherein, the alkyl of replacement; alkenyl, the alkenyl of replacement, alkynes base; the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, heterocyclic radical, the heterocyclic radical of replacement is as defined herein.

" thio-carbonyl-amino " refers to group-C (S) NRR, and wherein each R is independently selected from hydrogen, alkyl, the alkyl that replaces, alkenyl, the alkenyl of replacement, the alkynes base, the alkynes base of replacement, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical and replacement, wherein each R is connected to form heterocycle or substituted heterocycle with nitrogen-atoms, alkyl wherein, the alkyl of replacement, alkenyl, the alkenyl of replacement, alkynes base, the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the heterocyclic radical of replacement is as defined herein.

" acyloxy " refers to group alkyl-C (O) O-, the alkyl-C of replacement (O) O-, alkenyl-C (O) O-; alkenyl-C (O) O-that replaces, alkynes base-C (O) O-, alkynes base-C (O) O-of replacement; cycloalkyl-C (O) O-, the cycloalkyl-C of replacement (O) O-, aryl-C (O) O-; aryl-C (O) O-that replaces; heteroaryl-C (O) O-, the heteroaryl-C of replacement (O) O-, heterocyclic radical-C (O) O-; heterocyclic radical-C (O) O-that replaces; alkyl wherein, the alkyl of replacement, alkenyl; the alkenyl that replaces; the alkynes base, the alkynes base of replacement, cycloalkyl; the cycloalkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" alkenyl " refer to preferably to have 2-10 carbon atom and more preferably have 2-6 carbon atom and have at least one and preferably have the alkenyl in 1-2 the unsaturated site of alkenyl.

" alkenyl of replacement " refers to have 1-5 and is selected from following substituent alkenyl: alkoxyl group, the alkoxyl group of replacement, acyl group; acyl amino, 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 of replacement; the aryloxy aryl, the aryloxy aryl of replacement, cyano group; halogen, hydroxyl, nitro; carboxyl, carboxyalkyl, the alkyl of carboxyl substituted; the carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted, carboxyl aryl; the aryl of carboxyl substituted, carboxyl heteroaryl, the heteroaryl of carboxyl substituted; the carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted, cycloalkyl; the cycloalkyl that replaces, guanidine radicals, guanidine radicals sulfone; mercaptan, alkylthio, the alkylthio of replacement; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces; thio ceteroary, the thio ceteroary of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces; heteroaryl, the heteroaryl of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and wherein substituted radical is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the alkenyl of the replacement of the amino of formyl radical or the like protection, perhaps alkenyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkenyl base that NRR replaces.

" alkynes base " refers to preferably have 2-10 carbon atom and more preferably has 3-6 carbon atom and have at least one and the alkynes base that preferably has 1-2 the unsaturated site of alkynes base.

" the alkynes base of replacement " refers to have 1-5 and is selected from following substituent alkynes base: alkoxyl group, the alkoxyl group of replacement, acyl group; acyl amino, 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 of replacement; the aryloxy aryl, the aryloxy aryl of replacement, cyano group; halogen, hydroxyl, nitro; carboxyl, carboxyalkyl, the alkyl of carboxyl substituted; the carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted, carboxyl aryl; the aryl of carboxyl substituted, carboxyl heteroaryl, the heteroaryl of carboxyl substituted; the carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted, cycloalkyl; the cycloalkyl that replaces, guanidine radicals, guanidine radicals sulfone; mercaptan, alkylthio, the alkylthio of replacement; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces; thio ceteroary, the thio ceteroary of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces; heteroaryl, the heteroaryl of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino, dialkyl amido, one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents group and replaces amine, and wherein substituted radical is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example, Cbz; the alkynes base of the replacement of the amino of formyl radical or the like protection, perhaps alkynes base/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 and wherein R be hydrogen or alkyl-SO ₂The replacement alkynes base that NRR replaces.

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

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

" aminoacyl " refers to group-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) alkynes base, the alkynes base 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-NRC (O) replaces; wherein R is hydrogen or alkyl and alkyl wherein, the alkyl of replacement, alkenyl; the alkenyl that replaces; the alkynes base, the alkynes base of replacement, cycloalkyl; the cycloalkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" aminocarboxyl oxygen base " refers to group-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 alkynes base, the alkynes base 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-NRC (O) O replaces, wherein R is hydrogen or alkyl and alkyl wherein, the alkyl of replacement, alkenyl, the alkenyl that replaces, alkynes base, the alkynes base of replacement, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl that replaces, heterocyclic radical, the heterocyclic radical of replacement is as defined herein.

" oxygen base carbonylamino " refers to group-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-alkynes base, the alkynes base 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-OC (O) NR-replaces, wherein R is a hydrogen, alkyl, perhaps wherein each R and nitrogen-atoms connect the heterocycle that forms heterocycle or replacement, alkyl wherein, the alkyl of replacement, alkenyl, the alkenyl of replacement, alkynes base, the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement, aryl, the aryl that replaces, heteroaryl, the heteroaryl of replacement, heterocyclic radical, the heterocyclic radical of replacement as defined herein.

" oxygen base thio-carbonyl-amino " refers to group-OC (S) NH ₂,-OC (S) NRR ,-OC (S) NR-alkyl, the alkyl that-OC (S) NR-replaces, the alkenyl that-OC (S) NR-alkenyl-OC (S) NR-replaces ,-OC (S) NR-alkynes base, the alkynes base 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, the heterocyclic radical that-OC (S) NR-replaces, wherein R is a hydrogen, alkyl, and perhaps wherein each R and nitrogen-atoms connect the heterocycle that forms heterocycle or replacement, alkyl wherein, the alkyl of replacement, alkenyl, the alkenyl that replaces, the alkynes base, the alkynes base of replacement, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" amino carbonyl amino " refers to group-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-alkynes base; the alkynes base 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-NRC (O) NR-replaces, wherein each R is hydrogen independently, alkyl; perhaps wherein each R and nitrogen-atoms connect the heterocycle that forms heterocycle or replacement; and one of them is amino by by conventional blocking group Boc for example, Cbz, formyl radical or the like protection; alkyl wherein; the alkyl that replaces, alkenyl, the alkenyl of replacement; the alkynes base; the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement; aryl; the aryl that replaces, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement as defined herein.

" amino thio-carbonyl-amino " refers to group-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-alkynes base; the alkynes base that-NRC (S) NR-replaces ,-NRC (S) NR-cycloalkyl, the cycloalkyl that-NRC (S) NR-replaces;-NRC (S) NR-aryl; the aryl that-NRC (S) NR-replaces ,-NRC (S) NR-heteroaryl, the heteroaryl that-NRC (S) NR-replaces;-NRC (S) NR-heterocyclic radical; the heterocyclic radical that-NRC (S) NR-replaces, wherein each R is hydrogen independently, alkyl; perhaps wherein each R and nitrogen-atoms connect the heterocycle that forms heterocycle or replacement; and one of them is amino by conventional blocking group Boc for example, Cbz, formyl radical or the like protection; alkyl wherein; the alkyl that replaces, alkenyl, the alkenyl of replacement; the alkynes base; the alkynes base that replaces, cycloalkyl, the cycloalkyl of replacement; aryl; the aryl that replaces, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement as defined herein.

" aryl " (" Aryl " or " Ar ") refers to have the unsaturated aromatic carbon ring group with monocycle (for example phenyl) or a plurality of fused rings (for example naphthyl or anthryl) of 6-14 carbon atom, (the 2-benzoxazolinone for example that wherein the condensed ring can yes or no fragrance, 2H-1,4-benzoxazine-3 (4H)-ketone-7 base or the like).Preferred aryl groups comprises phenyl and naphthyl.

The aryl that replaces refers to be selected from the aryl that following substituting group replaces by 1-3: hydroxyl, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkyl; the alkyl that replaces, alkoxyl group, the alkoxyl group of replacement; alkenyl, the alkenyl of replacement, alkynes base; the alkynes base 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 of replacement, aryloxy; the aryloxy that replaces, cycloalkyloxy, the cycloalkyloxy of replacement; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base that replaces, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; the carboxyl amido, cyano group, thiol group; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces, thio ceteroary, the thio ceteroary of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, halogen; nitro, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base 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-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) ₂The heterocyclic radical of-replacement ,-SO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino and dialkyl amido; one-and two-(alkyl of replacement) amino; one-and two-arylamino; one-and the two-arylamino that replaces, one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents and replaces amine, and described substituting group is selected from alkyl; the alkyl that replaces; aryl, the aryl of replacement, heteroaryl; the heteroaryl that replaces; the heterocyclic radical of heterocyclic radical and replacement and with GPF (General Protection False group Boc for example, Cbz, amino on the substituted aryl of formyl radical or the like protection or should amino be hydrogen or alkyl-SO by R wherein ₂NRR replaces.

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

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

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

" the aryloxy aryl of replacement " refers to be selected from the aryloxy aryl that following substituting group replaces by 1-3 on one or two aryl rings: hydroxyl, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkyl; the alkyl that replaces, alkoxyl group, the alkoxyl group of replacement; alkenyl, the alkenyl of replacement, alkynes base; the alkynes base 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 of replacement, aryloxy; the aryloxy that replaces, cycloalkyloxy, the cycloalkyloxy of replacement; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base that replaces, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; the carboxyl amido, cyano group, thiol group; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces, thio ceteroary, the thio ceteroary of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, halogen; nitro, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base 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) ₂Heterocyclic radical-the OSO of-replacement ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino and dialkyl amido; one-and two-(alkyl of replacement) amino, one-and two-arylamino, one-and the two-arylamino that replaces; one-and two-heteroaryl amino; one-and the two-heteroaryl amino that replaces, one-and two-heterocyclic radical amino, one-and the two-heterocyclic radical amino that replaces; have asymmetric two of different substituents and replace amine; described substituting group is selected from alkyl, the alkyl of replacement, aryl; the aryl that replaces; heteroaryl, the heteroaryl of replacement, heterocyclic radical; with the heterocyclic radical that replaces with GPF (General Protection False group Boc for example; Cbz, the amino on the substituted aryl of formyl radical or the like protection is hydrogen or alkyl-SO by R wherein perhaps ₂NRR replaces.

" cycloalkyl " refers to have the monocyclic cycloalkyl of having of 3-8 carbon atom, comprises for example cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group or the like.This definition does not comprise multi-ring alkyl, for example adamantyl or the like.

" cycloalkenyl group " refer to have the single or multiple degrees of unsaturation of having of 3-8 carbon atom but be not the virtue bunch cycloalkenyl group.

" cycloalkyl of replacement " and " cycloalkenyl group of replacement " refers to preferably to have having 1-5 and being selected from following substituent cycloalkyl and cycloalkenyl group of 3-8 carbon atom: oxo (=O), sulfo-(=S), alkoxyl group; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, amino; amidino groups, alkyl amidine, sulfo-amidino groups; aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino; aminocarboxyl oxygen base, aryl, the aryl of replacement; aryloxy, the aryloxy of replacement, aryloxy aryl; the aryloxy aryl that replaces, cyano group, halogen; hydroxyl, nitro, carboxyl; carboxyalkyl, the alkyl of carboxyl substituted, carboxyl cycloalkyl; the cycloalkyl of carboxyl substituted, carboxyl aryl, the aryl of carboxyl substituted; the carboxyl heteroaryl, the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical; the heterocyclic radical of carboxyl substituted, cycloalkyl, the cycloalkyl of replacement; guanidine radicals; the guanidine radicals sulfone, mercaptan, alkylthio; the alkylthio that replaces; thioaryl, the thioaryl of replacement, sulfo-cycloalkyl; the sulfo-cycloalkyl that replaces; thio ceteroary, the thio ceteroary of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces; heteroaryl, the heteroaryl of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino; dialkyl amido, one-and two-(alkyl of replacement) amino, one-and two-arylamino; one-and the two-arylamino that replaces; one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces, one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces; have asymmetric two of different substituents and replace amine, described substituted radical is selected from alkyl, the alkyl of replacement; aryl; the aryl that replaces, heteroaryl, the heteroaryl of replacement; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example; Cbz, the alkynyl of the replacement of the amino of formyl radical or the like protection, perhaps alkynyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkynyl that NRR replaces.

" cycloalkyloxy " refers to-the O-cycloalkyl.

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

" guanidine radicals " refers to group-NRC (=NR) NRR ,-NRC (=NR) NR-the alkyl ,-NRC (=NR) alkyl that replaces of NR-;-NRC (=NR) NR-alkenyl ,-NRC (=NR) alkenyl that replaces of NR-,-NRC (=NR) NR-alkynes base;-NRC (=NR) the alkynes base that replaces of NR-,-NRC (=NR) NR-the aryl ,-NRC (=NR) aryl that replaces of NR-;-NRC (=NR) NR-cycloalkyl ,-NRC (=NR) NR-the heteroaryl ,-NRC (=NR) heteroaryl that replaces of NR-;-NRC (=NR) NR-heterocyclic radical;-NRC (=NR) heterocyclic radical that replaces of NR-, wherein each R is hydrogen and alkyl independently, and one of them is amino by conventional blocking group Boc for example; Cbz; formyl radical or the like protection, alkyl wherein, the alkyl of replacement; alkenyl; the alkenyl that replaces, alkynes base, the alkynes base of replacement; cycloalkyl; the cycloalkyl that replaces, aryl, the aryl of replacement; heteroaryl; the heteroaryl that replaces, heterocyclic radical, the heterocyclic radical of replacement is as defined herein.

" guanidine radicals sulfone " refers to group-NRC (=NR) NRSO ₂-alkyl ,-NRC (=NR) NRSO ₂-the alkyl that replaces ,-NRC (=NR) NRSO ₂-alkenyl ,-NRC (=NR) NRSO ₂-the alkenyl that replaces ,-NRC (=NR) NRSO ₂-alkynes base ,-NRC (=NR) NRSO ₂-alkynes the base that replaces ,-NRC (=NR) NRSO ₂-aryl ,-NRC (=NR) NRSO ₂-the aryl that replaces ,-NRC (=NR) NRSO ₂-cycloalkyl ,-NRC (=NR) NRSO ₂-the cycloalkyl that replaces ,-NRC (=NR) NRSO ₂-heteroaryl ,-NRC (=NR) NRSO ₂-the heteroaryl that replaces ,-NRC (=NR) NRSO ₂-heterocyclic radical ,-NRC (=NR) NRSO ₂-the heterocyclic radical that replaces, wherein each R is hydrogen and alkyl and alkyl wherein independently, the alkyl that replaces, alkenyl, the alkenyl of replacement, the alkynes base, the alkynes base of replacement, cycloalkyl, the cycloalkyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

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

Have 2-10 carbon atom and 1-4 in " heteroaryl " finger ring and be selected from oxygen, the heteroatomic aromatic carbon ring of nitrogen and sulphur.Such heterocyclic radical can have monocycle (for example pyridyl or furyl) or a plurality of condensed ring (for example indolizine base or benzothienyl).Preferred heteroaryl comprises pyridyl, pyrryl, indyl and furyl.

" heteroaryl of replacement " refers to be selected from the heteroaryl that following substituting group replaces by 1-3: hydroxyl, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, alkyl; the alkyl that replaces, alkoxyl group, the alkoxyl group of replacement; alkenyl, the alkenyl of replacement, alkynes base; the alkynes base 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 of replacement, aryloxy; the aryloxy that replaces, cycloalkyloxy, the cycloalkyloxy of replacement; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base that replaces, carboxyl, carboxyalkyl; the alkyl of carboxyl substituted, carboxyl cycloalkyl, the cycloalkyl of carboxyl substituted; the carboxyl aryl, the aryl of carboxyl substituted, carboxyl heteroaryl; the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical, the heterocyclic radical of carboxyl substituted; the carboxyl amido, cyano group, thiol group; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces, thio ceteroary, the thio ceteroary of replacement; the sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, halogen; nitro, heteroaryl, the heteroaryl of replacement; heterocyclic radical, the heterocyclic radical of replacement, cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryl oxygen base, the heteroaryl oxygen base of replacement, heterocyclyloxy base; the heterocyclyloxy base 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino and dialkyl amido; one-and two-(alkyl of replacement) amino; one-and two-arylamino, one-and the two-arylamino that replaces, one-and two-heteroaryl amino; one-and the two-heteroaryl amino that replaces; one-and two-heterocyclic radical amino, one-and the two-heterocyclic radical amino that replaces has asymmetric two of different substituents group and replaces amine; described substituted radical is selected from alkyl; the alkyl that replaces, aryl, the aryl of replacement; heteroaryl; the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement and with GPF (General Protection False group Boc for example, Cbz; formyl radical or the like protection is hydrogen or alkyl-SO by R wherein perhaps ₂Amino on the substituted aryl that NRR replaces.

" heteroaryl oxygen base " refers to group-O-heteroaryl; " the heteroaryl oxygen base of replacement " refers to the heteroaryl that group-O-replaces.

" heterocycle " or " heterocyclic radical " refers to have and has 1-10 carbon atom and 1-4 in the ring of monocycle or a plurality of fused rings and be selected from nitrogen, the heteroatomic saturated or undersaturated group of sulphur or oxygen, wherein in the condensed loop systems, one or more rings can be aryl or heteroaryl.

" saturated heterocyclic radical " refers to not have in all rings the monocycle of degree of unsaturation or the heterocycle of a plurality of fused rings (for example carbon-to-carbon is unsaturated, and carbon-nitrogen is unsaturated, and nitrogen-nitrogen is unsaturated or the like).

" undersaturated heterocyclic radical " refers to have the monocycle of degree of unsaturation (for example carbon-to-carbon is unsaturated, and carbon-nitrogen is unsaturated, and nitrogen-nitrogen is unsaturated or the like) or the non-aromatic heterocycle of a plurality of fused rings in the ring arbitrarily.

" heterocyclic radical of replacement " refers to be selected from the heterocyclic radical that following substituting group replaces by 1-3: oxo (=O), sulfo-(=S), alkoxyl group; the alkoxyl group that replaces, acyl group, acyl amino; thio-carbonyl-amino, acyloxy, amino; amidino groups, alkyl amidine, sulfo-amidino groups; aminoacyl, amino carbonyl amino, amino thio-carbonyl-amino; aminocarboxyl oxygen base, aryl, the aryl of replacement; aryloxy, the aryloxy of replacement, aryloxy aryl; the aryloxy aryl that replaces, cyano group, halogen; hydroxyl, nitro, carboxyl; carboxyalkyl, the alkyl of carboxyl substituted, carboxyl cycloalkyl; the cycloalkyl of carboxyl substituted, carboxyl aryl, the aryl of carboxyl substituted; the carboxyl heteroaryl, the heteroaryl of carboxyl substituted, carboxyl heterocyclic radical; the heterocyclic radical of carboxyl substituted, cycloalkyl, the cycloalkyl of replacement; guanidine radicals, guanidine radicals sulfone, mercaptan; alkylthio, the alkylthio of replacement, thioaryl; the thioaryl that replaces, sulfo-cycloalkyl, the sulfo-cycloalkyl of replacement; thio ceteroary, the thio ceteroary of replacement, sulfo-heterocyclic radical; the sulfo-heterocyclic radical that replaces; heteroaryl, the heteroaryl of replacement, heterocyclic radical; the heterocyclic radical that replaces; cycloalkyloxy, the cycloalkyloxy of replacement, heteroaryl oxygen base; the heteroaryl oxygen base that replaces; the heterocyclyloxy base, the heterocyclyloxy base of replacement, 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 ,-OSO ₂-NRR, wherein R is a hydrogen or alkyl ,-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; wherein R is a hydrogen or alkyl; one alkylamino; dialkyl amido, one-and two-(alkyl of replacement) amino, one-and two-arylamino; one-and the two-arylamino that replaces; one-and two-heteroaryl amino, one-and the two-heteroaryl amino that replaces, one-and two-heterocyclic radical amino; one-and the two-heterocyclic radical amino that replaces; have asymmetric two of different substituents group and replace amine, described substituted radical is selected from alkyl, the alkyl of replacement; aryl; the aryl that replaces, heteroaryl, the heteroaryl of replacement; the heterocyclic radical of heterocyclic radical and replacement and having with GPF (General Protection False group Boc for example; Cbz, the alkynyl of the replacement of the amino of formyl radical or the like protection, perhaps alkynyl/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 and wherein R be hydrogen or alkyl-SO ₂The substituted alkynyl that NRR replaces.

The example of heterocycle and heteroaryl includes but not limited to azetidine, pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, 2, naphthyl pyridine quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene ， isoxazole ， phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalimide, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl, piperidyl, pyrrolidyl, tetrahydrofuran base or the like.

The heterocycle of the replacement of " heterocyclic radical of saturated replacement " refer to there is not degree of unsaturation in all rings monocycle of (for example carbon-to-carbon is unsaturated, and carbon-nitrogen is unsaturated, and nitrogen-nitrogen is unsaturated or the like) or a plurality of fused rings.

" heterocyclic radical of undersaturated replacement " refers to have in any ring substituted heterocycle of the non-aromatic of the monocycle of degree of unsaturation (for example carbon-to-carbon is unsaturated, and carbon-nitrogen is unsaturated, and nitrogen-nitrogen is unsaturated or the like) or a plurality of fused rings.

" heterocyclyloxy base " refers to group-O-heterocyclic radical; " the heterocyclyloxy base of replacement " refers to the heterocyclic radical that group-O-replaces.

" alkyl-carbonyl-amino of replacement " refers to by the alkyl of group-NHC (O)-replacement.

" mercaptan " refers to group-SH.

" alkylthio " refers to group-S-alkyl.

" alkylthio of replacement " refers to the alkyl that group-S-replaces.

" sulfo-cycloalkyl " refers to group-S-cycloalkyl.

" the sulfo-cycloalkyl of replacement " refers to the cycloalkyl that group-S-replaces.

" thioaryl " refers to group-S-aryl; " thioaryl of replacement " refers to the aryl that group-S-replaces.

" thio ceteroary " refers to group-S-heteroaryl; " thio ceteroary of replacement " refers to the heteroaryl that group-S-replaces.

" sulfo-heterocyclic radical " refers to group-S-heterocyclic radical; " the sulfo-heterocyclic radical of replacement " refers to the heterocyclic radical that group-S-replaces.

" pharmaceutically-acceptable salts " refers to the pharmaceutically-acceptable salts of the compound of formula I, and described salt is derived from various organic and inorganic companion ions well known in the art, comprise, only as an example, sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium or the like; And when molecule contains basic functionality, be the salt of organic or inorganic acid, hydrochloride for example, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate or the like. Compound

Compound of the present invention can use the initiator preparation from easy acquisition of following general method and step.Be appreciated that except as otherwise noted the condition that provides usually is general or preferably treatment condition (being temperature of reaction, time, the mol ratio of reactant, solvent, pressure or the like); Also can use other treatment condition.Optimum reaction condition can be along with employed concrete reactant or solvent and difference, and such condition those skilled in the art can determine by the optimization routine method.

In addition, the GPF (General Protection False group may be necessary, and with the reaction that prevents that some functional group from not expecting, this point it will be apparent to those skilled in the art that.For the appropriate protection group and the protection of various functional groups with to go to protect the conditions suitable of concrete functional group be well known in the art.For example, a variety of blocking groups are described in T.W.Greene and G.M.Wuts, the blocking group in the organic synthesis (Protect Group in Organic Synthesis) second edition, Wiley, New York, 1991 and wherein the citation reference.

In addition, compound of the present invention generally can contain one or more chiral centres.Therefore, if expectation can or be separated into pure steric isomer with such compound, promptly various enantiomorphs or diastereomer are perhaps as the mixture of enrichment steric isomer.All such steric isomers (with the mixture of enrichment) comprise within the scope of the invention, except as otherwise noted.Pure steric isomer (or mixture of enrichment) can use optical activity initiator for example well known in the art or stereoselectivity reagent to prepare.Perhaps, the racemic mixture of such compound can use for example chiral column chromatogram, and chiral selectors or the like separates.

In a preferred synthetic method, wherein Q is-C (O) NR ⁷-formula I and the compound of IA as follows: the amino acid of the SULPHURYL CHLORIDE coupling formula II of formula III,

R wherein ², R ³And R ⁴As above definition,

R ¹-SO ₂-Cl III is R wherein ¹As above definition obtains the N-sulfuryl amino acid of formula IV: R wherein ¹-R ³As above definition.

Generally by for example make amino acid and at least one equivalent of formula II in the reagent such as methylene dichloride at inert solvent, preferably approximately 1.1 reacts to about 2 normal SULPHURYL CHLORIDE III and carries out in reaction.Generally speaking, being reflected at about-70 ℃ carried out about 1 to about 24 hours to the temperature of about 40 ℃ of scopes.Preferably, this is reflected at suitable alkali and exists and carry out the acid that produces with in the cleaning reaction process down.Suitable alkali comprises, tertiary amine for example, triethylamine for example, diisopropyl ethyl amine, N-methylmorpholine or the like.Perhaps, reaction can be used the aqueous solution of alkali, and for example sodium hydroxide or the like carries out under Schotten-Baumann type condition as alkali.After reacting completely, the N-sulfuryl amino acid IV that obtains reclaims by ordinary method, and described recovery method comprises neutralization, extraction, and precipitation, chromatogram is filtered or the like.

The amino acid of the formula II that uses in the reaction is compound known or can prepares from known compound by conventional synthetic method above.The suitable amino acid whose example that uses in this reaction includes but not limited to the L-proline(Pro), and is anti--4-hydroxyl-L-proline(Pro), suitable-4-hydroxyl-L-proline(Pro), instead-and 3-phenyl-L-proline(Pro), suitable-3-phenyl-L-proline(Pro), L-(2-methyl) proline(Pro), dl pipecolinic acid, L-azetidine-2-carboxylic acid, L-indoline-2-carboxylic acid, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-(5, the 5-dimethyl) thiazoline-4-carboxylic acid, L-thia morpholine-3-carboxylic acid, glycine, 2-tertiary butyl glycine, D, L-phenylglycocoll, the 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, 1-1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane carboxylic acid, 1-aminocyclopentanecarboxylic acid (cycloleucine), the amino cyclohexane carboxylic acid of 1-, L-Serine or the like.If expectation, the amino acid whose corresponding carboxylic acid ester that can use formula II is methyl esters for example, and ethyl ester or the like reacts with SULPHURYL CHLORIDE III in above-mentioned reaction.Next using conventional reagent and condition, promptly for example handle in the methanol at inert diluent with alkali metal hydroxide, is carboxylic acid with hydrolysis of ester group, obtains N-sulfuryl amino acid IV.

Similarly, the SULPHURYL CHLORIDE of the formula III that uses in the reaction above is compound known or can prepares from compound known by conventional synthetic method.Such compound generally uses phosphorus trichloride and phosphorus pentachloride from corresponding sulfonic acid, promptly from R wherein ¹Formula R as defined above ¹-SO ₃The compound of H.This reaction is not generally by having under the solvent or at inert solvent for example in the methylene dichloride, under about 0 ℃ of temperature to about 80 ℃ of scopes, make sulfonic acid contact about 1 with phosphorus pentachloride to about 48 hours, obtain SULPHURYL CHLORIDE with the phosphorus trichloride of about 2-5 molar equivalent.Perhaps, the SULPHURYL CHLORIDE of formula III can be by using chlorine (Cl under the popular response condition ₂) and water treatment mercaptan and from corresponding mercaptan compound promptly from R wherein ¹Formula R as defined above ¹The compound of-SH.

Being fit in the present invention, the embodiment of the SULPHURYL CHLORIDE of use includes but not limited to methylsulfonyl chloride, 2-propane SULPHURYL CHLORIDE, 1-butane SULPHURYL CHLORIDE, benzene sulfonyl chloride, 1-naphthalic sulfonic chloride, 2-naphthalic sulfonic chloride, Tosyl chloride, α-toluene sulfonyl chloride, 4-acetylsulphanilyl chloride, 4-amidino groups benzene sulfonyl chloride, 4-tert.-butylbenzene SULPHURYL CHLORIDE, 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 chlorides, 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, or the like.If expectation can be used sulfonic acid fluoride in the superincumbent reaction, sulfuryl bromide or sulfonic anhydride replace the N-sulfuryl amino acid of SULPHURYL CHLORIDE production IV.

The intermediate N sulfuryl amino acid of formula IV also can through type V sulphonyl ammonia and formula L (R ³) carboxylic acid derivative of CHCOOR reacts and prepares:

R ¹-SO ₂-NH-R ²V is R wherein ¹And R ²As above definition, L is a leavings group, chlorine for example, bromine, iodine, methylsulfonyl, tosyl group or the like, R ³As above definition and R are hydrogen or alkyls.This reaction generally suitable alkali for example triethylamine in the presence of, at inert diluent for example among the DMF, make sulphonyl ammonia V contact at least 1 equivalent under about 24 ℃ of temperature to about 37 ℃ of scopes, the preferred normal carboxylic acid derivative of 1.1-2 about 0.5 carried out to about 4 hours.This reaction is further described in Zuckermann etc., JACS (J.Am.Chem.Soc)., 1992,114,10646-10647.The preferred carboxylic acid derivative that is used for the present invention's reaction is α chlorine and α-bromine carboxylicesters, for example bromo-acetic acid tert-butyl or the like.When in this reaction, using carboxylicesters, use ordinary method to follow the hydrolysis ester group, obtain the N-sulfuryl amino acid of formula IV.

Come the compound of preparation formula I then by the intermediate N sulfuryl amino of coupling formula IV amino acid derivative sour and formula VI: R wherein ⁵-R ⁷As above definition.This linked reaction is general uses known coupling agent to carry out, carbodiimide for example, bop reagent (benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate) or the like.The suitable carbonization diimine comprises for example dicyclohexyl carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) or the like.If expectation also can be used the carbodiimide coupling agent of polymer supported form, comprise tetrahedron wall bulletin (Tetrahedron Letters) for example, those that describe in 34 (48), 7685 (1993).In addition, also can use for example N-hydroxy-succinamide of known coupling promotor, I-hydroxybenzotriazole or the like promotes linked reaction.

Linked reaction is generally by at inert diluent methylene dichloride for example; chloroform; acetonitrile; tetrahydrofuran (THF); N; in dinethylformamide or the like, make N-sulfuryl amino acid IV contact about 1 to about 2 normal coupling agent and at least 1 equivalent, preferably approximately 1 carries out to about 1.2 normal amino acid derivative VI.Generally speaking, this is reflected under about 0 ℃ of temperature to about 37 ℃ of scopes and carried out about 12 to about 24 hours.When reacting completely, the compound of formula I reclaims by ordinary method, comprises neutralization, extraction, and precipitation, chromatogram is filtered or the like.

Perhaps, N-sulfuryl amino acid IV can be converted into acyl halide, and acyl halide coupling amino acid derivative VI obtains the compound of formula I.The acyl halide of formula VI can prepare by make VI contact mineral acid halogenide under normal condition, thionyl chloride for example, and phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, perhaps preferably, with the oxalyl chloride coupling.Generally speaking, this is reflected at does not have under the solvent or at inert solvent for example in methylene dichloride or the tetracol phenixin, under about 0 ℃ of temperature to about 80 ℃ of scopes, use the mineral acid carboxylic acid halides of about 1-5 molar equivalent or oxalyl chloride to carry out carrying out in about 1 to about 48 hours.Also can use catalyzer in this reaction, N for example, dinethylformamide.

The acyl halide of N-sulfuryl amino acid IV is then at inert diluent for example in the methylene dichloride; under about-70 ℃ temperature to about 40 ℃ of scopes; coupling at least 1 equivalent, preferably approximately 1.1 to about 1.5 normal amino acid derivative VI about 1 to about 24 hours.Preferably, this is reflected under the suitable alkali existence and carries out, with the acid that produces in the cleaning reaction.Suitable alkali comprises for example tertiary amines, triethylamine for example, diisopropyl ethyl amine, N-methylmorpholine or the like.Perhaps, this reaction can under Schotten-Baumann type condition, use alkali aqueous solution for example sodium hydroxide or the like carry out.After reacting completely, the compound by ordinary method recovery type I comprises neutralization, extraction, and precipitation, chromatogram is filtered or the like.

Perhaps, the compound of formula I can prepare by the diamino acid derivative of production VII at first: R wherein ², R ³And R ⁵-R ⁷As above definition.The diamino acid derivative of formula VII can be by using conventional amino acid coupling technology and reagent, for example aforesaid carbodiimide, bop reagent or the like, the amino acid of coupling formula II and the amino acid derivative of formula VI and preparation easily.Diamino acid VII can use the SULPHURYL CHLORIDE of formula III then and use above-mentioned synthetic method sulfonylation, and the compound of formula I is provided.

The amino acid derivative of the formula VI that uses in the reaction is compound known or can prepares from compound known by conventional synthetic method above.For example, (Wisconsin USA) carries out the C-alkylation and prepares the alkyl halide that the amino acid derivative of formula VI can be by using alkyl or replacement for Aldrich, Milwaukee with commercially available 2-acetamino diethyl malonate.This reaction was generally carried out by handle the 2-acetamino diethyl malonate with the alkyl halide of 1 normal sodium ethylate and 1 normal alkyl or replacement in the ethanol that refluxes at least at least in about 6 hours to about 12 hours.By about 6 to about 12 hours deacetylations of heating in the aqueous hydrochloric acid that refluxes, hydrolysis and decarboxylationization obtain amino acid to the alkylating malonic ester of the C-that obtains, and generally are its hydrochlorides then.

The example of the amino acid derivative of the formula VI that uses in the suitable superincumbent reaction includes but not limited to L-4-oil of mirbane alanine methyl ester, the L-L-Tyrosine methyl ester, D, L-height-4-oil of mirbane alanine methyl ester, L-(O-benzyl) L-Tyrosine methyl ester, L-3,5-two iodo L-Tyrosine methyl esters, L-3-iodogorgonic acid methyl esters or the like.If expect, can certainly use other ester or the acid amides of above-claimed cpd.

For convenience synthetic, the compound of formula I generally is prepared into ester, i.e. R wherein ⁶It is alkoxyl group of alkoxyl group or replacement or the like.If expectation, this ester group can use normal condition and reagent hydrolysis, and corresponding carboxylic acid is provided.Typically, by at inert diluent for example in the mixture of methyl alcohol or first alcohol and water, about 0 ℃ to the temperature of about 24 ℃ of scopes, use at least 1 normal alkali metal hydroxide, lithium for example, the oxyhydroxide of sodium or potassium is handled ester about 1 and was carried out this reaction to about 12 hours.Perhaps, can by use palladium catalyst for example the carbon palladium carry out hydrogenolysis and remove benzene methyl.If expectation, the carboxylic acid that obtains can use above-mentioned conventional coupling agent and condition coupling amine, for example Beta-alanine ethyl ester, hydroxyl amine, for example oxyamine and N-hydroxy-succinamide, the alkoxylamine of alkoxylamine and replacement, for example O-methyl oxyamine and O-benzyl oxyamine or the like.

Other functional group that exists on any substituting group of the compound of formula I can use known synthetic method easily to be modified or the materialization of deriving before or after above-mentioned linked reaction, and this point it will be apparent to those skilled in the art that.For example the nitro that exists on the substituting group of the compound of formula I or its intermediate can be easily by palladium catalyst for example the hydrogenization in the presence of the carbon palladium reduce, obtain corresponding amino.This reaction was generally carried out in inert solvent about 6 to about 24 hours to about 50 ℃ temperature at about 20 ℃.R ⁵The compound that has nitro on the substituting group can be for example by using 4-oil of mirbane alanine derivatives or the like to prepare in above-mentioned linked reaction.

Similarly, pyridyl can be at platinum catalyst for example in the presence of the platinum oxide, and hydrogenation in acid thinner provides corresponding pyridine base analogue.Typically, by in the presence of catalyzer, about 20 ℃ to about 50 ℃ temperature at acid thinner for example in the mixture of methyl alcohol and aqueous hydrochloric acid, be about 20psi to about 60psi with pressure range, the hydrogen processing pyridine compounds of preferably approximately 40psi carries out this reaction.Have pyridyl compound can by for example use β-(2-pyridyl)-, β-(3-pyridyl)-, or β-(4-pyridyl)-L-alanine derivatives preparation easily in above-mentioned linked reaction.

In addition, as the R of the compound of formula I ⁵Substituting group or its intermediate contain uncle or secondary amino group, and the materialization of can further deriving before or after above-mentioned linked reaction of then such amino for example provides acid amides, sulphonamide, urea, thiourea, carbamate, secondary amine or tertiary amine or the like.R ⁵Having the compound of primary amino on the substituting group can be for example prepare by reducing corresponding nitro-compound as mentioned above.Perhaps, such compound can be by using from Methionin, and amino acid derivative of deutero-formula VI such as 4-amino-benzene L-Ala or the like prepares in above-mentioned linked reaction.

Explanation for example has and comprises for example R wherein of uncle or the substituting group of secondary amino group ⁵The compound or the intermediate that are the formula I of (4-aminophenyl) methyl can use conventional acylating reagent and condition N-acidylate easily, obtain corresponding amide.This acylation reaction is generally by at coupling agent carbodiimide for example; bop reagent (benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate) or the like exists down; at inert diluent methylene dichloride for example, chloroform, acetonitrile; tetrahydrofuran (THF); N, in dinethylformamide or the like, about 0 ℃ to the temperature of about 37 ℃ of scopes; with at least 1 equivalent, preferably approximately 1.1 is handled aminocompound about 4 to about 1.2 normal carboxylic acids and was carried out to about 24 hours.Preferably, use promotor, N-hydroxy-succinamide for example, I-hydroxybenzotriazole or the like promotes acylation reaction.The example that is adapted at the carboxylic acid of use in this reaction includes but not limited to N-tertiary butyl oxygen base carbonyl glycine; N-tertiary butyl oxygen base carbonyl-L-phenylalanine; N-tertiary butyl oxygen base carbonyl aspartic acid benzene methyl; phenylformic acid; the different 3-pyridine carboxylic acid of N-tertiary butyl oxygen base carbonyl, the different 3-pyridine carboxylic acid of N-methyl, N-tertiary butyl oxygen base carbonyl 3-pyridine carboxylic acid; N-tertiary butyl oxygen base carbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-alkylsulfonyl)-L-proline(Pro) or the like.

Perhaps, compound or its intermediate that comprises the formula I of uncle or secondary amino group can use acyl halide or carboxylic acid anhydride to generate corresponding amide and the N-acidylate.This reaction is general by at inert diluent for example in the methylene dichloride; approximately-70 ℃ to the temperature of about 40 ℃ of scopes; make aminocompound contact at least 1 equivalent, preferably approximately 1.1 to about 1.2 normal acyl halides or carboxylic acid anhydride about 1 carried out to about 24 hours.If the expectation, can use acylation reaction catalyst for example 4-(N, N-dimethylamino) pyridine promote acylation reaction.This acylation reaction is preferably carried out in the presence of suitable alkali, with the acid that produces in the cleaning reaction.Suitable alkali comprises for example tertiary amines, triethylamine for example, diisopropyl ethyl amine, N-methylmorpholine or the like.Perhaps, this reaction can under Schotten-Baumann type condition, use alkali aqueous solution for example sodium hydroxide or the like carry out.

Be adapted at the acyl halide of use in this reaction or the example of carboxylic acid anhydride and include but not limited to 2-methyl-prop acyl chlorides; trimethyl-acetyl chloride, phenyl Acetyl Chloride 98Min., Benzoyl chloride; the 2-bromo-benzoyl chloride; the 2-methyl benzoyl chloride, 2-trifluoromethyl benzoyl chloride, Yi Yansuan acyl chlorides; the nicotinic acid acyl chlorides; the pyridine formyl chloride, acetic anhydride, succsinic acid acid anhydrides or the like.Urea chloride, N for example, the N-dimethylcarbamyl chloride, N, N-diethylamino formyl chloride or the like also can use in this reaction, obtain urea.Similarly, also can use the carbonic acid hydrogen ester, for example the hydrogen-carbonate di tert butyl carbonate provides carbamate.

In similar method, the compound or its intermediate that comprise the formula I of uncle or secondary amino group can use sulfonic acid halide or sulfonic anhydride N-sulfonylation, generate sulphonamide.The sulfonic acid halide or the sulfonic anhydride that are adapted at using in this reaction include but not limited to methylsulfonyl chloride, chloromethyl SULPHURYL CHLORIDE, Tosyl chloride, trifluoromethanesulfonic acid acid anhydrides or the like.Similarly, can use sulphonamide chlorine, dimethylamino SULPHURYL CHLORIDE for example, obtain sulphonamide (for example＞N-SO ₂-N＜).

In addition, uncle who exists on the compound of formula I or the substituting group of its intermediate or secondary amino group can react with isocyanic ester or isothiocyanic acid ester respectively, obtain urea or thiocarbamide.This reaction is general by at inert diluent for example in the toluene etc., about 24 ℃ to about 37 ℃ of range temperature, make aminocompound contact at least 1 equivalent, preferably approximately 1.1 to about 1.2 normal isocyanic ester or isothiocyanic acid ester about 12 carried out to about 24 hours.The isocyanic ester and the isothiocyanic acid ester that use in this reaction are commercially available or can use known synthetic method from commercially available compound.For example isocyanic ester and isothiocyanic acid ester prepare by reacting suitable amine photoreactive gas or thiophosgene easily.Be adapted at the isocyanic ester of use in this reaction and the example of isothiocyanic acid ester and include but not limited to ethyl isocyanate, propyl isocyanate, isocyanic acid 4-cyanobenzene ester, isocyanic acid 3-methoxyl group phenyl ester, isocyanic acid 2-phenyl chlorocarbonate, methyl thio-isocyanate, the isothiocyanic acid ethyl ester, isothiocyanic acid 2-phenyl chlorocarbonate, isothiocyanic acid 3-phenyl propyl ester, isothiocyanic acid 3-(N, the N-diethylamino) propyl ester, isothiocyanic acid phenyl ester, isothiocyanic acid benzene methyl, isothiocyanic acid 3-pyridine ester, different thiocyanide of fluorescein (isomer I) or the like.

In addition, when the compound of formula I or its intermediate contained uncle or secondary amino group, amino can use aldehydes or ketones to carry out standard reductive alkylation, generates the second month in a season or uncle's amino.This reaction is general by at inert diluent methyl alcohol for example, tetrahydrofuran (THF), in its mixture etc. about 0 ℃ to about 50 ℃ temperature, make aminocompound contact at least 1 equivalent, preferably approximately 1.1 to about 1.5 normal aldehydes or ketones and at least based on 1 equivalent metal hydride reducing agent of aminocompound for example sodium cyanoborohydride about 1 carried out to about 72 hours.The aldehyde and the ketone that are adapted at using in this reaction comprise for example phenyl aldehyde, 4-chlorobenzaldehyde, valeral or the like.

In similar method, when the compound of formula I or its intermediate had the substituting group that contains hydroxyl, this hydroxyl can further be modified or the materialization of deriving before or after above-mentioned linked reaction, and ethers for example, amino formate or the like are provided.R for example ⁵On have the compound of hydroxyl, for example can use in above-mentioned reaction amino acid derivative preparation from deutero-formula VI such as tyrosine.

For example, has the substituting group R wherein for example that contains hydroxyl ⁵Be compound or the O-alkylation easily of its intermediate of the formula I of (4-hydroxy phenyl) methyl, generate ethers.This O-alkylation generally by at inert diluent acetone for example, in 2-butanone or the like, makes suitable basic metal or the alkaline earth metal alkali of oxy-compound contact, and for example salt of wormwood carries out, and generates the basic metal or the alkaline earth salt of hydroxyl.Usually do not separate this salt, but on the spot with the alkyl halide of at least 1 normal alkyl or replacement or sulphonate alkyl chloride for example, alkyl bromide, alkyl iodide, methanesulfonates or tosylate reaction obtain ether.Generally speaking, this is reflected at about 60 ℃ and carried out about 24 hours to about 72 hours to the temperature of about 150 ℃ of scopes.Preferably, when in reaction, using alkyl chloride or alkyl bromide, in reaction mixture, add the sodium iodide or the potassiumiodide of catalytic amount.

Be adapted at the alkyl of use in this reaction or the alkyl halide of replacement and the example of sulphonate and 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, N-ethylamino) ethyl chloride, 2-(N, the N-diisopropylaminoethyl) ethyl chloride, 2-(N, N-dibenzyl amino) ethyl chloride, 3-(N, the N-ethylamino) 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, toluenesulphonic acids N-tertiary butyl oxygen base carbonyl-3-piperidines methyl esters or the like.

Perhaps, the hydroxyl that exists on the substituting group of the compound of formula I or its intermediate can use Mitsunobu reaction carrying out O-alkylation.In this reaction, with alcohol 3-(N for example, the N-dimethylamino)-the 1-propyl alcohol or the like, at inert diluent for example in the tetrahydrofuran (THF), approximately-10 ℃ to the temperature of about 5 ℃ of scopes, reacted about 0.25 to about 1 hour with about 1.0 to about 1.3 normal triphenylphosphines and about 1.0 to about 1.3 normal diethylazodicarboxylates.Add about 1.0 to about 1.3 normal oxy-compound then, N-tertiary butyl L-Tyrosine methyl ester for example, reaction mixture stirs about 2 to about 48 hours at about 0 ℃ to about 30 ℃ temperature, obtain the O-alkylate.

In similar method, the compound or its intermediate that contain the formula I of aryl hydroxyl can obtain diaryl ether with the aryl iodide reaction.Generally speaking, this reaction is by at inert diluent for example in the dimethylbenzene, approximately-25 ℃ to about 10 ℃ temperature, uses suitable alkali for example an alkali metal salt of sodium hydride generation hydroxyl carry out.To the temperature of about 30 ℃ of scopes, handle this salt about 0.5 to about 2.0 hours at about 10 ℃ then with about 1.1 to about 1.5 normal cuprous bromide methyl-sulfide title complexs, then with about 1.1 to about 1.5 normal aryl iodides, for example processing such as 2-iodobenzoic acid sodium.This reaction is heated to about 70 ℃ extremely about 150 ℃ about 2 then to about 24 hours, obtains diaryl ether.

In addition, the compound that the contains hydroxyl generation carbamate of also can easily deriving.In a method of the such carbamate of preparation, the oxy-compound of formula I or its intermediate are at inert diluent for example in the methylene dichloride, approximately-25 ℃ to about 0 ℃ temperature, contact about 1.0 to about 1.2 normal chloroformic acid 4-nitro phenyl esters about 0.5 to about 2.0 hours.With excessive, preferably approximately 2 is to about 5 normal trialkylamines, and triethylamine is for example handled the carbonic ether about 0.5 that obtains to about 2 hours, then with about 1.0 to about 1.5 normal uncles or secondary amine processing, obtains carbamate.The example that is adapted at the amine of use in this reaction includes but not limited to piperazine, 1-methylpiperazine, 1-ethanoyl piperazine, morpholine, thiomorpholine, tetramethyleneimine, piperidines or the like.

Perhaps, in another method of preparation carbamate, the compound that contains hydroxyl is at inert diluent for example in the methylene dichloride, about 25 ℃ to the temperature of about 70 ℃ of scopes, contact about 1.0 to about 1.5 normal urea chlorides about 2 to about 72 hours.Generally speaking, this is reflected under the suitable alkali existence and carries out, with the acid that produces in the cleaning reaction.Suitable alkali comprises for example tertiary amines, triethylamine for example, diisopropyl ethyl amine, N-methylmorpholine or the like.In addition, 4-(N, the N-dimethylamino) pyridine that preferably adds at least 1 equivalent (based on oxy-compound) in reaction mixture helps reacting.The example that is adapted at the urea chloride of use in this reaction comprises for example dimethylcarbamyl chloride, diethylamino formyl chloride or the like.

Similarly, when the compound of formula I or its intermediate contained uncle or secondary hydroxyl, such hydroxyl can easily be converted into leavings group and displacement, to generate for example amine, sulfide and fluorochemical.For example the derivative of 4-hydroxyl-L-proline(Pro) can be converted into corresponding 4-amino by the nucleophilic displacement of deutero-hydroxyl, 4-sulfo-or 4-fluoro-L-proline derivative.Generally speaking, when using chipal compounds in these reactions, the stereochemistry at the carbon atom place that is connected with the deutero-hydroxyl is generally transformed.

These reactions general by at first by in pyridine, using for example mass treatment oxy-compound such as Tosyl chloride of at least 1 normal sulfonic acid halide, with hydroxyl be converted into leavings group for example tosylate carry out.This reaction was generally carried out about 1 to about 48 hours to about 70 ℃ temperature at about 0 ℃.The tosylate that obtains then can be for example by at inert diluent N for example, in the mixture of dinethylformamide and water, about 0 ℃ to about 37 ℃ temperature, make tosylate contact at least 1 normal sodiumazide about 1 to about 12 hours, obtain corresponding azido cpd, by this reaction, the tosylate that obtains is easily replaced with sodiumazide.Azido-can reduce by for example using carbon-palladium catalyst hydrogenation then, obtains amino (NH ₂) compound.

Similarly, the toluenesulphonic acids ester group can easily be replaced by mercaptan, generates sulfide.This reaction is general by at suitable alkali for example 1,8-diazabicyclo [5.4.0] undecane-7-alkene (DBU) exists down, at inert diluent N for example, in the dinethylformamide, about 0 ℃ to about 37 ℃ temperature, make tosylate contact at least 1 normal mercaptan about 1 to about 12 hours, obtain sulfide and carry out.In addition, at inert diluent for example in the methylene dichloride, about 0 ℃ to about 37 ℃ temperature, handle tosylate about 12 to about 24 hours with morpholinyl sulphur trifluoride, obtain corresponding fluorine cpd.

In addition, have and comprise the substituent of iodo aryl, for example, work as R ⁵Compound or its intermediate of formula I when being (4-iodophenyl) methyl can easily be converted into biaryl compound before or after above-mentioned linked reaction.Generally speaking, by at palladium catalyst for example in the presence of the tetrakis triphenylphosphine palladium, at inert diluent for example in the tetrahydrofuran (THF), about 24 ℃ to the temperature of about 30 ℃ of scopes, with about 1.1 to about 2 normal aryl zinc iodides for example 2-(methoxycarbonyl) phenyl zinc iodide processing iodo aryl compound carry out this reaction up to reacting completely.This reaction is further described in for example Rieke, organic chemistry magazine (J.Org.Chem) .1991,56,1445.

In some cases, the compound of formula I or its intermediate can contain the substituting group with one or more sulphur atoms.For example, the amino acid of the formula II that uses in reaction in the above is from L-thiazolidine-4-carboxylic acid, when L-(5, the 5-dimethyl) thiazolidine-4-carboxylic acid, L-thiomorpholine-deutero-such as 3-carboxylic acid, will have such sulphur atom.When existing, such sulphur atom can use conventional reagent and reaction conditions oxidation before or after linked reaction, obtain sulfoxide or sulphones.The suitable reagent that is used for sulfide oxidation and becomes sulfoxide comprises, for example, and hydrogen peroxide, 3-chloro-peroxy benzoic acid (MCPBA), sodium periodate or the like.General by at inert diluent for example in the methylene dichloride, approximately-50 ℃ to the temperature of about 75 ℃ of scopes, make sulfide contact about 0.95 to about 1.1 normal oxygenant about 1 and carried out this oxidizing reaction to about 24 hours.The sulfoxide that obtains then can be by making sulfoxide contact other at least 1 normal oxygenant, hydrogen peroxide for example, MCPBA, potassium permanganate or the like and further be oxidized to corresponding sulfone.Perhaps, can be by directly making sulfide contact at least 2 equivalents, preferred excessive oxygenant prepares sulfone.Such reaction is further described in " Advanced Organic Chemistry " (Advanced OrganicChemistry), the 4th edition, pp.1201-1202, Wiley publisher, 1992.

As mentioned above, R ²Substituting group is not the amino acid that the compound of the formula I of hydrogen can use the N-of formula II to replace, sarkosine for example, and N-methyl-L-phenylalanine or the like prepares in above-mentioned linked reaction.Perhaps such compound can be by using conventional synthetic method with the sulphonamide of formula I or IV (R wherein ²Being hydrogen) the N-alkylation prepares.Typically, by at suitable alkali for example in the presence of the salt of wormwood, at inert diluent acetone for example, in the materials such as 2-butanone, about 25 ℃ to the temperature of about 70 ℃ of scopes, make sulphonamide contact at least 1 equivalent, the alkyl halide about 2 of preferred 1.1 to 2 normal alkyl or replacement carried out the N-alkylated reaction to about 48 hours.The example that is adapted in this reaction the alkyl halide of the alkyl that uses or replacement includes but not limited to methyl iodide or the like.

In addition, R wherein ²Be hydrogen and R ¹Be that the formula I of 2-carbalkoxy aryl or the sulphonamide of IV can be generated 1,2-benzisothiazole-3-ketone derivatives or its analogue by intramolecular cyclization.This reaction is general by at inert diluent for example in the tetrahydrofuran (THF); about 0 ℃ to the temperature of about 30 ℃ of scopes; with about 1.0 to 1.5 normal suitable alkali for example alkalimetal hydride handle sulphonamide; for example N-(2-methoxycarbonyl phenyl alkylsulfonyl) glycine-L-phenylalanine benzene methyl about 2 carried out to about 48 hours; obtain 1 of cyclisation, 2-benzisothiazole-3-ketone derivatives.

At last, wherein Q is C (S) NR ⁷-the compound of formula I can use the thiocarbamoyl acid derivative to replace the amino acid II that in above-mentioned synthetic method, uses to prepare.Such thiocarbamoyl acid derivative can be by being described in Shalaky etc., organic chemistry magazine (J.Org.Chem.), 61:9045-9048 (1996) and Brain etc., organic chemistry magazine (J.Org.Chem.), method preparation among the 62:3808-3809 (1997), these documents are hereby incorporated by reference. Pharmaceutical formulations

When the medicine, the compound of formula I and IA is usually with the form administration of pharmaceutical composition.These compounds can pass through the number of ways administration, comprise oral, rectum, subcutaneous through skin, intravenously is in intramuscular and the nose.These compounds are effective as injection and oral compositions.Such composition is with the preparation of pharmaceutical field known method and comprise at least a active compound.

The present invention also comprises pharmaceutical composition, and it contains as one or more above-mentioned formula I of activeconstituents and compound and the pharmaceutical acceptable carrier of IA.In preparation composition of the present invention, activeconstituents by the vehicle dilution or be encapsulated in such carrier, can be a capsule usually and mixed with excipients, sachet, paper or other reservoir form.When vehicle worked as a kind of thinner, it can be the vehicle as activeconstituents, the solid that carrier or matrix work, semisolid, or fluent material.Therefore, composition can be a tablet, pill, pulvis, lozenge, sachet, cachet, the agent of speeding, suspension agent, emulsion, solution, syrup, aerosol (as solid or in fluid matrix) for example contains the nearly ointment of the active compound of 10% weight, soft hard gelatin capsule, suppository, the pulvis of aseptic parenteral solution and sterile packed.

In the preparation preparation, may need levigate active compound, with provide suitable granularity before other composition mixes.If active compound is undissolved basically, then be finely ground to usually less than 200 purpose granularities.If active compound is dissolved in water basically, then usually by grinding so that equally distributed granularity in preparation basically, for example about 40 orders to be provided.

Some examples of suitable vehicle comprise lactose, glucose, sucrose, Sorbitol Powder, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, water, syrup and methylcellulose gum.Preparation can comprise in addition: lubricant, talcum for example, Magnesium Stearate and mineral oil; Wetting agent; Emulsifying agent and suspension agent; Preservation agent, for example methyl-and propyl hydroxy benzoate; Sweeting agent; And correctives.Composition of the present invention can be prepared like this, so that by the snap-out release of activeconstituents is provided after using method well known in the art to patient's administration, and slowly-releasing and postpone to discharge.

Composition preferably is mixed with unit dosage form, and each dosage contains about 5 to about 100mg, more generally about activeconstituents of 10 to about 30mg.Term " unit dosage form " refers to be suitable for the physical sepn unit of people receptor and other mammiferous unitary dose, and each dosage contains calculating with the active substance of the predetermined amount of generation desired therapeutic effect and suitable pharmaceutical excipient.

Active compound is effective at wide dosage range, and generally with the pharmacy effective dose administration.But general clear, in fact the amount of administered compound will be determined by the doctor, consider the condition of being correlated with, comprise the symptom that will treat, the route of administration of selection, actual give with compound, each patient's age, body weight and reaction, severity of patient's symptom or the like.

For preparing for example tablet of solids composition, main active ingredient is mixed with pharmaceutical excipient, forms the solid preformulation composite of the mixture that contains uniform The compounds of this invention.When referring to that these pre-preparation compositions are uniform, the meaning is that activeconstituents is distributed in the composition equably, makes composition can easily be divided into EU Equivalent Unit dosage form, for example tablet, pill and capsule again.This solid preformulation and then be divided into the unit dosage form of the above-mentioned type contains for example 0.1 to about 500mg activeconstituents of the present invention.

Tablet of the present invention or pill can be allocated so that the dosage form with time-lag action advantage to be provided by dressing or by other.For example, tablet or pill can comprise internal dose and outside dose components, and the latter is the former shell form.These two kinds of compositions can be separated by enteric layer, and this enteric layer is resisted disintegration under one's belt, and allow internal component complete enter duodenum or postpone discharge.Multiple material can be used for such enteric layer or dressing, and such material comprises multiple polymers acid and polymeric acid and shellac, the mixtures of material that the pure and mild rhodia of hexadecyl is such.

Wherein can mix the aqueous solution syrup that liquid form that the new composition of the present invention is used for oral or drug administration by injection comprises suitable flavoring, water or oil suspension, with contain for example cotton seed oil of edible oil, sesame oil, the emulsion of the flavoring of Oleum Cocois or peanut oil, and speed agent and similar drug excipient.

The composition that is used for sucking or be blown into comprises the solution and the suspension of the acceptable water of pharmacy or organic solvent or their mixture, and pulvis.This liquid or solid composition can contain the acceptable above-described vehicle of suitable pharmacy.Preferably, composition can be used for part or general action by oral or nasal respiration administration.Preferably the composition in the pharmacy acceptable solvent can be by using the rare gas element spraying.The solution of spraying can be directly sucks or spraying plant can joint face cover cap, perhaps intermittent positive pressure power respiratory organ from spraying plant.Solution, suspension or dust composition be per os or nasal administration from the device that send delivery formulations with suitable manner preferably.

Following example of formulations describes pharmaceutical composition of the present invention in detail.

Example of formulations 1

Preparation contains the hard gelatin capsule of following composition: Composition Amount (mg/ capsule)Activeconstituents 30.0 starch 305.0 Magnesium Stearates 5.0

Mentioned component is mixed and be loaded in the hard gelatin capsule with the amount of 340mg.

Example of formulations 2

Use following composition to prepare tablet: Composition Amount (mg/ tablet)Activeconstituents 25.0 Mierocrystalline celluloses, Microcrystalline Cellulose 200.0 colloid silicas 10.0 stearic acid 5.0

Mix these compositions and be pressed into the heavy tablet of every 240mg.

Example of formulations 3

Preparation contains the dry powder inhalation of following composition: Composition Amount %Activeconstituents 5 lactose 95

Activated mixture mixes with lactose and mixture is packed in the dry powder suction apparatus.

Example of formulations 4

Be prepared as follows every tablet of tablet that contains the 30mg activeconstituents: Composition Amount (mg/ tablet)Active component 30.0mg starch 45.0mg microcrystalline cellulose 35.0mg polyvinylpyrrolidone 4.0mg (as 10% aqueous solution) sodium carboxymethyl starch 4.5mg dolomol 0.5mg talcum 1.0mg amounts to 120mg

Activeconstituents, starch and Mierocrystalline cellulose are by No.20 order U.S. sieve and thorough mixing.The solution of polyvinylpyrrolidone and the powder mixes that obtains, it is then by 16 order U.S. sieve.Zhi Bei particle is dry down also by 16 order U.S. sieve at 50 ℃ to 60 ℃ like this.Sodium starch glycolate, Magnesium Stearate and talcum by No.30 order U.S. sieve, join in the particle in advance then, and it mixes back compacting on pelleter and obtains the tablet of every heavy 150mg in flakes.

Example of formulations 5

Be prepared as follows the capsule that each contains the 40mg medicine: Composition Amount (mg/ capsule)Activeconstituents 40.0mg starch 109.0mg Magnesium Stearate 1.0mg amounts to 150.0mg

The mixed active composition, Mierocrystalline cellulose, starch, Magnesium Stearate, and pass through No.20 order U.S. sieve, and be loaded in the hard gelatin capsule with the amount of 150mg.

Example of formulations 6

Be prepared as follows the suppository that each contains the 25mg activeconstituents: Composition AmountThe saturated glycerin fatty acid ester of activeconstituents 25mg is to 2000mg

Activeconstituents is by No.60 order U.S. sieve, and is suspended in and uses in advance in the saturated fatty acid glyceride that essential minimum heating dissolves.Then mixture is poured into and indicated in the 2.0g volumetrical suppository mold and make cooling.

Example of formulations 7

Be prepared as follows every dose of suspension agent that contains the 50mg/5.0ml dose drug: Composition AmountActiveconstituents 50.0mg tragacanth gum 4.0mg Xylo-Mucine (11%) 50.0mg Microcrystalline Cellulose (89%) sucrose 1.75g Sodium Benzoate 10.0mg correctives and an amount of pure water of pigment are to 5.0ml

Hybrid medicine, sucrose and tragacanth gum, and by No.10 order U.S. sieve, the solution in water mixes with previously prepared Microcrystalline Cellulose and Xylo-Mucine then.Sodium Benzoate, correctives and pigment dilute with little water and under agitation add.The water that adds capacity then produces the volume that requires.

Example of formulations 8 Composition Amount (mg/ capsule)Activeconstituents 15.0mg starch 407.0mg Magnesium Stearate 3.0mg amounts to 425.0mg

The mixed active composition, Mierocrystalline cellulose, starch and Magnesium Stearate, and pass through No.20 order U.S. sieve, and be loaded in the hard gelatin capsule with the amount of 560mg.

Example of formulations 9

Followingly can prepare preparation for intravenous administration: Composition AmountActiveconstituents 250.0mg etc. open salt solution 1000ml

Example of formulations 10

Followingly can prepare topical preparation: Composition AmountActiveconstituents 1-10g emulsifying wax 30g whiteruss 20g white soft wax is to 100g

Heat white soft wax until dissolving.Mix whiteruss and emulsifying wax, stir until dissolving then.Add activeconstituents and continue and stir up to dispersion.Cooling mixture is up to curing then.

The another kind of preferred preparation that uses in the method for the present invention uses transdermal delivery device (" paster ").Such transdermal patch can be used to provide the amount continuous or discontinuous input of compound of the present invention with control.The structure of the transdermal patch of administration medicine preparation and use are well known in the art.Referring to, for example the United States Patent (USP) 5023252 of application on June 11st, 1991 is incorporated by reference here.Such paster can be prepared into continuously, the discontinuous or pharmaceutical preparation of administration as requested.

When expecting or needing, directly or indirectly introduce pharmaceutical composition to brain.Direct technology generally includes medicine sent and passs conduit and be placed into receptor's ventricular system to pass through hemato encephalic barrier.The employed a kind of such portable drug delivery system of concrete anatomic region transportation biotic factor to health is described in United States Patent (USP) 5011472, and it is incorporated by reference here.

Generally be that preferred non-direct technology generally includes compositions formulated so that the drug latenciation that transforms to the lipid soluble medicine by hydrophilic medicament to be provided.The hydroxyl that latentiation exists on the medicine by protection usually, carbonyl, sulfate radical and primary amine group realize, thereby making that medicine is fat-soluble can pass through hemato encephalic barrier byer force.Perhaps, sending of hydrophilic medicament passed and can be strengthened by the endoarterial infusion hypertonic solution, and described hypertonic solution can the instantaneous hemato encephalic barrier of opening. Purposes

Compound of the present invention can be used in conjunction with the VLA-4 (α in the biological material ₄β ₁Integrin), therefore, for example, in to such sample mensuration VLA-4, has purposes.In such test, this compound can be in conjunction with solid carrier and to wherein adding the VLA-4 sample.The amount of VLA-4 can be measured by ordinary method in the sample, for example uses the sandwich ELISA test.Perhaps, the VLA-4 of mark can make the existence that is used for measuring VLA-4 in the sample in the competition test.Other suitable test is well known in the art.

In addition, suppress of the adhesion of the white corpuscle of VLA-4 mediation in chemical combination objects more of the present invention, therefore can in the treatment of diseases of VLA-4 mediation, use endotheliocyte.Such disease comprises the inflammatory disease of mammalian subject, asthma for example, presenile dementia, atherosclerosis, aids dementia, diabetes (comprising the diabetes that acute teenager is taken place), enteritis (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, brain inflammation, apoplexy and other brain injury, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung of myocardial ischemia and the mediation of acute white corpuscle, for example injury of lung that is taken place in grownup's respiratory distress syndrome.

The biological activity of top compounds identified can be measured in multiple systems.For example, a kind of compound can be fixed on solid surface, and can measure the adhesion of the cell of expressing VLA-4.Make in such a way, can screen a large amount of compounds.The cell that is fit to this mensuration comprises all white corpuscles of known expression VLA-4, T cell for example, B cell, monocyte, eosinocyte and basophilic leukocyte.Can also use a large amount of leucocyte cell lines, example comprises Jurkat and U937.

Test compound can also be measured between VLA-4 and the VCAM-1, perhaps VLA-4 and known in conjunction with VLA-4 tagged compound compound for example of the present invention or the antibody of VLA-4 between competition suppress the bonded ability.In these were measured, VCAM-1 can be fixed on solid surface.VCAM-1 can also be expressed as have the Ig afterbody recombination fusion protein of (for example IgG), can detect the combination for VLA-4 like this in immunoassay.Perhaps, can use the VCAM-1 express cell, for example the inoblast of activated endotheliocyte or VCAM-1 transfection.About measuring the test of blocking-up for the adherent ability of brain endothelial cell, the test that is described in the open No.WO91/05038 of international patent application is particularly preferred.This application is in this hereby incorporated by reference.

A lot of test modes have been used the test composition of mark.Such Mk system can be a lot of forms.Marker can directly or indirectly be coupled to the composition according to the expectation of the test of method well known in the art.Can use multiple marker.Composition can be by any method mark.Measure the most frequently used method and be to use usefulness ³H, ¹²⁵I, ³⁵S, ¹⁴C, or ³²The radioautography of the compound of P mark etc.The nonradioactive labeling comprises the part of bonding mark antibody, fluorophore, and chemical illuminating reagent, the specificity of the enzyme and the part that serves as a mark is in conjunction with the antibody to the member.Desired susceptibility is depended in the selection of marker, with compound bonded difficulty or ease, stability requirement and obtainable instrument.

Be used to prove that the suitable body inner model of the drug effect for the treatment of inflammatory reaction is included in mouse, rat, the EAE in cavy or the primates (experimental autoimmune encephalomyelitis), and other inflammatory model that depends on alpha-4 integrin.

Bioactive compound with expectation can be modified as required, and the character of expectation is provided, and for example improved pharmaceutical properties (for example body internal stability, bioavailability) is perhaps wanted detected ability in diagnostic use.For example, contain one or more D-amino acid in the sulphonamide of the present invention and generally improve the body internal stability.Can measure stability with several different methods, for example by proteinic half life between mensuration and peptase or human plasma or serum incubation period.Described multiple such protein stability measure (referring to, Verhoef for example, etc., Eur.J.Drug Metab.Pharmacokinet., 1990,15 (2): 83-93).

For diagnostic purpose, multiple marker can connect compound, and it can directly or indirectly provide detectable signal.Therefore, compound of the present invention can be modified with several different methods for multiple final purpose, and the while is retains biological activity still.In addition, multiple reaction site can be connected to particle, solid substrate, and the end of macromole or the like is introduced.

The compound of mark can use in multiple body or in the external application.Can use multiple marker, radionuclide (for example launch gamma-ray radio isotope, for example technetium-99 or indium-111) for example, fluorophore (for example fluorescein), enzyme, enzyme substrates, enzyme cofactor, enzyme inhibitors, chemiluminescence compound, bioluminescent compound or the like.Other suitable marker in conjunction with title complex as well known to those skilled in the art perhaps can determine to use conventional test.Use well known to a person skilled in the art that standard technique realizes the combination of these markers.

External application comprises diagnostic use, for example monitors inflammatory reaction by detecting the leukocytic existence of expressing VLA-4.The cell that compound of the present invention can also be used to separating or mark is such.In addition, as mentioned above, compound of the present invention can be used for the mensuration of the interactional potential inhibitor of VLA-4/VCAM-1.

About identifying for example diagnosing image in inflammation site in the body, generally use radio isotope according to technique known.Radio isotope can use the direct or indirect binding peptide of intermediate functional group.For example, can use sequestrant for example diethylene triaminepentaacetic acid(DTPA) (DTPA) and ethylenediamine tetraacetic acid (EDTA) (EDTA) and similarly molecule protein is combined with the metal ion radio isotope.

Title complex can use the paramagnetism isotopic labeling that is used for the in-vivo diagnostic purpose, and as nuclear magnetic resonance (MRI) or spectrum (ESR), the both is known.Generally speaking, can use any ordinary method that is used for the viewable diagnostic imaging.Usually emission γ-or the radio isotope of positron be used for photographing imaging, and the paramagnetism isotropic substance is used for MRI.Therefore compound can be used for monitoring the process of the amelioration of individual inflammatory reaction.By measure expressing lymphocytic increase or the minimizing of VLA-4, may measure with the disease amelioration is whether the special treatment scheme of purpose is effective.

Pharmaceutical composition of the present invention can be used for blocking or inhibition and the multiple disease and the relevant cell adhesion of lacking of proper care.For example multiple inflammatory symptom is relevant with integrin or white corpuscle.Medicable disease comprises for example transplant rejection (for example homograft rejection), presenile dementia, atherosclerosis, aids dementia, diabetes (comprising the diabetes that acute teenager is taken place), the retinitis, metastases, rheumatoid arthritis, the injury of lung (for example injury of lung that is taken place in grownup's respiratory distress syndrome) of acute white corpuscle mediation, asthma, ephritis, and acute and chronic inflammation, comprise atopic dermatitis, psoriasis, myocardial ischemia, and enteritis (comprising ulcerative colitis and Crohn disease).In preferred embodiments, pharmaceutical composition is used for treating the inflammation disease of brain, multiple sclerosis (MS) for example, viral meningitis and brain inflammation.

Enteritis is the general name that is called ulcerative colitis and two kinds of similar diseases of Crohn disease.Ulcerative colitis is spontaneous chronic ulcerative inflammation, is characterised in that the granuloma inflammatory reaction comprises that for the intestines wall demarcation brightly and the typical case of all layers extend across wall.All sections of enteron aisle, all may be included to anus from mouth, but the most common terminal ileum and/or the colon of influencing of disease.Crohn disease is mainly to be confined to mucous membrane of colon and submucosal inflammatory reaction.Big amount lymphocyte and scavenger cell are arranged in the damage of enteritis, and the injury that can cause inflammation.

Asthma is a kind of disease, is characterised in that tracheobronchial tree has an enhanced responsiveness of stimulate diving for the multiple reinforcement paroxysmal of respiratory tract Shan is narrow.This stimulation causes that the IgE-bag is discharged multiple inflammatory mediator by mastocyte and comprises histamine, acidophilia and neutrophilic granulocyte chemokine, leukotriene, prostaglandin(PG) and platelet activating factor.The release of these factors replenishes basophilic granulocyte, eosinophilic granulocyte and neutrophilic granulocyte, and damage causes inflammation.

Atherosis is a kind of artery disease (for example coronal is carotid, aorta and condyle bone).The basis damage, atherosclerosis is made up of the focus patch that increases in the inner membrance, has the fibering lid of lipid core and covering.Atherosclerosis jeopardizes artery blood flow and artery that weakening influenced.Cardiac muscle and cerebral infarction are the main results of this disease.Scavenger cell and white corpuscle are replenished to atherosclerosis 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, may relate to wrist afterwards, elbow, naked joint and knee joint.Sacroiliitis results from synovial fluid cell and the leukocytic interaction that penetrates in the synovia lining in joint from circulation.Referring to, Paul for example, immunology (Immunology) (the 3rd edition, Raven Press, 1993).

Another indication of compound of the present invention is the tissue of treatment VLA-4 mediation or the repulsion of graft.Recent years, surgery transplanted tissue and organ be skin for example, kidney, and liver, heart, lung, the efficient of the technology of pancreas and marrow has considerable raising.Possible main outstanding problem is to lack the gratifying reagent that causes that the host has immune compatibility for the homotransplant of transplanting or organ.When homogeneous variant cell or organ are transplanted when giving host's (being that donor and host are the Different Individual from same species), host immune system may be provided with immunne response (host is to the graft disease) to the exotic antigen in the graft, causes transplanted disorganization.CD8 ⁺Cell, cd4 cell and monocyte all relate in transplanted tissue repels.Compound of the present invention in conjunction with α-4 integrin is useful especially for the intravital immunne response of blocking-up isoantigen inductive host, thereby prevents that such cell from participating in the destruction of transplanted tissue or organ.Referring to, Paul etc., Transplant International, 9,420-425 (1996); Georczynski etc., immunology (Immunology) 87,573-580 (1996); Georczynski etc., transplantation immunology (Transplant Immunology) 3,55-61 (1995); Yang etc. transplant (Transplantation) 60,71-76 (1995); Anderson etc., APMIS102,23-27 (1994).

Related application in conjunction with the compound of the present invention of VLA-4 is to regulate related immunne response in " graft is to the host " disease (GVHD).Referring to, for example, Schlegel etc., Journal of Immunology (J.Immunol.) 155,3856-3865 (1995).GVHD is the potential fatal disease, takes place when the immunologic competence cell is transferred to the allogeneic receptor.In this case, the immunologically competent cell of donor may be attacked receptor's tissue.Skin, organizing of internal organ epithelium and liver usually is target, and may be destroyed during GVHD.When immuning tissue is transplanted, bone marrow transplantation for example, there is the problem of especially severe in this disease; But not too serious GVHD also reports in other situation, comprises heart and liver transplantation.Special use therapeutical agent of the present invention is blocked the activation of donor T-cell, thereby disturbs the ability of the interior target cell of they dissolving hosts.

Another purposes of compound of the present invention is to suppress metastases.It is reported several tumor cells expression VLA-4 and in conjunction with the such cell adhesion endotheliocyte of VLA-4 compounds block.Steinback etc., Urol.Res, 23,175-83 (1995); Orosz etc., international journal of cancer (Int.J.Cancer) 60,867-71 (1995); Freedman etc., white corpuscle lymphoma (Leuk.Lymphoma) 13,47-52 (1994); Okahara etc., cancer research (CancerRes.) 54,3233-6 (1994).

Another purposes of compound of the present invention is the treatment multiple sclerosis.Multiple sclerosis is the neural autoimmune disease of carrying out property, and it is at about 250000 to 350000 populations of u.s. influence.Multiple sclerosis is considered to the invasion and attack of some of them white corpuscle and causes the result of the specificity autoimmune response of myelin (isolate the tip and cover nerve fiber).In the animal model of multiple sclerosis, the mouse monoclonal antibody of anti-VLA-4 guiding shows the adhesion of blocking leukocyte for endotheliocyte, therefore prevents the inflammation and the ensuing paralysis of animal central nervous system ¹⁶

Pharmaceutical composition of the present invention is adapted at using in the multiple drug delivery system.The appropriate formulation of Shi Yonging sees Lei Mingdun pharmacology (Remington ' s PharmaceuticalSciences), Mace Publishing Company, Philadelphia, PA, 17th.ed. (1985) in the present invention.

In order to improve the serum half life, compound can be made capsule, join in the chamber of liposome, be prepared into colloid, perhaps can use to provide to prolong compound serum other routine techniques of half life.The preparation liposome can use several different methods, as is described in, and Szoka etc. for example, U.S. Patent No. 4235871,4501728 and 4837028, it is hereby incorporated by reference separately.

To depend on the compound of administration to the amount of patient's administration, the purpose of administration, for example prevention or treatment, patient's state, administering mode or the like.In treatment is used, be enough to cure or to the amount of small part treatment disease or its syndromes to suffering from patient's administration composition of disease.Finish the suitable amount of this purpose and be referred to as " treatment effective dose ".The significant quantity of this application will depend on the disease symptoms of the treatment that the clinician judges and depend on some factors, the severity of inflammation for example, patient's age, body weight and general situation or the like.

Composition to patient's administration is the aforementioned pharmaceutical compositions form.These compositions can be by conventional sterilising technology sterilization, perhaps by sterile filtration.The aqueous solution that obtains can package spare or freeze-drying, perhaps is merged into freeze dried preparation with the sterilization aqueous carrier before administration.The pH of compound formulation generally between 3 and 11, more preferably 5-9, most preferably 7-8.Understand and use some above-mentioned vehicle, carrier or stablizer will cause the formation of pharmaceutical salts.

The therapeutic dose of The compounds of this invention will according to treatment institute for example at special purpose, the administering mode of compound, patient's health and situation and the doctor's that writes out a prescription judgement and different.For example, for intravenous administration, dosage generally is the about 20 μ g of every kg body weight to about 500 μ g scopes, and the about 100 μ g of preferred every kg body weight are to about 300 μ g.Suitable dosage ranges for intranasal administration generally is the about 0.1pg to 1mg of every kg body weight.Effective dose can be extrapolated from dose-response curve external or that animal model test system produces.

Provide following synthetic and biological Examples to describe the present invention in detail, but be not that in office where face limits the scope of the invention.Except as otherwise noted, all temperature is degree centigrade.Embodiment

In the following embodiments, following abbreviation has following meaning.If an abbreviation is not defined, then it has its meaning of accepting usually.Aq or aq.=water solution A cOH=acetate bd=wide bimodal bm=wide multimodal bs=wide unimodal Bn=benzyl Boc=tertbutyloxycarbonyl Boc ₂O=hydrogen-carbonate di tert butyl carbonate BOP=benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate Cbz=carbobenzoxy-(Cbz) CHCl ₃=chloroform CH ₂Cl ₂=methylene dichloride (COCl) ₂=oxalyl chloride d=bimodal dd=doublet of doublet dt=dual three peak DBU=1,8-diazabicyclo [5.4.0] undecane-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=1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride Et ₃N=triethylamine Et ₂O=ether EtOAc=ethyl acetate EtOH=ethanol eq or eq.=equivalent Fmoc=N-(9-fluorenylmethyloxycarbonyl) FmocONSu=N-(9-fluorenylmethyloxycarbonyl) succinimide g=gram h=hour H ₂O=water HBr=Hydrogen bromide HCl=hydrochloric acid HOBT=I-hydroxybenzotriazole hydrate hr=hour K ₂CO ₃=salt of wormwood L=rise m=multimodal MeOH=methyl alcohol mg=milligram MgSO ₄=sal epsom mL=milliliter mm=millimeter mM=millimolar concentration mmol=mmole mp=fusing point N=equivalent 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/inch ²PtO ₂The t of=platinum oxide q=quartet quint.=quintet rt=room temperature s=unimodal sat=saturated=triplet t-BuOH=tert-butyl alcohol TFA=trifluoroacetic acid THF=oxolane TLC or tlc=thin-layer chromatography Ts=tosyl TsCl=tosyl chlorine TsOH=tosylate μ L=microlitre

In the following embodiments, all temperature are degree centigrade (except as otherwise noted).Following method is used for preparing the compound that proposes below as noted.Method 1 N-tosylation method

Suitable amino acid whose N-tosylation effect is by Cupps, and the method for the organic chemistry magazine (J.Org.Chem.) 1985,50,3972 of Boutin and Rapoport is carried out.Method 2 The methyl esters preparation method

Use the Helv.Chim.Acta1953 of Brenner and Huber, 36,1109 method prepares amino acid methyl ester.Method 3 The BOP coupling method

By the amino acid (1 equivalent) of suitable N-protected and suitable amino acid ester or amino acid ester hydrochloride (1 equivalent); benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate [BOP] (2.0 equivalent), the dipeptides ester of triethylamine (1.1 equivalent) and the expectation of DMF prepared in reaction.Reaction mixture at room temperature stirs and spends the night.Crude product is through flash chromatography (flashchromatography) and purifying obtains the dipeptides ester.Method 4 Method for hydrogenation I

Using 10% carbon palladium (10% weight) to carry out hydrogenization in methyl alcohol under 30psi spends the night.Mixture filters through Celite pad, concentrated filtrate, the aminocompound that obtains expecting.Method 5 Method for hydrolysis I

Refrigerative (0 ℃) THF/H to suitable esters ₂O solution (2: 1,5-10ml) add LiOH (or NaOH) (0.95 equivalent).Temperature remains on 0 ℃, finishes reaction in 1-3 hour.Reaction mixture ethyl acetate extraction, and freeze-drying water, the carboxylate salt that obtains expecting.Method 6 Ester method for hydrolysis II

Refrigerative (0 ℃) THF/H to suitable esters ₂O solution (2: 1,5-10ml) add LiOH (1.1 equivalent).Temperature remains on 0 ℃ and complete at 1-3 hour internal reaction.Concentrated reaction mixture, resistates is dissolved in water, and regulates pH to 2-3 with aqueous hydrochloric acid.The product ethyl acetate extraction, the salt water washing of the organic phase of merging, dried over mgso is filtered, and concentrates the acid that obtains expecting.Method 7 Ester method for hydrolysis III

Suitable ester is dissolved in diox/H ₂Among the O (1: 1) and add 0.9 normal 0.5N sodium hydroxide.To react to stir after 3-16 hour and concentrate.Resistates is dissolved in water, and uses ethyl acetate extraction, freeze-drying water, the carboxylic acid sodium salt that obtains expecting.Method 8 Sulphonylation method I

Sulfonic acid fluoride (12mmol) back that adds expectation to the aminophenyl L-Ala analogue (11.2mmol) that is dissolved in methylene dichloride (25ml) and is cooled to-78 ℃ appropriate protection drips pyridine (2ml).Make solution be warmed to room temperature and stirred 48 hours.Reaction soln is transferred in the 250ml separating funnel with methylene dichloride (100ml) and with 1N hydrochloric acid (50ml * 3), salt solution (50ml) and water (100ml) extraction.Dry organic phase (sal epsom), the product that concentrated solvent obtains expecting.Method 9 The reductive amination method

Use acetate, nitrilotriacetic sodium borohydride, methylene dichloride make suitable aldehyde carry out reductive amination to Tos-Pro-p-NH2-Phe, and the mixture of merging at room temperature stirs and spends the night.Crude product is by the flash chromatography purifying.Method 10 BOC removal method

Under 0 ℃, in the methanol solution of suitable Boc-amino acid ester, fed dry hydrogen chloride (HCl) 15 minutes, and reaction mixture was stirred 3 hours.Solution concentration is become slurries, be dissolved in Et ₂O concentrates once more.Repeat this method, the solid that obtains is positioned under the high vacuum spends the night.Method 11 Tert-butyl ester method for hydrolysis I

Handle the tert-butyl ester that is dissolved in methylene dichloride with TFA.Internal reaction was complete in 1-3 hour, this moment concentrated reaction mixture, resistates is dissolved in water and freeze-drying, the acid that obtains expecting.Method 12 EDC coupling method I

Dichloromethane solution (5-20ml) to N-(toluene-4-alkylsulfonyl)-L-proline(Pro) (1 equivalent) mixes suitable amino acid ester hydrochloride (1 equivalent); N-methylmorpholine (1.1-2.2 equivalent) and I-hydroxybenzotriazole (2 equivalent); place ice bath, and add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalent).Making reaction rise to room temperature and stir spends the night.Reaction mixture is poured in the water, and organic phase is with saturated sodium bicarbonate, the salt water washing, and dry (sal epsom or sodium sulfate) filters the back and concentrates.Crude product is by the column chromatography purifying.Method 13 EDC coupling method II

In the DMF solution (5-20ml) of the amino acid (1 equivalent) of suitable N-protected, mix suitable amino acid ester hydrochloride (1 equivalent), Et ₃N (1.1 equivalent) and I-hydroxybenzotriazole (2 equivalent) place ice bath, and add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalent).Making reaction rise to room temperature and stir spends the night.Reaction mixture is distributed in EtOAc and H ₂Between the O, organic phase 0.2N citric acid, water, saturated sodium bicarbonate, the salt water washing, dry (sal epsom or sodium sulfate) filters the back and concentrates.Crude product is by column chromatography or preparation TLC purifying.Method 14 Sulphonylation method II

Suitable SULPHURYL CHLORIDE is dissolved in methylene dichloride and places ice bath.Add L-Pro-L-Phe-OMe.HCl (1 equivalent) and Et ₃N (1.1 equivalent) makes to be reflected to rise to room temperature under the nitrogen and stir and spends the night.Concentrated reaction mixture, resistates are distributed in EtOAc and H ₂Between the O, organic phase is with saturated sodium bicarbonate, the salt water washing, and dry (sal epsom or sodium sulfate) filters the back and concentrates.Crude product is by column chromatography or preparation TLC purifying.Method 15 Sulphonylation method III

Dichloromethane solution to L-Pro-L-4-(3-dimethylaminopropyl oxygen base)-Phe-OMe (the method preparation that using method 10 is described) (1 equivalent) adds Et ₃N (5 equivalent) back adds suitable SULPHURYL CHLORIDE (1.1 equivalent), makes to be reflected to rise to room temperature under the nitrogen and stir and spend the night.Enriched mixture is dissolved in EtOAc, with saturated sodium bicarbonate and the washing of 0.2N citric acid, makes water be alkalescence with solid sodium bicarbonate, and uses the EtOAc extraction product.Organic phase salt water washing, dry (sal epsom or sodium sulfate) filters and concentrates.The crude product methyl esters is by preparation TLC purifying.The corresponding acid of describing in the using method 7 of method preparation.Method 16 Method for hydrogenation II

Methanol solution (10-15ml) to azlactone adds NaOAc (1 equivalent) and 10%Pd/C.Mixture is placed 40psiH ₂Hydrogenator on.After 8-16 hour, reaction mixture filters by Celite pad, and concentrated filtrate obtains the dehydrogenation methyl dipeptide.This ester is dissolved in diox/water (5-10ml), to wherein adding 0.5N sodium hydroxide (1.05 equivalent).Stir after 1-3 hour, concentrated reaction mixture, resistates is dissolved in water, and washs with EtOAc.Use 0.2N hydrochloric acid to make water be acid, product extracts with EtOAc.(1 * 5ml) washing, dry (sal epsom or sodium phosphate) filter and concentrate the organic phase that merges, and obtain the acid as the mixture of about 1: 1 diastereomer with salt solution.Method 17 Tert-butyl ester method for hydrolysis II

The tert-butyl ester is dissolved in methylene dichloride (5ml) and handles with TFA (5ml).Internal reaction was complete in 1-3 hour, this moment concentrated reaction mixture, resistates is dissolved in water and concentrates, resistates is dissolved in water and freeze-drying once more, the acid that obtains expecting.Embodiment 1 (2) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-amino-benzene alanine methyl ester (2.00g, 4.67mmol) and the Boc glycine (1.1eq, 0.9g), Et ₃N (2.2eq, 1.43ml) and bop reagent (1.1eq 2.27g) is dissolved in the 50ml dry DMF together.Reaction mixture at room temperature stirred 12 hours.Add ethyl acetate (100ml).(5 * 50ml) wash organic layer with saturated sodium bicarbonate (50ml), 10% citric acid (20ml) and salt solution.The organic layer dried over mgso.Solvent evaporated under reduced pressure, crude product be wash-out (silica gel on column chromatography; Trichloromethane/methyl alcohol 9: 1).The ester of the productive rate separation expectation with 66% (1.90g, 3.1mmol).Ester at room temperature use sodium hydroxide (1.1eq, 176mg) at methyl alcohol: water [1: 1] (40ml) in hydrolysis 4 hours.Add ethyl acetate and water.Collect water layer and use the 1N hcl acidifying, and extract once more with ethyl acetate to pH2.5.The organic layer dried over mgso is filtered and solvent evaporated under reduced pressure is separated title compound, productive rate 73%, for oily matter (1.33g, 2.26mmol).

The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝8.65(bs，1H)，7.70(d，2H，J＝7.98Hz)，7.50(d，1H，J＝7.14Hz)，7.45(d，2H，J＝8.10Hz)，7.32(d，2H，J＝7.80Hz)，7.11(d，2H，J＝8.00Hz)，5.75(bs，1H)，4.82(m，1H)，4.11(m，1H)，3.90(bs，2H)，3.38(m，1H)，3.21 3.10(m，3H)，2.41(s，3H)，1.99(m，1H)，1.55(m，3H)，1.43(s，9H).

¹³C NMR(75MHz，CDCl ₃)：δ＝174.03，172.19，169.02，157.28，145.03，137.17，133.34，132.58，130.59，128.44，120.65，81.16，62.85，54.05，50.31，37.34，30.69，28.87，24.89，22.14，14.77.

Mass spectrum: (FAB) 589 (M+H). embodiment 2 (7) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(glycyl) amino]-the L-phenylalanine

(1.33g 2.26mmol) is dissolved in the anhydrous methylene chloride (20ml) of trifluoroacetic acid (1.00ml), and reaction mixture at room temperature stirred 12 hours from the product of embodiment 1 (2).Solvent is removed in decompression.Crude product places on the vacuum pump and spends the night, and is dissolved in methyl alcohol then and is cooled to 0 ℃.Add ethyl acetate and collect product, be trifluoroacetate, and productive rate 50% (660mg, 1.09mmol).The NMR data are as follows:

¹H NMR(300MHz，CD ₃OD)：δ＝7.51(d，2H，J＝8.25Hz)，7.31(d，2H，J＝8.25Hz)，7.19(d，2H，J＝7.92Hz)，7.03(d，2H，J＝8.25Hz)，4.43(m，1H)，3.87(m，1H)，3.63(s，2H)，3.13-2.82(m，4H)，2.21(s，3H)，1.56-1.26(m，4H).

¹³C NMR(75MHz，CD ₃OD)：δ＝174.39，165.97，146.34，139.50，135.38，135.21，131.28，129.57，121.47，67.47，63.86，51.16，42.72，38.39，32.20，25.87，22.09，16.02.

Mass spectrum: (FAB) 489 (M+). embodiment 3 (23) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(carboxyl) propionamido]-the L-phenylalanine

(455mg, (1.1eq is among DMF 110mg) (10ml) 1mmol) to be dissolved in triethylamine (1.1eq, 153 μ l) and succinyl oxide for N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-amino-benzene alanine methyl ester.Separate the monoesters of expectation, productive rate is 53%, and (288mg 0.52mmol), is foams.Monoesters (80mg, 0.15mmol) at room temperature use sodium hydroxide (2.2eq, 15mg) at methyl alcohol: water [1: 1] (5ml) in hydrolysis 4 hours.Add ethyl acetate and water.Collect water layer and use the 1N hcl acidifying, extract once more with ethyl acetate to pH2.5.The organic layer dried over mgso is filtered and solvent evaporated under reduced pressure, separates this diprotic acid, is foams.

The NMR data are as follows:

¹H NMR(300MHz，CD ₃OD)：δ＝7.51(d，2H，J＝8.31Hz)，7.28(d，2H，J＝8.34Hz)，7.19(d，2H，J＝8.10Hz)，6.99(d，2H，J＝8.43Hz)，4.48(m，1H)，3.91(m，1H)，3.17-2.83(m，4H)，2.43(s，4H)，2.21(s，3H)，1.44-1.29(m，4H).

¹³C NMR(75MHz，CD ₃OD)：δ＝176.87，174.68，174.53，173.30，149.74，146.31，139.33，135.50，134.24，131.61，131.44，129.53，121.66，80.05，63.81，55.37，51.17，38.25，32.87，32.24，30.55，25.89，22.11.

Mass spectrum: (FAB) 532 (M+H). embodiment 4 (27) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-L-alanyls) amino]-the L-phenylalanine

According to the test method that embodiment 1 (2) describes, and N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-amino-benzene alanine methyl ester (0.15g, 0.337mmol) and Et ₃N (2.0eq, 95 μ l), the Boc-L-L-Ala (1.1eq, 70mg), and bop reagent (1.1eq 163mg) is dissolved among the 5mlDMF together.The methyl esters that separates expectation, productive rate 49%, (102mg 0.16mmol) is oily matter.Ester is used sodium hydroxide then, and (1.1eq is 8mg) at methyl alcohol: hydrolysis in water [1: the 1] solution (4ml).Separate monoprotic acid with quantitative yield, be amorphous solid.

The NMR data are as follows:

¹H NMR (300MHz, CDCl ₃): δ=9.00 (wide honeybee s, 1H), 7.70 (d, 2H, J=8.25Hz), 7.45 (d, 2H, J=8.37Hz), 7.32 (d, 2H, J=8.25Hz), 7.09 (d, 2H, J=8.25Hz), 5.65 (bs, 1H), 4.82 (m, 1H), 4.35 (bs, 1H), 4.11 (m, 1H), 3.38-3.12 (m, 4H), 2.40 (s, 3H), 1.95 (m, 1H), 1.53 (m, 3H), 1.40 (s, 12H).

¹³C NMR(75MHz，CDCl ₃)：δ＝174.71，172.40，172.09，156.72，144.98，137.62，133.43，132.21，130.58，128.48，120.47，80.98，62.87，54.05，51.10，50.31，37.23，30.73，28.88，24.92，22.16，18.89.

Mass spectrum: (FAB) 603 (M+H). embodiment 5 (28) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-D-alanyls) amino]-the L-phenylalanine

According to the test method that embodiment 1 (2) describes, and N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-amino-benzene alanine methyl ester (0.15g, 0.337mmol) and Et ₃N (2.0eq, 95 μ l), the Boc-D-L-Ala (1.1eq, 70mg), and bop reagent (1.1eq 163mg) is dissolved among the 5mlDMF together.The methyl esters productive rate 33% that separates expectation, for oily matter (68mg, 0.11mmol).Ester is used sodium hydroxide then, and (1.1eq is 5mg) at methyl alcohol: hydrolysis in water [1: the 1] solution (4ml).Separate monoprotic acid with quantitative yield, be film.

The NMR data are as follows:

¹H NMR (300MHz, CDCl ₃): δ=8.90 (broad peak s, 1H), 7.70 (d, 2H, J=8.25Hz), 7.45 (d, 2H, J=8.37Hz), 7.32 (d, 2H, J=8.25Hz), 7.09 (d, 2H, J=8.25Hz), 5.65 (bs, 1H), 4.82 (m, 1H), 4.35 (bs, 1H), 4.11 (m, 1H), 3.38-3.12 (m, 4H), 2.40 (s, 3H), 1.95 (m, 1H), 1.53 (m, 3H), 1.40 (s, 12H).

Mass spectrum: (FAB) 603 (M+H). embodiment 6 (29) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl-D-phenylalanyls) amino]-the L-phenylalanine

According to the test method that embodiment 1 (2) describes, and N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-amino-benzene alanine methyl ester (0.15g, 0.337mmol) and Et ₃N (2.0eq, 95 μ l), the Boc-L-L-Ala (1.1eq, 99mg), and bop reagent (1.1eq 163mg) is dissolved among the 5mlDMF together.The methyl esters of the productive rate separation expectation with 16% (37mg, 0.05mmol).Ester is used sodium hydroxide then, and (1.1eq is 3mg) at methyl alcohol: hydrolysis in water [1: the 1] solution (2ml).Separate monoprotic acid with quantitative yield, be amorphous solid.

The NMR data are as follows:

¹H NMR (300MHz, CDCl ₃): δ=8.56 (broad peak s, 1H), 7.73 (d, 2H, J=8.13Hz), 7.43-7.22 (m, 10H), 7.09 (d, 2H, J=7.95Hz), 5.78 (m, 1H), 4.87 (m, 1H), 4.65 (m, 1H), 4.11 (m, 1H), 3.44 (m, 1H), 3.29-3.01 (m, 4H), 2.43 (s, 3H), 2.08 (m, 1H), 1.60 (m, 3H), 1.33 (s, 9H).

¹³C NMR(75MHz，CDCl ₃)：δ＝171.88，171.44，170.02，156.56，144.96，137.23，136.83，133.46，132.78，130.53，130.33，129.92，129.36，128.44，127.64，120.63，81.16，62.84，53.96，50.26，38.91，37.90，30.35，28.81，24.96，22.11.

Mass spectrum: (FAB) 679 (M+H). embodiment 7 (67) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[3-(fluorescein) sulfo-urea groups] kharophen }-the L-phenylalanine

In the second alcohol and water, use the product in sodium bicarbonate and the different thiocyanide of fluorescein (isomer I--is from the Aldrich Chemical Company) Processing Example 2 (7).Acidifying mixture also separates the precipitation that obtains, and obtains title compound, is amorphous orange solids.Mass spectrum: (+FAB, 3-nitrobenzyl alcohol) 878 (MH ⁺).Embodiment 8 (175) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertbutyloxycarbonyl glycyl) amino]-the L-phenylalanine methyl ester

(2.00g, 4.48mmol) 10%Pd-C with catalytic amount is dissolved in methyl alcohol (10ml) to N-(toluene-4-alkylsulfonyl)-L-prolyl-L-(4-nitro) phenylalanine methyl ester.Hydrogenation at room temperature carried out under 40psi 12 hours.Use the diatomite filtration reaction mixture, solvent evaporated under reduced pressure obtains pink foams with quantitative yield.The method that using method 12 is described prepares title compound from top product and N-Boc-glycine.The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝7.72(d，2H，J＝8.13Hz)，7.45(d，2H，J＝8.49Hz)，7.35(d，2H，J＝8.30Hz)，7.10(d，2H，J＝8.37Hz)，5.40(m，1H)，4.82(m，1H)，4.07(m，1H)，3.91(s，2H)，3.76(s，3H)，3.40(m，1H)，3.23(m，1H)，3.05(m，2H)，2.43(s，3H)，2.43(m，1H)，1.46(m，12H).

¹³C NMR(75MHz，CDCl ₃)：δ＝177.61，171.97，171.58，168.52，144.93，137.25，133.43，132.55，131.36，130.54，130.33，128.39，120.53，80.50，62.81，54.00，53.08，50.25，37.83，30.42，28.93，28.87，24.81，22.14.

Mass spectrum: (FAB) 603 (M+H). embodiment 9 (306) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[3-(3-aminomethyl phenyl) urea groups] kharophen }-the L-phenylalanine

Prepare methyl esters (DMF stirs under the room temperature and spends the night for BOP, triethylamine) by N-(toluene-4-alkylsulfonyl)-L-prolyl-L-(4-amino) phenylalanine and 2-(between 3--tolyl-urea groups) acetic acidreaction.Crude product is through flash chromatography purifying (silicon-dioxide, 9: 1 ethyl acetate: hexane), obtain methyl esters.The THF solution hydrolysis of 1M lithium hydroxide of this methyl esters.Be separated to title compound after acid/alkaline purification, be white solid.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.8(br s，1H)；9.96(s，1H)；8.70(s，1H)；8.04(d，1H，J＝7.9Hz)；7.68(d，2H，J＝8Hz)；7.48(d，2H，J＝8.3Hz)；7.39(d，2H，J＝8.3Hz)；7.21(s，1H)；7.16(d，3H，J＝8.56Hz)；7.08(t，1H，J＝7.79Hz)；6.7(d，1H，J＝7.68Hz)；6.38(t，1H，J＝5.6Hz)；4.43(m，1H)；4.1(dd，1H，J＝3.18，8.23Hz)；3.89(d，2H，J＝5.49Hz)；3.3(m，1H)；3.05(m，2H)；2.92(dd，1H，J＝8.34，13.63Hz)；2.38(s，3H)；2.22(s，3H)；138-1.62(m，4H).

IR(KBr，cm ^-1)：3380，2990，1650，1605，1540，1230，1155，660，580，545.

Mass spectrum: ((+) FAB, m/e (%)) 644 (100[M+Na]+); 622 (25[M+H]+). embodiment 10 (380) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[γ-(L-aspartoyl) amino]-the L-phenylalanine

Substitute the Boc-glycine and, obtain title compound with Boc-L-aspartic acid benzyl ester, be white solid, mp.=163-170 ℃ according to the preparation method of embodiment 1 (2) and 2 (7).

The NMR data are as follows:

¹H NMR(DMSO-d ₆)：δ＝8.05(d，1H)，7.70(d，1H)，7.45(dd，4H)，7.18(d，2H)，4.40(m，1H)，4.10(m，1H)，2.40(s，3H)，1.60(m，6H)

Mass spectrum: (FAB) (M+H) ⁺547. embodiment 11 (14) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(α-carboxyl benzyl oxygen base)-L-phenylalanines

(1.32g 2.95mmol) is dissolved in dry DMF (50ML) to N-under the room temperature (toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester.To wherein add salt of wormwood (1.1eq, 440mg) and α-bromophenyl ethyl acetate (1.1eq, 750mg).Reaction was at room temperature stirred 12 hours.Add ethyl acetate (100ml), organic layer with the salt water washing several times.The organic layer dried over mgso.Filter and solvent evaporated under reduced pressure, separate resistates, (1.1eq is 427mg) at methyl alcohol: hydrolysis in the water 1: 1 (30ml) to use sodium hydroxide then.The diprotic acid of the productive rate separation expectation with 88% (754mg, 1.33mmol).

The NMR data are as follows:

¹H NMR(300MHz，CD ₃OD)：δ＝7.50(d，2H，J＝8.25Hz)，7.35(d，2H，J＝7.14Hz)，7.15(m，5H)，6.95(d，2H，J＝8.13Hz)，6.71(d，2H，J＝8.37Hz)，5.48(s，1H)，4.51(m，1H)，3.87(m，1H)，3.10-2.79(m，4H)，2.15(s，3H)，1.45-1.01(m，4H).

¹³C NMR(75MHz，CD ₃OD)：δ＝174.71，174.49，173.98，158.25，146.39，138.08，135.37，132.28，131.74，130.53，130.36，129.60，129.00，117.18，79.95，63.94，55.31，38.00，32.23，25.88，22.32，15.22.

Mass spectrum: (FAB) 567 (M+H). embodiment 12 (15) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(carboxyl) phenyl]-the L-phenylalanine

With the product of Processing Example in sodium hydroxide Zai diox and the water 13 (178), acidifying, dried over mgso is used in extraction, after filtration and the Evaporation, obtains title compound, is clarifying oily matter.

The NMR data are as follows:

¹H NMR(CD ₃ODw/CD ₃ONa，300MHz)：δ＝7.75(d，J＝8.2，2H)，7.44-7.40(m，5H)，7.29-7.21(m，5H)，4.47(t，J＝5.8，1H)，4.03(dd，J＝8.5，J＝3.4，1H)，3.37-3.25(m，2H)，3.17-3.06(m，2H)，1.89-1.80(m，1H)，1.64-1.47(m，3H).

¹³C NMR(CD ₃ODw/CD ₃ONa，75MHz)：δ＝179.1，177.5，173.1，145.8，142.4，141.3，139.6，137.8，134.7，131.0，130.6，130.5，129.4，129.1，128.7，128.1，127.6，63.6，57.0，50.7，38.7，31.7，25.2，21.5.

Mass spectrum: (+FAB, glycerine) 537 (MH+). embodiment 13 (178) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(methoxycarbonyl) phenyl]-L-phenylalanine benzene methyl

Handle L-4-phenyl-iodide L-Ala [Phe (4-I)-OH] with methyl alcohol and hydrogen chloride gas, obtain HClPhe (4-I)-OMe after the evaporation.This product is used N-(toluene-4-alkylsulfonyl)-L-Pro-L-OH in DMF, EDAC, and HOBT and triethylamine are handled, and obtain N-(toluene-4-alkylsulfonyl)-L-Pro-L-Phe (4-I)-OMe after the water treatment.This product is used Pd (PPh in THF ₃) ₄Handle with 2-(methoxycarbonyl) the phenyl zinc iodide of the method preparation of passing through Rieke (J.Org.Chem.1991,56,1445), behind water treatment and the flash chromatography, obtain title compound, be clarifying oily matter.

The NMR data are as follows:

¹H NMR(CDCl ₃，300MHz)：δ＝7.81(d，J＝7.7，1H)，7.72(d，J＝8.2，2H)，7.54-7.49(m，1H)，7.42-7.16(m，9H)，4.93-4.86(m，1H)，4.11-4.07(m，1H)，3.80(s，3H)，3.64(s，3H)，3.42-3.28(m，2H)，3.15-3.08(m，2H)，2.43(s，3H)，2.09-2.04(m，1H)，1.58-1.45(m，3H).

¹³C NMR(CDCl ₃，75MHz)：δ＝171.3，170.8，169.1，144.3，141.9，140.1，135.0，132.9，131.2，130.8，130.6，129.9，129.7，129.0，128.4，127.8，127.1，62.2，53.3，52.5，52.0，49.7，37.6，29.7，24.2，21.5.

Mass spectrum: (+FAB, 3-nitrobenzyl alcohol) 565 (MH+). embodiment 14 (35) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[2-(N-benzyloxycarbonyl amino) ethyls] amino }-the L-phenylalanine

According to test method for the synthetic description of embodiment 3 (23), with sodium hydroxide (1.1eq, 3mg) at methyl alcohol: in the water 1: 1 (1ml) hydrolysis from the product of embodiment 15 (172) (32mg, 0.051mmol).With quantitative acquisition title substance, be foams.

The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝7.68(m，2H)，7.30(m，5H)，7.20(m，2H)，4.77(m，1H)，4.46(m，1H)，4.18(m，2H)，3.65(m，1H)，3.47(m，1H)，3.12(m，2H)，2.78(s，1.5H)，2.54(s，1.5H)，2.42(s，3H)，1.26(m，3H).

¹³C NMR(75MHz，CDCl ₃)：δ＝171.47，170.31，144.78，136.42，135.77，130.67，129.88，129.33，127.80，62.44，60.99，60.81，54.00，53.77，38.32，32.19，31.96，22.24，14.76.

Mass spectrum: (FAB) 449 (M+H). embodiment 15 (172) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[2-(N-benzyloxycarbonyl amino) ethyls] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-is right-and (316mg 0.7mmol) is dissolved in the KOAc-HOAc solution (10ml) [pH6.5] in the anhydrous methanol amino-phenylalanine methyl ester, adds NaCNBH ₃(10.0eq, 446mg) and benzyloxycarbonyl amino acetaldehyde (1.1eq).Reaction mixture at room temperature stirs and spends the night solvent evaporated under reduced pressure.Add ethyl acetate, dried over mgso is used in organic layer salt water washing.Filter and evaporating solvent, crude product is wash-out (silica gel, ethyl acetate/hexane 1: 1) on the preparation plate.Productive rate with 5% is separated to the title compound of expectation, and (40mg 0.06mmol), is film.

The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝7.71(d，2H，J＝6.90Hz)，7.38(m，5H)，7.26(m，2H)，6.93(d，2H，J＝7.20Hz)，6.54(d，2H，J＝7.50Hz)，5.12(m，1H)，5.10(s，2H)，4.73(m，1H)，4.06(m，1H)，3.75(s，3H)，3.41(m，4H)，3.26(m，1H)，3.14(m，2H)，2.99(m，1H)，2.43(s，3H)，2.04(m，1H)，1.53(m，3H).

Mass spectrum: (FAB) 623 (M+H). embodiment 16 (368) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{N-[3-(N, N-dimethylamino) propyl group]-the N-[trifyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-(4-amino) phenylalanine methyl ester in pyridine with the trifluoromethanesulfonic acid anhydride reaction, obtain corresponding fluoroform sulphonamide.This compound is using 3-dimethylamino-1-propyl alcohol alkylation on the nitrogen-atoms of fluoroform sulphonamide in THF under the Mitsunobu condition.By filtering purified mixture, obtain solid product, mp=45-55 ℃ after evaporating solvent and the water washing.

The NMR data are as follows:

¹H NMR(CDCl ₃，400Mhz)：δ＝7.70(d，2H)；7.34(d，3H)；7.25(m，3H)；4.88(m，1H)；4.10(m，1H)；3.85(brd s，2H)；3.79(s，3H)；3.32(m，2H)；3.08(m，2H)；2.43(s，3H)；2.18(brd s，5H)；1.98(brd s.1H)：1.75-1.30(brd m，9H).

IR(KBr，cm-1)：3400；2970；2800；1750；.1675；1525；1450；1400；1350；1225；1200；1165；1150；1100；1075；1000；950；825；675；600；550.

Mass spectrum: (+FAB) 663 ([M+H]+); 603; 507; 438; 306; 191; 155; 91. embodiment 17 (510) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-{N, N-two [4-(N, N-dimethylamino) benzyl] amino }-the L-phenylalanine

By using 4-N; N-dimethylamino benzaldehyde (acetate; sodium triacetoxy borohydride, methylene dichloride) N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-aminobenzyl-L-phenylalanine is carried out reductive amination, stirred under the room temperature and prepare methyl esters yesterday.Crude product obtains methyl esters by the flash chromatography purifying, and the method hydrolysis of its usefulness method 6 obtains title compound.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝7.7(d，2H，J＝8.34Hz)；7.54(d，1H，J＝5.71Hz)；7.40(d，1H，J＝8.34Hz)；7.02(d，4H，J＝8.78Hz)；6.75(d，2H，J＝8.78Hz)；6.62(d，4H，J＝8.78Hz)；6.48(d，2H，J＝8.78Hz)；4.39(s，4H)；3.92(dd，1H，J＝2.85，9.0Hz)；3.78(m，1H)；3.33(s，12H)；2.86(m，4H)；2.39(s，3H)；1.62(m，1H)；1.30(m，1H)；1.09(m，2H).

IR(KBr，cm ^-1)3380，1610，1520，1400，1350，1160，800，670.

MS((+)FAB，m/e(％))698(20[M+H] ^-).

Analytical calculation value C ₃₉h ₄₆N ₅O ₅Li ₃H ₂O:C, 61,76; H, 6.91; N, 9.23.

Measured value C, 61.73; H, 6.91; N, 9.15. embodiment 18 (138) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

(24.4g, 92.9mmol) (8.72g 84.5mmol) is dissolved in THF (200ml), and cools off on ice bath triphenylphosphine with 3-dimethylamino-1-propyl alcohol.By needle tubing dripped through 5 minutes the diethylazodicarboxylate (16.2g, 14.6ml, 92.9mmol), and add N-Boc-L-Tyrosine methyl ester by sleeve pipe as the solution among the 100mlTHF (24.95g 94.5mmol) stirred again 10 minutes before.Mixture stirred 30 minutes down and at room temperature stirred 19 hours at 0 ℃.Mixture concentrates and is dissolved in ether (500ml) in rotatory evaporator.(3 * 350ml), the acid extraction liquid of merging makes it to be alkalescence with solid sodium bicarbonate to mixture with the 0.2N hcl as extraction agent.(3 * 300ml), filter and vacuum-evaporation, obtains N-Boc-L-4-(3-N, N-dimethylamino propoxy) phenylalanine methyl ester (26.5g, 82%) by the extraction liquid drying (sodium sulfate) of merging with ethyl acetate extraction for this mixture.

(26.5g 69.5mmol) is dissolved in methyl alcohol (300ml) to N-Boc-L-4-(3-N, N-dimethylamino propoxy) phenylalanine methyl ester, and saturated with hydrogen chloride gas.Mixture was stirred 3 hours, and vacuum is removed volatile matter and is obtained L-4-(3-N, N-dimethylamino propoxy) phenylalanine methyl ester dihydrochloride (23.6g, 90%) then.

Method coupling N-(toluene-4-alkylsulfonyl)-L-proline(Pro) hydrate and L-4-(3-N with method 13 descriptions; the N-dimethylamino propoxy) phenylalanine methyl ester dihydrochloride; obtain N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-(3-N; the N-dimethylamino propoxy) phenylalanine methyl ester (16.3g, 89%).By using 0.5N sodium hydroxide hydrolysis methyl esters in THF/ water to prepare title compound (14.71g, 99%).

The NMR data are as follows:

¹H NMR(DMSO-d ₆)：δ＝7.75(d，2H，J＝8.2Hz)，7.67(d，1H，J＝5.6Hz)，7.42(d，2H，J＝8.2Hz)，7.00(d，2H，J＝8.5Hz)，6.71(d，2H，J＝8.5Hz)，3.98(m，2H)，3.90(t，2H，J＝6.5Hz)，3.14-2.97(4H)，2.40(s，3H)，2.32(t，2H，J＝7.0Hz)，2.13(s，6H)，1.83-1.75(3H)，1.45-1.36(3H).

¹³C NMR(DMSO-d ₆)：δ＝173.5，169.7，157.2，144.1，133.7，130.9，130.3，128.1，113.9，65.9，62.4，56.0，55.4，49.4，45.5，36.1，30.5，27.3，23.9，21.4.

Mass spectrum: FAB m/e 562 (M+2Na-H). embodiment 19 (282) synthetic N-(toluene-4-alkylsulfonyl)-N-methyl-L-seryl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine methyl ester

Method according to method 13 descriptions; N-methyl-N-(toluene-right-alkylsulfonyl)-L-Serine (655mg; 2.4mmol) be dissolved in DMF (100ml); add L-4-(3-dimethylamino-propyl group oxygen base) phenylalanine methyl ester hydrochloride [referring to the preparation of embodiment 18 (138)] (1.0g, 2.4mmol) .HOBT (1.1eq, 356mg); triethylamine (3.2eq; 1.1ml), and EDC (1.1eq, 500mg).Productive rate with 70% is separated to title compound, and (900mg 1.7mmol), is oily matter.

The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝7.68(d，2H，J＝8.40Hz)，7.29(d，2H，J＝8.10Hz)，7.08(d，1H，J＝7.80Hz)，7.04(d，2H，J＝8.70Hz)，6.82(d，2H，J＝8.70Hz)，4.71(m，1H)，4.43(m，1H)，3.94(t，2H，J＝6.60Hz)，3.75(s，3H)，3.69(m，1H)，3.51(m，1H)，3.14(m，1H)，2.91(m，1H)，2.59(s，3H)，2.45(m，2H)，2.42(s，3H)，2.20(s，6H)，1.87(m，2H).

¹³C NMR(75MHz，CDCl ₃)：δ＝172.04，170.15，158.66，144.56，136.02，130.72，130.46，128.19，127.87，115.31，66.70，60.86，60.65，56.87，54.01，53.08，45.95，37.39，31.85，27.91，22.13.

Mass spectrum: (FAB) 536 (M+H). embodiment 20 (284) synthetic N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[2-(N, N-dimethylamino) oxyethyl groups]-the L-phenylalanine

Triphenylphosphine (1.1eq) and 3-dimethylamino-1-propyl alcohol (1eq) is dissolved in THF, and cools off on ice bath.Dripped diethylazodicarboxylate (1eq) through 5 minutes by needle tubing, and stirred again before 10 minutes at the N-Boc-L-Tyrosine methyl ester (1.02eq) that adds as the solution among the 100mlTHF by sleeve pipe.Mixture stirred 30 minutes down and at room temperature stirred 19 hours at 0 ℃.Mixture concentrates and is dissolved in ether (500ml) in rotatory evaporator.(3 * 350ml), the acid extraction liquid of merging makes it to be alkalescence with solid sodium bicarbonate to mixture with the 0.2N hcl as extraction agent.(3 * 300ml), filter and vacuum-evaporation, obtains N-Boc-L-4-(3-dimethylamino propoxy) phenylalanine methyl ester by the extraction liquid dried over sodium sulfate of merging with ethyl acetate extraction for this mixture.

(26.5g 69.5mmol) is dissolved in methyl alcohol (300ml) to N-Boc-L-4-(3-dimethylamino propoxy) phenylalanine methyl ester, and saturated with hydrogen chloride gas.Before under vacuum, removing volatile matter mixture was stirred 3 hours, obtain L-4-(3-dimethylamino propoxy) phenylalanine methyl ester dihydrochloride (23.6g, 90%).

Method coupling N-(toluene-4-alkylsulfonyl)-L-(5 with method 13 descriptions; the 5-dimethyl) thioproline and L-4-(3-dimethylamino propoxy) phenylalanine methyl ester dihydrochloride; obtain N-(toluene-4-alkylsulfonyl)-L-(5; the 5-dimethyl) thia prolyl-L-4-(3-dimethylamino propoxy) phenylalanine methyl ester (16.3g, 89%).By using 0.5N sodium hydroxide hydrolysis methyl esters in THF/ water to prepare title compound, obtain solid, mp=＞200 ℃ (decomposition).

The NMR data are as follows:

¹H NMR(CD ₃OD，300MHz)：δ＝.85(s，3H)，.94(s，3H)，1.78(m，2H)，2.23(s，3H)，2.28(s，6H)，2.57(m，2H)，2.83(m，2H)，3.71-3.74(m，2H)，4.22-4.27.(m，2H)，4.41(d，1H，J＝9.1Hz)，6.58(d，2H，J＝8.6Hz)，6.98(d，2H，J＝8.6Hz)，7.20(d，2H，J＝8.3Hz)，7.54(d，2H，J＝8.3Hz).

¹³C NMR(CD ₃OD，75MHz)：δ＝22.2，25.3，27.8，30.5.39.4，45.2，51.9，56.0，57.6，58.2，67.2，75.1，115.8，129.8，131.6，132.1，132.5，135.4，146.7，159.5，170.9，178.2.

Mass spectrum: (FAB+) 586 (M+H). analyze HPLC:(Microsorb-MV C18 reversed-phase column, 4.6 * 150mm; 1: 1 acetonitrile of gradient/have water of 0.05%TFA; Flow velocity=1.0ml/ minute; 1=254nm; Volume of sample=20ml), Run#1:2.988 minute retention time (100.0% purity), Run#2:3.098 minute retention time (100.0% purity).Embodiment 21 (287) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-dimethylamino) oxyethyl groups]-the L-phenylalanine

According to embodiment 20 (138) preparation title compounds, substitute 3-dimethylamino-1-propyl alcohol except using the 2-dimethylaminoethanol.

The NMR data are as follows:

¹H NMR(DMSO-d ₆)：δ＝7.74(d，2H，J＝7.4Hz)，7.67(d，1H，J＝7.9Hz)，7.42(d，2H，J＝8.0Hz)，7.01(d，2H，J＝7.9Hz)，6.71(d，2H，J＝7.8Hz)，3.95(m，4H)，3.14-2.98(4H)，2.57(t，2H，J＝5.6Hz)，2.40(s，3H)，2.18(s，6H)，1.74(m，1H)，1.40(m，3H).

¹³C NMR(DMSO-d ₆)：δ＝173.5，169.7，157.0，144.1，133.8，131.0，130.9，130.3，128.1，113.9，66.0，62.4，58.0，55.4，49.4，45.9，36.2，30.5，23.9，21.4.

Mass spectrum: FAB m/e504 (M+H). embodiment 22 (317) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N-ethyl-N-phenyl amino) oxyethyl groups]-the L-phenylalanine methyl ester

By in the 2-butanone that is refluxing in the presence of salt of wormwood and the sodium iodide, using 2-(N-ethyl, N-phenyl) amino-ethyl chlorine that the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester is prepared methyl esters.The method that using method 7 is described prepares title compound.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400Mhz)：δ＝1.08(3H，t，J＝8，8Hz)；1.39(1H，m)；1.55(3H，m)；2.19(3H，s)；2.85-3.0(2H，m)；3.12(1H，dd，J＝6，10，6Hz)；3.41(2H，q，J＝6，8，6Hz)；3.6(3H，s)；3.62(2H，t，J＝5，5Hz)；4.01(2H，t，J＝5，5Hz)；4.04(1H，1，J＝8，8Hz)；4.43(1H，dd，J＝7，6，7Hz)；6.55(1H，t，J＝8，8Hz)；6.65(2H，d，J＝10Hz)；6.8(2H，d，J＝10Hz)；7.1(4H，m)；7.38(2H，d，J＝10Hz)；7.64(2H，d，J＝10Hz)；8.1(1H，d，J＝10Hz).

MS:+FAB, m/z 594 ([MH]+, 45%), 157 (100%). and embodiment 23 (321) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-diisopropylaminoethyl) oxyethyl groups]-the L-phenylalanine

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 2-diisopropylaminoethyl ethyl chloride.The method that using method 7 is described prepares title compound, is solid, mp.121-124 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400Mhz)：δ＝0.9(12H，d，J＝8Hz)；1.25-1.6(3H，m)；1.78(1H，m)；2.38(3H，s)；2.7(2H，t，J＝8，8Hz)；2.9(2H，m)；3.0(2H，q，J＝5，5，5Hz)；3.1(1H，dd，J＝3，4，3Hz)；3.35(1H，s)；3.78(1H，t，J＝7，7Hz)；3.8(2H，t，J＝5，5Hz)；3.95(1H，d，J＝10Hz)；6.5(1H，d，J＝10Hz)；6.65(1H；d，J＝10Hz)；6.85(1H，d，J＝10Hz)；6.9(1H，d，J＝10Hz)；7.4(2H，d，J＝10Hz)；7.62(1H，m)；7.75(2H，d，J＝10Hz).

MS:+FAB, m/z560 ([MH]+, 70%), 154 (100). and embodiment 24 (333) synthetic N-(thiophene-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

Using method 15 preparation title compounds, and separate white moisture absorptivity solid, mp.=＞200 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝8.03(br s，1H)；7.74(m，2H)；7.26(br s，1H)；7.04(d，2H，J＝7.0Hz)；6.75(d，2H，J＝6.0Hz)；4.16(m，1H)；4.06(m，1H)；3.85(m，2H)；3.33(m，1H)；3.13-3.00(br m，3H)；2.62(m，2H)；2.35(s，3H)；1.90(m，2H)；1.75(m，1H)；1.90-1.50(br m，3H)，

¹³C NMR(DMSO-d ₆，75MHz)：δ＝173.4，169.9，157.3，136.1，134.3，133.5，130.8，130.3，128.7，128.7，114.1，65.7，62.5，55.1，54.9，49.7，43.9，36.1，30.6，25.9，24.1，21.6.

Mass spectrum: (PI-FAB) 532, (M) ⁺. embodiment 25 (334) synthetic N-(5-chlorothiophene-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝7.62(m，2H)；7.44(m，2H)；6.99(m，2H)；6.71(m，2H)；4.05(m，1H)；3.92(m，3H)；3.26(m1H)；3.09-2.97(brm，3H)；2.30(m，2H)；2.13(s，6H)；1.82(m，2H)；1.79-1.51(br m，4H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝173.3，169.3，157.2，137.3，134.3，132.5，130.9，130.9，119.8，113.9，65.9，62.8，56.0，55.5，49.7，45.5，36.1，30.6，27.2，24.0，22.8.

Mass spectrum: (PI-FAB) 588, (M+Na) ⁺. embodiment 26 (336) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(N, N-diethylamino) oxyethyl groups]-the L-phenylalanine

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 2-diethylamino ethyl chloride.The method that using method 7 is described prepares title compound, is solid, mp.105-109 ℃.

The NMR data are as follows:

¹H-NMR(DMSO-d ₆，400Mhz)：δ＝1.0(6H，t，J＝8，8Hz)；1.25-1.45(4H，m)；1.65(2H，m)；2.18(3H，s)；2.26(2H，t，J＝2，2Hz)；2.65(4H，q，J＝5，4，5Hz)；2.8-3.1(4H，m)；3.84(1H，dd，J＝5，4，5Hz)；3.9(2H，t，J＝3，3Hz)；4.1(1H，d，J＝8Hz)；6.68(2H，d，J＝10Hz)；6.95(2H，d，J＝10Hz)；7.05(2H，d，J＝10Hz)；7.4(2H，d，J＝10Hz)；7.63(1H，d，J＝4Hz)；7.73(2H，t，J＝4，4Hz).

MS:+ESI, m/z532.4 ([MH]+, 100%). embodiment 27 (340) synthetic N-(2,5-dichloro-thiophene-3-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝7.77(d，1H，J＝6.6Hz)；7.43(s，1H)；7.07(d，2H，J＝7.4Hz)；6.76(d，2H，J＝7.4Hz)；4.33(m，1H)；4.15(m，1H)；3.89(t，2H，J＝6.1Hz)；3.29(m，2H)；2.97(m，2H)；2.57(t，2H，J＝7.1Hz)；2.31(s，6H)；1.85(m，4H)；1.65(m，2H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝173.4，172.5，170.0，157.3，134.2，130.8，130.5，130.3，127.7，126.9，114.1，65.8，61.9，55.3，54.9，49.2，44.2，36.2，30.9，26.1，24.3，21.6.

Mass spectrum: (PI-FAB) 600, (M) ⁺. embodiment 28 (341) synthetic N-(1-methylpyrazole-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

Prepare N-methylpyrazole SULPHURYL CHLORIDE by adding the N-methylpyrazole to refrigerative (0 ℃) chlorsulfonic acid.Reaction mixture is warmed to room temperature, and is heated to 100 ℃ spends the night under nitrogen.Then with the reaction mixture cool to room temperature and be quenched to 0 ℃.Add thionyl nitrogen (2.5eq) in solution, reaction is at room temperature stirred and is warmed to 70 ℃ of reactions 2 hours after 30 minutes.Quenching on ice bath behind the reaction cool to room temperature.In reaction mixture, slowly add entry and ice and precipitate white solid, solid collected by filtration.The SULPHURYL CHLORIDE of expectation cold water and hexane wash.Using method 15 preparation title compounds, and separate white moisture absorptivity solid, mp.=＞200 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝8.44(s，1H)；7.89(s，1H)；7.66(d，1H，J＝5.6Hz)；7.00(d，2H，J＝8.5Hz)；6.70(d，2H，J＝8.6Hz)；3.89(m，4H)，3.87(s，3H)；3.14-2.98(br m，4H)；2.34(t，2H，J＝7.2Hz)；2.30(s，6H)；1.86(m，3H)；1.81-1.75(br m，3H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝172.3，169.8，157.2，138.9，133.7，130.9，130.8，117.4，113.9，65.9，62.5，55.9，55.3，49.5，36.0，30.6，27.2，23.9.

Mass spectrum: (PI-FAB) 530, (M)+. embodiment 29 (346) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-diethylamino) propoxy-]-the L-phenylalanine methyl ester

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 3-diethylamino propyl chloride.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400Mhz)：δ＝1.0(6H，bs)；1.4-1.6(4H，m)；1.85(2H，m)；2.18(3H，s)；2.5(2H，bs)；2.5-2.8(4H，bs)；2.9(2H，m)；3.1(1H，dd，J＝8，10，8Hz)；3.35(1H，dd，J＝8，4，8Hz)；3.6(3H，s)；3.94(2H，t，J＝6，6Hz)；4.1(1H，m)；4.48(1H，dd，J＝8，6，8Hz)；6.8(2H，d，J＝10Hz)；7.1(2H，d，J＝10Hz)；7.4(2H，d，J＝10Hz)；7.7(2H，d，J＝10Hz)；8.2(1H，d，J＝10Hz).

MS:+ESI, m/z560.5 ([MH]+, 100%). embodiment 30 (351) synthetic N-(thiazole-2-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

According to Roblin and Clapp, JACS (JACS), 72,4890,1950 teaching prepares SULPHURYL CHLORIDE from mercaptan, using method 15 preparation title compounds, and separate white moisture absorptivity solid, mp.=＞200 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝8.24(d，1H，J＝3.1Hz)；8.15(d，1H，3.1Hz)；7.63(d，1H，J＝5.0Hz)；6.98(d，2H；J＝8.6Hz)；6.70(d，2H，J＝8.6Hz)；4.24(m，1H)；-3.88(m，3H)；3.36(m，2H)；3.28-2.98(m，2H)；2.31(t，2H，J＝7.0Hz)；2.12(s，6H)；1.83-1.79(br m，4H)；1.79(m，1H)；1.45(m，1H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝172.3，168.9，162.5，157.2，145.5，131.0，130.9，127.5，113.8，65.9，63.3，56.1，55.5，50.1，45.6，38.8，38.5，35.9，30.7，27.3，24.0.

Mass spectrum: (PI-FAB) 555, (M-H+Na) ⁺. embodiment 31 (353) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N-methyl-N-benzylamino) propoxy-]-the L-phenylalanine

The method that using method 7 is described prepares title compound from the product of embodiment 33 (356), is solid, mp=87-90 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.75 (d, 2H, J=10Hz); 7.65 (d, 1H, J=4Hz); 7.4 (d, 2H, J=10Hz); 7.1 8-7.3 (m, 5H); 6.96 (d, 2H, J=10Hz); 6.65 (d, 2H, J=10Hz); 3.97 (d, 1H, J=4Hz); 3.91 (t, 2H, J=4,4Hz); 3.8 (q, 1H, J=2,2,2Hz); 3.42 (s, 2H); 2.95-3.1 (m, 4H); 2.42 (t, 2H, J=8,8Hz); 2.38 (s, 3H); 2.08 (s, 3H); 1.85 (t, 2H, 6,6Hz); 1.7 (m, 1H); 1.3 (bs, 4H). embodiment 32 (354) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-diethylamino) propoxy-]-the L-phenylalanine

The method that using method 7 is described prepares title compound from the product of embodiment 29 (346), is solid, mp=76-82 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=1.0 (6H, t, J=8,8Hz); 1.38 (2H, m); 1.4-1.8 (4H, m); 2.38 (3H, s); 2.45 (2H, t, J=7,7Hz); 2.6 (4H, q, J=6,5,6Hz); 2.95 (2H, m); 3.05 (1H, dd, J=5,5,5Hz); 3.15 (1H, dd, J=4,5,4Hz); 3.9 (2H, t, J=5,5Hz); 4.0 (1H, t, J=6.6Hz); 4.1 (1H, m); 6.7 (2H, d, J=10Hz); 6.95 (2H, d, J=10Hz); 7.4 (2H, d, J=10Hz); 7.7 (1H, d, J=4Hz); 7.75 (2H, d, J=10Hz). embodiment 33 (356) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(N-methyl-N-benzylamino) propoxy-]-the L-phenylalanine methyl ester

By in the 2-butanone that is refluxing in the presence of salt of wormwood and the sodium iodide, using 3-(N-benzyl; the N-methyl) aminopropyl chlorine prepares title compound to the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester; be solid, mp=60-70 ℃.Embodiment 34 (372) synthetic N-(1-Methylimidazole-4-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝7.86(s，1H)；7.82(s，1H)；7.63(d，1H，J＝5.6Hz)；6.96(d，2H，J＝8.2Hz)；6.97(d，2H，J＝8.2hz)；4.12-4.09(br m，1H)；3.89(t，2H，J＝6.5Hz)；3.70(s，3H)；3.13(m，2H)；3.00(m，2H)；2.33(t，2H，7.2Hz)；2.13(s，6H)；1.82-1.75(m，3H)，1.60-1.40(br m，3H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝172.8，169.9，157.2，140.7，136.1，130.9，126.6，113.9，65.9，62.9，56.0，55.3，49.7，45.5，35.9，33.9，30.6，27.3，24.0，21.9.

Mass spectrum: (PI-FAB) 552, (M-H+Na) ⁺. embodiment 35 (373) synthetic N-(2-methyl thiazolium diazole-5-alkylsulfonyl)-L-prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

According to Roblin and Clapp JACS (JACS), 72,4890,1950 teaching prepares SULPHURYL CHLORIDE from mercaptan, using method 15 preparation title compounds, and separate white moisture absorptivity solid, mp.=＞200 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，300MHz)：δ＝7.66(d，1H，J＝3.2Hz)；7.02(d，2H，J＝8.5Hz)；6.72(d，2H，J＝8.2Hz)；4.28(t，1H；5.8Hz)；3.96-3.89(brm，3H)；3.37-3.23(br m，2H)；3.02(m，1H)；2.95(m，1H)；2.82(s，3H)；2.39(t，2H，J＝7.0Hz)；2.13(s，6H)；1.83(m，3H)；1.80-1.40(m，3H).

¹³C NMR(DMSO-d ₆，75MHz)：δ＝173.2，170.9，169.0，165.9，157.2，130.9，130.8，113.9，65.9，63.1，56.0，55.6，50.1，45.4，32.2，30.9，27.2，24.1，22.3，15.9.

Mass spectrum: (PI-FAB) 548, (M) ⁺. embodiment 36 (393) synthetic N-(toluene-4-alkylsulfonyl)-L-thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

According to embodiment 18 (138) preparation title compounds, but use the L-thioproline to substitute the L-proline(Pro).

The NMR data are as follows:

¹H NMR(300MHz，CD ₃OD)：δ＝7.57(d，2H，J＝8.40Hz)，7.20(d，2H，J＝8.10Hz)，6.92(d，2H，J＝8.40Hz)，6.58(d，2H，J＝8.40Hz)，4.50(dd，1H，J＝4.20，7.50Hz)，4.45(d，1H，J＝10.50Hz)，4.17(m，1H)，3.87(d，1H，J＝10.50Hz)，3.76(t，2H，J＝6.00Hz)，3.10(m，1H)，2.99(m，2H)，2.80(m，1H)，2.55(m，2H)，2.35(m，1H)，2.25(s，6H)，2.22(s，3H)，1.79(m，2H).

¹³C NMR(75MHz，CD ₃OD)：δ＝177.75，170.46，159.43，146.91，135.93，132.42，131.73，129.80，115.75，67.25，57.90，57.70，52.92，45.30，38.33，34.73，27.94，24.74，22.16.

Mass spectrum: (FAB) 546 (M+H). embodiment 37 (472) synthetic N-(4-cyano group benzenesulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine methyl ester

Prepare title compound according to the method for describing for preparing for embodiment 20 (284).

The NMR data are as follows:

¹H NMR(CDCl ₃)：δ7.98-7.95(d，2H)，7.83-7.80(d，2H)，7.06-7.03(d，2H)，6.80-6.77(d，2H)，4.80(m，1H)，4.48(m，1H)，3.95(m，3H)，3.73(s，3H)，3.02(m，2H)，2.45(m，2H)，2.26(s，6H)，1.94(m，2H)，1.21(s，3H)，1.17(s，3H).

¹³C NMR (CDCl ₃): δ 179.9,168.2, and 158.8,141.1; 133.7,130.9,128.1,117.9; 115.2,74.2,66.7,56.9; 55.3,53.9,53.0,51.1; 46.0,38.0,29.9; 28.0,24.4. embodiment 38 (514) synthetic N-(toluene-4-alkylsulfonyl)-L-(thia morpholine-3-carbonyl)-4-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

Method (Acta Chemical Scan.1994,48,517-525) preparation L-thia morpholine-5-carboxylic acid by Larsson and Carlson.The method that using method 1 is described prepares N-(toluene-4-alkylsulfonyl)-L-thia morpholine-5-carboxylic acid.Prepare title compound according to the method for describing for preparing for embodiment 20 (284).

The NMR data are as follows:

¹H NMR(CD ₃OD)：δ7.53-7.47(m，2H)，7.20-7.14(m，2H)，7.00-6.85(m，2H)，6.58-6.54(m，2H)，4.70-4.57(m，1H)，4.22-4.14(m，1H)，3.77-3.71(m，3H)，3.25-3.09(m，1H)，2.93-2.69(m，4H)，2.44(m，3H)，2.22(s，3H)，2.18(s，6H)，1.92(m，1H)，1.68(m，2H).

¹³C NMR (CD ₃OD): δ 177.9,177.8, and 169.6,169.4,159.6,159.5; 146.3,146.1,138.9,138.9,132.8,132.4; 131.8,130.5,129.8,129.2,126.9,115.8; 115.7,67.4,58.1,57.8,57.1,45.6; 44.9,38.8,37.9,28.2,28.2; 27.9,26.6,26.3,24.7,22.1. embodiment 39 (169) N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(carboxyl) phenoxy group]-the L-phenylalanine methyl ester

Under 0 ℃ in dimethylbenzene (50ml) suspension of sodium hydride (60% in oil, 1.1eq, 228mg) add N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester (2.14g, 5.16mmol).Mixture stirred 5 minutes, and adding cuprous bromide methyl-sulfide title complex (1.4eq, 1.48g).Reaction mixture stirred 0.5 hour down at 23 ℃.Adding 2-iodo-benzoic acid sodium (1.5eq, 8.06mmol), reaction mixture refluxed 12 hours.Add ethyl acetate (100ml), organic layer ammonium chloride, 10% hydrochloric acid and salt water washing, dried over mgso.Crude product is gone up in column chromatography (silica gel) and is used trichloromethane: 9: 1 wash-outs of methyl alcohol, isolate title compound, and be oily matter.

The NMR data are as follows:

¹H NMR(300MHz，CDCl ₃)：δ＝8.16(broad d，1H)，7.73(m，2H)，7.47(m，2H)，7.35(m，2H)，7.21(m，2H)，7.03(m，2H)，6.76(m，1H)，4.85(m，1H)，4.07(m，1H)，3.77(s，3H)，3.41(m，1H)，3.28(m，1H)，3.09(m，2H)，2.44(s，3H)，2.05(m，1H)，1.55(m，3H).

Mass spectrum: (FAB) 567 (M+H). embodiment 40 (309) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{2-[4-(pyrimidine-2-base) piperazine-1-yls] oxyethyl group)-the L-phenylalanine

According to the Mitsunobu prepared in reaction methyl esters of the method for describing for preparing of embodiment 20 (284) by N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester.The method that using method 7 is described prepares title compound, is solid, mp.102-105 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=1.35 (4H, s); 1.4 (1H, m); 1.76 (1H, m); 2.38 (3H, s); 2.5 (2H, m); 2.66 (2H, t, J=8,8Hz); 2.9-3.1 (4H, m); 3.68 (4H, t, J=5,5Hz); 3.8 (1H, q, J=4,6,4Hz); 3.95 (1H, dd, J=2,10,2Hz); 4.05 (2H, t, 6,6Hz); 6.6 (1H, t, J=5,5Hz); 6.7 (2H, d, J=10Hz); 6.96 (2H, d, J=10Hz); 7.4 (2H, d, J=10Hz); 7.65 (1H, d, J=4Hz); 7.74 (2H, d, J=10Hz); 8.35 (2H, d, J=5Hz). embodiment 41 (310) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(piperidines-1-yl) propoxy-]-the L-phenylalanine

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 1-(2-chloro propyl group) piperidines.The method that using method 7 is described prepares title compound, is solid, mp.122-125 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.74 (d, 2H, J=10Hz); 7.65 (d, 1H, J=4Hz); 7.4 (d, 2H, J=10Hz); 6.96 (d, 2H, J=10Hz); 6.65 (d, 2H, J=10Hz); 3.96 (dd, 1H, J=2,6,2Hz); 3.9 (t, 3H, J=7,7Hz); 2.95-3.1 (m, 4H); 2.46 (t, 1H, J=2,2Hz); 2.38 (s, 3H); 2.33 (t, 2H, J=8,8Hz); 2.24 (m, 2H); 1.78 (m, 3H); 1.45 (t, 4H, J=5,5Hz); 1.38 (m, 4H). embodiment 42 (311) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(tetramethyleneimine-1-yl) oxyethyl groups]-the L-phenylalanine

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 1-(2-chloro ethyl) tetramethyleneimine.The method that using method 7 is described prepares title compound, is solid, mp.127-130 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.73 (d, 2H, J=10Hz); 7.65 (d, 1H, J=4Hz); 7.4 (d, 2H, J=10Hz); 6.95 (d, 2H, J=10Hz); 6.65 (d, 2H, J=10Hz); 3.95 (t, 3H, J=4,6Hz); 3.7 (q, 1H, J=2,4,2Hz); 2.95-3.1 (m, 4H); 2.72 (t, 2H, J=6,6Hz); 2.48 (m, 3H); 2.38 (s, 3H); 1.74 (m, 1H); 1.64 (t, 4H, J=4,4Hz); 1.42 (m, 1H); 1.37 (s, 3H). embodiment 43 (316) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{3-[4-(3-chloro-phenyl-) piperazine-1-yls] propoxy-}-the L-phenylalanine

By in the 2-butanone that is refluxing in the presence of salt of wormwood and the sodium iodide, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters with 1-(3-chlorophenyl)-4-(3-chloropropyl) piperazine.The method that using method 7 is described prepares title compound, is solid, mp.116-8 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.74 (d, 2H, J=10Hz); 7.65 (d, 1H, J=4Hz); 7.4 (d, 2H, J=10Hz); 7.2 (t, 1H, J=8,8Hz); 6.96 (d, 2H, J=10Hz); 6.9 (s, 1H); 6.85 (d, 1H, J=10Hz); 6.75 (d, 1H, J=10Hz); 6.7 (d, 2H, J=10Hz); 3.95 (d, 2H, J=8Hz); 3.92 (t, 1H, J=8,8Hz); 3.83 (q, 1H, J=5,4,5Hz); 3.6 (t, 1H, 5,5Hz); 3.15 (t, 4H, J=4,4Hz); 2.95-3.1 (m, 4H); 2.5 (m, 3H); 2.45 (t, 2H, J=8,8Hz); 2.38 (s, 3H); 1.84 (t, 2H, J=7,7Hz); 1.75 (m, 1H); 1.4 (q, 1H, J=8,10,8Hz); 1.35 (s, 2H). embodiment 44 (318) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(1-tertiary butyloxycarbonyl phenylpiperidines-3-yls) methoxyl group]-the L-phenylalanine methyl ester

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared N-(toluene-4-alkylsulfonyl)-L-prolyl-O-[(1-tertiary butyloxycarbonyl phenylpiperidines-3-yl in the presence of salt of wormwood and the sodium iodide with toluenesulphonic acids N-Boc-3-piperidines methyl esters) methyl]-the L-L-Tyrosine methyl ester; obtain solid, mp.60-62 ℃.

The method that using method 7 is described prepares title compound, obtains solid, mp.82-84 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.77(br s，1H)，8.00(d，1H，J＝7.9Hz)；7.68(d，2H，J＝8.3Hz)；7.39(d，2H，J＝7.9Hz)；7.13(d，2H，J＝8.6Hz)；6.81(d，2H，8.6Hz)；4.42(m，1H)，4.10(m，1H)，3.78(m，3H)；3.07(dd，1H，J＝9.7，4.1Hz)；2.95(dd，1H，J＝19Hz，5.1Hz)；2.90(dd，1H，J＝19Hz)；2.8(m，2H)；1.80(m，2H)；1.58(m，4H)；1.34(br s 14H).

IR(KBr，cm ^-1)：3400，2900，1745，1700，1525，1450，1350，1250，1160，850，800，700，650，600.

Mass spectrum: (FAB, m/e (%)) 652 (75, (M+Na ^-)); 530.2 (75); 224 (100). embodiment 45 (322) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(morpholine-4-yl) oxyethyl groups]-the L-phenylalanine

By N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester alkylation being prepared methyl esters (reaction is 72 hours under 60 ℃ of argon gas for cesium carbonate, DMF) with N-(2-chloroethyl) morpholine.Product obtains methyl esters by flash chromatography purifying (silica gel, ethyl acetate), is the grey foams.The method that using method 6 is described prepares title compound, obtains solid, mp.99-101 ℃.

The NMR data are as follows:

NB contains trace Tos-Pro-Phe (NMR)

¹H NMR(DMSO-d ₆，400MHz)：δ＝7.73(d，2H，J＝8.6Hz)；7.62(d，1H，J＝5.5Hz)；7.40(d，2H，J＝8.2Hz)；6.69(d，2H)；3.95(m，3H)；3.8(m，1H)；3.55(m，4H)；3.1(m，3H)；2.62(t，2H，J＝4Hz)；2.4(m，4H)；2.38(s，3H)；1.7(m，2H)；1.4(m，3H).

IR(KBr，cm ^-1)：3400，2950，2850，1610，1510，1425，1340，1245，1150，1125，825，800，675，575，525.

Mass spectrum: (FAB, m/e (%)) 552 (100, (M+H ⁺)). embodiment 46 (325) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(piperidines-1-yl) oxyethyl groups]-the L-phenylalanine

According to the Mitsunobu prepared in reaction methyl esters of the method for describing for preparing of embodiment 20 (284) by use piperidines alcoholic acid N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester.The method that using method 7 is described prepares title compound, is solid, mp.102-106 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝7.73(d，2H，J＝8Hz)；7.60(d，1H，J＝5.5Hz)；7.39(d，2H，J＝8Hz)；6.96(d，2H，J＝8.6Hz)；6.68(d，2H，J＝8.6Hz)；3.96(m，3H)；3.84(dd，1H J＝5.2，4.8Hz)；2.97-3.10(m，4H)；2.56(t，2H，J＝5.9Hz)；2.38(br s，6H)；1.72(m，1H)；1.34-1.48(m，10H).

IR(KBr，cm ^-1)：3400，2900，1660，1610，1510，1450，1350，1150，875，675，600，550.

Mass spectrum: (FAB, m/e (%)) 542 (100, (M-H ^-)); 196 (10); 155 (75). embodiment 47 (326) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-{3-[4-(3-chloro-phenyl-) piperazine-1-yls] propoxy-}-the L-phenylalanine methyl ester

By in the 2-butanone that is refluxing in the presence of salt of wormwood and the sodium iodide, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters with 1-(2-chlorophenyl)-4-(3-chloropropyl) piperazine.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400Mhz)：δ＝8.2(d，1H，J＝10Hz)；7.68(d，2H，J＝10Hz)；7.4(d，2H，J＝10Hz)；7.19(t，1H，J＝8，8Hz)；7.13(d，2H，J＝10Hz)；6.9(s，1H)；6.85(d，1H，J＝10Hz)；6.82(d，2H，J＝10Hz)；6.75(d，1H，J＝10Hz)；4.45(q，1H，J＝8，5，8Hz)；4.08(t，1H，J＝4，4Hz)；3.94(t，2H，J＝5，5Hz)；3.3(s，3H)；3.12(bs，4H)；3.1(t，1H，J＝8，8Hz)；2.96(m，2H)；2.47(m，3H)；2.38(s，3H)；1.85(t，2H，J＝6，6Hz)；1.57(m，3H)；1.4(m，1H).

MS:EI, m/z682/684 ([MH]+, 18%), 209 (26%) embodiment, 48 (327) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(azepan-1-yl) oxyethyl groups]-the L-phenylalanine

The method that using method 7 is described prepares title compound from the product of embodiment 49 (328), is solid, mp.105-107 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.75 (t, 2H, J=8,8Hz); 7.45 (d, 1H, J=8Hz); 7.4 (t, 2H, J=8,8Hz); 7.05 (d, 1H, J=10Hz); 6.96 (d, 1H, J=10Hz); 6.7 (d, 1H, J=10Hz); 4.1 (t, 1H, J=5,5Hz); 3.92 (t, 3H, J=8,8Hz); 3.82 (m, 1H); 3.6 (t, 1H); 2.8 (t, 2H, J=6,6Hz); 2.66 (d, 4H, J=5Hz); 2.5 (d, 3H, J=10Hz); 1.76 (t, 1H, 7,7Hz); 1.65 (m, 1H); 1.5 (bs, 6H); 1.43 (t, 2H, J=8,8Hz); 1.36 (m, 2H); 1.28 (s, 1H); 1.15 (s, 1H). embodiment 49 (328) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(azepan-1-yl) oxyethyl groups]-the L-phenylalanine methyl ester

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared title compound in the presence of salt of wormwood and the sodium iodide with 2-(hexa-methylene-imino-) ethyl chloride.Be solid, mp.60-65 ℃.Embodiment 50 (347) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(4-methylpiperazine-1-yl) propoxy-]-the L-phenylalanine methyl ester

By in the 2-butanone that refluxes, the O-alkylating of N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester being prepared methyl esters in the presence of salt of wormwood and the sodium iodide with 3-(N methyl piperazine) propyl chloride.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400Mhz)：δ＝8.2(t，1H，J＝10，10Hz)；7.7(t，2H，J＝10，12Hz)；7.4(d，2H，J＝10Hz)；7.1(t，2H，J＝10，10Hz)；6.8(d，2H，J＝10Hz)；4.44(q，1H，J＝4，6，6Hz)；4.1(dd，1H，J＝14，8，8Hz)；3.93(t，2H，J＝6，6Hz)；3.6(s，3H)；3.08(q，1H，J＝6，4，4Hz)；3.0(dd，1H，J＝12，4，4Hz)；2.9(m，2H)；2.38(s，3H)；2.2-2.35(m，10H)；2.12(s，3H)；1.8(t，2H，J＝6，6Hz)；1.55(m，3H)；1.41(m，1H).

MS:+ESI, m/z587 ([MH]+, 100%). embodiment 51 (355) N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-(4-methylpiperazine-1-yl) propoxy-]-the L-phenylalanine

The method that using method 7 is described prepares title compound from the product of embodiment 50 (347), is solid, mp.80-83 ℃.

The NMR data are as follows:

¹H NMR (DMSO-d ₆, 400Mhz): δ=7.75 (d, 2H, J=10Hz); 7.63 (d, 1H, J=4Hz); 7.4 (d, 2H, J=10Hz); 7.05 (d, 2H, J=10Hz); 6.95 (d, 2H, J=10Hz); 6.67 (d, 2H, J=10Hz); 4.1 (d, 1H, J=8Hz); 3.94 (d, 1H, J=8Hz); 3.9 (t, 2H, J=5,5Hz); 3.8 (bs, 1H); 3.08 (m, 1H); 2.91 (d, 1H, J=10Hz); 2.85 (dd, 2H, J=6,18,6Hz); 2.38 (s, 3H); 2.15-2.35 (m, 8H); 2.14 (s, 3H); 1.78 (q, 2H, J=6,8,6Hz); 1.7 (m, 1H); 1.4 (m, 1H); 1.37 (m, 2H). embodiment 52 (345) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine methyl esters

By in pyridine, making N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-amino) phenylalanine methyl ester and trifluoromethanesulfonic acid anhydride reaction prepare title compound, obtain solid, mp.75-78 ℃.Embodiment 53 (370) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanines

The method that using method 6 is described prepares title compound from the product of embodiment 52 (345).

The NMR data are as follows:

¹H NMR(CDCl ₃，400MHz)：δ＝8.08(s，1H)；7.7(d，2H)；7.56(d，1H)；7.34(d，2H)；7.22(s，2H)；4.85(m，1H)；4.16(m，1H)；3.40(m，3H)；3.09(m，2H)；2.44(s，3H)；1.86(m，1H)；1.50(m，3H).

IR(KBr，cm-1)：3390；2950；1750；1650；1525；1425；1375；1340；1200；1150；950；825；625；590；550.

Mass spectrum: (+ESI) 564 ([M+H]+); 530; 462; 406; 362; 342; 335; 157. methoxyl group embodiment 54 (387) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-benzylamino carbonyls)]-the L-phenylalanine methyl ester

By N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester alkylation being prepared title compound (salt of wormwood, sodium iodide reflux under the argon gas and spend the night) in butanone with N-benzyl-2-chlor(o)acetamide.Product is by rapid column chromatography purifying (silica gel, 1: 1 hexane: ethyl acetate), obtain methyl esters, be white solid, mp.57-59 ℃.Embodiment 55 (389) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(carbobenzoxy-(Cbz)s) methoxyl group]-the L-phenylalanine

The method that using method 6 is described prepares title compound from the product of embodiment 4 (387), is solid, mp.79-81 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.2(br s，1H)；8.60(t，1H)；8.03(d，1H，J＝7.9Hz)；7.70(d， 2H，J＝6.6Hz)；7.39(d，2H，J＝8.4Hz)；7.15(d，2H，J＝8.6Hz)；6.87(d，2H，J＝8.6Hz)；4.48(s，2H)；4.42(m，1H)；4.31(d，2H，J＝6.3Hz)；4.10(m，1H)；3.0-3.2(m，2H)；2.8-2.9(m，2H)；2.38(s，3H)；1.2-1.6(m，4H).

IR(KBr，cm ^-1)：3400，2950，1725，1660，1525，1510，1450，1350，1240，1150，1080，670，575，550.

Mass spectrum: (FAB, m/e (%)) 602 (10, (M+Na ^-)); 580 (10, (M+H ⁺)); 131 (100). embodiment 56 (390) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(carboxyls) methoxyl group]-the L-phenylalanine

By with bromo-acetic acid tert-butyl to N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester alkylation (salt of wormwood; DMF; argon gas reacted 72 hours down); obtain N-(toluene-4-alkylsulfonyl)-L-prolyl-L-O-(tertiary butyloxycarbonyl ylmethyl) L-Tyrosine methyl ester; rapid column chromatography (silica 1: 1 hexane: obtain white solid ethyl acetate), mp.55 ℃.

The method that using method 6 is described prepares N-(toluene-4-alkylsulfonyl)-L-prolyl-L-O-(tertiary butyloxycarbonyl ylmethyl) tyrosine from N-(toluene-4-alkylsulfonyl)-L-prolyl-L-O-(tertiary butyloxycarbonyl ylmethyl) L-Tyrosine methyl ester, is solid, mp.69-70 ℃.

By preparing title compound from N-(toluene-4-alkylsulfonyl)-L-prolyl-L-O-(tertiary butyloxycarbonyl ylmethyl) tyrosine with the formic acid reaction.Splash into behind the removal formic acid and use ether, obtain desired compounds, be white solid, mp.70-73 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.85(br s，2H)；8.01(d，1H，J＝7.9Hz)；7.69(d，2H，J＝8.3Hz)；7.39(d，2H，J＝8.3Hz)；7.13(d，2H，J＝8.8Hz)；6.79(d，2H，J＝8.6Hz)；4.6(s，2H)；4.42(m，1H)；4.10(m，1H)；3.08(m，1H)；2.95(m，2H)；2.38(s，3H)；1.5(m，4H).

IR(KBr，cm ^-1)：3350，2950，1730，1625，1510，1425，1340，1175，1160，1075，825，675，575，550.

Mass spectrum: (FAB, m/e (%)) 513 (100. (M+Na ^-)) .491 (75, (M+H ⁺)). embodiment 57 (407) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(aminocarboxyls)]-the L-phenylalanine methyl ester

By N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester alkylation being prepared title compound (salt of wormwood, sodium iodide refluxed 48 hours under the argon gas) in butanone with the 2-chlor(o)acetamide.Product gets the column heading compound by rapid column chromatography purifying (silica gel, ethyl acetate are the ethyl acetate solution of 5% methyl alcohol then), is white solid, mp.60-64 ℃.Embodiment 58 (408) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(aminocarboxyls) methoxyl group]-the L-phenylalanine

The method that using method 6 is described prepares title compound from the product of embodiment 57 (407), is solid, mp.=195-196 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.2(br s，1H)；8.02(d，1H，J＝8.1Hz)；7.69(d，2H，J＝8.3Hz)；7.47，(br s，1H)；7.40(d，2H，J＝7.9Hz)；7.35(br s，1H)；7.14(d，2H，J＝8.6Hz)；6.84(d，2H，J＝8.6Hz)；4.40(m，1H)；4.35(s，2H)；4.11(dd，1H)；3.09(m，1H)；2.91(dd，1H)；2.39(s，3H)；1.45-1.55(m，3H)；1.40(m，1H).

IR(KBr，cm ^-1)：3500，3350，3250，2950，1725，1675，1660，1560，1510，1450，1400，1350，1225，1200，1150，1050，825，660，575，550.

Mass spectrum: (FAB, m/e (%)) 488 (100, (M-H ^-)). embodiment 59 (409) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tertiary butyl aminocarboxyls) methoxyl group]-the L-phenylalanine

By N-(toluene-4-alkylsulfonyl)-L-prolyl-L-L-Tyrosine methyl ester alkylation being prepared methyl esters (salt of wormwood, sodium iodide reflux under the argon gas and spend the night) in butanone with 2-chloro-N-tertiary butyl ethanamide.Product is by rapid column chromatography purifying (silica gel, 1: 1 hexane: ethyl acetate), obtain methyl esters, be white solid.The method that using method 6 is described prepares title compound, is solid, mp.=88-89 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝12.2(br s，1H)；8.02(d，1H，J＝8Hz)；7.68(d，2H，J＝8.3Hz)；7.39(d，3H，J＝8Hz)；7.14(d，2H，J＝8.8Hz)；6.82(dd，2H，J＝8.4，2Hz)；4.4(m，1H)；4.32(s，2H)；4.10(dd，1H，J＝2.9，8Hz)；3.07(m，1H)；3.0(dd，1H，J＝18.7，27.5Hz)；2.94(dd，1H，J＝17.8，26Hz)，2.39(s，3H)；1.5(m，3H)；1.4(m，1H)；1.29(s，9H).

IR(KBr，cm ^-1)：3400，2950，1745，1675，1525，1450，1350，1225，1160，1075，825，675，575，540.

Mass spectrum: (FAB, m/e (%)) 544 (100, (M-H ^-)). embodiment 60 (410) synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxy piperidine-1-yl) oxyethyl groups]-the L-phenylalanine methyl ester

By N-(toluene-4-alkylsulfonyl)-L-prolyl-L-O-(2-chloroethyl) L-Tyrosine methyl ester alkylation being prepared methyl esters (salt of wormwood, sodium iodide refluxed 72 hours under the argon gas) in butanone with the 4-hydroxy-4-phenyl piperidine.Product obtains methyl esters by rapid column chromatography purifying (silica gel, the chloroformic solution of 5% methyl alcohol), is the white foam body.The method that using method 6 is described prepares title compound, is solid, mp.=122-123 ℃.

The NMR data are as follows:

¹H NMR(DMSO-d ₆，400MHz)：δ＝7.72(m，2H)；7.61(d，1H，J＝5.5Hz)；7.39(d，2H，J＝7.2Hz)； 7.28(m，2H)；7.17(m，1H)；7.04(d，1H，J＝8.8Hz)；6.96(d，1H，J＝8.6Hz)；6.71(dd，2H，J＝2.4，8.8Hz)；4.75(s，1H)；4.1(m，1H)；4.0(m，2H)；3.9(q，1H)；3.8(q，1H)；2.8-3.1(m，4H，overlappingsignals)；2.7(m，4H，overlapping signals)；2.38(s，3H)；1.65(m，2H)；1.55(m，2H)；1.4(m，2H).

IR(KBr，cm ^-1)：3375，2890，1660，1610，1510，1390，1325，1250，1160，1075，1040，700，675，575，530.

Mass spectrum: (FAB, m/e (%)) 648 (100, (M+2Li-H) ⁺), 642 (90 (M+Li) ⁺). embodiment 61 (375) synthetic N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(amidino groups) phenylalanine

With N-(toluene-4-alkylsulfonyl) sarcosyl-D, (167mg 0.388mmol) is dissolved in pyridine (6ml) to L-4-cyano group phenylalanine methyl ester (referring to embodiment 61 (381)), and feeds hydrogen sulfide until saturated.The mixture stirring was removed volatile matter under the nitrogen gas stream in 19 hours then.Resistates is dissolved in ethyl acetate (50ml), and washs (2 * 25ml) with 5% aqueous potassium hydrogen sulfate.The organic solution dried over sodium sulfate is filtered and vacuum-evaporation, obtains N-(toluene-4-alkylsulfonyl) sarkosine-D, L-4-thioformamide phenylalanine methyl ester.This thioamides is dissolved in acetone (10ml).Add methyl iodide, mixture heating up refluxed 1 hour.Vacuum is removed volatile matter, obtains N-(toluene-4-alkylsulfonyl) sarkosine-D, L-4-methyl sulfo-imidate phenylalanine methyl ester iodate (256mg, 100%).This sulfo-imidate is dissolved in methyl alcohol (5ml).(52mg, 0.67mmol), mixture heating up refluxed 1.5 hours to add ammonium acetate.Vacuum is removed solvent, and resistates obtains N-(toluene-4-alkylsulfonyl) sarkosine-D, L-4-Amidinophenylalaninederivatives methyl esters (75mg, 38%) by preparation TLC purifying (90: 10: 1 methylene chloride/ammonium hydroxide).By using 0.5N sodium hydroxide hydrolysis methyl esters in THF/ water to prepare title compound (66mg, 87%).

The NMR data are as follows:

¹H NMR(DMSO-d ₆)：δ＝7.66(m，4H)，7.43(d，2H，J＝7.7Hz)，7.29(d，2H，J＝8.0Hz)，4.10(m，1H)，3.57(s，2H)，3.20-3.06(m，2H)，2.54(s，3H)，2.40(s，3H).

Mass spectrum: FAB m/e433 (M+H). embodiment 62 (381) synthetic N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(aminocarboxyl) phenylalanine

N-(toluene-4-alkylsulfonyl) sarkosine coupling 4-cyano group phenylalanine methyl ester hydrochloride (by Wagner, Voight and Vieweg Pharmazie 1984; 39; the method preparation of 226-230), obtain N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-cyano group phenylalanine methyl ester.By using 0.5N sodium hydroxide hydrolysis methyl esters in THF/ water to prepare this compound.

N-(toluene-4-alkylsulfonyl) sarcosyl-D, (300mg 0.699mmol) is dissolved in ethanol (3ml) and is slurries L-4-cyano group phenylalanine methyl ester.Add sodium hydroxide (10N, 98 μ l) and H ₂O ₂(475 μ l, 5.51mmol).Mixture heating up to 50 ℃ reaction 16 hours deposits white precipitate this moment.The mixture cool to room temperature is also used hydrochloric acid (6N) acidifying.Mixture water (20ml) dilutes and (4 * 25ml) extract with chloroform.The organic extract liquid dried over sodium sulfate, filter and from methyl alcohol recrystallization, obtain title compound, be white solid (135mg, 45%).

The NMR data are as follows:

¹H NMR(DMSO-d ₆)：δ＝8，31(br d，1H，J＝3.6Hz)，7.92(br s，1H)，7.72(d，2H，J＝7.8Hz)，7.62(d，2H，J＝7.9Hz)，7.40-7.21(5H)，4.47(m，1H)，3.59(m，2H)，3.15(m，1H)，2.94(m，1H)，2.53(s，3H)，2.39(s，3H).

¹³C NMR(DMSO-d ₆)：δ＝172.9，168.0，167.3，143.7，141.3，134.2，132.8，130.1，129.4，127.8，127.7，53.4，52.4，36.7，36.0，21.3.

Mass spectrum: FAB m/e434 (M+H).

By other compound of method for preparing, comprise those that list as the following Table II of embodiment 63-135.

Q=-C (O) NH is under all situations

R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	68
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[CH ₃(Boc)NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	69	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	68
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[CH ₃(Boc)NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-	-OH	69	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[φCH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-	-OH	70
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[HO(O)C(Cbz-NH)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	71	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[φCH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-	-OH	70
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[HO(O)C(Cbz-NH)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	71	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[HO(O)C(H ₂N)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	72
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH	73	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[HO(O)C(H ₂N)CHCH ₂CH ₂-C (O) NH-] benzyl-	-OH	72
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH	73	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-base	p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH	74
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OCH ₂CH ₃	75	p-CH ₃-φ-		p-[CH ₃(N-Boc)NCH ₂C (O) NH-] benzyl-	-OH	74

R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	76
p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-base		p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	77	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	76
p-CH ₃-φ-			p-[CH ₃NHCH ₂C (O) NH-] benzyl-	-OH	77	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	78
p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-base		p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	79	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	78
p-CH ₃-φ-			p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-	-OH	79	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(ten-hutyl-O(O)CCH ₂-O-benzyl)-the NH-benzyl-	-OCH ₃	80
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-(2-formyl radical-1,2,3,4-tetrahydroisoquinoline-3-base-CH ₂NH-) benzyl	-OH	81	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(ten-hutyl-O(O)CCH ₂-O-benzyl)-the NH-benzyl-	-OCH ₃	80
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)			-OH	81	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[OCH ₂CH(NHBoc)CH ₂Cyclohexyl-]-benzyl	-OCH ₃	82

R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	m-[OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	83
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂C(CH ₃) ₂		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OH	84	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	m-[OCH ₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-	-OH	83
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂C(CH ₃) ₂		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OH	84	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-base	p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OCH ₂CH ₃	85
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OCH ₃	86	p-CH ₃-φ-		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-	-OCH ₂CH ₃	85
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[2-(2-azabicyclo [3.2.2] octane-2-yl) ethyl-O-] benzyl-	-OCH ₃	86	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-	-COH	87
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-	-OCH ₃	88	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-	-COH	87
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-	-OCH ₃	88	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-[2-(2-azabicyclo [3.3.2] octane-2-yl)-ethyl-O-] benzyl-	-OH	89
p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	P-(cyclopentyl-C ≡ C-)-benzyl-	-OH	90	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-[2-(2-azabicyclo [3.3.2] octane-2-yl)-ethyl-O-] benzyl-	-OH	89

R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	P-[-C ≡ C-φ-p-φ]-benzyl-	-OH	91
p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂-O-S(O) ₂-p-CH ₃-φ]-benzyl-	-OH	92	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	P-[-C ≡ C-φ-p-φ]-benzyl-	-OH	91
p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂-O-S(O) ₂-p-CH ₃-φ]-benzyl-	-OH	92	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂NHC(O)NH ₂]-benzyl-	-OH	93
p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂-O-p-O-p-COOCH ₂CH ₃-φ]-benzyl-	-OH	94	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂NHC(O)NH ₂]-benzyl-	-OH	93
p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH ₂-O-p-O-p-COOCH ₂CH ₃-φ]-benzyl-	-OH	94	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH(NH ₂)-cyclohexyl]-benzyl-	-OH	95
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-O-phenyl]-benzyl-	-OH	96	p-CH ₃-φ-	H	-CH ₂-φ (L isomer)	p-[-C≡C-CH(NH ₂)-cyclohexyl]-benzyl-	-OH	95
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-O-phenyl]-benzyl-	-OH	96	p-CH ₃-φ-	-CH ₃	H	p-[-C≡C-CH ₂-O-phenyl]-benzyl-	-OH	97
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-OCH ₃]-benzyl-	-OH	98	p-CH ₃-φ-	-CH ₃	H	p-[-C≡C-CH ₂-O-phenyl]-benzyl-	-OH	97
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-OCH ₃]-benzyl-	-OH	98	p-CH ₃-φ-	-CH ₃	H	p-[-C≡C-CH ₂-OCH ₃]-benzyl-	-OH	99
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-O-p-(C-(O)OC ₂H ₅) phenyl]-benzyl-	-OH	100	p-CH ₃-φ-	-CH ₃	H	p-[-C≡C-CH ₂-OCH ₃]-benzyl-	-OH	99
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-C≡C-CH ₂-O-p-(C-(O)OC ₂H ₅) phenyl]-benzyl-	-OH	100	p-CH ₃-φ-	-CH ₃	H	p-[-C≡C-CH ₂-O-p-(C-(O)OC ₂H ₅) phenyl]-benzyl-	-OH	101

R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[-OCH ₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl-	-OCH ₃	111
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[-O-(3-(N-Boc)-piperidyl]-benzyl-	-OH	112	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		-OCH ₃	111
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[-O-(3-(N-Boc)-piperidyl]-benzyl-	-OH	112	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	M-[O-(N-methyl piperidine-4-yl]-benzyl-	-OH	113
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[O-(N-methyl piperidine-4-yl]-benzyl-	-OH	114	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	M-[O-(N-methyl piperidine-4-yl]-benzyl-	-OH	113
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[O-(N-methyl piperidine-4-yl]-benzyl-	-OH	114	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	115
p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-base		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	116	p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	115
p-CH ₃-φ-			P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	116	p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-base	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	117

R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring-CH ₂CH ₂-SO ₂-CH ₂-(L-1,1-dioxo thiomorpholine-3-base	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	118
p-CH ₃-φ-	R ²/R ³=ring-CH ₂-S-C(CH ₃) ₂-(L-5,5-dimethylthiazole alkane-4-base		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	119	p-CH ₃-φ-		P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	118
p-CH ₃-φ-			P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OH	119	φ-CH ₂-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	120
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-NHSO ₂-CH ₂Cl]-benzyl-	-OCH ₃	121	φ-CH ₂-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-[(1-methyl piperidine-4-yl)-and O-] benzyl-	-OCH ₂CH ₃	120
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[-NHSO ₂-CH ₂Cl]-benzyl-	-OCH ₃	121	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[-NHSO ₂-CH＝CH ₂]-benzyl-	-OCH ₃	122
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[N-3-methyl butyl-N-trifyl) amino] benzyl-	-OCH ₃	123	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[-NHSO ₂-CH＝CH ₂]-benzyl-	-OCH ₃	122
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[N-3-methyl butyl-N-trifyl) amino] benzyl-	-OCH ₃	123	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	The p-[N-vinylsulfonyl) amino] benzyl-	-OH	124

R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ⁶	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[-OCH ₂C (O) O-benzyl] benzyl-	-OCH ₃	125
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl-	-OH	126	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[-OCH ₂C (O) O-benzyl] benzyl-	-OCH ₃	125
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl-	-OH	126	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OCH ₃	127
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OH	128	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OCH ₃	127
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		p-[(CH ₃) ₂CH ₂NC(O)CH ₂-O-] benzyl-	-OH	128	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-(N-methyl kharophen) benzyl-	-OCH(CH ₃) ₂	129
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-(N-methyl kharophen) benzyl-	-OH	130	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-(N-methyl kharophen) benzyl-	-OCH(CH ₃) ₂	129
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-(N-methyl kharophen) benzyl-	-OH	130	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-(N-methyl trifluoro kharophen) benzyl-	-OCH ₃	131
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		(1-tosyl group imidazol-4 yl) methyl-	-OCH ₃	132	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-(N-methyl trifluoro kharophen) benzyl-	-OCH ₃	131

R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number
R ¹	R ²	R ³	R ⁵	R ^6′	The embodiment sequence number	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	1-([N, N-dimethylamino alkylsulfonyl]-imidazol-4 yl) methyl-	-OCH ₃	133
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[N-tosyl group amino] benzyl-	-OCH ₃	134	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		-OCH ₃	133
p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)		P-[N-tosyl group amino] benzyl-	-OCH ₃	134	p-CH ₃-φ-	R ²/R ³=ring last 3 carbon atoms (L-pyrrolidyl)	P-[N-tosyl group amino] benzyl-	-OH	135

Except top, prepare additional compounds: embodiment 136 synthetic N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-[3-(N, N-dimethylamino) propoxy-with embodiment 136-140]-the L-phenylalanine tert-butyl ester

According to embodiment 20 preparation title compounds, but substitute the N-Boc-L-Tyrosine methyl ester with the N-Boc-tyrosine tert-butyl ester.

MS：[(+)ESI]，(M+H) ⁺620。Embodiment 137 synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-(N-methyl piperidine oxygen base)-phenylalanine tert-butyl esters

By using the Tyr-O-1-picoline tert-butyl ester (by the Mitsunobu reaction) BOP coupling Tos-Pro-OH to prepare title compound.Crude product is by flash chromatography purifying (silica gel, 95: 5 ethyl acetate: triethylamine), obtain white solid (0.615g, 60%).

MS((+)ESI，m/z(％))586(100[M+H] ^-).

Analytical calculation value C ₃₁H ₄₃N ₃O ₆S:C, 63.57; H, 7.40; N, 7.17. measured value: C, 63.11; H, 7.37; N, 6.96. embodiment 138 synthetic N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-L-(4-methyl piperidine oxygen base) phenylalanine tert-butyl esters

The alternative suitable initiator of describing according to embodiment 137 of method prepares title compound.

Analytical calculation value C ₃₂H ₄₅N ₃O ₆S ₂0.25CH ₂Cl ₂C, 58.85; H, 7.02; N, 6.43. measured value: C, 58.75; H, 6.92; N, 6.48.

MS (+ESI): 632[M+H]+embodiment 139 synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine tert-butyl esters

From corresponding triflat (it is according to Tilley and colleague, J.Org.Chem, 55,906,1990 teaching is from N-(toluene-4-alkylsulfonyl)-L-prolyl-L-tyrosine tert-butyl ester preparation) preparation title compound.With this dipeptides (505mg, 0.8mmol), the tetrakis triphenylphosphine palladium of catalytic amount (O), salt of wormwood (201mg, 1.5eq), phenyl-boron dihydroxide (199mg, 2.0eq) and 15ml toluene under agitation refluxed 10 hours.Add ethyl acetate, the organic layer water, 1N sodium hydroxide, the salt water washing, and use dried over mgso.Filter solvent evaporated under reduced pressure.Crude product is purifying (1: 1 ethyl acetate: hexane) on the preparation plate.Silica gel is used acetonitrile and ethyl acetate rinse several times.The fraction that evaporation merges, the resistates drying under reduced pressure.

The NMR data are as follows:

¹H NMR(CDCl ₃，300MHz)：δ＝7.70(m，1H)；7.57(m，3.5H)；7.45(m，3.5H)；7.28(m，5H)；4.78(m，1H)；4.06(m，1H)；3.30(m，2H)；3.06(m，2H)；2.40(s，3H)；2.05(m，1H)；1.42(s，9H).

¹³C NMR (CDCl ₃): δ=171.02,169.98,144.4,140.78; 139.82,135.53,132.82,129.97; 129.9,129.41,128.78,127.86; 127.04,126.98,82.65,62.15; 53.74,49.49,37.43,29.67; 27.78,23.92,21.37. embodiment 140 synthetic N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanines

The method that using method 11 is described prepares title compound from the product of embodiment 139.

The NMR data are as follows:

¹H NMR(CD ₃OD，300MHz)：δ＝8.05(m，1H)；7.71(d，2H，J＝8.24Hz)；7.55(m，4H)；7.30(m，8H)；4.71(m，1H)；4.09(m，1H)；3.30(m，3.30)；3.15(m，3H)；2.37(s，3H)；1.78(m，1H)；1.62(m，4H).

¹³C NMR (CD ₃OD): δ=174.27,145.88,142.25,141.23,137.44,135.12,131.19,131.15,129.98,129.09,128.4,128.17,128.0,63.25,54.69,50.52,37.85,31.52,25.21,21.43. embodiment 141 measures the vitro test of candidate compound in conjunction with VLA-4

Use vitro test evaluate candidate compound and α ₄β ₁The combination of integrin.The bonded compound is used to estimate the VCAM-1 level in the biological test by conventionally test (for example competition test) in this test.This test is to IC ₅₀Value is responsive, and it is low like this to resemble about 1nM.

By solubility VCAM-1 and Jurkat cell (for example U.S. typical case culture center Nos.TIB152, TIB153 and CRL8163), express high-level α ₄β ₁α is measured in the interaction of integrin people T-clone ₄β ₁The activity of integrin.VCAM-1 and α ₄β ₁Cell surface interaction in the integrin dependence mode (Yednock etc., journal of biological chemistry (J.Biol.Chem.) 1995,270:28740).

Recombinant soluble VCAM-1 is expressed as 7 extracellular regions containing on N-end VCAM-1 and the human IgG of C-end ₁The chimeric protein of CH.Method preparation and purifying VCAM-1 fusion rotein by above Yednock description.

According to above Yednock is described, adding 10% foetal calf serum, penicillin is cultivated the Jurkat cell among the RPMI1640 of Streptomycin sulphate and glutamine.

On the ice bath, Jurkat cell and 1.5mM MnCl ₂Cultivated 30 minutes with 5 μ g/ml, 15/7 antibody.Mn ^{+ 2}Activated receptor to be strengthening the part combination, and the 15/7th, monoclonal antibody, the α that its identification activated/part occupies ₄β ₁The conformation of integrin, and blocker molecule enters this conformation, thus stablize VCAM-1/ α ₄β ₁Integrin interacts.Yednock etc. above.The antibody that is similar to 15/7 antibody prepares (Luque etc., 1996, journal of biological chemistry (J.bio.Chem.) 271:11067) by other researchist, can use in this test.

Cell then at room temperature with the candidate compound cultivation of the various concentration of 66 μ M to 0.01 μ M scopes of using standard 5-point serial dilution 30 minutes.Add 15 μ L solubilities reorganization VCAM-1 fusion rotein and cultivate 30 minutes (above Yednock etc.) on ice to the Jurkat cell then.

Cell is rinsed twice then, and again to be suspended in PE bonded goat F (ab ') at 1: 200 ₂(Immunotech, Westbrook ME), and cultivated 30 minutes on ice anti-mouse IgG Fc in the dark.Cell is rinsed twice, and according to above Yednock etc. is described, (" FACS ") analyzes with standard fluorescence activating cells sorter.

Has IC less than about 15 μ M ₅₀Compound have for α ₄β ₁Binding affinity.

When testing in this test, each compound of embodiment 1-135 has 15 μ M or littler IC ₅₀Embodiment 142 measures candidate compound for α ₄β ₁The external saturation ratio test of bonded

The vitro test that is determined at the blood plasma level of required active compound in experimental autoimmunization encephalomyelitis (" the EAE ") model is described below, and described model is described at next embodiment or in other body inner model.

The flushing logarithmic growth the Jurkat cell and be suspended in again in the Normal animal plasma that contains 20 μ g/ml, 15/7 antibody (describing among the top embodiment).

The Jurkat cell dilutes 2 times in the Normal animal plasma of the known candidate compound of the various concentration amounts of 66 μ M to 0.01 μ M that contain 12 serial dilution typical curves of use standard, perhaps 2 times of dilutions the plasma sample that the peripheral blood of the animal of handling from candidate compound obtains.

Cell was at room temperature cultivated 30 minutes then, washed twice to remove unconjugated 15/7 antibody with the phosphate buffered saline (PBS) (" PBS ") (test media) that contains 2% foetal calf serum and each calcium chloride of 1mM and magnesium chloride.

Cell is exposed to phycoerythrin bonded goat F (ab ') then ₂(ME), the latter, with 1: 200 and cultivated 30 minutes at 4 ℃ by having adsorbed all non-specific cross-reactions with 5% serum co-cultivation from the animal species of studying anti-mouse IgGFc in the dark for Immunotech, Westbrook.

The tested substratum flushing twice of cell, and be suspended in the test media again.Then according to Yednock etc., journal of biological chemistry (J.biol.Chem.) 1995,270:28740 is described, and (" FACS ") analyzes with standard fluorescence activating cells sorter.

For example, dosage is mapped data with fluorescence volume with normal dose-reactive mode.Cause the dosage level of curve top steady section to represent the needed level of acquisition drug effect in the body inner model.

This test can also be used to measuring for example α of saturated other integrin ₉β ₁The needed blood plasma level of the binding site of integrin, described α ₉β ₁Integrin is and α ₄β ₁The most closely-related integrin of integrin (Palmer etc., 1993, cytobiology (J.Cell Bio.), 123:1289).Such combination has indicated α ₉β ₁Purposes in the body of 6 integrin-mediated inflammatory disease, for example comprise air flue hyperreactive and the obturation of following chronic asthma to take place, smooth muscle cell proliferation in the atherosclerosis, the vascular occlusion that postangioplasty takes place, fibrosis and renal glomerulus wound as the ephrosis result, aortic stenosis, the hypertrophy of Synovial membrane and follow ulcerative colitis and the development of Crohn disease and the inflammation and the wound that take place in the rheumatoid arthritis.

Therefore, above-mentioned test can be used coding for alpha ₉The CCL188 SW480 (ATCC#CCL228) of the cDNA transfection of integrin (Yokosaki etc., 1994, journal of biological chemistry (J.Biol.Chem.) 269:26691) replaces the Jurkat cell to carry out, to measure α ₉β ₁The combination of integrin.In contrast, can use other α of expression and β ₁The SW480 cell of subunit.

Therefore, another aspect of the present invention relates to the α that treats mammalian subject ₉β ₁The method of the disease of mediation, this method comprise gives and the compound of the present invention for the treatment of significant quantity described patient.Such compound is preferably with the aforementioned pharmaceutical compositions administration.Effective dose will depend on patient's age every day, body weight and situation, and these factor treatment doctors can judge easily.But, in preferred embodiments, give the about 20-500 μ of drug compound g/kg every day.Embodiment 143 interior evaluatings

Use standard multiple sclerosis model, experimental autoimmunization (or allergy) encephalomyelitis (" EAE ") are measured candidate compound alleviates the motor damage in rat or cavy effect.The basis that alleviates of motor damage is adhesion between blocking leukocyte and the endotheliocyte and relevant with the anti-inflammatory activity of candidate compound.This model is described in Keszthelyi etc. in advance, neuroscience (Neurology), and 1996,47:1053-1059, and measure the delay that disease takes place.

Brain and the spinal cord homogenizing in isopyknic phosphate buffered saline (PBS) of adult Hartley cavy.In homogenate, add the Fu Shi (Freund's complete adjuvant (100mg mycobacterium tuberculosis (mycobacterium tuberculosis) adds the 10ml Freund's incomplete adjuvant) of Freund ' s).Emulsification is about 20 minutes by it being cycled through the 20ml syringe repeatedly with peristaltic pump.

With the female Lewis rat of isoflurane anesthesia (the 2-3 monthly age, 170-220g) or the Hartley cavy (20 day age, 180-200g), and the injection emulsion, each 0.1ml of each flank.Observed at about 9 days and to move former damage.

At the 8th day, only before symptom takes place, begin to treat with candidate compound.Subcutaneous (" SC "), oral (" PO ") or intraperitoneal (" IP ") are given drug compound.Test is given and dosage with 10mg/kg to 200mg/kg scope, and typical dosage is 10mg/kg to 100mg/kgSC, 10mg/kg to 50mg/kgPO and 10mg/kg to 100mg/kgIP.

Use and postpone the anti-α that symptom takes place ₄β ₁The antibody GG5/3 of integrin (Keszthelyi etc., neuroscience (Neurology), 1996,47:1053-1059) as positive control, at the 8th and 11 day with the 3mg/kg subcutaneous injection.

Measure the damage of body weight and motor every day.Motor damage is with following clinical scores evaluation: 0 not change 1 afterbody unable or benumb 2 afterwards skelasthenia 3 hind leg paralysis 4 are dying or dead

If it has postponed the generation of symptom, for example generation is not more than 2 clinical scores or has slowed down alleviating of body weight compared with the control, thinks that then candidate compound is activated.

When testing in this body build-in test, embodiment 5,12, and 18 and 20 compound has activity.Embodiment 144 asthmatic models

α ₄β ₁6 integrin-mediated inflammatory disease comprises air flue hyperreactive and the obturation of for example following chronic asthma to take place.Asthmatic model is described below, and it can be used for studying the interior effect of body that compound of the present invention is used for the treatment of asthma.

Following method is described in Abraham etc., Journal of Clinical Investigation (J.Clin.Invest.) 93:776-787 (1994) and Abraham etc., Am.J.Respir Crit Care Med, 156:696-703 (1997), these two pieces of document hereby incorporated by reference, compound of the present invention are mixed with aerosol and to the extremely sensitive sheep administration of Ascaris suum antigen.The compound that alleviates reaction of early antigen inductive tracheae and/or the reaction of blocking-up air flue in late period for example has the protection effect of the late phase response and the air flue hyperreactive (" AHR ") of anti-antigen induction, and it is active being considered in this model.

Use shows for sucking Ascaris suum antigen the air flue effect that allergy sheep early stage and tracheae reaction in late period is studied candidate compound takes place.With 2% lignocaine toponarcosis nasal meatus, the oesophagus below ballon catheter inserts by a nostril.Be to instruct the endotracheal tube that animal is inserted flange by another nostril with the softish fiberoptic bronchoscope then.

Estimate the chest pressure according to Abraham (1994).It is the disposable medicinal atomizer generation aerosol (referring to following preparation) of the aerosol of 3.2 μ m that use provides according to the quality center aerodynamic diameter of measuring with the Andersen cascade impactor.Atomizer connects the dosimeter system by magnetic valve and compressed air source (20psi).The outlet of atomizer directly inserts plastics T-sheet, and the one end connects the sucker part of piston respiratory organ.Magnetic valve was activated when the inspiratory cycle of respiratory organ begins 1 second.Aerosol is with V _τSend for the speed of 500ml and 20 breaths/min and to pass.Use 0.5% pure sodium bicarbonate in contrast.

In order to estimate bronchial reactivity, can be according to the concentration-response curve of Abraham (1994) preparation for the accumulative total of carbachol.Before or after beginning to handle and antigen attack and can get the segmental bronchus biopsy sample in back 24 hours.Can carry out the segmental bronchus examination of living tissue according to Abraham (1994).

Can carry out the external adhesion research of pulmonary alveolar macrophage according to Abraham (1994), and calculate the per-cent of adherent cell. Aerosol formulation

The solution for preparing the candidate compound in 0.5% sodium bicarbonate/salt solution (w/v) of 30.0mg/ml concentration in the following method: A. prepares 0.5% sodium bicarbonate/salt solution stock solution: 100.0ml

Composition	g/100.0ml	Ultimate density
Composition	g/100.0ml	Ultimate density	Sodium bicarbonate	0.5g	0.5％
Salt solution	Capacity is to 100.0ml	Capacity to 100%	Sodium bicarbonate	0.5g	0.5％

Method: the 1.0.5g sodium bicarbonate joins in the 100ml volumetric flask.2. add about 90.0ml salt solution and supersound process up to dissolving.With saltwater replenishment to 100.0ml, and thorough mixing.B. prepare 30.0mg/ml candidate compound: 10.0ml

Composition	g/10.0ml	Ultimate density
Composition	g/10.0ml	Ultimate density	Candidate compound	0.300g	30.0mg/ml
0.5% sodium bicarbonate/salt solution stock solution	Capacity is to 10.0ml	Capacity to 100%	Candidate compound	0.300g	30.0mg/ml

Method: the 1.0.300g candidate compound joins in the 10.0ml volumetric flask.2. add about 9.7ml 0.5% sodium bicarbonate/salt solution stock solution.3. supersound process is dissolved fully up to candidate compound.4. with 0.5% sodium bicarbonate/the salt solution stock solution is supplemented to 10.0ml, and thorough mixing.

Use conventional oral preparations, compound of the present invention is activated in this model.

Claims

1. the compound of formula IA:

Wherein

R ¹Be selected from the p-aminomethyl phenyl, 2-thienyl, 5-chloro-2-thiophenyl, 2,5-two chloro-4-thienyls, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 1-N-methyl-4-imidazolyl, 2-methyl-4-thiadiazolyl group;

R ²Be methyl

R ³Be selected from hydrogen ,-CH ₂OH

R ²And R ³With bonding R ²Nitrogen-atoms and bonding R ³Carbon atom form together and be selected from L-pyrrolidyl, L-3,3-pyrrolidyl, L-5,5-dimethylthiazole alkane-4-base, L-1, the heterocyclic radical of 1-dioxy thiomorpholine-3-base, thiazole-4-base;

R ⁵Be selected from

P-[-NHC (O) CH ₂NHBoc]-benzyl-,

P-[-NHC (O) CH ₂NH ₂]-benzyl-,

P-[-NHC (O) CH ₂CH ₂C (O) OH]-benzyl-,

4-[-NHC (O) CH ^*(CH ₃) NHBoc]-benzyl-( ^*Be equivalent to the L isomer),

4-[-NHC (O) CH ^*(CH ₂) NHBoc]-benzyl-( ^*Be equivalent to the D isomer),

[NHC (O) CH ₂NHC (O) NH-fluorescin] benzyl-,

4-[BocNHCH ₂C (O) NH]-benzyl-,

P-[-NHC (O) CH ₂NHC (O) NH-m-aminomethyl phenyl]-benzyl-,

P-[-NHC (O) CH (NHBoc) (CH ₂) ₄NHCbz]-benzyl-,

P-[-NHC (O) CH ₂C (C (O) OCH ₂) H-NHCbz]-benzyl-,

P-[-NHC (O) C (CH ₂CH ₂CH ₂CH ₂NH ₂) H-NHBoc]-benzyl-,

P-[NHC (O) CH ₂CH (NH ₂) COOH, p-(H ₂NCH ₂CH ₂CH ₂C (O) NH) benzyl-, p-(Boc-HNCH ₂CH ₂C (O) NH) benzyl-, p-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₃(Boc) NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-, p-[HO (O) C (Cbz-NH) CHCH ₂CH ₂-C (O) NH-] benzyl-, p-[HO (O) C (H ₂N) CHCH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₃(N-Boc) NCH ₂C (O) NH-] benzyl-, p-[CH ₃NHCH ₂C (O) NH-] benzyl-, p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-, p-[-O-CH (COOH)]-benzyl-, the p-[-o-carboxyl phenyl]-benzyl-, p-[o-carboxyl aminomethyl phenyl]-benzyl-, p-[CH ₂OC (O) NHCH ₂CH ₂NH]-benzyl-, p-[-N (SO ₂CH ₃) (CH ₂) ₃-N (CH ₃) ₂]-benzyl-, the p-[(tertiary butyl-O (O) CCH ₂-O-benzyl)-and NH-] benzyl-, p-[(N, N-two (4-N, N-dimethylamino) benzyl) and amino] benzyl-, p-(2-formyl radical-1,2,3,4-tetrahydroisoquinoline-3-base-CH ₂NH-) benzyl-, 4-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-]--CH2-p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-, p-[-OCH ₂CH ₂N () CH ₂CH ₃]-benzyl-, p-[two-different-propyl group amino-CH ₂CH ₂O-]-benzyl-, p-[-OCH ₂CH (NHBoc) CH ₂Cyclohexyl]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (CH ₃) ₂]-benzyl-, p-[-OCH ₂CH ₂N (C ₂H ₅) ₂]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (C ₂H ₅) ₂]-benzyl-, m-[-OCH ₂CH ₂CH ₂N (CH ₃) ₂]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (CH ₃) benzyl]-benzyl-, p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-, p-[2-(2-azabicyclic [3.2.2] octane-2-yl) ethyl-O-] and benzyl-, p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-, p-(cyclopentyl-CC-)-benzyl-, p-[-CC--p-]-benzyl-, p-[-CC-CH ₂-O-S (O) ₂-p-CH3-]-benzyl-, p-[-CC-CH ₂NHC (O) NH ₂]-benzyl-, p-[-CC-CH ₂-O-p-COOCH ₂CH ₃-]-benzyl-p-[-CC-CH (NH ₂)-cyclohexyl]-benzyl-, p-[-CC-CH ₂-O-phenyl]-benzyl-, p-[-CC-CH ₂-OCH ₃]-benzyl-, p-[-CC-CH ₂-O-p-(C (O) OC ₂H ₅) phenyl]-benzyl-, p-[-CC-CH ₂CH (C (O) OCH ₃) ₂]-benzyl-, p-[-CC-CH ₂C (NHC (O) CH ₃) HC (O) OH]-benzyl-, p-[-CC-CH ₂NH-(4,5-dihydro-4-oxygen-5-phenyl-azoles-2-yl)] benzyl-, p-[-O-(o-carboxyl phenyl)]-benzyl-, p-[-OCH ₂CH ₂-1-(4-pyrimidyl)-piperazinyl]-benzyl-, p-[-OCH ₂CH ₂-(piperidino)-benzyl-, p-[-OCH ₂CH ₂-(1-pyrrolidyl)]-benzyl-, p-[-OCH ₂CH ₂CH ₂-(1-piperazinyl)]-benzyl-, p-[-OCH ₂CH ₂CH ₂-1-(4-m-chloro-phenyl-)-piperazinyl-benzyl-, p-[-OCH ₂-3-(N-Boc)-piperidyl]-benzyl-, p-[-OCH ₂CH ₂-(N-morpholinyl)]-benzyl-, p-[OCH ₂CH ₂-(the N-piperidyl]-benzyl-, p-[-OCH ₂CH ₂-(N-homopiperidinyl)-benzyl-, p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-, m-[-OCH ₂CH ₂-(1-pyrrolidyl)]-benzyl-, p-[-OCH ₂CH ₂-(N-morpholino)]-benzyl-, p-[-OCH ₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl-, p-[-O-(3-(N-Boc)-piperidyl]-benzyl-, m-[O-(N-methyl-piperidin-4-yl]-benzyl-, p-[-O-(N-methyl-piperidin-4-yl)]-benzyl-, p-[(1-methyl piperidine-4-yl)-and O-] benzyl-, p-[-NHSO ₂CF ₃]-benzyl-, p-[-NHSO ₂-CH ₂C1]-benzyl-, p-{-NHSO ₂-CH=CH ₂]-benzyl-,

P-[N-3-methyl butyl-N-trifyl) amino] benzyl-,

The p-[N-vinylsulfonyl) amino] benzyl-,

P-[-OCH ₂C (O) NH-benzyl]-benzyl-,

P-[-OCH ₂C (O) O-benzyl]-benzyl-,

P-[-OCH ₂C (O) OH]-benzyl-,

P-[-OCH ₂C (O) NH ₂]-benzyl-,

P-[-OCH ₂C (O) the NH-tertiary butyl]-benzyl-,

P-[-OCH ₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl-,

P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl-,

P-[(CH ₃) ₂CH) ₂NC (O) CH ₂-O-] benzyl-,

P-[-C (=NH) NH ₂]-benzyl-,

P-[-C (O) NH ₂]-benzyl-,

P-(N-methyl kharophen) benzyl-,

P-(N-methyl trifluoro kharophen) benzyl-,

(1-tosyl group imidazol-4 yl) methyl-,

1-([N, N-dimethylamino alkylsulfonyl]-imidazol-4 yl) methyl-,

P-(N-tosyl group amino) benzyl-,

P-(3-N, N-dimethyl propoxy-)-benzyl-,

P-(N-methyl piperidine base oxygen)-benzyl-and

P-(phenyl)-benzyl-; And

R ⁶Be selected from-OH-OCH ₃,-OCH ₂CH ₃,-OC (CH ₃) ₃And-O-CH ₂-phenyl;

And their pharmacy acceptable salt.

2. the compound of claim 1, it is selected from:

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tert-butoxycarbonyl glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tert-butoxycarbonyl-L-alanyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(α-carboxyl benzyl oxygen)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(methoxycarbonyl) phenyl]-L-phenylalanine benzyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-{N-[3-(N, N-dimethylamino) propyl group]-the N-[trifyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(aminocarboxyl]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(amidino groups) phenylalanine

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

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[γ-(α-benzyl-N-carbobenzoxy-(Cbz)-L-aspartoyl) amino]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(the amino tert-butyl-carboxamide of 4-)-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-tert-butoxycarbonyl amino) butyrylamino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-methylamino) butyrylamino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[4-(N-tert-butoxycarbonyl-N-methylamino) butyrylamino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-{N-[3-(N, N-dimethylamino) propyl group]-the N-[methylsulfonyl] amino }-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-4-{N-[(2-formyl radical-1,2,3,4-tetrahydroisoquinoline-3-yl) methyl] amino }-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N-tert-butoxycarbonyl amino) propoxy-]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-[3-(N, N-dimethylamino) propoxy-]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(2-azabicyclic [3.2.2] octane-2-yl) oxyethyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[2-(2-azabicyclic [3.2.2] octane-2-yl) oxyethyl group]-the L-phenylalanine

I-(toluene-4-alkylsulfonyl)-L-prolyl-4-(3-tert.-butoxy piperidines-4-oxygen)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-3-(1-methyl piperidine-4-oxygen)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(1-methyl piperidine-4-oxygen)-D, the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-(1-methyl piperidine-4-oxygen)-L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-4-(1-methyl piperidine-4-oxygen)-L-phenylalanine

N-(tosyl group)-L-prolyl-4-(1-methyl piperidine-4-oxygen)-L-phenylalanine ethyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(vinylsulfonyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(carbobenzoxy-(Cbz)) methoxyl group]-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N, N-diisopropylaminoethyl carbonyl) methoxyl group)-the L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N, N-diisopropylaminoethyl carbonyl) methoxyl group)-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-(N-methyl trifluoro kharophen)-L-phenylalanine methyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-L-(4-(the N-methyl piperidine oxygen base)-phenylalanine) tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-(5, the 5-dimethyl) thia prolyl-L-(4-N-methyl piperidine oxygen base) phenylalanine) tert-butyl ester

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine tert-butyl ester and

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine.

3. in conjunction with the method for VLA-4 in the biological sample, this method comprises the compound contact biological sample with formula IA:

Wherein

R ²Be methyl

R ³Be selected from hydrogen ,-CH ₂OH

R ⁵Be selected from p-[-NHC (O) CH₂NHBoc]-benzyl-, p-[-NHC (O) CH₂NH ₂]-benzyl-, p-[-NHC (O) CH₂CH ₂C (O) OH]-benzyl-, 4-[-NHC (O) CH^*(CH ₃) NHBoc]-benzyl-(^*Be equivalent to the L isomers), 4-[-NHC (O) CH^*(CH ₂) NHBoc]-benzyl-(^*Be equivalent to the D isomers), [NHC (O) CH₂NHC (O) NH-dihydrofluorescein] benzyl-, 4-[BocNHCH₂C (O) NH]-benzyl-, p-[-NHC (O) CH₂NHC (O) NH-m-aminomethyl phenyl]-benzyl-, p-[-NHC (O) CH (NHBoc) (CH₂) ₄NHCbz]-benzyl-, p-[-NHC (O) CH₂C(C(O)OCH ₂) H-NHCbz]-benzyl-, p-[-NHC (O) C (CH₂CH ₂CH ₂CH ₂NH ₂) H-NHBoc]-benzyl-, p-[NHC (O) CH₂CH(NH ₂)COOH， p-(H ₂NCH ₂CH ₂CH ₂C (O) NH) benzyl-, p-(Boc-HNCH₂CH ₂C (O) NH) benzyl-, p-[CH₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH₃(Boc)NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH₂OCH ₂(H ₂N) CHC (O) NH] benzyl-, p-[HO (O) C (Cbz-NH) CHCH₂CH ₂-C (O) NH-] benzyl-, p-[HO (O) C (H₂N)CHCH ₂CH ₂-C (O) NH-] benzyl-, p-[CH₃(N-Boc)NCH ₂C (O) NH-] benzyl-, p-[CH₃NHCH ₂C (O) NH-] benzyl-, p-[(CH₃) ₂NCH ₂C (O) NH-] benzyl-, p-[-O-CH (COOH)]-benzyl-, the p-[-o-carboxyl phenyl]-benzyl-, p-[o-carboxyl aminomethyl phenyl]-benzyl-, p-[CH₂OC(O)NHCH ₂CH ₂NH]-benzyl-, p-[-N (SO₂CH ₃)(CH ₂) ₃-N(CH ₃) ₂]-benzyl-, the p-[(tert-butyl group-O (O) CCH₂-O-benzyl)-NH-] benzyl-, p-[(N, N-two (4-N, N-dimethylamino) benzyl) and amino] benzyl-, p-(2-formoxyl-1,2,3,4-tetrahydroisoquinoline-3-base-CH₂NH-) benzyl-, 4-[(CH₃) ₂NCH ₂CH ₂CH ₂-O-]--CH2-p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-, p-[-OCH₂CH ₂N()CH ₂CH ₃]-benzyl-, p-[two-different-propyl group amino-CH₂CH ₂O-]-benzyl-, p-[-OCH₂CH(NHBoc)CH ₂Cyclohexyl]-benzyl-, p-[-OCH₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-, p-[-OCH₂CH ₂N(C ₂H ₅) ₂]-benzyl-, p-[-OCH₂CH ₂CH ₂N(C ₂H ₅) ₂]-benzyl-, m-[-OCH₂CH ₂CH ₂N(CH ₃) ₂]-benzyl-, p-[-OCH₂CH ₂CH ₂N(CH ₃) benzyl]-benzyl-, p-[(CH₃) ₂NCH ₂CH ₂CH ₂O] benzyl-, p-[2-(2-azabicyclic [3.2.2] octane-2-yl) ethyl-O-] and benzyl-, p-[(CH₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-, p-(cyclopenta-CC-)-benzyl-, p-[-CC--p-]-benzyl-, p-[-CC-CH₂-O-S(O) ₂-p-CH3-]-benzyl-, p-[-CC-CH₂NHC(O)NH ₂]-benzyl-, p-[-CC-CH₂-O-p-COOCH ₂CH ₃-]-benzyl-p[-CC-CH (NH₂)-cyclohexyl]-benzyl-, p-[-CC-CH₂-O-phenyl]-benzyl-, p-[-CC-CH₂-OCH ₃]-benzyl-, p-[-CC-CH₂-O-p-(-C(O)OC ₂H ₅) phenyl]-benzyl-, p-[-CC-CH₂CH(C(O)OCH ₃) ₂]-benzyl-, p-[-CC-CH₂C(NHC(O)CH ₃) HC (O) OH]-benzyl-, p-[-CC-CH₂NH-(4,5-dihydro-4-oxygen-5-phenyl-azoles-2-yl)] benzyl-, p-[-O-(o-carboxyl phenyl)]-benzyl-, p-[-OCH₂CH ₂-1-(4-pyrimidine radicals)-piperazinyl]-benzyl-, p-[-OCH₂CH ₂-(1-piperidyl)-benzyl-, p-[-OCH₂CH ₂-(1-pyrrolidinyl)]-benzyl-, p-[-OCH₂CH ₂CH ₂-(1-piperazinyl)]-benzyl-, p-[-OCH₂CH ₂CH ₂-1-(4-m-chlorphenyl)-piperazinyl-benzyl-, p-[-OCH₂-3-(N-Boc)-piperidyl]-benzyl-, p-[-OCH₂CH ₂-(N-morpholinyl)]-benzyl-, p-[OCH₂CH ₂-(the N-piperidyl]-benzyl-, p-[-OCH₂CH ₂-(N-homopiperidinyl)-benzyl-, p-[-OCH₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-, m-[-OCH₂CH ₂-(1-pyrrolidinyl)]-benzyl-, p-[-OCH₂CH ₂-(N-morpholino)]-benzyl-, p-[-OCH₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl-, p-[-O-(3-(N-Boc)-piperidyl]-benzyl-, m-[O-(N-methyl-piperidin-4-yl]-benzyl-, p-[-O-(N-methyl-piperidin-4-yl)]-benzyl-, p-[(1-methyl piperidine-4-yl)-O-] benzyl-, p-[-NHSO₂CF ₃]-benzyl-, p-[-NHSO₂-CH ₂C1]-benzyl-, p-{-NHSO₂-CH＝CH ₂]-benzyl-, p-[N-3-methyl butyl-N-trifyl) amino] benzyl-, the p-[N-vinylsulfonyl) and amino] benzyl-, p-[-OCH₂C (O) NH-benzyl]-benzyl-, p-[-OCH₂C (O) O-benzyl]-benzyl-, p-[-OCH₂C (O) OH]-benzyl-, p-[-OCH₂C(O)NH ₂]-benzyl-, p-[-OCH₂C (O) the NH-tert-butyl group]-benzyl-, p-[-OCH₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl-, the p-[(piperidin-1-yl) and C (O) CH₂-O-] benzyl-, p-[(CH₃) ₂CH) ₂NC(O)CH ₂-O-] benzyl-, p-[-C (=NH) NH₂]-benzyl-, p-[-C (O) NH₂]-benzyl-, p-(N-methyl acetylamino) benzyl-, p-(N-methyl trifluoro acetylamino) benzyl-, (1-tosyl imidazol-4 yl) methyl-, 1-([N, the N-dimethylamino-sulfonyl]-imidazol-4 yl) methyl-, p-(the N-tosyl is amino) benzyl-, p-(3-N, N-dimethyl propoxyl group)-benzyl-, p-(N-methyl piperidine base oxygen)-benzyl-, and p-(phenyl)-benzyl-; And

And their pharmacy acceptable salt.

4. the method for claim 3, wherein said compound is selected from

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(amidino groups) phenylalanine

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

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(vinylsulfonyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine.

5. according to the method for claim 4, wherein said compound is N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tert-butoxycarbonyl glycyl) amino]-the L-phenylalanine.

6. contain pharmaceutical acceptable carrier and one or more formulas IA compound of treatment significant quantity and the pharmaceutical composition of pharmaceutically acceptable salt thereof:

Wherein

R ²Be methyl

R ³Be selected from hydrogen ,-CH ₂OH

R ⁵Be selected from

P-[-NHC (O) CH ₂NHBoc]-benzyl-,

P-[-NHC (O) CH ₂NH ₂]-benzyl-,

P-[-NHC (O) CH ₂CH ₂C (O) OH]-benzyl-,

4-[-NHC (O) CH ^*(CH ₃) NHBoc]-benzyl-( ^*Be equivalent to the L isomer),

4-[-NHC (O) CH ^*(CH ₂) NHBoc]-benzyl-( ^*Be equivalent to the D isomer),

[NHC (O) CH ₂NHC (O) NH-fluorescin] benzyl-,

4-[BocNHCH ₂C (O) NH]-benzyl-,

P-[-NHC (O) CH ₂NHC (O) NH-m-aminomethyl phenyl]-benzyl-,

P-[-NHC (O) CH (NHBoc) (CH ₂) ₄NHCbz]-benzyl-,

P-[-NHC (O) CH ₂C (C (O) OCH ₂) H-NHCbz]-benzyl-,

P-[-NHC (O) C (CH ₂CH ₂CH ₂CH ₂NH ₂) H-NHBoc]-benzyl-,

p-[NHC(O)CH ₂CH(NH ₂)COOH，

P-(H ₂NCH ₂CH ₂CH ₂C (O) NH) benzyl-,

P-(Boc-HNCH ₂CH ₂C (O) NH) benzyl-,

P-[CH ₃NHCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₃(Boc) NCH ₂CH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₂OCH ₂(H ₂N) CHC (O) NH] benzyl-, p-[HO (O) C (Cbz-NH) CHCH ₂CH ₂-C (O) NH-] benzyl-, p-[HO (O) C (H ₂N) CHCH ₂CH ₂-C (O) NH-] benzyl-, p-[CH ₃(N-Boc) NCH ₂C (O) NH-] benzyl-, p-[CH ₃NHCH ₂C (O) NH-] benzyl-, p-[(CH ₃) ₂NCH ₂C (O) NH-] benzyl-, p-[-O-CH (COOH)]-benzyl-, the p-[-o-carboxyl phenyl]-benzyl-, p-[o-carboxyl aminomethyl phenyl]-benzyl-, p-[CH ₂OC (O) NHCH ₂CH ₂NH]-benzyl-, p-[-N (SO ₂CH ₃) (CH ₂) ₃-N (CH ₃) ₂]-benzyl-, the p-[(tertiary butyl-O (O) CCH ₂-O-benzyl)-and NH-] benzyl-, p-[(N, N-two (4-N, N-dimethylamino) benzyl) and amino] benzyl-, p-(2-formyl radical-1,2,3,4-tetrahydroisoquinoline-3-base-CH ₂NH-) benzyl-, 4-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-]--CH2-p-[(CH ₃) ₂NCH ₂CH ₂O-]-benzyl-, p-[-OCH ₂CH ₂N () CH ₂CH ₃]-benzyl-, p-[two-different-propyl group amino-CH ₂CH ₂O-]-benzyl-, p-[-OCH ₂CH (NHBoc) CH ₂Cyclohexyl]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (CH ₃) ₂]-benzyl-, p-[-OCH ₂CH ₂N (C ₂H ₅) ₂]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (C ₂H ₅) ₂]-benzyl-, m-[-OCH ₂CH ₂CH ₂N (CH ₃) ₂]-benzyl-, p-[-OCH ₂CH ₂CH ₂N (CH ₃) benzyl]-benzyl-, p-[(CH ₃) ₂NCH ₂CH ₂CH ₂O] benzyl-, p-[2-(2-azabicyclic [3.2.2] octane-2-yl) ethyl-O-] and benzyl-, p-[(CH ₃) ₂NCH ₂CH ₂CH ₂-O-] benzyl-, p-(cyclopentyl-CC-)-benzyl-, p-[-CC--p-]-benzyl-, p-[-CC-CH ₂-O-S (O) ₂-p-CH3-]-benzyl-, p-[-CC-CH ₂NHC (O) NH ₂]-benzyl-, p-[-CC-CH ₂-O-p-COOCH ₂CH ₃-]-benzyl-p[-CC-CH (NH ₂)-cyclohexyl]-benzyl-, p-[-CC-CH ₂-O-phenyl]-benzyl-, p-[-CC-CH ₂-OCH ₃]-benzyl-, p-[-CC-CH ₂-O-p-(C (O) OC ₂H ₅) phenyl]-benzyl-, p-[-CC-CH ₂CH (C (O) OCH ₃) ₂]-benzyl-, p-[-CC-CH ₂C (NHC (O) CH ₃) HC (O) OH]-benzyl-, p-[-CC-CH ₂NH-(4,5-dihydro-4-oxygen-5-phenyl-azoles-2-yl)] benzyl-, p-[-O-(o-carboxyl phenyl)]-benzyl-, p-[-OCH ₂CH ₂-1-(4-pyrimidyl)-piperazinyl]-benzyl-, p-[-OCH ₂CH ₂-(piperidino)-benzyl-, p-[-OCH ₂CH ₂-(1-pyrrolidyl)]-benzyl-, p-[-OCH ₂CH ₂CH ₂-(1-piperazinyl)]-benzyl-, p-[-OCH ₂CH ₂CH ₂-1-(4-m-chloro-phenyl-)-piperazinyl-benzyl-, p-[-OCH ₂-3-(N-Boc)-piperidyl]-benzyl-, p-[-OCH ₂CH ₂-(N-morpholinyl)]-benzyl-, p-[OCH ₂CH ₂-(the N-piperidyl]-benzyl-, p-[-OCH ₂CH ₂-(N-homopiperidinyl)-benzyl-, p-[-OCH ₂CH ₂CH ₂-1-(4-methyl)-piperazinyl]-benzyl-, m-[-OCH ₂CH ₂-(1-pyrrolidyl)]-benzyl-, p-[-OCH ₂CH ₂-(N-morpholino)]-benzyl-, p-[-OCH ₂CH ₂-1-(4-hydroxyl-4-(3-methoxyl group pyrroles-2-yl)-piperazinyl]-benzyl-, p-[-O-(3-(N-Boc)-piperidyl]-benzyl-, m-[O-(N-methyl-piperidin-4-yl]-benzyl-, p-[-O-(N-methyl-piperidin-4-yl)]-benzyl-, p-[(1-methyl piperidine-4-yl)-and O-] benzyl-, p-[-NHSO ₂CF ₃]-benzyl-, p-[-NHSO ₂-CH ₂C1]-benzyl-, p-{-NHSO ₂-CH=CH ₂]-benzyl-, p-[N-3-methyl butyl-N-trifyl) amino] benzyl-, the p-[N-vinylsulfonyl) and amino] benzyl-, p-[-OCH ₂C (O) NH-benzyl]-benzyl-,

P-[-OCH ₂C (O) O-benzyl]-benzyl-,

P-[-OCH ₂C (O) OH]-benzyl-,

P-[-OCH ₂C (O) NH ₂]-benzyl-,

P-[-OCH ₂C (O) the NH-tertiary butyl]-benzyl-,

P-[-OCH ₂CH ₂-1-(4-hydroxy-4-phenyl)-piperidyl]-benzyl-,

P-[(piperidines-1-yl) C (O) CH ₂-O-] benzyl-,

P-[(CH ₃) ₂CH) ₂NC (O) CH ₂-O-] benzyl-,

P-[-C (=NH) NH ₂]-benzyl-,

P-[-C (O) NH ₂]-benzyl-,

P-(N-methyl kharophen) benzyl-,

P-(N-methyl trifluoro kharophen) benzyl-,

(1-tosyl group imidazol-4 yl) methyl-,

1-([N, N-dimethylamino alkylsulfonyl]-imidazol-4 yl) methyl-,

P-(N-tosyl group amino) benzyl-,

P-(3-N, N-dimethyl propoxy-)-benzyl-,

P-(N-methyl piperidine base oxygen)-benzyl-and

P-(phenyl)-benzyl-; And

Its condition is that wherein said compound is in conjunction with VLA-4.

7. the pharmaceutical composition of claim 6, wherein said compound is selected from:

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(glycyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(trifyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl) sarcosyl-D, L-4-(amidino groups) phenylalanine

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

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-[(N-tert-butoxycarbonyl-L-lysyl) amino]-the L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-4-N-(vinylsulfonyl) amino-L-phenylalanine

N-(toluene-4-alkylsulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine.

8. the purposes in the medicine of the compound of claim 1 inflammatory disease of VLA-4 mediation in preparation treatment patient.

9. the purposes of claim 8, wherein said inflammatory disease is selected from asthma, presenile dementia, atherosclerosis, aids dementia, diabetes (comprising the diabetes that acute teenager is taken place), inflammatory bowel (comprising ulcerative colitis and Crohn disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, metastases, meningitis, brain inflammation, apoplexy and other brain injury, ephritis, the retinitis, atopic dermatitis, psoriasis, the injury of lung of myocardial ischemia and the mediation of acute white corpuscle, for example injury of lung that is taken place in grownup's respiratory distress syndrome.