TW534910B - Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4 - Google Patents

Abstract

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

Description

534910 A 7 ^ __ B * 7 * -----— —.......-----------. ____________ V. Description of the Invention (1) Cross Reference of Drum Pass Application This case requests the United States The benefit of Patent Application No. 60 / __, which is in accordance with 37 CFR · § 1.53 (c) (2), US Patent Application No. 08 / 92〇, filed on July 31, 1997, No. 394 changed. Field of the Invention The present invention relates to a compound capable of inhibiting white blood cell adhesion, particularly white blood cell adhesion by VLA-4. References The following publications, patents, and patent applications are cited in this case: 1 European Patent Application Publication No. 330,506 by Hemler and Takada, published on August 30, 1989. 2 Elices, et al., Cell, 60.:557-584 (1990) 3 Springer, Nature, 346: 425-434 (1990) 4 Osborn, Cell, 62: 3-6 (1990) D Vedder, et al. , Surgery, 106: 509 (1989) 6 Pretolani, et al "J. Exp. Med., 180: 795 (1994) 7 Abraham, et al., J. Clin. Invest., 93: 776 (1994) Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page) 8 Mulligan, et al., Immunology, 150: 2047 (1993) 9 Cybulsky, et al ”Science, 251: 788 (1991) 1 0 Li, et al., Arterioslcer. Thiomb ·, 13_: 197 (1993) 1 1 Sasseville, et al., Am. J. Path., 144: 27 (1994) 12 Yang, et al., Proc. Nat Acad. Science (USA), 90: 10494 (1993) -4- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 ^ _________ 一 _ ________________________ _____ V. Description of the Invention (2) 13 Burkly, et al., Diabetes, 43: 529 (1994) 14 Baron, et al., J. Clin. Invest., 91: 1700 (1994) 1 D Hamann, et al ., J. Immunology, 152: 3238 (1994) 16 Ye dnock, et al., Nature, 356: 63 (1992) 17 Baron, et al., J. Exp. Med., 177: 57 (1993) 18 van Dinther-Janssen, et al., J. Immunology, 147: 4207 (1991) 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52: 672 (1993) 20 Elices, et al., J. Clin. Invest., 91: 405 (1994) 21 Postigo, et al ·, J. Clin. Invest ·, 8_9: 1445 (1991) 22 Paul, et al., Transpl. Proceed ·, 25: 813 (1993) 23 Okarhara, et al., Can. Res., 54: 3233 ( 1994) 24 Paavonen, et al., Int. J. Can., 58: 298 (1994) 2) Schadendorf, et al., J. Path., 170: 429 (1993) 26 Bao, et al., Diff. , 5,2: 239 (1993) 27 Lauri, et al., British J. Cancer, 68: 862 (1993) 2 8

Kawaguchi, et al., Japanese J, Cancer Res., 83: 1304 (1992) 29 Kogan et al. US Patent No. 5,5 10,332, April 23, 1996 was awarded International Patent Application Publication No. WO 96/01644 The aforementioned announcements, patents, and patent applications are also hereby incorporated by reference, as are individual announcements, patents, or patent applications with special or individual instructions. 210X297 mm) (Please read the notes on the back before filling this page)

、 1T-^ 9 ·. 534910 Λ? ΙΓ V. Description of the invention (3) One ...—— ~ ^… — General. VLA-4 (also known as α4βintegrin and CD49d / CD29) is recognized by Helmei 'and Takada1 for the first time. It is a member of the cell surface receptor β i integrin family, each of which contains two subunits, α Strand and beta strand. VLA-4 contains an α 4 chain and a β 1 chain. There are at least nine kinds of β integrin, all of which share the same β i chain 'and each has a discrete α chain. All nine receptors bind different components of a variety of cytoplasmic molecules such as fibrin glue, laininin, and colloid. For example VLA-4 binds fibrin glue. vla_4 also binds non-maternal molecules, which are expressed by endothelial cells and other cells. Non-maternal molecules include V c A M-1 which is expressed in human umbilical vein endothelial cells activated by cytokines in culture. Each epitope of V L A _ 4 is responsible for the binding activity of fibrin glue and ν c ΑΜ-1, and various activities can obviously be independently inhibited. 2 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) V L A-4 and other cell surface receptor mediators have various intercellular adhesions associated with various inflammatory reactions. Activated vascular endothelial cells show leukocyte adhesion molecules at injured or other irritated areas. The mechanical part of white blood cells that adhere to cells includes identifying and binding cell surface receptors on white blood cells to the corresponding cell surface molecules of endothelial cells. Once bound, white blood cells migrate through the vessel wall into the injured site and release chemical mediators to fight infection. For a comprehensive review of the adhesion receptors of the immune system, refer to Springer3 and Osborn40. Inflammatory brain disorders such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), and meningitis are caused by endothelium / leukocyte adhesion mechanism. Examples of Central Nervous System Disorders in Healthy Brain Tissue Destruction. A large number of white blood cells migrate through the blood-brain barrier (BBB) of individuals with these inflammatory diseases. White blood cells are released -6-This paper size applies Chinese National Standards (CNS) ΑβΙ grid (210 × 297 mm) — '" 534910 A7 V. Description of the invention 4 Toxic media, which causes the expansion of the Nexus, + +-crying-Department纟, 士 ,, 9 poor. ^ Causes impaired nerve conduction and hemiplegia. In the U system, tissue damage is also caused by the adhesion medium. After Qiu has praised myocardial infarction, the initial invasion of heart tissue can be complicated by the white blood cells who ^ ^ and the tissues cause further damage (Veddei et al .). For example, the conditions of the disease that were transferred from the sticky machine to the media are: ", including asthma Alzheimer's disease, and atherosclerosis 9-1. , Sense ... Did U: Diabetes ~ 4 (including acute juvenile onset sugars: :), genital bowel disease, including ulcerative colitis and Cohen II Γ 1: rheumatoid arthritis 18-21, tissue transplantation 'Tumor shifting two' 'boatboat' 'brain moxibustion' stroke and other brain trauma, nephritis, vision moxibustion 'atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury as seen in adult respiratory distress syndrome. In view of this, a test analysis for measuring the content of VLA-4 in a biological sample containing VLA · 4 can be used to diagnose the condition of the VLA_4 vector, for example. In addition, although there is such knowledge about white blood cell adhesion, the industry currently only uses adhesion inhibitors to treat other inflammatory conditions of inflammatory encephalopathy ~. . The present invention fulfills these and other needs. SUMMARY OF THE INVENTION Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics The present invention provides compounds that can bind VLA-4. These compounds can be analyzed, for example, with samples, and the presence of v L a _ 4 in pharmaceutical compositions, inhibiting cell adhesion by VLA-4 mediators, such as vcamj binding to v; la_ 4. The compounds of the present invention have binding affinity for VLA_4, as evidenced by IC50 of about 15 μM or less (measured by the following example n6), and these compounds are defined by the following formula I: -7- This paper applies Chinese national standards (CNS) Ad specifications (21〇 > < 297 mm) 534910 A7 Βη V. Description of the invention (5 R1 〇R, 's〇2 ^ N (R2) -CQ ^ CH-C-〇HI ί Η R5 Central Ministry of Economic Affairs Printed by the Standards Bureau Consumer Cooperatives where R is self-contained, including pit groups, substituted alkynyl'aryl groups, substituted aryl groups, cyclopentyl groups, substituted cycloalkyl groups, heterocyclic groups, substituted heterocyclic groups, heteroaryl groups and substituted Heteroaryl; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, destined ring, substituted heterocyclyl, aryl, substituted Aryl'heteroaryl, substituted heteroaryl S and R 1 and R 2 form a heterocyclic group or substituted heterocyclic group together with the nitrogen atom bound to R 2 and S 0 2 bonded to R 1: " R3 is selected from Including alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted Ring group, and when R2 does not form a heterocyclic group with Ri, it forms a heterocyclic group or substituted heterocyclic group in the same direction as the nitrogen bonded to R2 and the carbon atom bonded to R3: R3 is-(CH2) X -Ar-R5 ', where R5' is selected from the group consisting of (a) substituted fe-based polyamino, but at least one of the substituents is selected from the group consisting of alkoxy, substituted alkoxy, and fluorenyl, Fluorenylamino, thiocarbonylamino, fluorenyloxy, fluorenyl, amine, fluorenyl, alkylfluorenyl, thiofluorenyl-ft-

(Please read the precautions on the back before filling this page.) D. 、-口 534910 Λ7 B " 7 V. Description of the invention (6) group, aminoamino group, aminocarbonylamino group, aminothiocarbonylamino group, Aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, atom, hydroxyl, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl , Carboxyaryl, carboxy-substituted aryl, carboxy-heteroaryl, carboxy-substituted heteroaryl, cyclyl-heterocyclyl, acyl-substituted heterocyclyl, cyclopentyl, substituted cycloalkynyl, guanidyl , Guanidino, mirror group, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioaryl, substituted thiaaryl, thia Cyclo, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy 'heterofangoxy' substituted heterofangoxy 'heterocyclooxy, substituted heterocyclooxy 'Oxylamino, oxysulfanylamino, -0S (0) 2-alkenyl, 0S (0) 2-substituted alkyl, 0S (0) 2 -aryl, -0S (Ο) 2-Replace Group '· 08 (0) 2-heteroaryl' -0S (0) 2 · substituted heteroaryl, -0s (〇) 2 · heterocyclyl, -OS (0) 2-substituted heterocyclyl,- OS 〇2-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -nrs (o) 2-aryl, -NRS (0) 2-substituted aryl, -NRS (〇) 2-heteroaryl, -NRS (0) 2-substituted heteroaryl, -NRS (0) 2 -heterocyclyl, -nrs (o) 2 -substituted heterocyclic -Nrs (o) 2-nr_alkyl, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR -substituted aryl, -NRS (0) 2-NR · heteroaryl, -nrs (o) 2-nr_substituted heteroaryl , -NRS (0) 2-NR-heterocyclyl, -nrs (o) 2-nr_ substituted heterocyclyl, where r is hydrogen or alkyl, mono- and di-alkylamino, mono- And di- (substituted alkyl) amino groups, mono- and di-arylamino groups, mono- and di-substituted arylamino groups, mono- and di-heteroarylamine groups, mono- and __9_ ί paper Standards apply to Chinese National Standards (1nS) Α4 ^ ΐ 格 (210 ^ 75 ^ 7 ^ 4910 Λ Β *) Staff Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Description of the invention-Substituted heteroarylamino group and upper-heterocyclylamino group, mono- and di-substituted amino groups and asymmetric di-substituted amines having different substituents selected from fluorenyl substituted aryl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl Γ 雉% groups and substituted heterocyclic groups, and substituted alkyl groups have amine groups blocked by conventional blocking groups such as BOC 'CbZ, test group, etc., or pit groups / Substituted alkyl groups are substituted with —s02m2O2 —peptyl, —s02 —fluorenyl, —called • substituted alkenyl, —S02-ring:) ¾, and —s02- substituted cycloalkyl _S〇2 · aryl, -so2-substituted aryl, -S02-heteroaryl, -s02-substituted heteroaryl, -sOr heterocyclyl, -sOr substituted heterocyclyl And _s〇2_NRR, R is hydrogen or alkyl; (b) alkoxyaryl is substituted with a substituent based on the alkoxy moiety, and the substituent is selected from the group consisting of hydroxyl and -COOR, where r is alkyl and substituted alkyl Group, cycloalkyl group, aryl 'heteroaryl group and heterocyclic group, (c) aryl group and heteroaryl group: (d)-NR'R' wherein each R 'is selected from the group including alkyl group, substituted alkyl group, Aryl 'substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl , Substituted cyclopentyl 'heterocyclyl and substituted heterocyclyl, but at least one of R, is substituted alkyl' cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl, and also specified as R ' In the case of substituted alkyl, at least one substituent of the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenyloxy, fluorenyl, and amine , Fluorenyl, alkylfluorenyl, thiosulfanyl, aminoamino, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitrate Group, halogen atom, hydroxyl, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy- take here (please read the precautions on the back before filling this page) This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 ____ ΒΊ · —_______ V. Description of the invention (8) Substituted ring fe-based 'Jiji aryl' end-substituted aryl , Heteroaryl, aryl-substituted heteroaryl, carboxy-heterocyclyl, carboxy-substituted Cyclic, cycloalkyl, substituted cycloalkyl, guanidyl, guanidino, thiol, thioalkyl, substituted thioalkyl'thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, Heteroaryl 'substituted thiaheteroaryl, thioheterocyclyl, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryl Oxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonylamino, oxothioamino, -OS (0) 2-alkyl, -OS (0) 2-substituted alkyl,- Ο S (Ο) 2 -aryl, -0 S (Ο) 2 -substituted aryl, -0s (〇) 2 -heteroaryl, Ο S (〇) 2-substituted heteroaryl, -0 S ( 0) 2 Heterocyclyl, -0s (〇) 2-substituted heterocyclyl, _0S02-NRR where R is hydrogen or alkyl, -NRS (0) r alkyl, -NRS (0) 2-substituted Alkyl, -nrs (o) 2-aryl, _NRS (0) 2 substituted aryl, -nrs (o) 2-heteroaryl, _nrs (0) 2-substituted heteroaryl, -nrs (o) 2 -Heterocyclyl, -nrs (o) 2-substituted heterocyclyl, -NRS (0) 2-nr_alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR · aryl , -NRS (0) 2-NR_ substituted aryl, -NRS (0) 2-NR-heteroaryl -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl, -nrs (o) 2-nr- substituted heterocyclyl, where R is hydrogen or alkyl,- _ And di_ alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di · heteroaryl Amino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, and asymmetric disubstituted amines with different substituents Self-burning group, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and substituted alkyl group has amine group by the conventional blocking group _ _ 11 · The size of this paper applies Chinese National Standard (CNS) 210 × 297 mm) ---- (Please read the precautions on the back before filling out this page) Order 534910 Λ " V. Description of Invention (9) ―One ― —— ^ ^ ... · 一 ^ 'Blocking such as B 0 C' C bz 'methodyl, or alkyl / substituted alkyl substituted with -s 0 2 -alkyl, -s 0 2 -substituted alkyl, · s 〇 Wide alkenyl, _s〇2_ substituted alkenyl, -so2-cycloalkyl, -so2-substituted cycloalkyl, -s〇2- , -S 0 2 _substituted aryl '-S Ο 2 -heteroaryl, -S 〇2 -substituted heteroaryl, -S02-heterocyclyl, -S02-substituted heterocyclyl, and _s〇2 -NRR, where R is hydrogen or alkynyl: (e) -alkoxy-NR printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, where each '' is selected from the group consisting of alkyl, substituted alkynyl, and aryl , Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl 'heterocyclyl and substituted heterocyclyl, but when each R, is substituted alkyl, at least the substituted alkyl moiety One substituent is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenyl, alkenyl, amine, fluorenyl, alkylfluorenyl, thiofluorenyl , Aminomethyl, Aminocarbonylamino, Aminothiocarbonylamino, Aminocarbonyloxy, Aryloxy, Substituted Phenoxy's, Amino, Nitro, Halo, Acyl, Acyl Phenyl group alkoxy-substituted phenyl group, alkynyl-cycloalkyl, alkynyl-substituted environmental group, carboxyaryl group, carboxy-substituted aryl group, carboxyheteroaryl group, carboxy-substituted heteroaryl group alkoxy group- Heterocyclyl, -Substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidyl, guanidino, mercapto, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted sulfur Cycloalkyl, thiaheteroaryl 'substituted thiaheteroaryl, thioheterocyclyl, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy , Substituted heteroaryloxy, heterocyclic oxy, substituted heterocyclic oxy, oxycarbonylamino, oxanthane feeyl '-0S (0) 2-feyl' -0S (0) 2-substitution Group, -0S (0) 2-square group '-0S (0) 2-substituted aryl group'_OS (〇) 2-heteroaryl group, -12- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A7------- h1 — — — ____. ____ ______................. 5. Description of the invention (1 〇) — ^ — -0 S (Ο) 2 -substituted conical aryl, 〇s (〇) 2 -heterocyclyl, 〇s (〇) 2 -substituted heterocyclyl '-0S02-NRR where R is hydrogen Or alkyl, -NRS (0) 2-alkyl '-NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, _nrs (o) 2-substituted , -NRS (0) 2-heteroaryl, -nrs (0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclyl, -nrs (0) 2-substituted heterocyclyl, _NrS ( 〇) 2-NR- gauge group, -NRS (0) 2-NR-substituted alkyl group, -NRS (0) 2-NR-aryl group, _NRS (0) 2-NR-substituted aryl group, _NRS (RS2_NR_ Heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR · heterocyclyl, -NRS (0) 2-NR-substituted heterocyclyl, where R is hydrogen or alkane Groups, mono- and di-alkenylamino groups, mono- and di- (substituted alkyl) amino groups, mono- and di-arylamino groups, mono- and di-substituted arylamino groups, mono- and di -Heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, and asymmetric disubstituted amines have different The substituent is selected from the group consisting of an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group and a substituted heterocyclic group, and the substituted alkyl group has an amine group by a conventional blocking group such as Blocking such as Boc, Cbz, formamyl, or alkyl / substituted alkyl substituted with -S Ο 2 -feyl '-S Ο 2 -substituted alkynyl, -S 〇2 -fluorenyl, _ s Ο 2- Substituted fluorenyl group '-S Ο 2 · ring: fe group, -S Ο 2 · substituted ring Group, -S 0 2 · aryl, -S 0 2 -substituted aryl '-S 0 2 -heteroaryl, -S 0 2 -substituted heteroaryl, -S 0 2 · heterocyclyl' -S 0 2-substituted heterocyclyl, and j 〇2-NRR, where R is hydrogen or fluorenyl: (f) substituted, fine or substituted, but at least one of the substituents is selected from the group consisting of a base / block. Including alkyl, substituted alkyl, aryl, substituted aryl 'ring fe group' substituted ring pit group, heteroaryl group, substituted heteroaryl group, heterocyclic group-13- This paper is applicable to Chinese National Standards (CNS) A4 specification (210X297 mm) ^ '—-- (Please read the precautions on the back before filling out this page) Order Φ 534910 Λ? ΙΓ 5. Description of the invention (11) and substituted heterocyclic groups, but when substituted alkyl When the group is substituted, at least one substituent of the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, S1-based amino, thienylamino, fluorenyloxy, fluorenyl, amine, Fluorenyl, alkynyl, sulfanyl, amine, fluorenyl, aminecarbonylamino, aminethiocarbonylamino, aminecarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro ,#original , Hydroxy, complex, cumenyl, complex-substituted alkyl, ridge-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxy heteroaryl, carboxy-substituted Heteroaryl, carboxy-heterocyclyl, carboxy-substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidino, fluorenyl, thioalkyl, substituted thioalkyl, thioaryl, substituted Alkyl, sulfanyl, substituted thiocycloalkyl, thioheteroyl, substituted thioaryl, thioheterocyclyl, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy , Substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonylamino, oxythiocarbonylamino, -0S (0) 2 -alkyl Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) -〇 S (Ο) 2 -Substituted alkyl, -Ο S (Ο) 2 -Aryl, _ Ο S (0) 2 _ substituted aryl, -os (o) 2-heteroaryl, -os (o) 2-substituted heteroaryl, -os (o) 2-heterocyclyl, -0 S (Ο) 2 -Substituted heterocyclyl, -0 S Ο 2-NRR where R is hydrogen or alkyl, -nrs (o) 2-alkyl, -nrs (o) 2-substituted alkyl, -nrs (o) 2-aryl, -nrs (o) 2-substituted aryl, -nrs (o) 2-hetero Aryl, -nrs (o) 2-substituted heteroaryl, -nrs (o) 2-heterocyclyl, -nrs (o) 2-substituted heterocyclyl, -nrs (o) 2-nr-alkyl, -nrs (o) 2-nr-substituted alkyl, -nrs (o) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl , -Nrs (o) 2-nr-substituted heteroaryl, -nrs (o) 2-nr_heterocyclyl, -NRS (0) 2-NR-substituted heterocyclyl, where R is hydrogen or alkyl ， 一-和 二--14- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 ____ _____ 5. Description of the invention I a) Alkylamine , Mono- and di- € substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and Di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, and asymmetric disubstituted amines have different substituents selected from alkyl, substituted alkyl , Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl , And substituted alkyl groups have amine groups blocked by conventional blocking groups such as B 0c, C bz, formamidine, etc., or alkyl / substituted alkyl substituted with -S 〇2-alkyl, -S Ο 2 -Substituted alkyl, _ s 02-alkenyl, s s 02-substituted fluorenyl '· S 0 2 -cycloalkyl, -S 0 2-substituted cycloalkyl, _ s 02-aryl, _S 〇2-substituted aryl, _s〇2-heteroaryl, 4〇2-substituted heteroaryl, -S02-heterocyclyl, -S02-substituted heterocyclyl and _s〇2-NRR, here R is hydrogen or alkyl: (g) substituted aryloxy and substituted heteroaryloxy, but at least one substituent of substituted aryloxy / heteroaryloxy is not _ atom, hydroxyl, amine, nitro, tri Fluoromethyl, difluoromethoxy, alkyl, alkenyl, alkynyl, i, 2-dioxymethylene, 1,2-dioxoethyl, alkoxy, oxyoxy, oxydioxy , Alkylamino, fluorenylamino, alkynylamino, alkylcarbonyloxy, fluorenyl, fluorenylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, N-alkyl or n , N_dialkyl earners: '(h) -alkoxy-saturated heterocyclyl, · alkoxy-saturated substituted heterocyclyl, -substituted alkoxy-heterocyclyl and -substituted Oxy-substituted saturated heterocyclyl: (1) -0-heterocyclyl and 〇-substituted heterocyclyl: (j) tetrazolyl: (k) -NR-S02-substituted alkyl, where R is hydrogen , Alkyl or aryl, but __ 一 —__ _ 15 This paper size is applicable (Please read the precautions on the back before filling this page)

、 1T ΛΦ ·..-H. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A7 ______ V. Description of the invention (13) ^ At least one substituent of the alkyl group of the Bt amino group is not halogen. Atom 'hydroxy, amine, nitro, trifluoromethyl, trifluorofluorenyl, pit, fluorenyl, alkynyl, 1,2-dioxymethylene, 1,2 • dioxoethyl, Alkyloxy, alkoxyl, alkynyloxy, alkylamino, alkenylamino, alkynylamino, polyloxy 'Sfyl' SScarbonylcarbonylamino, oxalylamino, Alkenylcontinylamino, N-fluorenyl or N, N-dialkylenylurea; (l) Alkenylperylenefluorenyl, alkynylfluorinylamino, substituted alkenylfluorinylamine and substituted bulk sulfonyl Amido: (m) Substituted alkoxy, but the substitution of the alkyl portion of the substituted alkoxy does not include oxy-NR '' R '', unsaturated heterocyclic group, oxy, aryloxy, heteroaryl Oxy, aryl, heteroaryl, and aryl / heteroaryl substituted with tooth atom, hydroxy'amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, fluorenyl, bulk, 1,2-dioxomethylene, 1,2-dioxane Ethyl, alkoxy, alkoxy, alkynyloxy, alkylamino, alkenylamine, alkynylamino, alkylcarbonyloxy'fluorenyl, fluorenylcarbonylamino, alkoxycarbonylamino , Alkylsulfonamido 'N-or N, N-dipityl: (η) 脒 and 脒 are substituted with 1 to 3 selected from alkyl, substituted alkyl, fluorenyl, substituted alkenyl, Alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclyl substituents: ㈠ ^ ⑴ 川 ''… ... Each ruler ... selected from the group consisting of hydrogen, substituted alkyl, cycloalkyl , Substituted cycloalkyl, fluorenyl, substituted fluorenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl 'heterocyclyl and substituted heterocyclyl, but when an R' , Is an unsaturated heterocyclic alkyl, aryl, heteroaryl, or aryl / heteroaryl group substituted with a fluorene atom, a few __ _-16- This paper size applies to China National Standard (CNS) A4 specifications ( 210 × 297 mm) (Please read the precautions on the back before filling out this page), 1T 534910 A? In V. Description of the invention 14 Printing base, amine base of the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Nitro, trifluoromethyl, dioxinyl, alkynyl, alkenyl, alkynyl, 1,2-dioxinyl, 1,2 · -aminonan 7gpp, lactamyl ethyl , Alkoxy, ethoxy, 'deoxy', pitylamino, fluorenylamine and its α-glycine group, alkynylamino, alkylcarbonyloxy, halo, fluorenylcarbonylamino, In the case of oxycarbonylamino, alkylamino, N-alkyl or N, N-dialkylurea, the other one is an alkyl group, which is substituted with an alkyl group (not an unsaturated heterocyclic group-substituted alkyl group) Group), cycloalkyl, substituted cyclofluorenyl, fluorenyl, substituted alkenyl, decanyl, substituted block, and heterocyclyl and substituted heterocyclyl; (P) -NR] 2C (0) -R3 here R3 is selected from the group consisting of alkyl, substituted alkyl,% alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heterocyclyl and heterocyclic, and R i 2 For alkyl, substituted alkyl, square, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl: (q) -S02-aryl , -S02-substituted aryl, -8〇2-heteroaryl, -S〇2- substituted heteroaryl or -S Ο 2- Group: (r)-NR 'C (0) N R9 R 9 where R is selected from the group consisting of alkyl, substituted alkyl, aryl' substituted aryl 'cycloalkyl, substituted cycloalkyl, heteroaryl, Substituted heteroaryl 'heterocyclyl and substituted cyclic group, and each R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl , Substituted heteroaryl, heterocyclyl and substituted heterocyclyl: (s) -NR'C (〇) OR9 where R 'is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and cycloalkane Group, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aromatic Base, substituted aryl, heteroaryl-17- This paper size applies Chinese National Standard (CNS) A4 (2 Sichuan > < 297 mm) (Please read the precautions on the back before filling this page)

1T-Qin · 534910 Λ? Βη V. Description of the invention 15 groups, substituted heteroaryl groups, heterocyclic groups and substituted heterocyclic groups: (t) -aminocarboxy- (ν-formamylheterocyclyl); and (u) · -C () N Η -heterocyclyl and -alk · yl_C (〇) N η _ substituted heterocyclyl: Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl X is an integer of 1 to 4. Q is -C (X) NR7- wherein R7 is selected from the group consisting of hydrogen and alkyl: and χ is selected from the group consisting of oxygen and sulfur: and pharmaceutically acceptable salts thereof. In another specific example, the compound of the present invention can also be provided as a protozoan which is transformed (e.g., hydrolyzed, metabolized, etc.) into a compound of formula I in vivo. In a preferred example of this specific example, the carboxylic acid of the compound of formula I is changed to a base which will be converted into a carboxylic acid (including its salt) in vivo. In a particularly preferred embodiment, these primitives are represented by eight compounds of formula: R3 Ο R! -SOrN (R2) -CH CH-C-R6

IA (Please read the notes on the back before filling this page}

1T R5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where R1 is selected from the group consisting of alkyl, substituted alkyl, aryl 'substituted cycloalkyl, heterocyclic, substituted heteroaryl; ^ substituted aryl, Ring Burned Heteroaryl and Substituted Hetero-18- This paper is in accordance with Chinese National Standard (CNS) A4 specification (21〇xm ^ ty 53491ο A7 R · ^ V. Description of the invention 16 R2 is selected from the group consisting of hydrogen, alkyl, substitution Alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Rl & R2 Forms a heterocyclyl or substituted heterocyclyl together with S02 bound to a nitrogen atom and a nitrogen atom and R1: is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, , Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, and when R2 does not form a heterocyclyl with Ri, R2 and R3 are bonded to the nitrogen bonded to r2 and bonded to R3 Carbon atoms together to form a heterocyclic group or substituted heterocyclic group; the Ministry of Economic Affairs Central Standards Bureau employee consumer cooperatives India policy --------- ir — (Please read the notes on the back before filling out this page)--R is-(CH ^ -Ar-R) where V is selected from the group consisting of (a) substituted alkylcarbonylamino, but substituted alkyl At least one substituent is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenyl, alkenyl, amine, fluorenyl, alkylfluorenyl, and thiofluorene Group, aminoamino group, aminocarbonylamino group, aminothiocarbonylamino group, aminocarbonyloxy group, aryloxy group, substituted aryloxy group, cyano group, nitro group, self atom, hydroxyl group, & group, A few alkyl groups, a few alkyl groups, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group, a substituted alkyl group -Heterocyclyl, carboxy-substituted heterocyclyl, cycloalkynyl, substituted cycloalkyl, guanidyl, guanidino, thiol, sulfanyl, substituted sulfanyl, thioaryl, substituted thioaryl, sulfur ring Alkyl, substituted cycloalkyl, thiaheteroaryl, substituted thiaaryl, thioheterocyclyl, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy I ^ Fang Base, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonyl-19 This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 hr '------ b1---____________ .... ________ V. Description of the invention (17) · a " " 一一 " " -OS (〇) 2-alkyl, -〇s (〇) 2-substituted alkyl '-OS (0) 2-aryl, -OS (〇) 2-substituted aryl, -〇s (〇 ) 2-heteroaryl, _0S (0) 2-substituted heteroaryl, -0s (〇) 2-heterocyclyl, -0s (〇) 2-substituted fluorene ring group--SOS2-NRR Here R is hydrogen or alkyl, -NRS (0) 2-alkyl, -nrs (o) 2-substituted alkyl, -NRS (〇) 2__aryl, -NRS (〇) 2 -substituted aryl,- NRS (Q) 2-heteroaryl, -NRS (Q) 2 -substituted heteroaryl, -nrs (o) 2-heterocyclyl, -nrs (o) 2-substituted heterocyclyl, -Nrs (o) 2-NR -alkyl '-n RS (〇) 2-NR -substituted alkyl, -n RS (〇) 2-NR · aryl, -NRS (〇) 2-NR-substituted aryl, -NRS ( 0) 2-NR · heteroaryl, -nrs (〇) 2-NR-substituted heteroaryl, -NRS (〇) 2_NR_hetero Cyclic group, -NRS (Q) 2-NR-substituted heterocyclic group, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, one -And di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic Amines, mono- and di-substituted heterocyclyl amines, and asymmetric di-substituted amines with different substituents selected from k-substituted 'alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl 'Heterocyclyl and substituted heterocyclyl, and substituted alkyl groups have amine groups blocked by conventional blocking groups such as B 0 C, C b Z, formamyl, etc., or alkyl / substituted alkyl substituted with -S Ο 2 _alkyl, -s 〇2 -substituted alkyl, -s 〇2 • alkenyl, -s Ο 2 -substituted alkenyl, -S Ο 2 -cycloalkyl, -s Ο 2 -substituted cycloalkyl , -S Ο 2 -aryl '-S02-substituted aryl, -s〇2_heteroaryl, _s〇2_substituted heteroaryl' -S Ο 2 -heterocyclyl, -s 〇2 -substituted hetero Cyclic group, and _ s 〇 2-NRR, where R is a gas or an alkyl group: (b) oxoaryl is substituted based on an alkoxy moiety to be a substituent, and the substituent is selected _______ - 20 - this paper scale applicable Chinese National Standard (CNS) A4 size (210X 297 mm) (Please read the back of the precautions to fill out this page)

、 1T 534910 ---------- Η *? V. Description of the invention (18) —... 一 ~ '——…-一-Including # 基 和 -C00R, where R is an alkyl group, instead of Alkylaryl, heteroaryl and heterocyclyl, (C) aryl and heteroaryl: printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)% ·. — (D) -NR'R 'wherein each 11 is selected from the group consisting of alkyl, substituted alkyl, square, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and substituted cycloalkyl. And substituted heterocyclyl, but at least one of R is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl, and it is also specified that when R is substituted alkyl, substituted alkyl The at least one substituent of the base moiety includes alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenyl, fluorenyl, amine, fluorenyl, and alkylfluorenyl. , Thiomethyl group = aminomethylamino, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy'aryloxy, substituted aryloxy, cyano, nitro, fluorene atom, hydroxyl, carboxyl , Carboxyl Alkyl, carboxy-substituted alkyl, carboxy_cycloalkyl, carboxy_substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxy heteroaryl, aryl-substituted heteroaryl, sedyl-heterocycle Aryl, aryl-substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidino, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl , Substituted thiocycloalkyl, thioheteroaryl, substituted thiaheteroaryl, thioheterocyclyl, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonylamino, oxythioaminoamino '-0 S (Ο) 2 ~ pit, _ 〇S (Ο) 2-substituted alkyl, -0s (o) 2-aryl, -OS (〇h-substituted aryl, -0S (0) 2-heteroaryl, -0S (0) 2-substituted heteroaryl,- 0S (0) 2-heterocyclyl, -0s (0) 2-substituted heterocyclyl '-OS〇2_NRR where R is chloro or jt end, -NRS (0) 2_jing-21-this Paper size applies to China National Standard (CNS) A4 (210X297mmρ) ^ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A "? ~ _______—— — B1 V. Description of the invention (19) ~ " a ... · — — ^ group '-NRS (0) 2-substituted alkyl group, _nrs (〇) 2_aryl group, _NRS (0 ) 2-Substituted aryl '-NRS (0) 2-heteroaryl, -NRyohit heteroaryl, NRS (0) 2-heterocyclyl, -nrs (〇) 2-substituted heterocyclyl, · NRS (0) 2-NR_alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (〇) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (〇) 2_NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (〇) 2-NR · heterocyclyl, _NRS (0) 2-NR-substituted heterocyclyl, where R is hydrogen or Alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and Di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino 'and asymmetric disubstituted amines have Different substituents are selected from alkyl 'substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted alkyl groups have amine groups by conventional blocking groups Such as Boc, Cbz, formamidine, etc. Alkyl / substituted alkyl substituted with -S02-alkyl, -S02-substituted alkyl, _s〇2_alkenyl, _s〇2 · substituted alkenyl, -S02 · cycloalkyl, -SO "substituted cycloalkyl _S〇2-aryl, -S〇2 · substituted aryl, -S〇2_heteroaryl, -§〇2_ substituted heteroaryl, -S〇2_heterocyclyl, -S Ο 2 -substituted Heterocyclyl, and _ S 〇 2 _ NRR, where R is hydrogen or alkyl: (e) -Oxygen-NR "R" each of them! ^ "Are each selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, but when each R, when substituted alkyl, at least one substituent of substituted alkyl is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenyl-22- This paper size applies to China National Standard (CNS) A4 (210x197 male f) --------- (Please read the precautions on the back before filling this page)

534910 hr 'R * 7 V. Description of the invention (2Q) group, alkenyl group, amine group, fluorenyl group, alkyl fluorenyl group, thiofluorenyl group, amine fluorenyl group, amine carbonylamino group, amine thiocarbonylamino group , Aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, iS atom, hydroxyl, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkane Aryl, carboxyaryl, carboxy substituted aryl, carboxy heteroaryl, carboxy-substituted heteroaryl, carboxy-heterocyclyl, carboxy-substituted heterocyclyl, cycloalkyl, substituted cyclomorphyl, phosphono, guanidyl Hydrazone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thiaaryl, thioheterocyclyl, Substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonyl Amine, oxythiocarbonylamino, -os (o) 2-alkyl, -os (o) 2-substituted alkyl, -os (o) 2-aryl, -os (o) 2-substituted aryl _Os (o) 2 -heteroaryl, -Ο S (Ο) 2- Substituted heteroaryl, -0 S (Ο) 2 -heterocyclyl, -0 S (0) 2 -substituted heterocyclyl, -S02-NRR where R is hydrogen or alkyl, -nrs (o) 2- Alkyl, -nrs (o) 2-substituted alkyl, -nrs (o) 2-aryl, -nrs (o) 2-substituted aryl, -nrs (o) 2-heteroaryl, -nrs (o ) 2-Substituted heteroaryl, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) -nrs (o) 2-heterocyclyl, -nrs (o) 2-substituted Heterocyclyl, -nrs (o) 2-nr-alkyl, -nrs (o) 2-nr-substituted alkyl, -nrs (o) 2-nr-aryl, -nrs (o) 2-nr- Substituted aryl, -nrs (o) 2-nr · heteroaryl, -nrs (o) 2-nr-substituted heteroaryl, _nrs (o) 2-nr-heterocyclyl, -NRS (0) 2- NR-substituted heterocyclyl, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, one -And di-substituted arylamino groups, mono- and di-heteroarylamine groups, mono- and -23- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) ^ 4910 ^ ___ Ministry of Economic Affairs Printed by the Central Standards Bureau's Consumer Cooperatives 21 Λ-7 Description of the Invention Di-substituted heteroarylamine groups, mono-and-block, ρ # And although the cyclic amino group, mono- and di-substituted heterocyclic amino group, and asymmetric-take your n, en but W-substituted amines have different substituent options, take Wei, aryl, substituted aryl , Heteroaryl, Substituted Heteroaryl: Heterocyclyl and Substituted Heterocyclyl, and Hexyl has an amine group and is blocked by conventional blocking groups such as B0C'Cbz'fluorenyl, or alkyl / substituted alkyl The group is substituted with -s〇2_i group, · s〇2 is taken as a mirror group, _Sm "is substituted with alkenyl group, -so2-cycloalkyl, -S02_ substituted cycloalkyl, -s〇r aryl, -S 0 2_substituted aryl, _s 〇2_heteroaryl, _s 〇2_substituted heteroaryl,

-so2-heterocyclyl, -S02-substituted heterocyclyl, and -s〇2-nrr, where R is hydrogen or alkyl; (0 substituted alkenyl or substituted alkynyl, but substituted alkenyl / alkynyl At least one substituent of the base moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl'cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocycle But when substituted with a substituted alkyl, at least one substituent of the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, acidamino, thiocarbonylamino, fluorenyl, Alkenyl, amine, fluorenyl, alkylfluorenyl, thiofluorenyl, aminefluorenyl, aminecarbonylamino, aminethiocarbonylamino, aminecarbonyloxy, aryloxy, substituted aryloxy , Cyano, nitro, fluorene atom, warpyl, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxyl-substituted aryl, carboxy hetero Aryl, carboxy-substituted heteroaryl, carboxy-heterocyclyl, carboxy-substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidino, mercapto, sulfanyl, Substituted sulfanyl, sulfanyl, substituted sulfanyl, sulfanyl, substituted sulfanyl, thiaaryl, substituted thiaaryl, thicyclic-24 This paper is applicable to China National Standards ( CNS) M specification (2 丨 OX 297mm) --------------- Order ------ (Please read the precautions on the back before filling this page) Central Ministry of Economy Printed by the Consumer Bureau of Standards Bureau 534910 -______—__ JB * 7 V. Description of the invention (22) '~ " …… ― 一 ~ —… — ~ — group, substituted thioheterocyclyl, heterocyclyl, substituted heterocyclyl , Cycloalkoxy, substituted alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonylamino, oxythiocarbonylamino, _ 〇s (〇 ) 2 -alkyl, -os (o) 2-substituted, alkyl '-0S (0) 2-aryl, -08 (〇) 2-substituted aryl, -0S (0) 2-heteroaryl -0S (0) 2 • substituted heteroaryl, _〇s (〇) 2-heterophosphyl '-0S (0) 2-substituted heterocyclyl, -0s〇2_nrr where R is hydrogen or alkyl '_NRS (0) 2 · alkyl, -NRS (〇) 2- substituted alkyl, · NRS (〇) 2-aryl, -nrs (o) 2-substituted aryl, -nrs (0) 2-heteroaryl, -nrs (〇) 2-take Heteroaryl, -nrs (o) 2-heterocyclyl, -nrs (0) 2-substituted heterocyclyl, -nrs (0) 2-nr-alkyl, -NRS (0) 2-nr substituted alkyl,- nrs (〇) 2-NR_square, -NRS (0) 2-NR-substituted aryl, -NRS (〇) 2-NR_heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (〇) 2-NR-heterocyclyl, NRS (0) 2-NR-substituted heterocyclyl, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di · ( Substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted arylamine, mono- and di-heteroarylamine, mono- and di-substituted heteroarylamine , Mono- and di-heterocyclylamino groups, mono- and di-substituted hetero ¥ amino groups, and asymmetric disubstituted amines having different substituents selected from alkyl 'substituted alkyl, aryl, substituted aryl, Heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted alkyl have amine groups blocked by conventional blocking groups such as Boc, cbz, formamyl, etc., or alkyl / substituted alkyl Substituted with -so2-alkyl, _s〇2_ substituted alkyl, -s〇2_fluorenyl, -s〇2-substituted alkenyl'-S〇2-cycloalkyl, _s〇2 ·· substituted cycloalkane , _S〇2 · aryl, -S02-substituted aryl, _s〇2 _Heteroaryl, _s〇2_ substituted heteroaryl, -S Ο 2 -Although cyclic group '_ s Ο 2 -substituted heterocyclic group and _ s 〇 2 _ n RR, where R is ____ -25- This paper is suitable for CNS (A) (training; clock) ~ --- --------- Order (please read the precautions on the back before filling this page) 534910

Λ7 IP V. Description of the invention (23) X 1 —...— "-Hydrogen or alkyl: (g) substituted aryloxy and substituted heteroaryloxy, but substituted aryloxy / heteroaryloxy soil + A substituent is not an atom, a hydroxyl group, an amine group, a nitro group, a trifluorofluorenyl group, a trifluorofluorenyloxy group, an alkyl group, a fluorenyl group, an alkynyl group, and a 2-dioxinylene group. Oxyethyl, alkoxy, oxy, alkynyloxy, alkylamino 'alkenylamino, alkynylamino, alkylcarbonyloxy, fluorenyl, fluorenylcarbonylamino' 70 Ethylamino, alkylamino, N-alkyl or N, N_dialkylurea; (h) -oxyalkyl-saturated heterocyclyl, -alkoxy-saturated substituted heterocyclyl, -substituted Fe oxygen-heterocyclyl and -substituted alkoxy-substituted saturated heterocyclyl: (i)-Ο-heterocyclyl and -0-substituted heterocyclyl; (j) Tetrazolyl: Consumption by employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative --------- f (Please read the notes on the back before filling in this page (k)-NR-S Ο2-substituted alkyl, where r is hydrogen, alkyl or aryl , But at least one of the substituents in the alkyl portion of the substituted sulfonamido group is not a halogenogen Subunits, several groups, amino groups, nitro groups, trifluoromethyl groups, trifluoromethoxy groups, alkyl groups, fluorenyl groups, 1,2-dioxomethylene, 1,2-dioxoethyl groups , Alkoxy 'alkoxy, alkynyloxy, alkylamino, fluorenylamino, alkynylamine, alkynyl' fluorenyl, sulfonylamino, sulfonylamine Group, alkylsulfonamido, N-alkyl or N, N-dialkylurea: (1) sulfenylsulfonamido, alkynylsulfonamido, substituted alkenylsulfonamido and substituted Sulfoamido: (m) substituted alkoxy, but the substitution of the alkoxy group of the substituted alkoxy group does not include alkoxy-NR "R", unsaturated heterocyclic group, alkoxy, aryloxy, hetero Aryloxy, aryl, heteroaryl, and aryl / heteroaryl substituted with fluorene atom, -26- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ~~ '一' Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Education 534910 Λ7 ___ _____in _ 24 V. Description of the invention () group, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1 , 2-dioxymethylene, 1,2-dioxyethylene , Alkoxy, alkoxy, alkynyloxy, alkylamino, alkenylamine, alkynylamino, alkylcarboxyoxy, fluorenyl, fluorenylcarbonylamino, alkoxycarbonylamino, alkane Sulfoamido, N-alkyl or N, N-dialkylurea: (η) 脒 and 脒 are substituted with 1 to 3 selected from alkyl, substituted alkyl, alkenyl, substituted fluorenyl ' Substituents of the group 'substituted alkyne: aryl, aryl, heteroaryl and heterocyclic groups: (〇)-C (Ο) NR' '' 'R' ' , Alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl And substituted heterocyclyl, but when an r ,, is an unsaturated heterocyclyl, aryl, heteroaryl, or aryl / heteroaryl substituted with atom, hydroxyl, amine, nitro, tris Fluoromethyl, trifluoromethoxy, alkyl, fluorenyl, decyl, 1,2-dioxymethylene, 1,2-dioxoethyl, alkoxy, oxyoxy, alkynyloxy , Alkylamino, alkenylamino, alkynylamino, alkyl When carbonyloxy, fluorenyl, fluorenylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, N-alkyl or N, N-dialkylurea, the other R ,, is alkyl , Substituted alkyl (non-unsaturated heterocyclyl-substituted alkyl), cycloalkyl, substituted cycloalkyl, fluorenyl, substituted fluorenyl, alkynyl, substituted alkynyl, and heterocyclyl (P) -NR12C (0) -R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, 2-substituted aryl Group, heterocyclic group and substituted heterocyclic group, and R! 2 is alkyl group, substituted alkyl group ____-27 This paper applies the national fi standard (cNS) -——-___ (Please read the notes on the back before filling (This page)

、 1T 534910 V. Description of invention 25 A7 Printed base, aryl, substituted aryl, volume & substituted heteroaryl, heterocyclic and substituted hetero'yl substituted ^ alkyl ' Aryl, take (q) -S02_aryl, _s〇2_ substituted aryl, _ substituted heteroaryl or -S02_ alkyl: group, -S02-

(r) -NR'C (〇) NR9Ro where R group, Fangmei, substituted Xi, alkyl, substituted alkyl, substituted alkyl, cycloalkyl, substituted ring Fen, # 代 杂It ’s hard, it ’s hard for Lugan ^ Wutuo, although it is a square group, nitrogen, alkane A, and 1 are selected. Each R is selected from the group consisting of m group, substituted cycloalkyl group, * group, substituted vanillyl group, substituted Heteroaryl, heterocyclyl and substituted heterocyclyl. JS) -nr, C (〇) or9 where R is selected from the group consisting of alkyl, substituted: the group 'substituted aryl' cycloalkyl, substituted cycloalkyl, Heteroaryl, heterocycle, heterocyclyl and substituted heterocyclyl, and R9 are selected from the group consisting of hydrogen, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl; ^ aryl, Substituted heteroaryl, heterocyclyl and substituted heterocyclyl: (t) -aminocarbonyl- (N-formamylheterocyclyl): and U) -alkynyl-C (〇) NH-heterocyclyl and -Alkenyl sulfonium substituted heterocyclic group: A r is aryl, substituted aryl, heteroaryl or substituted heteroaryl: X is an integer of 1 to 4: R is selected from the group consisting of 2,4-dioxo Tetrahydrofuran_3_yl (3,4_enol), amino, alkoxy, substituted alkoxy, ring Oxygen, substituted for ambient oxygen odor, -0 · (N-butadiimido), -N Η-adamantyl, -〇chol- 5-3-β-group, where -NΗΟΥ here is Hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -N H (C H2) p COOY where ρ is an integer from 1 to 8, and γ -28- This paper applies Chinese National Standard (CNS) Α4 Specification (21〇χ297mm) Order (please read the precautions on the back before filling this page) 534910 A ， 一 --- ΒΊ " '' --- —— ______ 一 '· * "一 __ ^ I-, ... "_ —— V. Description of the invention (26) is as defined above, -0C Η 2 NR 9 R 1 ° Here R9 is selected from the group consisting of C (Ο) -aryl and -C (O) · Substituted aryl, and rH) are selected from hydrogen and -dCOOR11, where R11 is alkyl and -NHS02Z, where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl: Q is -C (X) NR7-where R7 is selected from the group consisting of hydrogen and alkyl: and X is selected from the group consisting of oxygen And sulfur: and its pharmaceutically acceptable salts, but when R1 is ρ- [Η3-φ-, R5 Methoxy, Q is · 〇 (0) ΝΗ_, and R2 and R3 together form a pyrrolidinyl group, R5 is not -p-[-OCH2CH2N (C2H5) 2] _benzyl-, -p-[-〇CH2CH2N ( Isopropyl) 2] · Benzyl-, -p-(-OCH2CH2-Pyrrolidinyl)-^ S-,-p-[-〇CH2CH2-1-(4-Pyrimidinyl) hexahydropyridyl] -芊 基 _,-p-[-〇 CH 2 C Η 2 · N · Morinyl] ^--or-Dingji] Yeji-〇 Better printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the aforementioned formula In the compounds I and IA, R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl. Still more preferably R 1 is selected from the group consisting of 4-methylphenyl, methyl, fluorenyl, n-butyl, 4-chlorophenyl, 1-fluorenyl, 2-fluorenyl, 4-methoxyphenyl, benzene Group, 2,4,6-trimethylphenyl, 2- (methoxycarbonylphenyl), 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3, 4-dichlorobenzyl, 3,4-dimethoxyphenyl, 4-([1 [(0)] \ ^-) phenyl, 4-trifluoromethoxybenzyl, 4-cyanophenyl, Isopropyl, 3,5-bis (trifluoromethyl) phenyl, 4-tert-butylphenyl, 4-tert-butoxyphenyl'4-nitrophenyl, 2-p-cephenyl, -29- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) 'One 534910 Λ 27 V. Description of the invention 1-N -methyl-3 -methyl-5-chloroexo-4- Phenyl, phenethyl '1-N-methylamidazole-4-yl, 4-bromophenyl, 4-fluorenylphenyl, 4-methylfluorenylphenyl, 4- [CH3SC (= NH)] Phenyl, 5-chloro-2-anthenyl, 2,5 · dichloro-4 · pyridinyl, 1 -N -methyl-4 -pyrazolyl, 2-pyrazolyl, 5-methyl- 1, 3,4-pyrimidazol-2-yl, 4- [H2NC (S)] phenyl, 4-aminophenyl, renfluorophenyl, 2-fluorophenyl, 3-fluorophenyl , 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4- (3, dimethylamino-n-propoxy) -phenyl, and 1-methylpyrazole- 4 base. In the compounds of the formula I and IA, R2 is preferably hydrogen, methyl, phenyl, fluorenyl,-(CH2) 2-2-pyrimyl, and _ ((: Η2) 2-φ. In a specific example, , R 1 and R 2 and the nitrogen atom bonded to R 2 and the S 0 2 group bonded to R 1 together form a heterocyclic group or a substituted heterocyclic group. Preferred heterocyclic groups and substituted heterocyclic groups include the ring containing 2 to 3 5 to 7 ring atoms selected from nitrogen, oxygen, and sulfur, the ring is optionally fused to another ring such as a benzene ring or a cyclohexyl ring, and the provided ring contains 2 to 4 selected from nitrogen, oxygen, and Sulfur heteroatoms are fused ring heterocycles containing 4 to 4 ring atoms. Particularly preferred RVR2 bonding groups include, for example, phenylisothiazolone (sakalim-2-yl). In a preferred embodiment, R2 and R3 together with the nitrogen atom bonded to the R2 substituent and the carbon atom bonded to the R3 substituent together form a heterocyclic group or substituted heterocyclic group containing 4 to 6 ring atoms, which contains 1 in the ring To 2 heteroatoms selected from nitrogen, oxygen and sulfur, the ring is optionally substituted with 1 to 2 substituents selected from fluorine, methyl, amino, amine, phenyl, thiophenyl, and thiobenzyl , Or netizens s another ring such as phenyl ring or cyclohexyl Ring to provide _ ring-containing heterocyclic ring containing 10 to 14 ring atoms, which contains 1 to 2 heterogens selected from nitrogen, oxygen and sulfur in the ring-30- This paper applies Chinese national standards (CNS ) A4 size (210X 297 mm) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 B * 7 —____ _____ _ Description of the invention (28). Heterocyclic rings include azetidinyl (such as L _azetidinyl), oxazolyl (such as L-π plug 4 alkyl), hexahydro p than pyridyl (such as L-six Hydrogen p ratio), hexahydropyridinyl (such as L-hexahydropyridyl), dihydroxandol (such as L-2,3-dihydro4 丨 indol-2 · yl), tetrahydrocarbyl P Hughyl (such as L -1,2,3,4 · tetrahydro-4lin-2-yl), thiomorphinyl (such as L -thiomorpholin-3 -yl), pyrrolidinyl (such as L -pyrrole Pyridyl), substituted p-pyridyl such as 4-light p-pyrrolidine (such as 4--α- (or β) -light-L-say p each)) '4-fluoro p-pyridyl ( Such as 4-α-(or β) -fluoro-L-p than slightly yl), 3-phenylpyrrolidinyl (such as 3-α-(or β) -phenyl_L -pyrrolidinyl), 3 -thiophenyl alkalyl (such as 3-α-(or β) -thiophenyl-L -erodondyl) ), 4-amino group p than pyrrolidyl (such as 4-α- (or β) -amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (such as 3-α- (or β)- (Methoxy-L-pyrrolidinyl), 4,4-dimethylpyrrolidinyl 'instead of hexahydrocarbyl, such as 4 Ν · C b ζ -hexahydroethyl, and replace 5,5-Dimethylporphyrin-4 -yl '1,1-oxyl group (such as L -1,1-dioxy-pyrazolidine-2-yl), substituted 1, 1 -dioxy- azolidinyl such as L-1,1-dioxy-5,5-dimethyloxazolidine 2-yl, 1,1.dioxythiomorpholinyl (such as L · 1, 1-dioxy-thiomorpholine-3-yl) and the like. Preferably, in the compounds of the formulae I and I A above, R 3 includes methyl, phenyl, benzyl, diphenylmethyl, -CH2CH2-C00H, -ch2-COOH, 2-aminoaminoethyl, isopropyl Butyl, tert-butyl, -CH20-fluorenyl and all isomers substituted with fluorenyl. In addition, in another preferred embodiment, R3 and R2 together with the nitrogen atom bonded to R2 form a heterocyclic group or a substituted heterocyclic group. Q is preferably -C (0) NH- or -C (S) NH-. R5 is preferably selected from all isomers that may be generated by substitution with the following groups: -31------------ a paper size applicable to China National Standard (CNS) A4 specifications (210X 297 mm ) --------- 0 ------ 1T ------ (Please read the notes on the back before filling out this page} 534910 ____ Η * 7 V. Description of Invention (29) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China (Please read the precautions on the back before filling in this page) 4-[-NH2CH2C (0) NH-] T group, 4-[-H00CCH2CH2C (0) NH_] 芊 基 ， 4-[-NHC (〇) CH2NBoc] fluorenyl, 4-[-NHC (0) CH (CH3) NHBoc] benzyl, 4-[-NHC (0) CH (CH2 (t)) NHBoc] -benzyl, 4-[-NHC (0) -CH2NHC (0) NH-3'-methylphenyl] benzyl, 4-[-NHC (0) CH (NHBoc) (CH2) 4NHCbz] benzyl, 4-[- NHC (0) CH2CH (C (0) 0CH2- (t))-NHCbz] -fluorenyl, 4-φ · fluorenyl, 4-[-NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] -benzyl, 4 · [H2NHCH2CH2CH2C (0) NH-] benzyl, 4- (BocHNCH2CH2 CH2-C (0) NH ·) fluorenyl, 4 _ [(|) -CH2OCH2 (BocHN) CHC (0) NH-] benzyl, 4- [ CH3NHCH2CH2CH2C (0) NH-] fluorenyl, 4- (N-fluorenylhexahydropyridine-4-oxo) -benzyl, 4- [CH3N (Boc) CH2CH2CH2C (0) NH-] benzyl, 4-[( () CH20CH2 (H2N) CH C (0) NH-] · benzyl, 4- [H0 (0) C (Cbz-NH) CHCH2CH2-C (0) NH] -fluorenyl, 4-[(l > CH20 (0) C (Cbz- NH) CHCH2CH2-C (0) NH] -fluorenyl, 4- [H0 (0) C (NH2) CHCH2CH2-C (0) NH-] benzyl, 4- [CH3 (N-Boc) NCH2C (0) NH-] fluorenyl, 4- [CH3NHCH2C (0) NH-] fluorenyl, 4-[(CH3) 2NCH2C (0) NH ·] benzyl, 4-[-0-CH (C00H) (|)] benzyl , 4- [2-carboxyphenyl-] benzyl, 4- [2-carboxymethylphenyl-]-fluorenyl, 4-[(|) CH20C (0) NHCH2CH2NH-] fluorenyl, 4-N -[-(S02) CH3-CH2CH2CH2N (CH3) 2] benzyl, 4-third butyl-0 (0) CCH2-0-benzylNH] benzyl, 4- [N, N-bis (4-N , N · dimethylamino) benzyl] amino] benzyl, 4-(2 -methylthiol-1,2,3,4-tetrahydroisopropylquinolin-3 -yl-C Η 2 Ν Η) fluorenyl, 4-[-Ο C Η 2 C Η 2-1 '-(4' -pyrimidinyl) -hexahydropyridyl] • benzyl, 4-[-OCH2CH2- (1 hexahydropyridine Base)-benzyl, 4- -32- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) '' 534910 ……. 一 ^ _____________ 5. Description of the invention (3) Central standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative (please read the precautions on the back before filling this page) [-0 (: Η2 (: Η2 · (1, -pyrrolidinyl)] · benzyl, 4-[-OCH2CH2CH2 · (1, hexahydropyridyl) _benzyl, 4-[(CH3) 2NCH2CH2CH2-0 ·] fluorenyl, 4-[((: ^ 13) 21 ^ 01 ^ 201 ~ 12-0-] benzyl, 4-[-0 (: 112 (: 112 (: 112-(Γ- (4 '· fluorenylhexahydropyridine) Phenyl))]-benzyl, 4-[-OCH2CH2CH2-4_ (3'-chlorophenyl) -hexahydropyridine-butyl] -benzyl, 4-[-〇CH2CH2N ((|)) CH2CH3] -Fluorenyl, 4-[-OCH2-3 '-(N-Boc) -hexahydropyridyl] -benzyl, 4-[-Ο-(3-(N-B oc) -hexahydropyridyl] benzyl Methyl, 3-[-0- (N-fluorenylhexahydropyridin-4-yl) benzyl, 4-[-0- (N-methylhexahydropyridin-4-yl) benzyl, 4- [bis -Iso-propylamino-CH2CH20-]-fluorenyl, 4- [N-3 -methylbutyl-N-trifluoromethanesulfonyl] amino] benzyl, 4-[-OCH2CH2- (N -Morpholinyl)]-fluorenyl, 4-[-OCH2CH (NHBoc) CH2 cyclohexylbenzyl, 4- [OCH2CH2- (N-hexahydropyridyl)]-benzyl, 4 _ [-OCH2CH2CH2- (4-m · Chlorophenyl) -hexahydropyrine-1-yl] -benzyl, 4-[-OCH2CH2- (N-Hexahydropyridyl) -benzyl, 4-[-OCH2CH2N (benzyl) 2]- Fluorenyl, 3-[-OCH2CH2CH2N (CH3) 2] _ benzyl, 4-[-OCH2CH2N (C2H5) 2] _ fluorenyl, 4- [-0CH2CH2 CH2N (C2H5) 2] · benzyl, 4-[-OCH2CH2N (C2H5) 2] -fluorenyl, 4-[-0CH2CH2CH2N (CH3) benzyl] • benzyl, 4- [2- (2-azabisi褎 [3.2.2] oct-2-yl) ethyl-0-] fluorenyl, [cyclopentylethynyl] -fluorenyl, 4 · [· 0 (: · φ · 4, -φ] · benzyl , 4- [OC-CH2-0_S (0) 2-4, _CH3-φ] -benzyl, 4-[-CtriC-CH2NHC (0) NH2] _ benzyl, 4- [C = C-CH2 -0- (4'-C00CH2CH3) ())]-fluorenyl, 4-[-CeC-CH (NH2) -phosohexyl] -fluorenyl '4-[-CeC-CH2-O-muyl]-+ Base, 4-[-CeC_ CH2-OCH3] -benzyl, 4-[-CeC-CH2-0- (4, -C (0) 0C2H5) benzene-33- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X 297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ *? __ Βη V. Description of the invention (31) radical] · benzyl, 4-[-C three C-CH2CH (C (0) 0CH3) 2] -fluorenyl, 4- [-CeC-CH2CH (NHC (0) NH3) C (0) 0H] -fluorenyl, 4-[-CtriC-CH2NH- (4,5-dihydro- 4-oxy-5-phenyl-azazol-2-yl)]-fluorenyl, 4-[-OCH2CH2CH2- (N-morpholinyl)]-fluorenyl, 4-[-OCH2COOH] benzyl, 4 -[-OCH2COOH-third butyl] -benzyl, 4-[-N (S02CH3) (CH2) 3-N (CH3) 2] -benzyl, 4-[-NHS (0) 2CF3] -fluorenyl , 4-[-C (= NH) NH2] -r Methyl, 4-[-NHS〇2-CH2l] -fluorenyl, 4-[-0CH2C (0) 0H] -benzyl, 4-[-OCH2CH2-l- (4-#-4- (3-methoxy Pyrrol-2-yl) -hexahydropyridyl)]-benzyl, 4-[-0CH2C (0) NH] · benzyl, 4-[-0CH2C (0) NH-third butyl] · fluorenyl , 4-[-OCH2CH2-l- (4-hydroxy-4-phenyl) -hexahydropyridyl] -fluorenyl, 4-[-NHS02-CH = CH2] -benzyl, 4-[-NHS02-CH2CH2l ] -Benzyl, 4-benzyl · benzyl, 4-B0CH2C (0) hexahydropyridin-1-yl] benzyl, 4-[-0CH2C (0) N (CH (CH3) 2) 2] Benzyl, 4-Mizylbenzyl, 4-Ethylaminobenzyl, 4- (N-methyl) Ethylaminobenzyl, 4-(-NHC (0) CH2NHC (0) NH-Fluorine Photon) benzyl, 4- (nhc (o) ch2ch (nh2) cooh, (1-tosylsulfonylimidazol-4-yl) -methyl-, [(1-N, N-dimethylamino Sulfonyl) -imidazol-4-yl] methyl-, 4- (N-toluenylamino) -methyl, and 4- (N-methyltrifluoroethylamino) phenyl. In the compound of the formula IA, R6 is preferably 2,4-dioxytetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, isopropoxy, n-butoxy, third Butoxy, cyclopentyloxy, neopentyloxy, 2-α · isopropyl- 4- β-methylcyclohexyloxy, 2-β-isopropyl- 4- β-methylcyclohexyloxy Base, · νη2, Ethoxyl '-NHCH2COOH' -NHCH2CH2COOH, -ΝΗ · King Kong-34- This paper size applies to China National Standard (CNS) A4 specification (21〇 ^ ϋ) ~ ------- -------- Order ------ (Please read the notes on the back before filling this page) 534910 Λ7 _ B1 V. Description of the invention (32) _ group, -NHCH2CH2COOHCH2CH3, -NHS〇2_p. CH3_ (|), -NHOR8 where R8 is hydrogen, methyl, isopropyl or benzyl, 0- (N-butanediimine), -0-cholest-5-en-3-β · yl _〇ch2_ 〇c (o) (ch3) 3, -o (ch2) 2nhc (o) w where 2 is 1 or 2, and W is selected from the group consisting of pyridin-3-yl, N-methylpyridyl And N-methyl-1,4-dihydrazone-pyridin-3-yl, NR "C (0) -R 'where Rf is aryl, heteroaryl or heterocyclyl, and R" is hydrogen or- CH 2 C (Ο) 〇 CH 2 C Η 3. Preferred compounds within the range of the above formulas I and IA include, for example: N- (toluene-4-kisperylene) _L-amine trap donyl second butoxylocylglycinyl) amino]] L-benzene Alanine N-(toluene-4 · Si group) -L · Proline amidino_ 4-[(Glycine) amino] -L-+ Alanine N-(toluene-4 -sulfonyl ) -L-Proline amine group-4-[3 _ (Carboxy) propylaminomethyl] -L · Phenylalanine N-(methylbenzene 4-aminomethyl) -L amine trap group-4-[( Ν_ 第: Butoxysuccinyl-L-propylaminofluorenyl) amino] -L-phenylalanine N- (toluene-4 · S-Shengyl) -L_base amine 8S-4--4-(( Ν-第: r butyloxy # based-D-propylamine donkey base): Base] -L-Dongylpropylamine 酉 Ai printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N- (Toluene-4-continued S) -L-Aminyl-Second Butoxyl-D-phenylpropylaminofluorenyl) amino] -L-Ethylalanine -4-Continued fluorenyl) _L -Alkaline amine group-4_ {2- [3_ (Rongguangsu) Thiourea] Ethylaminophenyl L · Phenylalanine N-(Benzene · 4-Benzyl group) ) -L-Proline donkey-4-[(n_th: Butoxy # yl-glycinyl) amine ] -L -Phenylalanine methyl ester-35- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) ~ ------ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7- ___________ Η1 _______________________________________________ 5. Description of the invention (33) N-(toluene-4 -sulfofluorenyl) -L -proline fluorenyl-4-丨 2-[3-(3 -methylbenzyl) ureido] acetamidine L-phenylalanine N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl 4-[(N α -Third butoxycarbonyl-N ε -formyloxy-L- Anaminyl) amino] -L-phenylalanine N- (toluene-4-methylfluorenyl: yl) -L-prolyl-4- [γ · (α-fluorenyl-Nα-formamidine Oxy-L-aspartyl) amino] -L-phenylalanine methyl ester N- (toluene-4-sulfofluorenyl) -L-proline methyl-4-[(Ν α- 三 丁丁Oxycarbonyl-L-Aminoamido) amino] -L-phenylalanine N- (toluene-4 -sulfoamido) -L-prolylamido-4-[γ-(L-aspartyl ) Amino] -L-phenylalanine N- (toluene-4-sulfofluorenyl) -L-prolylamino-4-(4-aminobutylamine) -L-aspartylamine Ν-(A -4 -sulfofluorenyl) -L -proline methyl-4-[4-(N -third butoxycarbonylamino) butylaminomethyl] -L -phenylalanine N- (methylwood-4 -S-basket) -L-amine trapping group- 4- [4- (N-fluorenylamino) butylamine group] -L-phenylalanine N- (methylwood-4- ) · L-Lapthylamine-4- [4- (N-third butoxycarbonyl-N-methylamino) butylamino] -L-phenylalanine N-(toluene-4 -S-Syl) -L -Aminyl-4-[(〇 ;;)-l-serineamido)-] -L-phenylalanine N-(methylbenzene-4- SS group) -L-prolyl-4-[δ-(D, L -Amine-Aminopyridyl) amino] _ L -Phenylalanine N_ (Acetylen-4-yl) -L · Aminyl-4-[(ν_Second butoxycytidine sarcosinyl) amino] -L -Dongylalanine-36- This paper is sized to Chinese National Standard (CNS) A4 (210X 297 mm) ^---------- Ρ — (Please read the notes on the back before filling this page} 、 1Τ 534910 Λ ·? -——_ I ”One ________ —___ V. Invention Note (34) (Please read the precautions on the back before filling out this page) N · (Benzene-4 -sulfofluorenyl) -L-(5, 5 -Dimethyl) pyrimidinyl-4-[(N-Third-butoxy-L-propylamine SS: yl) amino] -L-Derylpropylamine N- (toluene-4- Sulfonyl) -L -Proline sulfonyl-4-[(Inosamine fluorenyl) amino] -L -Lignoylalanine ethyl ester N-(Toluene-4 · sulfonyl sulfonyl) -L · proline sulfonium -4-[(inosinoamidinyl) amino] -L -phenylalanine N-(pyridin-4-sulfonyl) -L-(5,5_dimethyl) pyrimidinamine -4-[(inosinoamido) amino] -L -phenylalanine N-(toluene-4 -sulfofluorenyl) · L -prolylamino 4-[(N, N -dimethylglycine Aminomethyl) amino] -L · phenylalanine N-(toluene-4 -sulfofluorenyl) _ L-(5,5-diamidino) pyrimidinamino-4-[(N, N -Dimethylglycinyl) amino] _ L -Phenylalanine N- (Toluene-4 -Sulfuryl) -L -Proline Testyl-4- (α-Oxyloxy) -L -Phenylalanine N-(toluene-4 -sulfofluorenyl) -L -Proline amidino_ 4 [2-(carboxy) phenyl] -L -Phenylalanine N- (toluene-4-sulfonyl) ) -1 ^ _proline fluorenyl-4_ [2_ (methoxycarbonyl) phenyl] -L · phenylalanine methyl ester Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs S blue base) -L -Aminyl-4- {N- [2- (N-methylbenzyloxyamine) ethyl] amine}-L-phenylalanine 1 ^-(xylbenzene-4-sulfonyl) -1 ^ _proline methyl-4- {1- [2-(! ^-Formamylbenzyloxyamino) ethyl] amino group L-phenylalanine methyl ester N- (methylbenzene-4- Continued S blue group) -L-amine trap group-4_ {N- [3- (N, N-—methylamino) propyl] -N-[trifluoromethanesulfonyl] amino group}-L -Phenyl __ -37- _ This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 534910 AB * Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (35 methyl alanine N-(methylbenzyl _ 4 _sulfonyl) -L _proline sulfonyl _ 4 _ {N-[4 _ [(n · Second butoxycarbonyl) methoxy] benzyl] amino group L -benzene Methyl alanine N-(toluene-4-ruthenium g | yl) -l -proline methyl-4-{N, N -bis [4 (N, N -dimethylamino) benzyl] Amino group L _Phenylalanine N-(methylbenzyl-4 -sulfonamido) _ L _ Prolylamido-4 · {N _ [(2 _methylamido _ 1, 2, 3, 4 _ Tetrahydroisoquinoline-3 · yl) fluorenyl] amino}-L _ phenylalanine N _ (methylbenzyl_ 4 · sulfonyl) L proline fluorenyl-4-[3 _ (N, N-Dimethylamino) propoxy] _ L -Phenylalanine N- (Meto_4_Response) · ν_methyl-L -Seramine SS-4--4- (3, (N, N -Difluorenylamino) propoxy p L _phenylalanine methyl ester N-(methylbenzyl-4 -sulfofluorenyl) -L-(5,5-dimethyl) pyrimidinamine-4- [2- (N, N-dimethylamino) ethoxy] -L_phenylalanine N- (methylbenz-4-sulfonyl) -L-prolyl-4- [2_ (Ν , N -dimethylamino) ethoxy] -L_phenylalanine N- (fluoren-4-amino group) -L-3 pentamino-4- [2- (N -ethyl -Ν-phenylamino) ethoxy] -L -phenylalanine methyl ester N-(fluoren-4 -sulfofluorenyl) -L _prolylamino-4-[2-(Ν, Ν- Diisopropylamino) ethoxy] _L-phenylalanine N_ (stilbene-4 -sulfofluorenyl) -L-prolylfluorenyl-4-[3 -cyclohexyl-2-(N- Di-dioxoylamino) propoxy] -L-phenylalanine methylamine N- (methylphen · 2-sulfofluorenyl) -L · proline methyl-4 · [3-(Ν, Ν-dimethylamino) propoxy] -L-phenylalanine N- (5-chloro4-phen-2-sulfofluorenyl) -L-prolylamino-4-[3-(Ν, Ν- II-38- This paper size applies to Chinese National Standards (CNS) Α 4 specifications (210X 297 mm) order (please read the precautions on the back before filling out this page) 534910 Β1 V. Description of the invention (36) fluorenylamino) propoxy] -L -benzyl alanine N- (formaldehyde Dong-4-Shibuyao Hall; the base) -L-pentamidine-4_ [2- (N, N -monoethylamino) ethoxy] -L -phenylalanine N-(2, 5-dichlorop-sphene · 3 _ B & amp) -L Proline SS group-4- [3- (N, N -Diamidoamino) propoxy] -L -phenylalanine N -(1 -Methylpyrazole-4 -sulfofluorenyl) -L -prolylamino 4-[3-(N, N -dimethylamino) propoxy] -L -phenylalanine N -(曱 冬 -4- 绩 | 盈 基) -L -Amine-trapping BS-4- [3 · (N, N- ~ -ethylamino) propoxy] -L-phenylalanine methyl ester Ν -(Medong-4_continuous base) -L-il-Pramine S®- 3 · [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N-( Danzole-2 -sulfofluorenyl) · L-proaminefluorenyl-4-[3-(N, Ν -dimethylamino) propoxy] -L -phenylalanine >]-(fluorenylbenzene-4-sulfofluorenyl)-; 1-proline fluorenyl-4- [3-(\-fluorenyl-1 ^ -methylamino) propoxy] _L-phenylalanine N- (toluene- 4 · sulfofluorenyl) -L-proline -[3-(N, Ν -diethylamino) propoxy] -L -Phenylalanine Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) Ν · (Toluene-4-sulfofluorenyl) _L-proaminefluorenyl-4- [3- (N -methyl-N-fluorenylamino) propoxy] -L · phenylalanine methyl ester N-(1 _Methylimidazole · 4-sulfofluorenyl) -L-proline fluorenyl-4 _ [3-(N, N · dimethylamino) propoxy] -L -phenylalanine N · (2 methyl -Pyrimidazole-3 _sulfofluorenyl) · L-proline fluorenyl · 4 _ [3-(N, Ν-monomethylamino) propyl milk] -L -Mulylpropylamine 酉 parent N- (methyl Winter _4_ performance SS-based) -L · phthamidamine hall: base-4- [3 · (Ν, Ν -dimethyl-39-] This paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 mm) ) 534910 Λ7 —-------- V. Description of the invention (37) '— One ... ^… · — -aminoamino) propoxyl L _phenylalanine N- (4-cyanobenzenesulfonate Fluorenyl L- (5,5-dimethyl) pyrimidinamine fluorenyl_4_ [j-(N, N -Difluorenylamino) propoxyl L phenylphenylalanine methyl ester N-(toluene -4 -sulfofluorenyl) -L-(3,3-dimethyl) proline fluorenyl-4- [3- (N, N -dimethylamino) propoxyl L-phenylalanine N- (xylbenzene-4 -sulfofluorenyl) -L- (5,5-dimethyl) pyrimidamine Fluorenyl-4- [3-(N, N _ difluorenylamino) propoxy] _ L phenylalanine ethyl ester N-(methylbenzyl_ 4 -sulfofluorenyl) -L · proline fluorenyl- 4-[2-(2 -Azabicyclo [j.2.2] oct-2-yl) ethoxy] -L · phenylalanine methylamine N (fluorenyl 4-sulfonyl) -L-(? Phenyl-3 -carbonyl) -4-[3-(N, N -dimethylamino) propoxy] _ L -phenylalanine N-(toluene-4 -sulfofluorenyl) _ L -proline -4-[2-(2 -Acridinebicyclo [J.2.2] oct-2-yl) ethoxy] -L -phenylalanine N _ (methan-4 -kimonyl) -D, L · Phenylpropylamine Siyl-4-[2-(cyclopentyl) ethynyl] -D, L -phenylalanine N-(toluene-4 -sulfonyl) -D, L -phenylpropylamine fluorenyl- 4-丨 2-[4-(Phenyl) phenyl] acetylene: -D, L -phenylalanine N-(toluene-4 -sulfofluorenyl) _ D, L -phenylpropylaminofluorenyl- 4-[3-(Toluene-4 -Chrysyloxy) propyl-〗-Blocky] -D, L -Phenylalanine N- (Tochigi · 4_jig Turtleyl) -D, L -benzene Propylamino-4- [3- (lunyl) propan-1 -alkynyl] -D, L- Phenylalanine N-(toluene_ 4 -sulfofluorenyl) -D, L -Phenylalanine fluorenyl 4 · [3-(4-ethoxycarbonylphenoxy) propan · 1 -alkynyl] -D, L -Phenylalanine N-(Toluene-4 -continuous base) -D, L -Phenylalanine-4-[2-(1 -Amine-40-) This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm) --------- f (Please read the notes on the back before filling this page)

、 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Β " 7 —-_________-..…. 一 '·--一-—-One. — 一 ― _ 5. Description of the invention (38) ^ ~ Hex-1 -yl) ethynyl] · D, L-phenylalanine N · (toluene-4-phenylsulfonyl) -L-alkaliamine-4- [3_ (phenoxy) propane 1 (please Read the precautions on the back before filling out this page) Alkynyl] -D, L -phenylalanine N-(toluene-4 -sulfofluorenyl) inosaminofluorenyl-4-[3-(phenoxy) propane_丨 · Block group] -D, L -phenylalanine N-(toluene-4 -sulfofluorenyl) -L -proline fluorenyl-4-[3 · (methoxy) propane-i alkynyl]- D, L -Phenylalanine N-(Toluene-4 -Phenylamino) Inosinamide-4-[3 · (methoxy) propan-i _ block group] · D, L -Phenylalanine N · (Toluene-4 -sulfofluorenyl) -L -proamine group-4 _ [3-(4-ethoxycarboxyphenoxy) propan-1 -alkynyl] -D, L -phenylalanine N · (Xylbenzene-4 -sulfofluorenyl) inosamine fluorenyl-4-[3-(4 -ethoxycarbonylphenoxy) propan-1 -block] -D, L -phenylalanine N _ (toluene_ 4-Amino group) -L _proline fluorenyl group 4-[4,4 bis (fluorenylcarboxyl) but-1-ynyl] -D, L -phenylalanine N-(toluene · 4-sulfofluorenyl) inositino-4-[4,4-bis (methoxycarbonyl) but-1 -alkynyl] _ D, L- Phenylalanine printed by N- (toluene-4 -sulfofluorenyl) -L-proline fluorenyl-4 · (4 -acetamidine-4 -carboxybutan-1- Alkynyl) -D, L-phenylalanine N- (fluorenyl-4-sulfofluorenyl) inositinofluorenyl_ 4-(4 -acetamido 4 -carboxybutan-1 -block) -D , L-phenylalanine N (fluorenyl-4 -sulfofluorenyl) -L-proline fluorenyl-4-{3 [(4,5 -dihydro-4 -oxy-5 -phenylzazol -2 -Amino) amino] propan-1 -alkynyl}-D, L -phenylalanine -41-This paper size applies to China National Standard (CNS) A4 (210X297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative 534910 Λ7 ———_________ f… .________ — V. Description of the invention (39) N-(methylbenzyl-4 -sulfofluorenyl) inosamine amidino-4-丨 3 · [(4 , 5 -dihydro-4 · oxy-5 · benzylpyrazole_2 -yl) amino] propyl-propynylb D, L -phenylalanine N-(toluene-4 -sulfonyl) -L -Proline fluorenyl-4 · [2-(carboxy) phenoxyb L -benzene Methyl alanine N-(toluene · 4-sulfonyl) -L-proline methyl-4-{2-[4-(pyrimidin-2 -yl) hexamethylpyridin-1 -yl] ethoxy }-L Phenylalanine N-(Toluene-4 -sulfofluorenyl) -L · proline fluorenyl · 4 · [3-(hexahydropyridine-1 -yl) propoxy] -L -phenylalanine N _ (methylbenzyl_ 4 -sulfofluorenyl) -L -proline fluorenyl-4-[2 (pyrrolidin-1 _yl) ethoxy] -L -phenylalanine N-(fluorenyl-4 _ Sulfonyl) -L-Proline fluorenyl-4 · [3 _ (hexahydropyridine 1 -yl) propoxy] -L -phenylalanine methyl ester N (methylbenzyl-4 -sulfonyl)- L-proline fluorenyl-4-丨 3-[4 (3 _ phenylphenyl) hexahydropyridine-1 -yl] propoxy 丨 -L -phenylalanine N- (toluene-4 -sulfonyl) ) -L-Proline fluorenyl-4 [[(1 · Third-butoxycarbonylhexahydropyridine_3-yl) methoxy] -L-phenylalanine phosphonium ester N- (toluene-4-sulfonyl ) -L-proline fluorenyl-4-[2-(morpholin-4 -yl) ethoxy] -L -phenylalanine N-(toluene-4 -sulfonyl) -L · proline fluorenyl -4-[(1 -Third-butoxycarbonylhexahydropyridin-3 -yl) methoxy] -L -phenylalanine N-(toluene-4 -sulfonyl) -L -proline -[2-(hexahydropyridine Pyridin-1 -yl) ethoxy] _L-Mulylpropylamine parent N-(fluorenyl_ 4 -sulfofluorenyl) -L -prolylfluorenyl-4 {3 _ [4 (3 chlorophenyl) _- 42- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) --------------- IT ------ line · (Please read the back first Please pay attention to this page, please fill out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 ___________ f _____________________________________ …… __ 5. Description of the invention (40) Hexahydropyrimide-1 -yl] Propoxyl L-phenylalanine Esters N-(methylbenzyl-4 -sulfonamido) -L -prolylamino 4-[2-(azapyridin-1 -yl) ethoxy] -L -benzylalanine N-(toluene- 4-sulfofluorenyl) -L _proaminefluorenyl-4-[2-(aza leather-1 -yl) ethoxy] -L -phenylalanine methyl ester Syl-4-Hydroxy-4- [3- (4-methylhexahydropyridine-1 -yl) propoxy] -L -Phenylalanine methyl N-(toluene-4 -sulfonyl) -L- Proline group _ 3-[2-(pyrrolidin-1 _yl) ethoxy] -L -phenylalanine N- (methan-4-transg® group) -L -amine trapping group: group- 4- [3- (4-methylhexahydropyridine-1 -yl) propoxy] -L_phenylalanine N -(Toluene-4 sulfofluorenyl) -L Proline fluorenyl-3 · [2 _ (morpholine-4 -yl) ethyl milk] -L -phenylalanine N- (toluene-4-fluorenyl) -L -proline-4 · {2 · [4 · (3 · methoxyp-phenphen-2yl) -4 -hexadine-1 _yl] ethoxy 丨 -L phenylalanine Formamidine N-(toluene-4 -sulfofluorenyl) -L -prolylamino-3-(1 -methylhexahydropyridine-4 -oxo) -D, L -phenylalanine N-(fluorene Benzene 4-sulfofluorenyl) -L-proline fluorenyl-4-(1-methylhexahydropyridine-4 -oxo) -D, L-phenylalanine N_ (toluene-4 -sulfonyl) ) -L-(5,5-Dimethyl) pyrimidinamine-4-(1 -fluorinyl nitrogen p ratio p-4-oxygen) -L -aspartate alanine ethyl N-(toluene · 4-Sulfofluorenyl) -L- (1, 1-dioxythiomorpholine_3-carbonyl) · 4- (1-fluorenylhexahydropyridine · 4-oxo) -L_phenylalanine ethyl Ester-43- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) --------- f (Please read the precautions on the back before filling this page)

1. 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 hr 'ir. 41 5. Description of the invention () N-(toluene-4 -sulfofluorenyl) -L-(1,: 1 -dioxythio group Porphyrin-3 -carbonyl) -4-(1 · methylhexahydropyridine-4 -oxo) -L -phenylalanine N-(toluene-4 -sulfofluorenyl) -L-(5,5 -difluorene Amidino) pyrimidinyl-4 · (1 -methylhexahydroxyl-1: Yodo-4 · oxy) -L -phenylalanine N-(α -toluenesulfonyl) -L -proline -4-(1 -methylhexahydropyridine-4 -oxo) -L -phenylalanine ethyl ester N-(toluene_ 4 -sulfonyl) -L -prolyl-4-yl -N-(tri Fluoromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolylamino-4-Ν- (trifluoromethanesulfonyl) amino -L -phenylalanine N-(toluene-4 -sulfofluorenyl) -L -prolylamino 4-N-(chloromethanesulfonyl) amino-L -phenylalanine methyl ester N- (Toluene-4-carboxylic acid group) -L-Proline Hall: yl-4-Ν-(ethylamidino fluorenyl) amino group -L-winteryl propylamine δ dimethyl formaldehyde SS group) -L-proline fluorenyl: 4- (N-trifluoromethanesulfonyl-N-isobutyl Amino-L-phenylalanine methyl ester N- (toluene-4-sulfofluorenyl) · L-prolylamino 4 · (N -vinylsulfonyl) amino-L · phenylalanine Ν-(methon-4-Shiqi S-basket) -L-amine trap group-4-[(N-^ amino amine group) methoxy]-L-phenylalanine methyl ester N-( Toluene-4 · sulfofluorenyl) L-proline fluorenyl group · 4-[(benzyloxycarbonyl) methoxy] -L-phenylalanine methyl ester N-(toluene-4 -sulfofluorenyl) · L_proline Aminomethyl-4-[(benzyloxycarbonyl) methoxy] -L-phenylalanine-44-This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) — '------ --- Φ ------ 1T ------ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A?-^ ______ B1 ___________ —-5 Explanation of the invention (42) N- (Toluene-4-sulfofluorenyl) -L-proline fluorenyl_ 4-[(carboxy) methoxy] -L-phenylalanine N · (toluene-4 -sulfofluorene ) -L prolylmidino-4 _ [(carboxy) methoxy] -L -phenylalanine methyl ester N-(fluorenyl-4 -sulfonyl) -L -prolylfluorenyl-4-[ (Aminocarbonyl) methoxy] -L -phenylalanine N- (Toluene-4 -sulfofluorenyl) -L -Proline fluorenyl-4 [(N -Third-butylaminocarbonyl) methoxy] -L · phenylalanine N-(toluene-4 -sulfofluorenyl) ) -L Proline hydrazone-4-[2-(4 • Phenyl-4 · Hydroxyhexahydro p-pyridine -1 -yl) ethoxy] -L -Phenylalanine methylamine N-(Toluene -4 -sulfofluorenyl) -L -proline fluorenyl-4 · [(hexahydropyridin-1 -ylcarbonyl) methoxy] -L -phenylalanine N-(toluene-4 -sulfonyl)- L · proline methyl-4 · [(N, N -diisopropylamino coagulant) methoxy] -L -phenylalanine methyl ester N-(toluene-4 -sulfomethyl) -L- Proline fluorenyl-4-[(N, N _diisopropylaminocarbonyl) methoxy] -L -phenylalanine methyl ester N-(toluene-4 -sulfofluorenyl) inosaminol-D , L-4 · (fluorenyl) phenylalanine N-(toluene-4 -sulfofluorenyl) inositinofluorenyl-D, L-4-(aminocarboxy) phenylalanine N-(toluene-4 -Sulfofluorenyl) -L -proline fluorenyl-4-(N -methylethylamino) -L -phenylalanine isopropyl N-(toluene-4 -sulfonyl) · L -proline Aminomethyl-4-(N_methylacetamido) -L-phenylalanine-45- ^ Paper size applies to Chinese National Standard (CNS) Α4 ^ grid 210X 297 mm) ^^ ---------1 matters (please read the back of the note and then fill this page

、 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ? Β * 7 —--... ^. ·-. ·-· '. --- r- ~-\ x .. · »-, — · '··--· «·… 5. Description of the invention (a) N-(xylbenzene-4 -SiSi:-)-L-proline 4-4-(N-fluorenyltrifluoroacetamidamine ) -L-benzyl alanine methyl ester N- (toluene-4-sulfofluorenyl) -L · (5,5-dimethyl) pyrimidofluorenyl_4- [3-(N, N- Dimethylamino) propoxy]-^ phenylalanine tert-butyl ester N · (toluene_4-sulfofluorenyl) -L-prolylamino-L_4_ (N · methylhexahydropyridyloxy) _Phenylalanine tert-butyl ester N _ (toluene-4 · sulfofluorenyl) -L-(5 5 5 -dimethyl) sulfoproline fluorenyl L-(4 · methylhexahydrop-pyridyl Oxy) phenylalanine tert-butyl ester N-(xylbenzene-4 -sulfonyl) · L -proline sulfonyl · (4-phenyl) -L -phenylalanine tert-butyl ester N-( Toluene-4 -sulfofluorenyl) -L-proline methyl- (4-phenyl) · L-phenylalanine and its pharmaceutically acceptable salts, and any of the ester compounds cited above, one of which is an ester Replacement with another ester is selected from the group consisting of ethyl ester, ethyl ester, n-propyl ester, Propyl, n-butyl, isobutyl, tertiary butyl acetate and butyl second. The present invention also provides a method of combining VL A-4 in a biological sample, the method comprising contacting the biological sample with the aforementioned compound of formula I or IA under the condition that the compound is bound to VL A-4. Certain compounds of the formulae I and IA as described above can also be used in vivo to reduce inflammation in vla-4 vehicles. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of the above formula I or IA, but R3 and R5 are derived from L-amino acid or other similarly configured starting materials except. Alternatively, racemic mixtures can be used. -46-This paper size applies to China National Standard (CNS) A4 specification (210X297 male H '~---------- (Please read the precautions on the back before filling this page)

, 1T V. Description of the invention (44

Λ7 FP sauce composition can be used to treat # VLA_4 vector disease. These diseases include diseases such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset sugar-uria), and inflammatory bowel disease (including ulcerative colitis and colitis). Enns disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, "inflammation, encephalitis, stroke and other brain injuries, nephritis, retinitis, atopic dermatitis, dry addiction, myocardial ischemia And acute leukocyte-mediated lung injury occurs, for example, in adults with respiratory distress syndrome. In this way, the present invention also provides a method for treating the inflammation of vla-4 mediator in a patient, which method comprises administering to the patient the aforementioned pharmaceutical composition. Preferred compounds of formulae I and IA above include those listed in Table I below: ο

Rl-scv 曙) ~ U ， ch 』: r6,

I I H R5 --------- f (Please read the notes on the back before filling out this page) Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R1 R2 R3 R5, R6, P-〇Η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-NHC (0) -CH2NHBoc) _ benzyl · -0H ρ-〇η3 -Φ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-NHC (0) CH2NH2] -Nyl group --0H Ρ (Η3-φ R2 / R3 = Cyclic 3 carbon atoms (L -Pyrrolidinyl) p-[-nhc (o) ch2ch2c (o) oh] · 4 / -Glycyl- -0H p-CHs-φ R2 / R3 bicyclic 3 carbon atom (L- ^ p each symptom group) 4-[-NHC (0) CH * (CH3) NHBoc] -benzyl-(* corresponds to the L isomer) 0H p-CH'-i)) R2 / R3 = Cyclic 3 carbon atoms (L-pyrrole Pyridyl) 4-[-NHC (0) CH * (CH3) NHBoc] · fluorenyl-(* corresponds to D isomer) -0H -47 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 (Mm) 534910 Λ? Β1 V. Description of the invention (45 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

R1 R2 R3 R5 R6 'R2 / R3 = Cyclic 3 carbon atoms (L-? Bihabityl) 4-[-NHC (0) CH * (CH2 (1)) NHBoc] -Yeki-(* corresponds to D isomer) -OH R2 / R3 = cyclic 3 carbon atoms (Lp bilocidyl) [-nhc (o) ch2nhc (o) nh-fluorescein] yl group-OH P ^ Η3-φ R2 / R3 = cyclic 3 carbon atoms (Lp bihalidyl) 4- [BocNHCH2C (0) NH] -benzyl- -Och3 R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[- NHC (0) CH2NHC (0) NH · m · methyl] -fluorenyl- -OH p_CHr (j) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) P-[-NHC (0) CH (NHBoc) (CH2) 4 NHCbz] -benzyl- -OH ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-NHC (0) CH2CH-NHCbz] -benzyl (: (0) 0 <: Η2φ -〇ch3 ρ- (ZΉ: τφ R2 / R3 = cyclic 3 carbon atoms each)) p-[-NHC (0) CH-NHBoc] -benzylCH2CH2CH2CH2NH2 -OH ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-NHC (0) CH2CH (NH2) C00H -OH p-CH3- (|) R2 / R3 = cyclic 3 Carbon atom (L-said pyridinyl) p- (h2nch2ch2ch2c (o) nh) benzyl-OH ρ_ (ΓΗ3_φ R2 / R3 = cyclic 3 carbon atom (L-pyrrolidinyl) p- (Boc-HNCH2CH2CH2 (0 ) -NH) Hemyl- -OH ρ-ΟΊ3-φ R2 / R3 = Ring 3 broken atom (Lp bilocidyl) p- [CH3NHCH2CH2CH2-C (0) NH_] benzyl- -OH p_CH3- (j) R2 / R3 = ring 3 carbon atom (L-pjtp each symptom group) p- [CH3 (Boc) NCH2CH2CH2-C (0) NH ·] fluorenyl- _OH p-CH3 ^ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-plane [(() CH20CH2 (H2N) CHC (0) NH] benzyl- -OH p-CH3_ (j > R2 / R3 = Cyclic 3 carbon atoms (Lp), p- [H0 (0) C (Cbz-NH) CHCH2CH2-C ( 0) NH-] fluorenyl-OH p-CH3 ^ R2 / R3 = cyclic 3 carbon atoms (Lp is more than p each p-group) p- [H0 (0) C (H2N) CHCH2CH2-C (0) NH- ] Benzyl- -OH p-CH3- (j) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolyl) p- [CH3 (N-Boc) NCH2C (0) NH-] hexyl-- OH (Please read the precautions on the back before filling this page) -48- This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 534910 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ? Βη Invention Instructions (46)

R1 R2 R3 R5 R6 'ρ _ (: Η3_φ R2 / R3 bicyclic-ch2-sC (CH3) 2- (L_5,5_ dimethylpyrazolidine-4-yl) p- [CH3 (N-Boc) NCH2C (0) NH-] + group- -0Η ρ- (ΙΉ3_φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- [CH3NHCH2C (0) NH_] fluorenyl- _OCH2CH3 ρ-ανφ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p- [CH3NHCH2C (0) NH_] benzyl-OH ρ-(: η3-φ r2 / r3 = cyclic-ch2-sC (CH3) 2_ (L- 5,5-Dimethyl farinol-4-yl) p- [CH3NHCH2C (0) NH-] benzyl- -OH p_CH3_ (t) R2 / R3 = cyclic 3 carbon atoms (L_pyrrolidinyl) p-[(ch3) 2nch2c (o) nh ·]; group · -OH ρ-ΟΗ3-φ r2 / r3 = cyclic-ch2-sC (CH3ML-5,5-dimethyl far jun lake-4-yl ) P-[(ch3) 2nch2c (o) nh ·] benzyl- -OH ρ- (ZΉ3 · φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0_CH (C00H) ( ))]-Benzyl- -OH p-CH3- (|) R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p- [ortho-obtained phenyl] -type group--OH ρ- ( ΙΉ3 · φ R2 / R3 = cyclic 3 carbon atoms (Lp bilocidyl) p- [o-carboxymethylphenyl] -methyl-p-ch3 ^ R2 / R3 = cyclic 3 carbon atoms (L- Pyrrolidinyl) P-[(() CH20C (0) NHCH2CH2NH-]-family- -OH ρ-(: Η3-φ R2 / R3 = 3 carbon atoms (L-pyrrolidinyl) P-[(|) CH20C (0) NHCH2CH2NH-]-preyl- -och3 ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L_pyrrolidinyl ) P-[-N (CH2) 3-N (CH3) 2] benzyl so2ch3 och3 ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[(third butyl -o (o) cch2-o-fluorenyl) · NΗ_] fluorenyl · _〇ch3 ρ-ΟΗ ^ -φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) ρ-[(Ν, Ν -Bis (4-N, N-dimethylamino) benzyl) amino] fluorenyl- -OH ρ- (Zr, φ R2 / R3 = cyclic 3 carbon atoms 0- [2_methyl amidyl- 1,2,3,4-Four Rats Isoquina-OH (Please read the notes on the back before filling this page) -49- This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 534910 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy of the People's Republic of China Λ7 h1 Description of Invention (47)

R1 R2 R3 R5 R6, (LP than pyrrolidinyl) quinolin-3-yl-CH2NH-] fluorenyl ρ-οη3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) 4-[( CH3) 2NCH2CH2CH2-0-]-(t) · ch2 • 0H ρ-οη3-φ ch3 -αιοΗ (L isomer) p-[(ch3) 2nch2ch2o] _ nodule--〇ch3 R2 / R3 = 5, 5-Dimethyl p-septamedron-4-yl p-[(CH3) 2NCH2CH20] _ Hemyl-OH ρ-ΟΗ3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- [ (CH3) 2NCH2CH20] _ hexyl- -OH p-CH3 ^ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2N ((j)) CH2CH3] -benzyl- 〇ch3 p -CHs-φ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p- [di-isopropylamino_ch2ch2o-]-main group- -OH p-CH3- (t) R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p + OCH2CH (NHBoc) CH2 cyclohexyl] -Nyl group--Och3 2-Pyrimidyl R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidyl) ) P-[-OCH2CH2CH2N (CH3) 2] -benzyl · -OH 5-chloro-2-fluorenyl R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2CH2N (CH3) 2] -Yeyl-OH ρ · (ZΉ3_φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2N (C2H5) 2] -fluorenyl- -OH 2,5-dichloro- 4_ρ plug R2 / r3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p + OCH2CH2CH2N (CH3) 2] · benzyl- -OH 1 · N · fluorenyl-4-p oxazolyl R2 / R3 = cyclic 3-carbon atom (L-pyrrolidinyl) p-[_ OCH2CH2CH2N (CH3) 2] -benzyl- -OH ρ- [Η3 · φ R2 / R3 = cyclic 3-carbon atom (L-pyrrolidinyl) p- [-OCH2CH2CH2N (C2H5) 2] · benzyl · och3 ρ-Οί3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) m-[_ OCH2CH2CH2N (CH3) 2] · benzyl- -OH 2 -ρ 塞 Jun R2 / R3 = cyclic 3 carbon source p-[-OCH2CH2CH2N (CH3) 2] -Ye-OH (Please read the precautions on the back before filling this page) -50- This paper size applies to Chinese national standards (CNS) A4 specification (210X 297 mm) 534910 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Five Ministry of Economics. / R3 = cyclic 3 carbon atom (L-pyrrolidinyl) p + OCH2CH2CH2N (CH3) preyl group] -preyl group--OH ρ-ΟΗ ^ -φ R2 / R3 = cyclic 3 carbon atom (L-pyrrolidinyl group) Group) p-[-〇CH2CH2CH2N (C2H5) 2] -i? Group--OH ρ- (ΙΉ3 · φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2CH2N (CH3)芊 基]-Grandpa-- och3 1_N-methyl-4-amizolyl R2 / R3 = cyclic 3 carbon atoms (L_pyrrolidinyl) p-[-OCH2CH2CH2N (CH3) 2] -benzyl- -OH 2-methyl_ 4- Far diazolyl R2 / R3 = cyclic 3 carbon atoms (L_pyrrolidinyl) p + OCH2CH2CH2N (CH3) 2] -fluorenyl- -OH ρ-〇η3-φ R2 / R3 = pyrazol-4-yl p-[-OCH2CH2CH2N (CH3) 2] -fluorenyl- -OH ρ-〇η3-φ r2 / r3 = cyclic-ch2-sC (CH3) 2- (L-5,5-difluorenyl (Analytical-4-yl) p-[(ch3) 2nch2ch2ch20] benzyl- _och3 ρ-οη3-φ R2 / R3 = cyclic-ch2ch2c (ch3) 2- p-[(ch3) 2nch2ch2ch2o] benzyl- OH p- CH3_ (j) r2 / r3 = cyclic-ch2-s- ((: Η3) 2- (Ι ^ 5,5-diamidinoxazolidin-4-yl) p-[(ch3) 2nch2ch2ch2o] benzyl --OCH2CH3 p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- [2- (2-azinebicyclo [3.2.2] oct-2-yl) ethyl-〇 · ] Benzyl- -OCH, p-CHs-φ R2 / R3 = cyclic -CH2CH2-S_CH2- (L · thiomorphin-3-yl) p-[(CH3) 2NCH2CH2CH2-0-] benzyl--OH ρ-〇η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[(CH3) 2NCH2CH2CH2-0-] benzyl · OH ρ-οη3-φ R2 / R3 = cyclic 3 carbons Atom (L-errolidinyl) p-[(CH3) 2NCH2CH2CH2-0-] benzyl- -OCH3 (please (Please read the notes on the back before filling this page) -51-This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 534910 5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 Description of Invention (49)

R1 R2 R3 R5 R6, ρ-οη3-φ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p- [2- (2d γbicyclo [3.2.2] octyl · 2 · yl) ethyl_ 0] fluorenyl- -OH ρ-ΟΗ3-φ Η -ch2- Φα-isomer p- (cyclopentene-OC-)-benzyl-OH p-CH3 ^ Η -0Η: -φ (L-iso Structure ρ _ [-(^ Ξ (^ · φ-ρ-φ) · fluorenyl- -OH ρ-ΟΗ ^ -φ Η -ΟΗ, -φ (L-isomer P-[-C = C-CH2 -0-S (0) 2-p-CH3- ΦKil?--OH p-ch3 ^ Η -οη2-φ (L-isomer p-[_ CC_CH2NHC (0) NH2] · benzyl-OH p- CHs-φ Η-€ Η: -φ (L-isomer P-[-C = C-CH2-0-p-COOCH2CH3- (H-benzyl-OH p-ch3 ^ Η -0Η: -φ ( L-isomer p-[_ 〇C-CH (NH2) -cyclohexyl] -fluorenyl- -OH p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p + 〇c -ch2-o-phenyl] -fluorenyl- -OH p-CHs-φ -ch3 Η p-[-OC-CH2_0-phenyl], benzyl- -OH ρ-(: Η3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) P + 〇C-CH2-OCH3] _ benzyl- -OH ρ_ (ΙΉ3_φ ch3 Η P-[-CeC-CH2-OCH3] -benzyl-OH P_CH3_c |) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) P-[-C = C-CH2-0-p-(-c (o) oc2h5) phenyl] -methyl --- OH P-CHs- φ ch3 Η p-[-C = C-CH2-0-p- ( -c (o) oc2h5) phenyl] -family- -OH p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-t-pyridyl) p. [-C = C-CH2CH (C ( 0) 0CH3) 2]-benzyl- -OH (Please read the precautions on the back before filling this page) -52- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 534910 Central Ministry of Economic Affairs Printed by the Bureau of Consumers of Standards Bureau Λ7 B1 Invention Description (5Q)

R1 R2 R3 R5 R6, ρ-ΟΗ3-φ -ch3 Η p-[-oc-ch2ch (c (o) och3) 2]-Grandiyl--0H p-CH3_ (j) R2 / R3 = cyclic 3 carbon Atom (L-pyrrolidinyl) p-[-OC-CH2CHC (0) OH] -benzyl-NHC (0) CH3 -0H p_CH: r (t) _ch3 Η p-[-〇C_CH2CHC (0) 0H] -Benzyl-NHC (0) CH3 -0H ρ-ΟΗ ^ -φ R2 / R3 = Atom after ring 3 (L-pyrrolidinyl) p-[-OC_CH2NH- (4,5 · dihydro-4-oxy Phenyl-5-phenyl-fluoren-2-yl)] fluorenyl_0H -ch3 hydrazone p + OC-CH2NH- (4,5-dihydro-4-oxy-5-phenyl-izazol-2 -Yl)] benzyl-OH ρ_ (ΓΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0- (o-o-phenyl)]-fluorenyl- -〇ch3 ρ- (ΓΗ3-φ R2 / R3 = cyclic 3 carbon atoms (Lp bilocidyl) p _ [-OCH2CH2-l- (4-pyrimidinyl) -hexahydropyridyl] -benzyl- -OH ρ- 〇Η, -φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2- (l-hexahydropyridyl)]-benzyl OH p-CH3-([) R2 / R3 = 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2- (l-pyrrolidinyl)]-fluorenyl-OH p_CH3- (|) R2 / R3 = 3 carbon atoms (L-pyrrolidine) Group) group)]-benzyl group--〇ch3 ρ < price 3 · φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2CH2-1- (4 -M-chlorophenyl) -hexahydropyridyl] -fylyl-OH p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2-3- ( N-Boc) -Hexane leaf group l · Sylyl group-OH ρ-0Η3-φ R2 / R3 = Cyclic 3 carbon atoms (Lp ratio). P-[-OCH2CH2- (N-morpholinyl group) )]-Benzyl-OH ρ-0Η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2_ (N-hexahydropyridyl)] · fluorenyl-OH p-CH3_ (|) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p + OCH2CH2CH2- H4-m-chlorophenyl V hexahydropyridyl 1-benzyl- _〇ch3 ρ-0Η3-φ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2_ (N-Hexahydropyridyl)]-methyl- -OH (Please read the precautions on the back before filling this page)- 53- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 534910 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China B1 Invention Description (51) R1 R2 R3 R5 R6, ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2- (N-Hexahydropyridyl)]-character group--och3 ρ-〇η3-φ R2 / R3 = cyclic 3 Carbon atom (Lp than pyridyl) p-[-OCH2CH2CH2-l- (4-methyl)- Hexahydropyridyl)]-benzyl- -och3 ρ-οη3-φ R2 / R3 = cyclic 3 carbon atoms (Lp than pyrrolidyl) m-[-OCH2CH2- (l pyrrolidyl)]-fluorenyl -OH R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2CH2-1-(4-methyl) -hexazine ratio p well group] -fluorenyl- -OH p-CH3 ^ R2 / R3 = 3 carbon atoms (L-pyrrolidinyl) p-[_ OCH2CH2- (N-morpholinyl)]-benzyl-OH R2 / R3 = 3 carbon atoms (L-pyrrolidinyl) ) P + OCH2CH2_ 1- (4-hydroxy_4- (3 · methoxypyrrole-2-yl) -hexahydropyridyl) -benzyl- -och3 p-CHs-φ R2 / R3 = cyclic 3 carbons Atom (L-pyrrolidinyl) p-[-0- (3-Boc) -T ^ wind ^ pyridyl] pyrene · -OH ρ-〇Η3-φ R2 / R3 = cyclic 3 carbon atom (L -Pyrrolidinyl) m-[-0- (N-methylrho-pyridin-4-yl)] + group- -OH ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidine Group) ρ-[-0- (N-fluorenyl group: rc wind? Specific bite-4-yl)] _ fluorenyl group--OH p-CH3- (t) r2 / r3 = cyclic-ch2-sc (ch3 ) 2- ρ · [(1-methyl7T iron / Hyoto-4 · yl) -0-] glycanyl- -OCH2CH3 p-CH3- (t) r2 / r3 = cyclic-ch2ch2-so2-ch2_ (LU -Dioxythiomorpholine-3_yl) p-[(1-methylhexahydropyridin-4-yl) -0-] oxetyl--och2ch3 ρ · Οί3 · φ R2 / R3 = Cyclic_CH2CH2-S〇2-CH2- (L-1,1-dioxythiomorpholine-3_yl) p-[(1-methyl: rc 风 ^ Biyodo-4-yl) _0-] hexyl- -OH p-CHs-φ r2 / r3 = cyclic-ch2-sC (CH3) 2- (L-5,5-dimethyl far away bite-4 -Yl) p-[(1-methyl7T / Hyoden-4-yl) -0-] benzyl- -OH p-CH3- (j) R2 / R3 = cyclic 3-carbon proto-pair-[( 1-methyl: rc rat pibiline-4-yl) -0-] -OCH2CH3 (Please read the precautions on the back before filling this page) -54- This paper size applies to Chinese National Standard (CNS) Α4 specifications ( 210X297 mm) 534910 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Five Ministry of Economic Affairs Λ7 Βη Description of invention (52) R1 R2 R3 R5 R6, Child (L-supridinyl) Ethyl-ρ-ΟΗ3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p-[-NHS02CF3] -fluorenyl- -OCH3 ρ-ΟΗ3-φ R2 / R3 = 3 cyclic carbon atoms (L-sordinyl) p-[- NHS02CF3] -benzyl- -OH p-ch3 ^ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p _ [-NHS02_CH2Cl] _benzyl- -0CH3 p-ch3 ^ R2 / R3 = cyclic 3 Carbon atom (L-pyrrolidinyl) p _ [-NHS02-CHCH2] -benzyl- -OCH3 p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl P_ [N_3-methylbutyl-N- (trifluoromethane group) amino group] + group- -OCH3 ρ · [η3 · φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl group) P- [N_ (vinylsulfonyl) amino] -fluorenyl- -OH ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0CH2C (0) NH -Benzyl] • benzyl- -0CH3 ρ-ΟΗ ^ -φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0CH2C (0) 0_benzyl] -benzyl- -0CH3 ρ-οη3-φ R2 / R3 = cyclic 3 carbon atoms (L_pyrrolidinyl) p-[-0CH2C (0) NH-fluorenyl] _ fluorenyl- -OH ρ · (: η3 · φ R2 / R3 = Ring 3 carbon atoms (L_errolidinyl) p-[-0CH2C (0) 0H] _ benzyl-OH ρ-〇η3-φ R2 / R3 = ring 3 carbon atoms (L- said pyridine Group) p-[-0CH2C (0) NH2] · benzyl- -OCH3 p-CH3- (j) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0CH2C (0) NH2 ] -Benzyl- -OH ρ-ΟΗ ^ -φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-0CH2C (0) NH-third butyl] -fylyl- -OH ρ-Οί3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2-1 _ (4 · hydroxy4-phenyl) -hexahydropyridyl] -benzyl-OH ρ (η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) P-[(hexahydro Pyridin-1-yl) c (o) ch2_o-] preyl- -OH p-CH3- (j > R2 / R3 = cyclic 3-carbon proton p-[(CH3) 2CH2NC (0) CH2-0-]- OCH, ordering (please read the precautions on the back before filling out this page) -55- This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 534910 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Β * 7 Description of the invention (53)

R1 R2 R3 R5 R6, (L-pyrrolidinyl) group-ρ-ΟΗ3-φ R2 / R3 = cyclic 3 carbon atoms (L-errolidinyl) p-[(CH3) 2CH2NC (0) CH2- 0 ·] benzyl-OH P- [Η3 · φ -ch3 Η p-[-C (= NH) NH2] · fluorenyl- -OH Ρ_〇13-φ -ch3 Η p-[-C (0) NH2] -benzyl- -OH p-0Ή3_Φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- (N-methylethylSSamino) fluorenyl group -OCH (CH3) 2 ρ- Οί3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- (N-methyl ethyl hall: amino) fluorenyl-OH ρ- (2Η3 · φ R2 / R3 = cyclic 3 carbons Atom (L-pyrrolidinyl) p- (N-methyltrifluoroacetamido) benzyl- -Och3 ρ-〇Η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) (1-Toluene-2-yl) methyl-och3 ρ-(: η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) 1-[(N, N-di Fluorenylaminosulfonyl) imidazol-4-yl] methyl- • 〇ch3 p-CHr (J) R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- (N-fluorenylbenzene Amino group) fluorenyl group -och3 ρ-ΟΗ ^ -φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl group) p- (N-toluene donylamino group) fluorenyl group--OH p- CHs-i)) r2 / r3 = cyclic-ch2-sC (CH3) 2- (L-5,5-two Fluorenyl-4-azolidine-4-yl) p- (3-N, N-dimethylpropoxy) · fluorenyl · -OC (CH3) 3 p-ch3 ^ R2 / R3 = cyclic 3 carbon atoms (L -Batchpyridinyl) p- (N-methylhexahydropyridyloxy) -benzyl-oc (ch3) 3 ρ _ (: η3-φ r2 / r3 = cyclic-ch2-sC (CH3) 2- ( L-5,5-Dimethyl ρ-Sep-tetra-4-yl) p- (N-methyl-M-P-Pyridyloxy) -fluorenyl-oc (ch3) 3 ρ-ΟΗ ^ -φ R2 / R3 = Cyclic 3 carbon atoms (L-pyrrolidinyl) p- 基 -henyl- -OC (CH3) 3 ρ-〇η3-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- (φ) -Section Base- -OH Thread (please read the notes on the back before filling this page) -56- This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 534910 __________ Β, V. Description of the invention (54) ——— — — — ^ Detailed description of the invention As mentioned above, the present invention relates to compounds that can inhibit the adhesion of white blood cells, and particularly to the media by VLA-4 White blood cells stick. However, before further describing the details of the present invention, the following terms are first defined. -Definition As used herein, "alkyl" means an alkyl group preferably containing i to 10 carbon atoms, and more preferably i to 6 carbon atoms. This word can be exemplified by, for example, methyl, third butyl, n-heptyl, octyl and the like. '' Substituted alkyl V represents an alkyl group preferably containing 1 to 10 carbon atoms, containing 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino'thiocarboxyl Amine, alkoxyamino, fluorenyl, alkylfluorenyl, thiosulfanyl, aminefluorenyl, aminecarbonylamino, aminethiocarbonylamino, aminecarbonyloxy, aryl, substituted aryl Aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, self atom, hydroxyl, nitro, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-ring Alkyl, carboxy-substituted cycloalkyl, carboxyfang, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocyclyl'-substituted-heterocyclyl, cycloalkyl, substituted ring Alkyl, guanidino, guanidino, It, sulfanyl, substituted sulfanyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioaryl, substituted thia Aryl, thioheterocyclyl, substituted thioheterocyclyl, heteroaryl, substituted aryl, substituted heteroaryl 'heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy Base Heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarboxyamino, oxythiocarbonylamino, -0S (0) 2-alkyl, _〇s (〇) 2_ substituted alkyl, -0S (0) 2-aryl, -〇S (0) 2-substituted aryl, _〇s (〇) 2_ _ · 57_ This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) '' *---------- P · (Please read the notes on the back before filling this page} -Order 534910 Λ] R1 55 V. Description of the invention (heteroaryl, -Ο S (0) 2 -Substituted heteroaryl, -0S (〇) 2 -heterocyclyl, -OS (0) 2-substituted heterocyclyl, -0s〇2_NRR where R is hydrogen or alkyl, -NRS (0) 2 -fe group, -NRS (0) 2-substituted alkyl group, -nrs (o) 2-aryl group, -NRS (0) 2-substituted aryl group, -NrS (〇) 2-heteroaryl group, -nrs ( o) 2-substituted heteroaryl, -NrS (0) 2-heterocyclyl, -nrs (0) 2-substituted heterocyclyl, -NRS (〇) 2-NR-alkyl, -nrs (o) 2 -nr-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (〇) 2-NR _ substituted heteroaryl, -NRS (Ο) 2-NR · heterocyclyl, -n RS (Ο) 2-NR-substituted heterocyclyl Where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di · (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, and Asymmetric disubstituted amines have different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted alkyl having amine It is known that blocking groups such as B 0c, cbz, formamidine, etc., or alkyl / substituted alkyl with -S〇2_alkyl, -s〇2_ substituted alkyl, -so2-alkenyl -So2-substituted alkenyl, -s〇2-cycloalkyl, -80-2_ substituted cycloalkyl, -so2-aryl, -s〇2-substituted aryl, -s〇2 • heteroaryl , -S〇2-substituted heteroaryl, -s02-heterocyclyl, -s02-substituted heterocyclyl, and -so2-nrr substituted, where R is hydrogen or alkyl. "Alkoxy" means "alkyl-O," including, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, third butoxy, second butoxy , N-pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy and the like. -58- The paper size of the table applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297mm --------- (Please read the precautions on the back before filling this page),- Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed 534910 Λ? ----------- B1 V. Description of the Invention (56) ^ ... " `` Replace alkoxy '' Means "substituted alkyl_〇_ '," acid group means Η-C (0) ·, alkynyl-C (0)-, substituted alkynyl_c (O)-' alkenyl-C (〇)-, Substituted fluorenyl-C (〇)-, alkynyl_C (0)-, substituted alkynyl-C (0)-, cycloalkyl_c (〇) _, substituted cycloalkyl_c (〇) _, Vanyl-C (O)-'substituted aryl c (〇) _, heteroaryl_c (〇) _, substituted heterocubyl-C (0), heterocyclyl_c (〇b, and substituted Heterocyclic aryl-c (0 >, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl 'cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are as defined in the text. 'Represents-C (0) NRR group, where each R is selected from the group consisting of hydrogen' k group 'substituted alkynyl, fluorenyl, substituted fluorenyl, block, substituted alkynyl' aryl 'substituted aryl, cycloalkane Group, substituted cycloalkyl, heteroaryl, substituted heteroaryl 'heterocyclyl, substituted heterocyclyl and each R here is bonded to a nitrogen atom to form a heterocyclic ring or substituted heterocyclic ring, in which alkyl, Substituted alkyl, fluorenyl, substituted alkenyl, alkynyl, substituted block, cycloalkyl, substituted cycloalkyl'aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and substituted cycloalkane The definition of the group is as above. "Thiocarbonylamino" means -c (S) NRR group, where each R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted fluorenyl, alkynyl, substituted block 'Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl and each R here is bonded to a nitrogen atom to form a heterocyclic ring Or substituted heterocyclic ring, in which the alkyl group, the alkyl group is substituted, the alkenyl group, the alkynyl group, the substituted alkyl group, the cycloalkyl group, and the substituted cyclopentyl group are substituted. Substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and -59- ---------- (Please read the notes on the back before filling in this page j 、 = 口 4 paper size Applicable to China National Standard (CNS) A4 specification (2l0X297 public attack)

534910 Λ? Β * 7 V. Description of the invention (57 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to replace the fund-raising base. The definition is as follows. "文 oxy" means alkyl-C (〇) 〇_substituted alkyl < (〇) 〇_, alkenyl-c (o) o-, = substituted fluorenyl group ((〇) 〇_, block group < (〇) 〇_, substituted alkynyl-C (O)) 0-' Wanky-C (〇) 〇 •, substituted aryl_c (〇) 〇, cycloalkyl-C (0) 0-'substituted% alkyl-C (〇) 〇 ... heteroaryl_c⑴ 川 _, Substituted heteroaryl-(:( 0) 〇_, heterocyclyl-c (〇) 〇 ... and substituted heterocyclyl _ [(〇) 〇_, where alkyl, alkene is alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl,% k, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are as defined in the text. Alkenyl means Isc preferably contains 2 to 10 broken atoms, and more preferably contains 2 to 6 carbon atoms, and contains at least one, preferably 2 fluorenyl unsaturated fluorenyl groups. "Substituted alkenyl" means that the alkenyl group contains 1 to 5 substituents selected from alkoxy 'substituted feoxy, fluorenyl, fluorenylamino, thiocarbonylamino Ethyloxyamino group 'Phenyl' alkyl, thiomethyl, thiomethyl, aminoamino, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryl Oxy 'substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano' halogen ', nitro, carboxy, carboxyalkyl, carboxy_substituted alkyl, carboxy_cycloalkyl , Carboxy-substituted cycloalkyl, Carboxyaryl, Carboxy-substituted Aryl, Carboxheteroaryl 'Preparation: -Substituted sulfonyl, Carboxheterocyclyl, Complex-substituted heterocyclyl, Cycloalkyl Group, guanidino, guanidino, fluorenyl, sulfanyl, substituted thiomethyl'thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl 'substituted thioheteroaryl Group, thioheterocyclyl, substituted thioheterocyclyl, heteroaryl 'substituted aryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, ring-60 MPa scale applicable to Chinese national standards (mm- -------- 1 (Please read the notes on the back before filling this page)

1T line * 5Γ34910 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention 58 Alkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy 'substituted heterocycle Oxy, oxo sti- ylamino, oxoamino amine, A-0S (0) 2-feyl '-0S (0) 2-substituted alkyl, -0s (〇) 2-aryl,- 0S (0) 2-substituted aryl '-0S (0) 2-heteroaryl, -〇8 (〇) 2-substituted heteroaryl, -0S (0) 2-heterocyclyl, -〇S (0 ) 2-substituted heterocyclyl, _〇s〇 ”NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (〇) 2-substituted alkyl, -NRS (0) 2 -Aryl, -NRS (〇) 2 -substituted aryl, -nrs (o) 2-heteroaryl, -nrs (o) 2-substituted heteroaryl, -nrs (〇) 2- heterocyclic group,- NRS (0) 2 -substituted heterocyclyl, _ NR s (〇) 2 _ NR • alkyl, -nrs (o) 2-nr-substituted alkyl, -NRS (0) 2 —NR-aryl,- NRS (0) 2-NR-substituted aryl, -NRS (〇) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (〇) 2-NR-heterocyclyl, NRS (0) 2 NR-substituted fluorene ring group, where r is hydrogen or alkyl, and di-alkylamino, mono- and di _Substituted alkylamino groups, mono- and di-arylamino groups, mono- and di-substituted arylamine groups, mono- and di-heteroarylamine groups, mono- and di-substituted heteroarylamine groups , Mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, asymmetric disubstituted amines with different substituents selected from alkyl, substituted fe''aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted fluorenyl groups have amine groups. Blocking groups such as Boc'Cbz'methylamyl are known, or alkenyl / substituted alkenyl substitutions. With —s〇2_alkyl′-S02 · substituted alkyl, —.s〇2-fluorenyl, —s02-substituted alkenyl, —so2-cycloalkyl, —so wide substituted cycloalkyl, —s 〇2-aryl, —s〇2_ substituted aryl, —S 0 2 —heteroaryl, —s 〇2 —substituted heteroaryl, — s 〇 2 —heteroyl '-S 0 2 -substituted heterocyclic And _ s 〇2 — N r ruler replaced, where r is -61-Table paper size suitable for financial standards (CNS) M specifications public --------- I (Please read the back Please fill in this page again for instructions), 11-line * ^ 34910 ΑΊ Β * 7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (Hydrogen or alkynyl) "Deutero" means preferably containing 2 to 10 carbon atoms, and more preferably containing 3 to 6 carbon atoms, and containing at least one preferred Unsaturated alkynyl. "Substituted alkynyl" means that the alkynyl group contains 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, and fluorenylamino. Alkanyl, thiol, amino, ammonium, amido, amino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, Aryloxyaryl, substituted aryloxyaryl, cyano, tooth atom, hydroxyl, nitro, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxy Aryl, carboxy-substituted aryl, carboxyheteroaryl, quasi-substituted heteroaryl, carboxyheterocyclyl, acyl-substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidyl, guanidino, Thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiaaryl 'substituted thiaaryl, thioheterocyclyl, substituted thia Cyclo, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyl Oxy Substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -os (o) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl , -0S (0) 2 • substituted aryl, -0S (0) 2-heteroaryl, -0S (〇) 2-substituted heteroaryl, -0S (0) 2 · heterocyclyl, -〇S (0) 2-substituted heterocyclic group, _〇s〇_ NRR where R is hydrogen or alkyl, -NRS (0) 2-1, -NRS (〇)-substituted alkyl, -nrs (o) 2-aryl, -nrs (o) 2-substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2-substituted heteroaryl, — Chinese standard (CNS) for wood paper A4 specification (210X297 mm) (please read the precautions on the back before filling this page), 11-line Yili 4910 A7 B7 i, description of the invention (please read the precautions on the back before filling this page) Heterocyclyl,- NRS (0) 2-substituted heterocyclic group, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, ~ NRS (0) 2-NR- substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl, -nrs (o) 2-nr-substituted heterocyclyl, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-substituted alkyl Amino groups, mono- and di-arylamino groups, mono- and di "-substituted square amino groups' ·-and di-heteroarylamino groups, mono- and

1T di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, asymmetric disubstituted amino with different substituents selected from alkyl 'substitution Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted alkynyl have amine groups. Conventional blocking groups such as B0c'CbZ, Blocking such as methylamino, or alkynyl / substituted alkynyl with _s 〇2_alkenyl, -so2_ substituted alkyl, -s〇2_alkenyl, -s〇2_ substituted alkenyl, -so2- Cycloalkyl, -so2-substituted cycloalkyl, -s02-aryl, -s02-substituted aryl, -S02-heteroaryl, -80-2_ substituted heteroaryl, -80. 2_hetero-linear ring group, -so2 · substituted heterocyclic group, and -s02_NRR substitution, where the rule is hydrogen or alkyl. "Amidino" means H 2 N $-and the term "alkylfluorenyl" means i to 3 alkyl groups

NH compounds (such as alkyl Η N C-).

II ΝΗ ′, thiomethyl, represents RSf_, where R is hydrogen or alkyl

NH -63 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 54910 Λ? ______ Β * 7 · _ '* 1 · _- ▲.…'. · Ι ___ • 1. · ... (M) "Aminomethyl" means -NRC (O) alkyl, -NRC (0) substituted alkyl, -NRC (O) cycloalkyl, -NrC (〇) substituted cycloalkyl, -n; rc (〇 ) Alkenyl'-NRC (O) substituted fluorenyl, _NRc (〇) alkynyl, _Nrc (〇) substituted block'-NRC (O) aryl, -NRC (〇) substituted aryl, _NRc (〇) Heteroaryl'-NRC (O) substituted heteroaryl, -nRC (O) heterocyclyl, and -NRC (O) substituted heterocyclyl, where r is hydrogen or alkyl and its alkyl , Substituted alkyl, alkenyl, substituted alkenyl, block, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted hetero The cyclic group is as defined above. "Aminocarbonyloxy" means -NRC (〇) 〇-alkyl, -NRC (〇) 〇_substituted alkyl, -NRC (0) 〇-cycloalkyl, -n RC ( 〇) 0-substituted cycloalkyl, -NRC (0) 0-fluorenyl, · Κ (:( 0) 0-substituted alkenyl, -NRC (〇) 〇 ^, -NRC (0) 0-substituted alkyne , -NRC (0) 0 · aryl, -NRC (〇) 〇-substituted aryl, -NRC (0) 0-heteroaryl, -NRC (0) 0-substituted heteroaryl, -NRC (0) 0-heterocyclyl, and -NRC (0) 0-substituted heterocyclyl, where R is hydrogen or fluorenyl and its alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group and substituted block group. Ring:) ¾ 'is substituted for cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl as defined in the text. "· Oxycarbonylamino" means _〇C (0) NH2, -0C (0) NRR, -0C (〇) NR_alkyl, -OC (0) NR-substituted alkyl, -OC (0) NR-alkenyl, -0C (0) NR- Substituted alkenyl, _0C (0) NR · alkynyl, -OC (〇) Nr_ substituted alkynyl, _0C (0) NR · cycloalkyl, -OC (〇) NR-substituted cyclomorphoyl, -0C (0) NR-aryl group, -0C (0) NR-substituted aryl group, -0C (0) NR_ -64- I (Please read the precautions on the back before filling out this page} 、 11-line paper size applies Chinese national standard (CNS) A4 specification (21〇 > < 297 mm) ^ 34910 Λ7 b1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention Heterotactic radical, -0 C (〇) NR-Substituted heteroaryl , -0 C (0) N R-heterocyclyl, and -0C (〇) NR-substituted heterocyclyl, where r is hydrogen or alkyl, or each R here is bonded to a nitrogen atom to form a heterocyclyl or substituted heterocyclyl ring, and Wherein alkyl 'substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl' substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl And substituted heterocyclyl are as defined. Oxythiolamino, which represents -0C (S) N N2, -0C (S) NRR, -0C (S) NR, and a _Qc (s) NR_ substituted alkynyl group, 〇c (S) NR-alkenyl, -OC (S) NR-substituted alkenyl, -OC (S) NR-alkynyl, -OC (S) NR-substituted block, -OC ( S) NRdf alkyl, -OC (S) NR · substituted cycloalkyl '-OC (S) NR-aryl, -0C (S) NR-substituted aryl, -OC (S) NR-heteroaryl , -OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclyl, and -OC (S) NR-substituted heterocyclyl, where r is hydrogen or alkyl, or Here, each R is bonded to a nitrogen atom to form a heterocyclyl or substituted heterocyclyl ring, and an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted block group, and an environmental group 'substituted ring pit group, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are as defined above. "Aminocarbonylamino" means -NRC (0) NRR, -NRC (〇) NR_alkyl, -NRC (0) NR-substituted alkyl, -NRC (0) NR · fluorenyl, _NRC (0) NR-substituted alkenyl, -NRC (0) NR-alkynyl, -NRC (CoNR-substituted block, -NRC (0) NR-aryl, -NRC (〇) NR-substituted aryl, -NRC (0) NR-cycloalkyl, -NRC (0) NR-substituted cycloalkyl, -NRC (0) NR-heteroaryl, -NRC (0) NR-substituted heteroaryl, NRC (0) NR- Heterocyclyl, and -NRC (0) NRlq < heterocyclyl, this -65 paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) ---------- (please first Read the notes on the reverse side and fill out this page} 、 == Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives ^ 34910 Λ? ____ ΒΊ β〇 ' Hydrogen or alkyl, or where each R is bonded to a nitrogen atom to form a heterocyclyl or substituted heterocyclyl ring, and here an amine group is blocked by conventional blocking groups such as B 0c, Cbz, formamyl, etc. And its alkyl, substituted alkyl, fluorenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl 'heteroaryl, substituted hetero Aryl, heterocyclyl and substituted heterocyclyl are defined as above. "Aminothiocarbonylamino" means-NRC (S) NRR, -NRC (s) nr_alkyl, -NRC (S) NR-substituted alkyl _NRC (s) NR-fluorenyl, -NRC (S) NR_ substituted alkenyl, -NRC (S) NR-alkynyl, -NRC (s) nr_ substituted block, -NRC (S) NR-aryl , -NRC (S) NR · substituted aryl, -NRC (S) NR-ring: fe, -n RC (S) NR-substituted cyclofluorenyl, -NRC (S) NR-heteroaryl, -n RC (S) NR-substituted heteroaryl, -NRC (S) NR-heterocyclyl, and -NRC (S) NR-substituted heterocyclyl, where R is hydrogen or alkyl, or where each R and The nitrogen atoms are bonded to form a heterocyclyl or substituted heterocyclyl ring, and here an amine group is blocked by conventional blocking groups such as B 0c, C bz, methylamidyl, etc., and the alkyl group, substituted alkyl group Alkenyl, substituted alkenyl, block, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl'heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are defined as "Aryl" or "Ar" means an unsaturated group containing 6 to 14 carbon atoms containing a single ring (such as phenyl) or multiple fused rings (such as fluorenyl or anthracenyl). Aromatic carbocyclic rings, these fused rings may or may not be aromatic 丨 such as 2 _ Benzene humazolinone, 2 Η-丨, 4-Benzene sakigen-3 (4 Η) -one- 7-base, etc.). Preferred aryl groups include phenyl and fluorenyl. Substituted aryl means aryl substituted with 1 to 3 substituents, these substituents -66-This paper size applies Chinese National Standard (CNS) Ad specifications (21〇 > < 297 mm) ---- ----- φ-I (please read the precautions on the back and fill in this page) Ordering service 4910 V. Description of the invention (64) is selected from the group consisting of hydroxyl, fluorenyl, fluorenylamino, and thiocarbonylamine Group, fluorenyl group, alkynyl group, take parent group, stilyl group, substituted alkoxy group, # group, substituted dilute block group, substituted block 1 m group, bounded peptidyl group, thienyl group, amino group fe group 'amino group ssoxy group, amino group amino group, $ thiocarbonylamino group' aryl group, and the aryl group is substituted by aryl group, aryloxy group, substituted aryloxy group, cycloalkoxy group, substituted functional group, Heterosyl, substituted heteroaryloxy, heterocyclicoxy, substituted heteroepoxy H, H-like, oxo, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxylic hetero Aryl, carboxy-substituted heteroaryl, carboxyheterocyclyl, carboxy-substituted heterocyclyl, carboxyamido, cyano, phenyl, thioalkyl, thioalkyl, thioaryl, thioaryl , Thiazawanyl, replacing doping Group, fluorene cycloalkyl, substituted thiocycloalkyl, thioheterocyclyl, substituted thioheterocyclyl, cyclic morphyl, substituted cycloalkyl, guanidyl, guanidino, self atom, nitro, heteroaryl, Substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy poly, heterocyclyloxy, substituted heterocyclyloxy, oxygen Carbonylamino, oxythioaminoamino'-S (O) 2 · alkyl, -s (〇) widely substituted alkyl, -S (〇) 2 -phosphine, · S (〇) 2_ Substituted cycloalkyl, _s (〇) 2 -alkenyl, -S (〇) 2 • substituted alkenyl, -S (〇) 2 -aryl, -s (〇) 2 • substituted aryl, via;? Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China --------- I (Please read the precautions on the back before filling this page) -Line · -S (Ο) 2 -heteroaryl '-S (0 ) 2 -substituted heteroaryl, -s (〇) 2 -heterocyclyl, -S (〇) 2 -substituted heterocyclyl, _ 0 s (0) 2 -alkyl, _ 〇s (〇) Alkyl'-OS (〇) 2-aryl, -OS (〇) 2-substituted aryl, -OS (〇) 2-heteroaryl '-OS (0) 2-substituted heteroaryl , · 〇δ (〇) 2 ^ Group, _〇s (〇) 2 · substituted heterocyclic group, -0S (0) 2-nrr where R is hydrogen or alkyl, -nrs (0) 2-alkyl, -nrs (o) 2 substituted alkyl Base, -nrs (0) 2-aryl, —nrs (0) 2, -67- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 534910 A Η * Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Cooperative printed 5. Description of the invention (mono substituted aryl, —NRs (〇h-heteroaryl, -nrs (0) 2- substituted heteroaryl NRS (0) 2 ice ring group, -NRS (0) 2- Substituted heterocyclyl, -nrs (o) 2-nr-Polyl, -NRS (〇h -NR substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (〇) 2 -NR substituted aromatic , -Nrs (o) 2-nr-heteroaryl, -NRS (〇h nr substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl, -NRS (〇) 2 -NR_ substituted heterocyclic Group, where R is hydrogen or alkyl, and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted Arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-fluorenyl% radical, mono- and di-substituted heterocyclic amino , Asymmetric disubstituted amines have different substitutions The group is selected from alkyl, substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted arylamino groups are conventional blocking groups such as BQe, Cbz, formamidine, etc., or substituted with -SOJMRR, where R is hydrogen or alkyl. "'Aryloxy" means an aryl group including, for example, phenoxy, benzene, etc. "" Substituted aryloxy "means a substituted aryl_Q- group. "Aryloxyaryl" means -aryl-o-aryl. "Substituted square oxo" means an aryloxy aryl group substituted with 1 to 3 substituents on any one or two aryl rings, and these substituents are selected from the group consisting of several groups, senyl groups, fluorenylamino groups, Thiocarbonylamino, alkoxy, alkyl, substituted alkane, alkoxy, substituted alkoxy, fluorenyl, substituted fluorenyl, alkynyl, ^ block ^, fluorenyl, amido, fluorenyl, stone Fluorenyl, amine, amine, donkey, amine, oxygen, amine, amine, aminothiocarbonylamino, aryl, substituted for aromatic _______ -68- This paper size applies to Chinese national standards ( CNS) M size (210X 297 mm) (Please read the precautions on the back before filling this page) Order

^ 34910 V. Description of the invention A7 B1 ^ Substituted aryloxy group, cycloalkyloxy group, substituted alkyloxy group, heterocyclic ^ Bawanwanyl, heterocyclicoxy group, substituted heterocyclicoxy group, aryl group, aryl group --------- (Please read the notes on the back before filling out this page) " Amino I-substituted alkyl, carboxycycloalkyl, carboxy-substituted cycloalkyl, carboxy aromatic: substituted aryl , Carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, substituted cyclic group, carboxyamido, cyano, thiol, sulfanyl, substituted alkyl, sulfonyl, substituted thioaryl , Thiaheteroaryl, substituted thiaaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclyl, substituted thioheterocyclyl, cycloalkyl, substituted cycloalkyl, guanidyl, guanidyl sulfone, _Atom, nitrate 4aryl 'substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkoxy substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy substituted heterocyclyl Oxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2-alkyl, · δ (0) 2-substituted alkyl, · s (〇) cycloalkyl, -s ( o) 2 substituted cycloalkyl, δ (〇) 2-alkenyl, _s (〇h_substituted fluorenyl -S (0) 2-aryl, -s (〇) 2-substituted aryl, -s (〇) 2-heteroaryl, -S (0) 2 substituted hetero-square group '-S (〇) 2 Heterophosphyl'_§ (〇) 2 • Substituted heterocyclyl, -0S (0) 2-alkyl, -0S (0) 2- substituted alkyl, -0s (〇) 2-aryl, -0S (0) 2-substituted aryl, -0S (0) 2-heteroaryl, -0s (〇) r substituted heteroaryl, -0s (〇) 2-heterocyclyl, -0S (0) 2 -Substitute heterocyclic groups, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, where os (o) 2-nrr is R or hydrogen, j: end group, -nrs (o) 2-carbon group, -nrs (o) 2-substituted alkyl, -nrs (0) 2-aryl, -NRS (〇) 2-substituted aryl, -nrs (o) 2-heteroaryl, -nrs (o) 2-substituted heteroaryl, -nrs (o) 2-heterocyclyl, -nrs (o) 2-substituted heterocyclyl, -nrs (o) 2-NR-fe, -NRS (0) 2-NR -substituted: fe,- NRS (〇) 2-NR · aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR -heteroaryl-69- This paper is sized to Chinese National Standard (CNS) specifications ( 210X 297 mm) 534910

Inventive group '-NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl'-nrs (〇) 2- —NR_ substituted heterocyclyl, where R is Hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino 'mono- and di-substituted arylamino, mono- And di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterophosphinoamino, asymmetric disubstituted amines have Different substituents are selected from alkyl 'substituted fe'aryl, substituted aryl, heteroaryl, substituted heteroaryl, although cyclic and substituted heterocyclic groups, and amine substituted aryl groups are blocked by conventional methods Blocking such as B 0 C 'cb Z' fluorenyl, etc., or substituted with -0S2nrr, where R is nitrogen or alkyl. "Environmental group" means a cyclocyclic group containing 3 to 8 carbon atoms having a single ring group ring including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc. This definition does not include polycycloalkanes Groups such as adamantyl, etc. Cyclopentyl groups have single or multiple unsaturated groups, but are not aromatic cyclic alkenyl groups with 3 to 8 carbon atoms. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs --------- I (Please read the notes on the back before filling this page)

, 1T "substituted cycloalkyl" and "substituted cycloalkenyl" represent cycloalkyl and cyclofluorenyl groups preferably containing 3 to 8 carbon atoms, and containing 1 to 5 substituents selected from the group consisting of ), Thio (= S), alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenylamino, fluorenyl, alkylfluorenyl, thiofluorenyl, amine Hydrazone, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxy ^ square group, substituted square oxyaryl Group, cyano, _ atom, hydroxyl, nitro, carboxyl, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyl Heteroaryl, Carboxy-Substituted Heteroaryl, Carboxa-70- This paper size is applicable to China National Standard (CNS) A4 (2ΐ〇χ 297mm) 534910

Λ7 FP Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention Ring group, carboxy-substituted heterocyclic group, ring 梡, put as P t ,,,, & Guanidyl, guanidyl, sulfonyl, substituted methanthyl, postaryl, substituted thioaryl, thiocyclic pit, substituted thiocyclofluorenyl, thioheteroaryl, substituted thioheteroaryl, Sulfur ring, substituted heterocyclyl, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, protoxy, substituted cyclopentyloxy, heteroaryloxy, substituted Fluorenyloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxothioamino, _called 0) 2-alkyl, _〇s (〇) 2_ substituted alkyl,- os (0) 2-aryl, _0S (0) 2-substituted aryl, _〇s (〇) 2-heteroaryl,-(^ (〇) 2-substituted heteroaryl, -05 (〇) Cyclic group, -0S (0) 2 · substituted heterocyclic group, -0s〇2_NRR where R is hydrogen or aryl, -nrs (o) 2-alkyl, -NRS (0) 2-substituted alkyl , NRS (〇) 2 aryl, -NRS (O) 2-substituted aryl, -NRS (〇) 2-heteroaryl, -nrs (〇) 2- substituted heteroaryl, -NRS (O) 2- Cyclic group, —NR s (〇) 2 —substituted heterocyclic group, —NRS (0) 2-NR-alkyl, —nrs (0) 2-NR—substituted alkyl, —NRS (0) 2-NR_ aromatic , -NRS (0) 2-NR_ substituted aryl, -NRS (Q) 2-NR_heteroaryl, ~ NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR- Heterocyclyl, -NRS (0) 2-NR-substituted heterocyclyl, where R is hydrogen or alkyl, --- and di-alkylamino, mono- and di-substituted alkylamino, -And di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic Amines, mono- and di-substituted heterocyclylamines, asymmetric disubstituted amines with different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Heterocyclic groups and substituted heterocyclic groups, and substituted alkynyl groups have amine groups, such as B 0c, C bz, formamidine and other blocking groups, or block -71 This paper size applies Chinese national standards (CNS ) A4 size (210X297mm) ---------— (Please read the notes on the back before filling this page)

、 1T -line-printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ "? ______________}] 1 5. Description of the invention (69)-One base / substituted alkynyl group is replaced by -S Ο2 -alkyl, -S Ο2- Alkyl, _s 〇2 _alkenyl S 〇2-substituted ~ group '-S 〇2-eryl' -S Ο 2-substituted environmental group, -S 〇 2 -aryl, -s 〇 2 -substituted aryl -S 02-heteroaryl, -S 02-substituted heteroaryl, -S 0 2 -heterocyclyl, -S 0 2 -substituted heterocyclyl, and -s 0 2 -NRR substituted 'this Where R is a gas or a radical. "Cycloalkoxy" represents -0-cycloalkyl. "Substituted cycloalkyl" represents -0- substituted cycloalkyl. "Guanyl" represents -NRC (diNR) NRR, _NRC ( = NR) NR_alkyl, -NRC (= NR) NR-substituted alkyl, -NRC (diNR) NR-fluorenyl, -NRC (= NR) NR-substituted alkenyl, -NRC (= NR) NR- Bulk, -NRC (= NR) NR · substituted alkynyl, -NRC (= NR) NR-aryl, -NRC (di-NR) NR-substituted aryl, -NRC (di-NR) NR-cycloalkyl, -NRC (= NR) NR-substituted cycloalkyl, -NRCpNEONR-heteroaryl, -NRC (= NR) NR-substituted heteroaryl, -NRC (= NR) NR · heterocyclyl, and -NRC (= NR) NR-substituted heterocyclic groups, where each R is hydrogen and alkyl, and one of the amine groups is blocked by conventional blocking groups such as B 0c, C bz, formamyl, and the like. Group, substituted alkyl, alkoxy, fluorenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero The definition of cyclic group and substituted heterocyclic group is as follows: "guanidino" means -NRC (di-NR) NRS02-alkyl, -NRC (= NR) nrso2-substituted alkyl, -nrc (di-nr) nrso2-alkenyl , -Nrc ( = nr) nrso2-substituted alkenyl, -NRC (di-nr) nrso2-alkynyl, -nrc (= nr) nrso2-substituted alkynyl, -nrC (= NR) NRS02-aryl, -NRC (= NR)- 72- _-The standard of this paper is applicable ^ Standard ^ Can see the standard 料 ^ ^ mm) ^ --------- ^ w— (Please read the precautions on the back before filling this page)

Line 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Η1 V. Description of Invention (%)

NRSO2-substituted aryl, -NRC (= NR) NRS02-cycloalkyl, -NRC (di-nr) nrso2 · substituted cycloalkyl, -nrc (= nr) nrso2-heteroaryl, -NRC (= NR) NRS02 -Substituted heteroaryl, -NRC (= NR) NRS〇2 · heterocyclyl, and -NRC (= NR) NRS02_ substituted heterocyclyl, where each R is hydrogen and alkyl, and alkyl in it, Substituted alkyl, alkoxy, alkenyl, substituted fluorenyl, block, substituted decyl, cyclohexyl, substituted cyclomorphyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl And substituted heterocyclyl are as defined. "Halogen" or "halogen" means fluorine, chlorine, bromine and rhenium, and preferably chlorine or bromine. "Heteroaryl" means an aromatic carbocyclic ring containing 2 to 10 post atoms and 1 to 4 hetero atoms selected from oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups can be monocyclic (such as pyridyl or furyl) or multiple fused rings (such as indolyl or phenylfluorenyl). Preferred heteroaryl groups include p-pyridyl, various radicals, tasting radicals and succinyl radicals. "π-substituted heteroaryl" means a heteroaryl group which may be substituted with 1 to 3 substituents, and these substituents are selected from the group consisting of hydroxyl, fluorenyl, fluorenylamino, thiolamino, fluorenyloxy, alkyl , Substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, fluorenyl, alkyl fluorenyl, thiocarbenyl, amine, amine fluorenyl, amine Fluorenyloxy, aminofluorenylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted alkoxy, heteroaryloxy, Substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, alkyl, multiple alkyl, quasi-substituted alkyl, polycyclic fe, ki-substituted cycloalkyl, aryl, ki-substituted Base, several hetero aromatic -73- This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) --------- I (Please read the precautions on the back and save this page)

1T chain 534910 A7 V. Description of the invention 71 Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs H substituted heteroaryl H heterocyclyl' ^ substituted heterocyclyl, chloramine, cyano, thiol, weyl, substituted Alkenyl, thioaryl, substituted thianthioenyl, substituted thiocyclohexyl, thioheterocyclyl, substituted thioheterocyclyl, cycloalkyl, substituted cycloalkyl, guanidyl, guanidino, hydrazone Pro +, nitro, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , Substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, · S (〇) 2 -alkyl,-s (〇) 2 -substituted alkyl, · S (0) 2- Cycloalkyl '-S (0) 2 -substituted cycloalkyl, -s (〇) 2 -alkenyl, -S (0) 2 -substituted fluorenyl, -S (0) 2 -aryl, _ s ( 〇) 2-substituted aryl, · S (0) 2 -heteroaryl '-S (0) 2 · substituted heteroaryl, -S (〇) 2 -heterocyclyl' -8 (0) 2_ substituted Heterocyclyl, -08 (〇) 2-instyl, -0s (〇) 2-substituted alkyl, -0 S (0) 2 -aryl, -0 S (0) 2_substituted aryl, -0s (〇) 2 -heteroaryl, -0 S (0) 2 -substituted heteroaryl, -0 s (0) 2 -heterocyclyl, -0S (0) 2- Substituted heterocyclyl, -0S (0) 2_NRR where R is hydrogen or alkyl, -NRS (0) 2-morphyl, -NRS (0) 2-substituted tigeryl, -NRS (0) 2-aryl , -NRS (0) 2-substituted aryl, -nrs (o) 2-heteroaryl, -nrs (o) 2-substituted heteroaryl, --nrs (o) 2-heterocyclyl, -nrs ( o) 2-substituted heterocyclyl, -nrs (o) 2-nr-alkyl, -nrs (o) 2-nr-substituted alkyl, -nrs (o) 2nr-aryl, -nrs (o) 2 -nr_ substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl, -NRS (〇 ) 2-NR-substituted heterocyclyl, where R is hydrogen or alkyl,-and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamine Base, mono- and di-substituted arylamine-74- This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) # ^ 11 (Please read the precautions on the back before filling this page} 、-= Mouth line 534910 Λ7 ____ B * 7 V. Description of the invention (72) Earth, mono- and di-though arylamino, mono- and di-substituted heteroarylamino, mono- Di-heterocyclylamino, mono- and di-substituted heterocyclylamine, asymmetric disubstituted amines with different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, heterocyclyl and substituted heterocyclyl, and amine substituted aryl groups are blocked by conventional blocking groups such as B 0c, [bz, formamidine, etc., or substituted with -OSaNRR, here R is hydrogen or alkyl. 4aryloxy, which represents -o-heteroaryl, and "substituted heteroaryloxy" represents -o.substitued heteroaryl. "Heterocyclic" or "heterocyclic" means a saturated or unsaturated monocyclic or polycondensed ring containing one to four carbon atoms and four to four heteroatoms selected from nitrogen, sulfur, or oxygen Group, where one or more rings in the fused ring system may be aryl or heteroaryl. "Saturated fluorene" means that any ring is unsaturated (e.g. carbon-carbon unsaturated, carbon-nitrogen unsaturated, A nitrogen-nitrogen unsaturated, etc.) heterocyclic ring consisting of single or multiple fused rings. "Unsaturated heterocyclic group" means that any ring has unsaturated degree (such as carbon-carbon unsaturated, carbon-nitrogen unsaturated, nitrogen-nitrogen unsaturated, etc.) consisting of single or multiple fused rings Non-aromatic heterocycle. "Substituted Heterocyclyl" printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs means that heterocyclyl can be substituted with 3 to 3 substituents. These substituents are selected from the group consisting of oxo (20) and thiol. ), Alkoxy, substituted alkoxy, fluorenyl, fluorenylamino, thiocarbonylamino, fluorenylamino, fluorenyl, alkylfluorenyl, thiofluorenyl, aminefluorenyl, aminecarbonyl Amine, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, hydrazone -75- This paper size applies to Chinese national standards ϋ) a4 size (210X297 mm) 534910 R · 7 V. Description of invention 73 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, hydroxyl, nitro, carboxyl, carboxyalkyl Bis-substituted alkyl, carboxy-cycloalkyl, di-substituted cycloalkyl, carboxyaryl, bis-substituted aryl, hexaaryl, carboxy-substituted heteroaryl, carboxyheterocyclyl, carboxy-substituted Heterocyclyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidino, mercapto, thioalkyl, substituted thioalkyl, thioaryl, substituted sulfur Group, thiolane, substituted thiocycloalkyl, hard heteroaryl, substituted thioheteroaryl, thioheterocyclyl, substituted thioheterocyclyl, heteroaryl, substituted aryl 'substituted heteroaryl' heterocycle , Substituted heterocyclyl, environmental oxygen, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamine Group, -0 S (Ο) 2 -meryl, -0s (Ο) 2 -substituted alkyl, -0s (〇) 2 -aryl, • OS (0) 2-substituted aryl, -0s (o) 2-heteroaryl, _08 (0) 2-substituted heteroaryl, -0S (0) 2-heterocyclyl, -0S (0) 2-substituted heterocyclyl, NRR where R is hydrogen or Pit group,-] \ ^ 8 (〇) 2-Tigeryl, -nrs (〇) — substituted alkyl, -nrs (o) 2-aryl, -NRS (0) 2-substituted aryl, -NRS ( 0) 2-heteroaryl, -NRS (0) 2-substituted heteroaryl, -nrs (0) 2-heterocyclyl, -NRS (O) 2 -substituted heterocyclyl, -n R s (O) 2-n R -morphyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR_aryl, -nrs (0) 2-nr-substituted aryl, -nrs (o) 2-nr-heteroaryl, -nrs (o) 2-nr-substituted heteroaryl, -NRS (0) 2-NR-heterocyclyl, -NRS (0) 2-NR-substituted heterocyclic Group, where R is hydrogen or alkyl, mono- and mono-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino'mono- and mono-substituted aromatic Amino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclylamino, mono- and di-substituted heterocyclylamino, Asymmetric disubstituted amines with different substituents are selected from alkyl groups, -76- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page}

、 1T f Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 hi —_______-74 ~ ---______________________...._______ V. Description of the invention () Substituted alkyl, Wanji, substituted aryl, heteroaryl , Substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and substituted alkynyl have an amine group blocked by conventional blocking groups such as Boc, Cbz, formamyl, etc., or alkynyl / substituted alkynyl substituted with _ 8〇2_alkyl'-S02-substituted alkyl, -s02-alkenyl, -soy substituted fluorenyl, -so2-cycloalkyl, -sor substituted cycloalkyl, -s〇2_aryl Group, _s〇2 · substituted aryl '-S 0 2 -heteroaryl, -s 〇 2 -substituted heteroaryl, -s 〇 2 · heterocyclyl' -SO2 • substituted fluorene ring group, and -S〇2_NRR Substitute, where R is hydrogen or aryl. Examples of heterocycles and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, arbitrary, arbitrary, pyrimidine, daquan, vermidol, vermidol, indole, indoline, indole Azole, purine, quinoline, isoquinoline, quinoline, phthaloline's naphthylpyridine, quinoline, quinazoline, oxoline, pteridine, carbazole, carboline, phenanthrene, acridine 'phenanthroline , Isopyrazole, phenoxen, isoxazole, phenoxen, phenoxen, imidazolidine, imidazoline, hexahydropyridine, hexahydropyridox, oxin 'g big imine, 1, 2, 3 , 4 _tetrahydroiso4line, 4,5,6,7-tetrahydrophenylhydrazone [b] pyrimidine, pyrimazole, oxazolyl, fluorene, phenylhydrazone [b] fluorene, morpholine, sulfur? Phenyl, hexahydropyridyl, pyrrolidine, tetrahydrofuryl and the like. "Saturated substituted heterocyclyl" means a substituted heterocyclic ring consisting of a single or multiple fused rings with any degree of unsaturation (such as carbon-carbon unsaturated, carbon-nitrogen unsaturated, nitrogen-nitrogen unsaturated, etc.). "Unsaturated substituted fluorene ring group" means that any ring has unsaturation (such as carbon · carbon unsaturated, carbon-nitrogen unsaturated, nitrogen-nitrogen unsaturated, etc.), a single or multiple fused groups (non-square family) Substituted hetero. Ring. "Heterocyclooxy" means · 〇 · Heterocyclyl and "substituted heterocyclooxy" means _ 〇 • Take ______ 一 _77_} Paper size suitable for money _ Jiaxian (Please read the back (Please fill in this page again)

, 1T 3349ΐ〇

A V. Description of the invention 75 Substituted heterocyclic group printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. "'Substituted alkylcarbonylamino" means · NΗC (O) -substituted graft.' 'Yingyl "means -SS. "Sulfanyl '" represents -S-alkyl. "' Substituted sulfanyl" represents S-substituted alkyl. "Sulfur 5-methyl" refers to -S-cyclopit. "'Substituted thiocycloalkyl" refers to -s-substituted cycloalkyl. "Sulylaryl" means -S-aryl and "substituted thioaryl" means -s-substituted aryl. "Thioheteroaryl" means -S-heteroaryl, and "substituted thiaaryl" 'Represents -s-substituted heteroaryl. `` Thioheterocyclyl' indicates -S-heterocyclyl, and "substituted thioheterocyclyl" indicates -s-substituted heterocyclyl. '' Pharmaceutically acceptable salts '' Represents a pharmaceutically acceptable salt of a compound of formula I, these salts are derived from a variety of organic and inorganic counter ions well known in the industry, including, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc .: and equivalents When containing functional groups, it includes organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. Preparation of the compound The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that when listing typical or better process conditions (ie reaction temperature, time, reactant mole ratio, solvent, pressure, etc.), unless Otherwise specified, otherwise other process conditions can also be used. Optimal reaction conditions Please read the back with the use of C Notes on Jiang Complete this page)

• I 78- 534910

Λ / IP V. Description of the invention 76 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs < Specific reactants or agents change, these chromium strains can be obtained from this temple can be determined by the optimization procedures of borrowers. : In addition, if it is obvious to those in the industry, it is necessary to be familiar with fluorenyl groups to prevent certain functional groups from performing undesired reactions. Appropriate protecting groups for various functional groups and appropriate conditions for the protection and deprotection of specific energy groups are well known in the industry. For example, various protecting groups are described in Protecting Groups for Organic Synthesis by T. W. Greene and G. M. Wuts, 2nd Edition, Wiley Corporation, New York, 1991, and references cited therein. In addition, the compounds of the invention typically contain one or more optically active centers. Thus, if desired, these compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as a mixture of stereoisomers. Unless otherwise indicated, all such stereoisomers (and rich mixtures) are included within the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reactants well known in the industry. In addition, racemic mixtures other than these compounds can be separated using, for example, optically active column chromatography, optically active optical separating agents, and the like. In the synthesis method of Che Fujia, compounds of formula Ϊ and ϊ A where Q is-(〇) N R 7-are prepared by first coupling amino acid of formula II: R3 R2 ~ nh-ch-cooh

II (Please read the notes on the back before filling this page)

、 1T -79- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) 534910 A? V. Description of invention 77 where R, R, and R4 are as defined above, and formula III sulfonase, chlorine R 】 -So2-ci

III where R1 is as defined above, and a formula of 1VN-as aminoamino acid is obtained

R3 I Rl-S02-N (R2) -CH-COOH

IV Lu Piyi-(Please read the precautions on the back before filling out this page) where rLr3 is defined as before. This reaction is typically carried out via an amino acid of formula II with a minimum of 1.1 to about 2 equivalents of sulfonium gas in an inert diluent such as two: ^, preferably about the same. Usually the reaction is at about -7OX: to about 40 ° C for 24 hours. Preferably, such reverse editing is performed in the presence of an acid produced by the reaction. Suitable bases include, for example, third amines such as diethyl q * isopropylethylamine, N.methyl? 4 and the like. In addition, a pseudo-aqueous solution, such as hydrogen and the like, is used as the test y under anti-cycline type reaction conditions. When the reaction is completed, the obtained N-sulfoamidoamino acid and the V series of fluorene are known as neutralization, extraction, precipitation, chromatography, filtration, and recovery. The amino acid of formula U used in the above reaction may be a known compound or a compound prepared from a known compound by a conventional synthetic procedure. Appropriate amines for 7 use A this reaction

Basic acids include but are not limited to L, proline, trans-4, cardiac proline, cis-HL · proline, trans-3 · phenyl-L.proline, cis-3 · phenyl U- 80- This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm)

, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed 534910 5 ~ ..— Amino acids, L- (2-methyl) proline, L-piperidine, L · Acridine-2-carboxylic acid, L-indololine-2-carboxylic acid, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid Acid, L- (5,5-dimethyl) pyrazolidine-4 · carboxylic acid, L-pyrimoline-3-carboxylic acid, glycine, 2-tert-butylglycine, D, l · Phenylglycine, L-alanine, α-methylalanine, n-fluorenyl-L_phenylpropylamine I'L-diphenylalanine 'sarcosine, d, L-phenyl muscle Amino acid, L · aspartic acid β · third butyl ester, L _ glutamic acid γ _ third butyl ester, l-(〇Benzyl) serine so '1 -aminocyclopropanecarboxylic acid, 1- Aminocyclobutane | acid, 丨 aminocyclopentanoic acid (cycloleucine), 1-aminocyclohexanoic acid, L-serine and the like. If necessary, the formula 11 of the amino acid 4 corresponding to carboxylic acid esters such as methyl esters, ethyl acetates, etc. can be used in the aforementioned reaction with sulfonyl chloride III. Subsequently, the ester group is hydrolyzed to a carboxylic acid using conventional reactants and conditions, that is, using an alkali metal hydroxide in an inert diluent such as methanol / water to obtain N-sulfonamido acid. Similarly, the sulfonyl chloride of formula III used in the foregoing reaction is either a known compound or a compound that can be prepared from a known compound by a conventional synthetic method. These compounds are typically prepared from the corresponding sulfonic acid, i.e., the compound of formula Rl_SO3H, where Rl is defined as described above using tritradiated tritium or pentachloride. The reaction is usually carried out by contacting the acid with about 2 to 5 mole equivalents of trisgas lightly pentachloride, or in a net or inert solvent such as digas methane at a temperature ranging from about 1 to about 48 (rc). The result is obtained in 1 hour. The chlorine of formula m can be prepared from p-based compounds, that is, compounds of formula W-SH. Herein, the meaning is the same as above, and the thiol is treated by using chlorine gas (ci2) and water under conventional reaction conditions. Examples of achievements in the present invention include, but are not limited to, mochi gas, 2-propane scorch, i-buta-silk, phenylgallium chloride, u-phase chlorine, -81-This paper is suitable for Choi Myeon County (CNS) Α4 Specifications (210x ^ 97 公 楚) — —— -------- Clothing ------ Order ------ (Please read the precautions on the back before filling this page) Central Ministry of Economy Printed by the Consumer Cooperatives of the Standards Bureau 534910 Λ7 ------- B1 V. Description of the invention (79) …… One-on-one · 2-Nai% S warm gas' p-benzobenzene performance donkey chlorine, α-toluene performance Chlorine test, 4-Ethylaminobenzylsulfonium chloride '4-methylbenzylsulfenylchloride, 4.Third-butylbenzenesulfonyl chloride, 4 Chlorine, 4-Cyanobenzone chloride, 3,4 · Dichlorobenzite Buy 8 Chlorine'j, 5-dichlorobenzenesulfenyl chloride, 3,4 · dioxobenzoic acid chloride, 5-difluoromethylbenzylsulfonyl chloride, 4_fluorobenzenesulfonyl chloride, 4_fluorenylbenzene Sulfonium chloride '2 -methoxyisopropylbenzenesulfonyl chloride, 4 _methylsulfonylbenzenesulfonyl chloride, 4 _nitrophenylsulfinyl chloride, 4 _sulfanilinobenzenesulfonyl chloride, 4 _three Fluoromethylbenzenesulfonyl chloride '4 -difluoromethoxybenzylsulfonium chloride, 2,4,6 _trimethylbenzenesulfonyl chloride, 2 phenyl ethyl chloride, 2-fluorenylsulfonium chloride, 5 -Chloro-2, phenanthrenesulfonyl chloride, 2,5 -monochloro-4 -sulfonylsulfonyl chloride, 2 _tetrazolesulfonyl chloride, 2 _fluorenyl_ 4 -tetrazolesulfonyl chloride SS 1 -Methyl_4_imidazoliumsulfonyl chloride, 丨 methyl_4_pyrazolesulfonyl chloride, 5chloro1, J —monomethyl-4 -pyrazolesulfonyl chloride, 3 -pyridylsulfonyl chloride, 2 -Pyrimidine sulfonium chloride, etc. If necessary, sulfonium fluoride, sulfonium bromide, or sulfonic anhydride can be used to replace the sulfonium chloride to form the formula IVN-sulfonamido acid. Formula IV N Acid intermediates can also be prepared via the formula v Sulfamidamide: R] -so2-nh'r2 v where R1 and R2 are as defined above and prepared with a carboxylic acid derivative of the formula L (R3) CHCO.R where L is Leaving groups such as chlorine, bromine, and thallium Methanesulfonate, toluate, etc., R3 or R4 are as defined above, and r is hydrogen or a radical. This reaction is typically via sulfonamide V and at least i equivalent, preferably 1.1 to 2 equivalent carboxylic acid The derivative is carried out in the presence of a suitable base such as triethylamine in an inert diluent such as DMF at a temperature of about 2 4 C to about 37 ° C. for about 0.5 to about 4 hours. (Please read the notes on the back before filling this page)

, 1T f

534910 Λ7 ____________ P .. …… 一 ____ ^… ....______ V. Description of the invention (80) This reaction is described in Zuckermann et al., J. Am. Chem. Soc., 1992, 1 14 , 10646-10647. Preferred carboxylic acid derivatives used in this reaction are α-chloro and α-bromocarboxylic acid esters such as tert-butyl bromoacetate and the like. When a carboxylic acid ester is used in the present reaction, the ester group is subsequently hydrolyzed using conventional procedures to obtain a sulfonylamino acid of formula IV. The compound of formula I is then prepared by coupling the intermediates of formula IvN-sulfonamidoacid with the amino acid derivative of formula VI: 0 r7-nh-ch-c-r6 vt [. VI R5 (Please read the note on the back first Please fill in this page again,-口 # 1 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, where R3-R7 is defined as before. The coupling reaction is typically the use of well-known coupling agents such as methylenedimine and B 〇rP reaction Agent (benzyltriazole _ 1 _ oxo-ginseng (dimethylamino m hexafluorophosphonate), etc .. Suitable methylene diimines include, for example, dicyclohexyl methyldiamine (DCC), W3. Dimethylaminopropyl tomb) _3 Ethylmethylimine (EDC), etc. If necessary, a polymerized and supported form of methylenediimine coupling agent can also be used, as described in tetrahedral letter 34 7685 ( 1 993). In addition, well-known couplings can be used to promote the 'N-saidine diimine, Bu Gang Sanjun and other auxiliary coupling reactions. The coupling reaction is typically performed via a continuous donkey amino acid] to about ^ amount of coupling Mixture, and at least 1 equivalent, preferably to about 1 base acid derivative VI in an inert diluent such as Ergu Tianliyue Nu Li, appearance, chloroform, acetonitrile Four 83- This paper is suitable for the size of the paper _Jiaxian (CNS) 'grid (210x1 ^^> 349l〇Λ · \ Υ 5. Description of the invention (81 Hydrogen, N, N-dimethylformamide, etc. In general, the reaction is performed at a temperature of about 0π to about 37 ° C for about 12 to about 24 hours. When the reaction is completed, the compound of formula j is recovered by conventional methods including neutralization, extraction, precipitation, and chromatography. In addition, the N-fluorene amino group I v can be converted into halogen, halogen compounds coupled with amino acid derivatives vi to obtain compounds of formula I. The price of formula VI can be via VI and inorganic acid halides such as sulfur醯 Chlorine, phosphorus trichloride, phosphorus tribromide, or phosphorus pentachloride, or preferably contacted with grass chloride under conventional conditions. Usually this reaction uses about 5 to 5 mole equivalents of inorganic acid hydrazone or grass Krypton gas, either neat or in an inert solvent such as methane or carbon tetrachloride, is performed at a temperature of from about 8 to about 80 ° C for a time of from about i to about 48 hours. A halogenating agent such as N, N-dimethylformamide Amidoamine may also be used in this reaction. Then the N-sulfoamido acid is contacted with at least 1 equivalent, preferably about "to about 1.5 equivalents of the amino acid derivative VI in an inert diluent such as dichloride The alkane is at a temperature of about -7 ° C to about valence temperature for about 丨 to about μ hours. It is preferred that the reaction is performed in the presence of a general test, and the acid generated during the reaction is removed. Suitable tests include, for example, tertiary amines. , Such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc. In addition, the reaction can be tested in an aqueous solution such as sodium hydroxide, etc. " Dry and used by employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative (please read the notes on the back before filling this page) φ When the reaction is completed, the compound of formula I can be recovered by metallurgical methods including neutralization, tritium + extraction,> jidian, chromatography, filtration Wait. In addition, compounds of formula I may also be derived from the diamino acids of formula VII which are first formed. Paper ruler _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A7

—__________ FP V. Description of the invention (82) R3 R7 〇 R2-NH-CH-C (0) N-CH-C ~ R6

* I R5 where R2, R3 and-R7 are as defined above. The formula γ [diamino acid derivative is easy to use the two amino coupling technology and reagents such as hydrazine imines, Β 〇 P reactants, etc. as described in the aforementioned coupling formula 11 amino acid and formula v 11 Preparation of amino acid derivatives. The diamino acid VII is then sulfonated using sulfonyl chloride of formula III and using the aforementioned synthesis procedure to obtain a compound of formula I. The amino acid derivative of formula VI used in the foregoing reaction is either a known compound or a compound that can be prepared from a known compound by conventional synthetic procedures. For example, amino acid derivatives of formula VJ can be prepared via the use of alkyl or substituted alkyl halides c-alkylation of commercially available 2-ethylammonium malonic acid diethyl ester (Aldrfch, Milwaukee, Wisconsin, USA). The reaction is typically carried out using at least 1 equivalent of sodium ethoxylate and at least 1 equivalent of alkyl or substituted alkyl halides under reflux ethanol treatment. 2. Ethylaminomalonate diethyl ester @ Purpose calendar about 6 to about 12 hours get on. The resulting c-calcined malonate is then deacetylated, hydrolyzed, and decarboxylated by heating the aqueous hydrochloric acid solution at reflux for about 6 to about 12 hours to obtain an amino acid, which is typically a hydrochloride. Examples of amino acid derivatives of the formula VI suitable for the aforementioned reaction include, but are not limited to, L-4 methylnitrophenylalanine, methyl L-lanine, D, L-high_4-nitrophenylpropylamine Methyl esters, L-(0-fluorenyl) tyrosine methyl esters, L-3,5-dibromotyrosine methyl esters, L · 3-iodotyrosine methyl esters, and the like. Of course, if necessary, also -85- This paper size applies Chinese National Standard (CNS) A4 specification (210X297mmΊ '-(Please read the precautions on the back before filling this page)

534910 Λ * Β. V. Description of the Invention 83 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Other esters or amines of the aforementioned compounds can be used. For easy synthesis, the formula: [Compounds are typically prepared as esters, that is, γdialkoxy or substituted alkalyl groups, etc. here. If desired, the ester group can be hydrolyzed using conventional strips and reactants to obtain the corresponding carboxylic acid. Typically this reaction is carried out by using at least one equivalent of an alkali metal hydroxide such as lithium, sodium or potassium hydroxide in an inert state: the ester is treated with a methanol or water mixture at a temperature of about 0 to about 2 4 π, It takes about 1 to about 24 hours. In addition, the benzyl ester can be removed by hydrogenolysis using a palladium catalyst such as palladium / carbon. If desired, the resulting carboxylic acid can be coupled to amines such as β-alanine ethyl esters, hydroxylamines such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as 0-methyl Hydroxylamine, oxamidylhydroxylamine, and the like are carried out using the aforementioned conventional coupling agents and conditions. As is well known to those in the industry, other functional groups present in the substituents of the compounds of formula 丨 can be modified or derivatized using well-known synthetic procedures before or after the Baishu coupling reaction. For example, a nitro group which is a substituent of a compound of formula 丨 or an intermediate thereof can be conveniently reduced by hydrogenation in the presence of a palladium catalyst such as palladium / carbon to obtain the corresponding amine group. This reaction is typically carried out at a temperature of about 201: to about 50x :, in an inert diluent such as methanol for about 6 to about 24 hours. A compound having a nitro group on the & 5 substituent can be prepared, for example, by using a 4-nitrophenylalanine derivative in the aforementioned coupling reaction. In the same way, pyridyl can be hydrogenated in the presence of a platinum catalyst such as platinum oxide in an acidic diluent to obtain the corresponding hexahydropyridyl analog. Generally this reaction can be accomplished by using hydrogen at a pressure of about 20 psi to about 60 pSi, preferably about 40 psi, in the presence of a catalyst, in an acid diluent such as a mixture of methanol and aqueous hydrochloric acid at a temperature of about 20 C to about 50 C temperature treatment of p-biting compounds, which lasts about 2 to about 24 hours into 86- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 'x 297 mm ^^ clothing-(Please read the precautions on the back first) (Fill in this page again)

， 1T f Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ———— B1 V. Description of the invention (84) Ⅰ ~ —————— · １１-仃. Pyridinyl-containing compounds can be conveniently prepared using, for example, β_ (2_pyridyl) _, β _ (> pyridyl)-or β- (4-pyridylb-L-alanine derivatives in the aforementioned coupling reaction ... In addition, when the R5 substituent of the compound of formula I or its intermediate contains the first or:-amine group, these amine groups can be derivatized before or after the aforementioned coupling reaction to obtain, for example, amidine, chloramine, , Thiourea, urethane, second or monoamine, etc. Compounds in which the R 5 substituent contains the first amine group can be prepared, for example, by reduction of the corresponding nitro compound. In addition, such compounds can be produced by using From the free text, 4-aminobenzyl alanine and the like amino acid derivatives of formula v] are prepared in the aforementioned coupling reaction. For example, 4, the compound of formula I or an intermediate thereof has a first or second amine. The substituents of the group, for example, in which R5 is (4-aminophenyl) methyl, can be conveniently N _ hydration to obtain the corresponding fluorene amine using conventional Ionization and conditions. This type of reaction is typically used by At least 丨 equivalents, preferably about ii to about i 2 equivalents of carboxylic acid to a coupling agent such as formamidine, a BOP reactant Benzotriazolyloxy_ ginseng (monomethylamine) hexafluorophosphonate) etc. in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N_dimethylamidamine The treatment of the amine-based compound at a temperature equal to about 0 C to about 37 ° C is performed for about 4 to about 24 hours. It is preferred to use an accelerator such as N-hydroxybutanediimide, 丨 hydroxybenzotriazole, etc. Examples of carboxylic acids suitable for the reaction include, but are not limited to, N-third butoxycarbonyl glycine, N_third butoxycarbonyl_L_phenylalanine, N_third butoxycarbonyl- L-aspartic acid benzyl ester, behenic acid, N-third butoxycarbonyl isopiperidinic acid · [3] 'N -methyl isopiperidinic acid called · 3], n-third butoxycarbonyl piperidine Acid _ ____87_ I Paper Standard Applies to Zhongguanjia Standard (CNS) A4 Specification (2ω > α97) Chu 1-(Please read the precautions on the back before filling out this page), 1T 0 Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Printed 534910 Λ] —______… — V. Description of the Invention (85) One ... One ^ [3] 'N -Second butoxyfluorenyl-L -tetrahydroiso 4-leaching-3 -antimonic acid, N-( Toluene_ 4-continued ) -L-proline and the like: In addition, the compound of formula I or its intermediate containing the first or second amine group can be produced by using SS halide or multiple parent gf N-s to generate the corresponding si amine. This reaction Typically at least 1 equivalent, preferably from about 1.1 to about 1.2 equivalents of amidine or carboxylic anhydride in an inert diluent such as dichloromethane via an amine compound at a temperature ranging from about 700 to 400 It is carried out to about 24 hours. If necessary, a tritiation catalyst such as 4- (N, N-diamidoamino) pyridine can be used to promote the tritiation reaction. The tritiated reaction is better than carried out in the presence of appropriate tests, and tritiated scavenges the acid produced by the reaction. Suitable tests include, for example, secondary amines such as triethylamine, diisopropylethylamine, N-fluorenylmorphine, and the like. In addition, the reaction can be carried out using an aqueous alkali solution such as sodium hydroxide or the like under conditions of the Shawton Bowman type. Examples of halogens and meta-anhydrides suitable for this reaction include, but are not limited to, 2-methylpropanyl chloride, trimethylacetylsulfonyl chloride, phenylethylsulfonyl chloride, benzene trifluoride, 2-bromobenzyl chloride, 2 -Methyl benzamidine chloride, 2-trifluoromethyl benzamidine chloride, different from alkali ammonium chloride, nicotine ammonium chloride, piperidine ammonium chloride, acetic anhydride, succinic anhydride, etc. Aminoformamidine chlorides such as N, N-dimethylaminoformamidine chloride, N, N-diethylaminoformamidine chloride, etc. can also be used in this reaction to provide ureas. Similarly, urethanes can be provided by using dicarbonates such as di-tert-butyl dicarbonate. In a similar manner, a compound of formula I or an intermediate thereof containing a first or second amine group can be sulfonated by N · sulfonation using sulfonium or sulfonic anhydride. The sulfonium and sulfonic anhydrides suitable for this reaction include, but are not limited to, methanesulfonyl chloride, chlorosulfonium chloride, p-toluene chloride, SS chloride, and trifluoromethane acid fiber. In the same way, amines such as dimethylaminosulfonyl chloride can be used to obtain chloramines (for example> N _ -88- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ( (Please read the notes on the back before filling out this page)

T 49 3 5 ο A "? B * 7 The invention description (S〇2-N <) printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 0 In addition, the first of the substituents present in the compound of formula I or its intermediates And the second amine group can be reacted with isocyanate or thioisocyanate to obtain urea or thiourea. This reaction is typically carried out by contacting an amine compound with at least one equivalent, preferably from about ii to about 1.2 equivalents of an isocyanate or thioisocyanate in an inert diluent such as toluene at a temperature of about 2 4 ° C to about 37 ° C over a period of about 1 2 To about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are conveniently prepared by reacting a suitable amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, isocyanate 2-phenylethyl cyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3_phenylisocyanate 3-(N, N -diethylamino) propanine, phenyl thioisocyanate, benzyl thioisocyanate, 3-p-pyridine thioisocyanate, glorine isothiocyanate (Isomer I) and the like. In addition, when the compound of formula I or an intermediate thereof contains a first or second amine group, the amine group can be reduced and calcined using an aldehyde or ketone to form a second or third amine group. This reaction is typically performed via an amine compound and at least 1 equivalent, preferably about 1.1 to about 1.5 equivalents of an aldehyde or ketone, and a metal hydride reducing agent such as sodium cyanoborohydride based on the amine compound at least i equivalent. An inert diluent such as methanol, tetrahydrobutan 'and its mixture is equal to a temperature of about 0 ° C to about 50 ° C for about 1 to about 72 hours. Aldehydes and ketones suitable for use in the present invention include, for example, benzoic acid, 4-chlorobenzoic acid, valeric acid and the like. -89- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page), v " 534910 A7 ---------- 扪V. Description of the invention (87) — — — — — ~~-(Please read the notes on the back before filling this page) In a similar manner, when the compound of formula I or its intermediate has a hydroxyl-containing substitution In the case of hydroxyl groups, the hydroxyl group can be further modified or derivatized before or after the aforementioned coupling reaction to provide, for example, ethers, urethanes, and the like. The compound having a hydroxyl group on the R5 substituent can be prepared, for example, by using the amino acid derivative of formula V] derived from tyrosine and the like for the aforementioned reaction. For example, the compound of the formula I having a hydroxy-containing substituent or an intermediate thereof, for example, wherein R5 is a (4-hydroxyphenyl) fluorenyl group, can be conveniently alkylated to form ethers. The 0-calcination reaction is typically carried out by contacting a hydroxy compound with an appropriate alkali or alkaline earth metal base such as potassium carbonate in an inert diluent such as acetone, 2-butanone, etc. to form an alkali or alkaline earth metal salt of a hydroxyl group. Such salts are usually not isolated, but are reacted in situ with at least one equivalent of an alkyl or substituted alkyl- or sulfonate such as an alkyl chloride, bromine, iodine, methanesulfonate or tosylate to obtain an ether. The reaction is usually carried out at a temperature of about 60 ° C to 150 ° C for a time of about 24 to about 72 hours. Preferably, when alkyl chloride or bromine is used in the reaction, a catalytic amount of sodium iodide may be added to the reaction mixture. Examples of alkyl or substituted alkyl hydrazones and sulfonates suitable for this reaction are printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, including but not limited to bromoacetic acid, second butyl vinegar 'N-third butyl chloroethyl amine, 1 -Bromoethylbenzene, alpha-bromophenylethyl acetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) ethyl chloride, 2- (N, N-diisopropylamino) ethyl chloride '2-((N, N-dibenzylamino) ethyl chloride, 3-((N, N_ethylamino)) propyl chloride, 3-(N-benzyl-N-methylamino) propyl chloride, N- (2-chloroethyl)? 4,2- (hexamethyleneimino) ethyl chloride, 3-(N -Methyl hexahydrogen ρ) propyl gas '1- (3 -Gastyloyl) -4- (3 -gaspropyl) hexazine ratio ^ well' 2- (4- -4-Phenyl X rat p specific bite) Ethyl gas' N-Brother tributoxy post-base than lake -90- This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) ~ — Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printing 534910 V. Description of the invention (88) Monomethyltoluene acid g etc. In addition, the hydroxyl group of a substituent present in the compound of the formula I or an intermediate thereof can be reacted with Mhsunobu to perform alkylation. In this reaction, alcohols such as 3- (N, N-dimethylamino) -1 -propanol and the like with about 10 to about 13 equivalents of triphenylene 'and about 1.0 to about 1. j 当 漫Diethyl azodiacidic acid is intended to react with an inert diluent such as tetrahydrofuran at a temperature of about · 10 X to about 5 X: about 0.25 to about 1 hour. Then about 1.0 to about 1.3 equivalents of a compound such as methyl N-tert-butylbutyrimate is added, and the reaction mixture is stirred at about 0X: to about 30X: temperature for about 2 to about 48 hours to obtain O-alkylation. product. In the same manner, a compound of formula 丨 containing an aryl hydroxyl group or an intermediate thereof is reacted with aryl iodide to obtain a diaryl ether. Generally, this reaction is carried out by using a suitable base such as sodium hydride in an inert diluent such as xylenes to form an alkali metal salt of a hydroxyl group at a temperature of from about 25 ° F to about 10 °. The salt is then treated with about 5 to about 5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature of about 0 to about 30 for about 0.5 to about 2.0 hours, followed by about 1 to about 5 Equivalent aryl iodide, such as sodium 2-iodobenzoate. The reaction is then heated to about 70 π to about 150 π over about 2 to about 24 hours to obtain a diaryl ether. In addition, hydroxy-containing compounds can also be conveniently derivatized to form aminophosphonates. In this method for the preparation of methylformate, a hydroxy compound of the formula or its intermediate is contacted with from about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent such as dichloromethane at about -2 5 C to about 0 ° C temperature for about 05 to about 20 hours. The resulting carbonate is treated with an excess of preferably about 2 to about 5 equivalents of a trialkylamine such as triethylamine for about 0.5 to about 2 hours, followed by treatment with about 0 to about 15 equivalents of the first or second amine to obtain the aminomethyl ester. Acid ester. Examples of amines suitable for this reaction include but ___________-91 _ This paper size applies to Chinese national standards (CNS format (2ι〇χ 297 mm)) ----- (Please read the precautions on the back before filling this page

、 1T t 534910 Λ7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, and printed description of the invention (not limited to hexamethylpyridine ,, -methylhexahydropyridine, buhexylhexahydropyridine, morpholine, sulfur Phenol, pyrrolidine, hexahydropyridine, etc. In addition, in another method for the production of amino formic acid, the compound is contacted at about 1.0 to about 1.5 equivalents of aminoformamidine in an inert diluent such as dichloromethane at about 25.0 to The temperature is about 70X for about 2 to about 72 hours. Typically this reaction is performed in the presence of a general test, and the acid generated by the reaction is removed. Appropriate tests include third amines such as triethylamine, diisopropylethyl Amine, N-fluorenylmorpholine, etc. In addition, at least 1 equivalent (based on the hydroxy compound) 4_ (N N_dimethylamino) pyridine is preferably added to the reaction mixture to assist the reaction. Amine groups suitable for the reaction Examples of formamidine gas include, for example, dimethylaminomethane chloride, diethylaminomethane chloride, etc. Similarly, when a compound of formula I or an intermediate thereof contains a first or second hydroxyl group, the hydroxyl group can be conveniently converted Formation of leaving group and replacement to form, for example, amines, sulfides and fluorides. 4 · Hydroxy_1-proline derivatives can be converted to the corresponding 4-amino, 4-sulfur or 4-fluoro-L-proline derivatives by affinity replacement of the hydroxy groups produced by I. Usually used in these reactions In the case of optically active compounds, the stereochemistry of the carbon atoms attached to the derivatized hydroxyl group is decanted. Two of these reactions are typically carried out by treating the hydroxy compound with at least one equivalent of sulfonyl chloride such as p-toluenesulfonyl chloride equal to pyridine. The hydroxyl group is converted to a leaving group such as tosylate. The reaction is usually carried out at a temperature of about 0 to about 70 t for about 1 to about 48 hours. Then the toluene sulfonate is conveniently replaced with sodium azide ' For example, tosylate is contacted with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N, N-dimethylformamide and water, at a temperature of from about 0 to about 37, for about 1 to about 1 2 The corresponding azide compound is obtained in 1 hour. Then the azide-92- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -------------- Order ---- --Φ-- f Please read the precautions on the back before filling in this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 V. Description of the invention The (9Q) ^ ~ ^ group is obtained, for example, by using a palladium / carbon catalyst for hydrogenation to obtain an amine N η 2) compound. By the same token, the tosylate is conveniently substituted with a mercapto group to obtain a sulfide. This reaction is typically carried out via toluic acid and at least 1 equivalent of pyrrolol such as thiophenol in the presence of a suitable base such as 1,8_diazinebicyclo [5.4.0] undec-7_association (DBU) Sulfide is obtained by contacting an inert diluent such as v, N-dimethylformamide at a temperature of about 0 to about 37 ° C for about 2 to about 2 hours. In addition, the tosylate is treated with morpholinylsulfur trifluoride in an inert diluent such as dichloromethane at a temperature of about 0 to C to about 37 C for about 2 to about 24 hours to obtain the corresponding gaseous compound. In addition, a compound of formula I or an intermediate thereof having a fluorenylaryl-containing substituent such as when R3 is (4-iodophenyl) methyl can be conveniently converted into a bisaryl compound before or after the aforementioned coupling reaction. A typical reaction of this type is through the use of about 丨 · to about 2 when f square radicals such as 2- (methoxycarbonyl) phenyl zinc iodide are inert in the presence of a palladium catalyst such as tetrakis (diphenylphosphine) palladium A diluent such as tetrahydrofuran treats the iodoaryl compound at a temperature of from about 2 t to about 30 C until the reaction is complete. Such a reaction is described, for example, in Rieke, j. 0rg chem. 1991, 56, 1445. In some examples, the compound of formula I or an intermediate thereof may contain a substituent having one or more sulfur atoms. Sulfur atoms are present, for example, in the formulas used in the foregoing reactions. Amino acids are derived from L-oxazolidine-rencarboxylic acid, difluorenyl) oxazolidine_4-carboxylic acid, L · morpholine_ 3 _ In the case of carboxylic acids. When a sulfur atom is present, it can be 10,000; the conventional reaction reagents and reaction conditions are used to oxidize the sulfoxide or amidine compound before or after the coupling reaction. Suitable reactants for oxidizing sulfides to sulfoxides include, for example, hydrogen peroxide ' 3-chloroperoxybenzoic acid (McpBA), sodium peroxoate, and the like. The oxidation reaction is typically through contact with sulfide from about 0 95 to about 丨 i amount of oxygen _____—_ _93 · This paper ruler · (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 534910 Λ7 ———__ — h1 V. Description of the invention (91) —... one to one ^ ~ Chemical agent in an inert diluent such as dichloromethane at about -50 ° C to 7 5 ° C temperature for about 1 to about 24 hours. The resulting osmium is subsequently oxidized to the corresponding osmium, and the salty reaction is carried out by contacting the osmium with at least one additional equivalent of an oxidant such as hydrogen peroxide 'MCPBA, potassium permanganate, and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least 2 equivalents and a preferred peroxide. The reaction is described in

March ’’ ’Advanced Organic Chemistry’ 4th edition, pp. 1201-1202, Wiley Publishing House, 1992. As mentioned above, the compound of formula 丨 containing a non-hydrogen R2 substituent can be prepared in the aforementioned reaction using a formula of N · substituted amino acids such as sarcosinic acid, N-methyl-L · phenylalanine and the like. In addition, these compounds can be prepared by N-alkylation of a formula I or IV Si amine (where R2 is hydrogen) using conventional synthetic procedures. Typically this N-calcination reaction is carried out by contacting at least 1 equivalent, preferably 1 · 2 to 2 equivalents of an alkyl or substituted fe halide via sulfonamide in an inert diluent such as acetone, in the presence of potassium nitrate, 2 -Methyl ethyl ketone is equal to about 2 5 X: to about 70 ° C for about 2 to about 48 hours. Self-exemplified alkyl or substituted alkyl groups suitable for use in this reaction include, but are not limited to, stilbeneite. In addition, sulfonamides of formula I or IV in which R2 is hydrogen and R1 is a 2-alkoxycarbonylaryl group can be intramolecularly cyclized to form 1,2-benzidine, iso-3, 3-ketone street organisms or the like . This reaction is typically carried out by treating the sulfonamide such as N · with a temperature of from about 1.0 to about 1.5 equivalents such as alkali metal hydride in an inert diluent such as tetrahydrogenan at a temperature of from about 0 ° to about 30 ° C. ((2-methoxycarbonylphenylsulfonyl) glycinyl-L-phenylalanine benzyl ester over about 2 to about 48 hours to obtain cyclized 1,2-phenylammonium isocyanate-3 -fluorene derivative物 进行. Finally, the compound of formula I in which Q is-C (S) NR7 · can also pass the aforementioned combination -94- This paper is also applicable to the Chinese National Standard (CNS) A4 specification (210 ^ 297 mm clothing order ~ (please first Read the notes on the back and fill in this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 534910 Λ7 _______... one one ___ 92… — V. Description of the invention () Amino thio acid derivatives are used instead of amine groups Acid 11. This amine thio acid derivative can be obtained by Shalaky, et al., J. 0rg Chem 61. 9045-9048 (1996) and Brain, et al., J. Org. Chem., 38. 8-3809 (1997) and the procedures described in the references cited therein. Pharmaceutical Formulations When used in medicine, the compounds of formulae I and IA are usually administered in the form of a pharmaceutical composition. These compounds may be administered orally, Rectal, dermal, subcutaneous, intravenous, intramuscular, and intranasal routes. These compounds are effective as injections and oral, compositions. The compositions are prepared from a well-known formula in the medical field and contain at least one active compound. The present invention Also includes pharmaceutical compositions containing There are one or more of the aforementioned compounds of the formulae I and IA as active ingredients in combination with a pharmaceutically acceptable carrier. In the manufacture of the composition of the present invention, the active ingredient is usually mixed with an excipient, diluted with the excipient or wrapped in such a carrier. Wherein it can be in the form of capsules, kits, papers or other cryogenic forms. When the excipient is used as a diluent, it can be a solid, semi-solid or solid substance 'it is used as a vehicle, carrier or medium for the active ingredient. In this way, the composition can be in the form of a tablet, pill, powder, sublingual tablet, drug pack, bean capsule, elixir, suspension, emulsion, solution, syrup, aerosol (solid or in liquid medium) ), Containing, for example, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile powders, containing up to 10% by weight of active compound. When preparing the formulation, the active compound must be ground before the other ingredients are combined. When the particle size. If the active compound is generally insoluble, it is usually developed to a particle size of less than 200 mesh. If the active compound is generally water-soluble, -95- This paper size applies to Chinese national standards (CN S) A4 specification (210X297 mm) ------ (Please read the notes on the back before filling out this page, 11 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs j ^ 491q A7 __—_____ R1 V. Invention Note (93) '... then the size of the kernels is usually adjusted by grinding to obtain a substantially uniform distribution in the formula, such as about 40 mesh. Several examples of suitable excipients include lactose, glucose, sucrose, sorbus, mannitol , Starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup and methyl cellulose. The formula also includes ... Lubricating 剜 such as talc 'magnesium stearate and mineral oil: wetting agent: emulsifying and suspending agent: preservative such as methyl paraben and propyl ester; sweetener: and flavoring agent. The compositions of the present invention can be formulated using procedures known in the art to obtain rapid, sustained, or delayed release of the active ingredient after administration to a patient. The composition is preferably formulated in a unit dosage form, each dosage containing from about 5 to about! 〇〇 Pico 'is more commonly about 10 to about 30 mg of active ingredient. The term "unit dosage form" Table π is applicable to the human body and other mammals as a single discrete physical unit. Each unit contains an appropriate pharmaceutical excipient that is calculated to obtain the required therapeutic effect to a predetermined amount of active substance. The active compound is effective over a wide dosage range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of the compound to be administered can be determined by the doctor in view of the relevant circumstances including the situation to be treated, the route of administration, the actual compound to be administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms. For preparing solid compositions such as lozenges, the main active ingredients are mixed with pharmaceutical excipients to form a solid pre-formulated composition containing a homogeneous mixture of a compound of the present invention. When these pre-formulated compositions are referred to as homogeneous, it means that the active ingredients are uniformly dispersed in the composition, so the composition can be conveniently subdivided into equally effective 1__ -96 · This paper size applies to Chinese National Standard (CNS) A4 （210x7 ^^ 爱） — -----—— (Please read the notes on the back before filling this page)

534910 A7 R * 7 V. Description of the Invention (94) — printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, such as lozenges, pills and capsules. The solid pre-formulation is then subdivided into the aforementioned unit dosage forms containing, for example, 0.1 to about 500 t grams of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise mixed to obtain a dosage form that provides the benefits of long-lasting effects. For example, a tablet or pill contains an internal ingredient and an external ingredient, and the latter is wrapped around the former. The two components can be separated by an enteric coating, which is used to counteract breakdown in the stomach and allow the internal components to enter the duodenum intact or to be delayed. A variety of materials can be used as enteric layers or coatings. These materials include a variety of polymeric acids and mixtures of polymeric acids in suitable materials such as shellac, cetyl alcohol, and cellulose acetate. The novel compositions of the present invention can be mixed with liquid dosage forms for oral or injection administration including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil or Peanut oil flavored emulsions, tinctures and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions, suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain the aforementioned suitable pharmaceutically acceptable excipients. The preferred combination $ is administered via the oral or nasal respiratory pathway for local or systemic effects. The composition in the preferred pharmaceutically acceptable solvent can be atomized using an inert gas. The nebulizing solution can be directly inhaled by the nebulizing device, or the nebulizing device can be attached to the mask, tent or middle-pressure positive suction breathing machine. The solution and suspension composition is preferably delivered to the device in a suitable manner, and is preferably administered orally or nasally. The following formulation examples illustrate the pharmaceutical composition of the present invention. Recipe Example 1 -97- This paper is again applicable to China National Standard (CNS) A4 specification (210X297mm1 " (Please read the precautions on the back before filling this page) ΦΙ.

Description of the invention ° ^ 491q

IP Prepares hard gelatin capsules with the following ingredients: Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The aforementioned ingredients are mixed and filled into a hard gelatin capsule in an amount of 340 mg. The following ingredients are used to prepare a lozenge formulation: Active ingredient 25.0 Cellulose 'Micro Crystal 200.0 colloidal silica 20.0 stearic acid 5.0 The ingredients are mixed and compressed to form lozenges, each 240 mg of fixed weight. Austrian Example 3 The preparation of dry powder inhalant contains the following ingredients: Ingredient ϋ% _ Active ingredient 5 Lactose 9 5 The active ingredient is mixed with lactose and the mixture is added to the dry powder inhalation tool. Formulation Example 4: Each tablet containing 30 mg of active ingredient is prepared as follows: -98- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) (Please read the precautions on the back before filling in this page)

534910 Η * 7 V. Description of the invention (96) Number of printed matter (mg / ingot) of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 30.0 mg of starch 45.0 mg of microcrystalline cellulose 35.0 mg of polyvinylpyrrolidone (presenting 1 0% solution in water) 4.0 mg sodium carboxymethyl starch 4.5 mg magnesium stearate 0.5 mg talc 1.0 mg total 120 mg active ingredient, starch and cellulose are passed through a No. 20 US sieve and thoroughly mixed. The resulting powder was mixed with a solution of polyvinylpyrrolidone and passed through a No. 16 mesh sieve. The granules so produced are dried at 5 (TC to 60 ° C and passed through a No. 16 US sieve. Then sodium carboxymethyl starch, magnesium stearate and talc (passed through No. 30 US sieve beforehand) are added to the granules, which After mixing, the tablets were compressed in a tablet mill to obtain tablets each weighing 150 mg. Formulation Example 5 Each capsule containing 40 mg of the drug was prepared as follows: Number of ingredients (mg / capsule) Active ingredient 40.0 mg starch 109.0 mg magnesium stearate 1.0 mg A total of 150.0 mg of active ingredients, cellulose, starch, and magnesium stearate were mixed and passed No. 20 (please read the precautions on the back before filling this page) -99- This paper size applies to Chinese National Standards (CNS) A4 specifications (210X 297 mm) 534910 Λ7 B1 V. Description of the invention (97 US sieve and filled with 150 mg of hard gelatin capsules, 1 Example 6 Each suppository containing 25 mg of active ingredient is prepared as follows: The activity becomes 25 mg of saturated fat and acid glycerin. The purpose is to add 2,000 g of the active ingredient through a No. 60 US sieve and suspend it in a small amount of saturated fatty acid glycerides beforehand. The mixture was poured into a suppository mold with a nominal capacity of 2.0 grams and allowed to cool. Formula Example 7 Master batch 5.0 liters of a suspension agent containing 50 crocuses was prepared as follows: Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Active ingredient xanthan sodium carboxymethylcellulose sodium (11%) microcrystalline cellulose (89%) sodium sucrose benzoate perfume and color pure water add to the amount of 50.0 mg 4.0 mg 50.0 mg 1.75 g 10.0 mg An appropriate amount of 5.0 ml of medicine, sucrose and xanthan are mixed, passed through a No. 10 US sieve, and then the pre-made microcrystalline cellulose and sodium carboxymethyl cellulose are mixed in an aqueous solution. Sodium benzoate, spices and colorants are mixed in several amounts. Dilute with water and add with stirring. Then add enough volume to produce the volume required for production. '0 -100- This paper size applies to China National Standard (CNS) A4 specification (210X297) 534910 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs h1 Description of the Invention (98) Formula Example 8 Ingredients Tomb Capsules) Active ingredients: 150 g starch; 407.0 g; magnesium stearate; total g: 42.5 mg; active ingredient, cellulose, starch and hard Magnesium acid was mixed with a US sieve and filled into hard gelatin capsules in an amount of 560 mg. Formulation Example 9 The intravenous formula was prepared as follows: Number of ingredients Active ingredient 2 5 0.0 mg Isotonic saline 1000 ml Formulation Example 10 The topical formula was prepared as follows: Ingredients Quantitative active ingredients: 1-10 grams of emulsified wax, 30 grams of liquid paraffin, and 20 grams of white soft paraffin. Add 100 grams of white soft rock ± heat the rat to dissolve. Liquid paraffin and emulsified wax: Mix until dissolved. Add the active ingredients and keep stirring until the mixture is dispersed until it solidifies. Another preferred formula used in the method of the present invention is used by No. 20 (please read the precautions on the back before filling this page)

1T t _ 101-534910 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (Sticks). These * tablets can be used for continuous or discontinuous infusion of a compound of the invention in a controlled amount via u, ,, 'n, A slices. The structure and use of Zhiyun, Zhiyunle agent transdermal patch is well known in the industry. For example, water trapped t ^ > U.S. Patent No. 5,023,252, issued on June 11, 1991 (also described here for loss, # u ^ ^ 1, + test). Patches are available for continuous, pulsed, or as needed delivery. When the right genus or the right is needed, the pharmaceutical composition can be directly or indirectly introduced to the brain. Direct technique week ^ includes placing a drug delivery catheter in the host ventricle system to bypass the blood-brain barrier. Such an implantable delivery system for delivering biological factors to a specific anaphylaxis region of the body is described in U.S. Patent 5,001,472 (and is incorporated herein by reference). Indirect techniques are generally better than horses, and usually involve potentialization of a drug by converting a hydrophilic drug into a fat-soluble drug formulation composition. Latentization is usually achieved by blocking the hydroxyl, carbonyl, carbamate and primary amine groups present in the drug, thus making the drug more fat-soluble and suitable for crossing the blood-brain barrier. In addition, the delivery of hydrophilic drugs can be enhanced by glandular infusion of hypertonic solutions. Hypertonic solutions can temporarily open the blood-brain barrier. Uses The compounds of the present invention can be used in biological samples to bind VL A-4 (α4 β i integrin), and therefore can be used, for example, for the analysis of VL A-4 samples. In this assay, the 'compound' is bound to a solid support, and a VLA-4 sample is added to it. The V L A-4 amount of the sample can be determined by conventional methods such as analysis using a dislocated EUSA test. In addition, the labeled VLA-4 can be used for competition assays to measure the presence of V L A-4 in the sample. Other appropriate assays are well known in the industry. (Please read the notes on the back and save this page)

、 1T Φ ». -102 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 534910 A? 5. Description of the invention 100, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, some of this invention The compounds have been tested in vivo to inhibit endothelial cells of Bai Yu Hall A-4 mediators, so they can be used to treat VLA.4 mediator I (disease. This temple disease includes mammalian inflammatory diseases such as asthma, Amer's disease, atherosclerosis, Luo, i's mother, Tian Geng 1 Dystrophic dementia, diabetes (including juvenile onset diabetes mellitus), inflammatory gonads, ~ ^;% human disease (including ulcerative colitis and Cohen's disease) ), Sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke and other brain injuries, nephritis, retinitis, 'atopic dermatitis, psoriasis', ischemia and acute white blood cells Vector-based lung injury occurs, for example, in adults with respiratory distress syndrome. The biological activity of the compound of the above formula can be tested and analyzed in a variety of systems. For example, the compound is fixed on a solid surface, and cells that can express VLA_4 are measured. This mode can be used to screen a variety of compounds. Cells suitable for this assay include any white blood cells such as T cells, B cells, monocytes, eosinophils, and basophils that are known to express VLA-4. A variety of white blood cell lines such as Jurkat and U937 can also be used. Test compounds can also test for competitive inhibition of the binding between VLA_4 and VC AM · 1, or VLA-4 and labeled compounds known to bind VLA-4 Such as the binding between the compound of the present invention or the VLA-4 antibody. In these assays, VC AM-1 can be immobilized on a solid surface. VC AM-1 can also be expressed as a recombinant fusion protein with an Ig tail (eg, Ig G) In this way, the binding to VLA-4 can be monitored in immunoassay analysis. In addition, VC AM-1 expressing cells such as activated endothelial cells or VCAM-1 metastasis-infected fibroblasts can also be used. For assay analysis to measure occlusion and brain endothelial cells The ability to adhere is particularly good with the verification analysis described in International Patent Application Publication No. WO 91/05038. The case also states -103- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 2 97 mm) (Please read the notes on the back before filling out this page) Order ΦΙ. 534910 A Η 'V. Invention Description (101 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy for reference. Multiple verification analysis modes Uses assays such as markers to analyze components .: Includes multiple forms. Markers can be well known to those in the industry; the law is binary and can be used in a variety of ways. A wide variety of methods are available: f can be borrowed by several methods-tagging. Most commonly used The detection method may be used for radioactive radiography of tritium, η ,, 14 or 32p labeled compounds. Non-radioactive labeling includes a complexing group, a chemiluminescent agent, an enzyme, and an antibody bound to a labeled antibody as a labeled complex. The selection of the mark is based on the required sensitivity, and it is conjugated with the chemical substance (the customer's ease, stability requirements, and available equipment are determined. Suitable in vivo test modes for the effects of t syndrome on inflammation include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs and primates, as well as other inflammation modes associated with α4 integrin. Compounds with required biological activity can be modified to obtain desired properties, such as improved physiological properties (such as in vivo test stability, biological stability) or: detection for diagnostic purposes, such as the sulfonamides of the present invention Including one or more D-amino acids typically improves stability in vivo. Stability can be assayed in a variety of ways, such as measuring the half-life of a protein during incubation with peptidase or human plasma or serum. Various protein stability assays have been described (eg, Verhoef et al., Eur. J, Drug Metab. Pharmacokinet., 1990, 15 (2): 83-93). For diagnostic use, a variety of labels can be linked to compounds that can provide a detectable signal, either directly or indirectly. In this way, the compound of the present invention can be modified in a variety of ways (please read the notes on the back before filling this page) Order I. I ------- II ^^^^ 1. ______________-104-This paper is applicable to China ^ ^ Associate (CNS)-Grid (21〇χ29_) 534910 102, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ? Β * 7 5. The invention description is used for a variety of end uses, while still retaining biological activity. In addition, multiple sites can be introduced at the ends for attachment to particles, solid substrates, macromolecules, and labeled compounds. They can be used in a variety of in vivo or test tube applications. Various labels can be used, for example, radionuclides (such as gamma-ray-emitting radioactive isotopes such as pyran-99 or indium-111}, fluorescent agents (such as luciferin), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, Chemiluminescent compounds, bioluminescent compounds, etc. The industry understands that other appropriate labels can be incorporated into the complex, or can be determined using routine experimentation. The combination of labels can be achieved using standard techniques well known to those in the industry. Test tube uses include diagnostic uses, For example, inflammatory reactions can be monitored by detecting the presence of white blood cells that can express ^ _4. The compounds of the present invention can also be used to isolate or label cells. The compounds of the present invention can be used to test the potential of vla_ 4 / VC M A-1 interactions Inhibitors. For in vivo tests to diagnose and identify, for example, inflamed sites, radioisotopes are typically used in accordance with well-known techniques. Radioisotopes can be bound directly or indirectly to peptides using intermediate blind energy groups. For example, chelating agents such as diethylene glycol §§ (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules are used to bind proteins to metal ionization Ion isotope. The complex can be labeled with paramagnetic isotopes for diagnosis in vivo tests, such as magnetic resonance imaging (MR1) or electronic rotational resonance (ESR), both of which are well-known. Generally, any one of these can be used. Visual diagnostic diagnostic methods. Usually γ-ray- and positron-emissive radioisotopes are used for camera development, and paramagnetic isotopes are used for MRI. In this way, compounds can be used for individual 105-This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 Gongchu (Please read the precautions on the back before filling this page)

534910 V. Description of the invention (1Q3: A 'Β · The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the improvement process of cardiac inflammation response. With the increase or decrease of cells, it can be decided that VLA-4 lymphocytes are effective for improving T performance. ㊅ < A specific treatment plan of the present invention > The pharmaceutical composition can be used to block the cell adhesion of couplets. For example, a variety of bamboo shoots, diseases or conditions that can be treated, and diseases; " C-associated integrin or white blood cells. Zhai Graft rejection (such as xenograft rejection), Alzheimer's disease, atherosclerosis, Acute juvenile onset diabetes), vision, diabetes (including arthritis, 'Wu Huo, Luo Meng' Metastasis, rheumatoid group), asthma, nephritis, and acute ^ _〇 ^^ Junjun syndrome psoriasis, myocardial ischemia, and " sex two: including well-derived dermatitis, intestine ^. In the specific cases of car enthusiasm of minor diseases (including Cohen's disease and ulcerative test dogs), infants and males are used to treat inflammatory encephalopathy such as sclerosis (MS) , Viral meningitis and encephalitis. Inflammatory bowel disease is a term for two similar diseases called Cohen's disease and ulcerative colitis. Cohen's disease is an idiopathic chronic ulcerative constrictive inflammatory disease, which is characterized by sharp boundaries and typically involving granulosphere inflammatory reactions involving various layers of the intestine f through the mucosa. Any part of the gastrointestinal tract may be felt from the mouth to the anus, but the disease most often affects the terminal ileum and / or colon. Ulcerative colitis is an inflammatory response that is mostly limited to the colonic mucosa and the underlying mucosa. Lymphocytes and macrophages are not high in inflammatory bowel disease and may contribute to inflammatory injury. Asthma is a kind of increased paroxysmal contraction of the bronchial airway by increasing the response of the tracheobronchial tree to various stimuli. Stimulation causes multiple inflammatory mediators. Mast cells coated with I g E release multiple inflammatory mediators, including histamine 'eosinophil and neutrophil chemokines, leukotrienes, prostaglandins, and -106- This paper standard Applicable to China National Standard (CNS) A4 specifications (21〇 < 297 mm. II 11 " Lu Yi-(Please read the precautions on the back before filling this page), \ 吕 .I- — m · 1 1--I—. F 534910 104, printed by the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs)

A

IV V. Explanation of the Invention The small plate I is caused by inflammatory injury caused by cells and neutrophils. Atherosclerosis is an arterial disease (such as coronary arteries, carotid arteries, and arteries and t # arteries). The basic lesion, that is, the atheroma, is composed of vascular plaques, which have a lipid center and a fibrous covering layer. An atheroma can impede arterial blood flow and fragile associated arteries. < Myocardial infarction and cerebral infarction are the main consequences of this disease. Macrophages and white blood were not summoned to the atheroma to promote inflammation. Rheumatoid arthritis is a chronic recurrent inflammatory disease that mainly causes trauma and damage. Rheumatoid arthritis first affects the small joints of the hands and feet, but the heart # wrist, elbow, ankle and knee joints. Arthritis is caused by the interaction of synovial cells with white blood cells that line the synovial lining of the joint. See, for example, Paul Immunology (3rd ed., Raven Press, 1993). ^ Another indication of the compounds of the present invention is for the treatment of vla-4 mediator = organ or graft rejection. In recent years, surgical techniques for transplanting tissues such as skin, liver, lung, pancreas and bone marrow have made significant progress. Perhaps the biggest problem is pure recipients' lack of tolerance to induced immunity (satisfactory agents. When liquid cells or organs are transplanted into a host (that is, the donor and the donor are from different animal species), the host's immune system may Grafts: ^ Foreign antigens produce immune anti-blindness] U and ~ (Scared King on graft disease) results in damage to plant tissue. CD8, cells, CD4 cells and monocytes Cells /, evening, _ ,,,,, and 哉 reject the relevant D-binding 敕, .., 4 orthosexin < Compounds of the invention Γ1 ::: The recipient blocks the liquid antigen to induce an immune response, thus preventing seeding , Tian Daddy and the damage of transplanted tissues or organs' mouth and mouth g. For example, refer to Paul et al. I ------ ~ 107-This paper ruler (Please read the precautions on the back before filling this page}

534910 Λ? V. Description of the invention (105) —… —one-…-^^ International Transplantation 9,420-425 (1996); Georczynski et al. Immunology 87, 573 · 580 (1996); Grorcyznski et al. Transplantation lmmun. i 3, 55-61 (1995); Yang et al. Transplant 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). A related use of the compounds of the present invention to bind to VL A-4 is to modulate an immune response involving "plant-to-host" disease (GVHD). E.g. reference

Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD can be fatal when immune-competing cells migrate to a heterologous recipient. In this case, the donor's immune-competing cells are supplied to the recipient's tissue. Skin, intestinal epithelium, and liver tissue are often destroyed during GVHD in order to attack targets. These diseases become serious problems when transplanting immune tissues, especially bone marrow transplants: but other cases including heart and liver transplants have also reported less severe GVHD. The therapeutic agent of the present invention can be used to block the activation of the τ cells of the donor, thereby interfering with the target cells that are dissolved in the host. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Another use of the compounds of the present invention is to inhibit tumor metastasis. It has been reported that several tumor cells can express VL A-4 and compounds that can bind VL A-4 to block these cells from binding to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al ,, Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994). Another use of the compounds of the present invention is to treat multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease with an estimated 250,000 to 350,000 patients in the United States. Multiple sclerosis is believed to be the result of a specific autoimmune reaction, in which some white blood cells attack and cause myelin (Covering God-108- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-534910 Λ V. Description of the invention () The insulation film of the fiber) is damaged. In the animal model of multiple sclerosis, a mouse monoclonal antibody against VLA-4 can block white blood cell adhesion to the endothelium, thus preventing inflammation of the central nervous system and paralysis of the animal 16. The pharmaceutical composition of the present invention is applicable to various drug delivery systems. Formulations suitable for the present invention can be found in Remington Medical Sciences, Meth Publishing, Philadelphia, PA, 17th Edition (1985). To improve serum half-life, compounds can be encapsulated, introduced into the body cavity of liposomes, made into colloids, or other techniques used to extend the serum half-life of compounds. A variety of methods can be used to prepare liposomes as described in Szoka et al., U.S. Patent Nos. 4,235,87, 4,501,728, and 4,837,028 (also described herein by reference). The dosage of Patient I will vary depending on the quality of the drug administered, the purpose of the administration such as prevention or treatment, the condition of the patient, and the manner of administration. For therapeutic use, the composition is sufficient to cure or at least partially quell the symptoms of the disease and its complications in a patient who has had such a condition. The quantity applicable to this is defined as, "Treatment is, and the amount" ^ The effective amount will be determined according to the condition of the treatment and the clinician ^ According to the severity of the patient, the age, weight and general conditions of the patient. Central standard of the Ministry of Economic Affairs Group α printed by the Consumer Cooperative of the Bureau: the system is administered to the patient in the form of the aforementioned pharmaceutical composition. These compositions can be sterilized by sterilization technology or can be sterile filtered. The resulting aqueous solution can be packaged or lyophilized, and lyophilized The formulation is combined with a sterile aqueous vehicle, which is then available for administration. The ρ of a compound ^ formulation is typically 3 to Η, more preferably 5 to 9, and most preferably 7 to 8 to understand the use of some of the aforementioned 1 martial agents, carriers, or stabilizers. The agent will cause the production of pharmaceutical salts. _____ -109- This paper rule printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Finance and Economics 534910 Λ? Β " 7 1D7 Specific therapeutic uses, compound administration methods, patient health and condition, and changes in the judgment of the prescribing physician. For example, for intravenous administration, the dosage is typically about 20 micrograms to about 500 micrograms per thousand. Gram body weight, preferably in the range of about 100 micrograms to about 300 micrograms / kg body weight. The dosage range for proper intranasal administration is usually about 0.1 g / gram to 1 mg / kg body weight. Effective doses can be derived from in vitro or animal models The dose-response curve of the test system was extrapolated. The following synthetic and biological examples are provided to illustrate the invention and are not intended to limit the scope of the invention. Unless otherwise stated, the temperatures are in degrees Celsius. Examples In the following examples, the following The abbreviations are defined as follows. If no abbreviation is defined, it has a generally accepted definition. Aq or aq. = Water

AcOH = acetic acid bd-broad bimodal bm = broad multimodal bs-broad unimodal

Bn dibenzyl

Boc = N-Second-butoxyphenyl group Βο〇2〇 Bi '' 1 One Third Butyl purpose BP0 = Phenyltriazol-1-yloxan (dimethylamino) scale Fluorophosphate

Cbz = benzyl ester CHC13 = chloroform CH2C12 dichloromethane-110- This paper size is applicable to the Zhongguanjia Standard (CNS) A4 specification (21 (3X 297 mm))-(Please read the precautions on the back before filling in this page)

、 1T f 534910 Λ? Β * 7 V. Description of the invention (1C) 8) (C0C1) 2 = Grasshopper d = Doublet dd = Doublet of doublet dt = Doublet of doublet DBU = I, 8 -2 Azabicyclo [5.4.0.] Undecyl-7-ene DCC = 1,3-dicyclohexylmethyldiimine DMAP = 4-N, N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DMF = N, N-dimethylformamide DMSO = dimethylformamide EDC = 〖-(3-dimethylaminopropyl) -3-ethylformamide dihydrochloride

Et3N = triethylamine E t2 〇 ~ acetic acid

EtOAc = ethyl acetate

EtOH diethanol eq or eq.-Equivalent

Fmoc = N- (9-pentylmethoxycarbonyl)

FmocONSu = N-(9 -pentylmethoxycarbonyl)-succinimide g = printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) h = hour H20 = Water HBr Dihydrobromic acid HC1 = Hydrochloric acid HOBT = 1-Hydroxybenzotriazole hydrate hr = Hour -111-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 534910 Central Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Bureau of Standards. 09. V. Description of the invention () K2C〇3 L m MeOH mg MgS02 mL mm mM mmol mp N NaCl Na2C03 NaHC03 NaOEt NaOH NH4C1 NMM Phe Pro psi Pt02 q quint. Rt = Carbon dioxide discharge = liter = Multimodal = Methanol = Milligram = Sulfate Gu: = Milliliter = Millimeter = Millimolar Concentration 2 Millimolar = Melting Point Two Equivalent Concentration = Sodium Chloride 'Sodium Dicarbonate = Sodium Carbonate = Sodium Ethoxylate = Hydrogen Sodium Oxide = Ammonium Chloride Di-N-methylmorpholine = L · Phenylalanine = L -Proline Acid = Pounds per square 忖 = Oxidation Pin = Four Peaks Twenty Five Peaks = Room Temperature -112- (Please read first Note on the back then fill out this page

、 1T f This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 五 〇 5. Description of the invention Λ 'Β · 110, = Unimodal-Saturated = Trimodal Two Tertiary Butanol = Trifluoroacetic acid Tetrahydrohydrofuran = thin layer chromatography = tosylsulfonyl xylene continuous chlorine = toluenate = microliters In the following examples (unless otherwise indicated), the temperatures are in degrees Celsius. The following methods are used to prepare the following compounds. Method 1 N-toluenesulfonation of xylene sulfonation is carried out by the method of Cupps, Boutin and Rapopon J. Org. Chem. 1985, 50, 3972. Method 2 Methyl ester preparation process 庠 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards

S sat t t-BuOH TFA THF TLC or tic Ts TsCl TsOH pL (Please read the notes on the back before filling out this page) Yue Beiji S's purpose is to use Brenner and Huber Helv. Chim. Acta 1953, 36, Prepared by the method of 1 109. Method 3 The dipeptide vinegar required for the B 0 P coupling procedure is via the appropriate N-protected amino acid (1 equivalent) and the appropriate amino acid ester or amino acid hydrochloride (1 equivalent) 'benzotriazole-1 _Base oxygen ginseng (II-113- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 534910 Βη) V. Description of the invention (111 Methylamine-based printing by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy Hexafluorophosphate [Β Ο ρ] (2.0 equivalents), triethyl methanamine (ii equivalents) and DMF were prepared. The reaction mixture was stirred at room temperature and the crude product was purified by flash chromatography to obtain the dipeptide ester. Method 4 Imperialization procedure I Hydrogenation was performed using 10% palladium / carbon (10% by weight) in methanol over 30 days. The mixture was filtered through Cellte® and concentrated to obtain the desired amine compound. Method 5 Hydrolysis Procedure I Add lithium hydroxide (or sodium hydroxide) (0.95 equivalents) to a thf / h20 solution of an appropriate ester (21 s ± 1.5 to 10 liters) which is quenched (0 ° c). The temperature is maintained at and the reaction It was completed in 1-3 hours. The reaction mixture was ethyl acetate and water phase; The required acid salt is obtained. Method 6 llzK solution procedure 11 Lithium hydroxide (1.1 equivalents) is added to a quenched (0 ° C) TFH / H20 solution (2 "s • liters) of the appropriate ester. The temperature is maintained at (TC, After that, ττ should be completed in 1-3 hours. The reaction mixture was concentrated and the residue was taken up at 7k ττ ", ~ 'transρ Η adjusted with hydrochloric acid aqueous solution to 2-3. The product was extracted with ethyl acetate The combined organic phases were washed with brine, dehydrated with magnesium sulfate, filtered and concentrated to obtain the desired acid. Method 7 m solution procedure in the appropriate ester dissolved in dihumane / water (1: 1) and add 0.9 equivalents 0.5 N Chlorine Oxide (Please read the precautions on the back before filling this page)

、 1T φ «. -114- This paper size applies to Chinese National Standard (CNS) A4 (21 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A? P ^ 一 __________ Η7 — ____ — V. Invention Description (112) ^

sodium. The reaction was stirred for 3-I for 6 hours and then concentrated. The obtained residue was dissolved in water 'and extracted with ethyl acetate. The aqueous phase was passed through the 'Donggan to obtain the desired sodium salt. Method 8 Sulfonation Procedure I Add the desired sulfohydrazone to a suitably protected aminophenylphenylalanine analog (Π .2 mmol) dissolved in dichloromethane (25 ml) and cooled to -7 ° C. Chlorine (i 2 mol) was then added dropwise (2 ml). Allow the solution to warm to room temperature 'and stir for 48 hours. The reaction solution was transferred to 250 ¾ liter knife funnel 'with dichloromethane (100 ml) and extracted with in hydrochloric acid (50 ¾ liter x 3), brine (50 * liter), and water (100 ml). The organic phase is dehydrated (magnesium sulfate) and concentrated to obtain the desired product. Method 9 reductive amination procedure

The reductive amination reaction of Tos-Pro-p-NH ^ Phe using an appropriate aldehyde was carried out using acetic acid, sodium triethylsulfonium borohydride, and dichloromethane, and the mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography. Method 10 Β Ο C removal process 庠 Hydrogen chloride (H C 1) gas was passed at 0 C through an appropriate solution of b o c -amino acid g alcohol solution for 15 minutes, and the reaction mixture was stirred for 3 hours. The solution was concentrated to a syrup, dissolved in ether and concentrated. This procedure was repeated and the resulting solid was placed in a high altitude overnight. Method 1 1 _Third-Butyl Ester Hydrolysis Procedure I _ -115- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ~~~ '~-(Please read the precautions on the back before filling in this page)

1T f 534910 Λ7 B1 —___ V. Description of the invention (113) The third butyl vinegar was dissolved in dichloromethane and treated with T F A. The reaction was completed in 1-3 hours, at which time the reaction mixture was concentrated and the residue was dissolved in water and dried to obtain the desired acid. Method 1 2

EDC Coupling Procedure I Mix appropriate amino acid vinegar hydrochloride (1-20 mL) in a solution of N-(toluene-4-sulfonyl) -L-proline (1 equivalent) in dichloromethane (1-20 ml) (Equivalent) 'N -methylmorpholine (1.1-2.2 equivalents) and 1-hydroxyphenylhydrazone saponin (2 equivalents), put in an ice bath and add 1- (3-dimethylaminopropyl) -3- Ethylformamide (1.1 equivalents). Allow the reaction to warm to room temperature and stir overnight. The reaction mixture was poured into water, and the organic phase was dehydrated (magnesium sulfate or sodium sulfate) with saturated sodium bisulfate'salt'salt, filtered, and concentrated. The crude product was purified by column chromatography. Method 1 3 EDC coupling procedure 11 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this 100t in a suitable N-protected amino acid (1 equivalent) in DMF solution (5-2 0 ml) mixed with appropriate amino acid ester hydrochloride (1 equivalent), ΕηΝ (1.1 equivalent) and 丨 hydroxybenzotriazole (2 equivalent), put in an ice bath and add 1-(3-2 Methylaminopropyl) _3-ethylmethylene diimide (1.1 equivalents). The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was mixed with 0. 2 N citric acid, water, saturated sodium bicarbonate, brine washing, dehydration (phosphonium sulfate or sodium sulfate), dehydration and concentration. The crude product was purified by column chromatography or preparative TLC. Method 1 4 Sulfonation procedure 11 -116- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2! 0 ^ 297mm) ^ --- 534910 A? __________ V. Description of the invention (114) _ 、 Ⅰ- ~------ -------------- ~ Tongdang Sulfonium chloride is dissolved in digas methane and placed in an ice bath. L_pr〇_L_ Phe-〇Me_HC1 (1 equivalent) and triethylamine are added (1 "equivalent), the reaction was warmed to a mild temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, brine, and dehydrated ( Magnesium sulfate or sodium sulfate), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC. Method 15 5 Sulfonation procedure 111 in L-Pro-L-4- (3-dimethylaminopropyloxy) ) -Phe_〇Me [prepared using the method of method 10] (1 equivalent) Triethylamine (5 equivalents) was added to a solution of dichloromethane, followed by the appropriate sulfonyl chloride (丨 · 丨 equivalents). Any reaction Warm to room temperature and stir overnight under a nitrogen atmosphere. The mixture is concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate and 0.2N citric acid. The aqueous phase is adjusted with solid sodium bicarbonate for verification, and The product was extracted with ethyl acetate. The organic phase was washed with brine, dehydrated (magnesium sulfate or sodium sulfate), filtered and concentrated. Crude nail was purified by preparative TLC. The corresponding acid was prepared using the procedure described in Method 7. Method 1 6 Hydrogenation Procedure 11 Employees' Cooperatives of Central Bureau of Standards, Ministry of Economic Affairs To a solution of azalide in methanol (10-15 ml) was added sodium acetate (i equivalent) and 10% Pd / C. The mixture was placed in a hydrogenator at 40 psi hydrogen. After 8-16 hours, the reaction The mixture was filtered through a pad of Celite, and the filtrate was concentrated to obtain the dechlorinated dipeptide methyl ester. The ester was dissolved in dioxane / water (5-10 ml), and 0.5N sodium hydroxide (1.05 equivalent) was forcefully poured into it. After stirring for 1-3 hours, the reaction mixture was concentrated, and the residue was redissolved in water and washed with ethyl acetate. The water phase is -117- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 534910 Λ7 V. Description of the invention (115, 0.2 N hydrochloric acid adjusted to acidic, the product is extracted with ethyl acetate. Combined organic The phases were washed with brine (1 X 5 ml), dehydrated (phosphonium sulfate or sodium sulfate), filtered, and concentrated to obtain a 1: 1 mixture of acids approximately diastereomers. Method 1 7 Third butyl ester hydrolysis procedure 11 Tributyl ester was dissolved in dichloromethane (5 ml) and treated with TFA (5 ml). The reaction was completed in 1-3 hours, at which time the reaction mixture was concentrated, and the residue was dissolved in water and concentrated. The residue was redissolved in Water and lyophilization to obtain the desired product. Example 1 (2) N- (toluene-4 · sulfonyl) -L-proline fluorenyl-4-[(N-third butoxycarbonylglycinyl) Amine] -L-Phenylalanine Synthesized by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

II N-(Toluene-4 -sulfofluorenyl) -L-prolylamino_L-4 · Aminophenylalanine methyl ester (2.00 g, 4.67 mmol) was dissolved in 50 ml of anhydrous DMF, Boc-glycine (1.1 equivalent, 0.9 g), triethylamine (2.2 equivalent, 1.43 ml) and BOP reactant (1.1 equivalent, 2.27 g) were dissolved. The reaction mixture was stirred at room temperature for 12 hours. Ethyl acetate (100 ml) was added. The organic layer was washed with saturated sodium bicarbonate (50 ml), 10% citric acid (20 ml) and brine (5 x 50 ml). The organic layer was dehydrated with thorium sulfate. When the solvent was removed by evaporation under reduced pressure, the crude product was dissolved by column chromatography (silica gel; chloroform / methanol 9: 1). The resulting ester (1.90 g, 3.1 mmol) was isolated in 66% yield. The ester was then taken up with sodium hydroxide (1.1 equivalents, 176 mg) in methanol: water [1: 1] (40 ml) at room temperature for 4 hours. Add ethyl acetate and water. The aqueous layer was collected and acidified to pH 2.5 with 1 N hydrochloric acid, and re-extracted with ethyl acetate. -118- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 534910 A7 B * 7 _ _-----.... ^ 116 — * ------ 5. Description of the invention () When the organic layer was dehydrated with magnesium sulfate, filtered and evaporated to remove the solvent under reduced pressure, the title compound was isolated in 73% yield as an oil (1.33 g, 2.26 mmol). The NMR data are as follows: 1 H NMR (300 MHz, CDC13): δ -8.65 (bs, 1H) 1 70 (d 2H, J = 7.98 Hz), 7.50 (d, 1H, J-7.14 Hz), 7.45 (d, 2H, J-8.10 Hz), 7.32 (d, 2H, J-7.80 Hz), 7.11 (d, 2H, J = 8.00 Hz), 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 ih) i 55 (m 3H), 1.43 (s, 9H ). 13C NMR (75 MHz, CDC13): ^ -174.03, 172.19, 169.02, 157.28, 145.03, 137.17, 133.34, 132.58, 13〇 · 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 spectrometry: FAB 589 (M + H). Example 2 (7) N- (Toluene-4 -continylfluorenyl) -L-proline fluorenyl-4 _ [(glycinyl) amino amine L _ phenylalanine) Employee of Central Bureau of Standards, Ministry of Synthetic Economy Printed by a consumer cooperative (please read the precautions on the back before filling out this page) Example 1 (2) The product (1.33 g, 2.26 mmol) was ingested in anhydrous dichloromethane (20 ml) containing trifluoroacetic acid (1.00 ml) ), And the reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The crude material was left overnight on a vacuum pump, then dissolved in methanol and cooled to 0 ° C. Ether was added and the product was collected to be trifluoroacetate 50% yield (66 mg, 109 mmol). The N MR data is as follows: 1 H NMR (3 00 MHz, CD3OD): ^ = 7.51 (d, 2H, J = 8.25 Hz) -119 -This paper is suitable for Guancai County (CNS) A4 size (2U) X297 & Chu) '~~~-534910 A7 _ Βη V. Description of the invention () 7.31 (d, 2H, J = 8.25Hz), 7.19 (d, 2H, J = 7.92 Hz), 7.03 (d, 2H, J = 8.25 Hz), 4.43 (m, lH), 3.87 (m, lH), 3.63 (s, 2H), 3.13 · 2.82 (m, 4H), 2.21 (s, 3H), 1.56-1.26 (m, 4H). 13C NMR (75 MHz, CD3OD): 4 = 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 spectrometry: FAB 489 (M +). Example 3 (2 3) Synthesis of N-(toluene-4 -sulfofluorenyl) _ L -proline methyl-4-[3-(carboxy) propylamido] -L -phenylalanine Printed by the Consumer Bureau of the Standards Bureau (please read the precautions on the back before filling out this page) f N-(Benzene-4 -sulfofluorenyl) · L -Proline sulfonyl-L-4 Aminophenylalanine Methyl ester (455 mg, 1 mmol) was dissolved in DMF (10 μL) containing triethylamine (1.1 equivalents, 153 μl) and succinic anhydride (1.1 equivalents, 110 mg). The desired monoester was isolated and foamed in 53% yield (288 mg, 0.52 mmol). The monoester (80 mg, 0.15 mol) was then hydrolyzed at room temperature for 4 hours in methanol: water 1: 1 (5 ml) containing osmium sodium oxide (2.2 equivalents'15 gram). Add ethyl acetate and water. The aqueous layer was collected and acidified to pH 2.5 with 1 N hydrochloric acid, and re-extracted with ethyl acetate. The organic layer was dehydrated with magnesium sulfate. To take into account the reduction of evaporation, remove the solvent, separate the diacid into a foam. The NMR data are as follows: 4 NMR (300 MHz, CD3OD): J 2.7.51 (d, 2Η, J = 8 31 Hz), 7.28 (d, 2H, J = 8.34 Hz), 7.19 (d, 2H, J = 8.10 Ηζ ), 6.99 (d, 2H, J = 8.43 Hz), 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). ___-120- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) '534910 Λ? Β * 7 5. Description of the invention (118) " C NMR (75 MHz, CD3OD): = 176.87, 174.68 , 174.53, 1 73.30, 149.74, 146.3 1, 139.33, 135.50, 134.24, 131.61, 131.44, 129.53, 121.66, 80.05, 63.81, 55.37, 5 1.17, 38.25, 32.87, 32.24, 30.55. 25.89, .22.1 1. Mass spectrometry: FAB 532 (M + H). Example 4 (2 7) N-(Toluene-4 -sulfofluorenyl) -L -proline fluorenyl-4-[(N -Third butoxycarbonyl-L -propylaminofluorenyl) amino] -L -benzene Synthesis of glycylalanine follows the experimental procedure described in Example 1 (2). N- (fluorenyl-4-sulfofluorenyl) -L-proline methyl-L-4-aminophenylalanine methyl ester (0.15 G, 0.337 mmol) ingested in triethylamine (2.0 equivalents, 95 microliters), Boc-L-alanine (1.1 equivalents, 70 mg) and BOP (1.1 equivalents, 163 mg) 5 Ml DMF. The desired methyl ester was isolated as an oil in 49% yield (102 mg, 0.16 mmol). The ester was then hydrolyzed with sodium hydroxide (1.1 equivalents, 8 mg) in a 1: 1 methanol: water solution (4 ml). Monoacid was isolated as an amorphous solid in quantitative yield. The NMR information is as follows: Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) NMR (300 MHz, CDd3) · ^ = 9.00 (broad s, 1H), 7.70 (d, 2H , J = 8.25 Hz), 7.45 (d, 2H, J = 8.37 Hz), 7.32 (d, 2H, J = 8.25 Hz), 7.09 (d, 2H, J =: 8.25 Hz), 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). 1 3C NMR (75 MHz, CDC13): d = 174.71, 172.40, 172.09, 156.72, 144.98, 137.62, 133.43, 132.2 1, 130.58, 128.48, 120.47, 80.98, 62.87, 54.05, 51.10, 50.3 1, 37.23, 30.73, -121-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 534910 Λ Β ′ V. Description of the invention 119, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 28.88, 24.92, 22.16, 18.89. Mass spectrometry: FAB 603 (M + Η). Example 5 (2 8) N- (Toluene-4-phenylmethyl) -L-prolylamino LV «Third-butoxyalkyl-D-propylamine) amino] -L-phenylalanine Synthesis According to the experimental procedure described in Example 1 (2), N- (toluene_4-sulfofluorenyl) -L__proline fluorenyl-L-4-aminophenylalanine phosphonium ester (0.15 g, 0.337 mmol) ) Take 5 ml of DMF with triethylamine (2.0 equivalents, 95 μl), Boc-D-alanine (1.1 equivalents, 70 mg) and BOP (1.1 equivalents, 163 mg). The desired ethyl ester was isolated as an oil in 33% yield (68 mg, 0.1 mmol). The ester was then hydrolyzed with sodium hydroxide (1 1 vol, 5 mg) in a 1: i methanol: water solution (4 ml). Monoacids were isolated as a thin film and quantitative yields were obtained. The NMR data is as follows: 1U NMR (300 MHz, CDC13): ¢ ^ = 8.90 (broad s, 1H), 7.70 (d, 2H, J = 8.25 Hz), 7.45 (d, 2H, J = 8.37 Hz), 7.32 ( d, 2H, J = 8.25 Hz), 7.09 (d, 2H, J = 8.25 Hz), 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 (75 MHz, CDC13): Θ di , 22.16, 18.89] Mass spectrometry: FAB 603 (M + H). Example 6 (2 9) 122 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

、 1T Φ! 534910 Λ7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy Oxalyl _ D-winter propyl amine amine) amino] · l-phenylalanine was synthesized according to the experimental procedure described in Example 1 (2), N- (toluene_4 · sulfonyl) _l_proline Methyl amidino-L-4-aminophenylalanine (0 15 g, 0337 mmol) with triethylamine (2.0 equivalents,% microliters), Boc_D • phenylpropylamine ^ (1 1 equivalent , 99 mg) and BOP (11 equivalents' 163 g) were ingested in $ ml of DMF. The desired ester was isolated as an oil, 16% yield (37 mg, 0.05 mmol). The ester was then sodium hydroxide (L1 equivalent, 5 g) was hydrolyzed in a 1: 1 methanol: water solution (2 ml). The monoacid was isolated as an amorphous solid in quantitative yield. The NMR data was as follows: ^ NMR (300 MHz, CDC13): ^ 8.56 ( broad 1H), 7.73 (d, 2H, J = 8.13 Hz), 7.43-7.22 (m, 10H), 7.09 (d 2H,] 2 7.95 Hz), 5.78 (m, 1H), 4.87 (m , 1H), 4.65 (m, 1H), 4 n 1H), 3.44 (m, 1H), 3.29-3.01 (m, 4H), 2.43 (s, 3H), 2 〇8 (m, 1H), 160 (m, 3H), 1.33 (s, 9H) 〇13C NMR (75 MHz, CDC13): c ^ 171.88, m 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, 1260, 81, 62.84, 53.96, 50.26, 38.91, 37.90, 30.35, 28.81, 24 96 22 11. Mass spectrometry: FAB 679 (M + H). Example 7 (6 7) N-(Toluene-4 -sulfofluorenyl) _ L -proline fluorenyl-4-丨 2 3 _ (Glorin) thioureido] ethynylamino __ l-phenylpropylamine Acid Synthesis Example 2 (7) The product uses sodium bicarbonate and fluorescein isothiocyanate (isomeric-123) This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the back first (Notes for filling in this page)

、 1T t Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 Η " 7 --------- ~ --- ....... _ — —_ V. Description of the Invention (121) Object I- -Available from Aldrich Chemical Company) in ethanol and water treatment. The mixture was acidified, and the resulting precipitate was separated to obtain the title compound as an amorphous orange solid. Mass spectrum: (+ FAB, 3-nitrobenzyl alcohol) 878 (MH +). Example 8 (1 7 5) N- (Toluene-4-sulfofluorenyl) -L-proaminefluorenyl-4-[(N · third butoxycarboxyglycinamido) amino] -L-phenyl Synthesis of methyl alanine N- (toluene-4-continuous) -L-proline methyl-L_ (4-nitro) phenylalanine methyl (2.00 g, 4.48 mmol) to catalyze An amount of 10% Pd / C was dissolved in methanol (10 ml). The hydrogenation reaction was performed at 40 psi for 12 hours at room temperature. When the reaction mixture was filtered through Celite, the solvent was removed by evaporation under reduced pressure to obtain peach-colored foams' gross yield. The title compound was prepared from this and N_boc glycine using the procedure described in Method 12. The NMR data is as follows: ^ NMR (300 MHz, CDC13): ^ 7.72 (d, 2H, 1 = 8.13 Hz), 7.45 (d, 2H, ^ 8.49HZ), 7.35 (d, 2H, J: 8.30Hz), 7.10 (d, 2H, J = 8.j7 Hz), 5.40 (m, 1H), 4.82 (m, 1H), 4.07 (m9 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 (75 MHz, CDC13): d -177.61, 171.97, 171.58, 168.52, 144.93, 137.25, 133.43, 132.55, 13 1.36, 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 spectrometry: (FAB) 603 (M + H). -124- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 "-(Please read the precautions on the back before filling this page)

, 1T t 534910 Β * 7 V. Description of the invention (122) Example 9 (3 0 6) N-(toluene 4-sulfofluorenyl) -L-proline fluorenyl-4-{2-[3-(3- Methylphenyl) Lunesyl] Ethylamidob-L-benzylalanine is a synthetic ester of N- (methylbenzyl-4-sulfonyl) -L-prolyl-L- (4 -Amine) Prepared by reacting phenylalanine with 2- (3-m-tolyl-ureido) acetic acid (B 0 P, triethylamine, DMF and stirring overnight at room temperature). The crude product was purified by flash chromatography (silica, 9: 1 ethyl acetate: hexane) to give the ethyl ester. The methyl ester was hydrolyzed with THM using 1 M lithium hydroxide. After subsequent acid / base treatment, the title compound was obtained as a white solid. The NMR data are as follows: lU NMR (DMSO-d6, 400 MHz): ^ = 12.8 (br s, 1H); 9.96 (s, 1H); 8.70 (s, 1H); 8.04 (d, 1H, J-7.9 Hz) ; 7.68 (d5 2H, J = 8 Hz); 7.48 (d, 2H, J = 8.3 Hz); 7.39 (d, 2H, J = 8.3 Hz); 7.21 (s, 1H); 7.16 (d, 3H, J -8.56 Hz); 7.08 (t, 1H, J = 7.79 Hz); 6.7 (d, 1H, J = 7.68 Hz); 6.38 (t, 1H, J = 5.6 Hz); 4.43 (m, 1H); 4. · 1 (dd, 1H, J = 3.18, 8.23 Hz); 3.89 (d, 2H, J = 5.49 Hz); 3.3 (m, 1H); 3.05 (m, 2H); 2.92 (dd, 1H, J = 8.34, 13.63 Hz); 2.38 (s, 3H); 2.22 (s, 3H); 1.38-1.62 (m, 4H "Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page ) IR (Kbr, cm1): 3380, 2990, 1650, 1605, 1540, 1230, 1 155, 660, 580, 545. Mass spectrometry: ((+) FAB, m / e (%)) 644 (100 [M + Na] +); 622 (25 [M + H] +) 〇 Example 1 0 (3 8 0) N-(xylbenzene-4 -sulfofluorenyl) -L _proamine fluorenyl · 4-[γ _ (Asparagine) Amine group] · _-125- _ This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 534910 A \ y V. Description of the invention (123, The synthesis of L-phenylalanine printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Commerce uses B 0c _ L -aspartic acid benzyl ester instead of B 0c _glycine and follows examples 1 (2) and 2 (7) The method obtained the title compound as a white solid, mp 163-170 ° C. The NMR data are as follows: lH NMR (DMSO-d6): r; = 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 spectrometry (FAB) (M + H) 547. Example 1 Synthesis of 1 (1 4) N-(xylbenzene-4 -sulfofluorenyl) -L-proline fluorenyl-4-(α-carboxybenzyloxy) _L-phenylalanine 4-Sulfomethyl) -L-proline methyl-L-tyrosine methyl ester (.23 g, 2.95 mmol) was dissolved in anhydrous D μF (50 ml) at room temperature. To this was added potassium carbonate (1.1 equivalents, 44.0 mg) and α-bromophenylacetic acid ethyl acetate (1.1 equivalents, 750 mg). The reaction was stirred at room temperature for 12 hours. Ethyl acetate (100 ml) was added and the organic layer was washed several times with brine. The organic layer was dehydrated with iron sulfate. The residue was separated when the solvent was removed by filtration and evaporation under reduced pressure, and then taken up in methanol: water 1: 1 (30.0 liters) with sodium oxide (1.1 equivalents, 427 mg). Eight isolated diacids, 88% yield (754 mg, 1.33 mmol). The NMR data is as follows: 'Η NMR (300 MHz, CD3OD): ^ = 7.50 (d, 2H, J-8.25 Hz) 7.35 (d, 2H, Bu 7.14 Hz), 7.15 (m, 5H), 6.95 (d , 2H, 13 Hz), 6.71 (d, 2H, J = 8.37Hz), 5.48 (s, lH), 4,5l (m, 1H) (Please read the precautions on the back before filling this page)

， 1T φι. 126 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) 534910 Λ · B " 124. V. Description of the invention (please read the precautions on the back before filling this page) 3.87 (m, 1H), 3.10-2.79 (m, 4H), 2.15 (s, 3H), 1.45-1.01 (m, 4H). 13C NMR (75 MHz, CD300): ^ = 174.71, 174.49, 173.98, 158.25, 146.39, 138.08, 1 35.37, 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 spectrometry: (FAB) 567 (M + H). Example 1 Synthesis of 2 (1 5) N-(toluene-4 -sulfofluorenyl) -L -proline methyl-4-[2-(carboxy) phenyl] -L -phenylalanine 178) The product was treated with sodium hydroxide in dioxane and water. After acidification, extraction, magnesium sulfate dehydration, filtration and evaporation, the title compound was obtained as clear oil. The NMR data are as follows:] H NMR (CD3OD w / CD3ONa, 300 MHz): θ = 7.75 (d, J = 8.2, 2H), 7.44-7.40 (ΐΐΐ, 5H), 7.29-7.21 (m, 5H), 4.47 ( t, J2 5.8, 1H), 4.03 (dd, J = 8.5, J2 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 (CD3OD w / CD3ONa, 75 MHz) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs: 4 = 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, 3 1.7, 25.2, 2 1.5. Mass spectrometry: (+ FAB, glycerol) 537 (MH +). Example 1 3 (1 7 8) -127- This paper size applies the Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 -___ 一 _____ B " V. DESCRIPTION OF THE INVENTION (125) ONE " 一 ...'...—— ^^ · ONE — ^ " ONE ~ N-(Toluene-4 -sulfofluorenyl L-proline amidino_ 4 _ [2-(methoxy (Carbonyl) benzyl] _L-Synthesis of L-benzylalanine L-L-4-benzylalanine (phe (4 _) [) _ 〇η) Treated with methanol and hydrogen chloride gas to obtain HC 1 · P he (4 -1)-〇 M e. The product was treated with N-(toluene_4-sulfofluorenyl) -L -P r 〇-〇, EDAC, HOBT and triethylamine in DMF, and in water After subsequent treatment of the solution, N- (toluene · 4-sulfofluorenyl) -L-Pro_L-Phe (4-I) -OMe was obtained. The product was THF using Pd (PPh3) 4 and 2 · (methoxycarbonyl) benzene Zinc iodide [prepared by the Rieke method (j org Chem. 1991, 56, 1445)] treatment, after subsequent treatment with water and flash chromatography, the standard compound was obtained as a clear oil. NMR data are as follows: 4 NMR ( CDC1 ;, 300 MHz): d = 7.81 (d, J 2 7 · 7, 1Η), 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 (CDC13, 75 MHz): ό '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, 21.50. Mass spectrometry: (+ FAB, 3-nitrobenzyl alcohol) 565 (MH +). Example 1 4 (3 5) N-(xylbenzene-4 -Continued · Si-based) -L-proline fluorenyl-4-丨 N-[2-(N -methyl ferrioxamine) ethyl] amino group 丨 -L -phenylalanine synthesis -128- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before filling out this page) Order t Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A? P ^ ___________ 5 2. Description of the invention (126)-One was used in accordance with the experimental procedure described in Synthesis Example 3 (2 3). The product of Example 15 (172) (32 mg, 0.05 1 mmol) was used. Sodium oxide (Shushu eq, 3 mg.) In methanol: water 1: 1 (1 mL) is hydrolyzed. The title material was isolated in a quantitative yield as a foam. The NMR data are as follows:] H NMR (300 MHz, CDC13): ^ = 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, 1.5mm), 2.42 (s, 3H), 1.26 (m, 3H). 13C NMR (75 MHz, CDC13): 4 = 171.47, 170.3 1, 144.78, 136.42, 135.77, 130.67, 129.88, 129.33, 127.80, 62.44, 60.99, 60.81, 54.GG, 53.77, 38.32, 32.19, 3 1.96, 22.24 , 14.76. Mass spectrometry: (FAB) 449 (M + H). Example 1 5 (172) N _ (toluene-4 -sulfofluorenyl) _ L _proline fluorenyl _ 4 _ 丨 n-[2-(N -methyloxyamino) ethyl] amino group L -Phenylalanine methyl ester N- (toluene-4sulfonyl) -L-Proline methyl-L-p-amino-phenylalanine methyl ester (316 mg, 0.7 mmol) using cyanide Sodium borohydride (10.0 equivalents' 446 mg) and formamidine benzyloxyglycerol (1 equivalent) were dissolved in a solution of potassium acetate-acetic acid in anhydrous methanol (0 ml) [pH 6.5]. The reaction mixture was stirred at ▲ overnight, and the solvent was removed by evaporation under reduced pressure. Ethyl acetate was added and the organic layer was washed with brine 'and dried over magnesium sulfate. After taking into account the evaporation to remove the solvent, the crude material was dissolved in a preparative plate (silica gel: ethyl acetate / hexanes 丨: 丨). The title compound required for the separation was in a thin film, 5% yield (40 mg, 0.06 _ __-129-This paper is applicable to the standard (CNS) M specification (2 丨 〇 < 297 km)- (Please read the precautions on the back before filling this page), -5 mouth f 534910 Λ? Β * 7 _______ V. Description of the invention (127) Millimoles). The NMR data are as follows: lH NMR (300 MHz, CDC13): ^ = 7.71 (d, 2H, J = 6.90 Hz), 7.38 (m, 5H), 7.26 (m, 2H), 6.93 (d, 2H, J = 7.20 Hz), 6.54 (d, 2H, J = 7.50 Hz), 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 spectrometry: (FAB) 623 (M + H). Example 1 6 (368) N-(Toluene_ 4 -sulfofluorenyl) -L -proline methyl-4-{N-[3-(N, N -dimethylamino) propyl] -N- Synthesis of [trifluoromethanesulfonyl] methylamino-L-phenylalanine methyl N · (toluene-4_sulfonyl) -L Prolylamino-L-(4-amino) phenylpropylamine Methyl acid ester and trifluoromethanesulfonic anhydride are reacted in pyridine to produce the corresponding trifluoromethanesulfonium & amine. The compound was used to alkylate trifluoromethanesulfonamido nitrogen under the conditions of Mitsunobu using 3-dimethylamino-1 -propanol. After removing the solvent by evaporation and washing with water, the mixture was purified by filtration to obtain the product as a solid, mp = 4 5 _ 5 5 ° C. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The NMR data is as follows: 'Η NMR (CDC13, 400 MHz): d-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, 2H); 1.98 (brd s, 1H); 1.75-1.30 (brd m, 9H) 〇-130- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X 297 mm) — printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Β " 7 V. Description of the invention (128) 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 〇 Mass spectrometry: (+ FAB) 633 ([M + H] +); 630; 507 438; 306; 191; 155; 91. Example 1 7 (510) N- (Toluene_4-sulfofluorenyl) -L-proline fluorenyl-l 4-{N, N -bis [4-(N, N_monofluorenylamino) yl ] Amine 丨 -L-phenylalanine synthesis of synthetic phosphonium esters is prepared by using 4 -N, N -diamidoaminobenzaldehyde ('triacetoxy sodium borohydride acetate, dichloromethane) in the chamber It was prepared by reducing and aminating N- (toluene-4-sulfofluorenyl) -L-prolylamino-L-4-aminobenzyl-l-phenylalanine over night with warm stirring. The crude product was purified by flash chromatography to obtain ethyl ester, and methyl acetate was hydrolyzed in the same manner as in Method 6 to obtain the title compound. The NMR data are as follows: 1 H NMR (DMSO-d6, 400 MHz): ί -7.7 (d, 2Η, J = 8.34 Hz); 7.54 (d5 1H, J-5.71 Hz); 7.40 (d5 1H, 1 = 8.34 Hz ); 7.02 (d, 4H, J = 8.78 Hz); 6.75 (d, 2H, J = 8.78 Hz); 6.62 (d5 4H, J = 8.78 Hz); 6.48 (d, 2H, J = 8.78 Hz); 4.39 (s, 4H); 3.92 (dd, 1H, J = 2.85, 9.0 Hz); 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) 〇IR (KBr, cm · 1) 3380, 1610, 1520, 1400, 1350, 1160, 800, 670 〇MS ((+) FAB, m / e (%)) 698 (20 [M + H] +). Analysis and calculation 値 C39H46N 5 0 5 Li 3H20: C, 61.76; H, 6.91; N, -131-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ~~ (Please read the precautions on the back first (Fill in this page again)

, 1T 534910 Λ7 Five redundant descriptions (5 ^ · —- 9.2j. Continuous measurement: C. 61.73; H, 6.91; N, 9.15. Example 1 8 (13 8) N-(Chrysene-4-sulfonyl ) -L-proline hydrazone _ 4 _ [N _ (N, N _ dimethylamino) propoxy] -L-phenylalanine synthesis of diphenylphosphine (24.4 g, 92.9 mol) And 3-dimethylamino · propanol (8.72 g, 84.5 mmol) were dissolved in butane (200 liters) and cooled in an ice bath. The solution was added dropwise to the azo via a syringe over a period of 5 minutes. Diethyl dicarboxylate (16.2 g, 14.6 liters, 92.9 mol) was added via a cannula ^] 80 (: _ methyl tyrosine (24.95 g, 94.5 mol) in 100 ml The solution of tHf was stirred for another 10 minutes. The mixture was stirred at 01 for 30 minutes and at room temperature for 19 hours. The mixture was concentrated on a rotary evaporator and taken up in ether (500 ml). The mixture was treated with 0.2N hydrochloric acid (3 X (350 ml), the combined acidic extracts were made alkaline with solid sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x j00 strokes), and the combined extracts were dehydrated (sodium sulfate), filtered, and filtered. 2 Ready to get Ν-Β〇c-L -4-(3-Dimethylaminopropoxy) phenylalanine methyl ester (26.5 g, 82%). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) ) N_Boc-L-4- (3-N, N-dimethylaminopropoxy) phenylalanine (26.5 g '69.5 mmol) was dissolved in methanol (300 ml) and Saturated with hydrogen chloride gas. After the mixture was evacuated to remove volatiles, it was stirred for 3 hours to obtain L_4- (3-N, N-dimethylaminopropoxy) phenylalanine methyl dihydrochloride (23.6 g, 90 %). N- (Toluene-4-sulfofluorenyl) -L-proline hydrate is coupled to L-4- (3-N, N-diamidoaminopropoxy) using the procedure described in Method 13 _Phenylalanine dihydrochloride dihydrochloride obtained N-(toluene_ 4 -sulfofluorenyl) -L -proline fluorenyl-L-4-(3-_ -132- This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 534910 A7 -___ B * 7 ^ * 1 · 1-*, · »Private_ 丨 丨 __-···-·, · > — V. Description of the invention (130) N, N · Dimethylaminopropyloxy) benzylpropylalanine (16.3 g, 89 0 / 〇). Use 0.5N sodium hydroxide The title compound was prepared by hydrolysis of methyl ester in THF / water (14.71 g, 99% ". The NMR data are as follows:] H NMR (DMSO-d6): δ ^ 1.15 (d, 2H, J = 8.2 Hz), 7.67 (d 1H, J = 5.6 Hz), 7.42 (d, 2H, J-8.2 Hz), 7.00 (d, 2H, J-8.5 Hz) 6.71 (d, 2H, J-8.5 Hz), 3.98 (m, 2H), 3.90 (t , 2H, J-6.5 Hz) 3.14-2.97 (4H), 2.40 (s, 3H), 2.32 (t, 2H, Bu 7.0 Hz), 2.13 (s 6H), 1.83-1.75 (3H), 1.45-1.36 ( 3H). 1 3C NMR (DMSO-d6): β = 173.5, 169.7, 157.2, I44 l 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 spectrometry: FAB m / e 562 [M + 2Na-H). Example 1 9 (282) N- (Toluene-4-A S & yl) -N-methyl-L · seramine group 4- [3_ (N, K [ -Dimethylamino) propoxy] -L-Synthesis of methyl phenylalanine N -fluorenyl-N-(toluene-p-sulfofluorenyl) -L_serine (655 mg, 2.4 mmol Ear) Follow the procedure described in Method 13 with L-4-(3-dimethylamino-propoxy) phenylalanine methyl ester hydrochloride [Preparation of Reference Example 18 (138)] (1.0 g, 2.4 Millimoles), HOBT (1.1 equivalents, 356 mg), triethylamine (3.2 equivalents, 1.1 ml) and EDC (1.1 equivalents, 500 mg) were ingested in DMF (100 ml). The title compound was isolated in 70% yield (900 mg 1.7 mmol) as an oil. The NMR data is as follows: -133-I-This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ? ~ ^ __ ____… _____ 5. Description of the invention ( 131)} Η NMR (300 MHz, CDC13): ^ = 7.68 (d, 2H, J-8.40 Hz), 7.29 (d, 2H, J = 8.10Hz), 7.08 (d, 1H, J = 7.80Hz), 7.04 (d, 2H, J = 8.70 Hz), 6.82 (d, 2H, J = 8.70 Hz), 4.71 (m, 1H), 4.43 (m, 1H), 3.94 (t, 2H, J = 6.60 Hz), 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 (75 MHz, CDC13): ri = 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, 3 1.85, 27.91, 22.13. Mass spectrometry: (FAB) 563 (M + H). Example 20 (284) N-(toluene-4 -sulfofluorene ) -L-(5,5 -Dimethyl) pyrimidinamine_ 4-[2-(N, N -Diamidinoamino) ethoxyl L -phenylalanine Synthesis of Triphenyl Phosphine (1.1 equivalent) and 3-dimethylamino-1 -propanol (1 equivalent) were dissolved in THF and cooled in an ice bath. Diethyl azodicarboxylate was added dropwise via a syringe over 5 minutes ( 1 equivalent), and N-Boc-methyl tyrosine (1.02 equivalents) was added through a cannula to a solution of 100 ml of THF and stirred for another 10 minutes. The mixture was stirred at 0 ° C for 30 minutes, and Stir at room temperature for 19 hours. The mixture was concentrated on a rotary evaporator and taken up in ether (500 ml). The mixture was extracted with 0.2N hydrochloric acid (3 X 350 ml) and the acidic extracts were combined and adjusted with solid sodium bicarbonate It is basic. The mixture is extracted with ethyl acetate (3 X 300 ml), and the combined extracts are dehydrated (sodium sulfate), filtered and evaporated in vacuo to obtain N-Boc-L-4- (3-dimethylamino Propoxy) methyl phenylalanine. _ -134 · This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back and save this page)

、 1T t 53491ο Λ7 _____ V. Description of the invention (132)… ^ ~ (Please read the notes on the back before filling in this page) Ν_ΒΜ; ^ 4- (3-dimethylaminopropoxy) benzyl alanine Methyl vinegar (26.5 g, 69.5 mmol) was dissolved in methanol (30 liters) and saturated with hydrogen chloride gas. The mixture was stirred for 3 hours, and then the volatiles were removed by air removal to obtain 1-4 "3-dimethylaminopropoxy) phenylalanine methyl dihydrochloride (236 g, 90%). On- (toluene-4_sulfonic acid) Amidino) -L- (5,5-dimethyl) proline is coupled to L-4- (3-dimethylaminopropoxyphenylphenylalanine methyl ester using the procedure described in Method 13 Salt N- (toluene_4-continyl acid) _l_ (5,5-dimethyl) _L-4- (3-dimethylaminopropoxy) phenylalanine methyl ester (16.3 G, 89%). The title compound was prepared by hydrolysis of methyl ester with 0.5 N sodium hydroxide at τ η F / water to obtain a solid, m ρ 2 200 ° C (decomposition). The NMR data are as follows: 1h NMR (CD3OD, 300 MHz): ό '=. 85 (s, 3Η), .94 (s, 3Η), 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 = 9.1 Hz)? 6.58 (d, 2H, J-8.6 Hz), 6.98 (d, 2H, J = 8.6 Hz), 7.20 (d, 2H, J = 8.3Hz), 7.54 (d, 2H, J = 8.3Hz). 13C NMR printed by the Consumer Cooperatives of the Central Bureau of Quasi-Economy Bureau of the Ministry of Economic Affairs ( CD3OD, 75 MHz): d = 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 spectrometry: (FAB +) 5 86 (M + H). Analytical HPLC : (Microsorb-MV C18 reverse phase 4.6 x 150 mm: Gradient 1: acetonitrile / water with 0.05% TFA: flow rate = 1.0 ml / min: 1 = 254 nm: sample volume = 20 ml) Round: 2.988 points -135- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 Η * 7 ______ _______ · I -______ 133) Clock retention time (100.0% purity) Round 2: 3.098 minutes retention time (100.0% purity). Example 2 1 (287) Ν-(Benzene-4 -sulfofluorenyl) -L-proline fluorenyl-4 · [2-(Ν, Ν -dimethylamino) ethoxy] -L -phenyl Synthesis of alanine The title compound was prepared as in Example 20 (138), but using 2-dimethylaminoethanol instead of 3-diamidoamino-1 -propanol. The NMR data are as follows: lU NMR (DMSO-d6): δ = Ί.ΊΑ (d, 2H, J = 7.4 Hz), 7.67 (d, 1H, J = 7.9 Hz), 7.42 (d, 2H, J = 8.0 Hz ), 7.01 (d, 2H, J = 7.9 Hz), 6.71 (d, 2H, J = 7.8 Hz), 3.95 (m, 4H), 3.14-2.98 (4H), 2.57 (t, 2H, J = 5.6 Hz ), 2.40 (s, 3H), 2.18 (s, 6H), 1.74 (m, 1H), 1.40 (m, 3H). 13C NMR (DMSO-d6): β = 173.5, 169.7, 157.0, 144 i 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 Spectrometry · FAB m / e 504 (M + H). Example 22 (3 17) N-(Toluene-4 -sulfofluorenyl) _L Prolylamino-4-[2-(n -ethyl_N_phenylamino) ethoxy] -L -phenyl Methyl alanine is synthesized from methyl acetate by using 2- (N-ethyl, N-phenyl) aminoethyl gas in the presence of potassium carbonate and sodium sulfide under reflux 2_butanone 0-feN -(Methylbenzyl-4- 4-contanoic acid group) -L-proline methyl group · L-tyrosine methyl ester preparation. The title compound was prepared using the procedure described in Method 7. __-136- _— This paper size is applicable to the Chinese national standard ^ ⑽) A4 size (Xunfu don't be ^ " ~ ^-(Please read the precautions on the back before filling this page)

1.1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 — ^ ___ V. Description of the invention (134) The NMR data is as follows: 1 Η NMR (DMSO-d6, 400 MHz): 1.08 (3Η, t, J = 8 , 8Hz); 139 (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, 6 Hz); 3.6 (3H, s); 3.62 (2H, t, J = 5,5 Hz); 4.01 (2H, t, J = 5, 5Hz); 4.04 (1H , T, J = 8,8Hz); 4.43 (1H, dd, J = 7,6,7 Hz); 6.55 (1H, t, J = 8,8Hz); 6.65 (2H? D, J = 10Hz); 6.8 (2H, d, J-lOHz); 7.1 (4H, m); 7.38 (2H, d, J-lOHz); 7.64 (2H, d, J-lOHz); 8.1 (1H, d9 J = 10Hz). Mass spectrometry: + FAB, m / z 594 ([M + H] +, 45%), 157 (100%). Example 2 3 (32) N-(Toluene-4 -sulfofluorenyl) -l-proline methyl-4-[2-(N, N -diisopropylamino) ethoxy] -L -benzene Synthetic methyl ester of propylalanine is obtained by using 2-diisopropylaminoethyl chloride in the presence of potassium carbonate and sodium iodide under reflux, 2-butanone 0-alkylated N_ (toluene-4-sulfonyl) ) -L-proline methyl-L-tyrosine methyl ester. The title compound was prepared as a solid using the procedure described in Method 7, m p: = 12 1 -124 ° C. The NMR data are as follows: 4 NMR (DMSO-d6, 400 MHz): β = 0.9 (12Η, d, J 8 Hz); 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 , 4,3 Hz); 3.35 (1H, s); 3.78 (1H, t, J = 7,7 Hz); 3.8 (2H, t, J = 5,5 Hz); 3.95 (1H, d, J = 10Hz); 6.5 (1H, d, J = 10Hz); 6.65 GH; d, J = i0Hz); 6.85 (1H, d, J = 10Hz); 6.9 (1H, d, J = 10Hz); __- 137- This paper size applies to China (CNS) A4 specifications (210X297 mm 1 1-1 (Please read the precautions on the back before filling this page)

、 1T t) 349l0A7 V. Description of the invention 135 、 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 7.4 (2H, d, J = 10Hz): 7.62 (1H, m); 7.75 (2H, d, J = 10Hz). Mass spectrometry: + FAB, m / z 560 ([M + H] +, 70%), 154 (100%). Example 24 (333) N-(Pyrimidine-2 -sulfofluorenyl) -L -proline methyl-4 _ [3 _ (N, N • dimethylamino) propoxy] -L -phenylpropylamine The title compound of the acid synthesis was prepared using Method 15, mp > 2000 ° C. The NMR data are as follows: 〖H NMR (DMSO-d6, 300 MHz) (m, 2H); 7.26 (bl. S, 1H); 7.04 (d, 2H J = 7 〇Hz); 6 75 ⑷ present > 6.0 Hz ); 4.16 (m, 1H); 4.06 (m,) H); 3 85 (m, 2H); 3 33 ⑽, 1H); 3.13.3.00 (br m, 3H); 2.62 (m 2H); 2 35 (s, 3H); i 9〇 (m, 2H); 1.75 (m, 1H); 1.90-1.50 (brm 3H). 13cNMR (DMSO_d6. 75MHz): / = i73 4 i69 9 i573 136.1, 134.3, 133.5, 130.8, 130.3, 128? 5 128.7,, 14.] 65 ^ 62.5, 55 1, 54.9, 49_7, 43.9, 36.], 30.6W Mass spectrometry: (PI-FAB) 532, (M) +. Example 25 (334) N (5-M-p-thiophene-2-stone spring Sg group) -L. T. p., Aminino-4-[3-(N, N.dimethylamino) propoxy ] -L-Phenylalanine Synthesis The title compound was prepared using Method 15 and isolated as a white hygroscopic solid, mp> 200 ° C. The NMR data are as follows: lH NMR (DMSO-d6, 300 MHz) ·, ^ · "7.62 (m, 2H); 7.44 (m, and separated into white hygroscopic solid ^ = 8.03 (br s, 1H); 7.74 (Please read the notes on the back before filling this page)

、 1T f -138 、 The paper ruler M Caiguan family standard ^ NS) Α4 specifications (210X297 ^ 534910 Λ7 __ I) Ί 5. Description of the invention (136) 2H); 6.99 (m, 2H); 6.71 (m, 2H); 4.05 (m, ih); 3.92 (m, 3H); 3.26 (m, 1H); 3.09-2.97 (br m, 3H); 2.30 (m, 2H); 2.13 (s, 6H); 1.82 (m , 2H); 1.79-1.51 (br m, 4H). 1 3C NMR (DMSO-d6, 75 MHz): β 2 173 3, 169.3, 157.2, 137.3, 134.3, 132.5, 130.9, 130.9, 1 19 8, 1 13 9, 65.9, 62.8, 56.0, 55.5, 49.7, 45.5 , 36.1, 30.6, 27.2, 24.0, 22.8. Mass spectrometry: (PI-FAB) 588, (M + Na) +. Example 26 (336) N- (Toluene-4-sulfonamido) -L-prolylamino-4- [2- (n, N-diethylamino) ethoxy] · L-phenylalanine Synthesis of fluorenyl esters is carried out by using 2-ethylaminoethyl gas in the presence of potassium octanoate and sodium sulphate, and refluxing 2-butanone 0-alkylated N- (methylbenzyl-4-sulfonyl) _L_ Preparation of Proline-L-Tyramine. The title compound was prepared as a solid using the procedure described in Method 7, 105-109 ° C. The NMR data are as follows: lH NMR (DMSO-d6, 400 MHz): c? 〇 (6H, t, J = 8, 8Hz) · Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy 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 = 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). Mass spectrometry: + ESI 'm / z 532.4 ([M + H] +' 100%). Example 27 (340) -139- --- (please first Read the notes on the reverse side and fill in this page)-Order t The paper size applies the Chinese National Standard (CNS) A4 (210X297 mm) 534910 Λ7 B * 7 V. Description of the invention (137) N-(2, 5 · 2 Chlorophene-3 -sulfofluorenyl) -L -prolylamino-4-[3-(N, N -diamidinoamino) propoxy] -L -phenylalanine Method 15 Preparation and separation into white hygroscopic solid, mp > 2 0 0 C ° NMR data are as follows: lH NMR (DMSO-de, 300 MHz) δ .11 (d, 1Η, J = 6.6Hz); 7.43 (s, 1H); 7.07 (d, 2H, J = 7.4 Hz); 6.76 (d, 2H, J = 7.4 Hz); 4.33 (m, 1H ); 4.15 (m, 1H); 3.89 (t, 2H, J = 6.1 Hz); 3.29 (m, 2H); 2.97 (m, 2H); 2.57 (t, 2H, J = 7.1 Hz); 2.31 (s , 6H); 1.85 (m, 4H); 1.65 (m, 2H). 13C NMR (DMSO-d6, 75 MHz): d = 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 spectrometry: (PI-FAB) 600, (M) +. Example 2 8 (341) N-(1 -Methylpyrazole-4 -sulfofluorenyl) -L -prolylamino-4-[3 · (N, N dimethylamino) propoxy] · L-Phenylalanine is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Synthetic Economy (please read the precautions on the back before filling this page) N _methylpyrazolesulfonyl chloride is added to N Prepared cold (0 ° C) chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and heated to 100 ° C overnight under a stream of nitrogen. The reaction mixture was then cooled to room temperature and quenched to 0 ° C. Add hypochlorous chloride (2.5 equivalents) to the solution, and stir at room temperature for 30 minutes, then warm to 70 ° C for 2 hours. The reaction was cooled to room temperature and then quenched in an ice bath. Water and ice were slowly added until the reaction mixture precipitated a white solid, which was collected by filtration. The required sulfonium chloride was washed with cold water and hexane. Title compound-140- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 534910 Λ? Βη 138, V. The description of the invention is prepared using method 15 and separated into white hygroscopic solid, mp 2 200 ° C. (Please read the notes on the back before filling this page) NMR data are as follows:] H NMR (DMSO-d6, 300 MHz): ^ = 8.44 (s, 1H); 7.89 (s, 1H); 7.66 (d, 1H , J = 5.6 Hz); 7.00 (d, 2H, J = 8.5 Hz); 6.70 (d, 2H, J = 8.6 Hz); 3.89 (m, 4H); 3.87 (s, 3H); 3.14-2.98 (br m, 4H); 2.34 (t, 2H? J = 7.2 Hz); 2.30 (s, 6H); 1.86 (m, 3H); 1.81-1.75 (br m, 3H). 13C NMR (DMSO-d6, 75 MHz): d 2 172.3, 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 Technique: (PI-FAB) 530, (ΜΓ. Example 29 (346) N · (toluene-4 -sulfofluorenyl) _L-proline methyl-4-[3-(N, N · diethylamine Methyl) propionyl] -L-phenylalanine methyl ester is synthesized by the use of 3-diethylaminopropyl chloride in the presence of potassium carbonate and sodium iodide at reflux 2-butanone O-alkane Preparation of N- (toluene · 4-sulfofluorenyl) · L-proline methyl-L-tyrosine methyl ester. The MR data printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are as follows: NMR (DMSO-d6, 400 Mhz): Π · 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, -141 -This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A7 ............ ^ — _ — ___ 5. Description of the invention (139) — — ^ J = 10Hz); 7.4 (2H, d, J ... 〇Hz); 7.7 (2H, d, J = 10Hz); 8.2 (1H, d, J = 10Hz). Mass spectrometry: + ESI, m / z 560.5 ([M + H ] +, Loo%). Example 3 0 (35 1) N-(Shunjun · 2-hydrazone)-L-Proline ®-4-[3 _ (n, N-Diamidinoamino) Propionyl] -L-phenylalanine, combined with chlorine based systems such as Roblin and Clapp, JACS, 72, 4890, 1950. It is shown to be prepared from thiols. The title compound was prepared using method 15 and isolated as white hygroscopic Solid, mp > 20 (T (:. The NMR data are as follows: 1 H NMR (DMSO-d6, 300 MHz): β = 8.24 (d, 1Η J 2 3 1 Hz). 8.15 (d, 1H, 3.1 Hz); 7.63 (d, 1H, J ^ 5.0 Hz ); 6.98 (d, 2H, J = 8.6 Hz); 6.70 (d, 2H, J = 8.6 Hz); 4.24 (m, 1H); 3.88 (m 3H); 3.36 (m, 2H); 3.28-2.98 ( m, 2H); 2.31 (t, 2H, J = 7 〇H juice 2.12 (s, 6H); 1.83-1.79 (bi · m, 4H); 1.79 (m, 1H); 145 (m 1H)., NMR (DMSO-d6, 75 MHz): β 2 172 3, 168 9 l62 $ 157.2, 145.5, 131.0, 130.9, 127.5, 1 13.8, 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 spectrometry · (PI-FAB) 555, (M-H + Na). Example 3 1 (353) N-(toluene-4 -mercapto) · L -proline hydrazone; _ 4 · [3 _ (n · Methyl n # amine) propoxy] -L -phenylalanine The title compound was prepared from the product of Example 3 3 (356) using method 7 -142- This paper size applies to the standard (CNS) A4 specification (210χ297 ^ ϊ ^-~~ --- (Please read the precautions on the back before filling in this page)

534910 Λ] Η " 7 V. Description of the invention (14Q) Sequence preparation is solid, m p = 8 7-9 0 ° C. The NMR data are as follows: 1 H NMR (DMSO-d6, 400 MHz): ό '= 7.75 (d, 2H, J = 10Hz); 7.65 (d, 1H, J = 4Hz); 7.4 (d, 2H, J = 10Hz) ); 7.18-7.3 (m, 5H); 6.96 (d, 2H, J = 10Hz); 6.65 (d, 2H, J = 10Hz); 3.97 (d, 1H, J = 4Hz); 3.91 (t, 2H, h: 4.4Hz); 3.8 (q, lH, 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). Example 3 2 (354) N · (Toluene-4 -sulfofluorenyl) -L -proline methyl-4-[3-(N, N -diethylamino) propoxy] · L -phenylpropylamine Synthesis of the acid The title compound was prepared as a solid from the product of Example 29 (346) using the procedure described in Method 7, mp = 7 6-8 2 Ό. The NMR data is as follows: Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) NMR (DMSO-d6, 400 MHz): d = 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). Example 3 3 (356) N · (Toluene-4 -sulfofluorenyl) -L -proline fluorenyl-4-[3 · (N -fluorenyl-N -fluorenyl-143- (CNS) A4 specification (210X 297 mm); Printed by the Ministry of Standards and Staff's Consumer Cooperatives 534910 Λ " ------ Β * 7 V. Invention Description (141) — One " — · — · —— ^ " Amino) propoxy] -L-benzyl alanine methyl methyl ester The title compound was synthesized by using 3- (N-benzyl, N-methyl) aminopropyl chloride on potassium carbonate and iodine Preparation of 2-butanone 0-alkylated N_ (toluene_ 4-% S blue group) -L-proline methyl-l-tyrosine methyl ester in the presence of sodium chloride under reflux, mp = 6 0- 70 ° C. Example 3 4 (372) N _ (1 -methylimidazole 4 -sulfofluorenyl) _ L _proamine fluorenyl_ 4 _ [3 (N, N dimethylamino) propoxy] -L -benzene The title compound was synthesized using method 15 and isolated as a white hygroscopic solid, 200 ° C mp. The NMR data are as follows: NMR (DMSO-d6, 300 MHz): ^ = 7.86 (s, 1H); 7.82 (s, 1H); 7.63 (d, 1H, J = 5.6 Hz); 6.96 (d, 2H, J = 8.2 Hz); 6.97 (d, 2H, J = 8.2 Hz); 4.12-4.09 (br m, 1H); 3.89 (t, 2H, J-6.5 Hz); 3.70 (s, 3H); 3.13 (m, 2H ); 3.00 (m, 2H); 2.33 (t, 2H, 7.2 Hz); 2.13 (s, 6H); 1.82-1.75 (m, 3H), 1.60-1.40 (br m, 3H). 13C NMR (DMSO-d6, 75 MHz): Π72.8, 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 spectrometry: (PI-FAB) 552, (M-H + Na). Example 3 5 (373) N-(2 -Amidinofluorenediazole-5 -sulfofluorenyl) _ L -proline amidino-4-[3-(N, N -dimethylamino) propoxyl The combined grade of L-phenylalanine B blue chlorine series such as Roblin and Clapp, JACS, 72, 4890, 1950 -144- This paper is fully compliant with China National Standard (CNS) A4 (210X297 mm) ） — —, Order ~ (Please read the notes on the back before filling out this page) 534910 Λ? Β * 7 142 V. Description of the invention () It is prepared from thiol. The title compound was prepared using Method 15 and isolated as a white hygroscopic solid, mp 2200 ° C. The NMR data are as follows: 1 H NMR (DMSO-d6, 300 MHz): ^ = 7.66 (d, 1H, J = 3.2 Hz); 7.02 (d, 2H, J = 8.5 Hz); 6.72 (d, 2H, J = 8.2 Hz); 4.28 (t, 1H; 5.8 Hz); 3.96-3.89 (br m, 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 = 7.0 Hz); 2.13 (s, 6H); 1.83 (m, 3H); 1.80-1.40 (m, 3H). 13C NMR (DMSO-d6, 75 MHz): Θ 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], 32.2, 30.9, 27.2, 24.1, 22.3, 15.9 ° Mass spectrometry: (PI-FAB) 548, (M). Example 3 6 (393) N-(Toluene-4 -sulfofluorenyl) -L -4proline methyl-4-[3-(N, N -dimethylamino) propoxy] -L -phenyl Synthesis of alanine The title compound was prepared as in Example 18 (138), but using L-thioproline instead of L-proline. The NMR data is as follows: Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) NMR (300 MHz, CD3OD): ri = 7.57 (d, 2H, J = 8.4 Hz), 7.20 (d, 2H, J-8.10 Hz), 6.92 (d, 2H, J = 8.40 Hz), 6.58 (d, 2H, J = 8.40 Hz), 4.50 (dd, 1H, J = 4.20, 7.50 Hz), 4.45 (d, 1H, J = 10.50 Hz), 4.17 (m, 1H), 3.87 (d, 1H, J = 10.50 Hz), 3.76 (t, 2H, J = 6.00 Hz), 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 -145- This paper size applies China National Standard (CNS) A4 specification (210X 297 mm) 534910 ---------- B * 7 V. Description of the invention (143) — ~ · · .—— (m, 2Η). " C NMR (75 MHz, CD3〇D): 177.75, 170.46, 159.43, 146.91, 135.93, 132.42 '' 3 1.73, 129.80, 1 15.75, 67.25, 57.90, 57.70, 52.92, 45.30, 38.33, 34 · 73, 27.94, 24.74, 22.16. Mass spectrometry: (FAB) 546 (M + Η). Example 3 7 (472) Ν · (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) when proline fluorenyl_4_ [3_ (N, N-difluorenylamino) The title compound was synthesized according to the procedure outlined in Preparation Example 20 (284). The NMR data are as follows: 4 NMR (CDC1;): β di 7.98-7.95 (d, 2Η), 7.83-7.80 (d, 2Η), 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). ] 3C NMR (CDC13): ό '= 179.9, 168.2, 158.8, 141.1, 133.7, 130.9, 128.1, 1 17.9, 1 15.2, 74.2, 66.7, 56.9, 55.3, 53.9, 53.0, 51.1, 46.0, 38.0, 29.9, 28.0, 24.4. Example 38 (514) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) N-dimethylamino) propoxy] -L-phenylalanine Synthesis of L-pimorlin-5-carboxylic acid by Larsson and Carlson (Acta Chemica

Scan. 1994, sister, 517-525). N_ (methylbenzyl_4_continuyl) _L-pyrimoline-5-carboxylic acid was prepared using the procedure described in method i. The compound was prepared according to the procedure summarized in Preparation Example 20 (284).乂 不 化 -146- This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A / — ~ -____ V. Invention Explanation (144) The NMR data is as follows:] H NMR (CD3OD): ο = 7.53-7.47 (m, 2H), 7.20-7.14 ^ 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), 218 (s, 6H) 5 1.92 (m, 1H), 1.68 (m, 2H). 13C NMR (CD3OD): 6 = 177.9, 177.8, 169.6, 169 · 4, 159.6, 159.5, 146.3, 146.1, 138.9, 138.9, 132.8, 132.4, I31 · 8, 130.5, 129 · 8, 129.2, 126.9, 115.8, 115 · 7, 67.4, 58.1, 57 · 8, 5 7 丄 45 · 6, 44.9, 38.8, 37.9, 28.2, 28.2, 27 · 9, 26.6, 26.3, 24.7, 22.1. Example 39 (169) Synthesis of N- (toluene-4-phenylmethyl) L_prolinemethyl-4_ [2_ (carboxy) phenoxy] -L-benzylalanine methyl ester N- (methylbenzyl -4 Sulfamethyl) -L-proline methyl-l-tyrosine (2.14 g, 5.10 mmol) to sodium hydride (60% in oil, equivalent, 228 mg) in xylene Class (50 ml) suspension at 0 ° C. The reaction mixture was stirred for 5 minutes, and cuprous bromide · dimethylsulfide complex (14 equivalents, 1.48 g) was added. The reaction mixture was at 23 ° C. (: Stirred for 05 hours. Sodium basic benzoate (1.5 equivalents, 8.06 mmol) was added, and the reaction mixture was refluxed for 12 hours. Ethyl acetate (100 ml) was added, and the organic layer was treated with ammonium chloride, 100% hydrochloric acid. It was washed with brine and dehydrated with magnesium sulfate. The crude material was dissolved in a columnar layer (silica gel) using chloroform: methanol 9: 1, and the title compound was isolated as an oil. The NMR data is as follows: -147- This paper size is applicable China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling in this page j-, _ ^ τ t 534910 ___ Β1 V. Description of the invention (145) * 4 NMR (300 MHz, CDCh) : β = 8.16 (br〇ad d, 1Η), 7 73 (m, 2H), 7.47 (m, 2H), 7.35 (m, 2H), 7.21 (m, 2h), 7 〇3 (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 spectrometry: (FAB) 567 (M + H). Example 4 (3〇9) N- (Metodon _4 -continuous acid group)]] ^-amine trap SS group-4- {2_ [4- (t? 密 Bit_2some) bis · hydropyrine-1 -yl] ethoxy}-L -phenyl Propylamine The synthetic methyl ester was prepared by following the procedure described in Preparation Example 20 (284) via N_ (toluene-4-methylamino) -L-proline methyl-L. The title compound was prepared as a solid using the procedure described in Method 7, mp = 102-105 ° C. The NMR data is as follows: lli NMR (DMS0-d6, 400 MHz): ^ = 1.35 (4H, s); 1.4 (1H, Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) m); 1.76 (1H, m); 2.38 (3H, s); 2.5 (2H, m); 2.66 (2H , t, J2, 8,8Hz); 2.9-3.1 (4H, m); 3.68 (4H, t, J2, 5,5Hz); 3.8 (1H, q, J = 4, 6, 4Hz); 3.95 (1H, dd, J = 2, 10, 2 Hz); 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-lOHz); 7.65 (1H, d, J = 4Hz); 7.74 (2H, d, J = 10Hz); 8.35 ( 2H, d, J = 5Hz). Example 41 (310) Synthesis of N · (toluene-4 -sulfofluorenyl) -L -proline methyl-4-[3-(hexahydropyridine-1 -yl) propoxy] -L -dongylpropylamine- 148- The size of this paper applies Chinese National Standard (CNS) A4 (210X 297 mm) _ One 534910 π Βη V. Description of the invention 146 'methyl ester is reflowed by using I-(2 -chloropropyl) hexahydropyridine 2-Butanone was prepared by 0-alkylation of N- (xylbenzene-4.sulfofluorenyl) _L_proline-L-tyrosine methyl ester in the presence of potassium carbonate and sodium iodide. The title compound was prepared as a solid using the procedure described in Method 7, mp = 122-125 X :. The NMR data are as follows: H NMR (DMSO-d6, 400 Mhz): 4 = 7.74 (d, 2Η, J = 10 Hz); 7.65 (d, 1H, J = 4Hz); 7.4 (d, 2H, J = i〇) Hz); 6.96 (d, 2H, J = 10Hz); 6.65 (d, 2H ”and 10Hz); 3.96 (dd, 1H, J = 2, 6, 2Hz); 3.9 (t, 3H, J = 7 , 7Hz); 2.95_3.1 (in, 4H), 2.46 (t, 1H, J 2.2, 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). Example 42 (311) N- (toluene-4_sulfonyl) -L- Proline amidino_4 · [2- (pyrrolidin-butyl) ethoxy] -L-phenylalanine is synthesized by the use of 1- (2-gasethyl) pyrrolidine at reflux 2_but Ketones were prepared in the presence of carbonic acid bell and magnetized steel with 0-pit N_ (methylben_ensulfonate) _L_proline methyl-L-methanoate. The title compound was prepared using the procedure described in Method 7. Solid, mp = 127-: 130 ° C. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The NMR data is as follows: 1 H NMR (DMS〇-d6, 400 Mhz) : — 73% 2Η tablets 〇Ηζ); 7'65 (d, 1Η, HHz); 7.4 (d, 2Η, ㈣Hz); 6 95 (d, 2η J = 10Hz); 6.65 (d, 2H, .N10HZ); 3.95 (t, 3 ^ J = 4, 6Hz); 3.7 1H, J = 2, 4, 2HZ); 2.95-3 "( m, 4H); 2.72 〇2h j = 6 6Hz); 2 48 (m '3H); 2 38 (S, 3H); 1 74 (m, called; w (t, 4H, Bu 4, 4Hz). 149 -The size of this paper applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs) 349l〇Λ7 、 一 、 ^ ___ B1 V. Description of the Invention (147) 1]. 42 ( m, 1H); 1.37 (s, 3H). Example 4 3 (3 16) NU (Chrysene-4 -sulfofluorenyl) _ L _proline sulphonyl _ 4 _ 丨 3 _ [4 _ (3 _ chlorophenyl) hexahydropyridine-: 1 -yl ] Propyloxy 丨 _ L-phenylalanine is synthesized by using 1-(3-chlorophenyl) -4-(3-chloropropyl) hexahydropyridine to produce 2-butanone in%. 1 In the presence of sodium sulphate and sintered n_ (toluene_ 4 _ fluorenyl) L-proline methyl-L tyrosine methyl ester preparation. The title compound was prepared as a solid using the procedure described in Method 7, mp = 116_8 ° C. The NMR data are as follows: 4 NMR (DMSO-d6, 400 Mhz): A = 7.74 (d, 2Η, J = 10 Hz); 7.65 (d, 1H, J = 4Hz); 7.4 (d, 2H, J = l〇 Hz); 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 2 8, 10,8Hz); 1.35 (s, 2H). Example 44 (318) N-(Toluene-4 -sulfofluorenyl) -L. Prolylamino-4-[(1 -Third-butoxycarbonylhexahydropyridine · 3 -yl) methoxy] -L -benzene Synthesis of methyl alanine N- (toluene · 4-sulfofluorenyl) -L-proline fluorenyl-〇-[(1 -third butoxycarbonylhexahydropyridine · 3-yl) methoxy] -L Phenylalanine methyl ester is obtained through the use of B oc-3-hexahydropyridyl tyrosine at reflux 2-methyl ethyl ketone in potassium rotate and stone code -------- • clothing- ---- 1T ------ (Please read the notes on the back before filling this page)

This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 534910 Λ7 B " 7 — —------- -------- ---------------—... I .-------I ---- -I-—___ _ 5. Explanation of the invention (148) O-alkane in the presence of sodium chloride Preparation of N- (toluene-4-sulfofluorenyl) -L · proline test group_L 酉 methylamine amino acid to obtain a solid, mp = 6 0-6 2 ° C. The title compound was a solid prepared from this product using the procedure described in Method 7, mp = 8 2-84 C. The NMR data are as follows: lR NMR (DMSO-d6, 400 MHz): c? -12.77 (br s, 1H) 8 00 (d, 1H, J = 7.9Hz); 7.68 (d, 2H, J = 8.3 Hz); 7.39 (d, 2H, J 2 7 9 Hz); 7.13 (d, 2H, J = 8.6 Hz); 6.81 (d, 2H, 8.6 Hz); 4.42 (m 1H); 4.10 (m, 1H); 3.78 ( m, 3H); 3.07 (dd, 1H, J = 9, 7, 4 lHz); 2.95 (dd, 1H, J2 19Hz, 5.1Hz); 2.90 (dd, 1H, J2 19Hz); 2.8 (m, 2H); 1.80 (m, 2H); 1.58 (m, 4H); 1.34 (br s, 14H) 〇IR (Kbr, cm1): 3400, 2900, 1745, 1700, 1525, 1450, 1350, 1250, 1 160 , 850, 800, 700, 650, 600. Mass spectrometry: (FAB, m / e (%)) 652 (75, (M + Na +)); 530.2 (75); 224 (100). Example 45 Synthesis of (3 22) N-(xylbenzene-4 -sulfofluorenyl) -L -sulfonamidinyl-4-[2 _ (morpholin-4 -yl) ethoxy] _L • phenylalanine Methyl esters are calcined by using N-(2 -chloroethyl) morpholine (cesium carbonate, DMF at 60 ° C. under argon for 72 hours) ν-(toluene-4 _sulfonyl) -L -proline Preparation of Aminomethyl-L-Lactamide. The product was purified by flash column chromatography (silica, ethyl acetate) to obtain methyl ester as an off-white foam. The title compound was prepared as a solid using the procedure described in Method 6, mp = 99-101 ° C. The NMR data is as follows: 151 This paper is of suitable size ---------______ 丁 ______ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 V. Description of the Invention (149) NB contains trace amounts of Tos-Pro-Phe (NMR)] H NMR (DMSO-d6, 400 MHz): d 2.7.73 (d, 2H, J = 8.6 Hz); 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 2 4Hz); 2.4 (m, 4H): 2.38 (s, 3H); 1.7 (m, 2H); 1.4 (m, 3H). IR (KBr, cm1): 3400, 2950, 2850, 1610, 1510, 1425, 1340, 1245, 1150, 1 125, 825, 800, 675, 575, 525. Mass spectrometry: (FAB, m / e (%)) 552 (100, (M + H +)). Example 46 Synthesis of methyl ester of (325) N- (toluene-4-sulfofluorenyl) -L-prolylamino-4_ [2- (hexahydropyridine-butyl) ethoxy] L-phenylalanine It was prepared via Mitsunobu reaction of N- (toluene-4-sulfofluorenyl) -L-prolinamido-L-tyrosine methyl ester using hexahydropyridine ethanol following the procedure described in Preparation Example 20 (284). The title compound was prepared as a solid using the procedure described in Method 7, ηρ = 102-106Ό. The NMR data are as follows: lH NMR (DMSO-d6, 400 MHz): d = 7.73 (d, 2H, J = 8 Hz); 7.60 (d, lH, J = 5.5Hz); 7.39 (d, 2H, J = 8HZ ); 6.96 (d, 2H, J = 8.6 Hz); 6.68 (d, 2H, J = 8.6 Hz); 3.96 (m, 3H); 3.84 (dd, 1H, J-5.2, 4.8 Hz); 2.97 -3.10 (m, 4H); 2.56 (t, 2H, J \ 5.9 Hz); 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, 1 150, 875, 675, 600, 550. -152- This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) "

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7-__B, V. Description of the invention (15〇) — " " _ Quality control: (FAB, m / e (%)) 542 (100, (μ · Η ·)); 196 (10); 155 (75). Example 47 (326) N-(Toluene-4 -sulfofluorenyl) -L-prolylfluorenyl · 4-丨 3 · [4-(3 chlorophenyl) hexahydro? Ratio 4-1 _yl] propoxy 丨 -L-benzyl alanine methyl ester synthesis of formazan is through the use of 1-(2 -phenylphenyl)-4-(3 -chloropropyl) hexahydro p ratio Preparation by biting 1 at reflux 2-butanone in the presence of potassium carbonate and sodium iodide 0-alkylated n- (xylbenzene-4 sulfonyl) -L-proline methyl-L-tyrosine methyl ester. The NMR data are as follows: NMR (DMSO-d6, 400 MHz): = 8.2 (d, 1Η, J = 10 Hz); 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 = 8,5,8 Hz); 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). Mass spectrometry: El, m / z 682/684 ([ΜΗ], 18%), 209 (26%). Example 48 (327) N-(Toluene_4 -sulfofluorenyl) _ L -proline fluorenyl-4 · [2 · (—azepine_ 1 -yl) ethoxy] -L -phenylalanine The title compound was synthesized from the product of Example 49 (328) as a solid using the procedure described in Method 7, mp = 105-107 ° C. The NMR data are as follows: -153- This paper size applies to the Chinese National Standard (CNS) Α4 size (X 297 mm) (Please read the precautions on the back before filling this page), 1T 534910 Β * 7 ~ -— ________—- '" —. — Λ C-1 V. Explanation of the invention ()! Η NMR (DMSO-d6, 400 Mhz): ^ = 7.75 (t, 2H, J-8,8 Hz); 7.45 (d, 1H, J2 8Hz); 7.4 (t, 2H, J = 8,8Hz); 7.05 (d, 1H, J = 10Hz); 6.96 (d, 1H, 10Hz); 6.7 (d, 1H, J = l 〇Hz); 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,) H, 7,7Hz); 1.65 (m, 1H); 1.5 ( bs, 6H); 1.43 (t, 2H, J = 8, 8Hz); 1.36 (m, 2H); 1.28 (s, ih); 1.15 (s, 1H). Example 49 (328) N-(Benzene-4 -SiSi:-)-L-Prolinefluorenyl-4-[2 _ (—Azone_ 丨 _yl) ethoxy] · L -phenylpropylamine The title compound was synthesized via the use of 2- (hexamethylene-imino) ethyl chloride under reflux, 2-butanone in the presence of potassium postionate and sodium sulphate, O-alkylated N- (toluene- 4-Acid group) -L-Aminyl-L-Aminomethyl acetate was prepared to obtain a solid, Hi p = 6 0-6 5 ° C. Example 50 (347) N-(Dongdong-4 -Jinji group) L _Aminocapsid-4-[3-(4 · methylhexachloro p ratio well-1-yl) propoxy] -L -Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Synthetic Economy of the Ministry of Synthetic Economics (Phenylalanine methyl g) Propyl chloride was prepared by refluxing 2-butanone in the presence of potassium carbonate and sodium iodide and alkylating N- (toluene-4-sulfonyl) -L-proline-methyl-L-tyrosine in the presence of potassium carbonate and sodium iodide. The NMR data are as follows: XH NMR (DMSO-d6, 400 Mhz): ^ -8.2 (t, 1H, J = 10, 10Hz); 7.7 (t, 2H, J = 110, i2H2〇; 7.4 (d, 2H, J = 10Hz); 7.1 (t, 2H, ___ -154- Chinese national standard (CNS) for this paper A4i ^ 7210x297 Gongqiao 534910 Λ7 ιυ 5. Description of the invention (152) J = 10, 10Hz); 6 · 8 (d, 2Η, J = 10Hz); 4.44 (q, 1Η, J = 4, 6, 6Hz); 4.1 (dd, 1H, J = 14, 8, 8Hz); 3.93 (t, 2H, J = 6, 6Hz); 336 (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). Mass spectrometry: + ESI , M / z 587 ([MH] +, 100%). Example 51 (355) N-(Benzene-4 -sulfofluorenyl) -L · proline fluorenyl-4-[3-(4 -fluorenyl Synthesis of hexahydropyridin-1-yl) propoxy] -L-phenylalanine The title compound was prepared from the product of Example 50 (347) using the procedure described in Method 7 as a solid, mp ^ SO-SSC. The NMR data is as follows : Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) lH NMR (DMSO-d6, 400 Mhz): ^ = 7.75 (d, 2H, J = 10 Hz); 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) 〇 Example 52 (345) Synthesis of N- (fluorenyl-4-sulfonyl) -L-proline sulfanyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl acetate The title compound is via N-(toluene-4 -sulfofluorenyl) -L · proline fluorenyl · (4--155-) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 534910 Λ7 ______ _ 一 .... __ · ... One by one_ --- 5. Description of the invention (153) Amino) Phenylalanine and trifluoromethanesulfonic anhydride in pyridine to obtain a solid, mp 2 7 5-7 8 C 0 Example 53 (370) N-(Toluene · 4-sulfofluorenyl) -L-proline methyl-4-N-(trifluoromethylamino) amino-L-phenyl The title compound is synthesized using the method of leucine from Example 52 (345) 6 The product prepared program. The NMR data is as follows: lU NMR (CDC13, 400 MHz): d-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.!): 3 3 90; 2950; 1750; 1650; 1525; 1425; 13 75; 1340; 1200; 1150; 950; 825; 625; 590; 550. Mass spectrometry: (+ ESI) 564 ([MH] +): 530; 462: 406: 362; 342: 335: 157 〇 Example 54 (387) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the Note: Please fill in this page again} f N-(Toluene-4 -gf group) -L -Proline fluorenyl-4-[(n-Wordaminoamino) fluorenyl] -L-phenylalanine Synthesis of methyl ester The title compound was alkylated (toluene_4_ammonyl) _ by using N-benzyl-2-aminoacetamide (potassium carbonate, sodium iodide under reflux of methyl ethyl ketone overnight). Preparation of stilbene-L-succinic acid methyl vinegar. The product was purified by flash column chromatography (broken oxygen 'hexane: ethyl acetate) to obtain methyl vinegar as a white solid, mp = 57-59 ° C. -156 -This paper size applies Chinese National Standard (CNS) A4 Regulation BOX297 mm) '^ ~~~ --- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 R " 7 V. Description of Invention (154) Example 55 ( 3 89) Synthesis of N-(Toluene-4 -sulfofluorenyl) -L -Ceramine-4-[(fluorenyloxycarbonyl) methoxy] -L-aspartyl alanine The title compound was prepared from Example 4 (387 The product was prepared using the procedure described in Method 6. Solid, m p = 7 9-8 1 ° C. The NMR data are as follows: NMR (DMSO_d6, 400 MHz): β = 12.2 (br s, 1H); 8.60 (t, 1H); 8.03 (d, 1H, J = 7.9 Hz); 7.70 (d, 2H , J = 6.6 Hz); 7.39 (d, 2H, J = 8.4 Hz); 7.15 (d, 2H, J = 8.6 Hz); 6.87 (d, 2H, J = 8.6Hz); 4.48 (s, 2H); 4.42 (m, 1H); 4.31 (d, 2H, J = 6.3 Hz); 4.10 (m, 1H); 3.0-3.2 (m, 2H); 2.8-2.9 (m, 2H); 2.38 (s5 3H); 1.2-1.6 (m, 4H). IR (KBr, cm1): 3400, 2950, 1725, 1660, 1525, 1510, 1450, 1350, 1240, 1 150, 1080, 670, 575, 550. Mass spectrometry: (FAB, m / e (%)) 602 (10, (M + Na +)): 580 (10, (M + H)): 131 (100). Example 56 (390) Synthesis of N- (toluene-4-sulfofluorenyl) -L-proline methyl-4-[(carboxy) methoxy] -L-phenylalanine Amidino) -L-proline Amidino-L-tyrosine methyl ester was alkylated with tert-butyl bromoacetate (potassium carbonate, DMF under argon for 72 hours) to obtain N- (xylbenzene · 4-sulfonate Fluorenyl) -L-proline fluorenyl-L-〇- (third butoxycarbonylfluorenyl) -methyl tyrosine, purified by flash column chromatography (siloxy,): hexane: ethyl acetate Ester) to give a white solid, mp = 55 ° C. ___ -157-This paper size applies to Chinese National Standard (CNS) A4 (210 × 21097 mm) --- ---- (Please read the precautions on the back before filling this page)

1.1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 Βη _ „_ -----. _____-........ ι ··· ι ·. I, V. Description of the invention (π5) N-(toluene-4 -sulfofluorenyl) -L -proline fluorenyl-L — 0 tertiary butoxycarbonylmethyl) -glyoxylic acid system consists of N-(toluene-4 -sulfofluorenyl) -L- Proline S warmyl_L · 〇 · (third butoxycarbonylmethyl) -methyl tyrosine was prepared as a solid using the procedure described in Method 6, mp = 6 9 · 7 0 C. The title compound was prepared from N- (Toluene-4 -sulfofluorenyl) -L -proline methyl -L-0-(third butoxycarbonylmethyl) -tyrosine is prepared by reaction with formic acid. The formic acid is removed and the desired compound is developed by ether White solid, mp = 7 0-7 3 ° C. The NMR data are as follows: iH NMR (DMSO-d6, 400 MHz): β di 12.85 (br s, 2H); 8.01 (d, 1H, J = 7.9 Hz) ; 7.69 (d, 2H, J 2 8.3 Hz); 7.39 (d, 2H, J 2 8 3

Hz); 7.13 (d, 2H, J = 8.8 Hz); 6.79 (d, 2H, J = 8.6 Hz); 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, cm1): 3350, 2950, 1730, 1625, 1510, 1425, 134〇1 175, 1 160, 1075, 825, 675, 575, 550 〇 Mass spectrometry: (FAB, m / e (%)) 513 (100, (M + Na +)), 491 (75, (M + H +)). Example 57 (407) Synthesis of the title compound from N- (toluene-4-sulfofluorenyl) -L-prolylfluorenyl 4-[(aminocarbonyl) methoxyl L-phenylalanine methyl g 2-Acetoacetamide (potassium carbonate, sodium iodide, butadiene refluxed under chlorine for 48 hours) Pleasant N- (曱 ben_4_sulfomethyl) _l_proline methyl-L-tyrosine methyl acetate preparation. The product is purified by rapid column chromatography (silicon-158- This paper is in accordance with Chinese National Standard (CNS) A4 size (210X 297 mm) --- ~, __ (Please read the precautions on the back before filling in this page) , 11 534910 Λ 156, V. Description of the invention Oxygen 'acetic acid acetate' and then 5% formic acid in ethyl acetate) to obtain the title compound as a main white solid, mp = 60-64 C. Example 58 (408) Synthesis of N- (toluene-4-stilbyl) -L-prolinyl-4-[(aminopropyl) methoxymethoxy [_ benzylalanine) The title compound was prepared from Example 5 The 7 (4 0 7) product was prepared as a solid using the procedure described in Method 6, mp 195-196 ° C. The NMR data are as follows: 4 NMR (DMSO_d6, 400 MHz): d di 12.2 (br s, 1H); 8 02 (d, 1H, J-8.1 Hz); 7.69 (d, 2H, J-8.3 Hz); 7.47 ( br s9 1H); 7.40 (d, 2H, J 2 7.9 Hz); 7.35 (bi · s, 1H); 7.14 (d, 2H, J 2 8.6 Hz); 6.84 (d, 2H, J = 8.6 Hz ); 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, cm1): 3500, 3350, 3250, 2950, Π25, 1675, 1660, 1560, 1510, 1450, 1400, 1350, 1225, 1200, 1 1505 1〇5〇5 3 ^^ 660, 575 , 550 05 mass spectrometry: (FAB, m / e (%)) 488 (100, (M · Η-)). Example 59 (409) N-(Toluene-4 -sulfofluorenyl) · L -proline methyl 4 _M μ ^ ^ Η U Ν _ di-dibutylaminocarbonyl) methoxy] _L -phenylalanine The synthesis of the title compound was carried out by the use of 2-chloro-N-di- butanidine dibutylacetamide (carbonic acid, sodium iodide, refluxing methyl ethyl ketone overnight under argon) to burn N_ (methylben_4_ complex group ) -L-Proline Si-L-L-amino acid formazan preparation. The product uses the rapid column layer 159 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7 One by one ·· _ _ _ V. Description of the invention (157) ^^… ~ ^ Analysis and purification (silica, 1 ·· 1 hexane: ethyl acetate ) The title compound was obtained as a white solid. The title compound was prepared as a solid using the procedure described in Method 6, mp = 88-890C. The NMR data are as follows: H NMR (DMSO-de, 400 MHz) · d = 12.2 (br s, 1H); 8.〇2 (d, 1H, J-8 Hz); 7.68 (d, 2H, J = 8.3 Hz ); 7.39 (d, 3H, J-8 Hz); 7.14 (d, 2H, J = 8.8 Hz); 6.82 (dd, 2H, J = 8.4, 2 Hz); 4.4 (m, 1H); 4.32 (s, 2H); 4.10 (dd, 1H, J = 2.9, 8Hz); 3.07 (m5 1H); 3.0 (dd, 1H, J = 18.7, 27.5 Hz); 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, 135〇, 1225, 1 160, 1075, 825, 675, 575, 540. Mass spectrometry: (FAB, m / e (%)) 544 (100, (M-H ·)). Example 60 (410) N_ (methylben-4-yl i6 group) -L-amine trapping group: 4- 4- [2- (4-phenyl-4-Hexapyridine-1 -yl) ethoxy] -L -Phenylalanine synthesis by the Central Bureau of Quasi-Ministry of Economics g Printed by Industrial and Consumer Cooperatives (please read the precautions on the back before filling this page) f Phenyl a hydrogen p ratio (bell carbonate, sodium bicarbonate, refluxing butyl side under argon for 72 hours) alkylated N- (toluene_4_sulfofluorenyl) _ L -proline methyl-L-Ο- Preparation of (2-chloroethyl) tyrosine methyl ester. The product was purified by f-speed column chromatography (silica, 5% methanol in chloroform) to obtain the title compound 2 as a white foam. The title compound was described in Method 6. It was prepared as a solid by the procedure, mp = 122-123 ° C. The NMR data are as follows: 4 NMR (DMSO-d6, 400 MHz): β 2.7.72 (m 2H); 7 61 (d, -160- ^ 5: scale applicable to China National Standard (CNS) XT specification (210X297 mm) ^ ^^-534910 Λ7 — ^ _______… — ________ V. Description of the invention (158) 1H, J = 5.5Hz); 7.39 (d, 2H, J = 7.2 Hz); 7.28 (m, 2H); 7.17 (m, 1H); 7.04 (d, 1H. J = 8.8 Hz); 6.96 (d, 1H, J = 8.6 Hz); 6.71 (dd, 2H, J-2.4, 8.8 Hz); 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, overlapping signals); 2.7 (m, 4H, overlapping signals); 2.38 (s, 3H); 1.65 (m, 2H); 1.55 (m, 2H); 1.4 (m , 2H). IR (KBr, cm1): 3375, 2890, 1600, 1610, 1510, 1390, 1325, 1250, 1160, 1075, 1040, 700, 675, 575, 530. Mass spectrometry: (FAB, m / e (%)) 648 (100, (M + 2Li-H) +), 624 (90, (M + Li)). Example 61 (375) N-(toluene-4-hydrazone) inosamine hydrazone- D, L-4-(fluorenyl) phenylalanine synthesized by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics (please read the precautions on the back before filling out this page) N-(toluene-4 -sulfonyl) Inosinamide-d, L-4 Cyanophenylalanine (Reference Example 61 (381)) (167 mg, 0.388 mmol) was dissolved in pyridine (ό ml), and then hydrogen sulfide was passed to saturation . The mixture was stirred for 19 hours' and then the volatiles were removed under a stream of nitrogen. The residue was taken up in ethyl acetate (50 ml) and washed with 5% aqueous potassium hydrogen sulfate solution (2 x 2 5 ml). The organic solution was dehydrated (sodium sulfate), filtered, and evaporated in vacuo to obtain N_ (toluene-4 · amino acid) inosamine donkey-D, L-4_thiocarboxamidophenylphenylalanine methyl ester. Thiamine is dissolved in acetone (10 ml). Add panamari (丨 ml) and heat the mixture at reflux for 1 hour. Removal of volatiles to obtain N_ (toluene_4-sulfofluorenyl) inosamine hydrazone 1-based, D, L-4 -methylthiocarbamate phenylalanine methyl hydroiodate (256 φ g '1 〇〇%). Thioimidate is dissolved in methanol (5m -161-This paper rule applies to Chinese National Standard (CNS)-53491ο

A Economics; Printed by the Consumer Cooperatives of the Ministry of Standards of the People's Republic of China _____ V. Invention Description (159). ^ L). Ammonium acetate (52 mg, 0.67 mmol) was added and the mixture was heated at reflux for 1.5 hours. Removal of voiding agent and purification of the residue by preparative τ lc (90: 10: 1 dichloromethane / methanol / ammonium oxide) to obtain ^ _ (xylbenzene-4-% SS group) inosamine base- D, L-4-Amidinophenylalanine methyl ester (75 mg, J 8%) The title compound was prepared by hydrolyzing methyl esters with τ HF / water using 0.5N steel hydroxide (66 mg , 87.7%). The NMR data are as follows: H NMR (DMSO-d6): J = 7.66 (m, 4Η), 7.43 (d, 2Η J = 7 7 Hz), 7.29 (d, 2H, J = 8.0 Hz), 4.10 (m, 1H ), 3.57 (s, 2H), 3.20- 3.06 (m, 2H), 2.54 (s, 3H), 2.40 (s, 3H). Mass spectrometry: FAB m / e 433 (M + H). Example 62 Synthesis of (381) N- (toluene_4-sulfofluorenyl) inosinamide-D, L-4- (aminocarbonyl) phenylalanine Coupling of amino acid to 4-cyanophenylalanine acetic acid hydrochloride (prepared by the method of Wanger, Volght, and Vleweg pharmazine 1984, 39, 226-230) to obtain N_ (曱 笨 _4_sulfonyl ) Inosamine methyl 4, L-4-cyanophenylalanine methyl ester. Compounds were prepared by hydrolyzing methyl esters with THF / water using 0.05 N sodium hydroxide. N- (Toluene-4-sulfofluorenyl) inositino-D-L, L_4-cyanophenylalanine methyl acetate (0.00 mg, 0.699 mmol) in ethanol (3 ml) to prepare a slurry. Add sodium hydroxide (10N, 98 µl) and hydrogen peroxide (475 µl, 551 mmol) to the mouthpiece and heat to 50 ° C for 16 hours, at which time a white precipitate is deposited. The mixture was cooled to room temperature and adjusted to acidic with hydrochloric acid (6N). Mixture with water _____ -162- This paper size applies Chinese national standard TcNS) (21〇x2975y (Please read the precautions on the back before filling this page)

, 1T f I I----1. 534910 five Λ] Β1 Description of the invention (16.) (20 ml) diluted, and extracted with chloroform (4 X 2 5 liters). The organic extract was dehydrated (sodium sulfate), filtered, and reconstituted from methanol to give the compound as a white solid (135 mg, 45%). · NMR data are as follows: 1 H NMR (DMSO-d6): d = 8.31 (br d, 1H, Bu 3.6 · ζ), 7.92 (br s, 1H), 7.72 (d, 2H, J 2 7.8 Hz), 7.62 (d, 2H, J = 7.9 Hz), 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-d6): -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 spectrometry: FAB m / e 434 (M + H). Other compounds prepared by the aforementioned methods include those listed in Table 11 below as examples 63-135: R3 〇 | II · R] -S02-N (R3) -C-Q-CH-C-R6 '.

i IH R5, (please read the precautions on the back before filling this page), 1T printed in each case by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Q =-C (Ο) N N _ R1 R2 R3 R5 R6, instance number ρ-ΟΗ, -φ R2 / R3 bicyclic 3 carbon atom (L-pyrrolidinyl) P-[-NHC (0) CH (NHBoc) (CH2) 4 NHCbz] -benzyl- -OH 63 ρ-ΟΗ , -φ R2 / R3 bicyclic 3 carbon atoms (Lp than p each aryl group) p-[-NHC (0) -CH2CH-NHCbz] -benzyl 0 (〇) 〇0Η2φ -〇CH3 64 p-CH'- cj) R2 / R3 = ring 3 carbon source pl -NHC (0) CH-NHBoc] -benzyl-OH 65 -163- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 534910 5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 7 * 7 Description of the invention (161) R1 R2 R3 R5 R6, Example number (L-pyrrolidinyl) CH2CH2CH2CH2NH2 ρ-οη3-φ R2 / R3 = Ring 3 carbon (L-speaking pyridinyl) p- (H2NCH2CH2CH2C (0) NH) fluorenyl- -OH 66 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- (Boc-NHCH2CH2CH2C (0) NH) benzyl- -OH 67 ρ-ΟΗ ^ -φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) PI CH3NHCH2CH2CH2 -C (0) NH-] i? Group- -OH 68 ρ-ΟΉγφ R2 / R3 bicyclic 3 carbon atom (Lp ratio than the nicotyl group) p- [CH3 (Boc) NCH2CH2CH2C (0) NH- Ff group- -OH 69 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) P-[(|) CH20CH: (H2N) CHC (0) NH] benzyl- -OH 70 ρ-0Η3 -φ R2 / R3 = 3 cyclic carbon atoms (L-? Bilundyl) p- [H0 (0) C (Cbz-NH) CHCH2CH2C (O) NH-] benzyl- -OH 71 p-CHs- φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p- [H0 (0) C (H2N) CHCH2CH2-C (0) NH-] fluorenyl- -OH 72 p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (Lp is more than p each symptomatic group) p- [CH3 (N-Boc) NCH2C (0) NH_] fluorenyl-OH 73 p-CHs-φ R2 / R3 = cyclic-CH2-SC (CH3) 2- (L-5.5-dimethylp-sedetidine-4-yl) p- [CH3 (N-Boc) NCH2C (0) NH-] benzyl-OH 74 ρ-0Η3-φ R2 / R3 = ring 3 carbon atom (L-pyrrolidinyl) p- [CH3NHCH2C (0) NH-] benzyl · -oc'h2ch3 75 p-CH34 R2 / R3 = ring 3 carbon atom (L-pyrrolidinyl) ) PI ch3nhch2c (o) nh-] benzyl- -OH 76 ρ- € Η3-φ R2 / R3 = cyclic-CH2-S- < :( αι3) 2-α-5.5-dimethyl-Petazole Pyridin-4-yl) p- [CH3NHCH2C (0) NH ·] fluorenyl- -OH 77 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrole Pyridyl) p-[(CH3) 2NCH2C (0) NH_] benzyl- -OH 78 p-CHs-φ R2 / R3 = cyclic-CH2-S-(: ((: Η3) 2- (1 ^ 5 , 5-Dimethyl p- [(ch3) 2nch2c (o) nh-] benzyl- -OH 79 (Please read the notes on the back before filling out this page) -164- This paper size applies to Chinese National Standards (CNS) A4 specification (210X 297 mm) 534910 A7 ________B1 V. Description of the invention (162) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs R1 R2 R3 R5 R6, with the case number base ρSeritis-4-base) p-CHS- φ R2 / R3 = Cyclic 3 carbon atoms (Lp is slightly ρ-based) ρ-[(third butyl-0 (0) CCH2-0-benzyl) -NH-] benzyl- -och3 80 p-ch34 R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- (2-methylfluorenyl-U, 3,4-tetrahydroisoquinoline 3-yl-CH2NH-) benzyl- -OH 81 ρ-〇Η3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- | -OCH2CH (NHBoc) CH2 cyclohexyl] benzyl- -och3 82 p-CHs-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) m-[-OCH2CH2CH2N (CH3) 2] _ benzyl- -OH 83 ρ- € Η3-φ R2 / R3 = cyclic-ch2ch2c (ch3) 2- p- [ (ch3) 2nch2ch2ch2o) benzyl- -OH 84 p-CHs-φ R2 / R3 = cyclic -CH2-SC (CH3) 2- (L -5.5-dimethylpyrazolidine-4-yl) p-[(CH3) 2NCH2CH2CH20] benzyl- _oc'h2ch3 85 ρ-〇Η3-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl ) P- [2-〇 Bibicyclo [3.2.2] oct-2-yl) ethyl-O-] 7 ^--0CH3 86 ρ- € Η3-φ R2 / R3 = ring 3 carbon atom (L -Pyrrolidinyl) PI (CH3) 2NCH2CH2CH2-0-] benzyl- -OH 87 ρ- € Η3-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p-[(ch3) 2nch2ch2ch2- 0-] benzyl- -och3 88 ρ ^ Η3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- [2o γbicyclo [3 · 2.2] octyl) ethyl-0-] card --OH 89 ρ-ΟΗ3-φ Η -CH:-(j) (L-isomer) p- (cyclopentyl-OC-)-benzyl- -OH 90 ρ- € Η3-φ Η- CHr Φα-isomer) fluorenyl- -OH 91 ρ-ΟΗ3-φ Η -ch2- Φα-isomer) p-[-C = C-CH2-0-S (0) 2 ^ -CH34]- ir-OH 92 (Please read the notes on the back before filling out this page)

、 1T -165- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) '-______} V, ι〇A " Five Invention Notes (163) ~ s Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Γ --- R1 ^ —__ R2 R3 R5 R6, instance number Η -CH:-Φ0-isomer) p + c «h2nhc (o) nh2] -benzyl-0H 93 ρ ^ Η3-φ Η -CH : -Φ (ί-isomer) P-[-C = C-CH2-0-p-C00CH2CH3 ^]-fluorenyl-0H 94 Ρ '^ Η3-φ ~~~ ---- Η -ch2- Φ0-isomer) P + CM: -CH (NH2) -cyclohexyl] • benzyl-0H 95 ρ-〇Η3-φ R2 / R3 = cyclic 3-carbon proton (L-pyrrolidinyl) pM «-Ch2-o-phenyl] -benzyl-0H 96 -ch3 Η p + oc-ch2-o-phenyl] -benzyl-0H 97 ρ- € Η3.φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) ρ-Κ «η2-〇 (: η3) _ benzyl-0H 98 ££ Η3-Φ -ch3 Η P- | -C«: H2-0CH3] -benzyl-0H 99 Ρ -[Η3-φ R2 / R3 bicyclic 3 carbon atom (L-pyrrolidinyl) p + OC-CH2-Op-(-C (0) OC2H5) phenyl Kf group OH 100 ρ ^ Η 3.φ -CH ; Η p + C3C-CH2-0-p-(-C (0) 0C2H5) phenyl Kf group-OH 101 ρ- € Η3-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p + oc-ch2ch (c (o) och3) 2] -benzyl-OH 102 p-CH ^ -ψ -ch3 Η p-[«-CH2CH (C (0) 0CH3) 2Kf group-0H 103 p-CH : Pc () R2 / R3 = 3 cyclic carbon atoms (1-pyrrolidinyl) p + OC-CH2CHC (0) OHFf group NHC (0) CH3 -OH 104 ρ-ΟΗ ^ -φ -CH; Η p + oc-ch2chc (o) oh] -benzylNHC (0) CH3 -OH 105 ρ-ΟΗ, -φ R2 / R3 = 3 cyclic carbon atoms (L-say pyridyl) P- | -CeC-CH2NH- (4,5-dihydro-4-oxy- 5-phenyl-azazol-2-yl)] yl-0H 106 ρ-ΟΗ ^ -φ -CH; Η p-[-OC-CH2NH- ( 4,5-Dihydrobutoxy- 5-phenyl number 2--2-yl)] + group-0H 107 p-CH34 R2 / R3 = cyclic 3-carbon proton p + OCH2CH2CH2- (l-hexahydropyridyl )]--och3 108 (Please read the notes on the back before filling this page)

、 1T f -166-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 349i〇5 printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 __ _______ J * 7 Description of the invention (164) — ^ R1 ----- R2 R3 R5 R6, instance number, ^^ ___ product (L-pyrrolidinyl) benzyl P ^ Η3-φ R2 / R3 = ring 3 carbon atoms (L-? Pyridyl) m-[-OCH2CH2- (l-pyrrolidinyl)] · fluorenyl- -ΟΗ 109 P ^ Η3-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p-[-OCH2CH2- (N -Morpholinyl)]-benzyl- -ΟΗ 110 Ρ ^ Η3. Φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p- [-OCH2CH2 -1-(4-benzyl-4- ( 3-methoxy-p-pyrrole-2-yl) -hexahydropyridine) -fluorenyl- -och3 111 P ^ Η3-φ ---_ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p- [0_3- (N-Boc) -hexahydropyridyl]-; yl-OH 112 P-CH34 R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) m-[-0- (N- Methyl · hexachloro p-ratio-4-yl) -yl group- -OH 113 P-〇Η3.φ R2 / R3 bicyclic 3 carbon atom (L-pyrrolidinyl) p-[-0- (N -Methyl-hexahydropyridin-4-yl) -methyl-OH 114 1> 〇 15-φ R2 / R3 = cyclic -CH: -S-c (ch3) 2 P-[(1-methylhexahydrobex-4-yl) -〇-] benzyl- -och2ch3 115 P'〇Η3-φ R2 / R3 = cyclic -CH2CH2-SO: -CH2- (L -1, oxythiomorphine-]-yl) p-[(l-methylhexahydro-p-pyridin-4-yl) -〇-] benzyl- -och2ch5 116 P'〇Η3-φ R2 / R3 = Cyclic-CH2CH2-S02-CH2- (L-1,1_dioxythiomorphin-3-yl) p-[(1-fluorenylhexahydroexo-4-yl) -〇-] Benzyl- -och2ch3 117 ρ- € Η3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p-[(]-methylhexahydropyridine · 4-yl) -0 ·] Benzyl- -OH 118 p-CHs-φ R2 / R3 = cyclic C (CH3) 2- (L_5.5-dimethyl-p-phenone-4-yl) p-[(1-methylhexahydro Outer t. 4-yl) -0-] benzyl- -OH 119 p-CH ^ -cj) R2 / R3 = ring 3 carbon atoms (Lp than p each phenyl group) p-[(1-methyl Hexahydro-specific ratio _4_yl) -〇-] benzyl- -och2ch5 120 ρ-ΟΗ3-φ R2 / R3 bicyclic 3-carbon proton P + NΗ502-(: Η2 (: 1 > ^ group--och3 121 (Please read the precautions on the back before filling this page) Order f -167- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 534910 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 7 Βη Description of the invention (165) R1 R2 R3 R5 R6, Example number (L-pyrrolidinyl) ρ (Η3-φ R2 / R3 = ring 3 carbon atoms (Lp is slightly higher than phenyl) p + nhso2-ch = ch2] -benzyl- -och3 122 ρ- € 3-3-R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p- [N-3-methylbutyl-N- (trifluoromethanesulfonate Fluorenyl) amino] fluorenyl--och3 123 p-CHs-φ R2 / R3 = cyclic 3 carbon atoms (L-pyrrolidinyl) p- [N- (vinylamino) amino] fluorenyl · -OH 124 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p-[-0CH2C (0) 0-benzyl] -benzyl- -och3 125 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) P-[(hexahydropyridyl) c (o) ch2-o-] benzyl · -OH 126 p-CHs-φ R2 / R3 = Ring 3 carbon atom (L-pyrrolidinyl) p-[(ch3) 2ch2nc (0) ch2-0-] fluorenyl group--och3 127 ρ-ΟΗ ^ -φ R2 / R3 = ring 3 carbon atom (L -Pyrrolidinyl) pl (ch3) 2ch2nc (o) ch2-o-] fluorenyl · -och3 128 ρ-οη3-φ R2 / R3 = ring 3 carbon atoms (L-pyrrolidinyl) p- (N- Fluorenylethylamine) fluorenyl-OCH (CH3) 2 129 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- (N-fluorenylacetamido) --OH 130 ρ- € Η3-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- (N-methyldimuridine ethylamino) fluorenyl--och3 131 p-CHs -φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) (1-toluene). (Gui-4-yl) methyl-OCHs 132 p-CH3-c |) R2 / R3 = Cyclic 3 carbon atoms (L-supridinyl) 1-[(NN-dimethylaminosulfonyl ) -Imidazol-4-yl] fluorenyl- -och3 133 p-CHs-φ R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p- (N-toluene continuous amino group) + group- -och3 134 ρ- € Η3-φ R2 / R3 bicyclic 3 carbon atom (L-pyrrolidinyl) p- (N-toluenylamino) fluorenyl- -OH 135 (Please read the note on the back first Please fill in this page for more information) -168- This paper size is applicable to Chinese National Standard (CNS) Α4 specification (210X297 mm) 534910 Λ 7 ^^ —_____ Β * 7 —-— _ 一 丁 ". A — ... .. One-One-One-Fifth, Description of the invention (166) In addition, 'The following compounds are prepared as examples except where indicated 丨 3 6 _ 丨 4 〇: Example 1 3 6 Synthesis of L- (5,5-Difluorenyl) pyrimidinamine-4- [3- (N, N -dimethylamino) propoxyl L-phenylalanine tert-butyl ester The compound was prepared as in Example 2 but using N_B 0 butyl tyrosine second butyl ester instead of N-B 0c-methyl amine. MS: [(+) ESI], [M + H] '620 Example 1 3 7 N- (Benzene Synthesis of -4-sulfofluorenyl)-^ proaminefluorenyl-L- (4- (N-methylhexahydropyridyloxy) phenylalanine) third butyl ester The title compound is based on B 0p coupling T 〇s _ pr 〇_ 〇Η was prepared with T yr _ 〇_ i-methyl "hydrogen bite second butyl ester (prepared by] yjitsunobu reaction). The crude product was purified by flash chromatography (silica, 95: 5 ethyl acetate: triethylamine) to obtain a white solid (0.61 5 g, 60%). MS: ((+) ESI, m / z (%) 586 (100 [M + H]). Analytical calculation 値C31H43N 3 06S: C, 63.57; H, 7.40; N, 7.17. Measured 6: C, 63.1 〖; H, 7.37; N, 6.96. Example 1 3 8 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read first) Note on the back page, please fill in this page to order f N- (toluene-4-sulfonyl) -L_ (5,5-dimethyl) pyrimidofluorenyl_l_4_ (N -methyl (hexahydropyridyloxy) ) Phenylalanine) The synthesis of the third butyl ester The title compound was prepared following the procedure described in Example 丨 3, but substituted with appropriate starting materials. Analytical calculation 値 〔32} 145 > ^ 〇32 * 0.25 ^ 〇12; (:, 58.85; 1 ^ 7.02; N, 6.43. Found: C, 58.75; H, 6.92; N, 6.48. _ -169- China ^ ?? ^ Standard (CNS) A4 specification (210 × 29 ^ ϊ! &Quot; — 'Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 Λ7' ------------- B1 __________ V. Invention Explanation (167) to MS (+ ESI): 632 [M + H] ° Example 1 3 9 N-(Toluene · 4-Phenyl) _ l -f] Petamine iS group- (4-phenyl)- Synthesis of L-benzyl alanine tert-butyl ester The title compound was prepared from the corresponding trifluoromethanesulfonate (which is made from N- (toluene 4-sulfofluorenyl) -L-proline methyl-L-tyrosine Tertiary butyl acid was prepared by Tilley and coworkers, J. Org. Chem., 55 906, 1990). The dipeptide (505 mg, 0.8 mmol) was catalyzed by palladium (triphenylphosphine) palladium (0), potassium carbonate (201 mg, 1.5 equivalents), phenyldihydroxyboric acid (199 mg, 2.0 equivalents) and 15 ml of toluene under reflux with stirring for 10 hours. Ethyl acetate and the organic layer were added with water and oxidized with 1 N Wash with sodium, brine, and dehydrate with magnesium sulfate. During filtration, reduce pressure The solvent was removed by evaporation. The crude material was purified on a preparative plate (丨: 丨 ethyl acetate: hexanes). The silica gel was washed several times with acetonitrile and ethyl acetate. The combined fractions were evaporated and the residue was decompressed. The NMR data are as follows: NMR (CDC13, 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 ,): 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, 23.92 Example 1 4 0 -170- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm f ^ clothing-(Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. 534910 5. Description of the Invention (168) — N-(Toluene-4 -sulfofluorenyl) -L -Proline fluorenyl- (4 · phenyl) _ l _benzene The title compound was synthesized from the product of Example 1 39 using the procedure described in Method 11. The NMR data are as follows: NMR (CD3OD, 300MHz): δ 8.05 (m, ih); 7.71 (d, 2Η J = 8.24 Hz); 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). 3C NMR (CD30D): 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. Example 1 4 1 Test tube assay analysis of candidate compounds determined to be combined with VLA-4 A test officer test assay was used to evaluate candidate compounds and ... β! Integrin. In such assays, the combined compounds can be used to assess the VC AM-1 content of biological samples using conventional assays (such as a competitive assay). This kind of check points are discounted to approximately 5 of InM.値 Sensitive. α4β 1 integrin is soluble VCAM-1 and Jurkat cells (for example, American Seed Penalty, Silkworm Collection, Silkworm Collection No. TIB 152, TIB 153, and CRL 8163).埂 α4 β 丨 Integration of human T cell line interactions ° VCAM-〖α4 β 丨 Integrin-related interactions on the cell surface (Yednock, et al j βι〇chem ·, 1995, 210_: 28740) . ____171 This paper is suitable for households ^ 7 ^^; ^^ (Please read the notes on the back before filling out this page} -Order_ Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 534910 Λ7 Ⅴ-Description of Invention (169) ^ ~ ^ Recombinant soluble VC AM-1 line is an allelic fusion protein showing that it contains seven VC AM-1 extracellular domains at the N-terminus and a human IgGi weight region at the C-terminus. The VCAM-1 fusion protein was produced and purified in the manner described in Yednock (see above). Zucquet cells were grown on RPMI 1640, which was supplemented with 100 /. Fetal bovine serum, penicillin, streptomycin, and vitilamine, Growth lines were performed as described by Yednock (see above). Zukat cells were incubated with 丨 · 5 mM MnCl 2 and 5 μg / ml 1 5/7 antibody for 30 minutes on ice. Mn 2 activated the receptor to enhance ligand binding , And 15/7 is a single antibody that recognizes the activation / complexing configuration of α4βi integrin and locks the molecule into this configuration, thereby stabilizing the interaction of VCAM-1 / o ^ pi integrin. Yednock et al., Supra. Antibodies similar to 15/7 antibodies have been developed by other researchers (Lu que, et al, 1996, J. Bio. Chem. 2I1: ii〇67) were prepared and used for this assay. The cells were then used at room temperature with candidate compounds at various concentrations from 66 μM to 0.01 μM using a standard 5-point series. Incubate for 30 minutes in a diluted dilution. Then 15 microliters of soluble recombinant VC AM-1 fusion protein is added to the Zukaite cells, and the ice bath is incubated for 0 minutes (Yednock et al., Supra). The cells are then washed twice. And resuspended at 1: 200 in pE conjugated goat F (ab ') 2 anti-mouse igG Fc (Immunotech, Ind., Westbrook) and incubated for 30 minutes in the dark on ice. Cells Washed twice and analyzed using a standard fluorescent activated cell screen ("FACS") as described by Yednock et al., Supra. Compounds with IC 5 G below about 15 μM have binding affinity for ^ ... ___-172 -This paper size is applicable to China National Standard (CNS) Α4 specifications (2— '(Please read the precautions on the back before filling this page)

、 1T f 534910 Λ7 I ”One — _ ____ One One 1 One 1 One One ... One. · '· _One_« · _ V. Description of the Invention (170) At the time of this verification analysis test' The compound of Example 丨 -55 has an IC 5Q of 15 μM or less. Example 1 4 2 Test tube test saturation determination analysis to determine the combination of candidate compounds with α4 β 1 The following describes the test tube test analysis analysis to determine as described in the next example or other living organisms The plasma concentration required for the compound to be active in the experimental autoimmune encephalomyelitis ("EA E, ') model described in the experimental model. The logarithmic growth phase Zuket cells were washed and resuspended in normal animal plasma containing 20 μg / ml 15/7 antibody (as described in the previous example). Zukat cells are diluted twice, using a standard 12-point serial dilution using a standard curve, diluted into normal plasma samples containing varying amounts of candidate candidate compounds ranging from 66 μM to 0.01, or obtained from candidate compound treatment Plasma samples of peripheral blood of the animal ° Then the cells were incubated at room temperature for 30 minutes. Phosphate buffered saline ("PBS") containing 2% fetal calf serum, and 1 μM calcium chloride and magnesium chloride (assay analysis medium) ) Wash twice to remove unbound 15/7 antibody. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) and then expose the cells to phycoerythrin-conjugated goat p ( ab,) 2 anti-mouse IgG Fc (Immunotech, Westbrook, Maine), which has been absorbed for co-cultivation with 5% serum from study animal species for use in any non-specific cross-reactivity test, using 1: 200 dilution and culturing for 30 minutes at 4 C in the dark. Cells are washed twice with the assay medium and resuspended in it. Then use a standard fluorescent activated cell sorter ("FACS ”) The analysis is as described in Yednok et aL J. Bio. Chem., 1995, 270: 28740. -173-_ This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperative 534910 Λ7 __; _______ B " V. Description of the Invention (171) The data is then plotted against the dose in a normal dose-response manner. The dose obtained from the platform above the curve is shown in the live test mode The concentration required to obtain the effect. This assay can also be used to determine the plasma concentration required to saturate other integrin binding sites, such as α 9 β 1 integrin, which is the closest integrin to α 4 β i (Palmer et al., 1993 , J. Cell Bio., 123: 1289). This combination predicts the use of living organisms for the inflammatory condition of α9 β integrin-mediated diseases, including, for example, overreaction of the airways and obstruction of chronic asthma and atherosclerosis. Hyperplasia of smooth muscle cells, vascular occlusion after angiogenesis, fibrosis and glomerular scabs due to kidney disease, aortic constriction, excessive synovial hyperplasia of rheumatoid arthritis, Inflammation and scabs that occur during the development of ulcerative colitis and Cohen's disease. Therefore, the aforementioned assay can be performed using a human colon cancer cell line sw " ο (ATCC # CCL228) with a cDNA encoding α9 integrin transfer infection (Y (Okosaki et al., 1994, J. Bio. Chem., 269: 26691) was performed in place of Zukat cells, and the binding of α 9 β integrin was measured. As the control, SW 480 cells which can express other α and β i subunits can be used. As such, another aspect of the present invention is directed to a method for treating a disease in a mammalian disease, the disease caused by an α) βi vector, and the method comprising administering to the disease a therapeutically effective amount of a compound of the present invention. Such a compound is preferably administered as the aforementioned ft pharmaceutical composition. The effective daily dose will depend on the age, weight and condition of the patient, and these factors are conveniently determined by the clinician. However, in the preferred embodiment, the compound is administered at about 20 to 500 micrograms / kg / day. "Example 1 4 3 -174- Standard for this paper (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

、 1T Φ! Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 534910 A7 ^ Ming (^ 7 ~~ · · ^ ~ — --- — Evaluation criteria for in vivo tests Multiple sclerosis model, experimental autoimmune (or allergic) Cerebrospinal inflammation (EA E '') is used to determine the effect of candidate compounds on reducing sports injuries in rats or guinea pigs. The reduction of sports injuries is based on the blocking adhesion between white blood cells and the endothelium, and has an interactive relationship with the anti-inflammatory activity of the candidate compounds. . This type was previously described by Keszthelyi et al. Neurology, 1996, 47: ι053 · 1059, and measured the delayed onset of disease. Hartley adult guinea pig brains and chordal cords were homogenized with an equal amount of phosphate buffered saline An equal volume of Frode's complete adjuvant (100 mg of Mycobacterium tuberculosis plus 10 ml of Frode's incomplete adjuvant) was added to the homogenate. The mixture was repeatedly cycled through a 20 ml syringe using a pulse dish to emulsify for about 20 minutes. Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs (20-day old, 180-200 g) were anesthetized with isoflurane and injected 3 times each in the flank, each with an emulsion 0.1 ml. After 9 days, sports injuries were found. The treatment of the candidate compound started on the 8th day, just before the onset of symptoms. The compound was taken subcutaneously (" SC "), orally (,, p0") or intraperitoneally (,, IP " ) Dosage. The dosage is 10 mg / kg to 200 mg / kg twice daily for a total of $. The typical dose is subcutaneous injection of 10 to 100 mg / kg and oral administration of 10 to 50 mg / kg. And intraperitoneal injection of 10 to 100 mg / kg. Anti-ct4 β 1 I integrin antibody GG5 / 3 (Keszthelyi et al. Neurology, 1996 47 ·· 1053 · 1059) can delay the onset of symptoms and is used as a positive control And, it was injected subcutaneously at 3 mg / kg on the 8th and 11th. Daily weight and sports injuries were measured. Sports injuries are scored with the following clinical scores: _ _-175- This paper scale applies Chinese National Standard (CNS) A4 Specifications (210X 297mm) Order AWI (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ^ 4910 Λ7 V. Description of Invention (173) ~ ....... ......— ·… * — ~ 0 No change 1 Weak tail or itching 1 Weak hind limbs 3 Hind limbs Bi 4 Dying or dying, waiting compounds are considered to be active if they can delay the onset of symptoms, such as producing a clinical knife number of less than 2 points, or comparing the control group to reduce weight loss. When tested in a bioassay, The compounds of Examples 5, 12, 8, and 20 are active. Examples of asthma patterns Inflammation of CM β i integrin vectors include, for example, respiratory hyperresponsiveness and obstructive asthma. The asthma mode which can be used to study the living effect of the compound of the present invention in the treatment of asthma will be described later. In accordance with Abraham et al ”J. Clin. Invest, 93: 776-787 (1994) and

Abraham et al., Am J. Respir Crit Care Med, 156: 696-703 (1997) (also described herein for reference), the compounds of the present invention are formulated into aerosols and administered to ticks (Ascaris suum ) Antigen-allergic sheep. Compounds that can reduce early antigenic bronchial reactions and / or block late airway responses, such as positive reactions to antigenic late reaction and respiratory sensitization (" AHR ") are considered active in this mode. When inhaled tick antigens can Allergic sheep with early and late bronchial reactions were used to study the respiratory effects of candidate compounds. After using 2% lidocaine for local anesthesia, the balloon catheter was inserted through a nostril -176- This paper is for China National Standard (CNS) A4 Specification (21〇 > < 297 mm) (Please read the precautions on the back before filling this page) 534910 Λ7 ____________ B * 7 5. Inventory (174) Enter Shixiatong. Then sheep A flexible fiberoptic bronchoscope was used as a guide to guide an endotracheal tube with an annulus through another nostril. Thoracic pressure was estimated according to Abraham (1994). Aerosol was generated using a disposable medical nebulizer (see formula example below) ), The nebulizer can generate aerosols with a mass intermediate aerodynamic diameter of 3.2 microns measured using an = nderSen-class impactor. The carburetor is connected to a < delivery system consisting of a check valve and a source of compressed air (20 psi). The output of the aerosol is guided to a plastic τ-shaped piece, which is connected to the inhalation of the soil / tongue plug respirator Mouth. At the beginning of the breathing cycle of the respirator, the non-return valve is activated for sec. The aerosol is delivered at a rate of 500,000 ml and 20 breaths / minute I. A single 0.5% sodium bicarbonate solution is used as a countermeasure. Zhao 0 / ', \ In order to estimate the bronchial' response ', a progressive concentration-response curve was generated according to | 31. & | 18111 (1994) for (^ 1 ^ 〇11〇1. Before and after treatment initiation and antigen A bronchial biopsy is taken 24 hours after provocation. Bronchial biopsy can be performed according to Abraham 〇994). Test tube adhesion of alveolar macrophage cells can also be performed according to Abraham (1994) to determine the percentage of adherent fine maggots. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Formula Economy (please read the precautions on the back before filling this page) Use the following procedure to prepare the candidate compound at a concentration of 300 mg / ml in 0.5% Sodium Hydrogen Sodium / Brine ( \ V / v) Solution: A. Storm. Prepare sodium bicarbonate / brine solution : 1 〇.〇mL ingredients --- i-£ ± ___ / TJ / each> Junk / 100.0ml • ιυυ.υ after the final concentration outside the pen 0.5 g sodium bicarbonate 0.5% 0.5% saline to an appropriate amount Add appropriate amount to 100% -177- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297mm) 534910 Λ7 B * 7 5. Description of the invention (175) Procedure: 1. Add 0.5 grams of sodium bicarbonate to 100 ml volumetric flask. 2. Add about 90.0 ml of saline and sonicate until dissolved. 3. Add an appropriate amount of saline to 100.0 ml and mix thoroughly. B. Preparation of 30.0 mg / ml candidate compound: 10.0 ml of ingredients g / 10.0 ml of final concentration candidate compound 0.300 g of 30.0 mg / ml of 0.5% sodium bicarbonate / saline stock solution, add the appropriate amount to 10.0 ml and the appropriate amount to 100% (please read first Note on the reverse side, please fill this page again) Procedure: 1. Add 0.300 g of candidate compound to a 10.0 ml volumetric flask. 2. Add approximately 9.7 ml of a 0.5% sodium bicarbonate / saline stock solution. 3. Ultrasonic oscillation until the candidate compound is completely dissolved. 4. Use 0.5% sodium bicarbonate / saline stock solution to add to 10.0 ml and mix thoroughly. Printed by the Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -178- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

Claims (1)

534910 AB c D Patent Application No. 087112638 Chinese Application for Patent Scope Replacement (April 1992) VI. Application {Patent Model I Public " Positive. I supplement a compound selected from the group consisting of the following group A: One-to-one N- (toluene-4-sulfonyl) -L-proline fluorenyl-4-[(N-third butoxycarboxyglycinyl) amino] -L-phenylalanine; N-(toluene-4 -continuous base) -L -proline 4-[(glycine) amino] _ L -phenylalanine; N- (toluene-4-sulfonyl) -L-proline methyl-4- [3- (carboxy) propylamine methyl]-L-phenylalanine; N- (toluene-4-continyl) -L-proline methyl-4- [ (N-Third-butoxy-L-propylaminofluorenyl) amino] -L-phenylalanine; N- (toluene-4-continyl) -L-proline amino-4-[( N-Third-butoxy-D-propylaminofluorenyl) amino] -L-phenylalanine; N- (toluene-4 -sulfofluorenyl) -L-prolylamino-4-[(N -Third-butoxycarbonyl-D-phenylpropylaminofluorenyl) amino] -L-phenylalanine; N-(toluene-4 -sulfofluorenyl) -L-prolylamino-4-{2- [3-(luciferin) thioureido] acetoamido L-phenylalanine; N- (toluene-4-sulfohydrazone) ) -L-proline sulfanyl-4-[(N-third butoxycarbonyl-glycinyl) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L -proline fluorenyl- 4- {2- [3- (3-methylphenyl) ureido] acetamido-L-phenylalanine; N- (toluene-4-sulfonyl ) -L-prolylamino- 4- [Y- (l-aspartyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolylamine -4- (α-carboxyfluorenyloxy) -L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [2- (carboxy) phenyl] -L -The size of benzene paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 534910 AB c D 6. Application for patent scope Alanine; N- (Toluene-4-sulfonyl) -L-proline Methyl amidino-4- [2- (methoxycarbonyl) phenyl] -phenylalanine; N- (methan-4-continuous group) -L-cholylamino-4- {N- [ 2- (N-Methylmethylaminoamine) ethyl] amino group L-phenylalanine; N- (methan-4-methyl 8¾yl) -L-cholylamine group 4- {N- [2- (N-methyl donyloxyamine) ethyl] amino} -L-phenylalanine methyl ester; N- (methylfung-4-phenylamine) -L-cholylamine-4 -{N- [3- (N, N -dimethylamino) propyl] -N- [trifluoromethanesulfonyl] aminomethyl L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline methyl-4- {N- [4- [(N-Third-butoxycarbonyl) methoxy] fluorenyl] amino group L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline methyl-4- [ 3- (N, N-dimethylamino) propoxy; IL-phenylalanine; N- (toluene-4-sulfonyl) -N-.methyl-L-serine-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) Thiprolamino- 4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline Methyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline methyl-4- [2- (N -ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline [2- (N, N-Diisopropylamino) ethoxy] -L-phenylalanine; -2- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 534910 8 8 8 8 AB c D VI. Application scope of patent N- (toluene-4-sulfonyl) ) -L-proline methyl-4- [3-cyclohexyl-2- (N-third butoxycarbonylamino) propoxy] -L-phenylalanine methyl ester; N-(thiophene-2- Sulfonyl) -L-proline fluorenyl-4-[3-(N, N -dimethylamino) propoxy] -L -phenylalanine; N-(5 -chlorothiophene-2 -sulfo Fluorenyl) -L-proamine fluorenyl-4-[3-(N, N -dimethylamino) propoxy] -L-phenylalanine; N-(2,5-dichlorofluorenyl- 3 -sulfofluorenyl) -L-proaminefluorenyl-4-[3-(N, N -dimethylamino) propoxy] -L -phenylalanine; N-(1 -methylpyrazole -4 -sulfofluorenyl) -L-proline methyl-4-[3-(N, N -dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfo Fluorenyl) -L-proline fluorenyl-4- [3- (N, N-diethylamino) propoxy] -phenylalanine methyl ester; N- (thiazole-2-sulfonyl)- L-proline methyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline Fluorenyl-4- [3- (N-methyl-N-fluorenylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L gastric proline fluorenyl -4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine; N- (formaldehyde Benzene-4-sulfonyl) -L-proline fluorenyl-4- [3- (N -methyl-N-fluorenylamino) propoxy] phenylalanine methyl ester; N- (l -methyl Imidazole-4-sulfofluorenyl) -L-proline fluorenyl-4- [3- (N, N-dimethylamino) propoxy] phenylalanine; N- (2-methylsulfonyl Azole-5-sulfonyl) -L-proline fluorenyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine; -3- Applicable to this paper size Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding # Application for patent scope Dimethylamino) propoxy] -L-phenylalanine; N · (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) pyrimidinamine-4- [ 3- (N, N -dimethylamino) propoxy] -L-phenylalanine methyl ester; N-(toluene_ 4 _sulfofluorenyl-1- (thiamorpholine-3 -carbonyl) -4 -[3-(N, N -dimethylamino) propoxy] -L-phenylalanine; N- (tosylsulfonylprolylfluorenyl-heart [2_ (carboxy) phenoxy] _ ^ benzene Methyl alanine; N-(toluene-4 -sulfofluorenyl) -L -proline methyl-4-{2-[4-(pyrimidin-2 -yl) hexahydropyridine-1 -yl] B Oxygen}-L-phenylpropylamine Acid; N- (toluenesulfonyl) -L-proline fluorenyl-4- [3- (hexahydropyridin-1-yl) propoxy] -L-phenylalanine; N-(toluene-4- Sulfonyl) -L-proline fluorenyl-4-[2-(pyrrolidin-1 -yl) ethoxy] -L -phenylalanine; N- (toluene_4-sulfonyl) -L- Proline methyl-4- {3- [4- (3-chlorophenyl) hexahydropyridine-1 -yl] propoxy}-L-phenylalanine; N- (toluene-4-sulfonyl ) -L-proline methyl-4-[(1-tert-butoxycarbonylhexahydropyridine-3 -yl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl ) -L-proline fluorenyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline Fluorenyl-4- [2- (hexahydropyridin-1-yl) ethoxy] phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [3- [ 4- (3-Chlorophenyl) hexahydropyridin-1-yl] propoxy} -L-phenylalanine methyl ester; -4- This paper size applies to China National Standard (CNS) A4 (210 X 297 (Mm) D8 patent application scope N (methyl fulcrum-4-continuous base). -L-choline acid group 4- [2- (aza leather_ι 美) ethoxylate; IL-phenylalanine; N (甲 丰 -4-continued g Shengji) -L-alkali Amino acid group-4 ·-[2- (Aza leather-1 US) ethoxy] -L-phenylalanine methyl ester; (methane-4-4 amino acid group) -L-cholylamine-4 -[3 · (4-Methylhexachloroρ-Phen-1-yl) propoxy] -L-phenylalanine methyl ester; Ν- (toluene-4-continyl) -L-amine trapping group- 4- [3- (4-methylhexachloropyridin-1-yl) propoxy] -L-phenylalanine; Ν- (toluene-4-continyl) -L-proline 4_ Ν, (trifluoromethane difluorenyl) amino-L-phenylalanine methyl ester; Ν-(toluene-4 -methylfluorenyl) -L -proline methyl-4-Ν, (trifluoro Formamidine) Amino-L-phenylalanine; N- (toluene-4-continyl) -L-proline, 4-[(ν_benzylaminocarbonyl) methoxy] -L -methyl phenylalanine; N- (toluene-4-sulfonyl) -L-proline sulfanyl-4-[(benzyloxycarbonyl) methoxyl L-phenylalanine; N- ( Toluene-4-sulfofluorenyl) -L-proline fluorenyl-4-[(carboxy) methoxy] -phenylalanine; N- (toluene-4-sulfonyl) -L-proline fluorenyl- 4-[(Aminocarbonyl)]-L-phenylalanine methyl ester; N- (toluene-4-sulfofluorenyl) -L · proaminefluorenyl-4-[(aminocarbonyl) methoxy]- L-phenylalanine; N- (formaldehyde -4-sulfofluorenyl) -L-proaminefluorenyl-4-[(N-third butylaminocarbonyl) methoxy] -L-phenylalanine; -5- This paper size applies to Chinese national standards (CNS) A4 specification (21〇x 297 public love) N- (toluene_4-sulfofluorenyl) -L-proline fluorenyl-4- [2- (4-phenyl-4-hydroxyhexahydropyridine-1 -yl) ethoxy] -L-phenylpropylamine Methyl methyl ester; N- (toluene-4-sulfofluorenyl) inosinamide-D, L-4- (fluorenyl) phenylalanine; N · (methylfung-4-continuous) Acid group-D, L-4- (Aminoyl) phenylalanine; N- (Toluene-4-transmethyl) -L-aminopyridin-4- [γ- (α -Nyl- Να-formamyloxy-L-aspartyl) amino] phenylalanine methyl ester; Ν- (甲 本 -4- 横 基基) -LMamine 酿-4 · (4-aminobutane Amine group) _ L-phenyl filamic acid; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [4- (N-third butoxycarbonylamino) butylamine Fluorenyl] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4- [4- (N-methylamino) butylaminofluorenyl] -L -Phenylalanine; Ν- (toluene-4-sulfonyl) -L-prolylamino-4-[4- (N -third butoxycarbonyl-N-methylamino) butylamino ] -L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4-[(0-fluorenyl) -L-serine fluorenyl] amino] phenyl Alanine; N- (toluene-4-sulfonyl) -L-proline Methyl-4- {N- [3- (N, N-dimethylamino) propyl] -N- [methylbenzene] amino} -L-phenylalanine methyl ester; N- ( Amoto-4-chi-methyl group) -L-Ceramine-methyl- 4- [5- (D, L-face: amine group) Amine] -L-phenylalanine; N- (toluene-4 -Sulfofluorenyl) -L -proline fluorenyl- 4- {N-[(2 -methylsulfanyl- -6-6- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1,2,3,4-tetrahydroisoquinolin-3 -yl) methyl] amino group L-phenylalanine; N- (tosylsulfonyl) _L-prolylamino-heart [3- Cyclohexyl_2 _ (^ third butoxycarbonylamino) propoxy] -phenylalanine methyl ester; N- (toluene-4-sulfonamido)-] L-proline amidino-3- [3- (N, N -dimethylamino) propoxy] -L-phenylalanine; N-(toluene-4 _sulfofluorenyl) _ L _proline fluorenyl_ 4 _ [2 _ (2 _ acryl) Bicyclo [3 · 2 · 2] oct-2-yl) ethoxy] -L-phenylalanine methyl ester; Ν- (tosylsulfonyl) ^ prolylamino-4- [2_ (2-azinebicyclo [3 · 2 · 2] oct-2-yl) ethoxy] -L-phenylalanine; I- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- (3-third Butylhexahydropyridine-4-oxo) -D, L-phenylalanine; N- (toluene-4 -transmethyl) -L-cholamine donyl- 3- (1-methylhexaaza ^ 1 Biyodo-4 -oxy) -D, L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl- 4- (bumethylhexahydropyridine-4-oxo) -D , L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L- (5,5-dimethyl) pyrimidofluorenyl- 4- 0-methylhexahydro p-pyridine-4 -Oxy) -phenylalanine ethyl acetate, N- (toluene-4-sulfonate ) -L- (5,5-Dimethyl) p-sepaminofluorenyl-4-0-methylhexahydropyridine-4-oxo) phenylalanine; Ν- (α-toluenesulfonyl) -L-proline fluorenyl-4- (bumethylhexahydropyridin-4-oxo) -L-phenylalanine ethyl; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4 -N- (Chloromethanesulfonyl) Amino-L-phenylalanine methyl ester; This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 534910 AB c D κ, scope of patent application Ν-(toluene-4 -sulfofluorenyl) -L -prolylamino-4-Ν-(vinylsulfonyl) amino-L-phenylalanine methyl ester; Ν- (toluene-4-continued) S Shengji) -L-proline-4- (N-trifluoromethanesulfonyl-N-isobutyl) amino-L-phenylalanine methyl ester; Ν- (toluene-4- Sulfonyl) -L-prolylfluorenyl-4-(N-vinylsulfonyl) amino-L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline Methyl-4-[(fluorenyloxycarbonyl) methoxy] _L-phenylalanine methyl ester; N- (toluene-4-sulfofluorenyl) -L-prolylamino-4-[(hexahydropyridine- 1-ylcarbonyl) fluorenyloxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline -4-[(N, N-diisopropylaminocarbonyl) methoxy; IL-phenylalanine methyl ester; N- (toluene-4-sulfonamido) -L-proline methyl-4- [(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline methyl-4- (N -Methyltrifluoroacetamido) -L-phenylalanine methyl ester; N- (toluene-4-sulfofluorenyl) -L- (5,5-dimethyl) thiaprolamino-4_ [3- (N, N-dimethylamino) propoxy] -L-phenylalanine tert-butyl ester; Ν- (toluene-4-sulfonyl) -L-prolylamino-L- 4- (N-methylhexahydropyridyloxy) -phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaproline Fluorenyl-L- (4-methylhexahydropyridyloxy) phenylalanine tert-butyl ester; ~ N- (toluene-4-sulfonyl) -L-proline fluorenyl- (4-phenyl ) -L-Phenylalanine tert-butyl ester; and -8- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) Application scope of patent (Kamaki Bake Base) -L-Preserved Amine- (4-phenyl-phenylalanine). 2. A pharmaceutical composition for treating a patient suffering from a VLA-4 mediated inflammatory disease, which includes a compound selected from the group consisting of: N- (toluene-4-methylg) -L-proline -4-[(N -Third-butoxycarbonylglycinamido) amino] -phenylalanine; N- (toluene-4 -succinyl) -L -proline amidinyl-4-[(glycine Amine donkey) amino] -L-benzyl alanine; N- (fluorenyl-4-sulfonyl) -L-proline methyl-4- [3- (carboxy) propylaminomethyl L-benzene Alanine; N- (toluene-4 -acryloyl) -L-proline, 4-[(N -third butoxycarbonyl_L-propylamino) amino] -L-phenylpropylamine Acid; N- (toluene-4-sulfonamido) -L-prolylamino-4-[(N-third butoxycarbonyl-D-propylaminofluorenyl) amino] -L-phenylalanine; N- (toluene-4-continuous base) -L-proline alkynyl 4-[(N-third butoxycarbonyl_D-phenylpropylamine alkynyl) -amino] -L-aspartyl alanine; N- (toluene-4-continuous base) -L-proline tertiary-4- {2- [3- (fluorescein) thioureido] acetamido L-phenylalanine; N- (Toluene-4-sulfofluorenyl) -L_proaminefluorenyl-4-[(N-third butoxycarbonyl_glycine) amino] -phenylalanine methyl @ ; N- (toluene-4-sulfonyl) -L-proline fluorenyl_4- {2- [3- (3-methylphenyl) ureido] acetamidinyl L-phenylalanine ; N- (Toluene-4-sulfoamidoamidoamido- 4- [h (L aspartame) amino] -L-phenylalanine; -9- This paper is in accordance with the Chinese National Standard (CNS) A4 size (210 x 297 mm) N- (toluene-4-continyl) -L-proline glutamyl-4- (α-chiaoxy) -L-phenylalanine; N- (toluene-4_mercapto) _l_ Aminodonyl-4- [2- (severe) phenyl] _L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolylamino-4- [2- (methoxycarbonyl) ) Phenyl methyl L-phenylalanine methyl ester; N- (toluene, 4-methylamino) -L-proline methyl-4- {N- [2- (N-methyloxyamino) Ethyl] amino} -L-phenylalanine ) Ethyl] amino} -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolylamino-4- {N- [3- (N, N -di Methylamino) propyl] -N- [trifluoromethanesulfonyl] aminopropyl L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline 4- {N- [4-[(N -Third butoxycarbonyl) methoxy] fluorenyl] amino} -L_phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L -Proline methyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -N-methyl- L-serineamido-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine ; N- (Toluene-4 -sulfofluorenyl) -L- (5,5-dimethyl) pyrimidinamine- 4- [2- (N, N-dimethylamino) ethoxy]- L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] phenylalanine; N- (Toluene-4-sulfofluorenyl) -L-proline methyl-4- [2- (N-ethyl-N-benzene-10- X 297 mm) 534910 AB c D Six. Patent application scope Amino group) Ethoxy] -L-phenylalanine methyl ester; N- (Toluene-4 -sulfonyl) -L-proline 4- [2- (N, N-Diisopropylamino) ethoxy] -phenylalanine; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4- [3- Cyclohexyl- 2- (N-third-butoxycarbonylamino) propoxy: 1-L-phenylalanine methyl ester; N- (thiophene-2-sulfonyl) -L-prolylamino-4 -[3- (N, N-dimethylamino) propoxy] -L-phenylalanine; N-(5-chlorothiophene-2 -sulfofluorenyl) -L -proline methyl-4- [3-(N, N -dimethylamino) propoxy] -L -phenylalanine; N-(2,5-dichlorothiophene-3 -sulfonyl) -L -proline 4-[3-(N, N-Dimethyl Propylamino) propoxy] phenylalanine; N- (l -methylpyrazole-4-sulfofluorenyl) -L-proline fluorenyl-4- [3- (N, N -dimethylamine Propyl) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4- [3- (N, N-diethylamino) propoxy ] -L -Phenylalanine methyl ester; N- (thiazole-2-sulfonyl) -L-proline-4- [3- (N, N-dimethylamino) propoxy]- L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [3- (N-methyl-N-fluorenylamino) propoxy] phenylpropylamine Acid; N- (toluene-4-sulfonamido) -L-proline methyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine; N- (Toluene-4-sulfofluorenyl) -L-proline methyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine methyl ester; N- (l -methylimidazole-4-sulfofluorenyl) -L-proline fluorenyl-4- [3- (N, N-di-11-This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 534910 8 8 8 8 AB c D 6. Application for patents methylamino) propoxy] phenylalanine; N- (2-methylpyrimidazole-5-sulfonyl) -L- Prolyl-4- [3- (N, N-dimethylamino) Oxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-thiaprolamino-4- [3- (N, N-dimethylamino) propoxy]- L-phenylalanine; N- (4-cyanobenzenesulfonyl) -l_ (5,5-dimethyl) fluorenilamine-4- [3- (N, N-dimethylamino) ) Propoxy] phenylalanine methyl ester; N-(toluene-4 -sulfofluorenyl) -L-(pyrimoline-3 -carbonyl) -4-[3-(N, N -dimethylamino) ) Propoxy] -phenylalanine; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline fluorenyl-4- {2- [4- (pyrimidin-2-yl) hexahydropyridin-1-yl] ethoxy} -L-benzene Alanine; N-(toluene-4 -sulfonamido) -L -prolylamino-4-[3-(hexahydropyridine-1 -yl) propoxy] -L-phenylalanine; N- (Toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) ) -L-proline fluorenyl- 4- {3- [4- (3-chlorophenyl) hexahydropyrine-1-yl] propoxy} -L-phenylalanine; N- (toluene- 4-sulfofluorenyl) -L-proline fluorenyl-4-[(l -third butoxycarbonylhexahydropyridin-3-yl) Oxy] -L -phenylalanine methyl ester; N- (toluene-4 -sulfofluorenyl) -L -proline methyl-4- [2- (morpholin-4 -yl) ethoxy] -L- Phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl-4- [2- (hexahydropyridin-1-yl) -12- This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) 534910 Ethoxy] -L-phenylalanine; N-(toluene-4 __sulfofluorenyl) _ l -proline fluorenyl-4-{3-[4-(3 -chlorophenyl) hexahydropyridine -Boxy] propoxyl L-phenylalanine methyl ester; N- (toluene-4-sulfofluorenyl) -proline group 4- [2- (aza leather-1-yl) ethyl Oxy] phenylalanine; (Toluene_4-sulfofluorenyl ^ proline} -4- [2- (azapyridin-1-yl) ethoxy] -L-phenylalanine methyl ester; N (Toluene-4-sulfonylproline fluorenyl-4- [3- (4-methylhexahydropyrine-1-yl) propoxy] -L-phenylalanine phosphonium ester; N- (toluene -4-continued B Shengji) -LM amine brewing group- 4- [3- (4- -Hexylhexazolium p-butan-1-yl) propoxy] phenylalanine; N- (toluenesulfonyl) -L-proline methyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-proline methyl -4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine; N- (fluorenyl-4-sulfonyl) -L-proline methyl-4-[(N-fluorene Methylaminocarbonyl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-methylamino) -L-prolyl-4-[(deoxymethyl) methoxy] _ L-phenylalanine; N- (toluene-4-sulfonyl)- L-Proline methyl-4-[(carboxy) methoxy] phenylalanine; N- (toluene-4-sulfonyl) -L-proline methyl-4-[(aminocarbonylcarbonyl) ^ Phenylalanine methyl ester; N- (Toluene-4-sulfofluorenyl) -L-proline fluorenyl-4-[(aminocarbonyl) methoxol • 13-This paper size applies to Chinese National Standards (CNS) A4 specification (210 X 297 mm) AB c D 534910 VI. Patent application Fanyuan L-phenylalanine; N- (toluene-4-continuous base) -L-proline cracker base 4-[(N -Tertiary butylaminomethyl) methoxy] -L-phenylalanine; N- (toluene-4-transyl) -L-proline 4--4- (2-phenyl -4- # A hexahydropyridine-1-yl) ethoxy jL-phenylalanine methyl ester; N- (toluene-4-reading group) inosinol-D, L-4- (pulse group) Phenylalanine; N- (toluene-4 -continuous base) inosinol-D, L-4- (amino-epiyl) phenylalanine; N- (toluene-4-stone yellow donkey) -LM amine amino-4- [α- (〇 ^-基-Να-methoxo-L-aspartyl) amino group; IL-phenylalanine methyl ester; Ν- (toluene-4 -Sulfofluorenyl) -L-prolyl-4- (4-aminobutylamino) -L-phenylalanine; N- (toluene-4-sulfo ) -L-Proline fluorenyl-4- [4- (N-Third-butoxycarbonylamino) butylamine fluorenyl] -L-phenylalanine; N- (fluorenyl-4-sulfonyl ) -L -Proline fluorenyl- 4- [4- (N -methylamino) butylamine] -L -phenylalanine, N- (fluorenyl-4-sulfonyl) -L- Proline group-4 · [4- (N-third butoxycarbonyl-N-methylamino) butylamino group] phenylalanine; Ν- (toluene-4-sulfonyl) -L- Proline group-4-[(0 -fluorenyl) -L-serine group] Amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-proline group Methyl-4- {N- [3- (N, N-: T-based amino) propyl] [methanesulfonyl] amino} -L-phenylalanine methyl ester; -14- Suitable for this paper size China National Standard (CNS) A4 specification (210X297 mm) 534910 A8 B8 C8 D8 6. Application scope of patent N- (toluene-4-sulfonyl) -L-proline fluorenyl- 4- [S- (D, L-glutaminyl) amino] -phenylalanine; N- (toluene-4-sulfonyl) -L-prolylamino- 4- {N-[(2-methylamidino-1, 2,3,4-tetrahydroisoammon-3-yl) methyl] amino} -ethyl-phenylalanine; 1 (toluene-4-sulfonyl) -1 ^ proline-4 -[3-cyclohexyl-2- (. Third Oxycarbonylamino) propoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonamido) -L-prolylamino-3- [3- (N, N -dimethyl Amino) propoxy] -L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-prolylamino-4- [2- (2-azinebicyclo [3.2.2] octyl- 2-yl) ethoxy] -L-phenylalanine methyl ester; N- (toluene-4-stone yellow 8¾yl) -L-pentylamine-4- [2- (2-σ 丫 Bicyclo [ 3.2.2] oct-2-yl) ethoxy] 4-phenylalanine; 1- (toluene-4-branthyl) -L-prolylmidino- 4- (3-tert-butylhexahydro Exopyridin-4-oxo) -D, L-phenylalanine; Φ N- (toluene-4-sulfonyl) -L-prolylamino-3- (1-methylhexahydropyridine-4 -O) -D, L-phenylalanine; N- (toluene-4-continyl) -L-prolyl-4- (1-methylhexahydro p-pyridine-4-oxy)- D, L-phenylalanine; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thioprolamino- 4- (1-methylhexahydropyridine-4 -Oxy) -L-phenylalanine ethyl ester; N- (toluene-4-sulfofluorenyl) -L- (5,5-dimethyl) thioprolamino- 4- (1-methylhexan Hydropyridine-4-oxo) -L-phenylalanine; Ν- (α-tosylsulfonyl) prolyl-4- (1-methyl Hexahydropyridine-4- -15- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 534910 A BCD VI. Patent application for private oxygen) -L-phenylalanine ethyl ester; N -(Toluene-4-mercapto) -L-cholylamine- 4- N- (chloromethylbenzene g). Amino-L-phenylalanine methyl ester; N- (toluene-4- Sequential base) -L-Ceramine-4N- (Ethyl pentylpyridyl) Amino-L-phenylalanine methyl ester; N- (Toluene-4-sulfonyl) -L -Proline methyl-4- (N-trifluoromethanesulfonyl isobutyl) amino-L-phenylalanine methyl ester; N- (toluene-4-continyl) -L-base amine -4- (N-ethenyl-continuous-branched group) amino-L-phenylalanine; N- (toluene-4-continyl-acid) -L-amine-derived 4--4- Methyl) methoxy] _ L-phenylalanine methyl ester; N- (toluene-4-phenyl 8¾yl) -L-proline methyl-4-[(hexahydroeodo-1-ylcarbonyl) methoxy ] -L-phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline fluorenyl- 4-[(N, N -diisopropylaminocarbonyl) methoxy] -L- Methyl phenylalanine; N- (toluene-4-sulfofluorenyl) -L-proline methyl-4-[(N, N -diisopropylaminocarbonyl) methoxy ] -L-phenylalanine methyl ester; N- (toluene-4-sulfofluorenyl) -L-proline methyl-4- (N-methyltrifluoroacetamido) -L-phenylpropylamine Acid methyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) fluorenilamine-4- [3- (N, N-dimethylamino) propyl Oxy] -L-phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolylamino-L-4- (N-methylhexahydropyridyloxy)- Phenylalanine tert-butyl ester; N- (toluene-4-sulfofluorenyl) -L- (5,5-dimethyl) thioprolamino-L- (4--16- China National Standard (CNS) A4 (210 X 297 mm) ο 1X 49 3 5 Methyl hexahydropyridyloxy) phenylalanine tert-butyl ester; N- (toluene-4-sulfonylproline fluorenyl_ (4-phenyl) phenylalanine tert-butyl ester); and N- (Toluene-4-sulfonyl) -L-proline- (4-phenyl) -L-phenylalanine. For example, the pharmaceutical composition according to item 2 of the application, wherein the inflammatory disease is selected from the group consisting of Groups consisting of asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Cohen's disease) Multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke and other brain injuries, nephritis, retinitis, atopic dermatitis, dry addiction, myocardial ischemia and acute white blood cell Lung injury occurs, for example, in adults with respiratory distress syndrome. -17- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm)