TW200416214A - Phenethylamino sulfamic acids - Google Patents

Abstract

Compounds of formula (I): are effective in the treatment of protein tyrosine phosphatase (PTPase) mediated disorders such as diabetes.

Description

200416214 (1) 发明. Description of the invention [Technical field to which the invention belongs] The present invention relates to phenethylamino-aminosulfonic acid compounds that can be used to treat diseases related to protein tyrosine phosphatase. [Prior art] The regulation of protein tyrosine phosphorylation in vivo is mediated by the counteracting effects of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). The extent of protein tyrosine phosphorylation of intracellular proteins is determined by the balanced activity of PTKs and PTPases (Hunter, Cell 8 0: 22 5 -23 6 (19 95)). When the above-mentioned activity is not balanced, a disease state may occur. Based on reasonable derivation, the regulation of the tyrosine kinase / phosphatase balance can be used to treat the diseases caused by the above imbalance. For example, the mechanism of insulin action is strictly determined by the case of several proteins in the insulin signaling cascade. Phosphorylation of amino acid groups. Enzymes that dephosphorylate proteins, namely PTPases, are extremely important regulators of insulin action. Therefore, the use of PTPases inhibitors can enhance the effect of insulin on treatment. PTPases are involved in the insulin receptor signaling pathway. Insulin is an important regulator of different metabolic pathways and plays an important role in controlling glucose in the blood. Failure of insulin synthesis and signaling will lead to diabetes. The binding of insulin to its receptor results in the (auto) phosphorylation of several tyrosine groups in the intracellular part (beta subunit) of the insulin receptor. (2) 200416214 Three similar tyrosine groups (tyrosine-1 150) must be phosphorylated to obtain the full activity of the insulin receptor tyrosine kinase (IRTK), which uses other cells Matrix (including insulin receptor matrix-1 (IRS-1)) is tyrosine phosphorylated and retransmits downstream (W i 1 deneta I., J. Biol. C he m. 267: 16660-16668 ( 1 9 92); Myers and White, Diabetes 42: 643-650 (1993); Lee and Pilch, Am. J.

Physiol. 266: C319-C3 44 (1 994); White et al.? J. Biol.

Chem. 2 63: 2 969-2 9 8 0 (1 98 8)). The structural basis of the function of the tyrosine triad has recently been studied from the X-ray crystallographic spectrum of IRTK (which shows that its tyrosine-1 150 is autoinhibited in an unphosphorylated state) (Hubbard et al ., Nature 372: 746-754 (1 9 94)).

Several studies have shown that the activity of autophosphorylated IRTK can be reversed by in vitro dephosphorylation (for reviews see Goldstein, Receptor 3: 1-15 (1 9 9 3); Mooney and Anderson, J. Biol Chem. 264: 6 8 5 0-6 8 5 7 (1 9 8 9)), compared with the di- and mono-phosphorylated forms, the tri-phosphorylated tyrosine-1 1 50 region is protein tyramine The most sensitive target of acid phosphatase (PTP as es) (King et al., Biochem. J. 275: 413-418 (1 99 1)). Therefore, it is speculated that this tyrosine triad function is a control switch for IRTK activity. In fact, IRTK has been shown to be tightly regulated by PTP-related in vivo dephosphorylation (Khaneta 1., J. B i ο 1. chem. 2 6 4: 1 2 93 1-1 2 940 (1 98 9); Faure et al.? J. Biol. Che m. 2 67: 11215-11221 (1992); Rot hen berg et al.? J. Biol. Chem. 2 66 ·· 8 3 02- 8 3 1 1 (1 99 1)). In addition, the intimate association between PTPases and insulin signaling pathways has also been shown to regulate insulin in mouse liver cancer cells-6-(3) 200416214 (Meyer ovitch et al., Bioc he mist l. Y 31: 10338-10344 (1 992 )) And alloxan diabetic mice (Boyl an et al., J. Clin. Invest. 90: 1 74- 1 7 9 (1 9 92)) have different PTPase activities in the liver and are again Confirmed. In addition, when a strong PTPase inhibitor pervanadate is added to whole cells, it can be used in adipocytes (Fantus et al., Biochemistry 28: 8864-8871 (1 9 8 9); Erikssen et al.,

Diabetologia 3 9: 2 3 5 -242 (1 9 9 5)) and intramuscular (Leighton et al., Biochem. J. 276: 2 8 9 -2 92 (1 9 9 1)) produce almost all insulin reaction. From the above description, there is still a need for identifying PTPase inhibitors useful for the treatment of insulin receptor tyrosine kinase-related diseases. Another example is that acid phosphatase / PTPase may be involved in the negative regulation of osteoblast proliferation. Therefore, the use of PTPase inhibitors can enhance the proliferation of osteoblasts and thus treat bone diseases. The rate of bone formation depends on the number and activity of osteoblasts, and therefore it depends on the rate of proliferation and differentiation of the osteoblast's original cells. Histomorphological studies have shown that the number of osteoblasts is a major determinant of human bone formation rate (Gruber et al., Mineral Electrolyte Metab. 1 2: 246-254 (1987); for review see Lau et al., Biochem. J 257: 23-36 (1 9 8 9)). Acid phosphatase / PTPase may be involved in the negative regulation of osteoblast proliferation. Therefore, fluorides with phosphatase inhibitory activity have been found to increase vertebral bone density in patients with osteoporosis by increasing osteoblast proliferation (Lau et al., Supra). Consistent with the above findings, osteoblast acid phosphatase with PTPase activity has been found to be highly sensitive to fluoride mitosis-7- (4) (4) 200416214 concentration (L aueta 1 ·, J · B i ο · C hem. 2 6 0: 4 6 5 3 -4 6 6 0 (1 9 8 5); L a υ et a 1., J. Bio. Che m. 2 6 2: 1389-1397 (1 9 8 7 ); Lau et al. 5 A d v. Protein Phosphatases 4: 165-198 (19 8 7)). Interestingly, it was recently found that the concentration of cell membrane-bound PTPase activity was significantly increased when the osteoblast-like cell line UMR 1 06.06 was grown in collagen type I matrix compared to uncoated tissue culture dishes. Since a significant increase in PTPase activity was observed in density-dependent growth-stopped fibroblasts (Pallen and Tong5 Proc. Natl. Acad. Sci. 8 8: 6 9 9 6-7 000 (1 99 1)), It is speculated that an increase in PTPase activity directly inhibits cell growth. Therefore, the mitotic effect of fluoride and other phosphatase inhibitors (molybdate and vanadate) can be explained by the inhibitory effect of acid phosphatase / PTPase, which negatively regulates cell proliferation of osteoblasts. The recently identified novel parathyroid hormone-regulated receptor-like PTPase (OST-PTP), which is expressed in bone and 睪 九 Further suggests that PTPase involves the complex nature of bone formation (Main_o et al., J. Bio. Che m. 26 9: 3 06 5 9- 3 0667 (1 9 94)). OST-PTP is up-regulated after major osteoblast division and matrix formation and then down-regulated in osteoblasts that actively minimize bone in the culture medium. It can be hypothesized that PTPase inhibitors can prevent differentiation by inhibiting OST-PTP or other PTPases such that they continue to proliferate. This is in accordance with the above-mentioned effects of fluoride and the observed phenomenon that the tyrosine phosphatase inhibitor orthovanadate significantly enhances osteoblast proliferation and basal formation (Lau et al., Endocrinology 1 16: 2 4 6 3-2 4 6 8 (1 9 8 8)). In addition, it has recently been discovered that vanadate, vanadate, and pervanadate can all promote the growth of osteoblast-like cell lines UMR] 06 (5) 200416214 (Cortizo et al., Mol. Cell. Biochem. 1 4 5: 97-1 02 (1 9 9 5)). As another example, acid phosphatase / PTPase may be involved in the regulation of angiogenesis and tissue blood flow. Therefore, the use of PT Paase inhibitors can be used to treat angiogenesis-related diseases.

Endothelial cells form a protective lining of blood vessels and respond to a variety of stimuli that regulate the form and function of the vascular system. Activity similar to insulin receptor 'endothelial PTKs is likewise regulated by endothelial PTPs. To support this argument, several P T P s have been shown to be expressed in endothelial cells (F a c h i n g e r e t a 1., Oncogene 18: 5948-5953 (1999); Huang et al.? J. Bio.

Che m. 274: 38183-38188 (1 999); Bianchi et al., Exp. Cell Res. 24 8: 329-338 (1999); Gaits et al.? Biochem. J. 311: 97-103 (1995) Borges et al. 5 Circ. Res. 79: 570-580 (1996)). One of the above-mentioned phosphatases, UCPTPA, has been shown to interact with and block the activation of vascular endothelial growth factor (VEGF) receptor, VEGFR2, which inhibits downward signaling and angiogenesis associated with VEGF (Huang et al. al., J. Bio. Che m. 274: 38183-38188 (1999)). Another phosphatase, HPTPβ, is involved in and attenuates the activation of angiopoietin 1 (An g 1) and angiopoietin 2 (Ang 2), Tie2, receptors (Fach in ger et al., Oncogene 18: 5948-5953 (1 999)). The above studies show that the target endothelial phosphatase will regulate the activation of endothelial PTKs and provide a new target therapeutic agent that can regulate angiogenesis and function. Much evidence exists for the role of several PTKs in neoangiogenesis in adult tissues. For example, in animal models of cancer, inhibition of -9-(6) (6) 200416214 was found to inhibit tumor angiogenesis and tumorigenesis by the effects of VEGF or angiopoietin (Millauer et al. 5 Cancer Res. 56: 1615-1620 (1 9 9 6); Dias et al.? Proc. Natl. Acad. Sci. 9 8: 1 0 8 5 7-1 0 8 6 2 (2 0 0 1); Lin et al.? Proc. Natl. Acad. Sci. 9 5: 8 8 2 9 -8 8 3 4 (1 9 9 8)). Conversely, in animal models of occlusive cardiovascular disease, administration of exogenous VEGF and / or A ng 1 was found to improve the development of collateral circulation and improve blood flow to ischemic tissue (Witzenbich I eret al.? Am J. of Pathol. 1 5 3: 3 8 1-3 94 (1 9 9 8); Pearlman et al.? Nature Medicine 10: 1085-1089 (1995); Banai et al.? Circulation 89: 2 1 8 3 -2 1 8 9 (1 9 94); Shyu et al., 98: 2 0 8 1 -2087 (1998); Chae et al.? Arteriosclero. Thro mb. Vase.

Biol. 20: 25 7 3 -2 5 7 8 (200 0)). All in all, the above studies not only demonstrated the role of PTKs in neoangiogenesis, but they also demonstrated that regulating the function of endothelial PTKs has provided novel therapeutic approaches to the regulation of angiogenesis and tissue blood flow in many diseases. Diseases that are beneficial to promote vascular development include (but are not limited to) occlusive arteriosclerosis, cardiovascular disease, coronary artery disease, terminal vascular disease, cerebrovascular disease (stroke), Berger's disease, diabetic vascular disease, and traumatic blood vessels damage. Diseases that are beneficial for inhibiting neoangiogenesis include, but are not limited to, cancer, arthritis, diabetic retinopathy, macular degeneration, psoriasis, and endometrial tissue ectopic. From the above description, there is still a need for identifying PTPase inhibitors in a method that can be used to treat angiogenesis-related diseases. As another example, acid phosphatase / PTPase may be involved in the regulation of vascular tone. In addition to neoangiogenesis and vascular reconstruction, activation of PTKs (7) (7) 200416214 can affect some variables of vascular function. Therefore, the use of PTPase inhibitors can be used to treat diseases related to vascular tone. Vascular tone can be regulated by the endothelium, and endothelial factors that regulate vascular tone can be regulated by the endothelial P T K signaling. The administration of v EGF bolus elicited a hypotensive response, in part due to the activation of nitric oxide (NO) synthesis associated with VEGF and subsequent formation of a favorable vascular relaxant N 0 by the endothelium (Hariawala et al. 5 J Surgical Res. 63: 7 7-82 (1 996);

Ogasawara et al., Hypertension 39: 815-820 (2002)) ° Administration of fibroblast growth factor (FGF) has similar effects to VE GF on blood pressure, and this effect on blood pressure can also be increased by increasing the endothelium Nitric oxide production is regulated (Garcia-Calvo et al., Proc. Natl. Acad. Sci. 93: 1 1 99 6- 1 200 1 (1 996); Wu et al.? Am. J.

Physiol. 27 1: H 1 0 8 7-1 09 3 (1 9 96); Cuevas et al. 5

Science 2 5 4: 1 2 0 8-1 2 1 0 (1 9 9 1)). Therefore, modulating PTK activation and downward signaling provide novel approaches to treating diseases characterized by changes in vascular tone. Diseases that are beneficial for lowering vascular tone include primary hypertensive blood pressure 'secondary hypertension (ie hypertension associated with renal vascular or endocrine disease)' pulmonary hypertension and portal hypertension. As can be seen from the above description, there is still a need for identifying a P T Pa s e inhibitor in a method that can be used to treat vascular tone-related diseases. As another example, acid phosphatase / PTPase may be involved in the regulation of vascular permeability. Activation of endothelial PTKs has been shown to affect vascular permeability, so the use of PTPase inhibitors can be used to treat vascular permeability-related diseases. -11-(8) (8) 200416214 VEGF was first isolated as a factor that enhances vascular permeability (Senger et al., Cancer Metastasis Rev. 12: 303-324 (1993)). VEGF-induced vascular permeability can be triggered by the same high-affinity receptor PTKs that regulate other effects of VEGF (ie, angiogenesis and vascular relaxation) (Gomez et a 1.5 Endocrinology 1 43: 4339-4348 (2 0 02);

Murohara et al., Circulation 97: 99-107 (1998)). Unlike the osmotic effect of VEGF, Ang 1 uses various high-affinity receptors, Tie 2, to use a variety of reagents (including VEGF) to block the vascular permeability enhancer (Thurston et a 1.? Science 2 86: 251 1- 2514 (1 999); Thurston et al., Nature Medicine 6: 460-463 (2 000)). The above data demonstrate that activation and signal transduction of endothelial PTKs can increase or decrease vascular permeability, and demonstrate a method for specifically regulating endothelial PTK activation and signal transduction, providing a novel treatment for pathological conditions characterized by changes in vascular leakage. Diseases that are beneficial in reducing vascular permeability include, but are not limited to, stroke, septic shock, burns, RDS (respiratory distress syndrome), and congestive heart failure. From the above description, there is still a need for identifying PTPase inhibitors in a method that can be used to treat vascular permeability-related diseases. Another example is that acid phosphatase / PTPase may be involved in the regulation of VEGF, so the use of PTPase inhibitors can be used to treat VEGF-related diseases. In addition to directly affecting the formation and function of the vascular system, the activity of regulating the signaling of endothelial PTKs has been shown to have indirect beneficial effects on other tissues. For example, reducing the expression of VEGF in the myocardium leads to the development of ischemic cardiomyopathy (Carmeliet et al., Nat. Med. 5: 4 9 5 -502 -12- (9) 200416214

(1 9 99)). Conversely, in animal models of heart failure and myocardial infarction, exogenous VEGF input improves cardiac function (Suzuki et al., Circulation 104 [suppl I]: I-207-I-212 (2001); Leotta et al. 5 J. T horac. Cardiovasc. Sui. G. 1 2 3: 110 1-1 1 1 3 (2 0 02)). There is increasing evidence that VEGF can directly and indirectly affect the nervous system (Car meliet et al., Semin. Cell. Dev. Biol. 13: SPSS (2002)). The input of exogenous VEGF can reverse experimental diabetic neuropathy, and early evidence from small clinical trials suggests that this method can be extended to patients with diabetic neuropathy (S chratzbe 1.gereta 1., J. Clin. Invest 1 0 7: 1083-1092 (200 1); Veves et a 1.? J.

Clin. Invest. 1 07: 1 2 1 5-1 2 1 8 (200 1); Hum. Gene Ther. 12: 1 5 93-1 5 94 (200 1)). There is strong evidence that VEGF plays an important role in bone development and that exogenous V E G F input promotes bone healing (Zelzer et a 1.? Development 1 2 9: 1893-1904 (2 002);

Maes et al., Mech Dev 111: 61-73 (2002); Gerber et al., Nat. Med. 5: 623 -628 (1 999); Peng et al., J. Clin. Invest. 110: 751- 759 (2002); Street et al.? Proc. Natl. Acad. Sci. 99: 965 6- 9 66 1 (2002)). In addition to fracture healing, recent evidence suggests that increased VEGF signaling also accelerates skin wound healing, even in animal models of diabetes where wound healing is delayed (Di peppe et al., Gene Ther. 9: 1271-1277 (2002 )). Finally, VEGF and VEGF receptors are expressed in the hair follicles, and the gene transfection input of VEGF in the hair follicles promotes hair growth. In fact, inhibition of VEGF attenuates hair growth (Yano et al ·, J · Clin. Invest · 107 ·· 409 -4 1 7 (200 1)). Therefore, the enhancement of internal -13- (10) 200416214 skin PTKs for the treatment of heart failure and other hair loss VEGF phase I; therefore the related diseases [invention of the invention, the general summary of the disease, phenethylbental hair contains its salt: where : A) Ri is _ a) L, -OCO2 CON (R8) -generation c,-c and (especially) activation of VEGF receptor represents a novel cure, myocardial infarction, diabetic and ischemic neuropathy (And neurological disorders), osteoporosis, healing of fractures, and less healing of wounds. From the above description, there is still a need for identifying PTPase inhibitors that can be used to treat the surrounding diseases. From the above description, there is still a need for identifying PTPase inhibitors that can be used to treat PTP as e disease. Content] The above needs are met by identifying and providing amine-aminosulfonic acid compounds effective in treating PTPase-related diseases. The first aspect of the invention relates to the compounds represented by the following formula (I), some of which are mirror image isomers and non mirror image isomers and are pharmaceutically acceptable

lMc ^ r ^ r'ur7, where: 1 is selected from covalent bonds, -〇-, -S-, -N-, -CO2-, -CO_-, -SO-, -S02-, -CSN ( R8)-, -C0N (R8) 0_,-, -0C0N (R8)-; where R8 is hydrogen or substituted or unselected: 5 courtyards; -14-(11) 200416214 b) R6a and R6b are C〇2r9, -C〇n (r9) 2, _NHC0r9) 2 'HC〇2R, = NR9, 9 and mixtures thereof; wherein each R9 is rrk from hydrogen, substituted or unearthed CA i: the radical , And substituted or un ^^ · 1 a 9-generation square or alkylene 5 group, or an R may together form a substituted or unapplied carbocyclic ring containing 3 3 7 carbon atoms Or a heterocyclic ring; ^ c) m is a number selected from 0 to 5; substituted or unsubstituted l 1 _. Heteroalkyl, substituted or substituted heterocyclyl, substituted 戥 substituted or unsubstituted heteroaryl

d) R7 is absent or is selected from the group consisting of hydrogen, C0o, substituted or unsubstituted unsubstituted hydrocarbyl, substituted or unsubstituted aryl or alkylenearyl, or Hexyl heteroaryl; or e) R 7 and one R 9 may together form a carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms substituted by human t; 8) & 2 is-(^ ^ 2). 丨 42- [0 (111 "11 川); ^] 2, where: a) j is a number selected from 0 to 5; b) L2 is selected from a covalent bond, _〇C〇2 -, -SO-, -S02-, C〇N (R10) 0 ·, -〇CO〇N (Rl〇)-substituted Cl-C5 courtyard; '~ N-' -C〇2- λ ~ C〇CSN (R) V, -C〇N (R1 ()) where R1G is hydrogen or substituted or

Hydrogen,, 0R] 3, -N (R13) 2,, Nhco2R13, = NR13, c) R 1 1 a and R 1 1 b are each selected from

M 013… CON (R13) 2, -NHCOR13 C〇2 K

R] 3, and mixtures thereof, unsubstituted C 1 _ C wherein each R 13 alkyl group, and substituted are respectively selected from hydrogen, substituted or or unsubstituted aryl group, or (15), (12) 200416214 alkyl group Fangqi ·, _, t 'or-R13 can be-Qi Xingqing has 3 to 7 generations of Zhu Jing substituted 1U as the original carbocyclic or heterocyclic ring; d) g is selected from 0 to 5 Number; 疋 does not exist or is selected from hydrogen, substituted ~ C] 0 alkyl, terminal Iv, p, C, substituted C!-Substituted or unsubstituted hydrocarbyl, heterocyclic group g, substituted 1 φ fl substituted or unsubstituted or unsubstituted heteroaryl with 1 ^ k radical, 1 azimuth or alkylene heteroaryl radical; or with H 13 may form together Take 3 to 7 m ^, 4 and substituted carbocyclic or heterocyclic rings containing our carbon atoms; C) R3 is-((: Η2) Ι1) 6, where: a) 11 is a number selected from 0 to 5 ; M L3 is selected from covalent bonds ... 〇 ... I, I, ,, 〇Co-, ~ C〇2- > -c〇.

", -So ...- s〇2-, -CSNH-, -CONH-〇CO〇NH-; is selected from the group consisting of hydrogen, substituted or unsubstituted e, 繂 100 \ 7you · ^ 1 1 L]. Basic aryl radicals: Cl_C] ° heterocyclic radicals, substituted or unselected radicals or extended radicals, substituted or unsubstituted heterocyclic radicals, substituted or unsubstituted heterocyclic radicals Aryl or alkylheteroaryl; £ ~ R, and R5 are selected from hydrogen or substituted units, respectively; or R DR 4 a, P 4 a 门 · ρ 4 b, p 1 ^ R and RR and R2, or R1 and R3 may be taken as a whole with tt fl >. Substituted or unsubstituted carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. Another aspect of the present invention provides a pharmaceutical composition, and丄 一一 巴 曰 女 全 @ Effective dose of the above compound and a pharmaceutically acceptable carrier. Another aspect of the present invention is to provide a safe and effective dose above -16- (13) (13) 200416214 The compounds are used in patients to treat PTPase-related diseases. Those skilled in the art will have a clearer understanding of the above and other objectives, features and advantages from the following description and the scope of patent applications. Detailed explanation of the name 1 · Nouns and definitions The following are the definitions of the terms used in this article: The term "hydrocarbyl" in this text means any organic unit or group containing carbon and hydrogen atoms. The definition of hydrocarbyl includes the following Heterocyclic. Various unsubstituted non-heterocyclic hydrocarbon groups include pentyl, 3-ethyloctyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo [2.2.1] Heptyl- and naphthyl-2-yl. The definition of "hydrocarbon group" includes aromatic carbocyclic (aryl) and non-aromatic carbocyclic rings. Non-limiting examples include cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo [0.1.1] butyl, bicyclo [0.1 .2] pentyl, bicyclo [0.1.3] hexyl (thujanyl), bicyclo [ 0.2.2] hexyl, bicyclic [0.1.4] heptyl (caranyl), bicyclic [2.2.1] heptyl (orthobornyl), bicyclic [〇 · 2.4] octyl (caryophyllyl), spiropentyl, Bicyclopentylspiroalkyl, naphthylalkyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthracenyl, fluorenyl, pinenyl, 1, 2 , 3,4-tetrahydronaphthyl and the like. The term "heterocyclyl" includes aromatic heterocyclic rings (heteroaryl) and non-aromatic heterocyclic rings. Non-limiting examples include pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, and 2 Η-imidazole. Base, 1, 2 5 3 -triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1 5 2,4-oxadiazolyl, 2 fluorene -pyranyl, 4 Hydrazone -pyran-17- (14) 200416214 group, 2 hydrazone-D [; tran_ 2 -one-keto-group, D (t hydrazyl, pyridazinyl, hydrazine, hydrazinyl, piperazinyl , S-triazinyl, 4'-1,2-oxazinyl, 41 ^ 153_methylammonyl, 1,4-methylpyrazinyl, morpholinyl, azamask, oxaziridine, 2_diazamoyl, indenyl, 2H-indenyl, benzofuranyl, isobenzo-p-furanyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H_ 1-benzopyranyl, D quinolinyl, isoD quinolinyl, D quinazolinyl, 2η_1 4 · BenzoHoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, pyrene Mum,

Fluorenyl, benzimidazolyl, etc., and each of the above groups may be substituted or unsubstituted. "" An alkylaryl group, an example of a unit defined by ethyl is a benzyl unit of the formula:

An example is the following: "Alkylheteroaryl, a 2-pyridylmethyl unit of the formula defined by the ~ unit: -CH2

"Substituted, ethyl is used throughout the specification." Substituted, ethyl is defined herein as "a group or unit containing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms in a replaceable hydrocarbon group." ", Substituted also includes" replaces a hydrogen atom on two adjacent carbon atoms to form a new group or unit, "for example, a substituted unit that requires a hydrogen atom includes halogen, hydroxyl, and the like. The substitution of two hydrogen atoms includes a carbon group, a hydroxyimino group, etc. The substitution of two hydrogen atoms of an adjacent carbon atom includes an epoxy group, etc. The substitution of three hydrogen atoms includes a cyano group, etc. The epoxy unit is Requires hydrogen atom of adjacent carbon atom -18- (15) Substitute of substitution, the phrase is expressed in μ (special Γ !!; throughout the description, "lightly substituted hydrogen atom is replaced by ## 方 方 族 family Wang Ai, Yanji Chain) can be replaced by Bu Deji. When the 阃 w ρ__ ^ number of hydrogen atoms u — 'peaks are replaced by,, the basic base of the Fangxiang family warm ring L is "C8, which is taken as the basic unit, and 3, its acryl Is "replaced

2 An acryl group is ":: propyl is" a substituted ~ base unit, and, and the unit is marked as, taking: a substituted heteroaryl unit ,. The following is a non-limiting example of a nicotyl single unit "when substituted as a substituent of a hydrogen atom:)) iv) v) vi) vii) viii) [C (R 5) 2] p (CH = CH) qR15;, [c (r15) 2] pc (z) r15;] c (rI5) 2] pc (z) 2r15;

[C (Rl5) 2] pC (Z) CH = CH2; '[C (Rl5) 2] pC (Z) N (R) 5) 2; ^ C (Rl5) 2] pC (Z) NR15N (R15) 2;] C (R) 5) 2] PCN;-[C (R15) 2] pCN〇; iX-[C (RI5) 2] pCF3,-[C (R15) 2] pCC13,-[C (R -) 2] pCBr3 x)-[C (R) 5h] pN (R〗 5) 2; xi)-[c (R) 5) 2] pnr15cn; xii)-[C (R15) 2] pNR15C (Z ) R15; xiii)-[C (Rl5) 2] pNR15C (Z) N (R15) 2; xiv)-[C (R) 5) 2] pNHN (R) 5) 2; -19- (16) 200416214 xv)-[C (R15) 2] PNHOR15; xvi) [C (R] 5) 2] pNHS03M; xvii) [C (R] 5) 2] PNCS; xviii)-[C (R, 5) 2] pN02; xix)-[C (R15) 2] P〇R15; xx)-[C (R15) 2] P〇CN;

xxi)-[C (R] 5) 2] pOCF3,-[C (R〗 5) 2] P0CC13,-[C (R15) 2] pOCBr3; xxii)-[C (R15) 2] PF,-[ C (R) 5) 2] PC1,-[C (RM) 2] pBr,-[C (R15) 2] PI, and mixtures thereof; xxiii)-[C (R15) 2] PSCN; xxiv)-[ C (R15) 2] PS03M; xxv)-[C (R15) 2] p〇S03M; xxvi)-[C (R15) 2] pS02N (R) 5) 2; xxvii) [C (R15) 2] PS02NH (R15);

xxviii)-[C (R15) 2] PS02NHC0R15; xxix)-[C (R) 5) 2] pS02NHC00R】 5; xxx)-[C (R] 5) 2] pS02R15; xxxi)-[C (R15) 2] pP (0) H2; xxxii)-[C (R) 5) 2] pP02; xxxiii)-[C (R15) 2] pP (〇) (〇H) 2; xxxiv)-[C (R15) 2] pC02M; xxxv)-[C (R15) 2] pSR15; xxxvi) and mixtures thereof; -20- (17) 200416214 where R15 is hydrogen, substituted or unsubstituted C] _C2 () straight chain, Branched or cyclic group, C 6 -C 2 〇aryl, C 7 _ c 2 G alkylene aryl, and mixtures thereof; M is hydrogen or a salt-forming cation; z is = 〇, = s , = N R 15 and mixtures thereof; ρ is 0 to 12; q is 0 to] 2. Suitable cations to form salts include sodium, lithium, potassium, iron bow, magnesium, money, and the like. II. Compounds The first aspect of the invention relates to compounds represented by the formula:

Righteousness. The following are various non-limiting preferred groups, but are not intended to limit the repeated content and examples exemplified herein.

A) A single sulfonic acid amine group (H0S02NH-) of formula (I) is linked to the 4, 5, 6, 7 or 8 position of the phenethylamine structure. The commonly used numbers are as follows: 5 6 In a system, the sulfonamido group is at the 5 or 6 position of the structure. In another system, the sulfonic acid amine group is at the 6th position of the structure. B) R] is-L]-[C (R6aR6b)] mR7. L] is selected from a covalent bond, -21-(18) 200416214, _S-, _N-, _C〇2 ·,, _〇C〇2-, _SO ·,-s 0 2 ^ CSN (R8) ·, -CON (R8) _, _coon (R8) 0-, -〇coon (R8)-; where R8 is hydrogen or a substituted or unsubstituted C! -C5 courtyard. In another system, L1 is selected from the group consisting of covalent bonds, -co-2_, -CO-, -S02-, and -cois ^ R8) In another system, L] is selected from the group consisting of -C02-, -CO-, _SO2 •, and CON (R8)-. In another system, l1 is -CONH-. In another system,] L / is a covalent bond.

R6a and R6b are selected from the group consisting of hydrogen, _0R9, _n (r9) 2, < 0 ^ 9, CON (R9) 2, -NHC0R9, _NHC〇2R9, = nr9, _R9, and their compounds; each R9 Selected from the group consisting of hydrogen, substituted or unsubstituted c alkyl, and substituted or unsubstituted aryl or alkylene, respectively, and two R9 may be taken together to form a substituted or unsubstituted Carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. ^ ^ ^ 2 K. In the ~ system, 'R "and ⑼ are hydrogen, respectively. In the other system, r6, r6, are unsubstituted aryl groups. In another system, Rea is called]

. Another Xuan Chuan, one foot 疋 -NHC

In the force system, R "or R6b is -NHc0r9 alkyl group. In addition-髀 is from 6 R R is via the ear] In the II series, R6a is an unsubstituted alkyl, Ganshi" square group, And R6b " where the substitution unit is at least one fine &# radical. The number of carboxylates or functions is selected from a number system of 0 to 5, where m is]. In the other system, m is 0, a substituted or unsubstituted hydrogen-substituted or unsubstituted CK ", a signature group, a substituted or unsubstituted hetero- 22- (19) ring group, Substituted or unsubstituted hetero 2 aryl or phenylene aryl, substituted or selected from substituted or unsubstituted; Γ henyl heteroaryl. In the first system, Han 7 is a substituted aryl group, a second-generation C1-C1 ° group, a substituted or unsubstituted extension group, and a substituted heteroaryl group, a substituted or unsubstituted group, , Earth, and substituted or unsubstituted alkylene heteroaryl. In the system, R7 is substituted or unsubstituted c 1. In the other-system, R7 is an unsubstituted courtyard, where ;;; is a branched courtyard. S1. In the rh7 force system, R7 is the third butyl group. In another system

'R7 is selected from -ch3, _CH2CH3, _CH2CH2CH3, and (cH2) 3. (CH2) 4CH3 >-(CH2) 5CH3 ^ -C (CH3) 3' -cH2C (CH3) 3, .CH2C (CH3) 2CH2CH3 & gt -C (CH3) 2CH2CH3 '-CH (CH3) CH2CH, and -ch2ch (ch2ch3) 2. In another system, R7 is a substituted c] _Ci () alkyl, wherein the substituted unit is-[C (R) 5) 2] pC (Z) N (Ri5) 2. In addition, in the system, ruler 7 is a substituted CVC5 alkyl group, wherein the substitution unit is -coon2.

In another system, R7 is heteroalkyl. In another system, r7 is a C ^ C5 heteroalkyl group containing at least one heteroatom. In addition, in the system, R7 is a heteroatom group, in which the heteroatom is at least s. In one system, R7 is a substituted or unsubstituted alkylene. In another system, R7 is substituted or unsubstituted c! 2 butane and its aryl group. In another system, R7 is selected from ch2ch2 (c6h5) '-(ch2) 3c6h5,-(CH2) 4c6: HU,'] 〇H7), -CH2CH2 (C) 〇H7), (CH2) 3C] 〇H7 , And r 2) 4C] OH7, and mixtures thereof. In another system, R7 is a substituted alkylene aryl. Its -23- (20) 200416214 is a substituted unit selected from-[C (R) 5) 2] pS〇2N (R15) 2,-[ C (R) 5) 2] pS02NH (R15),-[c (R15) 2] pS02NHC0R15, and-[C (R15) 2] pS02NHC00R15, and mixtures thereof; in another system, the substitution unit is selected from -S〇2NH2, -S02NHC00CH3, -SO2NHCOOCH2CH3, -S02NHC0CH3, -SO2NHCOCH2CH3, _S02NHC0C (CH3) 3, -S02NH (C6H5), -so2nhco (c6h5), -S02NHCH2, C0H2C, and And its mixture.

In another system, R7 is a substituted or unsubstituted aryl group. In another system, R7 is a substituted aryl group, wherein the substituted unit is at least one selected from the group consisting of -CH3, -CH2CH3 ... ch2ch2ch3 ... C (CH3) 3, 0CH3, and R7 are substituted aryl OCH2CH3, and mixtures thereof. In another system, the radical '' in which the substituted unit is a halogen. In another system, RI is guanidyl or fluorenyl. In addition, in the system, L1 is a covalent bond; R7 does not exist; m is 丨; and R "is = NR9, and is ice 9

Or -n (R9) 2, where -n (r9) 2 is preferably _nhr9. Another body = a covalent bond; R7 does not exist; m is 丨; and 1 iNK at R6a, 9 9, and R6b is -R9 〆N (R) 2 where one of R 9 together forms a ^. ^ N or An unsubstituted carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. B) R2 is-(CHJj-LMc ^ R] laR]】 b)! R】 2 々々々 ～ 々Js. j is selected from ο to d. L is selected from the group consisting of covalent bonds, -〇_, ”, -CO", -CO -... 〇C〇2--S〇_ s, _c c〇NfR10, 〇)-, -CON (R, _, _ C〇N (R) 0… 〇c〇N (Ri v. Rl0 is a substituted C r ^ substituted or unsubstituted spoon 1 c5 i: elementary base. R] a and R 丨 b respectively Hydrogen, -OR] 3,--24- (21) 200416214 N (R) 3) 2, Γ (HP13r, -c〇2r, -con (rI3) 2, · NΗί: οκ13… NR13 n) 3 ^ _INHC〇2Rl3,-, and mixtures thereof. Each R13 is selected from the group consisting of substituted or unsubstituted C r ^ # hydrogen, lightly substituted C "C5 alkyl, and substituted or alkylene aryl; or , A j3 substituted aryl ^, and one R may together form a carbocyclic or heterocyclic ring containing 3 to 7 atoms and substituted by a substituted widow. The number up to 5 is qR12 $, is from 0, exists or Selected from hydrogen, substituted K1Q alkyl, substituted π-unsubstituted k-substituted or unsubstituted hydrocarbyl substituted heterocyclyl, substituted or substituted or unsubstituted or unsubstituted aryl, or Substituted or Unsubstituted Heteroaryl Heteroaryl: RI2 " Rl3 may-up to form a substituted or unsubstituted Carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. 3 has 3 as in a system, 'j is 0. In another system, j is !. In a system, L2 is selected from calix, L is covalent Bond, -CONRL -CONH-, -COi ^ Ci ^) ·, _c〇2-, · (: 〇—, CUN 〃 mixture. In another system, L2 is selected from -CONR ,, _c〇NH ... Another system In the other system, R 1 1 a and R]] b and its mixture are helium in another system, 111] 3 or Ru. C7. C20 alkylene aryl substituted or unsubstituted. In another system, a Water I is substituted with J ρ Γ ^ or R1 1 b is an unsubstituted C7-C1 () endyl group. In another system, Ra or Rnb is selected from ch2 (c6h5), -CH2CH2 ( C6H5), 2 3 C 6 H 5 >-(CH 2) 4 C 6 H 5, -CH2 (C10H7), -CH2CH2 (C) 〇h, 7 '(CH2) 3C] 〇H (CH2) 4C] GH7, and mixtures thereof. In addition, R] I CON (R) 3) 2.

Or R and are in one system, g is selected from 0 and in the other system, g is 0. 25- (22) 200416214 In a system, R 12 is a substituted or unsubstituted C] ο alkyl group. In another system, it is selected from -CH3, -CH2CH3, 彳 h2CH2 (: H3,-(CH2) 3CH3 ^-(CH2) 4CH3 >-(CH2) 5CH3'-C (CH3) 3 ^ CH2C (CH3) 3. -CH2C (CH3) 2CH2CH3, -c (CH3) 2CH2CH3, -CH (CH3) CH2CH3, and -ch2ch (ch2Ch3) 2, and mixtures thereof. In a system, R12 contains substituted or unsubstituted A heterocyclic ring of 3 to 7 carbon atoms. In another system, RI2 is a substituted or unsubstituted morpholinyl group. In another-system, R12 is a substituted or unsubstituted pyrimidinyl group. System R is Contains at least one heteroatom t Ci_C5 heteroalkyl. In the other body, R12 is a heteroalkyl group, wherein the heteroatom is 0 or 3. ^ In a system, R12 is hydrogen. C) R3 is-(CH2) rL3_R] 6 . 3, η 疋 The number L from 0 to 5 is transported from a covalent bond, -〇-, -§_, Ν N-, -C〇 ", -C〇-, 〇Cc, -SO-, -S02 -, -CSNh • ... coonh and -0C0NH-. Selected from hydrogen, substituted or unsubstituted — 10-fluorenyl, substituted C ”C | ° heterocyclic, substituted or unsubstituted Substituted aryl = Chenyl aryl, substituted or unsubstituted heterocyclyl, substituted second-generation heteroaryl or alkylene heteroaryl. ,, s without or

In a system, η is in a system in which L3 m,, Mg, and ^ are introduced from hydrogen, covalent bonds, -co_, and

In one system, R) 6 is an unsubstituted C system, and R16 is optional.

-CH2CH body " CH2CH2CH ,, -26- (23) (23) 200416214 (CH2) 3CH3 >-(CH2) 4CH3 >-(CH2) 5ch3 ^ .C (CH3) 3. CH2C (CH3) 3 ^ -CH2C (CH3) 2CH2CH3. -C (CH3) 2CH2CH3 ^. CH (CH3) CH2CH3, and -CH2CH (CH2CH3) 2. In addition, in the system, R16 is a substituted L-C5 alkyl group, wherein the alkyl group is substituted with at least one carboxylate group. In another system, R1 6 is a substituted or unsubstituted alkyl group, and the alkyl group is an alkenyl group (that is, it has at least one olefinic double bond). In a system, R is substituted by a substituted or unsubstituted c 7-c 丨 alkylene aryl group. R16 is selected from -CH2 (C6H5), 4Η < Η2γ6Η5), _ (C Η 2) 3 c 6 Η 5,-(CH2) 4C6H5, -CH2 (C10H7),. Φ CH2CH2 (C10H7),-(CH2) 3CI () H7, and-(CH2) 4CioH7. In the other system, 'R16 is a substituted ylenylaryl group, in which the substitution unit is at least [c (r15) 2] pnhso3m. D) R4a, R4b, R4e and R5 are each selected from hydrogen or substituted units. E) R and R, or R4a and R4b may together form a substituted or unsubstituted carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. II. Preparation of compounds φ The compounds of the present invention can be prepared by various methods. The starting materials used in the preparation of the compounds of the present invention are known, or can be prepared by known methods, or are commercially available. A particularly suitable synthetic method is disclosed in the following reaction scheme. (The R group in the reaction diagram is not necessarily related to each R group in the compound represented by the above formula (I). In other words, for example, R1 in the formula (I) does not represent the same R1 group in this reaction diagram). Specific examples of preparing the compounds of the present invention are disclosed in Section VI below. -27- (24) 200416214 Reaction Figure 1

1. reduction 2. S03 py, pyridine

In Reaction Figure 1, the reaction starting compound, 4-nitrophenylalanine (1) protected by a third butoxycarbonyl (Boc) group, undergoes an amidine formation reaction, via an asymmetric isobutyl carbonic anhydride formation reaction Reaction with a primary amine to obtain compound (2). A variety of secondary amines and alcohols can also be used under similar conditions. Alternatively, methods involving the use of a condensing agent to form amidine (see Bodansky, M .; Activation and Coupling. In Principles of Peptide Synthesis, 2nd ed .; Springer Publishing: New York, 1993, pp 9-61 ). In addition, multiple amine components can be introduced in this step to increase similar synthetic variability. Finally, the intermediate (2) is then directly prepared into a final arylaminosulfonic acid compound (3) through a 2-step method, including an arylnitro reduction reaction (a variety of methods can be used, see, for example, Hudlicky of Nitro , Nitroso, Diazo, and Azi do Derivatives of Hydrocarbons and Basic Heterocycles, In Reductions in Organic -28- (25) (25) 200416214

Chemistry, 2nd e d ·; ACS Monograph 188; American C h e mi i s 11 · y S o c i e t y: Was h i η g t ο n 5 D C, 19 9 6) and the subsequent aminosulfonic acid formation reaction. The final amine sulfonic acid compound formation reaction can be achieved by dissolving the reduced product in anhydrous pyridine (about 2-3 mL per 0.5 mmol) and adding a sulfur trioxide pyridine complex solid (3 mole equivalents). When sulfur trioxide D was added, the reaction mixture was stirred for about 5 minutes, and then the reaction was quenched with a dilute ammonium hydroxide aqueous solution (about 7% aqueous solution). The crude product is obtained after evaporation of all volatile materials, and the target compound is usually purified by RP-HPLC, usually with a yield of 30-65% (2 steps). In addition, other pyridine complexes of sulfur trioxide (ie, sulfur trioxide dioxane, etc.) can be used, for non-limiting examples see Gilbert (Che m. Rev. (1962) 62, 549-89). Reduced nitro compounds can also be functionalized into aminosulfonic acids by utilizing the action of chlorosulfonic acid in the presence of a suitable base (e.g., Sureau, RF M, et al; Preparation of Snip ham ic Acids, U.S. Patent 2,789,132), or the use of 0-trimethylsilyl chlorosulfonic acid and an appropriate base-29- (26) 200416214 Reaction Figure 2

RrX, several methods

Alternatively, as shown in Reaction Scheme 2, the intermediate (2) is used as a reaction initiator for other analogs after removing the Boc group i W. The removal reaction of the B oc protecting group is performed under acidic conditions (see, for example, G 1 · eeneand Wuts, PP 5 1 8-5 2 5), for example, using 4 M hydrochloric acid in 1,4-dioxane The hydrochloride (4) is obtained in high yield and purity.

Intermediate (4) is the substrate of many subsequent functionalization reactions, so a variety of electrophilic reagents (R2-X) can be introduced where appropriate. Non-limiting examples of the above types of reactions include urine formation reaction by adding isocyanate, thiourea formation reaction by adding isothiocyanate, ammonium formation reaction by reacting with ammonium chloride, and using a suitable condensation reagent to react with carboxylic acid Condensation amine formation reaction (see Bodansky, M. above), chloroformate carbamic acid formation reaction (see Greene and Wuts, Pr tectec ο η Groups in Organic Synthesis, 3rd ed .; Wiley & Sons: New York, 1 9 9 9), amine compound formation reaction using a suitable carbonyl compound for reductive alkylation reaction, amine formation reaction through alkylation reaction of alkyl halide 2. Various methods of guanidine formation reaction (see Burgess, K .; • 30- (27) 200416214

Chen, J .; Solid-Phase Synthesis of Guidelines. In Solid Phase Organic Synthesis; Kevin Burgess, Ed The sulfonamide formation reaction of the chlorine reaction. It is also possible to use two of the above reaction types, such as a reductive alkylation reaction and a subsequent halogenation reaction. The above-mentioned functionalization reaction is not exhaustive, but merely used to illustrate the type of conventional chemistry ', which can be used by those skilled in organic synthesis to obtain a compound represented by the general formula (5). Finally, as shown in Reaction Scheme 1, the intermediate (5) is then directly prepared into a final arylaminosulfonic acid compound (6) through a 2-step process, which includes an arylnitro reduction reaction and a subsequent aminesulfonic acid. Acid formation reaction; and any subsequent functionalization reaction. Reaction diagram 3 o2n

nh2

RrX, several methods; R2-x, several methods

1. Reduction of Z scvpy, pyridine compound (7) is the substrate of many subsequent functionalization reactions, so a variety of electrophilic reagents (R ^ X, optionally R2-X) can be introduced under appropriate conditions to obtain the general formula (8) The intermediate shown. Finally, as shown in Reaction Figure 1, the intermediate (8) is then directly prepared into a final arylaminosulfonic acid compound (9) through a two-step process, including an arylnitro reduction reaction and a subsequent aminesulfonic acid. Acid formation reaction; and any subsequent functionalization reaction. -31-(28) (28) 200416214 According to the principles disclosed in the above reaction diagrams, many compounds can be obtained by similar methods. The above steps can be varied to increase the yield of the desired product. Those skilled in the art agree that a clear choice of reactants, solvents, and temperature are important factors for any successful synthesis. Determining the optimal conditions is routine work, so anyone skilled in the art can use the principles disclosed in the above reaction diagrams to make many compounds. It must be understood that those familiar with organic synthesis techniques can use organic compounds in a standard manner without further instructions. In other words, the standard application methods described above are also within the knowledge and habits of those skilled in the art. These include (but are not limited to) reduction of carbonyl compounds to corresponding alcohols, oxidation reactions of hydroxyl groups, etc., tritiation reactions, aryl substitution reactions (including electrophilic reactions and nucleophilic reactions), etherification reactions, esters Reaction and saponification reaction. Examples of the above methods are disclosed in standard textbooks, such as March, Advanced Organic Chemistry (Wiely), Carey and Sundberg, Advanced Organic Chemistry (2 volumes), and other previous techniques familiar to those skilled in the art. Those skilled in the art will immediately understand that in order to avoid any undesired side reactions and / or increase the yield of the reaction, some reactions are preferably masked or protected by other possible reactive functional groups in the molecule Next. In general, those skilled in the art use protecting groups to achieve higher yields or to avoid unwanted reactions. The above reactions can be seen in the literature and are also within the knowledge of those skilled in the art. Examples of the above methods can be found in T. Greene, Protecting Groups in Organic Synthesis. While -32- (29) (29) 200416214 Of course, the amino acid having a reactive side chain as a reaction initiator should be protected to prevent undesired side reactions. The compounds of the invention may have one or more palm centers. Therefore, one of the optical isomers can be preferentially prepared selectively, including mirror isomers and non-mirror isomers, for example, using a palmitic reaction initiator, catalyst or solvent, or two stereoisomers can be prepared simultaneously. Structure or two optical isomers, including the simultaneous preparation of mirror isomers and non-mirro isomers (racemic mixtures). Since the compounds of the present invention can exist as racemic mixtures, optical isomers (including mirror isomers and non-mirror mirrors) can be separated by known methods (e.g., palmar salt, palmar chromatography, etc.). Isomers) or mixtures of stereoisomers. In addition, it must be understood that any optical isomer, including mirror isomers and non-mirro isomers, or stereoisomers, may have properties superior to the other optical isomer. Therefore, when revealing the content of the present invention and claiming the scope of a patent application, when a racemic mixture is disclosed, it can be clearly expected that optical isomers, including mirror isomers and non-mirror isomers, or substantially no other The stereoisomers of one of them are also included in the content disclosed in the present invention and the scope of patent application. I V. Method for treating diseases related to P τ P a s e The compounds of the present invention described above can be used in methods for treating diseases related to PTPase. In this context, "PTPase-related diseases" means "biological manifestations involving diseases, disorders, and / or conditions, biological cascades that cause disease, or undesired or elevated p that are symptoms of disease. TP ase activity (30) (30) 200416214. PTP ase activity in PTP ase-related diseases "is involved," and includes (but is not limited to) the following: (1) Undesired or elevated p T pase Activity is the "cause" of disease or biological manifestation, regardless of whether P TP ase activity is promoted through infection, autoimmunity, trauma, biomechanical factors, lifestyle or other factors. (2) Unwanted or elevated ρ τ p a s e activity is part of the manifestation of the observed disease or disorder. In other words, the disease or disorder can be measured in terms of increased P T Pa s e activity. From the clinical point of view, g's undesired or elevated P T Pa s e activity shows disease, however, PTP a se activity does not have to be a "marker" of disease or disorder. (3) Unwanted or elevated PTPase activity is part of the biochemical or cellular cascade that causes disease or disorder. In this regard, inhibition of PTPase can hinder the cascade and thus control the disease. Non-limiting examples of PTPase-related diseases that can be treated by the present invention include insulin tyrosine-related diseases, bone diseases, and vascular diseases. As used herein, "PTPase" means an enzyme having the ability to dephosphorylate a pTyr-containing protein or glycoprotein or segment. Non-limiting examples of PTPase include: intracellular PTPases (for example, PTP1B, TC-PTP, PTP1C, PTPID, PTPD1, PTPD2); receptor-type PTPases (for example, PITPa, PPTPe, PPTPβ, PPTPγ, CD45, PPTP, PPTP) ; Dual specificity phosphatases (V Η 1, V Η R, cdc 2 5); L M W-Ρ Τ Ρ ases; and acid phosphatase. All known intracellular PTPases contain a single retained catalytic phosphatase domain consisting of 220-240 amino acid groups. Non-limiting example of intracellular PTPases: PTPI B (Tonks et al. 5 J. Biol. (31) (31) 200416214

Che m. 263: 6722- 6 7 3 0 (1 9 8 8)); PTP 1 (C harb ο η neau et al.? Proc. Natl. Acad. Sci. USA 8 6: 5 2 5 2-5 2 5 6 (1 9 8 9);

Chemoff et al., Proc. Natl. Acad. Sci. USA 8 7: 2735-2789 (1 9 8 9)); T-cell PTPase (Cool et al., Proc. Natl. Acad. Sci. USA 86: 5257 -5261 (1989)); mouse brain PTPase (Guan et al.? Proc. Natl. Acad. Sci. USA 8 7: 1 5 0 1-1 5 02 (19 9 0)); neuron phosphatase STEP ( Lombroso et al., Proc. Natl. Acad. Sci. USA 8 8: 7242- 724 6 (1 99 1)); PTPases with ezrin-regions; PTPMEG1 (Gu et al., Proc. Natl. Acad. Sci. USA 88: 5 8 6 7- 5 8 7 1 (1 9 9 1)), PTTP I (Yang and Tonks, Proc.

Natl. Acad · Sci · USA 8 8: 5 94 9- 5 9 5 3 (1 9 9 1)), PTPD1 and PTPD2 (Moller et al. 5 Proc. Natl. Acad. Sci. USA 91: 7 4 7 7 -74 8 1 (1 9 94)); FAP-1 / BAS (Sato et a 1., Science 26 8: 411-415 (1995); Ban ville et al., J. Biol. Che m. 269: 223 2 0-223 27 (1 994); Maekawa et al.? FEBS Letters 3 3 7: 200-206 (1 994)); and SHTP-containing PTP1 (Plutzky et al.? Proc. Natl. Acad. Sci. USA 89 : 1 1 2 3-1 1 27 (1 9 92); Slien et al.? Nature Lond. 3 5 2: 7 3 6-7 3 9 (1991)) and PTP1D / Syp / SH-PTP2 (Vogel et al ·, Science 2 5 9: 1611-1614 (1993); Feng et al. 5 Science 2 5 9: 1 6 0 7-1 6 1 1 (1 9 9 3); B asteineta 1.? B iochem. B iophys Res. Comm. 196: 124-133 (1993)) ° Most receptor-type p τ Pases are extracellular regions bound by a) hypothetical ligands, b) membrane-penetrating fragments, and c) Intracellular catalytic region group -35- (32) 200416214. Non-limiting examples include CD45 / LCA (Ralph, S.J., EMBO J. 6: 1 2 5 1-1 2 5 7 (1 9 8 7); LAR (Streuli et al., J. Exp. Med 1 6 8: 1 5 2 3-1 5 3 0 (1 9 8 8); C harb ο η nea υ et a 1., Proc. Natl.

Acad. Sci. USA 8 6: 5 2 5 2-5 2 5 6 (1 9 8 9)); CD45 (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85-116 (1 994)); PTPa ( Krueger et al., EMBO J. 9: 3 24 1 -3 2 5 2

(1 9 90); PTPP (Krueger, ibid); PTδ (Krueger, ibid); PTε (Krueger, ibid); PTze (Krueger, ibid). Other examples of receptor-type PTPases include PTPγ (Bamea et al., Mol. Cell. Biol. 1 3: 1 497-1 5 06 (1 9 9 5)); PTTP μ (Gebbink et al.? FEB S Letters 2 90: 1 2 3-1 3 0 (1 99 1)); PTPk (Jiang et al.,

Mol. Cell. Biol. 1 3: 2 942-2 9 5 1 (1 9 9 3)); SAP-1 (Matozaki et al ”J. Biol. Chem. 269: 207 5 -20 8 1 (1 994) ); And PTP- U2 / GLEPP1 (Seimiya et al.? Oncogene 10: 1 73 1-1 7 3 8

(1 9 9 5)); (Thomas e t a 1.? J. Biol. Chem. 269: 19953-19962 (1 994)). Novel PTPases have been continuously identified, and it is expected that more than 500 different substances will be found in the human genome (that is, those close to the expected size of the protein tyrosine kinase family) (H a 11 ksand H unter 5 FASEB J. 9: 5 7 6-5 96 (1 995)). The bispecific protein tyrosine phosphatase (dsPTPase) defines one of the subtypes in the PTPase family, which hydrolyzes phosphate from phosphotyrosine and serine / threonine. dsPTPase contains the recognition sequence of PTPase: His_Cys-Xxx-Xxx-Gly-Xxx-Xxx-Arg. At least three types of dsPTPases have been shown to make extracellular message-regulated kinases (ERKs) / mitogens live -36- (33) (33) 200416214-ized protein kinase (MAPK): MAPK phosphatase (CL 1 0 〇, 3 C ] 3 4) Dephosphorylation and inactivation (C har 1 eseta 1., Proc. N a 11. A cad · S c i. USA 9 0: 5 2 92-5 2 96 (1 993)); PAC -1 (Ward et al.? Nature 367: 651-654 (1994)); rVH6 (Moure y et a 1., J. Biol.

Chem. 271: 3 7 9 5 -3 8 02 (1 9 96)). The transcription of dsPTPase is triggered by different stimuli, such as oxidative stress or heat shock (Ishibashi et al ”J. Biol. Chem. 269: 29897-29902 (1 994); Keyse and Emslie, Nature 3 5 9: 644- 647 (1 992)). In addition, it may be related to the regulation of the cell cycle: cdc25 (Millar and Russell, Cell 68: 407-410 (1 9 9 2)); KAP (Hannon et al., Proc Natl. Acad. Sci. USA 9 1: 1 73 1-1 73 5 (1 994); for review see Walton and

Dixon, A n u. Rev. Biochem. 62: 101-102 (1993)). Low-molecular-weight phosphotyrosine-protein phosphatase (LMW-PTPase) shows a small amount of sequence identity with intracellular PTPase as described above. However, this enzyme belongs to the PTPase family because it has at least a PTPase active site segment (Cirrieta 1., E u 1. · J. B i 〇chem · 2 1 4: 6 4 7-6 5 7 (1993)) . For further elaboration, see Chiarugi et al., FEBS Lett. 310: 9- 1 2 (1 9 92) and Su et a] ·, Nature 3 70: 5 7 5-5 7 8 (1 994) o For testing and The PTPase inhibitory activity is analyzed and the compounds of the invention are tested using a variety of methods familiar to those skilled in the art. For example, the DiFMUP phosphatase assay is used. DiFMUP ("6,8-difluoro-4 -methylcrotyl phosphate") (Μ ο 1 ecu 1 a 1 · P 1. 〇bes) (10 m Μ) and η Μ concentration of phosphatase in Incubate in a buffer containing 50 nM Tris (pH 7), 1 50 niM NaC and 5 mM DTT, (34) (34) 200416214] m EDTA, 0.1% BSA for 15 minutes. The resulting phosphatase product was measured at a wavelength of 3 55/460 nm (ex / em) using a Victor V-type plate counter (Wallac). The inhibitor (0.002-40 mM) was pre-incubated with phosphatase for 10 minutes before adding to the DiFMUP substrate. The I C 5 〇 curve was obtained using E X c e 1- F i t ®. C. Therapeutic methods The compounds of the present invention are useful in methods of treating PTPase-related diseases in patients, which comprise administering the compounds of the present invention. As used herein, the phrase "treatment" means, at a minimum, administration of a compound of the present invention to a patient (preferably a mammalian patient, more preferably a human) to reduce PTPase-related diseases. Therefore, the phrase "treatment" includes: preventing a patient's PTPase-related disease (especially when the patient is susceptible to a disease but not being diagnosed with the disease); inhibiting a PTPase-related disease; and / or reducing or reversing a PTPase-related disease . Therefore, the method of the present invention is related to the prevention of PTPase-related diseases. It must be understood that the word "prevention" does not require that the disease state be completely stopped (see Webster's Ninth Collegiate Di c t i ο n a r y). Conversely, the term "prevention" in this document means the ability of a person skilled in the art to identify patients affected by PTPase-related diseases, so that the compounds of the present invention can be administered before the onset of P Tase-related diseases. The word "prevention" does not mean that the disease state can be completely avoided. Patients with a high-risk group of diseases related to P T P a s e, taking type I diabetes as an example, are those who have been genetically susceptible to diabetes based on the family history of the disease. Other risk factors include obesity or diet. -38- (35) (35) 200416214 The different systems of the PTPase-related diseases of the present invention are explained as follows 1. Insulin receptor-related diseases In one aspect of the present invention, the PTPase-related diseases is an insulin receptor tyramine Acid kinase-related diseases. As used herein, "insulin receptor tyrosine kinase-associated disease" refers to a disease that involves the failure of the insulin receptor tyrosine signaling to cause biological manifestations of the disease, the biological cascade that causes the disease, or the symptoms that cause the disease Or disorders. In one system, the insulin receptor tyrosine kinase-related diseases are selected from the group consisting of type I diabetes, type II diabetes, glucose intolerance, insulin resistance, and obesity. In another system, the disease is type II diabetes. In order to measure and analyze the pharmacological activity against diseases related to the insulin receptor tyrosine kinase, animal testing of the compounds of the present invention is performed according to many analytical methods known in the prior art. For example, the anti-diabetic activity of the compounds of the present invention can be measured using an analytical method designed to measure the blood glucose level of experimentally induced diabetes mellitus in rats induced by tetraoxymidine (a 11 ο X a η). 2. Bone Disease In one aspect of the present invention, the PTPase-related disease is a bone disease. As used herein, "skeletal disease" refers to a disease or disorder that involves the failure of osteoblasts to proliferate and cause the biological manifestations of the disease, the biological cascade that causes the disease, or the symptoms that cause the disease. In one system, the bone and bone diseases are selected from osteoporosis and Paget's disease. In order to measure and analyze the pharmacological activity against skeletal diseases, the animal tests of the compound of the present invention -39- (36) (36) 200416214 are performed according to many analytical methods known in the prior art. For example, the anti-bone disease activity of the compound of the present invention can be demonstrated simply by using an analytical method designed to measure the ability of the compound of the present invention to increase bone mass, bone mass or density. An example of this analysis method is the analysis of mice with ovaries removed. In the analysis of ovarian-extracted mice, the ovaries of 6-month-old mice were removed, and 2 months later, the test compound was administered subcutaneously once daily. After completion of the study, bone energy and / or density were measured using dual-energy X-ray absorption spectroscopy (DXT) or inferior computerized tomography (pQCT) or microcomputer X-ray tomography (mCT). Alternatively, the increase or generation of bone mass can be measured using static and dynamic tissue morphometry. 3. Angiogenesis-related disease In one aspect of the present invention, a PTPase-related disease is an angiogenesis-related disease. In this article, "angiogenesis refers to the formation of new blood vessels in existing blood vessels. In this article," angiogenesis-related diseases include: (1) disorders characterized by undesired or elevated angiogenesis Diseases, diseases and / or undesired conditions, collectively referred to herein as "increased angiogenesis diseases"; or (2) disorders, diseases and / or undesired conditions characterized by desired or reduced angiogenesis The desired condition is collectively referred to herein as "a disease with reduced angiogenesis." a. Angiogenesis-increasing disease In this context, "increasing angiogenesis disease" refers to a biological manifestation involving a disorder, disease, and / or condition, the biological cascade that causes the disease, or the symptoms of the disease Desired or elevated angiogenic disease. -40- (37) (37) 200416214 "Involvement (relevance) of angiogenesis-related diseases and angiogenesis, including (but not limited to) the following: (1) Unwanted or elevated angiogenesis is a disease Or the "cause" of biological manifestation 'whether angiogenesis is genetically elevated through infection, autoimmunity, trauma, biomechanical factors, lifestyle or other factors ° (2) angiogenesis is the observed disease or disorder Part of the manifestation of the disease. In other words 'disease or disorder can be measured based on increased angiogenesis. From a clinical point of view, unwanted or elevated angiogenesis indicates disease' However, angiogenesis does not have to be Become a "sign" of disease or disorder. (3) Unwanted or elevated angiogenesis is part of the biochemical or cellular cascade that leads to the disease or disorder. In this regard, inhibition of angiogenesis can hinder the grade And thus control the disease. Non-limiting examples of diseases with increased angiogenesis that can be treated by the present invention are described below. The compounds of the present invention are useful in the treatment of the retina / choroid Diseases related to neoangiogenesis, including (but not limited to): diabetic retinopathy, macular degeneration, sickle cell anemia, sarcomatoid disease, syphilis, elastic fibrous pseudoxanthoma, Paget's disease, venous occlusion, arteries Occlusion, carotid obstructive disease, chronic uveitis / vitreitis, mycobacterial infection, Lyme's disease, systemic lupus erythematosus' retinopathy of prematurity, Eales disease, Behcet's disease, causing retinitis or choroiditis Infection, speculative ocular cytoplasmosis, Best's disease, myopia, eyeball depression, Stargardt's disease, inflammation of the flat part of the ciliary body, chronic retinal detachment, high viscosity syndrome, toxoplasmosis, Trauma and eruption after laser. Other diseases include (but are not limited to) diseases related to redness (angle angiogenesis) or caused by abnormal proliferation of fibrous blood vessels or tissues -41- (38) (38) 200416214 Disease, including all forms of proliferative vitreoretinopathy, whether or not it is associated with diabetes. The compounds of the present invention can be used to treat chronic Diseases related to inflammation. Diseases with symptoms of chronic inflammation include inflammatory bowel disease such as Crohn's disease and ulcerative colitis, psoriasis, sarcomatoid disease and rheumatoid arthritis. Angiogenesis is a common feature of the above chronic inflammatory diseases An important factor in chronic inflammation. It depends on the continuous formation of capillary buds to continuously inject inflammatory cells. The amount and presence of inflammatory cells produces granulomas, thus maintaining a chronic inflammatory state. The composition and method of the present invention are used to inhibit angiogenesis. It can prevent the formation of granuloma and reduce the disease. The compounds of the present invention can be used to treat patients suffering from inflammatory bowel disease (such as Crohn's disease and ulcerative colitis). Crohn's disease and ulcerative colitis are located in various places in the gastrointestinal tract It is characterized by chronic inflammation and angiogenesis. Crohn's disease is characterized by chronic granulomatous inflammation throughout the gastrointestinal tract, which consists of new capillary buds surrounding a column of inflammatory cells. The antiangiogenic effect of the compounds of the present invention inhibits the formation of buds and prevents the formation of granulomas. Crohn's disease occurs as a chronic transmural inflammatory disease that most often affects the terminal ileum and colon but may also appear anywhere in the gastrointestinal tract from the mouth to the anus and around the anus. Patients with C 1. 0 h η disease usually develop chronic diarrhea associated with abdominal pain, fever, anorexia, weight loss, and abnormal swelling. Ulcerative colitis is also a chronic, non-specific, inflammatory, and ulcerative disease that occurs in the colonic mucosa and is characterized by bloody diarrhea. Inflammatory bowel disease also shows extraintestinal manifestations, such as skin damage. This damage -42- (39) (39) 200416214 is characterized by inflammation and angiogenesis, and can also occur in many locations outside the gastrointestinal tract. The compounds of the present invention can treat such damage by preventing angiogenesis and thereby reducing the amount of inflammatory cells injected and the formation of damage. Sarcomatoid disease is another chronic inflammatory disease characterized by a multisystem granulomatous disease. Granulomas of this disease can occur anywhere in the body, so the symptoms depend on the location of the granulomas and whether the disease is active. Granulomas are produced by a fixed amount of inflammatory cells supplied by angiogenic capillary buds. The compounds of the present invention can also treat chronic inflammatory conditions associated with psoriasis. Psoriasis is a skin disease, another chronic and recurrent disease, characterized by pimples and patches of various sizes. Preventing the formation of new blood vessels necessary to maintain the characteristic damage allows the symptoms to be alleviated. Another disease that can be treated by the compounds of the present invention is rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory condition characterized by non-specific inflammation of the terminal joints. I believe it is the phenomenon of vascular proliferation in the blood vessels in the synovial lining of the joint. In addition to the formation of a new vascular network, endothelial cells release factors and reactive oxygen species that lead to the growth of articular condyles and the destruction of cartilage. Angiogenesis-related factors can actively promote and help maintain the chronic inflammatory state of rheumatoid arthritis. Other diseases that can be treated by the compounds of the present invention are hemangiomas, Osler-Weber-Rendu's disease, or hereditary hemorrhagic microangiectasis, solid or bloody bone tumors, and acquired immune deficiency syndromes. b. Diseases with reduced angiogenesis In this context, "disorders with reduced angiogenesis," the meaning refers to the desire or stimulation to treat -43-(40) (40) 200416214 diseases, disorders, and / or conditions. Angiogenesis-related disease. This disease is characterized by tissues at risk of ischemic injury, infection, and / or poor healing, or tissues at risk of ischemic injury, infection, and / or poor healing. As a result, diseases can occur when the supply of oxygenated blood is insufficient. In this article, the term “tissue” is used in a broad sense and includes (but is not limited to) the following: cardiac tissues such as the heart muscle and ventricles; erectile tissues; skeletal muscles; neural tissues such as the cerebellum Internal organs such as the brain, heart, pancreas, liver, spleen, and lungs; or general parts of the body such as the entire limbs, feet, or peripheral appendages such as fingers or toes. I. Methods of vascularizing ischemic tissue in In the method of treating a disease with reduced angiogenesis, the compound of the present invention can be used in a method of vascularizing ischemic tissue. Herein, "ischemic tissue" means Insufficient blood flow. Examples of ischemic tissue include, but are not limited to, tissues with insufficient blood flow due to myocardial and cerebral infarction, mesenteric or limb extremity ischemia or vascular occlusion or stenosis. One example is due to vascular occlusion. Oxygen blood supply is interrupted. This vascular occlusion can be caused by arteriosclerosis, trauma, surgical procedures, disease, and / or other scurvy. Determine whether the tissue has ischemic injury due to undesired vascular occlusion There are many ways to determine the dangers. Judgment methods are already known to medical professionals treating such conditions. For example, for heart diseases, the above methods include various imaging techniques (such as radiation tracking, X-ray and M RI) and physiological tests. Therefore, initiating angiogenesis in tissues suffering from or at risk of vascular occlusion is an effective method to prevent and / or alleviate the ischemic phenomenon of the tissue (41) (41) 200416214. Therefore, the treatment of bone fg muscle and myocardial ischemia, stroke, coronary artery disease, and peripheral vascular disease is to be expected. Anyone familiar with Those skilled in the art can detect vascularization of tissues using standard techniques. Non-limiting examples of detecting vascularization of patients include: SPECT (single photon emission computed tomography); pet (positron emission tomography); M RI (NMR imaging); and combinations thereof, obtained by measuring blood flow to the tissue before and after treatment. Angiography is used to analyze macroscopic vascular supply. Histological evaluation can be used to quantify small blood vessel levels Supply. For a discussion of the above and other technologies, see Simons, et al. 5 "Clinical trials in coronary angiogenesis", Circulation, 102, 73-86 (2000) ° ii. Methods for repairing tissues in methods for treating diseases with reduced angiogenesis The compounds of the present invention can be used in methods for repairing tissues. In this article, "repair tissue" means to promote tissue repair, regeneration, growth, and / or maintenance, including (but not limited to) wound repair or tissue engineering. Those skilled in the art will immediately understand that new angiogenesis is a tissue repair facility. Necessary. Second, tissue may be damaged by, but not limited to, the following factors: traumatic injuries or conditions include arthritis, osteoporosis and other bone diseases, and burns. Tissues may also be damaged due to surgical procedures, radiation, tearing Damage caused by cracks, toxic chemicals, viral infections, bacterial infections, or burns. Tissues that require repair also include unhealed wounds. Non-limiting examples of unhealed wounds include unhealed due to diabetic lesions A skin ulcer; or a fracture that does not heal immediately. The compounds of the present invention can also be used in guided tissue regeneration (GTR) (42) (42) 200416214 methods to help tissue repair. This method is currently familiar with medical technology The compounds are used to accelerate wound healing after an invasive surgical procedure. The compounds of the invention can also be used The method of tissue repair is characterized by enhancing the growth of tissue in the method of tissue engineering. In this paper, the term “tissue engineering” is defined as the device for creating, designing and manufacturing biological prosthesis, and synthetic or natural Materials are used to add or replace body tissues or organs. Therefore, the method of the present invention can be used outside the body to enhance the design and growth of human organs for future implantation in the repair or replacement of diseased tissues. For example The compound of the present invention can be used to promote the growth of skin graft replacements and used as a therapeutic agent in the treatment of burns. In another aspect of tissue engineering, the compound of the present invention can be contained in a cell-containing or cell-free device, and When the device is implanted in a location where regeneration is required, it can trigger regeneration of functional human tissue. As mentioned above, biomaterial-guided tissue regeneration can be used, for example, in periodontal disease to promote bone regeneration. Therefore 'AMP can be used in The location of a wound or other tissue requiring repair promotes the growth of repaired tissue in combination with a three-dimensional configuration. In another aspect of the process, the compounds of the present invention may be contained within or outside a device containing human tissue designed to replace diseased internal tissue. This method involves detaching cells from the human body and placing them in a structure Above or inside the stroma, and implanting a new system into the body or using the system in vitro. The method of the present invention can promote the growth of tissues contained in the stroma within the stroma. For example, a compound can be contained in a vascular graft with cells In order to promote the growth of cells in the graft. It is conceivable that the method of the present invention can be used in products (such as cartilage and bone, central nervous system tissue, -46- (43) (43) 200416214 muscle, liver and islet ( (Insulin-producing cells) to promote tissue repair, tissue regeneration, and tissue engineering. 4. Vascular tension-related diseases In one aspect of the invention, PTPase-related diseases are vascular tension-related diseases. In this article, "vascular tension-related disease" refers to a disease or disorder that involves the biological manifestation of the disease caused by the failure of endothelial PTK signaling, the biological cascade that causes the disease, or the symptoms that cause the disease. In one system, vascular tension-related diseases are selected from the group consisting of primary hypertension, secondary hypertension, pulmonary hypertension, and portal hypertension. 5. Diseases related to vascular permeability In one aspect of the present invention, diseases related to PTPase are diseases related to vascular permeability. As used herein, a "vascular permeability-related disease" refers to a disease or disorder that involves VEGF-induced vascular permeability failure and thus causes the biological manifestations of the disease, the biological cascade that causes the disease, or the symptoms that cause the disease. In one system, vascular permeability-related diseases are selected from the group consisting of stroke, septic shock, burns, respiratory distress syndrome, and congestive heart failure. 6. VEGF-related diseases In one aspect of the present invention, the PTPase-related diseases are VEGF-related diseases. As used herein, a "VEGF-related disease" is a disease or disorder that involves the biological manifestations of a disease resulting from the failure of VEGF signaling, the biological cascade that causes the disease, or the symptoms that cause the disease. In one system, VE G F-related diseases are selected from the group consisting of heart failure, myocardial infarction (MI), diabetic and ischemic neuropathy, osteoporosis, fracture healing, (44) (44) 200416214 wound healing and hair reduction

Mukherjee, R. et al., J. Cardiac Failure; 7 Suppl 2: 7 (2 0 0 1) revealed a suitable MI cardiac pharmacology model. In brief, pigs can be implanted in a curved coronary artery to cause myocardial infarction, and radioplaque markers are placed in the area of the intended infarct to measure infarct enlargement (see below). The distance between the volume of the left ventricle (hereinafter abbreviated as "LV") and the marker beads was measured at different time points before and after MI was triggered by activating the occlusion device. The efficacy of the compounds of the present invention in the effective treatment of MI can be investigated using a pig model that triggers MI by ligating a curved coronary artery. Animals were assigned to one of the following treatment groups: (1) 3 or more oral administration of a compound represented by formula (1) or 10 mg / kg three times daily before myocardial infarction; (2) 3rd after MI Orally administer 10 mg / kg of the above-mentioned compound three times a day starting from the day; (3) MI without active treatment; or (4) no myocardial infarction or drug treatment. On the 10th day after MI, ventricular angiography was used to measure the diastolic volume at the end of LV (hereinafter abbreviated as "LVEDV"). LVEDV in all MI groups has increased □. The decrease in the LVEDV booster due to the compound represented by formula (i) shows that the compound is effective in preventing or treating increasingly severe ventricular dilatation and the subsequent development of CHF. V. Compositions The compounds of the present invention may be administered in the form of a composition comprising: U) a safe and effective dose of a compound of the present invention; and (b) a pharmaceutically acceptable carrier. The composition of the present invention can be used to treat PTPase-related (45) (45) 200416214 diseases. A "safe and effective dose" of a compound of the present invention means that when used in the method of the present invention, it is effective in treating PTPase-related diseases without causing excessive adverse side effects (such as toxicity, irritation, or allergic reactions) and is reasonable Benefit / risk ratio dose. The specific "safe and effective dose will vary depending on a number of factors, such as the particular condition to be treated, the patient's physical condition, the duration of the treatment, the nature of the concurrent treatment (if any), the particular dosage form used, The excipients used, the solubility of the compounds of the invention contained, and the dosage form suitable for the composition. The term "pharmaceutically acceptable carrier" as used herein means one or more suitable for administration to animals (preferably lactating) Animal, more preferably human) compatible solid or liquid fillers, diluents or sealants. The term "compatible" in this context means that the ingredients of the composition can be mixed with the compounds of the present invention and between each other. They are mixed and do not produce a substantial reduction in the pharmaceutical efficacy of the composition under normal conditions of use. Of course, a pharmaceutically acceptable carrier must be high in purity and low in toxicity to make it suitable for administration to a treatment. Of patients (preferably mammals, more preferably humans). Examples of substances that can be used as a pharmaceutically acceptable carrier or component thereof are: sugars (e.g. lactose, Glucose and sucrose); starch; cellulose (such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose); tragacanth powder; malt; gelatin; talc; solid lubricants (such as stearin Acids and magnesium stearate); calcium sulfate; vegetable oils (such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter); polyols (such as propylene glycol, glycerin, sorbitol, mannitol, and Polyethylene glycol); alginic acid; emulsified hydrazone (eg-49- (46) 200416214

Tween®); moist! J (such as sodium lauryl sulfate); colorants; flavors; pastilles; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphonate buffer. The choice of a pharmaceutically acceptable carrier for use with a compound of the present invention is basically determined by the route of administration of the compound.

In particular, pharmaceutically acceptable carriers for systemic administration include sugar, starch, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers Liquids, emulsifiers, isotonic saline, and pyrogen-free water. Carriers for parenteral administration preferably include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Pharmaceutically acceptable carriers in the composition for parenteral administration preferably comprise at least about 90% of the total weight of the composition.

The composition of the present invention is preferably provided in a unit dosage form. The "unit dosage form" herein means a composition of the present invention containing a compound of the present invention in a dose suitable for administration to a patient according to good medical practice. The above composition preferably contains about 5 mg (mg) to about 1000 mg, preferably about 10 mg to about 500 mg, more preferably about 10 mg to about 300 mg of the compound of the present invention. The composition of the invention may be in any form suitable for, for example, oral, rectal, local, nasal, ocular or parenteral administration. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers known in the art can be used, including solid or liquid fillers, diluents, solubilizers (hydrotrope), surfactants, and sealants substance. The composition of the present invention may contain any pharmaceutically active substance which does not substantially interfere with the inhibitory activity of the compound of the present invention. The amount of the carrier used with the compound of the present invention is -50- (47) 200416214 when a unit dose of the compound of the present invention is administered in an amount sufficient to provide the actual amount of the substance. Techniques and compositions useful for the preparation of unit dosage forms for use in the method of the present invention have been disclosed in the following literature, the contents of which are fully incorporated herein by reference: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1 97 9); Lieberman et al. 5 Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

A variety of oral dosage forms can be used, including solid forms such as lozenges, capsules, granules, and powder granules. Oral dosage forms contain a safe and effective dose, usually a compound of formula (I) of at least about 5%, preferably about 25% to about 50%. Lozenges can be compressed, milled, enteric-coated, sugar-coated, coated, or multi-layered, and contain suitable binders, lubricants, diluents, disintegrating agents, colors, flavors, and bows. inducing agent), and fluxing agent (me 11 ing agent). Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foamed particles, foaming formulations reconstituted from foamed particles, containing suitable solvents, preservatives, Emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and fragrances. Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are known in the art. Lozenges usually contain conventional pharmaceutically compatible adjuvants as inert diluents such as carbonate, sodium carbonate, mannitol, lactose and cellulose; binding agents such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid And crosacarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants, such as dioxy-51-(48) (48) 200416214 siliconized silicon, can be used to improve the flow properties of powder mixtures. For appearance, colorants such as FD & C dyes can be added. Sweeteners and flavors, such as aSpartame, saccharin, menthol, peppermint oil, and fruit flavors, are useful adjuvants for chewable lozenges. Capsules usually contain one or more of the solid diluents described above. The choice of carrier ingredients depends on secondary considerations such as taste, cost, and storage stability. This is not a critical factor for the purposes of the present invention and can be achieved immediately by those skilled in the art. Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for use in the preparation of such compositions are known in the prior art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel® RC-59 1, tragacanth and sodium alginate; typical lubricants include lecithin and polysorbate 80; and Typical preservatives include methy 1 parabe η and sodium benzoate. Oral liquid compositions may also contain one or more components such as the sweeteners, flavors, and colorants described above. The composition can also be applied by conventional methods, usually by applying a pH or time-dependent coating, so that the compound of the present invention is released near the desired topical application site in the gastrointestinal tract, or released at different times. Extend the desired effect. This dosage form typically contains, but is not limited to, one or more cellulose acetate phthalates, polyvinyl acetate phthalates, hydroxypropyl methylcellulose phthalates, ethyl cellulose, Eudragit® coatings, waxes And shellac. Other composition packages useful for systemic delivery of compounds of the present invention -52-(49) (49) 200416214 Sublingual, buccal, suppository and intranasal dosage forms. The composition of the present invention can also be administered locally to a patient, for example, by directly applying or coating the composition on the patient's epidermis or epithelial tissue, or by transdermal administration using a "patch". Such compositions include, for example, lotions, creams, solutions, gels or solids. The above-mentioned topical composition preferably contains a safe and effective dose, usually at least about 0.1%, preferably about 1% to 5%, of the compound of formula (I). Carriers suitable for topical administration should stay on the skin in the form of a continuous film and not be removed by sweating or immersion in water. Generally, the support is organic in nature and allows the compound of formula (I) to be dispersed or dissolved therein. The carrier may include a pharmaceutically acceptable emollient, emulsifier, thickener, solvent, and the like. The specific administered dose of the compound or composition of the present invention and the duration of treatment are interdependent. Dosage and therapeutic approach will also depend on factors such as the specific compound used, the specific PTPase-related disease, the ability of the compound of the invention to achieve the lowest inhibitory concentration at the location of the disease, the nature of other diseases, if any, and Severity, the patient's personal factors (such as weight), compliance with the treatment regimen, the age and health of the patient, and the presence and severity of any other side effects of the treatment. Generally, for an adult (approximately 70 kg), from about 75 mg (preferably from about 200 mg, more preferably from about 500 mg) to about 30,000 mg (preferably from about 10,000 mg, more preferably from about 3,500) per day mg) of a compound of the invention. The therapeutic method should preferably last from about 1 day (preferably about 3 days) to about 56 days (preferably about 20 days). Prophylactic methods (such as osteoporosis prevention) can last up to 6 months or more, based on good medical experience. [Embodiment] -53- (50) 200416214 VI. Example The R group used to explain the compound example in this Section VI is not necessarily related to each R group in the compound represented by the above formula (I). Examples 1 to 36 The following chemical formulas and Table 1 show the structures of compounds that can be prepared according to the following Examples 1 to 36. 〇 12 〇

HO——S——NH 〇, N〆NH R8 L1——R7 Formula (Π) Table 1 Example * L1 R7 R8 R12 1 R -C〇2- H -ch3 2 R -C〇2 ~ H -ch3 3 S -C〇2_ H -ch3 4 s -C〇2 ~ H -ch3 5 R -C〇2 ~ H 6 R -C〇2 " H 7 S -C〇2- ^ 1 H 03 8 R -C02- H 9 S -C〇2 ~ KH 10 s -CO- H -ch3

-54- (51) 200416214

11 S -S〇2_ K λ- H -ch3 12 R -CO- rJO H -ch3 13 S -CO- rX) H -ch3 14 s -C〇2 ~ H 15 s -C〇2 ~ H i / X / V " 16 s -C〇2 ~ H 17 s -C〇2 ~ H 18 s -C〇2 ~ H 0 19 s -CONH- H -ch3 20 s -CONH- KO \ H -ch3 21 s -S 〇2 ~ H -ch3 22 s -S〇2- K >. / H -ch3 23 s -S〇2 ~ K \ /; H -ch3 24 s -C〇2 ~ -ch3 25 s -C〇2 ~ H N——N

-55- (52) (52) 200416214 26 S -C〇2- H 27 S -cor 28 S -CO- H -ch3 29 S -CO- KO H -ch3 30 S -C〇2- -ch3 -ch3 31 S -CO- H -ch3 32 S -CO- H -ch3 33 S -CO- H -ch3 34 S -CO- KJ H -ch3 35 S -CO- H 36 S -CO- /; XH • ch3 Example 1 (R)-[Bumethylaminomethyl-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: Step A

Boc-D-Phe (4_N02) -NMe: Boc-D-Phe (4-N02) -OH (4.0 g, 12.9 mmol) is dissolved in anhydrous tetrahydrofuran (20 mL) and 4-methylmorpholine-56- (53 ) (53) 200416214 (1.56 mL, 14.2 mmol). Isobutyl chloroformate (1.84 ml, 14.2 mm1) was added dropwise at 0 ° C and at 0 ° C. The reaction mixture was stirred at C for 1 hour. Methylamine (1 2.9 ml, 2.0 M tetrahydrofuran solution) 'was added dropwise at 0 ° C and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then recrystallized with 1: 1 DCM: methanol to give a white solid.

Boc-D-Phe (4-NH2) -NMe: Boc-D-Phe (4-N02) -NMe is dissolved in methanol (10 ml). To this was added palladium on carbon (0 wt.%, 0.1 mg). The reaction mixture was placed under a hydrogen atmosphere until the reaction was complete (tl c). The catalyst was removed by filtration and the filtrate was concentrated to give the amine, which was used directly in the next step without purification. (R)-[l-methylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid second butyl ester: In a dry flask, place 60 g of the aniline compound was dissolved in 2 ml of pyridine. To this solution was added 0.30 g of sulfur trioxide-pyridine complex. The reaction mixture was stirred for 5 minutes and then diluted with 25 mL of a 7% aqueous ammonium hydroxide solution. The reaction mixture was evaporated to an off-white solid. After purification, 0. 0 9 1 g of salt product was obtained. ] Η (d 2 Ο): 7.07-7.00 (q, 4H, J: 10.0Hz), 4.05 (t, 1H, J = 7.3Hz), 2.9b 2.69 (m '2H) 2.53 (s, 3H), 1.22 (s, 9H). Example 2 (R)-[l-methylaminomethylmethyl-2- (4-propanoateaminophenyl) -ethyl; benzyl I-aminoformate: Step B: HD-Phe (4- N02) -NMe: Boc-D-Phe (4-N02) -NMe (1.5 (54) 200416214 g, 4 · 6 4 mm ο 1) dissolved in HC 1 (1 0 m L, 4 · 0 Μ 1, 4 -Di-D-caustic solution), and the resulting reaction mixture was stirred at room temperature for 1 hour. Ether (60 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration to obtain a pure white product.

CBZ-D-Phe (4-N〇2) -NMe: HD-Phe (4-N02) -NMe (4 1 0 mg, 1.84 mmol) was dissolved in anhydrous DC Μ (10 m L) and diiso Propylethylamine (0.3 5 2 mL, 2.0 2 mmol). Add benzyl chloroformate (0.2 63 mL, 1.8 4 mmol) dropwise at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 72 hours. The solution was partitioned between DCM and IN HC1. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a crude white solid.

CBZ-D-Phe (4-NH2) -NMe: CBZ-D-Phe (4-N02) -NMe (80 mg, 0.224 mmol) was dissolved in EtOAc: ethanol (1: 1, 2 mL), and dihydrate was added Tin (II) chloride (25 2 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (25 mL) and 1 N NaOH (25 mL). The organic layer was washed more than twice with 1 N N a 0 Η (2 5 m L). The combined organic layer was dried over magnesium sulfate, filtered and evaporated to give a pure yellow oil. (RM methylmethylaminomethyl-2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid benzyl ester: According to the method of Step A, 0.1 g of an aniline compound was subjected to 0.1 5 Treatment with 6 g of sulfur trioxide-Dttidine complex. Packing the reaction and purification to obtain 0.056 g of ammonium salt product. 1H (D20): 7.26-7.20 (m, 3H), 7.η-6.96 (ηι, 6Η), 4.90-4.78 (m, 2H), 4.08 (t, 1H, J = 8.3Hz), 2.84-2.66 (m, 2H) 2.50 (s, 3H). -58- (55) (55) 200416214 Example 3 (S )-[l -Methylaminomethylmethyl 2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid benzyl ester: (SM1-methylaminomethylmethyl-2- (4 -Nitro-phenylethyl] -benzyl aminoformate: According to the method of Example 1, 5.00 g of BOCL-Phe (4-N02) -0H was subjected to 1.79 g of NMM, 2.20 g of isobutyl chloroformate, And 16.1 mL of methylamine solution. This gave a white solid product. According to the method of Example 1, 1.11 g of Boc-L-Phe (4-NH2) -NMe and 100 mg of palladium on carbon were reduced to obtain the desired (S)-[l-methylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid benzyl ester: According to the method of step A, let 0.1 4 9 g aniline The compound was treated with 0.2 1 8 g of sulfur trioxide-pyridine complex. Packing reaction and purification gave 0.091 g of ammonium salt product. 1H (D20): 7.20-7.14 (m, 3H), 7.05-6.94 (m , 6H), 4.84-4.72 (m, 2H), 4.06 (t, 1H, J = 7.7Hz), 2.80-2.62 (m, 2H) 2.47 (s, 3H). Example 4 (S) -H-methyl Carbamidyl-2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid third butyl ester: (3)-[1-methylaminecarbamethyl-2- (4- Nitro-phenyl) -ethyl] -carbamic acid third butyl ester: According to the method of step A, 0.5 00 g of a nitro compound and 0.05 g of palladium on carbon are subjected to a reduction reaction to obtain a desired product. (3 )-[1-methylaminomethylmethyl-2- (4-sulfonamido-phenyl) -ethyl] -carbamic acid third butyl ester: 0.4 20 g of aniline according to the method of step A -59- (56) 200416214 compound, 4.07, 1. Example base formic acid No. 02; mL I base formate. Lets pack up 7.03 4H) J — 8. Example base for 0.6 8 4 g sulfur trioxide- Dttidine complex treatment. The reaction was cleaned up and purified to obtain 0.106 g of ammonium salt product. 1H (D20): 7.04 (s, 4H), -4 · 0 5 (m, 1 Η), 2 · 9 2-2.6 8 (m, 2 Η) 2 · 5 5 (s, 3 Η) 24 (s , 9Η). (R)-[l-pentylamine formamyl- 2- (4-sulfonylamino-phenyl) -ethyl] -amino acid third butyl ester: (RM1-pentylaminoformamyl-2 -(4-nitro-phenyl) -ethyl] -aminomethyltributyl ester: According to the method of Example 1, 5.00 g of BCD-Phe (4-)-Ο Η was passed through 7.9 g Μ, 2.40 g of isobutyl chloroformate, and 3.73 goramine. Thereby a white solid was obtained. (R) -H-pentylamine formamidine-2- (4-sulfonylamino- Phenyl) -ethyl] -amino acid third butyl ester: According to the method of step A, 0.200 g of nitration and 100 mg of palladium on carbon were subjected to reduction reaction to obtain the desired product (tic). This crude aniline product was 0.25 2 g of sulfur trioxide-DU pyridine complex treatment and reaction to obtain 0.03 0 g of ammonium salt product. 1H (D20): -6.85 (in, 4H), 3.95 (m, 1H), 2.93 -2.68 (m, 1.14 (s, 9H), 1.10 (m, 6H), 0.61 (t, 3H, 2Hz). 6 (R Ml-benzylaminomethane-2- (4-sulfonylamino- Phenyl) -ethyl] -amino acid tert-butyl ester:

-60- (57) (57) 200416214 (R)-[l-Benzylaminomethane-2- (4-nitro-phenyl) -ethyl] • Third-butylaminoformate ·· The method of Example 1 treated 4.00 g of Boc-D-Phe (4-N02) -〇Η with 1.44 g of NMM, 1.94 g of isobutyl chloroformate, and 2.82 mL of benzylamine. This gave a yellow solid. (R)-[l-Benzylaminomethane- 2- (4-sulfonylamino-phenyl) -ethyl; | -aminocarbamic acid third butyl ester: According to the method of step A, let 0.3 0 0 g of a nitro compound and 50 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (11 c). This crude aniline product was treated with 0.35 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.028 g of an ammonium salt product. ] H (D20): 7.26- 7.23 (m > 3H), 7.05-6.97 (m, 6H), 4.29-4.08 (m, 3H), 3.04 (s, 2H), 1.26 (s, 9H). Example 7 (S)-[l-Benzylaminomethylamido-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: (S)-[Benzylaminomethyl Fluorenyl-2- (4-nitro-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester: According to the method of Example 1, 4.00 g of Bocc-Phe (4-N02) -〇Η Treated with 1.44 g NMM, 1.94 g isobutyl chloroformate, and 2.82 mL benzylamine. This gave a yellow solid. (S)-[l-Benzylaminomethane-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: According to the method of step A, make 0.3 00 g The nitro compound was reduced with 50 mg of palladium on carbon to obtain the desired product (11c). This crude aniline product was treated with 0.359 g of sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.066 g of ammonium salt product. ] H (D20): 7 ·] 〇--61-(58) 200416214 6 · 9 8 (m, 3 Η), 6. 7-6.7 1 (m, 6 Η), 4 · 0 7-3. 8 1 (m, 3 Η), 2.79 (s, 2H), 1.04 (s, 9H). Example 8 (R)-[1- (2-morpholin-4-ylethylaminomethylamidino) -2- (4-sulfonic acid amido-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester:

(R)-[1- (2-morpholin-4-ylethylaminomethylmethyl) -2- (4-nitro-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: according to examples In the method of 1., 4.00 g of Boc-D-Phe (4-N02) -OH was treated with 1.44 g of NMM, 1.94 g of isobutyl chloroformate, and 3.39 mL of 4- (2-aminomethyl) morpholine. Thus, a white solid was obtained.

(R)-[1- (2-morpholin-4-ylethylaminomethyl) -2- (4-sulfonylamino-phenyl) -ethyl: 1-aminocarboxylic acid third butyl ester · According to the method of step A, 0.3 0 0 g of a nitro compound and 100 mg of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.3 3 9 g of a sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.18 g of ammonium salt product. 1 Η (D2〇) 7.07-7.00 (q, 4H, J = 9.9Hz), 4.07 (m, 1H), 3.69 (s, 4H) 3.28-3.24 (m, 2H), 2.76-2.57 (m, 8H), 1.25 (s, 9H). Example 9 (S)-[l-pentylaminomethylamidino-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: (S)-[bupentyl Carbamidyl-2- (4-nitro-phenyl) -ethyl] -aminomethyl-62- (59) 200416214 Third butyl acid: According to the method of Example 1, make 5.00 g of Boc-L- Phe (4-N〇2) -OH was treated with 1.79 g of NMM, 2.42 g of isobutyl chloroformate, and 3.73 mL of pentylamine. This gave a white solid. (S)-[l-pentylaminomethylamidino-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: According to the method of step A, make 0.3 00 g A nitro compound is reduced with 100 mg of palladium on carbon to obtain the desired product (tic). This crude aniline product was treated with 0.378 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.78 g of an ammonium salt product. 1H (D2〇): 7.16- 6.9 8 (m, 4 Η), 4.0 8 (m, 1 Η), 3 · 0 6-2 · 8 1 (m, 4 Η), 1.27 (s, 9Η) , 1.21-1.02 (m, 6Η), 0.75 (t, 3Η, J = 7.1Hz). Example 1 (S)-[4- (2-Hexamidinylamino-2-methylaminomethylamidino-ethyl) -phenyl] -aminosulfonic acid:

(S) -hexanoic acid [methylaminomethyl-2- (4-nitro-phenyl) _ethyl] -fluorenamine: H-Phe (4-N02) -NMe (8 0 8 mg) was dissolved in 5 mL of DCM and 0.86 mL of triethylamine. Hexyl chloride (0.4 76 mL) was added dropwise at 0 ° C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and recrystallized with D CM: methanol to obtain a pure white product. (S)-[4- (2-Hexamidineamino-2-methylaminomethylamidino-ethyl) -phenyl] -aminosulfonic acid: According to the method of Step A, let 0.39 g A nitro compound and 100 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (t) c). This crude aniline product was treated with 0.460 g of sulfur trioxide-Dttidine complex. Packing up -63- (60) (60) 200416214 and purification, 0.04 6 g of ammonium salt product was obtained. 1H (D20): 7.11-7.02 (q, 4H, J = 10.9Hz), 4.39 (t, 1H, J = 10.0Hz), 3.02- 2.76 (m, 2H), 2.58 (s, 3H), 2.11 (t , 2H, J = 8.0Hz), 1.33 (t, 2H, J = 8.2Hz) 1.14 (t, 2H, J = 8.0 Hz) 1.03-0.95 (m, 2H), 0.73 (t, 3H, J = 8.1 Hz). Example 1 1 (S)-{4- [2-methylaminomethylmethyl-2- (toluene-4-sulfonamido) -ethyl] -phenyl} -aminosulfonic acid:

(S) -N-methyl- 3- (4-nitro-phenyl) -2- (toluene-4-sulfonamido) -propanamide: H-Phe (4-N02) -NMe (0.200 g) Dissolved in 5 mL of anhydrous DCM and 0.156 g of triethylamine. P-Toluenesulfonyl chloride (0.1 61 g) was added dropwise, and the reaction mixture was stirred at room temperature for 18 hours. Hexane (30 mL) was added to the reaction mixture, and the resulting solid was collected by filtration. The crude solid was purified by flash chromatography to obtain 0.079 g of the desired product.

(S) _ {4- [2-methylaminomethylamidino-2- (toluene-4-sulfonamido) -ethyl] -phenyltriphenylsulfonic acid: According to the method of step A, let 0.0 79 g of nitro compound and 50 mg of palladium on carbon were reduced to obtain the desired product (tic). This crude aniline product was treated with 0.1 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.020 g of an ammonium salt product. 111 (020): 7.61-7.42 (q, 4H, J = 9.2Hz), 7.07 (s, 4H), 3.94 (t, 1H, J = 6.5Hz), 3.10-2.80 (m, 2H), 2.73 (s, 3H), 2.60 (s, 3H). -64-(61) 200416214 Example 1 2 (as _ {4- [2-methylaminomethylamido-2- (3-phenyl-propanamido) -ethyl] -phenyl} • amine Sulfonic acid: (R) -N-methyl-3- (4-nitro-phenyl) -2- (3-phenyl-propanamido) -propanamide: According to the method of Example 2, 0.2 00 g of HD-Phe (4-N02) -NMe was treated with 0.164 g of triethylamine and 0.164 g of hydrogenated cinnamyl chloride, thereby obtaining 0.3 0 7 g of the desired product.

(R) _ {4- [2-methylaminomethylamido-2- (3-phenyl-propanamido) -ethyl] -phenyl} -aminosulfonic acid: according to the method of step A, 0.307 g of a nitro compound and 100 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.44 8 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.040 g of an ammonium salt product. 1H (D20): 7.24-7.20 (m, 3 Η), 7.07-6.91 (m, 6H) 4.27 (t, 1H, J = 8.8Hz), 2.87-2.67 (m, 4H), 2.52 (s, 3H) ^ 2.45 (t, 2H, J = 7.3Hz).

Example 1 3 (S)-{4- [2-methylaminomethylmethyl-2- (3-phenyl-propylamido) -ethyl] -phenyl} -aminosulfonic acid: (S) -N-methyl- 3- (4-nitro-phenyl) -2- (3-phenyl-propanamido) -propanamide: According to the method of Example 2, 0.2 00 g of HL-Phe (4 -N02) -NMe is treated with 0.164 g of triethylamine and 0.164 g of hydrogenated cinnamidine chloride, thereby obtaining 0.2 8 4 g of the desired product. (8)-{4- [2-methylaminomethylamido-2- (3-phenyl-propanamido) -ethyl] _ -65- (62) 200416214

Phenylphenylaminosulfonic acid: According to the method of step A, 0.284 g of a nitro compound and 100 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.41 g of a sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.88 g of an ammonium salt product. 1 H (D 2 Ο): 7.24-7.17 (m, 3H), 7.07-6.95 (m, 6H), 4.26 (t, lH, J = 8.2Hz), 2.87-2.67 (m, 4H), 2.5 1 ( s, 3H), 2.45 (t, 2H, J = 8.0 Hz).

Example 1 4 (S) _ [1- (2-methoxy-ethylamine formamidine) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester : (S)-[l- (2-methoxy-ethylaminomethylamidino) -2- (4-nitro-phenyl) -ethylaminocarboxylic acid third butyl ester: Method according to Example 1 'Order 1 〇〇 g

Boc-L-Phe (4-N〇2) -OH was treated with 0.359 g of NMM, 0.483 g of isobutyl chloroformate, and 0.54 1 mL of 2-methoxyethylamine. This gives 0.3 00 g

Desired product. (S)-[1- (2-methoxy-ethylaminomethylamidino) _2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: according to step A In the method, 0.30 g of a nitro compound and mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (t 1 c). This crude aniline product was treated with 0.390 g of a sulfur trioxide-amididine complex. The reaction was cleaned up and purified to obtain 0.181 g of ammonium salt product. ] Η

(D2〇): 7.09 -6.7 9 (q, 4H, J = 8.9Hz), 3.93 (m, 1H

), 3.25-2.62 (m, 6H), 3.01 (s, 3H), 1.07 (s, 9H -66-(63) (63) 200416214 Example 1 5 (S)-[l- (2-ethoxy- Ethylamine formamyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminoformic acid third butyl ester: (SM 1- (2-ethoxy-ethylamine formamidine ) -2- (4-nitro-phenyl) -ethyl; l. Tert-butylaminoformate: According to the method of Example 1, let 1. 00g Boc-L-Phe (4-N02) -OH Treated with 359 mg of NMM, 483 mg of isobutyl chloroformate, and 0.6 7 5 mL of 2-ethoxyethylamine. This gave 0.312 g of the desired product. (S)-[l- (2-ethoxy- Ethylaminomethane) -2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid third butyl ester: According to the method of step A, let 0.3 1 2 g nitro The compound and 100 mg of palladium on carbon were reduced to obtain the desired product (11 C). The crude aniline product was treated with 0.391 g of sulphur trioxide-pyridine [J fixed complex. Pack the reaction And purification to obtain 0.157 g of ammonium salt product 0] H (D 2〇): 7.21-6.98 (q, 4H, J = 0 • 2 Hz), 4.13 (t 1 Η J = 2 7 · 0 Hz) ,: L44-3. 1 6 (m; -6H ), 2.89- 2.80 (m, 2Η) 1.26 (s, 9H), 1.03 (t, 3H, J 7.9Hz). Example 16 (S)-[1- (2-ethylthio- Ethylaminomethyl) -2- (4-sulfonylamino-phenyl) -ethyl; l · Thirty-butylaminoformate: (S)-[l- (2-ethylthio-ethyl Trimethylaminomethyl) -2- (4-nitro-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester: According to the method of Example 1, let 1.0. G Boc-Phe (4- N02) -OH was treated with 0.685 g of NMM, 0.483 g of isobutyl chloroformate, and 0.912 g of 2- (ethylthio) ethylamine hydrochloride. This gave -67- (64) (64) 200416214 0.24 9 g of (S)-[1- (2-Ethylthio-ethylaminomethylmethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester : According to the method of step A, 0.249 g of a nitro compound and 50 mg of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.299 g of a sulfur trioxide-D-pyridine complex. The reaction was purified and purified to obtain 0.044 g of ammonium salt product. 1Η (D2〇): 7.39-7. 1 5 (q, 2H, J = 9.4Hz), 7.12-7.03 (q, 2H, J-7.3Hz), 4.13 (t, 1H, J = 8.8Hz), 3.30 -3.1 7 (m, 2H), 2.94-2.83 (m, 2H) 2.49-2.42 (m, 4H) 1.27 (s, 9H), 1.1 (t, 3H, J = 8.2Hz). Example 1 7 (S)-[1- (4-Phenyl-butylaminomethyl) -2- (4-sulfonylamino-phenyl) -ethyl; l · butylamino formate : (S)-[l- (4-phenyl-butylcarbamate) -2- (4-nitro-phenyl) -ethyl] -carbamic acid third butyl ester: Method according to Example 1 1.00 g of Boc-L-Phe (4-N02) -0H was treated with 0.359 g of NMM, 0.483 g of isobutyl chloroformate, and 0.96 1 mg of 4-phenylbutylamine. This gave 0.281 g of the desired product. (S)-[1- (4-Phenyl-butylaminomethylmethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: according to step A In the method, 0.21 8 g of a nitro compound and 50 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.2 3 6 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.015 g of ammonium salt product. 1H (D20-68- (65) (65) 200416214): 7.17-6.92 (m, 9H), 4.08 (m, 1H), 3.05-2.69 (m, 4H), 2.39 (t, 2H, J = 7.9Hz ) 1.37-1.24 (m, 4¾), 1.19 (s, 9H). Example 1 8 (S) -3- [2-Third-butoxyamine amino-3- (4-propanoate amino-phenylbuprofen) Amine] -propionic acid: (S) -3- [2-Third-butoxymineamine- 3-L- (4-nitro-phenyl) · propanamido] -methyl propionate: according to The method of Example 1 treated 0.5 00 g of Boc_L-Phe (4-N02) -0H with 0.342 g of NMM, 0.462 g of isobutyl chloroformate, and 0. 5 8 5 g of β-alanine tert-butyl ester hydrochloride Thereby 0.23 3 g of the desired product is obtained. (S) -3- [2-Third oxycarbamino-3-L- (4-nitro-phenyl) · propanamido] -Propionic acid: (S) -3- [2-Third-butoxycarbonylamino-3-L- (4-nitro-phenyl) _propionamidomethyl propionate (2 93 mg) In 15 mL of methanol: water (1: 1) and 0.2 3 1 g of lithium hydroxide hydrate. The reaction mixture was stirred at room temperature for 7 2 hours. The reaction mixture was then diluted with DCM (10 mL) and 1 N HC1 was washed and dried over magnesium sulfate to obtain 0.193 g of the desired product. (S) ~ 3- [2-Third-butoxycarbonyl 3- (4-sulfonylamino-phenylpropionamido] -propionic acid: According to the method of step A, 0.1 3g of a nitro compound and 50 mg of palladium on carbon were obtained by reduction reaction. The desired product (tic). This crude aniline product was treated with 0.24 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0. 0 2 0 g of ammonium salt product. 1 η ( D 2 Ο): 7.16-6.97 (q, 4H, J = 11.8Hz), 4.09 (t, 1H, J = 6.8Hz) '3.30- -69- (66) (66) 200416214 3. 1 4 (m, 2 Η), 2.9 5-2 · 7 0 (m, 2 Η), 2 · 2 3 (t, 2 Η, J = 1 0.0Hz), 1.23 (s, 9H). Example 1 9 (S)-{4- [2- (3-benzyl-ureido) -2-methylaminomethylmethyl-ethyl] -phenyl} -amino acid: (3) -2- (3 -Benzyl-ureido) -cardiomethyl-3- (4-nitro-phenyl) -propanamide: According to the method of Example 2, 0.150 g of HL-Phe (4-N02) -NMe was passed through 0.1. Treatment with 2 3 g of triethylamine and 0.8 5 g of benzyl isocyanate gave 0.0 8 2 g of the desired product. (S)-{4- [2- (3-Benzyl-ureido) -2-methylaminomethylmethyl-ethyl] -phenyl} -aminosulfonic acid: According to the method of Step A, let 0.0 8 2 g of a nitro compound and 50 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.110 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.024 g of an ammonium salt product. 1 H (D 2 Ο): 7 · 2 8-7 · 1 8 (m, 3Η), 7.06-6.98 (m, 6H), 4 · 21 (t, 1H, J = 7.3Hz), 4.12 to 4.08 ( q, 2H, J = 13.3Hz), 2.96- 2.70 (m, 2H), 2.54 (s, 3H). Example 2 0 (S)-(4- {2- [3- [2- (2-methoxy-phenyl) -ureido] -2-methylaminomethylmethyl-ethyl} -benzyl) -amino Acid expansion: (8) _2- [3- (2-methoxy-phenyl) -ureido] -cardiomethyl-3- (4-nitro-phenyl) -propanamide: according to Example 2 Method: 0.150 g of H-Phe (4-N02)--70- (67) (67) 200416214 NMe was treated with 0.123 g of triethylamine and 0.95 g of 2-methoxyphenyl isocyanate, thereby obtaining 0.0 7 3 g of the desired product. (S)-(4- {2- [3- (2-methoxy-phenyl) -ureido] -2-methylaminomethane-ethylphenylphenyl) -aminosulfonic acid: according to In the method of step A, 0.073 g of a nitro compound and 50 mg of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.094 g of a sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.0 3 3 g of ammonium salt product. 1H (D20): 7.3 1-7.28 (m, 1H), 7.02-6.99 (m, 5H), 6.90-6.82 (m, 2H), 4.23 (t, 1H, J = 7.0Hz), 3.66 (s, 3H ), 2.94-2.74 (m, 2H), 2.54 (s, 3H). Example 2 1 (S)-[4- (2-Benzylsulfonamido-2-methylaminomethylsulfanyl-ethyl) -phenyl] -aminosulfonic acid: (3) -2-benzenesulfonylsulfonium Amino-cardiomethyl-3- (4-nitro-phenyl) -propanilamine: According to the method of Example 2, 0.293 g of HL-Phe (4-N02) -NMe was passed through 0.179 g of pyridine and Treatment with 0.19 g of benzylsulfonium chloride gave 0.273 g of the desired product. (S)-[4- (2-benzenesulfonamido-2-methylaminomethylamidino-ethyl) -phenyl] -aminosulfonic acid: According to the method of Step A, let 0.2 3 7 g of nitro compound and 50 mg of palladium on carbon were reduced to obtain the desired product (tic). This crude aniline product was treated with 0.31 g of sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.085 g of ammonium salt product. 1H (D20): 7.5 5 -7.49 (m, 3H), 7.41-7.39 (m, 2H), 6.84 (s, 4H) ^ 3.73 (t -71-(68) 200416214, 1H, J = 6.8Hz), 2.86-2.59 (m, 2H), 2.42 (s, 3H) Example 2 2 (S)-{4- [2- (4-methoxy-benzenesulfonamido) -2-methylamine formamidine -Ethyl; l.phenyl} -aminosulfonic acid:

(S) -2- (4-methoxy-benzenesulfonamido) -N-methyl-3- (4-nitro-phenyl) -propanamide: According to the method of Example 2, 0.3 00 g HL-Phe (4-N02) -NMe was treated with 5 mL of pyridine and 0.262 g of 4-methoxybenzenesulfonyl chloride, thereby obtaining 0.0 8 6 g of the desired product. (S)-{4- [2- (4-methoxy-benzenesulfonamido) -2-methylaminomethylamido-ethyl] • phenylphenylamino acid: according to step A In the method, 0.0 8 6 g of a nitro compound and 25 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (t 1 c). This crude aniline product was treated with 0.1 105 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.016 g of ammonium salt product. 1H (D20)

: 7.35 and 7.31 (d, 2H, J = 7.7Hz), 6.82 and 6.79 (d, 2H, J = 7.7Hz), 6.76 (s, 4H), 3.74 (s, 3H), 3.64 (t, 1H, J = 9.2Hz), 2.81-2.48 (m, 2H), 2.41 (s, 3H) Example 2 3 (S) _ {4_ [2-methylaminomethylamidino-2- (naphthalene- Busulfonylamino) -ethyl] -phenyl} -aminosulfonic acid: (S) -N-methyl-2- (naphthalene-1-sulfonamido) -3- (4-nitro- Phenylpropionamidine-72- (69) (69) 200416214 Amine: According to the method of Example 2, 0.3 00 g of HL-Phe (4-N〇2) -NMe was determined by a 5 m LD ratio D to be 0. 2 8 7 g α-naphthalene chlorination, thereby obtaining 0.07 3 g of the desired product. (S)-{4- [2-methylaminomethylmethyl-2- (naphthalene-1-sulfonamido) ) _Ethylbuthylphenylaminosulfonic acid: According to the method of step A, 0.073 g of a nitro compound and 25 mg of palladium on carbon were subjected to a reduction reaction to obtain a desired product (11 c). The product was treated with 0.08 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.018 g of an ammonium salt product. 1 H (D 2 0): 8.07 and 8.04 (d, 1H, J = 8.9Hz), 7.97 and 7.94 (d, 1H, J = 9.2Hz), 7.83 (t '2H, J = 8.0 H z), 7.46-7.41 (m, 2H), 7.32 (t, 1H, J = 8.8Hz), 6.45 and 6.42 (d, 2H, J = 9.4Hz

), 6.29 and 6.27 (d, 2H, J = 7.5Hz), 3.64-3.58 (q, 1H, J = 5.5Hz), 2.7 1-2.31 (m, 2H), 2.36 (s, 3H). Example 24 (S)-[l-(; yl-methyl-aminomethylamino) -2- (4-sulfonic acid amino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: # ( SM1- (benzyl-methyl-carbamoyl) -2_ (4-nitro-phenylbethylethyl μ tertiary butyl carbamate: LBOC-Phe- (4-N02) -OH (0.3 90 g) and 0.203 g of 1-hydroxybenzotriazole hydrate were mixed with 12 mL of DMF and cooled in an ice bath. EDCI (0.5 7 5 g) and 0.39 mL of 1 methylbenzylamine were added. The reaction mixture was then warmed to At room temperature. After 18 hours, the reaction mixture was diluted with et OC, and washed once with NH C1 and dried over sodium sulfate. After chromatography, -73- (70) (70) 200416214 0.910 g of a white solid was obtained. (S)-[2- (4-Amino-phenyl) -1- (benzyl-methyl-carbamoyl) -ethyl] -carbamic acid third butyl ester: According to the method of step A, 0.90 g of a nitro compound was mixed with 10 ml of MeOH and 0.150 g of 10% Pd / C. After reduction and purification by flash chromatography, 0.427 g of the desired product was obtained. (S)-[l -(Benzyl-methyl-carbamoyl) -2- (4-sulfonylamino-phenyl) -ethyl; l · aminocarbamic acid third butyl ester: According to the method of step A, let 0 · 4 2 7 g The amine was mixed with 10 mL of pyridine and 0.5 3 0 g of sulfur trioxide-D-pyridine complex. After purification, 0.3 24 g of the product was obtained. NMR (DMSO) of the mixture of optical isomers: 7.73 (1H, s ), 7.68 (lH, s), 7.38-6.82 (9H, m), 6.79 (1 Η 5 d), 4.60-4.51 (1H, m), 4.41 (s, 2H), 4.36 (s, 2H ), 2.84 (s, 3H), 2.79-2.62 (m, 2H), 1.38 (s, 9H), 1.32 (s, 9H). Example 25 (S)-[l- (2-form -Phenyl-5-phenyl-2H-D-pyrazol-3-ylaminomethylmethyl) -2- (4-propanoate-phenyl) -ethyl] -Thirty-butyl aminoformate: (S )-[1- (2-methyl-5-phenyl-2 2H-DH: azole-3-ylaminomethylmethyl) -2- (4-nitro-phenyl) -ethyl] -aminocarboxylic acid Third butyl ester: According to the method of step A, 0.93 0 g of Boc-Phe- (4-N02) -OH was passed through 0.36 mL of N-methylmorpholine, 0.39 mL of isobutyl chloroformate, And 0.5 5 m L 2 -methyl-5 -phenyl-2 Η-Dtt Π -3-amine. Clean up the reaction and chromatography (71) 200416214 to get the desired product. (S)-[2- (4-Amino-phenyl) -1- (2-methyl-5-phenyl-2H-yrazol-3-ylaminomethyl) -ethyl] -amino Third butyl formate: According to the method of step A, 0.5 0 0 g of a nitro compound was dissolved in MeOH, and 0.150 g of 10% Pd / C was added daily. The reaction mixture was placed under a H2 atmosphere. After packing up the reaction and chromatography, 0.388 g of an off-white solid was obtained.

(S)-[l- (2-methyl-5-phenyl-2H-orbitazol-3-ylaminomethylmethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -Third butyl aminoformate: According to the method of step A, 0.3 8 8 g of aniline was dissolved in 8 m LD ratio π and treated with 0.4 1 0 g of pyridine-S 0 3 complex. After packing up the reaction and purification, 0.169 g of ammonium salt product was obtained. IH NMR (D20) of a mixture of optical isomers: 7.61-7.52 (m ^ 2H), 7.40-7.22 (m, 3H), 7.15-7.02 (m ^ 4 Η), 6.41-6.29 (m, 1H), 4.39-4.29 (m, 1H), 3.42-3.25 (m, 3H), 2.99-2.82 (m, 2H), 1.31 (s, 9H).

Example 2 6 (S)-[l-Phenylcarbamate-2- (4-mineral amine-phenyl) -ethyl] -carbamic acid third butyl ester: (S)-[2- ( 4-nitro-phenyl) -1-phenylaminomethylmethyl-ethyl] -aminocarboxylic acid third butyl ester: According to the method of Step A, make 0.93 0 g Boc-Phe- (4-N02)- OH was treated with 0.36 mL of Ν · methylmorpholine, 0.39 mL of isobutyl chloroformate, and 0.55 mL of aniline. After packing up the reaction and chromatography, 1.143 g of the desired product was obtained. -75- (72) (72) 200416214 (S)-[2- (4-Amino-phenyl) -1-phenylaminomethylethyl-ethyltriaminobutyrate: according to step A In this method, 0.5 0 g of a nitro compound was dissolved in MeOH, and 0.150 g of 10% P d / C was poured into the solution. The reaction mixture was placed under a Η 2 atmosphere. After packing up the reaction, 0.33 g of the desired product was obtained. (S)-[l-Phenylaminomethylmethyl-2- (4-sulfonamido-phenyl) -ethyl] -carbamic acid third butyl ester: According to the method of Step A, let 0.3 7 3 g of aniline was dissolved in 5 m of LD ratio and treated with 0.501 g of pyridine-S03 complex. After packing up the reaction and purification, 0.045 g of ammonium salt product was obtained. 1H NMR (D20): 7.36-7.24 (m, 1H), 7.21-7.12 (m, 5H), 7.11-7.02 (m, 3H), 4.31-4.11 (m, 1H), 3.00 (d, 2H, Jl 0.4 Hz), 1.32 (s, 9H). Example 2 7 (S)-[1-__ * Carboxyaminomethyl-2- (4-propanoate-phenyl) -ethyl] -Thirty-butyl carbamate: (S)-[ 1-_benzylaminomethyl 2- (4-nitro-benzyl) -ethyl] -aminocarboxylic acid third butyl ester: According to the method of Example 24, 0.9 3 0 g Boc-Phe- (4 -N02) -OH and 203 g of 1-hydroxybenzotriazole in 12 mL DMF. Add EDCI (0.5 7 5 g) and 0.5 7 mL of dibenzylamine. After packing up the reaction and purification, 0.72 6 g of a white solid was obtained. (S)-[2- (4-Amino-phenyl) -1-_carboxamidomethyl-ethyl] -amino-76- (73) (73) 200416214 third butyl formate: according to In the method of step A, 0.726 g of a nitro compound and 0.120 g of 10% Pd / C were mixed in 15 mL of MeOH. After packing up the reaction and purification by flash chromatography, 0.172 g of a white solid was obtained. (S)-[l-Dibenzylamine formamidine-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: According to the method of Step A, let 172 g of amine was dissolved in 5 ml of pyridine and treated with 0.177 g of pyridine-S03 complex. After packing up and purifying, 0.0 8 4 g of ammonium salt product was obtained. 1η NMR (D20) of a mixture of optical isomers: 7.35-7.23 (m, 5H), 7.1, 6.92 (m, 9H), 4.60-4.32 (m, 1 Η), 2.83 (d, 2H, J = 10.4Hz), 1.28 (s, 9H) ,: I. 0 2 (s, 9 H) ° Example 2 8 (S) -4- [Bumethylamine formamyl- 2_ (4-sulfonic acid amine- Phenyl) -ethylaminomethylamidinyl] -piperidine-1-third butyl formate: (S) -4- [Bromylaminomethylmethyl-2- (4-nitro-phenyl) -ethyl Carbamidinyl] -piperidine-1-carboxylic acid tert-butyl ester: HL-Phe (4-N02) -NMe (0.300 g) was dissolved in 10 m LDC Μ, and 0. 1 3 0 g triethylamine , 0 · 2 4 5 g EDCI and 0.3 0 5 g 1-BOC-piperidine-4-carboxylic acid. After 18 hours, the reaction mixture was partitioned between 0.1 N HC1 and DCM. The organic layer was dried and purified by flash chromatography to obtain 0.137 g of product. (S) -4- [1-Methylaminomethylamido-2- (4-sulfonamido-phenyl) -ethylaminomethylamidol · piperidine-1-third butyl formate: according to Method of Step A, Order -77- (74) 200416214

A reduction reaction of 0.137 g of a nitro compound and 25 mg of palladium on carbon gave the desired product (tic). This crude aniline product was treated with 0.150 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.015 g of an ammonium salt product. 1 Η (D2〇): 7.0 3-6.9 5 (q, 4H, J = 8.2Hz), 4.32 (t, 1H, J = 7.9Hz), 3.81 (m, 2H), 2.95-2.62 (m, 4H) 2.49 (s, 3 H), 2.28 (m, 1 H) 1 · 5 2 (m, 4 H), 1.2 7 (s, 9H).

Example 2 9 (S)-[4- (2-Benzylamidoamino-2-methylaminomethylamido-ethyl) -phenyl l · aminosulfonic acid: methylaminomethylamido-2 -(4-nitro-phenyl) -ethyl] -benzimidamine: According to the method of Example 2, 0,175 g of fluorene-L-Phe (4-N02) -NMe was treated with 0.143 g of triethylamine and 0.104 g of benzene Formaldehyde chloride treatment, whereby 0.110 g of product was obtained.

(S) _ [4- (2-Benzylamidoamino-2-methylaminomethylamido-ethyl) -phenyl] -aminosulfonic acid: According to the method of step A, make 0.1 10 g of nitrate The base compound is reduced with 0.050 g of palladium on carbon to obtain a desired product (tic). This crude aniline product was treated with 0.27 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.0 3 4 g of ammonium salt product. 1H (D20): 7.59- 7.32 (m, 5H), 7.16-6 · 99 (ιη, 4H), 4.53 (t, 1Η, J = 8.9Hz), 3.08-2.90 (m, 2H), 2.55 ( s, 3H). Example 3 0 -78- (75) (75) 200416214 (S)-[l-dimethylaminomethylamido-2- (4-sulfonylamino-phenyl) -ethyl] -carbamic acid Tributyl ester: (3)-[1-dimethylaminomethylmethyl-2- (4-nitro-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester: According to the method of Example 1, let 0.3 0 0 g of Boc-L-Phe (4-N02) -0H was treated with 0.108 g of NMM, 0.132 g of isobutyl chloroformate, and 0.9 67 mL of a dimethylamine solution (2M solution in THF). This gave 0.316 g of product. (S)-[l-Dimethylamine formamyl-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester · According to the method of Step A, let 0.3 16 g of the nitro compound and 0.1 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.4 77 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.168 g of ammonium salt product. 1H (D20): 7.05-6.97 (q, 4H, J = 8.1Hz), 4.53 (t, 1H, J = 7.9Hz), 2.73-2.57 (m, 8H), 1.21 (s, 9H). Example 3 1 (S)-(4- {2-Methylaminomethylmethyl-2-[(〇thiopyridin-3-carbonyl) -amino] -ethylphenylphenyl) -aminosulfonic acid: ( S) -N- [l-methylamine formamidine-2- (4-nitro-phenyl) -ethyl] -nicotinamine: According to the method of Example 2, 0.3 00 g of HL-Phe (4- N02) -NMe was treated with 0.3 8 7 g of triethylamine and 0.22 6 g of nicotine chloride. (S)-(4- {2-methylaminomethyl methyl-2-[(rhodium-3-methyl) -amino]-• ethylphenylphenyl) -aminosulfonic acid: according to the procedure In the method of A, 0.72 5 g of a nitro compound and 0.1 000 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product • 79- (76) 200416214 (11 c). This crude aniline product was treated with 1.054 g of sulfur trioxide-pyridine B complex. The reaction was purified and purified to obtain 0.02 5 g of ammonium salt product. 1H (D20): 8.57 (d, 1H, J = 2.3Hz), 8.47 (d, 1H, J = 5.6Hz), 8.88-7.85 (d, 1H, J = 9.2Hz), 7.35-7.31 (m, 1H ), 7.07-6.95 (q, 4H, J = 9.5Hz), 4.50 (t, 1H, J = 8.1Hz), 3.04-2.85 (m, 2H), 2.51 (s, 3H).

Example 3 2 (S) _ [4- (2-methylaminomethylmethyl-2-phenethylamido-ethyl) -phenyl] -aminosulfonic acid: (S) _N_methylnitro -Phenyl) -2-phenylethylamido-propylamidoamine: According to the method of Example 2, 0.3 0 0 g of H_L-Phe (4-N02) -NMe was passed through 0.2 5 8 g of triethylamine and 0.2 4 2 g Phenylacetamidine was treated, whereby 0.5 1 3 g of product was obtained.

(S)-[4- (2-methylaminomethylamido-2-phenylethylamidoamino-ethyl) -phenyl] -aminosulfonic acid: According to the method of step A, make 0.5 1 3 g The base compound and 0.0 7 5 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.716 g of a sulfur trioxide-oxidine complex. The reaction was purified and purified to obtain 0.03 0 g of ammonium salt product. 1H (D20): 7.19-7.13 (m, 3H), 6.92-6.89 (m, 6H), 4.32 (t, 1H, J = 6.7Hz), 3.42 · 3 · 30 (q, 2H, J = 8.9Hz) , 2.93-2.64 (m, 2 H), 2.50 (s, 3 H). Example 3 3 -80- (77) 200416214 (S)-(4- {2-methylaminomethylmethyl-2-[(Chua-1-mimetic) -amino] -ethyl} _benzyl) -Amino acid: (S) -Cai-2-carboxylic acid [1-methylamine methylamino- 2- (4-nitro-benzyl) -ethyl] -fluorenamine: According to the method of Example 2, 0.3 00 g of HL-Phe (4-N02) -NMe was treated with 0.2 5 8 g of triethylamine and 0.2 42 g of 2-naphthalenepyrene chloride, thereby obtaining 0.4 2 3 g of the product.

(S)-(4- {2-methylaminomethylamido-2-[(Cai-1-carbonyl) -amino] -ethyl} -phenyl) -aminosulfonic acid: method according to step A A 0.42 3 g nitro compound and 0.07 5 g palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.535 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.026 g of ammonium salt product. 1H (D20): 8.26 (s, 1H), 7.99 (s, 1H), 7.83-7.76 (m, 3H), 7.49-7.44 (m, 4H), 7.13-7.10 (d, 1H, J = 9.5Hz) , 7.02-6.99 (d, 1H, J = 9.5Hz), 4.59 (m, 1 H), 3.03- 2.96 (m, 2H), 2.55 (s, 3H).

Example 3 4 (S)-{4- [2- (i-pentyl ^ -amino) -2-methylaminomethyl-ethyl] -phenyl} -aminosulfonic acid: (S) -Cyclopentanoic acid [1-methylamine formamidine-2- (4-nitro ·· phenyl) -ethyl; I-amidamine ·· According to the method of Example 2, 0.3 00 g HL-Phe ( 4-N02) -NMe was treated with 0.2 5 8 g of triethylamine and 0.168 g of cyclopentamidine chloride, whereby 0.35 9 g of product was obtained. (S)-{4- [2- (Cyclopentylcarbonyl-amino) -2-methylaminomethylmethyl-ethyl]--81-(78) (78) 200416214 Benzoic acid · According to the method of step A, 0.3 5 9 g of a nitro compound and 0.0 50 g of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.537 g of sulfur trioxide-Dttidine complex. The reaction was purified and purified to obtain 0.0 3 2 g of ammonium salt product. 1H (D20): 7.06-6.98 (q, 4H, J = 9.3Hz), 4.34 (t, 1H, J = 9.0Hz), 2.97-2.77 (m, 2H), 2.52-2.49 (m, 4H), 2.55 (s, 3 H), 1. 6 7 (m, 2 H), 1. 4 4 (m, 5 H), 1.2 5-1.2. 1 (m, 1 H). Example 3 5 (S)-(4- {2-Benzylaminomethylamidino-2- [2- (4-propyl-phenyl) -acetamido] -ethylphenylphenyl) · amino Sulfonic acid: (S) -N-benzyl- 3- (4-nitro-phenyl) -2- [2- (4-propyl-phenyl) -acetamidopropionamine: (S) -[l-Benzylaminomethane-2- (4-nitro-phenyl) -ethyl; l · Thirty-butylaminoformate (0.971 g) mixed with 11 mL of 4 M HC1 / dioxane . After 1.5 hours, the reaction mixture was concentrated to obtain 0.9 1 4 g of the desired product. O (S) -3- (4-amino-phenyl) -N-benzyl-2- [2- (4-propyl- Phenyl) -acetamido] -propanamide: According to the method of Example 2, 0.3 00 g of amine was treated with 0.37 mL of triethylamine and 0.16 mL of 4-propylbenzyl chloride. After packing up the reaction and chromatography, 0.3 3 3 g of product was obtained. (S)-(4- {2-Benzylaminomethylamidino-2- [2- (4-propyl-phenyl) -acetamido] -ethylphenylphenyl) -aminosulfonic acid: According to the method of Step A, 0.3 2 5 g of a nitro compound and 0.2 60 g of Pd / C and 25 mL of THF / EtOAc (79) (79) 200416214 were mixed and subjected to a reduction reaction. Packing up the reaction gave 0.2 5 7 g of the desired product. According to the method of step A, 0.2 5 7 g of amine and 0.319 g of S03-pyridine were mixed in 5 ml of pyridine. The reaction was cleaned up and purified to give 0.12 g of product. 1 Η (DMSO-d6): 8.53 (1H, t, J = 5.7 Hz), 8.39 (1H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.4Hz), 7.35 6.90 (9H, m), 4.64 (lH, m), 4.31 (lH, d, J = 5.7Hz) ^ 2.98- 2.83 (2H, m), 2.60 (2H, t, 7.8Hz), 1.6 1 (2H, q, J = 7.5), 0.89 (3H, t, J = 10.5Hz).

Example 3 6 (3)-(4- {2- [3- (3-Ethylamidosulfonyl-phenyl) -propanamido]-2-methylaminomethylamido-ethyl Phenyl) -aminosulfonic acid: (S) -2- [3- (3-Ethylamidosulfonamido-phenylpropionamido] -N-methyl-3- (4-nitro vPhenyl) -propanamide: 3- (3-Ethylamidosulfonamido-phenyl) -propionic acid (0.214 g, 0.82 mmol) and HOBt (0.150 g) were dissolved in DMF (1.5 mL ) And cooled to 0 ° C. To this stirred solution was added EDCI (0.188 g), and the resulting slurry was stirred at 0 ° C for 45 minutes, at which time the reaction mixture became homogeneous. To this solution was added (S) 2-Amino-N-methyl, 3- (4-nitro-phenyl) -propanilamine hydrochloride (0.224 g5 0.8 2 mmol) in DMF (2 mL) and DiPEA (0.3 00 mL) The resulting solution. The resulting solution was warmed to room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (40 mL) and rinsed with 1 N HC1 (3 X 20 mL) and brine (1 X 25 mL). Dry over sodium sulfate. The crude product was purified by flash column chromatography on silica gel and eluted with 8: 1 chloroform / methanol to give an off-white solid (0.188 g) -83- (80) 200416214 (S)-(4- { 2- [3- (3-Ethylamino Fluorenyl-phenyl) -propanamido] -methylaminomethylamido-ethyl} -phenyl) -aminosulfonic acid: According to the method of step A, 0.188 g of a nitro compound and 100 mg of palladium The carbon is reduced to obtain the desired product (tic). This crude aniline product is treated with 0.134 g of sulfur trioxide-pyridine complex. The reaction is purified and purified to obtain 0.0 8 5 g of ammonium salt product.] H NMR (3 00MH, D20) δ 7.6 5-7 · 5 9 (m, 2 Η)

, 7.38-7.23 (m, 2H), 6.97-6.88 (m, 4H), 4.21 (dd, J = 7.4, 6.5Hz, 1H), 2.87-2.64 (m, 4H) ^ 2.4 8 (m, 5H), : 1.83 (s, 3H). Examples 3 7-3 8 The following chemical formulas and Table 2 illustrate the structures of the compounds prepared in Examples 3 7-3 8: Ο R11a

-84- (81) (81) 200416214

Example 3 7 (S)-{4- [2-Benzylamidoamino-2- (1-aminomethylamido-2-0) -phenyl-ethylaminomethylamido) -ethyl]- Phenylphenylaminosulfonic acid: (S)-[l- [l-aminomethylamido-2-phenyl-ethylaminomethylamido] -2- (S)-(4-nitro-phenyl ) -Ethyl] -aminocarbamic acid third butyl ester: According to the method φ of Example 1, 0.400 g of Boc-L-Phe (4-N02) -OH was passed through 143 mg NMM, 194 mg isobutyl chloroformate, and 25 5 mg L-Phenylamphetamine. Thus, a white solid product was obtained. (3) -1 ^ [1- (1-Aminomethylamidino-2-phenyl-ethylaminomethylamidino) -2- (3)-(4-nitro-phenyl) -ethyl]- Benzamidine: According to the method of step B, 0.3 0 0 g of the compound was treated with 5 mL of 4 M HC1 / dioxane. The crude product was then treated with 0.140 g of triethylamine and 0.102 g of benzamidine chloride. This gave 0.048 g of product. Φ (S)-{4- [2-benzylideneamino- 2- (1-aminoformyl-2- (8) -phenyl-ethylaminoformyl) -ethyl] -benzene } -Aminosulfonic acid: According to the method of step A, 0.048 g of a nitro compound and 40 mg of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.050 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.01 8 g of an ammonium salt product. ] H (CD3OD): 6.11-6.04 (m ^ 3H), 5.98-5.93 (m, 2 Η), 5.68-5 · 5 4 (m, 9 Η) 3.2 0 (m, 1 Η), 3 · 0 2 (m, 1 Η) 1.79- 1.3 4 (m ^ 4 H). -85- (82) 200416214 Example 3 8 (S)-[l- [l-Aminemethylamido-2- (4-hydroxy-phenyl) -ethylamine 2 (S)-(4-sulfonic acid amine -Phenyl) -ethyl] -aminocarboxylic acid tert-butyl acetate (3)-[1- [1-aminomethylamido-2- (4-hydroxy-phenyl) -ethylamine 2 (S) -(4-nitro-phenyl) -ethyl] -aminocarboxylic acid third butyl ester: 1 method, 1.56 g of Boc-L-Phe (4-N〇2) -OH was subjected to NM M, 0.7 5 5 g of isobutyl chloroformate, and 1.09 g of L-tyramine. This gave 0.166 g of the desired product. (S)-[l- [Brazimidinyl 2- (4-hydroxy-phenyl) -ethylamine 2 (S)-(4-sulfonylamino-phenyl) -ethyl] -amine In the method of step A of the third butyl carboxylic acid, 0.116 g of a nitro compound and 60 mg are subjected to a reduction reaction to obtain a desired product (tic). Let this aniline; f 0.1 17 g be treated with sulfur trioxide-pyridine complex. Pack up the reaction and 0.011 g of ammonium salt product. 1H (D20): 7.07-6.97 (m 6.78 (d, 2H, J = 9.3Hz), 4.39 (t, 1H, J = 6 4.08 (t, 1H, J = 8. 1 Hz)), 2.99-2.67 (m , 4H), 9H). Examples 39-54 The following chemical formulas and Table 3 illustrate the structures prepared in Examples 3 9-5 4: Formamyl; 1-formamyl]-Treating formazan according to Example 0.5 5 9 g Fluorenyl] -ester: The crude product was purified according to palladium on carbon to obtain, 6H), • 5Hz), 1,23 (-86- (83) 200416214 of compound s HO-S-〇

〇 Formula (IV) Table 3

Example L3 R7 R16 39 -C〇2 ~ ξ ~ Υ 40 Covalent bond μ ×) 41 Covalent bond 42 Covalent bond 43 Covalent bond c ί >) 44 Covalent bond '~ \ y ~ (D -87- ( 84) 200416214 (84)

45 -CO- 丨 ° h 46 -CO- 47 -C〇2 ~ κ > 48 -C〇2 ~ 49 -C〇2 ~ K /; 〆50 covalent bond H 51 covalent bond Kw) H 52 covalent Bond -ch3 H 53 covalent bond H 54 covalent bond K). / H Example 3 9

[4- (2-{(Third butoxycarbonyl) [(4-Tolyl) sulfofluorenyl] amino} ethyl) phenyl] aminosulfonic acid:

4-methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: Let 3.0 g of 4-nitrophenylethylamine hydrochloride and 20 · 6 A solution of m L of triethylamine in 120 m L of THF was treated with 2.81 g of p-toluenesulfonyl chloride. The reaction mixture was stirred for 65 hours, concentrated and redissolved in CH2C12. The solution was washed with water and a saturated aqueous sodium hydrogen carbonate solution, and then dried. Rolling with methanol and washing with ether gave 3.47 g of the desired product. -88- (85) (85) 200416214 [(4-Tolyl) sulfofluorenyl] [2- (4-nitro-phenyl) ethyl] amino formic acid second butyl vinegar: the compound obtained from 0.300 g) were treated with 0.0057 g of DMAP and 0.2 4 5 g of di-tert-butyl dicarbonate in 2.5 ml of dichloromethane and stirred overnight. The solution was washed with water, hexane was added to the organic layer, and the solution was extracted with water. The aqueous layer was concentrated and purified by flash chromatography to obtain 0.303 g of the desired product. [2- (4-Amino-phenyl) ethyl] [(4-Tolyl) sulfofluorenyl] carbamic acid third butyl ester: According to the method of Step A, let 0 · 3 0 1 g And 0.018 g of 10% Pd / C in 5 mL of EtOAc and 5 mL of MeOH under H2 and atmospheric pressure. After packing the reaction, 0.2 7 5 g of the desired product was obtained. [4- (2-{(Third-butoxycarbonyl) [(4-Tolyl) sulfofluorenyl] amino} ethyl) phenyl] aminosulfonic acid: 0.2 7 6 g The amine was treated with 0.3 3 7 g of sulfur trioxide-D-pyridine complex in 8 mL of pyridine. The reaction was purified and purified to obtain 0.11 g of ammonium salt product. 1H NMR (D20) 5 7.62 (d, J = 5Hz, 2H); 7.40 (d, J = 6Hz, 2H); 6.95 (m, 4H); 3.87 (t, J 14Hz, 2H); 2.80 (d , J = 6 H z, 2H); 2.36 (s, 3H); 1.22 (s, 9H). Example 4 0 (4- {2- [benzyl- (toluene-4-sulfonyl) -amino] -ethyl} -phenyl) -amino acid: N-benzyl-4-methyl- N- [2- (4-Nitro-phenyl) -ethyl] -benzenesulfonamide: 0.03 8 7 g of sodium hydride (60% oil dispersion) in 2 ml of anhydrous DMF. 0.3 0 0 g 4-methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide in -89- (86) (86) 200416214 4 mL of DMF deal with. After 15 minutes, 0.1 1 ml L benzylamine and 2 ml L D M F were added dropwise. The reaction mixture was stirred for 3 hours, and then water was added to quench the reaction. The solution was extracted with ether, and the combined organic extract was washed with brine and dried over sodium sulfate. After purification by flash chromatography, 208 g of the desired product were obtained. N- [2- (4-Amino-phenyl) -ethyl] -N-benzyl-4 -methyl-benzenesulfonamide: According to the method of Step B, let 0 · 2 8 8 g of a nitro compound Mix with 0.62 g of tin chloride dihydrate in 10 ml of ethanol. After packing the reaction, 0.262 g of the desired product was obtained. (4- {2- [benzyl- (toluene-4 · sulfonylamino)] ethylphenylphenylaminosulfonic acid: According to the method of step A, 0.262 g of amine and 8 m LD Bidudine was mixed with 0.3 2 9 g of sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.1 1 8 g of the desired product.] Η NMR (D 2 Ο): ο 7 · 4 5 ( d,

J = 8Hz, 2H); 7.16-7.20 (m, 5H); 7.07-7.09 (m, 2H); 6.85 (d, J = 8Hz, 2H); 6.70 (d, J = 8Hz, 2H); 4.13 (s , 2H); 3.09 (t, J = 14 Hz, 2H); 2.36 (t, J = 14 Hz, 2H); 2.22 (s, 3H). Example 4 1 (4- {2-[(3-methyl-but-2-enyl)-(toluene-4_sulfonyl) _amino] -ethyl} -phenyl) -aminosulfonic acid : 4-methyl-N- (3-methyl-but-2-enyl) -N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: according to Example 4 0 In this method, 0.6 g of 4-methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide was subjected to 0.0 7 3 g (87) 200416214

-N- (3-methyl-but-2-ene] g odor 2-methyl-2 · butene treatment. Pack the desired product of reaction g. G), 0.4 g of indium powder and mL of ethanol Mix and heat to reflux. After 4 hours, the reaction mixture was diluted with water and filtered with Yin's salt, and rinsed thoroughly with water and then with ethyl acetate. The filtrate was adjusted with 1 N N a 〇 Η to p Η = 1 0 ′ and extracted with ethyl acetate. The combined extract was washed with brine and dried to obtain 0.162 g of the desired product. (4- {2-[(3-methyl-but-2-enyl) _ (toluene-4-sulfonyl) -amino] -ethyl} -phenyl) -aminosulfonic acid: according to step In the method A, 0.2 6 2 g of amine and 0.32 9 g of sulfur trioxide-pyridine complex were mixed in 5 ml of pyridine. The reaction was cleaned up and purified to obtain 0.148 g of the desired ammonium salt product. 1 Η N MR (D2〇): (5 7 · 49 (d, J = 6Hz, 2H); 7.27 (d, J = 7Hz, 2H); 6.9 5-7.02 (m, 4H); 4.82 (s, 1H ); 3.67 (d, J = 7.0Hz, 2H); 3.26 (t, J = 14Hz, 2H); 2.66 (t, J = 14Hz, 2H); 2.29 (s, 3H); 1.49 (d, J = llHz 6H). Example 42 (4- {2-[(3-methyl-butyl) _ (toluene-4-sulfonyl) -amino] -ethyl} -phenyl) -aminosulfonic acid. N- [2- (4-Amino-phenyl) _ethyl] -4-methyl-N- (3-methyl-butyl) -benzenesulfonamide: According to the method of Step A, make 0.198 g 4-methyl (3-methyl-but-2-enyl) -N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide and (88) (88) 200416214 0.0 30 g of Pd / C was mixed in 20 mL of Me OH and reduced to obtain 0.192 g of the desired product. (4- {2-[(3-methyl-butyl)-(toluene-4-sulfonyl) ) -Amino] -ethyl} -phenyl) -Aminosulfonic acid: According to the method of step A, 0.192 g of amine was treated with 0.254 g of sulfur trioxide-D-pyridine complex in 5 mL of pyridine. Pack up The reaction and purification yielded 0.161 g of the desired ammonium salt product.] H NMR (D20): (5 7 · 50 (d, J = 7 Hz, 2H); 7.15 (d, J = 7 Hz, 2H ); 6.98 (q, J = 17Hz, 4H); 3.29 (t, J = 14Hz, 4H); 3.06 (t, J = 15Hz, 2H); 2.64 (t, J = 14Hz, 2H); 2.29 (s, 3H); 1.26-1.35 (m, 1H); 1.21-1.24 (m-2H); 0.70 (d, J = 7Hz, 6H). Example 4 3 [[2- (4-sulfonylamino-phenyl) -Ethyl]-(toluene-4-sulfonyl) -amino] -ethyl acetate: [[2- (4-nitro-phenyl) -ethyl]-(toluene-4-sulfonyl) -Amine] -Ethyl acetate: According to the method of Example 40, 0.6 00 g of 4-methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide and 0.094 g Sodium hydride (60% oil dispersion) was mixed in 5 mL of THF. Ethyl bromoacetate (0.33 g) was added. After the reaction, 0.798 g of the desired product was obtained. [[2- (4-Amino-benzene Group) -ethyl]-(toluene_4-sulfonyl) -amino] -ethyl acetate: According to the method of Step A, 0. 3 8 1 g of a nitro compound and 0.023 g of Pd / C in 10 mL EtOAc / MeOH was mixed and reduced to give 0.3 4 1 g of the desired product. -92- (89) (89) 200416214 [[2- (4-sulfonylamino-phenyl) -ethyl]-(toluene-4-sulfonyl) -amino group; l · Ethyl acetate: according to In the method of step A, 0.341 g of amine was treated with 0.432 g of sulfur dioxide-D-pyridine complex in 5 mL of D [: tn]. Pack up the reaction and purify to obtain 0.177 g of the desired ammonium salt product. 1 Η NMR (D20-d2) 7. 46 (d, J = 8 Η ζ, 2 Η) \ '7.24 (d, J = 8 Hz, 2H); 6.9 1 (s, 4H); 3.95-4.01 ( η, 4H); 3.37 (t, J = 14Hz, 2H) j 2.61 (t, J = 14Hz, 2Η); 2.29 (s, 3H); 1.07 (t J = 1 4 Ηz, 3Η) . Example 4 4 [[2- (4-sulfonylamino-phenyl) -ethyl]-(toluene-4_sulfonyl) -amino] -acetic acid: [[2- (4-nitro-benzene ) -Ethyl]-(toluene-4-sulfonyl) -amino] -acetic acid [[2- (4-nitro-phenyl) -ethyl] _ (toluene-4-sulfonyl) ·· Amine] • Ethyl acetate (0.4 7 1 g) was mixed with 15 m LM e 〇Η, 5 m L water and 0 · 1 2 3 g potassium carbonate and heated under reflux. After 4 hours, the reaction mixture was cooled to room temperature and evaporated to remove methanol. The solution was rinsed with hexane and acidified. The solution was extracted with chloroform and the combined organic layer was dried to obtain 0.2 8 5 g of the desired product. [[2- (4-Amino-phenyl) · ethyl] toluene-4-sulfonyl) -amino] -acetic acid According to the method of Step A, 0.285 g of a nitro compound and 〇7 g of Pd / C was mixed in 10 mL of EtOAc / MeOH and reduced to obtain 0.271 g of the desired product. -93- (90) 200416214 [[2-(4-sulfonylamino-phenyl) -ethyl]-(toluene-4-sulfonyl) -amino]] acetic acid: According to the method of step A, let 271 g of amine was treated with 0.37 g of sulfur trioxide-anhydropyridine complex in 5 ml of pyridine. Packing up the reaction and purification 'gave 0.023 g of the desired ammonium salt product. 1HNMR (D20-d2): 5 7.48 (d, J = 8Hz, 2H); 7.24 (d, J = 8Hz, 2H); 6.91 (q, J = 14Hz, 4H); 3.68 (s, 2H); 3.36 ( t, J = 15Hz, 2H)

; 2.57 (t, J = 15 Hz, 2H); 2.29 (s, 3H). Example 45 [4- (2-{[(4- Tolyl) sulfofluorenyl] [4- (sulfonylamino) benzylidene] amino} ethyl) phenyl] aminosulfonic acid: 4- Methyl-N- (4-nitro-phenyl) -N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: According to the method of Example 40, make 0.300 g 4- Methyl-N- [2- (4-nitro-phenyl) -ethyl; l. Besysulfame and 0.0 4 7 g of sodium hydride (60% oil dispersion) were mixed in 5 mL of THF, and Treat with 0.173 g of p-nitrobenzidine chloride. After packing up the reaction and purification, 0.2 05 g of the desired product was obtained. Ν · (4-amino-benzyl) -N- [2- (4-amino-phenyl) -ethyl] -4-methyl-benzenesulfonamide: According to the method of Step A, let 〇 2 0 7 g of a nitro compound and 0 · 0 2 2 g of P d / C were mixed and reduced in 1 〇 ni LE t 〇 A c / M e 〇 Η to obtain 0.1 3 7 g of the desired Product. [4- (2-{[(4-Tolyl) sulfofluorenyl] [4- (sulfonylamino) benzylfluorenyl] amine-94- (91) (91) 200416214 group} ethyl) phenyl ] Aminosulfonic acid: According to the method of step A, 0.137 g of amine was treated with 0.320 g of sulfur dioxide-pyridine complex in 5 mL of pyridine. The reaction was purified and purified to obtain 0.1 106 g of the desired ammonium salt product. 1 Η N M R (D 2 0): δ 7.55 (d

, J = 8Hz, 2H); 7.32 (d, J = 8Hz, 2H); 6.91 (s, 4H); 6.84 (d, J = 8Hz, 2H); 6.76 (d, J = 8Hz, 2H); 4.21 ( t, J = llHz, 2H); 2.74 (t, J = llHz, 2H); 2.30 (s, 3H). Example 4 6 (4- {2- [Benzylamidino- (toluene-4-sulfonyl) -amino] -ethylphenylphenyl) -aminosulfonic acid: N-benzyl-4- Methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: According to the method of Example 40, 0.3 00 g of 4-methyl-N- [2- (4- Nitro-phenyl) -ethyl; I-benzenesulfonamide is mixed with 0.047 g of sodium hydride (60% oil dispersion) in 5 mL of THF. And treated with 0.1 3 1 g p-nitrobenzidine chloride. After packing up the reaction and purification, 0.24 5 g of the desired product was obtained. N- [2- (4-Amino-phenyl) -ethyl] benzylidene-4-methyl-benzenesulfonamide: According to the method of Step A, make 0.2 4 5 g of a nitro compound and 0.0 1 5 g of Pd / C was mixed in 10 mL of EtOAc / MeOH and reduced to obtain 0.247 g of the desired product. (4- {2- [Benzylamidino- (toluene-4-sulfonyl) -amino] -ethylphenylphenyl-95- (92) 200416214) -aminosulfonic acid: Method according to step A Let 0.2 4 7 g of amine be treated with 0.2 9 9 g of sulfur trioxide-pyridine complex in 5 mL of pyridine. The reaction was cleaned up and purified to obtain 0.173 g of the desired ammonium salt product. 1 Η N M R (D 2〇): 5 7.73 (d, J = 8Hz, 2H); 7.3 3-7.3 5 (m, 1H); 7.28 (d, J = 8Hz

, 2H); 7.19 (t, J = 15Hz, 2H); 6.85 (d, J = 8Hz, 2H); 6.71 (d, J = 8Hz, 2H); 4.08 (t, J = 12Hz, 2H);

2.71 (t, J = 12Hz, 2H); 2.26 (s, 3H). Example 47 [4- (2-{(Third butoxycarbonyl) [(3-fluoro-4-tolyl) sulfofluorenyl] amino} ethyl) phenyl] aminosulfonic acid: 3-fluoro-4 -Methyl [2- (4-nitro-phenyl) -ethyl] • benzenesulfonamide: According to the method of Example 39, 0.5 00 g of 4-nitrophenylethylamine hydrochloride was passed through 3.6 mL of triethyl The amine and 0.515 g of 3-fluoro-4-methyl-benzenesulfonamide were treated in 20 mL of THF. After packing up the reaction and purification, 0.43 4 g of the desired product was obtained. [(3-Fluoro-4-tolyl) sulfofluorenyl] [2- (4-nitro-phenyl) ethyl] carbamic acid third butyl ester: According to the method of Example 39, 0.43 4 g of sulfonamide Mix with 0.08 g of DMAP and 0.542 g of di-tert-butyl dicarbonate in 25 mL of dichloromethane. Packing up the reaction gave 0.5 8 6 g of the desired product. [2- (4-Amino-phenyl) ethyl] [(3-fluoro-4-tolyl) sulfofluorenyl] carbamic acid third butyl ester: According to the method of Step A, let 0 · 5 3 3 g of a nitro compound and 0.03 2 -96- (93) (93) 200416214 g of Pd / C were mixed in 10 mL of EtOAc / MeOH and subjected to a reduction reaction to obtain 0.497 g of the desired product. [4- (2-{(Third-butoxycarbonyl) [(3-fluoro-4-tolyl) sulfofluorenyl] amino} ethyl) phenyl] aminosulfonic acid: According to the method of Step A, let 0.129 g of amine was treated with 0.151 g of sulfur trioxide-pyridine complex in 5 mL of pyridine. The reaction was purified and purified to obtain 0.044 g of the desired ammonium salt product. ] H NMR (D20): 5 7.3 3-7.3 4 (

m, 2H); 7.09 (d, J = 8Hz, 2H); 6.99 (d, J = 7Hz, 2H); 6.89 (s, lH); 4.00 (t, J = 13Hz, 2H); 2.85 (t, J = 13Hz, 2H); 2.21 (s, 3H); 1.09 (s, 9H). Example 4 8 [4- (2-{(Third butoxycarbonyl) [(3-fluorophenyl) sulfonamido] amino} ethyl) phenyl] aminosulfonic acid: 3-fluoro-N- [ 2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: According to the method of Example 39, 0.5 00 g of 4-nitrophenylethylamine hydrochloride was subjected to 3 · 6 mL of triethylamine and 0.4 80 g of 3-fluorobenzenesulfonyl chloride were treated in 20 mL of THF. After packing up the reaction and purification, 0.5 3 6 g of the desired product was obtained. [(3-Fluorophenyl) sulfofluorenyl] [2- (4-nitro-phenyl) ethyl] carbamic acid third butyl ester: According to the method of Example 39, 0.5 3 6 g of sulfanilamide and 0.0 1 0 g of DMAP and 0.433 g of di-tert-butyl dicarbonate were mixed in 25 mL of dichloromethane. Packing up the reaction gave 0.5 8 6 g of the desired product. [2- (4-Amino-phenyl) ethyl] [(3-fluorophenyl) sulfonamido] aminocarboxylic acid-97- (94) 200416214 Third butyl ester: According to the method of step A, let 0.5 86 g of a nitro compound and 0.035 g of Pd / C were mixed in 10 mL of EtOAc / MeOH and subjected to a reduction reaction to obtain 0.153 g of the desired product. [4- (2-{(Third butoxycarbonyl) [(3-fluorophenyl) sulfonamido] amino} ethyl) phenyl] amino] amino mineral acid:

According to the method of Step A, 0.153 g of amine was treated with 0.186 g of sulfur trioxide-pyridine complex in 5 mL of pyridine. The reaction was purified and purified to obtain 0.016 g of the desired ammonium salt product. 1HNMR (D20): 5 7.42-

7.43 (m, 4H); 6.91 (s, 4H); 3.11 (t, J = 13Hz, 2H) »2.57 (t j J = 7Hz, 2H); 1.10 (s, 9H). Example 49 [4- (2-{(Third butoxycarbonyl) [(2-fluorophenyl) sulfonamido] amino} ethyl) phenyl] aminosulfonic acid = 2-fluoro-N_ [2- (4-Nitro-phenyl) -ethylbenzylsulfonamide: According to the method of Example 39, 0.5 g of 4-nitrophenylethylamine hydrochloride was passed through 3.6 mL of triethylamine and 0.480. g 2-fluorobenzenesulfonyl chloride was treated in 20 nL of THF. After packing up the reaction and purification, 0.6 1 1 g of the desired product was obtained. [(2-Fluorophenyl) sulfofluorenyl] [2- (4-nitro-phenyl) ethyl] carbamic acid third butyl ester: According to the method of Example 39, 0.6 丨 g The amine was mixed with 0.2 g of DMAP and 0.493 g of di-tert-butyl dicarbonate in 25 mL of dichloromethane. The reaction was cleaned up to obtain 0.705 g of the desired product. -98- (95) (95) 200416214 [2- (4-Amino-phenyl) ethyl] [(2-fluorophenyl) sulfonyl] aminocarboxylic acid third butyl ester: Method according to step A , 0.70 5 g of a nitro compound and 0.042 g of Pd / C were mixed in 10 mL of EtOAc / MeOH and subjected to a reduction reaction to obtain 0.6 3 8 g of the desired product. [4- (2-{(Third-butoxycarbonyl) [(2-fluorophenyl) sulfonamido] amino} ethyl) phenyl] amino acid: According to the method of Step A, let 0.6 3 9 g of amine was treated with 0.7 7 2 g of sulfur trioxide-Dttidine complex in 8 mL of pyridine. The reaction was purified and purified to obtain 0.071 g of the desired ammonium salt product. 1H NMR (D20) 5 7.94 (t, J = 15Hz, lH); 7.78-7.85 (m, lH); 7.46-7.5 5 (m, lH); 6.88-7.12 (m, 4H); 6.54 (d, J = 8Hz, 1H); 3.83-3.90 (m, 2H); 2.7 8 -2.8 6 (m ^ 2H); 1.22 (s, 9H). Example 5 0 {4- [2- (Toluene-4-sulfonamido) -ethyl] -phenylblylsulfonic acid: N- [2- (4-amino-benzyl) · ethyl] -4 -Methyl-Benzene Diamine: According to the method of Step A, 0.407 g of 4-methyl-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide and 0.024 g of Pd / C was mixed in 16 mL of EtOAc / MeOH and reduced to obtain 0.3 6 8 g of the desired product. {4- [2- (Toluene-4-diasaminyl) -ethyl] -phenylbutanyl amino acid: According to the method of Step A, 0.3 6 8 g of amine was subjected to trioxidation-99 of 0.6 0 5 g -(96) 200416214 Sulfur-D-D complex was treated in 10 m L Dtt D-D complex. The reaction was cleaned up and purified to obtain 0.3 6 5 g of the desired ammonium salt product. 1H NMR (D20) 5 7.49 (d, Bu 7.0.0Ηζ, 2Η); 7.26 (d, J = 7.0Hz, 2H); 6.90 (s ^ 4H); 3.01-3.06 (m, 2H); 2.51-2.55 ( m, 2H); 2.30 (s, 3H). Example 5 1

[4- (2-benzenesulfonamido-ethyl) -phenyl] -aminosulfonic acid: N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: according to In the method of Example 39, 0.5 0 g of 4-nitrophenylethylamine hydrochloride was treated with 3.6 mL of triethylamine and 0.4 8 0 g of 3-fluorobenzenesulfonyl chloride in 20 mL of THF. After packing up the reaction and purification, 0.536 g of the desired product was obtained. N- [2- (4-Amino-phenyl) -ethyl] -benzenesulfonamide:

According to the method of step A, 0.705 g of a nitro compound and 0.042 g of Pd / C were mixed and reduced in 10 mL of EtOAc / MeOH to obtain 0.6 3 8 g of the desired product. [4- (2-benzenesulfonamido-ethyl) -phenyl] -aminosulfonic acid: According to the method of step A, 0.63 9 g of amine was subjected to 0.7 72 g of sulfur trioxide-H-D complex Processed in 8 m LD [t D centering. The reaction was purified and purified to obtain 0.071 g of the desired ammonium salt product. 1HNMR (D2〇) (5 7.54-7.64 (m, 3H); 7.43-7 · 48 (ηι, 2Η); 6.91 (s, 4H); 3 · 0 3-3. 0 7 (m, 2 Η ); 2 · 5 2-2 · 5 7 (m, 2 Η). Example 5 2 -100- (97) (97) 200416214 [4- (2-methylsulfonamido-ethyl) -phenyl] -Aminosulfonic acid: N- [2- (4-nitro-phenyl) -ethyl] -methanesulfonamide: According to the method of Example 39, 0.5 0 0 g 4 -nitrophenylethylamine hydrochloride The salt was treated with 3.6 mL of triethylamine and 0.4 8 0 g of 3-fluorobenzenesulfonyl chloride in 20 mL of THF. After packing and reaction, 0.5 3 6 g of the desired product was obtained. N- [2- ( 4-Amino-phenyl) -ethyl] -methanesulfonamide: According to the method of step A, 0.7 0 5 g of a nitro compound and 0.0 4 2 g of Pd / C were mixed and carried out in 10 mL of EtOAc / MeOH. The reduction reaction yielded 0.6 3 8 g of the desired product. [4- (2-Methanesulfonamido-ethyl) -phenyl] -aminosulfonic acid: According to the method of step A, 0.63 9 g of amine was passed through. .7 72 g of sulfur trioxide-pyridine complex was treated in 8 mL of pyridine. The reaction was purified and purified to obtain 0.07 1 g of the desired ammonium salt product. 1 HNMR (D20) ·· (5 7.18 (d, J = 8Hz, 2H); 7.08 (d, J = 8Hz, 2H); 3.27 (t, J = 6.8Hz, 2H); 2.83 (s, 3H); 2.74 (t, J = 6.8Hz, 2H). Example 5 3 [4- (2-Methanesulfonamido-ethyl) -phenyl] -amino group Sulfonic acid: N- [2- (4-nitro-phenyl) -ethyl] -C-phenyl-methanesulfonamide: According to the method of Example 39, 0.5 0 0 g 4-nitrobenzene Ethylamine hydrochloride was treated with 3.6 mL of triethylamine and 0.4 8 0 g of 3-fluorobenzenesulfonyl chloride in 20 mL of THF. After packing up the reaction and purification, 0.5 3 6 g of the desired product was obtained. N- [2 -(4-amino-phenyl) -ethyl] phenyl-methanesulfonamide: According to the method of Step A, 0.75 g of a nitro compound and 0.04 2 -101-(98) (98) 200416214 g P d / C was mixed in 10 m LE t OA c / M e Η and subjected to reduction reaction to obtain 0.6 3 8 g of the desired product. [4- (2-Methanesulfonamido group -Ethyl) -phenyl] -aminosulfonic acid: According to the method of step A, 0.63 9 g of amine was treated with 0.7 72 g of sulfur trioxide-pyridine complex in 8 mL of pyridine. The reaction was purified and purified to obtain 0.071 g of the desired ammonium salt product. 1HNMR (D20) 5 7.33-7.35 (m, 3H); 7.25-7.27 (m ^ 2H); 7.12 (d, J = 8.4Hz, 2H); 7.06 (d, J = 8.4Hz, 2H); 4.27 (s , 2H); 3.14 (t, J = 6.8 Hz, 2H); 2.66 (t, J = 6.8 Hz, 2H). Example 54 {4- [2- (4-Methoxy-benzenesulfonamido) -ethyl] -phenylbutanylsulfonic acid: (S)-[4-methoxy-N- [2- (4-nitro-phenyl) -ethyl] -benzenesulfonamide: According to the method of Example 39, 0.5 00 g of 4-nitrophenylethylamine hydrochloride was passed through 3.6 mL of triethylamine and 0.4 8 0 g 3 -Fluorosulfenyl chloride was treated in 20 mL of THF. After packing up the reaction and purification, 0.536 g of the desired product was obtained. (S) _N_ [2- (4-Amino-phenyl) -ethyl] -4-methoxy-benzenesulfonamide: According to the method of Step A, let 0.7 0 5 g of a nitro compound and 0.042 g of Pd / C was mixed in 10 mL of EtOAc / MeOH and subjected to a reduction reaction to obtain 0.6 3 8 g of the desired product. (S)-{4- [2- (4-Methoxy-benzenesulfonamido) -ethyl] -phenylbutanylsulfonic acid: According to the method of Step A, 0.63 9 g of amine was subjected to 0.7 72 g of sulfur trioxide-pyridine complex was treated in 8 mL of pyridine. The reaction was purified and purified to obtain -102 > (99) 200416214 0.0 7 1 g of the desired ammonium salt product. ] Η N M R (D 2 Ο) 5 7.5 2 (d,

J = 7.3Hz, 2H); 6.93 (d, J = 7.5Hz, 2H); 6.89 (s, 4H); 3.76 (s, 3H); 2.99 (t, J = 6.7Hz, 2H); 2.5 1 (t , J = 6.7 Hz, 2H). Examples 5 5-5 9 The following chemical formulas and Table 4 illustrate the structures of the compounds prepared in Examples 5 5-5 9:

Formula (V)

-103- (100) (100) 200416214

Example 5 5 (S)-[4- (2-Dibenzylaminomethylaminomethane-ethyl) _phenyl] · Amino acid: (S) -2-Dibenzylamino-N -Methyl · 3_ (4-nitro-phenyl) _propanamide: Η · L-Phe (4-N〇2) _NMe (0.500 g) was dissolved in 10 mL of water, and 1.07 g of carbonic acid was added to this solution. Potassium and 0.692 g of benzyl bromide. The reaction mixture was stirred for 48 hours and partitioned between DCM and 1 N H C1. The organic layer was dried over magnesium sulfate, filtered, evaporated, and purified by flash chromatography to obtain 0.472 g of the desired product. O (S)-[4- (2-dibenzylamino-2-methylaminomethylamidino) -Ethyl) -phenyl] -aminosulfonic acid: According to the method of Step A, 0.472 g of a nitro compound and 0.1 000 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). . This crude aniline product was treated with 0.869 g of a sulfur trioxide-pyridine complex. The reaction was purified and purified to obtain 0.88 g of an ammonium salt product. 1 H (D 2 0): 6.9 3-6.6 9 (m, 14Η), 3.37-3.03 (m '5H)' 2.68-2.46 (m, 2H), 2 · 2 7 (s, 3 Η) 〇Example 5 6 (S)-{4- [2- (Ethylfluorenyl-benzyl · amino) -2-methylaminomethylmethyl-ethyl] -phenyl} -aminosulfonic acid = (S) -2 -Diethylamino-methyl- 3- (4-nitro-phenyl) · propanamide: -104- (101) (101) 200416214 L-Phe (4-N02) -NMe (0.3 00 g) It was dissolved in 4 mL of MeOH and treated with 0.117 g of triethylamine and 0.1 8 5 g of benzaldehyde. The reaction mixture was stirred for 1.5 hours and then cooled on an ice bath. Add sodium borohydride (0.88 g) and stir at room temperature for 1.5 hours. The solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was dried and purified by flash chromatography to obtain 0.3 0 g of product. (S) -2- (Ethyl-benzyl-amino) -N-methyl- 3- (4-nitro-phenyl) -propanamidin: According to the method of Example 2, let 0.30 0 g of 2-benzylamino-N-methyl-3- (4-nitro-phenyl) propanilamine was treated with 0.051 g of triethylamine and 0.044 g of acetamidine chloride to obtain 0.1 2 6 g of the product. (S)-{4- [2- (Ethylfluorenyl-benzyl-amino) -2-methylaminomethylsulfanyl-ethyl l.phenylphenylaminosulfonic acid: According to the method of Step A, let A reduction reaction of 0.126 g of a nitro compound and 50 mg of palladium on carbon yields the desired product (tic). This crude aniline product was treated with 0.169 g of sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0.43 g of ammonium salt product. 1 H (D 2 Ο): 7.22-7.06 (m, 3Η), 7.00-6.89 (m, 6Η), 4.78-4.26 (m, 3H), 2.92 (t, 2H, J = 8.3Hz), 2.28 (s, 2H), 2.13 (s, 1H) ,: 1.90 (s, 2H) ,: 1.65 (s, 1H). Example 5 7 (S) -2- (Benzyl-tertiary butoxycarbonyl-amino) -3- (4-sulfonamido-phenyl) -propionic acid methyl ester: (S-amino-3- (4-Nitro-phenyl) -methyl propionate: According to the method of Example 56, 0.5 2 5 g of HL-Phe (4-N02) -0Me was passed through 0.2 04 g of triethylamine and 0.3 2 0 g of benzaldehyde. And ο.! 52 mg of sodium borohydride to obtain -105- (102) (102) 200416214 0.2 4 1 g of the product. (S) -2- (; ) -3- (4-nitro-phenylpropionic acid methyl ester: 2-benzylamino-3-(4-nitro-phenyl) -propionic acid methyl ester (0.2 4 1 g) dissolved in 10 mL D CM and treated with 0.78 g of triethylamine and 0.5 02 g of di-tert-butyl dicarbonate. The reaction mixture was stirred for 72 hours. The reaction mixture was partitioned between 25 mL of DCM and 0.1 N HC1. The water was rinsed with DCM. Layer, combined with the organic layer, dried over magnesium sulfate and purified by flash chromatography to obtain 0.1 2 3 g of the product. (S) -2- (benzyl-third butoxycarbonyl-amino) -3- (4 _Aminosulfonic acid-phenyl) -propionic acid methyl ester: According to the method of step A, 0.1 2 3 g of a nitro compound and 0.05 0 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). Let this crude aniline undergo 0 .1 42 g of sulfur trioxide-D [t-pyridine complex. Packing the reaction and purification to obtain 0.5 g of ammonium salt product.] H (D 2 0): 7 · 10 (s, 3H) , 6.9 8 -6.86 (m, 6H), 4.23-4.01 (m, 2H), 3.77 and 3.72 (d, 1H), 3.55-3 · 41 (m, 3H), 3.04-2.86 (m, 211) , 1.25 and 1.16 (d, 9H). Example 5 8 (S) -benzyl- [1-methylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl l · amino Methyl formate: (S) -Benzyl- [1-methylaminomethylmethyl-2- (4-nitro-phenyl) -ethyl] -carbamic acid methyl ester: According to the method of Example 2, let 0.2 00 g of 2-benzylamino-N-methyl-3- (4-nitro-phenyl) propanilamine was treated with 0.071 g of triethylamine and 0.0 6 6 g of methyl chloroformate to give 0.060 g of product -106- (103) 200416214 (s) -benzyl- [1-methylaminomethylmethyl-2- (4-sulfonic acid] -carbamic acid methyl ester: According to the method of Step A, the compound and 0.02 5 g of palladium on carbon was subjected to a reduction reaction to obtain the crude aniline product. After 0.07 7 g of sulfur trioxide-pyridine reaction and purification, 0.02 g of an ammonium salt product was obtained. ] T 7.11 (m, 3H), 7.03-6.88 (m, 5H), 4.35 (s, 2H), 3.49 (s, 3H), 2.95 (s, 3H). Example 5 9 (S) -Benzyl -[1-methylaminomethanemethyl-2- (4-sulfonic acid l · aminocarbamic acid third butyl ester:

(S) -Benzyl- [1-methylaminomethanemethyl-2- (4-nitroaminocarboxylic acid third butyl ester: 2- (benzyl-third butoxycarbonyl-phenyl) -propionic acid methyl The ester (0.245 g) was dissolved in 10 mL and treated with 0.1 24 g of lithium hydroxide hydrate.

Compound for 3 hours. The solvent was evaporated and the residue was partitioned in DCM. The combined WJB layers were dried, and the crude acid THF was obtained and mixed according to the method of Example 丨 with 0. 0 g g of isobutyl chloroformate and 0.4 5 0 mL of methylamine to dissolve 0 · 1 6 1 g desired product. (S) -Benzyl- [1-methylaminomethylmethyl-2- (4-stone |] -aminocarboxylic acid third butyl ester: according to step A, the base compound and 0.02 5 g of palladium on carbon Reduction was carried out to 0.060 g of amine-phenyl) -ethyl to nitrate the desired product. Order compound processing. Pack (D2〇): 7.26-4 · 5 1 (m, 1 Η) (s, 2 Η), 2.36 Amino-phenyl) -ethyl-phenyl) -ethyl] -amine- -amino ) -3- (4-Nitro 1: 1 EtOH: EtOAc was stirred at room temperature and the reaction was mixed with 0.1 N HC1. The acid was treated with 5 mL of 0.05 0 g NMM, so that amine-phenyl) -ethyl was obtained. 0.1 6 1 g of nitrate to obtain the desired product -107- (104) 200416214. Let's pack up 7.14 3H) 1.28 Example structure This crude aniline product was treated with 0.186 g of sulfur trioxide-Dtt D complex. The reaction and purification yield 0.0 5 8 g of ammonium salt product 4 (020): 7.26- (ill, 3 Η), 7. 0 7-7 · 0 0 (m, 6 Η), 4.3 4-4.0 1 (m, , 2.99 and 2.96 (d, 2H, J = 8.9), 2.45 (s, 3H), (s, 9H) 60-66 The following chemical formula and Table 5 illustrate the formula of the compound prepared in Example 60-66 ( VI)

-108- (105) (105) 200416214 Table 5 Examples * R7 R8 R9 R12 60 S 、 —— — H -ch3 61 S 〆, H -ch3 62 S, j〇H -ch3 63 S [, Wan H -ch3 64 S ιιιπιπ · ^^ H -ch3 65 S ^^ nh2, Chuan ... " · 0 H -ch3 66 S (\\\\ Wt ,, y // ^ DHK · -ch3 Example 6 0 N-[(l , L-dimethylethoxy) carbon group] -L-fluorenylaminofluorenyl-N-methyl-L-4-sulfonylamino-phenylpropylamine hydrazone: 1 [(1,1-dimethyl Ethoxy) carbonyl 1 ^ Leucylamine-1Methyl-1 ^ 4-nitro-phenylpropylamineamine: HL-Phe (4-N02) -NMe (200 mg) dissolved in 1 mL DMF It was treated with 0.209 g of diisopropylethylamine, 0.13 g of HOBt.H20, 0.211 g of L-Boc-Leu, and 0.162 g of EDCI. After 18 hours, the reaction mixture was treated with water and EtO Partitioned between Ac, and the combined organic layer was dried and purified by flash chromatography to obtain 0.193 g of product. N-[(l, l-dimethylethoxy) carbonyl] _L·leucinefluorenyl— N-methyl-109- (106) (106) 200416214 4-sulfonamido-phenylpropylamine sulfonamide: according to the method of step A 'let 193 g nitro compound and 0. 02 5 g palladium carbon Perform the reduction reaction to get the desired product (Tic). This crude aniline product was treated with 0.21 g of sulfur trioxide-pyridine complex. The reaction was cleaned up and purified to obtain 0. 04 8 g of ammonium salt product. 1 H (D2O): 7.19-6.99 (m 5 4H) '4.43 (t' 1H '1 = 8.5)' 3.86 (t, 1H, J = 6.3Hz), 3.04-2.86 (m, 2H), 2.58 (s, 1 Η), l · 4 8-1.40 (m, 3H), 1.33 (s, 9Η), 0.81-〇 · 7 Ο (m, 6 Η). Example 6 1 ^ [(1,1-dimethylethoxy) Carbonyl] -1 ^ methylthiaminefluorenyl-! ^-Methyl-L-4-sulfonylamino-phenylpropylaminesulfonylamine: N-[(l, l-dimethylethoxy) carbonyl] methyl Thiamine methyl-L-4-nitro · phenylpropylamine amine: According to the method of Example 60, 0.200 g of HL-Phe (4-N〇2) -NMe was passed through 0.209 g of diisopropylethylamine , 0.211 g L-Boc-Met, 0.130 g HOBt.H20, and 0.162 g EDCI treatment. This gave 0 · 1 2 2 g of product. 1 ^-[(1,1-dimethylethoxy) carbonyl] -1 ^ methylthiaminefluorenyl ^ -methyl-L-4-sulfonylamino-phenylpropylaminesulfonylamine: according to step a In the method, 0.122 g of a nitro compound and 0.025 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.128 g of a sulfur trioxide-D-pyridine complex. The reaction was cleaned up and purified to obtain 0.13 g of ammonium salt product. 1 Η (D2〇): 7.34-6.94 (m, 4H), 4.39 (t, 1H, J = 8.8), 3.96 (t, 1H, J = 8.3Hz), 2.98-2.76 (m, 2H), 2.53- 110- (107) (107) 200416214 (s, 3 Η), 2 · 3 1 (m, 2 Η), 1. 9 3 (s, 3 Η), 1. 7 0-1.5. 5 (ηι, 2 Η), 1 · 2 8 (s, 9 Η). Example 6 2 N-[(l, l-dimethylethoxy) carbonyl] -L-phenylpropylaminefluorenyl-N-methanesulfonylamino-phenylpropylaminesulfonylamine: N-[(l, l-dimethylethoxy) carbonyl] -L-phenylpropylaminefluorenylmethyl-L-4-nitro-phenylpropylaminesulfonylamine: According to the method of Example 60, 0.200 g of HL-Phe (4- N02) -NMe was treated with 0.209 g of diisopropylethylamine, 0.22 5 g of L-Boc-Phe, 0.130 g of HOBt.H20, and 0.162 g of EDCI. This gave 0.246 g of product. N-[(l, l-dimethylethoxy) carbonyl] -L-phenylpropylaminefluorenyl-N-methyl-L-4-sulfonylamino-phenylpropylaminesulfonyl: according to step A In the method, 0.246 g of a nitro compound and 0.0 50 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product. This crude aniline product was treated with 0.250 g of sulfur trioxide 4 ratio pyridine complex. The reaction was cleaned up and purified to obtain 0.043 g of ammonium salt product. 1Η (D2〇): 7.26-7.17 (m, 3H), 7.06-6.99 (m, 6H), 4.3 1 (t, 1H, J = 9.0), 4.12 (t, 1H, t = 8.3Hz), 2.84- 2.72 (m, 4H), 2.49 (s, 3H), 1,22 (s, 9H). Example 6 3 N-[(l, l-dimethylethoxy) carbonyl] -L-tyraminofluorenyl-N-methyl-L-4-sulfonylamino-phenylpropylamine ammonium amine:] ^ [(1,1-Dimethylethoxy) carbonyl] 4-tyraminefluorenyl-1 ^ -methyl-1 ^ -111-(108) (108) 200416214 4-nitro-phenylpropylamine : According to the method of Example 60, 0.200 g of HL-Phe (4-N02) -NMe was passed through 0.2 09 g of diisopropylethylamine, 0.2 3 8 g of L-Boc-Tyr, 0.130 g of H0Bt'H20, and 0.162 g EDCI processing. This gave 0.3 0 0 g of product. N-[(l, l-dimethylethoxy) carbonyl] -L-tyraminesulfonyl-N-methyl-L- 4-sulfonamido-phenylpropylaminesulfonamide: Method according to step A :, Make a reduction reaction of 0.3 00 g of a nitro compound and 0.0 50 g of palladium on carbon to obtain a desired product (tic). This crude aniline product was treated with 0.295 g of sulfur dioxide-pyridine complex. The reaction was purified and purified to obtain 0.062 g of ammonium salt product. ] Η (> 〇): 7 · 00-6.87 (m,, 6H), 6.69 and 6.66 (d, 2Η, J = 9.3Hz), 4.28 (t, 1Η, J =: 8.0) 4.05 ( t, 1 Η j J = 8.7 Hz) > 2.81-2.65 (m, 4 Η), 2. 47 (s, 3 Η), 1 · 2 1 (s, 9 Η) 〇 Example 64 N-[(l , L-dimethylethoxy) carbonyl] -L-valamine group-N-methyl-L-4-sulfonylamino group-phenylpropylamine group: Heart [(1,1-dimethyl Ethoxy) carbonyl] -1 ^ valaminomethyl-1 methyl-1 ^ 4-nitro-phenylpropylamine amine: According to the method of Example 60, make 0.2 00 g H, L-Phe (4-N02 ) -NMe was treated with 0.2 09 g of diisopropylethylamine, 0.184 g of L-Boc-Val, 0.130 g of HOBt-H20, and 0.162 g of EDCI. This gave 0.2 1 9 g of product. N-[(l, l-dimethylethoxy) carbonyl] -L-valamine group-N-methyl- fluorenesulfonylamino-phenylpropylamine amine: according to the method of step A, 0.219 -112- (109) (109) 200416214 g of a nitro compound and 0.05 0 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.24 7 g of sulfur trioxide-D [tidine complex. The reaction was cleaned up and purified to obtain 0.04 1 g of ammonium salt product. 1 Η (D2〇): 7.0 8-6.99 (q, 4H, J = 1 1 Hz), 4.40 (t, 1H, J = 8.3), 3.64 (t, 1H, J = 6.7Hz), 2.99-2.83 ( m, 2H), 2.52 (s, 3H), 1.81 (m, 1H), 1.25 (s, 9H), 0.68 (s, 6H). Example 6 5 N-[(l, l-dimethylethoxy ) Carbonyl] -L-glutamine-N-methyl-L-4-sulfonylamino-phenylpropylamine amine: N-[(l, l-dimethylethoxy) carbonyl] -L -Glutamine-N-methyl-nitro-phenylpropylamine amine: 0.300 g of H-L-Phe (4-N02) -NMe dissolved in 4 mL of anhydrous Me 0H and 0.3 15 g of diisopropyl Ethylamine and 0.414 g L-Boc-Glu-ONp treatment. The reaction mixture was heated at 60 ° C and stirred for 18 hours. The reaction mixture was cooled. The solution was partitioned between EtOAc and H20. The organic layer was washed with water and dried. The crude oily product was recrystallized from 1: 1 EtO Ac: hexane. 0.198 g of product was obtained. N-[(l / i-dimethylethoxy) carbonyl] glutamine-N-methyl-4-sulfonylamino-phenylpropylamine: According to the method of step A, 0.198 g of nitrate The base compound and 0.050 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.209 g of sulfur trioxide-Dttidine complex. The reaction was cleaned up and purified to obtain 0.0 8 2 g of ammonium salt product. 1 Η (D2〇): 7.08-7.00 (q, 4H, J 2 9.7Ηζ), 4.40 (t, 1H, -113- (110) (110) 200416214 J = 8.0), 3.83 (t, 1H, J = 9.0Hz), 2.95-2.85 (m, 2H), 2.54 (s, 3H), 2.07 (t, 2H, J = 7.3Hz), 1.73-1.66 (m, 2H), 1.30 (s, 9 H). Example 6 6 N-[(l, l-dimethylethoxy) carbonyl] -L-aspartyl-N-methyl-L-4-sulfonylamino · phenylpropylamine amine: N -[(l, l-dimethylethoxy) carbonyl] -L-aspartyl-N-methyl-L-4-nitro-phenylpropylamine amidin: According to the method of Example 65, let 0.300 g of HL-Phe (4-N〇2) -NMe was treated with 0.315 g of diisopropylethylamine and 0.388 g of L-Boc-Asn-ONp. This gave 0.176 g of product.

N-[(l, l-dimethylethoxy) carbonyl] -L-aspartylamino-N-methyl-L-4-sulfonylamino-phenylpropylamine In the method, 0.176 g of a nitro compound and 0.050 g of palladium on carbon are subjected to a reduction reaction to obtain a desired product (tic). This crude aniline product was treated with 0.192 g of a sulfur trioxide-D-pyridine complex. The reaction was purified and purified to obtain 0.047 g of ammonium salt product. 1Η (D2〇): 7.07-7.00 (q, 4H, J = 1 0.0Hz), 4.38 (t, 1H, J = 8.0), 4.25 (t, 1H, J = 1 0.0Hz), 2.97-2.85 (m , 2H), 2.54 (s, 3H), 2.48-2.30 (m, 2H), 1.29 (s, 9H). Examples 6 7-6 8 The following chemical formulas and Table 6 illustrate the structures of the compounds prepared in Examples 67-6 8: -114- (111) 200416214

Formula (νπ) Table 6 Examples * R2 R9 67 SC c Η Η 〇68 S () Η Example 6 7 N- {1- [1-pentylaminemethylamidino- 2- (4-sulfonylamino-benzene ) -Ethylaminomethylmethyl] -2-phenyl-ethylpyrosuccinic acid: [(lS)-; l-[(4-nitro-phenyl) -methyl] -2-one -2- (pentylamino) ethyl] -aminocarboxylic acid 1,2-dimethylethyl ester: 3.103 g of LBOc- (4-N02) Phe was added to 40 mL of dichloromethane. Temperature in ice bath EDCI (1.9 17 g) was added below. Amylamine (1.16 mL) was added and the reaction was allowed to warm to room temperature. After 18 hours, the reaction mixture was diluted with dichloromethane and washed twice with 1 N HC1 and dried over sodium sulfate. And purified by flash chromatography to give 1.86 g of product. (2 S) -2-amino-3- (4-nitro-phenylpentyl-propanamidin hydrochloride: [(IS) -1-[(4-nitro-phenyl) -methyl] -2-one-2- (pentylamino) ethyl] -aminocarboxylic acid 1,1-dimethylethyl ester (1.8 5 8 g ) Was treated with 18 mL of 4 M -115- (112) (112) 200416214 H C1 in dioxane. After 2 hours, the reaction mixture was concentrated and used directly in the next step without purification. N-[(l, l -Dimethylethoxy) carbonyl] -phenylpropylaminofluorenyl- 4-nitro-N-pentyl-L-phenylpropylamine amine: (2S) -2-amino-3- (4-nitro-phenyl) -N-pentyl-propylamine HCl Mix with 2 5 m L of dichloromethane and 2.1 m L of triethyl ether, and add HOBt (0.662 g) and 1.300 g of L-Boc-Plie. Add ED Cl ( 0.9 3 9 g). Then the reaction mixture was allowed to warm to room temperature. After 18 hours, the reaction mixture was diluted with ethyl acetate, washed twice with 1 NH C1, dried over sodium sulfate, and purified by flash chromatography to obtain 1. 7 3 2 g of product. L-phenylpropylamine amidino-4-nitro-N-pentyl-L-phenylpropylamine amidamine hydrochloride: N-[(l, budimethylethoxy) carbonyl ] Phenylpropylamine-4-nitro · N-pentyl-L-phenylpropylamine amine (0.40 g) was mixed with 8 ml L 4 MH HCl in dioxane. 1.5 After hours, the reaction mixture was concentrated and used directly in the next step without purification. N- (4-hydroxy-1,4-diketobutyl) -L-phenylpropylaminofluorenyl-4-nitro-N-pentyl Phenylpropylamine amine: L-phenylpropylamine amine 4-nitropentyl-L-phenylpropylamine amine hydrochloride was mixed with 0.22 m L of triethylamine. The solution was cooled in an ice bath, and 0.077 g of succinic anhydride was added. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated. The product was used directly in the next step without purification. N- (4-hydroxy-1,4-diketobutyl) phenylpropylamine-4-amino-N-pentyl · L-phenylpropylamine amine: 0.2 4 0 g N- (4-hydroxy-1,4-diketobutyl) phenylpropylaminofluorenyl-4-nitro_N-pentyl- -116- (113) (113) 200416214 L-phenylpropylaminephosphonium and 20 mL of 1 ·· 1 EtOH / THF and 0.200 g of 10% Pd / C were mixed and reduced to obtain 0.215 g of product. Amylaminomethane- 2- (4-sulfonamido-phenyl) -ethylaminomethane] -2-phenyl-ethylsuccinimide: according to the method of step A, 0.215 g The amine was treated with 0.191 g of a S03-pyridine complex. 0.096 g of product was obtained after purification. NMR (D20): 0.72 (3H, t, J = 7.1Hz), 0.94-1.22 (6H, m), 2.8 1-2.96 (10H, m), 4.26 (1Η, t, J = 7.7Hz), 4.37 (1 H, t, J = 7.7 H z), 6.99-7.06 (5H, m), 7.16-7.23 (4H, m). Example 6 8 N- {lL- [l-pentylaminomethylamidino-2- (4-sulfonylamino-phenyl) -ethylaminomethylamidino] phenyl-ethylpyridinecarboxylic acid Butyl ester: N-[(l, l-dimethylethoxy) carbonyl] phenylpropylaminefluorenyl-4-aminopentyl-L-phenylpropylaminesulfonamide: according to the method of step A, 0.2 8 0 g N-[(1J-dimethylethoxy) carbonyl] -L-phenylpropylaminefluorenyl-4-nitro-N-pentylphenylpropylaminesulfonamide with 10 mL 1 ·· 1 MeOH / THF and 0.165 g of Pd / C was mixed and placed under a hydrogen atmosphere. After packing up the reaction, the crude amine was used directly in the next step without purification. NUL- [Pentylaminomethylamido- 2- (4-sulfonamido-phenyl) -ethylaminomethylamido] -2-L-phenyl-ethyl} -aminocarboxylic acid tert-butyl Ester: According to the method of step A, 0.2 5 3 g of amine was treated with 0.4 70 g of sulfur trioxide-oxidine in 5 mL of pyridine. Packing the reaction and purification, 0.150 g of ammonium salt product was obtained. 1 Η NMR (D2〇): 7.26-7.20 (9H, m), 4.32 (lH, t, -117- (114) 200416214 J = 7.3 Η z), 4.16 (1H, t, J = 7.3 Hz), 2.96 -2.8 1) ,: 1.25 (9H, s), 1.22-1 · 09 (2Η, η), 0.98), 0.74 (3H, t, J = 7.2Hz). Examples 6 9-7 3 Example 6 9 (S) -2-Third-butoxycarbonylamino-sulfonic acid amine-phenyl ester: 6H, m 2H, m methyl propionate

Boc-L-Phe (4-N02) -NMe: Boc-L-Phe (4-N02) -OHH) was dissolved in 20 mL of methanol. (Trimethylmethyl; diazomethane (6.4 mL, 2.0 M hexane solution) was added dropwise at 0 ° C until the solution was maintained. AcOH was then added to the mixture to stop the reaction until the solution. Then the reaction mixture was concentrated, 0.423 g of the desired product is obtained. (S) -2-Third-butoxycarbonylamino-3- (4-sulfonamido-phenyl) -ester: According to the method of step A, make 0.42 3 g of a nitro compound Reduction reaction with palladium on carbon yields the desired product (tic). This benzene is treated with 0.62 3 g of sulfur trioxide-Dttidine complex. Packing the reaction yields 0.134 g of ammonium salt product. 1H (D20) : 7. 1 5-7.09 (q J = 1 0.1. 1 Η z), 4.34 (t, lH, J = 6.0 Hz), 3.68 (s, 3.08-2.83 (m, 2H), 1.32 (s, 9H) (0.400 alkyl group) yellow, colorless methyl propionate 100 mg amine crude and purified, 4H, 3H),

-118- (115) 200416214 Example 7 0 [2- (4-sulfonylamino-phenyl) _ethyl] -aminocarboxylic acid third butyl ester:

J

I 〇 = s = o

I

OH

[2- (4-nitro-phenyl) _ethyl] _aminocarboxylic acid third butyl ester: nitrophenylethylamine hydrochloride (0.5 00 g) dissolved in 5 mL ethanol and 0.72 3 mL triethylamine And BOC-ON (0.669 g). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated and partitioned between DCM (25 mL) and 0.1 N HC1. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to obtain a crude product, which was then purified by chromatography to obtain 0.352 g of the desired product. [2 4 -Aminosulfonic acid-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester

According to the method of step A, 0.352 g of a nitro compound and 1000 nl of palladium on carbon were subjected to a reduction reaction to obtain a desired product (11c). This crude aniline product was treated with 0.63 g of sulfur trioxide · rotidine complex. The reaction was cleaned up and purified to obtain 0.160 g of ammonium salt product. 1H (D20): 7.0 8-6.99 (q, 4H, J = 7.2 Η z), 3.16 (t, 2Η, J = 7.4 Η ζ), 2.59 (t, 3 ', J' = 7.4 ζ), 1.23 (s, 9Η). Example 7 1 [4- (2-Diphenylethylamido-ethyl) -phenyl] -aminosulfonic acid:

-119- (116) 200416214 1N- [2- (4-nitro-phenyl) -ethyl] -2,2-diphenyl-acetamidamine: 0.300 g 4-methylene chloride in 10 mL NO 2 phenethylamine hydrochloride was mixed with 0.49 ml L of triethylamine. To this solution was added 0.404 g of diphenylacetamidine chloride. After 18 hours, the reaction mixture was washed twice with 1 n H C1 and once with brine. The crude product was purified by flash chromatography to obtain 0.285 g of product.

1N- [2- (4-amino-phenyl) -ethyl] -2,2-diphenyl-acetamidamine: According to the method of Step A, make 0.2 8 5 g 1N- [2- (4- Nitro-phenyl) -ethyl 2,2-diphenyl-acetamidamine was treated with 0.200 g of 10% Pd / C in 6 mL of ethanol and 20 mL of THF and reduced to obtain the desired product. [4- (2-Diphenylethylamino-ethyl) -phenyl] -aminosulfonic acid: In a dry flask, add 1 N-[2-(4-amino-phenyl) -ethyl Benzyl] -2,2-diphenyl-ethyl-S-Synthrolol in chloroform. The solution was treated with 0.0 6 4 m L of pyridine and 0.1 2 m L · C1S03TMS. After 5 hours, the reaction mixture was concentrated and treated with 20 mL of water and 2 mL of ammonium hydroxide. The aqueous layer was washed twice with ether and then concentrated. After purification, 0.83 g of the product was obtained. 1 Η N M R (D 2 Ο): 2 · 6 2 (2 Η, t

, J = 6.6 Hz), 3.37 (2H, t, J = 6.6 Hz), 4.85 (1H, s), 6.95-7.01 (8H, m), 7.20-7.25 (6H, m). Example 7 2 (S)-[4- (3.Ethyl-2,2,2-trimethyl-5-one-imidazolidin-4-ylmethyl) -phenyl] -aminosulfonic acid: -120- (117) 200416214

(S) -2,2,3-trimethyl-5- (4-nitro-benzyl) -imidazolidine-4 -_: HL-P he (4-Ν Ο 2)-NM e (0.5 0 0 g) was dissolved in 2 ml of methanol and treated with 0.7 1 ml of acetone and 0.037 g of pTSA, and heated under reflux for 76 hours. The mixture was concentrated and purified by flash chromatography to give 0.339 g of product. (S) -3-Ethyl-2,2,3-trimethyl-5- (4-nitro-benzyl) -imidazolidin-4-one: According to the method of Example 2, let 0.3 3 9 g (S) -2,2,3-trimethyl-5- (4-nitro-benzyl) -imidazolidin-4-one was treated with 0.18 mL of triethylamine and 0.111 g of acetamidine chloride, thereby obtaining 0.3 44 g of product.

(S)-[4- (3-Ethylfluorenyl-1,2,2-trimethyl-5-one-imidazolidin-4-ylmethyl) -phenyl] -amino acid: according to step A The method 'reduced 0.3 4 4 g of a nitro compound and 0.0 50 g of palladium on carbon to obtain the desired product (tic). This crude aniline product was treated with 0.5 3 8 g of sulfur trioxide-D-pyridine complex. The reaction was purified and purified to obtain 0.049 g of ammonium salt product. 1H (D20): 6.97-6.76 (m, 4H), 4.50 (η, 1H), 3.09-3.03 (m

, 2H), 2.55 (s, 3H), 2.13 (s, 3H), 1.37 (s, 3H), 0.45 (s, 3H) ° Example 7 3 N-[(l, l-— • methylethoxy ) Mine-based] -L-Ceramine-N-methyl-L-4-aminosulfonic acid-phenylpropylamine amine: -121 (118) (118) 200416214 HN '

N-[(l, l-monomethylethoxy) mine] -L-Ceramine-N-methyl-L-4-nitro-phenylpropylamine hydrazone: According to the method of Example 60, 0.20 0 g of HL-Phe (4-N02) -NMe was treated with 0.2 09 g of diisopropylethylamine, 0.182 g of L-Boc-Pro, 0.130 g of H0Bt.H20, and 0.162 g of EDCI. This gave 0.2 2 0 g of product. 1 ^ [(1,1-dimethylethoxy) carbonyl] 4-proline fluorenyl-1 methyl-1 ^ 4-sulfonylamino-phenylpropylamine hydrazone: According to the method of step A, let 0.220 g of a nitro compound and 0.05 0 g of palladium on carbon were subjected to a reduction reaction to obtain a desired product (11 c). This crude aniline product was treated with 0.2 50 g of a sulfur trioxide-π fixed complex. The reaction was purified and purified to obtain 0.066 g of an ammonium salt product. 1Η (D2〇): 7.12-6.92 (m, 4H), 4.33 (t, 1H, J = 8.9), 4.06-4.01 (m, 1H), 3.24 (t, 2H, J = 7.5Hz), 2.87- 2.79 (m, 2H), 2.50 (s, 3H), 2.02 (m, 1H) ^ 1.68-1.50 (m, 3H), 1.15 (s, 9H).

Example A An oral tablet composition of the present invention was prepared, which contained the following ingredients: -122- (119) (119) 200416214 Component Content Example 1 Compound 15 0 mg lactose 12 0 mg corn source powder 70 mg talc 4 mg hard Magnesium stearate 1 mg Example B Preparation of an oral capsule containing 200 mg of the active compound of the present invention which contains the following ingredients = component content (% w / w) Example 2 Compound 1 5% hydrous lactose 43% microcrystalline cellulose 3 3% Cross-linked polyvinyl pyrrolidone 3.3% magnesium stearate 5.7% Other compounds of the present invention can achieve substantially similar results. Unless otherwise specified, it is important to understand that all quantifications, percentages, and ratios can be changed based on the word "about" and the quantities do not indicate significant digits. Unless specifically stated, (in the original description) "a", "an" and "the '' means" one or more '". -123- (120) (120) 200416214 All the cited documents are incorporated in the relevant content of this document for reference. The citation of all documents does not indicate that it is a prior art of the present invention. Although the particular system of the present invention has been exemplified, those skilled in the art will recognize that many other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, the scope of patent application also covers all the above-mentioned changes and improvements in η μ # μ. W% within the enclosure of the present invention

-124-

Claims (1)

200416214 (1) The scope of application for patents The following compounds are not included in formula I: HO-S-HN r4c / R4b 〇II (I) where: a A) R1 is, where: L1 is selected from covalent bonds, -〇 ... 'CO-, -0C02-, -so ·, _s〇2_, _Csn (r8), _c〇N (w) 〇 ~, C〇N (RV, .OCONdlV; its r8 is hydrogen or C, C-C5 courtyard; the block is not taken b) R "and R6b are selected from Hydrogen, · 〇r9, ⑻ C〇2R9, -C〇n (r9) 2, _nhcor9, _NHC〇2R9, = called 9,) ',-, and mixtures thereof, wherein each R9 is selected from hydrogen, Obtain unsubstituted Cl-C: 5 radicals, and substituted or unsubstituted aryl groups or their # groups; or two R9 may together form a substituted or unsubstituted containing ^^ 方 7 Carbocyclic or heterocyclic ring of 3 carbon atoms; 3 to c) m is a number selected from 0 to 5; d) R7 is absent or selected from hydrogen, Ke g · 3 I substituted or unsubstituted CV k group, Substituted or unsubstituted — 1 10 boxes, carbyl, substituted unsubstituted hydrocarbyl, substituted or unsubstituted n-alkyl, substituted or unsubstituted aryl, or alkylene aromatic ^^^^ / Λ ^ I substituted or unsubstituted heteroaryl or alkylene heteroaryl; or e ) R and one R9 can form together I substituted 孰 unsubstituted carbocyclic or heterocyclic ring containing -125- (2) 200416214 3 to 7 carbon atoms; B) R2 is-(CH2) rL2- [C ( R]] aRi] b 2, where: a) j is a number selected from 0 to 5; b) L2 is selected from a covalent bond, -0_,, N-, Co2-, -Co2 -, -SO-, -S02-, -CSn (r1〇, Bu, -C0N (R1 cON (R10) 〇-, -oconcr1.) ·; Wherein hydrazine or substituted C 1-C 5 College base; c) Rlla and Rllb are selected from the group consisting of hydrogen, or13 C02R13, -CON (r) 3) 2, -NHCOR13, \ TtT 'HC〇2Ru, ㈠R] 3, and mixtures thereof; each of R〗 3 ^ Not selected from hydrogen, terminal unsubstituted c] -C5 alkyl, and substituted or unselected: alkylaryl; or two R13 may together form a carbocyclic ring having 3 to 7 carbon atoms Or a heterocyclic ring; _ 'by d) g is a number selected from 0 to 5; e) R12 is absent or selected from hydrogen, substituted or unsubstituted IV 枰 C alkyl, substituted or unsubstituted Substituted hydrocarbyl group_ Substituted test: Hetero group of f, substituted or unsubstituted aryl group One comment: ^ substituted or unsubstituted heteroaryl group or alkylene group Aryl; or if) R12 and R13 may together form a substituted carbocyclic or heterocyclic ring having 3 to 7 carbon atoms; _ not c) R3 is-(CH2) nL ^ Ri6, where: a) η is a number selected from 0 to 5; b) L3 is selected from a covalent bond, _〇_, _s • CCK-, or non-N (r is substituted or substituted by C,-instead of the contained by ... 丨Only tear, -u _,-ύ ^, 〇C〇r, -S〇 ·, -called-, -CSNH-, -C〇Nh_ CO- -0C0NH-; -126- (3) 200416214 "H16 θ — What is selected from the group consisting of hydrogen, substituted or unsubstituted c Γ 弋 or Zhu Jing substituted c 丨 · ClQ hetero] c10 alkyl squaryl or phenylene aryl, substituted fluorene Take a substituted or unsubstituted heteroaryl or phenylene heteroaryl; the W group, R, R and R5 are selected from hydrogen or substituted units respectively; or) R and R4a, R41 R4b, R1 and R2, or Han] and R3 can — open _ / into t substituted or unsubstituted carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms. 2. If the compound in the scope of patent application No. 1 is represented by the following formula (11): -127- (4) (4) 200416214 c) g is 107. The compound according to item 6 of the patent application scope, wherein R3 is hydrogen. 8. The compound according to item 7 of the scope of patent application, wherein at least R 1 1 a or R 1 1 h is -CONH2. 9. The compound according to item 2 of the patent application, wherein R2 is hydrogen. 10. The compound according to item 9 of the patent application, wherein L1 is -S02- 〇1 1. The compound according to item 10 of the patent application, wherein L3 is selected from the group consisting of covalent bonds, -CO-, and -C02- . 1 2. A compound as claimed in item 10 of the scope of patent application, wherein R3 is hydrogen 0 1 3. A compound as claimed in item 10 of the scope of patent application, wherein a) m is a number selected from 1 and 2; and b) R7 Is a substituted or unsubstituted phenyl. 14. The compound as claimed in item 2 of the scope of patent application, wherein R3 is benzyl 〇5. The compound as described in item 14 of the scope of patent application, wherein 0 j is 0; b) L2 is selected from -C02- and- CON (R8)-. 16. The compound according to item 2 of the scope of patent application, wherein a) j is 0; b) L1 is -CO-; c) m is 1; d) ruler "or R6b is at least -NHC02R9; and -128- ( 5) (5) 200416214 e) L2 is -CON (R8)-. 1 7. If the compound in the scope of the patent application item 2, a) j is 0; b) L] is -CO-; c) m is 1; d) 1163 or R6b is at least -NHC02R9; and e) R7 is a group. 1 8. The compound according to item 1 of the scope of patent application, wherein the compound is selected from the following: (R)-[l-methylamine Formamyl-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester; (R)-[l-methylaminomethylamidino-2- (4-sulfo Acid amine-phenyl) -ethyl] -carbamic acid benzyl ester; (S)-[l-methylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl]- Benzyl aminoformate; (S)-[l-methylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl] -aminoformic acid third butyl ester; (11)- [Bupentylaminomethane- 2- (4-sulfonamido-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (R)-[l-benzylaminomethane-2 -(4-sulfonic acidamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (S) -Π-benzylaminomethyl 2- (4-sulfonylamino-phenyl) -ethyl; l · butylaminocarbamate; (R)-[l- (2-morpholin-4-ylethylaminoformamidine) ) -2- (4-sulfonylamino-phenylethyl] -aminocarboxylic acid third butyl ester; (S)-[l-pentylaminomethylamidino-2- (4-sulfonic acid amine group -Phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester; (S)-[4- (2-Hexamidineamino-2-methylaminomethylamidino-ethyl) -phenyl] -amine Sulfonic acid; (S)-{4- [2-methylaminomethylsulfanyl-2- (toluene-4-sulfonamido) -ethyl; I-phenyltriphenylsulfonic acid; (R) -{4- [2-methylaminomethylmethyl-2- (3-phenyl-propylamido) -ethyl] -phenyl} -aminosulfonic acid; (S)-{4- -129 -(6) (6) 200416214 [2-methylaminomethylmethyl-2- (3-phenyl-propylamino) -ethyl] -phenyltriphenylsulfonic acid; (S)-[l -(2-methoxy-ethylaminomethylamidino) -2- (4-sulfonylamino-phenyl) -ethyl: tert-butyl I-aminoformate; (S)-[l- (2-ethoxy-ethylaminomethylmethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (S)-[1- (2 -Ethylthio-ethylaminomethyl) -2- (4-sulfonylamino-phenyl) -ethyl; I-aminocarboxylic acid third butyl ester; (S)-[l- (4- benzene -Butyl-butylaminomethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (S) -3- [2-third butoxycarbonyl Amino-3- (4-sulfonylamino-phenyl) -propanamido] -propionic acid; (S)-{4- [2- (3-benzyl-ureido) -2-methyl Carbamoyl-ethyl] -phenyl-bromidesulfonic acid; (S)-(4- {2- [3- (2-methoxy-phenyl) -ureido] -2-methylamine Formamyl-ethyl} -phenyl) -aminosulfonic acid; (S)-[4- (2-benzenesulfonamido-2-methylcarbamate-ethyl) -phenyl] ~ amine Base acid; (S)-{4- [2- (4- (methoxy-benzenesulfonamido) -2-methylaminomethylamido-ethyl] -phenyl} -aminosulfonic acid; (S)-{4- [2-methylaminomethylamido- 2- (naphthalene-1-sulfonamido) -ethyl] -phenyl} -aminosulfonic acid; (S)-[l- (Benzyl-methyl • aminomethylamidino) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (S)-[l- (2-methyl Methyl-5-phenyl-2H-oxazol-3-ylaminomethylmethyl) -2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid tert-butyl ester; (S) -[Buphenylaminomethylmethyl-2- (4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; (S)-[l-Dibenzylaminomethylmethyl -2- (4-sulfonic acid amino-benzene ) -Ethyl; l · Thirty-butylaminoformate; (S) -4- [Bumethylaminoformyl-2- (4-sulfonylamino-phenyl) -ethylaminoformyl] -Piperidine-1-carboxylic acid tert-butyl ester; (S)-[4- (2-benzylideneamino-2-methylaminoformamido-ethyl) -phenyl] -aminosulfonic acid ; (S)-[l-dimethylaminomethylmethyl-2- (4-sulfonylamino-phenylethyl] -aminocarboxylic acid third butyl ester; (S)-(4- {2- Methylaminomethyl-130- (7) (7) 200416214 fluorenyl-2-[(romidin-3-carbonyl) -amino] -ethylphenylphenyl) -aminosulfonic acid; (S)-[ 4- (2-methylaminomethylamidino-2-phenylethylamidoamino-ethyl) -phenyl] -aminosulfonic acid; (S)-(4- {2-methylaminomethylamido- 2-[(naphthalene-carbonyl) -amino] -ethyl} -phenyl) -aminosulfonic acid; (S)-{4- [2- (cyclopentylcarbonyl-amino) -2-methyl Methylaminomethane-ethyl: l.phenylphenylaminosulfonic acid; (S)-(4- {2-benzylaminomethanemethyl- 2- [2- (4-propyl-phenylethyl Fluorenylamino] -ethyl} -phenyl) -aminosulfonic acid; (S)-(4- {2- [3- (3-ethylfluorenylaminosulfonyl-phenyl) -propanamide [] Methyl] -2-methylaminomethylamidino-ethyl} -phenyl) -aminosulfonic acid; (S)-{4- [2-benzylaminoamino-2- (1-aminomethyl) 2- (S) -phenyl-ethylaminomethylsulfanyl) -ethyl] -phenyl} -aminosulfonic acid; (S)-[l- [l-aminomethylsulfanyl-2- ( 4-hydroxy-phenyl) -ethylaminomethylmethyl] -2 (S)-(4-sulfonylamino-phenyl) -ethyl] -aminocarboxylic acid third butyl ester; [4- (2 -{(Third butoxycarbonyl) [(4-tolyl) sulfofluorenyl] amino} ethyl) phenyl] aminosulfonic acid; (4- {2- [benzyl- (toluene-4-sulfonic acid) Fluorenyl) -amino] -ethylphenylphenyl) -aminosulfonic acid; (4- {2-[(3-methyl-but-2-enyl)-(toluene-4-sulfonyl) -Amino] -ethylphenylphenyl) -aminosulfonic acid; (4- {2-[(3-methyl-butyl)-(toluene-4-sulfonyl) -amino] -ethyl } -Phenyl) -aminosulfonic acid; [[2- (4-sulfonic acidamino-phenyl) -ethyl]-(toluene-4-sulfonyl) -amino] -ethyl acetate; [ [2- (4-sulfonylamino-phenyl) -ethyl]-(toluene-4-sulfonyl) -amino; l · acetic acid; [4- (2-{[(4-tolyl) Sulfofluorenyl] [4- (sulfonylamino) benzylfluorenyl] amino} ethyl) phenyl] aminosulfonic acid; Fluorenyl) -amino] -ethylphenylphenyl) -aminosulfonic acid; [4- (2-{(third butoxycarbonyl) [(3-fluoro-4 -tolyl) sulfonyl) ] Amino} ethyl) phenyl] aminosulfonic acid; [4- (2-{(third butoxycarbonyl) [(3-fluorophenyl) sulfonyl] amino} ethyl) phenyl] Aminosulfonic acid; [4- (2-{(Third-butoxycarbonyl) [(2-fluorophenyl) sulfo (8) (8) 200416214 fluorenyl] amino} ethyl) phenyl] aminosulfonic acid Acid; {Heart [2- (toluene amine-amino) -ethyl] -phenyl-bromidesulfonic acid; [4- (2-Benzylamine-ethyl) -phenylbromidesulfonic acid ; [4_ (2-Methanesulfonylamino-ethyl) -phenyl-bromidesulfonic acid; [4_ (2-Methanesulfonylamino-ethyl) -phenyl] -aminosulfonic acid; {4 -[2_ (4_methoxy_benzenesulfonamido) _ethyl] -phenylbutanyl acid; (S)-[4- (2-dicarylamino-2-methylamine) Formamyl-ethyl) -phenyl] -aminosulfonic acid; (S)-{4- [2- (ethylamidino-benzyl-amino) -2-methylaminoformamyl-ethyl ] -Phenylphenylaminosulfonic acid; (S) -2- (benzyl-third butoxycarbonyl-amino) -3- (4-sulfonic acid amino-phenyl) monopropionate; ( S) -benzyl- [1-methylaminomethylmethyl-2-(4-sulfonylamino-phenyl) -ethyl] -carbamic acid methyl ester; (S) -benzyl- [trimethylamine Formamyl-2- (4-sulfoamino-phenyl) -ethyl; 1-aminocarboxylic acid Tributyl ester;. [(U-dimethylethoxy) carbonyl] Leucylamido-methyl-L_4 · sulfonic acid amine-phenylpropylamine amine; N-[(1,1-dimethyl Ethoxy) kistilbyl L-methionamine-N-methyl-L-4-sulfonylamino-phenylpropylamine amine; N-[(l, dimethyl ethoxy) carbonyl ] -L-Phenylpropylamine-N-methyl-L-4-sulfonylamino-phenylpropylamine sulfonamide; [(15 dimethylethoxy) carbonyl; IL · Tyramine N-[(l, dimethyl ethoxy) carbonyl] _L_valamine group-N-methyl-L-4-sulfonic acid amine group -Phenylpropylamine; N-KIJ-dimethylethoxy) carbonyl; IL-glutamine-N-methyl-L-4-sulfonylamino-phenylpropylamine; N- [ (l, dimethyl ethoxy) carbonyl] -L-aspartyl-N-methyl-L-4-sulfonylamino-phenylpropylamine; N- {1- [ Methylaminomethane- 2- (4-sulfonylamino-phenyl) -ethylaminomethane] -2-phenyl-ethyl} _succinimidine; pentylaminomethane-2 -(4-sulfonylamino-phenyl) -ethylaminomethyl] -2-L-phenyl-ethylpyridinecarboxylic acid -132- (9) (9) 200416214 tributyl ester ; (S) -2-Third-butoxycarbonylamino-3- (4-sulfonylamino-phenyl) · methyl propionate; [2- (4-sulfonylamino-phenyl) -ethyl Tert-butyl aminocarbamate; [4- (diphenylethylamido-ethyl) -phenyl] -aminosulfonic acid; (S)-[4- (3-ethylamido-1, 2,2-trimethyl-5-one-imidazolidin-4-ylmethyl) -phenyl] -aminosulfonic acid; and N-[(l, l-dimethylethoxy) carbonyl; | -L-proline amidino-N-methyl-L-4-sulfonylamino-phenylpropylamine amidinium. 19. A pharmaceutical composition for treating a protein tyrosine phosphatase (PTPase) -related disease, comprising the compound according to item 1 of the scope of patent application. 20. The pharmaceutical composition according to item 19 of the application, wherein the disease is selected from the group consisting of arteriosclerotic cardiovascular disease including terminal vascular disease, coronary artery disease and cerebrovascular disease; heart failure; hypertension; diabetes (type 1 or Type 2); skeletal muscle atrophy; osteoporosis; obesity; gastrointestinal diseases include inflammatory bowel disease and ulcers; wound healing / wrinkle repair / prevention; hair loss: and cancer. 2 1. A pharmaceutical composition comprising: a) a safe and effective dose of a compound as described in item 1 of the patent application scope; and b) a pharmaceutically acceptable carrier. -133- 200416214 柒, (a) (b), the designated representative figure in this case is: None, the component representative symbol of this representative figure is simply explained: None Top J. If the formula is: When there is a chemical formula, please disclose the chemistry that best shows the characteristics of the invention -4-200416214 (here, the barcode is pasted by the Bureau at the time of receipt Invention Patent Specification 1 (1 word and bold type in this application > Please lightly noodle pasta, ※ obey 841784 ※ Application number: 92123654 ※ Application date: August 27, 1992 ※ Shen classification: 1. Name of the invention: (middle) phenethylaminoaminosulfonic acid _ (outside) Phenethvlamino sulfamic acids_ Dai, applicant: ( A total of 1 people) 1. Name: (Chinese) Breguet Company _ (English) THE PROCTER & GAMBLE COMPANY_ Representative · (Chinese) 1 · Linda Loreer _ (English) 1.RQHRER. LINDA D, _ Address: (Chinese) One Plaza, Cincinnati, Ohio, United States _ (English) One Procter & Gamble Plaza, Cincinnati, Ohio 45202, USA · Nationality: (Chinese and English) US plaque ^ _U.SA · _ References, inventors: ( A total of 7 people). Name = Address: (Chinese) Jeffrey Grey (English) GRAY. JEFFREY LYLE (Chinese) 11313 Envart Road, Loveland, Ohio, USA 11313 Envart Road, Loveland, OH 45140, U.S_A 2 · Name: (Middle) Matthew Maier (English) MAIER. MATTHEW BRIAN Address: (Middle) 3160 Linwood Ave, 3160 Linwood Road, Cincinnati, Ohio, United States 3160 Linwood Ave . / Apt 308, Cincinnati, 3 · Name: (Middle) Sincroppus i C English) KLOPFEN STEIN, SEAN REES Address: (Central), Ohio, United States' Film 4. Name: (Central) David Jones (English) JONES, DAVID ROBERT 200416214 841784 (English) 55262 Wolfpen Pleasant Hill Rd., Milford, OH 45150. US L_ 5 · Name: (Chinese) Kevin Peters_ (English) PETERS, KEVIN GENE_ Address: (Chinese) 10202 Sleepy Ridge Road, Loveland, Ohio, USA _ (English) 10202 Sleepy Ridge Drive, Loveland, OH 45140, US A, 6. Last name 7. Last name place name: (Middle) Matthew Parker Cross (English) POKROSS, MATTHEW EUGENE Address: (Middle) Loving Dartmouth Road, Ohio, USA六六 九号 _ (English) 9669 Dartmouth Way, Loveland, OH 45140, US A. Name: (Chinese) Yasen Yvdqi Wufu Address: (English) EVDOKIMOV, ARIEM GENNADY (English) 22 Highridge Drive, Loveland OH 45140, US A Explained matters: ◎ Patent applications have been applied to the following countries (regions) before the application of this case □ Claiming international priority: 2. United States: 2003/02/20: 60 / 448,749 Μ has claimed priority 3. United States: 2003/03/18: 60 / 455,977 Μ has priority [Format please follow: receiving country (region); application date; note of application number sequence] 1 · United States_: 2002/08/29: 60 / 406,829 Μ No claim of priority -2- 200416214 841784 (English) 55262 Wolfpen Pleasant Hill Rd., Milford, OH 45150. US L_ 5 · Name: (Middle) Kevin Peters_ (English) PETERS, KEVIN GENE_ Address: (Middle) Loferland, Ohio 〇２０２_ (English) 10202 Sleepy Ridge Drive, Loveland, OH 45140, US A, 6. Last name and place 7. Last name and place name: (Chinese) Matthew Parker Cross (English) POKROSS, MATTHEW EUGENE Address: (Chinese) 9669 Dartmouth Way, Loveland, OH 45140, US A · Name: (Middle) Yassen Ivditch Wufu Address: (English) EVDOKIMOV, ARIEM GENNADY (English) 22 Highridge Drive, Loveland. OH 45140, US A. Declaration matters: ◎ Before the application of this case, patents have been applied to the following countries (regions) □ Claiming international priority: 2. United States: 2003/02 / 20: 60 / 448,749 Μ has priority claim 3. United States: 2003/03/18 : 60 / 455,977 Μ has priority claim [format please follow: receiving country (region); application date; application note number sequence notes] 1 · United States_: 2002/08/29: 60 / 406,829 Μ does not claim priority- 2-