TWI228499B - Compound which inhibits DV-IP mediated processes and pharmaceutical composition thereof - Google Patents

Abstract

Compounds selected from those of general formula, and A is selected from specified, aminoacyl compounds are inhibitors of DP-IV mediated processes.

Description

1228499 A7 B7 V_ Description of invention printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1) Background DP-IV (EC3.4.45.5) is a serine protease bound to a membrane. In the kidney, it is identified for its ability to cut out two wins from the N-terminal split of some wins (Hopsu-Havu, VK and Glenner, GG Histochemie, 1966, I, 197). The dioxin must be X-Pro or X-Ala, where X = any amino acid. X-proline is more efficiently cleaved than X-AU. DV-IV is widely distributed in mammalian tissues, and is abundant in epithelial cells and placenta of the kidney crest, small intestine (Yaron, A and Naider, F., Critucal Reviews in Biochem. Mol. Biol. 1993, 21 (1 ), 31). In human immune systems, this enzyme is almost exclusively expressed by activated CD4 + T-lymphocytes, and this enzyme is also shown to be identical to the cell-surface antigen CD26. The true role of DP-I V in human physiology is not fully understood, but recent research has shown that this enzyme obviously plays an important role in human physiology and pathophysiology, such as U> Immune response: DP-IV performance It is increased by stimulation of mitogens or antigens (Mattern, T. et al., Scand. J. Immuno. 1991, 3_1, 737). It reports that DP-IV inhibitors and antibodies to DP-IV can inhibit the proliferation of T-cells stimulated by mitogens and antigens in a dose-dependent manner (Sch E. etal., Biol. Chem. Hoppe-Sey -ler, 1991, 212_, 305 and references therein). Various other functions of T-lymphocytes, such as cytokinin production, IL-2-regulated cell proliferation, and B-cell helper cell activity have been shown. This paper is sized to the Chinese national standard (CNS > A4 size (210 X 297 mm) (Please read the cautions on the back of this page first page)-Packing · Silk 1228499 A7 B7 V. Description of the invention (2) Shows a dependence on DP-IV activity (Sch. Etal_, J_ Immunol. 1989. 2i, 127). Recently, DP ~ IV inhibition is based on boronamine, which has been reported (Flenkte, GR etal. Proc. Natl. Acad. Sci. USA, 1991, this, 1556). It is effective in inhibiting antigen-induced lymphoblastic proliferation and IL-2 production by CD4 + T-helper cells in mice. This boric acid inhibition has been shown to induce immune challenge in rats. It has an inhibitory effect on antibody production (Kubota, Tetal., Clin. Exp. Immunol., 1992, 192). Other recent reports provide evidence for DP-IV 渉 and immune responses (eg Tanaka, T. eta 1, Proc. Natl. Acad. Sci. NY, 1993, 9ϋ., 4586; Hegen, M. etal, Cell Immun 1993, 146,249; Subramanyan M. etal., J. Immunol., 1993, 150, 2544). The importance of DP-IV was attributed to the investigator's cell surface by its association with the transmembrane phosphatase CD45 ( Torimoto, Y, etal, J. Immunol. 1991, UI_, 2514). The CD45-DP-1 V binding may be disrupted by DP-IV inhibitory or inactive site ligands. CD45 is known as a T-cell message Traditional essential ingredients. (B) Recently, a report published by the Pasteur Research Center in Paris (and later AG Hovanessian at the 8th Gardes Meeting, Paris, 25-27th October, 1993) DP-I V is necessary for the penetration and infectivity of HI V-1 and HIV-1 viruses in CD4 + cells. The French research group claims that DP-IV can be compatible with the virus on the paper scale to apply Chinese national standards ( CNS) A4 specification (210X297 mm) (please read the notes on the back \ ^^ this page first), 1: Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, A7 B7 1228499 5. Invention Description (3) (Please read first Note on the back page) The V3 loop of gp 120 glycoprotein interacts and may cleave the V3 loop. They also report that inhibitors or antibodies to DP-1 V can successfully prevent the virus from entering cells. It was first known that cells infected with HI V-1 had a selective decrease in CD26 expression in T-cells (Valle-Blazquez, M. etal., J. Immunol. 1992, 149. 3073) and HIV- 1 Tak protein binds to DP-IV (Subramanuam, M. eta 1. J. Immuno 1. 1993.150, 2544). (c) DP-IV of the lung endothelium has recently been shown to be a pair of lung metastatic rats attached to breast or prostate cancer cells (Johnson, R.C. etal., J. Cell. Biol. 1993, 121, 1423). DP-IV is known to bind to fibronectin, and some metastatic tumor cells are known to have a large amount of fibronectin on their surface. (d) DP-IV has been shown to bind to the enzyme adenosine deaminase (ADA) on the surface of T-cells (Kaneoka, J. etal. Science, 1993, 2L6 L. 466). ADA deficiency can cause severe combined immunodeficiency (SC1D) in the body. This ADDA-CD26 interaction provides clues to the pathophysiology of SCID. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (e) High levels of DP-IV are found in human fibroblasts obtained from patients with psoriasis, rheumatoid arthritis (RA), and flat mange (Raynaud, F. etal. J. Cell. Physiol., 1992, 151, 378). (f) High DP-IV activity was found in tissue homogenates obtained from patients with benign prostatic hypertrophy and in patients with prostatosoeins. Prostate-derived organelles promote the sperm's forward lotus motility. The paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 1228499 Δ7 Α7 Β7 V. Description of the Invention (4) Essentials (Vanhoof, G. etal ·, Eur. J. Clin · Chem. Clin. Biochera. 1992,10., 333) (Please read the notes on the back ^^^ this page) (g) DP-IV has shown The N-terminal penultimate peptide is proline or alanine (such as substance P, growth hormone stimulating factor, and glucagon / vasoactive intestinal peptide). The circulating peptide will break down and make it lose 1993, 214 , 819). (h) The increased amount of DP-IV can be observed in the gums of patients with periodontitis (Cox, SWetal ·, ARch · Oral · Biol, 1992, 11, 167) 〇 (i) There are also many reports It is the amount of DP-I V increased (or decreased) under various pathological conditions. Based on the foregoing, an effective inhibitor of DP-IV can be used as a medicament for treating a human disease. The inhibitors can be used as: U) immunosuppressive agents, such as in an organ transplant; cytokinin release inhibitors, such as in various autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, RA. Printed by the Consumer Cooperative of the Bureau of Intellectual Property, Bureau of Economy, Ministry of Economic Affairs (b) An agent used to prevent HI V from entering human T-cells and thus used to prevent or treat AIDS, (c) Used to prevent metastasis of cancer cells, especially breast cancer tumors With prostate tumor metastasis to the lung. (d) A medicine for treating skin diseases, psoriasis and flattening. (e) Inhibition of sperm motility can therefore be used as a puppet male contraceptive. (f) A beneficial agent in benign prostatic hypertrophy. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1228499 A7 B7 V. Description of invention (5)

Inhibition of DP-IV advises that the enzyme activity of DP ~ IV reported above is only the above-mentioned boric acid with a competitive inhibitor (T-30 at pH 7 for 30-90 minutes). Bachovchin et al, W091 / 16339, October 1991 ) It has a value of 1 < 1 for DP-IV for DP-IV, and simple pyrrolidides or thiazolides (Neubert etal DD 296075 A5, November 1991) It has a medium potency (Kθ0. 1 μM). The amine-aminoproline aldehyde claimed in the German patent cannot be synthesized because the N-terminal amine can be easily intramolecularly condensed with the aldehyde functional group We now disclose a highly potent DP-IV competitive inhibitor (with a K1 value in the range of 10〃 to 10〃 °), which is chemically stable (ti > 24 hours). A wide range of compounds (groups I, I [, and I). 组 Group I This is a molecular system designed to tightly bind to the active site of DP-1 V and inhibit its proteolytic activity, but it does not interfere Any ligand that binds to the surface of DP-IV (that is, not its active site). This group I Can be used as immunosuppressants; anti-HIV infection agents; agents that inhibit the release of some cytokinins (such as IL-2, IL-6, 7-1 heart) from activated 1'-cells. Boric acid and pymlidides also fall into this category. 筮 I [Neucis was developed from a group I compound; but it has a long chain extension, and extends to the A defined in the general structure On the side chain of amino acid. The paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ---------- install-I > (Please read the precautions on the back first (This page) --- I Order-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1228499 A7 B7__ V. Description of the invention (6) The compound obtained is tightly bound to the active site of DP-IV, but the long chain extension system It is highlighted by the active site of this enzyme and prevents it from binding to other ligands that may bind to the surface of DP-IV. This group contains novel dimers in which DP-IV has two active site-related inhibitors , Is linked by the side chain M-long chain of the amino acid defined as A in the general structure. The dimer may be Inhibiting two DP-IV molecules at the same time can also prevent the attached ligands from binding to the surface of DP-IV. These dimers have the same purpose as the group I compounds, but they are more effective. The present invention provides DP-IV Inhibitors of the regulation process, the inhibitor is of the general formula-A-Β AB (Groups I and ϋ) or (Group M)

^ 6—A-B n = 1 or 2; m = 0, 1 or 2; X = CHa, 0, S, SO, SOa, NH or NR! Where lower alkyl ((^ to ");

A is bonded to Y -Y = -N, -CH or = C (where the -C0 group of A is M_CH = or -CF = when substituted); R = H, CN, CHO, B (0H) 2, C, C -117 or (: 114110; this paper size applies to Chinese National Standard (CNS) A4 size (210X297mm) (please read the precautions on the back page first))

(CH

Where B is -Y

CH * IR Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 9 1228499 A7 B7 V. Description of the invention (7) R7 = H, F, lower alkyl ((^ to ^), CN, NOa, ORg, ⑶ ^ "or COR9; Re = Ph, OH, OR3, OCOR3, or OBn; R3 = lower alkyl ((^ to (: 6); and ω or either of these two epsilons) may not exist. Α structure is in part B The properties of the compound vary with the properties of the group to which the obtained compound belongs. Group I compounds (a) R ^ Ji A is an alpha amine group with a cycloaliphatic side chain (such as C4 to CltJ, mono- or bicyclic) Α-amino-fluorenyl group derived from an acid, and its ring may contain one or more heteroatoms, such as L-cyclohexylglycine, L-cyclopentylglycine, L-decahydroglycine Acid, L-piperidinylglycine; or A is a / 9 amine-amino group based on the following formula (please read the precautions on the back page first) Printed (CH "| where p = 1-6 and the ring may also contain one or more: 夂 replaces the different atom of the cl unit. The above 〇 (and Θ amino-fluorenyl group may contain Saturation key, such as the paper ruler Applicable Chinese National Standard (CNS) Α4 Specification (2ΐ〇χ297 mm) 10 1228499 A7 B7 V. invention is described in (8)

H2N CO- and may also contain one or more heteroatoms. (h) R = CN; C ^: -R7 ^ CH = H-Rn A as defined in U) above, but it may also be an L-α-amino acid having a lipophilic side chain, such as lie , Derived from. (c) C = CHQgSB (OH) g A is a / 3-amino-fluorenyl group as defined by U) above. The obtained A-B compound is stable, and is different from the cx-amine group in the same form which is susceptible to intramolecular cyclization. In compound (c), B (OH) a may exist in the form of M-borate, such as ---------- packing-* Good (please read the precautions on the back page first)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This is free boric acid which is unstable in water.筮 I 如 化 会 物 where R = H, CN, (: three 0117 or 0 ^ 8,4 is a 10 (amino acid derivative, a side chain with a derivation to produce a termination at each base 1) The paper size of this paper applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1228499 A7 B7 V. Description of the invention (9). A can have the following three structures:

(i) H2N

(0-D CO

h2n or (CHya-sOrD1 CO Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where a = l-5; D = G- (CH2) b- (R4) q-R3; G = 0, NH or NMe; b = 0-12; q = 0-5 M = D and G off 0 R4 = Z-NH_ (CHa) c or -NH-Z- (CHa) c- where 01-12 and Z = CO, CHa or S02; and R3 = CoaH or an ester (eg any lower alkyl, fluoroalkyl or cycloalkyl (Ci to Ce), or an aromatic or heteroaromatic (5 or 6-membered ring, mono- or bicyclic) CONHa; CONHNHa; CONReRe; CONHNRBRs; PO3H; (or its esters, such as those defined in CoaHT); So3H; SOaNHa; S02NReRB; ORe; aryl or heteroaryl (5 or 6-membered ring , Mono or bicyclic) [including substituted aryl groups or heteroaryl groups having substituents, the substituents are preferably selected from F, Cl, Br, OH, 0Re, Noa, S03H, S〇2NH2, SOaNRBR6 , NH2, NRaR6, Co2Rb, CF3, CN, CONHa, CONReRe, NHCOaRe, CH (: NRe) NReR6, NH-CH (: NRe) NReRG and Re]; NH2; NReRs; NHC〇aRe; NHSOaReRG; NHCORe; NH-S〇2Re; NH-CH (: NRe) NReRe; NH-CONH; sugar (which can be joined by an ether or a glycoside bond); CO-amino sugar (which Can be connected via -NHa), such as glucosamine or (please read the precautions on the back page) • Packing. 17 Silk paper size applies to China National Standard (CNS) A4 (210X297 mm) -12 1228499 A7 B7 Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau. 5. Description of the invention (10) Galactosamine; NHC0-amino sugar or NH-CS-amino sugar. In the above definition of R3, the word "sugar" means any Carbohydrates or oligosaccharides, and Rs and 1 ^ are each selected from H, alkyl, fluoroalkyl, and cycloalkyl (up to 8 atoms), aryl, heteroaryl, and alkylheteroaryl (up to 11 atoms) ) Or% and 1? 6 together including a key and ("to"). Ν Η2 \ /

E 11 R N Λ or

-E where R ^ H, Me; the ring may also contain multiple heteroatoms; E = J-(CH a) b-(R 4) q_ R 3; J = C 0, CH a or S ϋ ϋ; and a, b, q, R3, and IU as defined in (i), N Η2 (Please read the precautions on the back first ^^^ this page)

, 1T m > 2 L · R ο / \ Ν > οPost C — or

OL where Ra = H, Me; the ring may also contain one or more heteroatoms; (CH2) e-NR1- (CHa) b- (R4) q-R3; 1 ^ 〇 or 1; (1 = 〇- 4; 6 = 2-4; and &, 1), < |, 113, and 1? 4 as defined in (i). This paper size applies to China National Standard (CNS) A4 (210X297 mm) -13-13 lines ·

1228499 A7 B7 V. Description of the invention (11) Group M Compounds in group m are defined by the following general formula:

/ —A-B — A-B where a > = CHa, 0, NH, CO, S, Soa, Phe or NM, and each e = CH2, 0, NH, CO, S, Soa, Phe or NM. This compound is a symmetric dimer, which may also have any B structure as previously defined. A can be selected from the group I structure [(i), (u), or (m)], but in this case, the terminal group R3 on each A residue is deleted, and M is shared by the symmetry The base [ε-ω-ε] is substituted, the symmetric group is connected to the two halves of the dimer; ω may be non-existent, in this case ^ the two e are bound together M constitutes a connection to the two Bonding of the A-B part; or the two e may not exist. In this case, ω alone joins the two A-B part. The structure ε-ω -e must of course be chemically implementable, such as NH-C 0-NH, C-NH-CO, S0a-NMe-S0a; those who are not applicable to the structural system are obvious to those familiar with this technology, such as -NH-NH-NH. A specific possible embodiment is shown in Table 7. Among the compounds of groups I, I and m, some -CH2- groups present in the long chain may be substituted with known bioisosteres plus M, such as -0-substituted without The inhibitory or binding activity of DP-IV by the influence group. At the same time, if a group such as -C0NHCH2CHaNHC0 occurs, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm), a 14----------- install-* 4 * (Please read the caution page on the back first) Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1228499 A7 B7 i. Description of the invention (12) For example, if the following formula is used, add M instead of -CON N-CO- Furthermore, for compounds in groups I, I, and II, any of the amidine linkages connecting A and B or any of the amido linkages on the A side chain (on the 1 [and Π [groups) may have been Known biosynthetic groups of amidine plus M substitution, for example, _c〇_N / is replaced by the following 5; ㈣-ch2-n '= C. -CS-N \,, see Table 8 for this substitution Of an embodiment. (Please read the caution page on the back first)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1T. All the compounds were tested in vitro against pure human DP-IV (purchased from M & E. Copenhagen, Demark) plus M test. Inhibition of DP-IV was measured by using the fluorescent substance Ala-PrO-AFC (Km 0 · 8 µM), and M was determined by adding M to three different concentrations of each inhibitor. A typical analysis (overall volume 0; 4 ml) contains Hepes sodium 83.3 mM, EDTA 1.67 mM, BSA 1.5 mg / ml pH 7.8, DP-IV 2 WU / ml, inhibitor (pH 4.0 in 10 mM acetic acid). The reaction was started by adding a matrix. For 7.5 minutes, each time was taken for 30 seconds. The excited state was at 395 nm and the emitted state was at 450ηπ ». Ki value is based on Chinese paper standard (CNS) A4 (210X297mm). 15-A7 B7 1228499 V. Description of the invention (13) Use D i X ο η for drawing and M test. The compounds of the 152 example synthesized by the chemical compound are shown in Tables 1 to 8, followed by the preparation procedures and detailed experimental contents of different structural forms. The properties of all final products were determined by M FAB mass spectrometry analysis and reverse phase HPLC; all intermediate products were determined by M 1 H NMR. Table 9 shows the Ki values against DP-IV as determined by inhibitors of different structural forms. ---------- install-* «r (Please read the precautions on the back first \ ^^ this page)

、 1T Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -16-1228499 B7 V. Description of the invention (14)

Table 1 Example of group I (a) x / N_Λ AR Number printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs AXR π formula calculated molecular fi F / \ B mass spectrometry analysis [Μ + ΙΙΓ 1 〇ch2 H 1 196.2 197.2 2 H ^ NI 0 I ch2 H 1 012Η22 ^ 2〇210.2 211.2 3 λ Ο 0 ch2 H 1 ^ 10 ^ 20 ^ 2 ^ 184.2 185.2 4 HaN g ch2 H 1 〇 2Η2〇Ν2〇208.2 209.2 5 cisζν NH, O ch2 H 1 C ^ H2〇N20 196.1 197.2 ---------- Meal-* Plus (Please read the note on the back page first) Threading This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 1228499 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

1228499 A7 B7 V. Description of the invention (16) Table 2 笫 I (b) Example of m

A R

Number A

X n R1 R Formula FAB Mass Molecular Weight Analysis [Μ + Η] 11 H-ΙΙθ CH2 1 H CN CnH19N30 209.3 210.2 12 H-Lys (Z) CH2 1 H CN 358.2 359.2 13 H-Pro 14 HN- CH2 1 H CN C1oH15N30 193.1 194.1 (Please read the precautions on the back before-this page).

O, S

CH 2 H CN C9H13N3OS 211.1 212.2

, 1T ^ --v CH2 1 H CN C9H13N3OS 211.1

O 212.2 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 17

CH2 1 H CN C13H21N30 235.2 236.3 CH2 1 H CN C12H19N30 221.2 222.2 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -19 * 1228499 A7 B7 V. Description of invention (17) Number

X n R1 R formula calculation molecular FABm spectrum analysis [M + H] 18 A Η, Μ

CHn H CN Ct1H19N30 209.2 210.2 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 19 H-lle s 1 H CN 227.1 228.1 20 H-lle s 1 CN H ^ 1〇 ^ 17 ^ 3〇S 227.1 228.1 21 ^ I 0 s 1 H CN c12h19n3os 253.1 254.1 22 H-Lys (Z) / ~ V s 1 H CN Gi8H24N403S 376.2 377.2 23 Η ^ Ν Ϊ 0 s 1 H CN G11H17N30S 239.1 240.2 24 H-lle 0 1 H CN ^ 10 ^ 17 ^ 3 ^ 2 211.1 212.2 25 H-lle ch2 2 H CN C12H21N3O 223.2 224.2 26 H-lle s 2 H CN G " H, 9N3OS 241.1 242.1 27 H-lle so2 1 H CN 259.1 260.1 28 H-lle S, " cT 1 H CN G1〇H, 7N302S 243.1 244.1 29 H-lle s ~ cf 1 H CN Ci〇H17N302S 243.1 244.2 ---------- ^-1 0 (Please read the notes on the back first ^^^ (This page)

1T line-This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) 20 1228499 A7 B7 V. Description of the invention (is)

Number A X n R1 R Calculate FAB mass spectrum formula. Molecular M analysis [Η + Η] 30

ΝΗ. Ah CHo 1 H CN C12H19N3〇 221.2 222.2

31 CH, NH, O H CN C; 2H1gN30 221.2 222.2 ---------- ^-Wide * (Please read the precautions on the back first ^^^ This page) 32

O CH2 1 H CN G11H17N3O 207.2 208.2 nh2 o 33

NH, CH2 1 H CN 207.2 208.2 34

Pv NH, 〇 CH2 1 H CN C12H17N30 219.1 220.1 Line Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Y 35 Ah, V " CH2 1 H CN C12H17N30 219.1 NH, 220.1 This paper size applies to Chinese National Standard (CNS) A4 specification (2IOX297 mm) 21-1228499 A7 B7 V. Description of invention (! 9) Number

A

X n R1 R formula calculation FABM spectrum molecular fi analysis [H + H]

Qy

36 I I ^. CH NH, O 2 H CN C12H19N30 221.2 222.2 〇Ύ

37 | 丨 / CH2 1 H CN C42H17N30 219.1 220.1 NK O ---------- install-Guang Qin (Please read the precautions on the back page first)

1, 1T Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 22 1228499 A7 B7 V. Description of the invention (2) Table 3 Section I (c) Group of puppets

A R number A X R η

Calculated FAB mass spectrometry. Molecular plutonium analysis [M + HP 38

NH,

Y CH2 CHO 1 224.2 225.2 • ft 39 〇 CH2 CHO 1 C " H18N2〇2 210.2 211.2 I-- (Please read the precautions on the back first \ ^^ € this page) 40

CH2 CHO 1 〇nH18N202 210.2 211.2 Order

H.N

V CH2 B · 1 〇2〇Η33ΒΝ2〇3 360.3 361.3

O 42 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 43 44

Qr nh2 o9y nh2 〇, NH,

V o line CH2 B · 1 C21H35BN203 374.3 375.1 CH2 B * 1 C21H35BN2〇3 374.3 375.1 CH2 B · 1 C2tH33BN2〇3 372.3 373.3 This paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm) 1228499 A7 B7 V. Invention description (21)

A

X

R formula calculation molecular FAB mass spectrometry analysis [M + H] NH, 45

0 CH〇Β · 1 C21H33BN2〇3 372.3 373.3 B * ------------ install-〆Μ (please read the precautions on the back ^^^ this page) The paper size printed by the Employees' Cooperative of the Property Bureau applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1228499 A7 A7 B7 V. Description of the invention (22)

Table 4 Example of group IT (i) · / Q

Ministry of Economic Affairs, Intellectual Property Bureau, Employee Consumption Cooperative, printed number of gates, QX m R formula to calculate molecular weight FAB »Analysis [M + H] 46 1 -C0NHCH2C02Bn ch2 1 H C17H23N3〇4 333.2 334.2 47 1 -conhch2co2h ch2 1 H Ct0 ^ 17 ^ 3 ° 4 243.1 244.2 48 1 -C0NH (CH2) 3C02H ch2 1 H c12h21n3o4 271.2 272.2 49 1 -C0NH (CH2) 2C02Bn ch2 1 H ^ 10 ^ 25 ^ 3 ^ 4 347.2 348.2 50 1 -C0NH (CH2) 2C02H ch2 1 H C11 ^ 19 ^ 3 ° 4 257.1 258.2 51 1 -C0NH (CH2) 5C02Bn ch2 1 H ^ 21 ^ 31N3 ° 4 389.3 390.3 52 1 -C0NH (CH2) 5C02H ch2 1 H ^ 14 ^ 25 ^ 3 ^ 4 299.2 300.2 53 1 -C0NH (CH2) 3C02Bn ch2 1 H c19h27n3o4 361.2 362.2 54 2 -C0NHCH2C02Bn ch2 1 H ^ 18 ^ 25 ^ 3 ^ 4 347.2 348.2 55 2 -conhch2co2h ch2 1 H ◦Η19Ν304 257.1 258.1 56 2 • C202 (2) 1 H c19h27n3o4 361.2 362.3 57 2 -C0NH (CH2) 3C02Bn ch2 1 H ^ 20 ^ 29 ^ 3 ^ 4 375.2 376.3 58 2 -C0NH (CH2) 3C02H ch2 1 H G13H23N3O4 285.2 286.2 (Please read the precautions on the back first and repeat this Pages) Binding and binding paper sizes are in accordance with Chinese National Standards (CNS) 8-4 specifications (210X 297 mm) 25 1228499 A7 B7 Consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by Sakusha V. Description of the invention (23) Number of III π QX m R Calculate molecular ΰΐ FAB mass Π analysis Π I + Η] · III Please 1 I 59 2 -C0NH (CH2) 5C02Bn ch2 1 H ^ 22 ^ 33 ^ 3 ^ 4 403.3 404.3 Read 1 1 60 2 -CONH (CH2) 5C〇2H ch2 1 H c15h27n3o4 313.2 314.2 Back 1 1 of the 1 1 61 2 -C0NH (CH2) 2C02H ch2 1 H ^ Ι2 ^ 21 ^ 3 ° 4 271.2 272.2 > Matter of Wang Yi 1 1 * I 62 2 -C0NH (CH2) 7C02Bn ch2 1 H ^ 24 ^ 37 ^ 3 ^ 4 431.3 432.4 again ▲ 1 1 63 2 -C0NH (CH2) 7C02H ch2 1 H C17H31N3O4 341.3 342.5 • This page '--- ά 1 I 64 2 4 -CONH (CH2) 7CONH- ch2 1 H ^ 20 ^ 45 ^ 5 ^ 5 531.3 532.3 1 1 (CH2) 3NHZ 1 I 65 2 -CONH (CH2) 6CONH- ch2 1 H ^ 29 ^ 46 ^ 4 ^ 5 530.4 531.2 1 1 (CH2) 5C02Bn Order 1 66 2 • CONH (CH2) 6CONH- ch2 1 H 〇22 " 4 (^ 4〇5 440.3 441.3 1 1 (CH2) 5C02H 1 1 67 2 -C0NH (CH2) 7C0NH- ch2 1 H ^ 20 ^ 39 ^ 5 ° 3 397.3 398.3 1 I (ch2) 3nh2 1 line 68 2 -0〇ΝΗ (0Η2) η0Ο2Βπ ch2 1 H ^ 28 ^ 45 ^ 3 ^ 4 487.3 488.4 1 1 69 2 -C0NH (CH2) nC02H ch2 1 H C21H3gN304 397.3 398.3 1 1 70 2 -C0NH (CH2) 6C02En ch2 1 H C23H35N3O4 417.3 418.3 1 1 71 2 -C0NH (CH2) 6C02H ch2 1 H ^ 16 ^ 29 ^ 3 ^ 4 327.2 328.2 η 1 1 72 2 • conh (ch2) 5c〇nh -ch2 1 H ^ 17 ^ * 29 ^ 3 ^ 4 ^ 3 394.2 395.3 1 1 ch2cf3 1 1 1 1 1 1 This paper size is applicable to China National Standards (CNS) (brittle gift) 1228499 A7 B7 V. Description of the invention ( 24) number η

Q

X m R time calculation FAB mass spectrometry molecular weight analysis [M + H] 73 2 -CONH (CH2) 5GOMH- CH2 1 H C19H2gF7N403 494.2 CH2 (CF2) 2CF3 495.2 Printed by Intellectual Property Bureau Staff Consumer Cooperatives 74 2- CONH (CH2) 5CONH- (〇η2) 6οη ch2 1 H C21 ^ 4〇 ^ 4 ° 4 412.3 413.2 75 2 -c〇nh (ch2) 5conh- (CH2) 3Ph ch2 1 H ^ 24 ^ 33 ^ 4 ^ 3 430.3 431.2 76 2 -CONH (CH2) 5CONH- (CH2) 4Ph ch2 1 H G25H40N4O3 444.3 445.2 77 2 -CONH (CH2) 5CON- (nBu) 2 ch2 1 H. 23 " 44 ~ 〇3 424.3 425.3 78 2 -CONH (CH2) 5CON- (πΗχ) 2 ch2 1 H g27h52n4o3 460.4 461.4 79 2 • conh (ch2) 5conh- CH2Ph ch2 1 H ^ 22 ^ 34 ^ 4 ^ 3 402.3 403.4 80 2 -C0NH (CH2) 4C02Bn ch2 1 H C21H3, N3〇4 389.2 390.3 Θ1 2 4 -C0NH (CH2) 4C02H ch2 1 H ^ 14 ^ 25 ^ 3 ^ 4 299.2 300.3 82 2 -CONH (CH2) 5CONH- ch2ch3 ch2 1 H ^ 17 ^ 32 ^ 4 ^ 3 340.3 341.3 83 2 -CONH (CH2) 6OH ch2 1 H G15H29N3O3 299.2 300.3 84 2 -CONH (CH2) 5CO-1-Pip ch2 1 H ^ 20 ^ 36 ^ 4 ^ 3 380.3 381.4 85 2 -CONH (CH2) 5CONH2 ch2 1 H ^ 15 ^ 28 ^ 4 ^ 3 312.2 313.3 ---------- installation — f J (Please read the precautions on the back page first) Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 27 1228499 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (25) III Eye-catching η QX m R Formula to calculate molecular weight FAB Mass spectrometry [M + Hj · III 86 2 -CONH (CH2) 5CONH- ch2 1 H ^ 25 ^ 48 ^ 4 ^ 3 452.4 453.5 Please read I (ch2) 9ch3 and read back I 87 2 • conh (ch2) 5conh -(CH2) 6CH3 ch2 1 H ^ 22 ^ 42 ^ 4 ^ 3 410.3 411.4 faces. 1 of 1 1 1 Ί 8 8 2 -CONH (CH2) 5CONH- ch2 1 H 〇2 ^ 4〇yang 4〇3 408.3 409.4 i 1 CH2Ch Ψ ψ f 89 2 -CONH (CH2) 5CONH- ch2 1 H ^ 26 ^ 41 ^ 5 ^ 5 503.3 504.4 Page 1 1 (CH2) 3NHZ 1 1 90 2 -CONH (CH2) 5CONH- ch2 1 H 〇, 8 ± 5 ~ 5〇3 369.3 370.3 1 1 (ch2) 3nh2 1 91 2 -CONH (CH2) 5CONH- ch2 1 H Ct9HI37N703 411.3. 412.4 Order 1 (CH2) 3-Gua 1 I 92 2 -CONH (CH2) 5CONH- ch2 1 H C2iH32N406S 468.2 469.2 1 1 Ph (4-S03H) 1 j 93 2 -CONH (CH2) 5CONH- 4- ch2 1 H C27H43N503 485.3 4B6.3 • f Pip (1-Bn) 1 1 94 2 -CONH (CH2) 5CONH- ch2 1 H G20H37N5O3 395.3 396.3 1 4-Pip 1 95 2 -CONH (CH2) 4N (Z )-ch2 1 H ^ 32 ^ 45 ^ 5 ^ 6 595.3 596.3 1 1 (CH2) 3NHZ 1 96 2 -CONH (CH2) 4NH- ch2 1 H ^ 16 ^ 33 ^ 5 ^ 2 327.2 328.2 1 1 (〇h2) 3nh2 1 1 1 1 1 1 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1228499 A7 B7 V. Description of invention (26) Printed by the Consumer Property Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs to calculate the number of FAB quality π QX m R-type molecule M · Analysis [Μ + Η] · 97 2 -C0 NH (CH2) 5C02Bn ch2 1 CN ^ 23 ^ 32 ^ 4 ^ 4 428.3 429.3 98 3 -C〇NH (CH2) 6C〇NH- ch2 1 H ^ 30 ^ 48 ^ 4 ^ 5 544.4 545.2 (CH2) 5C02Bn 99 3 -CONH (CH2) 6CONH- ch2 1 H 〇23 ^ 4 ^ 4〇5 454.3 455.3 (CH2) 5C02H 100 3 -C0NH (CH2) 5C02Bn 4 ch2 1 H G23H35N3O4 417.3 418.2 101 3 -C0NH (CH2) 5C02H ch2 1 H ^ 16 ^ 29 ^ 3 ^ 4 327.2 328.2. 102 2 -S02NH (CH2) 5C02H ch2 1 H ^ 14 ^ 27 ^ 3 ^ 5 ^ 349.2 350.2 103 2 -CONH (CH2) 0NH-G ^ ch2 1 H ^ 24 ^ 45 ^ 5 ^ 7 ^ 547.4 543.5

OH

---------- Meal-蟓 A (Please read the note on the back first \ ^^^ This page) The size of the paper is applicable to China National Standard (CNS) A4 (210 X297 mm) 1228499 A7 B7 V. Description of invention (27) Table 5 Example of group II (u)

/ HQ (CH2) n .X. H2N

Ο

On

R Number of copies printed by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs η QX m R Calculation or molecular M FAB mass spectrometry analysis [M + H 104 1 -c〇 (ch2) 6go2h ch2 1 H C15H27 ^ 3〇4 313.2 314.3 105 1 • C0 (CH2) 6C02Bn ch2 1 H C22H33N3O4 403.3 404.3 106 3 -C0 (CH2) 4C02H ch2 1 H 〇15 ^ 27 to 3〇4 313.2 314.3 107 3 -C0 (CH2) 4C02Me ch2 1 H. ^ 16 ^ * 29 ^ 3 ^ 4 327.2 328.3 108 4 -CO (CH2) 5NH2 ch2 1 H ^ 16 ^ 32 ^ 4 ^ 2 312.3 313.3 109 4 -CO (CH2) 3NH2 ch2 1 H C14 ^ 20N4 ° 2 284.2 285.2 110 4 • C0 (CH2 ) 3NHS02Pip ch2 1 H C2〇h27f5n4o4s 514.2 515.2 111 4 -CO (CH2) 3NHCOPip ch2 1 H G21H27F5N403 478.2 479.2 112 4 -CO (CH2) 0NHSO2- ch2cf3 ch2 1 H C16H29F3N404S 430.2 431.3CH-1CO-4 6NHZ ch2 1 H ^ 37 ^ 63 ^ 5 ^ 5 657.5 658.6 114 4 -CO (CH2) 1tNH- ch2 1 H ^ 29 ^ 57 ^ 5 ^ 3 523.4 524.4 CO (CH2) 6NH2 (Please read the precautions on the back before (This page)

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (210'〆297 mm) -30 1228499 Α7 Β7 V. Description of the invention (28) Number printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs π QX m R Molecular weight FABH spectrum analysis [M + HP 115 4 • co (ch2) 5nhco- (CH2) 5NHCO (CH2) 5. NHZ ch2 1 H ^ 36 ^ 60 ^ 6 ^ 6 672.5 673.6 116 4 -CO (CH2) 5NHCO -(CH2) 5NHCO (CH2) 5- nh2 ch2 1 H 538.4 539.4 117 4 • c〇 (ch2) 3go2h ch2 1 H Ct5H27N3 ° 4 313.2 314.3 '118 4 • C0 (CH2) 3C02Bn ch2 1 H 〇22 " 33 ^ 3〇4 403.3 404.3 119 4 -CO (CH2) 6NH2 ch2 1 H 326.3 327.3 120 4 -CO (CH2) 7NH2 ch2 1 H C18H36N4 ° 2 340.3 341.3 121 4 -CO (CH2) 16Me ch2 1 H ^ 2S ^ 55 ^ 3®2 465.4 466.4 122 4 -CO (CH2) 6 * Gua ch2 1 H C18 ^ 36N6 ^ 2 360.3 369.3 123 4 -S02 (CH2) 7CH3 ch2 1 HC 18 ^ 37 ^ 3 ^ 3 ^ 375.3 376.3 124 4 -CO (CH2) nNH2 CHa 1 H 396.4 397Λ 125 4 -COCH2NHZ ch2 1 H CANA 390.2 391.3 126 4 -CO (CH2) 2NHZ ch2 1 H C21H32N4O4 404.2 405.3 127 4co (ch2) 3nhz ch2 1 H ^ 22 ^ 34 ^ 4 ^ 4 418.3 419.3 128 4 -CO ch2 nh2 ch2 1 H C12H24N4〇2 256.2 257. 2 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Λ, 1 31 — 1228499 A7 B7 V. Description of the invention (29) Number printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs · η QX m R Computational molecular FAB mass spectrometry analysis [Η + Η] 129 4 -CO (CH2) 5NHZ ch2 1 H ◦24 * ^ 38 Bu 4〇4 446.3 447.4 130 4 -COCHyGuai ch2 1 H ^ 13 ^ 26 ^ 6 ^ 2 298.2 299.3 131 4 -CO (CH2) 2NH2 ch2 1 H 270.2 271.3 132 4 • CO (CH2) 2-Gua ch2 1 H 312.2 313.3 133 4 -CO (CH2) 3-Gua ch2 1 H ^ 15 ^ 30 ^ 6 ^ 2 326.3 327.3 '134 4 -CO (CH2) 5-Gua ch2 1 H ^ 17 ^ 34 ^ 6 ^ 2 3S4.3 355.3 135 4 -CO (CH2) 6NH2 ch2 1 CN ^ 10 ^ 33 ^ 5 ^ 2 351.3 352.4 136 4 -CO (CH2) 7NH2 ch2 1 CN ^ 19 ^ 35 ^ 5 ^ 2 365.3 366.3 (Please read the precautions on the back before UPb this page)-Pack.

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1228499 Δ7 Α7 Β7 V. Description of the invention (30) Table. 6 No. H 丨 贲 贲 贲. Number of cases R R1 X η Υ

Molecular formula analysis of FAB mass spectrometry calculated by U formula [M + ΙΠ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 137 Η -OCH2CONH (CH2) 5- co2h 138 Η -OCH2CONH (CH2) 5- C02Bn 139 Η -OCH2CONH (CH2) 4- C02Bn 140 Η -OCH2CONH (CH2) 4- co2h 141 ch3 • och3 142 ch3 -oc2h5 143 ch3 • o (ch2) 5ch3 144 ch3 -och2c〇nh (ch2) 5 · 145 ch3 -OCH2CQNH (CH2) 5- co2h ch2 1 H ^ 15 ^ 27 ^ 3 ° 5 329.2 CH2 1 H ^ 22 ^ 33 ^ 3 ^ 5 419.3 CH2 1 H C21 ^ 31 ^ 3 ° 5 405.2 CH2 1 H ^ 14 ^ 25 ^ 3 ^ 5 315.2 CH2 1 H ^ 9 ^ 18 ^ 2 ^ 2 186.1 CH2 1 H ^ 10 ^ 20 ^ 2 ^ 2 200.1 CH2 1 HC 14 ^ 28 ^ 2 ^ 2 256.2 CH2 1 H C23H35N3 ° 5 433.3 CH2 1 H C16H29N3〇5 343.2 330.3 420.3 406.3 316.3 187.2 201.2 257.3 434.3 344.3 (Please read the precautions on the back first, then this page). The size of the paper for 1T thread is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 1228499 Α7 Β7 V. Description of the invention (31) Number

X η Υ formula calculation molecule M

FAI3 quality, analysis [M + HJ 146 CH3 -OCH2CONH (CH2) 4- ch2 1 C02Bn H ^ 22 ^ 33 ^ 3 ^ 5 419.2 420.3 147 CH3 -OCH2CONH (CH2) 4- ch2 1 co2h 丨 H C15H27N305 329.2 330.3- -------- Installation-*-* (Please read the precautions on the back before @This page), 1TB printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Employee Consumer Cooperatives, this paper is printed in accordance with Chinese National Standards (CNS) A4 specification (210'〆297 mm) 1228499 A7 B7 V. Description of invention (32) Table 7 Example of IK Μ Structure calculation FAB mass spectrometer molecule.ill analysis [M + H] 148

C32H54N8 ° 4 614.4 615.4 (Please read the precautions on the back before this page). Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Printed by the Consumers' Cooperative of the Ministry of Economic Affairs, this paper applies the Chinese National Standard (CNS) A4 (210X297 mm) 1228499 A7 B7 V. Description of the invention (33) Table 8 Number of specific examples of compounds AB containing fenpronamine ill isoforms

A-B type calculation of molecular m-FAB mass spectrometry [M + H] 149

〇 ”Η21Ν 167.2 168.2 150

C, 2H2〇N2 192.2 193.2 (Please read the precautions on the back first, then this page) • Packing · 151

〇ΐ · 2Η2〇Ν2 192.2 193.2

1T 152

C1oH2〇N2S 200.1 201.2 The paper size printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 36 1228499 A7 B7 V. Description of the invention (34) Table 9 Number K | (Μ) 2 6.4 X 10 · 8 7 7.6 X 10 " 3 11 2.2 X 10 · 9 20 1 · 7 X 10 · 9 23 5.0 χ10 * 10 35 3.7x10 * «38 9.8 X 10 · 9 44 2.0 X 1〇 -9 59 1.5 X 10 * 7 66 1.8 X 10 * 7 97 5.0 X 10 · 10 110 2 · 5 Χ10 · 7 136 1.7 X 10- «143 9.4 X 10 * 7 150 1.7 χ10 * 6 (Please read the Note on this page again) Installation, 11 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is printed in accordance with Chinese National Standard (CNS) A4 specifications (210X297 mm) 1228499 A7 B7 V. Description of Invention (35) The general preparation scheme of the type of compound is represented in Table 1. The compound can be used as described in £. ^ (^ 613115 丨 〇1. (: [^ 111.11〇 卩 口 6-Seyler, 1991, 372, 305-311 The general path is prepared. Table 2

(a) R: -CN X., α

Boc-A-OH +

PyBop

U Ύ 2 〇 bT2

> Boc-A-N (please read the precautions on the back first and then mb this page) • Pack · POCl 3 pyrimidine 0m 吔

Boc-A-N V " H + x = s

CN mCPBA / X, r ^ H-A-N — ^

rCN order (〇) v ‘Όα

Boc-A-N *

rCN line H + Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy r (?) y X ^ Or

H-A-N

rCN y = 1, 2 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 38-1228499 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (36) (b) R: -CH = NPh, α

Boc-A-ONSu 4. · HN —L ^ 〇H

CH2C12 ('〇n --Boc-A-N ——L ^ OH

DMP

7CU

PhNH ^ toluene, △

(c) R: CH = N

Boc-A-N-L (I) X.

Boc-A-N-OR1

T H X) n > ^ NPh rxu —— ~ ► H-A-N —L = NPh (Please read the precautions on the back before this page) • Installation ·

N-OR 'On

Py, Ac20 I (II) -Boc-A-N ch2ci2 (Rl = H) (d) R = -OCR Ph3P, CBr4

Zn, CH2C12, Table 3 0 / (a) R = -B \ 0 H +, H + rx'〇n h-a-n-^ = n- OR1 Order " On N-OAc ^ H-A-N —One 〇Ac and

Boc-A-N ·

(b) R = CHO (I) V1 Br (i) nBuLi. (ii) " R + ”Br (iii) H + line X. 'On

H-A-N

-R was prepared as described by W.W. Bachovchim etal J. Biol. Chem., 1990, 265, 3738-3743. .X. H + 'On

♦ H-A-N

rCHO This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1228499 A7 B7 V. Description of invention (37)

Table 4 (W, P = security, P1, the basic toilet described in the corresponding table) (a) R = CN

X r α 0Ρ ΗΝΓ Boo Human 0H O H fVHs 〇

PyBop, CH2C12, Et3N

NH〇

(i) .Sweat removal (ii) HONSu, WSCD (丨) H2N (CH2) mPi

On X bucket

(ii) Modify P 1 4 P: m2

Boc-N HO 〇NSu On X '------: ---.---------- Please read the precautions on the back before this page) P0C13 Pyridine, 0 Mizole 〇 (m) Order ν Economic Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperative

^ i-NHiCH ^ P2 On again -► h2n Ο

rCN SC ^ NIKCHW On and (i) H2N (CH2) mPL (ii) Modified P 1 4 P2

Boc-N H

O

R line O u a y (IV) The above synthesis is completed (ΐν) ^ ήΙυί5ίβ !: 3ΐ ·, Τθ1; Ι ^ Ι ^ ·, 1993, 34, 23ίΠ-2392. (c) If R = 丨, modify the above steps as described in the example in Table 1. The paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) 1228499 A7 B7 Intellectual Property Bureau employees of the Ministry of Economic Affairs Printed by a cooperative

V. Description of the invention (38) Table 5 (a) R = CN

Boc-N Η

, NHW Γ On ΗΝ- .OH ΝΗ 2

PyBop, CH2C12i Et3N

⑴Remove w -—- ► Ch RChM A P (CH2) m ONSUf P (CH2) mS02Cl) v mm mm J

Boc-N H

Boc-N Η

On X vr—

nh7 / NHCO (CH2) n ^ On 'x N.

⑴ Modified P1 P 2 If 鼐 is required (ii) POCl3, Pyridine 0

H2N (Please read the precautions on the back before this page) Binding-Threading H + / NHCCKCT ^ 1 (>

CN (b) Shoe R = ll. 的 Repair the above steps as described in the examples in Table 1. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 41 1228499 A7 B7. 5. Description of the invention (39 ) Table 6 Prepared from (V) to (VI) using the method described in the example of Table 5 (a) R 0W Boc-N Η

OH (V)

R OH

N '(λ

rY (Please read the note on the back (i) NaH (ii) R1-Br (iii) H + v R OR1

X \) n Remarks on this page) • Equipment · h2n no

rY -0 (b) (VI)

(i) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, NaH

(ii) O OCH3 ⑴ LiOH, H20, dioxane; (ii) H2N (CH2) mP, iVB〇7 (iii) H + Y * = H, CN, -C = NPh, -C = NOR1, -CsCR2 〇 I ^^ och3 Boc-N ^ Ή 0 Λ

Ν · Y νη ^ ηα, ρ and

On

rY line 42 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1228499 A7 B7 V. Description of the invention (40) Table 7 Describes the compliance, dehydration and deprotection similar to the above process

(III) 0.5 Cheltang M: H2N (CH2) mNH2

V 〇 Π / -NtKCHANH eight () n

NH.

BocNH > r—N

NHn O (Please read the precautions on the back before mb this page) -Installed-, ιτ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (i) P0C13, U [t ϋ (ϋ) H + 0

CN The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 43 1228499 A7 B7 V. Description of Invention (41) Table 8

R (a) Boc-N Η

V

Benzene PPhn reflux

R

NH-Boc

R

(b) Boc-N H

V +

Toluene 〇 --► reflux PPh3

O

------ z--τ-^ —— (Please read the precautions on the back before this page)

R

CN

R

CN H + NH-Boc, ιτ

(i) (EtO) 2POCN LiCN, DMF (ii) Sml2, THF, ΐυΟΗ The thioamide is printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs by K. Clausen etal · Tetrahedran, 1981, 37, 3635-3639 The method of 逑 is prepared by adding M. Other amidine biosynthetic groups can be prepared by adding M in the previous literature (AF Spatolain `` Chemistry and Biochemistry of Amino Acids, Peptides and Protein ”Vol HI, B. Weinstein, Marcel, New York, 1983, p267 ) 〇 This paper size applies the Chinese National Standard (CNS) A4 size (210x297 mm) 44 1228499 Δ7 Α7 Β7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (42) Examination details Example 1 2-(S) -fluorenyl-isobutanolamine-pyrrolidine (11) CN Diisopropylethylamine was added to pyrene-ProNH ».HC1 (226ing, 1.50ιβπκ ) 1) Solution until pH is adjusted to 9. Under nitrogen pressure, add BocIleONSuM partly to it, and stir the mixture for 16 hours. Evaporate the solvent, and the residue is treated by M standard method and M treatment. That is, the residue was separated in ethyl acetate (60 cm3) and 0.3N KHS04 (10cni3). The organic layer was further washed with a saturated NaHC03 solution (10 cm3), water (10 cm3), and brine (5 cm3). Allow the solution to dry (NaaS04), and Evaporate it under reduced pressure. The crude product flows through a short plug of silica gel and elutes with hexane: ethyl acetate (10:90 to 0 ·· 100). M produces 301 «^ (92%>) as a colorless foam. 8o (: 116? 1 »〇2. LH NMR (CDC13), δ (ppm); 6.90 (1H, br.s); 5.51 (1H, br.s); 5.18 (1H, d, J = 9.6 Hz); 4.62 (1H, dd, J = 2.6, 7.0 Hz); 4.29, (1H, dd, J = 8.4, 9.2 Hz); 3.79-3.58 (2H, m); 2.36 (1H, m); 2.09-1.57 (5H, m); 1.43 (9H, s); 1.17 (1H, m); 0.95 (3H, df J = 6.6 Hz); 0.90 (3H, t, J = 7.3 Hz). Under gas Let oxazole (84ing, 1.24minol) be added to BocIleProNH2 in dry pyridine (10cm3). Before adding POCl3 (0.25cm3, 2.48 mmol) dropwise, the solution was cooled to -35 * 0. The reaction was stirred at -30 to -201: for 60 minutes. The solution was then evaporated and the crude product was subjected to column chromatography (silica gel). M produced 180 mg (94%) of a colorless oil.

(Please read the precautions on the back first-HI · this page) • Binding-Binding This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 45 1228499 Δ7 Α7 Β7 V. Description of the invention (43) 2- (S) -Fluoro-l [N- (t-butoxycarbonyl) isostilbamine] Bitrolidine. Also NMR (CDC13), δ (ppm); 5.14 (1H, d, J = 9.2 Hz); 4.80 (1H, dd, J = 2.6, 7.1 Hz); 4.22 (1H, dd, J = 7.9, 9.1 Hz); 3.81 (1H, m), 3.71 (1H, m), 230-2.12 (4H, m); 1.75 (1H, m); 1.60 (1H, m); 1.42 (9H, s) ; 1.19 (1H, m); 0.97 (3H, d, J = 6.9 Hz); 0.91 (3H, t, J = 7.3 Hz). 13C NMR (CDC13), δ (ppm); 171.7, 155.6, 118.0, 79.6 , 56.0, 46.5, 46.0, 37.8, 29.6, 28.1,25.0, 24.2, 15.2, 10.9. Deprotection by mixing with trifluoroacetic acid for 60 minutes. It was evaporated and freeze-dried in water to provide 60 mg of 2- (S) -cyano-isoplatinamine pyrrolidine (11) as a white fluffy solid. FAB mass spectrometry analysis: calculated value 209.3, actual value (M + H) + = 210.2 ln NMR (D20), δ (ppm); 4.3 (1H, m); 3.64 (1H, d, J = 5.6 Hz); 3 16 (2H, m); L86-I. 48 (5H, m); 0.98 (1H, ra); 0.68 (1H, m); 0.51 (3H, d, J = 6.9 Hz); 0.38 (3Hf t, J = 7.3

Hz): l3NMR (D20), δ (ppm); 169.7, 119.7, 57.3, 48.6, 48.1, 36.9, 30.2, 25.8, 24.5, 15.4, II. 5. Fenyu Example 2 (Please read the note on the back first Item again on this page)-Packing. Printing of H-Glu- [NH (CH2) 7C0NH (CHa) 3NHZ) pyrrolidine acetal (64)

Diisopropylethylamine is added to dry CH2Cl2 (6cm3) * tBocG. The paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). 〃 46-1228499 A7 A7 B7 Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed 5. Description of the invention (44) lu (OH) Bft solution (193mg, 0.64mmol) and PyBop (500mg, 0.96mmol) 226mg, 1.50mmol) solution until the pH of the mixture is adjusted to 9. After stirring for 5 minutes, 8-amino-benzyl octanoate (200 mg, 0.77 mfflOl) in CH2Cla was added. The mixture was stirred at room temperature for 16 hours. This reaction is performed by the standard method described in Example 1 plus M. The crude product was subjected to column chromatography (1¾ to 3% methanol in ethyl acetate) to obtain 344 mg (99: U of BocGlu [NH (CHa) 7C〇aBn] 0tt) as a colorless solid. Aldehyde. {B. NMR (CDC13), δ (ppm); 7.35 (5H, s); 6.63 (1H, br.t, J = 6.7 Hz); 5.65 (1H, d, J = 8.3 Hz); 5.11 (2H, s); 4.36 (1H, dt, J = 2.6, 8.9 Hz); 3.55, 3.20 (6H, m); 2.34 (2ΗΛ J = 7.3 Hz) ; 2.26 (2H, dd, J = 5.6, 7.3 Hz); 2.11-1.48 (10H, m); 1.43 (9Hf s); L32 -1.27 (6H, m). Hydrogen flows through an ethyl acetate (10cm3 Bubbling in a solution of BocGl u [NH (CH2) 7C02Bn] (230 mg, 0.43 miB0l), which contained 10% palladium on activated carbon (50 mg). After 90 minutes, the reaction vessel After washing, the solution was filtered through a pad of Celite, and the solvent was evaporated, yielding 187 mg (98%) of BocGlu [NH (CHa) 7COaH] Btli pyrrolal acetal as a colorless oil. Diisopropylethyl Amine was added to a solution of BocGlu [NH (CH2) C02H] (125 mg, 0.28 mmol) and PyBop (221 mg, 0.43 mmol) in dry CH2Cla (10 cm3) until the pH was adjusted to 9. After stirring for 5 minutes, ZNH (CH «) NHa. HC1 (90 mg, 0.37 mmol) and diisopropylethylamine (38 mg, 0.37 mmol) were added in portions. The mixture was stirred for 18 hours and then treated in the same manner as described in Example 1. This rough product (please read the precautions on the back first-HI · this page). The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1228499 A7 B7 V. Description of the invention (45) Column chromatography (2% to 15X methanol in ethyl acetate) to obtain 151 mg (85%) of BocGlu [NH (CHa) 7CONH (CH2) 3NHZ) Btt pyrrolidal acetal as a colorless oil. lH NMR (CDC13), δ (ppm); 7.35 (5Η, s); 6.60 (1H, br.t, J = 7.2 Hz); 6.14 (1H, br.tf J = 7.2 Hz); 5.63 (1H, d , J = 8.3 Hz); 5.39 (1H, br.t, J = 5.6 Hz); 5.10 (2Hf s); 4.38 (1H, dt, J = 2.3, 9.2 Hz); 3.52-3.13 (10H, ra); 2.26 (2H, t, J = 6.9 Hz); 2.17 (2H, t, J = 7.6 Hz); L98-1.48 (12H, m); 1.44 (9H, s); 1.38-1.23 (6H, m). In BocGlu [NH (CHa) 7CONH (CHa) 3 NHZ) pyrrolidine acetal (14fflg, 0-022mmol) in 4N HC1 / dioxane was stirred for 45 minutes, the solvent was evaporated, the residue was dissolved in water, filtered and freeze-dried In other words, M produced 13 mg of ^ 111- [old ((: ^) 7 (: 0 ((: 1 ^) 3 阙 2) | 1 & pyrrolacetal) which is a colorless oil. FAB mass spectrometry analysis: calculated value 531.3 Actual value 卬 + 11 = = 532.3. Example 3 1 1 1 3 [(: 0 ((^ 2) 3 501 ^ to] 11 «; pyrane acetal (110 > please read the note above)

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

NHCO

NHSO

ZNH (CHa) 3C0aNSu (570mg, 1.7minol) M Partial adding method plus 48 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm> 1228499 Printed by A7 B7__ of the Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs Description of the invention (46) [N- (t-butoxycarbonyl) lysamido] Bft pyrrolidal acetal (745ing, 2_2mmol) in dry CHaCla. The pH of diisopropylethylamine is adjusted to 9, and the mixture was stirred for 60 minutes. The solvent was evaporated, and the residue was treated with M in the standard method described in Example 1. Column chromatography (100% ethyl acetate to 15% methanol in ethyl acetate) 620 mg (68: 0 of BocLys [C0 (CH2> 3NHZ] »tfc pyrrolal acetal. LH NMR (CDC13), δ (ppm); 7.42 (5H, s); 6.31 (1H, br.t, J = 6.5 Hz); 5.58 (1H, dt J = 8.9 Hz); 5,39 (1H, bnt, J = 6.9 Hz); 5.17 (2H, s); 4.44 (1H, m); 3,72- 3.20 (8H, m); 2.29 (2H, t, J == 7.3 Hz); 2.14 -1.83 (8H, m); 1.78 -1.41 (4H, m); 1.43 (9Ht s). Hydrogen flows through a configuration at BocLys [C0 (CH2) 3NHZ] (620mg, 1. 16mmol) in methanol (10 cm3) containing one decubitus equivalent of 2N HC1 and Foam was formed in a mixture of 10 palladium in activated carbon. After 60 minutes, the reaction vessel was purged with nitrogen and filtered with M-C salt. The solvent was evaporated to obtain 282 mg (49%) of BocLys [CO (CHa) 3NHa.HCl] Bft Pyrrolid acetal. This product was dissolved in CH2C12 * (10cm3) and stirred under nitrogen pressure. Before the introduction of pentafluorobenzenesulfonyl chloride (45mg, 0.72mmol), diisocyanate was added. Propylethylamine M was adjusted to pH 9. The mixture was stirred for 16 hours, the solvent was evaporated, and the residue M was treated by the standard method described in Example 1. Column chromatography (100% ethyl acetate to 10% methanol in ethyl acetate) can give 33 111 (31%) of 80% (: 1 ^ 3 [(: 0 ([: 112) 3guan 503 ^ {?) Pyrrolidine condensation Aldehyde NMR (CDCi3), δ (ppm); 7.19 (1Η, br.t, J = 6.3 Hz); 6.18 (1H, br.t, J = 6.6 Hz); 5.50 (1H, d, J = 8.4 Hz ); 4.38 (1H, m); 3.65-3.16 (8H, ra); 2.36 (2H, t, J = 6.8 Hz); 2.01-1.82 (8H, m); 1.69-L41 (4H, m); 1.43 ( 9H, s). (Please read the precautions on the back of this page before you go to this page)-Binding-Binding This paper size is applicable to China National Standard (CNS) A4 specifications (21 ox 297 mm) 1228499 A7 B7 V. Description of the invention (47) This product was stirred in difluoroacetic acid (10cni3) for 30 minutes, and the solvent was evaporated. The residue was dissolved in water, filtered and freeze-dried, and 30 mg was produced as H-Lys [C0 (CH2) 3NHS0aPfp] pyrrolidine acetal (110) as a colorless oil. FAB mass spectrometry analysis: Calculated value 514.2 Actual value (M + Η "= 515 · 2. Example 4 H-Thr [(CHa) eCH3] pyrrolidine acetal (143)

Please read the first note of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Printed under nitrogen pressure, add pyrrolidine acetal (0.88g, 12.4mfflOl > add a configuration to dry (: 112 (: 12 (30 1113) of 80 (: 1 ^ 1-0 meaning 511 (3. (^, 9.51 * 1111〇1). The reaction was stirred at room temperature for 60 minutes. The solvent was evaporated, and the residue M Example 1 The residue was subjected to a standard method. The residue was subjected to column chromatography (hexane: ethyl acetate, 30:70) to obtain 2.5 g (96: 0 of l- [N- (t-butyl (Oxycarbonyl) threonyl] Bitrolidine acetal. Ln NMR (CDC13), δ (ppm); 5.52 (1H, d, J = 6.5 Hz); 4.30 (1H, d ,. J = 7.4 Hz) ; 4.16 (2H, ra); 3.72 (1H, m); 3.46 (3H, m); 1.98-1.82 (4H, ra); 1.43 (9H, s); L19 (3H, d, J = 7.1 Hz). Under Ot and a nitrogen pressure, sodium hydride (17 mg, 0.70 mmol) was added to 1- [N- (t-butoxycarbonyl) threonylamino] Utfc in dry THF. Before iodide (200 «ig, 0.94mmol), stir the paper at 0TC. The paper size applies the Chinese National Standard (CNS) A4 (210X297mm) -50-1228499 A7 B7 Explanation of the invention (48) (Please read the precautions on the back and then on this page) Stir the mixture for 15 minutes. Then allow the reaction to stir at room temperature for 16 hours. Evaporate the solvent and the residue described in Example 1 The standard method was treated with M. The crude product was subjected to column chromatography (hexane: ethyl acetate, 40:60) to obtain 25 mg (10%) of 80 (: 1 ^ 1 * [((: 1 ^) 11 (: 113] | 1 «1 pyridine acetal. LR NMR (CDC13), δ (ppm); 5.50 (1H, dt J = 6.9 Hz); 4.48 (1H, m); 3.70-3.32 (7H, m ); 1.92-1.80 (6H, ra); 1.52 (2H, m); 1.42 (9H, s); 1.30 (6Ht ra); 1.22 (8H, dt J = 6.9 Hz); 0.83 (3H, t, J = 7.9 Hz).

BocThr [(CH »> e CH3] Btt Pyrrolid acetal (20mg, 0_06mm〇l) was stirred in 4N HC1 / dioxane (5cm3) for 60 minutes, and the solvent was evaporated. The residue was taken out in water, filtered and Frozen, M produced H-Thr [(CHe) eCH3] pyrrolidine acetal (20 mg) as an orange oil, which was purified by reverse-phase HPLC to provide 15 mg of a colorless oil (143). FAB mass spectrometry : Calculated value 256 · 2 Actual value (Μ + Η 广 = 257.3. Example 5 H-Ile-ψ [CH = CH] pyrrolidine acetal Intellectual Property Bureau of the Ministry of Economic Affairs Employees' Cooperatives Co., Ltd. Printed under nitrogen pressure, let 1 6Nη Butyl lithium (0.50cffi3, 0.76mmol) was added to cyclopentyldiphenyl squamous bromide (288rng, 69mmol) in dry THF (6cm3), keeping the temperature at -301. Stir for 60 minutes The size of the paper after the solution is in accordance with the Chinese National Standard (CNS) A4 (210 X297 mm) 51 1228499 A7 B7 V. Description of the invention (49) Further cooling to -50t :, and then added in dry THF 1- (1: -butoxycarbonyl) -1 ^ isoleukinaldehyde (3〇1611 (^ 131) (125mg, 0.58nimol)), which is obtained by Fehrentz and Cast Ro, Syn-thesis, 1983, 676). After the addition is complete, the reaction is allowed to reach room temperature for more than 3.5 hours. The reaction is saturated with ammonium chloride (2cm3> quenched. Then with water (10cm3) diluted and extracted with ether (3X20cm3). The combined ether layers were washed with water (10cm3), dried (NaaSO4), and evaporated to yield 187 mg (> 100 υ) of crude product. Column Chromatography (hexane: EU0, 90:10) gave 53fflg (34%) of Boc-Ile-Ψ as a colorless oil [CH = CH] BHipyrrol acetal 0 lU NMR (CDC13), δ (ppm) ; 0.84 (3H, t, J = 6.9 Hz); 0.91 (3H, d, J = 7.3 Hz); 1.08; (1H, m); 1.44 (9H, s); 1.48 (lHt m); 1.64 (5H, m); 2:24-2.45 (4H, m); 4.08 (1H, br.s); 4.41 (1H, br.s); 5.12 (1H, dtt J = 2.3, 8.9 Hz) .13C NMR (CDC13) δ (ppm); 155.8, 147.4, 119.1, 79.2, 54.8, 40.1, 34.2, 29.6, 28.9, 26.8, 26.6, 26.1, 15.0, 12.1. The product M4N HC1 / dioxane treatment for 35 minutes to remove the Boc-protecting group The reaction was evaporated, and the residue was dissolved in water, filtered and freeze-dried to produce 24 mg (63U of H-IU-T [CH = CH] 8tt pyrrolidal acetal as a foamy solid). (149). FAB mass spectrometry analysis: Calculated value 167.2 Actual value (M + H) + = 168.2. Examples 6 to 7 H-Ile (2R) -fluoro-V [CH = CH] pyrrolidine acetal (150) 11-116 (23> -cyano- ¥ [(: [1 = (: [1] Pyrrolidine acetal (151) This paper size applies to Chinese National Standards (CNS> A4 size (210X297 mm) Please read the note printed by the Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperatives -52-1228499 A7 B7 V. Invention Explanation (5〇)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs under nitrogen pressure, N- (t-butoxycarbonyl) L-isoleucine (2.40g, 11.2mmol) and 2-oxo-1-diphenyl Phosphorone pentamidine (4.61 g, 13.4 mmol, which was prepared by the method of HO House and H. Babed, J. Org. Chem., 1963, 28, 90 plus M) was heated under reflux in toluene. After 15 hours, the mixture was cooled and its solvent was evaporated. Column chromatography (hexane: ethyl acetate, 80:20) of this crude product gave 2.33 g (74%) of Boc-Ile-Ψ [CH = CH] Bft pyran-2-one as a colorless oil. 〇H NMR (CDC13), δ (ppm); 6.29 (1H, dt, J = 2.6, 9.2 Hz); 4.59 (1H, br.d); 4.17 (1H, m), 2.82 (1H, m); 2.66 -2.50 (2H, m); 2.34 (2Ht t, J = 7.8 Hz); 1.96 (2H, q, J = 7.6 Hz); 1.44 (1H, m); 1.43 (9H, s); 1.12 (1H, m ), 0.89 (3H, d, J = 5.3 Hz); 0.88 (3H, tt J = 6.9 Hz). Under nitrogen pressure, add diethylfluorophosphorous carboxyacetic acid (0.3cm3) to dry DMF (2cm3 ) In Boc-1 le-ψ [CH = CH] pyrrolidin-2-one and LiCN (0.5M in DMF, .84 cm3, 1.92 mmol). The reaction was stirred at room temperature for 30 minutes, the mixture was diluted with water (20 cm3), and then extracted with ethyl acetate (2 × 30 cm3). The combined organic layers were washed with water (5 × 10 cm3), dried (Na2S04), and evaporated to give 360 mg (> 100%) of the crude product. A portion of this crude fluoro-phosphorous acid (284fflg, 0.64mmol) was dissolved In dry THF and stir under nitrogen pressure. Then add tert-butanol (47mg (please read the precautions on the back before this page) '— • Shang. Threading This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210 X297 mm) ^ -53-1228499 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (51), 0.64 mmol), and then add iodide iodide by dripping (in THF) (0.1M, 19.2cm3, 1.92minol). After the addition was complete, the reaction was stirred for an additional 30 minutes before adding 2N HC1 (20 cm3). This mixture was extracted with ether (3 × 30 cm3). The combined ether layers were washed with 10% NaaS03 solution (10 cm3), water (2 × 10 cm3) and brine (2 × 10 cm3), dried (Na2S04) and the solution was evaporated. The obtained crude residue was subjected to column chromatography (hexane: ethyl acetate, 90:10) to obtain 122 mg (66 J0 of BocIle- [2 (RS) -fluoro (CH = CH) pyrrolidine as a colorless oil). Acetal] diastereomeric mixtures. NMR (CDC13), δ (ppm); 5.52 (1H, d, J = 9.6 Hz); 4.5 (1H, br.s); 4.12 (1H, m); 3.35 (1H, m); 2.57 (1H, m); 2.38 (1H, m); 2.17 (1H, m); 1.91 (2H, m); 1.69 (2H, m); 1.53 (1H, m); 1.43 (9H, s); 1.12 (1H, m); 0.92 (1.5 H, d, J = 7.3 Hz); 0.91 (L5 H, d, J = 7.3 Hz); 0.89 (1.5 H, d, J = 6.6 Hz ); 0.86 (1.5 H, tt J = 6.9 Hz). The diastereomeric mixture M4N HC1 / dioxane was treated for 60 minutes to remove the protecting group. The solvent was evaporated, and the residue was subjected to reverse-phase HPLC to obtain Two pure diastereomers. (150), (47 mg, 60¾) FAB mass spectrometry analysis: Calculated value 192.2 Actual value (> 1 + 11 broad = 193.2 (151), (28 mg, 36%) FAB Mass spectrometry analysis: Calculated value 192.2 Actual value (M + H) + = 193.2 The preparation method is described in the relevant Tables 1 to 8, and Examples 1 to 7 form part of the invention. (Please read the notes on the back first This yellow) Pack - This paper book line scales applicable Chinese National Standard (CNS) A4 size (210X297 mm) 54

Claims (4)

1228499 The scope of patent application No. 88111301 Patent scope_Original 93 1. A dipeptidyl aminopeptidase_IV (DP_IV) regulates 3.03 · 2; Listed formulas ·· Known inhibitors, which have-Α-Β ...… ~ .................— 一, ~ W ·-^ where B is BU Zeer 1 1— &lt; I (Please read the note on the back first— i · • R n = m = l; X = CH2; Y = -N; ReH or CN; A is bonded to γ; and A is the following group -II n »* 1! = p ill — member of the Ministry of Economic Affairs, Hs-f Contains y- (Οί2) α · -CO—D CO when R is H or CN, a = 1.3; D = G- (CH2) b- (R4) q-R3; G = NH; b = l to 8, 10, or 11; q = 0-l; R4 = CONH- (CH2) c-, its s family for 4 years (CNShv! 1228499 A8 B8 C8 D8 patent scope c = 0, 1, 3, 4, 5, 6, or 9; and R3 = H, C02H, C02-phenylfluorenyl, NH-phenylfluorenyloxycarbonyl, NH2, CONH2, 0H, -CON (i-butyl), -CON (n-hexyl) , CONHCH2CF3, conhch2 (cf2) 2cf3, C0- (1 J-pyridinyl), phenyl, guanidyl, phenyl- (4-S03H), 4-piperidinyl, 4-piperidinyl- (1-benzene Fluorenyl); or A is Guan N-(CH ^ fl -NHE CO where E = J- (CH2) b-R3, J = CO or S〇2; and b = 1-7 or 11-16; R3 is Rhenium, C02H, C02CH3, C02-phenylfluorenyl, NH2, NH-phenylfluorenyloxycarbonyl, nh2so2-pentafluorophenyl, nhso2ch2cf3 'NHCO-pentafluorophenyl, guanidyl; or A is Chici Sheya, Ministry of Economic Affairs Bureau staff printed by Hezhu Club h2n, CO R2 OL ^ 5-7- = 1228499 A8 Βδ C8 -a---D8 Six, the scope of patent applications where R2 = H or Me; and L two (CH2) d- (CH2) b- (R4) q-R3; d-1, 3 or 4; R3 is CO2H, Co-2-benzyl or fluorene; 114 is CONH (CH2); c'c is 4 or 5; b = 0, 1, 2, or 5; and q = q or 1 0 2. The inhibitor of the dipeptide aminopeptidase-IV (DP-IV) regulation process of the scope of the patent application is selected from the compounds shown in Tables 4 to 8 below: Table 4 Group II (i) Example Q (Formula yx, (u 〇 Consumption of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs; 1 ¥¥ 1228499 A8 B8 C8 D8; Patent application scope No. η 〇 × m R Formula 46 1 -C0NHCH2C02Bn ch2 1 H C17H23N3〇4 47 1 -conhch2co2h ch2 1 H 48 1 • conh (ch2) 3co2h ch2 1 H c12h21n304 49 1 -C0NH (CH2) 2C02Bn ch2 1 H Cl8H25N3 0 4 50 1 -C0NH (CH2) 2C02H ch2 1 H .C ”H19N3〇4 51 1 -C0NH (CH2) 5C028n ch2 1 H C21H31N304 52 1 -C0NH (CH2) 5C02H ch2 1 H C14H25N304 53 1 -C0NH (CH2) 3C02Bn ch2 1 H g19h27n3o4 54 2 -C0NHCH2C02Bn ch2 1 H ^ -i 55 2 -conhch2co2h ch2 1 H 56 2 -C0NH (CH2) 2C02Bn ch2 1 H C19H27N3O4 57 2 -CONf &quot; 4 (CH2) 3C〇2 day n ch2 1 H ^ 20 ^ 29 ^ 3 ^ 4 58 2 -C0NH (CH2) 3C02H ch2 1 H C13H23N3O4 Awl »MIT ---------« (Please (Please read the notes on the back before filling this page) -SQ-1228499 A8 B8 C8 D8 VI. Patent Application No. π QX m R Formula 59 2 X0NH (CH2) 5C02Bn ch2 1 H ^ 22 ^ 33 ^ 3 ^ 4 60 2 ~ conh (ch2) 5co2h ch2 1 H c15h27n3o4 61 2 ~ C0NH (CH2) 2C02H ch2 1 H C12H21N304 62 2 -C0NH (CH2) 7C02Bn ch2 1 H c24h37n3o4 63 2 ~ C0NH (CH2) 7C02H ch2 ^ 31 ^ 3〇4 64 2 -C0NH (CH2) 7C0NH- (CH2) 3NHZ ch2 1 H CaaH 〇65 65 2 ~ CONH (CH2) 6CONH- (CH2) 5C02Bn CH2 1 H ^ 29 ^ 46 ^ 4 ^ 5 66 2 -CONH (CH2) 6CONH- {CH2) 5C02H ch2 1 H. 22 latch 40 ^ 4〇5 67 2 -conh (ch2) 7c〇nh- (ch2) 3nh2 ch2 1 H ^ 20 ^ 39 ^ 5 ^ 3 68 2 -CONHiCH ^^ CO ^ n ch2 1 H 〇29 ¥ 3. 4 69 2 ^ C〇m (CH2) ^ C02H ch2 1 H ^ 21 ^ 39 ^ 3 ^ 4 70 2 -C0NH (CH2) 6C02Bn ch2 1 H ^ 23 ^ 35 ^ 3 ^ 4 71 2 -C0NH (CH2) 6C02H ch2 1 H C16H29N3O4 72 2 -CONH (CH2) 5CONH- CH2CF3 ch2 1 H ^ 17 ^ 29 ^ 3 ^ 4 ^ 3 ----------- install ---- (Please read the note on the back first (Please fill out this page again). 1228499 A8 B8 C8 D8 Patent Application Range 62-No. η X m R 2 -CONH (CH2) 5CONH- CH2 1 H CH2 (CF2) 2CF3 74 2 -CONH (CH2) sCONH- CH2 1 H (CH2) 6OH 75 2 -CONH (CH2) 5CONH- CH2 1 H 〇24 ¥ 403 (CH2 ) 3Ph 76 2 -CONH (CH2) 5CONH- CH2 1 H 〇25 latch 4〇 ~ 4〇3 (CH2) 4Ph (Please read the precautions on the back before filling this page) 2 -CONH (CH2) 5CON- (nBu) 2 ch2 1 H C23H44N4O3 78 2 -C0NH (CH2) 5C0N- (nHx) 2 gh2 1 H 79 2 -CONH (CH2) 5CONH- CH2Ph ch2 H ^ 22 ^ 34 ^ 4 ^ 3 80 2 -C0NH (CH2) 4C02Bn ch2 1 H 〇2ΐΗ31Ν3〇4 81 2 -C0NH (CH2) 4C02H ch2 1 H C-J4H25N3O4 82 2 -CONH (CH2) 5CONH ~ ch2ch3 ch2 1 H C-17-H32N4O3 83 2 -CONH (CH2) 6〇H ch2 1 H Cl5H29N3〇3 S4 2 -CONH (CH2) 5CO-1-Pip ch2 1 H ^ 20 ^ 36 ^ 4¾ 85 2 -CONH (CH2) 5CONH2 ch2 1 H ------- Order i-1228499 VI.Applicable patent range 8 888 ABCD No, η QX m R Formula 2 -conh (ch2) 5conh- (CH2) 9CH3 ch2 1 H .CONH (CH2) 5CONH- (CH2 ) 6CH3 ch2 1 H 〇22Η42N4〇3 • CONH (CH2) 5CONH- CH2Ch ch2 1 H ^ 22 ^ 40 ^ 4¾ • CONH (CH2) 5CONH- (CH2) 3NHZ ch2 1 H ¥ 4outer 〇5 -C0NH (CH2) 5C0NH- (CH2) 3NH2 ch2 1 H C18H35N503 -CONH (CH2) 5CONH- (CHjg-Gua ch2 1 H ^ 19 ^ 37 ^ 7 ^ 3 -conh &lt; ch2) $ c〇nh- Ph (4-S03H) ch2 1 H C21H32N406S Aw—Installation · --- (Please read the precautions on the back before filling this page) ·. # Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2-CONH (CH2) 5CONI + 4_ CH2 1 Η 〇27Η43Ν5 ° 3 Ρϊρ (1 -Βη) 94 2 -C0NH (CH2) 5C0NH- CH2 1 Η 〇2〇Η37Ν5〇3 4-Pip 95 2 &gt; CONH {CH2) 4N (2)-CH2 1 H. Ai ~ %% (CH2) 3NHZ 2 -CONH (CH2) 4NH- CH2 1 H C16H33N502 (〇h2) 3nh2 1228499 A8 B8 C8 D8 VI. Application for Patent No. Gate 〇 × m R i Formula 97 2 -C0NH (CH2 ) 5C02Bn ch2 1 CN 98 3 -CONH (CH2) 6CONHl · ch2 1 H ^ 30 ^ 48 ^ 4〇5 (CH2) 5C02Bn 99 3 -C0NH (CH2) 6C0NH- ch2 1 H 〇23 latch 42% 〇5 (CH2 ) sC02H 100 3 -C0NH (CH2) 5C02Bn ch2 1 H ^ 23 ^ 35 ^ 3 ^ 4 101 3 X0NH (CH2) 5C02H ch2 1 H c16h29n3o4 102 2 -so2nh (ch2) 5go2h ch2 1 H C14H27N3Q5S 103 2 &CON; CH2) 8NH-G &quot; ch2 1 H oh j ΗΟγΑγ-〇Η G * = NH o person ^ Λ OH (please read the precautions on the back before filling this page) I -----1228499 -1-- -I ___ ί '. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 VI. Table 5 of the scope of patent application Group II (ii) ^ NHQ (CH2) f I ^ &lt; X, (), m h2n ^ S ] R 0 No. η 〇 × m R Formula 104 1 -C0 (CH2) 6C02H ch2 1 H 〇15 ^ 27 ~ 3〇4 105 1 -C0 (CH2) 6C02Bn ch2 1 H ^ 22 ^ 33 ^ 3 ^ 4 106 3 -C0 (CH2) 4C〇2H ch2 1 H 107 3 -CO &lt; CH2) 4C02Me ch2 1 H ^ 16 ^ 29 ^ 3 ^ 4 108 4 -CO (CH2) 5NH2 ch2 1 H * ^ 16 ^ 32 ^ 4 ^ 2 109 4 -CO (CH2) 3NH2 ch2 1 H 110 4 -C0 (CH2) 3NHS02Pfp ch2 1 H 111 4 -CO (CH2) 3NHCOPfp ch2 1 H ^ 21 ^ 27 ^ 5 ^ 4 ^ 3 112 4 -C0 (CH2) 3NHS02- ch2 1 H ch2cf3 113 4 -0Ο (0Η2) ηΝΗ0Ο- ch2 1 H C37H63NS ° 5 (CH2) 6NHZ 114 4 -COfCH—Nhi · ch2 1 H CO (CH2 6NH2 (Please read the notes on the back before filling this page) —-64 ^ 8 8 8 8 ABCD 1228499 Patent application scope No. n 〇 × m R Intellectual Property Bureau of the Ministry of Economic Affairs x- ^ t ^ 卞 土 115 4 -CO (CH2) 5NHCO- (CH2) 5NHCO {GH2) ^ NHZ 116 4 -CO (CH2) 5NHCO ~ (CH2) 5NHCO (CH2) r NHa ----------- 0-pack (please read the precautions on the back before filling this page) 117 4- C0 (CH2) 3C02H 118 4 -C0 (CH2) 3C02Bn 119 4 -CO (CH2) 6NH2 120 4 «C0 (CH2) 7NH2 121 4 -CO (CH2) 16Me 122 4 -CO (CH2) 6-Gua 123 4- S02 (CH2) 7CH3 124 4 -COiCH ^^ NHa 125 4 << 0CH2NHZ 12B 4 -CO (CH2) 2NHZ 127 4 -CO (CH2) 3NHZ 128 4 -CO ch2 nh2 ch2 1 H 〇28Η54Ν6〇4 ch2 1 H ^ 15 ^ 27 ^ 3 ^ 4 ch2 1 H. 22 ¥ 3〇4 ch2 1 H C17H34N4〇2 CHa * 1 H ch2 1 H ^ 28 ^ 55 ^ 3 ^ 2 ch2 1 H ^ 18 ^ 36 ^ 6 ^ 2 ch2 1 H C18H37N3Q3S ch2 1 H 〇22 »44 ^ 〇 2 CHa 1 H C20H3QN4O4 ch2 1 H ch2 1 H ^ 22 ^ 34 ^ 4 ^ 4 ch2 1 H '' iS i £: ¾ 芈 (CNS) A.:! Regulation ⑵ 297 1228499 A8 B8 C8 D8 Application scope of patent Να η QX m R Formula 129 4 -CO (CH2) 5NHZ ch2 1 H ^ 24 ^ 38 ^ 4 ^ 4 130 4 • COCH2-Gua ch2 1 H ^ 13 ^ 26 ^ 6¾ 131 4 -CO (CH2) 2NH2 ch2 1 H ^ 13 ^ 26 ^ 4 ^ 2 132 4 • CO (CH2) 2-Gua ch2 1 H ^ 14 ^ 29 ^ 6 ^ 2 133 4 «CO (CH2) 3-Gua ch2 1 H ^ 15 ^ 30 ^ 6 ^ 2 134 4 ^ CO (CH2) 5-Gua ch2 1 H C17H34N6〇2 135 4 ^ CO (CH2) 6NH2 ch2 1 CN Ci8H33N5〇2 136 4 -co (ch2) 7nh2 ch2 1 CN ^ 19 ^ 35 ^ 〇2 .-- ------ Order · -------- (Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Department of the Ministry of Economic Affairs and Staff Cooperatives i \: s κν; c * '1L_ Home 66 8 8 8 8 ABCD 1228499 VI. Table 6 for the scope of patent application Group Il (iii) \ / R1 η2ν π τυ ο No. R R1 X η 式 Formula 137. -.〇CH2CONH (CH2) 5- CH2 1 Η C15H27N305 C〇2H Consumption cooperation among employees of the Intellectual Property Bureau of the Ministry of Economic Affairs India ¾ 138 Η -OCH2CONH (CH2) s- C02Bn ch2 1 H C22H33N3O5 139 Η -OCH2CONH (CH2) ^ C02Bn ch2 1 H c21h31n3〇5 140 Η • OCH2CONH &lt; CH2) 4. Co2h ch2 1 H 141 ch H 09Η1βΝ2〇2 142 ch3 * 0〇2Hg ch2 1 H Ci〇H2〇N2〇2 143 ch3 * 0 (CH2) 5CH3 ch2 1 H Cl4H28N2〇2 144 ch3 • och2comh (ch2) 5-C〇2Bn ch2 1 H. 23 ¥ 3.55 145 ch3 -OCH2CONH (CH2) 5- ch2 1 H ^ 16 ^ 29 ^ 3 ^ 5 co2h 1228499 A8 B8 C8 D8 Six patent application scopes Ministry of Economic Affairs Intellectual Property 2-¾ member X-Xiao Xian t ipd No. R R1 X η Y Formula 146 CH3 -0CH2C0NH (CH2) r CH2 1 H 0 ^ 33 ^ 305 C02Bn 147 CH3 -0CH2C0NH (CH2) 4- CH2 1 H C15H27N305 C02H Table 7 Group III No. Structural formula * Installation ·-(Please read the notes on the back before filling this page) 148 CN-1228499 A8 B8 C8 D8 Patent application scope Table 8 Compounds containing amidine bonding isoforms A-B No. A-B Formula 149 〇 NH, c11h21n 150 NH CX CN C12H2〇N2 »* Equipment — (Please read the precautions on the back before filling this page] 151 a CN Ct ^ 2〇N2 order 152 Xiao Xiankou, Member of the Bureau of Intellectual Property, Ministry of Economic Affairs 3.-A pharmaceutical composition for treating or pre-shaping a disease in a patient's body caused by a process regulated by the dipeptide ammonia Geng Qi · dv (dmv), which contains- Dipeptide amylase-IV (DP_IV) inhibits the amount of the compound of item 1 or 2 in the second amount. ^ #J Envelope:] 〇.-=-65-