TW200817323A - Pyrrolidine derivatives - Google Patents

Abstract

Pyrrolidine compounds described herein and methods for using them to inhibit dipeptidyl peptidase IV or treat Type II diabetes.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a compound for inhibiting dipeptide peptidase IV and/or treating diabetes mellitus. [Previous technique #?] Glycoglycan peptide-1 (GLP-1) is an intestinal load produced by enteral glandular L cells for nutrient uptake (IV). GUM inhibits the secretion of glycoside and the money is released from the pancreas. It is known that administration of GLP-1 is effective in reducing the blood glucose level (bl〇〇d glucose level) of patients with type π diabetes (Zander M, et al. 2002, 359: 824-830).

• However, GLP-1 administered either in vitro or in vivo degrades rapidly (Kieffer TJ, etaL 'Endocrinology 1995, 136: 3585-3596; and Mentlein R, et al. E, /. Biochem. 1993, 214 · 829-839). This degradation can be attributed to the dipeptide peptide peptide, which is a member of the lysine peptide peptidase family. Recent clinical data indicate that inhibition of Dp^ leads to increased insulin sputum, decreased blood levels (10), and promotes _β cell wei (ped_ RA et al. Diabetes 1998, 47: 1253-1258; and Ahren B? et al. Diabetes Care 2002, 25. 869-875). Therefore, DPP-IV _, 丨 n n 【 【 【 【 【 【 【 【 【 【 【 【 【 【 【 【 【 - - - - - - - - - - - - - - - - - - - - - - - - - - - Rotary compound:

5 200817323 wherein R1 is H or CN; R2 is H, halogen, nitro, cyano, amino, hydroxy, alkyl, _alkyl, alkoxy, aryloxy, aralkyl, cycloalkyl, heterocycle An alkyl group, an aromatic group or a heterocyclic group; each of R3, R4, R5 and R6 is an anthracene, a halogen, a nitro group, a cyano group, an amino group, a hydroxyl group, an alkyl group, an alkyl group, an alkoxy group, an aryloxy group, An aralkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heterocyclic aryl group; or R3, R4 and the carbon atom to which they are attached form a three-to-human ring, or R, R and The linked carbon atoms together form a three to eight membered ring which may have one or two heteroatoms which may have _, CN, N 〇 2, _ 〇 Ra, alkane Base, aryl, heterocyclic aryl, haloalkyl, 〇Ra, _C(〇)Ra, _SRa, _s(〇)Ra, s(〇)2Ra, f -NR Ra > -C(0)0Ra >-C(0)NRaRa,> -0C(0)Ra - -NRaC(0)Ra, - -NRaC(0)0Ra, or -NRaC(0)NRaRa" substituent, the three to eight membered ring It may be fused to one of a cycloalkyl group, a heterocycloalkyl group, an aromatic group and a heterocyclic aromatic group, and each of Ra, Ra' and Ra" Is H, alkyl or aryl; m is 0, Bu 2, 3, 4 or 5; n is 〇, 1 or 2; W is CRbRb', NRb, Ο or S, wherein R and Rb are each H, Halogen, alkyl or aryl; X is 〇, s or CRc(NRc'RC"), wherein RC, RC' and Rc" are each H, alkyl or aryl; γ is 螓人"S(, RdN, (person, RdN righteous, righteous, RdN again, person, RdrS\

Wherein 1 is a hydrazine, an alkyl group or an aryl group; and z is NReRe', wherein each of Re and Re' is a fluorene, an alkyl group, an alkoxy group, a aryl group, a cycloalkyl group, a heterocyclic group, An aryl group, an arylalkyl group, a heterocyclic aryl group or a heterocyclic aralkyl group, or hydrazine is NReRe', which together is a three to eight membered ring, and the three to eight membered ring may have one or two hetero atoms. The three to eight membered ring may have a peptidin, CN, N〇2, -OR, alkyl, aryl, heterocyclic aryl, haloalkyl, _0R', _c(〇)R', _SR', -S( 0) R ^ -S(0)2R > -NR R >-C(0)〇R,> -C(0)NR R,5 ^ -0C(0)R ^ -NR C(0) R > -NR'C(0)0R" or -:^'(:(0) grabs 1"11"' substituent, which can be separated from cycloalkyl and heterocycloalkane 6 200817323 respectively H, alkyl or aryl, aryl, and heterocyclic aryl-fused, R, R, and R" aryl. R4 ^ , ^^subset) ^ X ^ chkh2 ϋχ R3 . R are each H, dentate base, can, aryloxy, aryl silk, sulfhydryl: == = chemical wealth 'R such as 5 (four) can ix n base:, ruler and ruler can be (1) (four) can be for it and rule ^ (four) can Are all ~ months, J = propyl mounted is formed with another coating composition Coming to which they are attached and the carbon atom of the compound gauge. Again, the combined feature is γ is c(〇). Another aspect of the invention relates to the following pyrrolidine compounds:

Z, nitro, cyano, amino, silk, aryl, halogen, alkoxy, aryloxy, aryl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl; m is 0, 1, 2, 3, 4 or 5; 11 is 〇, 1, 2, 3 or 4; 〇 is 〇, 1, 2 or 3; W is CRaRa', ^^, 〇 or s, where 圮And Ra are each a fluorene, halogen, alkyl or aryl group; X is NRb, wherein 0 is only an alkyl group or an aromatic group; Y is 0 II RCN Ο ιι 3, S\ RchTS,

Also, which is thought! ! Or an alkyl group or an aryl group; and z is NRdRd', wherein 1^ is a three- to eight-membered monocyclic ring which may have a peptidin, CN, N〇2, -OR', an alkyl group, Aromatic group, 7 200817323 heterocyclic aryl, haloalkyl, -OR', -C(0)R', -SR', -S(0)R', -S(0)2R', -NR'R ”, _C(0)〇R', _C(0 Hui R”, _〇C(〇)R', _NR'C(〇)R”, -NR'C^COOR” or -rc(o)nr” r'''substituent; and # is H, alkyl, alkoxyalkyl, haloalkyl, aralkyl or heterocyclic aralkyl; R', R" and R"' are each H, alkane Referring to the aforementioned pyrrole biting compound, the first combination is characterized by η being 1 and 〇 being 丨; X being nh; = being CH2 or CHF; Rd being a cyclopropene having an aromatic or heterocyclic aryl substituent The base ring; R3, R4, R7 and R8 are both oxime and R5 and R6 are both ch3. Again, the combination is characterized by γ being c(0). The following are exemplary compounds of the invention:

200817323

"Alkyl" as used herein refers to a straight chain or branched chain hindered compound containing MO carbon atoms. Examples of alkyl groups include, but are not limited to, mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and neobutyl. "Alkoxy" as used herein means _〇-alkyl. "Alkoxyalkyl" as used herein refers to an alkyl group having one or more alkoxy substituents. "Heteroalkyl" as used herein refers to an alkyl group having one or more halo substituents. "Hydroxyalkyl" as used herein refers to an alkyl group having one or more hydroxy substituents. i "Aromatic group" herein means a 6-carbon monocyclic, ίο-carbon bicyclic, μ-carbon tricyclic aromatic ring system in which each ring may have 1 to 4 substituents. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl and enyl. "Aromatic aryl" is used herein to mean _〇_aryl. "Aralkyl" as used herein refers to an alkyl group having an aryl substituent. By "cycloalkyl" is meant herein a saturated or partially unsaturated cyclic carbon gas compound having from 3 to 12 carbons. The group of the Weiji group contains but is secreted by cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl. ^衣香香基" has one or more heteroatoms in this system (such as nitrogen aromatic 5-8 membered monocyclic ring, 8-12 yuan bicyclic oxime into knife 0 again: 3⁄4 ii_m m system. Heterocyclic aromatic group 9 Examples of 200817323 include, but are not limited to, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, porphinyl, quinolyl, decyl and thiazolyl. "Heteroaralkyl" By a group having a heterocyclic aryl substituent. "Heterocyclic alkyl" is used herein to mean a non-aromatic 5-8 membered monocyclic ring having one or more heteroatoms (eg nitrogen, oxygen or sulfur), 8-12 membered bicyclic or 11-14 membered tricyclic system. Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxoalkyl, morpholinyl, and tetrahydrofuranyl. The alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, the heterocyclic aryl group, the aralkyl group, the heterocyclic aralkyl group, the alkoxy group and the aromatic oxy group contain a substituted or unsubstituted group. Examples include, but are not limited to, yl, hydroxy, amino, cyano, nitro, thiol, alkoxycarbonyl, amine, Wei, Sulfur-based, alkyl-based, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamide, alkyl, alkenyl , alkynyl, alkoxy, aryl, heterocyclic aryl, cycloalkyl, heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocyclic aryl, cycloalkyl The heterocycloalkyl group may have a further substituent. The monocyclic ring referred to herein may be substituted or unsubstituted, but may not be fused to other aromatic or non-aromatic rings. The pyrrole bite compound comprises a pharmaceutically acceptable salt thereof and a prodrug, if appropriate. This salt may be formed between a positively charged ionic group (e.g., an ammonium group) and a negatively charged counter ion (e.g., an unterion) (e.g., trifluoroacetic acid) of one of the pyrroleidine compounds. Similarly, a negatively charged ionic group (e.g., a carboxylic acid) in one of the pyrroleidine compounds may also form a salt with a positively charged counterion (e.g., sodium, potassium, calcium or magnesium). The bite compound may comprise a non-aromatic double bond and one or more asymmetric centers. Thus, they may exist in the form of racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and Heterogeneous form. All these forms of genius are foreseen. The above pyrrolidine compounds of the present invention are useful for inhibiting Dpp_jy. Therefore, another aspect of the present invention, 10 200817323, relates to a method for inhibiting DPMV by one or more transposable compounds. Inhibition of granules can lead to a decrease in blood glucose and an increase in insulin secretion, and the compounds of the present invention can also be used for the treatment of η-type diabetes. The invention therefore also encompasses the use of one or more of the effective amounts. The bidodidine compound is administered to a patient in need thereof to treat π-type diabetes. A pharmaceutical composition comprising one or more of the aforementioned η-pyrrolidine compounds and a pharmaceutically acceptable carrier, and the use of the composition for the manufacture of a medicament for the treatment of diarrhea-type diabetes are within the scope of the present invention. The details of many embodiments of the invention are described in the following description. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Embodiment] The pyrrolidine compound of the present invention can be synthesized by a method known in the art. The six exemplary synthetic pathways are shown in the following scheme μ6.

In Scheme 1, the starting compound is an amino-substituted dicarboxylic acid (1), one of which has an amino group and one of the two enradencies has been protected. This compound is reacted with 2-substituted hydrochloride (2) to give a monoamide intermediate (3). It is to be noted that the synthesis of the 2_substituted hydrochloride (2) is a well-known technique in the art. For example, the 2-substituted hydrochloride salt (2) can be obtained by the procedure described in C/^w. erythropoieth 11 200817323 仏 仏 i63 to remove the carbyl protecting group of the intermediate product (3) to obtain a monoamine " The σ substance (4) leads to the bisamine compound (5) by combining it with an amine. The compound (5) is removed and protected to obtain the desired compound (6). Scenario 2

Scheme 2 illustrates other synthetic routes for pyrrole biting compounds. The starting compound is the alpha-amino acid (7) whose amino group has been protected. This compound can be combined with the amine compound to obtain an amine compound (9). The amine compound (9) is removed from the protection and then reacted with 1H ethyl hydrazine hydrazine (11) to obtain the desired conversion compound (! 2). The value is that the 1_(2_漠_乙醯基比比洛 bite (1)) can be prepared by methods known in the art. See, for example, CW 2GG3, 46: 2774. Option 3

JuJ 12 200817323

In Scheme 3, the starting compound is N-protected 2-amino-2-methyl-propane-sulfinic acid sulfonate (13)' which is commercially available. It is reacted with sulfliryl chloride and then reacted with 2,3-dihydroisoindole to obtain sulfonic acid decylamine (16), followed by removal of sulfonic acid decylamine (16). Base compound (17). The amino compound is reacted with ?-bromo amide (18) to form the desired ratio of the bite compound (19). Option 4

In Scheme 4, thioxanthene chloride is continuously reacted with 2,3-dihydroisoindole (15) and (2. Aminoxy dimethylethyl)> amino amic acid (20). The product (not shown) (protected amino 13 200817323 compound) is removed to provide the free amino compound (21) which is then coupled to the fine amine (tetra) to form the desired compound (22). The two additional enthalpy ratios of the present invention are obtained by the similar steps of the following schemes 5 and 6. The starting material (24) synthesis has been published. See, for example, ' Boehringer M Etal., WO 2003037327 〇Scheme 5

Scheme 7 below illustrates the synthesis of a pyrrolidine compound containing a cyclopropyl group. The starting material (3〇) is N_protected β-amino acid. It is reacted with a cyclopropylamine in the presence of a coupling agent (e.g., dicyclohexylcarbodiimide) and then deprotected to give a fluorene-cyclopropyl decylamine (31) having a free amino group. The guanamine is then lightly coupled with piroxime (32) to form a pyridylpyridine (33) containing a cyclopropyl group. Ν-protection of β-amino acids (30) and ^Bilo 14 200817323 疋(32)T 乂鸰 方法 method preparation. See, for example, 』 she j [myocardial 2006, 49, 373; j;

Med·Chem.l9HS, q j _ T ^ r ^ ^ 广八 W, 92 ; and J· Afe<i· C/2e/w· 2002, 45, 2362. Option 7

R· = H or F 33 32 The following Scheme 8 shows the synthesis of a pyrrolidine compound having a longer chain (i.e., three carbon atoms between carbonyl groups). This chain may also have a substituent as shown in Scheme 9. The starting material (34) can be prepared by a conventional method. See, for example, /. MM. C7^w. 2001, W, 4252. Option 8

R' = various amines Y = H or F Scheme 9

Cold iaJ 15 200817323

R = various amines R3, R4 = H or F The foregoing nine schemes are for illustrative purposes only. Those of ordinary skill in the art, with reference to them, will be able to synthesize all of the present inventions with any necessary modifications in accordance with their skill. • Compound. Suitable chemical conversion and protecting group methods for the synthesis of useful pyrrolidine compounds - (protection and deprotection) are conventional, including, for example, R. Larock,

Organic Transformations > VCH Publishers (1989) ; TW Greene and PGM Wuts ^ Protective Groups in Organic Synthesis > 3rd Ed. ^ John Wiley and Sons (1999) , L. Fieser and M. Fieser ^ Fieser and Fieserfs Reagents for Organic Synthesis ^ John Wiley and Sons (1994); and L. Paquette ^ ed. > Encyclopedia i 〇/fine card (10)r 〇 此 伽 伽 伽 WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU WU The cockroach compound prepared by 瓒 can be further purified by column chromatography, high performance liquid chromatography or crystallization. The present invention encompasses a method for inhibiting DPP-IV, which is to bind to an effective amount of one or more (4) than pure b. The present invention is a treatment for fine-faced urinary tract, which gives an effective amount of or a plurality of the aforementioned transgenic compounds to a patient in need thereof. "Treatment" means the administration of a compound U or, ', mouth to a patient with π-type diabetes, having symptoms of type n diabetes or a tendency to plasticize diabetes, with the aim of treating, curing, alleviating, alleviating, changing, healing, and improving. Improve or affect the disease,

P〇%p^l -/i\J 16 200817323 Symptoms or the tendency. By "effective amount" is meant an amount of π to bite the compound sufficient to impart a desired effect to the patient. As recognized by those skilled in the art, an effective amount will vary depending on the route of administration, the amount of excipient, and the likelihood of using other treatments (e.g., other active agents). To practice the method of the present invention, a composition having one or more of the foregoing oxime sigma compounds can be administered parenterally, orally, nasally, rectally, topically or orally. "Parenteral" as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, slippery. Intrasynovial, intrastemal, intmthecal, intralesional or intracranial injection, and any suitable implantation technique. The innocuous injectable composition can be a solution or suspension (e.g., a solution of 1,3-butanediol) in a non-toxic parenterally acceptable diluent or solvent. In acceptable carriers and solvents, mannitol and water can be used. Further, it is known to use a fixed oil as a solvent or a suspending medium (e.g., synthetic mono- or diglyceride). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, and natural pharmaceutically acceptable oils such as eucalyptus oil or castor oil (especially in the form of polyoxyethylene) are also useful in the preparation of injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, and the base-based coatings may be side-by-side. For the purpose of fine (f_ulatiGn), other commonly used surfactants such as Tweens or Spans, or other similar emulsifiers, or bioavailability (bi〇availabi%) are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms. ) Enhancers can also be used. The oral composition can be any acceptable dosage form containing capsules, a key, an emulsion (emuki〇n) = and a water-suspension, dispersible bribe. In the ingot face, the regular noodles contain lactose and corn powder. A lubricant such as barium stearate is added. In the case of oral administration in a capsule form, it is useful as a mixture of suspicion and dried jade powder. #要财(四)丝丝或乳(四) When the main ingredient is suspended or dissolved in an oil base to which an emulsifier or suspending agent is added. Add specific sweetness, flavor or toner as needed. 17 200817323 Nasal sprays or inhalation compositions can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a group f should not be prepared as an aqueous salt solution, so that benzyl alcohol or other suitable preservatives known in the ugly art, absorption enhancers for improving the utilization rate of the body, and fluorocarbons _ 〇 赚 (4) private other Dissolving or dispersing agent. The composition of the eight live alive compound can also be administered through the rectum (like a suppository dosage form. The carrier in the pharmaceutical composition must be "acceptable" in the sense of its structure and composition. The main component is compatible (and preferably stabilizes the main component) and is harmless to the patient to be treated. One of them may be used as a delivery activity η piroxine compound Pharmaceutical excipients. Examples of other carriers include colloidal oxidized oxide, stearyl acid, cellulose, sodium lauryl sulfate and strontium & 匸鸠w (four). This month's pirate compound is tested by in vitro The desired activity (for example, inhibition is initially selected. The compound which has been confirmed to have high activity in the initial riding towel can be advanced). For example, the test compound can be administered to a patient having type n diabetes. Animals (eg, a mouse-handle type) are then evaluated for their therapeutic effect. These results can be determined by determining the appropriate dosage and the manner in which the specific mussels are administered by way of illustration only and not in any way limiting the remainder of the specification. Enter DETAILED DESCRIPTION OF THE INVENTION The present invention is fully described in the following description. All publications cited herein are hereby incorporated by reference.

Butoxy-amino-amino-L- face acid 5-methyl group (a522g, 2mm〇1) and N_pyridinium diimide (G.23 g, 2 _1) in 6 ml two gas A solution of A_CM)/1,4_two ships (. recommended) (2:1) was placed in an ice water bath towel to cool. Add a person to take _ dicyclohexylcarbazone, G45g, 2.2 moles). Stir the mixture in the room! Small day, then add 4_qi" than the mouth bite _2_ thief-brown amine 200817323 (0.264g, 2mmol) After stirring at room temperature for 4 hours, the mixture was filtered to remove DCC, then rinsed with DCM. The organic solution was washed with a 10% aqueous solution of EtOAc and aqueous NaHCO? Purified by flash column chromatography (extracted from DC/2/MeOH from 98/2 to 95/5) to give the title compound 4-tris-butoxycarbonylamino-5-(2-aminocarbazinyl-4) -Fluorine-σ-Bilo-in-1-base)_5_oxy-pentanoic acid methyl g (85%). 4-Tris-butoxycarbonylamino-5-(2-aminoforminylfluoro-pyrrolidinyl)-5-oxo-pentanoic acid methyl ester (0.361 g, 1 mmol) in THF/H20 The solution was cooled in an ice bath. LiOH (0.048 g, 2 mmol) was added. The mixture was stirred at low temperature for 3 hours, and the reaction solution was separated with ethyl acetate and a 1% aqueous solution of citric acid. Drying the organic layer with MgS04 and concentrating in vacuo to give 4- <RTI ID=0.0># </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Further purification is required. The above compound and a solution of N-hydroxybutylimine (0.361 g, 1 mmol) in 8 ml of DCM / 1,4-dioxane (2 / 1) were cooled in an ice water bath. DCC (0.23 g, 1.1 mmol) was added. After the mixture was stirred at room temperature for 1 hour, 2,3-dihydro-1H-isoindole (0.18 g, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, filtered to remove DCC and then rinsed with DCM. The organic solution was washed with a 10% aqueous solution of EtOAc and EtOAc EtOAc. Purification by flash column chromatography (extracting from 98/2 to 95/5 with cH2Cl2/MeOH) afforded [1-(2-amine-branyl- 4-fluoro-. -4_(1,3-Dihydro-isoindole-2-yl)-oxo-butyl]-aminodecanoic acid tert-butyl ester (83%). The previously prepared compound (0 Λ 62 g, 1 mmol) and sodium saliva (0.102 g, 1.5 mmol) were dissolved in acridine (4 ml). The solution was cooled to -20 0C. Phosphorus chloride (0.23 ml, 2.5 mmol) was added dropwise over 2 minutes, and the resulting mixture was stirred at -20 °C for 1 hour. The pyridine was removed in a high vacuum, and the crude product was washed with aq. Purification by flash column chromatography (eluting with hexane/EA = 1 / 3) afforded N? _B0C & [2-aminoisoindole] as a foam. _2_基)_5_oxypentanyl] glacial fluoropyrrolidine cyano group (Μ%). This compound was then dissolved in cold <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; The title compound is obtained in the form of a toffee. iHNMR (CDC13): 8.10-7.23 (m, 4H), 5.50 (s, 0 5 H), 5 34 (s, 〇 5 H) 5·01 (d, /= 9.3 Hz, 1H), 4.86-4.73 ( m,4H), 4.49 (brs,1H),4 〇7_3 8〇(m,2H), 2.78 (brs,2H), 2.63 (t,15.6 Hz, 1H), 2.50-2.42 (m,1H),2 36_2 21 (m, 2 il); MS (ESI) m/z: 345.1 (M+H)+, 367·1 (M+Na)+.

Pyridin-2·cyanotrifluoroacetic acid

The title compound was prepared in a similar manner as described in Example 1. NMR (CD3OD): 7.34-7.27 (m5 4H)5 4.87-4.81 (m? overlapped singlet at 4.86? 5H)? 4.40 (t5 7= 5.7 Hz, 1H)5 3.87-3.79 (m, iH)? 3.73.3 ^5 1H)? 2 ?? (dd? J= 7.2, 5.4 Hz, 2H), 2.37-2.12 (m, 6H); MS (ESI) m/z: 327.3 (M+H)+, 349.3 (M+ Na)+ 〇 益 m : Preparation 1 · "2_Amino-SL3-diyl group from 3_ dimethyl _5_ pentylene thiol 1-pyrrolidine-2 cyano trifluoroacetic acid

F〇f〇〇 20 200817323 Extracted with EtOAc. The organic layer was filtered with MgSCV and concentrated. The residue was purified with EtOAc / EtOAc (EtOAc) (EtOAc) The structure is as follows:

3,3-Dimethyl-5-oxo-pyrrole-1,2-dicarboxylic acid di-tertiary butyl g (298 mg, 0.95 mmol) in THF (6 mL) and water (6 mL The stirred solution was added to a solution of 丨.0 N lithium hydroxide (2.0 ml, 2.0 mmol). The reaction was stirred at 25 ° C for 1 hour. After removal of the THF in vacuo, the basic residue was acidified with EtOAc EtOAc andEtOAc. The organic layer was dried <RTI ID=0.0>: </RTI> <RTI ID=0.0> The structure is as follows:

In 2-tertiary-butoxymethylamino-3,3-dimethyl-glutaric acid μ tertiary _butyl ester (315 mg, 0.95 mmol) and HOBt (175 mg, 1.14 mmol) at 1, A solution of 4% dioxane (5 m£) in EDC (219 mg, 1.14 mmol) in CH^Cl2 (5 mL) was added. After 10 minutes at room temperature, the iso-porphyrin (135 mg, U4 mmol) in CH2C12 (2 mL) was stirred for 16 hours, then saturated aqueous solution of NaHC03 (10 mL), 1 N aqueous solution of citric acid (10) The reaction mixture was rinsed with mL) and concentrated brine (1 mL). The organic layer was dried over MgS04, then wept and concentrated. The residue was purified with EtOAc/Hexane (1:2) elute The structure is as follows:

2-tertiary-butoxycarbonylamino-5-(1,3-dihydro-iso-p-but-2-yl)-3,3-dimethyl-5-oxo in TFA (6 ml) The solution of tert-butyl valerate 36 (328 mg, 0.76 mmol) was scrambled for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo to afford TFA salt. 21 200817323 A solution of TFA in CH2C12 (8 ml) and a stirred solution of triethylamine (233 mg, 2.3 mmol) in hexanes and added to hexanes of di-ter-di-dicarbonate in CH2C12 (5 ml) 200 mg, 0.91 mmol) solution. After 30 minutes at 0 QC and 8 hours at rt, the reaction mixture was concentrated and purified eluting with CH2 C12 (30 ml) and 1 N aqueous citric acid (10 ml). The organic layer was dried with MgSO 4 , filtered and concentrated. The residue was purified on a silica gel eluting with CH2Cl2 /MeOH (95:5) to afford the desired compound 37 (207 mg, 0.55 mmol, 61%, 2 steps). The structure is as follows:

In the 1,4-dioxane (5 mL), 2-tris-butoxycarbonylamino-5-(l,3-diindole-isoindol-2-yl)-3, a stirred solution of 3-dimethyl-5-oxopentanoic acid 37 (207 mg, 0.55 mmol) and HOBt (102 mg, 0.66 mmol) in E.sub.2 (127 mg, 0.66 mmol) in CH2C12 (4 mL) . After ι〇 min at room temperature, (S)-pyrrolidine-2-carboxamide (75 mg, 0.66 mmol) was added in ch2C12 (3 mL). After 16 hours, the reaction mixture was washed with a saturated aqueous solution of NaHC03 (10 mL), 1N aqueous solution of citric acid (1 〇mL), and concentrated brine (1 〇 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated. The residue was purified on a silica gel eluting with CH.sub.2/MeOH (95:5) to give the desired compound 38 (2 〇3 mg, 〇43 mmol, 78%).

In the order of [1-(2-aminoformyl-pyrrolecarbonyl)(6)-hydrogen(isohydrazin-2-yl)_2,2-dimethyl-7-oxo-butyl]-carbamic acid- Butyl g is 38 (2〇3 mg, 0.43 mmol), imidazole (43 mg, 0·64 mmol) and acridine (5 ml^_3〇〇c mixture, added to the dish with chlorine in 5 minutes) Phosphoryl chloride) (263 mg, 1.72 mmol), and the resulting white solid mixture was stirred for 1 hour at -30 C. The pale yellow opaque mixture was concentrated in vacuo and taken in CH2C12 and 1 N aqueous citric acid (5 mL) The organic layer was dried over MgSO.sub.4, filtered, EtOAc (EtOAc: EtOAc (EtOAc) , 85%).

30 minutes. The reaction mixture was concentrated in vacuo to give the title compound 39. lH NMR (CDC13? 300 ΜΗζ5 δ): 7.33-7.24 (m? 4Η)? 4.87-4.72 (m5 5Η) 4 35 (brs,1Η),3·83_3·75 (m,1Η), 3.68-3.60 (m , 1Η), 2.80 (d, 17·4 Ηζ, 1H) 2 G3 (d, 17.4 Hz, 1H), 2.34-2.05 (m, 4H), 1.33 (s, 3H), 1.27 (s, 3H). MS (ESI) m/z: 355.2 (M+H)+, 377.2 (M+Na)+.

Example 4: Preparation Amino-^ -^1 π ^ \ ro -μ- ^ A 1-pyrrolidin-2-cyanotrifluoroacetic acid

The title compound was prepared in a similar manner as described in Example 3. W NMR (CDCI3, 300 ΜΗζ, δ): 7.32-7.26 (m, 4Η), 4.91 ·4·74 (m 5Η) 4 (brs,1H), 3.79-3.72 (m,2H),2_91-2_67 (m , 3H), 2.27-2.16 (m, 4H), U6 (d ^ 6.6 Hz, 3H). 5 MS (ESI) m/z: 341.2 (M+H)+, 363.2 (M+Na)+ 〇Example V: Preparation of l-"2_Ammonia-Ml,3·士氲^引哚_2_基y3_乙人备" -- 基1_吼洛 bite-2-cyanotrifluoro-Sf acid

The title compound was prepared in a similar manner as described in Example 3. NMR (CDC13? 300 ΜΗζ? δ): 7.32-7.23 (m5 4Η)? 4.92-4.75 (m, 5Η)5 4.55 (brs,1Η), 3.75-3.72 (m,2Η),2.87-2.71 (m,2Η) ), 2.41-2.05 (m, 5Η), 1.67_1·43 • (m, 2H), 0_99 (t, J = 7·2 Hz, 3H). MS (ESI) m/z: 355.2 (M+H)+, 377.2 (M+Na)+. Implementation of life] Six: Preparation of 1-"2肇amino-3-indolyl-5-oxo-5-(3-di-n-decyl-5,6-dihydro-8沁 "1 41 triazole and "4,341 Pyrazin-7-yl)-pentamethylene 1-pyrrolidin-2-cyanotrifluoroacetate Ν-Ν f3c^n^\

The title compound was prepared in a similar manner as described in Example 3. lH NMR (D20? 300 MHz, δ): 4.90 (s5 1H), 4.86 (d5 J= 3.3 Hz? 1H)5 4.70 -4.64 (m, 1H)5 4.34 (s5 1H)5 4.26-4.20 (m5 1H) 4.14 (t. J = 5.4 Hz, 1H)? 3.95-3.91 (m, 2H), 3.75-3.54 (m, 2H), 2.62-2.60 (m, 3H), 2.30-1.88 (m, 4H), 0.94 (t, "/ = 6.0 Hz, 3H). MS (ESI) m/z: 414.2 (M+H)+, 426.2 (M+Na)+. Implementation {Column VII·• Preparation 1-Γ2-Amino_3-facet ethyl-5-gas-5-(3-12 to methyl earn 5,6-dihydro-8沁"1,2,41 triazole 『4,341 pyrazin-7-yl)-indenyl 1-pyrrolidin-2-cyanotrifluoroacetic acid

The title compound was prepared in a similar manner as described in Example 3. Ln NMR (D20? 300 MHz, δ): 4.92-4.69 (m? 3H)? 4.31 (brs, 1H), 4.24-4.19 24 200817323 (m,1H), 4.11 (t,5·4 Ηζ,1Η), 3·98-3·80 (m, 2H), 3.71-3.53 (m, 2H), 2.74-2.48 (m5 2H), 2.36-1.83 (m? 5H), 1.46-1.22 (m? 2H)? 0.79 ( t. J = 7.2 Hz, 1.5 H), 0.77 (t, /= 7.2 Hz, 1.5 H). MS (ESI) m / z: 428.2 (M+H)+, 450.2 (M+Na)+. Example 8: Preparation of 1-(2-amino-3,3-dimethyl-5-gas-5-(3-trifluoromethyl-5,6-dihydro-8Η-Π, 2,41 triazole) And "4,3-alpyrazin-7-yl V-pentyl-l-pyrrolidin-2-cyanotrifluoroacetic acid

The title compound was prepared in a similar manner as described in Example 3. lH NMR (CDC13? 300 ΜΗζ? δ): 5.21-4.76 (m5 3Η)5 4.50 (d? 7 = 13.2 Hz, 1H), 4.36-4.20 (m, 2H), 4.17-4.02 (m, 2H), 3.89 -3.80 (m,1H),3.77-3.69 (m, 1H), 2.84_2_72 (m,2H),2·46·2·02 (m,4H),1.33 (s,3H),1.27 (s,3H) ). MS (ESI) m/z: 428.2 (M+H)+, 450-1 (M+Na)+. Example 9: Preparation of 1-"2-amino-5-gas-5-(3-trifluoromethyl-5,6-dihydro-8-"1,2,41 triazole and 4,3-aln Than -7-based) - brewing base V11 Biro.定-2_gas-based two-gas acetic acid

The title compound was prepared in a similar manner as described in Example 3. lU NMR (CDC135 300 ΜΗζ5 δ): 5.01-4.99 (m? 2H)? 4.81-4.77 (m, 1H), 4.40-3.99 (m, 5H), 3.86-3.79 (m, 1H), 3.71-3.61 (m , 1H), 2.83-2.64 (m, 2H), 2.42-2.08 (m, 6H). MS (ESI) m/z: 400.1 (M+H)+, 4221. 25 200817323 Really dragging Example 10: Preparation of N-"2_(3-gas-Momo V propyl 1-3-"2-(2-Cyanyl-吼略校-κ其乌气-ethyl乱基1 -3-methyl-butylamine

3-Tris-butoxycarbonylamino 3-methyl-butyric acid (2.17 g, 10 mmol) and N-hydroxybutane in 20 mL DCM/l, 4c oxane (2:1) The solution of quinone imine (U5g, 10 mm 〇1) was cooled in an ice water bath. DCC (2.3 g, 11 mmol) was added. The mixture was scrambled at room temperature for 1 hour and then 2·(3-phenylphenyl)-cyclopropylamine (2.5 g, 15 mmol) was added. After stirring at room temperature for 4 hours, the mixture was filtered to remove DCC and then rinsed with DCM. The organic solution was washed with a 10 〇 / 〇 aqueous citric acid solution and a saturated aqueous solution of NaH EtOAc, and dried over EtOAc EtOAc. Purification of 3_N+butoxycarbonylamino-N'-((1R,2S)_2_(3-chlorophenyl)cyclopropyl)_3 by flash column chromatography (extracted with Hexane/CHfU/EAMAl) Methylbutamol 2,2,2·trifluoroacetic acid (88%). This compound was dissolved in cooled trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 10 minutes and evacuated overnight. It is too sugary &gt; amino-N_((1R,2S)_2_(3_chlorophenyl)cyclopropyl)_3.methylbutyramine. A solution of the above compound ( 〇. 38 g, 1 mmol) in dry THF (6 ml) was added to EtOAc (3. The resulting mixture was filtered to remove K.sub.2.sub.3 and the filtrate was concentrated in vacuo. After the oily residue was diluted with THF (3 ml), (S)-l-(2-bromoethyl)pyrrolidine-2-cyano group was added dropwise. The resulting mixture was stirred at room temperature overnight, washed with EtOAc EtOAc EtOAc. Purification by flash column chromatography eluting with EtOAc EtOAc W NMR (CDCI3) (5/1 mixture of cis/transamined isomers): 8.65 (d, J = 3.3 Hz, 5/6H), 8.45 (d, = 3.3 Hz, 1/6H), 7· 18_7·09 (m,3H),7.02-6.98 (m,1H), 26 200817323 4.77-4.74 (m,5/6H),4.71 (d,2·4 Hz,1/6H),3.63-3.38 (m , 4H, overlapped two singlet at 3.46, 3.44), 2.93-2.89 (m, 1H), 2.35-2.15 (m, 6H, overlapped singlet at 2.32), 2.06-1.99 (m, 1H), 1.26-1.43 (m, 8H, overlapped singlet at 1.20). Example 11: Preparation of 3-(2-((2S,4SV2-cyano-4-fluoropyrrolidin-1-yl-V2-cycloethylamino)-3-indolyl-N-((lS,2SV2-) (5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)cyclopropyl)butanamine

The title compound was prepared in a similar manner as described in Example 10. iHNMRCCDCl;) (3/1 mixture of cis/transamined isomers)·· 8.81 (dd, J= 11.7, 3.3 Hz, 3/4H), 8.57 (br d? J = 11.7 Hz? 1/4H) , 5.54 (t? J= 3.3 Hz? 3/8H), 5.46 (t? J = 3.3 Hz? 1/8H), 5.37 (t? J= 3.3 Hz, 3/8H), 5.28 (t? J= 3.3 Hz, 1/8H), 4.96 (d5 J = 9.0 Hz, 3/4H), 4.84 (d, 9.0 Hz, 1/4H), 3.92 (dd, 23.4, 23.1 Hz, 3/4H), 3.78 (d, 3.9 Hz, 1/4H), 3.74 (d, 3.9 Hz, 1/4H), 3.68-3.62 (m, 3/4H), 3.49-3.28 (m, 3H), 2.79 (t, 15·6 Hz, 1 /4H), 2.71 (t, /= 15.6 Hz, 3/4H), 2.34-2.25 (m, 4H, overlapped singlet at 2.28), 1.58-1.46 (m, 2H), 1.17 (s, 3H), 1.16 ( s, 3H) 〇 Example 12: Preparation of N-((lS, 2RV2-(3-methane) cyclopropyl V3-(2-((2S,4SV2-mercapto-4-porto) The title compound was prepared in a similar manner as described in Example 10. WNMR (CDC13) (4/1 mixture of cis/transamined isomers) ): 8.41 (br d, /= 3·0 Hz, 4/5Η), 8.15 (br s, 3.0 Ηζ· 1/5Η), 7·17-6·99 (m, 4Η), 5.52 (t, / = 3·3 Ηζ, 2/5H), 5.42 (t, 3.3 Hz, 1/10H), 5·35 (t, /= 3.3 Hz, 2/5H), 5% (t, /= 3.3 Hz, 1/10H), 4.96 (d, 9·3 Hz) , 4/5H), 4.92 (d, /= 9.3 out, i/5H), 3 9i (dd, /= 23.4, 23.1 Hz, 4/5H), 3.77 (d, "/= 3.6 Hz, 1/5H ), 3.73 (d,3·9 Hz, 1/5H), 3.65-3.61 (m, 4/5H), 3.38 (q like, J= 16.5 Hz, 2H), 2.94-2.88 (m, 1H), 2.76 (t5 J= 15_3 Hz, 1/5H), 2.69 (t5 J= 15.3 Hz? 4/5H), 2.43-2.22 (m, 3H, overlapped singlet at 2.27), 2.05-1.99 (m, 1H), 1.24 1.16 (m, 8H, overlapped singlet at 1.16).

Example 13: By 3-(2-((2S,4g)-2U, red... group VN-((lS,2RV2-(4-methyl-yl-methyl)cyclopropyl-V3-

The title compound was prepared in a similar manner as described in Example 10 bNMR^CDCb) (3/1 mixture of cis/transamined isomers) mixture: S.29 (brd heart 8 fields, yeah, 6.80 d V rd , J".3Hz, 3/4H), 8.00 (br s, J = 3·3 Ηζ· 1/4H), 7.08 (d, h

3/8H), 5.24 (t, /= 3.0, 1/8H), 4.97 (d, /= 8·8 Hz, 1/4H) 4 % 8·8 Hz, 1/4H), 4 95 3/ 4H), 3.96-3.54 (m, 5H, overlapped singlet at 3. 3/4H), 3.96-3.54 (m, 5H, overlapped singlet at 3 2H), 2.88-2.82 (m, 1H), 2.73 (t, /= 15.6 Hz, 1/4]

,6·80 (d on 84 Hz 5.33 5

2H), 2.88-2.82 (m5 1H)? 2.73 (t5 J= 15.6 Hz, 1/4HV 2 ^ a T 2.45-2.23 (m? 3H5 overlapped singlet at 8H, overlapped singlet at 1 ·18) o

6 Hz, 3/4H), • l9'l.〇9

Example 14: Preparation of 3-(2-((2S,4SV2-j^) iv 28 200817323

The title compound was prepared in a similar manner as described in Example 10. w leg (CDCl3) (3/1 mixture of cis/transamined isomers): 8·43 (br d,j=3·3 he, 3/4Η), 8.42 (br s,3·3 Ηζ· 1/4Η), 7.20 (q like, 7 2 edge, iH), 6.94-6.81 (m, 3H), 5.51 (t, J=3·3 Hz, 3/8H), 5·43 (t, 3.3 Hz) , 1/8H), 5·34 (t, /= 3.3 Hz, 3/8H), 5·26 (t, J=3·3 Hz, 1/8H), 4.95 (d, 9·3 Hz, 1H ), 3.91 (dd, 23.7, 23.4 Hz, 3/4H)5 3.78 (d5 J= 3.6 Hz, 1/4H)5 3.74 (d? J= 3.9 Hz? 1/4H)? 3.66-3.61 .(m, 3/4H), 3·39 (q hke, 16.5 Hz, 2H), 2.95-2.88 (m, 1H), 2.74 (t, 15.3 Hz, 1/4H), 2.67 (t5 J 15.3 Hz, 3/4H) 2.45-2.22 (m3 3H, overlapped singlet at 2.27), 2·10_1·98 (m, 1H), 1.28-1.17 (m, 8H, overlapped singlet at 1.20). Example 15: Inhibition of DPP-IV activity DPP_IV is based on the method described by de Meester et al. (de Meester et al. (1996) J. Immun. Method 189. 99-105) (with minor modifications) Human semen purification. Briefly, the semen was diluted with 5 liters of this phosphate physiological saline and centrifuged at 900 x g for ten minutes. The supernatant was again centrifuged at 1 〇 5, 〇〇〇 xg for 12 〇, minutes to separate the prostasome and the seminal plasma. The prostatic bodies, ie pellets, and the seminal plasma, ie the supernatant, were used for further purification of DPp-IV. Pure (peuet) is washed twice with 2〇mM 1^41(:1(^7.4), then at 2〇11^1^^0(1)117.4), 1%1^〇11 and _100 Incubate for one hour at 4 °C. The previously produced solution was centrifuged at 4 Torr, 〇〇〇xg for 10 minutes before dialyzed with 20 mM Tris_HCl (pH 7.4), 70 mM NaCl and 0.1% Triton X-100 to remove the month. Il lists the residues of the prostasome. The solution was then passed through a DEAE-Sepharose fast flow column (2.6 x 10 29 2008 17323 cM) equilibrated with 20 mM Tris-HCl (pH 7.4) and 0.1% Triton X-100 at a flow rate of 2 mL/min. The column was then eluted with a linear gradient flow rate of 3 mL/min at 300 mL NaCl (70 to 350 mM). The positive fractions were concentrated and adjusted to :·5 M Tris-HCl (pH 8·0) to: ΡΗ 8_0, and then added to the adenosine deaminase-Sepharose column. The column was prepared as described in de Meester et al. After the column was rinsed with 10 column volumes of equilibration buffer and an equivalent amount of 50 mM Tris-HCl (pH 7.4) containing M·5 MNaCl and 0.1% Triton X-100, it contained ojo/o Triton X- 100% mMTris-HCl (pH 8.0) rushed DPP-IV. The supernatant was subjected to treatment at 20 《c at 20:1:1, and 1% of 1*^-100 was treated for one hour to denature it. The resulting solution was treated as described above to give purified DPP-IV. The dynamic constants of f DPP-IV were measured as follows: All reactions were carried out in PBS with H-Gly-Pr〇_pNA: as a genre in the presence of 1 〇 nM DPP-IV. The reaction was monitored at 0D 40511111. The initial rate was measured when less than 10% of the receptors were used up. - The steady state parameter ^at(=Vmax/[EM k is determined by the initial 300 second initial rate measurement at the 0.5-5 Km receptor concentration. The values are determined by Lineweaver-Burk plots (which utilize classical Michaelis-Menten) The linear regression of the equation (Equation 1) is obtained. The system is calculated from Vnm/[E], and the molecular weight of DPIMV is set to 85,000. V〇=V 师师知+冏) (Equation 1) (where v〇 is the starting rate [s] is the acceptor concentration, Vmax is the maximum rate, and L is the Mcadis constant. The correlation coefficient is better than 0.990 from beginning to end. : Several compounds of the present invention have been tested for their IC50 values for inhibiting DPP-IV. Purified human semen DPP_IV was performed in 2 mM Tris-HCl _ 8.0) or PBS at 37 °C. The receptor used for the measurement was 500 μΜ H-Gly-Pr〇-pNA. For the analysis of the solid concentration of the compound-concentration data points, IQ0 can be obtained from the Sigma plot. All tested compounds showed inhibitory activity against the current capture. It is striking that some of the compounds tested have a busy value of (4). Other Embodiments All of the features disclosed in this specification can be combined in any manner. The solidification feature 30 200817323 disclosed in this specification can be replaced by a replacement feature that satisfies the same, average 4 or similar target + ± one + &gt; unless there is another explicit table 7F, the parent feature of the revealed chromium is only An example of an equal or similar feature that is always a series. From the above, the basic features of the present invention can be readily ascertained by those skilled in the art, and the invention may be modified and modified without departing from the spirit and scope of the invention. E.g,

Compounds structurally similar to the pyrrolidine compounds of the present invention can also be made, screened for their inhibitory activity against DPP-W, and used to treat sputum type diabetes and are used in the practice of the present invention. Therefore, other embodiments are also within the scope of the patent application.

Claims (1)

200817323 X. Patent application scope 1. A compound whose structural formula is as follows: Wherein: R1 is hydrazine or CN; -R2 is hydrazine, halogen, nitro, cyano, amino, ·, alkyl, age, alkoxy, aryl, hetero, cyclo, hetero-wei, aromatic Base or heterocyclic aryl; RRR and R are each Ή, _, nitro, cyano, amino, secret, alkyl, ship, aryl, aryl, aromatic, ring, heterocyclic , an aromatic group or a heteroaryl group or R, R f, the carbon atom to which they are attached together form a three to eight membered ring, or r5, R and the carbon atom to which they are attached - form a three to a human element a ring, the three to human ring may have one or two heteroatoms, and the three to eight membered ring may have a halogen, CN, N〇2, _〇Ra, an alkyl group, an aromatic group, a heterocyclic aryl group, a halogen Base, -〇Ra, _C(〇)Ra, _SRa, _S(p)Ra, _s(〇)2Ra, -服^,, *C(0)〇Ra, -C(0)NRaRa,&gt; -〇 C(0)Ra &gt;-NRaC(0)Ra,&gt; -NRaC(0)0Ra, or -NRaC(0)NRa'Ra" substituent, which may be bonded to a cycloalkyl group or a heterocyclic ring One of an alkyl group, an aryl group and a heterocyclic aryl group is fused, and each of Ra, Ra' and Ra" is an anthracene, an alkyl group or an aromatic group; Π1 is 〇, 1, 2, 3, 4 or 5; η is 0, 1 or 2; W is CRbRb', NRb, 0 or S, wherein R^Rb' are each η, ghrelin, alkyl or aroma X; X is 〇, S or CRC(NRc'Rc"), wherein Rc, Rc' and Rc" are each H, alkyl or aryl; 32 200817323 γ is human, X, RdrA, human, _ human, /S,,RdN,S,,eight,RdN,S' Wherein Rd is H, an alkyl group or an aryl group; and hydrazine is NReRe', wherein each of them is Η, alkyl, alkoxyalkyl, _alkyl, cycloalkyl, heterocycloalkyl, An aryl group, an aralkyl group, a heterocyclic aryl group or a heterocyclic aralkyl group, or Z is f NReR6', which together are a three to eight membered ring, which may have one or two heteroatoms, The three- to eight-membered ring may have halogen, CN, N02, -OR', alkyl, aryl, heterocyclic aryl, A alkyl, -〇R, -C(0)R, -SR, -S ( 0) R', -S(0)2R, -NR R, -C(0)0R, . -C(0) - 'R' -m'C(0)R", -NR'C(0) 0R" or -NR'C(0)NR''R', R group, the three- to eight-membered ring may be fused to one of a cycloalkyl group, a heterocycloalkyl group, an aromatic group, and a heterocyclic aromatic group, R' And R" and R"' are each a fluorene, an alkyl group or an aromatic group. 2. The compound according to claim 1, wherein each of R3, R4, R5 and R6 is hydrazine, halogen, nitro, cyano, amino, silk, silk, dentate, alkoxy, Aryloxy, aralkyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl. 3. The compound of claim 2, wherein X is chjsjjj2. 4. The compound of claim 3, wherein η is a compound according to claim 4, wherein γ and Μ are both signals and γ and R6 are both H. Fo^oo 33 200817323 The compound of claim 4, wherein R3, R4, R5 and R6 are both η Ο 7. The compound of claim 4, wherein R3 is CHS and r4 And R5盥r6 is a compound of the third aspect of the patent application, wherein η is 〇. ^ The compound of claim 8, wherein r3 and r4 are both cH3 and r5 and R are both H. A compound as described in claim 8 wherein RS is CHS and Μ, y and both are H. 〃子~I is a compound as claimed in claim 1, wherein R3 and R4 and the carbon to which they are attached are opened to form a cyclopropyl ring. 10 ^ The compound of claim 11, wherein x is CHNH2. 13. The compound of claim 12, wherein η is 1. For example, the compound of claim 1 wherein η is 1. 15. The compound of claim 1, wherein the compound is: .岣卜 7(A) 34 200817323 H2n CN 16. A compound with the following structural formula: Wherein: R1 is Η or CN; 112, 113, :^4, 115, 116, 117 and 118 are each 11, halogen, nitro, cyano, ammonia 35 200817323, perylene, alkyl, iS alkyl , alkoxy, aryloxy, arylalkyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl; m is 0, Bu 2, 3, 4 or 5; η is 0, 1, 2, 3 or 4; 〇 is 0, 1, 2 or 3; W is CRaRa', NRa, 0 or S, of which Ra and Ra 'each is Η, halogen, alkyl or aryl; X is NRb wherein Rb is H, alkyl or aryl; Y is RCN 〇II RCN 〇II RCN , S, Wherein Re is H, alkyl or aryl; and S JL ί Z is NRdRd', wherein Rd is a three to eight membered monocyclic ring, and the three to eight membered monocyclic ring may have a halogen, CN, Ν〇2, - OR, alkyl, aryl, heterocyclic aryl, haloalkyl, -〇R', _c(〇)r', -SR &gt; -S(0)R &gt; -S(0)2R ^ -NR R &gt; -C(0)0R &gt; -C(0)NR R &gt; -0C(0)R &gt; -NR'C(0)R", -NR'C(0)0R" or -11 '0: (〇)^'" substituent; and 圮' is 1^, alkyl, alkoxyalkyl, haloalkyl, aralkyl or heterocyclic aralkyl; R', R" and R' Each of which is a hydrazine, an alkyl group or an aryl group, respectively. 17. The compound of claim 16, wherein R is a cyclopropyl ring. 18. The compound of claim 17, wherein The cyclopropyl ring has an aryl or heterocyclic aryl substituent. 36 200817323 19. The compound of claim 16, wherein η is 1 and 〇 is j. 2〇· as claimed in claim 19 The compound according to claim 20, wherein the compound is a cyclopropyl ring. The cyclopropyl ring has an aryl or heterocyclic aryl substituent. The compound of claim 21, wherein r3, R4, ^ and R8 are both h and R5 and R6 are both CH3. The compound of claim 22, wherein X is nh. The compound of claim 23, wherein w is CH2. 25 The compound of claim 23 Wherein w is CHF. • A compound according to claim 21, wherein X is nh. • A compound according to claim 16 wherein n is di, i, R3, r4, R ^ P8 tb ' ^ is H, and ^ and # are both Ch3. • The compound of claim 16 wherein the compound is: 37 200817323 f 29. A method for inhibiting a dipeptide-based peptide peptidase IV comprising contacting a compound described in the first item of the second peptide Peptidase. 3 30: A method for inhibiting dipeptide peptidase w, which comprises contacting dipeptide peptidase w with a compound described in claim 16 of the patent specification. 31. A method of treating n-type diabetes comprising administering an effective amount of a compound of claim 1 to a patient in need thereof. &amp; % * ' Μ · A treatment for type 11 diabetes comprising administering an effective amount of the compound described in claim 16 to a patient in need thereof. 38 200817323 VII. (1) The case is designated as: Figure _ Figure (2). The components of the figure are simple symbols: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: P070031-TW 4