TW201000096A - Four-membered ring-condensed pyrrolidine derivatives, and preparation method and medical use thereof - Google Patents

Abstract

The present invention is directed to a new four-membered ring-condensed pyrrolidine derivative represented by formula (I) [wherein each substituent in formula (I) has the same meaning as described in the specification], preparation method thereof, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, especially a dipeptidyl peptidase IV (DPPIV)inhibitor.

Description

201000096 ' IX. Description of the invention: * [Technical field to which the invention pertains] ' The present invention relates to a novel pyrrolidine four-membered ring derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent It is used as a dipeptidyl peptidase inhibitor (DPPIV). [Prior Art] Diabetes is a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat, and egg white matter metabolism caused by defects in insulin secretion and/or function. Diabetes is a very old disease. It is caused by the absolute or relative lack of insulin in the human body. The blood glucose level is increased, and then the sugar is discharged from the urine, and there are polydipsia, polyuria, polyphagia, - weight loss, dizziness. , fatigue and other symptoms. Dicformyl-IV (DPPIV) is a serine protease that cleaves N-terminal dipeptidase in a peptide chain containing a proline residue at the secondary end, despite the physiological effects of DPPIV on mammals. Not fully confirmed, but it plays an important role in neuroenzyme metabolism, T-cell initiation, cancer cell metastasis into the endothelium, and HIV virus entry into lymphoid cells. (W098/19998). Recently, studies have shown that DPPIV can block the secretion of glucagon-like peptide (GLP)_1, in particular, it can cleave the N-terminal group-propadipeptide enzyme in GLP-1 from the active form of GLP-1. (7_36) NH2 degraded to inactive GLP-1 (9-36) NH2 (Endocrinology, 1999, 140: 5356 to 5363). Due to physiological conditions, the half-life of intact GLP-1 in the circulating blood is very short, and the inactive metabolites after DPPIV degrades GLP-1 can bind to GLP-1 5 94334 201000096 • Receptor antagonistic activity GLP-1, thus shortening the pair. The physiological inverse of GLP·1 should be. DPPIV inhibitors completely protect endogenous and even exogenous GLP-1 from being inactivated by DPPIV, significantly increasing the physiological activity of GLP-1 (5 to 10 fold) due to GLP-1 secretion of insulin It is an important stimulator and can directly affect the distribution of glucose, so Dppiv inhibitors have a good effect on the treatment of non-insulin-dependent diabetes mellitus (NIDDM) (US6110949). SUMMARY OF THE INVENTION The present invention relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

And R2 wherein: I and R2 are each independently selected from hydrogen, alkoxy, halogen or hydroxy group © or Ri and I together form a carbonyl group; a bicycloalkyl group, a cyclyl group or a heteroaryl group. I is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, decyl, hydroxybicycloalkyl, hydroxytricycloalkyl, and further, the present invention includes a compound represented by the following formula (IA) or a pharmaceutically acceptable compound thereof Salt:

Wherein: 94334 6 201000096 'R3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl. Another aspect of the invention relates to a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein the formula (1) is in the form of a pharmaceutically acceptable free form or an acid addition salt, the salt The salt formed with the following acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, sulfuric acid, acid acid, citric acid, acetic acid or difluoroacetic acid, preferably hydrochloric acid or trifluoroacetic acid. Specifically, the compound of the formula (1) of the present invention includes the following compound 0 but is not limited thereto:

The present invention relates to a process for the preparation of a compound of the formula (I), which process comprises the steps of: 〇Μ 'COOEt [n 乂, COOEt b〇c boc t starting material (2R)_1·t-butoxycarbonyl-5 -Hydroxypyrrolidinecarboxylic acid acetamidine is reacted with 2,6-lutidine and N,N-dimethylaminopyridine and trifluoroacetic anhydride in a toluene solvent at room temperature to obtain (R)-K tert-butoxy Alkylcarbonyl-2, anthracene dihydrogenate ethyl 2-carboxylate;

(R)-l-Secondoxycarbonyl-2,3_dihydro „Bilo-2-carboxylic acid B 7 94334 201000096 'Ethyl ether and triethylamine in cyclohexane solution and dichloroethane The helium cyclohexane solution is reacted in an oil 'bath to give (lR,3R,5S)-2-tert-butoxycarbonyl-7,7-dichloro-6-o-oxy-2-aza- Bicyclo[3.2.0]heptane-3-carboxylic acid ethyl ester;

The obtained (lR,3R,5S)-2-tert-butoxycarbonyl-7,7-dichloro-6-oxirane-2-aza-double soil [3.2.0] gigazepine-3- Ethyl vinegar and gasification of methanol oxime solution and activated ruthenium are reacted at room temperature to obtain (18,311,58)-2-t-butoxycarbonyl-6-sideoxy-2-aza-bicyclo[3.2 .0] heptane_3_carboxylic acid ethyl ester;

The obtained (1 S,3R,5S)-2-t-butoxycarbonyl-6-sideoxy-.2•gas-bicyclo[3.2.0]heptane-3-carboxylic acid ethyl ester in dichloro a haloformation reaction or a reduction reaction in a methane solvent to obtain a pyrrolidine and a four-membered ring compound in which a carbonyl group is substituted by R1, R;

Boc COOEt

To a solution of diisopropylamine in tetrahydrofuran, a solution of n-butyllithium in tetrahydrofuran is added dropwise, and after completion, the reaction is added dropwise to the compound substituted by R1 and Rs, and further reacted to obtain an ester-terminated pyrrolidine and a four-membered ring compound; 94334 8 201000096

COOEt

The ester group of the COOH is turned over. The rhodamine and the four-membered ring compound are reacted with lithium argon oxide in an ice bath under an ice bath and then subjected to acidification and hydrolysis by 1N hydrochloric acid to obtain a 0-r-decane-tetra-cyclic carboxylic acid compound;

COOH

Boc

The pyrrolidine and four-membered cyclic carboxylic acid compound obtained by boc is reacted with pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate in an acetonitrile solvent at room temperature overnight to obtain a pyridyl-?

R1 Η boc UNH2 The pyrrolidine and four-membered cyclic guanamine compound is reacted with a solution of hydrochloric acid in diethyl ether to remove the amino-protecting group to obtain the hydrochloride salt of the pyrrolidine and four-membered ring 2-carbamide compound; R2

(I) The obtained pyrrolidine and four-membered ring-2-meramine compound hydrochloride in acetonitrile solvent with triethylamine, R3-CH(NHB0C)-C00H and 1-hydroxybenzotriazole and 1-B In the presence of benzyl-3-(3-dimethylaminopropyl)carbodiimide, the reaction is carried out in a chamber at 9 94334 201000096 - the temperature is then dehydrated to a cyano group, and the protecting group is removed to give the formula (1): a compound; wherein: R! and R2 are each independently selected from the group consisting of hydrogen, alkoxy, halogen or hydroxy, and the core and R2 may together form a carbonyl group; R3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, Hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl. Further, in the above preparation method, the obtained compound of the formula (I) is purified and directly subjected to an ice bath reaction in an acid dichloromethane solution to obtain an acid addition salt product. The acid described therein is hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. Preferred is hydrochloric acid or trifluoroacetic acid. Further, the present invention relates to a compound of the formula: which is an intermediate of the synthesis of the compound of the formula (I):

Still further, the present invention relates to a process for the preparation of the above-mentioned intermediate compound of the formula, comprising the steps of: 0 N ^COOEt COOEt ^oc boc starting material (2R)-1-secondbutoxymethyl_5-carbyl. It is reacted with 2,6-di-ylpyridine and guanidine dimethylaminopyridine and diacetic anhydride at room temperature to obtain a third butoxycarbonyl group. Dioxan 11 biro-2-carboxylic acid ethyl ester; 94334 10 201000096 COOEt

COOEt 9" boc obtained a ring of (R)-l-t-butoxycarbonyl 2,3-dihydropyrrole-2·carboxylate and diethylamine in cyclohexane and dichloroacetamidine The hexane solution is reacted in an oil bath to give (lR,3R,5S)-2-tert-butoxycarbonyl-7,7-dichloro.6_ oxo-2-aza-bicyclo[3.2.0] Heptane-3-carboxylic acid B g; 〇y η

(lR,3R,5S)-2-Tertoxycarbonyl-7,7-dichloro-6-o-oxy-2-aza-bicyclo[3.2.0]heptane-3-carboxyl obtained by Cl Ethyl acetate is reacted with a chlorinated sterol solution and activated lysate at room temperature to obtain (18,311,5 phantom _2_t-butoxy yl-6-sideoxy-2_aza-bicyclo[ 3.2.0] ethyl heptane-3-carboxylate;

Ethyl (1 S,3R,5S)-2-tert-butoxycarbonyl-6·t-oxy-2_aza-bicyclo[3.2.0]heptane-3-carboxylate obtained in dichloromethane a toothing reaction or a reduction reaction in a solvent to obtain a pyrrolidine-tetra-membered ring compound in which a carbonyl group is substituted by R1 or R2;

Η

Boc

COOEt 94334 11 201000096 To a tetrahydrofuran solution of diisopropylamine was added dropwise a tetrahydrogenate solution of n-butyllithium, and then the reaction was added dropwise to the R2-substituted pyrrolidine and four-membered ring compound, and further reacted. Cool base-turned sputum burnt and four-membered ring compound;

The obtained ester-based inverted pyrrolidine and four-membered ring compound is reacted with lithium hydroxide in an ethanol bath in an ice bath and acidified by 1N hydrochloric acid to obtain a 0-r-decane-tetra-cyclic carboxylic acid compound;

Boc

C00H

The obtained pyrrolidine and four-membered cyclic carboxylic acid compound is reacted with pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate in an acetonitrile solvent at room temperature overnight to obtain a pyrrolidine and a four-membered cyclic guanamine compound;

The resulting pyrrolidine and four-membered cyclic guanamine compound is reacted with a solution of hydrochloric acid in diethyl ether to remove the amine protecting group to give the hydrochloride salt of the pyrrolidine and the four-membered ring. Further, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier 12 94334 201000096. Further, the present invention relates to the use of a compound of the formula (i) or a salt thereof for the preparation of a medicament for dipeptidyl peptidase (DPPIV) inhibitor. Unless stated to the contrary, the following terms used in the specification and claims have the following meanings: "Alkyl" means an independent group or as part of another group, including straight having from 1 to 20 carbon atoms. a chain or branched alkyl group, preferably having a straight or branched alkyl group of up to 10 carbon atoms, more preferably a linear or branched alkyl group having from 1 to 8 carbon atoms, such as methyl, ethyl, Propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4_3 Mercapto-pentyl, decyl, decyl, undecyl, dodecyl and various branched isomers, etc., these groups can be further step by step! Substituted to 4 substituents selected from dentate, such as fluorine, bromine, chlorine or iodine or triaminomethyl, alkyl, alkoxy, aryl, aryloxy, aryl (aryl) Or diaryl, arylalkyl, arylalkyl alkoxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, amine, hydroxy, hydroxyalkyl, decyl, hetero Aryl, heteroaryloxy, heteroarylalkyl, heteroaralkyloxy, aryloxyalkyl, thioalkyl, thioarylalkyl, aryloxyaryl, arylamine, arylcarbonylamine Base, nitro, cyano, fluorenyl, halogenated alkyl, trihalogenated. "Cycloalkyl" refers to a separate group or as part of another group, which refers to a cyclic hydrocarbon group having a saturated or partially unsaturated (having fluorene or two double bonds), said group The group has 1 to 3 rings, including a monocyclic ring group, a bicycloalkyl group, a tricycloalkyl group, the group having 3 to 2 carbon atoms, and 94334 13 201000096 preferably having 3 to 1 carbon atoms. Cyclone' These rings may form a fused ring with one or two aromatic rings, such as aryl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and ring. Octyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, Q, octagonal, octagonal, fluorene, fluorene, 0, φ, The group may be optionally substituted by 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, hydroxyalkyl, alkylamino, A pendant oxy group, a fluorenyl group, an aryl decylamino group, an amine group, a nitro group or a cyano group. "Halogen" means an independent group or as other groups -chloro, 4, #, fluoro, iodo and trifluoromethyl, preferably chloro or fluoro. "Aryl" means an independent group or as another A part of a group means a bicyclic aromatic group having 6 to .10 carbon atoms (you:: group, naphthyl group including naphthyl group, 2. naphthyl group), and may also be included as needed The additional ring is fused to a stone or a heterocyclic ring (eg, an aryl, cycloalkyl or heterocycloalkyl ring such as:

94334 14 201000096 may also be substituted by 1, 2, or 3 groups, which are selected from the group consisting of a hydrogen atom, a dentate, a haloalkyl group, an alkyl group, an alkoxy group, a haloalkoxy group, an alkenyl group, a trifluoromethyl group. , trifluoromethoxy, alkynyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl , arylalkoxy, azaaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, makeup group, including 1 or Amino group of 2 substituents (the substituent may be selected from an alkyl group, an aryl group or other aryl compound mentioned in the definition herein), an alkyl fluorenyl group, an aryl fluorenyl group, an alkylamino group, a aryl group Alkyl fluorenyl, alkoxy fluorenyl, amino aryl, alkyl methoxy, aryl methoxy, alkyl fluorenyl, aryl fluorenyl, aryl sulfinyl, An arylsulfinylalkyl group, an arylsulfonylamino group or an aryl fluorenylamino group and/or any of the substituents mentioned herein. "Heteroaryl" means an independent group or as a part of another group, which refers to a 5- or 6-membered aromatic ring having 1, 2, 3 or 4 heterologous hazelnuts. For example, nitrogen, oxygen or sulfur, these rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring (for example thiol) and possibly N-oxide. The heteroaryl group may include any of 1 to 4 substituents such as any of the substituents defined above for the alkyl group. Heteroaryl groups include the following structures: heart, &, &, °, 〇α, , heart, 〇: y,

94334 15 201000096

The present invention adopts the following technical scheme. The preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

Wherein 'raw material (2R)-1-tert-butoxy-cut-5--perylene-n-pyrene-pyrrolidine-2-carboxylic acid ethyl ester in toluene solvent with 2,6-dimercaptopyridine and hydrazine, hydrazine - dimethylamino 0-pyridine and trifluoroacetic anhydride are reacted at room temperature to obtain ethyl (r)- 1 -t-butoxy-yl-2,3-dihydropyrrole-2-carboxylate; 1-cyclobutoxycarbonyl 2,3-dihydropyrrole-2-carboxylic acid ethyl ester and triethylamine in cyclohexane solution and dichloroacetic acid chloride in cyclohexane solution in oil bath 38 ° C The reaction is carried out to give (lR,3R,5S)-2-tert-butoxy-yl-7,7-dis-6-o-oxy-2-azabicyclo[3.2.0]heptane-3- Ethyl carboxylate; the (ir,3R,5S)-2-tert-butoxycarbonyl-7,7-dichloro-6-oxo-2-azabi-bicyclo[3.2.0]g Ethyl alkyl-3-carboxylate is reacted with ammonium chloride in methanol and activated zinc powder at room temperature to give (lS,3R,5S)-2-16 94334 201000096 'tributoxy-based winter side oxy group -2-Aza-bicyclo[3 2 〇]heptane _3_slow acid B. (1S,3R,5S)-2-tert-butoxymethyl _6_sideoxy_2_ Aza-bicyclo[3.2/]heptane·3·decanoic acid B is intended to be oxidized or reduced in a solvent of methylene chloride. A pyrrolidine-tetra-terminated ring compound in which a carbonyl group is substituted by R^R2, a solution of n-butyllithium in tetrahydrofuran is added dropwise to a solution of diisopropylamine in tetrahydrofuran at -78 C, and the reaction is added dropwise after 30 minutes. In the Ri, R2 substituted pyrrolidine and four member ring compounds, the reaction is carried out at -78t: to obtain an ester-inverted pyrrolidine and four-membered ring compound; the ester-inverted pyrrolidine-indenyl four-membered ring compound is in an ethanol solvent. It is reacted with lithium hydroxide in an ice bath and then subjected to acidification and hydrolysis by 1N hydrochloric acid to obtain a pyrrolidine and four-membered cyclic carboxylic acid compound; the pyrrolidine and four-membered cyclic carboxylic acid compound in acetonitrile solvent with pyridine, ammonium hydrogencarbonate and dicarbonate The third butyl ester is reacted at room temperature overnight to obtain a pyrrolidine and a four-membered cyclic guanamine compound; η is compared with the oxime and the four-membered cyclic guanamine compound is reacted with a solution of citric acid in diethyl ether to remove the amine protecting group. . The hydrochloride salt of a pyrrolidine and a four-membered ring 2-nonylamine compound; the pyrrolidine and four-membered ring _2 ❹ carbamide compound hydrochloride in acetonitrile solvent with triethylamine, R3_CH (NHB0C)-C00H and 1-Phenylbenzotrisole and 1-Ethyl_ In the presence of (3-didecylaminopropyl)carbodiimide, the reaction is carried out at room temperature, and then the decylamine is dehydrated to a cyano group, and the protecting group is removed to obtain a compound of the formula (I);

Ri and R2 are each independently selected from hydrogen, alkoxy, halogen, thiol, or R! and R2 may together form a carbonyl group; I is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkane Or a hydroxydicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl group. The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound or a salt thereof and a pharmaceutically acceptable carrier, Or the use of a compound of the general formula of the invention or a salt thereof for the preparation of a medicament for the dipeptidyl peptidase inhibitor. In other words, the present invention also provides a composition comprising a pharmaceutically effective amount of the above compound, and the use of the compound for the preparation of a dipeptidyl peptidase inhibitor. The following examples are provided to further describe the present invention', but these examples are not intended to limit the scope of the invention. @Example The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass-(Ms). The NMR shift (δ) is expressed in units of parts per million (ppm). The measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was determined to be decyl sterol (CDWD), deuterated chloroform (CDCI3), and the internal standard was trimethyl sulphur (TMS). The chemical shift was 1 (T6 (ppm). The unit was measured by FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: ❿ Therm, model: Finnigan LCQ advantage MAX). The average inhibitory rate of kinase and IC5G value were determined using Novo Star microplate reader (BMG, Germany) Thin layer tannin extract is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet column chromatography. Generally, Yantai Huanghai Tanji 200 to 300 mesh tannin is used as carrier. CD3OD: deuterated methanol; CDC13: deuterated chloroform; 18 94334 201000096 Example 1 '(lS ,2(2S),3S,5S)-2-[2-Amino-2-(3-hydroxy-adamantane-bu)-ethenyl]-3-cyano-6,6-difluoro- 2. Aza-bicyclo[3.2.0]heptane trifluoroacetate

Preparation of (R)-l-t-butoxycarbonyl-2,3-dihydropyrrole-2-carboxylic acid ethyl ester lb In a dry three-necked flask, (2R)-1·t-butoxy group was added. 5-hydroxy 0 σ ratio 11 each of the 2-carboxylic acid 2-carboxylic acid ethyl S (17 g, 65.6 mmol), dissolved in 30 ml of toluene with stirring, cooled to _60 ° C, added 2,6 _ 曱Pyridine (458 ml, 0.394 mmol) and N,N-dimethylaminopyridine (0.159 g, 1.31 mmol) 'At this temperature, trifluoroacetic anhydride (lh86 to 85 3 mmol) was added dropwise, and the mixture was dropped in 15 minutes. , slowly rise to room temperature. Reaction for 2 hours. The reaction was followed by thin layer chromatography, the starting material disappeared, and the reaction was quenched by the addition of saturated sodium chloride (5 〇ml) solution, and then glacial acetic acid (23 6 mg, 〇394 mm〇1) aqueous solution was added, and ethyl acetate (50 ml×4) was extracted. . The organic phases were combined and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography to give the title product 94334 19 201000096. (R)-1-dibutoxycarbonyl-2,3-dihydropyrrole-2-carboxylic acid ethyl ester ib (11.6 g 'white solid), yield 73.4%. 'MS m/z (ESI): 242.2 (M+1). (lR,3R,5S)-2-tert-butoxycarbonyl_7,7-dichloro_6_sideoxy-2_aza-bicyclo[3.2.0]Gengyuan-3_slow acid Preparation of lc Under a nitrogen atmosphere, a dry three-necked flask was charged with (R)·T-butoxycarbonyl-2,3-dihydropyrrole-2-carboxylic acid ethyl ester lb (2 g, 8.3 mm 〇). 1) A solution of 100 ml of triethylamine (2.32 m of 16.6 mmol) in cyclohexane was added. Oil bath 〇 38 C was added dropwise a solution of brewing chlorine (1.15 ml '11.95 mmol) in cyclohexane (60 ml), and the mixture was dropped over 2 hours. After reacting for 20 minutes, it was cooled to room temperature, and the reaction was followed by thin layer chromatography, the material disappeared, filtered, and filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the title product (1,,,,,,,,,,,,,,,,,,,,,,,,,,,, - Bicyclo[3.2.0] Glycol-3-carboxylate ethyl ester lc (2.53 g 'yellow yellow oil), yield 87%. MS m/z (ESI): 351.3 (MI). Preparation of hydrazine (lS,3R,5S)-2-t-butyl-6-yloxy-2-aza-bicyclo[3·2.〇]Gengyuan-3-carboxylic acid ethyl ester Id 'In a dry-fired two-necked flask was added (lR,3R,5S)-2-secondbutoxy-based-7,7-dichloro-6-oxirane-2-aza-bicyclo[3.2. 0] Geng--3 -carboxylate ethyl ester lc (2.53 g ' 7.19 mmol) 'Dissolved in 12 mL of ammonium chloride (5.096 g '78.3 mmol) in methanol, stirred, and added activated zinc powder, room Stir vigorously under temperature. Filtered by washing with methanol (50 ml). The solvent was evaporated to dryness, and then ethyl acetate (1··················· Suppression, liquid reduction 94334 20 201000096, - concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title product 〇S, 3R, 5, butyl butyl-oxy-H bis[3. 1 (1.68 lean, sound by 1111 ", g steam oil), yield 82.6 % 〇MS m/z (ESI): 284.2 (M+1) US, 3R, 5S)_2_ third Preparation of ethyloxy-6,6-difluoro-2-nitroza-bicyclo[32〇]heptane-3-carboxylic acid ethyl ester le. Under ice bath, diethylaminotrifluorosulfur (0.781, 5.918) mmQl:) Dissolved in dichloromethane (20 ml) with stirring and added dropwise to 〇s, 3r, 5jS)_2_t-butyl-6-o-oxy-2-aza-bicyclo[3.2.0] Ethyl heptane-3-carboxylate ld (0.67 g, 2.367 mmol) in dichloromethane (20 mL). After the completion of the dropwise addition to room temperature, the temperature was maintained at 20 ° C and allowed to react overnight. A saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added and extracted with dichloromethane (50 ml×4), and the organic phase was combined and washed with saturated sodium chloride (50 ml). The dichlorohydrazine phase is dried over anhydrous magnesium sulfate. The filtrate is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography to give the title product (1S, 3R, 5S) Ethylcarbonyl-6,6-difluoro-2.aza-bicyclo[3.2.0]heptane-3-carboxylic acid ethyl ester le (0.38 g, white solid), yield 53%. MS m/z (ESI): 305.9 (M+1). Preparation of (13,38,58)-2-t-butoxycarbonyl-6,6-difluoro-2-aza-bicyclo[3.2.0]heptane-3-carboxylic acid ethyl ester If Propylamine (1.25 ml, 8.85 mmol) was dissolved in tetrahydrofuran (10 ml) with stirring. An n-butyl clock (1.18 ml, 2.95 mmol) was added dropwise at -78 °C. The reaction was carried out at -78 ° C for 30 minutes, and (1S, 3R, 5S) 2 · 3rd butoxide 21 94334 201000096 * carbonyl-6,6_diox_2_aza-bicyclo[3.2.0]g Burned 3-carboxylic acid ethyl acetate, 4 (0.6 g, 1.967 mmol). After reacting at -78 ° C for 1 hour, the reaction was quenched by dropwise addition of 1N ammonium sulfate solution (5 ml). Naturally rise to room temperature and react for 3 minutes. The mixture was extracted with EtOAc (EtOAc)EtOAc. The filtrate was concentrated by suction filtration and reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc EtOAc (td. 0] Geng Hyun ^ 3 - Resorcinic acid vinegar 1 f (〇 · 323 g, white solid), ❹ yield 54%. MS m/z (ESI): 328·3 (Μ +1). Preparation of (1 S,3S,5S)-2-(t-butoxy-based)_6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-carboxylic acid lg (lS,3S,5S)-2-tert-butoxycarbonyl-6,6-difluoroaza-bicyclo[3.2.0]heptane-3.carboxylic acid ethyl ester lf (〇.323 g, 1.059 mmol) dissolved in ethanol 'drops of IN lithium hydroxide (6.35 nU, 6.35 mmol), thin layer chromatography to trace the disappearance of the reaction materials' evaporated ethanol, added ethyl acetate (5 〇 ml), adjusted with 1N hydrochloric acid The mixture was extracted with ethyl acetate (50 ml) <4> and the organic phase was combined and washed with saturated sodium chloride (50 ml). It was suction filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was the titled crude product lg (white solid). MS m/z (ESI): 276·7 (Μ +1). Preparation of (13,38,58)-2-t-butoxycarbonyl-3-I-aminoindenyl-6,6-difluoro_2_aza-bicyclo[3.2.0]heptane ih under nitrogen atmosphere '(18,38,58)-2-(Tertibutoxycarbonyl)-6,6-di|1 22 94334 201000096 ._2-Aza-bicyclo[3.2.0]heptane-3-carboxylic acid 4(0 293 §, 1.057 111111〇1) Dissolved in acetonitrile (10 ml) with stirring. Add pyridine (o.iii ml, 1375 mmol), ammonium hydrogencarbonate (0.108 g '1 375 mmol) and two under ice bath. Dibutyl carboxide (0.345 g '1.586 mmol) was reacted overnight at room temperature. The thin layer was separated from the vertical reaction, and the solvent was evaporated to dryness. ethyl acetate (5 ml) was evaporated. After suction filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled product (1S,3S,5S)-2-t-butoxycarbonyl-3-aminomethyl-bromo-6,6-difluoro 2-Aza-bicyclo[3.2.0]heptane ih (〇. 151 g, white solid) yield 51.36%. MS m/z (ESI): 277·6 (Μ +1). Preparation of (^38,58)-6,6-:fluoro-2-aza-bicyclo[3.2.0]heptane_3·carbamidine hydrochloride li (18,38,58)-2- Third butoxycarbonyl-3-3-aminomethyl.hydrazino-6,6·didon-2-aza-bicyclo[3.2.0]heptane 111 (0.14", 0.546 111111〇1) dissolved in B Add 1N hydrochloric acid in diethyl ether solution in 趟 (10 ml), stir at room temperature, precipitate solids, trace the reaction disappearance by thin layer chromatography, evaporate the solvent under reduced pressure, and transfer to the title product (18, 38, 58)-6 , 6-difluoro-2-aza-bicyclo[3.2.〇]heptane-3·cartoamine hydrochloride u (white solid). Used directly in the next step. MS m/z (ESI): 177·2 (Μ +1). (18,2(28),38,58)-[2-(6,6-di|1-2-aza-bicyclo[3.〇]glycan_2-yl--along____ Preparation of (2S,3S,5S)-6,6-difluoro-2-aza-bicyclo[3·2·〇庚烧烧-3-甲94334 23 201000096 Hydrazine hydrochloride H (196 mg, 0.923 mmol) and triethylamine (450 ul, 3.23 mmol) were dissolved in 2 〇mI acetonitrile with stirring, and stirred in an ice water bath. Minutes, add 10 inl(S)-di-dibutoxycarboxyamino-(3_carbyl-adamantazine_1-yl)-acetic acid lj (〇.3 g, 0.923 mmol) in acetonitrile, hydrazine-hydroxybenzene And triazole (〇44 g, 3.23 mmol) and 1-ethyl_3_(3-dimethylaminopropyl)carbodiimide (0.44 g, 2.3 mm〇l), reacted at room temperature for 36 hours, thin The layer chromatography and the vertical reaction 'the disappearance of the raw materials' were evaporated to dryness under reduced pressure. The residue was dissolved in water (2 mL), and then extracted with ethyl acetate. The organic phase was washed successively with saturated sodium chloride and water and dried over anhydrous magnesium sulfate The mixture was suction filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj nitrogen _bicyclo[3.2.0]heptane_2_yl)-1-(3-hydroxy-adamantan-1-yl)_2_sideoxy-ethyl]-aminocarboxylic acid second vinegar 1 k (0.22 g 'White solids, yield 5%. MS m/z (ESI): 484.2 (M+1). (18,2(28),38,58)-[2-(3-Aminomethyl-based 6-6-difluoro-2-azino-bicycloindole [3.2.0]heptan-2-yl Preparation of 2-oxooxy_ι_(3_triethyldecyloxy-adamantyl)-ethyl]-carbamic acid tert-butyl ester 11 (18, 2(23), 33, 5 8)-[2-(6,6-Difluoro_2-aza-bicyclo[3.2.0]heptan-2-yl)-1-(3-hydroxy-adamantan-1-yl)_2_ side Oxy-ethyl]-amino phthalic acid terpene vinegar lk (0.17 g, 0.35 mmol) was dissolved in 5 ml of dichloromethane with stirring, and diisopropylethylamine was added at -78 ° C ( 〇2 ml, i 23 mm〇1)

And diethyl ruthenium acetonate (0.24 ml, 1.056 mmol), reacted at -78 ° C for 1 hour, then reacted at 〇 ° C for 2 hours, added 200 mg of Shiqi gum, 0.5 ml of methanol, 〇·2 ml of water, stir at room temperature overnight. Thin layer chromatography tracking anti-94334 24 201000096 should, the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and the residue obtained was obtained with a silicone tube.

Purification by chromatography to give the title product (1 s, 2 (28), 33, 58) - [2-(3-aminocarbazin-6,6-difluoro-2-aza-bicyclo[3.2 .0]heptane-2•yl)-2-oxooxy_1_(3-triethyldecyloxy-adamantan-1-yl)-ethyl]-aminodecanoic acid tert-butyl ester 11 ( 0.15 g, white solid), yield. MS m/z (ESI): 598·2 (Μ +1). (13,2(23),33,58)-[2-(3-Cyano-6,6-difluoro-2-aza-bicyclo[3.2.0]heptan-2-yl)·2- Preparation of the side oxy 4-(3-triethyl decyloxy-adamantane-; μ-ethyl)-amino decanoic acid tert-butyl ester 1m (18, 2 (28), 38, 58) - [2-(3-Aminoguanidino-6,6-difluoro-2-nitro-1 hetero-bicyclo[3.2.0]heptan-2-yl)-2-oxooxy-1 _(3_ Triethyl oxetyl-adamant-1-yl)-ethyl]-amino decanoic acid tert-butyl ester (0.22 g, 〇.368 mmol) was dissolved in 6 ml of pyridine with stirring and cooled to 3. 〇ι, add imidazole (52.6 g, 〇.77 mm 〇 1), and then add trichlorophosphonium phosphate (〇14 丨, 15 mmol). After the completion of the reaction, _3 〇 ° c reaction for 1 hour. The reaction was carried out with the addition of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was combined with methylene chloride. The organic phase was combined, washed with saturated sodium chloride solution and water, dried over anhydrous magnesium sulfate, filtered, The crude product of the title product 〇3,2(28), 38, 58) _[2_(3_cyano-6,6-difluoro-2_aza-bicyclo[32〇]heptan-2-yl) _2_Sideoxy_1_(3_triethyldecyloxy-adamantyl)-ethyl]-tert-butyl methacrylate lm (〇.25g White solid). MS m/z (ESI): 597.4 (M+1). 2(28),38,58)_2_[2_Amino-2_(3-carbyl-金刚院小基)_Ethyl]-3-cyano-6,6-difluoro-2-nitrogen Hetero-bicyclo[3.2.〇]heptane_three i acetic acid 94234 25 201000096 'Preparation of 1' will (lS,2(2S),3S,5SH2-(3-cyano-6,6-difluoro_2· Aza-bicyclo '[3.2.0]heptan-2-yl)-2-oxo-oxime 3-triethyldecyloxy-adamantan-1-yl)-ethyl]-carbamic acid third Butyl ester lm (0.18 g, 0.31 mmol) was dissolved in 5 ml of methylene chloride under stirring, and 0.2 ml of water was added thereto, and 0.71 ml of trifluoroacetic acid was added thereto under ice-cooling, and the mixture was reacted for 2 hours under ice-cooling. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Indole-2-(3-hydroxy-adamantan-1-yl)-ethinyl]-3-cyano-6,6-difluoro-2-aza-bicyclo[3.2.0]heptane-trifluoroacetic acid Salt 1 (871), white solid), yield 76.65%. MS m/z (ESI): 366.6 (M+1). lU NMR (CD3OD, 400MHz) 53.785 (s, 1H), 3.72-3.58 (m, 1H), 3.1-3.0 (m, 1H), 2.8-2.64 (m, 1H), 2.48-2.3 (m, 2H), 2.2-2.06 (s, 2H), 1.6-l.28 (m, 12H). ❿Example.2 (1S'2(2S),3S,5S)-2-[2·Amino-based oximeyl)_ propyl fluorenyl] winter cyano-6,6-difluoro-2·aza _ Bicyclo[3 2 〇]heptane hydrochloride

2 (13,2(23),38,58)-[2-(3_Aminomethylindenyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl )-U(1H_n引哚_3_ylmercapto)_2_sideoxy-ethyl]_ 26 94334 201000096 Preparation of the third butyl carbamate 2b will be (lS,3S,5S)-6,6- Difluoro-2-aza-bicyclo[3.2 〇]heptane decylamine hydrochloride li (212.5 mg, 1 mm〇i) was dissolved in 1 〇 plus acetonitrile with stirring 'Addition of diethylamine (0.48 8 ml, 3.5 mmol), stir for 1 minute in an ice bath, add (S)-2-t-butoxycarbonylamino _3_(1H_吲哚_3_yl)-propionic acid 2a (0.304 g, 1 mm〇) l), 1_hydroxy benzotriazole (〇 472 3.5 melons) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (〇.479g, 2 5 mmol) After the reaction was carried out at room temperature overnight, the reaction mixture was evaporated to dryness, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The residue obtained is purified by silica gel column chromatography to give the title product (1S,2(2S),3S,5S)_[2-(3-aminocarbazinyl-6,6-difluoro-2-aza -bicyclo[3.2.0]heptane_2_yl)-i_ (1H- Indyl-3-ylindenyl)-2-oxo-ethyl]-aminocarboxylic acid tert-butyl ester-2b (0.39 g 'white solid), yield 84 4%. MS m/z (ESI): 463.6(M+1) 〇❹(lS,2(2S),3S,5S)-[2-(3-cyano-6,6-difluoro-2-aza-bicyclo[3.2.0] heptane Preparation of 2-butan-3-ylmethyl)·2_sideoxy-ethyl]-carbamic acid tert-butyl ester 2c (18,2(25),38,58)-[2 -(3-Aminomethylmercapto-6,6-difluoro-2-aza-bicyclo[3·2·0]heptan-2-yl)-1-(ιη·吲哚-3-基甲Tert-butyl 2-ethyloxy-ethyl]-carbamic acid tert-butyl ester 2b (〇.39 g, 0.844 mmol) and imidazole (〇·121 g, 1.77 mmol) were dissolved in 5 ml of pyridine with stirring. Cool to _35 C and add a second gas wall (0.323 ml, 3.46 mmol). After the dropwise addition, the reaction was allowed to rise to room temperature after 1 hiring at -35 ° C. Concentrate the reaction under reduced pressure and add water '27 94334 201000096 The mixture was extracted with ethyl acetate. EtOAc (EtOAc m.) [2-(3-Cyano-6,6-difluoro_2-aza-bicyclo[3.2.0]heptan-2-yl)-1-(11 1-Indol-3-ylmethyl)-2-oxo-ethyl]-aminobutyl phthalate 2c (0.366 g' white solid), yield. MS m/z (ESI): 445.3 (M+1). (1 S,2(2S),3S,5S)-2-[2-Amino-3·(1Η- °引β朵-3-yl)-propanyl]_3_cyano-6,6-one gas Preparation of 2-Aza-bicyclo[3.2.0] Gengyuan Hydrochloride 2 (lS,2(2S),3S,5S)-[2-(3-Cyano-6,6-difluoro- 2-Aza-bicyclo[3.2.0]heptan-2-yl)-1-(1Η-indol-3-ylmethyl)-2-yloxy-ethyl]· Aminocarbamic acid dibutyl The vinegar 2c (0.366 g, 0.824 mmol) was dissolved in 6 ml of a chloramphenicol in an ice bath, and 1.89 ml of trifluoroacetic acid was added thereto, and the mixture was reacted at 〇 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 3-(111-11 嗓-3-yl)-propyl aryl]-3- ❹ cyano-6,6-difluoro-2-aza-bicyclo[3.2.0]heptane hydrochloride 2 ( 0.1 g, white solid), yield 50%. MS m/z (ESI): 345.1 (M+1). lU NMR (CD3〇D, 400MHz) 57.466(d, 1H), 7.254(d, 1H), 7.046-6.971(m, 3H), 5.14(t, 1H), 4.38-4.23(m, 2H), 3.5- 3.38 (m, 1H), 3.354-3.301 (m, 2H), 2.92-2.68 (m, 1H), 2.253-2.226 (m, 2H). Example 3 (18'2(28), 38, 58)-2-(2-Amino-3-methyl-anthracene)-3-ylyl-6,6-di 28 94334 201000096 - chaos _ 2-gas hetero-bis% [3.2.0] heptane trifluoroacetate

(13,2(28),33,58)-[1-(3-aminocarbamimidyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carbonyl) Preparation of -2-methyl-butyl]-aminobenzoic acid tert-butyl ester ^^(1S,3S,5S)_6,6·difluoro-2-aza-bicyclo[3.2.0]heptane_ 3_ Methionine hydrochloride li (98 mg, 0.46 mmol) was dissolved in 5 ml of acetonitrile with stirring, and diethylamine (0.224 ml, 1.61 mmol) was added. The mixture was stirred for 1 min in an ice bath, and (S) was added. -2-tert-butoxycarbonylamino-3-3-methyl-pentanoic acid 3&(〇.1〇6 g, 0.46 111111〇1), 1-hydroxybenzotriazole (〇217^161111111〇1) and 1-ethyl-3-(3-didecylaminopropyl)carbodiimide (〇22 g, 115 mm〇i). The reaction was carried out at room temperature overnight, and the reaction mixture was evaporated to dryness. The solvent was evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained is purified by silica gel column chromatography to give the title product 6-6-difluoro-2-aza-bicyclo[no]heptane-2-carbonyl]_2-methyl-butyl]-amine Tribasic vinegar 3b (0.24 g, white solid). MS m/z (ESI): 390.4 (M+1). (18,2(28),38,58)-[1-(3-Cyano-6,6-difluoro-2-aza-bicyclo[32〇]heptane-2-carbonyl)-2-A Preparation of butyl-butyl]-tert-butyl methacrylate 3e 94343 29 201000096 Will (13,2(23),38,58)-[1-(3-aminomercapto-6,6_2 Fluorine 2_gas-bicyclo[3.2.0]heptan-2-carbonyl)-2-methyl-butyl]-aminocarboxylic acid tert-butyl ester 3b (0.15 g, 0.386 mmol) was dissolved in 2 with stirring In the nu pirate, imidazole (0.055 g, 0.81 mmol) was added and cooled to _35 ° C, and trichlorooxo disk (0.147 ml, 1.58 mmol) was added dropwise. After the dropwise addition, it naturally rose to room temperature after 1 hour of _35t reaction. The reaction mixture was concentrated under reduced pressure, and water was added, and the mixture was extracted with methylene chloride. The organic phase was washed with saturated aqueous sodium chloride and water, dried over anhydrous magnesium sulfate, filtered and filtered. Purification by column chromatography gave the title product (1S, 2 (2S), 3S, 5S)-[l-(3j*_6,6-difluoro-2_aza-bicyclo[3.2.0]heptane_2 _carbonyl)_2_fluorenyl-butyl]-tert-butyl butyl citrate 3c (0.13 g, white solid), yield 9.9%. MS m/z (ESI): 372.3 (M + 1). NMR (CDCls, 400 ΜΗζ) δ 5.153 (m5 1H), 4.940 (d, 1H), 4.82 (brs, 1H), 4.059-4.015 (m, 1H), 3 74_3 6 (m' m)' 3.18-3.0 ( m, 1H), 2.85-2.68 (m> iH), 2.68-2.55 (m 〇 2.4-2.3 (m, 1H), 1.45-1.28 (m, 9H), 0.9-0.7 (m, 6H) 〇' (13 , 2(28), 38,5 magic-2-(2-amino-3-methyl-pentanyl)|nitrogen-6,6-difluoro-2-aza-bicyclo[3.2.0] The preparation of heptane-trifluoroacetate 3 will be (1 S,2(2S),3S,5SHH3_cyano from the second 丄hetero-bicyclo[3.2.0]heptane-2-carbonyl)_2_A Butyl-butyl]-tert-butyl methacrylate 3c ((U3 g, 0.35 mmol) was dissolved in 6 ml of dichloromethane under ice-cooling, added with fluoroacetic acid, and reacted under sputum for 2 hours. The reaction mixture was purified by EtOAc EtOAc EtOAc (EtOAc) 3-decyl-pentyl)-3-cyano-6,6-difluoro-2-aza-bicyclo[3.2.0] • heptane-trifluoroacetate 3 (0.04 g, white solid) Yield 30%. ' MS m/z (ESI): 272.7 (M+1). Test Example: DPPIV Inhibitor Test Report Purpose: Human DPPIV (EC 3.14.21.5; Dipeptidyl peptidase IV; T cell activated antigen CD26; ADA binding protein) Chinese® name is dipeptidase IV, which has dipeptidyl peptidase activity and can be cleaved at the N-terminus of many polypeptides. Two amino acids, which change or lose their biological activity. Gene knockout, animal and human experiments show that effective and specific reduction of DPPIV activity in the body can increase insulin (Insulin) content, lower blood sugar levels, and effectively To improve the symptoms of diabetes. In recent years, studies have found that there are some proteins (DASH) that are similar to DPPIV activity and/or structure, including DPP8, DPP9, QPP, FAP, etc. Preclinical experiments show that inhibition of the activity of these DASH members It will lead to toxicity and even death. Therefore, screening for highly selective and highly effective DPPIV inhibitors is of great value for the treatment of diabetes. Experimental methods: Application of insect expression system, showing the recombination of DPPIV, DPP8, DPP9, QPP and FAP protein. The activity of these five enzymes was detected by fluorescence receptor. The inhibition of the activity of the enzyme by the compound was observed to evaluate the inhibitory effect of the compound. Experimental results: 31 94334 201000096 Table 1: IC50 of the five enzymes of Example 1 Example No. IC5〇(Μ) DPPIV DPP8 DPP9 QPP FAP 1 0.15 4.33 10.92 49.76 32.07 Conclusion: Example 1 has a significant inhibitory effect on DPPIV activity, It has obvious selectivity to QPP and has different degrees of selectivity for DPP8, DPP9 and FAP. [Simple description of the diagram] ❹No [Description of main component symbols] None ❹ 32 94334

Claims (1)

201000096 X. Patent application scope: 1. A compound represented by the following formula (I) or a pharmaceutically acceptable compound thereof Wherein: 1^ and R2 are each independently selected from the group consisting of hydrogen, alkoxy, halogen or hydroxy, or ©Ri and 尺2 represent a carbonyl group; R·3 is selected from the group consisting of a cyclyl group, a cycloalkyl group, a bicycloalkyl group, a tricyclic, a cycloalkyl, a hydroxybicycloalkyl, a hydroxytricycloalkyl, an aryl or a heteroaryl group. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the following formula (ΙΑ) or a pharmaceutically acceptable salt thereof: I is a group selected from the group consisting of an alkyl group, a cycloalkyl group, a bicycloalkyl group, a tricycloalkyl group, a transcycloalkyl group, a hydroxybicycloalkyl group, a hydroxytricycloalkyl group, an aryl group or a heteroaryl group. 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is a salt selected from the group consisting of hydrochloric acid, methanesulfonic acid 'sulfuric acid, dish 94334 33 201000096, acid, citric acid, acetic acid or Trifluoroacetate. 4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the acid is hydrochloric acid or trifluoroacetic acid. 5. If you apply for a patent scope! A compound of the formula or a pharmaceutically acceptable salt thereof wherein 'including' the following compounds: 6. A method of preparing a compound of the formula (1) as claimed in the scope of the patent application, comprising: 9' boc COOEt boc COOEt raw material (2R)-1-second butoxy group _5_base B is more than 2,6-diindenyl η in a solvent ν,Ν-diammonium-° ratio biting and trifluoroacetic anhydride at room temperature to obtain ethyl third butoxy carbonyl 2,3-dihydropyrrole-2-carboxylate; COOEt Isopropyl solution of (R)-l·t-butoxycarbonyl-2,3-dihydropyrrole-2-carboxylate and triethylamine in cyclohexane and cyclohexane of dichloroacetamidine chloride The solution is reacted in an oil bath to give (1R,3r,5S)-2-tert-butoxycarbonyl-gas-6-sideoxy-2-aza-bicyclo[3.2.0]heptane-2. Acid ethyl ester; 34 94334 201000096 COOEt (lR,3R,5S)-2-Tertoxycarbonyl-7,7-dichloro-6_ oxo-2-azabi-bicyclo[3.2.0]heptane-2-carboxylic acid obtained by COOEt The ethyl ester reacts with the ammonium carbonated methanol solution and the activated zinc powder at room temperature to obtain (1S,3R,5S)_2_t-butoxycarbonyl-6-sideoxy-2aza-bicyclo[3.2.0 Heptane-2_carboxylic acid ethyl ester; 〇❹ H R1 Η The resulting (1 S,3R,5S)-2-t-butoxycarbonyl-6-oxo-azepine-bicyclo[3.2.0]heptane-2-carboxylic acid ethyl ester in dichloromethane solvent The halogenation reaction or reduction reaction gives the carbonyl group substituted by R1, r2. Bihalane and a four-membered ring compound; COOEt A solution of n-butyl oxime in tetrahydrofuran was added dropwise to a solution of diisopropylamine in tetrahydrofuran, and then the reaction was added dropwise to R, substituted fluorene, and each of the four-membered ring compounds was further reacted. Obtaining an ester-flip-doped pentrolane and a four-membered ring compound; 94334 35 201000096 Η COOEt The ester-overturned α obtained by COOH is reacted with lithium hydroxide in an ethanol solvent in an ice bath and then acidified and hydrolyzed by 1 Torr hydrochloric acid to obtain a pyrrolidine and a four-membered cyclic carboxylic acid compound; The pyrrolidine and four-membered cyclic carboxylic acid compound obtained by conh2 is reacted with pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate in an acetonitrile solvent overnight to obtain a pyrrolidine-tetracycline compound; ❹ The obtained pyrrolidine and four-membered cyclic guanamine compound is reacted with a solution of hydrochloric acid in diethyl ether in an ethereal solvent to remove the amino-protecting group to obtain the pyrrolidine and the hydrochloride salt of the 4-membered ring-2-meramine compound; (0 obtained pyrrolidine and four-membered ring · 2 · decylamine compound hydrochloride in acetonitrile solvent with triethylamine, R3-CH(NHBOC)-COOH and 1-hydroxybenzotriazole and 1-ethyl -3-(3-dimethylaminopropyl)carbodiimide stock 36 94334 201000096 Under the reaction at room temperature, the guanamine is dehydrated to a cyano group, and the protecting group is removed to obtain the compound of the formula (I). 7. The preparation method of claim 6, wherein the obtained compound of the formula (I) is purified and directly subjected to an ice bath reaction in an acid dichloromethane solution to obtain an acid addition salt product. The preparation method of claim 7, wherein the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. 9. The preparation method according to claim 8 Wherein the acid is hydrochloric acid W or trifluoroacetic acid. 10. A compound of the formula shown in the following formula, which is an intermediate for the synthesis of the compound of the formula (1): 11 Red species, such as the preparation method of the compound of claim 10, package 0 丫COOEt boc COOEt boc 7 age 1; (R) L second butoxy group _5-pyrozyl ratio 嘻 · Two acid reagents are reacted with 2,6-dimethyl- and ca. dimethylamino-2, Γ_ί vinegar at room temperature (iv) (8)·1·t-butoxy'-oxygen ratio · Ethyl carboxylate; 94334 37 201000096 ^; co〇—CIS?, c〇〇Et boc (R)-l-t-butoxycarbonyl·2,3-dihydropyrrole_2-rebel B A cyclohexane solution of vinegar and triethylamine is reacted with a solution of dichloroacetamidine in cyclohexane in an oil bath to obtain (1 ft, 311, 53) _2_t-butoxycarbonyl-7,7-di Chloro-6-o-oxy-2-az-bicyclo[3.2.0]heptane-3-carboxylic acid ethyl ester; The obtained (lR,3R,5S)-2-tert-butoxycarbonyl-7,7-dichloro-6(o)oxy-2-aza-bicyclo[3.2.indole]heptane-3-carboxylic acid The ethyl ester is reacted with ammonium chloride in methanol and activated zinc powder at room temperature to obtain (ls, 3R, 5S)-2_t-butoxycarbonyl-6-o-oxy-2-aza-bicyclo[3.2. 0]heptane-3-indolecarboxylic acid ethyl ester; 〇^ riv y Η boc Η boc (1 S,3R,5S)-2-tert-butoxycarbonyl-6-sideoxy-2-nitrogen Tetra-bicyclo[3.2.0]heptane-3-carboxylate ethyl ester is subjected to a denation reaction or a reduction reaction in a dichloromethane solvent to obtain a pyrrolidine and a four-membered ring compound in which a carbonyl group is substituted by R1 and r2; 38 94334 201000096 COOEt COOEt ^ A solution of n-butyllithium in tetrahydrofuran is added dropwise to a solution of diisopropylamine in tetrahydrofuran, and then the reaction is added dropwise to a compound of Ri, substituted pyrrolidine and a four-membered ring, and further reacted to obtain an ester-inverted pyridyl group. 11 alkane four-membered ring compounds; 〇 The obtained ester-based inverted pyrrolidine and four-membered ring compound is reacted with lithium hydroxide in an ice bath in an ice bath and acidified by 1N hydrochloric acid to obtain a pyrrolidine and a four-membered cyclic carboxylic acid compound; R1 Η H L_H2 is obtained by enthalpy and a four-membered ring of tickic acid compound in an acetonitrile solvent. Comparing with biting, ammonium hydrogencarbonate and di-tert-butyl dicarbonate at room temperature overnight to obtain η-pyrrolidine and four-membered cyclic guanamine compound; Ri _y CONH, u N Boc H Shc?〇NH2 The pyrrolidine and four-membered cyclic guanamine compound is reacted with a solution of hydrochloric acid in diethyl ether to remove the amino protecting group to give pyrrolidine and 39 94334 201000096 / four-membered ring-2-decylamine The hydrochloride salt of the compound. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. If you apply for a patent! The use of the compound i or its pharmaceutical salt is to prepare a dibasic enzyme (DPPIV) inhibition: a drug. •: Application: The pharmaceutical composition of item 12 of the benefit range, which is used to produce a peptidyl peptidase (DPPIV) inhibitor drug. ❹ 94334 40 201000096 VII. Designated representative map: There is no schema in this case. (1) The representative representative figure of this case is: (). - (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R1 Ο CN (I) ❿ 4 94334 Description of invention patent畲 /)6//^ 3iA^2 ^apc Classification: c〇7P^^z· (This manual format, order and bold type, ※Application number: ※Application period: 涿一, invention name: (Chinese / English) Pyrrolidine and tetra-halogen derivatives, its preparation method and its use in medicine FOUR-MEMBERED RING FUSED PYRROLIDINE DERIVATIVES, PREPARING METHOD AND USE THEREOF II Applicant: (1 in total) 姓名 Name or Name: (Chinese / English) SHANGHAI HENGRUI PHARMACEUTICAL CO., LTD. , "γ Representative: (Chinese / English) (Signature) Sun Flying / SUN, PIAO YANG Address of residence or business office: (Chinese / English) 279 Wenjing Road, Economic and Technological Development Zone, Minhang District, Shanghai, China Post Code: 200245 No. 279 Wenjing Road, Minhang District, Shanghai 200245, People's Republic of China Nationality: (Chinese / English) China/CHINA Q III. Inventor: (6 in total) Name: (Chinese/English) 1. Deng Bingchu/TANG, PENG CH0 2. Lin Zhigang/LIN, ZHIGANG 3. Yang Jialiang/YANG, JIALIANG 4. Zhao Fuqiang/ZHAO, FUQIANG 5. Wang Yang/WANG, YANG, 6. Wang Wei/WANG, QIAN Nationality: (Chongwen/English) 1. to 6. Mainland China/CHINA 94334 Amendment Page 201000096 ί. V. Chinese Invention Abstract: ~ The present invention relates to a novel one of the formula (1). a four-membered ring-like street organism, a preparation method thereof, and a drug containing the derivative (IV) and a therapeutic agent thereof, particularly as a dipeptidyl peptidase inhibitor (DPPIV), wherein each substitution of the formula The base is the same as defined in the specification. Ο R1 V. The present invention is directed to a new four-membered ring fused pyrrolidine derivative represented by formula (I) [wherein each substituent in formula (I) has the same meaning as described in the specification], preparation Method thereof, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, especially as a dipeptidyl peptidase IV (DPPIV) inhibitor. R1 R3h·"/~V"HH eight VO CN rf-R2 ο (I) 94334 Revision page