WO2008148279A1 - Cyclobutyl-fused pyrrolidine derivatives, their preparation methods and their medical use - Google Patents

Abstract

A novel cyclobutyl-fused pyrrolidine derivatives of formula (I) in which the substituents are defined in the description, their preparation methods, their compositions and their use as therapeutical agent, particularly as dipeptidyl peptidase IV (DPPIV) inhibitor.

Description

 TECHNICAL FIELD The present invention relates to a novel pyrrolidine and four-membered ring derivative, a process for preparing the same, and a pharmaceutical composition containing the same And its use as a therapeutic agent, in particular as a dipeptidyl peptidase inhibitor (DPPIV). BACKGROUND OF THE INVENTION Diabetes is a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. Diabetes is a very old disease. It is caused by an absolute or relative lack of insulin in the human body. The blood glucose level is increased, and then a large amount of sugar is excreted from the urine, and there are polydipsia, polyuria, polyphagia, weight loss, and dizziness. , fatigue and other symptoms.

 Dipeptidyl Peptidase-IV (DPPIV) is a serine protease that cleaves N-terminal dipeptidase in a peptide chain containing a proline residue at the secondary end, although DPPIV has no physiological effects on mammals. It is fully confirmed, but it plays an important role in the metabolism of nerve enzymes, activation of T-cells, metastasis of cancer cells into the endothelium and entry of HIV into lymphoid cells. (W098/19998).

Recently, studies have shown that DPPIV can prevent the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-propadipeptide enzyme of GLP-1 from the active form of GLP- 1 (7-36) NH ₂ degraded to inactive GLP-1 (9-36) NH ₂ (Endocrinology, 1999, 140: 5356~5363). Due to physiological conditions, the half-life of intact GLP-1 in circulating blood is very short, and the inactive metabolites after DPPIV degrades GLP-1 can bind to GLP-1 receptor antagonistic activity GLP-1, thereby shortening the physiology of GLP-1. reaction. DPPIV inhibitors can completely protect endogenous and even exogenous GLP-1 from being inactivated by DPPIV, greatly increasing the physiological activity of GLP-1 (5 to 10 times), due to the secretion of insulin from pancreas by GLP-1. It is an important stimulator and can directly affect the distribution of glucose. DPPIV inhibitors play a very good role in 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:

其巾：

Its towel:

 And each independently selected from hydrogen, alkoxy, halogen or hydroxy, or together to form a carbonyl group;

R _{3 is} selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, Hydroxytricycloalkyl, aryl or heteroaryl.

 Further, the present invention includes a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof:

Its towel _:

R _{3 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 (I) or a pharmaceutically acceptable salt thereof, wherein the formula ω is present in the form of a pharmaceutically acceptable free form or an acid addition salt, the salt being A salt formed with an acid selected from the group consisting of hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid, preferably hydrochloric acid or trifluoroacetic acid. Specifically, the compound of the formula (I) of the present invention includes the following compounds and 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:

0 N COOEt N COOEt

 Boc boc

 Raw material (2R)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent with 2,6-lutidine and N,N-dimethylaminopyridine And trifluoroacetic anhydride is reacted at room temperature to obtain (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate; oOEt

得到 (lR，3R，5S)-2-叔丁基 3-乙基 7，7-二氯 -6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二 羧酸酯与氯化铵的甲醇溶液及活化锌粉在室温下反应得到 (lS，3R，5S)-2-叔丁基 3- 乙基 6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二羧酸酯； COOEtA solution of (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine in cyclohexane and a solution of dichloroacetyl chloride in cyclohexane are obtained. Reaction in an oil bath to give (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2 , 3-dicarboxylate;

Yield (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxyl The ester is reacted with ammonium chloride in methanol and activated zinc powder at room temperature to give (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0 Heptane-2,3-dicarboxylate; COOEt

Obtaining (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate in dichloromethane solvent occur reduction reaction or the halogenation reaction is carbonyl, R ₂ is a substituted pyrrolidine compound, and four-membered ring;

 R1 b R1 H

^ N ,' COOEt N eight COOEt

H ■■ H ¹

 Boc boc

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 R, R ₂ substituted compound, and further reacted to obtain an ester-inverted pyrrolidine and a tetracyclic compound. ;

Obtaining an ester-based inverted pyrrolidine and a four-membered ring compound in an ethanol solvent and reacting with lithium hydroxide in an ice bath and then acidifying and hydrolyzing with 1N hydrochloric acid to obtain a carboxylic pyrrolidine and a four-membered ring compound;

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

The obtained amide pyrrolidine and four-membered ring 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 hydrochloride of the aminopyrrolidine and four-membered ring compound;

 (I)

 The obtained aminopyrrolidine and four-membered ring compound hydrochloride is in an acetonitrile solvent with triethylamine,

R3-CH(NHBOC)-COOH and 1-hydroxy-3-benzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide are reacted at room temperature to dehydrate the amide a cyano group, which removes a protecting group to give a compound of the formula (I);

 Its towel:

 And each being independently selected from the group consisting of hydrogen, alkoxy, halogen or hydroxy, and together with, may form a carbonyl group;

R _{3 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. It is preferably hydrochloric acid or trifluoroacetic acid.

Further, the present invention relates to a compound of the formula: as an intermediate of the synthesis of the compound of the formula (I): (should be of the formula)

 - Step, the present invention relates to a process for the preparation of an intermediate compound of the above formula, comprising the steps of:

0 N 'COOEt N COOEt

 Boc boc

Raw material (2R)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent with 2,6-lutidine and N,N-dimethylaminopyridine And trifluoroacetic anhydride is reacted at room temperature to obtain (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate;

The obtained (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine in cyclohexane solution and dichloroacetyl chloride in cyclohexane solution in the reaction in an oil bath, to give (lR, 3R, 5S) -2- tert-butyl 3-ethyl _7,7 - dichloro-6-oxo-2-N - bicyclo [3.2.0] heptane - 2,3-dicarboxylate;

 The obtained (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-di The carboxylic acid ester is reacted with ammonium chloride in methanol and activated zinc powder at room temperature to obtain (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2. 0] heptane-2,3-dicarboxylate; COOEt

The obtained (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate in dichloromethane a halogenation reaction or a reduction reaction in a solvent to obtain a carbonyl-substituted, R ₂ -substituted pyrrolizino-tetra-cyclic compound;

 R1 b R1 H

^ N '' COOEt N eight COOEt

H ■■ H ¹

 Boc boc

To a solution of diisopropylamine in tetrahydrofuran, a solution of n-butyllithium in tetrahydrofuran is added dropwise, and then the reaction is added dropwise to the R ₂ -substituted pyrrolidine and tetra-cyclic compound to further react to obtain an ester-substituted pyrrolidine. Quaternary ring compound;

The obtained ester-inverted pyrrolidine and four-membered ring compound is reacted with lithium hydroxide in an ice bath in an ice bath and then subjected to acid hydrolysis treatment with 1N hydrochloric acid to obtain a carboxylic pyrrolidine and a four-membered ring compound;

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

Further, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier. 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. SUMMARY OF THE INVENTION Unless otherwise stated, the following terms used in the specification and claims have the following meanings: "mercapto" refers to a separate group or as part of another group, including from 1 to 20 carbon atoms. a linear or branched alkyl group, preferably a linear or branched alkyl group having 1 to 10 carbon atoms, more preferably a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group or an ethyl group. , propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2, 2, 4-tri Methyl-pentyl, decyl, decyl, undecyl, dodecyl and various branched isomers, etc., these groups may be further substituted by 1 to 4 substituents selected from the group consisting of Halogen, such as fluorine, bromine, chlorine or iodine or trifluoromethyl, alkyl, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkoxy Base, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, hetero Oxy, heteroarylalkyl, heteroaralkyloxy, aryloxyalkyl, thioalkyl, thioarylalkyl, aryloxyaryl, arylamino, arylcarbonylamino, nitro, cyano , mercapto, haloalkyl, trihaloalkyl.

、 、 ∞ 、 、 、 、 ， 所述基团可任意的被 1〜4个取代基取代， 例如卤素、 烷基、烷氧基、羟基、 芳基、 芳氧基、 芳基烷基、 环烷基、 羟基烷基、 烷基氨基、 氧代、 酰基、 芳基酰基氨基、 氨基、 硝基或氰基。 "Cycloalkyl" means an independent group or as part of another group, which refers to a cyclic hydrocarbon group having a saturated or partially unsaturated (having 1 or 2 double bonds), said group The group has 1 to 3 rings including a monocycloalkyl group, a bicycloalkyl group, a tricycloalkyl group, and the group has 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 10 carbon atoms, and these rings It may be a silk and a ring with 1 or 2 aromatic rings, such as an aryl group, and the group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptane, a cyclooctane, a cyclodecyl group, Cyclodecyl, cyclodecyl, cyclododecyl, adamantane,

, ∞ , , , , , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, A hydroxy group, an alkylamino group, an oxo group, an acyl group, an aryl acylamino group, an amino group, a nitro group or a cyano group.

 "Halogen" means an independent group or as part of another group, and refers to chlorine, bromine, fluorine, iodine and trifluoromethyl, preferably chlorine or fluorine.

"Aryl" means an independent group or as part of another group, and refers to a monocyclic, bicyclic aromatic group having from 6 to 10 carbon atoms (eg, phenyl, naphthyl including 1-naphthalene) The base, 2-naphthyl) may also optionally include from 1 to 3 additional rings and carbocyclic or heterocyclic silks and (for example, aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings, such as:

It may also be optionally substituted by 1, 2, or 3 groups selected from a hydrogen atom, a halogen, a halogenated alkyl group, an alkyl group, an alkoxy group, a alkoxy group, an alkenyl group, a trifluoromethyl group, Trifluoromethoxy, aryl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, aryl Alkoxy, azaaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, including 1 or 2 substituents The amino group of the group (the substituent may be selected from an alkyl group, an aryl group or other aryl compound mentioned in the definition herein), an alkyl acyl group, an aryl acyl group, an alkylamino acyl group, an arylamino acyl group, an alkoxy group , aminoacyl, alkyl acyloxy, aryl acyloxy, alkyl acylamino, aryl acylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonyl Aminoacyl and/or any of the alkyl substituents mentioned herein.

 "Heteroaryl" means an independent group or as part of another group, and refers to a 5- or 6-membered aromatic ring having 1, 2, 3 or 4 heteroatoms such as nitrogen and oxygen. Or sulfur, these rings may be bonded to aryl, cycloalkyl, heteroaryl or cycloheterocyclohexyl and (for example: fluorenyl) 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:

本发明化合物的合成方法 为了完成本发明的目的， 本发明采用如下技术方案：

Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:

其中， 原料 (2R)-1-叔丁基 2-乙基 5-羟基吡咯烷 -1，2-二羧酸酯在甲苯溶剂中与 2，6-二甲基吡啶和 N，N-二甲氨基吡啶及三氟醋酸酐在室温下反应得到 (R 1-叔丁基 2-乙基 2，3-二氢吡咯 -1,2-二羧酸酯；（R)-l-叔丁基 2-乙基 2，3-二氢吡咯 -1,2-二羧酸 酯和三乙胺的环己烷溶液与二氯乙酰氯的环己烷溶液在油浴 38 °C下反应， 得到 (lR，3R，5S)-2-叔丁基 3-乙基 7，7-二氯 -6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二羧酸酯； 所述的 (lR，3R，5S)-2-叔丁基 3-乙基 7，7-二氯 -6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二羧 酸酯与氯化铵的甲醇溶液及活化锌粉在室温下反应得到 (lS，3R，5S)-2-叔丁基 3-乙 基 6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二羧酸酯；（lS，3R，5S)-2-叔丁基 3-乙基 6-氧代 -2-氮 -二环 [3.2.0]庚烷 -2,3-二羧酸酯在二氯甲烷溶剂中发生卤化反应或还原反应得 到羰基被 ， R₂取代的吡咯烷并四元环化合物； 在 -78°C下， 在二异丙胺的四氢呋 喃溶液中滴加正丁基锂的四氢呋喃溶液， 反应 30分钟后将此反应液滴加到 R， R₂ 取代的吡咯烷并四元环化合物中， 在 -78°C下反应得到酯基翻转的吡咯烷并四元环 化合物； 酯基翻转的吡咯烷并四元环化合物在乙醇溶剂中与氢氧化锂在冰浴下反 应再经 1N盐酸酸化水解处理得到羧酸吡咯烷并四元环化合物； 羧酸吡咯烷并四元 环化合物在乙腈溶剂中与吡啶、 碳酸氢铵和二碳酸二叔丁酯在室温下反应过夜得 到酰胺吡咯烷并四元环化合物； 酰胺吡咯烷并四元环化合物在乙醚溶剂中与盐酸 的乙醚溶液反应脱掉氨基保护基得到氨基吡咯烷并四元环化合物的盐酸盐； 所述 的氨基吡咯烷并四元环化合物盐酸盐在乙腈溶剂中与三乙胺、 R₃-CH(NHBOC)-COOH及 1-羟基苯并三唑和 1-乙基 -3-(3-二甲基胺丙基)碳化二亚 胺存在下在室温下反应， 再将酰胺脱水成氰基， 除去保护基得到通式 (I)所示的化 合物； The method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

Wherein the starting material (2R)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent with 2,6-lutidine and N,N-dimethyl Aminopyridine and trifluoroacetic anhydride are reacted at room temperature to give (R 1-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate; (R)-l-tert-butyl 2 - a solution of ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine in cyclohexane and a solution of dichloroacetyl chloride in cyclohexane in an oil bath at 38 ° C to obtain (lR , 3R, 5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate; The (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3- The dicarboxylic acid ester is reacted with a solution of ammonium chloride in methanol and activated zinc powder at room temperature to obtain (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2 .0]heptane-2,3-dicarboxylate; (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane 2,3-dicarboxylate in dichloromethane halogenation reaction occurs in a solvent or reduction reaction is carbonyl, R ₂ is a substituted pyrrolidine compound, and four-membered ring; at -78 ° C, in Isopropylamine in tetrahydrofuran was added dropwise a solution of n-butyllithium in tetrahydrofuran, and reacted for 30 minutes The reaction mixture was added dropwise R, R ₂ a substituted pyrrolidine compound, and four-membered ring to give a reaction at -78 ° C Ester-inverted pyrrolidine and four-membered ring compound; ester-transferred pyrrolidine and quaternary ring compound in ethanol solvent and lithium hydroxide in an ice bath and then acidified by 1N hydrochloric acid to obtain carboxylic pyrrolidine and four a cyclic compound; a pyrrolidine quaternary ring compound of carboxylic acid in acetonitrile solvent and pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate at room temperature overnight to obtain an amide pyrrolidine and a four-membered ring compound; amide pyrrolidine and four The amino ring compound is reacted with a solution of hydrochloric acid in diethyl ether to remove the amino protecting group to give the aminopyrrolidine and the hydrochloride of the four-membered ring compound; the aminopyrrolidine and four-membered ring compound hydrochloride in acetonitrile solvent Reacts in the presence of triethylamine, R ₃ -CH(NHBOC)-COOH and 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at room temperature And dehydrating the amide to a cyano group, Deprotected to give the compound of formula (the I);

 Its towel:

 And each independently selected from the group consisting of hydrogen, alkoxy, halogen, hydroxy, or and may form a carbonyl group;

R _{3 is} selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, Hydroxytricycloalkyl, aryl or heteroaryl.

 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound or a salt thereof and a pharmaceutical carrier, or the use of a compound of the formula of the present invention or a salt thereof for the preparation of a medicament for 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. detailed description

 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). NMR was measured with BrukerAVANCE-400 NMR instrument, measurement solvent deuterated methanol (CD ₃ OD), deuterated chloroform (CDC1 _3), trimethylsilane as the internal standard (TMS), chemical shifts are ^10-6 ( Ppm) is given as a unit.

 The MS was assayed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

The average inhibition rate of the kinase and the IC _5Q value were determined using a NovoStar plate reader (BMG, Germany)

 Thin layer of silica gel using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate

 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

CD ₃ OD: deuterated methanol;

CDC1 ₃ : deuterated chloroform; Example 1

 (lS,2(2S),3S,5S)-2-[2-Amino-2-(3-hydroxy-adamantan-1-yl)-acetyl]-6,6-difluoro-2-nitrogen- Second ring

[3.2.0]heptane-3-cyanotrifluoroacetate

 Preparation of (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate 1b In a dry three-necked flask, (2R)-1-tert-butyl 2- Ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate la (17 g, 65.6 mmol), dissolved in 30 ml of toluene with stirring, cooled to -60 ° C, and added 2,6-dimethylhydrazine Bipyridine (45.8 ml, 0.394 mmol) and N,N-dimethylaminopyridine (0.159 g, 1.31 mmol), trifluoroacetic anhydride (11.86 ml, 85.3 mmol) was added dropwise at this temperature, and the mixture was dropped over 15 minutes. Rise to room temperature. Reaction for 2 hours. The reaction was followed by thin-layer chromatography, and the material was evaporated. The mixture was evaporated and evaporated to ethyl acetate (50 ml). The organic phases were combined and dried over anhydrous magnesium sulfate. The obtained residue was purified to silica gel column chromatography toiel Solid), yield 73.4%.

MS m/z (ESI): 242.2 (M+l

(lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylic acid Preparation of ester lc

 (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate lb (2 g, 8.3 mmol) was added to a dry three-necked flask under nitrogen atmosphere. 100 ml of triethylamine (2.32 ml, 16.6 mmol) in cyclohexane. Oil bath A solution of dichloroacetyl chloride (1.15 ml, 11.95 mmol) in cyclohexane (60 ml) was added dropwise at <RTI ID=0.0>> After reacting for 20 minutes, it was cooled to room temperature, and the reaction was followed by thin layer chromatography, the material disappeared, suction filtered, and filtrate was concentrated. The obtained residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut [3.2.0] Heptane-2,3-dicarboxylate lc (2.53 g, pale yellow oil), yield 87%.

MS m/z (ESI): 351.3 (M-l

Preparation of (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate Id under argon atmosphere , (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane was added to a dry three-necked flask. -2,3-dicarboxylate lc (2.53 g, 7.19 mmol), dissolved in 120 ml of ammonium chloride (5.096 g, 78.3 mmol) in methanol, stirred, stirred, stirred, stirred, stirred at room temperature . Filter by suction and wash the zinc powder with methanol (50 ml). Evaporate the solvent and add ethyl acetate (100 ml). Wash with acetic acid, water (50 ml) and saturated sodium chloride (50 ml). After suction filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography toield -2,3-dicarboxylate ldG.68 g, yellow oil), yield 82.6

%.

MS m/z (ESI): 284.2 (M + 1).

Preparation of (lS,3R,5S)-2-tert-butyl 3-ethyl 6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate le

 Under ice-cooling, diethylaminotrifluorosulfide (0.781 ml, 5.918 mmol) was dissolved in dichloromethane (20 ml) and added dropwise to (lS,3R,5S)-2-tert-butyl 3-ethyl A solution of 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate ld (0.67 g, 2.367 mmol) in dichloromethane (20 ml). After the dropwise addition, the temperature was raised to room temperature, and the temperature was maintained at 20 ° C, and the reaction was continued overnight. A saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added, and dichloromethane (50 ml, 4), and the organic phase was combined and washed with saturated sodium chloride (50 ml). The methylene chloride phase was dried over anhydrous magnesium sulfate (MgSO4). 6,6-Difluoro-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate le (0.38 g, white solid), yield 53%.

 MS m/z (ESI): 305.9 (M+1).

Preparation of (lS,3S,5S)-2-tert-butyl 3-ethyl 6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate If Diisopropylamine G.25 ml, 8.85 mmol) was dissolved in tetrahydrofuran (10 mL) with stirring. n-Butyllithium (1.18 ml, 2.95 mmol) was added dropwise at -78 °C. The reaction was carried out at -78 ° C for 30 minutes, and (18,311,58)-2-tert-butyl 3-ethyl 6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2 was added dropwise. , 3-dicarboxylate le (0.6 g, 1.967 mmol). After reacting at -78 ° C for 1 hour, the reaction was quenched by dropwise addition of 1N ammonium chloride solution (5 ml). Naturally rise to room temperature and react for 30 minutes. The mixture was extracted with EtOAc (EtOAc)EtOAc. After suction filtration, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut Heptan-2,3-dicarboxylate lf (0.323 g, white solid), yield 54%.

MS m/z (ESI): 328.3 (M+1). Preparation of ClS, 3S, 5S)-2-(; tert-butoxycarbonyl)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-carboxylic acid lg (lS,3S,5S)-2-tert-butyl 3-ethyl 6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate lf (0.323 g 1.059 mmol) was dissolved in ethanol, 1N lithium hydroxide (6.35 ml, 6.35 mmol) was added dropwise, and the reaction mixture was traced by thin layer chromatography. Ethanol was evaporated, ethyl acetate (50 ml) was added, and pH was adjusted with IN hydrochloric acid. 3, extracted with ethyl acetate (50 ml×4), EtOAc (EtOAc) It was suction filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was the title crude product lg (white solid). MS m/z (ESI): 276.7 (M+l

Preparation of (1S,3S,5S)-tert-butyl 3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carboxylate 1h under nitrogen atmosphere (lS,3S,5S)-2-(tert-Butoxycarbonyl)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-carboxylic acid lg (0.293 g, 1.057 Methyl acetate (10 ml) was added with stirring. pyridine (0.111 ml, 1.375 mmol), ammonium hydrogencarbonate (0.108 g, 1.375 mmol) and di-tert-butyl dicarbonate (0.345 g, 1.586 mmol) , react at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. After suction filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography (jjjjjjjjj Heptane-2-carboxylate 1 h (0.151 g, white solid yield 51.36%).

 MS m/z (ESI): 277.6 (M+l

Preparation of (lS,3S,5S)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-acylamine hydrochloride li (1S,3S,5S)-tert-butyl 3-3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carboxylate 1 h (0.141 g, 0.546 mmol) was dissolved in diethyl ether (10 ml). The title compound (lS, 3S, 5S)-6,6-difluoro-2-nitrogen-II was obtained by adding a solution of 1% hydrochloric acid in diethyl ether and stirring at room temperature to precipitate a solid. Cyclo [3.2.0] heptane-3-acylamine hydrochloride li (white solid). Used directly in the next step.

MS m/z (ESI): 177.2 (M+1).

(lS,2(2S),3S,5S)-[2-(6,6-Difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl) small (3-hydroxy-adamantane) Preparation of -1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester lk

 (lS,3S,5S)-6,6-Difluoro-2-nitro-bicyclo[3.2.0]heptane-3-acylamine hydrochloride li (196 mg, 0.923 mmol) and triethylamine ( 450 ul, 3.23 mmol) was dissolved in 20 ml of acetonitrile with stirring, stirred for 10 minutes in an ice water bath, and 10 ml of (S)-tert-butoxycarbonylamino-(3-hydroxy-adamantan-1-yl)-acetic acid lj was added. (0.3 g, 0.923 mmol) in acetonitrile, 1-hydroxybenzotriazole (0.44 g, 3.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.44 g) , 2.3 mmol), react at room temperature for 36 hours, trace the reaction by thin-layer chromatography, disappear the starting materials, evaporate the solvent under reduced pressure, dissolve the residue in 20 ml of water, extract with ethyl acetate, combine the organic phases, and then use saturated sodium chloride The solution was washed with water, dried over anhydrous MgSO.sub.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(;6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1-(3-hydroxy-adamantan-1-yl)-2-oxo-B Base]-tert-butyl carbamate lk (0.22 g, white solid), yield 50%.

MS m/z (ESI): 484.2 (M+l

(lS,2(2S),3S,5S)-[2-(3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-2 -Oxo-(3-triethylsiloxy-adamantan-1-yl)-ethyl]-carbamic acid tert-butyl ester 11 (lS,2(2S),3S,5S)-[2-(;6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-l-0 hydroxy- Adamantyl-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester lk (0.17 g, 0.35 mmol) was dissolved in 5 ml of dichloromethane with stirring, at -78 ° C, two Isopropylethylamine (0.2 ml, 1.23 mmol) and triethylsilyl trifluoromethanesulfonate (0.24 ml, 1.056 mmol) were reacted at -78 ° C for 1 hour and then reacted at 0 ° C for 2 hours. Add 200 mg of silica gel, 0.5 ml of methanol, 0.2 ml of water and stir at room temperature overnight. The reaction was followed by thin layer chromatography, the material was evaporated, and the residue was evaporated. The residue obtained was purified by silica gel column chromatography to give the title product (1S, 2 (2S), 3S, 5S)-[2-(3-aminomethyl) Acyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-2-oxo-1-(3-triethylsiloxy-adamantane-1- Tert-butyl tert-ester 11 (0.15 g, white solid), yield 71%.

MS m/z (ESI): 598.2 (M+1).

(lS,2(2S),3S,5S)-[2-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-2- Preparation of oxo-l-(3-triethylsilyloxy-adamantan-1-yl)-ethyl]-carbamic acid tert-butyl ester lm (lS,2(2S),3S,5SM2-0 amino group Formic acid-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-2-oxotriethylsilyloxy-adamantan-1-yl)-ethyl] - tert-butyl carbamate 11 (0.22 g, 0.368 mmol) was dissolved in 6 ml of pyridine with stirring, cooled to -30 ° C, imidazole (52.6 g, 0.77 mmol) was added, and phosphorus oxychloride was added dropwise. Ml, 1.5 mmol). After the dropwise addition, the reaction was carried out at -30 ° C for 1 hour. The reaction was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. The filtrate was reduced to give the crude product of the title product (1S, 2 (2S), 3S, 5S)-[2-(3-cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]g Alkyl-2-yl)-2-oxo-1-(3-triethylsilyloxy-adamantan-1-yl)-ethyl]-carbamic acid tert-butyl ester lm (0.25 g, white solid).

MS m/z (ESI): 597.4 (M+l) o

(lS,2(2S),3S,5S)-2-[2-Amino-2-(3-hydroxy-adamantan-1-yl)-acetyl]-6,6-difluoro-2-nitrogen- Second ring

 [3.2.0] Preparation of heptane-3-cyanotrifluoroacetate 1

 (1 S,2(2S),3S,5S)-[2-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)- 2-oxo-1 -(3-triethylsilyloxy-adamantan-1-yl)-ethyl]-carbamic acid tert-butyl ester lm (0.18 g, 0.31 mmol) dissolved in 5 ml of dichloro To the methane, 0.2 ml of water was added, and under ice bath, 0.71 ml of trifluoroacetic acid was added, and the mixture was reacted for 2 hours under ice cooling. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 2-(3-Hydroxy-adamantan-1-yl)-acetyl]-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-cyanotrifluoroacetate 1 (87 mg, white solid), yield 76.65 %.

MS m/z (ESI): 366.6 (M+1).

1H NMR (CD ₃ OD, 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), 1.6-1.28 (m, 12H). Example 2 (lS,2(2S),3S,5S)-2-[2-Amino-3-(1Η-indol-3-yl)-propionyl]-6,6-difluoro-2-nitro-bicyclo[ 3.2.0] heptane

 3-cyano hydrochloride

(lS,2(2S),3S,5S)-[2-(3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1- Preparation of (1H-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 2b (lS,3S,5S)-6,6-difluoro-2-nitrogen- Bicyclo[3.2.0]heptane-3-acylamine hydrochloride li (212.5 mg, 1 mmol) was dissolved in 10 ml of acetonitrile with stirring, triethylamine (0.488 ml, 3.5 mmol) 10 minutes, (S)-2-tert-butoxycarbonylamino-3-(1Η-indol-3-yl)-propionic acid 2a (0.304 g, 1 mmol) 1-hydroxybenzotriazole (0.472 3.5) Methyl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.479 g, 2.5 mmol, reacted at room temperature overnight, the reaction material disappeared by thin layer chromatography, and the solvent was evaporated under reduced pressure. The title product (lS, 2 (2S)) was obtained by chromatography. 3S,5S)-[2-(3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1-GH-indol-3-yl Methyl)-2-oxo-ethyl]-carbo tert-Butyl ester 2b (0.39 g, white solid), yield 84.4%.

MS m/z (ESI): 463.6 (M+l

(lS,2(2S),3S,5S)-[2-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1-( Preparation of 1Η-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 2c (lS,2(2S),3S,5SM2-0carbamoyl-6,6 -difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1-(1Η-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl Ester 2b (0.39 g, 0.844 mmol) and imidazole (0.121 g, 1.77 mmol) were dissolved in 5 ml of pyridine with stirring, cooled to -35 ° C, and added with phosphorus oxychloride (0.323 ml, 3.46 mmol). After the reaction was carried out at -35 ° C for 1 hour, then the mixture was evaporated to dryness. The filtrate was concentrated to give the crude product of the title product ((18, 2 (; 28), 38, 58)-[2-0 cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0] Heptan-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 2c (0.366 g, white solid), yield 98% .

MS m/z (ESI): 445.3 (M+l (lS, 2 (2S), 3S, 5S)-2-[2-amino-3-(1Η-indol-3-yl)-propanoyl] - 6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane

 Preparation of 3-cyanohydrochloride 2

(lS,2(2S),3S,5S)-[2-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptan-2-yl)-1- (1Η-吲哚 tert-Butyl -3-ylmethyl)-2-oxo-ethyl]-carbamic acid 2c (0.366 g, 0.824 mmol) was dissolved in 6 ml of dichloromethane with stirring. Acetic acid was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj GH-indol-3-yl)-propionyl]-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-cyanohydrochloride 2 (0.1 g, white solid) The yield was 50%.

MS m/z (ESI): 345.1 (M+l

1H NMR (CD ₃ OD, 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

 (lS,2(2S),3S,5S)-2-(2-Amino-3-methyl-pentanoyl)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3 -Cyanotrifluoroacetate

(lS,2(2S),3S,5S)-[l-(3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carbonyl)-2- Preparation of ethyl-butyl]-carbamic acid tert-butyl ester 3b

 (lS,3S,5S)-6,6-Difluoro-2-nitro-bicyclo[3.2.0]heptane-3-acylamine hydrochloride li (98 mg, 0.46 mmol) was dissolved in 5 with stirring To the acetonitrile, triethylamine (0.224 ml, 1.61 mmol) was added, and the mixture was stirred for 10 min under ice-cooling, and (S)-2-tert-butoxycarbonylamino-3-methyl-pentanoic acid 3a (0.106 g, 0.46 mmol) 1-Hydroxybenzotriazole (0.217 g, 1.61 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.22 g, 1.15 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 was purified by silica gel column chromatography eluting elut elut elut elut eluting eluting 0]heptane-2-carbonyl)-2-ethyl-butyl]-tert-butyl carbamate 3b (0.24 g, white solid). MS m/z (ESI): 390.4 (M+l

(lS,2(2S),3S,5S)-[l-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carbonyl)-2-B Preparation of butyl-butyl]-tert-butyl carbamate 3c

(lS,2(2S),3S,5S)-[l-(3-carbamoyl-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carbonyl)-2 -ethyl-butyl]-tert-butyl carbamate 3b (0.15 g, 0.386 mmol) was dissolved in 2 ml of pyridine with stirring, added Imidazole (0.055 g, 0.81 mmol) was cooled to -35 ° C and phosphorus oxychloride (0.147 ml, 1.58 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was allowed to naturally rise to room temperature after reacting at -35 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification by silica gel column chromatography gave the title product (1S, 2 (2S), 3S, 5S)-[l-(3-cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane 2-Chloro)-2-ethyl-butyl]-tert-butyl carbamate 3c (0.13 g, white solid), yield 90.9%.

MS m/z (ESI): 372.3 (M+l)o

 1H NMR (CDCls, 400MHz) 55.153 (m, 1H), 4.940 (d, 1H), 4.82 (brs, 1H), 4.059-4.015 (m, 1H), 3.74-3.6 (m, 1H), 3.18-3.0 ( m, 1H), 2.85-2.68 (m, 1H), 2.68-2.55 (m, 1H), 2.4-2.3 (m, 1H), 1.45-1.28 (m, 9H), 0.9-0.7 (m, 6H).

(lS,2(2S),3S,5S)-2-(2-Amino-3-methyl-pentanoyl)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3 -Preparation of cyanotrifluoroacetate 3

 (lS,2(2S),3S,5S)-[l-(3-Cyano-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-2-carbonyl)-2- Ethyl-butyl]-carbamic acid tert-butyl ester 3c (0.13 g, 0.35 mmol) was dissolved in 6 ml of dichloromethane with stirring, and then, under ice-cooled, 1.07 ml of trifluoroacetic acid, and reacted at 0 ° C for 2 hours. . The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj 3-methyl-pentanoyl)-6,6-difluoro-2-nitro-bicyclo[3.2.0]heptane-3-cyanotrifluoroacetate 3 (0.04 g, white solid), yield 30 %.

MS m/z (ESI): 272.7 (M+1). Test case:

 DPPIV inhibitor test report

Purpose:

 Human DPPIV (EC 3.14.21.5; Depeptidyl peptidase IV; T cell activated antigen CD26; ADA binding protein) Chinese name is dipeptidase IV, with dipeptide aminopeptidase activity, can cut off the first two at the N-terminus of many polypeptides Amino acids, thereby altering or causing them to lose biological activity. Gene knockout, animal and human experiments have shown that effective and specific reduction of DPPIV activity in the body can increase the level of Insulin in the blood, lower the blood sugar level, and effectively 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 in the human body, including DPP8, DPP9, QPP, and FAP. Preclinical studies have shown that inhibition of these DASH-forming activities will result in toxicity and even death. Therefore, screening for highly selective, highly potent DPPIV inhibitors is of great value for the treatment of diabetes. experimental method:

Recombinant eggs expressing DPPIV, DPP8, DPP9, QPP and FAP using an insect expression system White. Fluorescent substrates were used to detect the activity of these five enzymes. The inhibition of the activity of the compound by the compound was observed to evaluate the inhibitory effect of the compound. Experimental results:

Table 1: Example 1 for five enzyme ICs:

Conclusion: Example 1 has a significant inhibitory effect on DPPIV activity, has obvious selectivity for QPP, and has different degrees of selectivity for DPP8, DPP9 and FAP.

Claims

Claims:  A compound represented by the following formula (I): or a pharmaceutically acceptable salt thereof:

 (I) and each independently selected from hydrogen, alkoxy, halogen or hydroxy, or together represent a carbonyl group; is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxy a group of a bicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl group. The 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:

 (ΙΑ) Its towel _:  It is a group selected from an alkyl group, a cycloalkyl group, a bicycloalkyl group, a tricycloalkyl group, a hydroxycycloalkyl group, a hydroxybicycloalkyl group, a hydroxytricycloalkyl group, an aryl group or a heteroaryl group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a salt selected from the group consisting of hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the acid is hydrochloric acid or trifluoroacetic acid. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises the following compounds:

 6. A process for the preparation of a compound of formula (I) according to claim 1 comprising: COOEt

Raw material (2R)_1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent with 2,6-lutidine and N,N-dimethylaminopyridine and Trifluoroacetic anhydride is reacted at room temperature to obtain (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate;

a cyclohexane solution of (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine and a cyclohexane solution of dichloroacetyl chloride Reaction in an oil bath to give (1^31^,58)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane -2, 3_dicarboxylate;

 (lR,3R,5S)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane-2, 3-di The carboxylic acid ester is reacted with ammonium chloride in methanol solution and activated zinc powder at room temperature to obtain (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate;

 The obtained (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate in dichloromethane a halogenation reaction or a reduction reaction in a solvent to obtain a carbonyl-substituted, pyrrolidine-tetra-cyclic compound;  R1 b R1 H N "COOEt N eight COOEt HH ¹  Boc boc To a solution of diisopropylamine in tetrahydrofuran, a solution of n-butyllithium in tetrahydrofuran is added dropwise, and then the reaction is added dropwise to a substituted pyrrolidine and a tetracyclic compound to further react to obtain an ester-substituted inverted pyrrolidine and quaternary Ring compound

The obtained ester-inverted pyrrolidine and four-membered ring compound is reacted with lithium hydroxide in an ice bath in an ice bath and then subjected to acid hydrolysis treatment with 1N hydrochloric acid to obtain a carboxylic pyrrolidine and a four-membered ring compound;

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

 The obtained amide pyrrolidine and four-membered ring compound is reacted with a solution of hydrochloric acid in diethyl ether in an ethereal solvent to remove an amino-protecting group to obtain an aminopyrrolidine and a hydrochloride of a four-membered ring compound;

The obtained aminopyrrolidine and four-membered ring compound hydrochloride in triacetonitrile solvent, triethylamine, R ₃ -CH (NHB0C)-C00H and 1-hydroxybenzotriazole and 1-ethyl-3-yl (3-di) The reaction is carried out at room temperature in the presence of methylaminopropyl)carbodiimide, and the amide is dehydrated to a cyano group, and the protecting group is removed to obtain a compound of the formula (I). The process according to claim 6, which further comprises subjecting the obtained compound of the formula (I) to an acid bath salt in an acid dichloromethane solution to obtain an acid addition salt product. The production method according to 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 production method according to claim 8, wherein the acid is hydrochloric acid or trifluoroacetic acid. 10. A compound of the formula: wherein the compound of the formula (I) is synthesized as an intermediate of the formula:

11. A method of preparing a compound according to claim 10, comprising: ON COOEt N COOEt  Boc boc  Starting material (2R)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent 2,6-lutidine and N,N-dimethylaminopyridine and trifluoroacetic anhydride are reacted at room temperature to obtain (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1. 2-dicarboxylate;

a cyclohexane solution of (R)-l-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine and a cyclohexane solution of dichloroacetyl chloride Reaction in an oil bath to give (1^31^,58)-2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0]heptane -2, 3_dicarboxylate;

 The obtained (1R, 3R, 5S)_2-tert-butyl 3-ethyl 7,7-dichloro-6-oxo-2-nitro-bicyclo[3.2.0] heptane-2,3-dicarboxyl The acid ester is reacted with ammonium chloride in methanol solution and activated zinc powder at room temperature to obtain (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate;  H R1 H  K COOEt COOEt  Boc boc  The obtained (lS,3R,5S)-2-tert-butyl 3-ethyl 6-oxo-2-nitro-bicyclo[3.2.0]heptane-2,3-dicarboxylate in dichloromethane a halogenation reaction or a reduction reaction in a solvent to obtain a carbonyl-substituted, pyrrolidine-tetra-cyclic compound;  R1 b R1 H N "COOEt N eight COOEt HH ¹  Boc boc  To a solution of diisopropylamine in tetrahydrofuran, a solution of n-butyllithium in tetrahydrofuran is added dropwise, and then the reaction is added dropwise to a substituted pyrrolidine and a tetracyclic compound to further react to obtain an ester-substituted inverted pyrrolidine and quaternary Ring compound

The obtained ester-based inverted pyrrolidine and four-membered ring compound in an ethanol solvent with lithium hydroxide in an ice bath The reaction is further subjected to acid hydrolysis hydrolysis with IN hydrochloric acid to obtain a pyrrolidine carboxylic acid and a four-membered ring compound;

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

A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the dipeptidyl peptidase (DPPIV) inhibitor. 14. Use of a pharmaceutical composition according to claim 12 for the manufacture of a dipeptidyl peptidase (DPPIV) inhibitor drug.