CN113861196A - DPP-IV inhibitor with 4, 6-disubstituted pyrimidine structure and application thereof - Google Patents

DPP-IV inhibitor with 4, 6-disubstituted pyrimidine structure and application thereof Download PDF

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CN113861196A
CN113861196A CN202111402030.1A CN202111402030A CN113861196A CN 113861196 A CN113861196 A CN 113861196A CN 202111402030 A CN202111402030 A CN 202111402030A CN 113861196 A CN113861196 A CN 113861196A
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林超
李沛伍
邢琦
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Yantai Institute Of Materia Medica
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Abstract

The invention relates to a DPP-IV inhibitor with a 4, 6-disubstituted pyrimidine structure, which comprises an effective amount of a compound shown in formula (I) or/and a pharmaceutically acceptable derivative thereof:

Description

DPP-IV inhibitor with 4, 6-disubstituted pyrimidine structure and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a DPP-IV inhibitor with a 4, 6-disubstituted pyrimidine structure and application thereof.
Background
Diabetes mellitus is a common endocrine metabolic disease which is mainly clinically manifested by protein and lipid metabolism disorder and is caused by hyperglycemia caused by absolute or relative insufficiency of insulin secretion in a human body. The most important biochemical indicator is hyperglycemia. Chronic hyperglycemia significantly increases the risk of macrovascular and microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic heart disease, and diabetic neuropathy, which have become the leading cause of death in diabetic patients.
Type ii diabetes is a chronic progressive disease, and as the course of disease increases, blood sugar tends to rise gradually, so the treatment intensity for controlling blood sugar is also gradually increased, and a combination treatment of a plurality of treatment modes is required. The blood sugar reducing treatment mainly comprises comprehensive treatment measures such as diet control, reasonable exercise, blood sugar monitoring, taking of blood sugar reducing medicines and the like. Lifestyle interventions such as diet control and rational exercise are fundamental therapeutic measures throughout the treatment of type ii diabetes. If blood glucose cannot be effectively controlled by lifestyle intervention alone, drug therapy should be initiated. Metformin is the first choice therapeutic for type ii diabetes. If no contraindications exist, metformin should be kept in the treatment regimen. If metformin alone is not effective in controlling blood glucose, a combination therapy of oral drugs such as thiazolidinediones, insulin secretagogues, DPP-IV inhibitors, alpha-glucosidase inhibitors, SGLT-2 inhibitors and the like can be used. The combination of two oral drugs still cannot effectively control blood sugar, and can increase insulin treatment. GLP-1 analogs can be used as a three-line therapy.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a DPP-IV inhibitor with a 4, 6-disubstituted pyrimidine structure and application thereof.
The first purpose of the invention is to provide a DPP-IV inhibitor with a 4, 6-disubstituted pyrimidine structure, which comprises an effective amount of a compound shown as a formula (I) or/and a pharmaceutically acceptable derivative thereof:
Figure BDA0003364888300000021
wherein the Ar ring isC optionally substituted by 1 to 5 groups selected from substituent group a6-C10An aryl group;
substituent group a includes: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -NHOH, -NH-O- (C)1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2；
R1And R2Each independently selected from hydrogen atom, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, Ar' ring;
ar' ring is C optionally substituted with 0 to 5 groups selected from substituent group b6-C10An aryl group;
substituent group b includes: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -OCH2O-、-NHOH、-NH-O-(C1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2。
Further, the derivatives include salts, esters, solvates, hydrates, isomers, crystal forms or prodrugs thereof.
Further, Ar is phenyl optionally substituted with 1 to 5 halogen atoms.
Further, R1And R2Are each independently selected from hydrogen atoms, C1-C6Alkyl, halogenated C1-C6Alkyl, Ar' ring;
wherein, the Ar' ring is a C6-10 aryl optionally substituted by 0-5 groups selected from substituent group b;
substituent group b includes: c1-C6Alkyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -OCH2O-、-NHOH、-NH-O-(C1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2。
Further, the DPP-IV inhibitor has the following structural formula:
Figure BDA0003364888300000041
the second purpose of the invention is to provide the application of the DPP-IV inhibitor in the field of treating and/or preventing diseases related to DPP-IV over-activity or DPP-IV over-expression, in particular the application in the field of treating diabetes, atherosclerosis, non-alcoholic fatty liver disease and heart failure.
Compared with the prior art, the invention has the following beneficial effects:
the compound or/and pharmaceutically acceptable salts, esters, solvates, hydrates, isomers, crystal forms or prodrugs thereof provided by the invention can be used for treating and/or preventing diseases related to DPP-IV (dipeptidyl peptidase IV) activity overhigh or DPP-IV overexpression, such as diabetes, atherosclerosis, nonalcoholic fatty liver, heart failure and the like, have a good inhibitory effect on DPP-IV and have good hypoglycemic activity.
Detailed Description
The principles and features of this invention are described below in conjunction with examples, which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Example 1
Preparation of the compound 1-9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -7,8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000051
step 1:
Figure BDA0003364888300000052
to a solution of N-Boc-3-cyano-4-piperidone (1.12g,5mmol,1.0eq) in ethanol (10mL) was added hydrazine hydrate (20mmol, 4.0eq), and the reaction was refluxed at 80 ℃. TLC detection reaction is complete, cooling to room temperature, decompressing and concentrating the solvent, extracting with ethyl acetate and water, washing the organic phase with saturated common salt water, drying with anhydrous sodium sulfate, decompressing and distilling to obtain a crude product, namely, a white solid compound, namely, 3-amino-6, 7-dihydro-2H-pyrazolo [4,3-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester. The reaction mixture was used in the next reaction without purification. The yield thereof was found to be 87%. Step 2:
Figure BDA0003364888300000061
to a solution of 3-amino-6, 7-dihydro-2H-pyrazolo [4,3-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (1.19g,5mmol,1.0eq) in acetic acid (10mL) was added malondialdehyde (6mmol,1.2eq) and the reaction was heated at 80 ℃ under reflux. TLC detection reaction is completed, cooling to room temperature, decompressing and concentrating the solvent, extracting by ethyl acetate and water, washing the organic phase by saturated saline, drying by anhydrous sodium sulfate, decompressing and distilling to obtain a crude product, and purifying and separating by column chromatography to obtain the product of 7, 8-dihydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine-9 (10H) -carboxylic acid tert-butyl ester.
And step 3:
Figure BDA0003364888300000062
the compound, 7, 8-dihydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine-9 (10H) -carboxylic acid tert-butyl ester (2.3mmol, 1.2eq) was dissolved in trifluoroacetic acid (2.3mL) and reacted at room temperature with TLC detection complete. The temperature is reduced to 0 ℃, DMAc (9.2mL) is added, triethylamine (1.6mL) is added, the reaction is carried out for 10 minutes, and the pH value of the system is adjusted to be alkaline. Tert-butyl N- [ (2R,3S) -2- (2, 5-difluorophenyl) tetrahydro-5-oxo-2H-pyran-3-yl ] carbamate (1.9mmol,1.0eq) was added to the system and reacted at room temperature for 2 hours. The temperature is reduced to 0 ℃, sodium triacetoxyborohydride (2.85mmol,1.5eq) is added in three batches, and the reaction is carried out overnight. The post-treatment is extracted by ethyl acetate and water, the organic phase is washed by saturated brine, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product, and the crude product is purified and separated by column chromatography to obtain the final product, namely 9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -7,8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine. The yield of the two steps is 36%.
Example 2
Preparation of the compound 2-9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-dimethyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000071
synthesis method of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound pentane-2, 4-dione to finally obtain the compound 9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-dimethyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 3
Preparation of compound 3- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-methyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000072
synthesis method of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 1,1, 1-trifluoropentane-2, 4-dione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-methyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 4
Preparation of compound 4- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-bistrifluoromethyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000081
synthesis of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 1,1,1,5,5, 5-hexafluoropentane-2, 4-dione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-bistrifluoromethyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 5
Preparation of compound 5- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-phenyl-6-methyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000082
synthesis method of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 1-phenylbutane-1, 3-dione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-phenyl-6-methyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 6
Preparation of compound 6- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-diphenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000091
synthesis method of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 1, 3-diphenylpropane-1, 3-dione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4, 6-diphenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 7
Preparation of compound 7- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000101
synthesis of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 4,4, 4-trifluoro-1-phenylbutane-1, 3-dione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 8
Preparation of compound 8- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-p-methylphenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000102
synthesis of the Compound referring to example 1, the starting material malondialdehyde in example 1 was changed to the compound 4,4, 4-trifluoro-1- (4-tolyl) -1, 3-butanedione to finally obtain the compound (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6-p-methylphenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 9
Preparation of compound 9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-chloro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000111
the synthesis of this compound is described in reference to example 1 to give finally (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-chloro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 10
Preparation of compound 10- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-fluoro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000112
the synthesis of this compound is described in reference to example 1 to give finally (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-fluoro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 11
Preparation of compound 11- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000121
the synthesis of this compound is described in reference to example 1 to give finally (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Example 12
Preparation of compound 12- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (2, 4-dichloro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000122
the synthesis of this compound is described in reference to example 1, and finally (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (2, 4-dichloro) phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine is obtained.
Example 13
Preparation of compound 13- (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (3, 4-dioxo) cyclopenta-phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine:
Figure BDA0003364888300000131
the synthesis of this compound is described in reference to example 1 to give finally (9- ((3R,5S,6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydro-2H-pyran-3-yl) -4-trifluoromethyl-6- (3, 4-dioxo) cyclopenta-phenyl-7, 8,9, 10-tetrahydropyrido [4',3':3,4] pyrazolo [1,5-a ] pyrimidine.
Test results
Process for preparation of the Compounds obtained in examples 1 to 13 of the invention1The results of H-NMR and HRMS measurements are shown in Table 1.
Of the compounds of Table 11H-NMR and HRMS test results
Figure BDA0003364888300000132
Figure BDA0003364888300000141
Figure BDA0003364888300000151
Figure BDA0003364888300000161
Figure BDA0003364888300000171
Biological evaluation
Test 1: DPP-IV inhibitor cell screening assay
Reagent:
name (R) Suppliers of goods Goods number
DMSO Beijing Solaibao D8317
DPP(IV)Inhibitor Screening Assay Kit CAYMAN KA1311
Serum Gibco 10091-148
DMEM medium Gibco C11995500BT
Gly-Pro-pNA Sigma G0513-25MG
The test method comprises the following steps:
taking Caco-2 cells in logarithmic growth phase at 1 × 105Cells are inoculated into a 96-well culture plate at each concentration per mL, 200 mu L of cells are inoculated into each well, after the cells are attached to the wall 24 hours, the culture solution of Caco-2 cells in the 96-well plate is sucked out, a new Caco-2 cell culture solution is added into a control group, and the experimental group is treated by compounds with different concentrations, wherein each well is 200 mu L. After 36h, each culture solution in the 96-well plate was aspirated again and washed once with PBS, and the substrate 15. mu.L and the buffer 85. mu.L were added to the 96-well plate in this order to make the total volume in each well 100. mu.L. The reaction temperature in each well was 37 ℃ and the reaction time was 120 min. The OD value of the absorbance measured at 405nm by a microplate reader is largeIs small. The results of the cell screening are shown in Table 2.
TABLE 2
Figure BDA0003364888300000172
Figure BDA0003364888300000181
As shown by the test data in Table 2, the above compound has a good inhibitory effect on DPP-IV, and the compound 4 has the best inhibitory effect on DPP-IV.
Test 2: hypoglycemic test of Compound 4
The experimental method comprises the following steps:
ICR mice are selected for experiments, blood sugar values of the mice are detected one day before the experiments, the mice are divided into groups, 7 mice are detected in each group, the blood sugar values are detected again after 8 hours of fasting, then administration is started in each group, the administration dosage of the Orogliptin group is 5.2mg/kg, the administration dosage of the compound 4 is 5.2mg/kg, glucose solution (2g/kg) is injected into the abdominal cavity after 60 minutes, and the blood sugar values are detected 15, 30, 60, 90 and 120 minutes after the injection. The results are shown in Table 3.
The experimental result shows that the compound 4 has the hypoglycemic activity equivalent to that of the alogliptin, even superior to that of the alogliptin.
TABLE 3 results of hypoglycemic experiments for Compound 4
Time (min) 0 15 30 60 90 120
Blank group 8.03±0.52 13.21±0.25 14.13±1.71 10.09±0.74 8.05±0.56 8.16±0.19
Augustine 5.89±0.40 14.13±1.18 11.43±0.91* 8.39±0.16* 6.17±0.21* 6.07±0.16*
Compound 4 5.12±0.28 11.91±1.06* 9.18±0.72* 6.13±0.41* 4.16±0.63* 4.02±0.73*
Note: all data are mean ± SEM (n ═ 7). P <0.05vs blank group.
Preparation of pharmaceutical tablets:
compound 4(1g) prepared in example was mixed with lactose (23g) and microcrystalline cellulose (5.7g) with a mixer. And pressing and molding the obtained mixture by using a roller compactor to obtain the flaky pressed material. The resulting flaky compacted material was ground into powder with a hammer mill, and the resulting powdery material was sieved through a 20-mesh sieve. Light silica (0.3g) and magnesium stearate (0.3g) were added to the sieved material and mixed. The resulting mixed product was tableted with a tableting machine to prepare tablets.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (6)

1. A DPP-IV inhibitor with a 4, 6-disubstituted pyrimidine structure is characterized by comprising an effective amount of a compound shown as a formula (I) or/and a pharmaceutically acceptable derivative thereof:
Figure FDA0003364888290000011
wherein the Ar ring is C optionally substituted by 1 to 5 substituents selected from substituent group a6-C10An aryl group;
substituent group a includes: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -NHOH, -NH-O- (C)1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2；
R1And R2Each independently selected from hydrogen atom, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, Ar' ring;
ar' ring is C optionally substituted with 0 to 5 groups selected from substituent group b6-C10An aryl group;
substituent group b includes: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -OCH2O-、-NHOH、-NH-O-(C1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2。
2. The DPP-IV inhibitor according to claim 1, wherein said derivative comprises a salt, an ester, a solvate, a hydrate, an isomer, a crystalline form or a prodrug thereof.
3. The DPP-IV inhibitor according to claim 1 or 2, wherein Ar is phenyl optionally substituted with 1-5 halogen atoms.
4. The DPP-IV inhibitor according to claim 1 or 2, characterized in that R1And R2Are each independently selected from hydrogen atoms, C1-C6Alkyl, halogenated C1-C6Alkyl, Ar' ring;
wherein, the Ar' ring is a C6-10 aryl optionally substituted by 0-5 groups selected from substituent group b;
substituent group b includes: c1-C6Alkyl, halogenated C1-C6Alkyl, halogen, cyano, amino, hydroxy, -OCH2O-、-NHOH、-NH-O-(C1-C6Alkyl), -NH- (C)1-C6Alkyl), -N (C)1-C6Alkyl radical)2、-C(O)NH2、-C(O)NH-(C1-C6Alkyl), -C (O) N (C)1-C6Alkyl radical)2、-NHC(O)-(C1-C6Alkyl), -NHC (O) - (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl) C (O) - (C)1-C6Alkyl), -NHC (O) NH2。
5. The DPP-IV inhibitor according to claim 1 or 2, characterized by the following structural formula:
Figure FDA0003364888290000031
6. the use of the DPP-IV inhibitor as defined in any one of claims 1 to 5 in the treatment and/or prevention of diseases associated with DPP-IV hyperactivity or DPP-IV overexpression.
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