CN103012379A - Phenylalanine derivatives, preparation method and application thereof - Google Patents

Abstract

The invention provides a class of phenylalanine derivatives and their physiologically acceptable salts. Using iodo-phenylalanine derivatives as starting materials, a terminal alkyne compound is obtained through two-step reactions of Sonogashira coupling and deprotection. The terminal alkyne compound further undergoes a click reaction with an azide compound to obtain a 1,2,3-triazole derivative, which is then deprotected to obtain the target compound in a higher yield. Preliminary pharmacological experiments show that the compound of the present invention has strong inhibitory activity on DPP-IV, and can be used in the preparation of anti-type 2 diabetes drugs as a new DPP-IV inhibitor of structure. The synthesis route of the invention is reasonable and short in design, mild in reaction conditions, conducive to energy saving and environmental protection, easy in purification treatment, high in yield, and suitable for practical use. The general structural formula of the compound is as follows.

Description

Phenylalanine derivatives and their preparation and use

technical field

The invention belongs to the synthesis of organic compounds, and mainly relates to the preparation method of phenylalanine derivatives with dipeptidyl peptidase-IV (Dipeptidyl peptidase IV, DPP-IV) inhibitory activity, and the preparation of the compound for treatment or prevention Application in medicine for diseases related to DPP-IV, such as diabetes, especially type 2 diabetes.

Background technique

Diabetes is currently one of the major diseases that seriously endanger human health, and its incidence is still rising year by year. According to the World Health Organization's forecast, there are 194 million people with diabetes worldwide. By 2030, this number will increase to 366 million, of which More than 90% of patients have type 2 diabetes. There are more than 90 million people with diabetes in my country, ranking second in the world. If not treated in time, serious microvascular complications will occur, which will affect the lives of patients. Although the pathogenesis of diabetes is still unclear, chronic hyperglycemia, insulin resistance and relative insufficiency of pancreatic β -cell secretion are the main features of diabetes.

In addition to lifestyle intervention, diabetic patients mainly maintain blood sugar balance through insulin injections and oral hypoglycemic drugs. Oral hypoglycemic drugs commonly used in clinical practice mainly include insulin secretion enhancers (sulfonylureas and glitazones), insulin sensitizers (biguanides and thiazolidinones) and carbohydrate regulators (α-glucosidase inhibitors). However, these drugs are accompanied by severe hypoglycemia, weight gain and gastrointestinal side effects in clinical application. Therefore, it is urgent to develop new hypoglycemic drugs. In recent years, with the continuous and in-depth research on the etiology of diabetes, people have discovered a variety of new targets for the prevention and treatment of diabetes, among which, dipeptidyl peptidase IV (DPP-IV) is an interesting and extremely potential targets. DPP-IV is a special serine protease that can specifically degrade and inactivate glucagon-like peptide 1 (GLP-1), which regulates blood glucose homeostasis. Selective inhibition of DPP-IV can increase the concentration of GLP-1 and prolong its half-life, thereby improving and alleviating the symptoms of diabetes without side effects such as weight gain and hypoglycemia caused by other diabetes drugs. Therefore, research on small molecule inhibitors targeting DPP-IV is highly favored. So far, five small-molecule DPP-IV inhibitors have been approved for marketing, and several small-molecule DPP-IV inhibitors have entered different stages of clinical research. These inhibitors have shown obvious hypoglycemic effects in clinical applications and tolerance. Therefore, designing and synthesizing small-molecule DPP-IV inhibitors as antidiabetic drugs has become a research hotspot (M. Pal, et al., Bioorg. Med. Chem ., 2009 , 17 , 1783-1802; Y. Liu, et al., Curr. Med. Chem. , 2012 , 19 , 3982-3999).

Contents of the invention

The first object of the present invention is to provide a class of phenylalanine derivatives with novel structure and DPP-IV inhibitory activity and physiologically acceptable salts thereof, said compound has the following general structural formula:

in:

R ₁ and R ₂ are selected from hydrogen or methyl;

_R3 is selected from:

① Straight chain or branched alkyl or alkoxy groups containing 1-6 carbon atoms, preferably methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, pentyl group, hydroxyethyl group, etc.;

② For substituents containing 3-7 membered rings, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, etc. are preferred;

③Benzyl, phenyl, substituted benzyl or substituted phenyl, where the substituents include mono-substitution, di-substitution, tri-substitution, the substituents are generally fluorine atom, chlorine atom, bromine atom, methoxy, tertiary Butyl, formamido, hydroxyl, carboxyl, ester, cyano, trifluoromethyl, linear or branched alkyl or alkoxy with 1-3 carbon atoms;

④-CH ₂ R ₄ , R ₄ is a heterocycle, the heterocycle is preferably furan, thiophene, pyridine and furan, thiophene, pyridine with substituents, the substituents are generally fluorine atoms, chlorine atoms, methyl, etc.;

⑤ Phenylethyl or phenylacetyl. the

Another object of the present invention is to provide the preparation method of above-mentioned target compound, realize through the following steps:

The general reaction formula above is the reaction formula used to prepare the target compound V. The starting material I undergoes a Sonogashira reaction with trimethylsilylacetylene under the catalysis of Pd(PPh ₃ ) ₂ Cl ₂ and CuI, and obtains in a higher yield Compound II . Here we use triethylamine or acetonitrile as solvent, the reaction temperature is controlled at room temperature, and the reaction time is 1-3 hours. Compound II removes the trimethylsilyl protecting group to obtain compound III , ( n -Bu ₄ )NF is used as a desiliconization reagent, THF is used as a solvent, the reaction temperature is room temperature, and the reaction time is 0.5-3 hours. Under the catalysis of CuSO ₄ ·5H ₂ O and sodium ascorbate, compound III undergoes a click reaction with various azides in ethanol solution to obtain compound IV almost quantitatively. The reaction is carried out at room temperature and the reaction time is 2-8 hours. The compound IV removes the Boc protecting group under acidic conditions to obtain the target compound V , and the reaction is carried out at room temperature, and the reaction time is 1-2 hours.

Reaction formula:

The definitions of R ₁ , R ₂ and R ₃ are the same as those in the general structural formula.

Throughout the entire process flow, the innovation of the present invention can be clearly seen: mild reaction conditions are used, and the above-mentioned several steps of reaction are carried out at room temperature without heating or cooling, which is conducive to energy saving and environmental protection. Secondly, the synthetic route uses the classic click reaction, which has the characteristics of fast rate and high atom utilization. The compounds involved in the present invention are all obtained in relatively high yields, are easy to purify, and are suitable for large-scale industrial production.

Specifically prepared by the following steps:

(1) Compound I and trimethylsilylacetylene undergo Sonogashira reaction under the catalysis of Pd(PPh ₃ ) ₂ Cl ₂ and CuI to obtain compound II . The ratio of compound I to trimethylsilylacetylene is generally 1:1-1 : 3, the feed ratio of compound I and catalyst is generally 100:1-10:1, commonly used Et _N or acetonitrile is made solvent;

(2) In the presence of ( n -Bu ₄ )NF, compound II removes the silicon protecting group to obtain compound III . The ratio of compound II to ( n -Bu ₄ )NF is generally 1:2-1:10, and THF is commonly used as a solvent;

( 3) Compound III reacts with R ₃ N ₃ under the catalysis of CuSO ₄ 5H ₂ O and sodium ascorbate to obtain compound IV . The ratio of compound III to R ₃ N ₃ is generally 1:1-1:5. Compound The feed ratio of III to the catalyst is generally 20:1-10:1, and ethanol, water, acetonitrile, etc. are commonly used as solvents;

(4) Compound IV removes the Boc protecting group in an acidic solution to obtain the target compound V. Commonly used acidic systems include CF ₃ COOH/CH ₂ Cl ₂ , EtOAc/HCl, Et ₂ O/HCl or Dioxane/HCl, etc., preferably Choose Et ₂ O/HCl system.

Another object of the present invention is to provide the application of phenylalanine derivatives and their physiologically acceptable salts in the preparation of anti-type 2 diabetes drugs. Preliminary pharmacological experiments show that most compounds have strong inhibitory activity on DPP-IV.

The prepared drug can also be used in combination with other types of hypoglycemic drugs, which can reduce the toxic and side effects of a single drug and improve the curative effect. Other classes of hypoglycemic drugs include: insulin sensitizers, such as rosiglitazone and piroglitazone; biguanides, such as metformin and phenformin; alpha-glucosidase inhibitors, such as acarbose and miglitol ; Insulin and insulin mimics; Sulfonylureas; GLP-1 and GLP-1 analogs, etc.

The notable feature of the present invention is that a class of DPP-IV inhibitors with a new structure can be rapidly obtained through a short synthetic route, the reaction conditions are mild, and the operation and industrial production are easy. Preliminary pharmacological experiments show that most compounds have strong inhibitory activity on DPP-IV.

Detailed ways

The present invention is described further in conjunction with embodiment. The following examples illustrate the present invention, but do not limit the present invention in any way.

Example 1: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-{4-[(trimethylsilyl)ethynyl ]phenyl}propan-2-ylcarbamate ( Ⅱ )

Compound I was synthesized by the method of reference (L. Qiao, et al., Bioorg. Med. Chem . Lett. , 2006 , 16 , 123-128). Under nitrogen protection, compound 1 (469mg, 1.0 mmol), CuI (3.8 mg, 0.02 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (7 mg, 0.01 mmol) were added to Et ₃ N (10 mL) solution After the solution was cooled for a period of time, trimethylsilylacetylene (117.8 mg, 1.2 mmol) was slowly added, the reaction was stirred at room temperature after the addition, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was filtered with a short silica gel column. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain a light yellow oil with a yield of 85%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.45 (d, 2H, J = 8.5 Hz, ArH ), 7.21 (d, 2H, J = 8.5 Hz, ArH ), 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.68 (m, 1H, CH CN), 4.52-4.48 (m, 1H, CH ), 3.39-3.35 (m, 1H, CH ₂ ), 3.02-3.01 (d, 2H, J = 7.5 Hz, CH ₂ ), 2.64-2.60 (m, 1H, CH ₂ ), 2.17-2.13 (m, 1H, CH ₂ ), 2.11-2.06 (m, 1H, CH ₂ ), 1.95-1.91 (m, 1H, CH ₂ ), 1.86-1.84 (m, 1H, CH ₂ ), 1.43 (s, 9H, t-Bu-H ), 0.24 (s, 9H, Si- 3CH ₃ ) ppm; ESI-MS: m/ z = 440 [M + H] ⁺ .

Example 2: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-(4-ethynylphenyl)-1-oxapropane-2-yl Urethane ( III )

Compound II (3.10 g, 7.05 mmol) was dissolved in anhydrous THF (40 mL) solution, and after cooling the reaction solution for a period of time, ( n -Bu ₄ )NF (2.77 g, 10.58 mmol) was added slowly, and the addition was completed , stirred the reaction at room temperature, and monitored the reaction progress by TLC. After the reaction was completed, the solvent was recovered under reduced pressure, the residue was dissolved with CH ₂ Cl ₂ (50 mL), the organic phase was washed with saturated brine (3 x 15 mL), and anhydrous Na _{2 SO4} was dried, filtered with suction, and the solvent was recovered under reduced pressure. The crude product was separated and purified by column chromatography to obtain a light yellow oil with a yield of 95%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.48 (d, 2H, J = 8.5 Hz, ArH ), 7.24 (d, 2H, J = 8.5 Hz, ArH ), 5.33 (d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.69 (m, 1H, CH CN), 4.54-4.49 (m, 1H, CH ), 3.42-3.34 (m, 1H, CH ₂ ), 3.08 (s, 1H, ≡CH ) , 3.04 (d, 2H, J = 7.0 Hz, CH ₂ ), 2.69-2.65 (m, 1H, CH ₂ ), 2.19-2.14 (m, 1H, CH ₂ ), 2.11-2.06 (m, 1H, CH ₂ ), 1.98-1.92 (m, 1H, CH ₂ ), 1.89-1.84 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 368 [ M + H] ⁺ .

Example 3: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-methyl-1H-1,2,3-tri Azol-4-yl)phenyl]-1-oxapropan-2-ylcarbamate ( IV1 )

Compound III (353 mg, 1.0 mmol), NaN ₃ (98 mg, 1.5 mmol), CH ₃ I (402 mg, 1.5 mmol), CuSO ₄ ·5H ₂ O (25 mg, 0.1 mmol), sodium ascorbate (20 mg, 0.1 mmol) and absolute ethanol (10 mL) were added into a sealed reaction flask, and the reaction was stirred at room temperature, and the reaction progress was monitored by _{TLC .} ) was dissolved, the organic phase was washed with saturated brine (3 x 10 mL), dried over anhydrous Na ₂ SO ₄ , suction filtered, and the solvent was recovered under reduced pressure. The crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 95 %.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.75 (s, 1H, =CH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ) , 5.36 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.55-4.51 (m, 1H, CH ), 4.13 (s, 3H, CH ₃ ), 3.39 -3.35 (m, 1H, CH ₂ ), 3.08-3.00 (m, 2H, CH ₂ ), 2.70-2.66 (m, 1H, CH ₂ ), 2.09-2.05 (m, 2H, CH ₂ ), 1.90-1.87 (m, 1H, CH ₂ ), 1.77-1.74 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 425 [M + H] ⁺ .

Example 4: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-ethyl-1H-1,2,3-tri Azol-4-yl)phenyl]-1-oxapropan-2-ylcarbamate ( IV2 )

The operation process is the same as in Example 3, and the azide methane is replaced with azidoethane, and column chromatography obtains a colorless oil, and the yield is 91%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.83 (d, 2H, J = 7.5 Hz, ArH ), 7.80 (s, 1H, =CH ), 7.35 (d, 2H, J = 7.5 Hz, ArH ) , 5.35 (d, 1H, J = 9.0 Hz, NH Boc), 4.72-4.70 (m, 1H, CH CN), 4.58-4.53 (m, 1H, CH ), 4.50 (q, 2H, J = 7.5 Hz, CH ₂ ), 3.42-3.37 (m, 1H, CH ₂ ), 3.11-3.07 (m, 2H, CH ₂ ), 2.71-2.67 (m, 1H, CH ₂ ), 2.14-2.07 (m, 1H, CH ₂ ), 1.92-1.88 (m, 1H, CH ₂ ), 1.81-1.75 (m, 1H, CH ₂ ), 1.73-1.70 (m, 1H, CH ₂ ), 1.64 (t, 3H, J = 7.5 Hz, CH ₃ ), 1.44 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 439 [M + H] ⁺ .

Example 5: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-propyl-1H-1, 2,3-triazol-4-yl)phenyl]propan-2-ylcarbamate ( IV3 )

The operating process is the same as in Example 3, replacing azidomethane with azidopropane, and column chromatography obtains a colorless oily substance with a yield of 89%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.81 (d, 2H, J = 7.5 Hz, ArH ), 7.75 (s, 1H, =CH ), 7.33 (d, 2H, J = 7.5 Hz, ArH) , 5.38 (d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.69 (m, 1H, CH CN), 4.57-4.53 (m, 1H, CH ), 4.37 (t, 2H, J = 7.0 Hz, CH ₂ ), 3.41-3.36 (m, 1H, CH ₂ ), 3.09-3.03 (m, 2H, CH ₂ ), 2.71-2.66 (m, 1H, CH ₂ ), 2.13-2.06 (m, 2H, CH ₂ ), 1.99-1.94 (m, 2H, CH ₂ ), 1.91-1.86 (m, 1H, CH ₂ ), 1.78-1.75 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) , 1.01 (t, 3H, J = 7.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 453 [M + H] ⁺ .

Example 6: tert-butyl ( S )-3-[4-(1-butyl-1H-1,2,3-triazol-4-yl)phenyl]-1-[( S )-2- Cyanopyrrolidin-1-yl]-1-oxapropan-2-ylcarbamate ( IV4 )

The operation process is the same as in Example 3, and azidomethane is replaced with azidobutane, and column chromatography obtains a colorless oil, and the yield is 93%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.0 Hz, ArH ), 7.73 (s, 1H, =CH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ) , 5.41 (d, 1H, J = 8.5 Hz, CH ), 4.69-4.66 (m, 1H, CH CN), 4.55-4.51 (m, 1H, CH ), 4.38 (t, 2H, J = 7.5 Hz, CH ₂ ), 3.39-3.37 (m, 1H, CH ₂ ), 3.04-3.01 (m, 2H, CH ₂ ), 2.70-2.67 (m, 1H, CH ₂ ), 2.07-2.03 (m, 1H, CH ₂ ) , 1.94-1.86 (m, 4H, CH ₂ ), 1.77-1.67 (m, 1H, CH ₂ ), 1.40 (s, 9H, t-Bu-H ), 1.38-1.33 (m, 2H, CH ₂ ), 0.95 (t, 3H, J = 7.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 467 [M + H] ⁺ .

Example 7: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-isopropyl-1H-1,2,3- Triazol-4-yl)phenyl]-1-oxapropan-2-ylcarbamate ( IV5 )

The operating process is the same as in Example 3, with isopropane azido instead of methane azido, and column chromatography obtains a colorless oily substance with a yield of 87%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.76 (s, 1H, =CH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ) , 5.39 (d, 1H, J = 8.5 Hz, NH Boc), 4.89-4.84 (m, 1H, CH ), 4.70-4.68 (m, 1H, CH CN), 4.55-4.52 (m, 1H, CH ), 3.39-3.38 (m, 1H, CH ₂ ), 3.07-3.00 (m, 2H, CH ₂ ), 2.69-2.64 (m, 1H, CH ₂ ), 2.10-2.05 (m, 2H, CH ₂ ), 1.90- 1.85 (m, 1H, CH ₂ ), 1.78-1.72 (m, 1H, CH ₂ ), 1.63-1.60 (m, 6H, CH ₃ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI- MS: m/z = 453 [M + H] ⁺ .

Example 8: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-isobutyl-1H-1,2,3- Triazol-4-yl)phenyl]-1-oxapropan-2-ylcarbamate ( IV6 )

The operating process is the same as in Example 3, with azide isobutane instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 83%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.72 (s, 1H, =CH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ) , 5.36 (d, 1H, J = 8.5 Hz, NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.55-4.53 (m, 1H, CH ), 4.21-4.18 (m, 2H, CH ₂ ) , 3.40-3.39 (m, 1H, CH ₂ ), 3.07-3.03 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.28-2.23 (m, 1H, CH ₂ ), 2.09 -2.04 (m, 1H, CH ₂ ), 1.91-1.77 (m, 3H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ), 0.98 (d, 3H, J = 1.0 Hz, CH ₃ ) , 0.97 (d, 3H, J = 1.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 467 [M + H] ⁺ .

Example 9: tert-butyl ( S )-3-[4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl]-1-[( S )-2- Cyanopyrrolidin-1-yl]-1-oxapropan-2-ylcarbamate ( IV7 )

The operation process is the same as that in Example 3, with benzyl azide instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 94%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.66 (s, 1H, =CH ), 7.40-7.36 (m, 3H, ArH ), 7.33- 7.32 (m, 2H, ArH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ), 5.56 (d, 2H, J = 4.5 Hz, CH ₂ Ar), 5.35 (d, 1H, J = 9.0 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.39-3.35 (m, 1H, CH ₂ ), 3.06-3.02 (m, 2H, CH ₂ ) , 2.70-2.65 (m, 1H, CH ₂ ), 2.08-2.04 (m, 2H, CH ₂ ), 1.90-1.85 (m, 1H, CH ₂ ), 1.78-1.69 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 501 [M + H] ⁺ .

Example 10: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-{4-[1-(2-hydroxyethyl)-1H-1, 2,3-Triazol-4-yl]phenyl}-1-oxapropan-2-ylcarbamate ( IV8 )

The operation process is the same as in Example 3, and azidomethanol is replaced with ethanol azide, and column chromatography obtains a colorless oily substance with a yield of 76%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.88 (s, 1H, =CH ), 7.72 (d, 2H, J = 8.0 Hz, ArH ), 7.29 (d, 2H, J = 8.0 Hz, ArH ) , 5.42 (d, 1H, J = 8.5 Hz, NH Boc), 4.68-4.66 (m, 1H, CH CN), 4.58-4.49 (m, 3H, CH , CH ₂ ), 4.09-4.07 (m, 2H, CH ₂ ), 3.43-3.38 (m, 1H, CH ₂ ), 3.05-3.01 (m, 2H, CH ₂ ), 2.77-2.73 (m, 1H, CH ₂ ), 2.11-2.05 (m, 2H, CH ₂ ), 1.89-1.87 (m, 1H, CH ₂ ), 1.81-1.76 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 455 [ M + H] ⁺ .

Example 11: tert-butyl ( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-{4-[1-(cyclopropylmethyl)-1H-1,2 ,3-triazol-4-yl]phenyl}-1-oxapropan-2-ylcarbamate ( IV9 )

Operation process is the same as embodiment 3, replaces azidomethane with azidocyclopropyl methane, and column chromatography obtains colorless oily matter, and yield is 88%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.87 (s, 1H, =CH ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.33 (d, 2H, J = 8.0 Hz, ArH ) , 5.36 (d, 1H, J = 9.0 Hz, NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.56-4.52 (m, 1H, CH ), 4.26-4.23 (m, 2H, CH ₂ ) , 3.41-3.36 (m, 1H, CH ₂ ), 3.09-3.03 (m, 2H, CH ₂ ), 2.70-2.59 (m, 2H, CH ₂ ), 2.08-2.05 (m, 1H, CH ₂ ), 1.92 -1.85 (m, 1H, CH ₂ ), 1.80-1.68 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ), 0.95 (t, 1H, J = 7.0 Hz, CH ), 0.75-0.70 (m, 2H, CH ₂ ), 0.49-0.45 (m, 2H, CH ₂ ) ppm; ESI-MS: m/z = 465 [M + H] ⁺ .

Example 12: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-cyclopropyl-1H-1,2,3 -Triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV10 )

The operating process is the same as in Example 3, with azidocyclopropane instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 77%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.76 (s, 1H, =CH ), 7.33 (d, 2H, J = 8.0 Hz, ArH ) , 6.09-6.03 (m, 1H, CH ), 5.40-5.38 (m, 2H, CH ₂ ), 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 5.02 (d, 2H, J = 6.5 Hz, CH ₂ ), 4.70-4.68 (m, 1H, CH CN), 4.56-4.52 (m, 1H, CH ), 3.41-3.36 (m, 1H, CH ₂ ), 3.09-3.01 (m, 2H, CH ₂ ) , 2.71-2.67 (m, 1H, CH ₂ ), 2.12-2.02 (m, 2H, CH ₂ ), 1.92-1.87 (m, 1H, CH ₂ ), 1.80-1.72 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 451 [M + H] ⁺ .

Example 13: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-cyclobutyl-1H-1,2,3 -Triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV11 )

The operating process is the same as in Example 3, with azidocyclobutane instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 86%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.84-7.82 (m, 3H, ArH , =CH ), 7.34 (d, 2H, J = 7.5 Hz, ArH ), 5.32 (d, 1H, J = 8.0 Hz, NH Boc), 5.11-5.07 (m, 1H, CH ), 4.70-4.68 (m, 1H, CH CN), 4.55-4.52 (m, 1H, CH ), 3.40-3.38 (m, 1H, CH ₂ ), 3.10-3.03 (m, 2H, CH ₂ ), 2.70-2.61 (m, 5H, CH ₂ ), 2.10-2.05 (m, 2H, CH ₂ ), 2.02-1.94 (m, 2H, CH ₂ ), 1.86-1.80 (m, 2H, CH ₂ ), 1.43 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 465 [M + H] ⁺ .

Example 14: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-cyclopentyl-1H-1,2,3 -Triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV12 )

The operation process is the same as in Example 3, and azidecyclopentane is used to replace azidomethane, and column chromatography obtains a colorless oil, and the yield is 90%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.74 (s, 1H, =CH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ) , 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 4.98-4.95 (m, 1H, CH ), 4.69-4.67 (m, 1H, CH CN), 4.54-4.52 (m, 1H, CH ), 3.39-3.36 (m, 1H, CH ₂ ), 3.07-3.02 (m, 2H, CH ₂ ), 2.69-2.64 (m, 1H, CH ₂ ), 2.30-2.25 (m, 2H, CH ₂ ), 2.11- 2.05 (m, 3H, CH ₂ ), 1.94-1.85 (m, 4H, CH ₂ ), 1.81-1.76 (m, 3H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI- MS: m/z = 479 [M + H] ⁺ .

Example 15: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-cyclohexyl-1H-1,2,3- Triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV13 )

The operating process is the same as in Example 3, and azidocyclohexane is used to replace azidomethane, and column chromatography obtains a colorless oily substance with a yield of 96%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.77 (s, 1H, =CH ), 7.33 (d, 2H, J = 8.0 Hz, ArH ) , 5.33 (d, 1H, J = 8.0 Hz, NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.56-4.46 (m, 2H, 2CH ), 3.41-3.36 (m, 1H, CH ₂ ) , 3.09-3.03 (m, 2H, CH ₂ ), 2.69-2.65 (m, 1H, CH ₂ ), 2.27-2.25 (m, 2H, CH ₂ ), 2.12-2.05 (m, 2H, CH ₂ ), 1.96 -1.94 (m, 3H, CH ₂ ), 1.91-1.87 (m, 1H, CH ₂ ), 1.83-1.73 (m, 5H, CH ₂ ), 1.43 (s, 9H, t-Bu-H ), 1.35- 1.29 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 493 [M + H] ⁺ .

Example 16: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(4-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV14 )

The operation process is the same as in Example 3, and 4-fluorobenzyl azide is used to replace azidomethane, and column chromatography obtains a colorless oily substance with a yield of 93%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.76 (d, 2H, J = 8.5 Hz, ArH ), 7.66 (s, 1H, =CH ), 7.32-7.28 (m, 4H, ArH ), 7.07 ( t, 2H, J = 8.5 Hz, ArH ), 5.52 (d, 2H, J = 2.5 Hz, CH ₂ Ar), 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.66 (m, 1H , CH CN), 4.54-4.52 (m, 1H, CH ), 3.39-3.35 (m, 1H, CH ₂ ), 3.05-3.02 (m, 2H, CH ₂ ), 2.71-2.67 (m, 1H, CH ₂ ), 2.09-2.04 (m, 2H, CH ₂ ), 1.89-1.86 (m, 1H, CH ₂ ), 1.76-1.70 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 519 [M + H] ⁺ .

Example 17: tert-butyl{( S )-3-[4-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1-[ ( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV15 )

The operating process is the same as in Example 3, with 4-chlorobenzyl azide instead of azidomethane, and column chromatography gives a colorless oily substance with a yield of 94%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.0 Hz, ArH ), 7.66 (s, 1H, =CH ), 7.38 (d, 2H, J = 8.0 Hz, ArH ) , 7.31 (d, 2H, J = 8.0 Hz, ArH ), 7.27 (d, 2H, J = 8.0 Hz, ArH ), 5.53 (s, 2H, CH ₂ Ar), 5.32 (d, 1H, J = 8.5 Hz , NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.40-3.37 (m, 1H, CH ₂ ), 3.08-3.03 (m, 2H, CH ₂ ), 2.71-2.67 (m, 1H, CH ₂ ), 2.09-2.03 (m, 2H, CH ₂ ), 1.90-1.85 (m, 1H, CH ₂ ), 1.78-1.72 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 536 [M + H] ⁺ .

Example 18: tert-butyl{( S )-3-[4-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1-[ ( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV16 )

The operating process is the same as in Example 3, with 4-bromobenzyl azide instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 91%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.67 (s, 1H, =CH ), 7.52 (d, 2H, J = 8.5 Hz, ArH ) , 7.30 (d, 2H, J = 8.0 Hz, ArH ), 7.20 (d, 2H, J = 8.5 Hz, ArH ), 5.51 (s, 2H, CH ₂ Ar), 5.33 (d, 1H, J = 8.5 Hz , NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.41-3.36 (m, 1H, CH ₂ ), 3.06-3.02 (m, 2H, CH ₂ ), 2.71-2.67 (m, 1H, CH ₂ ), 2.10-2.05 (m, 1H, CH ₂ ), 1.90-1.86 (m, 2H, CH ₂ ), 1.78-1.73 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 580 [M + H] ⁺ .

Example 19: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(4-methoxybenzyl)-1H -1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV17 )

The operating process is the same as in Example 3, except that 4-methoxybenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 96%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.76 (d, 2H, J = 8.0 Hz, ArH ), 7.62 (s, 1H, =CH ), 7.31-7.27 (m, 4H, ArH ), 6.92 ( d, 2H, J = 8.0 Hz, ArH ), 5.49 (d, 2H, J = 3.0 Hz, CH ₂ Ar), 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 4.68-4.64 (m, 1H , CH CN), 4.54-4.50 (m, 1H, CH ), 3.80 (s, 3H, O CH ₃ ), 3.40-3.35 (m, 1H, CH ₂ ), 3.06-3.00 (m, 2H, CH ₂ ) , 2.68-2.64 (m, 1H, CH ₂ ), 2.11-2.03 (m, 2H, CH ₂ ), 1.89-1.85 (m, 1H, CH ₂ ), 1.81-1.69 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 531 [M + H] ⁺ .

Example 20: tert-butyl{( S )-3-[4-(1-(4-cyanobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1- [( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV18 )

The operating process is the same as in Example 3, except that 4-cyanobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 97%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.72 (s, 1H, =CH ), 7.70 (d, 2H, J = 8.5 Hz, ArH ) , 7.41 (d, 2H, J = 8.5 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 5.63 (s, 2H, CH ₂ Ar), 5.31 (d, 1H, J = 8.5 Hz , NH Boc), 4.71-4.69 (m, 1H, CH CN), 4.57-4.52 (m, 1H, CH ), 3.44-3.39 (m, 1H, CH ₂ ), 3.06-3.04 (m, 2H, CH ₂ ), 2.75-2.71 (m, 1H, CH ₂ ), 2.12-2.05 (m, 2H, CH ₂ ), 1.91-1.89 (m, 1H, CH ₂ ), 1.80-1.74 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 526 [M + H] ⁺ .

Example 21: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-(4-(trifluoro Methyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl]propan-2-yl}carbamate ( IV19 )

The operating process is the same as in Example 3, except that 4-(trifluoromethyl) benzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 92%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.0 Hz, ArH ), 7.70 (s, 1H, =CH ), 7.66 (d, 2H, J = 8.5 Hz, ArH ) , 7.44 (d, 2H, J = 8.5 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 5.63 (s, 2H, CH ₂ Ar), 5.32 (d, 1H, J = 8.5 Hz , NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.08-3.03 (m, 2H, CH ₂ ), 2.73-2.68 (m, 1H, CH ₂ ), 2.12-2.04 (m, 2H, CH ₂ ), 1.91-1.87 (m, 1H, CH ₂ ), 1.80-1.73 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 569 [M + H] ⁺ .

Example 22: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(3,4-difluorobenzyl)- 1H-1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV20 )

The operation process was the same as in Example 3, except that 3,4-difluorobenzyl azide was used instead of azidomethane, and column chromatography gave a colorless oily substance with a yield of 89%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.0 Hz, ArH ), 7.69 (s, 1H, =CH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ) , 7.19-7.13 (m, 2H, ArH ), 7.07-7.06 (m, 1H, ArH ), 5.52 (s, 2H, CH ₂ Ar), 5.34 (d, 1H, J = 8.5 Hz, NH Boc), 4.70 -4.67 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.40-3.37 (m, 1H, CH ₂ ), 3.05-3.03 (m, 2H, CH ₂ ), 2.72-2.68 ( m, 1H, CH ₂ ), 2.12-2.05 (m, 2H, CH ₂ ), 1.90-1.87 (m, 1H, CH ₂ ), 1.78-1.72 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 537 [M + H] ⁺ .

Example 23: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(3,4-dimethoxybenzyl )-1H-1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV21 )

The operation process was the same as in Example 3, except that 3,4-dimethoxybenzyl azide was used instead of azidomethane, and column chromatography gave a colorless oily substance with a yield of 90%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.64 (s, 1H, =CH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ) , 6.94-6.91 (m, 1H, ArH ), 6.87-6.84 (m, 2H, ArH ), 5.48 (d, 2H, J = 4.0 Hz, CH ₂ Ar), 5.33 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.88 (s, 3H, O CH ₃ ), 3.85 (s, 3H, O CH ₃ ), 3.40 -3.35 (m, 1H, CH ₂ ), 3.07-3.01 (m, 2H, CH ₂ ), 2.70-2.65 (m, 1H, CH ₂ ), 2.11-2.03 (m, 2H, CH ₂ ), 1.90-1.84 (m, 1H, CH ₂ ), 1.79-1.71 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 561 [M + H] ⁺ .

Example 24: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-(pyridin-4-yl Methyl)-1H-1,2,3-triazol-4-yl)phenyl]propan-2-yl}carbamate ( IV22 )

The operation process is the same as in Example 3, except that 4-picolyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 87%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 8.62 (d, 2H, J = 6.0 Hz, pyridine- H ), 7.78 (d, 2H, J = 8.0 Hz, ArH ), 7.75 (s, 1H, = CH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 7.17 (d, 2H, J = 6.0 Hz, pyridine- H ), 5.59 (d, 2H, J = 1.5 Hz, CH ₂ Ar), 5.38 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.43-3.38 (m, 1H, CH ₂ ), 3.05 -3.03 (m, 2H, CH ₂ ), 2.75-2.71 (m, 1H, CH ₂ ), 2.11-2.04 (m, 2H, CH ₂ ), 1.92-1.86 (m, 1H, CH ₂ ), 1.79-1.73 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 502 [M + H] ⁺ .

Example 25: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-(thiophen-2-yl Methyl)-1H-1,2,3-triazol-4-yl)phenyl]propan-2-yl}carbamate ( IV23 )

The operating process is the same as in Example 3, except that 2-thiophenemethyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 85%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.5 Hz, ArH ), 7.72 (s, 1H, =CH ), 7.35 (d, 1H, J = 5.0 Hz, thiophene- H ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 7.16 (d, 1H, J = 3.0 Hz, thiophene- H ), 7.04-7.02 (m, 1H, thiophene- H ), 5.74 (d, 2H, J = 1.5 Hz, CH ₂ Ar), 5.33 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.55-4.51 (m, 1H, CH ), 3.40-3.35 (m, 1H, CH ₂ ), 3.07-3.02 (m, 2H, CH ₂ ), 2.69-2.65 (m, 1H, CH ₂ ), 2.12-2.05 (m, 2H, CH ₂ ), 1.90- 1.86 (m, 1H, CH ₂ ), 1.80-1.72 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 507 [M + H] ⁺ .

Example 26: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(2,6-difluorobenzyl)- 1H-1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV24 )

The operation process is the same as in Example 3, except that 2,6-difluorobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 81%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.76 (s, 1H, =CH ), 7.41-7.35 (m, 1H, ArH ), 7.30 ( d, 2H, J = 8.0 Hz, ArH ), 7.01-6.97 (m, 2H, ArH ), 5.66 (s, 2H, CH ₂ Ar), 5.33 (d, 1H, J = 8.5 Hz, NH Boc), 4.68 -4.66 (m, 1H, CH CN), 4.54-4.50 (m, 1H, CH ), 3.39-3.34 (m, 1H, CH ₂ ), 3.07-3.01 (m, 2H, CH ₂ ), 2.68-2.63 ( m, 1H, CH ₂ ), 2.11-2.04 (m, 2H, CH ₂ ), 1.89-1.84 (m, 1H, CH ₂ ), 1.78-1.73 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 537 [M + H] ⁺ .

Example 27: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(3,4-dichlorobenzyl)- 1H-1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV25 )

The operation process was the same as in Example 3, except that 3,4-dichlorobenzyl azide was used instead of azidomethane, and column chromatography gave a colorless oily substance with a yield of 86%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.70 (s, 1H, =CH ), 7.46 (d, 1H, J = 8.5 Hz, ArH ) , 7.43-7.41 (m, 1H, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 7.16-7.14 (m, 1H, ArH ), 5.51 (s, 2H, CH ₂ Ar), 5.36 ( d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.05- 3.02 (m, 2H, CH ₂ ), 2.74-2.69 (m, 1H, CH ₂ ), 2.10-2.03 (m, 2H, CH ₂ ), 1.90-1.85 (m, 1H, CH ₂ ), 1.79-1.73 ( m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 570 [M + H] ⁺ .

Example 28: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(3-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV26 )

The operating process is the same as in Example 3, except that 3-fluorobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 84%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.70 (s, 1H, =CH ), 7.37-7.33 (m, 1H, ArH ), 7.30 ( d, 2H, J = 8.0 Hz, ArH ), 7.10 (d, 1H, J = 7.5 Hz, ArH ), 7.07-7.03 (m, 1H, ArH ), 7.01-6.99 (m, 1H, ArH ), 5.55 ( d, 2H, J = 2.5 Hz, CH ₂ Ar), 5.43 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.66 (m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.41-3.37 (m, 1H, CH ₂ ), 3.05-3.02 (m, 2H, CH ₂ ), 2.73-2.68 (m, 1H, CH ₂ ), 2.10-2.03 (m, 2H, CH ₂ ), 1.89-1.87 (m, 1H, CH ₂ ), 1.78-1.74 (m, 1H, CH ₂ ), 1.40 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 519 [M + H] ⁺ .

Example 29: tert-butyl{( S )-3-[4-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1-[ ( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV27 )

The operating process is the same as in Example 3, except that 3-chlorobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 89%. the

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.70 (s, 1H, =CH ), 7.33-7.28 (m, 5H, ArH ), 7.19- 7.18 (m, 1H, ArH ), 5.52 (d, 2H, J = 2.5 Hz, CH ₂ Ar), 5.38 (d, 1H, J = 8.0 Hz, NH Boc), 4.68-4.66 (m, 1H, CH CN ), 4.55-4.50 (m, 1H, CH ), 3.41-3.36 (m, 1H, CH ₂ ), 3.03-3.01 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.10 -2.03 (m, 2H, CH ₂ ), 1.89-1.85 (m, 1H, CH ₂ ), 1.78-1.70 (m, 1H, CH ₂ ), 1.40 (s, 9H, t-Bu-H ) ppm; ESI -MS: m/z = 535 [M + H] ⁺ .

Example 30: tert-butyl{( S )-3-[4-(1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1-[ ( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV28 )

The operating process is the same as in Example 3, except that 3-bromobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 88%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.5 Hz, ArH ), 7.69 (s, 1H, =CH ), 7.51-7.49 (m, 1H, ArH ), 7.47 ( s, 1H, ArH ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 7.26-7.23 (m, 2H, ArH ), 5.53 (d, 2H, J = 2.5 Hz, CH ₂ Ar), 5.34 ( d, 1H, J = 8.0 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.07- 3.03 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.09-2.05 (m, 2H, CH ₂ ), 1.90-1.85 (m, 1H, CH ₂ ), 1.81-1.73 ( m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 579 [M + H] ⁺ .

Example 31: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(3-methoxybenzyl)-1H -1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV29 )

The operating process is the same as in Example 3, except that 3-methoxybenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 93%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.67 (s, 1H, =CH ), 7.30 (d, 3H, J = 7.5 Hz, ArH ) , 6.90-6.87 (m, 2H, ArH ), 6.84 (s, 1H, ArH ), 5.52 (d, 2H, J = 4.0 Hz, CH ₂ Ar), 5.35 (d, 1H, J = 8.5 Hz, NH Boc ), 4.68-4.66 (m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.78 (s, 3H, O CH ₃ ), 3.40-3.35 (m, 1H, CH ₂ ), 3.05- 3.01 (m, 2H, CH ₂ ), 2.70-2.66 (m, 1H, CH ₂ ), 2.11-2.02 (m, 2H, CH ₂ ), 1.90-1.86 (m, 1H, CH ₂ ), 1.78-1.68 ( m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 531 [M + H] ⁺ .

Example 32: tert-butyl{( S )-3-[4-(1-(3-cyanobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1- [( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV30 )

The operating process is the same as in Example 3, except that 3-cyanobenzyl azide replaces azidomethane, and column chromatography obtains a colorless oily substance with a yield of 86%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.72 (s, 1H, =CH ), 7.69-7.66 (m, 1H, ArH ), 7.60 ( m, 1H, ArH ), 7.56-7.50 (m, 2H, ArH ), 7.33 (d, 2H, J = 8.0 Hz, ArH ), 5.61 (s, 2H, CH ₂ Ar), 5.32 (d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.68 (m, 1H, CH CN), 4.56-4.53 (m, 1H, CH ), 3.41-3.38 (m, 1H, CH ₂ ), 3.07-3.03 (m, 2H , CH ₂ ), 2.74-2.70 (m, 1H, CH ₂ ), 2.09-2.06 (m, 2H, CH ₂ ), 1.91-1.89 (m, 1H, CH ₂ ), 1.80-1.74 (m, 1H, CH 2 ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 526 [M + H] ⁺ .

Example 33: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV31 )

The operating process is the same as in Example 3, except that 2-fluorobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 82%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.75 (s, 1H, =CH ), 7.46-7.45 (m, 1H, ArH ), 7.35- 7.27 (m, 5H, ArH ), 5.71 (s, 2H, CH ₂ Ar), 5.32 (d, 1H, J = 8.5 Hz, NH Boc), 4.70-4.67 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.06-3.03 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.12-2.04 (m, 2H, CH ₂ ), 1.91-1.85 (m, 1H, CH ₂ ), 1.82-1.74 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/ z = 519 [M + H] ⁺ .

Example 34: tert-butyl{( S )-3-[4-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)]-1- [( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV32 )

The operating process is the same as in Example 3, except that 2-chlorobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 84%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 8.5 Hz, ArH ), 7.75 (s, 1H, =CH ), 7.45-7.44 (m, 1H, ArH ), 7.34- 7.21 (m, 5H, ArH ), 5.70 (s, 2H, CH ₂ Ar), 5.36 (d, 1H, J = 8.5 Hz, NH Boc), 4.69-4.64 (m, 1H, CH CN), 4.56-4.51 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.06-3.02 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.11-2.05 (m, 2H, CH ₂ ), 1.92-1.85 (m, 1H, CH ₂ ), 1.81-1.76 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/ z = 535 [M + H] ⁺ .

Example 35: tert-butyl{( S )-3-[4-(1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1-[ ( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV33 )

The operating process is the same as in Example 3, except that 2-bromobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 79%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.78 (d, 2H, J = 7.5 Hz, ArH ), 7.76 (s, 1H, =CH ), 7.63-7.61 (m, 1H, ArH ), 7.33- 7.28 (m, 3H, ArH ), 7.24-7.18 (m, 2H, ArH ), 5.69 (s, 2H, CH ₂ Ar), 5.40 (d, 1H, J = 8.5 Hz, NH Boc), 4.70-4.66 ( m, 1H, CH CN), 4.55-4.50 (m, 1H, CH ), 3.42-3.37 (m, 1H, CH ₂ ), 3.03-3.02 (m, 2H, CH ₂ ), 2.73-2.69 (m, 1H , CH ₂ ), 2.11-2.03 (m, 2H, CH ₂ ), 1.91-1.84 (m, 1H, CH ₂ ), 1.81-1.73 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu -H ) ppm; ESI-MS: m/z = 579 [M + H] ⁺ .

Example 36: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-3-[4-(1-(2-methoxybenzyl)-1H -1,2,3-triazol-4-yl)phenyl]-1-oxapropan-2-yl}carbamate ( IV34 )

The operating process is the same as in Example 3, except that 2-methoxybenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 93%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.70 (s, 1H, =CH ), 7.36-7.33 (m, 1H, ArH ), 7.29 ( d, 2H, J = 8.0 Hz, ArH ), 7.24-7.22 (m, 1H, ArH ), 6.97-6.92 (m, 2H, ArH ), 5.57 (d, 2H, J = 1.5 Hz, CH ₂ Ar), 5.33 (d, 1H, J = 8.5 Hz, NH Boc), 4.68-4.66 (m, 1H, CH CN), 4.54-4.50 (m, 1H, CH ), 3.88 (s, 3H, O CH ₃ ), 3.39 -3.37 (m, 1H, CH ₂ ), 3.05-3.01 (m, 2H, CH ₂ ), 2.68-2.64 (m, 1H, CH ₂ ), 2.11-2.05 (m, 2H, CH ₂ ), 1.90-1.85 (m, 1H, CH ₂ ), 1.77-1.71 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 531 [M + H] ⁺ .

Example 37: tert-butyl{( S )-3-[4-(1-(2-cyanobenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1- [( S )-2-cyanopyrrolidin-1-yl)]-1-oxapropan-2-yl}carbamate ( IV35 )

The operating process is the same as in Example 3, except that 2-cyanobenzyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 96%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.87 (s, 1H, =CH ), 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.75-7.73 (m, 1H, ArH ), 7.63- 7.60 (m, 1H, ArH ), 7.50-7.47 (m, 1H, ArH ), 7.42 (d, 1H, J = 7.5 Hz, ArH ), 7.32 (d, 2H, J = 7.5 Hz, ArH ), 5.79 ( s, 2H, CH ₂ Ar), 5.35 (d, 1H, J = 8.5 Hz, NH Boc), 4.70-4.68 (m, 1H, CH CN), 4.56-4.52 (m, 1H, CH ), 3.43-3.38 (m, 1H, CH ₂ ), 3.06-3.03 (m, 2H, CH ₂ ), 2.75-2.71 (m, 1H, CH ₂ ), 2.12-2.06 (m, 2H, CH ₂ ), 1.92-1.88 (m , 1H, CH ₂ ), 1.83-1.75 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 526 [M + H] ⁺ .

Example 38: tert-butyl{( S )-3-[4-(1-(4-(tert-butyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl] -1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV36 )

The operating process is the same as in Example 3, except that methane azide is replaced by p-tert-butylbenzyl azide, and column chromatography obtains a colorless oily substance with a yield of 96%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.76 (d, 2H, J = 8.0 Hz, ArH ), 7.65 (s, 1H, =CH ), 7.41 (d, 2H, J = 8.5 Hz, ArH ) , 7.29-7.25 (m, 4H, ArH ), 5.52 (d, 2H, J = 2.5 Hz, CH ₂ Ar), 5.34 (d, 1H, J = 8.5 Hz, NH Boc), 4.68-4.66 (m, 1H , CH CN), 4.54-4.50 (m, 1H, CH ), 3.40-3.35 (m, 1H, CH ₂ ), 3.03-3.01 (m, 2H, CH ₂ ), 2.70-2.65 (m, 1H, CH ₂ ), 2.09-2.02 (m, 2H, CH ₂ ), 1.90-1.83 (m, 1H, CH ₂ ), 1.78-1.75 (m, 1H, CH ₂ ), 1.41 (s, 9H, t-Bu-H ) , 1.30 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 557 [M + H] ⁺ .

Example 39: tert-Butyl{( S )-3-[4-(1-(4-carbamoylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl]-1 -[( S )-2-cyanopyrrolidin-1-yl]-1-oxapropan-2-yl}carbamate ( IV37 )

The operating process is the same as in Example 3, except that methane azide is replaced by p-formamidobenzyl azide, and column chromatography obtains a colorless oily substance with a yield of 86%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.84 (d, 2H, J = 8.5 Hz, ArH ), 7.76 (s, 1H, =CH ), 7.75 (d, 2H, J = 6.5 Hz, ArH ) , 7.37 (d, 2H, J = 8.5 Hz, ArH ), 7.30 (d, 2H, J = 8.5 Hz, ArH ), 6.45 (br, 1H, NH ₂ CO), 6.09 (br, 1H, NH ₂ CO) , 5.60 (s, 2H, CH ₂ Ar), 5.44 (d, 1H, J = 8.0 Hz, NH Boc), 4.69-4.67 (m, 1H, CH CN), 4.56-5.52 (m, 1H, CH ), 3.44-3.39 (m, 1H, CH ₂ ), 3.04-3.03 (m, 2H, CH ₂ ), 2.76-2.72 (m, 1H, CH ₂ ), 2.10-2.06 (m, 2H, CH ₂ ), 1.91- 1.88 (m, 1H, CH ₂ ), 1.82-1.73 (m, 1H, CH ₂ ), 1.42 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 544 [M + H] .

Example 40: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-phenethyl-1H- 1,2,3-Triazol-4-yl)phenyl]propan-2-yl}carbamate ( IV38 )

The operating process is the same as in Example 3, except that phenylethyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 88%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.75 (d, 2H, J = 8.0 Hz, ArH ), 7.51 (s, 1H, =CH ), 7.32-7.29 (m, 4H, ArH ), 7.26- 7.23 (m, 1H, ArH ), 7.16-7.14 (d, 2H, J = 8.0 Hz, ArH ), 5.38 (d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.69 (m, 1H, CH CN ), 4.64 (t, 2H, J = 7.0 Hz, CH ₂ ), 4.57-4.52 (m, 1H, CH ), 3.43-3.38 (m, 1H, CH ₂ ), 3.27 (t, 2H, J = 7.0 Hz , CH ₂ ), 3.09-3.03 (m, 2H, CH ₂ ), 2.74-2.69 (m, 1H, CH ₂ ), 2.13-2.07 (m, 2H, CH ₂ ), 1.91-1.88 (m, 1H, CH 2 ₂ ), 1.79-1.73 (m, 1H, CH ₂ ), 1.43 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 515 [M + H] ⁺ .

Example 41: tert-butyl{( S )-1-[( S )-2-cyanopyrrolidin-1-yl]-1-oxa-3-[4-(1-(2-oxa- 2-Phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl]propan-2-yl}carbamate ( IV39 )

The operating process is the same as in Example 3, except that phenylacetyl azide is used instead of azidomethane, and column chromatography obtains a colorless oily substance with a yield of 93%.

¹ H NMR (500 MHz, CDCl ₃ ): δ = 8.05 (d, 2H, J = 7.0 Hz, ArH ), 7.96 (s, 1H, =CH ), 7.86 (d, 2H, J = 7.5 Hz, ArH ) , 7.71-7.68 (m, 1H, ArH ), 7.59-7.56 (m, 2H, ArH ), 7.36 (d, 2H, J = 7.5 Hz, ArH ), 5.92 (s, 2H, CO CH ₂ ), 5.37 ( d, 1H, J = 8.5 Hz, NH Boc), 4.71-4.69 (m, 1H, CH CN), 4.59-4.54 (m, 1H, CH ), 3.43-3.38 (m, 1H, CH ₂ ), 3.10- 3.06 (m, 2H, CH ₂ ), 2.72-2.68 (m, 1H, CH ₂ ), 2.15-2.08 (m, 2H, CH ₂ ), 1.92-1.89 (m, 1H, CH ₂ ), 1.84-1.78 ( m, 1H, CH ₂ ), 1.,44 (s, 9H, t-Bu-H ) ppm; ESI-MS: m/z = 529 [M + H].

Example 42: ( S )-1-{( S )-2-amino-3-[4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V1 )

Under nitrogen protection, compound IV1 (0.01 mmol) was dissolved in CH ₂ Cl ₂ (1.0 mL) solution, then HCl/Et ₂ O (3.0 mL) was added, and reacted at room temperature. After the reaction was completed, the solvent was recovered under reduced pressure. A white solid residue was obtained, which was washed with ether to obtain the pure target compound V1 with a yield of 97%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.55 (s, 1H, =CH ), 8.41 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 4.81-4.78 (m, 1H, CH CN), 4.35-4.34 (m, 1H, CH ), 4.09 (s, 3H, CH ₃ ), 4.03-4.02 (m, 1H, CH ₂ ), 3.19-3.15 (m, 1H, CH ₂ ), 3.07-3.03 (m, 1H, CH ₂ ), 2.77-2.76 (m, 1H, CH ₂ ), 2.14-2.11 (m , 1H, CH ₂ ), 2.04-2.00 (m, 1H, CH ₂ ), 1.85-1.81 (m, 1H, CH ₂ ), 1.66-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m/ z = 325 [M + H] ⁺ .

Example 43: ( S )-1-{( S )-2-amino-3-[4-(1-ethyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V2 )

The operation process is the same as in Example 42, except that IV2 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.62 (s, 1H, =CH ), 8.40 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 4.79-4.75 (m, 1H, CH CN), 4.43-4.37 (q, 2H, J = 7.0 Hz, CH ₂ CH ₃ ), 4.34-4.32 (m , 1H, CH ), 3.52-3.43 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.09-3.01 (m, 1H, CH ₂ ), 2.76-2.72 (m, 1H, CH ₂ ), 2.14-2.08 (m,1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ), 1.66-1.62 (m, 1H, CH ₂ ), 1.48 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ) ppm; ESI-MS: m/z = 339 [M + H] ⁺ .

Example 44: ( S )-1-{( S )-2-amino-3-[4-(1-propyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V3 )

The operation process is the same as in Example 42, except that IV3 is substituted for IV1 , and the yield is 96%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.63 (s, 1H, =CH ), 8.42 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.34 (d, 2H, J = 8.0 Hz, ArH ), 4.81-4.77 (m, 1H, CH CN), 4.37-4.32 (m, 3H, CH ₂ , CH ), 3.20-3.16 (m, 1H, CH ₂ ), 3.10-3.03 (m, 2H, CH ₂ ), 2.83-2.75 (m, 1H, CH ₂ ), 2.17-2.10 (m, 1H, CH ₂ ), 2.04-1.99 (m, 1H, CH ₂ ), 1.92-1.80 (m, 3H, CH ₂ ), 1.69-1.63 (m, 1H, CH ₂ ), 0.90 (t, 3H, J = 7.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 353 [ M + H] ⁺ .

Example 45: ( S )-1-{( S )-2-amino-3-[4-(1-butyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V4 )

The operation process is the same as in Example 42, except that IV4 is substituted for IV1 , and the yield is 97%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.61 (s, 1H, =CH ), 8.36 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 4.80-4.77 (m, 1H, CH CN), 4.38 (t, 2H, J = 7.0 Hz, CH ₂ ), 4.34-4.32 (m, 1H, CH ), 3.39-3.35 (m, 1H, CH ₂ ), 3.16-3.13 (m, 1H, CH ₂ ), 3.06-3.02 (m, 1H, CH ₂ ), 2.78-2.76 (m, 1H, CH ₂ ), 2.14-2.11 (m, 1H, CH ₂ ), 2.03-2.00 (m, 1H, CH ₂ ), 1.86-1.80 (m, 3H, CH ₂ ), 1.67-1.64 (m, 1H, CH ₂ ), 1.30- 1.25 (m, 2H, CH ₂ ), 0.91 (t, 3H, J = 7.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 367 [M + H] ⁺ .

Example 46: ( S )-1-{( S )-2-amino-3-[4-(1-isopropyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V5 )

The operation process is the same as in Example 42, except that IV5 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.68 (s, 1H, =CH ), 8.44 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 4.86-4.80 (m, 1H, CH ), 4.79-4.75 (m, 1H, CH CN), 4.34-4.31 (m, 1H, CH ), 3.49- 3.44 (m, 1H, CH ₂ ), 3.20-3.17 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.72-2.70 (m, 1H, CH ₂ ), 2.14-2.08 ( m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.83-1.79 (m, 1H, CH ₂ ), 1.66-1.60 (m, 1H, CH ₂ ), 1.53 (d, 6H, J = 7.0 Hz, CH ₃ ) ppm; ESI-MS: m/z = 353 [M + H] ⁺ .

Example 47: ( S )-1-{( S )-2-amino-3-[4-(1-isobutyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V6 )

The operation process is the same as in Example 42, except that IV6 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.59 (s, 1H, =CH ), 8.37 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 4.80-4.77 (m, 1H, CH CN), 4.35-4.32 (m, 1H, CH ), 4.21 (d, 2H, J = 7.5 Hz, CH ₂ ), 3.50-3.47 (m, 1H, CH ₂ ), 3.17-3.13 (m, 1H, CH ₂ ), 3.07-3.02 (m, 1H, CH ₂ ), 2.80-2.79 (m, 1H, CH ₂ ), 2.18-2.11 (m, 2H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.84-1.80 (m, 1H, CH ₂ ), 1.69-1.65 (m, 1H, CH ₂ ), 0.89 ( d, 6H, J = 6.5 Hz, CH ₃ ) ppm; ESI-MS: m/z = 367 [M + H] ⁺ .

Example 48: ( S )-1-{( S )-2-amino-3-[4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V7 )

The operation process is the same as in Example 42, except that IV7 is substituted for IV1 , and the yield is 92%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.67 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.40-7.33 (m, 5H, ArH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ), 5.63 (s, 2H, CH ₂ Ar), 4.79-4.76 (m, 1H, CH CN), 4.33- 4.32 (m, 1H, CH ), 3.47-3.45 (m, 1H, CH ₂ ), 3.16-3.13 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.76-2.74 (m , 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.83-1.78 (m, 1H, CH ₂ ), 1.67-1.61 (m, 1H , CH ₂ ) ppm; ESI-MS: m/z = 401 [M + H] ⁺ .

Example 49: ( S )-1-{( S )-2-amino-3-[4-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V8 )

The operation process is the same as in Example 42, except that IV8 is substituted for IV1 , and the yield is 89%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.63 (s, 1H, =CH ), 8.45 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 4.82 (s, 1H, OH ), 4.79-4.76 (m, 1H, CH CN), 4.43 (t, 2H, J = 5.0 Hz, CH ₂ ), 4.34-4.31 (m, 1H, CH ), 3.82 (t, 2H, J = 5.0 Hz, CH ₂ ), 3.49-3.46 (m, 1H, CH ₂ ), 3.20-3.16 (m, 1H, CH ₂ ), 3.07-3.01 (m, 1H, CH ₂ ), 2.73-2.70 (m, 1H, CH ₂ ), 2.12-2.09 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.83- 1.80 (m, 1H, CH ₂ ), 1.65-1.61 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 355 [M + H] ⁺ .

Example 50: ( S )-1-{( S )-2-amino-3-[4-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)benzene Base]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V9 )

The operation process is the same as in Example 42, except that IV9 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.77 (s, 1H, =CH ), 8.40 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 4.80-4.77 (m, 1H, CH CN), 4.35-4.33 (m, 1H, CH ), 4.26 (d, 2H, J = 7.0 Hz, CH ₂ ), 3.49-3.46 (m, 1H, CH ₂ ), 3.18-3.15 (m, 1H, CH ₂ ), 3.06-3.01 (m, 1H, CH ₂ ), 2.76-2.74 (m, 1H, CH ₂ ), 2.12-2.10 (m, 1H, CH ₂ ), 2.03-2.00 (m, 1H, CH ₂ ), 1.83-1.80 (m, 1H, CH ₂ ), 1.66-1.62 (m, 1H, CH ₂ ), 1.32- 1.29 (m, 1H, CH ), 0.60-0.56 (m, 2H, CH ₂ ), 0.46-0.43 (m, 2H, CH ₂ ) ppm; ESI-MS: m/z = 365 [M + H] ⁺ .

Example 51: ( S )-1-{( S )-2-amino-3-[4-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V10 )

The operation process is the same as in Example 42, except that IV10 is substituted for IV1 , and the yield is 98%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.58 (s, 1H, =CH ), 8.47 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.5 Hz, ArH ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 6.12-6.05 (m, 1H, CH ), 5.31-5.28 (m, 1H, CH ₂ ), 5.26-5.22 (m, 1H, CH ₂ ), 5.06 -5.04 (m, 2H, CH ₂ ), 4.79-4.76 (m, 1H, CH CN), 4.32-4.31 (m, 1H, CH ), 3.48-3.46 (m, 1H, CH ₂ ), 3.21-3.17 ( m, 1H, CH ₂ ), 3.06-3.01 (m, 1H, CH ₂ ), 2.75-2.74 (m, 1H, CH ₂ ), 2.12-2.09 (m, 1H, CH ₂ ), 2.02-2.00 (m, 1H, CH ₂ ), 1.83-1.80 (m, 1H, CH ₂ ), 1.67-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 351 [M + H] ⁺ .

Example 52: ( S )-1-{( S )-2-amino-3-[4-(1-cyclobutyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V11 )

The operation process is the same as in Example 42, except that IV11 is replaced by IV1 , and the yield is 93%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.77 (s, 1H, =CH ), 8.43 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.16-5.13 (m, 1H, CH ), 4.79-4.77 (m, 1H, CH CN), 4.34-4.30 (m, 2H, CH ₂ ), 3.49 -3.44 (m, 1H, CH ₂ ), 3.19-3.16 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.74-2.70 (m, 1H, CH ₂ ), 2.56-2.51 (m, 3H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.91-1.86 (m, 2H, CH ₂ ), 1.82-1.79 (m , 1H, CH ₂ ), 1.66-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 365 [M + H] ⁺ .

Example 53: ( S )-1-{( S )-2-amino-3-[4-(1-cyclopentyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V12 )

The operation process is the same as in Example 42, except that IV12 is substituted for IV1 , and the yield is 85%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.65 (s, 1H, =CH ), 8.39 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.00-4.98 (m, 1H, CH ), 4.79-4.77 (m, 1H, CH CN), 4.34-4.32 (m, 1H, CH ), 3.37- 3.35 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.74-2.72 (m, 1H, CH ₂ ), 2.22-2.17 ( m, 2H, CH ₂ ), 2.13-2.10 (m, 1H, CH ₂ ), 2.02-1.95 (m, 3H, CH ₂ ), 1.84-1.79 (m, 3H, CH ₂ ), 1.74-1.63 (m, 3H, CH ₂ ) ppm; ESI-MS: m/z = 379 [M + H] ⁺ .

Example 54: ( S )-1-{( S )-2-amino-3-[4-(1-cyclohexyl-1H-1,2,3-triazol-4-yl)phenyl]propionyl }pyrrolidine-2-carbonitrile hydrochloride ( V13 )

The operation process is the same as in Example 42, except that IV13 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ = 8.67 (s, 1H, =CH ), 8.44 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 4.79-4.75 (m, 1H, CH CN), 4.52-4.46 (m, 2H, CH ₂ ), 3.49-3.44 (m, 1H, CH ₂ ), 3.19-3.16 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.73-2.69 (m, 1H, CH ₂ ), 2.15-2.09 (m, 3H, CH ₂ ), 2.03- 1.97 (m, 1H, CH ₂ ), 1.84-1.74 (m, 5H, CH ₂ ), 1.70-1.60 (m, 2H, CH ₂ ), 1.49-1.41 (m, 2H, CH ₂ ), 1.28-1.20 ( m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 393 [M + H] ⁺ .

Example 55: ( S )-1-{( S )-2-amino-3-[4-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V14 )

The operation process is the same as in Example 42, except that IV14 is substituted for IV1 , and the yield is 93%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.66 (s, 1H, =CH ), 8.41 (br, 3H, NH ₃ ⁺ ), 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.45-7.42 (m, 2H, ArH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ), 7.24-7.20 (m, 2H, ArH ), 5.62 (s, 2H, CH ₂ Ar), 4.78-4.74 (m, 1H, CH CN), 4.34-4.29 (m, 1H, CH ), 3.40-3.35 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.08-3.01 (m, 1H, CH ₂ ), 2.76-2.71 (m, 1H, CH ₂ ), 2.15-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.84-1.77 (m, 1H, CH ₂ ), 1.67-1.60 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 419 [M + H] ⁺ .

Example 56: ( S )-1-{( S )-2-amino-3-[4-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V15 )

The operation process is the same as in Example 42, except that IV15 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): 8.66 (s, 1H, =CH ), 8.37 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.5 Hz, ArH ), 7.46 ( d, 2H, J = 8.5 Hz, ArH ), 7.39 (d, 2H, J = 8.5 Hz, ArH ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 5.63 (s, 2H, CH ₂ Ar) , 4.79-4.75 (m, 1H, CH CN), 4.34-4.30 (m, 1H, CH ), 3.39-3.31 (m, 1H, CH ₂ ), 3.17-3.13 (m, 1H, CH ₂ ), 3.07- 3.01 (m, 1H, CH ₂ ), 2.77-2.72 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.83-1.78 ( m, 1H, CH ₂ ), 1.68-1.61 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 436 [M + H] ⁺ .

Example 57: ( S )-1-{( S )-2-amino-3-[4-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V16 )

The operation process is the same as in Example 42, except that IV16 is substituted for IV1 , and the yield is 97%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.66 (s, 1H, =CH ), 8.37 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.60 (d, 2H, J = 8.0 Hz, ArH ), 7.32-7.29 (m, 4H, ArH ), 5.62 (s, 2H, CH ₂ Ar), 4.79-4.77 (m, 1H, CH CN), 4.34- 4.32 (m, 1H, CH ), 3.37-3.32 (m, 1H, CH ₂ ), 3.15-3.11 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.77-2.74 (m , 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ), 1.67-1.63 (m, 1H , CH ₂ ) ppm; ESI-MS: m/z = 480 [M + H] ⁺ .

Example 58: ( S )-1-{( S )-2-amino-3-[4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl )phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V17 )

The operation process is the same as in Example 42, except that IV17 is substituted for IV1 , and the yield is 99%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.61 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.79 (d, 2H, J = 8.0 Hz, ArH ), 7.35 (d, 2H, J = 8.0 Hz, ArH ), 7.30 (d, 2H, J = 8.5 Hz, ArH ), 6.94 (d, 2H, J = 8.5 Hz, ArH ), 5.53 (s, 2H, CH ₂ Ar), 4.79-4.76 (m, 1H, CH CN), 4.35-4.31 (m, 1H, CH ), 3.73 (s, 3H, O CH ₃ ), 3.37-3.35 (m, 1H, CH ₂ ), 3.15 -3.12 (m, 1H, CH ₂ ), 3.05-3.00 (m, 1H, CH ₂ ), 2.75-2.73 (m, 1H, CH ₂ ), 2.13-2.09 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.83-1.78 (m, 1H, CH ₂ ), 1.65-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 431 [M + H] ⁺ .

Example 59: ( S )-1-{( S )-2-amino-3-[4-(1-(4-cyanobenzyl)-1H-1,2,3-triazol-4-yl )phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V18 )

The operation process is the same as in Example 42, except that IV18 is substituted for IV1 , and the yield is 96%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.70 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.88 (d, 2H, J = 8.5 Hz, ArH ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.51 (d, 2H, J = 8.5 Hz, ArH ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 5.76 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.34-4.32 (m, 1H, CH ), 3.47-3.45 (m, 1H, CH ₂ ), 3.17-3.15 (m, 1H, CH ₂ ), 3.09-3.02 (m, 1H, CH ₂ ), 2.79-2.76 (m, 1H, CH ₂ ), 2.16-2.08 (m, 1H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.84- 1.79 (m, 1H, CH ₂ ), 1.67-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 426 [M + H] ⁺ .

Example 60: ( S )-1-{( S )-2-amino-3-[4-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazole -4-yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V19 )

The operation process is the same as in Example 42, except that IV19 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.70 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.55 (d, 2H, J = 8.0 Hz, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.76 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.36-4.31 (m, 1H, CH ), 3.39-3.34 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.09-3.02 (m, 1H, CH ₂ ), 2.80-2.74 (m, 1H, CH ₂ ), 2.16-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.85- 1.78 (m, 1H, CH ₂ ), 1.69-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 469 [M + H] ⁺ .

Example 61: ( S )-1-{( S )-2-amino-3-[4-(1-(3,4-difluorobenzyl)-1H-1,2,3-triazole-4 -yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V20 )

The operation process is the same as in Example 42, except that IV20 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.67 (s, 1H, =CH ), 8.40 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.5 Hz, ArH ), 7.53-7.43 (m, 2H, ArH ), 7.31 (d, 2H, J = 8.5 Hz, ArH ), 7.25-7.18 (m, 1H, ArH ), 5.63 (s, 2H, CH ₂ Ar), 4.79-4.74 (m, 1H, CH CN), 4.34-4.31 (m, 1H, CH ), 3.49-3.44 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.06-3.01 (m, 1H, CH ₂ ), 2.77-2.72 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.83-1.79 (m, 1H, CH ₂ ), 1.67-1.61 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 437 [M + H] ⁺ .

Example 62: ( S )-1-{( S )-2-amino-3-[4-(1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazole -4-yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V21 )

The operation process is the same as in Example 42, except that IV21 is substituted for IV1 , and the yield is 91%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.61 (s, 1H, =CH ), 8.34 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.5 Hz, ArH ), 7.30 (d, 2H, J = 8.5 Hz, ArH ), 7.05-7.03 (m, 1H, ArH ), 6.95-6.90 (m, 2H, ArH ), 5.52 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.35-4.33 (m, 1H, CH ), 3.74 (s, 3H, O CH ₃ ), 3.72 (s, 3H, O CH ₃ ), 3.44-3.39 (m, 1H, CH ₂ ), 3.15-3.12 (m, 1H, CH ₂ ), 3.05-3.00 (m, 1H, CH ₂ ), 2.78-2.74 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.84-1.78 (m, 1H, CH ₂ ), 1.65-1.61 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 461 [M + H] ⁺ .

Example 63: ( S )-1-{( S )-2-amino-3-[4-(1-(pyridin-4-ylmethyl)-1H-1,2,3-triazole-4- Base) phenyl] propionyl} pyrrolidine-2-carbonitrile hydrochloride ( V22 )

The operation process is the same as in Example 42, except that IV22 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.83-8.80 (m, 2H, pyridine- H ), 8.76 (s, 1H, =CH ), 8.48 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.69-7.66 (m, 2H, pyridine- H ), 7.33 (d, 2H, J = 8.0 Hz, ArH ), 5.97 (s, 2H, CH ₂ Ar) , 4.79-4.77 (m, 1H, CH CN), 4.33-4.32 (m, 1H, CH ), 3.51-3.48 (m, 1H, CH ₂ ), 3.22-3.18 (m, 1H, CH ₂ ), 3.07- 3.02 (m, 1H, CH ₂ ), 2.78-2.73 (m, 1H, CH ₂ ), 2.14-2.09 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.85-1.80 ( m, 1H, CH ₂ ), 1.67-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 418 [M + H] ⁺ .

Example 64: ( S )-1-{( S )-2-amino-3-[4-(1-(thiophen-2-ylmethyl)-1H-1,2,3-triazole-4- Base) phenyl] propionyl} pyrrolidine-2-carbonitrile hydrochloride ( V23 )

The operation process is the same as in Example 42, except that IV23 is substituted for IV1 , and the yield is 89%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.65 (s, 1H, =CH ), 8.40 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.54 (d, 1H, J = 5.0 Hz, thiophene- H ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 7.24 (d, 1H, J = 3.5 Hz, thiophene- H ), 7.04 (t, 1H, J = 5.0 Hz, thiophene- H ), 5.84 (s, 2H, CH ₂ Ar), 4.78-4.76 (m, 1H, CH CN), 4.34-4.32 (m, 1H, CH ), 3.50-3.44 ( m, 1H, CH ₂ ), 3.18-3.15 (m, 1H, CH ₂ ), 3.06-3.01 (m, 1H, CH ₂ ), 2.76-2.72 (m, 1H, CH ₂ ), 2.13-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.83-1.78 (m, 1H, CH ₂ ), 1.66-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 407 [M + H] ⁺ .

Example 65: ( S )-1-{( S )-2-amino-3-[4-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4 -yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V24 )

The operation process is the same as in Example 42, except that IV24 is substituted for IV1 , and the yield is 95%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.64 (s, 1H, =CH ), 8.33 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.56-7.49 (m, 1H, ArH ), 7.30 (d, 2H, J = 8.0 Hz, ArH ), 7.21-7.14 (m, 2H, ArH ), 5.68 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.37-4.30 (m, 1H, CH ), 3.47-3.45 (m, 1H, CH ₂ ), 3.17-3.10 (m, 1H, CH ₂ ), 3.11-3.09 (m, 1H, CH ₂ ), 2.81-2.75 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.02-1.97 (m, 1H, CH ₂ ), 1.85-1.77 (m, 1H, CH ₂ ), 1.65-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 437 [M + H] ⁺ .

Example 66: ( S )-1-{( S )-2-amino-3-[4-(1-(3,4-dichlorobenzyl)-1H-1,2,3-triazole-4 -yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V25 )

The operation process is the same as in Example 42, except that IV25 is substituted for IV1 , and the yield is 97%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.68 (s, 1H, =CH ), 8.36 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.68-7.65 (m, 2H, ArH ), 7.35-7.33 (m, 1H, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.66 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.36-4.30 (m, 1H, CH ), 3.49-3.44 (m, 1H, CH ₂ ), 3.18-3.13 (m, 1H, CH ₂ ), 3.06-3.02 (m, 1H, CH ₂ ), 2.80-2.74 (m, 1H, CH ₂ ), 2.16-2.09 (m, 1H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.85-1.80 (m, 1H, CH ₂ ), 1.69-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 470 [M + H] ⁺ .

Example 67: ( S )-1-{( S )-2-amino-3-[4-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V26 )

The operation process is the same as in Example 42, except that IV26 is substituted for IV1 , and the yield is 97%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.69 (s, 1H, =CH ), 8.41 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.46-7.41 (m, 1H, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 7.23-7.16 (m, 3H, ArH ), 5.66 (s, 2H, CH ₂ Ar), 4.79-4.77 (m, 1H, CH CN), 4.35-4.31 (m, 1H, CH ), 3.49-3.44 (m, 1H, CH ₂ ), 3.16-3.13 (m, 1H, CH ₂ ), 3.06-3.01 (m, 1H, CH ₂ ), 2.76-2.74 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ), 1.66-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 419 [M + H] ⁺ .

Example 68: ( S )-1-{( S )-2-amino-3-[4-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V27 )

The operation process is the same as in Example 42, except that IV27 is substituted for IV1 , and the yield is 92%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.71 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.83 (d, 2H, J = 8.5 Hz, ArH ), 7.47-7.41 (m, 3H, ArH ), 7.34-7.31 (m, 3H, ArH ), 5.67 (s, 2H, CH ₂ Ar), 4.81-4.76 (m, 1H, CH CN ), 4.37-4.33 (m , 1H, CH ), 3.48-3.45 (m, 1H, CH ₂ ), 3.18-3.15 (m, 1H, CH ₂ ), 3.07-3.03 (m, 1H, CH ₂ ), 2.80-2.75 (m, 1H, CH ₂ ), 2.17-2.10 (m, 1H, CH ₂ ), 2.05-2.01 (m, 1H, CH ₂ ), 1.86-1.80 (m, 1H, CH ₂ ), 1.70-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 435 [M + H] ⁺ .

Example 69: ( S )-1-{( S )-2-amino-3-[4-(1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V28 )

The operation process is the same as in Example 42, except that IV28 is substituted for IV1 , and the yield is 93%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.69 (s, 1H, =CH ), 8.37 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 7.5 Hz, ArH ), 7.59 (s, 1H, ArH ), 7.57-7.54 (m, 1H, ArH ), 7.36-7.34 (m, 2H, ArH ), 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.65 (s, 2H , CH ₂ Ar), 4.78-4.77 (m, 1H, CH CN), 4.35-4.31 (m, 1H, CH ), 3.49-3.44 (m, 1H, CH ₂ ), 3.16-3.14 (m, 1H, CH ₂ ), 3.06-3.02 (m, 1H, CH ₂ ), 2.78-2.75 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.01-1.97 (m, 1H, CH ₂ ) , 1.84-1.79 (m, 1H, CH ₂ ), 1.66-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 479 [M + H] ⁺ .

Example 70: ( S )-1-{( S )-2-amino-3-[4-(1-(3-methoxybenzyl)-1H-1,2,3-triazole-4- Base) phenyl] propionyl} pyrrolidine-2-carbonitrile hydrochloride ( V29 )

The operation process is the same as in Example 42, except that IV29 is substituted for IV1 , and the yield is 94%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.68 (s, 1H, =CH ), 8.43 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.5 Hz, ArH ), 7.32-7.29 (m, 3H, ArH ), 6.96-6.89 (m, 3H, ArH ), 5.60 (s, 2H, CH ₂ Ar), 4.80-4.76 (m, 1H, CH CN ), 4.35-4.31 (m , 1H, CH ), 3.50-3.46 (m, 1H, CH ₂ ), 3.20-3.16 (m, 1H, CH ₂ ), 3.08-3.02 (m, 1H, CH ₂ ), 2.77-2.73 (m, 1H, CH ₂ ), 2.15-2.09 (m, 1H, CH ₂ ), 2.04-1.99 (m, 1H, CH ₂ ), 1.86-1.80 (m, 1H, CH ₂ ), 1.69-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 431 [M + H] ⁺ .

Example 71: ( S )-1-{( S )-2-amino-3-[4-(1-(3-cyanobenzyl)-1H-1,2,3-triazol-4-yl )phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V30 )

The operation process is the same as in Example 42, except that IV30 is substituted for IV1 , and the yield is 96%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.70 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.87 (s, 1H, ArH ), 7.84 (d, 1H , J = 7.5 Hz, ArH ), 7.80 (d, 2H, J = 8.5 Hz, ArH ), 7.70 (d, 1H, J = 8.0 Hz, ArH ), 7.62 (t, 1H, J = 7.5 Hz, ArH ) , 7.31 (d, 2H, J = 8.0 Hz, ArH ), 5.71 (s, 2H, CH ₂ Ar), 4.79-4.74 (m, 1H, CH CN), 4.35-4.31 (m, 1H, CH ), 3.49 -3.44 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.08-3.01 (m, 1H, CH ₂ ), 2.77-2.73 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.97 (m, 1H, CH ₂ ), 1.83-1.79 (m, 1H, CH ₂ ), 1.67-1.61 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 426 [M + H] ⁺ .

Example 72: ( S )-1-{( S )-2-amino-3-[4-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V31 )

The operation process is the same as in Example 42, except that IV31 is substituted for IV1 , and the yield is 93%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.63 (s, 1H, =CH ), 8.39 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.5 Hz, ArH ), 7.54-7.52 (m, 1H, ArH ), 7.43-7.36 (m, 2H, ArH ), 7.32-7.27 (m, 3H, ArH ), 5.74 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.36-4.32 (m, 1H, CH ), 3.51-3.45 (m, 1H, CH ₂ ), 3.18-3.14 (m, 1H, CH ₂ ), 3.07-3.02 (m, 1H, CH ₂ ), 2.79-2.74 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ) , 1.68-1.62 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 419 [M + H] ⁺ .

Example 73: ( S )-1-{( S )-2-amino-3-[4-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V32 )

The operation process is the same as in Example 42, except that IV32 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.63 (s, 1H, =CH ), 8.40 (br, 3H, NH ₃ ⁺ ), 7.82 (d, 2H, J = 8.0 Hz, ArH ), 7.54-7.52 (m, 1H, ArH ), 7.43-7.36 (m, 2H, ArH ), 7.32-7.27 (m, 3H, ArH ), 5.74 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.34-4.31 (m, 1H, CH ), 3.50-3.45 (m, 1H, CH ₂ ), 3.18-3.15 (m, 1H, CH ₂ ), 3.07-3.02 (m, 1H, CH ₂ ), 2.79-2.74 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ) , 1.68-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 435 [M + H] ⁺ .

Example 74: ( S )-1-{( S )-2-amino-3-[4-(1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl) Phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V33 )

The operation process is the same as in Example 42, except that IV33 is substituted for IV1 , and the yield is 89%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.64 (s, 1H, =CH ), 8.42 (br, 3H, NH ₃ ⁺ ), 7.84 (d, 2H, J = 8.0 Hz, ArH ), 7.72 (d, 1H, J = 8.5 Hz, ArH ), 7.45-7.41 (m, 1H, ArH ), 7.36-7.34 (m, 1H, ArH ), 7.32-7.31 (d, 2H, J = 8.0 Hz, ArH ), 7.27-7.26 (m, 1H, ArH ), 5.73 (s, 2H, CH ₂ Ar), 4.81-4.76 (m, 1H, CH CN), 4.37-4.32 (m, 1H, CH ), 3.52-3.47 (m, 1H, CH ₂ ), 3.20-3.16 (m, 1H, CH ₂ ), 3.08-3.03 (m, 1H, CH ₂ ), 2.81-2.76 (m, 1H, CH ₂ ), 2.17-2.10 (m , 1H, CH ₂ ), 2.05-1.99 (m, 1H, CH ₂ ), 1.86-1.81 (m, 1H, CH ₂ ), 1.70-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m/ z = 480 [M + H] ⁺ .

Example 75: ( S )-1-{( S )-2-amino-3-[4-(1-(2-methoxybenzyl)-1H-1,2,3-triazole-4- Base) phenyl] propionyl} pyrrolidine-2-carbonitrile hydrochloride ( V34 )

The operation process is the same as in Example 42, except that IV34 is substituted for IV1 , and the yield is 98%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.52 (s, 1H, =CH ), 8.39 (br, 3H, NH ₃ ⁺ ), 7.81 (d, 2H, J = 8.0 Hz, ArH ), 7.38-7.33 (m, 1H, ArH ), 7.30 (d, 2H, J = 8.5 Hz, ArH ), 7.17-7.14 (m, 1H, ArH ), 7.07 (d, 1H, J = 8.0 Hz, ArH ), 6.96 (t, 1H, J = 7.5 Hz, ArH ), 5.56 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.37-4.30 (m, 1H, CH ), 3.50- 3.44 (m, 1H, CH ₂ ), 3.17-3.14 (m, 1H, CH ₂ ), 3.07-3.01 (m, 1H, CH ₂ ), 2.78-2.73 (m, 1H, CH ₂ ), 2.14-2.10 ( m, 1H, CH ₂ ), 2.03-1.98 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ), 1.67-1.63 (m, 1H, CH ₂ ) ppm; ESI-MS: m /z = 431 [M + H] ⁺ .

Example 76: ( S )-1-{( S )-2-amino-3-[4-(1-(2-cyanobenzyl)-1H-1,2,3-triazol-4-yl )phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V35 )

The operation process is the same as in Example 42, except that IV35 is substituted for IV1 , and the yield is 96%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.69 (s, 1H, =CH ), 8.37 (br, 3H, NH ₃ ⁺ ), 7.93 (d, 1H, J = 8.0 Hz, ArH ), 7.83 (d, 2H, J = 8.0 Hz, ArH ), 7.76 (t, 1H, J = 7.5 Hz, ArH ), 7.59 (t, 1H, J = 7.5 Hz, ArH ), 7.47 (d, 1H, J = 7.5 Hz, ArH ), 7.32 (d, 2H, J = 8.0 Hz, ArH ), 5.84 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN), 4.36-4.32 (m, 1H , CH ), 3.52-3.43 (m, 1H, CH ₂ ), 3.17-3.13 (m, 1H, CH ₂ ), 3.09-3.02 (m, 1H, CH ₂ ), 2.80-2.76 (m, 1H, CH ₂ ), 2.16-2.09 (m, 1H, CH ₂ ), 2.04-1.97 (m, 1H, CH ₂ ), 1.84-1.79 (m, 1H, CH ₂ ), 1.68-1.63 (m, 1H, CH ₂ ) ppm ; ESI-MS: m/z = 426 [M + H] ⁺ .

Example 77: ( S )-1-{( S )-2-amino-3-[4-(1-(4-(tert-butyl)benzyl)-1H-1,2,3-triazole- 4-yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V36 )

The operation process is the same as in Example 42, except that IV36 is substituted for IV1 , and the yield is 90%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.66 (s, 1H, =CH ), 8.38 (br, 3H, NH ₃ ⁺ ), 7.80 (d, 2H, J = 8.0 Hz, ArH ), 7.41 (d, 2H, J = 8.5 Hz, ArH ), 7.30 (d, 4H, J = 7.5 Hz, ArH ), 5.57 (s, 2H, CH ₂ Ar), 4.79-4.75 (m, 1H, CH CN) , 4.34-4.30 (m, 1H, CH ), 3.50-3.44 (m, 1H, CH ₂ ), 3.16-3.14 (m, 1H, CH ₂ ), 3.05-3.01 (m, 1H, CH ₂ ), 2.75- 2.72 (m, 1H, CH ₂ ), 2.14-2.08 (m, 1H, CH ₂ ), 2.03-1.98 (m, 1H, CH ₂ ), 1.84-1.78 (m, 1H, CH ₂ ), 1.68-1.61 ( m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 457 [M + H] ⁺ .

Example 78: 4-{[4-(4-(( S )-2-amino-3-(( S )-2-cyanopyrrolidin-1-yl)-3-oxapropyl)phenyl )-1H-1,2,3-triazol-1-yl]methyl}benzamide hydrochloride ( V37 )

The operation process is the same as in Example 42, except that IV37 is substituted for IV1 , and the yield is 88%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.69 (s, 1H, =CH ), 8.39 (br, 3H, NH ₃ ⁺ ), 7.98 (br, 1H, NH ₂ CO), 7.89 (d , 2H, J = 8.0 Hz, ArH ), 7.82 (d, 2H, J = 8.5 Hz, ArH ), 7.43 (d, 2H, J = 8.0 Hz, ArH ), 7.39 (br, 1H, NH ₂ CO), 7.32 (d, 2H, J = 8.5 Hz, ArH ), 5.70 (s, 2H, CH ₂ Ar), 4.80-4.78 (m, 1H, CH CN), 4.36-4.33 (m, 1H, CH ), 3.52- 3.46 (m, 1H, CH ₂ ), 3.19-3.15 (m, 1H, CH ₂ ), 3.07-3.03 (m, 1H, CH ₂ ), 2.80-2.75 (m, 1H, CH ₂ ), 2.17-2.10 ( m, 1H, CH ₂ ), 2.05-2.00 (m, 1H, CH ₂ ), 1.87-1.80 (m, 1H, CH ₂ ), 1.71-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m /z = 444 [M + H] ⁺ .

Example 79: ( S )-1-{( S )-2-amino-3-[4-(1-phenethyl-1H-1,2,3-triazol-4-yl)phenyl]propane Acyl}pyrrolidine-2-carbonitrile hydrochloride ( V38 )

The operation process is the same as in Example 42, except that IV38 is substituted for IV1 , and the yield is 92%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.55 (s, 1H, =CH ), 8.41 (br, 3H, NH ₃ ⁺ ), 7.77 (d, 2H, J = 8.0 Hz, ArH ), 7.32 (d, 2H, J = 8.5 Hz, ArH ), 7.28 (d, 2H, J = 8.0 Hz, ArH ), 7.23-7.21 (m, 3H, ArH ), 4.81-4.77 (m, 1H, CH CN) , 4.67 (t, 2H, J = 7.0 Hz, CH ₂ ), 4.35-4.32 (m, 1H, CH ), 3.51-3.47 (m, 1H, CH ₂ ), 3.24 (t, 2H, J = 7.0 Hz, CH ₂ ), 3.19-3.15 (m, 1H, CH ₂ ), 3.08-3.03 (m, 1H, CH ₂ ), 2.81-2.77 (m, 1H, CH ₂ ), 2.16-2.11 (m, 1H, CH ₂ ), 2.06-1.99 (m, 1H, CH ₂ ), 1.87-1.81 (m, 1H, CH ₂ ), 1.71-1.64 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 415 [M + H] ⁺ .

Example 80: ( S )-1-{( S )-2-amino-3-[4-(1-(2-oxa-2-phenethyl)-1H-1,2,3-triazole- 4-yl)phenyl]propionyl}pyrrolidine-2-carbonitrile hydrochloride ( V39 )

The operation process is the same as in Example 42, except that IV39 is substituted for IV1 , and the yield is 93%.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ= 8.56 (s, 1H, =CH ), 8.42 (br, 3H, NH ₃ ⁺ ), 8.12 (d, 2H, J = 8.0 Hz, ArH ), 7.86 (d, 2H, J = 8.5 Hz, ArH ), 7.78 (t, 1H, J = 8.0 Hz, ArH ), 7.65 (t, 2H, J = 8.0 Hz, ArH ), 7.36 (d, 2H, J = 8.5 Hz, ArH ), 6.27 (s, 2H, CH ₂ CO), 4.82-4.79 (m, 1H, CH CN), 4.38-4.35 (m, 1H, CH ), 3.53-3.48 (m, 1H, CH ₂ ), 3.21-3.18 (m, 1H, CH ₂ ), 3.09-3.05 (m, 1H, CH ₂ ), 2.81-2.77 (m, 1H, CH ₂ ), 2.18-2.11 (m, 1H, CH ₂ ), 2.07-2.01 (m, 1H, CH ₂ ), 1.88-1.83 (m, 1H, CH ₂ ), 1.77-1.66 (m, 1H, CH ₂ ) ppm; ESI-MS: m/z = 429 [M + H ] ⁺ .

Example 81: In vitro inhibitory activity test of the compound of the present invention on dipeptidyl peptidase IV

Experimental instruments and materials: microplate reader (Envision, PerkinElmer, USA), human DPP-IV (expressed in insect cells using baculovirus expression system), substrate (Ala-Pro-AMC), positive control (MK -0431, Sigma), 37 ° C incubator, white 96-well plate, Tris buffer;

Sample treatment: The sample was dissolved in DMSO and stored at low temperature. The concentration of DMSO in the final system was controlled within the range that did not affect the detection activity.

Process: DPP-IV can specifically hydrolyze the substrate Ala-Pro-AMC to generate the product AMC, AMC is excited by 355 nm ultraviolet light to generate 460 nm emission light, and the fluorescence value at 460 nm wavelength changes linearly in the dynamic measurement unit time, The inhibitory strength of the compound on DPP-IV was calculated, and its IC ₅₀ value was determined by nonlinear analysis. The test samples were added to the enzyme and Tris buffer, and a positive control group, a negative control group, and a blank control group were set up at the same time, incubated at 37 °C for 10 min, and then the substrate was added to initiate the reaction, and the changes in UV absorbance were continuously monitored. Divided into multiple parallel experiments, each sample compound was measured 3 times, and the average value was taken. The results are shown in Table 1 below.

Data processing: the initial screening selects a single concentration condition, such as 20 μg/ml, to test the activity of the sample. For samples that exhibit activity under certain conditions, for example, the inhibition rate (%) is greater than 50, and the dose-dependent relationship of the test activity, that is, the IC ₅₀ /EC ₅₀ value, is obtained by nonlinear fitting of the sample activity to the sample concentration, and the software used for calculation For Graphpad Prism 4, the model used for fitting was sigmoidal dose-response (variable slope), and for most inhibitor screening models, the bottom and top of the fitted curve were set to 0 and 100. In general, multiple holes (n ≥ 2) are set for each sample in the test, and the results are expressed as standard deviation or standard error.

In summary, the phenylalanine derivatives of the present invention can effectively inhibit DPP-IV, and can be used to prepare drugs for treating diabetes, and have application prospects.

Claims (4)

1. class phenylalanine derivative and a physiologically acceptable salt thereof has following general structure V:

Wherein:

R ₁And R ₂Be selected from hydrogen or methyl;

R ₃Be selected from:

1. contain alkyl or the alkoxyl group of the straight or branched of 1-6 carbon atom, select methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, the tertiary butyl, tertiary amyl or hydroxyethyl;

2. the substituting group that contains 3-7 unit ring is selected cyclopropyl, ring the third methyl, cyclobutyl, ring fourth methyl, cyclopentyl, methyl cyclopentane, cyclohexyl or cyclohexyl methyl;

3. benzyl, phenyl, the benzyl of replacement is arranged or the phenyl of replacement is arranged, wherein substituting group is that single replacement, two replaces, three replacements, and substituting group is selected fluorine atom, chlorine atom, bromine atoms, methoxyl group, the tertiary butyl, formamido-, hydroxyl, carboxyl, ester group, cyano group, trifluoromethyl, contained alkyl or the alkoxyl group of the straight or branched of 1-3 carbon atom;

4. styroyl or phenylacetyl;

5.-CH ₂R ₄, R wherein ₄Be heterocycle, heterocycle selects furans, thiophene, pyridine to reach with substituent furans, thiophene or pyridine, and wherein substituting group is selected fluorine atom, chlorine atom or methyl.

2. the preparation method of a class phenylalanine derivative and physiologically acceptable salt thereof is characterized in that, realizes by following steps:

Starting material compound IAt Pd (PPh ₃) ₂Cl ₂With under the catalysis of CuI with trimethylsilyl acetylene the Sonogashira reaction occurs, obtain compound II, as solvent, temperature of reaction is controlled at room temperature with triethylamine or acetonitrile, and the reaction times is 1 ~ 3 hour; Compound IISlough the trimethyl silicane protecting group, obtain compound III, ( n-Bu ₄) NF is as desiliconization reagent, THF is as solvent, and temperature of reaction is room temperature, and the time is 0.5 ~ 3 hour; Compound IIIAt CuSO ₄5H ₂Under O and the sodium ascorbate catalysis, occur in ethanolic soln with multiple triazo-compound ClickReaction obtains compound IV, reaction is at room temperature carried out, and the reaction times is 2 ~ 8 hours; Compound IVUnder acidic conditions, slough the Boc protecting group, obtain target compound V, reaction is at room temperature carried out, and the reaction times is 1 ~ 2 hour;

Reaction formula:

R in the formula ₁, R ₂And R ₃Definition with claim 1.

3. the preparation method of a class phenylalanine derivative according to claim 2 and physiologically acceptable salt thereof is characterized in that, specifically prepares by following steps:

(1) compound IWith trimethylsilyl acetylene, at Pd (PPh ₃) ₂Cl ₂Obtain compound with generation Sonogashira reaction under the CuI catalysis II, compound IWith the feed ratio of trimethylsilyl acetylene be 1:1 ~ 1:3, compound IWith the feed ratio of catalyzer be 100:1 ~ 10:1, use Et ₃N or acetonitrile are made solvent;

(2) compound II( n-Bu ₄) NF exists down, slough the silicon protecting group and obtain compound III, compound IIWith ( n-Bu ₄) feed ratio of NF is 1:2 ~ 1:10, makes solvent with THF;

(3) compound IIIAt CuSO ₄5H ₂Under O and the sodium ascorbate catalysis with R ₃N ₃Occur ClickReaction obtains compound IV, compound IIIWith R ₃N ₃Feed ratio be 1:1 ~ 1:5, compound IIIWith the feed ratio of catalyzer be 20:1 ~ 10:1, make solvent with ethanol, water, acetonitrile etc.;

(4) compound IVIn acidic solution, slough the Boc protecting group, obtain target compound V, acid system is selected CF ₃COOH/CH ₂Cl ₂, EtOAc/HCl, Et ₂O/HCl or Dioxane/HCl;

Reaction formula and R ₁, R ₂And R ₃Definition with claim 2.

4. a class phenylalanine derivative according to claim 1 and physiologically acceptable salt thereof the application in the anti-diabetes B medicine of preparation.