Imidazolyl and aromatic heterocyclic derivatives, pharmaceutical compositions and uses thereof

Abstract

This invention discloses an imidazoaromatic heterohydric derivative, a pharmaceutical composition, and its application. The imidazoaromatic heterohydric derivative has the general structural formula as shown in Formula I. Compared with peptide agonists, small molecule drugs have significant advantages in bioavailability when taken orally, and are easier to take, without being restricted by food or time of administration. In addition, the imidazoaromatic heterohydric derivative, as a small molecule agonist, shows good efficacy at the cellular level and has good prospects for drug application.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, and more specifically, to an imidazo[a]aromatic heteroyl derivative, a pharmaceutical composition, and its application. Background Technology

[0002] Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia caused by defects in insulin secretion, insulin action, or both. The abnormalities in carbohydrate, fat, and protein metabolism observed in diabetic patients are a result of abnormal insulin action on target tissues and lead to structural changes in many organ systems, particularly those related to the vascular system. Chronic hyperglycemia in diabetes is associated with serious long-term complications, including microvascular (such as retinopathy, nephropathy, and neuropathy) and macrovascular (including fatal and non-fatal myocardial infarction, peripheral vascular disease, and stroke) disease. Diabetes is not a single disease but a chronic syndrome requiring aggressive and long-term pharmacological treatment to limit its complications, effectively manage them as they develop, and prevent premature death. Therefore, in addition to glycemic control, diabetic patients require continuous medical care, including multifactorial risk reduction strategies.

[0003] Diabetes is classified into four subtypes: Type I, Type II, gestational diabetes, and others (i.e., specific types of diabetes caused by other reasons).

[0004] The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological response to the incretin hormone glucagon-like peptide-1 (GLP-1), and due to the wide range of effects mediated by its activation, including promoting glucose-dependent insulin secretion, increasing insulin biosynthesis, preserving β-cell mass, improving peripheral insulin action, and promoting weight loss, it is a major therapeutic target for the treatment of type 2 diabetes.

[0005] GLP-1 receptor agonists play an irreplaceable role in the treatment of diabetes. Since 2005, seven GLP-1 receptor agonists have been approved, including exenatide, liraglutide, dulaglutide, albiglutide, lixisenatide, semaglutide, and tirzepatide. Currently, all approved GLP-1 receptor agonists are peptide agonists; there are no marketed small molecule agonists (the most advanced being in Phase II clinical trials). Compared to peptide agonists, small molecule drugs have significantly better oral bioavailability and are easier to administer, without being restricted by food or timing of administration.

[0006] Therefore, it is necessary to propose an imidazo-aromatic heterol derivative as a small molecule drug for GLP-1 receptor agonist to promote its application in drug preparation. Summary of the Invention

[0007] In view of this, the present invention provides an imidazo-aromatic heteromethyl derivative small molecule for use as a GLP-1 receptor agonist small molecule drug in drug preparation.

[0008] Based on this, the technical solution of the present invention is as follows:

[0009] Imidazolidine heterohydric derivatives have the general structural formula as shown in Formula I:

[0010]

[0011] in:

[0012] A is selected from 8- to 10-membered condensed aromatic rings;

[0013] R1 is independently selected from hydrogen, halogen, cyano, alkyl or substituted alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic alkyl;

[0014] n = 0, 1, 2 or 3;

[0015] W is O, NH, S, S(O)2 or C(=O);

[0016] Q1, Q2, Q3, and Q4 are independently selected from CR Z Or N, R Z It can be hydrogen, fluorine, cyano, methyl, or chlorine independently;

[0017] X is CH or N;

[0018] R2 is hydrogen, methyl, or mono- or poly-substituted methyl, and the substituent is fluorine;

[0019] Y1, Y2, and Y3 are independently selected from CR Z Or N, R Z It can be hydrogen, fluorine, cyano, methyl, or chlorine independently.

[0020] Furthermore, the imidazoaryl derivative is selected from one of the structural formulas as shown in formulas II to IX:

[0021]

[0022] Another object of the present invention is to provide isomers of the imidazo-aromatic heteromethyl derivatives described above, including one or more mixtures of tautomers, meso compounds, racemates, enantiomers, and diastereomers.

[0023] Another object of the present invention is to provide pharmaceutically acceptable salts of the imidazo-aromatic heterohydric derivatives described above.

[0024] Another object of the present invention is to provide the use of a pharmaceutical composition in the preparation of a medicament for activating GLP-1 receptors, said pharmaceutical composition comprising the imidazolide derivatives, or the isomers, or the pharmaceutically acceptable salts described above, and pharmaceutically acceptable excipients, diluents, or carriers.

[0025] Furthermore, the composition is used to prepare a medicine for treating and / or preventing type 1 diabetes, type 2 diabetes, young adult-onset diabetes, adult latent immune diabetes, gestational diabetes, diabetes complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia, or insulin resistance.

[0026] The beneficial effects of this invention are as follows:

[0027] Compared with peptide agonists, the imidazo[a]aromatic heteromethyl derivatives provided by this invention have significant advantages in oral bioavailability as small molecule drugs, and are easier to administer, without being restricted by food or timing. Furthermore, these imidazo[a]aromatic heteromethyl derivatives, as small molecule agonists, exhibit good therapeutic effects at the cellular level and possess promising prospects for pharmaceutical application. Attached Figure Description

[0028] Figure 1 This is the general structural formula of Formula I described in this invention. Detailed Implementation

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] In one embodiment of the present invention, an imidazo[a]aromatic heteroyl derivative is provided, a compound having the structure described in general formula I, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0031]

[0032] in:

[0033] A is selected from 8- to 10-membered condensed aromatic rings;

[0034] R1 is independently selected from hydrogen, halogen, cyano, alkyl or R5 substituted alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic alkyl;

[0035] n = 0, 1, 2 or 3;

[0036] W is O, NH, S, S(O)2 or C(=O);

[0037] Q1, Q2, Q3, and Q4 are independently selected from CR Z Or N, R Z Individually, they can be hydrogen, fluorine, cyano, methyl, or chlorine;

[0038] X is CH or N;

[0039] R2 is hydrogen, methyl, or mono- or poly-substituted methyl, and the substituent is fluorine;

[0040] Y1, Y2, and Y3 are independently selected from CR Z Or N, R Z Individually, they can be hydrogen, fluorine, cyano, methyl, or chlorine.

[0041] In a preferred embodiment, the imidazoaryl derivative is selected from one of the structural formulas as shown in formulas II to IX:

[0042]

[0043] In a preferred embodiment, by testing the agonistic activity of compounds of formulas II to IX against the GLP-1 receptor at the cellular level, it was found that compounds of formulas II to IX possess high agonistic activity against the GLP-1 receptor. This can be used to prepare a drug for agonizing the GLP-1 receptor. The drug comprises one or more mixtures of tautomers, meso compounds, racemic compounds, enantiomers, and diastereomers of compounds of formulas II to IX, and a biopharmaceutical acceptable salt, as well as a pharmaceutically acceptable excipient, diluent, or carrier.

[0044] In preferred embodiments, the above-described medicaments can be used to prepare medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, young adult-onset diabetes, latent immune diabetes in adults, gestational diabetes, diabetic complications, obesity, malnutrition-related diabetes, hyperglycemia, impaired glucose tolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia, or insulin resistance. Preferably, they are used to prepare medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease.

[0045] Example 1

[0046] The preparation method of intermediate 4 is as follows:

[0047]

[0048] The reaction conditions for the above routes are: (a) Et3N, MeCN, rt; (b) Pd / C, H2, MeOH, THF, rt

[0049] 1) Synthesis of intermediate 3a (X in the structural formula refers to C)

[0050] Methyl 3-chloro-4-nitrobenzoate (2a, 10.8 g, 50.2 mmol) was dissolved in acetonitrile (100 mL), and (S)-oxetane-2-methylamine (5.25 g, 60.2 mmol) was added with stirring, followed by triethylamine (20.9 mL, 150.6 mmol). The reaction was allowed to proceed for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and saturated NH4Cl solution (200 mL) was added. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and eluted by column chromatography to give intermediate 3a (9.36 g, 70%) as an orange solid. MS (ESI): 267.2 [M+1].

[0051] 2) Synthesis of intermediate 4a

[0052] Pd / C (10% (w / w), 1.8 g, 1.69 mmol) was added to a mixed solution of intermediate 3a (9.0 g, 33.8 mmol) in methanol (240 mL) and tetrahydrofuran (40 mL). The mixture was reacted under a hydrogen atmosphere (35 psi) for 4 hours. After filtration through diatomaceous earth and washing with methanol, the solution was concentrated under reduced pressure to obtain intermediate 4a (8.0 g, >99%), a white oily substance. MS (ESI): 237.5 [M+1].

[0053] 3) Synthesis of intermediate 3b (where X in the structural formula represents N)

[0054] Using the synthetic route of intermediate 3a, methyl 3-chloro-4-nitrobenzoate was replaced with methyl 6-chloro-5-nitropyridine-2-carboxylate to prepare intermediate 3b. MS (ESI): 268.2 [M+1].

[0055] 4) Synthesis of intermediate 4b

[0056] Using the synthetic route of intermediate 4a, intermediate 3a was replaced with intermediate 3b to obtain intermediate 4b. MS(ESI): 238.5 [M+1].

[0057] Example 2

[0058] The preparation method of imidazoaromatic heteromethyl compounds with the structural formula of formula II is as follows:

[0059]

[0060] The reaction conditions for the above route are: (a) LiHMDS, THF, -78℃; (b) i. NaOH, MeOH, 50℃; ii. DCE, 105℃; (c) TFA, CH2Cl2, rt; (d) TCDI, CH3CN, 0℃ to rt; (e) 4, CH3CN, 50℃; (f) ICH3, EtOH, reflux; (g) Pd(OAc)2, trixiephos, Cs2CO3, Dioxane, 100℃; (h) LiOH, H2O / MeCN, rt.

[0061] 1) Synthesis of intermediate 7

[0062] Methyl 4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (30.88 g, 120 mmol) and 2,6-dichloropyridine (14.8 g, 100 mmol) were dissolved in toluene, and a tetrahydrofuran solution of LiHMDS (1 M, 140 mL) was added at -78 °C. After reacting for 10 hours, the pH was adjusted with dilute hydrochloric acid. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and eluted by column chromatography to give intermediate 7 (18.44 g, 50%) as a colorless oil. MS (ESI): 370.0 [M+1].

[0063] 2) Synthesis of intermediate 8

[0064] Intermediate 7 (18.0 g, 48.8 mmol) was dissolved in MeOH solution (200 mL), and sodium hydroxide solution (2 N, 120 mL) was added at 60 °C. After reacting for 5 hours, the solution was cooled to room temperature, and the pH was adjusted to acidic with dilute hydrochloric acid (1 N). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a solid. The solid was dissolved in dichloroethane, refluxed for 2 hours, concentrated under reduced pressure, and 80 mL of methanol and water (3 / 1) were added. After four hours, the mixture was filtered and dried under reduced pressure to obtain intermediate 8 (12.9 g, 85%). MS (ESI): 312.0 [M+1].

[0065] 3) Synthesis of intermediate 9

[0066] Intermediate 8 (12.0 g, 38.6 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 2 hours, then distilled under reduced pressure, slurried with ethyl acetate, and filtered to obtain intermediate 9 (7.32 g, 90%). MS (ESI): 212.0 [M+1].

[0067] 4) Synthesis of intermediate 10a

[0068] 1,1'-Thiocarbonyldiimidazole (7.1 g, 39.84 mmol) was dissolved in acetonitrile (100 mL). Intermediate 9 (7.0 g, 33.2 mmol) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 4 hours. Then, intermediate 4a (11.78 g, 49.8 mmol) was added, and the reaction was carried out at 50 °C for another 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and column chromatography was used to elute intermediate 10a (10.7 g, 66%). MS (ESI): 490.1 [M+1].

[0069] 5) Synthesis of intermediate 11a

[0070] Intermediate 10a (10 g, 20.4 mmol) was dissolved in ethanol (150 mL), and iodomethane (3.8 mL, 61.2 mmol) was added in portions. The mixture was reacted at 70 °C for 2 hours. The reaction solution was concentrated under reduced pressure and eluted by column chromatography to obtain intermediate 11a (6.0 g, 65%). MS (ESI): 456.0 [M+1].

[0071] 6) Synthesis of intermediate 12a

[0072] Intermediate 11a (5.5 g, 12.1 mmol), 4-cyano-2-fluorobenzyl alcohol (1.92 g, 12.7 mmol), Pd(OAc)2 (0.10 g, 0.61 mmol), Trixiephos (0.243 g, 0.61 mmol), and Cs2CO3 (7.88 g, 24.2 mmol) were placed in a reaction vessel equipped with a reflux condenser. 1,4-Dioxane (60 mL) was added, and the reaction was carried out under a nitrogen atmosphere at 105 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and eluted by column chromatography to obtain intermediate 12a (5.86 g, 85%). MS (ESI): 470.5 [M+1].

[0073] 7) Synthesis of Compound II

[0074] LiOH (0.92 g, 38.6 mmol) was dissolved in 2 mL of water and added to an acetonitrile solution (10 mL) of intermediate 12a (5.5 g, 9.66 mmol). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, dilute hydrochloric acid (1 N) was added to adjust the pH to acidic to precipitate the precipitate. The precipitate was filtered and dried under vacuum to obtain Example 1 (5.26 g, 98%). MS (ESI): 556.2 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.89(d,J=9.8Hz,1H),7.75(t,J=8.2Hz,1H),7.70(brs,2H),7.6 4(t,J=7.8Hz,1H),7.56(d,J=8.3Hz,1H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.3Hz,1H),5.46(s,2H),5 .16-5.05(m,1H),4.86-4.75(m,1H),4.72(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.93(d,J=13.4Hz,1H) ,3.84-3.75(m,1H),3.76(d,J=13.4Hz,1H),3.01-2.95(m,1H),2.29-2.14(m,2H),1.98-1.76(m,8H).

[0075] Example 3

[0076] The preparation method of imidazoaromatic heterohydric compounds with the structural formula of Formula III is as follows:

[0077]

[0078] The reaction conditions for the above route are: (a) CH3CN, 0℃ to rt; (b) 4, CH3CN, 50℃; (c) ICH3, EtOH, reflux; (d) TFA, CH2Cl2, rt; (e) Et3N, NMP, 150℃, 30min, microwave; (f) Pd(OAc)2, trixiephos, Cs2CO3, Dioxane, 100℃; (g) LiOH, H2O / MeCN, rt.

[0079] 1) Synthesis of intermediate 15a

[0080] 1,1'-Thiocarbonyldiimidazole (7.1 g, 39.84 mmol) was dissolved in acetonitrile (100 mL). 1-Boc-4-aminopiperidine (13 g, 6.65 g, 33.2 mmol) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 4 hours. Then, intermediate 4a (11.78 g, 49.8 mmol) was added, and the reaction was carried out at 50 °C for another 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and column chromatography was used to elute intermediate 15a (10.3 g, 65%). MS (ESI): 479.5 [M+1].

[0081] 2) Synthesis of intermediate 16a

[0082] Intermediate 15a (10 g, 20.9 mmol) was dissolved in ethanol (150 mL), and iodomethane (3.9 mL, 62.7 mmol) was added in portions. The mixture was reacted at 70 °C for 2 hours. The reaction solution was concentrated under reduced pressure and eluted by column chromatography to obtain intermediate 16a (6.0 g, 65%). MS (ESI): 445.5 [M+1].

[0083] 3) Synthesis of intermediate 17a

[0084] Intermediate 16a (6.0 g, 13.5 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 2 hours, then distilled under reduced pressure, slurried with ethyl acetate, and filtered to obtain intermediate 17a (4.4 g, 95%). MS (ESI): 345.4 [M+1].

[0085] 4) Synthesis of intermediate 18a

[0086] Intermediate 17a (4.0 g, 11.6 mmol) was dissolved in NMP (10 mL), and triethylamine (4.84 mL, 34.8 mmol) was added. The mixture was microwaved at 150 °C for 30 minutes. After the reaction was completed, intermediate 18a (4.65 g, 88%) was obtained by silica gel column chromatography. MS (ESI): 456.9 [M+1].

[0087] 5) Synthesis of intermediate 19a

[0088] Intermediate 18a (4.5 g, 9.87 mmol), 4-cyano-2-fluorobenzyl alcohol (1.57 g, 10.4 mmol), Pd(OAc)2 (0.082 g, 0.61 mmol), Trixiephos (0.197 g, 0.61 mmol), and Cs2CO3 (6.43 g, 19.74 mmol) were placed in a reaction vessel equipped with a reflux condenser. 1,4-Dioxane (60 mL) was added, and the reaction was carried out under a nitrogen atmosphere at 105 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and eluted by column chromatography to obtain intermediate 19a (4.73 g, 84%). MS (ESI): 471.5 [M+1].

[0089] 6) Synthesis of Compound III

[0090] Using the synthetic method of Example 2, intermediate 12a was replaced with intermediate 19a to obtain compound of formula III. MS (ESI): 557.5 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.89(d,J=9.8Hz,1H),7.76(t,J=8.2Hz,1H),7.70(brs,2H),7.56(d,J=8. 3Hz,1H),7.44(t,J=7.8Hz,1H),6.58(d,J=7.3Hz,1H),6.36(d,J=8.3Hz,1H),5.45(s,2H),5.16-5.05(m,1H),4 .86-4.75(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.92(d,J=13.4Hz,1H),3.80-3.71(m,1H),3.76-3. 70(m,2H),3.75(d,J=13.4Hz,1H),3.63-3.55(m,2H),2.29-2.14(m,2H),2.02-1.95(m,2H),1.93-1.87(m,2H).

[0091] Example 4

[0092] The preparation method of compound IV is as follows:

[0093]

[0094] 1) Synthesis of intermediate 10b

[0095] Intermediate 10b was prepared by replacing intermediate 4a with intermediate 4b using the same synthesis method as intermediate 10a. MS(ESI): 491.1 [M+1].

[0096] 2) Synthesis of intermediate 11b

[0097] Intermediate 11b was prepared by replacing intermediate 10b with intermediate 10a using the same synthesis method as intermediate 11a. MS(ESI): 457.0 [M+1].

[0098] 3) Synthesis of intermediate 12b

[0099] Intermediate 12b was prepared by replacing intermediate 11a with intermediate 11b using the same synthesis method as intermediate 12a. MS(ESI): 471.5 [M+1].

[0100] 4) Synthesis of Compound IV

[0101] Using the synthetic method of Example 2, intermediate 12a was replaced with intermediate 12b to obtain compound of formula IV. MS (ESI): 557.5 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=8.2Hz,1H),8.01(d,J=8.2Hz,1H),7.70(brs,2H),7.64(t,J=7. 8Hz,1H),7.56(d,J=8.3Hz,1H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.3Hz,1H),5.46(s,2H),5.43-5 .32(m,1H),5.13-5.02(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.93(d,J=13.4Hz,1H),3 .84-3.75(m,1H),3.76(d,J=13.4Hz,1H),3.01-2.95(m,1H),2.29-2.14(m,2H),1.98-1.76(m,8H).

[0102] Example 5

[0103] The preparation method of compound V is as follows:

[0104]

[0105] 1) Synthesis of intermediate 15b

[0106] Intermediate 15b was prepared by replacing intermediate 4a with intermediate 4b using the same synthesis method as intermediate 15a. MS (ESI): 480.5 [M+1].

[0107] 2) Synthesis of intermediate 16b

[0108] Intermediate 16b was prepared by replacing intermediate 15b with intermediate 15a using the same synthesis method as intermediate 16a. MS(ESI): 446.5 [M+1].

[0109] 3) Synthesis of intermediate 17b

[0110] Intermediate 17b was prepared by replacing intermediate 16b with intermediate 16a using the same synthesis method as intermediate 17a. MS(ESI): 346.4 [M+1].

[0111] 4) Synthesis of intermediate 18b

[0112] Intermediate 18b was prepared by replacing intermediate 17b with intermediate 17a using the same synthesis method as intermediate 18a. MS(ESI): 457.9 [M+1].

[0113] 5) Synthesis of intermediate 19b

[0114] Intermediate 19b was prepared by replacing intermediate 18a with intermediate 18b using the same synthesis method as intermediate 19a. MS(ESI): 472.5 [M+1].

[0115] 6) Synthesis of compound V

[0116] Using the synthetic method of Example 2, intermediate 12a was replaced with intermediate 19b to obtain compound V. MS (ESI): 558.5 [M+1]. 1H NMR(400MHz, DMSO-d6)δ8.25(d,J=8.2Hz,1H),8.01(d,J=8.2Hz,1H),7.70(brs,2H),7.56(d,J=8.3Hz,1H), 7.44(t,J=7.8Hz,1H),6.58(d,J=7.3Hz,1H),6.36(d,J=8.3Hz,1H),5.45(s,2H),5.16-5.05(m,1H),4.86-4 .75(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.92(d,J=13.4Hz,1H),3.80-3.71(m,1H),3.76-3.70 (m,2H),3.75(d,J=13.4Hz,1H),3.63-3.55(m,2H),2.29-2.14(m,2H),2.02-1.95(m,2H),1.93-1.87(m,2H).

[0117] Example 6

[0118] The preparation method of compound VI is as follows:

[0119]

[0120] 1) Synthesis of Pre-VI compounds

[0121] Intermediate 12a (0.5 g, 0.88 mmol) was dissolved in DMF (4.0 mL), and NaH (0.106 g, 4.4 mmol) was added at 0 °C. The mixture was stirred for 15 minutes, and then iodomethane (82 μL, 1.32 mmol) was added dropwise. The mixture was then allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with methanol, concentrated under reduced pressure, and eluted by column chromatography to obtain intermediate Pre-Example 5 (0.385 g, 75%). MS (ESI): 584.5 [M+1].

[0122] 2) Synthesis of compound VI

[0123] Using the synthesis method of Example 2, intermediate 12a was replaced with intermediate Pre-form VI compound to obtain form VI compound. MS (ESI): 570.5 [M+1]. 1HNMR(400MHz,DMSO-d6)δ8.07(s,1H),7.89(d,J=9.8Hz,1H),7.75(t,J=8.2Hz,1H),7.70(brs,2H),7 .64(t,J=7.8Hz,1H),7.56(d,J=8.3Hz,1H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.3Hz,1H),5.46(s,2H ),5.16-5.05(m,1H),4.86-4.75(m,1H),4.72(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.93(d,J=13.4Hz ,1H),3.76(d,J=13.4Hz,1H),3.30(s,3H),3.01-2.95(m,1H),2.29-2.14(m,2H),1.98-1.76(m,8H).

[0124] Example 7

[0125] The preparation method of compound VII is as follows:

[0126]

[0127] 1) Synthesis of Pre-Form VII compounds

[0128] The Pre-Form VI compound was prepared by replacing intermediate 12a with intermediate 19a using the synthetic method of Pre-Form VI compounds. MS (ESI): 585.5 [M+1].

[0129] 2) Synthesis of compound VII

[0130] Using the synthetic method of Example 2, intermediate 12a was replaced with intermediate Pre-formula VII compound to obtain formula VII compound. MS (ESI): 571.5 [M+1]. 1HNMR(400MHz, DMSO-d6)δ8.07(s,1H),7.89(d,J=9.8Hz,1H),7.76(t,J=8.2Hz,1H),7.70(brs,2H),7.56(d,J= 8.3Hz,1H),7.44(t,J=7.8Hz,1H),6.58(d,J=7.3Hz,1H),6.36(d,J=8.3Hz,1H),5.45(s,2H),5.16-5.05(m,1H ),4.86-4.75(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.92(d,J=13.4Hz,1H),3.80-3.71(m,1H),3.7 6-3.70(m,2H),3.75(d,J=13.4Hz,1H),3.28(s,3H),2.29-2.14(m,2H),2.02-1.95(m,2H),1.93-1.87(m,2H).

[0131] Example 8

[0132] The preparation method of compound VIII is as follows:

[0133]

[0134] 1) Synthesis of Pre-Form VIII Compounds

[0135] The Pre-Formula VIII compound was prepared by replacing intermediate 12b with intermediate 12a using the synthetic method of Pre-Example 6 (compound of Formula VI). MS (ESI): 585.5 [M+1].

[0136] 2) Synthesis of compound VIII

[0137] Using the synthetic method of Example 2, intermediate 12a was replaced with intermediate Pre-form VIII compound to obtain formula VIII compound. MS (ESI): 571.5 [M+1]. 1HNMR(400MHz,DMSO-d6)δ8.25(d,J=8.2Hz,1H),8.01(d,J=8.2Hz,1H),7.70(brs,2H),7.64(t,J= 7.8Hz,1H),7.56(d,J=8.3Hz,1H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.3Hz,1H),5.46(s,2H),5.4 3-5.32(m,1H),5.13-5.02(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.93(d,J=13.4Hz,1 H), 3.76 (d, J = 13.4Hz, 1H), 3.28 (s, 3H), 3.01-2.95 (m, 1H), 2.29-2.14 (m, 2H), 1.98-1.76 (m, 8H).

[0138] Example 9

[0139]

[0140] The preparation method of compound IX is as follows:

[0141] 1) Synthesis of Pre-Form IX Compounds

[0142] Using the synthetic method of Pre-Example 6 (Compound of Formula VI), intermediate 12a was replaced with intermediate 19b to obtain Pre-Formula IX compound. MS (ESI): 586.5 [M+1].

[0143] 2) Synthesis of compound IX

[0144] Using the synthesis method of Example 2, intermediate 12a was replaced with intermediate Pre-form IX compound to obtain formula IX compound. MS (ESI): 572.5 [M+1]. 1HNMR(400MHz,DMSO-d6)δ8.25(d,J=8.2Hz,1H),8.01(d,J=8.2Hz,1H),7.70(brs,2H),7.56(d,J=8.3Hz,1H ),7.44(t,J=7.8Hz,1H),6.58(d,J=7.3Hz,1H),6.36(d,J=8.3Hz,1H),5.45(s,2H),5.16-5.05(m,1H),4.8 6-4.75(m,1H),4.73(s,1H),4.38(dt,J=6.0,8.8Hz,1H),3.92(d,J=13.4Hz,1H),3.76-3.70(m,2H),3.73( d,J=13.4Hz,1H),3.63-3.55(m,2H),3.30(s,3H),2.29-2.14(m,2H),2.02-1.95(m,2H),1.93-1.87(m,2H).

[0145] Evaluation of GLP-1 receptor agonist activity in experimental cases

[0146] Experimental objective: To test the agonistic activity of the compound on the GLP-1 receptor at the cellular level.

[0147] Experimental Method: This experiment uses ONE-Glo TM The luciferase assay system works by activating the GLP-1 receptor, which activates its downstream signaling pathway, leading to increased cAMP expression. cAMP binds to the CRE, initiating the transcriptional expression of the downstream luciferase gene. The luciferase then reacts with its substrate to emit fluorescence. Therefore, it can be detected via ONE-Glo TM The activity of the compound in activating the GLP-1 receptor was evaluated by detecting the fluorescence signal. First, a stable cell line transfected with the CHO-K1 / CRE-luc / GLP-1 receptor was constructed. The cells were then cultured at 2.5 × 10⁻⁶ cells / year. 5 Cells were seeded at a density of [number] cells / mL in 96-well cell culture plates and cultured for 16 hours. Then, the cells were treated with different concentrations of compounds for 6 hours. The 96-well cell culture plates were then removed, and the specified dose of ONE-Glo was added according to the instructions. TM The reagents were incubated at room temperature for 10 minutes, and the fluorescence signal was measured using an ELISA reader.

[0148] Data Analysis:

[0149] The data were processed and analyzed using Graphpad Prism 5. The EC values ​​of the compounds were obtained. 50 The values ​​are shown in the table below.

[0150] EC50 of the disclosed compound on GLP-1 receptor agonistic activity 50(nM), with the agonistic activity of exenatide (1μM) being 100%.

[0151]

[0152]

[0153] Conclusion: The compound disclosed herein exhibits high agonistic activity against the GLP-1 receptor.

[0154] Finally, it should be noted that although the present invention has been described in detail above with general descriptions and specific embodiments, the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Imidazolidine heterohydric derivatives, characterized in that, It has a structural formula as shown in Formula III, Formula V, Formula VII or Formula IX: 。 2. A pharmaceutically acceptable salt of the imidazo[a]ary heteroary derivative of claim 1.

3. The use of the pharmaceutical composition in the preparation of a medicament for activating GLP-1 receptors, characterized in that, The pharmaceutical composition comprises the imidazoaryl derivative of claim 1, and a pharmaceutically acceptable carrier.

4. The application according to claim 3, characterized in that, The composition is used to prepare a medicine for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, young adult-onset diabetes, adult latent immune diabetes, gestational diabetes, diabetes complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia, or insulin resistance.

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