An aryl benzimidazole compound, a pharmaceutical composition thereof and application thereof

Abstract

The application discloses aryl benzimidazole compounds of formula I, pharmaceutical compositions and applications thereof. The compounds and the pharmaceutical compositions have specific GLP-1 agonistic activity, and are agonists of glucagon-like peptide-1 receptor (GLP-1R). Therefore, the compounds can be used for preparing medicines for preventing and / or treating GLP-1 mediated diseases or related diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an arylbenzimidazole compound, its pharmaceutical composition, and its applications. This type of compound can act as a GLP-1 receptor agonist and can be used to prepare drugs for the prevention or treatment of GLP-1-mediated diseases and related diseases. Background Technology

[0002] The prevalence of type 2 diabetes mellitus (T2DM) is rising globally, closely linked to increased waist circumference and a rise in overweight and obesity. The landmark UK Prospective Diabetes Study (UKPDS) provided the first high-quality evidence that improving glycemic control in newly diagnosed T2DM patients can ultimately reduce the incidence of microvascular complications and long-term macrovascular disease. To date, many novel drugs for treating T2DM have been developed and subsequently marketed, effectively lowering blood glucose levels while minimizing the risk of hypoglycemia and promoting weight loss.

[0003] Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone derived from the precursor of proglucagon. Proglucagon is a protein expressed in enteroendocrine cells, pancreatic α cells, and the nucleus tractus solitarius (NTS) in the brainstem. In the pancreas, proglucagon is post-translationally processed by pro-hormone convertase 2 to produce glucagon, GRPP, and the major proglucagon fragment (MPGF). A small amount (10-20%) of MPGF is cleaved to produce GLP-1.

[0004] GLP-1 has long been considered an effective stimulant of insulin secretion and a key regulator of energy homeostasis. GLP-1 receptors are distributed in the gastrointestinal tract, the endocrine pancreas, the vagus afferent nerve, and the central nervous system. Activation of GLP-1 receptors (GLP-1R) stimulates insulin release and inhibits glucagon secretion in a glucose-dependent manner, thereby lowering blood glucose levels. Furthermore, GLP-1R activation delays gastric emptying, increases satiety, inhibits food intake, and reduces human weight. Recently, GLP-1 in the brain has been increasingly recognized for its involvement in a series of neural circuits that regulate appetite and reward-related behaviors, thereby achieving its blood glucose-lowering effect.

[0005] Early GLP-1 receptor agonists were GLP-1 analogs, all belonging to the peptide class, including liraglutide and semaglutide. A drawback was the need for injection. Oral semaglutide has been shown to effectively lower blood glucose levels and is generally well-tolerated. However, oral peptides are still limited by various adverse factors such as administration time, dosage, and gastrointestinal disturbances, resulting in very low bioavailability (only 1%) and poor patient compliance. In recent years, researchers have discovered that GLP-1 receptor function can also be modulated using small molecule compounds, leading to the development of small molecule GLP-1 receptor agonists, including oral small molecule GLP-1RA drugs from Pfizer, Chugai Pharmaceutical / Eli Lilly, and Vtv Therapeutics. However, existing small molecule agonists have structural limitations, resulting in low safety, significant side effects, and limited glycemic and weight-loss effects. Therefore, it is essential to develop GLP-1 receptor agonists with novel structures, low side effects, and good patient compliance.

[0006] The number of obese people worldwide increased from 994.9 million in 2016 to 1210.7 million in 2020, while the number of obese people in my country increased from 180.9 million to 219.7 million. Therefore, the development of novel small molecule drugs for the GLP-1 receptor is urgently needed. Summary of the Invention

[0007] Purpose of the invention: The present invention aims to provide an aryl benzimidazole compound with specific GLP-1 agonist activity, its pharmaceutical composition and application.

[0008] One objective of this invention is to provide an arylbenzimidazole compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:

[0009]

[0010] in,

[0011] Ring A is C6-C 10 Aryl or C5-C 10 Mixed aromatics;

[0012] Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl;

[0013] R 1 Selected from hydrogen, deuterium, oxo, halogen, alkyl, haloalkyl, alkoxy, alkylamine or nitrile groups;

[0014] R 2 Selected from C 1-3 Alkyl, C 0-3 Alkylene, C3-6 cycloalkyl, C 5-6 Heteroaryl; the alkyl, alkylene, cycloalkyl, and heteroaryl groups may be selectively converted to C 1-9 Alkyl, -O-(C 1-9 alkyl), -S-(C 1-9 Alkyl), -S(O)2-(C 1-9 Alkyl), C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl substitution;

[0015] R 3 Selected from hydrogen, halogens, or haloalkyl groups;

[0016] L is selected from -O- and -(CH2). n CHR 4 O-, -(CH2) n CHR 4 NH-, -CHR 4 (CH2) n -、-OCHR 4 (CH2) n -、-NHCHR 4 Or (CH2) n -;

[0017] R 4 Selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or alkylheterocycloalkyl;

[0018] X is selected from C or N;

[0019] n = 0, 1, or 2.

[0020] Through rational drug design, this invention synthesized a series of derivatives. Bioactivity evaluation showed that the designed compounds have significant GLP-1 receptor agonist activity.

[0021] In some preferred embodiments,

[0022] Ring A is selected from the following groups:

[0023]

[0024] In some preferred embodiments,

[0025] Ring B is selected from the following groups:

[0026]

[0027] In some further preferred embodiments,

[0028] Ring B is selected from:

[0029]

[0030] In some preferred embodiments,

[0031] R 1 Selected from -F, -CF3, -Cl or nitrile groups;

[0032] R 3 Selected from H or CF3;

[0033] L is selected from -CH2O-;

[0034] R 2 Selected from:

[0035]

[0036] In some preferred embodiments, the pharmaceutically acceptable salt includes, but is not limited to, salts formed by compounds of general formula I with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, tartaric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid, or malonic acid.

[0037] The compounds of Formula I of the present invention are preferably the following compounds:

[0038]

[0039]

[0040] The compounds of Formula I involved in this invention can also exist in the form of their salts, hydrates, or solvates, which are converted into Formula I compounds in vivo. For example, within the scope of this invention, the compounds of this invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and used in salt form.

[0041] All tautomer forms of compounds of Formula I of this invention are included within the scope of this invention. Compounds of this invention may exist in specific geometric or stereoisomer forms. Additional asymmetric carbon atoms may be present in alkyl or other substituents; all such isomers and mixtures thereof are included within the scope of this invention.

[0042] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

[0043] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other drugs. Oral compositions can be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, etc.

[0044] Sterile injectable compositions may be formulated using suitable dispersants or wetting agents and suspending agents in accordance with techniques known in the art. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution, etc.

[0045] Topical compositions can be formulated as oils, lotions, creams, etc. Carriers used in the compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols. Pharmaceutically acceptable carriers are those in which the active ingredient is soluble.

[0046] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and route of administration, and is non-toxic to the patient. The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition used, the age, sex, weight, general health condition, and medical history of the patient being treated, and similar factors known in the medical field.

[0047] Another object of the present invention is to provide the use of compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof in the preparation of medicaments for the prevention and / or treatment of GLP-1 mediated diseases or related diseases.

[0048] The GLP-1-mediated diseases or related diseases include diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia.

[0049] The diabetes mellitus includes type 1 diabetes and / or type 2 diabetes mellitus (T1D), idiopathic T1D, early-onset T2D, latent autoimmune diabetes, atypical diabetes mellitus in adolescents, or gestational diabetes mellitus.

[0050] Beneficial effects:

[0051] (1) The compounds of formula I prepared in this invention, as well as their pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates, exhibit significant agonistic activity against GLP-1 receptors. Therefore, the above compounds can be used to prepare drugs for the prevention and / or treatment of GLP-1-mediated diseases or related diseases.

[0052] (2) The preparation method of the compound of the present invention is simple and easy to operate.

[0053] (3) The pharmacokinetic properties of the compound of the present invention are significantly improved, and it has good oral bioavailability. Detailed Implementation

[0054] The preparation method of the compound of general formula I of the present invention is described below with reference to specific embodiments, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art.

[0055] The starting materials and reaction reagents used in the specific embodiments of this invention are all commercially available. This invention can be prepared into a salt form using methods commonly used in the art, such as: dissolving the compound in hydrochloric acid-ethanol at room temperature to generate hydrochloride; or adding benzenesulfonic acid to generate benzenesulfonate.

[0056] Example 1: Synthesis of Compound 01

[0057]

[0058] (1) Synthesis of intermediates 1-7:

[0059]

[0060] Step a:

[0061] A solution of compound 1-1 (500 mg, 3.01 mmol, 1 eq) and compound 1-2 (314.68 mg, 3.61 mmol, 1.2 eq) was added to THF (30 mL) and DMF (4 mL). The mixture was stirred at 25 °C for 3 hours. After the reaction was complete as monitored by TLC, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1, v / v). Intermediate 1-3 (740 mg) was given as a yellow solid in 80% yield. HR-MS (ESI): Calculated value C 11H 11 N3O3[M+H] + 234.0834, measured value 234.0821.

[0062] Step b:

[0063] Intermediates 1-3 (490 mg, 2.10 mmol, 1 eq) were dissolved in EtOH (20 mL), and TEA (425.20 mg, 4.20 mmol, 584.87 μL, 2 eq) and NH₂OH·HCl (292.00 mg, 4.20 mmol, 2 eq) were added. The mixture was stirred at 85 °C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated by vacuum filtration to obtain intermediates 1-4. The crude product could be used in the next step without purification. HR-MS (ESI): Calculated value C 11 H 14 N4O4[M+H] + :267.1049, measured value 267.1018.

[0064] Step c:

[0065] Intermediates 1-4 (600 mg, 2.25 mmol, 1 eq) were dissolved in THF (10 mL), and TFAA (700 mg, 3.38 mmol, 1.5 eq) was added at room temperature. The reaction was stirred at 20 °C for 2 hours. After the reaction was complete, the reaction was quenched with saturated NaHCO3 solution (20 mL), and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (40 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give intermediates 1-5. The crude product was used in the next step without purification. HR-MS (ESI): Calculated value C 13 H 13 F3N4O4[M+H] + 347.0922, measured value 347.0935.

[0066] Step d:

[0067] Intermediate 1-5 (700 mg, 0.076 mmol, 1 eq) was dissolved in 5 mL of anhydrous ethanol, and NH₂·H₂O (80% w / w 0.5 mL, 5 eq) was added dropwise at 0 °C. The mixture was then stirred at 60 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete as monitored by TLC, 10 mL of water was added, and the mixture was extracted with EA / iPrOH = 2:1 (v / v, 10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated by vacuum filtration. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1, v / v). 500 mg of intermediate 1-6 was obtained, in 72% yield. HR-MS (ESI): Calculated value C 13 H 12 F3N5O3[M+H] + 344.0926, measured value 344.0936.

[0068] Step e:

[0069] Pd / C (10% (w / w), 100 mg) was added to a methanol (5 mL) solution of intermediate 1-6 (400 mg, 1.16 mmol), and the mixture was reacted under a hydrogen atmosphere (35 psi) for 4 hours. The mixture was filtered through diatomaceous earth, washed with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give intermediate 1-7 (350 mg), yield 95%. HR-MS (ESI): Calculated value C 13 H 14 F3N5O[M+H] + 314.1184, measured value 314.1169.

[0070] (2) Synthesis of intermediates 1-10:

[0071]

[0072] Step f:

[0073] Compounds 1-8 (2 g, 13.2 mmol, 1 eq) were added to 100 mL of dry THF. NaH (60% w / w, 0.507 g, 13.2 mmol, 1 eq) was added under a nitrogen atmosphere at 0 °C, and the mixture was stirred for 30 min. Then, 2,6-dibromopyridine (compounds 1-9) (3.13 g, 13.2 mmol, 1 eq) dissolved in 50 mL of THF was added, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the mixture was filtered, and the filtrate was diluted with ethyl acetate (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1, v / v) to give intermediate 1-10 (3 g), yield 75%. HR-MS (ESI): Calculated value C 13 H8BrFN2O[M+H] + 306.9877, measured value 306.9899.

[0074] (3) Synthesis of intermediates 1-13:

[0075]

[0076] Step g:

[0077] Compound 1-11 (500 mg, 2.10 mmol, 1 eq) was dissolved in MeOH (20 mL), and SOCl2 (425.20 mg, 4.20 mmol, 584.87 μL, 1.2 eq) was slowly added dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated by vacuum filtration to give intermediate 1-12. The crude product could be used in the next step without purification.

[0078] Step h:

[0079] Intermediate 1-12 (500 mg, 1.68 mmol, 1 eq) was dissolved in 10 mL of dioxane, and neopentyl glycol diboronate (1-13) (850 mg, 3.36 mmol, 1.2 eq), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (140 mg, 0.17 mmol, 0.1 eq), and potassium propionate (740 mg, 5.88 mmol, 3 eq) were added sequentially. The mixture was heated at 100 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete as monitored by TLC, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated by vacuum filtration to obtain intermediate 1-13. The crude product could be used in the next step without purification.

[0080] (4) Synthesis of intermediates 1-16:

[0081]

[0082] Step i:

[0083] Intermediates 1-13 (1.16 g, 3.90 mmol, 1.2 eq) and I-10 (1 g, 3.26 mmol, 1 eq) were dissolved in 10 mL of dioxane. Potassium carbonate (1.12 g, 8.84 mmol, 2.7 eq) and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (241 mg, 0.33 mmol, 0.1 eq) were added sequentially, and the mixture was heated at 100 °C for 5 hours under a nitrogen atmosphere. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated by vacuum filtration. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give intermediate 1-15 (800 mg). HR-MS (ESI): Calculated value C 22 H 15 F3N2O3[M+H] + :413.1068, measured value 413.1038.

[0084] Step j:

[0085] Intermediate 1-5 (1.25 g, 3.03 mmol, 1 eq) and lithium hydroxide (0.2 M, 1.97 mL, 3.94 mmol, 1.2 eq) were added to acetonitrile (10 mL) and heated at 50 °C for 2 hours. The mixture was acidified with 1 N hydrochloric acid to pH 6-7. A large amount of solid precipitated; this solid was filtered and dried to obtain intermediate 1-16. HR-MS (ESI): Calculated value C 21 H 13 F3N2O3[M+H] +399.0912, measured value 399.0955. 1 HNMR(300MHz, CD3OD)δ(ppm)7.83-7.77(m,1H),7.78-7.65(m,2H),7.64-7.59(m,2H),7.58 -7.51(m,1H),7.26-7.14(m,1H),6.91(d,J=8.2Hz,1H),5.63(s,2H),3.73(d,J=1.2Hz,2H).

[0086] (5) Synthesis of Compound 1:

[0087] Step k:

[0088]

[0089] Intermediates 1-7 (76 mg, 0.24 mmol, 1.2 eq) and 1-16 (80 mg, 0.20 mmol, 1 eq) were dissolved in DMF (5 mL), and HATU (92 mg, 0.24 mmol, 1.2 eq) and DIPEA (129.7 mg, 1.00 mmol, 1.2 eq) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1, v / v) to give intermediate 1-17 (80 mg), in 57% yield. HR-MS (ESI): Calculated value C 34 H 25 F6N7O3[M+H] + :694.1957, measured value 694.1966.

[0090] Step 1:

[0091]

[0092] Intermediate 1-17 (100 mg, 0.14 mmol) was dissolved in acetic acid (5 mL) and heated at 120 °C for 2 hours. Acetic acid was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give compound 1 (60 mg) in 61% yield. HR-MS (ESI): Calculated value C 34 H 23 F6N7O2[M+H] + :676.1851, measured value 676.1855. 1H NMR (300MHz, DMSO-d6) δ (ppm) 9.06 (s, 1H), 7.93-7.87 (m, 2H), 7.79-7.71 (m, 4H), 7.59 (d, J = 8. 4Hz,1H),7.53(dd,J=1.2,6.4Hz,1H),7.40(dd,J=6.4,5.2Hz,1H),7.00(d,J=8.4Hz,1H),5.59( s,2H),5.08(dd,J=2.8,7.8Hz,1H),4.77(dd,J=7.2,8.4Hz,1H),4.63(dd,J=2.4,13.2Hz,1H),4 .54-4.49(m,2H),4.46(d,J=6Hz,1H),4.36-4.33(m,1H),2.70-2.67(m,1H),2.37-2.32(m,1H).

[0093] Example 2: Synthesis of Compound 15

[0094]

[0095] (1) Synthesis of intermediate 2-2

[0096]

[0097] Step m:

[0098] Intermediate 1-3 (1.13 g, 4.85 mmol, 1 eq) and dibutyltin acetate (1.7 g, 4.84 mmol, 1 eq) were added to toluene (10 mL), and the mixture was purged with nitrogen. Trimethylsilyl azide (1.12 g, 9.70 mmol, 2 eq) was slowly added dropwise. The reaction was carried out at 30 °C for 24 hours. After the reaction was complete as monitored by TLC, n-hexane was added, and the mixture was filtered and dried to obtain intermediate 2-1 as an orange solid, which could be used in the next step without further purification. HR-MS (ESI): Calculated value C 11 H 12 N6O3[M+H] + 277.1004, measured value 277.1014.

[0099] Step n:

[0100] Pd / C (10% (w / w), 100 mg) was added to a methanol (5 mL) solution of intermediate 2-1 (400 mg, 1.16 mmol), and the mixture was reacted under a hydrogen atmosphere (35 psi) for 4 hours. The mixture was filtered through diatomaceous earth, washed with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give intermediate 2-2 (350 mg). HR-MS (ESI): Calculated C 13 H14 F3N5O[M+H] + 314.1184, measured value 314.1169.

[0101] (2) Synthesis of compound 15:

[0102] Step o:

[0103]

[0104] Intermediate 2-2 (74 mg, 0.30 mmol, 1.2 eq) and intermediate 1-16 (100 mg, 0.25 mmol, 1 eq) were dissolved in DMF (5 mL). HATU (115 mg, 0.30 mmol, 1.2 eq) and DIPEA (161.6 mg, 1.25 mmol, 5 eq) were added sequentially, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 1-18 (80 mg), yield 51%. HR-MS (ESI): Calculated value C 32 H 25 F3N8O3[M+H] + :627.2035, measured value 627.2059.

[0105] Step p:

[0106]

[0107] Intermediate 1-18 (80 mg, 0.13 mmol) was dissolved in acetic acid (5 mL) and heated at 120 °C for 2 hours. Acetic acid was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, v / v) to give compound 15 (50 mg) in 64% yield. HR-MS (ESI): Calculated value C 32 H 23 F3N8O2[M+H] + :609.1930, measured value 609.1911. 1H NMR(300MHz, DMSO-d6)δ(ppm)9.27(s,1H)7.89(t,J=7.6,8Hz,1H),7.83(t,J=6.4,4.4Hz,1H),7.79(t,J= 7.2,1.2Hz,1H),7.62-7.58(m,2H),7.52-7.48(m,2H),7.41(dd,J=6.4,5.2Hz,1H),7.34(dd,J=6.4,1.6H z,1H),6.95(d,J=8.4Hz,1H),5.50(s,2H),5.08-5.04(m,1H),4.78(dd,J=7.2,8Hz,1H),4.64(dd,J=2,13 .2Hz,1H),4.54-4.49(m,2H),4.47-4.42(m,1H),4.38-4.33(m,1H),2.74-2.67(m,1H),2.45-2.33(m,1H).

[0108] Example 3: Synthesis of Compound 02

[0109]

[0110] The preparation method is the same as in Example 1, except that 4-chloro-2-fluorobenzyl alcohol is used as the raw material, MS(ESI)[M+H] + : 685.1509.

[0111] Example 4: Synthesis of Compound 03

[0112]

[0113] The preparation method is the same as in Example 1, except that 2,4-difluorobenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 669.1804.

[0114] Example 5: Synthesis of Compound 04

[0115]

[0116] The preparation method is the same as in Example 1, except that 4-(hydroxymethyl)benzonitrile is used as the raw material, and MS (ESI) [M+H] is used. + : 658.1945.

[0117] Example 6: Synthesis of Compound 05

[0118]

[0119] The preparation method is the same as in Example 1, except that p-chlorobenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is used.+ : 667.1603.

[0120] Example 7: Synthesis of Compound 06

[0121]

[0122] The preparation method is the same as in Example 1, except that p-fluorobenzyl alcohol is used as the raw material, MS(ESI)[M+H] + : 651.1898.

[0123] Example 8: Synthesis of Compound 07

[0124]

[0125] The preparation method is the same as in Example 1, except that p-trifluoromethylbenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is used. + : 701.1867.

[0126] Example 9: Synthesis of Compound 08

[0127]

[0128] The preparation method is the same as in Example 1, except that 5-fluoro-6-(hydroxymethyl)nicotinonitrile is used as the raw material, and MS(ESI)[M+H] is used. + : 677.1803.

[0129] Example 10: Synthesis of Compound 09

[0130]

[0131] The preparation method is the same as in Example 1, except that (5-chloro-3-fluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 686.1461.

[0132] Example 11: Synthesis of Compound 10

[0133]

[0134] The preparation method is the same as in Example 1, except that (3,5-difluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 670.1757.

[0135] Example 12: Synthesis of Compound 11

[0136]

[0137] The preparation method is the same as in Example 1, except that 6-hydroxymethylpyridine-3-nitrile is used as the raw material, and MS(ESI)[M+H] is used. + : 659.1898.

[0138] Example 13: Synthesis of Compound 12

[0139]

[0140] The preparation method is the same as in Example 1, except that (5-chloro-2-pyridyl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 668.1555.

[0141] Example 14: Synthesis of Compound 13

[0142]

[0143] The preparation method is the same as in Example 1, except that (5-fluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 652.1851.

[0144] Example 15: Synthesis of Compound 14

[0145]

[0146] The preparation method is the same as in Example 1, except that 5-trifluoromethylpyridine-2-methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 702.1819.

[0147] Example 16: Synthesis of Compound 16

[0148]

[0149] The preparation method is the same as in Example 2, except that 4-chloro-2-fluorobenzyl alcohol is used as the raw material, MS(ESI)[M+H] + : 618.1587.

[0150] Example 17: Synthesis of Compound 17

[0151]

[0152] The preparation method is the same as in Example 2, except that 2,4-difluorobenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 602.1883.

[0153] Example 18: Synthesis of Compound 18

[0154]

[0155] The preparation method is the same as in Example 2, except that 4-(hydroxymethyl)benzonitrile is used as the raw material, and MS(ESI)[M+H] is used. + :591.2024.

[0156] Example 19: Synthesis of Compound 19

[0157]

[0158] The preparation method is the same as in Example 2, except that p-chlorobenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is used. + : 600.1682.

[0159] Example 20: Synthesis of Compound 20

[0160]

[0161] The preparation method is the same as in Example 2, except that p-fluorobenzyl alcohol is used as the raw material, MS(ESI)[M+H] + : 584.1977.

[0162] Example 21: Synthesis of Compound 21

[0163]

[0164] The preparation method is the same as in Example 2, except that p-trifluoromethylbenzyl alcohol is used as the raw material, and MS(ESI)[M+H] is used. + : 634.1945.

[0165] Example 22: Synthesis of Compound 22

[0166]

[0167] The preparation method is the same as in Example 2, except that 5-fluoro-6-(hydroxymethyl)nicotinonitrile is used as the raw material, and MS(ESI)[M+H] is used. + : 610.1882.

[0168] Example 23: Synthesis of Compound 23

[0169]

[0170] The preparation method is the same as in Example 2, except that (5-chloro-3-fluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 619.1540.

[0171] Example 24: Synthesis of Compound 24

[0172]

[0173] The preparation method is the same as in Example 2, except that (3,5-difluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 603.1835.

[0174] Example 25: Synthesis of Compound 25

[0175]

[0176] The preparation method is the same as in Example 2, except that 6-hydroxymethylpyridine-3-nitrile is used as the raw material, and MS(ESI)[M+H] is prepared. + : 592.1976.

[0177] Example 26: Synthesis of Compound 26

[0178]

[0179] The preparation method is the same as in Example 2, except that (5-chloro-2-pyridyl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 601.1634.

[0180] Example 27: Synthesis of Compound 27

[0181]

[0182] The preparation method is the same as in Example 2, except that (5-fluoropyridin-2-yl)methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 585.1930.

[0183] Example 28: Synthesis of Compound 28

[0184]

[0185] The preparation method is the same as in Example 2, except that 5-trifluoromethylpyridine-2-methanol is used as the raw material, and MS(ESI)[M+H] is prepared. + : 635.1898.

[0186] Example 29: Measurement of in vitro cAMP signal activation by a compound in human GLP1R cells

[0187] I. Experimental Methods

[0188] 1. Cell Culture

[0189] The CHO cell line stably expressing human GLP-1R (purchased from Beijing Aisiyipu Biotechnology Co., Ltd.) was cultured in F-12 medium (Gibco) containing 10% fetal bovine serum + 200 μg / mL Hygromycin B medium at 37℃ and 5% carbon dioxide concentration.

[0190] 2. cAMP assay

[0191] Stable cell lines expressing human GLP-1R receptor were incubated with different concentrations of test compounds, and the agonistic effect of the compounds on human GLP-1R receptor was determined using the TR-FRET cAMP kit (PerkinElmer, catalog number: TRF0264).

[0192] (1) Prepare 1×Stimulation Buffer according to the kit instructions.

[0193] (2) The positive compound GLP1(7-37) purchased from Aladdin Shanghai was serially diluted to 10 concentrations (initial concentration of 100 nM) with DMSO, and the test compound was serially diluted to 5 concentrations (initial concentration of 10000 nM) and then diluted to 10× with 1× Stimulation Buffer.

[0194] (3) The stable cell line was cultured to 80% confluence, and the cells were collected by trypsin digestion. After counting, 9 μL / well was seeded into a 384-well plate.

[0195] (4) Take 1 μL of the diluted 10× compound from step (2) and add it to the corresponding experimental well. After centrifugation, incubate at 37°C for 30 minutes.

[0196] (5) Dilute the Eu-cAMP in the kit to the working concentration with detection buffer, and add 5 μL / well to the corresponding experimental well.

[0197] (6) Dilute the ULight-anti-cAMP in the kit to the working concentration with detection buffer, and then add 5 μL / well to the corresponding experimental well; centrifuge and incubate at room temperature for 1 hour.

[0198] (7) After incubation, use an enzyme-linked immunosorbent assay (ELISA) reader to detect the readings at 665 nm and 620 nm under excitation at a wavelength of 330 nm.

[0199] 3. Data Processing

[0200] Calculate the ratio of donor to acceptor emission signals per well: HTRF rate = 665nm signal / 620nm signal * 10 4Then, the HTRF rate is converted into a reaction rate (%).

[0201] The following nonlinear fitting formula was used to create concentration-response curves for the compounds in each embodiment, and the half-maximum (50%) effective concentration (EC50) was calculated. 50 We used Graphpad 7.0 software for data analysis.

[0202] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)×HillSlope))

[0203] II. Experimental Results

[0204] The GLP-1 receptor agonistic activity of the compounds of this invention is shown in Table 1:

[0205] Table 1. GLP-1 receptor agonistic activity of some compounds in this invention (EC) 50 Value (nM)

[0206]

[0207]

[0208] Note: A: <1nM, B: 1-100nM, C: >100nM;

[0209] Conclusion: The compounds of this invention exhibit significant agonistic activity against human GLP-1R. Therefore, the compounds of this invention can be used as small molecule GLP-1 receptor agonists.

[0210] Example 30: Pharmacokinetic Study of the Compounds of the Invention in Rat

[0211] I. Experimental Methods

[0212] The compounds of this invention were formulated using a DMSO-PEG400-physiological saline (5:60:35, v / v / v) system. Fasted SD rats (male, 180-250g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were administered the compound by gavage (PO) at a dose of 5 mg / kg body weight. Plasma samples were collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h post-administration. Compound concentrations were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using WinNonlin 8.2 software, employing a non-compartmental model method.

[0213] II. Experimental Results

[0214] The pharmacokinetic results of the compounds of this invention in rats are shown in Table 2:

[0215] Table 2. Pharmacokinetics of some compounds in this invention on rats.

[0216] 01 5 155 932 36.6 15 5 173 806 32.2 Positive control 5 53 215 3.0

[0217] Conclusion: The compound of the present invention is better absorbed orally in rats than the reference compound, and has better exposure and bioavailability.

[0218] Positive control:

[0219]

[0220] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. An arylbenzimidazole compound of formula I or a pharmaceutically acceptable salt thereof: ； in, Selected from: ； Ring B is selected from: ； R2 is selected from: ； R3 is selected from hydrogen or trifluoromethyl; L is selected from -CH2O-; X is selected from C or N.

2. The compound according to claim 1, characterized in that, The pharmaceutically acceptable salts include salts formed by compounds of general formula I with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, tartaric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid, or malonic acid.

3. The compound according to claim 1, characterized in that... Selected from: ； ； ； ； ； 。 4. A pharmaceutical composition, characterized in that, It includes the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1-3 in the preparation of a medicament for the prevention and / or treatment of GLP-1 mediated diseases or related diseases.

6. The application according to claim 5, characterized in that, The GLP-1-mediated diseases or related diseases are diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia.

7. The application according to claim 6, characterized in that, The diabetes mellitus referred to are type 1 diabetes and / or type 2 diabetes mellitus, latent autoimmune diabetes, juvenile atypical diabetes, or gestational diabetes.

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