A drug for lowering blood sugar and its preparation method

Abstract

The present invention relates to a drug for reducing blood sugar and a preparation method thereof. The drug compound of the present invention has very excellent GPR119 agonist activity and can be used as a potential drug for treating diabetes, especially type II diabetes. The preparation method of the present invention is simple, the compound yield is high, the impurities are few, the quality is good, the drug effect is outstanding, and it is suitable for industrial application.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a drug for lowering blood sugar and a preparation method thereof. Background Art

[0002] Diabetes is a metabolic disease and its complications characterized by elevated blood glucose (blood sugar) levels. The main pathological and physiological mechanisms that cause elevated blood sugar are insufficient insulin secretion and defective or missing insulin action sites. Diabetes itself is progressive in nature, and the various complications that may occur with the progressive development of diabetes seriously damage human health and threaten human life. The high blood sugar caused by diabetes can cause damage to body tissues and lead to microvascular and macrovascular diseases, such as retinopathy, nephropathy, neuropathy, stroke, and coronary atherosclerosis, and can also induce oral health, sleep apnea, and inhibit wound healing and infection and gangrene of the lower limbs. Persistent high blood sugar can also aggravate insulin resistance and damage to pancreatic β cells, thereby accelerating cell apoptosis.

[0003] In recent years, with the development of social economy and the improvement of living standards of residents in various countries around the world, the incidence and prevalence of diabetes have increased year by year, becoming a major social problem threatening people's health, and has attracted the attention and attention of governments, health departments and medical workers in various countries. The prevalence of type I diabetes is much lower than that of type II diabetes. In recent years, the prevalence of type II diabetes in various countries around the world has shown a trend of rapid increase, and the surge in type II diabetes patients is the main reason for the sharp increase in the total number of diabetes patients in the world.

[0004] As people deepen their research on the pathogenesis of diabetes, anti-diabetic drugs suitable for different stages of development have been developed. There are relatively few types of traditional anti-diabetic drugs, including sulfonylureas, biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors and insulin, etc. These drugs have good clinical efficacy, but they also cause adverse reactions such as weight gain, hypoglycemia, heart failure, etc. In recent years, the development of new target drugs for diabetes has become a research hotspot.

[0005] GPR119 (G protein-coupled receptor 119) is a special target. It is a member of the Rhodopsin family of G protein-coupled receptors. GPR119 is mainly expressed in pancreatic β cells and PP cells in pancreatic tissue, as well as intestinal L cells and K cells. Scientific experiments have confirmed that stimulating GPR119 can increase the intracellular cyclic adenosine monophosphate concentration, stimulate the stimulation-secretion coupling in the cell, thereby increasing the secretion of glucose-dependent glucagon-like peptide-1 (GLP-1) and insulin, thereby playing a role in lowering blood sugar and treating diabetes. It has become one of the new targets for hypoglycemic drugs for type 2 diabetes, and has great advantages and development prospects in hypoglycemic treatment. Summary of the invention

[0006] The purpose of the present invention is to provide a new GPR119 agonist, which has a hypoglycemic effect and can be used for anti-diabetes, especially type II diabetes.

[0007] To this end, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate thereof:

[0008]

[0009] Among them, R 1 , R 2 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C6-C18 aryl;

[0010] R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C3-15 cycloalkyl, substituted or unsubstituted C6-C18 aryl, substituted or unsubstituted 5-15 membered heteroaryl;

[0011] R 6 , R 7 are each independently selected from hydrogen, deuterium, -OH, substituted or unsubstituted C1-12 alkyl, or R 6 , R 7 Together with the carbon atom to which it is attached,

[0012] R 8 Selected from hydrogen, deuterium, -OH, -NH 2 、-NO 2 , -CN, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C6-C18 aryl.

[0013] The present invention also provides a pharmaceutical composition, which comprises the compound of formula I of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate thereof and a pharmaceutically acceptable excipient.

[0014] The present invention also provides a combination drug, which comprises the compound of formula I of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate, and other drugs helpful for the treatment of hypoglycemia / diabetes.

[0015] The present invention also provides the use of the compound of formula I of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate in the preparation of medicines.

[0016] The present invention also provides a method for preparing the compound of formula I of the present invention.

[0017] Beneficial Effects

[0018] The present invention relates to a drug for reducing blood sugar and a preparation method thereof. The drug compound of the present invention has very excellent GPR119 agonist activity and can be used as a potential drug for treating diabetes, especially type II diabetes. The preparation method of the present invention is simple, the compound yield is high, the impurities are few, the quality is good, the drug effect is outstanding, and it is suitable for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 For compound 1 1 H NMR spectrum;

[0020] Figure 2 For compound 4 1 H NMR spectrum. DETAILED DESCRIPTION

[0021] The following will be clearly and completely described in conjunction with the technical solutions of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0022] The term halogen denotes fluorine, chlorine, bromine or iodine.

[0023] The term alkyl refers to a hydrocarbon group formed by removing a hydrogen atom from an alkane molecule, which may be a straight chain alkyl group or a branched chain alkyl group, preferably having 1 to 15 carbon atoms, more preferably 1 to 12 carbon atoms, and particularly preferably 1 to 6 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0024] The term alkenyl refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond. There may be 1 to 3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, preferably having 2 to 15 carbon atoms, more preferably 2 to 12 carbon atoms, and particularly preferably 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, etc.

[0025] The term cycloalkyl refers to a hydrocarbon group formed by removing a hydrogen atom from a cycloalkane molecule, preferably having 3 to 15 carbon atoms, more preferably 3 to 12 carbon atoms, and particularly preferably 3 to 7 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0026] The term aryl refers to a monovalent group remaining after removing a hydrogen atom from the aromatic carbon nucleus of an aromatic compound molecule, preferably having 6 to 18 carbon atoms, more preferably 6 to 14 carbon atoms, particularly preferably 6 to 12 carbon atoms, and further preferably 6 to 10 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, perylenyl, and the like.

[0027] The term heteroaryl refers to a general term for groups in which 1, 2, 3 or 4 aromatic carbon atoms in an aromatic group are replaced by heteroatoms, including but not limited to oxygen, sulfur, nitrogen or phosphorus atoms. The heteroaryl group preferably has 5-15 ring atoms, more preferably 5-10 ring atoms, and particularly preferably 5-7 ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, triazine, pyridazine, indolyl, quinolyl, isoquinolyl, benzimidazolyl, etc.

[0028] The "substituted..." refers to being monosubstituted or polysubstituted by groups independently selected from but not limited to deuterium, -OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted amino, etc., preferably being monosubstituted or polysubstituted by groups selected from deuterium, -OH, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl, methoxy, ethoxy, phenyl, naphthyl, amino, dimethylamino, and diethylamino.

[0029] In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate thereof:

[0030]

[0031] Among them, R 1 , R 2Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C6-C18 aryl;

[0032] R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C3-15 cycloalkyl, substituted or unsubstituted C6-C18 aryl, substituted or unsubstituted 5-15 membered heteroaryl;

[0033] R 6 , R 7 are each independently selected from hydrogen, deuterium, -OH, substituted or unsubstituted C1-12 alkyl, or R 6 , R 7 Together with the carbon atom to which it is attached,

[0034] R 8 Selected from hydrogen, deuterium, -OH, -NH 2 、-NO 2 , -CN, substituted or unsubstituted C1-15 alkyl, substituted or unsubstituted C6-C18 aryl.

[0035] In one embodiment, the "substituted..." refers to being mono- or poly-substituted by groups independently selected from deuterium, -OH, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl, methoxy, ethoxy, phenyl, naphthyl, amino, dimethylamino, diethylamino.

[0036] In one embodiment, the compound of formula I is selected from the following compounds of formula II or formula III:

[0037]

[0038] In one embodiment, R 1 , R 2 Each is independently selected from hydrogen, deuterium, C1-6 alkyl, and substituted or unsubstituted C6-C14 aryl.

[0039] Preferably, R 1 , R 2 Each is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl, pentyl, hexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted phenanthrenyl.

[0040] In one embodiment, R 3 , R 4 , R5 Each is independently selected from hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, substituted or unsubstituted C6-C14 aryl, and substituted or unsubstituted 5-7 membered heteroaryl.

[0041] Preferably, R 3 , R 4 , R 5 and each is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl, pentyl, hexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted phenanthrenyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridinyl, and substituted or unsubstituted pyrimidinyl.

[0042] Preferably, R 3 , R 5 Each is independently selected from hydrogen and deuterium.

[0043] Preferably, R 4 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl.

[0044] In one embodiment, R 6 , R 7 are each independently selected from hydrogen, deuterium, -OH, or R 6 , R 7 Together with the carbon atom to which it is attached,

[0045] Preferably, R 6 , R 7 Each is independently selected from hydrogen and deuterium.

[0046] Preferably, R 6 , R 7 One of them is selected from hydrogen and deuterium, and the other is selected from -OH.

[0047] Preferably, R 6 , R 7 Together with the carbon atom to which it is attached,

[0048] In a particular embodiment, the compound of formula I is selected from the following compounds of formula III-1 to III-3:

[0049]

[0050] In a particular embodiment, the compound of formula I is selected from the following compounds of formula II-1 to II-3:

[0051]

[0052] In one embodiment, R 8 Selected from hydrogen, deuterium, -OH, -NH 2 、-NO 2 , -CN, substituted or unsubstituted C1-6 alkyl.

[0053] Preferably, R 8 Selected from hydrogen, deuterium, -NH 2 、-NO 2 , methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, n-butyl.

[0054] In a specific embodiment, the compound of formula I is selected from:

[0055]

[0056]

[0057] Some specific chemical structures of the compounds of formula I of the present invention are listed above, but the present invention is not limited to these listed chemical structures, and all compounds based on formula I and having substituents as defined above should be included.

[0058] The compounds of the present invention include pharmaceutically acceptable salts thereof. Typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with acids, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, octanoate, formate, acrylate, isobutyrate, hexanoate, oxalate, malonate, succinate, suberate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, citric acid, maleic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, naphthalene-1-sulfonate, mandelate, pyruvate, stearate, ascorbate, and salicylate. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salt may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as salts formed with ammonia, alkylamines, hydroxyalkylamines, amino acids, N-methylglucamine, etc.

[0059] The "prodrug" of the present invention refers to a compound that is converted into the original active compound after metabolism in the body. Typically, the prodrug is an inactive substance, or is less active than the active parent compound, but can provide convenient handling, administration or improved metabolic characteristics.

[0060] The compounds of the present invention may contain one or more asymmetric centers and may therefore exist as racemates and racemic mixtures, single enantiomers, mixtures of diastereomers and individual diastereomers. Other asymmetric centers may exist, depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, which means that all possible optical isomers and diastereomers in the form of mixtures and purified or partially purified compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separations can be accomplished by appropriately modifying the methods disclosed herein according to methods known in the art. If necessary, the racemic mixture of the compound can be separated in order to separate a single enantiomer. Separation can be performed by methods known in the art, such as coupling the racemic mixture of the compound with an enantiomer-pure compound to form a mixture of diastereomers, followed by standard methods such as fractional crystallization or chromatographic separation of a single diastereomer.

[0061] The compounds may exist in crystalline form, which are also included within the scope of the present invention.

[0062] The compounds of the present invention may form solvates with common organic solvents, or form hydrates with water, and such solvates or hydrates are also included in the scope of the present invention.

[0063] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate thereof and a pharmaceutically acceptable excipient.

[0064] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0065] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one excipient, the excipient including: (a) fillers or bulking agents, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (d) wetting agents, for example, cetyl alcohol and glyceryl monostearate; and (f) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

[0066] Besides these inert diluents, the preparations may also include other adjuvants, such as emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0067] Preparations for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0068] The exact dosage and dosage regimen of the compounds of the present invention and compositions thereof will depend on the biological activity of the compound itself, the age, weight and sex of the patient, the needs of the individual receiving the drug administration, the degree of pain or need, and the judgment of the practitioner. Usually, parenteral administration requires a lower dosage than other methods of administration that are more dependent on absorption. However, for people, the dosage is preferably 0.001-10 mg / kg body weight. Usually, the dosage of enteral and parenteral administration will be within the range of 0.1 to 1000 mg of total active ingredients per day.

[0069] The compounds of the present invention may be used alone or in combination with other therapeutic agents. Combination therapy may provide a synergistic effect, that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the compounds when used separately.

[0070] Therefore, the present invention provides a combination drug comprising the compound of formula I of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate, and other drugs helpful for the treatment of hypoglycemia / diabetes.

[0071] In yet another aspect, the present invention provides the use of a compound of formula I of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate thereof in the preparation of a medicament for lowering blood sugar in a patient in need thereof.

[0072] Preferably, the patients in need include type I diabetes patients and type II diabetes patients.

[0073] Preferably, the present invention provides the use of the compound of formula I of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, crystal, solvate or hydrate in the preparation of a medicament for treating diabetes, including type I diabetes and type II diabetes.

[0074] In the last aspect, the present invention also provides a method for preparing the compound of formula I of the present invention, which comprises the following steps:

[0075]

[0076] Step 1: The compound of formula A reacts with the compound of formula B to form an intermediate compound of formula C;

[0077] Step 2: The intermediate compound of formula C reacts with the compound of formula D to form the intermediate compound of formula E;

[0078] Step 3: The intermediate compound of formula E reacts with the compound of formula F to produce the compound of formula I;

[0079] Among them, X 1 , X 2 each independently represents a halogen, preferably chlorine or bromine;

[0080] R 1 -R 8 is defined as described herein.

[0081] Preferably, step 1 is carried out under the action of a strong base; preferably, the strong base is selected from NaH.

[0082] Preferably, step 2 is carried out under the action of an acid or base catalyst; the acid or base catalyst may be a conventional catalyst used in the art for acid and alcohol esterification reactions. Preferably, the catalyst may be at least one of p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid.

[0083] Preferably, step 3 is carried out under the action of a base, a palladium catalyst and a ligand; the base is preferably sodium tert-butoxide or potassium tert-butoxide; the palladium catalyst is preferably palladium acetate; the ligand is preferably a phosphorus ligand, more preferably tri-tert-butylphosphine and its salts.

[0084] Example 1: Preparation of Compound 1

[0085]

[0086] Preparation of intermediate C-1: Compound A-1 (12.96 g, 50 mmol) was dissolved in DMF (100 ml), and NaH (1.44 g, 60 mmol, 70%) was added in batches after cooling to 0°C. The mixture was stirred at 45°C for 2 h. Then, the solution was cooled to 0-5°C, and a solution of compound B-1 (5.34 g, 55 mmol) in DMF (20 ml) was added dropwise while maintaining this temperature. After the addition was completed, the mixture was naturally warmed to room temperature and stirred overnight. The reaction solution was poured into water, stirred, refrigerated, the solid precipitated and filtered out, recrystallized with 80% ethanol, and dried to obtain intermediate C-1 (10.81 g, yield 78.6%). ESI-MS: 276.1 [M+H] + .

[0087] Preparation of intermediate E-1: Add intermediate C-1 (5.50 g, 20 mmol), compound D (3.87 g, 30 mmol), p-toluenesulfonic acid (6.89 g, 40 mmol), and toluene (300 ml) to a reactor equipped with a reflux condenser and a Dean-Stark water separator, and reflux for 18 h under stirring, while separating the water produced by the reaction. After the reaction, the reaction solution was naturally cooled to room temperature, neutralized by adding a saturated sodium carbonate aqueous solution, the organic phase was separated and washed with water several times, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and then recrystallized with ethanol / cyclohexane (volume ratio 5:1), and dried to obtain intermediate E-1 (6.93 g, yield 89.6%). ESI-MS: 387.3 [M+H] + .

[0088] Preparation of compound 1: Under nitrogen protection, intermediate E-1 (3.87g, 10mmol), sodium tert-butoxide (2.4g, 25mmol), palladium acetate (0.22g, 1mmol), tri-tert-butylphosphine tetrafluoroborate (0.58g, 2mmol), toluene (100ml) were added to the reactor, heated to 60°C, and a solution of compound F-1 (2.18g, 12mmol) in toluene (20ml) was added dropwise under stirring, and continued to heat to reflux and react for 6h. After the reaction, the reaction solution was naturally cooled to room temperature, filtered with diatomaceous earth, and the solvent was evaporated under reduced pressure, and purified with a silica gel column (ethyl acetate / petroleum ether = 1:18) to obtain compound 1 (4.25g, yield 80.1%), HPLC purity ≧99.3%.

[0089] ESI-MS: 532.2[M+H] + .

[0090] Element analysis: Theoretical element content (%) C 33 H 29 N 3 O 4: C, 74.56; H, 5.50; N, 7.90; Measured element content (%): C, 74.59; H, 5.56; N, 7.93.

[0091] 1 H NMR (400 MHz, DMSO-d 6 ): δ11.22(s,1H),7.85(d,J=9.0Hz,2H),7.69(d,J=7.7Hz,1H),7.54(d,J=9.0Hz ,2H),7.49-7.40(m,5H),7.27(s,1H),7.18(d,J=9.8Hz,1H),6.99(d,J=6.9Hz,1 H),6.06(d,J=6.9Hz,1H),5.79(t,J=4.2Hz,1H),5.12(s,2H),4.34(d,J=4.2Hz, 2H), 3.84 (m, 2H), 3.50 (m, 2H), 2.72 (p, J = 6.1Hz, 1H), 2.00 (m, 2H), 1.87 (m, 2H).

[0092] Example 2: Preparation of Compound 2

[0093]

[0094] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-2, intermediate C-1 was replaced by an equal molar amount of C-2, and E-1 was replaced by an equal molar amount of E-2 to obtain compound 2 (4.89 g) with HPLC purity ≧99.2%.

[0095] ESI-MS: 588.4[M+H] + .

[0096] Element analysis: Theoretical element content (%) C 37 H 37 N 3 O 4 : C, 75.62; H, 6.35; N, 7.15; Measured element content (%): C, 75.67; H, 6.30; N, 7.13.

[0097] Example 3: Preparation of Compound 3

[0098]

[0099] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-3, intermediate C-1 was replaced by an equal molar amount of C-3, E-1 was replaced by an equal molar amount of E-3, and compound F-1 was replaced by an equal molar amount of F-3 to obtain compound 3 (4.77 g) with HPLC purity ≧99.0%.

[0100] ESI-MS: 591.3[M+H] + .

[0101] Element analysis: Theoretical element content (%) C 34 H 30 N 4 O 6 : C, 69.14; H, 5.12; N, 9.49; Measured element content (%): C, 69.17; H, 5.10; N, 9.51.

[0102] Example 4: Preparation of Compound 4

[0103]

[0104] According to the same preparation method as Example 1, compound F-1 was replaced by an equal molar amount of F-4 to obtain compound 4 (4.27 g) with HPLC purity ≧99.0%.

[0105] ESI-MS: 518.3[M+H] + .

[0106] Element analysis: Theoretical element content (%) C 33 H 31 N 3 O 3 : C, 76.57; H, 6.04; N, 8.12; Measured element content (%): C, 76.64; H, 6.08; N, 8.10.

[0107] 1 H NMR (400 MHz, DMSO-d 6): δ8.21(t,J=4.1Hz,1H),7.86(d,J=9.0Hz,2H),7.67(d,J=8.0Hz,1H),7.55(d,J =9.0Hz,2H),7.47(m,4H),7.28(s,1H),7.02(m,2H),6.92(s,1H),6.07(d,J=6.9H z,1H),5.80(t,J=4.2Hz,1H),5.13(s,2H),4.36(d,J=4.2Hz,2H),4.22(d,J=4.1H z,2H),3.85(m,2H),3.51(m,2H),2.73(p,J=6.1Hz,1H),2.01(m,2H),1.88(m,2H).

[0108] Example 5: Preparation of Compound 5

[0109]

[0110] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-5, intermediate C-1 was replaced by an equal molar amount of C-5, E-1 was replaced by an equal molar amount of E-5, and compound F-1 was replaced by an equal molar amount of F-4 to obtain compound 6 (4.36 g) with HPLC purity ≧99.1%.

[0111] ESI-MS: 594.4[M+H] + .

[0112] Element analysis: Theoretical element content (%) C 39 H 35 N 3 O 3 : C, 78.90; H, 5.94; N, 7.08; Measured element content (%): C, 78.95; H, 5.91; N, 7.04.

[0113] Example 6: Preparation of Compound 6

[0114]

[0115] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-6, intermediate C-1 was replaced by an equal molar amount of C-6, E-1 was replaced by an equal molar amount of E-6, and compound F-1 was replaced by an equal molar amount of F-4 to obtain compound 6 (4.42 g) with HPLC purity ≧99.4%.

[0116] ESI-MS: 546.3[M+H] + .

[0117] Element analysis: Theoretical element content (%) C35 H 35 N 3 O 3 : C, 77.04; H, 6.47; N, 7.70; Measured element content (%): C, 77.01; H, 6.43; N, 7.73.

[0118] Example 7: Preparation of Compound 7

[0119]

[0120] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-6, intermediate C-1 was replaced by an equal molar amount of C-6, E-1 was replaced by an equal molar amount of E-6, and compound F-1 was replaced by an equal molar amount of F-7 to obtain compound 7 (4.54 g) with HPLC purity ≧99.1%.

[0121] ESI-MS: 546.3[M+H] + .

[0122] Element analysis: Theoretical element content (%) C 35 H 35 N 3 O 3 : C, 77.04; H, 6.47; N, 7.70; Measured element content (%): C, 77.07; H, 6.45; N, 7.71.

[0123] Example 8: Preparation of Compound 8

[0124]

[0125] According to the same preparation method as Example 1, compound F-1 was replaced by an equal molar amount of F-8 to obtain compound 8 (4.06 g) with HPLC purity ≧99.5%.

[0126] ESI-MS: 534.4[M+H] + .

[0127] Element analysis: Theoretical element content (%) C 33 H 31 N 3 O 4 : C, 74.28; H, 5.86; N, 7.87; Measured element content (%): C, 74.33; H, 5.84; N, 7.84.

[0128] Example 9: Preparation of Compound 9

[0129]

[0130] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-3, intermediate C-1 was replaced by an equal molar amount of C-3, E-1 was replaced by an equal molar amount of E-3, and compound F-1 was replaced by an equal molar amount of F-8 to obtain compound 9 (4.19 g) with HPLC purity ≧99.2%.

[0131] ESI-MS: 548.4[M+H] + .

[0132] Element analysis: Theoretical element content (%) C 34 H 33 N 3 O 4 : C, 74.57; H, 6.07; N, 7.67; Measured element content (%): C, 74.52; H, 6.11; N, 7.62.

[0133] Example 10: Preparation of Compound 10

[0134]

[0135] According to the same preparation method as Example 1, compound A-1 was replaced by an equal molar amount of A-2, B-1 was replaced by an equal molar amount of B-10, intermediate C-1 was replaced by an equal molar amount of C-10, E-1 was replaced by an equal molar amount of E-10, and compound F-1 was replaced by an equal molar amount of F-8 to obtain compound 10 (4.55 g) with HPLC purity ≧99.3%.

[0136] ESI-MS: 604.5[M+H] + .

[0137] Element analysis: Theoretical element content (%) C 38 H 41 N 3 O 4 : C, 75.60; H, 6.85; N, 6.96; Measured element content (%): C, 75.65; H, 6.84; N, 6.93.

[0138] Example 11 Test of the agonist activity of the compounds of the present invention on GPR119 receptor

[0139] The cAMP (cyclic adenosine monophosphate) experimental method was used. Main reagents: human GPR119 gene fragment, HTRF CAMP kit, cell lysis buffer were purchased from Invitrogen Life Sciences, Inc.; CHO-K1 cells (hamster ovary cells) were purchased from Wuhan Pronocell Life Sciences, Inc.

[0140] The DNA fragment containing human GPR119 gene was transfected into CHO-K1 cells, and the cells were cultured in DMEM / F12 (1:1) medium, 10% FBS and G418 culture medium to obtain a cell line stably expressing GPR119. The above cells were inoculated on a 96-well plate and placed at 37°C and 5% CO 2 The cells were cultured for 48 hours under the same conditions, the culture medium was removed, 100L buffer (HBSS, 0.1% BSA, 0.5mM IBMX and 0.5mM HEPES) was added, and the cells were incubated at room temperature for 15 minutes. The test compound was given at different concentrations, and the cells were incubated again for 0.5 hours. The buffer was removed, 75L pre-cooled lysis solution was added, and the cells were incubated on ice for 20 minutes to fully lyse the cells. The cells were transferred to a 1.5mL centrifuge tube and centrifuged at 14000rpm for 10 minutes. 50L of the supernatant was taken and the intracellular cAMP concentration was determined using the standard procedure of the HTRF CAMP kit. The compound EC was obtained from the dose-dependent change in cAMP concentration. 50 Value; oleoylethanolamine (OEA) was used as a positive control. The results are recorded in the following Table 1:

[0141] Table 1 GPR119 agonist activity of the compounds of the present invention

[0142]

[0143] The above results show that the compounds of the present invention have very excellent GPR119 agonist activity, which is significantly better than the positive control OEA.

[0144] The above describes the preferred embodiments of the present invention, but it is not intended to limit the present invention. Those skilled in the art may make improvements and changes to the embodiments disclosed herein without departing from the scope and spirit of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, The compound of formula I is selected from the following compounds of formula II or formula III: R1 is selected from hydrogen, deuterium, C1-6 alkyl; R2 is selected from hydrogen, deuterium, C1-6 alkyl, phenyl; R3 and R5 are each independently selected from hydrogen and deuterium; R4 is selected from hydrogen, deuterium, C1-6 alkyl; R6 and R7 are each independently selected from hydrogen and deuterium, or one of R6 and R7 is selected from hydrogen and deuterium and the other is selected from -OH, or R6 and R7 together with the carbon atom to which they are attached form R8 is selected from hydrogen, deuterium, -NO2.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 and R2 are each independently selected from hydrogen, deuterium, and C1-6 alkyl; the R3, R4, and R5 are each independently selected from hydrogen and deuterium.

3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R8 is selected from hydrogen and deuterium.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula I is selected from:

5. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

6. Use of a compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for lowering blood sugar in a patient in need thereof.

7. Use of the compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diabetes, including type I diabetes and type II diabetes.

8. A method for preparing the compound of formula I as claimed in claim 1, comprising the following steps: Step 1: The compound of formula A reacts with the compound of formula B to form an intermediate compound of formula C; Step 2: The intermediate compound of formula C reacts with the compound of formula D to form the intermediate compound of formula E; Step 3: The intermediate compound of formula E reacts with the compound of formula F to produce the compound of formula I; Wherein, X1 and X2 each independently represent a halogen; R1-R8 are as defined in claim 1.

9. The preparation method according to claim 8, characterized in that: X1 and X2 each independently represent chlorine or bromine.

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