Glp-1r agonist pharmaceutical composition and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

A GLP-1R agonist pharmaceutical composition and its application Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations and relates to a GLP-1R agonist pharmaceutical composition and its application. Background Art

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its effects by binding to its ubiquitous specific receptors. GLP-1 receptors are known to be present in pancreatic islet cells, the gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and the cardiovascular system. GLP-1 receptors may also be found in the liver, adipose tissue, and skeletal muscle. GLP-1 not only acts on β-cells to promote insulin secretion but also acts on α-cells to inhibit glucagon secretion. Serum GLP-1 levels generally do not differ significantly between patients with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. However, the β-cell response to GLP-1 after a meal is impaired, and under certain conditions, this response is significantly enhanced by continuous GLP-1 infusion. Because the body's own GLP-1 has a very short duration of action (t½ <1.5 minutes after intravenous administration), it is not suitable for the clinical treatment of diabetes.

[0003] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the potential to lower fasting and postprandial glucose levels and improve glycemic control in patients with type 2 diabetes. However, peptide GLP-1s have poor oral bioavailability and poor patient compliance with parenteral administration. Therefore, the development of small molecule GLP-1 receptor agonists with improved oral bioavailability is highly desired.

[0004] Published patent applications for GLP-1 receptor small molecule agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1, etc. Summary of the Invention

[0005] The present disclosure provides a pharmaceutical composition comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0006] in,

[0007] Ring A is selected from phenyl or 5- or 6-membered heteroaryl;

[0008] R 1 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0009] R 2 is selected from 3 to 6 membered heterocycloalkyl or 5 or 6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0010] Ring B is selected from 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;

[0011] R 3 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group,

[0012] Or any two R 3 Forming C with adjacent atoms 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0013] L 1 Selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 1a R 1b )-、-OC(R 1a R 1b )-、-C(R 1a R 1b )O-、-C(O)N(R 1c)-、-N(R 1c )(O)C-、-S(O)2N(R 1d )-、-N(R 1e )-or key,

[0014] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 substituted with alkoxy;

[0015] Ring C is selected from C 6-10 aryl or 5- or 10-membered heteroaryl;

[0016] R 4 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0017] L 2 Selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 2a R 2b )-、-OC(R 2a R 2b )-、-C(R 2a R 2b )O-、-C(O)N(R 2c )-、-N(R 2c )(O)C-、-S(O)2N(R 2d )-、-N(R 2e )-or key;

[0018] R 2a 、R 2b 、R 2c 、R 2d 、R2e Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 substituted with alkoxy;

[0019] Ring D is selected from C 6-10 aryl or 5- or 10-membered heteroaryl;

[0020] R 5 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0021] n is selected from 0, 1, 2, 3 or 4;

[0022] m is selected from 0, 1, 2, 3 or 4;

[0023] o is selected from 0, 1, 2, 3 or 4;

[0024] p is selected from 0, 1, 2, 3 or 4.

[0025] In some embodiments, the pharmaceutical composition further comprises an antacid compound. An antacid compound refers to any pharmaceutically acceptable compound that can neutralize an acid. In some embodiments, the antacid compound is a water-soluble antacid compound, including but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0026] In other embodiments, the antacid compound in the pharmaceutical composition is sodium carbonate.

[0027] On the other hand, the pharmaceutical composition disclosed herein further contains a pharmaceutically acceptable excipient, which is well known or identifiable to those skilled in the art and is selected from but not limited to at least one of a disintegrant, a filler, a binder, and a lubricant.

[0028] Fillers provide bulk, making the tablet a practical size for processing, and may also aid processing and improve the physical properties of the solid dosage form, such as flowability, compressibility, and hardness of the solid dosage form. The fillers described in this disclosure are known or identifiable by those skilled in the art and are selected from, but not limited to, at least one of lactose, sucrose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, and microcrystalline cellulose. In some embodiments, the amount of the filler accounts for 20-95% by weight of the pharmaceutical composition, and may be 20%, 22%, 25%, 28%, 30%, 32%, 35%, 38%, 40%, 42%, 45%, 47%, 50%, 52%, 55%, 58%, 60%, 62%, 65%, 68%, 70%, 72%, 75%, 78%, 80%, 82%, 85%, 88%, 90%, 92%, or 95%. In some embodiments, the amount of the filler is 20-80% by weight of the pharmaceutical composition. In some embodiments, the amount of the filler is 60-80% by weight of the pharmaceutical composition. In some embodiments, the amount of the filler is 50-70% by weight of the pharmaceutical composition.

[0029] The disintegrants disclosed herein are known or identifiable to those skilled in the art, and are selected from, but not limited to, at least one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and alginic acid. In some embodiments, the amount of the disintegrant is 1 to 20% by weight of the pharmaceutical composition, and may be 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%. In some embodiments, the amount of the disintegrant is preferably 5 to 15% by weight of the pharmaceutical composition. In some embodiments, the amount of the disintegrant is preferably 5 to 10% by weight of the pharmaceutical composition. In some embodiments, the amount of the disintegrant is preferably 1 to 5% by weight of the pharmaceutical composition.

[0030] The binder disclosed herein is known or identifiable by those skilled in the art, and is selected from, but not limited to, at least one of copovidone, povidone, starch, methylcellulose, carboxylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropyl cellulose. In some embodiments, the amount of the binder is 0.5-10% by weight of the pharmaceutical composition, and may be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, the amount of the binder is 0.5-5% by weight of the pharmaceutical composition, and in some embodiments, the amount of the binder is 1-5% by weight of the pharmaceutical composition. In some embodiments, the amount of the binder is 1-4% by weight of the pharmaceutical composition.

[0031] The lubricant disclosed herein is known or identifiable to those skilled in the art and is selected from, but not limited to, at least one of magnesium stearate, stearic acid, palmitic acid, talc, and sodium stearyl fumarate. In some embodiments, the amount of the lubricant is 0.1-5% by weight of the pharmaceutical composition, and may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%. In some embodiments, the amount of the lubricant is 0.1-2% by weight of the pharmaceutical composition. On the other hand, in the compound of Formula I or its pharmaceutically acceptable salt disclosed herein, ring D is selected from phenyl.

[0032] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a 3- to 6-membered heterocycloalkyl group, including a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a 6-membered heterocycloalkyl group, for example:

[0033] In other embodiments, R 2 is selected from 4- to 5-membered heterocycloalkyl or 5-membered heteroaryl, for example

[0034] In other embodiments, R 2 Selected from

[0035] In other embodiments, R 2 Selected from

[0036] In other embodiments, R 2 Selected from

[0037] Some embodiments provide that the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1 or a pharmaceutically acceptable salt thereof,

[0038] Among them, M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond; Ring A, Ring C, R 1 、R 2 、R 3 、R 4 、R 5 、L 1 、L 2 , n, m, o, and p are defined in the compound represented by Formula I.

[0039] Furthermore, in some embodiments, the ring A in the compound represented by Formula I or Formula II-1 or a pharmaceutically acceptable salt thereof is selected from phenyl or 5-membered heteroaryl, for example

[0040] In other embodiments, R 1 are the same or different and are each independently selected from halogen (eg, -F or -Br), hydroxyl or cyano.

[0041] In other embodiments, R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino or C 1-6 Alkyl substituted.

[0042] In certain embodiments, R 3 are the same or different and are each independently selected from halogen (eg, -F or -Br), hydroxyl or cyano.

[0043] In certain embodiments, R 3 are the same or different and are each independently selected from halogen, C1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino or C 1-6 Alkyl substituted.

[0044] In other embodiments, any two R 3 Forming C with adjacent atoms 3-4 Cycloalkyl (e.g., cyclopropyl) or 3 to 5 membered heterocycloalkyl (e.g., tetrahydrofuranyl), wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, nitro, amino or C 1-6 Alkyl substituted.

[0045] Furthermore, some embodiments provide compounds of Formula I or Formula II-1 or pharmaceutically acceptable salts thereof wherein Ring C is selected from

[0046] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1a or a pharmaceutically acceptable salt thereof

[0047] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0048] In some embodiments, the compound represented by formula II-1a or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0049] Some embodiments provide a compound of formula II-1a or a pharmaceutically acceptable salt thereof as a compound of formula II-1a-a or a pharmaceutically acceptable salt thereof

[0050] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1a; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0051] In some embodiments, L in the compound represented by Formula I, Formula II-1a, or Formula II-1a-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0052] In some embodiments, L in the compound represented by Formula I, Formula II-1a, or Formula II-1a-a, or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0053] In some embodiments, L in the compound represented by Formula I, Formula II-1a, or Formula II-1a-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0054] In some embodiments, R in the compound represented by Formula I or Formula II-1a or Formula II-1a-a or a pharmaceutically acceptable salt thereof 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0055] In some embodiments, R in the compound represented by Formula I or Formula II-1a or Formula II-1a-a or a pharmaceutically acceptable salt thereof 2a 、R 2b Selected from hydrogen.

[0056] In some embodiments, L in the compound represented by Formula I, Formula II-1a, or Formula II-1a-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2Selected from -OCH2- or -CH2O-.

[0057] In some embodiments, L in the compound represented by Formula I, Formula II-1a, or Formula II-1a-a, or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0058] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1b or a pharmaceutically acceptable salt thereof

[0059] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 、L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0060] In some embodiments, the compound represented by formula II-1b or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0061] Some embodiments provide that the compound represented by formula II-1b or a pharmaceutically acceptable salt thereof is a compound represented by formula II-1b-a or a pharmaceutically acceptable salt thereof

[0062] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 、L 2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1b; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0063] In some embodiments, L in the compound represented by Formula II-1b or Formula II-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0064] In some embodiments, L in the compound represented by Formula II-1b or Formula II-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0065] In some embodiments, L in the compound represented by Formula II-1b or Formula II-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0066] In some embodiments, R 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0067] In some embodiments, R 2a 、R 2b Selected from hydrogen.

[0068] In some embodiments, L in the compound represented by Formula II-1b or Formula II-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0069] In some embodiments, L in the compound represented by Formula II-1b or Formula II-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0070] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1c or a pharmaceutically acceptable salt thereof

[0071] Among them, ring A, R 1 、R 2 、R3 、R 4 、R 5 、L 1 、L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0072] In some embodiments, the compound represented by formula II-1c or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0073] Some embodiments provide that the compound represented by formula II-1c or a pharmaceutically acceptable salt thereof is a compound represented by formula II-1c-a or a pharmaceutically acceptable salt thereof

[0074] where R 1 、R 2 、R 3 、R 4 、R 5 、L 1 , L 2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1c; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0075] In some embodiments, L in the compound represented by Formula II-1c or Formula II-1c-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0076] In some embodiments, L in the compound represented by Formula II-1c or Formula II-1c-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0077] In some embodiments, L in the compound represented by Formula II-1c or Formula II-1c-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0078] In some embodiments, R 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0079] In some embodiments, R 2a 、R 2b Selected from hydrogen.

[0080] In some embodiments, L in the compound represented by Formula II-1c or Formula II-1c-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0081] In some embodiments, L in the compound represented by Formula II-1c or Formula II-1c-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0082] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1d or a pharmaceutically acceptable salt thereof

[0083] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 、L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0084] In some embodiments, the compound represented by formula II-1d or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0085] Some embodiments provide that the compound represented by formula II-1d or a pharmaceutically acceptable salt thereof is a compound represented by formula II-1d-a or a pharmaceutically acceptable salt thereof

[0086] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1d; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0087] In some embodiments, L in the compound represented by Formula II-1d or Formula II-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0088] In some embodiments, L in the compound represented by Formula II-1d or Formula II-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0089] In some embodiments, L in the compound represented by Formula II-1d or Formula II-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0090] In some embodiments, R 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0091] In some embodiments, R 2a 、R 2b Selected from hydrogen.

[0092] In some embodiments, L in the compound represented by Formula II-1d or Formula II-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0093] In some embodiments, L in the compound represented by Formula II-1d or Formula II-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0094] On the other hand, in the compound of formula I or a pharmaceutically acceptable salt thereof, ring D is selected from a 5- or 10-membered heteroaryl group, for example

[0095] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein ring D is selected from

[0096] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein ring D is selected from

[0097] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula II-1e or a pharmaceutically acceptable salt thereof

[0098] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0099] In some embodiments, the compound represented by formula II-1e or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0100] Some embodiments provide that the compound represented by formula II-1e or a pharmaceutically acceptable salt thereof is a compound represented by formula II-1e-a or a pharmaceutically acceptable salt thereof

[0101] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 、L 2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1e; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0102] In some embodiments, L in the compound represented by Formula I, Formula II-1e, or Formula II-1e-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0103] In some embodiments, L in the compound represented by Formula I, Formula II-1e, or Formula II-1e-a, or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0104] In some embodiments, L in the compound represented by Formula I, Formula II-1e, or Formula II-1e-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0105] In some embodiments, R 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0106] In some embodiments, R 2a 、R2b Selected from hydrogen.

[0107] In some embodiments, L in the compound represented by Formula I, Formula II-1e, or Formula II-1e-a, or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0108] In some embodiments, L in the compound represented by Formula I, Formula II-1e, or Formula II-1e-a, or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0109] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula II-1f or a pharmaceutically acceptable salt thereof

[0110] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0111] In some embodiments, the compound represented by formula II-1f or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0112] Some embodiments provide that the compound represented by formula II-1f or a pharmaceutically acceptable salt thereof is a compound represented by formula II-1f-a or a pharmaceutically acceptable salt thereof

[0113] where R 1 、R 2 、R 3 、R 4 、R 5 、L 1 , L 2 、n、m、o、p、M 1 As defined in the compound represented by formula II-1f; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0114] In some embodiments, L in the compound represented by Formula II-1f or Formula II-1f-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0115] In some embodiments, L in the compound represented by Formula II-1f or Formula II-1f-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0116] In some embodiments, L in the compound represented by Formula II-1f or Formula II-1f-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OC(R 2a R 2b )-or-C(R 2a R 2b )O-,R 2a 、R 2b As defined above.

[0117] In some embodiments, R 2a 、R 2b are independently selected from hydrogen, halogen, hydroxyl or C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and amino.

[0118] In some embodiments, R 2a 、R 2b Selected from hydrogen.

[0119] In some embodiments, L in the compound represented by Formula II-1f or Formula II-1f-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0120] In some embodiments, L in the compound represented by Formula II-1f or Formula II-1f-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0121] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula III-1b or a pharmaceutically acceptable salt thereof

[0122] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0123] In some embodiments, the compound represented by formula III-1b or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0124] In some embodiments, the compound represented by formula III-1b or a pharmaceutically acceptable salt thereof, Ring A is selected from

[0125] In some embodiments, the compound represented by formula III-1b or a pharmaceutically acceptable salt thereof is a compound represented by formula III-1b-a or a pharmaceutically acceptable salt thereof

[0126] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 、n、m、o、p、M 1 As defined in the compound represented by formula III-1b; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0127] In some embodiments, L in the compound represented by formula III-1b or formula III-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0128] In some embodiments, L in the compound represented by formula III-1b or formula III-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2Selected from -OCH2- or -CH2O-.

[0129] In some embodiments, L in the compound represented by formula III-1b or formula III-1b-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0130] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula III-1d or a pharmaceutically acceptable salt thereof

[0131] Among them, ring A, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 , n, m, o, p are as defined in the compound represented by formula I; M 1 is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0132] In some embodiments, the compound represented by formula III-1d or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl or 5-membered heteroaryl, for example

[0133] In some embodiments, the compound represented by formula III-1d or a pharmaceutically acceptable salt thereof, Ring A is selected from

[0134] In some embodiments, the compound represented by formula III-1d or a pharmaceutically acceptable salt thereof is a compound represented by formula III-1d-a or a pharmaceutically acceptable salt thereof

[0135] where R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 、n、m、o、p、M 1 As defined in the compound represented by formula III-1b; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, It is a single bond or a double bond.

[0136] In some embodiments, L in the compound represented by formula III-1d or formula III-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Select from keys.

[0137] In some embodiments, L in the compound represented by formula III-1d or formula III-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from -O-, L 2 Selected from -OCH2- or -CH2O-.

[0138] In some embodiments, L in the compound represented by formula III-1d or formula III-1d-a or a pharmaceutically acceptable salt thereof 1 Selected from the key, L 2 Selected from -OCH2- or -CH2O-.

[0139] On the other hand, in some embodiments, R 1 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0140] In some embodiments, R 1 are the same or different and are each independently selected from halogen or C 1-6 Alkoxy, such as fluoro, methoxy or ethoxy.

[0141] In some embodiments, R 1 are the same or different and are each independently selected from halogen or C 1-6 Alkyl groups such as fluoro, methyl or ethyl.

[0142] In some embodiments, R 1 are the same or different and are independently selected from halogen, cyano, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0143] In some embodiments, R1 are the same or different and are each independently selected from halogen or C 1-6 Cycloalkyl, for example fluoro, cyclopropyl or cyclobutyl.

[0144] In some embodiments, R 5 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl or 3 to 6 membered heterocycloalkyl, the alkyl or heterocycloalkyl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0145] In some embodiments, R 5 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0146] In some embodiments, R 5 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl or 3- to 6-membered heterocycloalkyl, for example, fluoro, chloro, cyano, methyl, ethyl, oxetanyl or tetrahydrofuranyl.

[0147] In some embodiments, R 4 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0148] In some embodiments, R 4 are the same or different and are each independently selected from halogen, cyano or C 1-6 Alkyl groups such as fluoro, chloro, cyano, methyl or ethyl.

[0149] The compound of formula I or a pharmaceutically acceptable salt thereof is selected from:

[0150] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from

[0151] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from

[0152] On the other hand, some embodiments provide pharmaceutical compositions comprising 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as an active agent, and an antacid compound.

[0153] Furthermore, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition of the present disclosure is 1:1 to 1:40, and can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, or a value between any two numbers.

[0154] In some embodiments, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition is 1:1 to 1:10. In some embodiments, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition is 1:2 to 1:10. In some embodiments, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition is 1:2. In some embodiments, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition is 1:3. In some embodiments, the weight ratio of the antacid compound to the active ingredient in the pharmaceutical composition is 1:4.

[0155] In some embodiments, the pharmaceutical composition includes 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as an active agent, and sodium carbonate.

[0156] In some embodiments, the pharmaceutical composition comprises 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as an active agent, and sodium carbonate, wherein the weight ratio of sodium carbonate to the active ingredient is 1:1 to 1:40.

[0157] On the other hand, in some embodiments, the active ingredient content is 1-30%, which can be 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 2%, 27%, 28%, 29%, 30%, or any two values ​​therebetween. In some embodiments, the amount of the active ingredient accounts for 5-15% by weight of the pharmaceutical composition. In some embodiments, the amount of the active ingredient accounts for 10-25% by weight of the pharmaceutical composition.

[0158] In some embodiments, the content of the antacid compound is 0.5-10%, which can be 0.5%, 0.7%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4. .8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10% or any value therebetween. In some embodiments, the amount of the antacid compound is 1-10% by weight of the pharmaceutical composition. In some embodiments, the amount of the antacid compound is 2-6% by weight of the pharmaceutical composition.

[0159] In some embodiments, the pharmaceutical composition comprises:

[0160] 1) 1%-30% of the active ingredient: a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0161] 2) 20-95% filler;

[0162] 3) 0.5-10% antacid compound;

[0163] 4) 1-20% disintegrant;

[0164] 5) 0.5-10% adhesive.

[0165] In some embodiments, the pharmaceutical composition comprises:

[0166] 1) 1%-30% of the active ingredient: a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0167] 2) 20-95% filler, wherein the filler is selected from microcrystalline cellulose and mannitol

[0168] 3) 0.5-10% antacid compound;

[0169] 4) 1-20% of a disintegrant selected from croscarmellose sodium;

[0170] 5) 0.5-10% of a binder, wherein the binder is selected from povidone.

[0171] In some embodiments, the pharmaceutical composition comprises:

[0172] 1) 1%-30% of the active ingredient: a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0173] 2) 20-95% filler;

[0174] 3) 0.5-10% antacid compound;

[0175] 4) 1-20% disintegrant;

[0176] 5) 0.5-10% of an adhesive, wherein the weight ratio of the antacid compound to the active ingredient is 1:1-1:40.

[0177] In some embodiments, the pharmaceutical composition comprises:

[0178] 1) 1%-30% of the active ingredient: a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0179] 2) 20-95% filler, wherein the filler is selected from microcrystalline cellulose and mannitol

[0180] 3) 0.5-10% of the antacid compound sodium carbonate;

[0181] 4) 1-20% of a disintegrant selected from croscarmellose sodium;

[0182] 5) 0.5-10% of a binder, wherein the binder is selected from povidone.

[0183] In some embodiments, the pharmaceutical composition comprises:

[0184] 1) 1%-30% of the active ingredient: a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0185] 2) 20-95% filler, wherein the filler is selected from microcrystalline cellulose and mannitol

[0186] 3) 0.5-10% of the antacid compound sodium carbonate;

[0187] 4) 1-20% of a disintegrant selected from croscarmellose sodium;

[0188] 5) 0.5-10% of a binder, wherein the binder is selected from povidone, wherein the weight ratio of the antacid compound to the active ingredient is 1:1-1:40.

[0189] In some embodiments, the pharmaceutical composition comprises:

[0190] 1) 1% to 30% of the active ingredient 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0191] 2) 20-95% filler;

[0192] 3) 0.5-10% antacid compound;

[0193] 4) 1-20% disintegrant;

[0194] 5) 0.5-10% adhesive.

[0195] In some embodiments, the pharmaceutical composition comprises:

[0196] 1) 1% to 30% of the active ingredient 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0197] 2) 20-95% filler;

[0198] 3) 0.5-10% antacid compound;

[0199] 4) 1-20% disintegrant;

[0200] 5) 0.5-10% of an adhesive, wherein the weight ratio of the antacid compound to the active ingredient is 1:1-1:40.

[0201] In other embodiments, one or more atoms in the compound of Formula I or a pharmaceutically acceptable salt thereof are replaced by an isotope having an atomic weight or mass number different from the atomic weight or mass number typically found in nature, forming an isotopic substitution. In some embodiments, the isotopic substitution is a deuterated substance.

[0202] The disclosed pharmaceutical composition can continuously and slowly release the active ingredient in the formulation (pharmaceutical composition), avoiding the fluctuations in effective blood drug concentration that occur after frequent administration of conventional or immediate-release formulations due to excessive fluctuations in blood drug concentration. Furthermore, the active ingredient in the slow-release formulation (pharmaceutical composition) can effectively reduce the side effects of GLP-1R absorption after administration, such as gastrointestinal side effects (nausea, vomiting, diarrhea, etc.) and impaired liver function, thereby improving patient compliance after administration.

[0203] In some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a subject, a T of at least 4 h is provided. max , for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0204] In some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of at least 4 h is provided. max , for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0205] In some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state, a T of 6 to 12 hours is provided. max .

[0206] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of at least 4 h is provided. max .

[0207] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state, a T of 4 to 12 hours is provided. max, for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0208] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state, a T of 6 to 12 h is provided. max In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state, a T of 6 h is provided. max .

[0209] In some embodiments, when Compound A or a pharmaceutically acceptable salt thereof is administered to a subject, a T of 4 to 12 hours is provided. max .

[0210] In some embodiments, when Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of 4 to 12 hours is provided. max .

[0211] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of 4 to 12 hours is provided. max .

[0212] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of 6 to 12 h is provided. max .

[0213] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a T of 6 h is provided. max .

[0214] On the other hand, in some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state, a T of at least 7 h is provided. max , for example, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0215] In some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state, a T of 7 to 16 hours is provided. maxIn some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state, a T of 12 h is provided. max .

[0216] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a satiety state, a T of at least 7 h is provided. max .

[0217] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state, a T of 7 to 16 h is provided. max In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state, a T of 12 h is provided. max .

[0218] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a T of 7 to 16 h is provided. max , for example, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0219] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a T of 12 h is provided. max .

[0220] The time point Tmax at which the pharmaceutical composition of the present disclosure reaches the maximum concentration in the blood after oral administration is calculated as an average value. In some embodiments, the time point Tmax at which the pharmaceutical composition reaches the maximum concentration in the blood after oral administration is calculated as a geometric mean value.

[0221] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects, a T of 6 to 8 h is provided. 1 / 2 .

[0222] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of 6 to 8 h is provided. 1 / 2 .

[0223] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a mean plasma C of 1370 ± 548 ng / mL is provided. max .

[0224] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a mean plasma C of 1370 ± 548 ng / mL is provided. max .

[0225] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a mean plasma C max .

[0226] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a mean plasma C of 810 ± 280 ng / mL is provided. max .

[0227] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, an average plasma AUC of 22700 ± 3382 h*ng / mL is provided. 0- t.

[0228] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a mean plasma AUC of 22700 ± 3382 h*ng / mL is provided. 0-t .

[0229] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a satiety state, an average plasma AUC of 17900 ± 4439 h*ng / mL is provided. 0- t .

[0230] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a mean plasma AUC of 17900 ± 4439 h*ng / mL is provided. 0-t .

[0231] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, an average plasma AUC of 23200 ± 3387 h*ng / mL is provided.0- ∞ .

[0232] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state, a mean plasma AUC of 23200 ± 3387 h*ng / mL is provided. 0-∞ .

[0233] In some embodiments, when a 90 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a satiety state, an average plasma AUC of 20500 ± 2112 h*ng / mL is provided. 0- ∞ .

[0234] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, a mean plasma AUC of 20500 ± 2112 h*ng / mL is provided. 0-∞ .

[0235] On the other hand, in some embodiments, when a 60 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of at least 7 h is provided. max .

[0236] In some embodiments, when a 60 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of 7 h to 16 h is provided. max , for example, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0237] In some embodiments, when a 60 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of 9 h to 12 h is provided. max , such as 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0238] In some embodiments, when a 60 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of 10 h to 12 h is provided. max .

[0239] In some embodiments, when a 60 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a T of at least 7 h is provided. max .

[0240] The time point Tmax at which the pharmaceutical composition of the present disclosure reaches the maximum concentration in the blood after oral administration is calculated as an average value. In some embodiments, the time point Tmax at which the pharmaceutical composition reaches the maximum concentration in the blood after oral administration is calculated as a geometric mean value.

[0241] In some embodiments, when a 60 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a mean T of 7 to 15 h is provided. max .

[0242] In some embodiments, when a 60 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a geometric mean T of 7 to 15 h is provided. max .

[0243] In some embodiments, when a 60 mg dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a mean plasma C of 480 ng / mL is provided. max .

[0244] In some embodiments, when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, an average plasma AUC of 9437 h*ng / mL is provided. 0-t .

[0245] In some embodiments, when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects, a mean plasma AUC of 9437 h*ng / mL is provided. 0-t .

[0246] On the other hand, in some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of subjects in a satiety state, a T of at least 7 h is provided. max , for example, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0247] In some embodiments, when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of subjects, a T of at least 6 h is provided. max , for example, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0248] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0249] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0250] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0251] The present disclosure further provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance. Preferably, the use of the pharmaceutical composition in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease.

[0252] On the other hand, the present disclosure also provides a method for preventing and / or treating type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance diseases, comprising administering an effective amount of the aforementioned pharmaceutical composition to a patient.

[0253] On the other hand, the present disclosure also provides the aforementioned pharmaceutical composition for preventing and / or treating type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and insulin-resistant liver diseases.

[0254] On the other hand, the present disclosure also provides a sustained-release pharmaceutical composition comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0255] in,

[0256] Ring A is selected from phenyl or 5- or 6-membered heteroaryl;

[0257] R 1 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0258] R 2 is selected from 3 to 6 membered heterocycloalkyl or 5 or 6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0259] Ring B is selected from 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;

[0260] R 3 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group,

[0261] Or any two R 3 Forming C with adjacent atoms 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0262] L 1 Selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 1a R 1b )-、-OC(R 1a R 1b )-、-C(R 1a R 1b )O-、-C(O)N(R 1c )-、-N(R 1c )(O)C-、-S(O)2N(R 1d )-、-N(R 1e )-or key,

[0263] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 substituted with alkoxy;

[0264] Ring C is selected from C 6-10 aryl or 5- or 10-membered heteroaryl;

[0265] R 4 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0266] L 2 Selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 2a R 2b )-、-OC(R 2a R 2b )-、-C(R 2a R 2b )O-、-C(O)N(R 2c )-、-N(R 2c )(O)C-、-S(O)2N(R 2d )-、-N(R 2e )-or key;

[0267] R 2a 、R 2b 、R 2c 、R 2d 、R 2e Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 substituted with alkoxy;

[0268] Ring D is selected from C 6-10 aryl or 5- or 10-membered heteroaryl;

[0269] R 5 are the same or different and are each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0270] n is selected from 0, 1, 2, 3 or 4;

[0271] m is selected from 0, 1, 2, 3 or 4;

[0272] o is selected from 0, 1, 2, 3 or 4;

[0273] p is selected from 0, 1, 2, 3 or 4.

[0274] Some embodiments provide sustained-release pharmaceutical compositions comprising 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as an active agent.

[0275] The time point Tmax at which the sustained-release pharmaceutical composition of the present disclosure reaches the maximum concentration in the blood after oral administration is calculated as the average value. In some embodiments, the time point Tmax at which the sustained-release pharmaceutical composition of the present disclosure reaches the maximum concentration in the blood after oral administration is calculated as the geometric mean value.

[0276] In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 4 hours when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a subject. max , for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0277] In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 4 h when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of subjects in a fasting state. max , for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0278] In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 4 hours when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max .

[0279] In some embodiments, the sustained-release pharmaceutical composition provides a T of 4 to 12 hours when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max , for example, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h or any value in between.

[0280] In some embodiments, the sustained-release pharmaceutical composition provides a T of 6 to 12 hours when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max .

[0281] In some embodiments, the sustained-release pharmaceutical composition provides a median T of 6 h when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max .

[0282] In some embodiments, the sustained-release pharmaceutical composition provides a T of 4 to 12 hours when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max .

[0283] In some embodiments, the sustained-release pharmaceutical composition provides a T of 6 to 12 hours when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fasting state. max .

[0284] In some embodiments, the sustained-release pharmaceutical composition provides a T of 6 h when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fasting state. max .

[0285] In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 7 h when the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a subject in a full stomach state. max , for example, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0286] In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 7 h when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state. max .

[0287] In some embodiments, the sustained-release pharmaceutical composition provides a T of 7 to 16 hours when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state. max, for example, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0288] In some embodiments, the sustained-release pharmaceutical composition provides a T of 12 h when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state. max .

[0289] In some embodiments, the sustained-release pharmaceutical composition provides a T of 7 to 16 hours when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state. max .

[0290] In some embodiments, the sustained-release pharmaceutical composition provides a T of 12 h when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a full stomach state. max .

[0291] On the other hand, in some embodiments, the sustained-release pharmaceutical composition provides a T of at least 7h when a 60mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. max .

[0292] In some embodiments, the sustained-release pharmaceutical composition provides a T of 7h-16h when a 60mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. max , for example, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h or any value in between.

[0293] In some embodiments, the sustained-release pharmaceutical composition provides a T of 9h-12h when a 60mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. max .

[0294] In some embodiments, the sustained-release pharmaceutical composition provides a T of 10h-12h when a 60mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. max In some embodiments, the sustained-release pharmaceutical composition provides a T of at least 7 h when a 60 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects.max .

[0295] In some embodiments, the sustained-release pharmaceutical composition provides an average plasma C of 480 ng / mL when a 60 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. max .

[0296] In some embodiments, the sustained-release pharmaceutical composition provides an average plasma AUC of 9437 h*ng / mL when a 90 mg dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects. 0- t .

[0297] In some embodiments, the sustained-release pharmaceutical composition provides an average plasma AUC of 9437 h*ng / mL when a 90 mg dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects. 0-t .

[0298] In some embodiments, the sustained-release pharmaceutical composition contains an antacid compound. In some embodiments, the antacid compound is selected from water-soluble antacid compounds, such as sodium carbonate. In some embodiments, the sustained-release pharmaceutical composition contains 0.5-10% of the antacid compound. In some embodiments, the weight ratio of the antacid compound to the active ingredient in the sustained-release pharmaceutical composition is 1:1 to 1:40.

[0299] The "sustained-release pharmaceutical composition" disclosed herein is known to those skilled in the art, and releases drugs slowly and non-constantly in a prescribed release medium. Compared with corresponding conventional preparations (pharmaceutical compositions), the administration frequency is reduced by half or to a certain extent.

[0300] The granules or tablets can be further coated or filled into capsules as needed.

[0301] As used herein, "by weight of the pharmaceutical composition" or "weight of the pharmaceutical composition" refers to the amount of active ingredient or other pharmaceutical excipients calculated based on the weight of the tablet core, excluding the coating agent. Pharmaceutically acceptable salts of the compounds described herein may be selected from inorganic or organic salts, such as tromethamine salts.

[0302] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0303] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0304] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations.

[0305] For example There are chiral isomers, including and Two configurations, such as

[0306] On the other hand, if there is more than one chiral central carbon in a compound, multiple diastereomers will exist, e.g. There are two chiral center carbons in it, including multiple diastereomers, such as wait.

[0307] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure.The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier.

[0308] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0309] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0310] the term:

[0311] The "weight of the pharmaceutical composition" mentioned in the present disclosure is the numerical range of the amount of active ingredients or other types of pharmaceutical excipients calculated based on the weight of the tablet core excluding the coating agent.

[0312] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0313] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0314] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0315] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0316] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 6 carbon atoms, such as 4 carbon atoms or 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, cyano, nitro, amino, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0317] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms, such as 4 ring atoms or 5 ring atoms, wherein one or more ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Non-limiting examples of "heterocycloalkyl" include: Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0318] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0319] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0320] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0321] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, such as 7-membered, 8-membered or 9-membered, more preferably 5-membered or 6-membered. For example. Non-limiting examples include:

[0322] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0323] Heteroaryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0324] The term "heterocycle" refers to a ring containing atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl. "Heterocycloalkyl" and "heteroaryl" are as defined above.

[0325] The term "hydroxy" refers to an -OH group.

[0326] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0327] The term "cyano" refers to -CN.

[0328] The term "amino" refers to -NH2.

[0329] The term "nitro" refers to -NO2.

[0330] The term "oxo" refers to "=0".

[0331] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort.

[0332] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0333] The numerical values ​​in this disclosure are instrumental measurements and are subject to a certain degree of error. Generally speaking, within a reasonable error range of plus or minus 10%. The context in which the numerical value is used must be considered. For example, the particle size of an active ingredient, where the error after measurement does not exceed plus or minus 10%, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0334] Pharmacokinetic parameters table

[0335] The pharmaceutical excipients or reagents described in the present disclosure can all be obtained from commercial channels, such as hydroxypropyl methylcellulose can be purchased externally; Compound A: 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, prepared with reference to the method in WO2022007979, and the relevant content is cited in this text for illustration. DETAILED DESCRIPTION

[0336] The following are specific implementation methods of the present disclosure. The examples are intended to further describe the present disclosure rather than to limit the present disclosure. All technical solutions equivalent to the present disclosure fall within the protection scope of the present disclosure.

[0337] Example 1

[0338] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A), microcrystalline cellulose, mannitol, povidone, anhydrous sodium carbonate, and magnesium stearate were mixed according to the amounts shown in Table 1. The mixture was then dry-granulated, sized, and uniformly mixed with croscarmellose sodium and magnesium stearate. The resulting granulated mixture was compressed into tablets.

[0339] Table 1

[0340] Dissolution test

[0341] Tablets of Formulations 1 and 2 were tested for dissolution according to the second method (paddle method) in the appendix to Part II of the Chinese Pharmacopoeia (2020 edition). Dissolution tests were performed using 1000 ml of pH 5.0 acetate buffer (containing 0.2% cetyltrimethylammonium bromide (CTAB)) at 37 ± 0.5°C and a paddle speed of 50 rpm.

[0342] Table 2

[0343] Note: " / " is not detected

[0344] The results showed that Compound A in Formulation 1 exhibited sustained release, with a cumulative dissolution of 74% in 12 hours, while Formulation 2 exhibited 89% dissolution in 0.75 hours (45 minutes), achieving near-complete dissolution. Formulation 1, which contained sodium carbonate, exhibited sustained release compared to Formulation 2.

[0345] Example 2

[0346] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A), anhydrous calcium hydrogen phosphate, mannitol, and povidone were mixed according to the amounts shown in Table 3. The mixture was then wet-granulated using an aqueous sodium carbonate solution, sized, and uniformly mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The resulting granules were compressed into tablets.

[0347] Table 3

[0348] The dissolution test was performed according to the first method (basket method) of the appendix to Part II of the Chinese Pharmacopoeia 2020. 900 ml of pH 5.0 acetate buffer (containing 0.2% cetyltrimethylammonium bromide (CTAB)) was used as the dissolution medium, and the dissolution test was performed at 37 ± 0.5 ° C and 100 rpm.

[0349] Table 4

[0350] The results showed that prescription 3 was slowly released, with a cumulative dissolution of 100% in 8 hours. Compared with prescription 2, prescriptions 1 and 3 containing sodium carbonate showed sustained release characteristics.

[0351] Test Example 1: Pharmacokinetic Study in Healthy Humans

[0352] 1.1 Research Objectives

[0353] To investigate the pharmacokinetic characteristics of a single oral dose of 90 mg of Prescription 3 tablets in healthy subjects on an empty stomach or full stomach.

[0354] 1.2 Research Plan

[0355] A single-center, double-blind trial design was designed to enroll 10 healthy subjects. The drug was administered sequentially on a full and fasting stomach, with a washout period of at least 3 days. Blood samples were collected at serial time points for safety testing. Plasma drug concentrations at various time points after dosing were determined using HPLC-MS / MS. Pharmacokinetic parameters were calculated and statistically analyzed.

[0356] 1.3 Dosage regimen

[0357] The subjects entered the research center on D-2. After a unified meal on the evening of D-2, they fasted for 10 hours and did not drink water overnight. The next day, 5 fingertip blood glucose monitoring was performed and a unified meal was performed. After a unified meal on the evening of D-1, they fasted for at least 10 hours and did not drink water overnight. After collecting a fasting blood sample on the morning of D1, they started eating a high-fat meal (high-fat, high-calorie meal) 30 minutes ± 1 minute before taking the medicine, and finished the meal within 30 minutes. Then, they took 3 prescription tablets or placebo with 240 ml of water. They were prohibited from drinking water from 1 hour before to 1 hour after taking the medicine, and were not allowed to eat any food within 4 hours after taking the medicine. If the subject develops hypoglycemia, they can eat as needed to remedy it.

[0358] After completing the postprandial dosing study, the subjects will undergo at least 1 day of washout and then undergo a fasting dosing baseline examination (intended postprandial dosing D3). If there are no unimproved / recovered adverse events, the subjects can directly enter the fasting dosing phase; if new adverse events are found during the day's examination or existing adverse events have not improved / recovered, the subjects will continue to be followed up until the researcher assesses that they can enter the fasting dosing phase or withdraw from the study. A 5-point fingertip blood glucose monitoring will be performed on the following day. After eating a unified meal that night, fast for at least 10 hours, but do not drink water overnight. The next morning, after a fasting blood sample is collected, take 3 prescription tablets or placebo with 240 ml of water. Do not drink water from 1 hour before to 1 hour after taking the medicine, and do not allow any food to be consumed within 4 hours after taking the medicine. If the subject develops hypoglycemia, he or she may eat as needed to remedy the situation.

[0359] 1.4 Trial Drugs

[0360] Test preparation (T): Prescription 3, specification: 15 mg, dosage: 90 mg.

[0361] 1.5 Pharmacokinetic results

[0362] Table 5

[0363] Example 3

[0364] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A), microcrystalline cellulose, mannitol, povidone, anhydrous sodium carbonate, and magnesium stearate were mixed according to the amounts shown in Table 6. The mixture was then dry-granulated, sized, and uniformly mixed with croscarmellose sodium and magnesium stearate. The resulting granules were compressed into tablets.

[0365] Table 6

[0366] Dissolution test

[0367] The dissolution test was performed on the tablets of Formulations 4, 5, 6, and 7 according to the second method (paddle method) of the appendix to Part II of the Chinese Pharmacopoeia 2020. 1000 ml of pH 5.0 acetate buffer (containing 0.2% cetyltrimethylammonium bromide (CTAB)) was used as the dissolution medium, and the dissolution test was performed at 37 ± 0.5°C and a paddle speed of 50 rpm.

[0368] Table 7

[0369] Example 4

[0370] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A), microcrystalline cellulose, mannitol, povidone, anhydrous sodium carbonate or calcium carbonate, and magnesium stearate were mixed according to the amounts shown in Table 8. The mixture was then dry-granulated, sized, and uniformly mixed with croscarmellose sodium and magnesium stearate. The resulting granulated mixture was compressed into tablets.

[0371] Table 8

[0372] Dissolution test

[0373] Tablets of Formulations 1 and 2 were tested for dissolution according to the second method (paddle method) in the appendix to Part II of the Chinese Pharmacopoeia (2020 edition). Dissolution tests were performed using 1000 ml of pH 5.0 acetate buffer (containing 0.2% cetyltrimethylammonium bromide (CTAB)) at 37 ± 0.5°C and a paddle speed of 50 rpm.

[0374] Table 9

[0375] Note: " / " is not detected

[0376] The results showed that compared with water-soluble sodium carbonate, the formulation containing calcium carbonate was basically dissolved within 1 hour and did not show sustained-release properties.

[0377] Test Example 2:

[0378] 1.1 Research Plan

[0379] Twelve healthy adult male subjects were randomly divided into two groups, six in each. Blood samples were collected at serial time points and safety tests were performed. Plasma drug concentrations at different time points after administration were determined using HPLC-MS / MS. Pharmacokinetic parameters were calculated and statistically analyzed.

[0380] 1.2 Dosage regimen

[0381] The subjects will be admitted to the clinical trial ward in the afternoon of the day before the trial, and will have a uniform light meal in the evening, and then fast for 10 hours overnight. The subjects will have a standard breakfast at around 7:30 and will take the medicine at around 8 o'clock with 240mL of water. Please be sure to ask the doctor to check the oral cavity to ensure that the medicine is taken. Except for 1 hour before and after taking the medicine, you can drink water as needed at other times, and eat a standard meal 4 hours after the medicine is taken (around 12:00). During hospitalization (must be hospitalized for observation 24 hours after the medicine is taken), it is required to eat the standard meals provided by the hospital. During the trial, avoid smoking and drinking, alcohol, coffee, carbonated drinks, dragon fruit, grapefruit, mango and juice containing the above fruits, avoid strenuous exercise and prolonged bed rest, and the drug washout period between cycles is 72 hours (3 days)

[0382] Blood collection time points: 4 ml of blood samples were collected before administration (0h) and 1h, 2h, 4h, 6h, 10h, 12h, 14h, 16h, 24h, 30h, and 48h after administration.

[0383] The blood samples were anticoagulated with sodium heparin, the actual blood collection time was accurately recorded, and the samples were centrifuged at 3500 rpm / min for 10 min to separate the plasma and stored at -80°C until testing.

[0384] 1.3 Trial Drugs

[0385] Test preparations (T): Prescription 8 and Prescription 9, dosage: 60 mg.

[0386] 1.4 Pharmacokinetic results

[0387] Table 10

[0388] There was 1 case of dizziness, 6 cases of nausea and 5 cases of vomiting in the prescription 9 group. Compared with the sustained-release prescription 8 group, prescription 9 had 5 cases of vomiting and the gastrointestinal reaction was more obvious.

[0389] Example 5

[0390] According to the dosage in Table 11, 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A), microcrystalline cellulose, mannitol, povidone, alkaline excipients (sodium carbonate, calcium hydroxide, meglumine or trishydroxymethylaminomethane) and cross-linked sodium carboxymethyl cellulose were mixed, magnesium stearate was added, and the mixture was compressed into tablets.

[0391] Table 11

[0392] Note: “ / ” has no

[0393] Dissolution method: According to the first method (basket method) of the appendix to Part II of the Chinese Pharmacopoeia 2020 edition, 900 ml of pH 5.0 acetate buffer (containing 0.2% cetyltrimethylammonium bromide CTAB) was used as the dissolution medium, and the dissolution test was carried out at 37±0.5°C and a paddle speed of 100 rpm.

[0394] Table 12

[0395] The above results show that different types of alkaline excipients have different effects on dissolution and release.

Claims

1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and an antacid compound, Among them, ring A is selected from phenyl or a 5- or 6-membered heteroaryl; R 1 identical or different, and each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; R 2 selected from 3- to 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, said heterocycloalkyl or heteroaryl being optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; ring B is selected from a 3- to 6-membered heterocycloalkyl, phenyl or a 5- or 6-membered heteroaryl; R 3 Same or different, and each independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, or any two Rs 3 form a C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; L 1 selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 1a R 1b )-, -OC(R 1a R 1b )-, -C(R 1a R 1b )O-, -C(O)N(R 1c )-, -N(R 1c )(O)C-, -S(O)2N(R 1d )-, -N(R 1e )- or a bond, R 1a 、R 1b 、R 1c 、R 1d 、R 1e each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy; Ring C is selected from C 6-10 aryl or 5- or 10-membered heteroaryl; R 4 identical or different, and each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; L 2 selected from -O-, -S-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -C(R 2a R 2b )-, -OC(R 2a R 2b )-, -C(R 2a R 2b )O-, -C(O)N(R 2c )-, -N(R 2c )(O)C-, -S(O)2N(R 2d )-, -N(R 2e )- or a bond; R 2a 、R 2b 、R 2c 、R 2d 、R 2e each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heteroalkyl, said alkyl, alkoxy, cycloalkyl or heteroalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy; Ring D is selected from C 6-10 aryl or 5- or 10-membered heteroaryl; R 5 identical or different, and each independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally being substituted by one or more members selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; o is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2, 3 or 4.

2. The pharmaceutical composition according to claim 1, wherein the antacid compound is a water-soluble antacid compound, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.

3. The pharmaceutical composition according to claim 1 or 2, which further contains a pharmaceutically acceptable excipient, and the excipient is preferably at least one of a filler, a disintegrant, a binder, and a lubricant.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the compound of formula II-1 or a pharmaceutically acceptable salt thereof, Where M 1 is an N atom or a C atom; is a single bond or a double bond; when M is an N atom, is a single bond. When M is a C atom, is a single bond or a double bond; ring A, ring C, R 1 、R 2 、R 3 、R 4 、R 5 、L 1 、L 2 、n, m, o, p are as defined in claim 1.

5. The pharmaceutical composition according to claim 1 or 4, wherein ring A is selected from phenyl or a 5-membered heteroaryl, preferably 6. The pharmaceutical composition according to claim 1 or 4, wherein ring C is selected from 7. The pharmaceutical composition according to claim 1 or 4, wherein the compound of formula I or its pharmaceutically acceptable salt is selected from the compound of formula II-1a or its pharmaceutically acceptable salt, the compound of formula II-1b or its pharmaceutically acceptable salt, the compound of formula II-1c or its pharmaceutically acceptable salt, the compound of formula II-1d or its pharmaceutically acceptable salt, the compound of formula II-1e or its pharmaceutically acceptable salt, or the compound of formula II-1f or its pharmaceutically acceptable salt, wherein ring A, R 1 、R 2 、R 3 、R 4 、 R 5 、L 1 、L 2 、n, m, o, p are as defined in claim 1; is a single bond or a double bond; M 1 is as defined in claim 7.

8. The pharmaceutical composition according to claim 1, 4 or 7, wherein L 1 is selected from a bond, and L 2 is selected from a bond.

9. The pharmaceutical composition according to claim 1, 4 or 7, wherein R 5 are the same or different and each independently selected from halogen, cyano, C 1-6 alkyl or 3- to 6-membered heteroalkyl, said heteroalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy; or R 5 are the same or different and each independently selected from halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy.

10. The pharmaceutical composition according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from:

11. The pharmaceutical composition according to claim 3, wherein the filler is selected from at least one of lactose, sucrose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, and preferably the amount of the filler accounts for 20-95% by weight of the pharmaceutical composition; The disintegrant is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and preferably the amount of the disintegrant accounts for 1-20% by weight of the pharmaceutical composition; The binder is selected from at least one of povidone, copovidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, and preferably the amount of the binder accounts for 0.5-10% by weight of the pharmaceutical composition; The lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, talc, sodium stearyl fumarate, and preferably the amount of the lubricant accounts for 0.1-5% by weight of the pharmaceutical composition.

12. The pharmaceutical composition according to claim 1 or 11, which contains: 1) 1%-30% of the active ingredient 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof; 2) 20-95% of a filler; 3) 0.5-10% of an antacid compound; 4) 1-20% of a disintegrant; 5) 0.5-10% of a binder.

13. The pharmaceutical composition according to claim 2, wherein the weight ratio of the antacid compound to the active ingredient is 1:1-1:40, preferably 1:1-1:10, such as 1:1, 1:2, 1:3 or 1:

4.

14. The pharmaceutical composition according to claim 1, wherein when a 90 mg dose of the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered to a population of healthy subjects in a fed state, an average plasma C of 810 ± 280 ng / mL is provided max .

15. The pharmaceutical composition according to claim 1, wherein when the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects in a fed state, a T of at least 7 h is provided max .

16. The pharmaceutical composition according to claim 1, wherein when the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered to a group of healthy subjects, a T of 6 to 8 h is provided 1 / 2 .

17. Use of the pharmaceutical composition according to claims 1-16 in the preparation of a medicament for preventing and / or treating type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular diseases, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably for the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular diseases.