Pharmaceutical composition comprising GLP-1r agonist and preparation method therefor

Abstract

The present invention provides a pharmaceutical composition and a pharmaceutical formulation prepared from the pharmaceutical composition. The pharmaceutical composition comprises: (a) a GLP-1R agonist; (b) copovidone; and (c) poloxamer.

Description

A pharmaceutical composition comprising a GLP-1R agonist and its preparation method thereof

[0001] This disclosure claims priority to the following applications:

[0002] Chinese Patent Application No. 202510096328.6, entitled "A pharmaceutical composition comprising a GLP-1R agonist and a method for preparing the same," was filed with the China National Intellectual Property Administration on January 21, 2025; Chinese Patent Application No. 202510095829.2, entitled "A pharmaceutical composition comprising a GLP-1R agonist and a method for preparing the same," was filed with the China National Intellectual Property Administration on January 21, 2025. The entire contents of these documents are incorporated herein by reference. Technical Field

[0003] This invention relates to the pharmaceutical field, and more specifically, to pharmaceutical compositions of GLP-1R agonists, formulations thereof, and their uses. Background Technology

[0004] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the gut in response to diet. GLP-1 is thought to play a role in postprandial blood glucose regulation by directly increasing diet-induced insulin secretion from pancreatic β-cells and by promoting satiety through delaying food transport through the intestines. GLP-1 mediates intracellular signaling via the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor family located on the cell membrane, which, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Nonalcoholic steatohepatitis (NASH) is associated with features of metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0005] GLP-1R agonists are currently being extensively investigated for their use in treating diabetes, obesity, and NASH. GLP-1R agonists include peptides such as exenatide, liraglutide, and duraglutide, which have been approved for the treatment of type 2 diabetes. These peptides are primarily administered via subcutaneous injection. Oral GLP-1 agonists are also being investigated for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, duraglutide, and exenatide, are resistant to the rapid degradation of dipeptidyl peptidase 4, resulting in a longer half-life than endogenous GLP-1.

[0006] In the treatment of GLP-1R-mediated diseases and conditions, there remains a need for compounds with ideal therapeutic properties, metabolic properties, and / or ease of administration, as well as pharmaceutical formulations that reduce dosing frequency and improve treatment adherence. Summary of the Invention

[0007] Overview

[0008] This invention relates primarily to pharmaceutical compositions of GLP-1R agonists and the delivery of therapeutic drugs to reduce dosing frequency, improve bioavailability, provide greater patient privacy and satisfaction, and improve treatment adherence.

[0009] On the one hand, this disclosure provides a pharmaceutical composition comprising the following components:

[0010] (a) GLP-1R agonists;

[0011] (b) Copolyvinylpyrrolidone;

[0012] (c) Polosham;

[0013] The GLP-1R agonist described herein is a compound having the structure of formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0014] in

[0015] X is selected from N or -CR a ;R a Selected from hydrogen atoms, halogens, or C atoms 1-6 alkyl;

[0016] Y is -C(=O)-;

[0017] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 Z 11 Z 12 Z 13 Each is independently selected from N or C;

[0018] Q1 is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl or 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substitution of alkoxy groups;

[0019] Q2 is a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the 3- to 12-membered heterocyclic group and the 5- to 10-membered heteroaryl group are optionally selected by 1 to 3 independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR Qa R Qb Substituents, or optionally two Cs 1-6 Alkyl groups, together with the carbon atoms they are attached to, form C14 groups.3-8 Carbon ring; and R Qa and R Qb Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or (C 1-6 alkyl)carbonyl;

[0020] R1, R2, R3, R1', R2', and R3' are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cycloalkyl, or heterocycloalkyl; wherein C 1-6 Alkyl, cycloalkyl, or heterocycloalkyl groups may optionally be selected independently from one or more halogen atoms, C... 1-6 Substitution of alkoxy or hydroxyl groups; or

[0021] R2 and R3 together with the carbon atoms they are attached to form 4- to 8-membered heterocyclic alkyl groups;

[0022] R4, R5, and R6 are each independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0023] R7 and R8 are independently selected from hydrogen or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 3-15 Substituents of cycloalkyl groups;

[0024] Alternatively, R7 and R8 together with the carbon atoms they are attached to form C 3-15 Carbon ring; the C 3-15 The carbon ring can be selectively divided by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may be selected independently from one or more halogens, hydroxyl groups, and -NR groups. 7a R 7b C 1-6 Substitution with alkoxy or 3 to 12-membered heterocyclic groups, and R 7a and R 7b Independently selected from hydrogen and C 1-6 Alkyl or (C 1-6 Alkyl) carbonyl; any two C 1-6 Alkyl groups may optionally form C10 with the carbon atoms to which they are attached. 3-15 Carbon rings;

[0025] n1 is 0, 1, 2, or 3;

[0026] n2 is 0, 1, 2, 3, 4 or 5;

[0027] n3 is 0 or 1;

[0028] R9 is selected from the following groups:

[0029] -CO2R 9f or -C(=O)-NR 9g R 9h And R 9a R 9b R 9c R 9d and R 9g Each is independently selected from hydrogen, C 1-6 Alkyl or (C 1-6 alkyl)carbonyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 1-6 Substitution of alkoxy groups; R 9e It is hydrogen or C that is optionally substituted with one or more halogen atoms. 1-6 Alkyl; R 9f Is it hydrogen or C? 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 Alkyl) carbonyl, cyano, or -S (=O) n9 -R 9i n9 is 0, 1, or 2; R 9i It is C 1-6 alkyl;

[0030] Z1 is selected from the following groups:

[0031] Where R za Selected from hydrogen, C 1-6 Alkyl or (C 1-6 alkyl)carbonyl, R zb and R zc Independently selected from hydrogen or C 1-6 Alkyl; n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0032] Z2 is a 5- to 10-membered heteroaryl group, Z2 is reacted with a halogen and a -C3-C... 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution, wherein the cycloalkyl or alkyl group is optionally selected independently from halogen, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy or (C 1-6 The alkyl group is substituted with a substituent of the carbonyl group, wherein the alkyl or alkoxy group may be selectively substituted with a halogen. On the other hand, this disclosure provides a gastric-coated tablet comprising the pharmaceutical composition described in any one of the claims of this disclosure, and a filler, a lubricant, and a gastric-coating material;

[0033] Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate;

[0034] Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate;

[0035] Preferably, the gastric coating material comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0036] On the other hand, this disclosure provides an enteric-coated tablet comprising the pharmaceutical composition described in any one of the claims of this disclosure, and a filler, lubricant, pH buffer, and enteric coating material;

[0037] Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate;

[0038] Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate;

[0039] Preferably, the pH buffer is selected from one or more of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, sodium citrate, or sodium acetate.

[0040] Preferably, the enteric coating material is selected from one or more of the following: cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose succinate (HPMCAS), and methacrylic acid copolymer.

[0041] On the other hand, this disclosure relates to a method for treating GLP-1-mediated diseases or symptoms, comprising the steps of administering to an individual in need of the method a therapeutically effective amount of any of the pharmaceutical compositions of this disclosure, gastrointestinal-coated tablets, or enteric-coated tablets.

[0042] In some implementations, the GLP-1-mediated diseases or symptoms are selected from: T1D (type 1 diabetes), T2DM (type 2 diabetes), prediabetes, idiopathic T1D (idiopathic type 1 diabetes), LADA (late-onset autoimmune diabetes in adults), EOD (early-onset diabetes), YOAD (young-onset adult diabetes), MODY (mature-onset diabetes in young adults), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to other medications, excessive sugar consumption, dyslipidemia, hyperinsulinemia, NAFLD (non-alcoholic fatty liver disease), NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, etc. Myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout. Erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, substance addiction, weight management, long-term weight management, chronic kidney disease, atherosclerotic cardiovascular disease, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, diabetes prevention, or obstructive sleep apnea.

[0043] Detailed Explanation

[0044] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that the embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0045] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0046] When used in this disclosure and the appended claims, a singular designation without a quantity indication includes a plural designation unless the context clearly specifies otherwise.

[0047] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0048] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated in the text. Thus, for example, a sustained-release tablet containing “pharmaceutically acceptable excipients” includes one, two, or more pharmaceutically acceptable excipients.

[0049] I. Definition

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for convenience in indicating the connection point with the parent molecule; chemical groups may or may not be described with one or more dashes without losing their ordinary meaning. Prefixes such as "C" u-v "or"C u -C v "This indicates that the following groups have u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0051] Solid dispersion particles: refer to dispersion particles that exist in solid form, formed by uniformly dispersing drugs in a highly dispersed state such as molecules, amorphous, or microcrystalline in a carrier.

[0052] GLP-1R agonist: An active agent that has an agonistic effect on the GLP-1 receptor. In the embodiments of this disclosure, the active compound or API refers to a GLP-1R agonist.

[0053] "Substitution" here means that one or more hydrogen atoms in the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more). Substituents include, but are not limited to, the following groups: alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, haloyl, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate carbonyl, cyanothioisocyanate carbonyl, isothiocyanate carbonyl, nitro, methyldimethylsilyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure), or protected amino.

[0054] "Alkyl" is a monovalent or divalent linear or branched saturated hydrocarbon group. For example, alkyl groups can have 1 to 10 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-10 Alkyl groups or 1 to 8 carbon atoms (i.e., C14) 1-8 Alkyl groups or 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. Examples of alkyl groups include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH3), 3-pentyl (-CH(CH2CH3) )2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2C H3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2). 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3). The alkyl group can be unsubstituted or substituted.

[0055] "Alkenyl" is a monovalent or divalent linear or branched hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2C2). 2-8 Alkenyl) or 2 to 6 carbon atoms (i.e., C) 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0056] "Alynyl" is a monovalent or divalent linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C64-C ... 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyne group. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkyne groups can be unsubstituted or substituted.

[0057] "Alkoxy" refers to the "-O-alkyl" group, where the alkyl group is as described above. For example, C 1-4 An alkoxy group refers to an "O-alkyl" group containing 1 to 4 carbon atoms. Alkoxy groups can be unsubstituted or substituted.

[0058] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, thus making the alkyl group divalent. For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups may be unsubstituted or substituted.

[0059] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0060] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a halogen, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen can be any of those described above. In some embodiments, the haloalkyl group determines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). The alkyl halogens can be unsubstituted or substituted.

[0061] "Aryl" refers to a monovalent or divalent mono- or divalent all-carbon aromatic ring or a multi-condensed all-carbon ring system, wherein the ring is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. An aryl group includes a phenyl group. An aryl group also includes multiple condensed ring systems having about 9 to 20 carbon atoms (e.g., ring systems consisting of 2, 3, or 4 rings), wherein the rings are aromatic. Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds. It is also understood that when referring to a member aryl group within a certain atomic range (e.g., a 6-10 member aryl group), the atomic range refers to the total number of ring atoms in the aryl group. For example, a 6-member aryl group includes a phenyl group, and a 10-member aryl group includes a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. An aryl group can be unsubstituted or substituted.

[0062] "5-10 membered aromatic heterocycle" or "heteroaromatic ring" refers to a single aromatic ring having at least one atom other than a carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple condensation ring systems having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" comprises a single aromatic ring of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple condensation ring systems (e.g., ring systems consisting of 2, 3, or 4 rings), wherein the heteroaryl as defined above is condensed with one or more rings selected from heteroaryl (forming, for example, 1,8-naphthidyl) and aryl (forming, for example, benzimidazolyl or indazolyl) to form multiple condensation ring systems. Therefore, a heteroaryl group (a single aromatic ring or multiple condensed ring system) can have approximately 1-20 carbon atoms and approximately 1-6 heteroatoms within the heteroaryl ring. For example, a tetrazolium group has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds. It should be understood that the individual rings of multiple condensed ring systems can be interconnected in any order. It should be understood that the connection points of a heteroaryl group or a heteroaryl multiple condensed ring system can be any suitable atom of the heteroaryl group or a heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a member heteroaryl group of a certain atomic range (e.g., a heteroaryl group with 5 to 10 members), that atomic range refers to the total ring atoms of the heteroaryl group, including carbon atoms and heteroatoms. It should also be understood that the rings in a multi-condensation ring system may include an aryl ring fused to a heterocycle (e.g., a 3, 4, 5, 6, or 7-membered ring) having saturated or partially unsaturated bonds, the ring having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. For example, 5-membered heteroaryl groups include thiazolyl groups, and 10-membered heteroaryl groups include quinolinyl groups. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazole, quinoxazolyl, quinazolyl, benzofuranyl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group may be unsubstituted or substituted.

[0063] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a system of multiple condensed all-carbon rings, wherein the ring in each instance is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems having about 7 to 12 carbon atoms (e.g., ring systems comprising 2 rings). Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds, solenoids, or bridging bonds. Exemplary polycyclic cycloalkyl groups include octahydropentene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2ene, and spiro[2.5]octane. The cycloalkyl groups may be unsubstituted or substituted.

[0064] The term “cycloalkyl” is intended to include cycloalkyl groups as defined above, which may optionally be substituted with one or more of the following substituents: cycloalkyl, aryl, heteroaryl, heteroaliphatic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, isocyanate, cyanothio, isothiocyanate, nitro, -NR'R” (R' and R” are alkyl groups as defined in this disclosure) or amino groups including monosubstituted and disubstituted amino groups, and derivatives thereof.

[0065] In some embodiments, "C" 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms as defined above. 3-6 The "cycloalkyl" group can be optionally substituted as defined above for cycloalkyl groups.

[0066] In some embodiments, "C" 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms as defined above. 3-8 The "cycloalkyl" group can be optionally substituted as defined above for cycloalkyl groups.

[0067] In some embodiments, "C" 3-15 "Cycloalkyl" refers to a cycloalkyl group having 3 to 15 carbon atoms as defined above. 3-15 The "cycloalkyl" group can be optionally substituted as defined above for cycloalkyl groups.

[0068] As used herein, "heterocycle" or "heterocyclic group" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system containing at least one heteroatom (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to approximately 20 cyclic atoms, for example, 3 to 12 cyclic atoms, 4 to 12 cyclic atoms, 4 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Therefore, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence requirements permit, the rings of a system of multiple condensed rings (such as bicyclic heterocycles) can be interconnected by fusion bonds, solenoids, and bridging bonds. Heterocycles include, but are not limited to, nitrogen heterocycles, aziridines, imidazolides, morpholine, ethylene oxide, oxygen heterocycles, thioheterocycles, piperazines, and piperidines. Pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxo-6-azaspiro[3.3]heptane-6-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2-thia-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptane-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like. The heterocyclic group may be unsubstituted or substituted.

[0069] "(C1-6 alkyl)carbonyl" refers to a (C1-6 alkyl)-C(O)- group, where the alkyl group is as described above. A carbonyl group is a C(O)- group, meaning a carbon atom is bonded to an oxygen atom via a double bond. Examples include methyl carbonyl (acetyl), ethyl carbonyl (propionyl), n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, 1-methylpropyl carbonyl, n-pentyl carbonyl, isopentyl carbonyl, 2-methylbutyl carbonyl, 1,1-dimethylpropyl carbonyl, 1-ethylpropyl carbonyl, n-hexyl carbonyl, 4-methylpentyl carbonyl, and 2-ethylbutyl carbonyl.

[0070] As used herein, "substituted" means that one or more hydrogen atoms of a group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more), as shown.

[0071] "Compounds of this disclosure", "active compounds of this disclosure" or "API" refers to the GLP-1R agonist compounds of this disclosure, such as compounds of general formulas (I)-(XI) and specific compounds.

[0072] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0073] As used herein, "therapeutic effective amount" or "effective amount" means an amount that effectively elicits the desired biological or medical response, including, when administered to a subject treating a disease, an amount sufficient to affect the treatment of that disease. Effective amounts will vary depending on the compound, the disease and its severity, and factors such as the age and weight of the subject being treated. Effective amounts can include a range of amounts. As understood in the art, an effective amount can be one or more doses, meaning that one or more doses may be required to achieve the desired therapeutic endpoint. An effective amount can be considered when administering one or more therapeutic agents, and if, when used with one or more other agents, a desired or beneficial result may have been achieved, the single agent may be considered to have been administered at an effective amount. Due to the combined effects of compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compound may be selectively reduced.

[0074] Pharmaceutically acceptable salts, hydrates, solutions, isomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0075] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human use.

[0076] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of compounds in their free base form, possessing the pharmacological activity required for a free base. These salts can be extracted from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, disulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propoxides, oxalates, malonates, ferrousates, sebates, and fumarates. Maleate, butyn-1,4-diacidate, hexyn-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propanesulfonate. Benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in *Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006*.

[0077] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N (C1-C4 alkyl). 4+ It also includes base addition salts, such as sodium or potassium salts.

[0078] Also provided are compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein, wherein one to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of the compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein when administered to mammals. See “Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984)”. Such compounds are synthesized by methods well known in the art, for example using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0079] Examples of isotopes that can be included in the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, 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, 36 Cl, 123 I and 125 I. Using positron emission of isotopes, such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compound of formula (IA-1) can generally be prepared using conventional techniques known to those skilled in the art, or by a process similar to that described in the examples below, replacing the previously used unlabeled reagent with a suitable isotopically labeled reagent.

[0080] The compounds of embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus potentially yielding enantiomers, diastereomers, and other stereoisomers that are (R)- or (S)- in absolute stereochemistry, or, for amino acids, (D)- or (L)-. This statement is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)- isomers can be prepared using chiral synthesis or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these compounds are intended to include E and Z geometric isomers unless otherwise specified. Similarly, all isomer forms are included. When a compound is represented in its chiral form, it should be understood that the embodiment includes, but is not limited to, a specific diastereomer or enantiomer-enriched form. If chirality is not specified but present, it can be understood that the embodiment is for a specific diastereomer or enantiomer-enriched form; or a racemic or scalar mixture of such a compound. As used herein, a "scalar mixture" means a mixture of stereoisomers in a non-1:1 ratio.

[0081] As used herein, "stereoisomers" refers to compounds composed of identical atoms but with different three-dimensional structures, and they are not interchangeable. This disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0082] As used herein, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, this disclosure includes tautomers of the compounds.

[0083] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0084] As used herein, “hydrate” refers to the compound of this invention that is chemically bonded to one or more water molecules.

[0085] "Prevention" or "protection" means any treatment that results in the non-development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition.

[0086] As used in this article, "prodrug" refers to a derivative of a drug that, after being administered to the human body, is converted into the parent drug via a chemical or enzymatic pathway. In some implementations, the prodrug is a bioactive derivative of the drug that, after being administered to the human body, is converted into the bioactive parent drug via a chemical or enzymatic pathway.

[0087] As used herein, “treatment” or “curative therapy” refers to a method of achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, reducing symptoms and / or lessening the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” or “curative therapy” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, for example, resulting in the resolution of clinical symptoms, improvement of disease status, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, “at-risk individual” means an individual who is at risk of developing a disease requiring treatment. An individual “at risk” may or may not have a detectable disease or condition and may or may not have a detectable disease prior to the treatments described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters related to the development of a disease or condition and are known in the art to have a higher probability of developing the disease or condition than an individual without such risk factors.

[0088] Metabolic diseases refer to a class of diseases caused by abnormal metabolism of substances or energy, resulting in metabolic disorders. They are usually diseases that affect multiple systems throughout the body. In this article, metabolic diseases specifically refer to diseases related to abnormal lipid metabolism, preferably including obesity, overweight, and weight-related conditions.

[0089] BMI (Body Mass Index) is an internationally recognized standard for measuring a person's fatness and health status. It is calculated by dividing weight (kg) by the square of height (m), with the formula: BMI = weight (kg) / height² (m²).

[0090] "Obesity" refers to an individual's BMI ≥ 30 kg / m². 2 .

[0091] "Overweight" refers to an individual's weight exceeding the healthy weight range, with a BMI of 25 kg / m². 2 ≤BMI<30kg / m 2 The preferred value is 27 kg / m 2≤BMI<30kg / m 2 .

[0092] "Weight management" refers to the behaviors, techniques, and physiological processes that help an individual achieve and maintain a healthy weight. A healthy weight for a particular patient can be determined in consultation with a healthcare professional; in one implementation, "weight management" refers to weight loss and / or changes in body fat composition.

[0093] Long-term weight management therapy helps patients achieve their healthy weight goals. In one embodiment, "long-term weight management" means that the subject achieves their healthy weight goal and maintains their weight within that target range for a certain period of time. In another embodiment, "long-term weight management" means that the subject achieves their healthy weight goal and maintains their weight within that target range for at least 13 weeks. In yet another embodiment, the subject achieves their healthy weight goal and maintains their weight within that target range for at least 26 weeks. In yet another embodiment, "long-term weight management" means that the subject achieves their healthy weight goal and maintains their weight within that target range for at least 52 weeks. In yet another embodiment, "long-term weight management" means that the subject achieves their healthy weight goal and maintains their weight within that target range for at least 104 weeks.

[0094] II. Preparations

[0095] On the one hand, this disclosure provides a pharmaceutical composition comprising the following components:

[0096] (a) GLP-1R agonists;

[0097] (b) Copolyvinylpyrrolidone;

[0098] (c) Polosham.

[0099] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0100] in

[0101] X is selected from N or -CR a ;R a Selected from hydrogen atoms, halogens, or C atoms 1-6 alkyl;

[0102] Y is -C(=O)-;

[0103] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 Z 11 Z 12 Z 13 Each is independently selected from N or C;

[0104] Q1 is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl or 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substitution of alkoxy groups;

[0105] Q2 is a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the 3- to 12-membered heterocyclic group and the 5- to 10-membered heteroaryl group are optionally selected by 1 to 3 independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR Qa R Qb Substituents, or optionally two Cs 1-6 Alkyl groups, together with the carbon atoms they are attached to, form C14 groups. 3-8 Carbon ring; and R Qa and R Qb Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or (C 1-6 alkyl)carbonyl;

[0106] R1, R2, R3, R1', R2', and R3' are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cycloalkyl, or heterocycloalkyl; wherein C 1-6 Alkyl, cycloalkyl, or heterocycloalkyl groups may optionally be selected independently from one or more halogen atoms, C... 1-6 Substitution of alkoxy or hydroxyl groups; or

[0107] R2 and R3 together with the carbon atoms they are attached to form 4- to 8-membered heterocyclic alkyl groups;

[0108] R4, R5, and R6 are each independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0109] R7 and R8 are independently selected from hydrogen or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 3-15 Substituents of cycloalkyl groups;

[0110] Alternatively, R7 and R8 together with the carbon atoms they are attached to form C 3-15 Carbon ring; the C 3-15 The carbon ring can be selectively divided by one to three Cs. 1-6Alkyl substitution, wherein C 1-6 Alkyl groups may be selected independently from one or more halogens, hydroxyl groups, and -NR groups. 7a R 7b C 1-6 Substitution with alkoxy or 3 to 12-membered heterocyclic groups, and R 7a and R 7b Independently selected from hydrogen and C 1-6 Alkyl or (C 1-6 Alkyl) carbonyl; any two C 1-6 Alkyl groups may optionally form C10 with the carbon atoms to which they are attached. 3-15 Carbon rings;

[0111] n1 is 0, 1, 2, or 3;

[0112] n2 is 0, 1, 2, 3, 4 or 5;

[0113] n3 is 0 or 1;

[0114] R9 is selected from the following groups:

[0115] -CO2R 9f or -C(=O)-NR 9g R 9h And R 9a R 9b R 9c R 9d and R 9g Each is independently selected from hydrogen, C 1-6 Alkyl or (C 1-6 alkyl)carbonyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 1-6 Substitution of alkoxy groups; R 9e It is hydrogen or C that is optionally substituted with one or more halogen atoms. 1-6 Alkyl; R 9f Is it hydrogen or C? 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 Alkyl) carbonyl, cyano, or -S (=O) n9 -R 9i n9 is 0, 1, or 2; R 9i It is C 1-6 alkyl;

[0116] Z1 is selected from the following groups:

[0117] Where R za Selected from hydrogen, C 1-6 Alkyl or (C 1-6alkyl)carbonyl, R zb and R zc Independently selected from hydrogen or C 1-6 Alkyl; n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0118] Z2 is a 5- to 10-membered heteroaryl group, Z2 is reacted with a halogen and a -C3-C... 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution, wherein the cycloalkyl or alkyl group is optionally selected independently from halogen, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy or (C 1-6 Substituents of alkyl (carbonyl) groups, wherein the alkyl or alkoxy group may be selectively substituted with a halogen.

[0119] In some embodiments, in the compound of formula (I), wherein Z2 is an indazole group.

[0120] In some embodiments, in the compound of formula (I), the indazole group is reacted with a halogen and a -C3-C... 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution.

[0121] In some embodiments, in the compound of formula (I), wherein Q1 is C 6-10 Aryl, the C 6-10 The aryl group is optionally selected by one to five independent compounds chosen from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substitution of alkoxy groups.

[0122] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (III) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0123] in,

[0124] X is selected from -CR a ;R a Selected from hydrogen atoms;

[0125] Y is selected from -C(=O)-;

[0126] Z3, Z4, Z5, Z 6， Z8, Z9, Z 10， Z 12 and Z 13 The answer is C;

[0127] Z7 andZ11 Let N be the number of people in the group.

[0128] Q1 is C 6-10 Aryl, of which C 6-10 The aryl group is optionally selected by one to five independent halogens, C 1-6 Alkyl substituents;

[0129] Q2 is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally composed of 1 to 3 independently selected halogen atoms, and C 1-6 Alkyl substituents, and two of the carbon atoms are C14-C ... 1-6 Alkyl groups may optionally form C10 with the carbon atoms to which they are attached. 3-8 Carbon rings;

[0130] R1, R2, R1', and R2' are each independently selected from hydrogen or C. 1-6 alkyl;

[0131] R3 and R3' are independently selected from hydrogen or C. 1-6 alkyl;

[0132] R4, R5 and R6 are hydrogen;

[0133] R7 and R8 are independently selected from hydrogen or C. 1-6 Alkyl groups; or R7 and R8 together with the carbon atoms they are attached to form C24 groups. 3-15 Carbon ring; wherein the C 3-15 The carbon ring can be selectively divided by one to three Cs. 1-6 Alkyl substitution;

[0134] n1 is 0 or 1;

[0135] n2 is 0 or 1;

[0136] n3 is 1;

[0137] R9 is selected from And R 9a Selected from hydrogen;

[0138] Z1 is selected from:

[0139] Z2 is selected from 5- to 10-membered heteroaryl groups. Z2 is reacted with a halogen and a -C3-C... 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution, wherein the cycloalkyl or alkyl group is optionally selected independently from halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy or (C 1-6 Substituents of alkyl (carbonyl) groups, wherein the alkyl or alkoxy group may optionally be substituted with a halogen.

[0140] In some embodiments, in compounds of formula (I) and formula (III), wherein Q1 is selected from... Among them, R n1 R n3 Each is independently selected from hydrogen, methyl, or ethyl; R n2 It is a halogen.

[0141] In some embodiments, in compounds of formula (I) and formula (III), wherein Q2 is... Where R qm and R qn Each is independently selected from H, methyl or ethyl, or R qm and R qn Together with the carbon atoms they are attached to, they form C 3-6 The cycloalkyl group, p is selected from 0, 1 or 2.

[0142] In some embodiments, in compounds of formula (I) and formula (III), the Z2 is selected from...

[0143] R z1 For halogens, m1 is 1;

[0144] R z2 Selected from C 3-8 cycloalkyl or -C 1-6 Alkyl-C 3-8 cycloalkyl; R z2 Halogen can be selected, C 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0145] In some embodiments, in compounds of formula (I) and formula (III), wherein Z2 is...

[0146] R z1 Selected from hydrogen, F, Cl or Br,

[0147] R z2 Selected from

[0148] In some embodiments, in compounds of formula (I) and formula (III), the Z2 is selected from...

[0149] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (IV) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0150] Wherein, X, Z4, and Z6 are independently selected from N or CH;

[0151] Where R z1 Selected from halogens, C 1-3 Alkyl or C 3-8 cycloalkyl;

[0152] R z2 Selected from C 3-8 cycloalkyl or C 1-6 Alkyl-C 3-8 cycloalkyl; R z2 Halogens can be selected, -OH, C 1-6 Alkyl or -C 1-6 Alkyl substitution;

[0153] m1 is selected from 0, 1, 2 or 3;

[0154] R m Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0155] R n Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0156] m is independently selected from 0, 1, 2, or 3;

[0157] R3 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0158] In some embodiments, in the compound of formula (IV), wherein the R... z1 Selected from F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl;

[0159] m is independently selected from 0, 1, 2, or 3;

[0160] R z2 Selected from

[0161] R m Selected from hydrogen, methyl, ethyl, or methoxy;

[0162] R n Independently selected from methyl, ethyl, F or Cl;

[0163] R3 is a methyl group.

[0164] In some embodiments, in the compound of formula (IV), wherein Q2 is Where Rqm and R qn Each is independently selected from H, methyl or ethyl, or R qm and R qn Together with the carbon atoms they are attached to, they form C 3-6 The cycloalkyl group, p is selected from 0, 1 or 2.

[0165] In some embodiments, in the compound of formula (IV), Q2 is selected from...

[0166] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (V) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0167] in,

[0168] X, Z4, and Z6 are independently selected from N or CH;

[0169] Q2 is selected independently from:

[0170] R n Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0171] Where m is 0, 1, 2 or 3;

[0172] R z2 Selected from C 3-8 cycloalkyl or C 1-6 Alkyl-C 3-8 cycloalkyl; R z2 Optional halogenated, -OH, C 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0173] In some embodiments, in the compound of formula (V), wherein the R of the compound z2 Selected from

[0174] R n It is independently selected from methyl, ethyl, F or Cl.

[0175] In some embodiments, the GLP-1R agonist has a structure of formula (VI):

[0176] Where X, Z4, and Z6 are independently selected from N or CH;

[0177] R z2 Selected from C3-8 cycloalkyl or C 1-6 Alkyl-C 3-8 cycloalkyl; R z2 Optional halogenated, -OH, C 1-6 Alkyl or C 1-6 Alkyl substitution;

[0178] Q2 is selected from:

[0179] In some embodiments, in the compound of formula (VI), wherein the R... z2 Selected from

[0180] In some embodiments, the GLP-1R agonist has a structure of formula (VII):

[0181] R z2 Selected from C 3-8 cycloalkyl or C 1-6 Alkyl-C 3-8 cycloalkyl; R z2 Optional halogenated, -OH, C 1-6 Alkyl or C 1-6 Alkyl substitution;

[0182] Q2 is selected independently from:

[0183] In some embodiments, in the compound of formula (VII), wherein the R... z2 Selected from

[0184] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (VIII) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound:

[0185] Wherein, X, Z4, and Z6 are independently selected from N or CH;

[0186] R m Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0187] R n1 R n3 Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6Haloalkoxy; R n2 It is a halogen;

[0188] R3 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0189] R z1 Selected from hydrogen, halogens, C 1-3 Alkyl or C 3-8 cycloalkyl;

[0190] R z2 Selected from

[0191] R qm and R qn Each is independently selected from H, methyl, ethyl, or R. qm and R qn Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl groups.

[0192] In some embodiments, in the compound of formula (VIII), wherein,

[0193] R m Selected from hydrogen, methyl, ethyl, or methoxy;

[0194] R n1 R n3 Each is independently selected from hydrogen, methyl, or ethyl;

[0195] R n2 For F;

[0196] R3 is a methyl group;

[0197] R z1 It is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0198] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (IX) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0199] Wherein, X, Z4, and Z6 are independently selected from N or CH;

[0200] Z2 is selected from the following groups:

[0201] R n Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C1-6 Alkoxy;

[0202] Where m is independently selected from 0, 1, 2 or 3;

[0203] R m Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0204] R3 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0205] R 10 R 11 Each is independently selected from H, F, Cl, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl.

[0206] In some embodiments, in the compound of formula (IX), wherein,

[0207] R m Selected from hydrogen, methyl, ethyl, or methoxy;

[0208] R n Independently selected from methyl, ethyl, F or Cl;

[0209] R3 is a methyl group.

[0210] In some embodiments, in the compound of formula (IX), Z2 is selected from...

[0211] In some embodiments, in the compound of formula (IX), Q2 is selected from... Where R qm and R qn Each is independently selected from H, methyl or ethyl, or R qm and R qn Together with the carbon atoms they are attached to, they form C 3-6 The cycloalkyl group, p is selected from 0, 1 or 2.

[0212] In some embodiments, in the compound of formula (IX), Q2 is selected from...

[0213] In some embodiments, the GLP-1R agonist is selected from:

[0214] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0215] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (X) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0216] Wherein, X, Z4, and Z6 are independently selected from N or CH;

[0217] m is independently selected from 0, 1, 2, or 3;

[0218] R p Selected from -CH2-P(=O)R zm R zn or -P(=O)OR zm OR zn ;

[0219] R q Selected from halogens, -NH-C 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, 3 to 12-membered heterocyclic group, -C3-C 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 cycloalkyl;

[0220] Where R zm and R zn Independently selected from H, C 1-6 Alkyl or C 6-10 Aryl; or R zm and R zn Together with the phosphorus atoms to which they are attached, they form 5-8 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally bonded by 1-3 carbon atoms. 1-6 Alkyl substitution.

[0221] In some embodiments, in the compound of formula (X), wherein R p Selected from;

[0222] R m Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0223] R n Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0224] R3 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C1-6 Halogenated alkoxy groups.

[0225] In some embodiments, in the compound of formula (X), wherein R m Selected from hydrogen, methyl, ethyl, or methoxy;

[0226] R n Independently selected from methyl, ethyl, F or Cl;

[0227] R3 is a methyl group.

[0228] In some embodiments, in the compound of formula (X), Q2 is Where R qm and R qn Each is independently selected from H, methyl or ethyl, or R qm and R qn Together with the carbon atoms they are attached to, they form C 3-6 The cycloalkyl group, p is selected from 0, 1 or 2.

[0229] In some embodiments, in the compound of formula (X), Q2 is selected from...

[0230] In some embodiments, the GLP-1R agonist is selected from:

[0231] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0232] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (XI) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0233] Where Q1 is C 6-10 Aryl, of which C 6-10 The aryl group is optionally selected by one to five independent halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substitution of alkoxy groups;

[0234] Q2 is selected from 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups, wherein the 3- to 12-membered heterocyclic groups and the 5- to 10-membered heteroaryl groups are optionally composed of 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group substituents; where two carbons are substituents. 1-6 Alkyl groups may optionally form C10 with the carbon atoms they are attached to. 3-8 Carbon rings;

[0235] X1, X2, X3 are independently selected from N or C;

[0236] X4 and X5 are independently selected from N or C;

[0237] R m Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0238] R z2 Selected from C 3-8 cycloalkyl, -C 1-6 Alkyl-C 3-8 Cycloalkyl.

[0239] In some embodiments, in the compound of formula (XI), Q1 is selected from... Among them, R n1 R n3 Each is independently selected from hydrogen, methyl, and ethyl; R n2 Selected from halogens;

[0240] Q2 is selected from

[0241] R z2 Selected from

[0242] In some embodiments, the GLP-1R agonist is selected from:

[0243] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0244] In some embodiments, the GLP-1R agonist is selected from:

[0245] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0246] In some embodiments, the pharmaceutically acceptable salt is selected from the sodium, calcium, potassium, magnesium, or lithium salts of any of the compounds disclosed herein.

[0247] In some embodiments, the GLP-1R agonist is selected from...

[0248] In some embodiments, the GLP-1R agonist is selected from:

[0249] In some embodiments, the GLP-1R agonist is

[0250] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0251] In some embodiments, the GLP-1R agonist is

[0252] Or its sodium or calcium salt.

[0253] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound:

[0254] in

[0255] X is selected from N or -CR a ;R a Selected from hydrogen atoms, halogens, or C 1-6 alkyl;

[0256] Y is selected from -C(=O)-;

[0257] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 Z 11 Z 12 Z 13 Selected from N or C;

[0258] Q1 is selected from C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl or 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens or C. 3-8 Substituents of cycloalkyl groups;

[0259] Q2 is selected from 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups, wherein the 3- to 12-membered heterocyclic groups and the 5- to 10-membered heteroaryl groups are optionally selected by 1 to 3 independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR Qa R Qb Substituent substitution, wherein optionally, both C2C ... 1-6 Alkyl groups, together with the carbon atoms they are attached to, form C14 groups. 3-8 Carbon ring; and R Qa and R Qb Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl or (C1-6 alkyl)carbonyl;

[0260] R1, R2, R3, R1', R2', and R3' are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cycloalkyl, or heterocyclic alkyl; wherein C 1-6 Alkyl, cycloalkyl, or heterocycloalkyl groups may be optionally selected by one or more independently from halogens, C 1-6 Substitution of alkoxy or hydroxyl groups;

[0261] R2 and R3 together with the carbon atoms they are attached to form 4- to 8-membered heterocyclic alkyl groups;

[0262] R4, R5, and R6 are each independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0263] R7 and R8 are independently selected from hydrogen or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 3-15 Substituents of cycloalkyl groups;

[0264] Alternatively, R7 and R8 together with the carbon atoms they are attached to form C 3-15 Carbon ring; the C 3-15 The carbon ring can be selectively divided by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may be selected from one or more independently of halogens, hydroxyl groups, and -NR. 7a R 7b C 1-6 Substitution with alkoxy or 3 to 12-membered heterocyclic groups, and R 7a and R 7b Independently selected from hydrogen and C 1-6 Alkyl or (C 1-6 Alkyl) carbonyl; or any two Cs 1-6 Alkyl groups may optionally form C10 with the carbon atoms to which they are attached. 3-15 Carbon rings;

[0265] n1 is 0, 1, 2, or 3;

[0266] n2 is 0, 1, 2, 3, 4 or 5;

[0267] n3 is 0 or 1;

[0268] R9 is selected from:

[0269] -CO2R 9f or -C(=O)-NR9g R 9h And R 9a R 9b R 9c R 9d and R 9g Each is independently selected from hydrogen and C. 1-6 Alkyl or (C 1-6 alkyl)carbonyl, wherein C 1-6 Alkyl groups may optionally be selected independently from halogens or C. 1-6 Substitution of alkoxy groups;

[0270] R 9e It is hydrogen or C that is optionally substituted with one or more halogen atoms. 1-6 alkyl;

[0271] R 9f Is it hydrogen or C? 1-6 alkyl;

[0272] R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 Alkyl) carbonyl, cyano, or -S (=O) n9 -R 9i ;

[0273] n9 is 0, 1, or 2;

[0274] R 9i It is C 1-6 alkyl;

[0275] Z1 is selected from the following groups:

[0276] Where R za Selected from hydrogen, C 1-6 Alkyl or (C 1-6 alkyl)carbonyl, R zb and R zc Each is independently selected from hydrogen or C. 1-6 alkyl;

[0277] n4 is 1, 2, or 3;

[0278] n5 and n6 are independent integers from 0 to 10;

[0279] Z2 is selected from 5 to 10 heteroaryl groups; and Z2 is reacted with a halogen and a -C3-C 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution, wherein the cycloalkyl or alkyl group is optionally selected independently from one or more halogens, oxo-substituted groups, C-substituted groups. 1-6 Alkyl, C 1-6 Alkoxy or (C 1-6Substituents of alkyl (carbonyl) groups, wherein the alkyl and alkoxy groups may be selectively substituted with halogens.

[0280] In some embodiments, in the compound of formula (I), Q1 may optionally be converted by two C2C ... 1-6 Alkyl substitution, wherein the two Cs 1-6 Alkyl groups, together with the carbon atoms they are attached to, form C14 groups. 3-8 Carbon rings or 4-10 membered heterocycles.

[0281] In some embodiments, in the compound of formula (I), Q1 is selected from C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl or 5- to 10-membered heteroaryl groups are bound by at least one C 3-8 The cycloalkyl group is substituted and optionally substituted with one to four halogens. In some embodiments, the C... 3-8 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, or cyclopentyl groups that have been optionally substituted.

[0282] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (II) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0283] Q2 is selected independently from:

[0284] Q1 is selected from

[0285] p is 0, 1, 2, or 3;

[0286] R n It is C 3-8 cycloalkyl;

[0287] Ha is selected from fluorine, chlorine, bromine, or iodine;

[0288] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 Z 11 Z 12 Z 13 Each is independently selected from N or C;

[0289] X is selected from N or CR a ;R a Selected from hydrogen, halogen or C 1-6 alkyl;

[0290] R m Selected from C 1-6 alkyl;

[0291] Z2 is a 5- to 10-membered heteroaryl group, and Z2 is bonded by a halogen and a -C3-C group.15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl substitution, wherein the cycloalkyl or alkyl group is optionally selected independently from one or more halogens, oxo-substituted groups, C-substituted groups. 1-6 Alkyl, C 1-6 Alkoxy or (C 1-6 The alkyl)carbonyl group is substituted with a substituent, wherein the alkyl or alkoxy group may optionally be substituted with a halogen.

[0292] In some embodiments, the GLP-1R agonist is a compound having the structure of formula (XII) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0293] X, Z4, and Z6 are each independently selected from N or CH;

[0294] Where R n C 3-8 cycloalkyl;

[0295] Q2 is selected from 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups, wherein the 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups are optionally selected by 1 to 3 independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR Qa R Qb Substituents, where two Cs are substituents. 1-6 Alkyl groups optionally form C10 with the carbon atoms to which they are attached. 3-8 Carbon ring; and R Qa and R Qb Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl or (C 1-6 alkyl)carbonyl;

[0296] R z3 Selected from C3-C8 cycloalkyl or C1-C6 alkyl-C3-C8 cycloalkyl.

[0297] In some embodiments, in compounds of formula (III), R z3 Selected from:

[0298] Q2 is selected from:

[0299] In some embodiments, the GLP-1R agonist is selected from:

[0300] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0301] In some embodiments, the GLP-1R agonist is a compound having formula (XIII) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0302] in

[0303] X, Z4, and Z6 are each independently selected from N or CH;

[0304] p is 0, 1, 2 or 3;

[0305] R z3 Selected from -C 1-6 Alkyl, -C 3-8 cycloalkyl or -C 1-6 Alkyl-C 3-8 cycloalkyl; R z3 Optional selection from halogen, -OH, -C 1-6 Alkyl or -C 1-6 Substitution of alkoxy groups;

[0306] Q2 is selected from 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups, wherein the 3- to 12-membered heterocyclic groups or 5- to 10-membered heteroaryl groups are optionally selected by 1 to 3 independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR Qa R Qb Substituents, where two Cs are substituents. 1-6 Alkyl groups optionally form C10 with the carbon atoms to which they are attached. 3-8 Carbon ring; where R Qa and R Qb Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl or (C 1-6 Alkyl)carbonyl.

[0307] In some implementations, in compounds of formula (IV), R z3 Selected from

[0308] Q2 is selected from:

[0309] In some embodiments, in the compound of formula (I), the GLP-1R agonist is selected from...

[0310] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0311] In some embodiments, the GLP-1R agonist is a compound having formula (XIV) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0312] in,

[0313] X, Z4, and Z6 are independently selected from N or CH;

[0314] m is 0, 1, 2, or 3;

[0315] R p Selected from -CH2-P(=O)R zm R zn or -P(=O)OR zm OR zn ;

[0316] R q Selected from halogens, -NH-C 1-6 Alkyl, -C 1-6 Alkyl, -OC 1-6 Alkyl, 3 to 12-membered heterocyclic groups, -C3-C 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 cycloalkyl;

[0317] Where R zm and R zn Independently selected from H and C 1-6 Alkyl, or C 6-10 aryl; or R zm and R zn Together with the phosphorus atoms to which they are attached, they form 5-8 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally surrounded by 1-3 carbon atoms. 1-6 Alkyl substitution;

[0318] R m Selected from hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be replaced by halogens.

[0319] R n Selected from halogen or C 3-8 Cycloalkanes;

[0320] R3 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0321] Q2 is selected from:

[0322] In some embodiments, in compounds of formula (XIV), wherein Rp Selected from;

[0323] In some embodiments, the GLP-1R agonist is selected from...

[0324] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0325] In some embodiments, the GLP-1R agonist is a compound having formula (XV) or a stereoisomer thereof, a pharmaceutically acceptable salt, or a deuterated compound.

[0326] in,

[0327] X1, X2, X3 are independently selected from N or C;

[0328] X4 and X5 are independently selected from N or C;

[0329] R m Selected from hydrogen or C 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally replaced by halogens.

[0330] Q1 is selected from

[0331] p is 0, 1, 2, or 3;

[0332] R n It is C 3-8 cycloalkyl;

[0333] Ha is selected from F, Cl, Br, or I;

[0334] Q2 is selected independently from:

[0335] R z3 Selected from -C3-C 15 cycloalkyl or -C1-C6 alkyl-C3-C 15 Cycloalkyl.

[0336] In some embodiments, the GLP-1R agonist is selected from:

[0337] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0338] In some embodiments, the GLP-1R agonist is selected from:

[0339] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0340] In some embodiments, the GLP-1R agonist is selected from:

[0341] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0342] In some embodiments, the pharmaceutically acceptable salt is selected from the sodium, calcium, potassium, magnesium, or lithium salts of any of the compounds disclosed herein.

[0343] In some embodiments, the GLP-1R agonist is selected from:

[0344] In some embodiments, the GLP-1R agonist is

[0345] Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

[0346] In some embodiments, the GLP-1R agonist is Or its sodium or calcium salt.

[0347] In some embodiments, the copovidone is copovidone VA64; and the poloxamer is poloxamer 407.

[0348] In some embodiments, the mass fractions of each component of the pharmaceutical composition disclosed herein are as follows:

[0349] (a) GLP-1R agonist: 1 dose;

[0350] (b) Copovidone: 0.1–50 parts;

[0351] (c) Poloxamer: 0.05–25 parts.

[0352] In some embodiments, the mass fractions of each component of the pharmaceutical composition disclosed herein are as follows:

[0353] (a) GLP-1R agonist: 1 dose;

[0354] (b) Copovidone: 0.1–10 parts;

[0355] (c) Poloxamer: 0.05 to 1 part.

[0356] In some embodiments, the pharmaceutical composition disclosed herein is a solid dispersion of particles.

[0357] In some embodiments, the solid dispersion particles of this disclosure are prepared by rotary granulation, which includes the following steps:

[0358] (1) Dissolve components (a), (b), and (c) in ethanol and dry them by rotary evaporation at 40–60 °C.

[0359] (2) The dried product obtained in step (1) is crushed, sieved and dried to obtain solid dispersed particles.

[0360] In some embodiments, the solid dispersion particles of this disclosure are prepared by spray drying, which includes the following steps: dissolving components (a), (b), and (c) in ethanol and spray drying at 80–100°C to obtain solid dispersion particles.

[0361] In some embodiments, the pharmaceutical compositions disclosed herein further comprise component (d): polyethylene glycol.

[0362] In some embodiments, the polyethylene glycol is polyethylene glycol 6000, and its mass ratio with the GLP-1R agonist is 0.5:1-10:1. In some embodiments, the solid dispersion particles of this disclosure are prepared by hot melt extrusion, which includes the following steps: mixing components (a), (b), (c), and (d) uniformly, placing them in a hot melt extruder, and hot-melting them at 110-130°C; the resulting extrudate is then mechanically pulverized to obtain solid dispersion particles.

[0363] On the other hand, this disclosure provides a gastric-coated tablet comprising any of the pharmaceutical compositions provided in this disclosure, and a filler, a lubricant, and a gastric-coating material;

[0364] Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate;

[0365] Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate;

[0366] Preferably, the gastric coating material comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0367] In some embodiments, the gastric-coated tablets provided in this disclosure further comprise a disintegrant, preferably selected from one or more of the following: croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, starch, pregelatinized starch, or low-substituted hydroxypropyl cellulose.

[0368] In some embodiments, the gastric-coated tablets provided in this disclosure further comprise a pH buffer, preferably selected from one or more of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, sodium citrate, or sodium acetate.

[0369] In some embodiments, the filler for the gastric-coated tablets provided in this disclosure is mannitol and / or microcrystalline cellulose; the lubricant is magnesium stearate; the disintegrant is croscarmellose sodium and / or croscarmellose; and the pH buffer is sodium carbonate.

[0370] In some embodiments, the percentage (w / w) of each component of the gastrointestinal coated tablets provided in this disclosure by weight of the gastrointestinal coated tablets are as follows:

[0371] Filler: 30%–80%;

[0372] Lubricant: 0.5%–3%;

[0373] Gastric coating material: 2%–4%.

[0374] Disintegrant: 3%–10%;

[0375] On the other hand, this disclosure provides an enteric-coated tablet comprising any of the pharmaceutical compositions provided in this disclosure, and a filler, lubricant, pH buffer, and enteric coating material;

[0376] Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate;

[0377] Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate;

[0378] Preferably, the pH buffer is selected from one or more of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, sodium citrate, or sodium acetate.

[0379] Preferably, the enteric coating material is selected from one or more of the following: cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose succinate (HPMCAS), and methacrylic acid copolymer.

[0380] In some embodiments, the enteric-coated tablets provided in this disclosure further comprise a disintegrant, preferably selected from one or more of the following: croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, starch, pregelatinized starch, or low-substituted hydroxypropyl cellulose.

[0381] In some embodiments, the enteric-coated tablets provided in this disclosure further comprise an isolation packing material.

[0382] In some embodiments, preferably, the enteric-coated tablets provided in this disclosure have mannitol and / or microcrystalline cellulose as fillers; magnesium stearate as a lubricant; sodium carbonate as a pH buffer; methacrylic acid copolymer as an enteric coating material; croscarmellose sodium carboxymethyl cellulose and / or croscarmellose as a disintegrant; and hydroxypropyl methylcellulose as a release agent.

[0383] In some embodiments, the percentage (w / w) of each component of the enteric-coated tablets provided in this disclosure by weight of the enteric-coated tablets are as follows:

[0384] Filler: 30%–80%;

[0385] Lubricant: 0.5%–3%;

[0386] Enteric-coated packaging material: 5%–10%;

[0387] Disintegrant: 3%–10%;

[0388] Insulation pack material: 2%–4%

[0389] III. Treatment Methods

[0390] On the other hand, this disclosure relates to a method of treating GLP-1-mediated diseases or symptoms, comprising the steps of administering to a subject an effective amount of any of the pharmaceutical compositions of this disclosure, gastric-coated tablets, or enteric-coated tablets.

[0391] In some implementations, the GLP-1-mediated diseases or symptoms are selected from: T1D (type 1 diabetes), T2DM (type 2 diabetes), prediabetes, idiopathic T1D (idiopathic type 1 diabetes), LADA (late-onset autoimmune diabetes in adults), EOD (early-onset diabetes), YOAD (young-onset adult diabetes), MODY (mature-onset diabetes in young adults), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to other medications, excessive sugar consumption, dyslipidemia, hyperinsulinemia, NAFLD (non-alcoholic fatty liver disease), NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, etc. Myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout. Erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, substance addiction, weight management, long-term weight management, chronic kidney disease, atherosclerotic cardiovascular disease, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, diabetes prevention, or obstructive sleep apnea. Example

[0392] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0393] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0394] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0395] Example 1: Preparation of API

[0396] The API-related information of this application is recorded in WO2025057134A2 and WO2025109387A1, which are incorporated herein by reference in their entirety.

[0397] The compounds of the present invention can be prepared using the methods disclosed herein and their conventional modifications, which are readily apparent from the methods disclosed herein and those well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used.

[0398] General synthesis methods

[0399] Typical embodiments of the compounds disclosed herein can be synthesized using the general reaction schemes and / or examples described below. Given the description herein, it is apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures, resulting in correspondingly different products. The subsequent synthetic descriptions provide numerous examples illustrating how starting materials can be varied to yield corresponding products. Starting materials are typically obtained from commercial sources or synthesized using methods for synthesizing compounds that are embodiments of this disclosure. Examination of the structure of the compound to be synthesized will provide the identity of each substituent, and given the examples here, the identity of the final product will generally become apparent through a simple examination process that reveals the identity of the necessary starting materials. The group labels (such as R1, R2) used in the reaction schemes herein are for illustrative purposes only and, unless otherwise stated, do not necessarily correspond in name or function to labels used elsewhere to describe compounds of Formula I or aspects or fragments thereof.

[0400] Synthesis reaction parameters

[0401] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the general methods and procedures described below. It will be understood that while typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0402] Furthermore, conventional protecting groups may be necessary for those skilled in the art to prevent certain functional groups from undergoing undesirable reactions. Protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in TW Greene and GMWuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0403] Furthermore, the compounds disclosed herein may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and mixtures enriched with stereoisomers) are included within the scope of this statement. Pure stereoisomers (or mixtures enriched with stereoisomers) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Additionally, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral dissociation agents, etc.

[0404] The starting materials for the following reactions are generally known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures described in standard references or obvious modifications thereof, such as Fieser's *Organic Synthetic Reagents*, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's *Chemistry of Carbon Compounds*, Volumes 1-5, and Supplements (Elsevier Science Press, 1989); *Organic Reactions*, Volumes 1-40 (John Wiley and Sons, 1991); and March's *Advanced Organic Chemistry* (John Wiley and Sons, 1991). th Edition, 2001), and Larock's Comprehensive Organic Transformation (VCH Publishing, 1989).

[0405] The terms "solvent," "inert organic solvent," or "inert solvent" refer to an inert solvent under the associated reaction conditions (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, dichloromethane (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0406] The term "qs" refers to the amount added sufficient to achieve the stated function, for example, to bring the solution to the desired volume (i.e., 100%).

[0407] The compounds described herein can be synthesized according to the general protocols provided below. In the protocols described below, it should be understood that each compound shown may have a protecting group present as required at any step. Standard protecting groups are within the knowledge of those skilled in the art.

[0408] Intermediate preparation:

[0409] Preparation of intermediate A

[0410] Dissolve A-1 (5 g, 18.65 mmol), potassium carbonate (5.16 g, 37.3 mmol), and sodium iodide (0.28 g, 1.86 mmol) in DMF (30 mL). Add bromoacetonitrile (3.36 g, 28.0 mmol) dropwise to the reaction solution and heat to 70 °C for 16 hours. After cooling to room temperature, add water (60 mL) to precipitate a solid, which is then filtered to give 4 g of a brown solid. Yield: 49.0%.

[0411] A-2 (2.0 g, 6.51 mmol), A-3 (1.71 g, 7.16 mmol), cesium carbonate (3.18 g, 9.77 mmol), and Pd(dppf)₂Cl₂ (0.5 g, 0.6 mmol) were dissolved in dioxane (20 mL) and reacted at 100 °C for 4 hours under N₂. The reaction mixture was cooled, and the organic phase was extracted with water (30 mL) and ethyl acetate (30 mL). The organic phase was concentrated to dryness and purified by column chromatography to obtain 1.2 g of a white solid. The obtained solid was dissolved in methanol, and Pd / C (0.12 g, 30% wt.) was added. The mixture was reacted overnight at room temperature under hydrogen. After filtration, the filtrate was concentrated to dryness. The obtained solid was then subjected to chiral preparative liquid chromatography (using the liquid with the shortest retention time) to prepare A-4, 0.6 g, yield: 27.3%.

[0412] A-4 (0.6 g, 1.76 mmol) was dissolved in methanol / water (4 ml / 2 ml), and sodium hydroxide (0.28 g, 7.05 mmol) was added. The mixture was reacted at room temperature for 4 hours. The pH was adjusted to 5.0 with dilute hydrochloric acid, and the organic phase was extracted with ethyl acetate (5 ml). The solution was concentrated under reduced pressure to dryness to give solid A-5, 0.53 g, yield: 96.3%.

[0413] A-5 (300 mg, 1.1 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (520 mg, 4.4 mmol) and 1 drop of DMF were added. The reaction mixture was reacted at room temperature for 6 hours. The reaction solution was concentrated to dryness to obtain an acyl chloride oil, which was then dissolved in 5 mL of dichloromethane and set aside. N-methylaniline (180 mg, 1.65 mmol) and triethylamine (222 mg, 2.2 mmol) were dissolved in dichloromethane (10 mL). The acyl chloride solution was added dropwise under ice bath conditions, and the reaction was continued at room temperature for 1 hour. The organic phase was extracted with water (10 mL) and concentrated to dryness under reduced pressure to obtain A-6, 350 mg, 87.9%.

[0414] A-6 (100 mg, 0.25 mmol) and (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide (103.6 g, 0.75 mmol) were dissolved in THF (5 mL). The solution was cooled to -20 °C, and bis(trimethylsilylaminolithium) (1 mL, 1 M in THF) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 24 hours. The reaction was quenched by slow dropwise addition of water (5 mL), and 10 mL of ethyl acetate was added. The organic phase was extracted and concentrated under reduced pressure to dryness to obtain an oily substance. The oil was then purified by column chromatography to obtain A-7, 40 mg, in 36.4% yield.

[0415] A-7 (10 mg, 0.023 mmol) was dissolved in DMSO (2 ml), and hydroxylamine aqueous solution (0.6 ml, 50%) was added. The mixture was reacted at room temperature for 16 hours. Extraction was performed with water (10 ml) and ethyl acetate (10 ml), the organic phase was dried, and the solution was concentrated to dryness to obtain an oil. The oil was dissolved in DMSO (3 ml), and CDI (10 mg, 0.062 mmol) and DBU (10 mg, 0.066 mmol) were added. The mixture was reacted at room temperature for 6 hours. Extraction was performed with water (10 ml) and ethyl acetate (10 ml), the organic phase was dried, and the solution was concentrated to dryness to obtain A-8, 10 mg, yield: 88.2%.

[0416] A-8 (220 mg, 0.44 mmol) was dissolved in ethylene glycol methyl ether (3 ml), potassium hydroxide (494 mg, 8.8 mmol) was added, and the mixture was heated to 130 °C for 5 hours. After cooling to room temperature, the pH was adjusted to 5.0 with hydrochloric acid (6N), and the mixture was extracted with ethyl acetate (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate A, 180 mg, yield: 99.0%.

[0417] Preparation of intermediate B1:

[0418] A-1 (120 g, 447.58 mmol) and B1-1 (103.43 g, 492.34 mmol) were dissolved in dioxane (1200 mL) and water (300 mL). Cesium carbonate (123.72 g, 895.16 mmol) and Pd(dppf)₂Cl₂ (18.28 g, 22.38 mmol) were then added. The mixture was heated to 90 °C for 12 hours under nitrogen protection. After the reaction was complete, NH₄Cl (500 mL) and ethyl acetate were added to extract the organic phase. The extract was concentrated under reduced pressure and then purified by column chromatography to obtain a white solid. The obtained solid was dissolved in THF (1000 mL), and Pd / C (12 g, 50% wet palladium on carbon) was added. The mixture was reacted at room temperature for 4 hours under a hydrogen flow. The solution was filtered and concentrated to dryness to obtain B1-2, 120 g.

[0419] B1-2 (80 g, 292.69 mmol) was dissolved in DMF (1000 mL). NaH (23.42 g, 585.38 mmol, 60%) was added in portions at 0 °C. After stirring for about 30 minutes, chloroacetonitrile (26.52 g, 351.23 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, NH4Cl (500 mL) was added dropwise, and the mixture was stirred for 10 minutes. A large amount of solid precipitated out, and the solid was filtered to obtain B1-3, 75 g.

[0420] For subsequent reactions, refer to the preparation of intermediate A to obtain B1.

[0421] Preparation of intermediates B, C, A1, A2, A3, A4 and A5

[0422] Based on the preparation methods of intermediates A and B1, the following intermediates can be obtained:

[0423] Preparation of intermediate D

[0424] D-1 (2.0 g, 8.4 mmol), D-2 (1.29 g, 8.4 mmol), and pyridine hydrochloride (0.97 g, 8.4 mmol) were dissolved in toluene (10 mL), and the mixture was heated to reflux for 1 hour. After cooling the reaction solution, water (10 mL) and ethyl acetate (10 mL) were added, and the organic phase was extracted. The extract was concentrated under reduced pressure to give the target compound D-3, 2.4 g, yield: 76.4%.

[0425] Dissolve D-3 (2.0 g, 5.34 mmol) in DCM (20 ml), and add dropwise a solution of 2-isocyano-1,1-dimethoxyethane (0.84 g, 6.41 mmol) in dichloromethane (5 ml) at room temperature. Stir for 2 hours at room temperature. Add water (20 ml), extract, separate the organic phase, and dry under reduced pressure to obtain an oily substance, which can be directly used for the next reaction.

[0426] Under ice bath conditions, the oily substance of D-4 was dissolved in dichloromethane (20 ml), followed by the addition of formic acid (10 ml), and stirred overnight at room temperature. 20 ml of water was added, and the organic phase was extracted and separated. The extract was dried under reduced pressure to obtain a crude product, which was then slurried with ethyl acetate and n-heptane to obtain D-5, 1.2 g.

[0427] Preparation of intermediate D'

[0428] Add 400 mL of 1,4-dioxane to a 1000 mL single-necked flask, and add D'-1 (30 g, 158 mmol), cyclopropylboronic acid (20.37 g, 236 mmol), palladium acetate (1.78 g, 7.9 mmol), triphenylphosphine (4.14 g, 15.8 mmol), potassium phosphate (100 g, 471 mmol), and water (40 mL) all at once. Under N2 protection, the reaction was heated to 100℃ for 8 hours. After cooling to room temperature, the reaction solution was poured into 1L of water and extracted with EA (400mL*3). The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness. 30g of the crude product was dissolved in 200mL of LEtOH, and 10g of ZnCl2 was added. A large amount of yellow solid precipitated. The mixture was pulped for more than 8 hours and filtered to obtain 45g of yellow solid. The solid was poured into water, and the pH was adjusted to alkaline with NaOH (2M) aqueous solution. The aqueous phase was then extracted with EA, and the organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness to obtain 20g of brown oily liquid.

[0429] D'-2 (15 g, 99 mmol) was added to a mixture of 60 mL water and 60 mL concentrated hydrochloric acid, resulting in the precipitation of a large amount of yellow solid. The mixture was cooled to -5 °C with stirring, and a 10 mL aqueous solution of NaNO2 (7.53 g, 109 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained below 0 °C for 1 h. The mixture was then cooled to approximately -5 °C, and a 56 mL solution of concentrated hydrochloric acid containing SnCl2 (37.67 g, 199 mmol) was slowly added dropwise. A pale red gas was released during this process, and finally, a large amount of pale pink solid precipitated in the system. The mixture was stirred at approximately 0 °C for 3 h, and the pH was slowly adjusted to alkaline (pH = 8) with NaOH aqueous solution. The aqueous phase was extracted with DCM (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain 12 g of a pink oily substance. The crude product was used directly in the next step.

[0430] D'-3 (12 g, 72.3 mmol), D'-4 (16.33 g, 72.3 mmol), and pyridine hydrochloride (840 mg, 7.2 mmol) were added to 100 mL of ethanol. The mixture was heated to 85 °C and reacted for 3 h. After cooling to room temperature, a large amount of ethanol solvent was evaporated, and the mixture was poured into water. The mixture was extracted with EA (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give 21 g of a light brown solid.

[0431] In a 500 mL three-necked flask, triphosgene (4.66 g, 38.9 mmol) and DCM (250 mL) were added under N2 protection. The mixture was stirred and dissolved in an ice-water bath until clear. D'-5 (15 g, 38.9 mmol) and DCM (80 mL) solution were slowly added dropwise over 30 min. After the addition was complete, triphosgene (1.16 g, 3.9 mmol) and DCM (20 mL) were added, and the reaction was stirred for another 30 min. TEA (11.8 g, 116.6 mmol) was slowly added dropwise over 10 min, and the reaction was stirred for another 20 min. Aminoacetaldehyde dimethyl acetal (12.24 g, 116.6 mmol) was slowly added dropwise over 10 min, and the reaction was stirred for another 1 h. The reaction mixture was then quenched with 100 mL of water. After separation, the organic phase was collected, and the aqueous phase was extracted once more with DCM (100 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate, then evaporated to dryness. 19.6 g of crude product was obtained as a pale yellow oily liquid.

[0432] D'-6 (19.6 g, 37.9 mmol) and methanesulfonic acid (4 g, 41.7 mmol) were added to 400 mL of THF. The reaction was heated to 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with EA (200 mL x 2), and the organic phase was washed with Brine water, dried over anhydrous sodium sulfate, and then evaporated to dryness. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give 9 g of pale yellow solid D'.

[0433] Preparation of intermediates E and F:

[0434] E-1 (5.0 g, 24.12 mmol) and triethylamine (7.31 g, 72.36 mmol) were dissolved in dichlorohexane (25 ml). MsCl (6.08 g, 53.07 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Water (20 ml) was added, and the organic phase was extracted and separated. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain E-2, 7.5 g, in 85.6% yield.

[0435] E-2 (3.0 g, 8.25 mmol) was dissolved in EMF (30 ml), and NaCN (850 mg, 17.3 mmol) was slowly added. The mixture was reacted at 60 °C for 1 hour. After cooling, a saturated sodium hypochlorite solution (30 ml) was added and the mixture was stirred for 1 hour. Ethyl acetate (30 ml) was added, the organic phase was extracted, and the solution was concentrated to dryness to give E-3, 1.54 g, yield: 82.8%.

[0436] E-3 (1.2 g, 5.33 mmol) was dissolved in a 1 M, 7 mL solution of hydrogen chloride in methanol and stirred overnight at room temperature. Water was then added and stirred for 2 hours. Ethyl acetate (20 mL) was added, and the organic phase was extracted and separated. The extract was evaporated under reduced pressure to obtain an oil, which was then purified by column chromatography to obtain E-4, 0.6 g, yield: 43.6%.

[0437] E-4 (0.5 g, 1.9 mmol) was dissolved in THF (5 ml), and potassium tert-butoxide (1.09 g, 9.7 mmol) was added. The mixture was reacted overnight at room temperature. The pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. After evaporation under reduced pressure, the extract was further purified by column chromatography to obtain E-5, 0.34 g, yield: 68%.

[0438] E-5 (0.2 g, 0.88 mmol), D-2 (126 mg, 0.88 mmol), and pyridine hydrochloride (0.1 g, 0.88 mmol) were dissolved in toluene (4 mL), and the mixture was heated to reflux for 1 hour. After cooling the reaction solution, water (10 mL) and ethyl acetate (10 mL) were added, and the organic phase was extracted. The extract was concentrated under reduced pressure to give the target compound E, 260 mg, in 81.2% yield.

[0439] Intermediate F was prepared using the same method:

[0440] Preparation of intermediate E': E' can be prepared according to the preparation method of intermediate D'.

[0441] Based on the preparation method of intermediate D', E' can be obtained by using E'-1 as the starting material.

[0442] Preparation of intermediate G:

[0443] G-1 (5.0 g, 41.5 mmol), ethyl 3-bromopyruvate (8.90 g, 45.61 mmol), and cesium carbonate (20.3 g, 62.2 mmol) were dissolved in DMF (100 mL), heated to 65 °C, and reacted for 4 hours. After cooling to room temperature, 200 mL of water was added, and a solid precipitated. The solid was filtered to give G-2, 4.80 g, yield: 58.4%.

[0444] G-2 (4.0 g, 20.2 mmol), (Boc)₂O (6.6 g, 30.3 mmol), and triethylamine (6.13 g, 60.5 mmol) were dissolved in THF (40 ml) and stirred overnight at room temperature. Water (50 ml) and ethyl acetate (50 ml) were added, and the organic phase was extracted and concentrated under reduced pressure to give G-3, 5.6 g, 93.2%.

[0445] G-3 (5.6 g, 18.8 mmol) was dissolved in THF (50 ml), and potassium tert-butoxide (10.5 g, 94 mmol) was added. The mixture was reacted overnight at room temperature. The pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. After evaporation under reduced pressure, the extract was further purified by column chromatography to obtain G-4, 3.6 g, yield: 76%.

[0446] G-4 (2.0 g, 7.93 mmol), D-2 (1.22 g, 7.93 mmol), and pyridine hydrochloride (0.9 g, 7.93 mmol) were dissolved in toluene (40 mL), and the mixture was heated to reflux for 1 hour. After cooling the reaction solution, water (40 mL) and ethyl acetate (40 mL) were added, and the organic phase was extracted. The extract was concentrated under reduced pressure to give the target compound G, 1.2 g, yield: 39%.

[0447] Preparation of intermediate H:

[0448] Compound G (200 mg, 0.52 mmol) was dissolved in DCM (2 ml). Under ice bath conditions, DAST (165 mg, 1.0 mmol) was added, and the mixture was stirred overnight at 0 °C. Saturated sodium bicarbonate solution (4 ml) and DCM (4 ml) were added, followed by extraction. The organic phase was separated, dried under reduced pressure, and then purified by column chromatography to obtain compound H, 0.12 g, yield: 56.8%.

[0449] Preparation of intermediate I:

[0450] Compound I-1 (5.0 g, 23.3 mmol), cyclopropylboronic acid (3.99 g, 46.5 mmol), copper acetate (3.48 g, 23.2 mmol), 2,2'-bipyridine (3.9 g, 23.3 mmol), and sodium carbonate (4.9 g, 46.5 mmol) were added to dichloroethane (50 mL) and reacted overnight at room temperature under oxygen bulb. The reaction solution was filtered, and the filtrate was extracted with water and dichloromethane. The organic phase was separated, dried under reduced pressure, and purified by column chromatography to give I-1, 3.6 g, yield: 61%.

[0451] Preparation of intermediate J

[0452] I-1 (2.0 g, 9.3 mmol) was dissolved in DMF (20 mL), and iodocyclobutane (1.78 g, 9.8 mmol) and Cs₂CO₃ (4.55 g, 13.9 mmol) were added. The mixture was stirred at 50–60 °C for 6 hours. Water (50 mL) was added to the mixture, and a solid precipitated. The suspension was filtered to give product J, 1.6 g, yield: 63.9%.

[0453] Preparation of intermediate J-1

[0454] I-1 (1.0 g, 4.65 mmol) was dissolved in DMF (10 mL), and (iodomethyl)cyclopropane (0.89 g, 4.9 mmol) and Cs₂CO₃ (2.27 g, 6.98 mmol) were added. The mixture was stirred at 50–60 °C for 4 hours. Water (50 mL) was added to the mixture, and a solid precipitated. The suspension was filtered to give product J-1, 0.87 g, yield: 69.51%.

[0455] Preparation of intermediates K, L, M and N

[0456] K, L, M, and N can be obtained by following the preparation method of intermediate D.

[0457] Preparation of intermediate O (Ulman reaction)

[0458] O-1 (1 eq.) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.5 eq.), CuI (0.5 eq.), the bromide (1.5 eq.), and potassium carbonate (3 eq.) were added to NMP and reacted overnight at room temperature under an oxygen bulb. The mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phase was purified under reduced pressure and then subjected to deprotection reactions (debenzylidene or deBoc reaction) to obtain the target compound.

[0459] The following compounds can be obtained using this method:

[0460] Preparation of intermediate P:

[0461] P-1 (1.0 g, 4.46 mmol), 2-fluoro-5-iodo-1,3-xylene (1.12 g, 4.46 mmol), CuI (0.8 g, 4.46 mmol), TMEDA (0.52 g, 4.46 mmol), and potassium carbonate (0.92 g, 6.69 mmol) were dissolved in dioxane and reacted at 80 °C for 4 hours. After cooling, the mixture was filtered, the filtrate was discarded, and ethyl acetate (20 ml) and water (20 ml) were added. The organic phase was extracted and separated, concentrated under reduced pressure, and then purified by column chromatography to obtain P, 0.6 g, yield: 38.8%.

[0462] Preparation of intermediate Q:

[0463] Under N2 protection, acetonitrile (15.57 g, 379.34 mmol) was added to THF (300 ml), the temperature was lowered to below -78 °C, and LiHMDS (63.47 g, 379.34 mmol) was added dropwise. The reaction was maintained at this temperature for 1 hour, followed by the addition of a THF (5 ml) solution of compound Q1 (45.0 g, 189.67 mmol). The temperature was then raised to -50 °C and the reaction was carried out for 30 minutes. The reaction was quenched by the addition of saturated ammonium chloride solution, and then extracted with ethyl acetate (150 ml). The organic phase was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain a yellow oil.

[0464] Q2 (246.26 mg, 1 mmol) and triethylamine (202.38 mg, 2 mmol) were dissolved in DCM (10 mL), and cyclopropylformyl chloride (209.06 mg, 2 mmol) was added dropwise. The mixture was reacted overnight at room temperature. The reaction solution was quenched with water, and then 10 mL of DCM was added to extract and separate the organic phase. The mixture was then washed with brine, dried over magnesium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain an oily substance.

[0465] Q3 (150 mg, 0.47 mmol) and Pd / C (15 mg, 30% wt) were dissolved in methanol (15 mL) and reacted at room temperature for 3 hours under a hydrogen balloon. The reaction solution was filtered, and the filtrate was purified by SFC to obtain Q3, 32 mg, yield: 40.8%. ¹H NMR (d-DMSO, 500 MHz): δ 4.12 (d, 1H, J = 8.0 Hz), 3.35 (m, 1H), 3.12–3.07 (m, 2H), 2.63–2.55 (m, 2H), 1.47–1.32 (m, 5H).

[0466] Preparation of intermediate R:

[0467] R-1 (10.0 g, 68.87 mmol) and triethylamine (13.9 g, 138 mmol) were dissolved in DCM, and (Boc)₂O (18.0 g, 82.64 mmol) was added. The mixture was reacted overnight at room temperature. The reaction solution was quenched with 100 mL of water, and then extracted with 100 mL of DCM. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give R-2, 15.3 g, yield: 90.56%.

[0468] R-2 (15.0 g, 61.1 mmol) was dissolved in an ammonia-methanol solution (10 M, 300 ml), then transferred to an autoclave and heated to 90–100 °C for 4 hours. After cooling, the reaction solution was concentrated to dryness under reduced pressure to obtain R-3, which was then directly applied to the next reaction step without purification.

[0469] R-3, TFAA (6.90 ml, 49.5 mmol), and pyridine (8.0 ml, 99.0 mmol) were added to a three-necked flask and reacted at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic phase was extracted and separated. The organic phase was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain R-4, 5.3 g.

[0470] R-4 (5.3 g, 26.7 mmol) was added to ethyl hydrochloride solution (4 M, 30 mL) and stirred at room temperature for 2 hours. The precipitated solid was filtered to give R-5, 3.2 g, yield: 88.9%.

[0471] R-5 (3.2 g, 23.7 mmol) and triethylamine (7.22 g, 71.3 mmol) were dissolved in ethanol (20 mL), and then methyl acrylate (2.15 g, 24.9 mmol) was added. The mixture was heated to 70 °C and reacted for 3 hours. After cooling to room temperature, (Boc)₂O (6.74 g, 30.9 mmol) was added, and the reaction was continued overnight. Water (50 mL) and ethyl acetate were added, and the organic phase was extracted and separated. The organic phase was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain R-7, 4.3 g, yield: 63.6%.

[0472] R-7 (4.0 g, 14.1 mmol) and potassium tert-butoxide (2.37 g, 21.1 mmol) were dissolved in THF and reacted at room temperature for 1 hour. The reaction was quenched with 2N hydrochloric acid, and the mixture was extracted with water and ethyl acetate. The organic phase was separated, washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain R, 2.5 g, yield: 70.4%.

[0473] Preparation of intermediate S:

[0474] Based on the preparation method of intermediate R, intermediate S can be obtained by chiral separation via SFC.

[0475] Preparation of intermediate T:

[0476] T-1 (10.0 g, 59.3 mmol) was dissolved in THF (100 ml), and boron tribromide (120 ml, 1 M in DCM) was added dropwise. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated sodium carbonate solution, and then extracted with DCM. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain T-2, 8.5 g, yield: 92.7%.

[0477] T-2 (8.0 g, 51.8 mmol) and triethylamine (7.8 g, 77.6 mmol) were dissolved in DCM, cooled to 0 °C, and Cb2-Cl (9.71 g, 56.9 mmol) was added dropwise. After reacting for 2 hours, the reaction solution was quenched with saturated sodium carbonate solution, and then DCM was added again. The organic phase was extracted, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain T-3, 11.2 g, yield: 74.9%.

[0478] T-3 (10.0 g, 34.6 mmol), Pd / C (1.0 g, 30% wt), and 0.5 mL HCl (1 M in H2O) were dissolved in methanol and reacted at a hydrogen pressure of 50 Psi for 2 hours. The reaction solution was filtered, and the solvent was removed under reduced pressure. DCM and saturated sodium bicarbonate solution were added to extract the organic phase. The extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by FLASH to obtain the racemic compound. The racemic compound was then purified by SFC chiral purification to obtain T, 1.2 g, yield: 21.8%.

[0479] Preparation of intermediate AA:

[0480] Compound AA-1 (1.0 g, 4.35 mmol) was dissolved in ethanol (10 ml), and 5 ml of hydrogen peroxide (30%, 10 ml) was added at room temperature. The reaction mixture was allowed to react overnight. The reaction solution was filtered to obtain AA, 1.1 g, yield: 96.6%.

[0481] Preparation of intermediate AB:

[0482] AB-1 (5.0 g, 20.2 mmol) was dissolved in 25 mL of concentrated sulfuric acid. Potassium nitrate (2.1 g, 20.2 mmol) was added in portions at -20 °C, and the reaction was maintained at this temperature for 4 hours. The reaction solution was poured into ice water, and a solid precipitated. After drying the solid, AB-2 (0.7 g) was obtained by column chromatography, yielding 11%.

[0483] AB-2 (0.7 g, 2.4 mmol) was dissolved in methanol (5 ml), followed by the addition of saturated ammonium chloride (5 ml) and iron powder (0.54 g, 9.6 mmol). The mixture was heated to 80 °C and reacted for 3 hours. After cooling to room temperature, 20 ml of ethyl acetate was added, and the mixture was extracted to obtain AB-3, 0.54 g, yield: 86%.

[0484] AB-3 (0.54 g, 2.0 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.20 g, 2.0 mmol) and (Boc)₂O (0.45 mmol) were added at room temperature, and the mixture was stirred overnight at room temperature. Iodomethane (0.29 g, 2.0 mmol) was added dropwise to the reaction mixture, and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated to dryness, and ethyl hydrochloride solution (5 mL, 2N) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered to obtain AB, 0.32 g, yield: 49.7%.

[0485] Preparation of intermediate AC:

[0486] At 0 °C, D-3 (290 mg, 0.77 mmol), 1H-imidazolium-1-sulfonyl azide (139.99 mg, 0.81 mmol), and potassium carbonate (212.84 mg, 1.54 mmol) were added to methanol (3 mL), followed by copper sulfate hydrate (1.9 mg, 0.0077 mmol). The reaction mixture was reacted at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine, respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain an oily substance AC, 0.15 g, 48%.

[0487] Preparation of intermediate AD:

[0488] AD-1 (2.0 g, 7.84 mmol), TMSCN (1.16 g, 11.8 mmol), triethylamine (1.59 g, 15.7 mmol), cuprous iodide (1.49 g, 7.8 mmol), and tetraphenylphosphine palladium (900 mg, 0.8 mmol) were added to dioxane (20 mL). The mixture was heated to 70°C overnight under nitrogen protection. After cooling to room temperature, water and ethyl acetate were added, and the mixture was extracted, concentrated, and then purified by column chromatography to obtain AD-2, 1.1 g, yield: 51.5%.

[0489] AD-2 (1.1 g, 4.0 mmol) was added to methanol, followed by potassium carbonate (1.1 g, 8.1 mmol). The mixture was stirred at room temperature for 4 hours. After extraction with water and ethyl acetate, the organic phase was concentrated to dryness and purified by column chromatography to give AD, 0.35 g, yield: 43.3%.

[0490] Preparation of intermediate AE:

[0491] AC (100 mg, 0.25 mmol) and AD (55 mg, 0.27 mmol) were dissolved in PEG200 (2 ml), and CuI (9.5 mg, 0.05 mmol) was added. The mixture was reacted at 50 °C for 2 hours. After cooling to room temperature, the reaction solution was filtered and purified by preparative liquid chromatography (C18) to obtain AE, 123 mg, 82%.

[0492] Preparation of intermediate AF:

[0493] Compound AF-1 (300 mg, 1.00 mmol) was dissolved in DMSO (10 mL), followed by the addition of diphenyl(vinyl)sulfonium trifluoromethanesulfonate (0.40 g, 1.1 mmol) and DBU (0.46 g, 3 mmol). The reaction was carried out at room temperature for 2 hours. Ethyl acetate (50 mL) and water (20 mL) were added dropwise to the reaction mixture, and the organic phase was extracted and separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give AF, 154 mg, yield: 47.22%.

[0494] Preparation of Compound 1

[0495] Intermediate A (180 mg, 0.44 mmol), O-6 (280 mg, 0.57 mmol), HATU (250.95 mg, 0.66 mmol), and DIPEA (170 mg, 1.32 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 3 hours. 5 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined. The solution was concentrated under reduced pressure and then purified by preparative liquid chromatography (acetonitrile: 0.1% formic acid aqueous solution) to obtain 1,200 mg of the target compound, yield: 51%.

[0496] Preparation of sodium salt of compound 19

[0497] Compound 19 (1 g, 1.14 mmol) was added to dichloromethane (5 ml) and methanol (5 ml), and stirred until homogeneous. A methanol solution of NaOH (50 mg, 1.25 mmol, 1 ml) was added dropwise at room temperature, and the reaction mixture was stirred overnight. The reaction solution was concentrated to dryness, then slurried with methyl ether and dried to obtain 0.95 g of the sodium salt of compound 19, yield 95%. Melting point: 255-260 °C.

[0498] Preparation of calcium salt of compound 19

[0499] Sodium salt of compound 19 (0.5 g, 0.55 mmol) was added to THF (5 ml) and stirred until homogeneous. After adding calcium acetate (89.34 mg, 0.56 mmol) and clarifying the reaction solution, stirring was continued for 8 hours. The reaction solution was concentrated to dryness, slurried with a mixture of dichloromethane (1 ml) and methyl ether (10 ml), filtered, and dried to obtain a white solid, 0.45 g, yield: 88%. Melting point: 272-277℃.

[0500] Preparation of compound 33

[0501] B (3.36 g, 6.3 mmol), O-1 (3.66 g, 9.4 mmol), HOBT (1.29 g, 9.4 mmol), and DIEA (2.47 g, 18.9 mmol) were added sequentially to 15 mL of DMA under stirring. The system was cooled to 0 °C, and EDCI (1.84 g, 9.4 mmol) was added. The mixture was then stirred overnight at room temperature. The reaction solution was poured into water and extracted with EA (100 mL x 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. The crude product was purified by column chromatography (PE:EA = 1:2) to give the target compound 33, 2.587 g, yield: 97%.

[0502] Preparation of sodium salt of compound 33

[0503] Compound 33 (2 g, 2.24 mmol) was added to dichloromethane (5 ml) and methanol (5 ml), and stirred until homogeneous. A methanol solution of NaOH (94 mg, 2.35 mmol, 1 ml) was added dropwise at room temperature, and the reaction mixture was stirred overnight. The reaction solution was concentrated to dryness, then slurried with methyl ether and dried to obtain 1.95 g of the sodium salt of compound 33, with a yield of 95%.

[0504] Preparation of calcium salt of compound 33

[0505] Sodium salt of compound 33 (1 g, 1.09 mmol) was added to THF (5 ml) and stirred until homogeneous. After adding calcium acetate (181 mg, 1.15 mmol) and clarifying the reaction solution, stirring was continued for 8 hours. The reaction solution was concentrated to dryness, slurried with a mixture of dichloromethane (1 ml) and methyl ether (10 ml), filtered, and dried to obtain a white solid, 0.85 g, yield: 85.3%.

[0506] The following compounds were prepared according to the preparation method described herein, using appropriate starting materials and intermediates, and, where necessary, appropriate protecting group chemistry. Their structures were analyzed by MS and... 1 HNMR confirmed.

[0507] Table 1. Compound structures and MS data. 1 HNMR parameters

[0508] Example 2: In vitro activity evaluation

[0509] (1).hGLP-1R cAMP Assay

[0510] 1. Cell line and reagent preparation

[0511] 1) Cell line: Flp-In-293-hGLP1R

[0512] 2) Culture medium: DMEM + 10% FBS + 1X Penicillin-Streptomycin + 200μg / mL HB

[0513] 3) Test buffer: 1X HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX

[0514] 2. Agonist Testing

[0515] a) Flpin-293-GLP1R cells were seeded in a 384-well assay plate (6007680-50, PE) using complete culture medium, with 2,000 cells per well.

[0516] b) Prepare the 4X complex working solution using the detection buffer.

[0517] c) Add 5 μL of 4X compound working solution to the cell plate and incubate at 37°C for 30 minutes.

[0518] d) Dilute the Eu-cAMP tracer (1 / 50) with lysis buffer, and then add 10 μl / well to the detection plate.

[0519] e) Dilute Ulight-anti-cAMP (1 / 150) with lysis buffer, then add 10 μl / well to the detection plate.

[0520] f) Incubate at a constant temperature for 1 hour.

[0521] g) Read the tablet at wavelengths of 665 nm and 615 nm on the Envision2105 tablet reader.

[0522] 3. Data Analysis

[0523] 3.1% Activity is calculated using the following formula: %Activity = 100 - (Signal) cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100.

[0524] 3.2 Calculate EC 50 And plot the effect-dose curve of cmpds: Y=Bottom+(Top-Bottom) / (1+10^((LogEC) 50 -X)*HillSlope)).

[0525] X: Logarithm of agonist concentration;

[0526] Y: Percentage of activity.

[0527] Table 2 shows the bioactivity of different compounds in the hGLP-1R agonist cAMP stimulation assay as follows:

[0528] Table 2: Bioactivity of different compounds in the hGLP-1R agonist cAMP stimulation assay (EC50)

[0529] Example 3: Pharmacokinetic Study

[0530] 1. PK study of single subcutaneous administration in SD rats

[0531] PK studies of compounds Orforglipron 1, 13, 18, 19, 21, or 20 administered via single subcutaneous injection: Animals: Male Sprague-Dawley (SD) rats (n=3); Solvent formulation: 80% MCT + 20% benzyl alcohol; Dosage: 30 mg / kg; Concentration: 30 mg / mL; Volume: 1 mL / kg; Administration site: Subcutaneous injection into the skin on the back. Blood collection time points: 0h, 1h, 2h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 216h, 312h, 480h, 696h. Sample collection: Approximately 0.15 mL of blood was collected from the jugular sinus at each time point and placed in EDTA-K2 anticoagulant tubes. Blood samples were collected, precipitated for protein, and analyzed using a liquid chromatography-mass spectrometry (LC / MS / MS) system. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software, and the data are shown in Table 3.

[0532] Table 3. Drug exposure of different compounds after a single subcutaneous injection. Note: AUC 0-696h It is an important parameter in pharmacokinetics, referring to the area under the curve from 0 to the end of the study (696 hours), representing the amount of drug exposed in the body during that time period.

[0533] The structure of Orforglipron is as follows:

[0534] 1. Single-dose oral administration pharmacokinetic study

[0535] Single-dose oral pharmacokinetic (PK) studies of compounds 19, 20, 33, 45, 65, and orforglipron: Animals: Male Sprague-Dawley (SD) rats (n=3); Solutol:PEG400:Tween80:Saline = 10:40:2:48 (v / v / v / v); Dosage: 5 mg / kg; Dosage concentration: 0.5 mg / mL; Dosage volume: 10 mL / kg; Sampling time points: before administration, 0.25, 0.5, 1, 2, 3, 4, 8, 12, 18, 24, 32, 40, 48 hours; Sample collection: Approximately 0.15 mL of blood was collected from the jugular sinus at each time point and placed in EDTA-K2 anticoagulant tubes. Blood samples were collected, precipitated for protein, and analyzed by liquid chromatography-mass spectrometry (LC / MS / MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 software, and the data are shown in Table 4.

[0536] Table 4: Pharmacokinetic parameters of different compounds after a single oral administration Note: Cmax This refers to the highest blood drug concentration in plasma after administration.

[0537] Example 4: Preparation of solid dispersion particles by rotary evaporation granulation

[0538] Sodium salts of the active compounds disclosed herein (i.e., sodium salts of API, including but not limited to sodium salts of compounds 19 and 33), copovidone VA64, and poloxamer 407 were dissolved in ethanol at a prescribed amount, and then dried by rotary evaporation at 40–60°C. The dried product was then mechanically pulverized, sieved through a 140-mesh sieve, and dried at 60°C to obtain solid dispersion particles 1, 2, 3, and 4.

[0539] Table 5: Formulation of solid dispersion particles

[0540] Ethanol is removed during the process, and the final solid dispersion particles do not contain ethanol.

[0541] Example 5: Preparation of solid dispersion particles by spray drying

[0542] Sodium salts of the active compounds of this disclosure (i.e., API sodium salts, including but not limited to sodium salts of compounds 19 and 33), copovidone VA64, and poloxamer 407, in the prescribed amounts of solid dispersed particles 1 in Table 5, are dissolved in ethanol and spray-dried at a temperature of 80–100°C and an atomization pressure of 0.5–4 Bar. The dried product is then sieved through a 140-mesh sieve to obtain solid dispersed particles 5.

[0543] Example 6: Preparation of solid dispersion particles by hot melt extrusion

[0544] The sodium salts of the active compounds disclosed herein (i.e., API sodium salts, including but not limited to sodium salts of compounds 19 and 33), copovidone VA64, polyethylene glycol 6000, and poloxamer 407 were mixed evenly and placed in a hot melt extruder. The mixture was then hot melt extruded at 120±10°C. The resulting extrudate was then mechanically pulverized at 28,000 rpm for 5 minutes and sieved through a 60-mesh sieve to obtain solid dispersed particles 6 and 7.

[0545] Table 6: Formulation of solid dispersion particles

[0546] Example 7: In vitro dissolution detection

[0547] Take 1-7 solid dispersion particles containing 10mg API according to the prescription amount and add them to 900mL of 0.7% Tween 80 pH 6.8 phosphate buffer solution. Maintain the medium temperature at 37℃ and the stirring speed at 75rpm. Take a sample 60min after stirring and filter it through a 0.45um filter membrane. Perform HPLC dissolution test on the filtrate.

[0548] The API is either compound 19 or compound 33.

[0549] The results showed that the dissolution rate of the solid dispersion particles was above 85%, indicating that the solid dispersion particles all had good in vitro release rate.

[0550] Comparative Example 1:

[0551] According to the formulation amount of solid dispersion particles 1 in Table 5, the active compound of this disclosure (i.e., API, including but not limited to the sodium salt of compound 19) was co-pulverized with copovidone VA64 and poloxamer 407 at 28,000 rpm for 5 min to obtain a pulverized mixture. 13.4 mg of the pulverized mixture was placed in 900 mL of 0.7% Tween 80 pH 6.8 phosphate buffer solution, maintaining a medium temperature of 37°C and a stirring speed of 75 rpm. A sample was taken 60 min after stirring and filtered through a 0.45 μm filter. The filtrate was then subjected to HPLC dissolution analysis. The results showed that the above-mentioned pulverized mixture was almost impossible to dissolve.

[0552] Comparative Example 2:

[0553] According to the formulation amount of solid dispersion particles 3 in Table 5, the active compound of this disclosure (i.e., API, including but not limited to the sodium salt of compound 33) was co-pulverized with copovidone VA64 and poloxamer 407 at 28,000 rpm for 5 min to obtain a pulverized mixture. 13.5 mg of the pulverized mixture was placed in 900 mL of 0.7% Tween 80 pH 6.8 phosphate buffer solution, maintaining a medium temperature of 37°C and a stirring speed of 75 rpm. A sample was taken 60 min after stirring and filtered through a 0.45 μm filter membrane. The filtrate was then subjected to HPLC dissolution analysis. The results showed that the above-mentioned pulverized mixture was almost insoluble.

[0554] Example 8: Preparation of gastric-coated tablets

[0555] Take the prescribed amount of sodium salt of the active compound of this disclosure (i.e., API sodium salt, including but not limited to sodium salt of compound 19), copovidone VA64 and poloxamer 407, and prepare solid dispersion particles according to the preparation method in "Example 4", and further add other excipients to prepare gastric-coated tablets.

[0556] Table 7: Prescription for Gastric Coated Tablets

[0557] Ethanol is removed during the manufacturing process, and the final tablets do not contain ethanol.

[0558] Film coatingpremix 85F18422-CN1 The gastric coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0559] Example 9: Preparation of enteric-coated tablets

[0560] Take the prescribed amount of sodium salt of the active compound of this disclosure (i.e., API sodium salt, including but not limited to sodium salt of compound 19), copovidone VA64 and poloxamer 407, and prepare solid dispersion particles according to the preparation method in "Example 5", and further add other excipients to prepare enteric-coated tablets.

[0561] Table 8: Formula for Enteric-Coated Tablets

[0562] Ethanol is removed during the manufacturing process, and the final tablets do not contain ethanol.

[0563] Film coatingpremix 03K19229-CN 1 The isolation coating material's main component is hydroxypropyl methylcellulose.

[0564] Film coatingpremix 93A19326-CN 2 Enteric coating material, the main component of which is methacrylic acid copolymer.

[0565] Example 10: Preparation of enteric-coated tablets

[0566] Take the prescribed amount of sodium salt of the active compound of this disclosure (i.e., API sodium salt, including but not limited to sodium salt of compound 19 and compound 33), copovidone VA64, polyethylene glycol 6000, and poloxamer 407, and prepare solid dispersion particles according to the preparation method in "Example 6". Further add other excipients to prepare enteric-coated tablets.

[0567] Table 9: Formula for Enteric-Coated Tablets

[0568] Film coatingpremix 03K19229-CN 1 The isolation coating material's main component is hydroxypropyl methylcellulose.

[0569] Film coatingpremix 93A19326-CN 2 Enteric coating material, the main component of which is methacrylic acid copolymer.

[0570] Example 11: Oral PK Test in Beagles

[0571] Oral pharmacokinetic (PK) tests were conducted on the formulations of Examples 8 to 10 in beagle dogs. Dosage information and PK results are shown in Table 10.

[0572] The sodium salt of API is the sodium salt of compound 19.

[0573] Compound 19

[0574] Table 10: Dosage information and PK results of oral PK test in beagle dogs AUC last * Area under the plasma drug-time curve

[0575] Specifications refer to the weight of each tablet containing compound 19.

[0576] The various dosage forms disclosed herein can achieve high exposure levels in beagle dogs.

[0577] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A pharmaceutical composition comprising the following components: (a) GLP-1R agonists; (b) Copolyvinylpyrrolidone; (c) Polosham; wherein the GLP-1R agonist has the structure of Formula (VI), or a stereoisomer, pharmaceutically acceptable salt, or deuterated compound thereof: Where X, Z4, and Z6 are independently selected from N or CH; R z2 selected from C 3-8 cycloalkyl or C 1-6 alkyl-C 3-8 cycloalkyl; R z2 optionally substituted with halo, -OH, C 1-6 alkyl or C 1-6 alkoxy; Q2is selected from:

2. The pharmaceutical composition of claim 1, wherein the R z2 selected from 3. A pharmaceutical composition comprising the following components: (a) GLP-1R agonists; (b) Copolyvinylpyrrolidone; (c) Polosham; wherein the GLP-1R agonist is selected from the group consisting of: Or its stereoisomers, pharmaceutically acceptable salts, or deuterated compounds.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutically acceptable salt is selected from sodium salts, calcium salts, potassium salts, magnesium salts, or lithium salts.

5. The pharmaceutical composition of claim 3, wherein the GLP-1R agonist is selected from Or its sodium salt.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the copovidone is copovidone VA64; and the poloxamer is poloxamer 407.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the mass parts of each component are as follows: (a) GLP-1R agonist: 1 dose; (b) Copovidone: 0.1–50 parts; (c) Poloxamer: 0.05–25 parts.

8. The pharmaceutical composition of claim 6, wherein the mass parts of each component are as follows: (a) GLP-1R agonist: 1 dose; (b) Copovidone: 0.1–10 parts; (c) Poloxamer: 0.05 to 1 part.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition is a solid dispersion particle.

10. The pharmaceutical composition of claim 9, wherein the solid dispersion particles are prepared by rotary granulation, the rotary granulation method comprising the following steps: (1) Dissolve components (a), (b), and (c) in ethanol and dry them by rotary evaporation at 40–60 °C. (2) The dried product obtained in step (1) is crushed, sieved and dried to obtain solid dispersed particles.

11. The pharmaceutical composition of claim 9, wherein the solid dispersion particles are prepared by a spray-drying method comprising the steps of: Components (a), (b), and (c) were dissolved in ethanol and spray-dried at 80–100 °C to obtain solid dispersed particles.

12. The pharmaceutical composition according to any one of claims 1-8, further comprising component (d): polyethylene glycol.

13. The pharmaceutical composition of claim 12, wherein the polyethylene glycol is polyethylene glycol 6000, preferably, the mass ratio of which to the GLP-1R agonist is 0.5:1-10:

1.

14. The pharmaceutical composition of any one of claims 12-13, wherein the pharmaceutical composition is a solid dispersion granule, and the solid dispersion granule is prepared by a hot-melt extrusion method comprising the steps of: After the components (a), (b), (c) and (d) are mixed evenly, they are placed in a hot melt extruder and hot melt extruded at 110-130°C. The resulting extrudate is then mechanically crushed to obtain solid dispersed particles.

15. A gastric-coated tablet comprising the pharmaceutical composition as described in any one of claims 1-14, and a filler, a lubricant, and a gastric-coating material; Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate; Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate; Preferably, the gastric coating material comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

16. The gastric-coated tablet of claim 15, further comprising a disintegrant, preferably selected from one or more of the following: croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, starch, pregelatinized starch, or low-substituted hydroxypropyl cellulose.

17. The gastric-coated tablet of any one of claims 15-16, further comprising a pH buffer, preferably selected from one or more of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, sodium citrate, or sodium acetate.

18. The gastric-coated tablet of claim 17, wherein the filler is mannitol and / or microcrystalline cellulose; the lubricant is magnesium stearate; the disintegrant is croscarmellose sodium and / or croscarmellose; and the pH buffer is sodium carbonate.

19. The gastrointestinal coated tablet of claim 18, wherein the percentage (w / w) of each component in the gastrointestinal coated tablet is as follows: Filler: 30%–80%; Lubricant: 0.5%–3%; Gastric coating material: 2%–4%. Disintegrant: 3%–10%; 20. An enteric-coated tablet comprising the pharmaceutical composition as described in claims 1-14, and a filler, a lubricant, a pH buffer, and an enteric coating material; Preferably, the filler is selected from one or more of the following: mannitol, silicified microcrystalline cellulose, starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, sucrose, or magnesium silicate; Preferably, the lubricant is selected from one or more of the following: magnesium stearate, sodium fumarate, stearic acid, or calcium stearate; Preferably, the pH buffer is selected from one or more of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, sodium citrate, or sodium acetate. Preferably, the enteric coating material is selected from one or more of the following: cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose succinate (HPMCAS), or methacrylic acid copolymer.

21. The enteric-coated tablet of claim 20, further comprising a disintegrant, preferably selected from one or more of the following: croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, starch, pregelatinized starch, or low-substituted hydroxypropyl cellulose.

22. The enteric-coated tablet of any one of claims 20-21, further comprising a release liner material.

23. The enteric-coated tablet of claim 22, wherein the filler is mannitol and / or microcrystalline cellulose; preferably, the lubricant is magnesium stearate; preferably, the pH buffer is sodium carbonate; preferably, the enteric coating material is a methacrylic acid copolymer; preferably, the disintegrant is croscarmellose sodium and / or croscarmellose; preferably, the release liner material comprises hydroxypropyl methylcellulose.

24. The enteric-coated tablet of claim 23, wherein the percentage (w / w) of each component in the enteric-coated tablet is as follows: Filler: 30%–80%; Lubricant: 0.5%–3%; Enteric-coated packaging material: 5%–10%; Disintegrant: 3%–10%; Insulation pack material: 2%–4% 25. A method of treating a GLP-1 mediated disease or condition comprising: Administer to an individual who requires the method a therapeutically effective amount of the pharmaceutical composition as described in any one of claims 1-14, the gastric-coated tablet as described in any one of claims 15-19, or the enteric-coated tablet as described in any one of claims 20-24; Preferably, the GLP-1-mediated diseases or symptoms are selected from: type 1 diabetes, type 2 diabetes, prediabetes, weight management, overweight, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic neuropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, excessive sugar consumption, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, hypertension, endothelial dysfunction, arthritis, osteoporosis, Parkinson's disease, metabolic syndrome, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, Alzheimer's disease, and schizophrenia.

26. The method of claim 25, wherein the GLP-1-mediated disease or symptom is selected from: long-term weight management, chronic kidney disease, non-alcoholic steatohepatitis, malnutrition-related diabetes, gestational diabetes, hepatic insulin resistance, diabetic nephropathy, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, and angioplasty. Restenosis, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperapolipoprotein B lipoproteinemia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or substance addiction.

Images