Norscopolamine pyrazole compound as well as preparation method and application thereof

Abstract

The present invention relates to novel compounds of formula (I) and pharmaceutically acceptable salts thereof, which are capable of modulating the GLP-1 receptor; the invention also relates to salts, solvates, stereoisomers or tautomers thereof, pharmaceutical compositions, processes for their preparation and therapeutic uses.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine.

[0002] This invention relates to compounds for treating GLP1 receptor-mediated diseases (such as diabetes, obesity, and non-alcoholic steatohepatitis), and more specifically to indazolinone GLP1 receptor agonists and their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxygen compounds, isotope labels, prodrugs, etc. Background Technology

[0003] GLP1R (Glucagon-like peptide 1 receptor) belongs to the class B GPCR family. After food is ingested, intestinal L cells secrete incretin GLP1. This hormone stimulates GLP1 receptors in a glucose-dependent manner, promoting insulin secretion from pancreatic β cells and regulating blood glucose homeostasis. At the same time, it leads to decreased gastrointestinal motility, increased satiety, and decreased appetite.

[0004] In the fields of type 2 diabetes and obesity, several peptide GLP1 receptor agonists have been launched. In the fields of NASH and neurodegenerative diseases, GLP1R agonists have also shown preclinical / clinical therapeutic potential, and related clinical explorations are actively underway. However, most currently marketed peptide drugs require subcutaneous injection, affecting patient adherence. Among the marketed peptide drugs, only semaglutide can be taken orally; the rest require subcutaneous injection, impacting patient adherence. Although semaglutide uses absorption enhancers, its oral bioavailability is still only 1-2%, resulting in a significantly higher oral dosage compared to injectable formulations. Furthermore, oral semaglutide requires a 6-hour fast and a further 30-minute fast after administration, which to some extent affects patient convenience and fails to achieve the intended goal of convenient oral administration. Therefore, there is a clinical and market demand for oral small molecule GLP1R agonists.

[0005] Publicly available patent applications for small molecule GLP-1 receptor agonists include WO2009111700A2, WO2010114824A1, WO2019239319A1, CN109790161A, CN116390926A, CN117069743A, and WO2023169456A1. OWL833, TTP-273, PF-06882961, and LY-3502970 are several representative small molecule oral drugs currently undergoing clinical trials, possessing distinct molecular structures and modes of action. PF-06882961, an original small molecule drug developed by Pfizer, demonstrated good blood sugar lowering and weight control effects in Phase 2 clinical trials. However, based on publicly available information, this drug still has some attributes that can be optimized, such as reducing the frequency of clinical dosing and reducing the risk of potential off-target adverse reactions. Therefore, there is a need for an orally administered GLP1R agonist that is effective and has few side effects. Summary of the Invention

[0006] This invention relates to a class of novel compounds or their salts, solvates, stereoisomers, or tautomers. The compounds of this invention regulate GLP-1 levels in vivo by activating GLP-1 receptors, thereby promoting insulin secretion from pancreatic β-cells and regulating blood glucose homeostasis. The compounds of this invention can be used to treat or prevent GLP-1 receptor-mediated diseases or disorders, or to regulate GLP-1 receptors, including the treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity.

[0007] 1. This invention provides a compound of formula (Ⅰ):

[0008]

[0009] or its salts, solvates, stereoisomers or tautomers, wherein:

[0010] yes

[0011] Q 1 It can be optionally used by 0-3 identical or different Rs. a Substituted monocyclic or bicyclic aryl or cycloalkyl;

[0012] Q 2 It can be optionally used by 0-3 identical or different Rs. b Substituted monocyclic or bicyclic aryl, cycloalkyl, heterocyclic or heteroaryl groups;

[0013] Q 3 It can be optionally used by 0-2 identical or different Rs c Substituted monocyclic heteroaryl or heterocyclic group;

[0014] T is selected from the following groups:

[0015]

[0016] Where T 1 Is it a key or C? 1-10 Alkylene, R T It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl)-, R T1 and R T2 Each is independently hydrogen or C 1-6 Alkyl group, m is 1, 2 or 3 (* indicates the connection position with the pyrazolopyridine structure, ** indicates the connection position with Q). 2 (connection location);

[0017] L is -C(O)-, -CR L1 R L2 -、-S(O)2-、-S(O-)- or -NHC(O-), where R L1 and R L2 Each is independently hydrogen, halogen, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0018] A can be optionally represented by 0-3 identical or different Rs. 4 Substituted bicyclic heteroaryl groups;

[0019] B can be optionally represented by 0-3 identical or different Rs. 5 Substituted monocyclic or bicyclic heteroaryl or heterocyclic groups;

[0020] R 1 Each is independently hydrogen, halogen, or C. 1-6 Alkyl; or, R 1 The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted;

[0021] R 2 and R 3 Each is independently hydrogen, halogen, or C. 1-6 Alkyl; or R 2 and R 3 The atoms bonded to them together form cycloalkyl or heterocyclic groups, which may optionally be formed by 0-3 identical or different halogens or carbon atoms. 1-6 Alkyl groups are substituted;

[0022] R 4 Each is independently a halogen, C 1-6 Alkyl, C1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted;

[0023] R 5 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl-substituted; or, R 5 The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted;

[0024] R a Each is independently a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted;

[0025] R b Each is independently a halogen, amino, or C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or -P(O)R b1 R b2 The amino group, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl-substituted; or, R b The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted;

[0026] R b1 and R b2 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0027] R c Each is independently an oxygen, hydroxyl, or C group. 1-6 alkyl;

[0028] n is an integer from 1 to 3.

[0029] On the other hand, the specific compounds provided by the present invention include, but are not limited to, the following compounds:

[0030]

[0031]

[0032] On the other hand, this invention is intended to include all isotopes of atoms in all compounds. The isotope-labeled compounds of this invention can generally be prepared using conventional techniques known in the art or by methods similar to those described in this application, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0033] On the other hand, this invention is intended to include tautomers of all compounds, unless otherwise specified. A tautomer is a proton that has moved from one atom of a molecule to another atom of the same molecule, examples of which include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, etc.

[0034] On the other hand, this invention is intended to include all stereoisomers of compounds, such as enantiomers and diastereomers, unless otherwise specified. Compounds of this invention containing asymmetrically substituted carbon atoms can be separated in either optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Various geometrical isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers should be included in this invention.

[0035] On the other hand, the present invention provides a method for preparing compound (I):

[0036]

[0037] in:

[0038] PG1 is an amino protecting agent, such as alkoxycarbonyl, benzyl, or acyl protecting agents. More specific examples include benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, triphenylmethyl, trifluoroacetyl, phthaloyl, p-toluenesulfonyl, etc., preferably benzyloxycarbonyl and tert-butoxycarbonyl, and even more preferably tert-butoxycarbonyl. LG1 is a leaving group, such as trifluoromethanesulfonyloxy, -Br, -I, -B(OH)2, alkoxyboronyl, etc., preferably -Br and -B(OH)2.

[0039] The reaction conditions for each step are as follows:

[0040] Step 1: The reactant of formula 1-1 undergoes a substitution reaction with a cyaniding reagent in the presence of a base to obtain formula 1-2. The base includes sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, LDA, butyllithium, etc., preferably LDA. The cyaniding reagent includes cyanogen chloride, benzene cyanate, N-cyano-N-phenyl-p-toluenesulfonamide, 4-toluenesulfonyl cyanide, preferably 4-toluenesulfonyl cyanide and N-cyano-N-phenyl-p-toluenesulfonamide, more preferably 4-toluenesulfonyl cyanide. The reaction is carried out in a suitable solvent, including 1,4-dioxane, tetrahydrofuran, methyl tert-ethyl ether, ethylene glycol dimethyl ether, etc., preferably tetrahydrofuran.

[0041] Step 2: The reactant of formula 1-2 with an aromatic hydrazine intermediate yields the cyclic-closed aminopyrazole intermediate of formula 1-3. The reaction is carried out in a suitable solvent, including methanol, ethanol, tert-butanol, etc., preferably ethanol. The reaction is carried out at a suitable equivalence ratio, with the equivalence ratio of reactant formula 1-2 to aromatic hydrazine ranging from 0.9:1 to 1:0.9. The reaction is carried out at a suitable temperature, for example, 30-70°C, preferably 40-60°C. The reaction is carried out for a suitable time, for example, 4-24 hours, preferably 8-16 hours.

[0042] Step 3: The reactants of formula 1-3 undergo dehydration condensation with glyoxal-1,1-dimethylacetal to form formula 1-4. The reaction is carried out under suitable equivalence conditions, with the equivalence ratio of reactants of formula 1-3 to glyoxal-1,1-dimethylacetal ranging from 1:1 to 1:6, preferably 1:4. The reaction is carried out in a suitable solvent, including pyridine, toluene, dichloromethane, ethanol, etc., preferably pyridine.

[0043] Step 4: The reactants of formulas 1-4 undergo further condensation and ring closure under acid catalysis to form formulas 1-5. The acid used for catalysis includes methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc., preferably methanesulfonic acid. The reaction is carried out at a suitable equivalence ratio, with the equivalence ratio of reactants of formulas 1-4 to the catalytic acid ranging from 1:1 to 1:4, preferably 1:2. The reaction is carried out in a suitable solvent, including tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, etc., preferably tetrahydrofuran. The reaction is carried out at a suitable temperature, ranging from 40-80°C, for example 50°C, 60°C, etc., preferably 60°C. The reaction is carried out for a suitable time, which is 1-4 hours.

[0044] Step 5: The starting materials of formulas 1-5 undergo a coupling reaction with aromatic intermediates substituted with leaving group LG1 to obtain formulas 1-6. The catalysts used in the coupling reaction include Cu(OAc)2, CuI, CuBr, CuF2, PdCl2, Pa(OAc)2, Pd2dba3, Pd(dppf)Cl2, etc., preferably CuI, CuF2, Pa(OAc)2, Pd2dba3, etc. The ligands used in the coupling reaction include (1R,2R)-N1,N2-dimethylcyclohexyl-1,2-diamine, 4,7-dimethoxy-1,10-o-diazaphenanthroline, 1,10-phenanthroline, X-Phos, S-Phos, BrettPhos, JohnPhos, etc., preferably (1R,2R)-N1,N2-dimethylcyclohexyl-1,2-diamine.

[0045] Step 6: Remove the amine protecting agent from the raw material formulas 1-6 to obtain intermediate formulas 1-7. The deprotection is carried out using classic methods, such as: for benzyl protecting agents, catalytic hydrogenolysis is generally used; for methoxybenzyl, CAN or DDQ oxidation can also be considered; for tert-butyloxycarbonyl, acid hydrolysis is generally used for deprotection.

[0046] In step seven, the reactants of formulas 1-7 are condensed with aromatic carboxylic acid compounds to obtain formula 1. The condensing agents used in the reaction include DCC, EDC, HATU, TBTU, BOP, PyBOP, TCFH, etc.

[0047] Step 8: Formula 1 is separated by SFC to obtain the single-chiral product Formula 1A.

[0048] On the other hand, the present invention provides pharmaceutical formulations suitable for use in human patients, comprising any of the compounds shown above (e.g., compounds of the present invention, such as compounds having formula (I)) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulations may be used to treat or prevent the conditions or diseases described herein.

[0049] On the other hand, this invention discloses methods for treating or preventing GLP-1 receptor-mediated diseases or disorders, or for modulating GLP-1 receptors. These diseases or disorders include, but are not limited to, metabolic-related diseases such as non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia.

[0050] On the other hand, the present invention discloses a combination therapy of compounds having formula (I) with hypoglycemic drugs, which can enhance the therapeutic benefits for metabolic diseases such as diabetes and obesity beyond the ability of monotherapy.

[0051] The compounds involved in this invention possess agonistic activity against the GLP-1 receptor, for example, according to the assay method described below, the compounds of this invention exhibit ECG activity against GLP-1R. 50 Values ​​less than 100 nM; in some embodiments, the compounds of the present invention exhibit EC50 saturation for GLP1R. 50 Value less than 50 nM; in some embodiments, the compound of the present invention has an EC50 value for GLP1R. 50 Value less than 20 nM; in some embodiments, the compounds of the present invention have an EC50 value for GLP1R. 50 Values ​​less than 10 nM; in some embodiments, the compounds of the present invention exhibit EC50 saturation for GLP1R. 50 Values ​​less than 1 nM; in some embodiments, the compounds of the present invention exhibit EC50 saturation for GLP1R. 50 The value is less than 0.1 nM.

[0052] Terminology Explanation

[0053] Alkyl or alkane are fully saturated straight-chain or branched non-aromatic hydrocarbons. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms. Non-limiting examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also called "lower alkyl groups".

[0054] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, non-limiting examples of such substituents include, for example, halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetate, or thioformate), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azides, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moiety components. Those skilled in the art will understand that, where appropriate, the substituted portion on the hydrocarbon chain can itself be substituted. For example, non-limiting examples of substituted alkyl groups include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphonite), sulfonyl (including sulfate, sulfonamide, aminosulfonyl and sulfonate), and silyl, as well as substituted and unsubstituted forms of ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic esters and esters), -CF3, -CN, etc.

[0055] The cycloalkyl group preferably has 3 to about 20 ring carbon atoms and can be in substituted or unsubstituted forms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, or methylcyclopentyl. The cycloalkyl group can be further substituted with alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0056] Aryl groups are cyclic aromatic groups having 5 to 20 ring carbon atoms. Generally, unless otherwise defined, heteroaryl groups are monocyclic or bicyclic. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, or 2-naphthyl, or bicyclic fused derivatives containing phenyl, such as indanyl, dihydro, or tetrahydronaphthyl.

[0057] A heteroaryl group is an aromatic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Generally, unless otherwise defined, heteroaryl groups are monocyclic or bicyclic. Monocyclic heteroaryl groups include 5- or 6-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Non-limiting examples of heteroaryl groups include pyrroleyl, thiopheneyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, etc., or bicyclic fused derivatives containing a monocyclic heteroaryl group, such as indolyl, benzimidazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, purineyl, etc.

[0058] Heterocyclic groups refer to saturated, partially saturated, or unsaturated monocyclic or bicyclic groups containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, morpholinyl, piperazine, dioxolane, or tetrahydropyranyl, or bicyclic fused derivatives containing a monocyclic heterocyclic group, such as benzopyrrolidinyl, benzopiperidinyl, etc.

[0059] The aryl, heteroaryl, or heterocyclic group may be optionally substituted or unsubstituted. In the optionally substituted aryl, heteroaryl, or heterocyclic group, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl, thio, alkylamino, halogen, mercapto, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo, or carboxylic acid ester group, etc.

[0060] The alkenyl group contains one or more, for example two or three double bonds and is preferably a lower alkenyl group, such as 1- or 2-butenyl, 1-propenyl, allyl or vinyl.

[0061] The alkynyl group is preferably a lower alkynyl group, such as propynyl or ethynyl.

[0062] In the optionally substituted alkenyl or alkynyl group, the substituent is preferably a lower alkyl, lower alkoxy, halo, or di(lower alkyl)amino group and is attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0063] Acyl groups, for example, represent alkyl carbonyl groups, cyclohexyl carbonyl groups, aryl carbonyl groups, aryl-lower alkyl carbonyl groups, or heteroaryl carbonyl groups. Lower acyl groups are preferably lower alkyl carbonyl groups, especially propionyl or acetyl groups.

[0064] Hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl group, preferably a hydroxy-lower alkyl group, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, and hydroxyisopropyl.

[0065] Cyanoalkyl refers to an alkyl group that is substituted with at least one cyano group, preferably a cyano-lower alkyl group, such as cyanomethyl or cyanoethyl.

[0066] A haloalkyl group refers to an alkyl group that is substituted with at least one halogen, preferably a halogen-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0067] Halogens are fluorine, chlorine, bromine or iodine.

[0068] Lower alkoxy groups, especially methoxy, ethoxy, isopropoxy, or tert-butoxy.

[0069] Arylalkyl groups include aryl and alkyl groups as defined above, and are, for example, benzyl, 1-phenylethyl, or 2-phenylethyl.

[0070] Heteroarylalkyl groups include heteroaryl and alkyl groups as defined above, and are, for example, 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolithylmethyl, 1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or 3-(1-imidazolyl)propyl.

[0071] Two adjacent substituents that can form a 5- or 6-membered carbon ring or heterocycle with the atoms of an aryl or heteroaryl group are, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoro-methylenedioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutene, ethylenedioxy, 1- or 2-azabutene, or 1- or 2-azabutadiene, or such groups carrying other substituents as defined above. Detailed Implementation

[0072] Synthesis method

[0073] The abbreviations used in this article have the following meanings:

[0074] Abbreviation meaning

[0075] TLC (Thin Layer Chromatography)

[0076] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0077] DMF N,N-dimethylformamide

[0078] DMSO (dimethyl sulfoxide)

[0079] EA (ethyl acetate)

[0080] PE petroleum ether

[0081] THF Tetrahydrofuran

[0082] LDA (Lithium diisopropylamino)

[0083] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0084] HOBT 1-Hydroxybenzotriazole

[0085] Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0086] SFC Supercritical Fluid Chromatography

[0087] ee enantiomer excess percentage

[0088] PPA polyphosphate

[0089] DCE 1,2-Dichloroethane

[0090] DCM dichloromethane

[0091] DMF N,N-dimethylformamide

[0092] DMSO (dimethyl sulfoxide)

[0093] NBS N-bromosuccinimide

[0094] AIBN (Azobisisobutyronitrile)

[0095] TBD 157-Triazidobicyclo(4.4.0)dec-5-ene

[0096] Solutol 2-hydroxyethyl-12-hydroxyoctadecanoate

[0097] (Boc)2O ditert-butyl dicarbonate

[0098] HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0099] The structures of the compounds described in the following examples were obtained by nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1 Confirmation can be made using 1H-NMR or mass spectrometry (MS).

[0100] 1 H-NMR measurements were performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), with tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) are given in parts per million (ppm).

[0101] The mass spectrometry (MS) instrument used was an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0102] Thin-layer chromatography (TLC) was performed using Merck aluminum plates (20×20cm), while preparative thin-layer chromatography was performed using GF254 silica gel plates (0.4–0.5 mm).

[0103] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The developing solvent system was adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0104] The instrument used for the preparative high-performance liquid chromatography (HPLC) was an Agilent 1260. The column used was a Waters XBridgePrep C18OBD (19 mm × 150 mm × 5.0 μm). The column temperature was 25℃. The flow rate was 20.0 mL / min. The detection wavelength was 214 nm. The elution gradient was (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B). Mobile phase A was 100% acetonitrile, and mobile phase B was 0.05% ammonium bicarbonate aqueous solution.

[0105] Unless otherwise specified, the reaction temperature is room temperature (20℃~30℃).

[0106] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Teber Chemical Technology Co., Ltd., etc.

[0107] Intermediate:

[0108] Preparation of common intermediates

[0109] Preparation of intermediate (Int 1):

[0110]

[0111] Weigh triphosgene (1.98 g, 6.66 mmol) and add it to a three-necked flask. Add dichloromethane (50 mL), purge three times with nitrogen, and cool the system in an ice-water bath. While stirring, slowly add a dichloromethane solution (50 mL) containing INT 1-1 (2.0 g, 19.02 mmol) and triethylamine (3.85 g, 38.05 mmol). After the addition is complete, heat to room temperature and stir for 20 minutes, then reflux for 20 minutes. Cool to room temperature and continue stirring for 3 hours. Wash the system once with water (100 mL) and once with saturated brine (100 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate at 35°C to obtain a yellow liquid INT 1 (2.0 g, yield: 48%, purity: ~60%). HNMR (400MHz, CDCl3), δ: 4.41 (t, J = 5.4Hz, 1H), 3.35 (s, 6H), 3.25 (d, J = 5.6Hz, 2H).

[0112] Preparation of intermediate (Int 2):

[0113]

[0114] Step 1: Add INT 2-1 (4.4 g, 21.67 mmol) and THF (50 mL) to a three-necked flask, purge with nitrogen three times, cool the reaction system to -70°C, and slowly add n-butyllithium solution (9.5 mL, 2.5 M) dropwise. After the addition is complete, continue the reaction at this temperature for 1 hour. Then, heat the system to -40°C and slowly add THF solution (30 mL) containing diethyl diazidocarboxylate (4.99 g, 21.67 mmol) dropwise. After the addition is complete, continue the reaction at this temperature for half an hour. After the reaction was complete, a saturated ammonium chloride solution was slowly added to the reaction mixture, and the temperature was slowly raised to room temperature with stirring for 10 minutes. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether: methyl tert-butyl ether (v / v) = (100:0-50:50)] to give a brown oily substance INT 2-2 (2.8 g, yield: 34%, purity: 92%). LCMS m / z 199.1 [M-100-56+H] + .

[0115] Step 2: Add INT 2-2 (2.2 g, 6.21 mmol), anisole (2.69 g, 24.83 mmol), and dioxane (30 mL) to the reaction flask. While stirring, add dioxane hydrochloride solution (30 mL, 4N). Stir overnight at room temperature under nitrogen protection. After the reaction is complete, filter the reaction system directly. Wash the filter cake three times with a small amount of dichloromethane. Concentrate to obtain a white solid INT 2 (965 mg, yield: 59%, purity: 86%). LCMS m / z 155.1 [M+H] + .

[0116] Example 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyl-2H-4-tetrahydropyranyl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epamidocycloheptane[c]pyrazol-9-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (CMP) 1a) Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyl-2H-4-tetrahydropyranyl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epamidocyclohepta[c]pyrazol-9-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Cmp 1b)

[0117]

[0118] Step 1: Add tetrahydrofuran (30 mL) to a three-necked flask, purge with nitrogen three times, add diisopropylaminolithium (9.6 mL, 1 M), cool the reaction system to -70°C, and slowly add 15 mL of tetrahydrofuran solution containing 1A (1.8 g, 7.99 mmol) dropwise. After the addition is complete, continue the reaction at this temperature for 30 minutes. Slowly add 15 mL of tetrahydrofuran solution containing 4-toluenesulfonyl cyanide (2.9 g, 15.98 mmol) dropwise. After the addition is complete, continue the reaction at -70°C for 30 minutes. Slowly add 3 mL of ammonia water to the reaction, then slowly heat to room temperature and stir for 2 hours. After the reaction was complete, the pH was adjusted to 7 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (60 mL x 2). The organic phases were combined and washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-50:50)] to give a colorless oily substance 1B (1.01 g, yield: 49%, purity: 98%). LCMS m / z 251.1 [M+H] + .

[0119] Steps 2 and 3: INT 2 (785 mg, 3.46 mmol), ethanol (35 mL), hydrochloric acid solution (14 mL, 2 M), and 1B (865 mg, 3.46 mmol) were added sequentially to a single-necked flask. The mixture was purged with nitrogen three times, and the reaction system was stirred overnight at 50°C. After the reaction was complete, saturated sodium bicarbonate solution (30 mL) and tetrahydrofuran (30 mL) were slowly added to the reaction flask, followed by di-tert-butyl dicarbonate (1.13 g, 5.18 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL x 2), the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-50:50)] to obtain a pale yellow solid 1D (1.05 g, two-step yield: 78%, purity: 99%). LCMS m / z 387.3 [M+H] + .

[0120] Step 4: Weigh raw material 1D (510 mg, 1.32 mmol) into a single-necked flask, add pyridine (15 mL), and under nitrogen protection, place the system in an ice-water bath. Slowly add INT 1 (692 mg, 5.28 mmol) with stirring, purging with nitrogen three times, and stirring overnight at room temperature. After the reaction is complete, dilute the system with ethyl acetate. Wash the organic phase with 0.5 N hydrochloric acid solution until no pyridine is visible, wash once with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate to obtain the crude product, and purify by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-40:60)] to obtain a white solid 1E (550 mg, yield: 77%, purity: 96%). LCMS m / z 518.3 [M+H] + .

[0121] Steps 5 and 6: Add 1E (550 mg, 1.06 mmol), THF (10 mL), and methanesulfonic acid (204 mg, 2.13 mmol) sequentially to a single-necked flask. Purge the mixture three times with nitrogen. Stir the reaction mixture at 60°C for 2 hours. After the reaction is complete, slowly add saturated sodium bicarbonate solution (10 mL) and THF (10 mL) to the reaction flask, then add di-tert-butyl dicarbonate (232 mg, 1.06 mmol). Stir overnight at room temperature. After the reaction is complete, extract the mixture with ethyl acetate (15 mL x 3). Combine the organic phases and wash once with saturated brine. Dry the mixture on anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify the crude product by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-40:60)] to obtain 1 G of white solid (330 mg, two-step yield: 66%, purity: 97%). LCMS m / z 454.2 [M+H] + .

[0122] Step 7: Add 1g (330mg, 0.73mmol), 5-bromo-4-fluoro-1-methylindazole (333mg, 1.46mmol), K2CO3 (302mg, 2.18mmol), (1R,2R)-N1,N2-dimethylcyclohexyl-1,2-diamine (52mg, 0.36mmol), CuI (35mg, 0.18mmol), and NMP (7mL) sequentially to the reaction flask. Purge the mixture with nitrogen three times and stir overnight at 130°C. After the reaction is complete, dilute the reaction system with water (21mL), extract with ethyl acetate (20mL x 3), combine the organic phases, wash three times with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain the crude product, and purify by silica gel column chromatography [petroleum ether: ethyl acetate (v / v) = (100:0-30:70)] to obtain brown solid 1H (60mg, yield: 13%, purity: 93%). LCMS m / z602.2[M+H] + .

[0123] Step 8: Add 1H (60 mg, 0.10 mmol) and dichloromethane (2 mL) to a three-necked flask, and add dioxane hydrochloride solution (2 mL, 4N) while stirring. Stir at room temperature for 3 hours. After the reaction is complete, remove the solvent under reduced pressure, adjust the pH to 8 with saturated sodium bicarbonate solution, extract with dichloromethane (5 mL x 3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain brown solid 1I (40 mg, yield: 72%, purity: 90%).

[0124] LCMS m / z 502.0 [M+H] + .

[0125] Step 9: In a reaction flask, add 1I (40 mg, 0.80 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (33 mg, 0.80 mmol), N,N-diisopropylethylamine (21 mg, 1.60 mmol), DMF (1.5 mL), and HATU (30 mg, 0.80 mmol) sequentially, and stir at room temperature for 3 hours. After the reaction is complete, filter, and purify the filtrate by preparative high-performance liquid chromatography to obtain CMP1a and CMP1b.

[0126] The spectral data for CMP 1a is LCMS m / z 895.0 [M+H]. + HPLC m / z 894.8 [M+H] +.HNMR(400MHz,DMSO-d6)δ:12.14-11.75(m,1H),8.30-8.20(m,1H),7.66-7.51(m,1.3H),7.46-7.11(m, 5H),7.09-6.97(m,2H),6.91-6.79(m,1H),6.74(s,0.7H),5.61-4.89(m,2H),4.10-4.07(m,3H),3.71-3 .42(m,2.5H),3.20-3.16(m,0.5H),3.03-2.80(m,2H),2.33-2.05(m,9H),1.99-1.77(m,2H),1.68-1.56 (m,3H),1.51-1.40(m,2H),1.36-1.34(m,1.5H),1.27-1.24(m,2.5H),1.18-1.10(m,4H),0.99(br,2H).

[0127] The spectral data for CMP 1b is LCMS m / z 895.0 [M+H]. + HPLC m / z 894.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:11.81(br,1H),8.32(br,1H),7.82-7.42(m,2H),7.39-7.15(m,5H),7. 11-6.97(m,2H),6.92-6.82(m,1H),5.65-5.38(m,1H),5.26-4.82(m,1H),4.11-4.08(m,3H),3.71 -3.52(m,2.5H),3.29-3.24(m,0.5H),3.03-2.83(m,1.5H),2.64-2.60(m,0.5H),2.45-2.07(m,9H ),2.03-1.83(m,2H),1.67-1.54(m,3H),1.49-1.37(m,3H),1.28-1.11(m,6H),1.08-1.04(m,3H).

[0128] Biology section:

[0129] Biological Example:

[0130] Cellular Experiment 1: Assay for Flp-in-293-GLP1R Cell Agonistaltic Activity

[0131] 1. Experimental materials and equipment

[0132] reagents and consumables brand Item number Fetal bovine serum, 500ml AUSGenex FBS500-S DMEM Gibco 10566-016 Penicillin and streptomycin, liquid, 100ml (100X) Gibco 15140122 Hygromycin B (solution) 5g (1 x 50ml, 100mg / ml) Invivogen ant-hg-5 Bovine serum albumin stabilizer 7.5%, 50ml PerkinElmer CR84-100 cAMP package PerkinElmer TRF0263 Isobutylmethylxanthine (IBMX) Sigma I5879 HEPES buffer, 1M, 100ml Gibco 15630080 instrument brand model EnVision PerkinElmer 2105

[0133] 2. Experimental Methods

[0134] 2.1 Cell Culture and Reagent Preparation

[0135] 2.1.1 Cell line: Flp-in-293-GLP1R

[0136] 2.1.2 Complete culture medium: DMEM + 10% fetal bovine serum + 1× penicillin-streptomycin + 200 μg / ml hygromycin

[0137] 2.1.3 Experimental buffer: 1×HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX

[0138] 2.2 Determination of the compound's agonistic activity against GLP1R receptors

[0139] a) Digest the cells, resuspend them in experimental buffer, and seed them into 384 cell culture plates at a density of 20,000 cells per well and a seeding volume of 15 μl per well.

[0140] b) Dilute the compound with experimental buffer.

[0141] c) Add 5 μl of the compound to each well and incubate at 37°C for 30 minutes.

[0142] d) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, then dilute them with lysis buffer.

[0143] e) Add 10 μl of Eu-cAMP tracer to the well, and then add 10 μl of Ulight-anti-cAMP to the well.

[0144] f) After centrifuging the reaction plate at 200g for 30s at room temperature and letting it stand at 25℃ for 1h, data were collected using Envision.

[0145] 2.3 Data Analysis: Calculation of compound EC using GraphPad nonlinear fitting formula 50 .

[0146] 3. Experimental Results

[0147] compound <![CDATA[EC 50 (nM)]]> Cmp1a 0.0445 Cmp1b >1

Claims

1. A compound of formula (Ⅰ): or its salts, solvates, stereoisomers or tautomers, wherein: yes Q 1 It can be optionally used by 0-3 identical or different Rs. a Substituted monocyclic or bicyclic aryl or cycloalkyl; Q 2 It can be optionally used by 0-3 identical or different Rs. b Substituted monocyclic or bicyclic aryl, cycloalkyl, heterocyclic or heteroaryl groups; Q 3 It can be optionally used by 0-2 identical or different Rs c Substituted monocyclic heteroaryl or heterocyclic group; T is selected from the following groups: Where T 1 Is it a key or C? 1-10 Alkylene, R T It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl)-, R T1 and R T2 Each is independently hydrogen or C 1-6 Alkyl group, m is 1, 2 or 3 (* indicates the connection position with the pyrazolopyridine structure, ** indicates the connection position with Q). 2 (connection location); L is -C(O)-, -CR L1 R L2 -、-S(O)2-、-S(O-)- or -NHC(O-), where R L1 and R L2 Each is independently hydrogen, halogen, C 1-6 Alkyl or C 3-6 cycloalkyl; A can be optionally represented by 0-3 identical or different Rs. 4 Substituted bicyclic heteroaryl groups; B can be optionally represented by 0-3 identical or different Rs. 5 Substituted monocyclic or bicyclic heteroaryl or heterocyclic groups; R 1 Each is independently hydrogen, halogen, or C. 1-6 Alkyl; or, R 1 The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted; R 2 and R 3 Each is independently hydrogen, halogen, or C. 1-6 Alkyl; or R 2 and R 3 The atoms bonded to them together form cycloalkyl or heterocyclic groups, which may optionally be formed by 0-3 identical or different halogens or carbon atoms. 1-6 Alkyl groups are substituted; R 4 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted; R 5 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl-substituted; or, R 5 The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted; R a Each is independently a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted; R b Each is independently a halogen, amino, or C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or -P(O)R b1 R b2 The amino group, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl-substituted; or, R b The two atoms attached to them together form a cycloalkyl or heterocyclic group, which may optionally be formed by 0-3 identical or different halogens or C atoms. 1-6 Alkyl groups are substituted; R b1 and R b2 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkyl or C 1-6 Alkoxy; R c Each is independently an oxygen, hydroxyl, or C group. 1-6 alkyl; n is an integer from 1 to 3.

2. The compound of claim 1 or its salt, solvate, stereoisomer, or tautomer, wherein: Q 1 It is phenyl or cyclohexyl; Q 2 It is phenyl, cyclohexyl, or an 8-10 membered bicyclic heteroaryl group, wherein the heteroaryl group contains two nitrogen atoms; Q 3 Selected from the following groups: Where Z is an oxygen atom or a sulfur atom; A is a 9-membered bicyclic heteroaryl group, wherein the heteroaryl group contains 1-3 nitrogen atoms; B is 3. The compound according to claim 1 or 2, wherein the compound has formula (IIa) or (IIb): The structure of its salts, solvates, stereoisomers or tautomers.

4. The compound of claim 3 or a salt, solvate, stereoisomer, or tautomer thereof, wherein the compound has a specified stereochemical structure of formula (III):

5. The compound of claim 3 or its salt, solvate, stereoisomer or tautomer, wherein A is selected from the following groups: (aa represents the connection position with L, and bb represents the connection position with B).

6. The compound of claim 3 or its salt, solvate, stereoisomer, or tautomer, wherein: Q 1 It is phenyl; Q 2 It is phenyl or Q 3 yes T is Where T 1 Is it a key or C? 1-10 Alkylene; L is -C(O)-; A is selected from the following groups: (aa represents the connection position with L, and bb represents the connection position with B); B is R 2 and R 3 Each is independently hydrogen or C 1-6 Alkyl; or R 2 and R 3 Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be composed of 0-3 identical or different carbon atoms. 1-6 Alkyl groups are substituted; R 4 Each is independently halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted; R 5 Each is independently halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted; R a Each is independently a halogen, C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be 0-3 halogens or C 1-6 Alkyl groups are substituted; R b Each is independently a halogen, amino, or C 1-6 Alkyl or -P(O)R b1 R b2 The amino or C 1-6 Alkyl groups may optionally be 0-3 halogens or C 1-6 Alkyl-substituted; or, R b The two atoms connected to them together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be substituted with 0-3 identical or different halogens or C groups. 1-6 Alkyl groups are substituted; R b1 and R b2 Each is independently hydrogen, hydroxyl, or C. 1-6 alkyl; R c Each is independently a hydroxyl group or a C. 1-6 alkyl.

7. The compound of claim 6 or its salt, solvate, stereoisomer, or tautomer, wherein: R 2 and R 3 Each is independently hydrogen or methyl; or R 2 and R 3 Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be substituted with 0-1 methyl groups; R 4 Each is independently either fluorine or methyl, and the methyl group may optionally be replaced by 0-3 fluorine molecules; R 5 Each is independently either fluorine or methyl, and the methyl group may optionally be replaced by 0-3 fluorine molecules; R a Each is independently fluorine, methyl, or cyclopropyl, and the methyl or cyclopropyl group may optionally be substituted by 0-3 fluorine or methyl groups; R b Each is independently fluorine, amino, methyl, or -P(O)R b1 R b2 The amino or methyl group may optionally be replaced by 0-3 fluorine or methyl groups; R b1 and R b2 Each is independently either methyl or ethyl; R c Each is a methyl group independently.

8. The compound of claim 7 or its salt, solvate, stereoisomer or tautomer, wherein R 2 and R 3 Together with the atoms attached to them, a cyclobutyl group is formed, which may optionally be replaced by 0-1 methyl groups.

9. The compound of claim 1 or its salt, solvate, stereoisomer, or tautomer, wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound as described in any one of claims 1-9 or a salt thereof, a solvate, a stereoisomer or tautomer, and a pharmaceutically acceptable carrier.

11. Use of the compound or its salt, solvate, stereoisomer or tautomer of any of claims 1-9, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating or preventing GLP-1 receptor-mediated diseases or disorders or for modulating GLP-1 receptors.

12. Use of the compound or its salt, solvate, stereoisomer or tautomer of any one of claims 1-9, or the pharmaceutical composition of claim 10, in the preparation of a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia.

13. A preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity, comprising, as an active ingredient, a compound or salt, solvate, stereoisomer or tautomer of any of claims 1-9.

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