Heterocyclic GLP-1 derivative and therapeutic application thereof

Abstract

The present application relates to a heterocyclic GLP-1 derivative, a pharmaceutically acceptable salt thereof, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a method of treating or preventing a GLP-1 receptor mediated disease or disorder or modulating a GLP-1 receptor thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a heterocyclic GLP-1 derivative, its pharmaceutically acceptable salts, and methods for treating or preventing GLP-1 receptor-mediated diseases or disorders or modulating GLP-1 receptors. Background Art

[0002] Diabetes is a metabolic disease characterized by hyperglycemia, which is caused by defective insulin secretion or impaired insulin biological action, or both. Type 2 diabetes, also known as non-insulin-dependent diabetes, is the most common acquired disease, accounting for more than 90% of diabetes cases. Typical onset occurs in obese or sedentary adults and begins with insulin resistance, followed by a combination of impaired insulin secretion and insulin resistance associated with elevated blood glucose levels. Although lifestyle changes help control the disease, patients with type 2 diabetes may need to take antidiabetic drugs, including dipeptidyl peptidase 4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin secreted by intestinal cells when nutrients pass through the gastrointestinal tract. Mediated by the GLP-1 receptor, it has multiple effects, including enhancing glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing food intake. GLP-1 analogs have been practically used to treat diabetes and are regarded as one of the most effective antidiabetic drugs due to their powerful HbA1c-lowering and weight-reducing effects. However, currently, the vast majority of them require invasive subcutaneous administration. Therefore, there is a desire to develop GLP-1 receptor agonists that can be administered non-invasively. For example, the use of an absorption enhancer (sodium N-(8-(2-hydroxybenzoyl)amino)octanoate: SNAC) has improved the oral bioavailability of the GLP-1 analog Semaglutide, but further improvement of its drug properties, including activity, metabolic stability, and bioavailability, is still needed.

[0004] LY3502970 is a novel, highly effective, orally administered non-peptide GLP-1R agonist. Preclinical studies have shown that the hypoglycemic effect of LY3502970 is comparable to exenatide. The results of pharmacokinetic experiments conducted in cynomolgus monkeys showed that the half-life of LY3502970 was 3.4 - 4.6 h, and the bioavailability reached 21 - 28%.

[0005]

[0006] Currently, the development of small molecule GLP-1 receptor agonists aims to improve patient compliance, medication convenience, and reduce drug side effects, and has broad clinical market prospects. Summary of the Invention

[0007] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] wherein,

[0010] X and Y are each independently selected from CR1 or N.

[0011] R1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxy, or when X and Y are each independently CR1 and R1 is selected from C1-C6 alkyl or C1-C6 alkoxy, two R1s together with the carbon atom to which they are attached can form a 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 1-3 heteroatoms selected from N, O, and S.

[0012] n is selected from 1-3.

[0013] E is selected from CR2R2, NR2, or O.

[0014] R2 is independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C 10 cycloalkyl, C 1- C6 alkoxy.

[0015] R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl or (CR C R C ) 0-2 -heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, or C3-C6 cycloalkyl, and the cycloalkyl is a spiro cycloalkyl, a bridged cycloalkyl, or a monocyclic cycloalkyl; each R C is independently H, C1-C3 alkyl, or C1-C3 haloalkyl.

[0016] A is selected from or is empty.

[0017] B is selected from C3-C 10A cycloalkyl group, a phenyl group, a heterocyclic group containing one or two 5- or 6-membered rings and 1 - 3 heteroatoms selected from N, O, and S, or a heteroaryl group containing one or two 5- or 6-membered rings and 1 - 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocyclic group, or heteroaryl group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, P(=O)RaRb, S(=O)2Ra or wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group, and each of Ra and Rb is independently selected from halogen, C1-C6 alkyl, C3-C 10 A cycloalkyl group, a phenyl group.

[0018] When A is empty, B is Or

[0019] Z is selected from CH or N.

[0020] C is selected from CH2, C=O or

[0021] Selected from

[0022] R4 is independently selected from halogen, C3-C 10 A cycloalkyl group, C1-C6 alkoxy, a phenyl group, vinyl, ethynyl, a heterocyclic group containing one or two 3- to 6-membered rings and 1 - 3 heteroatoms selected from N, O, and S, or a heteroaryl group containing one or two 5- or 6-membered rings and 1 - 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, alkoxy, phenyl group, vinyl, ethynyl, heterocyclic group, or heteroaryl group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or NO2, -C1-C6 alkyl C1-C6 alkyl.

[0023] L is selected from C3-C 10A cycloalkyl group, a phenylene group or a heteroaryl group containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl group, phenylene group or heteroaryl group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or halogen, or wherein when the phenylene group is substituted with two substituents attached to adjacent carbon atoms in the phenylene ring, the two substituents together with the carbon atoms to which they are attached can form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1-3 heteroatoms selected from N, O and S.

[0024] R6 and R7 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C 10 cycloalkyl group, the C3-C 10 cycloalkyl group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0025] T is selected from C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or a heteroaryl group containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo.

[0026] R3 is selected from halogen, C1-C6 alkyl, C3-C 10 cycloalkyl group, phenyl, wherein, C1-C6 alkyl, C3-C 10 cycloalkyl group, phenyl is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or NO2.

[0027] In some embodiments of the present invention, X and Y as described above are selected from CH or N.

[0028] In some embodiments of the present invention, X and Y as described above are selected from CR1, R1 is selected from C1-C6 alkyl, and two R1 together with the carbon atom to which they are attached can form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1-3 heteroatoms selected from N, O and S.

[0029] In some embodiments of the present invention, n is selected from 2 and E is selected from O.

[0030] In some embodiments of the present invention, the above is selected from

[0031] In some embodiments of the present invention, R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl or (CR C R C ) 0-2 -heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, or C3-C6 cycloalkyl.

[0032] In some embodiments of the present invention, B is selected from a heterocyclic group containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S or a heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group or the heteroaryl is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, or NO2.

[0033] In some embodiments of the present invention, Z is selected from N.

[0034] In some embodiments of the present invention, C is selected from C=O.

[0035] In some embodiments of the present invention, the above is selected from

[0036] In some embodiments of the present invention, R4 is selected from C3-C 10 cycloalkyl, and the C3-C 10The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, or NO2, wherein the cycloalkyl is a spirocyclic, bridged, or monocyclic cycloalkyl.

[0037] In some embodiments of the present invention, the above R4 is selected from vinyl and ethynyl, and the vinyl and ethynyl are optionally substituted by one or more substituents independently selected from the following:

[0038] In some embodiments of the present invention, the above-mentioned R4 is selected from tetrahydropyranyl, and the tetrahydropyranyl is optionally substituted by one or more substituents selected from N, O and S, and optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN and NO2.

[0039] In some embodiments of the present invention, the above L is selected from R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C6 alkyl group. 10 Cycloalkyl, the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0040] In some embodiments of the present invention, the above-mentioned T is selected from a heteroaryl group comprising a 5-membered or 6-membered ring and 1-3 heteroatoms selected from N, O and S, and the heteroaryl group is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo.

[0041] In some embodiments of the present invention, the above R3 is selected from halogen and C1-C6 alkyl.

[0042] In some embodiments of the present invention, the above R5 is selected from

[0043] In some embodiments of the present invention, the above R4 is selected from

[0044] In some embodiments of the present invention, the above L is selected from

[0045] In some embodiments of the present invention, the above T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolone or thiadiazolone, each of which is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo.

[0046] In some embodiments of the present invention, the above T is

[0047] In some embodiments of the present invention, the above compound has the formula (I-1), formula (I-2), formula (I-3), formula (I-3), formula (I-4), formula (I-5) or formula (I-6):

[0048]

[0049] Wherein, A, B, L, T, R4, R5 and R1 are as defined in the present invention.

[0050] There are also some embodiments of the present invention which are formed by any combination of the above variables.

[0051] The present invention also provides the following compound or its pharmaceutically acceptable salt, which is selected from:

[0052]

[0053]

[0054]

[0055] The present invention also provides the following compound or its pharmaceutically acceptable salt, which is selected from:

[0056]

[0057]

[0058]

[0059] The present invention also provides the following compound or its pharmaceutically acceptable salt, which is selected from:

[0060]

[0061]

[0062]

[0063] The present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt as an active ingredient.

[0064] The present invention provides a method for treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating a GLP-1 receptor, which comprises administering a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a subject having a corresponding need.

[0065] The present invention provides a method for treating non-insulin-dependent diabetes (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease or dementia, which method comprises administering a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a subject in need of such treatment.

[0066] The present invention provides a method for treating non-insulin-dependent diabetes (type 2 diabetes) or obesity, which method comprises administering a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a subject in need of such treatment.

[0067] Technical effects

[0068] The compounds of the present invention have a good agonistic effect on the GLP-1 receptor.

[0069] Definitions and explanations

[0070] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0071] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0072] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent.

[0073] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or basic groups. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.

[0074] "Pharmaceutical composition" means a composition containing one or more compounds, isomers or pharmaceutically acceptable salts thereof described in the present application, and other components such as physiological / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0075] The term "therapeutically effective amount" refers to an amount of a compound which, when administered, is sufficient to prevent or slow down the development of one or more symptoms of a disease or a therapeutic condition to a certain extent. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to detect a biological or drug response (e.g., a protein, an enzyme, RNA, or DNA) in a biomolecule, a cell, a tissue, a system, an animal, or a human. Such a response is desired by a researcher, a veterinarian, a doctor, or a clinician.

[0076] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers, and tautomers.

[0077] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0078] The compounds, isomers or pharmaceutically acceptable salts described in this application include solvate-added or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. For example, hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of general formula (1) can be conveniently prepared or formed according to the methods described herein. For example, the hydrates of the compounds of general formula (1) can be conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, and the organic solvents used include but are not limited to tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in non-solvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered equivalent to the non-solvated forms.

[0079] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0080] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0081] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0082] Unless otherwise specified, "(+)" represents dextrorotation, "(-)" represents levorotation, and "(±)" represents racemization.

[0083] Unless otherwise specified, the wedge solid bond and the wedge dashed bond represent the absolute configuration of a stereocenter, and the straight solid bond and the straight dashed bond represent the relative configuration of the stereocenter, and the wavy line represents the wedge solid bond or the wedge dashed bond or the wavy line represents the straight solid bond or the straight dashed bond

[0084] Unless otherwise specified, the terms "enriched in one isomer", "isomer-enriched", "enriched in one enantiomer", or "enantiomer-enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0085] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0086] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then the diastereomers are separated by conventional methods well known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and optionally in combination with chemical derivatization methods (such as forming carbamates from amines).

[0087] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Another example is that hydrogen can be replaced by deuterium to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All transformations of the isotope composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0088] The term "optional" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and this description includes both the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0089] The term "substituted" or "substitution" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0090] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 0 - 2 R's, the group may optionally be substituted by up to two R's, and each R has an independent option in each case. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

[0091] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0092] When the number of a substituent is 0, it means that the substituent is absent. For example, -A-(R)0 means that the structure is actually -A.

[0093] When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in A-X, it means that the structure is actually A.

[0094] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.

[0095] When the bond of a substituent can cross-link to more than two atoms on a ring, such a substituent can bond to any atom on this ring. For example, the structural unit indicates that its substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When it is not specified which atom of the listed substituents connects to the substituted group, such a substituent can bond through any of its atoms. For example, a pyridyl group as a substituent can connect to the substituted group through any carbon atom on the pyridine ring.

[0096] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0097] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy lines in the phenyl group represent the connection to other groups through the carbon atoms at positions 1 and 2 in the phenyl group.

[0098] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0099] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12and so on; similarly, "n - to n + m - membered ring" means a ring having from n to n + m atoms in the ring. For example, a 3 - to 12 - membered ring includes 3 - membered ring, 4 - membered ring, 5 - membered ring, 6 - membered ring, 7 - membered ring, 8 - membered ring, 9 - membered ring, 10 - membered ring, 11 - membered ring, and 12 - membered ring, and also includes any range within n to n + m. For example, a 3 - to 12 - membered ring includes 3 - to 6 - membered ring, 3 - to 9 - membered ring, 5 - to 6 - membered ring, 5 - to 7 - membered ring, 6 - to 7 - membered ring, 6 - to 8 - membered ring, and 6 - to 10 - membered ring, etc.

[0100] Unless otherwise specified, the term "C1 - C6 alkyl" is used to denote a straight - chain or branched - chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1 - C6 alkyl includes C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4, and C3 alkyls, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-8 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), butyl (including n - butyl, isobutyl, s - butyl, and t - butyl), pentyl (including n - pentyl, isopentyl, and neopentyl), hexyl, heptyl, octyl, etc.

[0101] Unless otherwise specified, the term "C 1-4 alkyl" is used to denote a straight - chain or branched - chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl includes C 1-2 、C 1-3 and C 2-3 alkyls, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), butyl (including n - butyl, isobutyl, s - butyl, and t - butyl), etc.

[0102] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight - chain or branched - chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyls, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), etc.

[0103] Unless otherwise specified, "C3-C 10 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro, fused and bridged rings. The C3-C 10 cycloalkyl includes C 3-8 、C 3-6 、C 3-5 、C 4-10 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, spiro[2.4]cyclohexane, etc.

[0104] Unless otherwise specified, "C3-C6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro, fused and bridged rings. The C3-C6 cycloalkyl includes C 3-6 、C 3-5 、C 4-6 、C 4-5 、or C 5-6 etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0105] Unless otherwise specified, the term "3-10 member heterocycloalkyl" alone or in combination with other terms respectively represents a saturated cyclic group composed of 3 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, N, P and Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S(O) p and P(O) p, where p is 1 or 2). It includes monocyclic, bicyclic and tricyclic systems, and the bicyclic and tricyclic systems include spirocycles, fused rings and bridged rings. In addition, for the "3- to 10-membered heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3- to 10-membered heterocycloalkyl includes 3- to 9-membered, 3- to 8-membered, 3- to 6-membered, 5- to 9-membered, 5-membered, 6-membered, 7-membered, 8-membered and 9-membered heterocycloalkyls, etc. Examples of 3- to 10-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0106] Unless otherwise specified, the term "5-membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated cyclic group composed of 5 ring atoms, where 1, 2 or 3 of the ring atoms are heteroatoms independently selected from O, S, N, P and Se, and the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S(O) p and P(O) p , where p is 1 or 2). Examples of 5-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, etc.

[0107] Unless otherwise specified, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic, or tricyclic or more rings) fused or unfused group or ring system having at least one aromatic ring and having from five to ten ring atoms (where one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon). Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl and similar groups.

[0108] Unless otherwise specified, the term "heterocyclic group" or "heterocyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic monocyclic ring system of 3-, 4-, 5-, 6-, 7- or 8-membered, a bicyclic ring system of 7-, 8-, 9-, 10-, 11- or 12-membered (fused, bridged or spiro), or a tricyclic ring system of 11-, 12-, 13- or 14-membered (fused, bridged or spiro), wherein (i) each ring contains one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bond, and each 6-membered ring has 0 to 2 double bonds, (iii) nitrogen heteroatoms and sulfur heteroatoms may optionally be oxidized, and (iv) nitrogen heteroatoms may optionally be quaternized. Representative heterocyclic hydrocarbon groups include, but are not limited to, [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-azaspiro[3.3]hept-5-amine, 1-azaspiro[3.3]hept-5-amine, 1-oxa-6-azaspiro[3.3]hept-3-amine, 2-azaspiro[3.3]hept-6-amine, 1-azaspiro[3.3]hept-6-amine, 6-azaspiro[3.4]oct-2-amine, 5-azaspiro[3.4]oct-2-amine, 6-azaspiro[3.4]oct-1-amine, 5-azaspiro[3.4]oct-1-amine, 5-oxa-2-azaspiro[3.4]oct-7-amine, 7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]oct-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide and similar groups.

[0109] According to the present application, any one of the aryl, substituted aryl, heteroaryl and substituted heteroaryl described herein may be any aromatic group. The aromatic group may be substituted or unsubstituted.

[0110] The compounds of the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0111] The structure of the compounds of the present invention can be confirmed by conventional methods well-known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD). The diffraction intensity data of the cultivated single crystal is collected using a Bruker D8 venture diffractometer, with the light source being CuKα radiation and the scanning mode: / ω scan. After collecting the relevant data, the crystal structure is further analyzed using the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0112] The solvents used in the present invention are commercially available.

[0113] The present invention uses the following abbreviations:

[0114] ACN represents acetonitrile; Boc represents tert-butoxycarbonyl; Bn represents benzyl; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; °C represents degrees Celsius; hr represents hours; LiBH4 represents sodium borohydride; THF represents tetrahydrofuran; Ts represents p-toluenesulfonyl; Ac represents acetyl; Me represents methyl; Et represents ethyl; N2 represents nitrogen; PE represents petroleum ether; EA represents ethyl acetate; DIEA or DIPEA represents N,N-diisopropylethylamine; K2CO3 represents potassium carbonate; CuI represents copper iodide; TBAF represents tetrabutylammonium fluoride; CuBr represents copper bromide; DMF represents N,N-dimethylformamide; HCl represents hydrochloric acid; MeOH represents methanol; TEA represents triethylamine; Pd(dppf)Cl2 represents 1,1-bis(diphenylphosphino)ferrocene dichloropalladium; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)dichloropalladium; BH3 represents borane; MsCl represents methanesulfonyl chloride; TEA represents triethylamine; NBS represents N-bromosuccinimide; FmocOSu represents 9-fluorenylmethoxycarbonyl succinimide; Dioxane represents dioxane; I2 represents iodine; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NCS represents N-chlorosuccinimide; P2O5 represents phosphorus pentoxide; NaBH4 represents sodium borohydride; BBr3 represents boron tribromide; DEA represents diethylamine.

[0115] Compounds are named according to the conventional naming principles in the art or using Software naming, for commercially available compounds, the supplier's catalog name is adopted. Detailed implementation manners

[0116] The present invention will be described in detail below through examples, but this does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific implementation manners have also been disclosed. For those skilled in the art, various changes and improvements to the specific implementation manners of the present invention will be obvious without departing from the spirit and scope of the present invention.

[0117] Example 1

[0118]

[0119] Synthesis route:

[0120]

[0121]

[0122] Step 1: Synthesis of compound 1-2

[0123] Dissolve compound 1-1 (5.00 g, 33.07 mmol) in 50 mL of dichloromethane, slowly add triethylamine (6.69 g, 66.14 mmol) and acetyl chloride (2.60 g, 33.07 mmol) at 0 °C, stir at 0 °C for half an hour, and then transfer to room temperature and continue the reaction for 2 h.

[0124] Work-up: Add saturated ammonium chloride solution, adjust the pH to neutral, slowly add 50 mL of water to quench the system, add dichloromethane (50 mL) and water (50 mL) for liquid separation, extract the aqueous phase with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (200 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / MeOH (V / V) = 30 / 1) to obtain white solid compound 1-2, 5.89 g, yield 92.17%. MS: (ESI, pos. ion) m / z: 194.1222 [M+H] + .

[0125] Step 2: Synthesis of compound 1-3

[0126] Dissolve compound 1-2 (2.00 g, 10.35 mmol) in 40 mL of N,N-dimethylformamide, add N-chlorosuccinimide (1.66 g, 12.42 mmol), and place it at 80 °C and stir for 1 h.

[0127] Workup: Add saturated sodium thiosulfate to quench the system, add saturated sodium bicarbonate solution to adjust the pH of the system to neutral, add ethyl acetate (50 mL) and water (50 mL) for liquid separation, extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (200 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / MeOH (V / V) = 30 / 1) to obtain the yellow oily compound 1-3, 2.30 g, with a yield of 97.60%. MS: (ESI, pos. ion) m / z: 228.0848 [M+H] + .

[0128] Step 3: Synthesis of compound 1-4

[0129] Dissolve compound 1-3 (1.00 g, 4.39 mmol) in acetonitrile (30 mL), add phosphorus pentoxide (3.74 g, 26.35 mmol), and react at 80 °C for 2 h.

[0130] . Workup: After concentrating the system under reduced pressure, slowly add water (30 mL) to quench the system in an ice bath, stir at 40 °C for 1 h, adjust the pH to neutral with saturated sodium bicarbonate solution, add ethyl acetate (80 mL) and water (50 mL) for liquid separation, extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (200 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / MeOH (V / V) = 30 / 1) to obtain the title compound as a white solid compound 1-4, 0.69 g, with a yield of 74.93%. MS: (ESI, pos. ion) m / z: 210.0725 [M+H] + .

[0131] Step 4: Synthesis of compound 1-5

[0132] Dissolve compound 1-4 (2.50 g, 11.92 mmol) in methanol (40 mL), slowly add sodium borohydride (901.86 mg, 23.84 mmol) at 0 °C, and transfer to room temperature for reaction for 2 h after half an hour.

[0133] Workup: Purify by column chromatography (DCM / MeOH (V / V) = 30 / 1) to obtain the title compound as a white solid compound 1-5, 1.69 g, with a yield of 66.96%. MS: (ESI, pos. ion) m / z: ⒉12.0889 [M+H] + .

[0134] Step 5: Synthesis of compound 1-6

[0135] Compound 1-5 (1.00 g, 4.72 mmol) was dissolved in a 1,4-dioxane:water 10:1 solution (50 mL), and (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (3.19 g, 9.45 mmol) and sodium bicarbonate (1.59 g, 18.90 mmol) were added. The reaction was carried out at room temperature for 2 h.

[0136] Workup: Ethyl acetate (100 mL) and water (100 mL) were added for liquid separation. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 3 / 1) gave the title compound as a white solid, compound 1-6, 1.34 g, yield 65.37%. MS: (ESI, pos. ion) m / z: 434.1566 [M+H] + .

[0137] Step 6: Synthesis of compound 1-7-1

[0138] Compound 1-6 (1.30 g, 3.00 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N-bromosuccinimide (639.86 mg, 3.60 mmol) was added. The mixture was stirred at 80 °C overnight.

[0139] Workup: Saturated sodium thiosulfate was added to quench the system. Saturated sodium bicarbonate solution was added to adjust the pH of the system to neutral. Ethyl acetate (50 mL) and water (50 mL) were added for liquid separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse-phase C18 (0.1% TFA / ACN = 25 / 75) gave the title compound as a yellow oily compound 1-7-1, 950.00 mg, yield 61.83%. MS: (ESI, pos. ion) m / z: 514.0616 [M+H] + . Step 7: Synthesis of compound 1-7-2

[0140] 5-Bromo-2-fluoro-1,3-dimethylbenzene (8.00 g, 39.40 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (20.01 g, 78.80 mmol), potassium acetate (11.60 g, 118.19 mmol), and Pd(dppf)Cl2 (2.88 g, 3.94 mmol) were added to a clean two-necked flask. 1,4-Dioxane (80 mL) was added, and the system was purged with nitrogen three times. The reaction was stirred at 80 °C for 2 h.

[0141] Workup: Ethyl acetate (150 mL) and water (100 mL) were added for liquid separation. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 3 / 1) afforded the title compound as a white solid, compound 1-7-2, 7.50 g, with a yield of 76.11%.

[0142] Step 8: Synthesis of compound 1-8

[0143] Compound 1-7-1 (202 mg, 393.89 μmol) was dissolved in a 1,4-dioxane:water 4:1 solution (4 mL). Compound 1-7-2 (197.04 mg, 787.79 μmol), Pd(dppf)Cl2 (28.820 mg, 39.389 μmol), and potassium carbonate (163.31 mg, 1.182 mmol) were added. The mixture was purged with nitrogen three times and then reacted at 95 °C for 4 h.

[0144] Workup: Ethyl acetate (20 mL) and water (20 mL) were added for liquid separation. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 3 / 1) afforded the title compound as a white solid, compound 1-8, 71.00 mg, with a yield of 32.41%. MS: (ESI, pos. ion) m / z: 556.2098 [M+H] + 。

[0145] Step 9: Synthesis of compound 1-9

[0146] Compound 1-8 (70.00 mg, 125.88 μmol) was dissolved in dichloromethane (2 mL). The mixture was purged with nitrogen three times and then 700 μL of a 1 M boron tribromide solution was slowly added at -78 °C. After 10 min, the reaction mixture was transferred to room temperature and reacted overnight.

[0147] Workup: 3 mL of methanol was slowly added at -78 °C to quench the boron tribromide. The reaction mixture was transferred to a fume hood and stirred at room temperature for 1 h until no more foggy gas evolved. Saturated sodium bicarbonate was added to adjust the pH of the system to neutral. Dichloromethane (10 mL) and water (10 mL) were added for liquid separation. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid, compound 1-9, 68.00 mg, with a yield of 99.66%. MS: (ESI, pos. ion) m / z: 542.1920 [M+H]+ 。

[0148] Step 10: Synthesis of Compound 1-10

[0149] Dissolve Compound 1-9 (68.00 mg, 125.45 μmol) in 3 mL of tetrahydrofuran, add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (44.82 mg, 125.45 μmol), potassium carbonate (52.01 mg, 376.35 μmol), and potassium iodide (62.48 mg, 376.35 μmol), and react overnight at room temperature.

[0150] Workup: Adjust the pH of the system to neutral with saturated sodium bicarbonate, add ethyl acetate (10 mL) and water (10 mL) for liquid separation. Extract the aqueous phase with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound, a yellow solid, Compound 1-10, 84.00 mg, with a yield of 99.33%. MS: (ESI, pos. ion) m / z: 674.1412 [M+H] + 。

[0151] Step 11: Synthesis of Compound 1-10-2

[0152] Add Compound 1-10-1 (4.00 g, 17.46 mmol), dioxane (40 mL), diphenylmethanimine (4.75 g, 26.19 mmol), cesium carbonate (8.53 g, 26.19 mmol), Pd2(dba)3 (1.56 g, 1.75 mmol), and XantPhos (0.51 g, 0.87 mmol) to a clean 100 ml two-necked flask. Replace the air with nitrogen and protect. Heat to 110 °C and stir for 20 h.

[0153] Workup: Directly filter to remove the insoluble solid, then mix with basic silica gel and purify by column chromatography (PE / EA (V / V) = 10 / 1) to obtain N-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,1-diphenylmethanimine as a brown solid, 5.30 g, with a yield of 92.20%. MS: (ESI, pos. ion) m / z: 330.1427 [M+H] + .

[0154] Add N-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,1-diphenylmethanimine (5.30 g, 16.09 mmol), methanol (53 ml), hydroxylamine hydrochloride (559.06 mg, 8.05 mmol) and potassium acetate (79 mg, 0.80 mmol) to a clean 100 ml single-neck flask and stir at room temperature for 2 h.

[0155] Work-up: Filter the reaction mixture to remove insoluble solids, and directly purify the filtrate by column chromatography (PE / EA (V / V) = 5 / 1) to obtain the brown solid compound 1-10-2, 2.35 g, with a yield of 87.88%. MS: (ESI, pos.ion) m / z: 166.0778 [M+H] + .

[0156] Step 12: Synthesis of compound 1-10-3

[0157] Dissolve compound CDI (7.71 g, 47.56 mmol) in ethyl acetate (20 mL), and dropwise add 2,2-dimethoxyethylamine (5.00 g, 47.56 mmol) under an ice bath. After the addition, allow the reaction to return to room temperature naturally.

[0158] [[ID=1??]]Work-up: Purify by column chromatography (PE / EA / TEA (V / V) = 4 / 1 / 0.001), collect the product, concentrate to constant weight, add EA (18 mL), stir at -5 °C for 2 h, then filter, wash with MTBE (10 mL × 2), and dry the filter cake under reduced pressure at 40 °C to obtain the white solid compound 1-10-3, 4.40 g, with a yield of 46.46%. MS: (ESI, pos.ion) m / z: 200.1030 [M+H] + .

[0159] Step 13: Synthesis of compound 1-10-4

[0160] Dissolve compound 1-10-2 (0.45 g, 2.72 mmol) and compound 1-10-3 (597 mg, 3.00 mmol) in 5 mL of DMA, add potassium tert-butoxide (1.22 g, 10.88 mmol), and react at room temperature for 2.5 h.

[0161] Work-up: Add ethyl acetate (20 mL) and water (20 mL) for liquid separation. Extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / EA (V / V) = 3 / 1) to obtain the reddish-brown solid compound 1-10-4, 438 mg, with a yield of 54.26%. MS: (ESI, pos.ion) m / z: 297.1360 [M+H] + It should be noted that there seems to be a typo in the "1??" in the translation of step 12. It should be "14" according to the original text..

[0162] Step 14: Synthesis of Compound 1-10-5

[0163] Dissolve Compound 1-10-4 (0.44 g, 1.48 mmol) in 4 mL of THF, add methanesulfonic acid (0.11 g, 1.15 mmol), and react at 60 °C for 3 h.

[0164] Workup: Concentrate the solvent to obtain a reddish-brown solid, Compound 1-10-5, 343 mg, yield 100%. MS: (ESI, pos. ion) m / z: 233.0853 [M+H] + .

[0165] Step 15: Synthesis of Compound 1-11

[0166] Dissolve Compound 1-10 (50.00 mg, 74.17 μmol) in toluene (3 mL), add Compound 1-10-5 (34.45 mg, 148.35 μmol), Pd(OAc)2 (6.66 mg, 29.67 μmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP) (27.71 mg, 44.50 μmol), cesium carbonate (60.4 mg, 185.43 μmol), displace with nitrogen 3 times, and react at 110 °C for 4 h under nitrogen protection.

[0167] Workup: Filter through diatomaceous earth, concentrate the system under reduced pressure, and perform thin-layer chromatography separation (DCM / MeOH (V / V) = 20 / 1) to obtain the title compound, yellow solid Compound 1-11, 38.00 mg, yield 67.74%.

[0168] Step 16: Synthesis of Compound 1-12

[0169] Dissolve Compound 1-11 (38.00 mg, 50.25 μmol) in dichloromethane (2 mL), add diethylamine (2 mL), and react overnight at room temperature.

[0170] Workup: Concentrate the system under reduced pressure to obtain the title compound, yellow solid Compound 1-12, 26.00 mg, 96.90%. MS: (ESI, pos. ion) m / z: 534.1810 [M+H] + .

[0171] Step 17: Synthesis of Compound 1

[0172] The synthesis of compound 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 (1-13) was obtained by referring to the synthesis method of compound 76 in Patent CN109790161.

[0173] Dissolve 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 (24.04 mg, 58.43 μmol) in DMF (3 mL), add 1-(bis(dimethylamino)methylene)-3-oxo-1,3-dihydro-[1,2,3]triazolo[4,5-b]pyridine-1,3-diium-2-imine hexafluorophosphate (27.77 mg, 73.03 μmol), N,N-diisopropylethylamine (31.46 mg, 243.44 μmol), activate in an ice bath for half an hour, add compound 1-12 (26.00 mg, 48.69 μmol), and react at room temperature for 2 h.

[0174] Work-up: Add ethyl acetate (20 mL) and water (20 mL) for liquid separation. The aqueous phase is extracted with ethyl acetate (20 mL × 3). The organic phases are combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the system is concentrated under reduced pressure and then separated by thin-layer chromatography (DCM / MeOH (V / V) = 20 / 1) to obtain 133.00 mg of the yellow solid title compound, with a yield of 73.08%. MS: (ESI, pos. ion) m / z: 927.3480 [M + H] + .

[0175] Example 2

[0176] It can be seen from the in vivo / in vitro GLP-1 receptor activity test that the compounds of the present invention have good agonist effects on the GLP-1 receptor.

[0177] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, X, Y are selected from CR1 or N, R1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, or when X, Y are selected from CR1, R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, two R1 together with the carbon atom to which they are attached can form a 5-membered or 6-membered ring, the 5-membered or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O and S, Preferably, X and Y are selected from CH or N; Alternatively, X and Y are selected from CR1, R1 is selected from C1-C6 alkyl, and the two R1s together with the carbon atoms to which they are attached can form a 5-membered or 6-membered ring, wherein the 5-membered or 6-membered ring optionally contains 1 to 3 heteroatoms selected from N, O and S; n is selected from 1 to 3; E is selected from CR2R2, NR2 or O; Preferably, n is selected from 2, and E is selected from O; R2 is independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C 1- C6 alkoxy; R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl or (CR) containing one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S C R C ) 0-2 -heteroaryl, wherein the cycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2 or C3-C6 cycloalkyl, wherein the cycloalkyl is a spirocyclic cycloalkyl, a bridged cycloalkyl or a monocyclic cycloalkyl, Preferably, R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl or (CR) containing one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S C R C ) 0-2 -heteroaryl, said cycloalkyl, phenyl or heteroaryl being optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2 or C3-C6 cycloalkyl, More preferably, R5 is selected from Each R C are independently H, C1-C3 alkyl or C1-C3 haloalkyl; A is selected from or empty; B is selected from C3-C 10 cycloalkyl, phenyl, heterocyclyl comprising one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein the cycloalkyl, phenyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, P(=O)RaRb, S(=O)2Ra, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group or a monocyclic hydrocarbon group, and the Ra and Rb are each independently selected from halogen, C1-C6 alkyl, C3-C 10 Cyclic hydrocarbon group, phenyl group; when A is empty, B is or Preferably, B is selected from a heterocyclic group comprising one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, or a heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl optionally substituted by C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or NO2; Z is selected from CH or N, Preferably, Z is selected from N; C is selected from CH2, C=O or Preferably, C is selected from C=O; Selected from Preferably, the Selected from R4 is independently selected from halogen, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, heterocyclyl containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O and S, or heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or NO2, -C1-C6 alkyl C1-C6 alkyl; L is selected from C3-C 10 a cycloalkyl, phenylene, or heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenylene, or heteroaryl group is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halogen, or wherein when the phenylene group is substituted with two substituents attached to adjacent carbon atoms in the phenylene ring, the two substituents, together with the carbon atoms to which they are attached, are capable of forming a 5- or 6-membered ring optionally comprising 1 to 3 heteroatoms selected from N, O, and S; R6 and R7 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C6 alkyl radical. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; T is selected from C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or heteroaryl comprising a 5-membered or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein the heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo, Preferably, T is selected from a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo; R3 is selected from halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl are optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or NO2, Preferably, R3 is selected from halogen, C1-C6 alkyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Selected from 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R4 is selected from C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, or NO2, wherein the cycloalkyl is a spirocyclic, bridged, or monocyclic cycloalkyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R4 is selected from vinyl and ethynyl, and the vinyl and ethynyl are optionally substituted by one or more substituents independently selected from the following:

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R4 is selected from tetrahydropyranyl, which is optionally substituted by one or more substituents selected from N, O and S, optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN and NO2.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The L is selected from R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C6 alkyl group. 10 Cycloalkyl, the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R4 is selected from 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The L is selected from 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolone or thiadiazolyl, each of which is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo. Preferably, the T is 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound has formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) or formula (I-6): wherein A, B, L, T, R4, R5 and R1 are as defined in any one of claims 1-9.

11. A compound of the formula: or a pharmaceutically acceptable salt thereof: Preferably, the compound is selected from the group consisting of More preferably, the compound is selected from, 12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A method for treating or preventing a GLP-1 receptor-mediated disease or disorder or for modulating the GLP-1 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12.

14. A method for treating 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, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12.

15. A method for treating non-insulin-dependent diabetes mellitus type 2 or obesity, comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12.

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