CN113493447A - GLP-1 receptor agonists - Google Patents

GLP-1 receptor agonists Download PDF

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CN113493447A
CN113493447A CN202010632709.9A CN202010632709A CN113493447A CN 113493447 A CN113493447 A CN 113493447A CN 202010632709 A CN202010632709 A CN 202010632709A CN 113493447 A CN113493447 A CN 113493447A
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CN113493447B (en
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刘斌
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Xuanzhu Beijing Pharm Co Ltd
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Abstract

The invention belongs to the technical field of medicines. In particular, the invention relates to a compound which can be used as a GLP-1 receptor agonist, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof.

Description

GLP-1 receptor agonists
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to GLP-1 receptor agonist compounds, pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, the pharmaceutically acceptable salts or the stereoisomers thereof, and application of the compounds, the pharmaceutically acceptable salts or the stereoisomers thereof.
Background
Diabetes mellitus has become one of the important diseases seriously threatening human health and life in modern society. This disease is a group of clinical syndromes caused by the interaction of genetic and environmental factors, and two major forms of diabetes, type 1 and type 2, are currently recognized. Type 1 diabetes (T1D) develops when the body's immune system destroys the pancreatic beta cells, and clinical treatment is dominated by insulin supplementation. Type 2 diabetes (commonly referred to as T2DM) accounts for more than 95% of the diseased population, often beginning with insulin resistance or when insulin production is insufficient to maintain acceptable glucose levels. Insulin resistance is a key factor in the development and progression of type 2 diabetes.
T2DM is most commonly associated with hyperglycemia and insulin resistance, and other diseases associated with T2DM include hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD), among others.
The glucagon-like peptide 1 receptor (GLP-1R) belongs to the B1 family of seven transmembrane G-protein coupled receptors. The natural agonist ligand is GLP-1 (glucagon-like peptide-1), which is a peptide hormone encoded by human glucagon gene and secreted by intestinal tract L cells, and belongs to the incretin family. Under physiological conditions, GLP-1 stimulates insulin secretion in a glucose-dependent manner while suppressing glucagon secretion, lowering postprandial blood glucose and maintaining a constant level. GLP-1 also has nerve regulating effect, and can inhibit gastric emptying, reduce appetite, and stimulate beta cell proliferation. In non-clinical trials, GLP-1 promotes sustained beta cell capacity by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta cell neogenesis (Meier et al Biodrugs.2003; 17(2): 93-102). In addition, GLP-1 also plays an important role in the cardiovascular system. It has effects of lowering blood pressure and dilating blood vessel, and can improve left ventricular contraction function in myocardial hypertrophy experiment by acute injection of GLP-1. It also reduces cardiomyocyte damage in the context of reperfusion following myocardial ischemia (J.Hypertens, 2003,21: 1125-1135; Am J Physiol endothelial Metab,2004,287: E1209E 1215; Circulation,2004,110: 955-961; Diabetes,2005,54: 146-151).
Currently, marketed GLP-1R drugs and drugs in the research are mainly focused on polypeptide analogs. However, due to the defects of low oral bioavailability, easy degradation and the like of polypeptide drugs, the research and development of novel non-peptide GLP-1R agonists with higher bioavailability and good biological stability have important significance for treating related diseases mediated by GLP-1R.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and good agonism on a GLP-1 receptor. Furthermore, the compounds can be used for preparing medicaments for treating and/or preventing diseases mediated by GLP-1R or related diseases.
The technical scheme of the invention is as follows:
in one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
Figure BDA0002566319670000021
wherein, X1、X2、X3、X4、X5Are each independently selected from-C (R)3) -or-N-;
y, Z are each independently selected from-N-or-C (R)2)-；
Each L1Are each independently selected from-C (R)4R5)-、-N(R4) -, -O-or-S-;
R1selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl;
ring A is optionally substituted with 1 to 4Q2Substituted 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
ring B is optionally substituted with 1 to 4Q3Substituted 6-10 membered aryl or 5-10 membered heteroaryl;
each Q1Each Q2Each Q3Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
each R2、R3、R4、R5Each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, cyano C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
p, m, n are each independently selected from 0, 1,2,3 or 4.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X1、X2、X3are each independently selected from-C (R)3) -or-N-;
X4、X5each independently selected from-N-;
y, Z are each independently selected from-N-or-CH-;
each L1Are each independently selected from-C (R)4R5)-、-N(R4) -, -O-or-S-;
R1selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
ring A is optionally substituted with 1 to 4Q2Substituted 3-7 membered heterocycloalkyl or 5-8 membered heteroaryl;
ring B is optionally substituted with 1 to 4Q3Substituted phenyl or 5-6 membered heteroaryl;
each Q1Each Q2Each Q3Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
each R2、R3、R4、R5Each independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group;
p, m, n are each independently selected from 0, 1,2,3 or 4.
In certain embodiments, said X1、X2、X3Are each independently selected from-C (R)3)-；
Each R3Each independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
In certain embodiments, said X1、X2、X3Are each independently selected from-C (R)3)-；
Each R3Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy.
In certain embodiments, said X1、X2、X3Are each independently selected from-C (R)3)-；
Each R3Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
In certain embodiments, said X4、X5Each independently selected from-N-.
In certain embodiments, each of said Y, Z is independently selected from-N-or-CH-, and at least one of Y, Z is selected from-N-.
In certain embodiments, each L is as defined above1Are each independently selected from-C (R)4R5) -or-O-;
each R4、R5Each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
In certain embodiments, each L is as defined above1Are each independently selected from-C (R)4R5) -or-O-;
each R4、R5Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy.
In certain embodiments, each L is as defined above1Are each independently selected from-C (R)4R5) -or-O-;
each R4、R5Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
In certain embodiments, said R is1Selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; each Q1Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group.
In certain embodiments, said R is1Selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; each Q1Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
In certain embodiments, said R is1Selected from the group consisting of optionally substituted 1-3Q1Substituted of the following groups: oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidineA group, piperidinyl, oxazolidinyl, imidazolidinyl, pyrazolidinyl, 1, 3-oxazinane, hexahydropyrimidyl, piperazinyl, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2, 4-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 1,2, 4-triazinyl, or pyrazinyl;
each Q1Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain embodiments, said R is1Selected from the group consisting of optionally substituted 1-3Q1Substituted of the following groups: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, azetidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, or thiomorpholinyl; each Q1Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, said R is1Selected from the group consisting of optionally substituted 1-3Q1Substituted of the following groups: imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxazolyl, isoxazolyl or 1,2, 4-oxazolyl; each Q1Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, ring A is optionally substituted with 1-4Q2Substituted 3-7 membered heterocycloalkyl or 5-8 membered heteroaryl; each Q2Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxy ammoniaBase, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group.
In certain embodiments, ring A is optionally substituted with 1-4Q2Substituted 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl; each Q2Independently selected from halogen, hydroxyl, sulfydryl, amino, nitro, cyano, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
In certain embodiments, ring A is optionally substituted with 1-3Q2Substituted with the following groups: tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, or pyridazinyl;
each Q2Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain embodiments, ring A is optionally substituted with 1-3Q2Substituted with the following groups: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, or pyridazinyl; each Q2Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, ring B is optionally substituted with 1-4Q3Substituted phenyl or 5-6 membered heteroaryl; each Q3Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group.
In certain embodiments, ring B is optionally substituted with 1-3Q3Substituted with the following groups:
Figure BDA0002566319670000051
Figure BDA0002566319670000061
each Q3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain embodiments, ring B is optionally substituted with 1-3Q3Substituted with the following groups:
Figure BDA0002566319670000062
each Q3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R is2Each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
In certain embodiments, each R is2Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-aminoisopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, monofluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, monofluoromethoxyethyl, difluoromethoxyethyl or trifluoromethoxyethyl.
In certain embodiments, each R is2Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, difluoromethoxymethyl, trifluoromethoxy methyl, difluoromethoxyethyl, or trifluoromethoxyethyl.
In certain embodiments, each R is2Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl and isopropylA group or a trifluoromethyl group.
In certain embodiments, p, m, n are each independently selected from 0, 1,2, or 3.
In certain preferred embodiments, m is 1.
In certain preferred embodiments, n is 0 or 1.
In certain preferred embodiments, p is 2 or 3.
The technical solutions of the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.
In certain embodiments of the present invention, particularly preferred compounds of formula (I), pharmaceutically acceptable salts thereof, and stereoisomers thereof, are selected from the following compounds:
Figure BDA0002566319670000071
Figure BDA0002566319670000081
the invention also provides a pharmaceutical composition, which contains the compound shown in the general formula (I), the pharmaceutically acceptable salt or the stereoisomer thereof, and one or more pharmaceutical carriers and/or diluents; the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection, sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays and the like.
In certain embodiments of the invention, the above-described pharmaceutical formulations may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, and the like. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or a spray.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the art of pharmaceutical formulation, and the selection of a particular carrier and/or diluent will depend on the mode of administration or the type and state of the disease used to treat a particular patient. The preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical art.
In another aspect, the invention also relates to the use of the compound of the general formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof in the preparation of a medicament for preventing and/or treating GLP-1R mediated diseases and related diseases, wherein the medicament can be combined with one or more other medicaments for preventing or treating GLP-1R mediated diseases and related diseases. The diseases and related diseases include diabetes and related diseases, NAFLD and related diseases, and cardiovascular diseases and related diseases.
Furthermore, the invention also relates to application of a pharmaceutical preparation containing the compound shown in the general formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof in preparing a medicament which can be combined with one or more medicaments for treating and/or preventing GLP-1R mediated diseases and related diseases.
In another aspect, the invention relates to a medicament comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described above, administered alone or in combination with one or more second therapeutic agents. Thus, in certain embodiments, the pharmaceutical composition further comprises one or more second therapeutic agents. In certain embodiments, the second therapeutic agent is selected from a hypoglycemic agent, an anti-obesity agent, and/or an agent that treats NASH, among others.
In certain embodiments, the ingredients to be combined (e.g., the compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the second therapeutic agent) may be administered simultaneously or separately, sequentially and separately. For example, the second therapeutic agent can be administered prior to, concurrently with, or subsequent to the administration of the compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate and distinct formulations.
In another aspect, the present invention also provides a method for treating GLP-1R mediated diseases and related diseases, which comprises administering to a patient in need thereof an effective amount of a compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the aforementioned formulation or pharmaceutical composition; the GLP-1R mediated disease and related diseases are as defined above.
By "effective amount" is meant a dosage of a drug that reduces, delays, inhibits or cures a condition in a subject. The size of the administered dose is determined by the administration mode of the drug, the pharmacokinetics of the medicament, the severity of the disease, the individual physical signs (sex, weight, height, age) of the subject, and the like.
[ DEFINITIONS AND GENERAL TERMS ]
In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name and chemical structural formula of a compound do not match when the same compound is represented, the chemical structure is taken as the standard.
In the present invention, unless otherwise defined, scientific and technical terms used herein have meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. To the extent that the definitions and explanations of terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" according to the invention1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C1-4Alkyl group "," C1-3Alkyl group "," C1-2Alkyl group "," C2-6Alkyl group "," C2-5Alkyl group "," C2-4Alkyl group "," C2-3Alkyl group "," C3-6Alkyl group "," C3-5Alkyl group "," C3-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl (propyl), isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention1-4Alkyl "means C1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.
"C" according to the invention1-6Alkoxy "means" C1-6alkyl-O- ", said" C1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy "means" C1-4alkyl-O- ", said" C1-4Alkyl "is as defined above.
"C" according to the invention1-6Alkylthio "means" C1-6alkyl-S- ", said" C1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkylthio "means" C1-4alkyl-S- ", said" C1-4Alkyl "is as defined above.
The "hydroxy group C" of the present invention1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl "meansC1-6One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. Said "C1-6Alkyl "is as defined above.
The "hydroxy group C" of the present invention1-6Alkoxy, amino C1-6Alkoxy, halo C1-6Alkoxy "means" C1-6One or more hydrogens of "alkoxy" are replaced with one or more hydroxy, amino, or halogen.
The "hydroxy group C" of the present invention1-6Alkylthio, amino C1-6Alkylthio, halo C1-6Alkylthio "means" C1-6Alkylthio "is one in which one or more hydrogens are replaced with one or more hydroxy, amino, or halogen.
"C" according to the invention1-6Alkylamino radical, di (C)1-6Alkyl) amino "means independently C1-6alkyl-NH-),
Figure BDA0002566319670000101
The "6-to 10-membered aryl" as referred to in the present invention includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused ring aryl".
The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.
The "5-to 10-membered heteroaryl" as used herein includes "5-to 8-membered monocyclic heteroaryl" and "8-to 10-membered fused heteroaryl".
The "5-to 8-membered monocyclic heteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-to 8-membered monocyclic heteroaryl" includes, for example, "5-to 7-membered monocyclic heteroaryl", "5-to 6-membered nitrogen-containing monocyclic heteroaryl", "6-membered nitrogen-containing monocyclic heteroaryl", and the like, in which the heteroatom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azepinyl, and the like. The "5-6 membered monocyclic heteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-to 10-membered thick heteroaryl", "8-to 9-membered thick heteroaryl", "9-to 10-membered thick heteroaryl containing 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur", etc., which may be fused in a benzo-5-to 6-membered heteroaryl, 5-to 6-membered heteroaryl and 5-to 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The "3-to 10-membered cycloalkyl" described herein includes "3-to 7-membered monocyclic cycloalkyl" and "8-to 10-membered fused ring cycloalkyl".
The "3-7 membered monocyclic cycloalkyl group" as referred to herein means a saturated or partially saturated monocyclic cyclic group having 3 to 7 ring atoms and having no aromaticity, and examples thereof include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexene, etc.
The "8-to 10-membered fused ring cycloalkyl" as referred to herein means a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, and examples thereof include, but are not limited to:
Figure BDA0002566319670000111
and the like.
The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 7-membered heteromonocyclic group" and "8-to 10-membered fused heterocyclic group".
The "3-to 7-membered heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3, 4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 3 to 7 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-7 membered heteromonocyclic group" described herein includes "3-7 membered saturated heteromonocyclic group" and "3-7 membered partially saturated heteromonocyclic group". Preferably, the "3-7 membered heteromonocyclic group" described herein contains 1-3 heteroatoms; preferably, the "3-7 membered heteromonocyclic group" of the present invention contains 1 to 2 heteroatoms selected from nitrogen atom and/or oxygen atom; preferably, the "3-7 membered heteromonocyclic group" described herein contains 1 nitrogen atom. The "3-to 7-membered heteromonocyclic group" is preferably "3-to 6-membered heteromonocyclic group", "4-to 7-membered heteromonocyclic group", "4-to 6-membered heteromonocyclic group", "6-to 8-membered heteromonocyclic group", "5-to 7-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", "3-to 6-membered saturated heteromonocyclic group", "3-to 6-membered nitrogen-containing heteromonocyclic group", "3-to 6-membered saturated nitrogen-containing heteromonocyclic group", "5-to 6-membered saturated nitrogen-containing heteromonocyclic group", etc. For example, containing only 1 or 2 nitrogen atoms, or, alternatively, containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-7 membered heteromonocyclic group" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 3H-diazacyclopropenyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidyl, piperidonyl, tetrahydropyridinyl, piperidyl, piperazinyl, morpholinyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, and the like, Oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like.
The "8-to 10-membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which may be an aromatic ring, but the fused ring as a whole does not have aromaticity, formed by two or more cyclic structures sharing two adjacent atoms with each other, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, and includes, but is not limited to, "8-to 9-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group", and the like; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl-cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, pyrimido-tetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydro cyclopenta [ c ] pyrrolyl, 4H-1, 3-benzoxazinyl and the like.
The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed2The structure of (1).
The term "optionally substituted" as used herein means both the case where one or more hydrogen atoms on a substituent may be "substituted" or "unsubstituted" by one or more substituents.
"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound3H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compound (e.g. -NH)2Etc.) with a suitable inorganic or organic anion (acid), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"stereoisomers" as used herein refers to compounds of the invention when they contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.
The "dosage form" of the present invention refers to a form prepared from the drug suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.
The technical solutions cited in the references cited in this application are included in the disclosure of the present invention, and can be used to explain the contents of the present invention.
Advantageous effects of the invention
1. The compound of formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof has excellent GLP-1 receptor agonism and can be safely used for treating diseases mediated by GLP-1R or related diseases.
2. The compound of formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof has good biological stability and high bioavailability, shows good pharmacokinetic property and has good clinical application prospect.
3. The compound of formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof shows lower toxicity, good drug resistance and high safety.
Detailed description of the preferred embodiments
The technical solutions of the present invention will be described below in conjunction with the specific embodiments, and the above-mentioned contents of the present invention will be further described in detail, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
1 preparation example of the Compound of the present invention
In the preparation examples, the abbreviations have the following meanings:
TFA: trifluoroacetic acid K2CO3: potassium carbonate DCM: methylene dichloride
MeOH: methanol Pd2(dba)3: tris (dibenzylideneacetone) dipalladium Cs2CO3: cesium carbonate
EA: ethyl acetate Johnphos: 2- (di-tert-butylphosphine) Biphenyl LiOH-2O: lithium hydroxide monohydrate
THF: tetrahydrofuran PE: petroleum ether
tBuxphospd-G3: methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)
EXAMPLE 1 preparation of (S) -2- ((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-methyl (methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 1-1)
Preparation of methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate
Figure BDA0002566319670000141
Methyl 3-fluoro-4-nitrobenzoate (3.5g,17mmol), (S) -oxetan-2-methanamine (2.0g,23mmol), triethylamine (6.8mg,68mmol), DMF (10mL), THF (10mL) was reacted at 25 ℃ for 4 h. After the reaction was completed, saturated sodium bicarbonate solution (20mL) was added, EA (3 × 30mL) was extracted three times, EA was combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and subjected to normal phase preparative chromatography (PE: EA ═ 3:1) to obtain 3.2g of a product with a yield of 71.1%.
Preparation of methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate
Figure BDA0002566319670000142
Methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate (3.1g,11.6mmol) and Pd/C (10%, 310mg) were dissolved in THF (30mL) and reacted at 15 ℃ for 4h, after the reaction was completed, suction filtration was carried out, and the filtrate was spin-dried to obtain a crude product of 2.9 g.
Preparation of (S) -methyl 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000143
Methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate (2.9g crude product from the previous step), 2-chloro-1, 1, 1-trimethoxyethane (2.3g,15mmol), p-toluenesulfonic acid (1.1g,6.1mmol), acetonitrile (20mL) were reacted at 60 ℃ for 3h, water (15mL) was added after the reaction was completed, DCM was extracted three times (3X 30mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun dried, and separated by normal phase preparative chromatography (PE: EA ═ 1:1) to give 1.6g of product, 46.6% yield from the two steps.
Preparation of 4- (6-chloropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0002566319670000151
2, 5-dichloropyridine (2.0g,13.6mmol), piperazine-1-carboxylic acid tert-butyl ester (3.0g,16.3mmol), potassium carbonate (5.6g,40.8mmol) were dissolved in N-methylpyrrolidone (30mL), reacted at 150 ℃ for 8 hours, after completion of the reaction, water (30mL) was added, EA was extracted three times (3 × 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and separated by normal phase preparative chromatography (PE: EA ═ 3:1) to obtain the objective compound 3.0g, with a yield of 74.3%.
Preparation of 1- (6-chloropyridin-2-yl) piperazine trifluoroacetate
Figure BDA0002566319670000152
Tert-butyl 4- (6-chloropyridin-2-yl) piperazine-1-carboxylate (500mg,1.7mmol), TFA (3mL) was dissolved in DCM (3mL) and reacted at 20 ℃ for 2h, after completion of the reaction, spin-dried to give 600mg of crude product.
Preparation of methyl (S) -2- (((4- (6-chloropyridin-2-yl) piperazin-1-yl) methyl-1-oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000153
1- (6-chloropyridin-2-yl) piperazine trifluoroacetate (600mg crude), (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (464mg,1.7mmol), potassium carbonate (1.16g,8.4mmol) were dissolved in acetonitrile (10mL) and reacted at 50 ℃ for 8H, after completion of the reaction, the reaction was dried by spin-drying and subjected to normal phase preparative chromatography (PE/EA, EA: 0-100%) to give 550mg of the objective compound in 71.8% yield over two steps.
Preparation of methyl (S) -2- (((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000161
Reacting (S) -2- (((4- (6-chloropyridin-2-yl) piperazin-1-yl) methyl-1-oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (150mg,0.33mmol), 4-fluoro-5- (hydroxymethyl) thiophene-2-carbonitrile (7)8mg,0.49mmol)，Pd2(dba)3(30mg,0.033mmol)，Johnphos(20mg,0.066mmol)，Cs2CO3(215mg,0.66mmol) in 1, 4-dioxane (8mL), N2Reacting at 100 deg.C for 10H under protection, spin-drying, and separating by C18 reverse phase preparative chromatography (MeOH: H)2O ═ 4:5) to give the target compound 90mg, yield 47.4%.
Preparation of (S) -2- ((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-methyl (methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 1-1)
Figure BDA0002566319670000162
Reacting (S) -2- (((4- (6- ((5-cyano-3-fluorothien-2-yl) methoxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d [ -d [ ]]imidazole-6-Carboxylic acid methyl ester (50mg,0.087mmol), LiOH-2O (15mg,0.35mmol), dissolved in THF (5mL), water (2.5mL) was added and the reaction was carried out at 40 ℃ for 2 h. After the reaction, the pH was adjusted to 5-6 with diluted hydrochloric acid, EA was added and extracted three times (3 × 10mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and separated by preparative plate (DCM: MeOH ═ 40:3) to give the target compound 7mg, with a yield of 11.3%.
Molecular formula C28H27FN6O4Molecular weight of S562.6 LC-MS (M/e):563.2(M + H)+)
1H-NMR(400MHz,CD3OD)δ:8.35(s,1H),7.97-7.99(d,1H,J＝8.0Hz),7.70-7.68(d,1H,J＝8.0Hz),7.56(s,1H),7.46-7.48(d,1H,J＝8.0Hz),6.32-6.34(d,1H,J＝8.0Hz),6.07-6.09(d,1H,J＝8.0Hz),5.49(s,2H),5.28(m,1H),4.7-4.9(m,2H),4.6-4.7(m,1H),4.4-4.5(m,1H),4.10-4.14(d,1H J＝16.0Hz),3.99-4.03(d,1H,J＝16.0Hz),3.66(s,4H),2.8-2.9(m,1H),2.70(s,4H),2.5-2.6(m,1H)。
EXAMPLE 2 preparation of (S) -2- ((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-methyl (methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 2-1)
Preparation of 2-chloro-6- (piperidin-4-yl) pyridine trifluoroacetate
Figure BDA0002566319670000171
Tert-butyl 4- (6-chloropyridin-2-yl) piperidine-1-carboxylate (500mg,1.7mmol), TFA (2mL) was dissolved in DCM (3mL) and reacted at 20 ℃ for 3h, after completion of the reaction, which was spin-dried to give crude 550 mg.
Preparation of methyl (S) -2- (((4- (6-chloropyridin-2-yl) piperidin-1-yl) methyl-1-oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000172
2-chloro-6- (piperidin-4-yl) pyridine trifluoroacetate (550mg crude), (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (494mg,1.7mmol), K2CO3(1.16g,8.4mmol), dissolved in acetonitrile (10mL), reacted at 50 ℃ for 8h, dried and separated by normal phase preparative chromatography (DCM: MeOH ═ 20:1) to give 523mg of the title compound in 67.8% yield.
Preparation of methyl (S) -2- (((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000173
Reacting (S) -2- (((4- (6-chloropyridin-2-yl) piperidin-1-yl) methyl-1-oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (215mg,0.55mmol), 4-fluoro-5- (hydroxymethyl) thiophene-2-carbonitrile (130mg,0.83mmol), Pd2(dba)3(50mg,0.055mmol)，Johnphos(32.8mg,0.11mmol)，Cs2CO3(358mg,1.1mmol) in 1, 4-dioxane (10mL), N2Reacting at 105 deg.C for 8h under protection, spin-drying, and reverse-phase preparing with C18Preparative chromatography (MeOH: H)2O ═ 9:1) to give 215mg of the target compound in 68% yield.
Preparation of (S) -2- ((4- (6- ((5-cyano-3-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-methyl (methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 2-1)
Figure BDA0002566319670000181
Reacting (S) -2- (((4- (6- ((5-cyano-3-fluorothien-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]imidazole-6-Carboxylic acid methyl ester (195mg,0.34mmol), LiOH-2O (28mg,0.68mmol), dissolved in THF (10mL), water (5mL) was added and the reaction was carried out at 40 ℃ for 1 h. After the reaction is finished, adjusting the pH value to 5-6 by dilute hydrochloric acid, adding EA for extraction for three times (3 × 10mL), combining organic phases, and adding anhydrous Na2SO4Drying, filtering, spin-drying, and plate separation (DCM: MeOH ═ 40:3) afforded the title compound in 20mg, 10.5% yield.
Molecular formula C29H28FN5O4Molecular weight of S561.6 LC-MS (M/e):562.2(M + H)+)
1H-NMR(400MHz,CD3OD)δ:8.30(s,1H),7.95-7.97(d,1H,J＝8.0Hz),7.65-7.67(d,1H,J＝8.0Hz),7.58-7.62(m,1H),7.57(s,1H),6.87-6.89(d,1H,J＝8.0Hz),6.61-6.63(d,1H,J＝8.0Hz),5.55(s,2H),5.24-5.27(m,1H),4.7-4.8(t,2H),4.6-4.7(m,1H),4.4-4.5(m,1H),4.10-4.14(d,1H,J＝16.0Hz),3.99-4.03(d,1H,J＝16.0Hz),3.16-3.19(d,1H,J＝12.0Hz),3.05-3.08(d,1H,J＝12.0Hz),2.73-2.81(m,2H),2.41-2.54(m,3H),1.96-1.98(d,4H,J＝8.0Hz)。
EXAMPLE 3 preparation of (S) -2- (((4- (6- ((5-cyano-3-fluoro-4-methylthiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 4-1)
(1) Preparation of (3-fluorothien-2-yl) methanol
Figure BDA0002566319670000182
Methyl 3-fluorothiophene-2-carboxylate (3g,18.7mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0 deg.C, and lithium aluminum hydride (1.1g,29mmol) was added and reacted at 0 deg.C for 0.5 hours. Water was added to quench the reaction, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product (2.2g, 89%).
(2) Preparation of (5-bromo-3-fluorothiophen-2-yl) methanol
Figure BDA0002566319670000183
(3-fluorothien-2-yl) methanol (2.2g,16.6mmol) was dissolved in N, N-dimethylformamide (35mL), N-bromosuccinimide (3.2g,18.0mmol) was added, the reaction solution was reacted at 20 ℃ for 2h, the reaction solution was concentrated, and column chromatography (ethyl acetate/petroleum ether ═ 0-15%) was performed to obtain a product (2.6g, 74%).
(3) Preparation of 2- ((5-bromo-3-fluorothiophen-2-yl) methoxy) tetrahydro-2H-pyran
Figure BDA0002566319670000191
(5-bromo-3-fluorothiophen-2-yl) methanol (2.6g,12.3mmol) was dissolved in dichloromethane (25mL), dihydropyran (2.1g,25.0mmol), p-toluenesulfonic acid monohydrate (106mg,0.56mmol) were added in this order, reaction was carried out at 20 ℃ for 16h, the reaction solution was concentrated, and column chromatography (ethyl acetate/petroleum ether ═ 0-15%) was carried out to obtain a product (3.1g, 85%).
(4) Preparation of 4-fluoro-5- ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-carbonitrile
Figure BDA0002566319670000192
2- ((5-bromo-3-fluorothiophen-2-yl) methoxy) tetrahydro-2H-pyran (3.1G,10.5mmol) was dissolved in tetrahydrofuran/water (5/25mL), zinc cyanide (1.5G,12.8mmol), tBuxphosPd-G3(834mg, 1.0mmol) was added, and the reaction was carried out at 40 ℃ for 8 hours under nitrogen. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (ethyl acetate/petroleum ether ═ 0 to 15%) to obtain a product (2.2g, 86%).
(5) Preparation of 4-fluoro-3-methyl-5- ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-carbonitrile
Figure BDA0002566319670000193
4-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-carbonitrile (2.2g,9.0mmol) was dissolved in tetrahydrofuran (10mL), cooled to-45 ℃ under nitrogen blanket, 1M tmpmcgllicl (17.9mL,17.9mmol) was added dropwise, reacted at 45 ℃ for 1 hour, iodomethane (8.9g,62.7mmol) was added, reacted at 45 ℃ for 2 hours, the reaction was quenched by addition of saturated sodium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution of the organic phase, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and column chromatography (ethyl acetate/petroleum ether ═ 0-15%) gave the product (1.2g, 52%).
(6) Preparation of 4-fluoro-5- (hydroxymethyl) -3-methylthiophene-2-carbonitrile
Figure BDA0002566319670000194
4-fluoro-3-methyl-5- ((((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-carbonitrile (1.2g,4.7mmol) was dissolved in methanol (30mL), p-toluenesulfonic acid monohydrate (997mg,5.2mmol) was added, the reaction was reacted at 20 ℃ for 16 hours, pH was adjusted to 7 with triethylamine, the reaction solution was concentrated, extracted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give 810mg of crude product.
(7) Preparation of methyl (S) -2- (((4- (6- ((5-cyano-3-fluoro-4-methylthiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000201
4-fluoro-5- (hydroxymethyl) -3-methylthiophene-2-carbonitrile (112mg crude) was dissolved in dioxane (20mL) and (S) -2- (((4- (6-chloropyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] c]Imidazole-6-carboxylic acid methyl ester (198mg,0.44mmol), Pd2(dba)3(40mg,0.044mmol), John Phos (27mg,0.09mmol), cesium carbonate (287mg,0.88mmol), protected with nitrogen, reacted at 105 ℃ for 8 hours. Concentrating the reaction solution, and performing column chromatography (MeOH/H)2O ═ 0-85%) to give the product (153mg, yield 59%).
(8) Preparation of (S) -2- (((4- (6- ((5-cyano-3-fluoro-4-methylthiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid
Figure BDA0002566319670000202
Methyl (S) -2- (((4- (6- ((5-cyano-3-fluoro-4-methylthiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate (153mg,0.26mmol) was dissolved in tetrahydrofuran/water (8/3mL), lithium hydroxide monohydrate (22mg,0.52mmol) was added, the reaction was reacted at 20 ℃ for 8 hours, pH was adjusted to 7 with 1M hydrochloric acid, the reaction was concentrated, and preparative plate separation (MeOH/DCM ═ 1/8) gave the product (22.8mg, 15%).
Molecular formula C30H30FN5O4Molecular weight of S575.7 LC-MS (M/e):576.1(M + H)+)
1H-NMR(400MHz,CD3OD)δ:8.28(s,1H),7.99-7.89(m,1H),7.71-7.52(m,2H),6.92-6.85(m,1H),6.65-6.55(m,1H),5.52(s,2H),5.31-5.20(m,1H),4.75-4.41(m,3H),4.15-3.92(m,2H),3.38-3.22(m,1H),3.18-2.95(m,2H),2.85-2.64(m,2H),2.58-2.31(m,3H),2.25(s,3H),2.05-1.85(m,4H)。
EXAMPLE 4 preparation of (S) -2- ((4- (6- ((5-cyano-4-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 5-1)
(1) Preparation of methyl 3-fluoro-5-iodothiophene-2-carboxylate
Figure BDA0002566319670000211
3-fluorothiophene-2-carboxylic acid methyl ester (6.0g,37.5mmol) is dissolved in tetrahydrofuran (50mL), 2,6, 6-tetramethylpiperidyl magnesium chloride lithium chloride complex tetrahydrofuran solution (1M,63.7mL,63.7mmol) is added at-45 ℃ under the protection of nitrogen, reaction is carried out at 45 ℃ for 0.5 hour, iodine (10.1g,39.7mmol) solution in tetrahydrofuran (15mL) is added, reaction is carried out at-45 ℃ for 0.5 hour, saturated saline solution (50mL) is quenched, ethyl acetate (100mL) is extracted, organic phase anhydrous sodium sulfate is dried, and the crude product is obtained by spin-drying and is directly used in the next step.
(2) Preparation of 3-fluoro-5-iodothiophene-2-carboxylic acid
Figure BDA0002566319670000212
Dissolving the crude product of the previous step of 3-fluoro-5-iodothiophene-2-carboxylic acid methyl ester in methanol (75mL) and water (75mL), adding lithium hydroxide monohydrate (11g,262.5mmol), reacting at 70 ℃ for 0.5 hour, adjusting the pH to 3 with 2N hydrochloric acid, extracting with ethyl acetate (100mL), washing with saturated saline (50mL), drying with anhydrous sodium sulfate of an organic phase, and spin-drying to obtain the crude product which is directly used in the next step.
(3) Preparation of 3-fluoro-5-iodothiophene-2-carbonyl chloride
Figure BDA0002566319670000213
The crude 3-fluoro-5-iodothiophene-2-carboxylic acid from the previous step was dissolved in dichloromethane (150mL), DMF (0.1mL) was added, oxalyl chloride (9.5g,75.0mmol) was slowly added dropwise at 25 deg.C, the addition was completed at 25 deg.C and reacted for 0.5 h, and the crude was spin-dried and used directly in the next step.
(4) Preparation of 3-fluoro-5-iodothiophene-2-carboxamide
Figure BDA0002566319670000214
The crude product of 3-fluoro-5-iodothiophene-2-carbonyl chloride obtained in the previous step is added dropwise into 25% ammonia water (100mL) at 20 ℃, ethyl acetate (100mL) is used for extraction, saturated saline solution (50mL) is used for washing, an organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by spin-drying and is directly used in the next step.
(5) Preparation of 3-fluoro-5-iodothiophene-2-carbonitrile
Figure BDA0002566319670000221
The crude 3-fluoro-5-iodothiophene-2-carboxamide from above, triethylamine (11.4g,112.5mmol) dissolved in dichloromethane (100mL), trifluoroacetic anhydride (11.8g,56.2mmol) added at 0 ℃, reaction at 25 ℃ for 1 hour, quenched with saturated brine (50mL), dried over anhydrous sodium sulfate of the organic phase, spun dry, and column chromatographed (ethyl acetate/petroleum ether ═ 0-10%) to give the product (5.5g, 58.0% yield over five steps).
(6) Preparation of 3-fluoro-5-formylthiophene-2-carbonitrile
Figure BDA0002566319670000222
3-fluoro-5-iodothiophene-2-carbonitrile (2.5g,9.9mmol) was dissolved in THF (30mL), isopropylmagnesium chloride (2M,5.4mL,10.9mmol) was added at-78 deg.C under nitrogen protection, reaction was carried out at 78 deg.C for 1 hour, DMF (1.5g,20.5mmol) was added, reaction was carried out at-78 deg.C for 1 hour, saturated ammonium chloride (100mL) was quenched, ethyl acetate (100mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (ethyl acetate/petroleum ether ═ 0-10%) was carried out to give a product (470mg, 30.7%).
(7) Preparation of 3-fluoro-5- (hydroxymethyl) thiophene-2-carbonitrile
Figure BDA0002566319670000223
3-fluoro-5-formylthiophene-2-carbonitrile (470mg,3.0mmol) was dissolved in ethanol (35mL), sodium borohydride (181mg,4.8mmol) was added at 0 deg.C, reaction was carried out at 20 deg.C for 1 hour, and then quenched with saturated brine (50mL), extracted with ethyl acetate (100mL), dried over anhydrous sodium sulfate for the organic phase, spun-dried, and subjected to column chromatography (ethyl acetate/petroleum ether ═ 0-30%) to obtain a product (450mg, 94.6%).
(8) Preparation of tert-butyl (S) -2- ((4- (6- ((5-cyano-4-fluorothien-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate
Figure BDA0002566319670000224
Tert-butyl (S) -2- ((4- (6-chloropyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate (400mg,0.8mmol), 3-fluoro-5- (hydroxymethyl) thiophene-2-carbonitrile (190mg,1.2mmol), cesium carbonate (521mg,1.6mmol), 2- (di-tert-butylphosphino) biphenyl (48mg,0.16mmol) and tris-dibenzylideneacetone dipalladium (73mg,0.08mmol) were dissolved in 1, 4-dioxane (20mL), reacted at 105 ℃ under nitrogen protection for 16 hours, suction filtered, the filtrate was dried by spinning, and prepared by medium pressure reverse phase (methanol/water 0-60%) to give the product (230mg, 46.3%).
(9) Preparation of (S) -2- ((4- (6- ((5-cyano-4-fluorothien-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid
Figure BDA0002566319670000231
Tert-butyl (S) -2- ((4- (6- ((5-cyano-4-fluorothiophen-2-yl) methoxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate (230mg, 0.37mmol) was dissolved in dichloromethane (20mL) and trifluoroacetic acid (5mL), reacted at 25 ℃ for 5 hours, saturated sodium bicarbonate adjusted to pH 6-7, the organic phase dried over anhydrous sodium sulfate, spun dried, prepared on reverse phase at medium pressure (acetonitrile/water 0-40%) to give the product (76mg, 36.3%).
The molecular formula is as follows: c29H28FN5O4S molecular weight: 561.6 LC-MS (M/e): 561.9(M + H)+)
1HNMR(400MHz,CDCl3):δ:8.10(s,1H),8.03(d,J＝7.6,1H),7.80(d,J＝8.0,1H),7.55-7.45(m,1H),6.87(s,1H),6.80(d,J＝7.2,1H),6.61(d,J＝8.4,1H),5.47(s,2H),5.25-5.15(m,1H),4.75-4.55(m,3H),4.45-4.35(m,1H),4.06(s,2H),3.20-3.10(m,2H),2.80-2.60(m,2H),2.50-2.30(m,3H),2.00-1.80(m,4H)。
2 pharmacological Activity test of Compounds of the present invention
The advantageous effects of the compounds of the present invention are further illustrated below by pharmacological test examples, but this should not be construed as the compounds of the present invention having only the following advantageous effects.
Experimental example 1: in vitro cytological Activity of Compounds of the invention
And (3) testing the sample: the structural formula and the preparation method of the compound are shown in the examples.
1. Purpose of experiment
The GLP1R receptor cAMP assay is used to determine whether a test compound has agonist activity at the GLP1R receptor.
2. Experimental material and instrument and equipment
2.1 Experimental reagent consumables
Figure BDA0002566319670000232
Figure BDA0002566319670000241
2.2 Experimental instrumentation
Figure BDA0002566319670000242
3. Experimental methods
3.1 cell culture and reagent preparation
1) Cell lines: Flpin-293-GLP1R
2) Complete culture medium DMEM + 10% fetal calf serum + 1-fold penicillin streptomycin +200 mu g/ml hygromycin
3) Experiment buffer solution of 1-fold HBSS +20mM HEPES + 0.1% BSA + 500. mu.M IBMX
3.2 GLP1R receptor Activity assay
3.2.1 cell culture and plating
1) HEK293-GLP1R cell line was cultured at 37 ℃ with 5% CO2In complete medium under ambient conditions;
2) after trypsinization, the cells were resuspended in assay buffer and plated in 384 cell culture plates at a density of 20,000 per well in a volume of 15 μ l.
3.2.2 detection of Activity
1) Compounds were diluted with assay buffer;
2) add 5. mu.l of compound per well, incubate 30 minutes at 37 ℃;
3) freezing and thawing cAMP-d2 and Anti-cAMP-Eu3+Diluting the sample by 20 times with experiment buffer;
4) add 10. mu.l cAMP-d2 to the experimental wells, then add 10. mu.l Anti-cAMP-Eu3+Into an experimental well;
5) the reaction plate was centrifuged at 200g for 30s at room temperature and allowed to stand at 25 ℃ for 1h, after which data were collected by Envision.
3.3 data analysis
Compound EC was calculated using GraphPad non-linear fitting equation50。
3.4 results of the experiment
TABLE 1 GLP-1R agonist Activity of the compounds of the invention
Figure BDA0002566319670000243
Figure BDA0002566319670000251
And (4) conclusion: as can be seen from Table 1, the compound 1-1 and the compound 2-1 of the present invention have good agonistic activity against GLP-1R.
Experimental example 2: in vitro cytological Activity of Compounds of the invention II
Abbreviations Chinese full scale
GLP1R Glucagon-like peptide 1 receptor
cAMP Cyclic adenosine monophosphate
FBS Fetal bovine serum
PBS Phosphate buffer
BSA Bovine serum albumin
IBMX 1-methyl-3-isobutylxanthines
DMSO Dimethyl sulfoxide
HBSS Balanced salt solution
TrypLE Buffer solution
buffer Common buffer solution
lysis buffer Lysis buffer
And (3) testing the sample: the structural formula and the preparation method of the compound are shown in the examples.
Experimental reagent:
Figure BDA0002566319670000252
Figure BDA0002566319670000261
1. the experimental method comprises the following steps:
1.1 cell culture and reagent preparation
4) Cell lines: Flpin-293-GLP1R
5) Complete medium DMEM + 10% fetal bovine serum +1 penicillin streptomycin + 200. mu.g/ml hygromycin
6) Experimental buffer 1 × HBSS +20mM HEPES + 0.1% BSA +500 μ M IBMX
1.2 information on the test Compound
Figure BDA0002566319670000262
1.3GLP1R receptor Activity assay
1.3.1 cell culture and plating
1) HEK293-GLP1R cell line was cultured at 37 ℃ with 5% CO2In complete medium under ambient conditions;
2) after TrypLE digestion, cells were resuspended in experimental buffer and plated in 384 cell culture plates at a plating density of 20,000 per well in a plating volume of 15 μ l.
1.3.2 detection of Activity
1) Diluting the compound with buffer;
2) add 5. mu.l of compound per well, incubate 30 minutes at 37 ℃;
3) freezing and thawing cAMP-d2 and Anti-cAMP-Eu3+It was diluted 20-fold with lysis buffer.
4) Add 10. mu.l cAMP-d2 to the experimental wells, then add 10. mu.l Anti-cAMP-Eu3+Into the experimental well.
5) The reaction plate was centrifuged at 200g for 30s at room temperature and allowed to stand at 25 ℃ for 1h, after which data were collected by Envision.
1.4 data analysis
Compound EC was calculated using GraphPad non-linear fitting equation50:
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
X is the log value of the concentration of the compound; y is Activation%; bottom is the lowest value; top value for Top; slope of HillSlope
2. Results of the experiment
TABLE 2 in vitro cytological Activity data for Compounds of the invention
Figure BDA0002566319670000271
3. Conclusion of the experiment
For cAMP experiments, the compounds of the invention all exhibit agonistic activity against GLP-1R, and the compound 4-1 is superior in activity.
Experimental example 3: pharmacokinetic experiment of the Compound of the invention
1. The structural formula and the preparation method of the test sample compound are shown in the examples.
2. Experimental animals CD-1 mice, 6/dose.
3. Preparation of test solution
(1) Iv bolus administration (iv): taking the compound 2-1(2.52mg), adding 70.0 mu L of DMSO (dimethyl sulfoxide), carrying out vortex dissolution, then adding 400116.0 mu L of PEG, carrying out vortex mixing, finally adding 2.14mL of 28% HP-beta-CD solution, carrying out vortex mixing, and carrying out heat preservation at 50 ℃ for 20min to obtain a clear solution with the concentration of 1 mg/mL.
(2) Oral administration (po): taking the compound 2-1(3.96mg), adding 3.66mL of solvent 2% HPC + 0.1% Tween 80 into a tissue grinder, and grinding uniformly at the rotating speed of 1200rpm to obtain a uniform suspension with the final concentration of 1 mg/mL.
4. Experimental methods
4.1 administration of drugs
(iv) the test sample is administered by intravenous bolus injection, wherein the administration dose is 5mg/kg, and the administration volume is 5 mL/kg;
oral administration (po) was carried out at a dose of 10mg/kg and a volume of 10 mL/kg.
4.2 blood sampling
Blood was collected from the orbit at 0.083, 0.25, 0.5, 1,2,4, 6, 8, 24h after administration, 6 animals per dose were divided into two groups, blood was collected alternately, about 100. mu.L of whole blood was collected from each animal at each time point, plasma was separated by centrifugation at 8000rpm for 6min, and plasma was frozen at-80 ℃ in a freezer.
4.3 plasma sample analysis
Adopting a protein precipitation method: 10 μ L of plasma was put into a 96-well deep-well plate, and 200 μ L of acetonitrile solution containing an internal standard of TBTM (tolbutamide) at a concentration of 50ng/mL was added. Vortexing for 10min, centrifuging at 4000 rpm for 20min, collecting 100 μ L supernatant, adding 100 μ L water, and vortexing for 3 min; LC-MS/MS analysis.
4.4 results of the experiment
TABLE 3 mouse PK evaluation results for the Compounds of the invention (iv)
Figure BDA0002566319670000272
Table 4 mouse PK evaluation results (po) for compounds of the invention
Figure BDA0002566319670000281
Note: t is1/2Represents the half-life; t ismaxRepresents the time to peak; cmaxRepresents the maximum blood concentration value; AUClastArea under curve 0 → t when drug is represented; CL represents clearance; MRT represents the mean residence time; vss stands for apparent distribution capacitanceAnd (4) accumulating.
4.5 conclusion of the experiment
The experimental data in tables 3 and 4 show that the compound of the invention has higher exposure in organisms, proper half-life and clearance rate, good pharmacokinetic property and good clinical application prospect when being injected or orally taken.
Experimental example 4: pharmacokinetic experiment of the Compound of the invention II
1. And (3) testing the sample: the structural formula and the preparation method of the compound are shown in the examples.
2. Experimental animals: CD-1 mice, female, in number 6/mode of administration/compound, purchased animal production license number from experimental animals technologies ltd, viton, beijing: SCXK (Kyoto) 2016-.
3. Preparation of test liquid
3.1 preparation of Compound 4-1 solution
(1) IV bolus administration (IV): taking the compound 4-1(2.13mg), adding 97.5 mu L of PEG400 solution, dissolving by vortex, then adding 1.85mL of 28% HP-beta-CD solution, uniformly mixing by vortex, preserving heat at 50 ℃ for 20min, and filtering by a 0.45 mu m filter membrane to obtain a clear solution with the concentration of 1 mg/mL.
(2) Oral administration (PO): placing compound 4-1(3.34mg) in a tissue grinder, adding 3.06mL of solvent 2% HPC + 0.1% Tween 80, and grinding at 1200rpm to obtain 1mg/mL of uniform suspension.
3.2 preparation of Compound 5-1 solution
(1) IV bolus administration (IV): taking the compound 5-1(1.86mg), adding 91.5 mu L of PEG400 solution, dissolving by vortex, then adding 1.74mL of 28% HP-beta-CD solution, uniformly mixing by vortex, and keeping the temperature at 50 ℃ for 10min to obtain a clear solution with the concentration of 1 mg/mL.
(2) Oral administration (PO): weighing compound 5-1(3.17mg) and placing in a tissue grinder, adding 3.12mL solvent 2% HPC + 0.1% Tween 80, and grinding at 1000rpm to obtain 1mg/mL homogeneous suspension.
4. Experimental methods
4.1 administration of drugs
Intravenous bolus (IV) administration, the administration dose is 5mg/kg, and the administration volume is 5 mL/kg;
oral administration (PO) was performed at a dose of 10mg/kg and a volume of 10 mL/kg.
4.2 blood sampling
Blood was collected at 0.083, 0.25, 0.5, 1,2,4, 6, 8, 24h after administration, in particular in the manner shown in the following table.
Figure BDA0002566319670000291
At each time point approximately 50. mu.L of whole blood was collected from each animal by canthus and placed in the eye containing EDTA-K2Centrifuging at 8000rpm at 4 deg.C for 6min in an anticoagulant tube to obtain plasma sample, and freezing at-80 deg.C.
4.3 plasma sample analysis
Adopting a protein precipitation method: and taking 20 mu L of a plasma sample, adding 200 mu L of an internal standard (acetonitrile solution containing 50ng/mL of tolbutamide), vortexing for 10min, then centrifuging for 20min at 4000 rpm, taking 100 mu L of supernatant, adding 100 mu L of water, vortexing and uniformly mixing for 3min, and then carrying out LC-MS/MS analysis.
4.4 results of the experiment
TABLE 5 evaluation results of mouse PK of the Compound CD1 of the present invention
Figure BDA0002566319670000292
AUC0-tArea under curve 0 → t when drug is represented; CL represents clearance; vssRepresenting the steady state apparent distribution volume; t is1/2Represents a terminal elimination half-life; t ismaxRepresents the time to peak; cmax(ii) surrogate expression peak concentration; f% represents the absolute bioavailability.
4.5 conclusion of the experiment
As can be seen from the data in table 5, the compound of the present invention has higher exposure and bioavailability, and thus has good pharmacokinetic properties.

Claims (10)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure FDA0002566319660000011
wherein, X1、X2、X3、X4、X5Are each independently selected from-C (R)3) -or-N-;
y, Z are each independently selected from-N-or-C (R)2)-；
Each L1Are each independently selected from-C (R)4R5)-、-N(R4) -, -O-or-S-;
R1selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl;
ring A is optionally substituted with 1 to 4Q2Substituted 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
ring B is optionally substituted with 1 to 4Q3Substituted 6-10 membered aryl or 5-10 membered heteroaryl;
each Q1Each Q2Each Q3Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
each R2、R3、R4、R5Each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, haloGeneration C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, cyano C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
p, m, n are each independently selected from 0, 1,2,3 or 4.
2. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to claim 1,
X1、X2、X3are each independently selected from-C (R)3) -or-N-;
X4、X5each independently selected from-N-;
y, Z are each independently selected from-N-or-CH-;
each L1Are each independently selected from-C (R)4R5)-、-N(R4) -, -O-or-S-;
R1selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
ring A is optionally substituted with 1 to 4Q2Substituted 3-7 membered heterocycloalkyl or 5-8 membered heteroaryl;
ring B is optionally substituted with 1 to 4Q3Substituted phenyl or 5-6 membered heteroaryl;
each Q1Each Q2Each Q3Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxyamino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino groupsC1-6An alkylthio group;
each R2、R3、R4、R5Each independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group;
p, m, n are each independently selected from 0, 1,2,3 or 4.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
R1selected from the group consisting of optionally substituted 1-4Q1Substituted of the following groups: 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl;
each Q1Each independently selected from halogen, hydroxy, cyano, amino, nitro, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
4. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claims 1-3,
ring A is optionally substituted with 1 to 4Q2Substituted 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl;
each Q2Independently selected from halogen, hydroxyl, sulfydryl, amino, nitro, cyano, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group.
5. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claims 1-4,
X1、X2、X3are each independently selected from-C (R)3)-；
X4、X5Each independently selected from-N-;
y, Z are each independently selected from-N-or-CH-, and at least one of Y, Z is selected from-N-;
each L1Are each independently selected from-C (R)4R5) -or-O-;
R1selected from the group consisting of optionally substituted 1-3Q1Substituted of the following groups: oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, pyrazolidinyl, 1, 3-oxazinane, hexahydropyrimidyl, piperazinyl, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2, 4-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 1,2, 4-triazinyl, or pyrazinyl;
each Q1Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring A is optionally substituted by 1 to 3Q2Substituted with the following groups: tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, or pyridazinyl;
each Q2Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxyIsopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy or 1,1, 1-trifluoroisopropoxy;
ring B is optionally substituted by 1 to 3Q3Substituted with the following groups:
Figure FDA0002566319660000031
each Q3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
each R2Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, difluoromethoxymethyl, trifluoromethoxy methyl, difluoromethoxyethyl, or trifluoromethoxyethyl;
each R3Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy;
each R4、R5Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy;
p, m, n are each independently selected from 0, 1,2,3 or 4.
6. The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claims 1-5,
R1selected from the group consisting of optionally substituted 1-3Q1Substituted of the following groups: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, azetidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, or thiomorpholinyl;
each Q1Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy;
ring A is optionally substituted by 1 to 3Q2Substituted with the following groups: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, or pyridazinyl; each Q2Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy;
ring B is optionally substituted by 1 to 3Q3Substituted with the following groups:
Figure FDA0002566319660000041
each Q3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy;
each R2Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
each R3Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
each R4、R5Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
7. The compound of any one of claims 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:
Figure FDA0002566319660000042
Figure FDA0002566319660000051
8. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in a pharmaceutically acceptable dosage form, comprising one or more pharmaceutically acceptable excipients.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that it comprises one or more second therapeutically active agents selected from sugar-lowering agents, anti-obesity agents and/or agents for the treatment of NASH and the like.
10. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical formulation of claim 8, or a pharmaceutical composition of claim 9, for the manufacture of a medicament for the treatment and/or prevention of GLP-1R mediated diseases and related disorders, including diabetes and related disorders, NAFLD and related disorders, and cardiovascular diseases and related disorders.
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