Composition containing phenylalanine derivative and application of composition in promoting pancreatic beta cell proliferation

Abstract

The invention provides a pharmaceutical composition for promoting pancreatic beta cell proliferation. The pharmaceutical composition comprises a compound shown in a formula I or a stereoisomer, a hydrate, a solvate, an isotope label, a prodrug or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier of the compound. The invention also provides a compound as shown in a formula I or a stereoisomer, a hydrate, a solvate, an isotope label, a prodrug or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt containing the compound as shown in the formula I or the stereoisomer, the hydrate, the solvate and the isotope label of the compound. The invention also discloses application of a pharmaceutical composition of the prodrug or pharmaceutically acceptable salt thereof in preparation of drugs for promoting pancreatic beta cell proliferation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of phenylalanine derivatives and compositions thereof in promoting the proliferation of pancreatic beta cells. Background Art

[0002] Diabetes is a chronic heterogeneous metabolic disease. Impaired pancreatic β-cell function and insufficient insulin secretion lead to elevated blood sugar, which is an important pathophysiological basis for the onset of diabetes. As a common and frequently occurring disease, diabetes is second only to cancer in terms of its harm to the human body. The latest official data released internationally show that about 1 in 10 adults in the world suffer from diabetes, a total of about 537 million people. It is estimated that the number of patients will increase to 643 million by 2030 and to 783 million by 2045. The global prevalence, number of cases, number of deaths, and medical and health expenditures are increasing day by day, and the health problems caused are very challenging for the world today.

[0003] Over the years, diabetes has brought a huge socioeconomic burden. Traditional therapeutic drugs mainly focus on insulin secretion and insulin sensitization, which can cause adverse side effects to patients, leading to drug noncompliance and treatment failure. Moreover, most patients need multiple therapies to achieve good blood sugar control in the long term. When multiple drugs are used in combination, hypoglycemia is one of the main risk factors that need to be paid attention to. The loss of pancreatic β-cell mass is a pathological hallmark of the development of type I and type II diabetes. Therefore, sustainable generation of functional β-cells or pancreatic islets is a promising approach to treat diabetes, that is, increasing the endogenous mass of β-cells, which has always been a hot topic in the field of diabetes treatment. β-cell mass is defined as the total weight of β-cells in the pancreas, which is determined by the balance between β-cell death (apoptosis / necrosis) and birth (replication and regeneration / transdifferentiation of existing cells) and the volume of individual cells (atrophy / hypertrophy). There is a great demand for β-cell regeneration therapy in the clinic. Many patients with type I diabetes and type II diabetes with pancreatic β-cell defects can benefit from treatment to restore functional β-cell masses. Especially for patients with type 1 diabetes, severe deficiency of β cells may lead to life-threatening blood sugar fluctuations, and their need for β cell regeneration is particularly urgent.

[0004] Therefore, seeking new ways to restore the quality and function of pancreatic beta is of great significance for the treatment of diabetes. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a phenylalanine compound, which can play a role in preventing, treating, curing or alleviating diabetes by promoting the proliferation of pancreatic β cells. Specifically, the present invention verifies the proliferation effect of the amino acid compound on rat pancreatic β cell line INS-1832 / 13 and the improvement effect on type I diabetic rats, proving that it has the use of preventing, treating, curing or alleviating diabetes.

[0006] In one aspect, the present invention provides a pharmaceutical composition for promoting pancreatic β-cell proliferation, comprising a compound represented by Formula I or its stereoisomers, hydrates, solvates, prodrugs thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier;

[0007]

[0008] in:

[0009] R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl;

[0010] R 6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0011] R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-;

[0012] R 8 and R 9 Each independently selected from H, -NHR c 、-OR d, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-CH 2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-; wherein R c is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl -CH2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutylC(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-, R dSelected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)- and phenyl-C(=O)-.

[0013] X is -OR 10 or -NR 11 R 12 ;

[0014] Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

[0015] On the other hand, the present invention also provides the use of the compound of formula I or its stereoisomer, hydrate, solvate, isotope label, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I or its stereoisomer, hydrate, solvate, isotope label, prodrug or pharmaceutically acceptable salt thereof in the preparation of a drug for promoting pancreatic β cell proliferation;

[0016]

[0017] in:

[0018] R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2, R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl;

[0019] R 6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0020] R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-;

[0021] R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; wherein R c Selected from H, C1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-, R d Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-; wherein R c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C6-10 Aryl-C 1-2 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-, R d Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-;

[0022] X is -OR 10 or -NR 11 R 12 ;

[0023] Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

[0024] In some embodiments, R 1 , R2 , R 3 , R 4 and R 5 Each is independently selected from H, D, F, Cl, Br, I, -CN, -NO2, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenyl, naphthyl, phenanthrenyl, phenoxy, naphthyloxy, phenanthrenoxy, CH3C(=O)O-, CH3CH2C(=O)O-, CH3CH2CH2C(=O)O-, (CH3)2CHC(=O)O-, (CH3)3C(=O)O-, cyclopropyl-C(=O)O-, cyclobutyl-C(=O)O-, cyclopentyl-C(=O)O-, cyclohexyl-C(=O)O-, phenyl-C(=O)O-, CH3S(=O)2O-, CF3S(=O)2O-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2O-, quinolyl-S(=O)2O-, isoquinolyl-S(=O)2O- and p-CH3-phenyl-S(=O)2O-; wherein the C 6-14 Aryl, C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, F, Cl, Br, I, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached they form a phenyl or naphthyl group.

[0025] In some embodiments, R 6 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0026] In some embodiments, R 7 Selected from H, D, OR b ; where R b Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)- and phenyl-C(=O)-.

[0027] In some embodiments, R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, (CH3)3C-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-; wherein R c is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, (CH3)3C-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-OC(=O) -, CH3C(=O)-, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-, R d Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)- and phenyl-C(=O)-.

[0028] In some embodiments, R 10 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl;

[0029] R 11 and R12 are each independently selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl, or R 11 , R 12 Together with the atoms to which they are attached they form a pyrrolidinyl, piperidinyl or piperazinyl.

[0030] In some embodiments, Formula I has one of the following structures:

[0031]

[0032] In some embodiments, Formula I has one of the following structures:

[0033]

[0034] In some embodiments, the drug for promoting pancreatic β cell proliferation is used to prevent, treat or alleviate type I diabetes or prevent, treat, treat or alleviate type II diabetes.

[0035] Terminology

[0036] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0037] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0038] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0039] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0040] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0041] The term "subject" refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0042] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0043] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0044] When substituents are described by a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0045] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0046] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0047] The terms "racemate," "racemate" or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0048] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0049] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0050] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the fact that double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms cannot rotate freely.

[0051] The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate and this may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0052] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0053] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0054] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0055] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0056] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0057] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed by compounds and bases, including but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, choline salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts and tromethamine salts.

[0058] Pharmaceutically acceptable acid addition salts can be formed by the compounds of the present invention and inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by the compounds of the present invention and inorganic or organic base. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahland Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0059] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, isopropylbenzene or a mixture thereof, etc.

[0060] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0061] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.

[0062] The term "isotopically labeled compound" means that a compound of the present invention is labeled with an isotope. It is identical to those compounds described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0063] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitution may offer some therapeutic advantage of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0064] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in in vivo half-life or a reduction in dosage requirements or an improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of compounds of formula I to VI. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0065] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo into a compound of Formula I. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0066] Unless explicitly stated otherwise, the descriptions used in the present invention such as "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense, which may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0067] The terms "optional", "optionally" or "arbitrarily", "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with..." means that the substitution may or may not occur.

[0068] When the term "each independently" is used in combination with "arbitrarily", for example, "each independently arbitrarily replaced by..." means that the specific options are replaced by... or not by... without affecting each other.

[0069] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0070] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0071] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0072] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N). In the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent rules and composition rules of organic compounds.

[0073] The term "heterocyclyl" or "heterocycle" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms and heteroatoms. The heteroatoms have the meanings as described herein. Saturated or partially unsaturated heterocyclyls may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings may be present. In one embodiment, the heterocyclyl group is a 3-8 membered ring, such as a 3-8 membered saturated or partially unsaturated heterocyclyl (2-7 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2), which may be represented as a 3-8 membered heterocyclyl. In one embodiment, the heterocyclyl is a 3-6 membered heterocyclyl. In one embodiment, the heterocyclyl is a 5-6 membered heterocyclyl. In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from the group consisting of a saturated monocyclic heterocyclic group, a saturated bicyclic heterocyclic group, a saturated tricyclic heterocyclic group, a partially unsaturated monocyclic heterocyclic group, a partially unsaturated bicyclic heterocyclic group, and a partially unsaturated tricyclic heterocyclic group. Bicyclic heterocyclic groups refer to heterocyclic groups of bicyclic ring systems. Monocyclic heterocyclic groups refer to heterocyclic groups of monocyclic ring systems. 5-6 membered heterocyclic groups refer to heterocyclic groups with 5-6 ring atoms. 4-7 membered heterocyclic groups refer to heterocyclic groups with 4-7 ring atoms. 3-6 membered heterocyclic groups refer to heterocyclic groups with 3-6 ring atoms.

[0074] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms. Saturated or partially unsaturated cycloalkyl groups may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms, such as C 3-10 Saturated or partially unsaturated cycloalkyl, represented by C 3-10 In some embodiments, the cycloalkyl group is C 3-8 In some embodiments, the cycloalkyl group is C 3-6 Cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms.

[0075] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10-membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5-8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8-membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5-7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7-membered heteroaryl group. ; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6 membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.

[0076] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". 6-14 membered aryl refers to an aromatic group containing 6-14 ring carbon atoms, also represented by C 6-14Aryl. 6-10 membered aryl refers to an aromatic group containing 6-10 ring carbon atoms, also represented by C 6-10 Aryl. Examples include, but are not limited to, phenyl, naphthyl, and the like.

[0077] The term "hydrogen" means 1 H; "deuterium" means 2 H.

[0078] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0079] The term "amino" refers to -NH2.

[0080] The term "hydroxy" refers to -OH.

[0081] The term "cyano" refers to -CN.

[0082] The term "nitro" refers to -NO2.

[0083] The term "carboxyl" refers to HO(C=O)-.

[0084] The term "O=" refers to oxo, that is, when the substituent is O=", O is connected to the substituted group through a double bond.

[0085] The term "alkyl" or "alkyl group" refers to a saturated straight or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkyl group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0086] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkoxy group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 Alkoxy.

[0087] The term "alkylamino" means an alkyl group attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkylamino group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkylamino group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkylamino group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1-3 Alkylamino.

[0088] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0089] The term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0090] The compound of formula I of the present invention can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical preparation for promoting the proliferation of pancreatic β cells.

[0091] The compound of formula I of the present invention can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical preparation for preventing, treating, curing or alleviating diabetes.

[0092] The present invention relates to a pharmaceutical composition, which comprises a compound represented by formula I or its stereoisomer, hydrate, solvate, isotope-labeled substance, prodrug or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0093] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents, and further excipients such as excipients, binders, fillers, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0094] Compound shown in formula I of the present invention or its pharmaceutical composition is formulated for non-parenteral administration, such as nose, oral cavity, rectum, lung, vagina, sublingual, topical, transdermal, eye, or especially for oral administration, such as in the form of oral solid dosage form, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (applicably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, particularly people, such as in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions can include a single active ingredient, or preferably, together with a pharmaceutically acceptable carrier.

[0095] The compound shown in formula I of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition can be processed with pharmaceutically inert inorganic or organic excipients to produce oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, and flow agents such as fumed silica can be used as such excipients for preparing and manufacturing oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are such as vegetable oils, waxes, fats, semisolid and liquid polyols, etc.

[0096] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0097] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0098] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0099] The dosage can vary within wide limits and, of course, will be in accordance with individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0100] The compound of formula I of the present invention or its pharmaceutical composition can also be used in combination with one or more other pharmacologically active compounds, which are also effective against the same disease, preferably using different modes of action, or reducing or preventing possible undesirable side effects of the compound. The combination partners can be used simultaneously in this treatment, for example, by incorporating them into a single pharmaceutical formulation, or by using two or more different dosage forms (each dosage form containing one or more than one combination partner) and continuously.

[0101] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in at least partially preventing, treating, curing, or alleviating type I diabetes or preventing, treating, curing, or alleviating type II diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1 The cell proliferation graph at 10 μM concentration measured in the proliferation experiment of rat pancreatic β cell line INS-1832 / 13 in Example 1. (A) is the result of compounds 10-b19 and 22; (B) is the result of compounds 7, 10-a, 23 and 25. Growth rate: Growth rate

[0103] Figure 2 This is the blood glucose change trend of each group of rats in the insulin tolerance experiment of T1DM rats in Example 2.

[0104] Figure 3 It is the area under the IPITT curve of the insulin tolerance test in T1DM rats in Example 2.

[0105] Figure 4 This is HE staining of pancreatic islets of T1DM rats in Example 2 (400×). Specific embodiments

[0106] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0107] The test compound reagents used in the present invention can be purchased from the market.

[0108] Compound 7 was purchased from Shanghai BiDe Pharmaceutical Technology Co., Ltd. with ID name: MFCD01318878.

[0109] Compounds 10-a and 19 were purchased from Anhui Zesheng Technology Co., Ltd. with ID names: MFCD00002598 and MFCD00004186.

[0110] Compound 10-b was purchased from Shanghai Titan Technology Co., Ltd. with ID name: MFCD00063061.

[0111] Compounds 22 and 23 were purchased from Shanghai Yuanye Biotechnology Co., Ltd. with ID names: MFCD00799030 and MFCD00038958, respectively.

[0112]

[0113] Example 1: Proliferation experiment of rat pancreatic β cell line INS-1832 / 13

[0114] 1. Experimental purpose:

[0115] The proliferation effect of the compounds of the present invention on rat pancreatic β cell line INS-1832 / 13 was determined.

[0116] 2. Experimental methods:

[0117] (1) Cell treatment: The rat pancreatic β cell line INS-1832 / 13 was cultured in 1640 medium (containing 10% fetal bovine serum, 1 mmol / L sodium pyruvate, 25 mmol / L HEPES buffer, and 50 μmol / L β-mercaptoethanol). INS-1832 / 13 cells in logarithmic growth phase were digested with trypsin, centrifuged and resuspended to obtain a cell suspension, diluted 10 times and mixed, and 20 μL was aspirated and dropped on a cell counting plate. The cell density was controlled at 10 according to the grid counting method. 7 / mL. The counted cell suspension was evenly distributed in a 96-well plate, 100 μL per well. Because the outermost wells of the 96-well plate are prone to evaporation, resulting in a reduction in the culture medium content, they are not used in experiments and sterile PBS can be added.

[0118] (2) Activity assay: After the cells adhere, add the test compound to a final concentration of 10 μM. After 24 h, dilute the CCK8 detection solution with fresh 1640 culture medium and mix well. Aspirate the old culture medium in the well and replace it with the newly mixed culture medium so that each well contains 10 μL of CCK8 detection solution. Place the wells in an incubator and incubate in the dark for 3 h. Then use an ELISA reader to detect the absorbance at 450 nm, and calculate and draw a statistical graph.

[0119] The experimental reagent information is shown in Table 1.

[0120] Table 1

[0121]

[0122] 3. Test results:

[0123] When the compound concentration was 10 μM, the test results were as follows Figure 1 As shown in the (A) (B) part: (A) is the result of compounds 10-b, 19 and 22; (B) is the result of compounds 7, 10-a, 23 and 25. Compounds 7, 10-a, 10-b, 19, 22, and 23 can promote the proliferation of in vitro cell line β cells to a certain extent.

[0124] The experimental results show that the compound of the present invention has good activity in promoting the proliferation of rat pancreatic β cells.

[0125] Example 2: Diabetic rat experiment

[0126] 1. Experimental purpose:

[0127] The inhibitory effect of the compounds of the present invention on diabetic rats was determined.

[0128] 2. Experimental methods:

[0129] (1) Rat modeling: 8-week-old SPF SD male rats were selected for this experiment. After one week of adaptive feeding, rats with normal fasting blood glucose (FBG) were included in the experiment. One week later, they were randomly divided into a normal control group (NC group) and a modeling group. They fasted overnight and drank normal water. The next morning, rats in the modeling group were intraperitoneally injected with 65 mg / kg streptozotocin (2% STZ, dissolved in sodium citrate buffer). After the injection, the activity changes of the rats were closely observed. If necessary, glucose was given to the rats to prevent hypoglycemia and death caused by STZ injection. The T1DM rat modeling was considered successful when the random blood glucose of the rats was >16.7 mmol / L for 3 consecutive days.

[0130] (2) Drug administration: The rats with successful modeling were randomly divided into a type 1 diabetes group (T1DM group) and a drug intervention group (T1DM+drug group). Both experiments were performed by intragastric administration for 28 consecutive days. The daily intragastric dose of compounds 10-b and 19 was 5 mg kg -1 (Dissolved in 0.5% CMCNa solution to prepare 5 mg mL -1 The normal control group and the type 1 diabetes group were given the same amount of 0.5% CMCNa solution in the same time period. After drug intervention, the blood glucose level and body weight of rats in each group were measured every week.

[0131] (3) Insulin tolerance test (IPITT): After 4 weeks of intervention, all rats were fasted overnight but not watered. The FBG of the rats was tested on the second day, and then 1 U / kg insulin was injected intraperitoneally. Blood samples were collected from the tail vein at 0 min, 30 min, 60 min, 90 min, and 120 min, and the blood glucose levels at the corresponding time were measured. The AUC was calculated to evaluate the insulin tolerance of each group of rats.

[0132] (4) Experimental records: 28 days later, rats in each group were fasted but not watered for 12 hours after the last administration. After weighing, blood samples were collected from the rats by orbital vein blood sampling. The collected whole blood samples were centrifuged at 4°C, 4500r / min, 15min, and the supernatant was taken as serum samples and stored in a -80°C refrigerator. After the 4-week intervention, the pancreatic tissue of the rats was collected, and a part of the pancreatic tissue was fixed in 4% paraformaldehyde for HE and immunohistochemistry experiments. The experimental reagent information is shown in Table 2.

[0133] Table 2

[0134]

[0135] 3. Experimental results

[0136] The test results are shown in Table 3, Table 4, Figure 2 , Figure 3 As shown, HE staining of pancreatic islets in T1DM rats (400×) Figure 4 Compounds 10-b and 19 can effectively improve the degree of diabetes in T1DM rats and have a significant repair effect on the pancreatic islet cells of diabetic T1DM rats.

[0137] Table 3

[0138]

[0139] Table 4

[0140]

[0141] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0142] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A pharmaceutical composition for promoting pancreatic β-cell proliferation, comprising a compound of formula I or its stereoisomers, hydrates, solvates, isotope-labeled substances, prodrugs thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier; in: R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl; R 6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; wherein R c Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-, R d Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-; wherein R c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-2 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-, R d Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; X is -OR 10 、-NR 11 R 12 ; Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

2. Use of the compound of formula I or its stereoisomers, hydrates, solvates, isotope-labeled substances, prodrugs thereof or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the compound of formula I or its stereoisomers, hydrates, solvates, isotope-labeled substances, prodrugs thereof or pharmaceutically acceptable salts thereof in the preparation of a drug for promoting pancreatic β-cell proliferation; in: R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl; R 6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; wherein R c Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-, R d Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-; wherein R c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-2 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-, R d Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; X is -OR 10 or -NR 11 R 12 ; Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

3. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from H, D, F, Cl, Br, I, -CN, -NO2, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenyl, naphthyl, phenanthrenyl, phenoxy, naphthyloxy, phenanthrenoxy, CH3C(=O)O-, CH3CH2C(=O)O-, CH3CH2CH2C(=O)O-, (CH3)2CHC(=O)O-, (CH3)3C(=O)O-, cyclopropyl-C(=O)O-, cyclobutyl-C(=O)O-, cyclopentyl-C(=O)O-, cyclohexyl-C(=O)O-, phenyl-C(=O)O-, CH3S(=O)2O-, CF3S(=O)2O-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2O-, quinolyl-S(=O)2O-, isoquinolyl-S(=O)2O- and p-CH3-phenyl-S(=O)2O-; wherein the C 6-14 Aryl, C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, F, Cl, Br, I, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached they form a phenyl or naphthyl group.

4. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: R 6 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

5. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: R 7 Selected from H, D, OR b ; where R b Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)- and phenyl-C(=O)-.

6. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: R 8 and R 9 Each independently selected from H, -NHR c 、-OR d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-CH 2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-; wherein R c is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl -CH2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutylC(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2- and p-CH3-phenyl-S(=O)2-, R d Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)- and phenyl-C(=O)-.

7. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: R 10 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl; R 11 and R 12 are each independently selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl, or R 11 , R 12 Together with the atoms to which they are attached they form a pyrrolidinyl, piperidinyl or piperazinyl.

8. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: Formula I has one of the following structures:

9. The pharmaceutical composition according to claim 1 or the use according to claim 2, characterized in that: Formula I has one of the following structures:

10. The use according to claim 2, characterized in that: The drug for promoting the proliferation of pancreatic β cells is used for preventing, treating or alleviating type I diabetes or preventing, treating, treating or alleviating type II diabetes.

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