Phosphoenol compound as well as preparation method and application thereof in body inflammatory diseases

Abstract

The invention relates to a phosphoenol compound and application thereof in body inflammatory diseases, in particular to a general formula of a compound shown in a formula (I) and a derivative of the compound, and relates to application of the medicine to treatment of the inflammatory diseases. The general formula of the compound shown in the formula (I) has the advantages of high efficacy, high specificity and the like on inflammatory diseases. # imgabs0 # Formula (I) (injection: a compound of general formula (I) and pharmaceutically acceptable salts thereof).

Description

Technical Field

[0001] The present invention relates to the field of biological therapy, and in particular to a class of phosphoenol compounds, a preparation method thereof and an application thereof in treating inflammatory diseases of the body. Background Art

[0002] In recent years, the number of patients with inflammatory diseases related to the immune system has been increasing, such as psoriasis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. Many researchers have devoted themselves to synthesizing and searching for small molecule drugs that can have therapeutic effects on these diseases. However, there are very few small molecules that can be used as clinical drugs. This makes the treatment of inflammatory diseases an important issue that needs to be solved urgently. To study inflammatory diseases, it is necessary to study the body's immune system. Given the characteristics that immune cells can be rapidly activated and proliferate when encountering foreign or self-antigens, the exploration of their cell metabolism has become a major research hotspot. Some researchers have used the effects of cell metabolism regulators on T cells to illustrate that molecular glues such as pyruvate kinase (PKM2) promote the tight binding of PKM2 monomers in cells to form polymers, thereby affecting the differentiation of T cells and further regulating immune responses. There are also studies that attempt to block the therapeutic effects of cell metabolism in mouse tumor models. However, these small molecule compounds have not yet become clinical drugs for treating diseases. Moreover, the proliferation and killing functions of these existing compounds on cancer cells are contrary to our purpose of treating inflammatory diseases.

[0003] Currently, no researchers have developed new compounds and their compositions as regulators of cellular metabolism to study their functions and therapeutic effects in autoimmune and inflammatory diseases. Summary of the invention

[0004] In one aspect of the present invention, the present invention provides a compound, which is a compound as shown in general formula (I) or a stereoisomer or a pharmaceutically acceptable salt of the compound as shown in formula (I). In another aspect of the present invention, according to an embodiment of the present invention, the drug is used to treat inflammatory diseases.

[0005]

[0006] Formula (I),

[0007] in,

[0008] R 1 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0009] R 2 For hydrogen, deuterium, C1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0010] R 3 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0011] R 4 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0012] R 5 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0013] L 0 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0014] L 1 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0015] L 2 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0016] L 3 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0017] X 1 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0018] X 2 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0019] Optionally, the compound comprises a compound selected from the following:

[0020]

[0021]

[0022] In another aspect of the present invention, the present invention also proposes the use of a pharmaceutical composition in the preparation of a drug. According to an embodiment of the present invention, the pharmaceutical composition is used to treat an inflammatory disease, and the pharmaceutical composition includes the aforementioned compound. According to an embodiment of the present invention, the inventor first discovered that the pharmaceutical composition can be used to treat an inflammatory disease, and thus the pharmaceutical composition for treating an inflammatory disease is also first discovered by the inventor, and has the advantages of high efficacy, high specificity, low toxicity, etc.

[0023] According to an embodiment of the present invention, the above-mentioned use further includes at least one of the following technical features:

[0024] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutical excipient.

[0025] According to an embodiment of the present invention, the content of the compound is 0.01-500 mg / kg. It should be noted that the content here refers to the amount of drug that needs to be given to each kg of mice, which can be converted into the content required by infants or adult patients according to conventional conversion. The inventors found that if the dose is too high, it has obvious side effects on the intestinal tract of mice, which can be lethal in severe cases. If the dose is too low, the therapeutic effect is poor.

[0026] According to an embodiment of the present invention, the inflammatory disease is selected from autoimmune diseases and asthma.

[0027] According to an embodiment of the present invention, the inflammatory disease is caused by differentiation of at least one selected from T cells, dendritic cells, eosinophils, neutrophils, macrophages, natural lymphocytes and monocytes. The inventors have found that the compound combination can inhibit the differentiation of cells such as T cells, dendritic cells, eosinophils, neutrophils, macrophages, natural lymphocytes and monocytes.

[0028] According to an embodiment of the present invention, the autoimmune disease is an immune response caused by self-antigens.

[0029] According to an embodiment of the present invention, the allergic disease is induced by allergens.

[0030] According to an embodiment of the present invention, the compound can be used alone or in combination with other compounds to treat inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a graph showing the results of the in vitro cell experiment of the phosphoenol compound in Test Example 1.

[0032] Figure 2 This is a diagram showing the results of the model experiment in which the phosphoenol compound in Test Example 2 was applied to multiple sclerosis mice. DETAILED DESCRIPTION

[0033] Definitions and general terms

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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" by 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.

[0038] 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.

[0039] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0040] As used herein, the terms "optionally", "optional" or "optionally" generally 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.

[0041] In this article, the terms "optionally substituted", "optionally substituted" and "substituted or unsubstituted" can be used interchangeably. In general, the term "optionally", whether or not it is preceded by the term "substituted", means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner. The substituents can be, but are not limited to, F, Cl, Br, etc.

[0042] In the present context, the term "at least one" means "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".

[0043] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can 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.

[0044] The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl.

[0045] The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.

[0046] The term "halogen" refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.

[0047] In this document, the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b It means containing "a" to "b" carbon atoms. 0～n ” refers to a straight or branched saturated / unsaturated carbon chain containing 0, 1, 2, 3, 4, 5, ... or n carbon atoms; further understand that “C 0～n " shall be interpreted as including any sub-ranges included therein, such as C 0～6 Including C 0～6 , C 0～3 , C 0～2 , C 2～6 , C 2～5 , C 2～4 , C 2～3 , C 3～6 , C 3～5 , C 3～4 , C 4～6 , C 4～5 ; "C 1～n ” refers to a straight or branched saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, ... or n carbon atoms; further understand that “C 1～n " shall be interpreted as including any sub-ranges included therein, such as C 1～6 Including C 1～6 , C 1～3 , C 1～2 , C 2～6 , C 2～5 , C 2～4 , C 2～3 , C 3～6 , C 3～5 , C 3～4 , C 4～6 , C 4～5 , the term "C 1 -C 10“Alkyl” is understood as meaning a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.

[0048] In this context, the term "3- to 10-membered cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-10 carbon atoms, and is understood to mean a cycloalkyl having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon ring such as a decalin ring. For example, the term "C 3 -C 6 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, and is understood to mean 3, 4, 5 or 6 carbon atoms.

[0049] In this article, the term "3 to 10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3-10 carbon atoms and heteroatoms, and should be understood to mean having 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms and heteroatoms, for example, including 1-5 heteroatoms, preferably 1-3 heteroatoms, which heteroatoms can be selected from N, O and S. In particular, the heterocyclyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.

[0050] The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 Aryl), especially a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0051] As used herein, the terms "aryl," "aromatic group," and "aromatic ring" are synonymous.

[0052] In the present context, the term "6- to 10-membered aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0053] The term "heteroaryl" is understood to mean a monocyclic, bicyclic and tricyclic ring system containing 5-20 ring atoms, 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms (e.g., N, O, S, Se, etc.), wherein each ring system contains a ring consisting of 5-7 atoms, and has one or more connection points connected to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl consisting of 5-10 atoms contains 1,2,3 or 4 heteroatoms independently selected from O, S, Se and N. In other embodiments, the heteroaryl consisting of 5-6 atoms contains 1,2,3 or 4 heteroatoms independently selected from O, S, Se and N.

[0054] In the present context, the term "5- to 10-membered heteroaryl" is to be understood as including monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, 10 ring atoms, in particular 5, 6, 7, 8, 9 carbon atoms, and which contain 1, 2, 3, 4, 5, preferably 1, 2, 3 heteroatoms which are each independently selected from N, O and S, and which in each case may additionally be benzo-fused.

[0055] Monocyclic examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, Indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0056] The term "heterocyclyl" means a monocyclic, bicyclic or tricyclic ring system, wherein one or more atoms in the ring are independently optionally substituted by heteroatoms, the ring can be fully saturated or contain one or more unsaturations, but are not aromatic, and have one or more points of attachment to other molecules. One or more hydrogen atoms in the ring can be independently unsubstituted or substituted by one or more substituents described herein. Some embodiments are that "heterocyclyl" is a monocyclic ring composed of 3-7 atoms, or a bicyclic ring composed of 7-10 atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O, S and Se. In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl.

[0057] Unless otherwise indicated, heterocyclic groups and heteroaryls include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl or pyridinylene includes pyridine-2-yl, pyridine-2-ylene, pyridine-3-yl, pyridine-3-ylene, pyridine-4-ylene and pyridine-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene.

[0058] As used herein, the term "treat" and other similar synonyms include alleviating, reducing or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to the cure or improvement of the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of prophylactic effects, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.

[0059] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0060] As used herein, the terms "administering", "administering", "administering", etc. refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0061] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

[0062] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0063] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0064] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0065] The term "subject" as used in the present invention 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.

[0066] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0067] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0068] The stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compound of formula (I) of the present invention are all within the protection scope of the present invention.

[0069] The compounds of the present invention can be purchased commercially, prepared according to known methods, or synthesized according to routes designed by chemical synthesis theory.

[0070] "Stereoisomers" refer to compounds that have the same 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.

[0071] "Chiral" refers to a molecule that is non-superimposable on its mirror image; "achiral" refers to a molecule that is superimposable on its mirror image.

[0072] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0073] "Diastereoisomers" refer 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.

[0074] The stereochemical definitions and conventions 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.

[0075] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate 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 a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0076] 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.

[0077] 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.

[0078] Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers, for example, by chromatography and / or fractional crystallization, based on the differences in the physicochemical properties of the components.

[0079] The racemates of any resulting end product or intermediate can be resolved into the optical enantiomers by methods known to those skilled in the art, such as, by separation of the diastereomeric salts obtained therefrom. The racemic products 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 (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. 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).

[0080] 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.

[0081] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. 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 prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0082] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0083] The "pharmaceutically acceptable salt" used in the present invention refers to organic salts 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., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other 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, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0084] Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing alkaline or acidic moieties by conventional chemical methods. Usually, this salt can be prepared by reacting the free acid or alkaline form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0085] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0086] As used herein, "inflammatory disease" refers to any disease, disorder or symptom resulting from excessive inflammatory symptoms, host tissue damage or loss of tissue function due to an excessive or uncontrolled inflammatory response."Inflammatory disease" also refers to a pathological state mediated by leukocyte influx and / or neutrophil chemotaxis.

[0087] As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction, which is used to destroy, dilute or isolate (isolate) harmful substances and damaged tissues. Inflammation is significantly associated with leukocyte influx and / or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses as well as non-infectious means, such as trauma or reperfusion after myocardial infarction or stroke, immune response to foreign antigens and autoimmune response. Therefore, inflammatory diseases that can be treated with the compounds disclosed in the present invention include: diseases associated with specific defense system reactions and non-specific defense system reactions.

[0088] The present invention provides a pharmaceutical composition, which comprises the compound disclosed in the present invention, or the compound listed in the embodiments; and pharmaceutically acceptable adjuvants, excipients, carriers, solvents or a combination thereof.

[0089] Compound

[0090] The present invention provides a compound, which is a compound as represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt of the compound as represented by formula (I):

[0091]

[0092] in,

[0093] R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, deuterium, optionally substituted by at least one R a Substituted C 1 -C 18 Alkyl, optionally with at least one R a Substituted C 1 -C 18 heteroalkyl, optionally substituted by at least one R a substituted 6 to 18 membered aryl, optionally substituted with at least one R asubstituted 5- to 18-membered heteroaryl;

[0094] Each R a are independently selected from halogen, OH, CN, =O, NO 2 NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyloxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyloxy, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy;

[0095] L 0 , L 1 , L 2 , L 3 Each independently selected from: a single bond, optionally with at least one R 6 Substituted C 0-6 Alkyl, optionally with at least one R 6 Substituted C 0-6 heteroalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Cycloalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Heterocycloalkyl, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 );

[0096] X 1 , X 2 Each independently selected from: methylene, O, S, As, Se, NR 6 , hydrogen, optionally replaced by at least one R 6 Substituted C 1-6 Alkyl, optionally with at least one R 6 Substituted C 1-6 heteroalkyl, optionally substituted by at least one R 6 Substituted C3-18 Cycloalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Heterocycloalkyl, optionally substituted by at least one R 6 substituted 6 to 18 membered aryl, optionally substituted with at least one R 6 substituted 5- to 18-membered heteroaryl;

[0097] Each R 6 are independently selected from halogen, OH, CN, =O, NO 2 NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyloxy.

[0098] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (II):

[0099]

[0100] in,

[0101] R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, deuterium, optionally substituted by at least one R a Substituted C 1 -C 18 Alkyl, optionally with at least one R a Substituted C 1 -C 18 heteroalkyl, optionally substituted by at least one R a Substituted C 3 -C 18 Cycloalkyl, optionally substituted by at least one R a Substituted C 3 -C 18 Heterocycloalkyl, optionally substituted by at least one R a substituted 6 to 18 membered aryl, optionally substituted with at least one R a substituted 5- to 18-membered heteroaryl;

[0102] Each R a are independently selected from halogen, OH, CN, =O, NO 2 NH 2 , C1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyloxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyloxy, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy;

[0103] L 1 Selected from: a single bond, optionally with at least one R 6 Substituted C 0-6 Alkyl, optionally with at least one R 6 Substituted C 0-6 heteroalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Cycloalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Heterocycloalkyl, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 );

[0104] X 1 , X 2 Each independently selected from: methylene, O, S, As, Se, NR 6 , hydrogen, optionally replaced by at least one R 6 Substituted C 1-6 Alkyl, optionally with at least one R 6 Substituted C 1-6 heteroalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Cycloalkyl, optionally substituted by at least one R 6 Substituted C 3-18 Heterocycloalkyl, optionally substituted by at least one R 6 substituted 6 to 18 membered aryl, optionally substituted with at least one R 6 substituted 5- to 18-membered heteroaryl;

[0105] Each R6 are independently selected from halogen, OH, CN, =O, NO 2 NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyloxy.

[0106] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0107] According to an embodiment of the present invention, the present invention provides a compound, which is a compound as shown in formula (I) or a stereoisomer or a pharmaceutically acceptable salt of the compound as shown in formula (I):

[0108]

[0109] in,

[0110] R 1 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0111] R 2 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0112] R 3 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0113] R 4 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0114] R 5 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;

[0115] L0 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0116] L 1 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0117] L 2 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0118] L 3 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 )、C(O)O、OC(O、SO、SO 2 ,PO 3 、N(R 6 )SO 2 or SO 2 N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0119] X 1 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl;

[0120] X 2 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl.

[0121] According to an embodiment of the present invention, the compound includes compounds selected from the following:

[0122]

[0123]

[0124] Use of pharmaceutical composition in preparing medicine

[0125] According to an embodiment of the present invention, the pharmaceutical composition is used for treating inflammatory diseases, and the pharmaceutical composition comprises the compound described in the first aspect of the present invention.

[0126] According to an embodiment of the present invention, the compound regulates the metabolic level in cells, and the compound is used in an amount of 0.1 to 500 mg / kg.

[0127] According to an embodiment of the present invention, the inflammatory disease is selected from autoimmune diseases and asthma.

[0128] According to an embodiment of the present invention, the inflammatory disease is caused by differentiation of at least one selected from T cells, dendritic cells, eosinophils, neutrophils, macrophages, natural lymphocytes and monocytes.

[0129] According to an embodiment of the present invention, the autoimmune disease is an immune response caused by self-antigens.

[0130] According to an embodiment of the present invention, the allergic disease is induced by an allergen.

[0131] According to an embodiment of the present invention, the compound can be used alone or in combination with other compounds to treat inflammatory diseases.

[0132] Certain compounds of the present invention may be used in free form for treatment, or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that can directly or indirectly provide the compounds of the present invention or their metabolites or residues when administered to a patient in need thereof.

[0133] The pharmaceutical composition disclosed in the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound shown in formula (I) can be extracted and then administered to the patient in the form of a powder or syrup. Alternatively, the pharmaceutical composition disclosed in the present invention can be prepared and packaged as a unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound shown in formula (I). When prepared in a unit dosage form, the pharmaceutical composition disclosed in the present invention can generally contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of the compound disclosed in the present invention.

[0134] As used herein, "pharmaceutically acceptable excipients" means pharmaceutically acceptable materials, mixtures or solvents that are relevant to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, have a sufficiently high purity.

[0135] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that help carry or transport the disclosed compounds from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0136] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled person will recognize that certain pharmaceutically acceptable excipients may provide more than one function and provide selectable functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

[0137] Technicians master the knowledge and skills in this area so that they can select suitable pharmaceutically acceptable excipients for the appropriate amount of the present invention. In addition, there are a large number of resources available to technicians, which describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0138] In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, various carriers for configuring pharmaceutically acceptable compositions, and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated by reference into the present invention. Except any commonly used carriers such as those which are incompatible with the disclosed compounds of the present invention due to any undesirable biological effects or any other components in the pharmaceutically acceptable compositions interacting in a harmful manner, it is noted that their application belongs to the scope of the present invention.

[0139] The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. Some common methods described in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0140] Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable adjuvant, excipient, carrier, solvent or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising a compound disclosed herein can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

[0141] The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0142] In one embodiment, the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein can be formulated into inhalation dosage forms. In another embodiment, the compounds disclosed herein can be formulated into nasal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated into transdermal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated into topical dosage forms.

[0143] The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, tablets, chewable lozenges, instant tablets, composite compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help mask unpleasant tastes or odors and prevent tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. Composite compressed tablets are compressed tablets prepared over more than one compression cycle, including multilayer tablets, and compression coatings or dry coating tablets.

[0144] Tablet dosage forms can be prepared from active ingredients in powder, crystal or granular form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0145] The pharmaceutical composition provided by the present invention can be provided in a soft capsule or a hard capsule, which can be prepared by gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also referred to as a dry-filled capsule (DFC), consists of two sections, one section is inserted into the other section, and thus the active ingredient is completely encapsulated. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

[0146] The pharmaceutical compositions provided by the present invention can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of globules, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are transparent, sweet-tasting aqueous alcoholic solutions. Syrups are concentrated sugars such as sucrose in water, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with sufficient pharmaceutically acceptable liquid carriers such as water for accurate and convenient administration.

[0147] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided by the present invention and secondary mono- or poly-alkylene glycols, including: 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, 750 refer to the approximate average molecular weight of polyethylene glycol. These preparations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium pyrosulfite, thiodipropionic acid and its esters and dithiocarbamates.

[0148] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. They may also be prepared to prolong or sustain the release of the composition, for example, by coating or embedding particulate material in polymers, wax or the like.

[0149] The oral pharmaceutical composition provided by the present invention can also be provided in the form of liposomes, micelles, microspheres or nanosystems. The micelle dosage form can be prepared by the method described in US Pat. No. 6,350,458.

[0150] Pharmaceutical composition provided by the invention can be provided with non-effervescent or effervescent granules and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0151] Coloring and flavoring agents may be used in all of the above dosage forms.

[0152] Compound disclosed by the present invention can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or the polyoxyethylene polylysine substituted by palmitoyl residues. In addition, compound disclosed by the present invention can be combined with a class of biodegradable polymers used in realizing the controlled release of medicine, for example, crosslinked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

[0153] The pharmaceutical compositions provided by the present invention can be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

[0154] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect.

[0155] Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0156] Pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nano system and the solid form suitable for making solution or suspension in liquid before injection. Such dosage form can be prepared according to the conventional method known to the technicians in the field of pharmaceutical science (referring to Remington:The Science and Practice of Pharmacy, the same).

[0157] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrants or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters and inert gases.

[0158] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, medium chain triglycerides of hydrogenated soybean oil and coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide and dimethyl sulfoxide.

[0159] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to procaine hydrochloride. Suitable suspending agents and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestrants or chelating agents include, but are not limited to EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS).

[0160] The pharmaceutical composition provided by the present invention can be formulated into single dose or multiple dose administration. The single dose preparation is packaged in an ampoule, a vial or a syringe. The multiple dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or antifungal concentration. All parenteral preparations must be sterile, as known and practiced in the art.

[0161] In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product that is reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

[0162] The pharmaceutical compositions disclosed herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

[0163] The pharmaceutical composition can be formulated as a suspension, solid, semisolid or thixotropic liquid for use as an implanted depot for administration. In one embodiment, the pharmaceutical composition disclosed herein is dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

[0164] Suitable inner matrices include polymethyl methacrylate, polybutyl methyl acrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of coach.

[0165] Suitable outer polymeric films include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0166] On the other hand, the pharmaceutical composition disclosed in the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition. In one embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients using dry powder. In another embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients through a nebulizer. The dry powder composition delivered to the lungs by inhalation generally comprises a fine powder of the compound disclosed in the present invention and one or more fine powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, size-reduced (e.g., micronized) compounds can be prepared by a D of about 1 to 10 microns. 50 values ​​(measured, for example, by laser diffraction).

[0167] Aerosols can be prepared by suspending or dissolving the compounds disclosed herein in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the compounds disclosed herein are typically administered to patients via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

[0168] Aerosols may contain additional pharmaceutically acceptable excipients that may be used with MDIs, such as surfactants, lubricants, co-solvents, and other excipients to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

[0169] Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches, intended to remain in close contact with the patient's epidermis for an extended period of time. For example, active ingredients can be delivered from the patch by ion permeation, as generally described in Pharmaceutical Research, 3(6), 318(1986).

[0170] The pharmaceutical composition that is suitable for topical administration can be formulated into ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.For example, ointment, cream and gel can be configured with water or oil base, and applicable thickener and / or gel and / or solvent.Such matrix can include, water, and / or oil such as liquid liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Thickener and gel used according to matrix properties include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and / or glyceryl monostearate and / or nonionic emulsifier.

[0171] Lotions may be formulated with an aqueous or oily base, and generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

[0172] Powders for external use may be formulated in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersants, solubilizers, suspending agents or preservatives.

[0173] Topical preparations can be administered by application to the affected area once or more per day; occlusive dressings covering the skin are preferred. Adhesive reservoir systems allow for continuous or prolonged administration.

[0174] When treating the eye, or other organs such as the mouth and skin, the composition can be applied as a topical ointment or cream. When formulated as an ointment, the compounds disclosed herein can be used with a paraffinic or water-soluble ointment base. Alternatively, the compounds disclosed herein can be formulated into a cream with an oil-in-water cream base or an oil-in-water base.

[0175] In one embodiment, the treatment method disclosed in the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need. The various embodiments disclosed in the present invention include methods for treating the above-mentioned diseases by administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need.

[0176] In one embodiment, the compounds disclosed in the present invention or pharmaceutical compositions comprising the compounds disclosed in the present invention can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, ear, vaginal, inhalation and intranasal administration. In one embodiment, the compounds disclosed in the present invention or pharmaceutical compositions comprising the compounds disclosed in the present invention can be administered orally. In another embodiment, the compounds disclosed in the present invention or pharmaceutical compositions comprising the compounds disclosed in the present invention can be administered by inhalation. In another embodiment, the compounds disclosed in the present invention or pharmaceutical compositions comprising the compounds disclosed in the present invention can be administered intranasally.

[0177] In one embodiment, the compounds disclosed in the present invention or the pharmaceutical composition comprising the compounds disclosed in the present invention can be administered once, or several times at different time intervals within a specified time period according to the dosing regimen. For example, once, twice, three times or four times a day. In one embodiment, the drug is administered once a day. In another embodiment, the drug is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the compounds disclosed in the present invention or the pharmaceutical composition comprising the compounds disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by technicians. In addition, the appropriate dosing regimen of the compounds disclosed in the present invention or the pharmaceutical composition comprising the compounds disclosed in the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., within the knowledge and experience of the technician. Such technicians should also understand that the dosing regimen of the matter may be required to adjust the individual patient's response to the dosing regimen, or when the individual patient's needs change over time.

[0178] The compounds disclosed in the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after the administration thereof. The compounds disclosed in the present invention can be administered separately with other therapeutic agents through the same or different administration routes, or can be administered together with the other therapeutic agents in the form of a pharmaceutical composition.

[0179] For individuals of about 50-70 kg, the pharmaceutical compositions and combinations disclosed herein can be in the form of unit doses containing about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the individual, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian with common skills can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disorder or disease.

[0180] The above-cited dosage characteristics have been confirmed in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and specimens. The compounds disclosed in the present invention are used in vitro in the form of solutions, such as aqueous solutions, and can also be used in vivo in the form of suspensions or aqueous solutions, such as enteral, parenteral, and especially intravenous.

[0181] In one embodiment, the therapeutically effective dose of the disclosed compound is about 0.1 mg to about 2,000 mg per day. Its pharmaceutical composition should provide about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, the prepared drug dosage unit form can provide about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg, about 20 mg to about 500 mg, or about 25 mg to about 250 mg of the main active ingredient or a combination of the main ingredients in each dosage unit form. In a specific embodiment, the prepared drug dosage unit form can provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the main active ingredient.

[0182] In addition, the compounds disclosed in the present invention can be administered in the form of prodrugs. In the present invention, the "prodrug" of the compounds disclosed in the present invention is a functional derivative that can eventually release the compounds disclosed in the present invention in vivo when administered to a patient. When administering the compounds disclosed in the present invention in the form of prodrugs, those skilled in the art may implement one or more of the following methods: (a) changing the in vivo onset time of the compound; (b) changing the in vivo duration of action of the compound; (c) changing the in vivo transport or distribution of the compound; (d) changing the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of compounds that are chemically or enzymatically cleaved in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0183] Biological Experimental Methods

[0184] The present invention is described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0185] Compound preparation route:

[0186]

[0187] The first step of the reaction:

[0188] Pyruvic acid A (5mmol, 1.0 equivalent), alcohol B (10mmol, 2.0 equivalent) and pyridine (12.5mmol, 2.5 equivalent) were added to a round-bottom flask containing 50mL of tetrahydrofuran (THF) in sequence, and the mixture was cooled to 0°C. Methanesulfonyl chloride (6mmol, 1.2 equivalent) was then slowly added dropwise to the flask. The reaction temperature was gradually raised to room temperature and stirred for 10 hours. 20mL of water was added to the reaction flask to terminate the reaction. The resulting solution was extracted three times with 40mL of ethyl acetate. The extracted organic phases were combined. After drying over anhydrous sodium sulfate, the organic solvent was removed under vacuum to obtain a crude product. Further purification by rapid column chromatography gave ester C.

[0189] Second step of reaction:

[0190] Add ester C (3 mmol, 1.0 equivalent) to a round-bottom flask containing 50 mL of anhydrous ether. Then slowly add bromine (4.5 mmol, 1.5 equivalent) to the solution at room temperature. Slowly heat the reaction to 50 ° C and reflux for 4 hours. After the reaction is completed, wash the organic phase twice with water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, concentrate in vacuo and purify by flash column chromatography to obtain bromopyruvate D.

[0191] The third step of reaction:

[0192] Bromoacetonate D (2 mmol, 1.0 equiv) was added to a round-bottom flask containing 50 mL of tetrahydrofuran (THF). Triethylphosphine (2 mmol, 1.0 equiv) was then added dropwise at 0°C. The reaction was heated to 80°C and refluxed at this temperature for 2 hours. After the reaction was completed, the organic solvent was removed in vacuo to obtain a crude product. Cpd4 was purified by flash column chromatography.

[0193] Reaction Step 4:

[0194] Cpd4 (1.0 equivalent) was added to a round-bottom flask containing 20 mL of dichloromethane (DCM). After the solution was cooled to 0 °C, trimethylsilyl bromide (TMSBr, 10 equivalents) was slowly added dropwise to the reaction. The reaction was then stirred at room temperature for 4 hours. After the reaction was completed, 10 mL of water was added and stirred vigorously for 10 minutes to promote the dissolution of the product 5 in the aqueous phase. The aqueous phase was washed twice with dichloromethane and then concentrated under vacuum to obtain Cpd 5.

[0195] Embodiment 1:

[0196]

[0197] For the preparation of compound 1, see the compound preparation route

[0198] 1 H NMR (400 MHz, CDCl3 )δ5.94(s,1H),5.60(s,1H),4.44-3.98(m,6H),1.50-0.89(m,9H).

[0199] Embodiment 2:

[0200]

[0201] For the preparation of compound 2, see the compound preparation route

[0202] 1 H NMR (400 MHz, CDCl 3 )δ5.96(t,J=2.3Hz,1H),5.61(t,J=2.4Hz,1H),4.28(q,J=7.1Hz,2H),3.87(d,J=11.4Hz,6H),1.69-0.84(m,3H).

[0203] Embodiment 3:

[0204]

[0205] For the preparation of compound 3, please refer to the compound preparation route

[0206] 1 H NMR (400 MHz, CDCl 3 )δ5.95(s,1H),5.62(s,1H),4.23(dd,J=12.6,6.7Hz,6H),1.80-1.62(m,2H),1.48-1.34(m,8H),0.95(t,J=7.4Hz,3H).

[0207] Embodiment 4:

[0208]

[0209] For the preparation of compound 4, please refer to the compound preparation route

[0210] 1 H NMR (400 MHz, CDCl 3 )δ7.31(s,2H),7.21(s,3H),5.96(s,1H),5.66(s,1H),4.26(d,J=5.1Hz,6H),2.75(d,J=4.9Hz,2H),2.06(d,J=5.8Hz,2H),1.40(d,J=5.5Hz,6H).

[0211] Embodiment 5:

[0212]

[0213] For the preparation of compound 5, please refer to the compound preparation route

[0214] 1 H NMR (400 MHz, CDCl 3 )δ5.96(t,J=2.3Hz,1H),5.63(t,J=2.2Hz,1H),4.39-4.00(m,6H),1.89-1.58(m,2H),1.50-1.13(m,16H),0.90(t,J=6.6Hz,3H).

[0215] Embodiment 6:

[0216]

[0217] For the preparation of compound 6, see the compound preparation route

[0218] 1 H NMR (400 MHz, CDCl 3 )δ5.96(t,J=2.3Hz,1H),5.63(t,J=2.2Hz,1H),4.45-3.83(m,6H),1.83-1.55(m,2H),1.35(ddd,J=10.7,10.2,5.4Hz,12H),0.91(t,J=6.7Hz,3H).

[0219] Embodiment 7:

[0220]

[0221] For the preparation of compound 7, see the compound preparation route

[0222] 1 H NMR (400 MHz, CDCl 3 )δ5.98(t,J=2.2Hz,1H),5.65(t,J=2.2Hz,1H),4.26(p,J=7.3Hz,4H),3.85(s,3H),1.39(t,J=7.1Hz,6H).

[0223] Embodiment 8:

[0224]

[0225] For the preparation of compound 8, see the compound preparation route

[0226] 1 H NMR (400 MHz, CDCl 3)δ5.95(s,1H),5.62(s,1H),4.79(dq,J=12.6,6.3Hz,2H),4.29(q,J=7.1Hz,2H),1.60-1.11(m,15H).

[0227] Embodiment 9:

[0228]

[0229] For the preparation of compound 9, see the compound preparation route

[0230] 1 H NMR (400 MHz, CDCl 3 )δ7.91(dd,J=13.9,7.4Hz,2H),7.60(t,J=7.4Hz,1H),7.50(dt,J=12.2,6.2Hz,2H),5.91(d,J=2.1Hz,1H) ,5.56(d,J=2.1Hz,1H),4.27(ddd,J=21.4,11.1,4.2Hz,4H),1.39(t,J=7.1Hz,3H),1.29(t,J=7.1Hz,3H).

[0231] Embodiment 10:

[0232]

[0233] For the preparation of compound 10, see the compound preparation route

[0234] 1 H NMR(400MHz,MeOD)δ5.91(s,1H),5.58(s,1H),5.00-4.78(m,6H).

[0235] Embodiment 11:

[0236]

[0237] For the preparation of compound 11, see the compound preparation route

[0238] 1 H NMR (400MHz, MeOD) δ5.93 (d, J = 8.8 Hz, 1H), 5.59 (dd, J = 7.8, 2.0 Hz, 1H), 4.87 (s, 4H), 4.44-3.49 (m, 3H), 1.50-1.09 (m, 4H).

[0239] Embodiment 12:

[0240]

[0241] For the preparation of compound 12, see the compound preparation route

[0242] 1 H NMR (400 MHz, D 2 O) δ5.83(t,J=2.4Hz,1H),5.47(dt,J=4.6,2.3Hz,1H),4.18(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,2H).

[0243] Embodiment 13:

[0244]

[0245] For the preparation of compound 13, see the compound preparation route

[0246] 1 H NMR (400 MHz, D 2 O)δ5.67(s,1H),5.35(s,1H),3.97(s,2H),1.40(s,2H),1.12(d,J=6.3Hz,2H),0.65(s,3H).

[0247] Embodiment 14:

[0248]

[0249] For the preparation of compound 14, see the compound preparation route

[0250] 1 H NMR(400MHz,MeOD)δ7.29(t,J=7.5Hz,2H),7.21(d,J=7.4Hz,3H),5.89(t,J=2.2Hz,1H) ,5.62(t,J=2.2Hz,1H),4.19(t,J=6.4Hz,2H),2.71(t,J=7.5Hz,2H),2.05-1.57(m,2H).

[0251] Test Example 1: Application of phosphoenol compounds in in vitro differentiation experiments of T cells.

[0252] (1) Supplies: surgical instruments (ophthalmic surgical scissors, ophthalmic forceps), pipette, 70 μM filter, 1 ml syringe, mouse fixation plate, LS column, magnetic stand, flow tube with cap, 70 μM flow tube with cap, 50 mL centrifuge tube, 15 mL centrifuge tube, 1.5 mL EP tube, 200 μL EP tube, flat-bottom 96-well plate, U-bottom 96-well plate.

[0253] (2) Reagent preparation: staining buffer (1xPBS + 2% super fine FBS), red blood cell lysis buffer, Miltenyi CD4 (L3T4) Microbeads, T cell culture medium (1640 + 10% super fine FBS + 1% penicillin-streptomycin solution + 0.1% β-mercaptoethanol), phosphoenol compounds to be tested (freezing concentration in -80 refrigerator is 50 mM solvent DMSO), anti-CD3, anti-CD28, IL6 (50 ng / μL), IL23 (25 ng / μL), IL1β (10 ng / μL), TGFβ (2 ng / μL), IL-2 (40 ng / μL), IL12 (10 ng / μL), anti-IL4 (20 ng / μL), anti-IFN γ, MOG35-55, OVA257-264, GolgiStop, Ionomycin, PMA, cell membrane perforation solution, cell fixation solution, cell nucleus perforation solution, perforation solution cleaning solution (1xPerm), flow cytometry antibodies CD4, CD44, CD62L, CD25, Live / Dead, CD8, IL17A, IL17F, IFNγ, IL4, GM-CSF, RORγt, FoxP3, Phospho-STAT3, Phospho-STAT5.

[0254] (3) Use mice with special genotypes for in vitro culture. Take 8-12 week old 2D2, OT-I genotype mice raised in an SPF animal breeding room. After euthanasia, use sterile surgical instruments in a cell clean bench to separate the mouse spleen, place it in a 70μM filter placed on a 50mL tube, use the handle of a 1mL syringe to fully grind the tissue, use staining buffer to rinse all the cells on the filter into the 50mL tube, and centrifuge at 500G for 5 minutes. After discarding the supernatant, add 8mL / mouse of red blood cell lysis buffer to the tube, resuspend the cells, let stand at room temperature for 5 minutes, add an equal volume of staining buffer to mix and stop lysis; centrifuge at 500G to remove the supernatant. Resuspend the cells with 1mL staining buffer, filter the cells using a 70μM flow tube with a cap, centrifuge at 500G again to remove the supernatant, and resuspend the cells with T cell culture medium to obtain a whole spleen cell suspension of mice with special genotypes.

[0255] (4) In vitro cell culture of whole spleen cells of mice with special genotypes. Count the cells of 1 mL of cell suspension, adjust the concentration of the cell suspension to 2×10^6 cells / mL, add cytokines for differentiation to Th17 or Tc17 (IL6 working concentration is 20 ng / mL, TGFβ working concentration is 1 ng / mL), cytokines for differentiation to Th2 (IL4 working concentration is 100 ng / mL, anti-IFNγ working concentration is 5 μg / mL), cytokines for differentiation to Th1 (IL2 working concentration is 20 ng / mL, IL12 working concentration is 10 ng / mL), cytokines for differentiation to Treg (TGFβ working concentration is 1 ng / mL), and add 50 μg / mL of peptide MOG35-55 (2D2 genotype mice) or 0.5 μg / mL of peptide OVA257-264 (OT-I genotype mice) and mix well. Obtain the cell fluid of the phosphoenol compound to be tested.

[0256] (5) When using C57BL / 6 wild-type mice for in vitro culture, it is necessary to coat the cell culture plates with antibodies in advance: dilute anti-CD3 and anti-CD28 in PBS at a working concentration of 5 μg / mL the night before the experiment, add the dilution to a 96-well plate at 100 μL / well; seal the 96-well plate with sealing film and place it in a 4°C refrigerator, away from light overnight.

[0257] (6) Childish Isolation of CD4-positive T cells. Take 8-12 week old C57BL / 6 wild-type mice raised in SPF animal breeding room, euthanize them, separate the spleen and peripheral lymph nodes of mice using sterile surgical instruments in the cell clean bench, put them in a 70μM filter placed on a 50mL tube, grind the tissue thoroughly with the handle of a 1mL syringe, rinse all the cells on the filter into the 50mL tube with staining buffer, and centrifuge at 500G for 5 minutes. After discarding the supernatant, add 8mL / mouse of red blood cell lysis buffer to the tube, resuspend the cells, let stand at room temperature for 5 minutes, add an equal volume of staining buffer and mix to stop lysis; centrifuge at 500G to remove the supernatant. Resuspend the cells with 0.5mL staining buffer, filter the cells using a 70μM flow tube with a cap, then add 50μL CD4(L3T4) Microbeads and mix, let stand at 4℃ in the dark for 15 minutes. Add 4mL staining buffer to the flow tube, centrifuge at 500G and discard the supernatant, resuspend the cells with 1mL staining buffer / mouse, add to the LS column placed on the magnetic stand, wait for the liquid to drip clean, and then add staining buffer three times, 3mL / time. Remove the column, flush the cells into a 15mL tube with staining buffer, centrifuge and discard the supernatant. Dilute the flow antibodies CD4, CD44, CD62L and CD25 (500μL / mouse) with staining buffer at a ratio of 1:400, resuspend the cells with the antibody dilution solution, incubate at 4℃ in the dark for 30 minutes, and then wash the cells with staining buffer. After resuspending the cells with staining buffer, filter them into the tube using a 70μM flow tube with a cap, and finally sort the cells marked as CD4 positive, CD44 negative, CD62L positive and CD25 negative into the collection tube through a flow sorter to obtain naive cells. CD4 positive T cells.

[0258] (7) C57BL / 6 wild-type mice from selected naive mice In vitro cell culture of CD4 positive T cells. CD4 positive T cells were resuspended in T cell culture medium (concentration of 5×10^5 cells / mL), and cytokines used to differentiate into Th17 were added (IL6 working concentration of 20 ng / mL, TGFβ working concentration of 1 ng / mL, IL1β working concentration of 10 ng / mL, IL23 working concentration of 25 ng / mL), and mixed evenly to obtain the cell fluid to be mixed with the phosphoenol compound to be tested.

[0259] (8) Divide the cell suspension mixed with the phosphoenol compound to be tested in the previous step into several 1.5mL EP tubes, 400μL / tube. Dilute the compound to be tested with T cell culture medium to 100 times the working concentration, then add it to the cell suspension and mix well. 400μL of cell suspension requires 4μL of 100X compound diluent. For the control group, add the same volume of the phosphoenol compound to be tested to the corresponding T cell culture medium and mix well. Pipet the same volume of liquid as the 100X compound diluent and mix it with the cell suspension. After mixing the liquid in each 1.5mL EP tube, add it to the corresponding 96-well plate, 100μL / well. Place in a 37℃ cell culture incubator and culture for 48 hours or 96 hours.

[0260] (9) 48 hours (whole spleen cells from mice of specific genotypes cultured in vitro) or 96 hours (naive cells from C57BL / 6 wild-type mice sorted) After in vitro cell culture of CD4-positive T cells), the cells were resuspended and transferred to a U-bottom 96-well plate, centrifuged at 500G to remove the supernatant, 100 μL T cell stimulation solution (GolgiStop, Ionomycin, PMA) was added to each well, and the plate was placed in a 37°C cell culture incubator for stimulation for 4 hours. The cell plate was removed and the cells were washed with staining buffer, centrifuged at 500G to remove the supernatant, and 50 μL surface antibody dilution solution was added to each well for flow staining of the cells (Live / Dead dilution ratio of 1:4000; according to the cell type, Th is CD25 and CD4; Tc is CD25 and CD8, dilution ratio 1:400), placed in a 4°C refrigerator away from light for staining for 30 minutes, and the staining was performed. The cells were washed with buffer, centrifuged at 500G to remove the supernatant, fixed and perforated with perforation solution for 50 minutes or overnight, washed with 1xPerm, centrifuged at 800G to remove the supernatant, 50 μL of cytokine (IL17A, IL17F, GM-CSF, IFNγ, IL4, dilution ratio 1:400) or transcription factor (RORγt, FoxP3, Phospho-STAT3, Phospho-STAT5 dilution ratio 1:200) antibody dilution solution was added to each well, the cells were stained for 2 hours or overnight, and finally the experimental results were recorded by flow cytometry.

[0261] (10) The experimental results showed that phosphoenol compounds (administered group) could inhibit the secretion of cytokines IL17A, IL17F, GMCSF and IFNγ by Th cells. Figure 1 -A). The experimental results further showed that the acid enol compound (administration group) could significantly inhibit the expression of RORγt ( Figure 1 -B), but significantly increased the expression of transcription factor FoxP3 ( Figure 1 -C).

[0262] Test Example 2: Application of phosphoenol compounds in mouse autoimmune model.

[0263] (1) Supplies: Supplies required for in vitro cell culture are as described in Example 1, including 24-well plates, BD brand 1 mL syringes, and ordinary 1 mL syringes.

[0264] (2) Reagents: The reagents required for in vitro cell culture are as described in Example 1, including peptide MOG35-55, pertussis toxin, PBS, DMF, Tween 80, and anesthetic.

[0265] (3) The spleen cells of 2D2 genotype mice were induced to differentiate into Th17 in vitro (for detailed operation, see Test Example 1 above), IL6, TGFβ, IL1β, IL23 and peptide MOG35-55 were added, and the cell solution was added to a 24-well plate at 500 μL / well and placed in a 37°C cell culture incubator. After 34 hours, 20 μM of the phosphoenol compound to be tested was added and incubated for another 14 hours. The cells were washed out and injected into RAG1 knockout mice through the tail vein using a BD brand 1 mL syringe at a cell number of 1.5x10^6 per recipient mouse, 300 μL / mouse. After 24 hours, the mice were intraperitoneally injected with pertussis toxin using an ordinary 1 mL syringe, 300 ng of the solvent was PBS / mouse, 200 μL / mouse.

[0266] (4) Administration to mice. PBS, DMF, and Tween80 were fully mixed in a ratio of 88:10:2, and filtered through a 0.22 filter to obtain a PDT solvent. The phosphoenol compound to be tested was added to the PDT solvent at 250 μg / 200 μL; an equal amount of DMSO was added to the control group. The prepared drug was injected into the mouse intraperitoneally at 200 μL / mouse. The drug was administered daily for 18 consecutive days. After 28 days, the popliteal lymph nodes of the mice were isolated and a cell suspension was prepared for flow cytometry analysis of Th17 cell-related characteristic molecules. 24 hours later, the phosphoenol compound to be tested was injected into the mouse intraperitoneally using an ordinary 1 mL syringe. The dosage was 20 μL of the drug per mouse per day (the concentration of the drug solution was 50 mM), and the drug was administered for 18 consecutive times.

[0267] (5) Starting from the return of cells through the tail vein, the weight of the mice was recorded every day, and the clinical scores of the diseases were observed. Clinical scores of the diseases: healthy state (0 points); weak tail (1 point); slow walking, uncoordinated movement of the left and right hind limbs, and involuntary tremors of the hind limbs (2 points); paralysis of the hind limbs alone (3 points); paralysis of both hind limbs (4 points); paralysis of the forelimbs, or death of the mice (5 points). On the 28th day after the return of cells through the tail vein, the central nervous system (CNS) of the mice was removed and a single cell suspension was prepared, and the proportion and number of cells contained therein of Th17 were analyzed by flow cytometry.

[0268] (6) The experimental results showed that the incidence score of autoimmune encephalomyelitis (EAE) in the drug group was significantly lower than that in the control group ( Figure 2 -A), and the weight loss of the drug group was significantly lower than that of the control group mice ( Figure 2 -B). It revealed that phosphoenol compounds can significantly delay the progression of autoimmune diseases in mice.

[0269] Definitions and explanations of terms

[0270] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0271] It should be understood that the above brief description and the following detailed description are exemplary and are only used for explanation, and do not limit the subject matter of the present application. In this application, unless otherwise specified, the terms "or" and "or" used mean "and / or". In addition, the terms "including" and other forms, such as "comprising", "including" and "containing" used are not restrictive.

[0272] The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl.

[0273] The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.

[0274] The term "halogen" refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.

[0275] The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 Aryl), especially a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0276] The term "heteroaryl" is understood to mean a monocyclic, bicyclic and tricyclic ring system containing 5-20 ring atoms, 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms (e.g., N, O, S, Se, etc.), wherein each ring system contains a ring consisting of 5-7 atoms, and has one or more connection points connected to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl consisting of 5-10 atoms contains 1,2,3 or 4 heteroatoms independently selected from O, S, Se and N. In other embodiments, the heteroaryl consisting of 5-6 atoms contains 1,2,3 or 4 heteroatoms independently selected from O, S, Se and N.

[0277] Monocyclic examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, Indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0278] The term "heterocyclyl" means a monocyclic, bicyclic or tricyclic ring system, wherein one or more atoms in the ring are independently optionally substituted by heteroatoms, the ring can be fully saturated or contain one or more unsaturations, but are not aromatic, and have one or more points of attachment to other molecules. One or more hydrogen atoms in the ring can be independently unsubstituted or substituted by one or more substituents described herein. Some embodiments are that "heterocyclyl" is a monocyclic ring composed of 3-7 atoms, or a bicyclic ring composed of 7-10 atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O, S and Se. In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl.

[0279] Unless otherwise indicated, heterocyclic groups and heteroaryls include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl or pyridinylene includes pyridine-2-yl, pyridine-2-ylene, pyridine-3-yl, pyridine-3-ylene, pyridine-4-ylene and pyridine-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene.

[0280] As used herein, the term "treat" and other similar synonyms include alleviating, reducing or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to the cure or improvement of the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of prophylactic effects, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.

[0281] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0282] As used herein, the terms "administering", "administering", "administering", etc. refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0283] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

[0284] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0285] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0286] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0287] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound and has no adverse effects in biology or other aspects. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines), alkaline or organic salts of acidic residues (such as carboxylic acids), etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed by, for example, non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, salicylic acid, p-aminobenzenesulfonic acid, etc.

[0288] Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing alkaline or acidic moieties by conventional chemical methods. Usually, this salt can be prepared by reacting the free acid or alkaline form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0289] 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.

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt of the compound represented by formula (I): in, R 1 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R 2 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R 3 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R 4 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R 5 For hydrogen, deuterium, C 1-18 Alkylene, C 1-18 heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; L 0 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 ), C(O)O, OC(O), SO, SO2, PO3, N(R 6 )SO2 or SO2N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; L 1 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 ), C(O)O, OC(O), SO, SO2, PO3, N(R 6 )SO2 or SO2N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; L 2 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 ), C(O)O, OC(O), SO, SO2, PO3, N(R 6 )SO2 or SO2N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; L 3 Selected from: single bond, C 0-6 Alkylene, C 0-6 Heteroalkylene, C 3-18 Cycloalkylene, C 3-18 Heterocyclylene, N(R 6 )、O、S、C(O,N(R 6 )C(O), C(O)N(R 6 ), C(O)O, OC(O), SO, SO2, PO3, N(R 6 )SO2 or SO2N(R 6 ), where R 6 Selected from: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; X 1 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; X 2 Selected from: methylene, O, S, As, Se, NR 6 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; Optionally, the compound comprises a compound selected from the following:

2. Use of the pharmaceutical composition in the preparation of a drug, characterized in that: The pharmaceutical composition is used for treating inflammatory diseases, and the pharmaceutical composition comprises the compound according to claim 1.

3. The use according to claim 2, characterized in that: The compound regulates the metabolic level in cells, and the compound is used in an amount of 0.1 to 500 mg / kg.

4. The use according to claim 2 or 3, characterized in that The inflammatory disease is selected from the group consisting of autoimmune diseases and asthma.

5. The use according to claim 4, characterized in that The inflammatory disease is caused by differentiation of at least one selected from the group consisting of T cells, dendritic cells, eosinophils, neutrophils, macrophages, natural lymphocytes and monocytes.

6. The use according to claim 4, characterized in that The autoimmune disease is an immune response caused by self-antigens.

7. The use according to claim 4, characterized in that The allergic disease is induced by allergens.

8. The use according to claim 4, characterized in that The compounds can be used alone or in combination with other compounds to treat inflammatory diseases.

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