Compound and application thereof

Abstract

The invention discloses a compound and application thereof. The compound is a compound as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure as shown in the formula (I). The invention also discloses application of the compound in preparation of medicines for treating ophthalmic diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to a compound, stereoisomer, tautomer, nitroxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester, and its use in the manufacture of a medicament for treating ophthalmic diseases. BACKGROUND

[0002] Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, with atrophic (dry) AMD being the more prevalent form. There is currently no FDA-approved therapy for dry AMD. Given the lack of treatment and high prevalence, the development of a drug for dry AMD is of great importance.

[0003] The age-dependent accumulation of cytotoxic lipofuscin bisretinoids in the retina can significantly contribute to the pathogenesis of the dry form of AMD. The synthesis of intraocular bisretinoids depends on the flow of all-trans retinol from serum into the retina, which requires the formation of a complex of retinol-binding protein 4 (RBP4)-transthyretin (TTR)-retinol in serum.

[0004] By selecting an RBP4 antagonist to reduce the rate of formation of cytotoxic bisretinoid dimers (the main component of lipofuscin) in the retinal pigment epithelium (RPE), it will prevent further geographic atrophy in patients with atrophic (dry) age-related macular degeneration (AMD), thereby improving the condition characterized by excessive accumulation of lipofuscin in the retina.

[0005] In addition to AMD, significant accumulation of lipofuscin is also a feature of ocular fundus macular fleck syndrome (Stargardt) and vitelliform macular degeneration (Best), where Stargardt disease is a genetic form of juvenile-onset macular degeneration, and Best disease is caused by autosomal dominant inheritance of the vitelliform macular dystrophy gene.

[0006] WO2015168286 discloses a class of substituted 4-phenylpiperidine compounds, as shown in compound (A); WO2014152018 discloses a class of substituted cyclopentanetetrahydropyrrole compounds, as shown in compound (B); WO2014151936 discloses a class of substituted octahydropyrrolopyrrole compounds, as shown in compound (C). As RBP4 antagonists, they provide a therapeutic basis for treating dry AMD and other diseases characterized by excessive accumulation of lipofuscin, but there is still room for improvement in terms of inhibitory effect, membrane permeability, pharmacokinetics, drugability and drug safety.

[0007] SUMMARY

[0008] In view of the deficiencies of the prior art, the present application provides, in one aspect, a compound having a structure as shown in Formula (I), or a stereoisomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure shown in Formula (I);

[0009]

[0010] wherein ring A is a heteroaromatic ring;

[0011] R 1 is hydrogen, deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy or -SR 4 ;

[0012] R 4 is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl or heteroaryl;

[0013] R 2 is hydrogen, deuterium, alkyl, cycloalkyl or halocycloalkyl;

[0014] R 3 is hydrogen, deuterium, alkyl, heterocyclylalkyl, R 5 C(=O)NR 6 -(CH2) n -, -(CH2) n C(=O)NR 5 R 6 or heterocyclyl; the heterocyclyl is optionally substituted with 1, 2 or 3 substituents selected from deuterium, hydroxyl, nitro, amino, alkoxy, carboxyl, thiol, cyano, oxo (=O), halogen, carboxyl, alkyl, alkenyl, alkynyl, alkoxycarbonyl or cycloalkyl; n is 0, 1, 2, 3, 4 or 5;

[0015] R 5 is hydrogen, deuterium, alkyl, haloalkyl, amino, alkylamino, cycloalkyl or halocycloalkyl;

[0016] R 6 is hydrogen, deuterium, alkyl or haloalkyl.

[0017] In some embodiments, in the compound, ring A is selected from C 1-9 heteroaromatic ring; preferably, ring A is a 5-6 membered heteroaromatic ring containing 1-2 nitrogen atoms;

[0018] R 1 is deuterium, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -SR 4 ;

[0019] R 4 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl.

[0020] In some embodiments, ring A is a pyridine ring or a pyrazole ring.

[0021] In other embodiments, in the compounds, ring A is

[0022] In some embodiments, ring A is

[0023] In some embodiments, ring A is

[0024] * - indicates the position of attachment to the piperidine ring, indicates the position of attachment to R 1 .

[0025] In some embodiments, R 1 is selected from deuterium, cyano, nitro, methyl, ethyl, propyl, isopropyl, C 1-3 alkyl substituted with 1-3 F, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, C 1-3 alkoxy substituted with 1-3 F, or -SR 4 ;

[0026] R 4 is hydrogen, deuterium, methyl, ethyl, propyl, n-butyl, isobutyl, t-butyl, C 1-3 alkyl substituted with 1-3 F, cyclopropyl, cyclobutyl, or cyclopentyl.

[0027] In some embodiments, in the compounds, R 2 is hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl;

[0028] R 3 is deuterium, C 1-6 alkyl, C 1-9 heterocyclyl-C 1-6 alkyl-, R 5 C(=O)NR 6 -(CH2) n-, -(CH2) n C(=O)NR 5 R 6 or C 2-9 heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, or 3 deuterium, hydroxy, nitro, amino, C 1-6 alkoxy, carboxy, thiol, cyano, oxo (=O), halogen, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxycarbonyl, or C 3-8 cycloalkyl; n is 0, 1, 2, 3, 4, or 5;

[0029] R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl;

[0030] R 6 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.

[0031] In some embodiments, the compound is one wherein R 2 is hydrogen, deuterium, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or C 3-6 cycloalkyl substituted with 1-3 F;

[0032] R 3 is deuterium, C 1-3 alkyl, C 2-9 heterocyclyl-C 1-3 alkyl-, R 5 C(=O)NR 6 -(CH2) n -, (CH2) n C(=O)NR 5 R 6 or C 2-9 heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, or 3 deuterium, hydroxy, nitro, amino, C 1-3 alkoxy, carboxy, thiol, cyano, oxo (=O), halogen, carboxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxycarbonyl, or C 3-6 cycloalkyl; n is 0, 1, 2, 3, 4, or 5;

[0033] R5 is C 1-3 alkyl, C 1-3 haloalkyl, amino, C 1-3 alkylamino, C 3-6 cycloalkyl or C 3-6 halocycloalkyl;

[0034] R 6 is hydrogen, C 1-3 alkyl or C 1-3 alkyl substituted with 1-3 F.

[0035] In some embodiments, R 3 is C 4-9 heterocyclyl-C 1-3 alkyl-, R 5 C(=O)NR 6 -(CH2) n -, -(CH2) n C(=O)NR 5 R 6 or C 2-9 heterocyclyl; said heterocyclyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, hydroxy, nitro, amino, C 1-3 alkoxy, carboxy, thiol, cyano, oxo (=O), halogen, carboxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxycarbonyl or C 3-6 cycloalkyl; n is 0, 1, 2, 3, 4 or 5;

[0036] said C 4-9 heterocyclyl is selected from the group consisting of 5-6 membered heterocyclyl containing at least one heteroatom selected from the group consisting of N, O, S;

[0037] Preferably, said C 4-9 heterocyclyl is selected from the group consisting of morpholino, piperazino, piperidino, tetrahydropyranyl, pyrrolidino, thiomorpholino.

[0038] In some other embodiments, in said compound, R 3 has one of the following structures:

[0039]

[0040] In some embodiments, in said compound, R 3 has one of the following structures:

[0041]

[0042] In another aspect, the present application also provides a pharmaceutical composition comprising (a) a compound described above or a stereoisomer, a tautomer, a nitroso compound, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or ester thereof, and (b) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0043] In another aspect, the present application provides a use of a compound described above or a stereoisomer, a tautomer, a nitroso compound, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing, managing, treating or alleviating a retinol binding protein 4 (RBP4)-related disease.

[0044] In some embodiments, the retinol binding protein 4 (RBP4)-related disease is characterized by excessive accumulation of lipofuscin in the retina.

[0045] In some embodiments, the retinol binding protein 4 (RBP4)-related disease is age-related macular degeneration, dry (atrophic) age-related macular degeneration, ocular fundus fleck syndrome (Stargardt disease), vitelliform macular degeneration (Best disease) or a macular dystrophy similar to Stargardt disease.

[0046] In some embodiments, the retinol binding protein 4 (RBP4)-related disease is age-related macular degeneration, Stargardt disease or Best disease.

[0047] In another aspect, the present application provides a method of inhibiting the formation of RBP4-TTR complex in a cell, comprising contacting the cell with an effective amount of a compound described in the first aspect of the present application or a pharmaceutical composition described in the second aspect of the present application.

[0048] In another aspect, the present application provides a method of inhibiting the excessive accumulation of lipofuscin in a cell, comprising contacting the cell with an effective amount of a compound described in the first aspect of the present application or a pharmaceutical composition described in the second aspect of the present application.

[0049] In another aspect, the present application provides a method of inhibiting the formation of RBP4-TTR complex in the serum of a subject, comprising administering to the subject an effective amount of a compound described in the first aspect of the present application or a pharmaceutical composition described in the second aspect of the present application.

[0050] In another aspect, the present application provides a method of inhibiting the excessive accumulation of lipofuscin in the retina of a subject, comprising administering to the subject an effective amount of a compound described in the first aspect of the present application or a pharmaceutical composition described in the second aspect of the present application.

[0051] Compared with the prior art, the present application has the following beneficial effects:

[0052] The compounds of the present application can reduce the rate of formation of cytotoxic retinal pigment epithelium (RPE) celluorablin dimers, the main component of lipofuscin, will prevent further geographic atrophy in patients with atrophic (dry) age-related macular degeneration (AMD), thereby improving conditions characterized by excessive accumulation of lipofuscin in the retina. DETAILED DESCRIPTION

[0053] Definitions and General Terminology

[0054] Unless otherwise indicated, the terms used in the specification and claims have the following definitions.

[0055] Certain embodiments of the application are now described in detail by referring to the following illustrative figures and examples. The application is intended to cover all alternatives, modifications and equivalents thereof that are included within the scope of the application as defined by the claims. Those skilled in the art will recognize that many methods and materials equivalent to those described herein can be used in the practice of the present application. Nothing in this detailed description or the claims limits the scope of the present application to any particular method or material. In the event that any one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term application, described techniques, and the like, this application controls.

[0056] It should be further recognized that certain of the described features come within the purview of a single integrated embodiment, but alternatives can be separately provided. Conversely, a variety of present features are described in dependence on a single embodiment or figure for clarity's sake, but are also provided in any appropriate subcombination.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0058] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the "Handbook of Chemistry and Physics", 75thEd., 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0059] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "at least one") of the enumerated items, unless otherwise indicated by the context of use. The terms "the" and "said" are defined and used herein to refer to one or to more than one (i.e., to "at least one") of the enumerated items unless otherwise indicated by context of use. For example, "a member" refers to one or more members, and "the member" refers to one or more members.

[0060] The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to a primate (e.g., human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0061] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0062] The term "comprising" is to be read to be inclusive of the enumerated elements, but not to the exclusion of additional elements.

[0063] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0064] "Diastereomers" refer to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, even if they have the same chemical composition and absolute three-dimensional structure. Mixtures of diastereomers can be separated by high resolution analytical techniques, such as electrophoresis and chromatography, e.g., HPLC.

[0065] The stereochemical definitions and rules used herein generally follow S. P. 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.

[0066] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer; a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate; such occurrence is typically observed only when there has been no stereocontrol in a synthetic reaction or process.

[0067] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in the form of a racemic or enantiomeric enrichment, e.g., in the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess in the (R)- or (S)- configuration, 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.

[0068] Depending on the choice of starting materials and methods, the compounds of the present application can be present in the form of one or more of possible isomers, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms), in the form of an enantiomeric or stereoisomeric mixture, or in the form of an enantiomeric or stereoisomeric pure form. The optically active forms can be prepared using chiral synthons or chiral reagents, or by resolution of a mixture of compounds. If a compound contains a double bond, the substituents can be in the E or the Z configuration; if a compound contains a disubstituted cycloalkyl ring, the substituents can be in the cis- or trans-configuration.

[0069] Any mixture of stereoisomers resulting can be separated into the pure or substantially pure geometric or optical isomers according to the differential physico-chemical properties of the constituents, for example, by chromatography and / or fractional crystallization.

[0070] Unless otherwise stated, the structural formulae described herein are meant to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers) of the structural formulae: for example, where a structural formula contains an asymmetric center, both the R and S (or E and Z) configurations are intended; where a structural formula contains a double bond, both the (Z) and (E) isomers are intended; and where a structural formula contains a disubstituted pyridine ring, both the (l) and (2) isomers are intended. Thus, individual stereochemical isomers and mixtures of its enantiomeric, diastereomeric, or geometric (or conformational) isomers, are within the scope of the present application.

[0071] The term "prodrug" as used herein refers to a compound that is converted into a compound of Formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or by enzymatic conversion in blood or tissue to the parent structure. The prodrug form of the compounds of the present application can be an ester, and in the present application the ester can be a benzoate, aliphatic (C 1-24 ) ester, acyloxymethyl ester, carbonate, carbamate, and amino acid ester. For example, a compound of the present application containing a hydroxyl group can be acylated to provide a prodrug form of the compound. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium 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 S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0072] Any resulting racemate of an end product or intermediate can be resolved by methods known in the art, such as by separation of the resulting diastereomeric salts thereof. The racemate product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey 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).

[0073] The term "tautomer" or "tautomerism" refers to structural isomers that differ in energy and can interconvert by a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, protontautomerism (also known as prototropic tautomerism) includes interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomerism includes interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of the pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0074] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, and organic acid salts formed with carboxylic acids such as, but not limited to, methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, succinic acid, benzoic acid, succinic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptonic acid, mandelic acid, 1,2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, carbonic acid, trifluoroacetic acid, glycolic acid, glyceryl sulfonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, malonic acid, phenylsulfonic acid, p-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, lactobionic acid, or oxalic acid, or by other methods such as ion exchange procedures as art-recognized. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, besylate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. Additionally, pharmaceutically acceptable salts can include salts of acidic groups formed by appropriate bases, such as alkali, alkaline earth, ammonium and N+(C 1-4 alkyl)4 salts. The present application also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable 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, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic amines to acidic groups, such as halogen, carboxylic acid, sulfates, phosphoric acid, nitric acid, C 1-8 sulfonic acid, and aromatic sulfonic acid.

[0075] Medicinal salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonide, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0076] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0077] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

[0078] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming 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 when the solvent molecules are water.

[0079] The term "protecting group" or "PG" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0080] "Pharmaceutical composition" means a salt of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug, mixed with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0081] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0082] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0083] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as... 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 C. Compounds enriched by this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compounds of formula (I) can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagent with a suitable isotopic labeling reagent, as described in the examples and preparation procedures of this invention.

[0084] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered a substituent in compounds of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. The term "isotope enrichment factor" as used in this invention refers to the ratio between the isotopic abundance of the specified isotope and its natural abundance. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0085] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O)2, carboxyalkoxy, etc.

[0086] As used in this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used herein to refer to both straight-chain and branched saturated carbon chains. The term "alkane" is used herein to refer to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon; examples of such groups include, but are not limited to, methylene, methine, methinepropyl, etc.

[0087] The term "alkoxy" as used in this invention refers to an alkyl group, as defined herein, that is attached to the main carbon chain by an oxygen atom. Examples of such alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. Furthermore, the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0088] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described in this invention, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0089] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0090] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocyclic rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocyclic rings with 9 or 10 atoms can be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of cyclic aliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Furthermore, the "cyclic aliphatic group" or "carbocyclic", "carbocyclic group", and "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0091] The terms “heterocyclic,” “heterocyclic group,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic systems in which one or more carbon atoms on the ring are independently and optionally substituted with heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has only one connection point to another molecule. One or more hydrogen atoms on the ring are independently and optionally substituted with one or more substituents described herein. Some of these embodiments are that the "heterocycle", "heterocyclic group", "heterocyclic alicyclic group" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2, and when the ring is a three membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2).

[0092] Heterocyclic groups can be carbonyl or heteroatomyl. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, aziridine, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, aziridineheptyl, oxacycloheptyl, thiohexacycloheptyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxacyclobutyl... 2-diazine Base, sulfur nitrogen 1-pyrrololin-1-yl, 2-pyrrololin-3-pyrrololin-1-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl) acetone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridin-5-yl, 3H-indolyl-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinide groups. Furthermore, the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo(=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0093] The term "aryl" can be used alone or as a part of "aranyl," "aranalkoxy," or "aranoxyalkyl," referring to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 membered rings, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with only one attachment point connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0094] The term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic system containing 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning as described in this invention, wherein each ring system contains 3-7 membered rings and has only one attachment point connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic compound." Furthermore, the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxylated alkoxy, hydroxylated alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxylated alkyl-S(=O)-, hydroxylated alkyl-S(=O)2-, carboxyalkoxy, etc.

[0095] Other embodiments include, but are not limited to, the following monocyclic compounds: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following bis Cyclic, but not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazolyl-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0096] The term “heteroatom” refers to one or more O, S, N, P, and Si atoms, including N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrole), NH (e.g., NH in pyrroleyl), or NR (e.g., NR in N-substituted pyrroleyl).

[0097] The term "halogen" refers to F, Cl, Br, or I.

[0098] In this invention, "halogenated" means replacing the following group with a halogen, and the number of halogens can be one or more.

[0099] In this invention, "hydroxyl-substituted" means that the group following it is replaced by a hydroxyl group, and the number of substitutions can be one or more.

[0100] When the term "substituted" is used between two groups in this invention, it is preceded by a substituent, such as "aryl-substituted alkyl" indicating that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" indicating that the alkyl group has an alkoxycarbonyl substituent.

[0101] When multiple groups of the present invention are used in combination, from left to right, they are in a substitution relationship, such as "arylalkyl", which means aryl-substituted alkyl, and "alkoxyalkoxy", which means alkoxy-substituted alkoxy.

[0102] The term "unsaturated" as used in this invention means that a structural portion contains one or more degrees of unsaturation.

[0103] Description of the compounds of the present invention

[0104] On the one hand, the present invention provides a compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in Formula (I);

[0105]

[0106] Among them, ring A is a heteroaromatic ring;

[0107] R 1 It can be hydrogen, deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, or -SR. 4 ;

[0108] R 4 It can be hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclic, aryl, or heteroaryl;

[0109] R 2 It is hydrogen, deuterium, alkyl, cycloalkyl, or halocycloalkyl;

[0110] R 3 Hydrogen, deuterium, alkyl, heterocyclic alkyl, R 5 C(=O)NR 6 -(CH2) n -、-(CH2) n C(=O)NR 5 R 6 Or a heterocyclic group; the heterocyclic group may be optionally substituted by 1, 2 or 3 substituents selected from deuterium, hydroxyl, nitro, amino, alkoxy, carboxyl, mercapto, cyano, oxo (=O), halogen, carboxyl, alkyl, alkenyl, alkoxycarbonyl or cycloalkyl; n is 0, 1, 2, 3, 4 or 5;

[0111] R 5 It can be hydrogen, deuterium, alkyl, haloalkyl, amino, alkylamino, cycloalkyl, or halocycloalkyl;

[0112] R 6 It is hydrogen, deuterium, alkyl, or haloalkyl.

[0113] In some embodiments, in the compound, ring A is selected from C. 1-9Mixed fragrance ring.

[0114] In some implementations, ring A is a 5-6 membered heteroaromatic ring containing 1-2 nitrogen atoms.

[0115] In some implementation schemes, R 1 For deuterium, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -SR 4 ;

[0116] R 4 For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0117] In some embodiments, ring A in the compound is a pyridine ring or a pyrazole ring.

[0118] In other embodiments, in the compound, ring A is...

[0119] In some implementations, ring A is

[0120] In some implementations, ring A is

[0121] * indicates the position where it connects to the piperidine ring. Indicates with R 1 The location of the connection.

[0122] In some implementation schemes, R 1 Selected from deuterium, cyano, nitro, methyl, ethyl, propyl, isopropyl, and C atoms substituted with 1-3 F atoms. 1-3 Alkyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, C substituted with 1-3 Fs 1-3 alkoxy or -SR 4 ;

[0123] R 4 It is hydrogen, deuterium, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, or C substituted with 1-3 F atoms. 1-3 Alkyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0124] In some embodiments, R in the compound2 For hydrogen, deuterium, C 1-6 Alkyl, C 3-8 cycloalkyl or C 3-8 Halogenated cycloalkyl groups;

[0125] R 3 For deuterium, C 1-6 Alkyl, C 1-9 Heterocyclic group -C 1-6 Alkyl-, R 5 C(=O)NR 6 -(CH2) n -、-(CH2) n C(=O)NR 5 R 6 Or C 2-9 Heterocyclic group; the heterocyclic group is optionally surrounded by 1, 2 or 3 deuterium, hydroxyl, nitro, amino, C 1-6 Alkoxy, carboxyl, mercapto, cyano, oxo (=O), halogen, carboxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxycarbonyl or C 3-8 Cycloalkyl substituted; n is 0, 1, 2, 3, 4 or 5;

[0126] R 5 C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, C 1-6 alkylamine group, C 3-8 cycloalkyl or C 3-8 Halogenated cycloalkyl groups;

[0127] R 6 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0128] In some other embodiments, in the compound, R 2 For hydrogen, deuterium, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or C substituted with 1-3 F atoms. 3-6 cycloalkyl;

[0129] R 3 For deuterium, C 1-3 Alkyl, C 2-9 Heterocyclic group -C 1-3 Alkyl-, R 5 C(=O)NR 6 -(CH2) n -、-(CH2) n C(=O)NR 5 R6 Or C 2-9 Heterocyclic group; the heterocyclic group is optionally surrounded by 1, 2 or 3 deuterium, hydroxyl, nitro, amino, C 1-3 Alkoxy, carboxyl, mercapto, cyano, oxo (=O), halogen, carboxyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxycarbonyl or C 3-6 Cycloalkyl substituted; n is 0, 1, 2, 3, 4 or 5;

[0130] R 5 C 1-3 Alkyl, C 1-3 Halogenated alkyl, amino, C 1-3 alkylamine group, C 3-6 cycloalkyl or C 3-6 Halogenated cycloalkyl groups;

[0131] R 6 For hydrogen, C 1-3 Alkyl groups or C groups substituted with 1-3 F atoms 1-3 alkyl.

[0132] In some implementation schemes, R 3 C 4-9 Heterocyclic group -C 1-3 Alkyl-, R 5 C(=O)NR 6 -(CH2) n -、-(CH2) n C(=O)NR 5 R 6 Or C 2-9 Heterocyclic group; the heterocyclic group is optionally composed of 1, 2, or 3 groups selected from deuterium, hydroxyl, nitro, amino, C 1-3 Alkoxy, carboxyl, mercapto, cyano, oxo (=O), halogen, carboxyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxycarbonyl or C 3-6 Substituents of cycloalkyl groups; n is 0, 1, 2, 3, 4 or 5;

[0133] The C 4-9 The heterocyclic group is selected from 5-6 membered heterocyclic groups containing at least one heteroatom selected from N, O, or S;

[0134] In some implementations, the C 4-9 The heterocyclic group is selected from morpholinoyl, piperazine, piperidinyl, tetrahydropyranyl, pyrrolidinyl, and thiomorpholinoyl.

[0135] In some other embodiments, in the compound, R 3 It has one of the following structures:

[0136]

[0137] In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug:

[0138]

[0139]

[0140]

[0141]

[0142] Compositions, formulations and administration of the compounds of the present invention

[0143] The pharmaceutical composition comprises one or more compounds of the present invention, or stereoisomers, tautomers, nitrides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters of said compounds. The pharmaceutical composition may further comprise pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators, or combinations thereof.

[0144] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0145] When applicable for treatment, a therapeutically effective amount of the compound of the present invention may be administered as an unprocessed chemical drug or as an active ingredient in a pharmaceutical composition. Therefore, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "therapeuticly effective amount" as used herein refers to the total amount of each active component sufficient to demonstrate a meaningful patient benefit (e.g., reduction of viral load). When administered alone using a single active ingredient, the term refers only to that component. When used in combination, the term refers to the combined amount of active ingredients that, regardless of combination, sequential or simultaneous administration, produce a therapeutic effect. The carrier, diluent, or excipient must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients. As used in this invention, the term "pharmaceutically acceptable" means that the compounds, raw materials, compositions, and / or dosage forms of this invention are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, within the limits of reasonable medical judgment.

[0146] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may also include other ingredients commonly used in the art in relation to the type of formulation, such as flavoring agents, for example, such formulations suitable for oral administration may include flavoring agents.

[0147] Uses of the compounds and compositions of the present invention

[0148] The pharmaceutical composition can be used to prevent, treat, or alleviate retinol-binding protein 4-related diseases.

[0149] In some embodiments, the retinol-binding protein 4-related disease is characterized by an excessive accumulation of lipofuscin in the retina;

[0150] In some embodiments, the retinol-binding protein 4-related diseases are age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt's disease, Best's disease, or Stargardt's disease-like macular dystrophy.

[0151] The retinol-binding protein 4-related diseases mentioned above are age-related macular degeneration, Stargardt's disease, or Best's disease.

[0152] The present invention provides a method for inhibiting the formation of RBP4-TTR complex in cells, comprising contacting the cells with an effective amount of the compound or pharmaceutical composition of the present invention.

[0153] The present invention provides a method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the compound or pharmaceutical composition of the present invention.

[0154] The present invention provides a method for inhibiting the formation of RBP4-TTR complex in the serum of a subject, comprising administering an effective amount of the compound or pharmaceutical composition of the present invention to the subject.

[0155] The present invention provides a method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering an effective amount of the compound or pharmaceutical composition of the present invention to the subject.

[0156] The “effective amount” or “effective dose” of a compound of the present invention, or its stereoisomers, tautomers, nitrides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, or pharmaceutically acceptable compositions, refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compound and its compositions can be administered at any dosage and via any route of administration to effectively treat or reduce the severity of the disease. The precise amount required will vary depending on the patient’s condition, which may depend on race, age, the patient’s general condition, the severity of the infection, specific factors, route of administration, etc. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed in the present invention.

[0157] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0158] General Synthesis Process

[0159] Generally, the compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0160] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0161] The examples described below are in Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0162] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0163] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0164] Silica gel columns were used. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets were observed, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants were expressed in Hertz (Hz).

[0165] The following abbreviations are used throughout this invention:

[0166] AcOH: Acetic acid

[0167] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0168] Boc: tert-butyloxycarbonyl

[0169] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0170] CH3CN: Acetonitrile

[0171] DCM: Dichloromethane

[0172] DIPEA: N,N-Diisopropylethylamine

[0173] EA: Ethyl acetate

[0174] HCl: Hydrogen chloride

[0175] HCl / EA: Ethyl acetate solution of hydrogen chloride

[0176] H2O: water

[0177] NaOH: Sodium hydroxide

[0178] NaI: Sodium iodide

[0179] K2CO3: Potassium carbonate

[0180] rt, rt: room temperature

[0181] TBAF: Tetrabutylammonium fluoride

[0182] Example

[0183] Example 1

[0184] N-((4-methyl-3-(4-(2-(methylthio)pyridin-3-yl)piperidin-1-carbonyl)-1H-pyrazole-5-yl)methyl)acetamide (compound 1)

[0185]

[0186] Step 1: 4-(2-(methylthio)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (1b)

[0187] In a 100 mL round-bottom flask, compound 1a (2 g, 9.80 mmol), 1-Boc-4-bromopiperidine (3.11 g, 11.77 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (0.48 g, 0.98 mmol), sodium iodide (2.94 g, 19.60 mmol), potassium carbonate (2.44 g, 17.64 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxane) (4.48 g, 17.64 mmol) were added sequentially. Finally, dimethylacetamide (30 mL) was added. The air was purged with nitrogen three times, and the reaction was carried out at 65 °C for 6 h. After the reaction was detected by TLC, the solution was filtered through diatomaceous earth. The filtrate was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), and the organic phases were combined. The solutions were then washed with water (2 x 50 mL), and finally washed with saturated brine (2 x 50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 1b, a yellow oily substance, 3.503 g. LCMS: 309.4 [M+1] + .

[0188] Step 2: 2-Methylthio-3-(piperidin-4-yl)pyridine hydrochloride (1c)

[0189] In a 50 mL round-bottom flask, compound 1b (3.503 g, 11.36 mmol) was dissolved in 1,4-dioxane (20 mL). 1,4-dioxane hydrochloride (25 mL) at 4 mol / L was added dropwise, and the mixture was stirred at 0 °C for 3 h. The reaction was confirmed by LC-MS. The reaction solution was then concentrated under reduced pressure to give compound 1c, a yellow solid, 2.4 g. LC-MS: 209.3 [M+1] + .

[0190] Step 3: N-((4-methyl-3-(4-(2-(methylthio)pyridin-3-yl)piperidin-1-carbonyl)-1H-pyrazole-5-yl)methyl)acetamide (compound 1)

[0191] In a 25 mL round-bottom flask, compound 1c (100 mg, 0.4 mmol) and 5-(acetamidomethyl)-4-methyl-1H-pyrazole-3-carboxylic acid (188 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.43 mL, 2.45 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (442 mg, 1.22 mmol) were added sequentially at 0 °C. The mixture was stirred at 0 °C for 1 h, and then reacted at room temperature for 12 h. The reaction was stopped by TLC. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 1, 10 mg of an off-white solid. LCMS: 388.5 [M+1] + ; 1 H NMR(500MHz, CDCl3)δ11.09(s,1H),8.37–8.30(m,1H),7.36–7.31(m,1H),6.99–6.95(m,1H),6.53(t,J=5.0Hz,1H),5.00–4.73(m,1H),4.39 –4.18(m,3H),3.28–3.12(m,1H),3.11–3.04(m,1H),3.01–2.82(m,1H),2.57(s,3H),2.10(s,3H),2.03–2.00(m,3H),1.66–1.62(m,4H)ppm.

[0192] Compounds 2–91 were synthesized according to Example 1, by replacing the corresponding carboxylic acid fragment with the corresponding ammonia fragment, and then condensing them under the same condensation conditions. The compounds and their characterization are shown in Table 1.

[0193] Table 1

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Bioactivity test

[0207] This embodiment uses the HTRF method to test the inhibitory effect of the compound of the present invention on the formation of the RBP4-TTR complex. The test compound was prepared into a 10 mM stock solution using DMSO, and then the stock solution was further diluted to different test concentrations (1 μM starting, 3-fold dilution, 8 concentrations, 2 replicates) using reaction buffer (50 mM Tris-HCl pH 7.5, 1 mM DTT, 0.05% NP-40, 0.05% Prionex, 6% glycerol). 1 μL of each of the above-mentioned compounds was added to a 384-well plate (Perkin Elmer, Proxiplate), followed by 2 μL of RBP4-hFc (MCE, final concentration 12.5 nM) protein, and incubated at room temperature for 20 min. 1 μL of all-trans Retinol (Sigma, final concentration 1 μM) was added to each well, and incubated at room temperature for 20 min. 1 μL of Human Transthyretin-His (Acro, final concentration 2 nM) was added to each well, and incubated at room temperature for 20 min. 2.5 μL of 1×PAbAnti Human IgG-XL665 (Cisbio) and 2.5 μL of 1×MAb Anti-6His-Tb cryptate (Cisbio) were added to each well, and incubated at room temperature for 1 h. The emission intensity at 615 nm and 665 nm in each well was measured using a Varioskan LUX microplate reader (Thermo Fisher), and the 665 / 615 ratio was calculated. The wells without compound (0 nM) were treated as 100%. After background subtraction, data processing and curve fitting (non-linear fitting, 4 parameters) were performed using Graphpad Prism 8.0 software, followed by IC analysis. 50 The calculations were performed. The results are shown in Table 2. A represents 100–500 nm, and B represents greater than 500 nm.

[0208] Table 2

[0209] Compound No. HTRF IC 50 ]]> Compound No. HTRF IC 50 ]]> Compound 1 B Compound 2 A Compound 3 B Compound 5 A Compound 6 B Compound 7 B Compound 8 B Compound 10 A Compound 11 A Compound 16 B Compound 30 B Compound 34 B Compound 35 B Compound 38 B Compound 39 B Compound 40 B Compound 41 B Compound 42 B Compound 43 B Compound 45 B Compound 46 B Compound 47 B Compound 48 B Compound 49 B Compound 50 A Compound 51 B Compound 52 B Compound 53 B Compound 55 B Compound 56 B Compound 57 B Compound 58 B Compound 59 B Compound 61 B Compound 62 B Compound 64 B Compound 66 B Compound 67 A Compound 68 B Compound 69 A Compound 70 B Compound 72 A Compound 74 B Compound 82 B Compound 84 B Compound 85 A

[0210] The experimental results show that the compound of the present invention has a strong inhibitory effect on the formation of RBP4-TTR complex.

[0211] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A compound having a structure according to Formula (I), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure according to Formula (I); wherein Ring A is a heteroaromatic ring; R 1 is hydrogen, deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, or -SR 4 ; R 4 is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, deuterium, alkyl, cycloalkyl or halocycloalkyl; R 3 is hydrogen, deuterium, alkyl, heterocyclylalkyl, R 5 C(=O)NR 6 -(CH2) n -, -(CH2) n C(=O)NR 5 R 6 or heterocyclyl; said heterocyclyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, hydroxyl, nitro, amino, alkoxy, carboxyl, thiol, cyano, oxo (=O), halogen, carboxyl, alkyl, alkenyl, alkynyl, alkoxycarbonyl or cycloalkyl; n is 0, 1, 2, 3, 4 or 5; R 5 is hydrogen, deuterium, alkyl, haloalkyl, amino, alkylamino, cycloalkyl, or halocycloalkyl; R 6 is hydrogen, deuterium, alkyl or haloalkyl.

2. The compound of claim 1, wherein, Ring A is selected from C 1-9 heteroaromatic ring; preferably, ring A is a 5-6 membered heteroaromatic ring containing 1-2 nitrogen atoms; R 1 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -SR 4 ; R 4 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl.

3. The compound of claim 1 or 2, wherein, Ring A is a pyridine ring or a pyrazole ring; Preferably, ring A is Preferably, ring A is * - indicates the position of attachment to the piperidine ring, represents the position of attachment to R 1 .

4. The compound according to any one of claims 1-3, wherein, R 1 selected from deuterium, cyano, nitro, methyl, ethyl, propyl, isopropyl, C 1-3 alkyl substituted with 1-3 F, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, C 1-3 alkoxy substituted with 1-3 F, or -SR 4 ; R 4 is hydrogen, deuterium, methyl, ethyl, propyl, n-butyl, i-butyl, t-butyl, C 1-3 alkyl, cyclopropyl, cyclobutyl or cyclopentyl.

5. The compound according to any one of claims 1-4, wherein, R 2 is hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl or C 3-8 halogenated cycloalkyl; R 3 For deuterium, C 1-6 Alkyl, C 1-9 Heterocyclic group -C 1-6 Alkyl-, R 5 C(=O)NR 6 -(CH2) n -、-(CH2) n C(=O)NR 5 R 6 Or C 2-9 Heterocyclic groups; said heterocyclyl is optionally substituted with 1, 2 or 3 deuterium, hydroxy, nitro, amino, C 1-6 alkoxy, carboxy, thiol, cyano, oxo (=0), halogen, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxycarbonyl or C 3-8 cycloalkyl; n is 0, 1, 2, 3, 4 or 5; R 5 is C 1-6 alkyl, C 1-6 haloalkyl, amino, C 1-6 alkylamino, C 3-8 cycloalkyl or C 3-8 halocycloalkyl; R 6 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

6. The compound according to any one of claims 1-5, wherein, R 2 is hydrogen, deuterium, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or C 3-6 cycloalkyl; R 3 is deuterium, C 1-3 alkyl, C 2-9 heterocyclyl-C 1-3 alkyl-, R 5 C(=O)NR 6 -(CH2) n -, -(CH2) n C(=O)NR 5 R 6 or C 2-9 heterocyclyl; which heterocyclyl is optionally substituted with 1, 2 or 3 deuterium, hydroxy, nitro, amino, C 1-3 alkoxy, carboxy, thiol, cyano, oxo (=O), halogen, carboxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxycarbonyl or C 3-6 cycloalkyl; n is 0, 1, 2, 3, 4 or 5; R 5 is C 1-3 alkyl, C 1-3 haloalkyl, amino, C 1-3 alkylamino, C 3-6 cycloalkyl or C 3-6 halocycloalkyl; R 6 is hydrogen, C 1-3 alkyl or C 1-3 alkyl substituted by 1-3 F; R is preferably C 3 is C 4-9 heterocyclyl-C 1-3 alkyl-, R 5 C(=O)NR 6 -(CH2) n -, -(CH2) n C(=O)NR 5 R 6 or C 2-9 heterocyclyl; said heterocyclyl being optionally substituted with 1, 2 or 3 substituents selected from deuterium, hydroxy, nitro, amino, C 1-3 alkoxy, carboxy, thiol, cyano, oxo (=O), halogen, carboxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxycarbonyl or C 3-6 cycloalkyl; n is 0, 1, 2, 3, 4 or 5; The C 4-9 heterocyclyl is selected from 5-6 membered heterocyclyl comprising at least one heteroatom selected from N, O, S; Preferably, said C 4-9 heterocyclyl is selected from morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, thiomorpholinyl; Further preferably, R 3 has one of the following structures: Further preferably, R 3 has one of the following structures:

7. The compound of any one of claims 1-6, having one of the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

8. A pharmaceutical composition comprising a compound of any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

9. Use of a compound of any one of claims 1-7 or a pharmaceutical composition of claim 8 for the manufacture of a medicament for treating a retinal -binding protein 4- associated disease, preferably, the retinal -binding protein 4-associated disease is characterized by an excess accumulation of lipofuscin in the retina; preferably, the retinal -binding protein 4-associated disease is age-related macular degeneration, dry (atrophic) age-related macular degeneration, ocular fundus fleck-syndrome (Stargardt disease), vitelliform macular degeneration (Best disease), or a macular dystrophy similar to Stargardt disease.

10. The use of claim 9, wherein the retinal -binding protein 4-associated disease is age-related macular degeneration, Stargardt disease, or Best disease.

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