Heteroaryl piperidine compound and application thereof

Abstract

The invention discloses a heteroaryl piperidine compound and application thereof. The heteroaryl piperidine compound provided by the invention has a structure as shown in a formula (0), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a prodrug of the structure as shown in the formula (0), or a pharmaceutically acceptable salt or ester of the stereoisomer, the tautomer, the nitrogen oxide, the solvate, the metabolite and the prodrug. The invention also discloses application of the heteroaryl piperidine compound in preparation of medicines for treating ophthalmic diseases.

Description

Technical Field

[0001] This invention relates to a heteroarylpiperidine compound or its stereoisomers, tautomers, nitrides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, and their use in the preparation of medicaments for treating ophthalmic diseases. Background Technology

[0002] Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, with atrophic (dry) AMD being the most prevalent form. Currently, there are no FDA-approved treatments for dry AMD. Given the lack of treatments and its high prevalence, the development of drugs for dry AMD is of paramount importance.

[0003] Age-dependent accumulation of cytotoxic lipofuscin-like bisretinoids in the retina may significantly contribute to the pathogenesis of dry AMD. Intraocular bisretinoid synthesis depends on the influx of all-trans retinol from the serum into the retina, which requires the formation of a tertiary retinol-binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex in the serum.

[0004] By selecting RBP4 antagonists to reduce the rate of formation of cytotoxic visual pigment dimers (the main component of lipofuscin) in the retinal pigment epithelium (RPE), further geographic atrophy will be prevented in patients with atrophic (dry) age-related macular degeneration (AMD).

[0005] Besides AMD, significant accumulation of lipofuscin is also characteristic of Stargardt disease and Best macular degeneration. Stargardt disease is the inherited form of adolescent episodic macular degeneration, while Best disease is caused by autosomal dominant inheritance of the gene for yolk-like macular dystrophy.

[0006] Currently, the main treatment strategy for dry AMD and other diseases characterized by excessive accumulation of lipofuscin is to reduce the concentration of visual pigment dimers in the retina, thereby improving the condition characterized by excessive accumulation of lipofuscin in the retina, such as atrophic (dry) age-related macular degeneration (AMD).

[0007]

[0008] WO2015168286 discloses a class of substituted 4-phenylpiperidine compounds, as shown in compound (A); WO2014152018 discloses a class of substituted cyclopentanotetrahydropyrrole compounds, as shown in compound (B); and WO2014151936 discloses a class of substituted octahydropyrrolopyrrole compounds, as shown in compound (C). As RBP4 antagonists, they exhibit significant pharmacological activity, but further improvements are needed in terms of inhibitory effect, membrane permeability, pharmacokinetics, druggability, and drug safety. Summary of the Invention

[0009] In order to solve one of the aforementioned technical problems in the prior art, the present invention provides a heteroarylpiperidine compound and its uses.

[0010] In a first aspect, the present invention provides a compound having a structure as shown in formula (0), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (0).

[0011]

[0012] Where A represents a heteroaryl ring;

[0013] R 1 Selected from deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy or -SR 2 ;

[0014] R 2 It can be hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclic, aryl, or heteroaryl;

[0015] R 3 Hydrogen, deuterium, CN, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, carboxyl-substituted alkyl, halocycloalkyl, alkoxyalkyl, heterocyclic, -C(=O)R 4 -S(=O)2-alkyl, -alkylene-COO-alkyl, aryl or heteroaryl;

[0016] R 4 It can be amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0017] In some embodiments, ring A in the compound is a nitrogen-containing heteroaromatic ring. In some embodiments, ring A is a heteroaromatic ring containing 1-4 nitrogen atoms.

[0018] In some embodiments, ring A in the compound is a 5-6 membered heteroaromatic ring containing a nitrogen atom.

[0019] In some embodiments, ring A in the compound is a 5-6 membered heteroaromatic ring containing 1-2 nitrogen atoms.

[0020] In some embodiments, ring A in the compound is * indicates the position where it connects to the piperidine ring. Indicates with R 1 The location of the connection.

[0021] In some embodiments, ring A in the compound is * indicates the position where it connects to the piperidine ring. Indicates with R 1 The location of the connection.

[0022] In other embodiments, in the compound, ring A is [a specific ring]. * indicates the position where it connects to the piperidine ring. Indicates with R 1 The location of the connection.

[0023] In some embodiments, R in the compound 1 Selected from deuterium, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -SR 2 ;R 2 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.

[0024] In other embodiments, in the compound, 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 2 ;R 2 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.

[0025] In some preferred embodiments, R 1Selected from deuterium, cyano, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, -S-CH3, -O-CF3 or -S-CF3.

[0026] In some preferred embodiments, R 2 It can be hydrogen, deuterium, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0027] In some implementation schemes, R 3 For hydrogen, deuterium, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl C 3-8 Cycloalkyl, carboxyl-substituted C 1-6 Alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl C 1-6 Alkoxy, C 1-9 Heterocyclic groups, -C(=O)R 4 -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkylene-COO-C 1-6 Alkyl, C 6-10 Aryl or C 1-9 heteroaryl; R 4 For amino, C 1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 cycloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0028] In some implementation schemes, R 3 Hydrogen, deuterium, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkyl C 3-6 Cycloalkyl, carboxyl-substituted C 1-4 Alkyl, C 3-6 Halogenated cycloalkyl, C 1-4 Alkyl C 1-4 Alkoxy, C 2-6 Heterocyclic groups, -C(=O)R 4 -S(=O)2-C 1-4 Alkyl, -C 1-4 Alkylene-COO-C1-4 Alkyl, phenyl, or pyridyl; R 4 For amino, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -NH-C 3-6 cycloalkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 2-6 Heterocyclic group, C 1-4 Alkyl-COO-C 1-4 Alkyl, phenyl, or pyridyl.

[0029] In some implementation schemes, R 3 For hydrogen, deuterium, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, CH2C H(CH3)2, CH2C(CH3)3, -CH2CF3, -CH2CH2CF3, -OCH3, -OCH2CH3, -CH2OCH3, -CH2CH2OCH3, -SO2-CH3, R 4 It is amino, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, CH2CH(CH3)2, CH2C(CH3)3, -OCH3, -OCH2CH3, -NHCH3, phenyl, pyridyl, pyrrolidinyl, piperidinyl, piperazine.

[0030] In some preferred embodiments, R 3 -C(=O)R 4 ;R 4 C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl, ethyl, propyl, and isopropyl.

[0031] In some preferred embodiments, the compound has a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (I);

[0032]

[0033] Among them, rings A and R 1 and R 4 The definition is the same as the definition for the foregoing in this invention.

[0034] In some preferred embodiments, the compound has a structure as shown in Formula (I-1), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in Formula (I-1);

[0035]

[0036] Among them, rings A and R 1 The definition is the same as the definition for the foregoing in this invention.

[0037] In some embodiments, the compound has a structure as shown in formula (II), formula (III) or formula (IV), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof;

[0038]

[0039] Among them, R 1 The definition is the same as the definition for the foregoing in this invention.

[0040] In some embodiments, the compound is selected from the following structures or their stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0041]

[0042] On the other hand, the present invention also provides a pharmaceutical composition comprising (a) the compound described above, and (b) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0043] On the other hand, the present invention provides the use of the above-described compound or pharmaceutical composition in the preparation of a medicament for the prevention, treatment, or relief of retinol-binding protein 4-related diseases.

[0044] In some implementations, the retinol-binding protein 4 is associated with diseases such as age-related macular degeneration, Stargardt's disease, or Best's disease.

[0045] On the other hand, the present invention also provides a method for inhibiting the formation of RBP4-TTR complex in cells, comprising contacting cells with an effective amount of the above-described compound or pharmaceutical composition of the present invention.

[0046] On the other hand, the present invention also provides a method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the above-described compound or pharmaceutical composition of the present invention.

[0047] On the other hand, the present invention also provides a method for inhibiting the formation of RBP4-TTR complex in the serum of a subject, comprising administering an effective amount of the above-described compound or pharmaceutical composition of the present invention to the subject.

[0048] On the other hand, the present invention also provides a method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering an effective amount of the above-described compound or pharmaceutical composition of the present invention to the subject.

[0049] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0050] Detailed Description of the Invention

[0051] Definitions and general terms

[0052] Unless otherwise stated, the terms used in the specification and claims of this invention have the following definitions.

[0053] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0054] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0055] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0056] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS version of the periodic table and the *Handbook of Chemistry and Physics* (75th edition, 1994). Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0057] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0058] As used in this invention, the term "test subject" (or "subject") refers to an animal, typically a mammal. Test subjects (or subjects) also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject (or subject) is a primate. In other embodiments, the test subject (or subject) is a human.

[0059] The term "patient" as used in this invention refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0060] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0061] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0062] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0063] The stereochemical definitions and rules used in this invention generally follow those of 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.

[0064] Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the plane-polarized light rotation caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

[0065] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some 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 the (R)- or (S)- configuration.

[0066] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0067] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0068] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers), diastereomers, and geometric isomers (or conformations): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformations. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformations) thereof, is within the scope of this invention.

[0069] The term "prodrug" as used in this invention refers to the conversion of a compound in vivo into a compound represented by formula (0), (I), (I-1), (II), (III), or (IV). Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs 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.

[0070] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, 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).

[0071] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0072] The salts mentioned in this invention are pharmaceutically acceptable salts, and the term "pharmaceutically acceptable salts" is well known in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Pharmaceutically acceptable, non-limiting examples of salts include inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, bis(hydroxynaphthyl) salts, salicylates, galactobionates, gluconates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, hydroxyethylsulfonates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalic acid, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. Furthermore, pharmaceutically acceptable salts also include those obtained by means of appropriate bases, such as alkali metals, alkaline earth metals, ammonium, and N+(C) salts. 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0073] 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.

[0074] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0075] 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.

[0076] As used herein, the term "nitrogen oxide" refers to an N-oxide formed by oxidizing one or more nitrogen atoms when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0077] 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.

[0078] As used in this application, the term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this application includes metabolites of compounds, including metabolites produced by sufficiently exposing the compound of this application to mammals for a period of time.

[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. 18F-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., 2 Substitution 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-diaza 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] In one aspect, the present invention provides a compound having a structure as shown in formula (0), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (0);

[0105]

[0106] Where A represents a heteroaryl ring;

[0107] R 1 Selected from deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy or -SR 2 ;

[0108] R 2 It can be hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclic, aryl, or heteroaryl;

[0109] R 3 Hydrogen, deuterium, CN, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, carboxyl-substituted alkyl, halocycloalkyl, alkoxyalkyl, heterocyclic, -C(=O)R 4 -S(=O)2-alkyl, -alkylene-COO-alkyl, aryl or heteroaryl;

[0110] R 4 It can be amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0111] In some preferred embodiments, the compound has a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (I);

[0112]

[0113] Among them, rings A and R 1 and R 4 The definition is the same as that in equation (0).

[0114] In some preferred embodiments, the compound has a structure as shown in Formula (I-1), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in Formula (I-1);

[0115]

[0116] Among them, rings A and R 1 The definition is the same as that in equation (0) or equation (I).

[0117] In some embodiments, ring A in the compound is a 5-6 membered heteroaromatic ring containing a nitrogen atom.

[0118] In some embodiments, ring A in the compound is * indicates the position where it connects to the piperidine ring. Indicates with R 1 The location of the connection.

[0119] In some embodiments, R in the compound 1 Selected from deuterium, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -SR 2 ;R 2 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.

[0120] In other embodiments, in the compound, 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 2 ;R 2 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.

[0121] In some preferred embodiments, R 1Selected from deuterium, cyano, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, -S-CH3, -O-CF3 or -S-CF3.

[0122] In some implementation schemes, R 3 Hydrogen, deuterium, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl C 3-8 Cycloalkyl, carboxyl-substituted C 1-6 Alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl C 1-6 Alkoxy, C 1-9 Heterocyclic groups, -C(=O)R 4 -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkylene-COO-C 1-6 Alkyl, C 6-10 Aryl or C 1-9 heteroaryl; R 4 For amino, C 1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 cycloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Mixed aromatic compounds.

[0123] In some implementation schemes, R 3 Hydrogen, deuterium, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkyl C 3-6 Cycloalkyl, carboxyl-substituted C 1-4 Alkyl, C 3-6 Halogenated cycloalkyl, C 1-4 Alkyl C 1-4 Alkoxy, C 2-6 Heterocyclic groups, -C(=O)R 4 -S(=O)2-C 1-4 Alkyl, -C 1-4 Alkylene-COO-C 1-4 Alkyl, phenyl, or pyridyl; R 4 For amino, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -NH-C3-6 cycloalkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 2-6 Heterocyclic group, C 1-4 Alkyl-COO-C 1-4 Alkyl, phenyl, or pyridyl.

[0124] In some implementation schemes, R 3 For hydrogen, deuterium, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, CH2C H(CH3)2, CH2C(CH3)3, -CH2CF3, -CH2CH2CF3, -OCH3, -OCH2CH3, -CH2OCH3, -CH2CH2OCH3, -SO2-CH3, R 4 It is amino, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, CH2CH(CH3)2, CH2C(CH3)3, -OCH3, -OCH2CH3, -NHCH3, phenyl, pyridyl, pyrrolidinyl, piperidinyl, piperazine.

[0125] In some preferred embodiments, R 3 -C(=O)R 4 ;R 4 C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl, ethyl, propyl, and isopropyl.

[0126] In some embodiments, the compound has a structure as shown in formula (II), formula (III) or formula (IV), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof;

[0127]

[0128] Among them, R 1 The definition is the same as the definition for the foregoing in this invention.

[0129] In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug:

[0130]

[0131] Compositions, formulations and administration of the compounds of the present invention

[0132] 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.

[0133] The carrier can be solid or liquid, and the type of carrier is typically chosen based on the type of administration used. The active agent can be co-administered in tablet or capsule form, as a liposome, or in liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsules or tablets are easy to formulate and can be easily swallowed or chewed; other solid forms include granules and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable oils, alcohols, or other organic solvents (including esters), emulsions, syrups or elixirs, suspensions, solutions, and / or suspensions reconstituted from non-effervescent particles, as well as effervescent formulations reconstituted from effervescent particles. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorings and colorants. Parenteral and intravenous forms may also include minerals and other materials to make the form compatible with the type of injection or delivery system of choice.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] Uses of the compounds and compositions of the present invention

[0138] The pharmaceutical composition can be used to prevent, treat, cure, or alleviate retinol-binding protein 4-related diseases, including age-related macular degeneration, Stargardt's disease, or Best's disease.

[0139] 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 exact amount required will vary depending on the patient’s condition, which depends on age, the patient’s general condition, the severity of the infection, specific factors, the route of administration, etc. The compounds or compositions of the present invention can be administered in combination with one or more other therapeutic agents, as discussed in the present invention. Detailed Implementation

[0140] 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.

[0141] General Synthesis Process

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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).

[0148] The following abbreviations are used throughout this invention:

[0149] AcOH: Acetic acid; Boc2O, BOC anhydride: di-tert-butyl dicarbonate; Boc: tert-butyloxycarbonyl; Bu4NHSO4: tetrabutylammonium hydrogen sulfate; CH3CN: acetonitrile; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; HCl: hydrogen chloride; HCl / EA: ethyl acetate solution of hydrogen chloride; H2O: water; NaOH: sodium hydroxide; NaI: sodium iodide; K2CO3: potassium carbonate; rt, rt: room temperature; TBAF: tetrabutylammonium fluoride.

[0150] Example 1

[0151] Synthesis of 1-(3-(4-(2-(trifluoromethyl)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 1)

[0152]

[0153] Step 1: Synthesis of tert-butyl 4-(2-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylic acid (1b)

[0154] In a 100 mL round-bottom flask, compound 1a (5 g, 22.12 mmol), 1-Boc-4-bromopiperidine (7.01 g, 26.54 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (1.08 g, 2.22 mmol), sodium iodide (6.63 g, 44.23 mmol), potassium carbonate (5.50 g, 39.80 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxane) (10.11 g, 39.81 mmol) were added sequentially. Finally, dimethylacetamide (100 mL) was added. The air was purged with nitrogen three times, and the reaction was carried out at 70 °C for 5.5 h. After the reaction was detected by TLC, the solution was filtered through diatomaceous earth. The filtrate was quenched with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined. The mixture was then washed with water (2 × 100 mL), and finally washed with saturated brine (2 × 100 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, 3.9477 g. LCMS: 331.1 [M+1] + .

[0155] Step 2: Synthesis of 3-(piperidin-4-yl)-2-(trifluoromethyl)pyridine hydrochloride (1c)

[0156] In a 50 mL round-bottom flask, compound 1b (280 mg, 0.85 mmol) was dissolved in ethyl acetate (1 mL). Ethyl hydrochloride (4 mol / L) (10 mL) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction was monitored by LC-MS until complete. The reaction solution was then concentrated under reduced pressure to obtain compound 1c, yielding 200 mg of a yellow solid. LC-MS: 231.1 [M+1] + .

[0157] Step 3: Synthesis of 1-(3-(4-(2-(trifluoromethyl)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 1)

[0158] In a 25 mL round-bottom flask, compound 1c (195 mg, 0.73 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (458.9 mg, 2.19 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (0.89 mL, 4.39 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (395.1 mg, 1.1 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. After the reaction was detected by TLC, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (2 × 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, an off-white solid of 113 mg. LCMS: 422.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.5Hz,1H),7.81(d,J=7.7Hz,1H),7.48(dd,J=12.0,7.2Hz,1H),5.04–4.14(m,4H ),3.92–3.65(m,2H),3.33–2.67(m,5H),2.24–2.15(m,3H),2.00(s,1H),1.93–1.86(m,2H),1.80–1.70(m,2H)ppm; 19 F NMR (377MHz, CDCl3) δ-62.57(s)ppm.

[0159] Example 2

[0160] Synthesis of 1-(3-(4-(2-(methylthio)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 2)

[0161]

[0162] Step 1: Synthesis of tert-butyl 4-(2-(methylthio)pyridin-3-yl)piperidine-1-carboxylic acid (2b)

[0163] In a 100 mL round-bottom flask, compound 2a (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-dioxacyclopentaborane) (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 × 50 mL), and the organic phases were combined. The solutions were then washed with water (2 × 50 mL), and finally washed with saturated brine (2 × 50 mL). The solutions were 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 2b, a yellow oily substance, 3.5032 g. LCMS: 309.1 [M+1] + .

[0164] Step 2: Synthesis of 2-methylthio-3-(piperidin-4-yl)pyridine hydrochloride (2c)

[0165] In a 50 mL round-bottom flask, compound 2b (3.5032 g, 11.36 mmol) was dissolved in 1,4-dioxane (20 mL). 1,4-dioxane hydrochloride (4 mol / L, 25 mL) was added dropwise at 0 °C, 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 2c, a yellow solid, 2.4 g. LC-MS: 209.1 [M+1] + .

[0166] Step 3: Synthesis of 1-(3-(4-(2-(methylthio)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 2)

[0167] In a 25 mL round-bottom flask, compound 2c (300 mg, 1.23 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (769.2 mg, 3.68 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (1.3 mL, 7.38 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (662.3 mg, 1.8 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. After the reaction was detected by TLC, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (2 × 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 2, 135 mg of an off-white solid. LCMS: 400.1 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ12.09(s,1H),8.38–8.24(m,1H),7.37–7.30(m,1H),7.00–6.93(m,1H),4.84–4.60(m,3H),3.89–3.58(m,2H), 3.31–2.99(m,2H),2.98–2.61(m,3H),2.55(s,3H),2.44–2.21(m,1H),2.20–2.15(m,3H),2.02–1.89(m,2H),1.70–1.53(m,2H)ppm.

[0168] Example 3

[0169] Synthesis of 1-(3-(4-(2-methoxypyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 3)

[0170]

[0171] Step 1: Synthesis of tert-butyl 4-(2-methoxypyridin-3-yl)piperidine-1-carboxylic acid (3b)

[0172] In a 100 mL round-bottom flask, compound 3a (2 g, 10.64 mmol), 1-Boc-4-bromopiperidine (3.37 g, 12.77 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (0.52 g, 1.06 mmol), sodium iodide (3.19 g, 21.28 mmol), potassium carbonate (2.65 g, 19.15 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxane) (4.86 g, 19.15 mmol) were added sequentially. Finally, dimethylacetamide (30 mL) was added. The air was replaced 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 × 50 mL), and the organic phases were combined. The solutions were then washed with water (2 × 50 mL), and finally washed with saturated brine (2 × 50 mL). The solutions were 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 3b, a yellow oily substance, 2.8973 g. LCMS: 293.1 [M+1] + .

[0173] Step 2: Synthesis of 2-methoxy-3-(piperidin-4-yl)pyridine hydrochloride (3c)

[0174] In a 50 mL round-bottom flask, compound 3b (2.8973 g, 9.90 mmol) was dissolved in 1,4-dioxane (10 mL). 20 mL of 1,4-dioxane hydrochloride (4 mol / L) was added dropwise at 0 °C, 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 3c, a white solid, 2.4 g. LC-MS: 193.1 [M+1] + .

[0175] Step 3: Synthesis of 1-(3-(4-(2-methoxypyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 3)

[0176] In a 25 mL round-bottom flask, compound 3c (150 mg, 0.66 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (343 mg, 1.64 mmol) were dissolved in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (0.69 mL, 3.93 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (354.4 mg, 0.99 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. After the reaction was detected by TLC, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to give the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 3, an off-white solid (62 mg, yield: 25%). LCMS: 384.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ11.73(s,1H),8.02(td,1H),7.41–7.35(m,1H),6.86–6.81(m,1H),5.07–4.06(m,4H),3. 95(s,3H),3.85–3.62(m,2H),3.27–2.62(m,5H),2.22–2.14(m,3H),2.00–1.86(m,2H),1.71–1.56(m,2H)ppm.

[0177] Example 4

[0178] Synthesis of 1-(3-(4-(2-((trifluoromethyl)thio)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 4)

[0179]

[0180] Step 1: Synthesis of 3-bromo-2-((trifluoromethyl)thio)pyridine (4b)

[0181] In a 100 mL round-bottom flask, compound 4a (500 mg, 2.11 mmol), trifluoromethylthio(2,2-bipyridine)copper(I) (779.0 mg, 2.43 mmol), and finally 1,4-dioxane (21 mL) were added sequentially. The air was purged three times with nitrogen, and the reaction was carried out at 110 °C for 7 h. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, and the filtrate was quenched with water (50 mL). Extraction was performed with ethyl acetate (3 × 50 mL), and the organic phases were combined. The mixture was then washed with water (2 × 50 mL), and finally washed with saturated brine (2 × 50 mL). The mixture 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) to give compound 4b, a yellow oily substance, 439.4 mg. LCMS: 258.2 [M+1] + .

[0182] Step 2: Synthesis of tert-butyl 4-(2-((trifluoromethyl)thio)pyridin-3-yl)piperidine-1-carboxylic acid (4c)

[0183] In a 100 mL round-bottom flask, compound 4b (439.4 mg, 1.70 mmol), 1-Boc-4-bromopiperidine (539.7 mg, 2.04 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (82.9 mg, 0.17 mmol), sodium iodide (510.4 mg, 3.4 mmol), potassium carbonate (423.6 mg, 3.06 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxacyclopentaborane) (778.3 mg, 3.06 mmol) were added sequentially. Finally, dimethylacetamide (20 mL) was added. The air was replaced with nitrogen three times, and the reaction was carried out at 65 °C for 12 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 × 50 mL), and the organic phases were combined. The solutions were then washed with water (2 × 50 mL), and finally washed with saturated brine (2 × 50 mL). The solutions were 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 4c, a colorless oil, 450.7 mg. LCMS: 363.2 [M+1] + .

[0184] Step 3: Synthesis of 3-(piperidin-4-yl)-2-((trifluoromethyl)thio)pyridine hydrochloride (4d)

[0185] In a 50 mL round-bottom flask, compound 4c (450.7 mg, 1.24 mmol) was dissolved in 2 mL of 1,4-dioxane. 10 mL of 1,4-dioxane hydrochloride (4 mol / L) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction was confirmed by LC-MS. The reaction solution was then concentrated under reduced pressure to give compound 4d, a yellow solid, in a volume of 520 mg. LC-MS: 263.2 [M+1] + .

[0186] Step 4: Synthesis of 1-(3-(4-(2-((trifluoromethyl)thio)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 4)

[0187] In a 25 mL round-bottom flask, compound 4d (300 mg, 1.00 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (273 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (540.4 mg, 1.5 mmol) were added sequentially at 0 °C, and the mixture was stirred at 0 °C for 1.5 h. After TLC detection, the reaction was quenched with water (5 mL), extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined. The mixture was washed with saturated brine (2 × 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 4, 90 mg of an off-white solid. LCMS:454.1[M+1] + ; 1 H NMR (500MHz, CDCl3) δ11.62(s,1H),8.51(d,J=4.8Hz,1H),7.62(d,J=7.6Hz,1H),7.31(dd,J=7.9,4.6Hz,1H),4.99–4.60(m,4 H),3.90–3.62(m,2H),3.32(t,J=12.0Hz,1H),3.26–2.68(m,4H),2.23–2.16(m,3H),1.95–1.85(m,2H),1.76–1.64(m,2H)ppm.

[0188] Example 5

[0189] Synthesis of 1-(3-(4-(2-(trifluoromethoxy)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetoone

[0190]

[0191] Step 1: Synthesis of tert-butyl 4-(2-(trifluoromethoxy)pyridin-3-yl)piperidine-1-carboxylic acid (5b)

[0192] In a 100 mL round-bottom flask, compound 5a (2 g, 8.26 mmol), 1-Boc-4-bromopiperidine (2.62 g, 9.92 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (0.52 g, 1.06 mmol), sodium iodide (2.48 g, 16.53 mmol), potassium carbonate (2.06 g, 14.88 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxane) (3.7 g, 14.87 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 × 50 mL), and the organic phases were combined. The solutions were then washed with water (2 × 50 mL), and finally washed with saturated brine (2 × 50 mL). The solutions were 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 5b, a yellow oily substance, 2.5 g. LCMS: 347.3 [M+1] + .

[0193] Step 2: Synthesis of 3-(piperidin-4-yl)-2-(trifluoromethoxy)pyridine hydrochloride (5c)

[0194] In a 50 mL round-bottom flask, compound 5b (2.5 g, 7.22 mmol) was dissolved in 1,4-dioxane (10 mL). 20 mL of 1,4-dioxane hydrochloride (4 mol / L) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 3 h. The reaction was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure to obtain 5c, a white solid (2 g). The crude product was used directly in the next reaction without further purification. LC-MS: 247.3 [M+1] + .

[0195] Step 3: Synthesis of 1-(3-(4-(2-(trifluoromethoxy)pyridin-3-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 5)

[0196] In a 25 mL round-bottom flask, compound 5c (100 mg, 0.35 mmol), 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (88 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (137 mg, 1.06 mmol) and butyl phosphoric anhydride (50% ethyl acetate solution) (407 mg, 0.53 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. After the reaction was detected by TLC, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 5, 60 mg of an off-white solid. LCMS: 438.3 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ11.73(s,1H),8.02(td,1H),7.41–7.35(m,1H),6.86–6.81(m,1H),5.07–4.06(m, 4H),3.85–3.62(m,2H),3.27–2.62(m,5H),2.22–2.14(m,3H),2.00–1.86(m,2H),1.71–1.56(m,2H)ppm.

[0197] Examples 6-10

[0198] The synthesis of compounds 6-10 in Table 1 below is based on Example 1, where the corresponding carboxylic acid fragments are condensed with the corresponding ammonia fragments under the same condensation conditions.

[0199] Table 1

[0200]

[0201]

[0202] Example 11

[0203] Synthesis of 1-(3-(4-(3-(trifluoromethyl)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 11)

[0204]

[0205] Step 1: Synthesis of 4-(3-amino-6-chloropyridazine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (11b)

[0206] In a 500 mL round-bottom flask, compound 11a (10.0 g, 47.97 mmol) was dissolved in 1,4-dioxane (100 mL), followed by the addition of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (15.58 g, 50.37 mmol) and tetrakis(triphenylphosphine)palladium (5.54 g, 4.80 mmol). Finally, 2 M sodium carbonate aqueous solution (48 mL, 95.95 mmol) was added, air was purged, nitrogen was introduced, and the reaction was carried out at 100 °C for 10 h. The reaction was stopped by TLC, and the reaction was quenched with pure water. Ethyl acetate was added for extraction (3 × 150 mL), the organic phase was collected and concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 10:1) to obtain compound 11b, an off-white solid, 11.0 g. LCMS: 313.8 [M+1] + .

[0207] Step 2: Synthesis of 4-(3-aminopyridazine-4-yl)piperidine-1-carboxylic acid tert-butyl ester (11c)

[0208] In a 500 mL round-bottom flask, compound 11b (8.0 g, 25.74 mmol) was dissolved in methanol (160 mL), followed by the addition of palladium on carbon (4.0 g) and triethylamine (5.36 mL, 38.61 mmol). Air was purged, and hydrogen gas was introduced. The reaction was allowed to proceed at room temperature for 24 h. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, and the filtrate was collected, concentrated, and purified by column chromatography (DCM:MeoH = 10:1) to give compound 11c, a white solid (6.0 g). LCMS: 279.4 [M+1] + .

[0209] Step 3: Synthesis of 4-(3-ioridazine-4-yl)piperidine-1-carboxylic acid tert-butyl ester (11d)

[0210] In a 250 mL round-bottom flask, compound 11c (3.0 g, 10.78 mmol) was dissolved in a 30 mL / 30 mL mixture of dichloromethane and pure water. Sodium nitrite (3.72 g, 53.89 mmol) and diiodomethane (5.77 g, 21.56 mmol) were then added. The mixture was cooled to 0 °C, and acetic acid (12.34 mL, 215.55 mmol) was slowly added dropwise. The reaction was allowed to proceed for 12 h at room temperature. LC-MS analysis confirmed the reaction was complete. The reaction was quenched with pure water, extracted with dichloromethane (3 x 50 mL), and the organic phase was collected and concentrated. The organic phase was purified by column chromatography (PE:EA = 1:1) to give compound 11d, a 1.5 g yellow solid. LC-MS: 390.2 [M+1] + .

[0211] Step 4: Synthesis of tert-butyl 4-(3-(trifluoromethyl)pyridazine-4-yl)piperidine-1-carboxylic acid (11e)

[0212] In a 50 mL round-bottom flask, compound 11d (500 mg, 1.28 mmol) was dissolved in 10 mL of DMF, followed by the addition of trifluoromethyl(1,10-diazaphenanthroline)copper(I) (482 mg, 1.54 mmol). Air was purged, and nitrogen was introduced. The reaction was carried out at 100 °C for 4 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give compound 11e, a white solid, 250 mg. LC-MS: 332.3 [M+1] + .

[0213] Step 5: Synthesis of 4-(piperidin-4-yl)-3-(trifluoromethyl)pyridazine (11f)

[0214] In a 50 mL round-bottom flask, compound 11e (250 mg, 0.75 mmol) was dissolved in ethyl acetate (1 mL), followed by the addition of 3 mL (12 mmol) of 4 M ethyl acetate hydrochloride solution. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped by LC-MS. The organic phase was concentrated to give compound 11f, 170 mg of an off-white solid. LC-MS: 232.2 [M+1] + .

[0215] Step 6: Synthesis of 1-(3-(4-(3-(trifluoromethyl)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 11)

[0216] In a 50 mL round-bottom flask, compound 11f (170 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (0.61 mL, 4.41 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (230 mg, 1.1 mmol). The mixture was cooled to 0 °C, and T4P (50% ethyl acetate solution) (794 mg, 1.1 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was confirmed by LC-MS. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 10 mL), and the concentrated organic phase was collected to obtain the crude product. The crude product was separated by a C18 reverse-phase column (acetonitrile / water: 0-100%) to obtain compound 11, 45 mg of an off-white solid. LC-MS: 423.4 [M+1] + . 1 H NMR (400MHz, DMSO) δ12.81(s,1H),8.24(s,1H),7.79–7.42(m,1H),7.54–7.47(m,1H),4.69(d,1H),4.40(d,1H ),4.24(d,2H),3.15(s,2H),2.84–2.78(m,1H),2.02(s,3H),1.85(s,3H),1.78–1.67(m,3H),1.25(s,1H)ppm.

[0217] Example 12

[0218] Synthesis of 1-(3-(4-(3-(methylthio)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 12)

[0219]

[0220] Step 1: Synthesis of tert-butyl 4-(3-(methylthio)pyridazine-4-yl)piperidine-1-carboxylic acid (12a)

[0221] In a 30 mL microwave-safe reaction tube, compound 11d (500 mg, 1.28 mmol) was dissolved in 10 mL of DMSO. Then, cuprous iodide (294 mg, 1.54 mmol), triethylenediamine (294 mg, 1.54 mmol), and 1,10-phenanthroline (231 mg, 1.28 mmol) were added. Air was purged, and nitrogen was introduced. The reaction was carried out in a microwave reactor at 170 °C for 2 h. The reaction was monitored by LC-MS until completion. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give compound 12a, 80 mg of a white solid. LC-MS: 310.4 [M+1] + .

[0222] Step 2: Synthesis of 3-methylthio-4-(piperidin-4-yl)pyridazine (12b)

[0223] In a 50 mL round-bottom flask, compound 12a (80 mg, 0.25 mmol) was dissolved in ethyl acetate (1 mL), followed by the addition of 3 mL (12 mmol) of 4 M ethyl acetate hydrochloride solution. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped by LC-MS. The organic phase was concentrated to give compound 12b, 50 mg of an off-white solid. LC-MS: 210.3 [M+1] + .

[0224] Step 3: Synthesis of 1-(3-(4-(3-(methylthio)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 12)

[0225] In a 50 mL round-bottom flask, compound 12b (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (0.20 mL, 1.43 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (75 mg, 0.35 mmol). The mixture was cooled to 0 °C, and T4P (50% ethyl acetate solution) (258 mg, 0.36 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was confirmed by LC-MS. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 10 mL), and the concentrated organic phase was collected to obtain the crude product. The crude product was separated by a C18 reverse-phase column (acetonitrile / water: 0-100%) to give compound 12, 6 mg of an off-white solid. LC-MS: 401.5 [M+1] + ; 1H NMR(400MHz,DMSO)δ12.92(s,1H),8.93(d,1H),7.48(d,1H),4.61(s,2H),3.68–3.63(m,2H),3.3 7(s,4H),3.26–2.92(m,2H),2.84–2.80(m,1H),2.68(s,3H),2.11(d,3H),1.90–1.55(m,4H)ppm.

[0226] Example 13

[0227] Synthesis of 1-(3-(4-(3-((trifluoromethyl)thio)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetoone (compound 13)

[0228]

[0229] Step 1: Synthesis of tert-butyl 4-(3-((trifluoromethyl)thio)pyridazine-4-yl)piperidine-1-carboxylic acid (13a)

[0230] In a 50 mL round-bottom flask, compound 11d (400 mg, 1.03 mmol) was dissolved in DMF (10 mL), followed by the addition of (2,2'-dipyridine)trifluoromethylthiocopper (396 mg, 1.23 mmol). Air was purged, and nitrogen was introduced. The reaction was carried out at 100 °C for 4 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give compound 13a, a white solid (320 mg). LC-MS: 364.4 [M+1] + .

[0231] Step 2: Synthesis of 4-(piperidin-4-yl)-3-((trifluoromethyl)thio)pyridazine (13b)

[0232] In a 25 mL round-bottom flask, compound 13a (300 mg, 0.83 mmol) was dissolved in ethyl acetate (1 mL), followed by the addition of 4 M ethyl acetate hydrochloride solution (3 mL, 12 mmol). The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped by LC-MS. The organic phase was concentrated to give compound 13b, 200 mg of an off-white solid. LC-MS: 264.3 [M+1] + .

[0233] Step 3: Synthesis of 1-(3-(4-(3-((trifluoromethyl)thio)pyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetoone (compound 13)

[0234] In a 50 mL round-bottom flask, compound 13b (200 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (0.64 mL, 4.56 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (238 mg, 1.14 mmol). The mixture was cooled to 0 °C, and T4P (50% ethyl acetate solution) (547 mg, 0.76 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped by LC-MS. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 10 mL), and the concentrated organic phase was collected to obtain the crude product. The crude product was separated by a C18 reverse-phase column (acetonitrile / water: 0-100%) to give compound 13, 70 mg of an off-white solid. LC-MS: 455.5 [M+1] + ; 1 H NMR (400MHz, DMSO) δ12.95(s,1H),9.25(d,1H),7.86(d,1H),4.87–4.60(m,3H),3.70–3.63(m,2H),3.37–3.33(m,2 H),3.23–3.17(m,2H),2.92–2.83(m,1H),2.70–2.57(m,1H),2.12–2.10(m,3H),1.85(s,2H),1.69–1.61(m,2H)ppm.

[0235] Example 14

[0236] Synthesis of 1-(3-(4-(3-methoxypyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)aceto-1-one (compound 14)

[0237]

[0238] Step 1: Synthesis of tert-butyl 4-(3-(methoxypyridazine-4-yl)piperidine-1-carboxylic acid (14a)

[0239] In a 50 mL round-bottom flask, compound 11d (100 mg, 0.26 mmol) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and methanol (1 mL). Then, BINAP (32 mg, 51.38 μmol), tris(dibenzylacetone)dipalladium (23 mg, 25 μmol), and cesium carbonate (251 mg, 0.78 mmol) were added. Air was purged, and nitrogen was introduced. The reaction was carried out at 100 °C for 4 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give compound 14a, 70 mg of an off-white solid. LC-MS: 294.4 [M+1] + .

[0240] Step 2: Synthesis of 3-methoxy-4-(piperidin-4-yl)pyridazine (14b)

[0241] In a 25 mL round-bottom flask, compound 14a (80 mg, 0.28 mmol) was dissolved in ethyl acetate (1 mL), followed by the addition of 3 mL (12 mmol) of 4 M ethyl acetate hydrochloride solution. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped by LC-MS. The organic phase was concentrated to give compound 14b, 50 mg of an off-white solid. LC-MS: 194.3 [M+1] + .

[0242] Step 3: Synthesis of 1-(3-(4-(3-methoxypyridazin-4-yl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acet-1-one (compound 14)

[0243] In a 50 mL round-bottom flask, compound 14b (50 mg, 258 μmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (0.21 mL, 1.55 mmol) and 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (81 mg, 388 μmol). The mixture was cooled to 0 °C, and T4P (50% ethyl acetate solution) (279 mg, 388 μmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was confirmed by LC-MS. The reaction was quenched with pure water, extracted with ethyl acetate (3 × 10 mL), and the concentrated organic phase was collected to obtain the crude product. The crude product was separated by a C18 reverse-phase column (acetonitrile / water: 0–100%) to give compound 14, 6 mg of an off-white solid. LC-MS: 385.4 [M+1] + ; 1H NMR (500MHz, DMSO) δ12.85(s,1H),8.80(d,1H),7.48(d,1H),4.62(d,2H),4.07(s,3H),3.70–3.60(m,2H),3.33–3.30( m,2H),3.23–3.02(m,2H),2.91–2.73(m,1H),2.61–2.55(m,2H),2.10(d,3H),1.91–1.76(m,2H),1.58–1.50(m,2H)ppm.

[0244] Example 15

[0245] The synthesis of compound 15 in Table 2 below involved condensing 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid with the corresponding ammonia fragment, and the condensation conditions were obtained according to Example 14.

[0246] Table 2

[0247]

[0248] Bioactivity test

[0249] The inhibitory effect of the compounds of this invention on the formation of the RBP4-TTR complex was tested using the HTRF method.

[0250] The test compound was prepared into a 10 mM stock solution using DMSO, and then further diluted to different test concentrations (1 μM starter, 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×PAb Anti-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 was measured using a Varioskan LUX microplate reader (Thermo Fisher), and the 665 / 615 ratio was calculated. The wells without compound (0 nM) were taken as 100%. After background subtraction, data processing and curve fitting (non-linear fitting, 4 parameters) were performed using Graphpad Prism 8.0 software, and IC analysis was conducted. 50 The calculations were performed. The results are shown in Table 3. A represents 100–500 nm, and B represents greater than 500 nm.

[0251] Table 3

[0252] <![CDATA[HTRF IC 50 ]]> Compound 1 B Compound 2 A Compound 3 B Compound 4 A Compound 11 B Compound 12 B Compound 13 B Compound 14 B

[0253] The experimental results show that the compound of the present invention has a strong inhibitory effect on the formation of RBP4-TTR complex.

[0254] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments are intended to be illustrative and non-limiting in all respects, and reference should be made to the appended claims rather than to the foregoing embodiments; thus, all variations within the meaning and scope of the equivalents of the appended claims are included herein.

Claims

1. A compound having a structure according to Formula (0), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure according to Formula (0); wherein A is a heteroaromatic ring; R 1 selected from deuterium, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, or -SR 2 ; R 2 is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl; R 3 is hydrogen, deuterium, CN, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, carboxyl-substituted alkyl, halocycloalkyl, alkoxyalkyl, heterocyclyl, -C(=O)R 4 , -S(=O)2-alkyl, -alkylene-COO-alkyl, aryl or heteroaryl; R 4 is amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

2. The compound of claim 1, wherein, Ring A is a 5-6 membered heteroaromatic ring containing a nitrogen atom; Preferably, Ring A is a 5-6 membered heteroaromatic ring containing 1-2 nitrogen atoms; More preferably, ring A is Further preferably, ring A is * indicates the position of attachment to the piperidine ring, indicates the position of attachment to R 1 indicates the position of attachment to R 3. The compound of claim 1, wherein, R 1 selected from deuterium, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -SR 2 ; R 2 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; Preferably, 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 2 ;R 2 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; More preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, -S-CH3, -0-CF3, or -S-CF3. 1 More preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, -S-CH3, -0-CF3, or -S-CF3.

4. The compound of claim 1, wherein, R 3 is hydrogen, deuterium, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 3-8 cycloalkyl, carboxyl-substituted C 1-6 alkyl, C 3-8 halocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-9 heterocyclyl, -C(=O)R 4 , -S(=O)2-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, C 6-10 aryl or C 1-9 heteroaryl; R 4 is amino, C 1-6 alkyl, -NH-C 1-6 alkyl, -NH-C 3-8 cycloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; Preferably, R 3 is hydrogen, deuterium, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, CH2CH(CH3)2, CH2C(CH3)3, -CH2CF3, -CH2CH2CF3, -OCH3, -OCH2CH3, -CH2OCH3, -CH2CH2OCH3, -SO2-CH3, Preferably, R 4 is amino, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, CH2CH(CH3)2, CH2C(CH3)3, -OCH3, -OCH2CH3, -NHCH3, phenyl, pyridyl, pyrrolidinyl, piperidinyl, or piperazinyl.

5. The compound of claim 1 or 4, wherein, the compound has 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 the definitions of ring A, R 1 and R 4 are the same as in claim 1.

6. The compound of claim 5, wherein, R 4 is C 1-6 alkyl; Preferably, R 4 is C 1-3 alkyl; Preferably, R 4 is methyl.

7. The compound according to any one of claims 1-6, wherein, the compound has a structure according to Formula (II), Formula (III), or Formula (IV), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof; wherein R 1 is as defined in any one of claims 1 or 3.

8. The compound of claim 1, wherein, the compound is selected from the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

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

10. Use of a compound according to any one of claims 1-8, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of 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 flavimaculosis (Stargardt disease), vitelliform macular degeneration (Best disease), or a macular dystrophy similar to Stargardt disease.

Images