Compound and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to a compound, stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, and use thereof in preparing drugs for treating ophthalmic diseases. Background Art

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

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

[0004] Reducing the rate of formation of cytotoxic retinoid dimers (the main component of lipofuscin) in the retinal pigment epithelium (RPE) by select RBP4 antagonists will prevent further geographic atrophy in patients with atrophic (dry) age-related macular degeneration (AMD).

[0005] In addition to AMD, significant accumulation of lipofuscin is also a characteristic of fundus macular degeneration (STARGARDT) and Best disease. Stargardt disease is a hereditary form of juvenile-onset macular degeneration, while Best disease is caused by autosomal dominant inheritance of the vitelliform macular dystrophy gene.

[0006] WO2015168286 discloses a class of substituted 4-phenylpiperidine compounds, such as Compound A, WO2014152018 discloses a class of substituted cyclopenta-tetrahydropyrrole compounds, such as Compound B, and WO2014151936 discloses a class of substituted octahydropyrrolo-pyrrole compounds, such as Compound C. As RBP4 antagonists, these compounds have significant pharmacological effects, but their inhibitory efficacy, membrane permeability, pharmacokinetics, drugability, and safety still need to be improved.

[0007] Summary of the Invention

[0008] In view of the deficiencies of the prior art, the present invention provides, on one hand, a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I);

[0009]

[0010] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ;

[0011] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0012] Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0013] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0014] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0015] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0016] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0017] R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0018] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0019] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0020] The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely a carbon position containing a group connecting bond;

[0021] A is -NR 14 -, -SO2- or bond;

[0022] R 14 is selected from hydrogen, deuterium or alkyl;

[0023] B is selected from

[0024] Y1, Y2, and Y3 are each independently selected from CR 19 NR 20 or heteroatoms;

[0025] R 19 、R 20 Each is independently selected from H, deuterium, alkyl, and hydroxy-substituted alkyl;

[0026] F is selected from a bond or -CO-.

[0027] In some embodiments, in the compound of formula (I), L is selected from C containing 0 to 2 nitrogen atoms. 6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups;

[0028] C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0029] In some embodiments, R 14 The alkyl group is C 1-6 alkyl.

[0030] In some embodiments, Y1, Y2, and Y3 are each independently selected from CR 19 、O、N、NR 20 or S;

[0031] R 19 、R 20 Selected from H, deuterium, C 1-6alkyl, hydroxy-substituted C 1-6 alkyl.

[0032] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0033]

[0034] wherein X 1 , X 2 each independently is CR 15 or N;

[0035] R 15 , R 16 , R 17 , R 18 each independently is selected from hydrogen, deuterium, alkyl, hydroxy, amino, alkoxy, or haloalkyl;

[0036] m, n are integers from 0 to 5.

[0037] In some embodiments, B is selected from

[0038] In some embodiments, B is

[0039] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0040]

[0041] In some embodiments, when L is B is not

[0042] In some embodiments, when L is A is a bond, B is

[0043] In some embodiments, in the compound of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 alkyl, cycloalkyl, heterocyclyl, alkoxy, and haloalkyl are C 1-6 alkyl, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 1-6 alkoxy, and C 1-6 haloalkyl.

[0044] In some embodiments, R 6 is selected from hydrogen, deuterium, hydroxy, amino, C 1-6Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0045] In some embodiments, R 7 、R 8 、R 9 Selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0046] In some embodiments, R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0047] In some embodiments, R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0048] In some embodiments, R 12 and R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or R 12 、R 13 and the P atoms connected to it to form phosphorus-containing C 1-9 Heterocycle.

[0049] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0050] In some embodiments, in the compound of formula (I), R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl;

[0051] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane;

[0052] Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group;

[0053] R6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl;

[0054] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0055] R 10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0056] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0057] R 12 and R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0058] In some embodiments, B is

[0059] In some embodiments, R 1 Selected from fluorine, chlorine, CF3, cyano, SCH3, methoxy.

[0060] In some embodiments, R 2 、R 3 、R 4 、R 5 Each is independently selected from fluorine, chlorine, and CF3.

[0061] In some embodiments, the compound has a structure as shown in formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II);

[0062]

[0063] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ;

[0064] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0065] Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0066] R 6is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0067] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0068] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0069] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0070] R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0071] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0072] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0073] The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely the carbon position containing the group connecting bond;

[0074] A is -NR 14 - or key;

[0075] R 14 is selected from hydrogen, deuterium or alkyl.

[0076] In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0077]

[0078]

[0079] In another aspect, the present invention also provides a pharmaceutical composition comprising (a) the above-mentioned compound or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, and (b) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0080] In another aspect, the present invention provides a use of the compound of the present invention or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters or pharmaceutical compositions in the preparation of a medicament for preventing, treating, curing or alleviating retinol binding protein 4-related diseases.

[0081] In some embodiments, the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease, or Best disease.

[0082] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0083] Detailed description of the present invention

[0084] Definitions and General Terms

[0085] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0086] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0087] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0088] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0089] Unless otherwise indicated, the following definitions shall apply as used herein. For purposes of the present invention, the chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may 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.

[0090] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0091] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0092] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0093] The term "comprising" is used in the inclusive sense, i.e., that it means "including, but not limited to".

[0094] "stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0095] "diastereomers" refer to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, e.g., HPLC.

[0096] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0097] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, in which (-) or 1 indicates that the compound is levorotatory. A compound, which is dextrorotatory is designated (+) or d. A particular stereoisomer is the enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate. A racemic mixture of a stereocenter that is not a chiral center (i.e., a center that does not produce optical activity) can be produced by means of atomic replacement techniques known to those skilled in the art.

[0098] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present application can exist in the form of a racemic or enantiomeric enrichment, e.g., in the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom has at least a 50% enantiomeric excess in the (R)- or (S)- configuration, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least an 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0099] Depending on the choice of starting materials and methods, the compounds of the present application can be present in the form of one or more of possible isomers, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms), in the form of geometric isomers, in the form of tautomers, or as mixtures of isomers. The optically active forms of (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 can be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can be in the cis- or trans-configuration.

[0100] Any mixture of stereoisomers of the compounds can be separated into their individual stereoisomers using standard techniques, such as preparative chromatography.

[0101] Unless otherwise stated, the formulae described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational isomers): e.g., for asymmetric centers, the (R)- or (S)-configurational forms; for double bonds, the (Z) or (E) geometric isomers; and for (Z) or (E) conformational isomers. Thus, individual stereochemical isomers and mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers), where possible, are within the scope of the present application.

[0102] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0103] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0104] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0105] The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, 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, pamoates, salicylates, galactarates, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or such salts may be 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, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0106] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0107] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0108] 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, and the like.

[0109] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0110] The term "protecting group" or "PG" refers to a substituent that blocks or protects a specific functionality when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl-protecting group" refers to a substituent attached to a carboxyl group that blocks or protects the carboxyl functionality. Typical carboxyl-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0111] A "pharmaceutical composition" refers to a mixture of one or more salts of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0112] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0113] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 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.

[0114] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or may be used in the context of radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the previously used unlabeled reagent with an appropriate isotopically labeled reagent as described in the examples and preparations herein.

[0115] In addition, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0116] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, such as the compounds of the general formula above, or as specifically exemplified in the Examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position. The substituents can be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, thiol, 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, carboxylalkoxy and the like.

[0117] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl radicals 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, -CH(CH3)CH2CH3), ... -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, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0118] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, connected to the main carbon chain via an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc., and the alkoxy group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0119] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, 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), and the like.

[0120] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 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 with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH2C≡CH), and the like.

[0121] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocycles having 7-12 atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocycles having 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way 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, and the like. And the "cyclic aliphatic group" or "carbocycle", "carbocyclic group", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, 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 and the like.

[0122] The terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring(s) are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings herein, the ring(s) may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to another molecule. One or more hydrogen atoms in the ring(s) are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" 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 give groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), 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 give groups such as SO, SO2, PO, PO2).

[0123] Heterocyclic groups can be carbon groups or heteroatom groups. "Heterocyclic group" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethan-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]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. The heterocyclic group may be substituted or unsubstituted, and the substituents may be, but are not limited to, oxo (=O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, 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, and the like.

[0124] The term "aryl" can be used alone or as part of "aralkyl," "aralkoxy," or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," and aromatic rings can include, for example, phenyl, naphthyl, and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, 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, and the like.

[0125] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, at least one of which is aromatic and at least one of which contains one or more heteroatoms, wherein the heteroatoms have the meanings herein, and each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" is used interchangeably with the terms "heteroaromatic" or "heteroaromatic compound." Furthermore, the heteroaryl group may be substituted or unsubstituted, wherein the substituents may include, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, 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, and the like.

[0126] In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, 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, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 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 dioxadiazolyl ring, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0127] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).

[0128] The term "halogen" refers to F, Cl, Br or I.

[0129] The term "halogenated" used in the present invention means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

[0130] The term "hydroxy substituted" used in the present invention means that the group following it is substituted with a hydroxy group, and the number of substitutions may be one or more.

[0131] When "substituted" in the present invention is used between two groups, it is preceded by a substituent, such as "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means that the alkyl group has an alkoxycarbonyl substituent.

[0132] When multiple groups of the present invention are used in combination, they are in a substitution relationship from left to right, such as "arylalkyl" represents an alkyl substituted by an aryl group, and "alkoxyalkoxy" represents an alkoxy substituted by an alkoxy group.

[0133] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0134] Description of the compounds of the present invention

[0135] In one aspect, the present invention provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I);

[0136]

[0137] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8or -P(O)R 12 R 13 ;

[0138] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0139] Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0140] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0141] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0142] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0143] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0144] R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0145] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0146] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0147] The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely a carbon position containing a group connecting bond;

[0148] A is -NR 14 -, -SO2- or bond;

[0149] R 14 is selected from hydrogen, deuterium or alkyl;

[0150] B is selected from

[0151] Y1, Y2, and Y3 are each independently selected from CR 19 NR 20 or heteroatoms;

[0152] R 19 、R 20 Each is independently selected from H, deuterium, alkyl, and hydroxy-substituted alkyl;

[0153] F is selected from a bond or -CO-.

[0154] In some embodiments, in the compound of formula (I), L is selected from C containing 0 to 2 nitrogen atoms. 6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups;

[0155] C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted by a substituent in the haloalkyl group.

[0156] In some embodiments, R 14 The alkyl group is C 1-6 alkyl.

[0157] In some embodiments, Y1, Y2, and Y3 are each independently selected from CR 19 、O、N、NR 20 or S;

[0158] R 19 、R 20 Selected from H, deuterium, C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl.

[0159] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0160]

[0161] Among them, X 1 、X 2 Each independently CR 15 or N;

[0162] R 15 、R 16 、R 17 、R 18 are each independently selected from hydrogen, deuterium, alkyl, hydroxy, amino, alkoxy or haloalkyl;

[0163] m and n are integers of 0 to 5.

[0164] In some embodiments, B is selected from

[0165] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0166]

[0167] In some embodiments, when L is B is not

[0168] In some embodiments, when L is When A is a key, B is not

[0169] In some embodiments, in the compound of formula (I), R 1 、R 2 、R 3 、R 4 、R 5alkyl, cycloalkyl, heterocyclyl, alkoxy and haloalkyl in the group R 1-6 alkyl, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 1-6 alkoxy and C 1-6 haloalkyl;

[0170] R 6 is selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;

[0171] R 7 , R 8 , R 9 is selected from the group consisting of hydrogen, deuterium, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;

[0172] R 10 is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkenyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;

[0173] R 11 is selected from the group consisting of hydrogen, deuterium, amino, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;

[0174] R 12 and R 13 is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl, or R 12 , R 13 and the P atom to which they are attached form a phosphorus containing C1-9 heterocyclic ring;

[0175] R 1 ~R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0176] In some embodiments, in the compound of formula (I), R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl;

[0177] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane;

[0178] Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group;

[0179] R 6is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl;

[0180] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0181] R 10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0182] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0183] R 12 and R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0184] In some embodiments, B is

[0185] In some embodiments, the compound has a structure as shown in Formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in Formula (I);

[0186]

[0187] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or -P(O)R 12 R 13 ;

[0188] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0189] Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0190] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0191] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0192] R 10is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0193] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0194] R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0195] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0196] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0197] The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely the carbon position containing the group connecting bond;

[0198] A is -NR 14 - or key;

[0199] R 14 is selected from hydrogen, deuterium or alkyl.

[0200] In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0201]

[0202]

[0203] Compositions, formulations and administration of the compounds of the present invention

[0204] The pharmaceutical composition comprises one or more compounds of the present invention or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters of the compounds. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0205] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, 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 cellulose, ethylcellulose 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; glycol compounds 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 saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0206] When used for treatment, a therapeutically effective amount of a compound of the present invention can be administered as a raw chemical or as an active ingredient in a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a significant patient benefit (e.g., a reduction in viral load). When a separate active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that causes a therapeutic effect, whether in combination, sequentially, or simultaneously. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless 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. The term "pharmaceutically acceptable" as used in the present invention refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment, and are effectively used for the intended purpose.

[0207] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0208] Uses of the compounds and compositions of the present invention

[0209] The pharmaceutical composition can be used to prevent, treat, cure or alleviate diseases related to retinol binding protein 4. The diseases related to retinol binding protein 4 are age-related macular degeneration, Stargardt disease or Best disease.

[0210] An "effective amount" or "effective dose" of a compound of the present invention, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester, or pharmaceutically acceptable composition thereof, is an amount effective to treat or lessen the severity of one or more of the conditions described herein. According to the methods of the present invention, the compounds and compositions thereof may be administered in any amount and by any route of administration effective to treat or lessen the severity of the condition. The exact amount required will vary depending on the patient's condition, including race, age, general condition of the patient, severity of the infection, special factors, mode of administration, and the like. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein. DETAILED DESCRIPTION

[0211] In order 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 further illustrate the present invention in detail.

[0212] General synthesis process

[0213] 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 present invention.

[0214] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0215] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. 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 Ocean Chemical Plant.

[0216] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0217] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0218] Silica gel columns were used for chromatography. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectra were performed using CDC13, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0219] The following abbreviations are used throughout this disclosure:

[0220] AcOH: acetic acid

[0221] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0222] Boc: tert-butyloxycarbonyl

[0223] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0224] CH3CN: acetonitrile

[0225] DCM: dichloromethane

[0226] DIPEA: N,N-diisopropylethylamine

[0227] EA: ethyl acetate

[0228] HCl: hydrogen chloride

[0229] HCl / EA: Hydrogen chloride in ethyl acetate

[0230] H2O: water

[0231] NaOH: sodium hydroxide

[0232] NaI: sodium iodide

[0233] K2CO3: Potassium carbonate

[0234] rt, rt: room temperature

[0235] TABF: Tetrabutylammonium fluoride

[0236] Example

[0237] Example 1

[0238] 1-(3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 1)

[0239]

[0240] Step 1: tert-Butyl 6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1b)

[0241] Under nitrogen, 1a (2.00 g, 7.66 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in a 100 mL three-necked flask. The mixture was cooled to -78°C in a dry ice bath, and n-butyl lithium (3.68 mL, 9.20 mmol, 2.5 M / tetrahydrofuran) was slowly added dropwise. The reaction was allowed to proceed at -78°C for 30 min. After 30 min, a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2.43 g, 11.50 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was allowed to proceed at -78°C for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 1b as a white solid (1.2 g, 39% yield). LC-MS: 394.1 [M+H] + .

[0242] Step 2: 6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-ol (1c)

[0243] In a 50 mL round-bottom flask, 1b (500 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 h. The reaction was monitored for completion by TLC. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 1c as a colorless oily solid (153 mg, 40% yield). LC-MS: 294.1 [M+H] + .

[0244] Step 3: tert-Butyl 3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (1d)

[0245] To a 50 mL round-bottom flask, 1c (153 mg, 0.53 mmol), 6-(1,1-dimethylethyl) 6H-pyrazolo[3,4-c]1,4,5,7-tetrahydropyridine-3,6-carboxylate (142 mg, 0.53 mmol), triethylamine (107 mg, 1.06 mmol), 1-hydroxybenzotriazole (15 mg, 0.11 mmol), and dichloromethane (5 mL) were added sequentially. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.63 mmol) was added with stirring and allowed to react at room temperature for 6 h. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 1d as a white solid (150 mg, 46% yield). LC-MS: 543.2 [M+H] + .

[0246] Step 4: (6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone (1e)

[0247] In a 50 mL round-bottom flask, 1d (150 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 h. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 1e as a white solid (106 mg, 86% yield). LC-MS: 443.2 [M+H] + .

[0248] Step 5: 1-(3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 1)

[0249] In a 50 mL round-bottom flask, 1e (106 mg, 0.24 mmol) and triethylamine (37 mg, 0.36 mmol) were dissolved in anhydrous dichloromethane (5 mL). The mixture was cooled to 0°C in an ice bath, and acetyl chloride (21 mg, 0.26 mmol) was slowly added dropwise. The mixture was allowed to react at 0°C for 2 h. The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 1 as a white solid (72.9 mg, 62% yield). LC-MS: 485.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ:12.98(d,J=22.4Hz,1H),7.68–7.56(m,1H),7.52–7.38(m,1H),6.05(d,J=11.0Hz,1H),4.66–4.48(m,3H),4.38(s,1H), 4.20–4.09(m,1H),3.93(s,1H),3.69–3.53(m,2H),3.21–3.15(m,1H),2 .93–2.82(m,2H),2.76(s,1H),2.61–2.55(m,2H),2.15–2.07(m,3H)ppm.

[0250] Example 2

[0251] 1-(3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 2)

[0252]

[0253] Step 1: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (2b)

[0254] Under nitrogen, 2a (5.30 g, 25.09 mol) was dissolved in anhydrous tetrahydrofuran (60 mL) in a 500 mL round-bottom flask. The mixture was cooled to -78°C in a dry ice bath and slowly added dropwise with sodium bis(trimethylsilyl)amide (51 mL, 50.18 mmol, 1 M solution in tetrahydrofuran). After the addition was complete, the mixture was slowly warmed to room temperature and allowed to react for 1 hour. After 1 hour, the mixture was cooled to -78°C and a solution of N-phenylbis(trifluoromethanesulfonyl)imide (17.92 g, 50.18 mmol) in tetrahydrofuran was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 2b as a white solid (1.2 g, 13% yield). LC-MS: 344.1 [M+H] + .

[0255] Step 2: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (2c)

[0256] Under nitrogen, a 100 mL round-bottom flask was charged with 2b (1.20 g, 3.50 mmol), pinacol diboron (1.33 g, 5.24 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (64 mg, 0.087 mmol), potassium acetate (1.03 g, 10.49 mmol), and 1,4-dioxane (20 mL). The mixture was heated to 90°C for 4 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 2c as a white solid (270 mg, 24% yield). 1 H NMR (400MHz, CDCl3) δ6.89(s,1H),4.09(s,4H),2.78(s,2H),1.47(s,9H),1.30(s,12H)ppm.

[0257] Step 3: tert-Butyl 6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (2d)

[0258] Under nitrogen, a 100 mL three-necked flask was charged with 2c (270 mg, 0.84 mmol), 2,3-difluoro-6-bromobenzotrifluoride (330 mg, 1.26 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (62 mg, 0.084 mmol), sodium carbonate (268 mg, 2.52 mmol), and 1,4-dioxane / water (20 mL / 5 mL). The mixture was heated to 90°C and reacted for 8 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 2d as a white solid (270 mg, 85% yield). LC-MS: 376.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.38-7.29(m,1H),7.17-7.11(m,1H),6.45(s,1H),4.14(s,4H),3.04(s,2H),1.48(s,9H)ppm.

[0259] Step 4: tert-Butyl 6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (2e)

[0260] In a 100 mL round-bottom flask, 2d (270 mg, 0.72 mmol) and palladium on carbon (135 mg) were dissolved in ethanol (5 mL). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 24 h. After the reaction, 2e was filtered under reduced pressure to obtain a colorless oily solid (218 mg, 80% yield). LC-MS: 378.1 [M+H]+ .

[0261] Fifth step: 6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane (2f)

[0262] In a 50 mL round-bottom flask, 2e (218 mg, 0.58 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise slowly under ice bath, and the reaction was allowed to proceed at room temperature for 2 h after the addition was completed. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give 2f as a white solid (100.8 mg, yield 63%). LC-MS: 278.1 [M+H] + .

[0263] Sixth step: 3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-2- ylcarbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (2g)

[0264] In a 50 mL round-bottom flask, 2f (95 mg, 0.34 mmol), 6H-pyrazolo[3,4-C]1,4,5,7- tetrahydropyridine-3,6-carboxylic acid 6-(1,1-dimethylethyl) ester (92 mg, 0.34 mmol), triethylamine (70 mg, 0.69 mmol), 1-hydroxybenzotriazole (10 mg, 0.074 mmol), and dichloromethane (5 mL) were added in sequence, and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol) was added with stirring. The reaction was allowed to proceed at room temperature for 6 h. The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give 2g as a white solid (100 mg, yield 55%). LC-MS: 527.2 [M+H] + .

[0265] Seventh step: (6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-2- yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone (2h)

[0266] In a 50 mL round-bottom flask, 2g (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise slowly under ice bath, and the reaction was allowed to proceed at room temperature for 2 h after the addition was completed. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to give 2h as a white solid (76 mg, yield 93%). LC-MS: 427.2 [M+H]+ .

[0267] Step 8: 1-(3-(6-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 2)

[0268] In a 50 mL round-bottom flask, 2h (76 mg, 0.18 mmol) and triethylamine (27 mg, 0.27 mmol) were dissolved in anhydrous dichloromethane (5 mL). The mixture was cooled to 0°C in an ice bath, and acetyl chloride (16 mg, 0.20 mmol) was slowly added dropwise. The mixture was allowed to react at 0°C for 2 h. The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 2 as a white solid (63 mg, 75% yield). LC-MS: 469.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.82–7.73(m,1H),7.45(s,1H),4.58(s,3H),4.35(s,1H),4.14(s,1H),3.92(s,1H) ,3.64(s,2H),3.60(s,2H),2.75(s,1H),2.63(s,1H),2.61–2.54(m,2H),2.41–2.33(m,2H),2.09(s,3H)ppm.

[0269] Example 3

[0270] 1-(3-(6-(2-chloro-5-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 3)

[0271]

[0272] Step 1: tert-Butyl 6-(2-chloro-5-fluorophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (3b)

[0273] Under nitrogen, 2c (150 mg, 0.46 mmol), 3a (146 mg, 0.70 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (34 mg, 0.046 mmol), sodium carbonate (117 mg, 1.10 mmol), and 1,4-dioxane / water (10 mL / 2.5 mL) were added sequentially to a 100 mL three-necked flask and heated to 90°C for 8 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 3b as a colorless oil (120 mg, 80% yield). LC-MS: 324.1 [M+H] + .

[0274] Step 2: tert-Butyl 6-(2-chloro-5-fluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate (3c)

[0275] In a 100 mL round-bottom flask, 3b (120 mg, 0.37 mmol) and palladium on carbon (60 mg) were dissolved in ethanol (5 mL). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 24 h. After the reaction, 3c was filtered under reduced pressure to obtain a colorless oily solid (110 mg, 90% yield). LC-MS: 326.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.30(s,1H),6.97(dd,1H),6.89(dd,1H),4.12(s,1H),3.90(s,1H),3.87(s,1H), 3.63(t,1H),2.73–2.64(m,1H),2.26(td,1H),2.15(d,1H),1.85(dd,1H),1.63(s,1H),1.47(s,9H)ppm.

[0276] Step 3: 6-(2-chloro-5-fluorophenyl)-2-azaspiro[3.3]heptane (3d)

[0277] In a 50 mL round-bottom flask, 3c (105 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 h. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 3d as a white solid (91 mg, 86% yield). LC-MS: 226.1 [M+H] + .

[0278] Step 4: 1-(3-(6-(2-chloro-5-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 3)

[0279] To a 50 mL round-bottom flask, 3d (85 mg, 0.38 mmol), 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (79 mg, 0.38 mmol), triethylamine (58 mg, 0.57 mmol), 1-hydroxybenzotriazole (11 mg, 0.081 mmol), and dichloromethane (5 mL) were added sequentially. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol) was added with stirring and allowed to react at room temperature for 6 h. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford compound 3 as a white solid (91 mg, 57% yield). LC-MS: 417.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.50–7.42(m,1H),7.33–7.25(m,1H),7.17–7.04(m,1H),4.60(s,3H),4.36(s,1H),4.17(s,1H),3.93 (s,1H),3.68–3.63(m,2H),3.63–3.60(m,2H),2.81–2.74(m,1H),2.67–2.61(m,2H),2.41–2.27(m,2H),2.15–2.07(m,3H)ppm.

[0280] Example 4

[0281] 1-(3-(6-(3,5-bis(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 4)

[0282]

[0283] Step 1: tert-Butyl 6-(3,5-bis(trifluoromethyl)phenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (4b)

[0284] Under nitrogen, 2c (150 mg, 0.46 mmol), 4a (204 mg, 0.70 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (34 mg, 0.046 mmol), sodium carbonate (117 mg, 1.10 mmol), and 1,4-dioxane / water (10 mL / 2.5 mL) were added sequentially to a 100 mL three-necked flask and heated to 90°C for 8 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 4b as a colorless oil (160 mg, 84% yield). LC-MS: 408.1 [M+H] + Step 2: tert-Butyl 6-(3,5-bis(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (4c)

[0285] In a 100 mL round-bottom flask, 4b (155 mg, 0.38 mmol) and palladium on carbon (78 mg) were dissolved in ethanol (5 mL). The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed at room temperature for 24 h. After the reaction, 4c was filtered under reduced pressure to obtain a colorless oily solid (126 mg, 83% yield). LC-MS: 410.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 7.61 (s, 2H), 4.11 (s, 2H), 3.89 (s, 2H), 3.59–3.47 (m, 1H), 2.72–2.65 (m, 2H), 2.37–2.30 (m, 2H), 1.47 (s, 9H)ppm.

[0286] Step 3: 6-(3,5-bis(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane (4d)

[0287] In a 50 mL round-bottom flask, 4c (120 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 h. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 4d as a white solid (75 mg, 82% yield). LC-MS: 310.2 [M+H] + Step 4: 1-(3-(6-(3,5-bis(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 4)

[0288] In a 50 mL round-bottom flask, 4d (70 mg, 0.23 mmol), 6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (48 mg, 0.23 mmol), triethylamine (41 mg, 0.41 mmol), 1-hydroxybenzotriazole (7 mg, 0.052 mmol), and dichloromethane (5 mL) were added sequentially. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol) was added with stirring and allowed to react at room temperature for 6 h. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 4 as a white solid (61 mg, 53% yield). LC-MS: 501.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.95(s,2H),7.93(s,1H),4.68–4.54(m,3H),4.38(s,1H),4.17(s,1H),3 .95(s,1H),3.72–3.54(m,3H),2.81–2.73(m,1H),2.71–2.59(m,3H),2.47–2.38(m,2H),2.13–2.08(m,3H)ppm.

[0289] Example 5

[0290] 1-(3-((3aR,6aS)-5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-H)ethan-1-one (Compound 5)

[0291]

[0292] Step 1: 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid trifluoroacetate (5b)

[0293] In a 500 mL round-bottom flask, 5a (2.68 g, 10.00 mmol) was dissolved in dichloromethane (200 mL). 20 mL of trifluoroacetic acid was added at room temperature and the mixture was allowed to react for 2 h. The mixture was then concentrated under reduced pressure to afford 5b as a white solid (2.7 g, yield: 100%). LC-MS: 168.2 [M+H] + .

[0294] Step 2: 6-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (5c)

[0295] In a 500 mL round-bottom flask, 5b (2.68 g, 12.81 mmol) was dissolved in tetrahydrofuran (200 mL). Triethylamine (3.03 g, 30.00 mmol) was added, and the mixture was cooled to 0°C in an ice bath. Acetyl chloride (870 mg, 11.00 mmol, 10 mL of dichloromethane) was slowly added dropwise. The mixture was allowed to react at 0°C for 2 h. The reaction was quenched with trifluoroacetic acid and concentrated under reduced pressure to afford the crude product. Purification by column chromatography afforded compound 5c as a white solid (1.2 g, 57% yield). LC-MS: 210.2 [M+H] + .

[0296] Step 3: 2,5-Ditoluenesulfonyl-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (5e)

[0297] In a 500 mL round-bottom flask, 5d (20.00 g, 50.04 mmol) was dissolved in N,N-diformamide (200 mL). 4-Methylbenzenesulfonamide (30.80 g, 180.12 mmol) and potassium carbonate (34.60 g, 251.60 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 24 h. The reaction mixture was poured into ice water to precipitate a white solid. The filter cake was washed with 100 mL of ethanol and dried to afford 5e as a white solid (18.0 g, yield: 86%). LC-MS: 419.2 [M+H] + .

[0298] Step 4: 1,2,3,4,5,6-Hexahydropyrrolo[3,4-c]pyrrole (5f)

[0299] In a 250 mL three-necked flask, 5e (17.00 g, 40.62 mmol) was dissolved in 48% hydrogen bromide solution (20 mL). Phenol (22.94 g, 243.73 mmol) was added and the temperature was slowly raised to 120°C for 8 h. The organic solvent was removed under reduced pressure, and the residue was stirred with dichloromethane / MeOH (v:v = 10:1, 20 mL) to precipitate a yellow solid. The solid was filtered, washed with dichloromethane, and dried to afford 5f as a yellow solid (8.20 g, yield: 74%). LC-MS: 111.2 [M+H] + .

[0300] Step 5: Di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate (5 g)

[0301] In a 250 mL round-bottom flask, 5f (5.40 g, 49.02 mmol) was dissolved in a mixture of water / methanol (60 mL / 15 mL) and sodium bicarbonate (5.80 g, 70.00 mmol) was added. The solution was cooled to 0 °C in an ice bath and di-tert-butyl dicarbonate (10.84 g, 50.00 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 24 h. The solution was filtered and washed twice with distilled water. The filter cake was dried to give 5 g of white solid (4.77 g, yield: 77%). LC-MS: 311.2 [M+H] + .

[0302] Sixth step: 4,5-dihydropyrrolo[3,4-c]pyrrole-2(lH,3H,4H)-carboxylic acid tert-butyl ester 4-methylbenzene (5h)

[0303] In a 250 mL three-necked flask, 5 g (4.77 g, 15.40 mmol) was dissolved in isopropyl acetate (100 mL) and 4-methylbenzenesulfonic acid (2.91 g, 16.90 mmol) was added slowly. The solution was heated to 55 °C and stirred for 12 h. The solution was filtered and the filter cake was washed with isopropyl acetate (20 mL) to give 5h as a white solid (5.30 g, yield: 90%). LC-MS: 211.2 [M+H] + .

[0304] Seventh step: 5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylic acid tert-butyl ester (5i)

[0305] In a 100 mL round-bottom flask, 5h (2.60 g, 12.36 mmol), 4-bromo-l,2-difluoro-3- (trifluoromethyl)benzene (1.20 g, 4.60 mmol), and cesium carbonate (4.49 g, 13.80 mmol) were dissolved in 1,4-dioxane (50 mL). Finally, tris(dibenzylideneacetone) palladium (420 mg, 0.46 mmol), and l,l'-binaphthalene-2,2'-biphosphine (570 mg, 0.92 mmol) were added. The solution was heated to 100 °C and stirred for 8 h. The solid was removed by filtration and the filter cake was washed with dichloromethane. The filtrate was distilled under reduced pressure to give a crude product, which was purified by column chromatography to give compound 5i as a yellow oil (1.45 g, yield: 81%). LC-MS: 391.2 [M+H] + .

[0306] Eighth step: (3aR,6aS)-5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3a,6a dihydroxyhexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylic acid tert-butyl ester (5j)

[0307] In a 100 mL round-bottom flask, 5i (600 mg, 1.54 mmol) was dissolved in acetone / tetrahydrofuran / water (5 mL / 5 mL / 2.5 mL). 4-Methylmorpholine-N-oxide (270 mg, 2.31 mmol) was added and stirred at room temperature for 2 min. Potassium osmate dihydrate (28 mg, 0.077 mmol) was dissolved in 2.5 mL of water and slowly added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched with saturated sodium sulfite (1 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was stirred with petroleum ether / ethyl acetate (50:1) to precipitate a solid, which was filtered to afford compound 5j as a yellow solid (550 mg, yield: 84%). LC-MS: 425.2 [M+H] + .

[0308] Step 9: ((3aR,6aS)-2-(3,4-difluoro-2-(trifluoromethyl)phenyl)tetrahydropyrrolo[3,4-c]pyrrole-3a,6a(1H,4H)-diol (5k)

[0309] In a 100 mL round-bottom flask, 5j (120 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL). 1 mL of 4 M HCl (dissolved in 1,4-dioxane) was added and the mixture was allowed to react at room temperature for 2 h. The organic solvent was removed by direct concentration under reduced pressure to afford 5k as a yellow solid (105 mg, yield: 100%). LC-MS: 325.2 [M+H] + .

[0310] Step 10: 1-(3-((3aR,6aS)-5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-H)ethan-1-one (Compound 5)

[0311] In a 100 mL round-bottom flask, 5k (105 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL). 5c (71.0 mg, 0.34 mmol), 1-hydroxybenzotriazole (8 mg, 0.060 mmol), triethylamine (85 mg, 0.85 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. The reaction was quenched with 1 M hydrochloric acid (1 mL) and the organic solvent was removed by direct concentration under reduced pressure. The crude product was separated by reverse phase chromatography on a C18 column to afford compound 5 as a white solid (100 mg, yield: 63%). LC-MS: 516.2 [M+H] + . 1H NMR(500MHz,MeOD)δ7.52–7.41(m,1H),7.18–7.08(m,1H),4.81–4.51(m,4H),4.32–4.19(m,1H),4.16–4.05(m,1H),3 .98(d,1H),3.88–3.70(m,3H),3.54–3.41(m,2H),3.40–3.35(m,1H),3.32–3.28(m,1H),2.84(m,2H),2.22(m,3H)ppm.

[0312] Example 6

[0313] 1-(3-((3aR,6aS)-5-(2-chloro-5-fluorophenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 6)

[0314]

[0315] Step 1: tert-Butyl 5-(2-chloro-5-fluorophenyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6a)

[0316] In a 100 mL round-bottom flask, 5h (1.30 g, 6.18 mmol), 4-bromo-1,2-difluoro-3-(trifluoromethyl)benzene (0.60 g, 2.87 mmol), and cesium carbonate (2.80 g, 8.59 mmol) were dissolved in 1,4-dioxane (50 mL). Finally, tris(dibenzylideneacetone)palladium (262 mg, 0.29 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (356 mg, 0.58 mmol) were added. The mixture was heated to 100°C and reacted for 8 h. The solid was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was then distilled under reduced pressure to obtain the crude product, which was purified by column chromatography to afford compound 6a as a yellow solid (0.40 g, yield: 41%). LC-MS: 339.2 [M+H] + .

[0317] Step 2: ((3aR,6aS)-5-(2-chloro-5-fluorophenyl)-3a,6a-dihydroxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (6b)

[0318] In a 100 mL round-bottom flask, 6a (370 mg, 1.09 mmol) was dissolved in acetone / tetrahydrofuran / water (5 mL / 5 mL / 2.5 mL). 4-Methylmorpholine-N-oxide (191 mg, 1.64 mmol) was added and stirred at room temperature for 2 min. Potassium osmate dihydrate (20 mg, 0.055 mmol) was dissolved in 2.5 mL of water and slowly added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched with saturated sodium sulfite (1 mL) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was stirred with petroleum ether / ethyl acetate (100:1) to precipitate a solid, which was then filtered to afford 6b as a yellow solid (350 mg, yield: 86%). LC-MS: 373.2 [M+H] + .

[0319] Step 3: (3aR,6aS)-2-(2-chloro-5-fluorophenyl)tetrahydropyrrolo[3,4-c]pyrrole-3a,6a(1H,4H)-diol (6c)

[0320] In a 100 mL round-bottom flask, 6b (300 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL). 2 mL of 4 M HCl (dissolved in 1,4-dioxane) was added and the mixture was allowed to react at room temperature for 2 h. The organic solvent was removed by direct concentration under reduced pressure to afford 6c as a yellow solid (274 mg, yield: 100%). LC-MS: 274.2 [M+H] + .

[0321] Step 4: 1-(3-((3aR,6aS)-5-(2-chloro-5-fluorophenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 6)

[0322] In a 100 mL round-bottom flask, 5c (160 mg, 0.52 mmol) was dissolved in dichloromethane (5 mL). 6c (119 mg, 0.44 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), triethylamine (104 mg, 1.03 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. The reaction was monitored by TLC. The reaction was quenched with 1 M HCl (1 mL) and concentrated under reduced pressure to remove the organic solvent. The crude product was separated by reverse phase chromatography on a C18 column to afford compound 6 as a white solid (47 mg, 20% yield). LC-MS: 464.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.34 - 7.25 (m, 1H), 6.69 (d, 1H), 6.65 - 6.57 (m, 1H), 5.71 - 5.17 (m, 2H), 4.58 (s, 2H), 4.15 - 4.01 (m, 1H), 3.99 - 3.85 (m, 1H), 3.75 - 3.53 (m, 6H), 3.52 - 3.38 (m, 2H), 2.80 - 2.57 (m, 2H), 2.11 - 2.05 (m, 3H) ppm.

[0323] Example 7

[0324] 1-(3-((3aR,6aS)-5-(2-chloro-3-fluorophenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 7)

[0325]

[0326] First Step: tert-butyl 5-(2-chloro-3-fluorophenyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (7a)

[0327] In a 100 mL round bottom flask, 5h (1.30 g, 6.18 mmol), 4-bromo-1,2-difluoro-3- (trifluoromethyl)benzene (0.60 g, 2.87 mmol), cesium carbonate (2.80 g, 8.59 mmol) were dissolved in 1,4-dioxane (50 mL) and finally tris(dibenzylideneacetone) palladium (262 mg, 0.29 mmol), 1,1’-binaphthalene-2,2’-biphosphine (356 mg, 0.58 mmol) were added and heated to 100 °C for 8 h. The solid was removed by filtration, the filter cake was washed with dichloromethane and the filtrate was distilled under reduced pressure to get the crude product which was purified by column chromatography to get 7a as yellow solid (0.44 g, yield: 45%). LC-MS: 339.2 [M+H] + Second Step: tert-butyl ((3aR,6aS)-5-(2-chloro-3-fluorophenyl)-3a,6a dihydroxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (7b)

[0328] In a 100 mL round-bottom flask, 7a (300 mg, 0.89 mmol) was dissolved in acetone / tetrahydrofuran / water (5 mL / 5 mL / 2.5 mL). 4-Methylmorpholine-N-oxide (155 mg, 1.33 mmol) was added and stirred at room temperature for 2 min. Potassium osmate dihydrate (16 mg, 0.044 mmol) was dissolved in 2.5 mL of water and slowly added dropwise to the reaction mixture. The reaction was allowed to react at room temperature for 1 h. The reaction was quenched with saturated sodium sulfite (1 mL). The combined organic phases were extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 7b as a yellow solid (300 mg, yield: 91%). LC-MS: 373.2 [M+H] + .

[0329] Step 3: (3aR,6aS)-2-(2-chloro-3-fluorophenyl)tetrahydropyrrolo[3,4-c]pyrrole-3a,6a(1H,4H)-diol (7c)

[0330] In a 100 mL round-bottom flask, 7b (300 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL). 2 mL of 4 M HCl (dissolved in 1,4-dioxane) was added and the mixture was allowed to react at room temperature for 2 h. The organic solvent was removed by direct concentration under reduced pressure to afford 7c as a yellow solid (265 mg, yield: 100%). LC-MS: 274.2 [M+H] + .

[0331] Step 4: 1-(3-((3aR,6aS)-5-(2-chloro-3-fluorophenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 7)

[0332] In a 100 mL round-bottom flask, 5c (121 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (188 mg, 1.46 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (221 mg, 0.58 mmol) were added sequentially. The mixture was stirred at room temperature for 2 min, and 7c (150 mg, 0.55 mmol) was added. The reaction was allowed to react at room temperature for 2 h. The reaction was quenched with 2 M sodium carbonate (2 mL) and stirred for 10 min. The pH was adjusted to 6 with 2 M HCl, and the organic solvent was removed by concentration under reduced pressure. The crude product was compressed to obtain compound 7 as a white solid (177 mg, yield: 79%). LC-MS: 464.2 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.25 - 7.11 (m, 1H), 6.80 (t, 1H), 6.71 (d, 1H), 5.50 (s, 2H), 4.68 - 4.52 (m, 2H), 4.24 - 3.88 (m, 2H), 3.82 - 3.56 (m, 6H), 3.55 - 3.40 (m, 2H), 2.80 - 2.57 (m, 2H), 2.14 - 2.04 (m, 3H) ppm.

[0333] Example 8

[0334] 1-(3-(5-(3,5-bis(trifluoromethyl)phenyl)-3a,6a-dihydroxypyrrolo[3,4-c]pyrrole-2- carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 8)

[0335]

[0336] First Step: 5-(3,5-bis(trifluoromethyl)phenyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (8a)

[0337] In a 100 mL round bottom flask, 5h (0.78 g, 3.71 mmol), 5-bromo-1,3-bis(trifluoromethyl)benzene (0.50 g, 1.70 mmol), cesium carbonate (1.67 g, 5.10 mmol) were dissolved in 1,4-dioxane (30 mL), finally tris(dibenzylideneacetone)dipalladium (156 mg, 0.17 mmol), 1,1’-binaphthalene-2,2’-bisdiphenylphosphine (212 mg, 0.34 mmol) were added, heated to 100 °C for 8 h. The solid was removed by filtration, the filter cake was washed with dichloromethane, the filtrate was distilled under reduced pressure to get the crude product, which was purified by column chromatography to get 8a as yellow oil (0.44 g, yield: 61%). LC-MS: 423.2 [M+H] + Second Step: 5-(3,5-bis(trifluoromethyl)phenyl)-3a,6a dihydroxypyrrolo[3,4- c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (8b)

[0338] In a 100 mL round-bottom flask, 8a (250 mg, 0.59 mmol) was dissolved in acetone / tetrahydrofuran / water (5 mL / 5 mL / 2.5 mL). 4-Methylmorpholine-N-oxide (104 mg, 0.89 mmol) was added and stirred at room temperature for 2 min. Potassium osmate dihydrate (10.9 mg, 0.03 mmol) was dissolved in 2.5 mL of water and slowly added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched with saturated sodium sulfite (1 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was stirred with petroleum ether / ethyl acetate (50:1) to precipitate a solid, which was filtered to afford 8b as a yellow solid (230 mg, yield: 85%). LC-MS: 457.2 [M+H] + .

[0339] Step 3: 2-(3,5-bis(trifluoromethyl)phenyl)tetrahydropyrrolo[3,4-c]pyrrole-3a,6a(1H,4H)-diol (8c)

[0340] In a 25 mL round-bottom flask, 8b (256 mg, 0.56 mmol) was dissolved in dichloromethane (11 mL). Trifluoroacetic acid (2 mL) was added and the mixture was allowed to react at room temperature for 3.5 h. The pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated by reverse phase separation on a C18 column to obtain 8c as a white solid (130 mg, yield: 64%). LC-MS: 357.2 [M+H] + .

[0341] Step 4: 1-(3-(5-(3,5-bis(trifluoromethyl)phenyl)-3a,6a-dihydroxyoctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 8)

[0342] In a 100 mL round-bottom flask, 5c (93 mg, 0.45 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) was added and stirred at room temperature for 3 min. Finally, 8c (125 mg, 0.32 mmol) was added and allowed to react at room temperature for 3.5 h. The reaction was quenched with saturated sodium carbonate solution (2 mL) and stirred for another 30 min. The pH was adjusted to 6 with 2 M HCl, and the organic solvent was removed by direct concentration under reduced pressure. The crude product was separated by reverse phase chromatography on a C18 column to afford compound 8 as a white solid (114 mg, yield: 62%). LC-MS: 548.2 [M+H]+ . 1 H NMR (500MHz, DMSO-d6): δ12.97(s,1H),7.14(s,1H),6.98(s,2H),5.67–5.48(m,2H),4.63–4.55(m,2H),4.16–4.08(m ,1H),4.03–3.93(m,1H),3.72–3.67(m,2H),3.64–3.56(m,4H),3.44(t,2H),2.77–2.57(m,2H),2.10–2.07(m,3H)ppm.

[0343] Example 9

[0344] 1-(3-(6-(2-chloro-3-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 9)

[0345]

[0346] Step 1: tert-Butyl 6-(2-chloro-3-fluorophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (9b)

[0347] Under nitrogen, 2c (800 mg, 2.49 mmol), 9a (783 mg, 3.74 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (183 mg, 0.25 mmol), sodium carbonate (528 mg, 4.95 mmol), and 1,4-dioxane / water (20 mL / 5 mL) were added sequentially to a 100 mL three-necked flask and heated to 90°C for 8 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 9b as a colorless oil (644 mg, 80% yield). LC-MS: 324.2 [M+H] + Step 2: tert-Butyl 6-(2-chloro-3-fluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate (9c)

[0348] In a 100 mL round-bottom flask, 9b (640 mg, 1.98 mmol) and palladium on carbon (128 mg) were dissolved in ethanol (10 mL). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 24 h. 9c was obtained by filtration under reduced pressure as a colorless oily solid (600 mg, 93% yield). LC-MS: 326.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ7.30 (s, 1H), 6.97 (dd, 1H), 6.89 (dd, 1H), 4.12 (s, 1H), 3.90 (s, 1H), 3.87 (s, 1H), 3.63 (t, 1H), 2.73–2.64 (m, 1H), 2.32–2.20 (m, 1H), 2.15 (d, 1H), 1.90–1.79 (m, 1H), 1.63 (s, 1H), 1.47 (d, 9H) ppm. Step 3: 6-(2-chloro-3-fluorophenyl)-2-azaspiro[3.3]heptane (9d)

[0349] In a 25 mL round-bottom flask, 9c (467 mg, 1.43 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated by reverse phase separation on a C18 column to obtain compound 9d as a white solid (103 mg, yield: 23.87%). LC-MS: 226.2 [M+H] + .

[0350] Step 4: 1-(3-(6-(2-chloro-3-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 9)

[0351] In a 100 mL round-bottom flask, 9d (100 mg, 0.44 mmol), 5c (111 mg, 0.49 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.89 mmol) were dissolved in dichloromethane (6 mL). Triethylamine (89 mg, 0.88 mmol) and 1-hydroxybenzotriazole (12 mg, 0.089 mmol) were added sequentially. The mixture was reacted at room temperature for 5 h. The organic solvent was removed by direct concentration under reduced pressure. The crude product was separated by reverse phase chromatography on a C18 column to afford compound 9 as a white solid (117.3 mg, yield: 63%). LC-MS: 417.1 [M+H] + . 1H NMR (500MHz, DMSO-d6): δ13.07–12.89(m,1H),7.42–7.33(m,1H),7.29–7.25(m,1H),7.25–7.21(m,1H),4.63–4.53 (m,3H),4.35(s,1H),4.15(s,1H),3.90(s,1H),3.68–3.54(m,3H),2.77–2.59(m,4H),2.32(t,2H),2.08(d,3H)ppm.

[0352] Example 10

[0353] 6-Acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-hydroxyphenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 10)

[0354]

[0355] Step 1: 6-((1R,3S,5R,7S)-3-aminoadamantan-1-yl)-4-bromo-2,3-difluorophenol (10c)

[0356] Under nitrogen, 10a (1.60 g, 9.5 mmol), 10b (2.00 g, 9.50 mmol), and methanesulfonic acid (40 mL) were added sequentially to a 100 mL three-necked flask and heated to 100°C for 4 h. The reaction solution was poured into ice water, whereupon a large amount of solid precipitated. The solid was collected and dried under reduced pressure to obtain compound 10c methanesulfonate as a white solid (2.5 g, crude product), which was used directly in the next reaction without further purification. LC-MS: 358.1 [M+H] + Step 2: 6-acetyl-N-((1S,3R,5R,7S)-3-(5-bromo-3,4-difluoro-2-hydroxyphenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (10d)

[0357] In a 100 mL round-bottom flask, 5c (300 mg, 1.40 mmol) was dissolved in N,N-dimethylformamide (15 mL). N,N-diisopropylethylamine (0.71 mL, 4.30 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (654 mg, 1.70 mmol) were added sequentially in an ice bath. The mixture was stirred at room temperature for 30 minutes, followed by the addition of 10c (1027 mg, 2.86 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. Water (45 mL) and ethyl acetate were added directly to the reaction solution, the mixture was separated, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain compound 10d as a white solid (260 mg, yield: 33%). LC-MS: 349.1 / 351.1 [M+H] + .

[0358] Step 3: 6-acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-hydroxyphenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 10)

[0359] In a 100 mL round-bottom flask, 10d (260 mg, 0.47 mmol) was dissolved in methanol (20 mL), followed by the addition of triethylamine (0.13 mL, 0.95 mmol) and palladium on carbon (100 mg, 10% water content). The mixture was reacted under a hydrogen atmosphere at room temperature for 16 hours. Upon completion of the reaction, methanol (20 mL) was added for dilution, followed by celite filtration, and the filtrate was collected and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain compound 10 as a white solid (50 mg, yield: 21%). LC-MS: 471.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.92(s,1H),10.04(s,1H),7.01(s,1H),6.91(t,1H),6.78(q,1H),4.59(s,2H),3 .63(m,2H),2.71(m,2H),2.37(s,2H),2.21(s,2H),2.11(s,2H),2.08(m,5H),2.01(s,4H),1.67(s,2H)ppm.

[0360] Example 11

[0361] 6-Acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluorophenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 11)

[0362]

[0363] Step 1: tert-Butyl ((1S,3R,5R,7S)-3-(5-bromo-3,4-difluoro-2-hydroxyphenyl)adamantan-1-yl)carbamate (11a)

[0364] 10c (1.00 g, 2.79 mmol) was dissolved in dichloromethane (40 mL), followed by the addition of triethylamine (1.2 mL, 9.90 mmol) and di-tert-butyl dicarbonate (731 mg, 3.40 mmol), and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was directly poured into water (100 mL), separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to obtain the crude product. 11a was separated and purified by column chromatography to obtain 11a as a white solid (660 mg, yield 51%). LC-MS: 458.1 / 460.1 [M+H] + .

[0365] Step 2: 4-Bromo-6-((1R,3S,5R,7S)-3-((tert-Butoxycarbonyl)amino)adamantan-1-yl)-2,3-difluorophenyl trifluoromethanesulfonate (11b)

[0366] Dissolve 11a (660 mg, 1.44 mmol) in dichloromethane (20 mL). Add pyridine (0.23 mL, 2.88 mmol) at 0°C. Add trifluoroacetic anhydride (0.29 mL, 1.73 mmol) dropwise while maintaining the temperature. Continue the reaction for 2 hours. Upon completion of the reaction, the reaction mixture was directly separated by wet-process silica gel column chromatography to obtain 11b as a white solid (780 mg, 92% yield). LC-MS: 590.1 / 592.1 [M+H] + .

[0367] Step 3: tert-Butyl ((1S,3R,5R,7S)-3-(3,4-difluorophenyl)adamantan-1-yl)carbamate (11c)

[0368] 11b (780 mg, 1.33 mmol) was dissolved in anhydrous methanol (20 mL) and ethyl acetate (10 mL), followed by the addition of triethylamine (0.37 mL, 2.65 mmol), palladium carbon (100 mg), and palladium hydroxide (100 mg). The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. After the reaction, the reaction solution was directly passed through celite, the filter cake was washed with 20 mL of methanol, the filtrate was combined, and the mixture was directly concentrated to dryness to obtain the crude product. The crude product was separated and purified by column chromatography to obtain 11c as a white solid (280 mg, yield 58%). LC-MS: 364.1 [M+H] + .

[0369] Step 4: (1S,3R,5R,7S)-3-(3,4-difluorophenyl)adamantan-1-amine (11d)

[0370] 11c (280 mg, 0.77 mmol) was dissolved in ethyl acetate (2 mL), followed by the addition of 4 M hydrochloric acid / ethyl acetate (20 mL) and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was concentrated to dryness under pressure to obtain crude product 11d as a white solid (170 mg), which was used directly in the next reaction without purification. LC-MS: 264.1 [M+H] + .

[0371] Step 5: 6-acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluorophenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 11)

[0372] 5c (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (0.47 mL, 2.88 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (218 mg, 0.57 mmol) in an ice bath. The mixture was stirred at room temperature for 30 minutes, and solid 11d (170 mg, 0.65 mmol) was added. The mixture was then allowed to react at room temperature for 16 hours. After the reaction was complete, 1 mL of saturated ammonium chloride solution was added to quench the reaction. The resulting liquid was directly purified to obtain compound 11 as a white solid (70 mg, 31% yield). LC-MS: 455.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),7.45–7.32(m,2H),7.22(s,1H),7.06(s,1H),4.56(s,2H),3.68–3. 56(m,2H),2.84–2.62(m,2H),2.23(s,2H),2.17(s,2H),2.12–1.97(m,7H),1.81(s,4H),1.67(s,2H)ppm.

[0373] Example 12

[0374] 6-Acetyl-N-((1S,3R,4S,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-4-hydroxyadamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 12)

[0375]

[0376] Step 1: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-4-hydroxyadamantane-1-carboxylic acid methyl ester (12b)

[0377] Under nitrogen, a 50 mL three-necked flask was charged with 1-bromo-3,4-difluoro-2-trifluoromethylbenzene (1000 mg, 3.83 mmol) and tetrahydrofuran (10 mL). The air was expelled, nitrogen was introduced, and the temperature was lowered to -78°C. Then, n-butyllithium (1.83 mL, 2.5 mol / L n-hexane solution) was slowly added. After reacting for 0.5 h, a solution of 12a (725 mg, 3.48 mmol) in tetrahydrofuran was added, and the temperature was slowly returned to 0°C for 2 h. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 12b as an off-white solid (1100 mg, 74% yield). LC-MS: 391.1 [M+H] + .

[0378] Step 2: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-4-hydroxyadamantane-1-carboxylic acid (12c)

[0379] In a 100 mL round-bottom flask, 12b (1100 mg, 2.82 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL), methanol (4 mL), and purified water (2 mL). Lithium hydroxide (202 mg, 8.45 mmol) was then added and the mixture was allowed to react at 40°C for 4 h. LC-MS confirmed the completion of the reaction, and the organic solvent was removed by direct concentration under reduced pressure to obtain the crude product. The crude product was then separated using a C18 reverse-phase column to afford 12c as an off-white solid (600 mg, yield: 57%). LC-MS: 377.1 [M+H] + .

[0380] Step 3: (1R,3S,5S,7S)-5-amino-2-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-2-ol (12d)

[0381] In a 50 mL round-bottom flask, 12c (600 mg, 1.59 mmol) was dissolved in N,N-dimethylacetamide (10 mL). Triethylamine (0.27 mL, 1.91 mmol) was added at room temperature. After stirring at room temperature for 5 minutes, DPPA (0.41 mL, 1.91 mmol) was slowly added. After reacting at room temperature for 2 hours, the mixture was added to 45°C hydrochloric acid (10 mL, 3 M) and reacted at 45°C for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution and separated using a C18 reverse-phase column to obtain compound 12d as an off-white solid (450 mg, yield: 81%). LC-MS: 348.1 [M+H] + .

[0382] Step 4: 6-acetyl-N-((1S,3R,4S,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-4-hydroxyadamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 12)

[0383] In a 50 mL round-bottom flask, 5c (72 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.17 mL, 0.86 mmol) was then added and the mixture was allowed to react on ice for 0.15 h. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142 mg, 0.37 mmol) was then added and the mixture was allowed to react on ice for 0.5 h. Then, 12d (100 mg, 0.28 mmol) was added and the mixture was allowed to react at room temperature for 2 h. The reaction was quenched by adding pure water and extracted with ethyl acetate. The organic phase was collected and concentrated to obtain the crude product, which was separated on a C18 reverse-phase column to obtain a mixture. The mixture was chirally resolved to give compounds 12-1 and 12-2.

[0384] Compound 12-1, off-white solid (19 mg, yield 12%): LC-MS: 539.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.88(s,1H),7.63–7.53(m,2H),7.08–6.82(m,1H),5.50(s,1H),4.54(s,2H),3.63–3. 53(m,2H),2.72(s,3H),2.32(d,2H),2.11–1.98(m,7H),1.93(d,2H),1.58–1.41(m,2H),1.33–1.18(m,2H)ppm.

[0385] Compound 12-2, off-white solid (11 mg, yield: 7%): LC-MS: 539.1 [M+H]+ . 1 H NMR(500MHz,DMSO-d6)δ12.88(s,1H),7.63–7.53(m,2H),7.08–6.82(m,1H),5.50(s,1H),4.54(s,2H),3.63–3. 53(m,2H),2.72(s,3H),2.32(d,2H),2.11–1.98(m,7H),1.93(d,2H),1.58–1.41(m,2H),1.33–1.18(m,2H)ppm.

[0386] Example 13

[0387] 6-Acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-methoxyphenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 13)

[0388]

[0389] Step 1: tert-Butyl ((1S,3R,5R,7S)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)adamantan-1-yl)carbamate (13a)

[0390] In a 50 mL round-bottom flask, 10c (1000 mg, 2.18 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (1.42 g, 4.36 mmol) was added, the temperature was lowered to 0°C, and iodomethane (0.15 mL, 2.40 mmol) was added. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched by the addition of pure water and extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford compound 13a as an off-white solid (900 mg, yield: 87%). LC-MS: 472.1 [M+H] + .

[0391] Step 2: tert-Butyl ((1S,3R,5R,7S)-3-(3,4-difluoro-2-methoxyphenyl)adamantan-1-yl)carbamate (13b)

[0392] In a 100 mL round-bottom flask, 13a (750 mg, 1.59 mmol) was dissolved in ethyl acetate (40 mL). Triethylamine (0.62 mL, 4.77 mmol) and palladium on carbon (100 mg, 0.93 mmol) were added sequentially. The air was purged and hydrogen was introduced. The reaction was allowed to react at room temperature for 12 h. The reaction solution was filtered through celite, and the filtrate was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 13b as an off-white solid (600 mg, yield: 96%). LC-MS: 394.1 [M+H] + .

[0393] Step 3: (1S,3R,5R,7S)-3-(3,4-difluoro-2-methoxyphenyl)adamantan-1-amine (13c)

[0394] In a 50 mL round-bottom flask, 13b (600 mg, 1.52 mmol) was dissolved in ethyl acetate (2 mL). 10 mL of 4 M HCl (dissolved in ethyl acetate) was added and the mixture was allowed to react at room temperature for 4 h. The organic solvent was removed by concentration under reduced pressure to afford compound 13c as a white solid (400 mg, yield: 89%). LC-MS: 294.1 [M+H] + .

[0395] Step 4: 6-acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-methoxyphenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 13)

[0396] In a 50 mL round-bottom flask, 5c (76 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.30 mL, 1.52 mmol) was then added and the mixture was allowed to react on ice for 0.15 h. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (149 mg, 0.39 mmol) was then added and the mixture was allowed to react on ice for 0.5 h. Then, 13c (100 mg, 0.30 mmol) was added and the mixture was allowed to react at room temperature for 2 h. The reaction was quenched by the addition of pure water and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated and collected to obtain the crude product, which was then separated using a C18 reverse-phase column to afford compound 13 as an off-white solid (50 mg, 34% yield). LC-MS: 485.2 [M+H]. + . 1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),7.19–6.94(m,3H),4.58(s,2H),3.96(s,3H),3.60–3.65m,2 H),2.80–2.64(m,2H),2.31(s,2H),2.22(s,2H),2.13–2.00(m,7H),1.95(s,4H),1.68(s,2H)ppm.

[0397] Example 14

[0398] 1-(3-((3aR,6aS)-5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3a,6a-dihydroxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 14)

[0399]

[0400] Step 1: 3,4-bis(bromomethyl)-1-toluenesulfonyl-2,5-dihydro-1H-pyrrole (14b)

[0401] In a 500 mL round-bottom flask, 5d (25.00 g, 62.50 mmol) was dissolved in N,N-diformamide (300 mL). 4-Methylbenzenesulfonamide (12.80 g, 75.0 mmol) and potassium carbonate (22.56 g, 163.23 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to afford 14b (4.20 g, yield: 16%). LC-MS: 408.1 [M+H] + .

[0402] Step 2: Diethyl 2-toluenesulfonyl-2,3,4,6-tetrahydrocyclopentadiene-5,5(1H)-dicarboxylate (14c)

[0403] In a 250 mL round-bottom flask, diethyl malonate (1.98 g, 12.35 mmol) was dissolved in tetrahydrofuran (50 mL) under an ice bath. NaH (988 mg, 41.17 mmol) was added and stirred for 30 min. 14b (4.20 g, 10.29 mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the reaction mixture. The reaction was allowed to react at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to afford 14c (1.70 g, yield: 41%). LC-MS: 408.1 [M+H] + .

[0404] Step 3: 2-Tosyl-2,3,4,6-tetrahydrocyclopenta[c]pyrrole-5,5(1H)-dicarboxylic acid (14d)

[0405] In a 250 mL round-bottom flask, 14c (1.60 g, 3.93 mmol) was dissolved in 1,4-dioxane / water (v / v, 1:1, 20 mL). Lithium hydroxide (460 mg, 20.00 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction mixture was poured into water and the pH was adjusted to 2 with 2N HCl. A white solid precipitated, which was filtered, washed, and dried to afford 14d (1.3 g, 94% yield). LC-MS: 352.1 [M+H] + .

[0406] Step 4: 2-Tosyl-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid (14e)

[0407] In a 100 mL round-bottom flask, 14d (1.30 g, 3.72 mmol) was dissolved in dimethyl sulfoxide (20 mL). Sodium chloride (1.30 g, 22.22 mmol) was added and the mixture was allowed to react at 120°C for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to afford 14e (1.00 g, yield: 88%). LC-MS: 308.1 [M+H] + .

[0408] Step 5: 1,3-Dioxoisoindol-2-yl-2-toluenesulfonyl-1,2,3,4,5,6-hexahydrocyclopentadienyl[c]pyrrole-5-carboxylate (14f)

[0409] In a 100 mL round-bottom flask, 14e (1.00 g, 3.26 mmol) was dissolved in dichloromethane (20 mL). N-hydroxyphthalimide (797 mg, 4.89 mmol), 4-dimethylaminopyridine (39 mg, 0.33 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (937 mg, 4.89 mmol) were added sequentially. The mixture was reacted at 25°C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by slurrying with methanol / water (1:1) to afford 14f (1.1 g, yield: 74%). LC-MS: 453.1 [M+H] + Step 6: 5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-2-toluenesulfonyl-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrole (14 g)

[0410] To a 100 mL reaction tube, 14f (1.0 g, 2.21 mmol), Ir[(dtbbpy)(ppy)2] (40 mg, 0.044 mmol), NiBr2.DME (136 mg, 0.22 mmol), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (1.68 g, 6.63 mmol), N,N-dimethylacetamide (10 mL), and 6-bromo-2,3-difluorobenzotrifluoride (2.3 g, 8.84 mmol) were added sequentially. The mixture was irradiated with a 455 nm blue light at 25°C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to afford 14g (0.20 g, 20.4% yield). LC-MS: 444.1 [M+H] + .

[0411] Step 7: 5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrole (14h)

[0412] In a 100 mL round-bottom flask, 14 g (200 mg, 0.45 mmol) was dissolved in 48% hydrogen bromide solution (10 mL). Phenol (846 mg, 9.00 mmol) was added and the temperature was slowly raised to 120°C for 4 h. The solvent was removed under reduced pressure, and the residue was neutralized with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to obtain 14 h (60 mg, yield: 46%). LC-MS: 290.1 ​​[M+H] + .

[0413] Step 8: 1,1'-(3-(5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrole-2-carbonyl)-4,7-dihydro-1H-pyrazolo[3,4-c]pyridine-1,6(5H)-diyl)bis(ethane-1-one) (14i)

[0414] In a 100 mL round bottom flask, 1,6-diacetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridine-3-carboxylic acid (100 mg, 0.40 mmol) was dissolved in N,N- dimethylformamide (5.0 mL), N,N-diisopropyl ethylamine (103 mg, 0.80 mmol) was added, followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152 mg, 0.40 mmol) at 0 °C for 5 min. 14h (60 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and added to the above reaction solution, which was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and sodium chloride aqueous solution was added to the residue. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 14i (74 mg, yield: 71%). LC-MS: 523.1 [M+H] + .

[0415] Ninth step: 1-(3-((3aR,6aS)-5-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3a,6a- dihydroxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)ethan-1-one (Compound 14)

[0416] In a 100 mL round bottom flask, 14i (74 mg, 0.14 mmol) was dissolved in acetone / tetrahydrofuran / water (2 mL / 2 mL / 2 mL), 4-methylmorpholine-N-oxide (25 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 2 min. Potassium osmate dihydrate (3 mg, 0.0070 mmol) was dissolved in 0.5 mL of water and slowly added to the reaction solution, which was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium sulfite (1 mL) and extracted with ethyl acetate. The concentrated organic phase was collected to give a crude product, which was separated by C18 reverse phase column to give a mixture (45 mg). The mixture was purified by preparative chromatography to give Compound 14-1 (20 mg) and Compound 14-2 (3.0 mg).

[0417] Compound 14-1: LC-MS: 515.1 [M+H] + . 1H NMR(500MHz,DMSO)δ12.94(s,1H),7.80–7.66(m,1H),7.54–7.43(m,1H),5.17(d,2H),4.60(s,2H),4.22(d,1 H),3.99–3.87(m,2H),3.84(d,1H),3.69–3.50(m,3H),2.70(3,2H),2.20–2.04(m,5H),2.02–1.82(m,2H)ppm.

[0418] Compound 14-2: LC-MS: 515.1 [M+H] + .

[0419] Example 15

[0420] 6-Acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-yl)-3a,5,6,7-tetrahydro-4H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 15)

[0421]

[0422] Step 1: (1R,3S,5R,7S)-3-bromoadamantane-1-carboxylic acid methyl ester (15b)

[0423] 15a (5.00 g, 192.90 mmol) was dissolved in methanol (100 mL), followed by the addition of concentrated sulfuric acid (0.1 mL, 19.20 mmol), and the reaction mixture was heated to reflux for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, followed by the addition of ethyl acetate (100 mL), washed with 15% sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 15b as a colorless oil (5.3 g), which was used directly in the next reaction.

[0424] Step 2: (1S,3S,5R,7S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)adamantane-1-carboxylic acid methyl ester (15c)

[0425] Bis(pinacol)boronate (6.40 g, 25.26 mmol), potassium methoxide (1.77 g, 25.26 mmol), copper chloride (452 ​​mg, 3.37 mmol), and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ene (1.30 g, 3.37 mmol) were dissolved in anhydrous tetrahydrofuran (60 mL) and reacted at room temperature under nitrogen for 30 minutes. A solution of 15b (4.60 g, 16.84 mmol) in tetrahydrofuran (5 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes, then heated to 60°C and allowed to react for another 4 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to afford compound 15c as a white solid (3.0 g, 55% yield). 1 H NMR (500MHz, DMSO-d6) δ3.57 (s, 3H), 1.92 (d, 2H), 1.82–1.76 (m, 4H), 1.74 (s, 2H), 1.64 (d, 4H), 1.57 (d, 2H), 1.16 (s, 12H)ppm.

[0426] Step 3: (1S,3R,5R,7S)-3-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantane-1-carboxylic acid methyl ester (15d)

[0427] 1-Bromo-3,4-difluoro-2-trifluoromethylbenzene (1.50 g, 5.75 mmol), compound 15c (2.76 g, 8.62 mmol, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl] nickel(II) dichloride (228 mg, 0.58 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridyl][2-2'-bi(4-tert-butylpyridyl)]iridium di(hexafluorophosphate) (128 mg, 0.11 mmol), morpholine (751 mg) , 8.62mmol) was dissolved in anhydrous N,N-dimethylformamide (60mL), protected by nitrogen, and irradiated with 35W blue light (455nm) for 8 hours. After the reaction was completed, the reaction solution was directly poured into ice water (240mL), followed by extraction with ethyl acetate, the organic phases were combined, and washed with water (50mL) and saturated brine (50mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Further separation and purification by silica gel column chromatography gave 15d, a colorless oil (1.40g). LC-MS: 375.1[M+H] + .

[0428] Step 4: (1S,3R,5R,7S)-3-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantane-1-carboxylic acid (15e)

[0429] 15d (1.40 g, 3.70 mmol) was dissolved in methanol (20 mL), followed by the addition of aqueous sodium hydroxide solution (2 mL, 2 mol / L). The reaction mixture was heated to 60°C for 4 hours. Upon completion of the reaction, the reaction mixture was concentrated to dryness, water (10 mL) was added, and the pH was adjusted to 4-5 with 1N hydrochloric acid. 15e was purified by reverse-phase column preparative separation to obtain 15e as a white solid (80 mg). LC-MS: 361.1 [M+H] + .

[0430] Step 5: (1S,3R,5R,7S)-3-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-amine (15f)

[0431] 15e (80 mg, 0.22 mmol) was dissolved in N,N-dimethylacetamide (10 mL), followed by the addition of triethylamine (30 mg, 0.29 mmol) and diphenylphosphoryl azide (80 mg, 0.29 mmol). The reaction was maintained at room temperature for 30 minutes, and then the reaction was directly added dropwise to a 1N aqueous hydrochloric acid solution at 60°C and the reaction was continued for 1 hour. After the reaction was completed, the pH of the reaction solution was directly adjusted to a weak base. Extraction was performed with ethyl acetate (50 mL × 3), and the organic phases were combined, dried, filtered, and concentrated to obtain the crude product. 15f was separated and purified by reverse phase chromatography and lyophilized to obtain 15f as a white solid (50 mg). LC-MS: 332.1 [M+H] + .

[0432] Step 6: 6-acetyl-N-((1S,3R,5R,7S)-3-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-yl)-3a,5,6,7-tetrahydro-4H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 15)

[0433] 5c (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (0.22 mL, 1.44 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109 mg, 0.28 mmol) in an ice bath. The mixture was stirred at room temperature for 30 minutes, and solid 15f (50 mg, 0.15 mmol) was added. The mixture was then allowed to react at room temperature for 16 hours. 1 mL of saturated ammonium chloride solution was added to quench the reaction, and the resulting liquid was directly subjected to preparative separation and purification by reverse phase chromatography. After lyophilization, compound 15 was obtained as a white solid (30 mg). LC-MS: 523.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),7.62–7.58(m,1H),7.38-7.35(m,1H),7.13(s,1H),4.56(s,2H),3.68 –3.56(m,2H),2.84–2.62(m,2H),2.23(s,2H),2.17(s,2H),2.12–1.97(m,7H),1.81(s,4H),1.67(s,2H)ppm.

[0434] Example 16

[0435] 6-Acetyl-N-((3R,5R)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compounds 16-1 and 16-2)

[0436]

[0437] Step 1: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-4-hydroxyadamantane-1-carboxylic acid methyl ester (16b)

[0438] In a 100 mL three-necked flask, 16a (2.26 g, 10.85 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The reaction solution was then cooled to -78 ° C. n-Butyl lithium (3.6 mL, 9.00 mmol, 2.5 mol / L n-hexane solution) was added dropwise and the temperature was maintained for 30 minutes. Then, a tetrahydrofuran solution of 1a (1.50 g, 7.20 mmol) (10 mL) was added dropwise and the temperature was maintained for 2 hours. After the reaction was completed, the reaction solution was directly added dropwise to 50 mL of water, the reaction was quenched, and the mixture was returned to room temperature and stirred for 30 minutes. The pH was then adjusted to weak acidity, extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. 16b was separated by silica gel column chromatography as a white solid (2.5 g, yield 88%). LC-MS: 391.1 [M+H] + .

[0439] Step 2: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantane-1-carboxylic acid methyl ester (16c)

[0440] In a 100 mL round-bottom flask, 16b (2.50 g, 6.40 mmol) was dissolved in anhydrous dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (20 mL). The resulting solution was cooled directly to 0°C, and triethylsilyl hydrochloride (10 mL) was slowly added dropwise. The reaction was returned to room temperature and the reaction continued for 6 hours. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate. The organic phases were combined and washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. The crude product was separated and purified by silica gel column chromatography to obtain 16c as a white solid (2.0 g, 83% yield). LC-MS: 375.1 [M+H] + .

[0441] Step 3: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantane-1-carboxylic acid (16d)

[0442] In a 100 mL round-bottom flask, 16c (1.70 g, 4.54 mmol) was dissolved in methanol (20 mL) and water (2 mL). The reaction mixture was then heated to 60°C for 1 hour. The reaction mixture was concentrated to 100 mL, and then 50 mL of water was added. The pH was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 16d as an off-white solid (1.5 g, 91%). LC-MS: 361.1 [M+H] + .

[0443] Step 4: (1S,3R,5S,7S)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-amine (16e)

[0444] In a 50 mL round-bottom flask, 16d (560 mg, 1.55 mmol) was dissolved in anhydrous N,N-dimethylacetamide (10 mL), followed by the addition of triethylamine (204 mg, 2.02 mmol) and diphenylphosphoryl azide (556 mg, 2.02 mmol) and stirred at room temperature for 1 hour. The reaction solution was then added dropwise to a 70°C aqueous solution of 2M dilute hydrochloric acid (50 mL) and the temperature was maintained for 1 hour. The reaction solution was directly concentrated to remove most of the water and organic solvent (~10 mL). The resulting liquid was directly subjected to MPLC reverse preparative purification to obtain 16e as a white solid (500 mg, 97% yield). LC-MS: 332.1 [M+H] + .

[0445] Step 5: 6-acetyl-N-((3R,5R)-4-(3,4-difluoro-2-(trifluoromethyl)phenyl)adamantan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compounds 16-1 and 16-2)

[0446] In a 50 mL round-bottom flask, 16e (113 mg, 0.34 mmol) and N,N-diisopropylethylamine (175 mg, 1.36 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The reaction solution was then cooled to 0°C and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (206 mg, 0.54 mmol) was added as a solid. The reaction was maintained at this temperature for 15 minutes. Compound 6 (150 mg, 0.45 mmol) was then added and the temperature maintained for 2 hours. The reaction solution was directly poured into 50 mL of water and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. After preparative separation using high-pressure liquid chromatography, compound 16-1 was obtained as a white solid (10 mg, 4% yield); and compound 16-2 was obtained as a white solid (8 mg, 4% yield). LC-MS: 523.1[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.92(s,1H),7.59(t,1H),7.55–7.48(m,1H),7.04(s,1H),4.59(s,2H),3.62(t,2H),2. 84(ddd,3H),2.32(d,2H),2.25–2.17(m,2H),2.16–1.98(m,7H),1.97–1.82(m,1H),1.76(d,2H),1.59(d,2H)ppm.

[0447] Example 17

[0448] (1-(1-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)cyclohexane-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compounds 17-1 and 17-2)

[0449]

[0450] Step 1: Ethyl 4-(methylphenyloxy)cyclohexane-1-carboxylate (17b)

[0451] In a 250 mL round-bottom flask, 17a (3.40 g, 20.00 mmol) and p-toluenesulfonyl chloride (4.56 g, 24.00 mmol) were dissolved in DCM (50 mL). Triethylamine (4.04 g, 40.00 mmol) and 4-dimethylaminopyridine (244 mg, 2.00 mmol) were then added and allowed to react at 25°C for 48 h. The reaction was quenched with water and extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 17b as a colorless oil (5.54 g, 85% yield). LC-MS: 327.1 [M+H] + .

[0452] Step 2: Ethyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)cyclohexane-1-carboxylate (17c)

[0453] In a 250 mL round-bottom flask, 17b (5 g, 15.3 mmol), (2,2'-bipyridyl)nickel(II) dibromide (389 mg, 1.04 mmol), pinacol diboron (3.66 g, 14.40 mmol), potassium carbonate (1.99 g, 14.40 mmol), sodium iodide (2.40 g, 16.00 mmol), and 19b 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (2.61 g, 8.00 mmol) were sequentially dissolved in N,N-dimethylacetamide (250 mL) and reacted at 80°C for 10 h. The reaction was quenched by water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford 17c as a colorless oil (0.45 g, 16% yield). LC-MS: 337.1 [M+H]. + .

[0454] Step 3: 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)cyclohexane-1-carboxylic acid (17d)

[0455] In a 100 mL round-bottom flask, 17c (0.45 g, 1.34 mmol) and lithium hydroxide (308 mg, 12.86 mmol) were dissolved in methanol / water (5:1, 20 mL) and reacted at 50°C for 1 h. 2M hydrochloric acid was added to adjust the pH to 3. Water was added to precipitate the solid, which was filtered and dried to afford 17d as a white solid (340 mg, yield: 82%). LC-MS: 309.1 [M+H] + .

[0456] Step 4: (1-(1-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)cyclohexane-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compounds 17-1 and 17-2)

[0457] In a 100 mL round-bottom flask, 17d (155 mg, 0.50 mmol) and 1-(1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (165 mg, 1.00 mmol) were dissolved in dichloromethane (50 mL), and then triethylamine (10 mg, 0.10 mmol), 1-hydroxybenzotriazole (13 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol) were added and the reaction was carried out at 25 °C for 1 h. The reaction was quenched with water, extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford compound 20 (155 mg, yield: 68%), as well as purified compounds 17-1 (85 mg) and 17-2 (50 mg) as white solids. LC-MS: 456.2 [M+H] + Compound 17-1: 1 H NMR(400MHz, CDCl3)δ8.06(s,1H),7.41–7.31(m,1H),7.22(s,1H),4.83(s,1H),4.69(s,1H),3.88(s,1H),3.78-3.62(m,2H), 3.12–3.00(m,1H),2.84–2.66(m,2H),2.24(s,3H),2.17(d,2H),2.09–1.91(m,2H),1.88–1.73(m,2H),1.72–1.58(m,2H)ppm.

[0458] Example 18

[0459] 1-(3-((4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)sulfonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 18)

[0460]

[0461] Step 1: tert-Butyl 3-bromo-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-6-carboxylate (18b)

[0462] In a 250 mL round-bottom flask, 18a (5.34 g, 20.00 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium carbonate (3.36 g, 31.7 mmol) and bromosuccinimide (5.34 g, 30.00 mmol) were then added sequentially. The mixture was reacted at 60°C for 4 h, and then sodium sulfite solution was added to quench the reaction. Purified water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated to obtain a crude product, which was purified on a silica gel column to obtain compound 18b as a colorless oil (4.2 g, 70% yield). LC-MS: 302.2 [M+H] + .

[0463] Step 2: Di-tert-butyl 3-bromo-4,7-dihydro-1H-pyrazolo[3,4-c]pyridine-1,6(5H)-dicarboxylate (18c)

[0464] In a 250 mL round-bottom flask, 18b (4.20 g, 14.00 mmol) was dissolved in dichloromethane (50 mL). Triethylamine (2.80 g, 28.00 mmol) and di-tert-butyl dicarbonate (3.66 g, 16.80 mmol) were then added sequentially. The mixture was reacted at room temperature for 4 h. 100 mL of pure water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated to obtain the crude product, which was purified on a silica gel column to obtain 18c as a colorless oil (5.0 g, 89% yield). LC-MS: 402.2 [M+H] + .

[0465] Step 3: Di-tert-butyl 3-(benzylthio)-4,7-dihydro-1H-pyrazolo[3,4-c]pyridine-1,6(5H)-dicarboxylate (18d)

[0466] In a 100 mL round-bottom flask, 18c (4.00 g, 10.00 mmol), benzyl mercaptan (1.64 g, 13.00 mmol), and N,N-diisopropylethylamine (2.58 g, 20 mmol) were dissolved in 1,4-dioxane (100 mL). Finally, tris(dibenzylideneacetone)palladium (915 mg, 1.00 mmol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (1.00 g, 2.00 mmol) were added. The mixture was heated to 100°C and reacted for 8 h. The solid was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was then distilled under reduced pressure to obtain the crude product, which was purified by column chromatography to afford 18d as a yellow oil (3.56 g, 80% yield). LC-MS: 446.2 [M+H] + .

[0467] Step 4: 3-(Benzylthio)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine hydrochloride (18e)

[0468] In a 100 mL round-bottom flask, 18d (4.00 g, 9.00 mmol) was dissolved in dichloromethane (10 mL). 5 mL of hydrochloric acid / 1,4-dioxane (4 mol / L) was added and the mixture was allowed to react at room temperature for 2 h. The organic solvent was removed by direct concentration under reduced pressure. The mixture was dispersed with petroleum ether, filtered, and dried to afford 18e as a white solid (2.1 g, yield: 83%). LC-MS: 246.2 [M+H] + .

[0469] Step 5: 1,1'-(3-(Benzylthio)-4,7-dihydro-1H-pyrazolo[3,4-c]pyridine-1,6(5H)-diyl)bis(ethan-1-one) (18f)

[0470] In a 250 mL round-bottom flask, 18e (2.00 g, 7.11 mmol) was dissolved in dichloromethane (50 mL). N,N-diisopropylethylamine (1.84 g, 14.22 mmol) and acetyl chloride (1.38 g, 17.78 mmol) were then added sequentially. The mixture was reacted in an ice bath for 4 h. 100 mL of pure water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated to obtain the crude product, which was purified on a silica gel column to afford 18f as a colorless oil (1.75 g, 75% yield). LC-MS: 330.1 [M+H] + .

[0471] Step 6: 1,6-diacetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-sulfonyl chloride (18 g)

[0472] In a 100 mL round-bottom flask, 18f (1.65 g, 5.00 mmol) was dissolved in acetic acid / water (v / v, 3 / 1, 30 mL) and placed in an ice bath. Chlorosuccinimide (1.99 g, 15.00 mmol) was then added and the mixture was allowed to react in an ice bath for 1 h. 200 mL of water was then added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by column chromatography to afford 18f as an off-white solid (0.85 g, 54% yield). LC-MS: 306.1 [M+H] + Step 7: 1-(3-((4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)sulfonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 18)

[0473] In a 100 mL round-bottom flask, 18 g (305 mg, 1.00 mmol) was dissolved in dichloromethane (15 mL) and placed in an ice bath. 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine (302 mg, 1.00 mmol) and triethylamine (200 mg, 2.00 mmol) were then added and the mixture was allowed to react in an ice bath for 30 min. After the reaction was complete, 1 mL of aqueous ammonia was added, followed by 100 mL of water. Extraction was performed with ethyl acetate, and the organic phase was collected and concentrated to obtain the crude product. The crude product was separated on a C18 reverse phase column to obtain compound 18 as an off-white solid (120 mg, 24% yield). LC-MS: 493.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),7.85–7.66(m,1H),7.59–7.43(m,1H),4.71–4.60(m,2H),3.90–3.75(m,2H),3 .76–3.63(m,2H),2.91–2.78(m,1H),2.79–2.67(m,2H),2.67–2.54(m,2H),2.16–2.07(m,3H),1.90–1.69(m,4H)ppm.

[0474] Biological activity test

[0475] The inhibitory ability of Example compounds 1 to 18 of the present invention on RBP4-TTR complex formation was tested by HTRF. The test compounds were prepared as 10 mM stock solutions using DMSO, and then the stock solutions were further diluted to different test concentrations (1 μM starting, 3-fold dilution, 8 concentrations, 2 replicates) using reaction buffer (50 mM Tris-HCl pH 7.5, 1 mM DTT, 0.05% NP-40, 0.05% Prionex, 6% glycerol). 1 μL of each compound at various concentrations was added to a 384-well plate (Perkin Elmer, Proxiplate). 2 μL of RBP4-hFc (MCE, final concentration 12.5 nM) protein was added 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 in each well 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 deducting the background value, data processing and curve fitting (non-linear fitting, 4 parameters) were performed using Graphpad Prism 8.0 software, and IC 50 The results are shown in Table 1.

[0476] Table 1

[0477]

[0478] In conclusion, the compounds of the present invention have certain inhibitory ability on the formation of RBP4-TTR complex, especially compound 2 and compound 18.

[0479] 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. It is therefore intended that the embodiments be considered in all respects as illustrative and non-restrictive, and that reference should be made to the appended claims rather than to the foregoing embodiments, and all changes coming within the meaning and range of equivalents of the appended claims are intended to be embraced herein.

Claims

1. A compound having a structure as represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure represented by formula (I); in, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl; Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group; R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl; R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups; L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms; The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely a carbon position containing a group connecting bond; A is -NR 14 -, -SO2- or bond; R 14 is selected from hydrogen, deuterium or alkyl; B is selected from Y1, Y2, and Y3 are each independently selected from CR 19 NR 20 or heteroatoms; R 19 、R 20 Each is independently selected from H, deuterium, alkyl, hydroxy-substituted alkyl; F is selected from a bond or -CO-.

2. The compound according to claim 1, wherein L is selected from C containing 0 to 2 nitrogen atoms 6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups; C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 substituted by a substituent in a haloalkyl group; and / or R 14 The alkyl group is C 1-6 Alkyl; and / or Y1, Y2, and Y3 are each independently selected from CR 19 、O、N、NR 20 or S; R 19 、R 20 Selected from H, deuterium, C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl.

3. The compound according to claim 1, wherein L has one of the following structures: in, X 1 、X 2 Each independently CR 15 or N; R 15 、R 16 、R 17 、R 18 are each independently selected from hydrogen, deuterium, alkyl, hydroxy, amino, alkoxy or haloalkyl; m and n are integers of 0 to 5; and / or B is selected from Preferably, B is 4. The compound according to claim 1, wherein L has one of the following structures: Preferably, when L is B is not Preferably, when L is When A is a key, B is not 5. The compound according to claim 1, wherein R 1 、R 2 、R 3 、R 4 、R 5 The alkyl, cycloalkyl, heterocyclic, alkoxy and haloalkyl groups are C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 1-6 Alkoxy and C 1-6 alkyl halide; R 6 Selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 7 、R 8 、R 9 Selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 12 and R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or R 12 、R 13 and the P atoms connected to it to form phosphorus-containing C 1-9 heterocyclic ring; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

6. The compound according to claim 1, wherein R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane; Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group; R 6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl; R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 12 and R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

7. The compound according to any one of claims 1 to 6, which has a structure as represented by formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure represented by formula (II); in, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl; Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group; R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl; R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 12 and R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups; L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms; The bridged ring group, spirocyclic group, monocyclic group or paracyclic group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxyl, amino, alkoxy or haloalkyl, and when L is a monocyclic group or paracyclic group, the number of substituents is not 0, and the substitution position is not solely the carbon position containing the group connecting bond; A is -NR 14 - or key; R 14 is selected from hydrogen, deuterium or alkyl.

8. The compound according to any one of claims 1 to 7, which has one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

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

10. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating retinol binding protein 4-related diseases; Preferably, the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease or Best disease.

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