Phenylpiperidine compound and use thereof

Abstract

A phenylpiperidine compound and a use thereof. The phenylpiperidine compound is a compound represented by formula (0), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a prodrug, or a pharmaceutically acceptable salt or ester thereof. Also provided is a use of the phenylpiperidine compound in preparation of drugs for treating ophthalmic diseases.

Description

A phenylpiperidine compound and its application Technical Field

[0001] The present invention relates to a phenylpiperidine compound and application thereof in preparing medicines 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, as shown in compound (A), WO2014152018 discloses a class of substituted cyclopenta-tetrahydropyrrole compounds, as shown in compound (B), and WO2014151936 discloses a class of substituted octahydropyrrolo-pyrrole compounds, as shown in compound (C). These compounds, as RBP4 antagonists, still need to be improved in terms of inhibitory effect, membrane permeability, pharmacokinetics, drugability and drug safety. Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present invention provides, on one hand, a phenylpiperidine compound having a structure as shown in formula (0), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (0);

[0008] Among them, R 1 Selected from hydrogen, deuterium, cyano, nitro, cycloalkyl, heterocyclic, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 ;

[0009] R 2 ~R 5 are each independently selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl, and when R 1 When it is hydrogen, R 2 ~R 5 At least one of them is deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, thiol, cyano or cycloalkyl;

[0010] Or, R 1 ~R 5Connect at any ortho position to form a carbocyclic group or a heterocyclic group;

[0011] R a is selected from amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0013] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0014] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0015] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0016] R 12 ~R 13 are each independently 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;

[0017] R 1 ~R 13 and R a 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.

[0018] In some embodiments, in the compound of formula (0), R 1 ~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 Halogenated alkyl.

[0019] In some embodiments, in the compound of formula (0), R a Selected from amino, C1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0020] In some embodiments, in the compound of formula (0), 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.

[0021] In some embodiments, in the compound of formula (0), R 7 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.

[0022] In some embodiments, in the compound of formula (0), R 8 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.

[0023] In some embodiments, in the compound of formula (0), 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.

[0024] In some embodiments, in the compound of formula (0), 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, C6-10 Aryl or C 1-9 Heteroaryl.

[0025] In some embodiments, in the compound of formula (0), 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.

[0026] In some embodiments, in the compound of formula (0), R 12 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.

[0027] In some embodiments, in the compound of formula (0), 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.

[0028] In some embodiments, in the compound of formula (0), 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 2-6Alkenyl, 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.

[0029] In some embodiments, in the compound of formula (0), 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, azetyl, thietanyl or thiolanyl.

[0030] In some embodiments, in the compound of formula (0), R 2 is selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0031] In some embodiments, in the compound of formula (0), R 3 is selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0032] In some embodiments, in the compound of formula (0), R 4 is selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0033] In some embodiments, in the compound of formula (0), R 5 is selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0034] In some embodiments, in the compound of formula (0), R 1 ~R 5 They are connected at any ortho position to form a 4-6 membered carbocyclic group or a 4-6 membered oxoheterocyclic group.

[0035] In some embodiments, in the compound of formula (0), R a is selected from amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-isopropyl, -NH-n-butyl, -NH-tert-butyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl or piperazinyl.

[0036] In some embodiments, in the compound of formula (0), 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.

[0037] In some embodiments, in the compound of formula (0), R 7 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0038] In some embodiments, in the compound of formula (0), R 8 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0039] In some embodiments, in the compound of formula (0), R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0040] In some embodiments, in the compound of formula (0), 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.

[0041] In some embodiments, in the compound of formula (0), R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0042] In some embodiments, in the compound of formula (0), R 12 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0043] In some embodiments, in the compound of formula (0), R 13is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0044] In some embodiments, the compound has the structure shown in Formula (I):

[0045] In formula (I), R 1 ~R 5 The definition of is the same as that in formula (0).

[0046] In some embodiments, in Formula (I), R 4 and R 5 In some embodiments, in formula (I), R 4 and R 5 All are hydrogen.

[0047] 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 thereof;

[0048] Among them, R 1 Selected from deuterium, cyano, nitro, cycloalkyl, heterocyclic, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 、-P(=O)R 12 R 13 ;

[0049] R 2 ~R 3 Each is independently selected from hydrogen, deuterium, hydroxy, nitro, amino, -SF5, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0050] Or, R 1 ~R 3 Connect at any ortho position to form a carbocyclic group or a heterocyclic group;

[0051] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl;

[0052] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0053] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0054] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0055] R 12 ~R 13 are each independently 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;

[0056] R 1 ~R 3 and R 6 ~R 13The alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, cycloalkyl, 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.

[0057] In other embodiments, in the compound of formula (II), R 1 ~R 3 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 Halogenated alkyl.

[0058] In some embodiments, in the compound of formula (II), R 2 Selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, C 1-6 Alkoxy, carboxyl, mercapto, cyano, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, or C 1-6 Halogenated alkyl.

[0059] In some embodiments, in the compound of formula (II), R 3 Selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, C 1-6 Alkoxy, carboxyl, mercapto, cyano, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, or C 1-6 Halogenated alkyl.

[0060] In some embodiments, in the compound of formula (II):

[0061] 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;

[0062] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C1-9 heteroaryl;

[0063] 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;

[0064] 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;

[0065] R 12 ~R 13 are each independently 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.

[0066] In some embodiments, in the compound of formula (II), R 1 ~R 3 and R 6 ~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 1-6Halogenated 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, C 6-10 Halogenated aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0067] In some embodiments, in the compound of formula (II), R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetane, oxolane, azetidinyl, azetidine, thietanyl or thiolanyl; R 2 ~R 3 Each is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0068] In some embodiments, in the compound of formula (II), R 1 ~R 3 In some embodiments, in the compound of formula (II), R 1 and R 2 In some embodiments, in the compound of formula (II), R 2 and R 3 They are connected to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen-containing heterocyclic group.

[0069] In some embodiments, in the compound of formula (II):

[0070] 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;

[0071] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0072] R 10is 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;

[0073] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0074] R 12 ~R 13 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0075] In some embodiments, in the compound, R 1 Selected from: cyano, nitro, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, -OR 10 、-C(O)NR 7 R 8 、-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 ;

[0076] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano or C 1-6 alkyl;

[0077] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl or C 3-8 Halogenated cycloalkyl;

[0078] R 11Selected from hydrogen, deuterium, amino, C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0079] R 12 ~R 13 are each independently selected from hydrogen, deuterium or C 1-6 alkyl;

[0080] R 1 、R 7 ~R 13 C in 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl and C 1-9 The heterocyclic group 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.

[0081] In some embodiments, in the compound, R 1 Selected from the group consisting of:

[0082] -CN, -CF2CN, -NO2, -S-CH3, -S-CH2CH3, -S-CF3, -S-CF2H, -S-CF2CF3, -S-CF2CF2H, -S-CF2CF2C F3, -C(=NH)NH2, -C(=O)NH2, -OCH3, -O-CF3, -O-CF2H, -O-CF2CF3, -O-CF2CF2H, -O-CF2CF2CF3,

[0083] In some embodiments, in the compound, R 1 Selected from the group consisting of:

[0084] -S-CH3, -S-CH2CH3, -S-CF3, -S-CF2H, -S-CF2CF2H, -O-CF3, -O-CF2H, -O-CF2CF2H,

[0085] In some embodiments, in the compound, R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl or C 3-8 Halogenated cycloalkyl.

[0086] In some embodiments, in the compound, R 2 and R 3 Each is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0087] In some embodiments, in the compound, R 2 and R 3 are each independently selected from hydrogen, deuterium or halogen.

[0088] In some embodiments, in the compound, R 2 and R 3 All are F.

[0089] 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:

[0090] 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.

[0091] 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.

[0092] In some embodiments, the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease, or Best disease.

[0093] In another aspect, the present invention further provides a method for inhibiting the formation of an RBP4-TTR complex in a cell, comprising contacting the cell with an effective amount of the above-mentioned compound or pharmaceutical composition of the present invention.

[0094] In another aspect, the present invention also provides a method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the above-mentioned compound or pharmaceutical composition of the present invention.

[0095] In another aspect, the present invention also provides a method for inhibiting the formation of an RBP4-TTR complex in the serum of a subject, comprising administering an effective amount of the above-mentioned compound or pharmaceutical composition of the present invention to the subject.

[0096] In another aspect, the present invention also provides a method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering an effective amount of the above-mentioned compound or pharmaceutical composition of the present invention to the subject.

[0097] 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.

[0098] Detailed description of the present invention

[0099] Definitions and General Terms

[0100] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0109] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0110] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0111] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0112] Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. A compound prefixed with (+) or d is right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0113] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0114] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0115] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0116] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers), diastereomers, and geometric isomers (or conformers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0117] 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.

[0118] 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).

[0119] 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 that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through 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.

[0120] 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.

[0121] 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.

[0122] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] In another aspect, the compounds of the present 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described in the present invention, including groups with "trans", "cis" or "E", "Z" orientation, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0135] 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.

[0136] 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.

[0137] 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).

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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).

[0143] The term "halogen" refers to F, Cl, Br or I.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0149] Description of the compounds of the present invention

[0150] In one aspect, the present invention provides a compound having a structure as shown in formula (0), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (0);

[0151] Among them, R 1 Selected from hydrogen, deuterium, cyano, nitro, cycloalkyl, heterocyclic, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 R13 ;

[0152] R 2 ~R 5 are each independently selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl, and when R 1 When it is hydrogen, R 2 ~R 5 At least one of them is deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, thiol, cyano or cycloalkyl;

[0153] Or, R 1 ~R 5 Connect at any ortho position to form a carbocyclic group or a heterocyclic group;

[0154] R a is selected from amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0155] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0156] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0157] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0158] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0159] R 12 ~R 13 are each independently 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;

[0160] R 1 ~R 13 and R aThe 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.

[0161] In some embodiments, in the compound of formula (0):

[0162] R 1 ~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;

[0163] R a Selected from amino, C 1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0164] 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;

[0165] R 7 ~R 9 are each independently 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;

[0166] 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, C3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0167] 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;

[0168] R 12 ~R 13 are each independently 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;

[0169] R 1 ~R 13 and R a 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.

[0170] In some embodiments, in the compound of formula (0):

[0171] 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;

[0172] R 2 ~R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane;

[0173] Or, R 1 ~R 5 Connected at any ortho position to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen heterocyclic group;

[0174] R a is selected from amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-isopropyl, -NH-n-butyl, -NH-tert-butyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl or piperazinyl;

[0175] 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;

[0176] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0177] 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;

[0178] R 11is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0179] R 12 ~R 13 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0180] In some embodiments, the compound has the structure shown in Formula (I):

[0181] In formula (I), R 1 ~R 5 The definition of is the same as that in formula (0).

[0182] In some embodiments, in formula (I), R 4 and R 5 At least one of them is hydrogen.

[0183] In some embodiments, in formula (I), R 4 and R 5 All are hydrogen.

[0184] 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 thereof;

[0185] Among them, R 1 Selected from deuterium, cyano, nitro, cycloalkyl, heterocyclic, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)NR 7 R 8 、-C(=O)R 6 、-C(=O)OR 10 、-C(=O)NR 7 R8 、-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 、-P(=O)R 12 R 13 ;

[0186] R 2 ~R 3 Each is independently selected from hydrogen, deuterium, hydroxy, nitro, amino, -SF5, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0187] Or, R 1 ~R 3 Connect at any ortho position to form a carbocyclic group or a heterocyclic group;

[0188] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl;

[0189] R 7 ~R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0190] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0191] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0192] R 12 ~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;

[0193] R 1 ~R 3 and R 6 ~R 13The alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, cycloalkyl, 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.

[0194] In other embodiments, the compound of formula (II), R 1 ~R 3 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 Halogenated alkyl.

[0195] In some embodiments, the compound of formula (II), R 1 Selected from deuterium, cyano, nitro, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 NR9 、-C(=NR 9 )NR 7 R 8 、-P(=O)R 12 R 13 ;

[0196] R 2 ~R 3 Each independently selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, C 1-6 Alkoxy, carboxyl, mercapto, cyano, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, or C 1-6 Halogenated alkyl.

[0197] In some embodiments, the compound of formula (II), R 1 and R 2 are connected to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen-containing heterocyclic group. In some embodiments, the compound of formula (II), R 2 and R 3 Connected to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen-containing heterocyclic group

[0198] In some embodiments, the compound of formula (II), 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;

[0199] R 7 ~R 9 are each independently 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;

[0200] 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;

[0201] 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;

[0202] R 12 ~R 13 are each independently 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.

[0203] In some embodiments, the compound of formula (II), R 1 ~R 3 and R 6 ~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, C 6-10 Halogenated aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0204] In some embodiments, in the compound, R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl;

[0205] R 2 ~R 3 Each is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0206] In some embodiments, in the compound of formula (II):

[0207] 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;

[0208] R 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0209] 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;

[0210] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0211] R 12 ~R 13 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0212] In some embodiments, in the compound of formula (II):

[0213] R 1 Selected from cyano, nitro, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, -OR 10 、-C(O)NR 7 R8 、-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 7 ~R 9 Selected from hydrogen, deuterium, cyano or C 1-6 Alkyl; R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl or C 3-8 Halogenated cycloalkyl; R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl or C 3-8 Cycloalkyl; R 12 ~R 13 Selected from hydrogen, deuterium or C 1-6 alkyl;

[0214] R 1 、R 7 ~R 13 C in 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl and C 1-9 The heterocyclic group 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.

[0215] In some embodiments, the compound of formula (II), R 1 Selected from the group consisting of:

[0216] -CN, -CF2CN, -NO2, -S-CH3, -S-CH2CH3, -S-CF3, -S-CF2H, -S-CF2CF3, -S-CF2CF2H, -S-CF2CF2C F3, -C(=NH)NH2, -C(=O)NH2, -OCH3, -O-CF3, -O-CF2H, -O-CF2CF3, -O-CF2CF2H, -O-CF2CF2CF3,

[0217] In some embodiments, the compound of formula (II), R 1 Selected from the group consisting of:

[0218] -S-CH3, -S-CH2CH3, -S-CF3, -S-CF2H, -S-CF2CF2H, -O-CF3, -O-CF2H, -O-CF2CF2H,

[0219] In some embodiments, the compound of formula (II), R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl or C 3-8 Halogenated cycloalkyl.

[0220] In some embodiments, the compound of formula (II), R 2 and R 3 Each is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane.

[0221] In some embodiments, the compound of formula (II), R 2 and R 3 are each independently selected from hydrogen, deuterium or halogen.

[0222] In some embodiments, the compound of formula (II), R 2 and R 3 All are halogens.

[0223] In some embodiments, the compound of formula (II), R 2 and R 3 All are F.

[0224] 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:

[0225] Compositions, formulations and administration of the compounds of the present invention

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] Uses of the compounds and compositions of the present invention

[0231] 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.

[0232] 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

[0233] 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.

[0234] General synthesis process

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] Silica gel was used as the chromatographic column. 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 the reference standard. 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).

[0241] The following abbreviations are used throughout this disclosure:

[0242] AcOH: acetic acid

[0243] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0244] Boc: tert-butyloxycarbonyl

[0245] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0246] CH3CN: acetonitrile

[0247] DCM: dichloromethane

[0248] DIPEA: N,N-diisopropylethylamine

[0249] EA: ethyl acetate

[0250] HCl: hydrogen chloride

[0251] HCl / EA: Hydrogen chloride in ethyl acetate

[0252] H2O: water

[0253] NaOH: sodium hydroxide

[0254] NaI: sodium iodide

[0255] K2CO3: Potassium carbonate

[0256] rt, rt: room temperature

[0257] TBAF: Tetrabutylammonium fluoride

[0258] Example 1

[0259] 1-(3-(4-(3,4-difluoro-2-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 1)

[0260] Step 1: tert-Butyl 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine-1-carboxylate (1c)

[0261] Under nitrogen protection, compound 1a (478 mg, 2.0 mmol), compound 1b (792 mg, 3.0 mmol), nickel chloride dimethoxyethane (22 mg, 0.1 mmol), 4-4'-di-tert-butylbipyridine (27 mg, 0.1 mmol), 2,6-lutidine (1.07 g, 10.0 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (112 mg, 0.1 mmol) and ethylene glycol dimethyl ether (30 mL) were added in sequence in a 100 mL three-necked flask and irradiated with 420 nm LED light at room temperature for 2 h. The mixture was quenched with water, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1 to 10:1) to afford compound 1c as a yellow oil (295 mg, yield: 43%). LCMS: 344.1 [M+H] + .

[0262] Step 2: tert-Butyl 4-(3,4-difluoro-2-(methylsulfonyl)phenyl)piperidine-1-carboxylate (1d)

[0263] In a 100 mL round-bottom flask, compound 1c (270 mg, 0.79 mmol) was dissolved in dichloromethane (20 mL). Meta-chloroperbenzoic acid (406 mg, 2.36 mmol, purity: 85%) was added and allowed to react at room temperature for 4 h. The mixture was quenched with aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated under reduced pressure to remove the organic solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1 to 5:1) to obtain compound 1d (210 mg, yield: 70%) as a white solid. LCMS: 376.1 [M+H] + .

[0264] Step 3: 4-(3,4-difluoro-2-(methylsulfonyl)phenyl)piperidine hydrochloride (1e)

[0265] In a 100 mL round-bottom flask, compound 1d (200 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL). 2 mL of HCl (4 M 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 compound 1e (165 mg, 100% yield) as a white solid. LCMS: 312.1 [M+H] + .

[0266] Step 4: 1-(3-(4-(3,4-difluoro-2-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 1)

[0267] In a 100 mL round-bottom flask, compound 1d (165 mg, 0.53 mmol) and compound 1f (111 mg, 0.53 mmol) were dissolved in dichloromethane (10 mL) at room temperature. Diisopropylethylamine (388 mg, 3.0 mmol), 1-hydroxybenzotriazole (14 mg, 0.11 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) were added sequentially. The mixture was allowed to react at room temperature for 4 h. The reaction was quenched with 1 M HCl (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 1 (85 mg, 34% yield) as a white solid. LCMS: 467.1 [M+H] + ; 1 H NMR(500MHz, CDCl3)δ11.46(s,1H),7.47–7.36(m,1H),7.27–7.18(m,1H),5.00–4.52(m,4H),4.25(s,1H),3.93–3.58( m,2H),3.35(s,3H),3.31–2.88(m,2H),2.88–2.65(m,2H),2.25–2.17(m,3H),2.03–1.88(m,2H),1.77–1.60(m,2H)ppm.

[0268] Example 2

[0269] 1-(3-(4-(3,4-difluoro-2-(methylthio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 2)

[0270] Step 1: 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine hydrochloride (2a)

[0271] In a 100 mL round-bottom flask, compound 1c (100 mg, 0.29 mmol) was dissolved in dichloromethane (10 mL). 1 mL of hydrochloric acid / 1,4-dioxane solution (4 mol / L) was added and allowed to react at room temperature for 2 h. TLC confirmed the reaction was complete, and the organic solvent was removed by direct concentration under reduced pressure to obtain compound 2a (80 mg) as a white solid. LCMS: 234.1 [M+H] + .

[0272] Step 2: 1-(3-(4-(3,4-difluoro-2-(methylthio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 2)

[0273] In a 100 mL round-bottom flask, compound 2a (80 mg, 0.29 mmol) and compound 1f (65 mg, 0.31 mmol) were dissolved in dichloromethane (10 mL) at room temperature. Diisopropylethylamine (116.33 mg, 0.9 mmol), 1-hydroxybenzotriazole (4 mg, 0.03 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg, 0.38 mmol) were added sequentially. The mixture was allowed to react at room temperature for 4 h. The reaction was quenched with 1 M HCl (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 (acetonitrile / water: 0-60%) to afford compound 2 (45 mg, 36% yield) as a white solid. LCMS: 435.2 [M+H] + ; 1 H NMR (500MHz, CDCl3) δ7.16–7.06(m,1H),7.00–6.92(m,1H),5.03–4.56(m,4H),3.98–3.65(m,2H),3.65–3.54(m,1H ),3.43–2.90(m,2H),2.94–2.63(m,2H),2.47(s,3H),2.26–2.18(m,3H),1.92-1.81(m,2H),1.72-1.60(m,2H)ppm.

[0274] Example 3

[0275] 6-(1-(6-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorobenzonitrile (Compound 3)

[0276] Step 1: tert-Butyl 4-(2-cyano-3,4-difluorophenyl)piperidine-1-carboxylate (3b)

[0277] Under nitrogen protection, compound 1b (1036 mg, 3.3 mmol), compound 3a (500 mg, 2.3 mmol), nickel chloride dimethoxyethane (6 mg, 0.03 mmol), tris(trimethylsilyl)silane (1.43 g, 5.7 mmol), 4-4'-di-tert-butylbipyridine (7 mg, 0.03 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (30 mg, 0.03 mmol) and ethylene glycol dimethyl ether (40 mL) were added in sequence in a 100 mL single-necked bottle and irradiated with 420 nm LED light at room temperature for 3 h. The mixture was quenched with water, extracted with ethyl acetate (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 (petroleum ether:ethyl acetate = 10:1) to afford compound 3b as a yellow oil (470 mg, yield 56%). LCMS: 323.2 [M+H] + .

[0278] Step 2: 2,3-Difluoro-6-(piperidin-4-yl)benzonitrile (3c)

[0279] In a 100 mL round-bottom flask, compound 3b (470 mg, 1.46 mmol) was dissolved in ethyl acetate (2 mL). 10 mL of a 4 M hydrochloric acid / ethyl acetate solution was added and the mixture was allowed to react at room temperature for 4 h. The organic solvent was removed by direct concentration under reduced pressure to afford compound 3c (324 mg, 100% yield) as a white solid. LCMS: 223.1 [M+H] + .

[0280] Step 3: (6-(1-(6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorobenzonitrile (Compound 3)

[0281] In a 50 mL round-bottom flask, compound 1f (112 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (0.44 mL, 2.25 mmol). The mixture was cooled to 0°C and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (222 mg, 0.58 mmol) was added. The mixture was stirred at 0°C for 10 min, followed by the addition of compound 3c (100 mg, 0.45 mmol). The reaction was allowed to react at room temperature for 3 h. The reaction was quenched by the addition of pure water and extracted with ethyl acetate (3 × 10 mL). The organic phase was concentrated to obtain the crude product, which was separated using a C18 reverse phase column (acetonitrile / water: 0-100%) to afford compound 3 (80 mg, 43% yield) as an off-white solid. LCMS: 414.2 [M+H] + .1 H NMR (400MHz, DMSO) δ12.98(s,1H),7.86–7.80(m,1H),7.48–7.42(m,1H),4.62(s,2H),3.68–3.64(m,2H),3.19–3.11(m, 2H),2.92–2.82(m,1H),2.76–2.54(m,3H),2.11(d,J=6.2Hz,3H),1.91–1.81(m,2H),1.78–1.61(m,2H),1.25(s,1H)ppm.

[0282] Example 4

[0283] 1-(3-(4-(2,3-dihydrobenzofuran-6-H)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 4)

[0284] Step 1: tert-Butyl 4-(2,3-dihydrobenzofuran-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4c)

[0285] Under nitrogen, compound 4a (800 mg, 4.0 mmol), compound 4b (4.85 g, 15.7 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (292 mg, 0.4 mmol), potassium phosphate (1.70 g, 8 mmol), and 1,4-dioxane / water (20 mL / 2 mL) were added sequentially to a 100 mL three-necked flask and heated to 100°C for 8 h. The reaction was monitored by TLC, cooled to room temperature, quenched with water, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1 to 10:1) to afford compound 4c (1.1 g, yield: 91%) as a white solid. LCMS: 302.2 [M+H] + .

[0286] Step 2: tert-Butyl 4-(2,3-dihydrobenzofuran-6-yl)piperidine-1-carboxylate (4d)

[0287] In a 100 mL round-bottom flask, compound 4c (600 mg, 2.0 mmol) was dissolved in methanol (20 mL). 10% palladium on carbon (400 mg) was added and the mixture was reacted under 1 atm of hydrogen pressure for 8 h. The mixture was filtered and the filtrate was directly concentrated under reduced pressure to remove the organic solvent, affording compound 4d (620 mg, yield: 100%) as a white solid. LCMS: 304.2 [M+H] + .

[0288] Step 3: 4-(2,3-dihydrobenzofuran-6-yl)piperidine hydrochloride (4e)

[0289] In a 100 mL round-bottom flask, compound 4d (303 mg, 1 mmol) was dissolved in DCM (5 mL). 2 mL of HCl (4 M 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 compound 4e (210 mg, yield: 100%) as a white solid. LCMS: 240.1 [M+H] + .

[0290] Step 4: 1-(3-(4-(2,3-dihydrobenzofuran-6-H)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 4)

[0291] In a 100 mL round-bottom flask, compound 1f (210 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (10 mL) under ice. Diisopropylethylamine (387.75 mg, 3.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (494 mg, 1.3 mmol), and compound 4e (210 mg, 0.88 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. The reaction was quenched with 1 M HCl (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 (acetonitrile / water: 0-60%) to afford compound 4 (200 mg, 50% yield) as a white solid. LCMS: 395.2 [M+H] + ; 1 H NMR (500MHz, CDCl3) δ11.06 (s, 1H), 7.14 (d, J = 7.5Hz, 1H), 6.73–6.66 (m, 2H ),4.78(s,2H),4.67(s,1H),4.58(t,J=8.7Hz,3H),3.86(s,1H),3.70(t,J=5 .7Hz,2H),3.20(t,J=8.6Hz,3H),2.86–2.84(m,2H),2.80–2.75(m,1H),2.7 2–2.69(m,1H),2.23–2.21(m,3H),1.97–1.91(m,2H),1.76–1.68(m,2H)ppm.

[0292] Example 5

[0293] 1-(3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 5)

[0294] Step 1: tert-Butyl 4-(3,4-difluoro-2-methoxyphenyl)piperidine-1-carboxylate (5b)

[0295] Compound 5a (2.00 g, 8.968 mmol), compound 1b (2.84 g, 10.76 mmol), bispinacol boronate (4.10 g, 16.14 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl) nickel dibromide (0.44 g, 0.90 mmol), sodium iodide (2.69 g, 17.94 mmol) and potassium carbonate (2.48 g, 17.94 mmol) were added to N, N -dimethylacetamide (20 mL) solution, stirred at 60 ° C under nitrogen protection for 8 hours. After the reaction is completed, water (80 mL) is added to quench the reaction, and ethyl acetate is extracted (80 mL × 2). The combined organic phase is washed with saturated brine (150 mL × 5), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 5b (1.40 g, yield: 48%). LCMS: 328.1 [M+H] + .

[0296] Step 2: 2,3-Difluoro-6-(piperidin-4-yl)phenol (5c)

[0297] In a 100 mL three-necked flask, compound 5b (1.40 g, 4.277 mmol) was dissolved in anhydrous dichloromethane (10 mL). The temperature was lowered to 0°C, and boron tribromide (21.4 mL, 21.383 mmol, 1 mol / L) was slowly added dropwise. After the addition, the mixture was stirred at 25°C for 1 h. After the reaction was complete, the mixture was slowly added dropwise to methanol (20 mL) to quench the reaction. After quenching, the mixture was directly dried under reduced pressure to obtain crude product 5c (1.00 g). LCMS: 214.1 [M+H] + .

[0298] Step 3: tert-Butyl 4-(3,4-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate (5d)

[0299] Compound 5c (900 mg, 4.22 mmol), triethylamine (2.14 g, 21.10 mmol), and di-tert-butyl dicarbonate (1.38 g, 6.331 mmol) were added sequentially to a solution of dichloroethane (10 mL) and stirred at 25°C for 8 h. The reaction was quenched by adding water (20 mL), and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford compound 5d (850.00 mg, yield: 64%). LCMS: 314.0 [M+H] + .

[0300] Step 4: tert-Butyl 4-(2-(bromodifluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (5e)

[0301] In a 50 mL pressure bottle, compound 5d (1.00 g, 3.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled to 0°C, and sodium hydroxide (255.31 mg, 6.38 mmol, purity: 60%) was added. After the addition, the mixture was stirred for 30 minutes. Difluorodibromomethane (3.35 g, 15.96 mmol) was then added and stirred at 25°C for 8 hours. After completion, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (40 mL × 5), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 5e (800 mg, yield: 57%). LCMS: 442.0, 444.0 [M+H] + .

[0302] Step 5: 4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine (5f)

[0303] Compound 5e (800.00 mg, 1.81 mmol) and silver tetrafluoroborate (1.76 g, 9.05 mmol) were added sequentially to a solution of 1,2-dichloroethane (15 mL). The mixture was stirred at 60°C under nitrogen for 1 h. After completion, water (0.5 mL) was added to quench the reaction, and the mixture was filtered. The filtrate was then dried to give a crude product, which was then separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 5f (400 mg, yield: 79%). LCMS: 282.1 [M+H] + .

[0304] Step 6: 1-(3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 5)

[0305] Compound 5f (200 mg, 0.71 mmol), compound 1f (223 mg, 1.07 mmol), N,N-diisopropylethylamine (460 mg, 3.56 mmol), and butylphosphonic anhydride (1.03 g, 1.42 mmol, 50% ethyl acetate solution) were added sequentially to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition, the mixture was stirred at 25°C under nitrogen for 8 h. After the reaction was completed, methanol was added to quench the reaction. The mixture was then directly isolated and purified by preparative liquid chromatography (neutral, mobile phase acetonitrile and water) to obtain compound 5 (120 mg, yield: 36%). LCMS: 473.1 [M+H] + . 1 H NMR(500MHz,d-DMSO)δ13.12–12.88(m,1H),7.60–7.47(m,1H),7.42–7.35(m,1H),4.83–4.61(m,4H) ,3.71–3.60(m,2H),3.20–3.08(m,2H),2.81–2.57(m,3H),2.15–2.06(m,3H),1.80–1.58(m,4H)ppm.

[0306] Example 6

[0307] 1-(3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 6)

[0308] Step 1: tert-Butyl 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (1c)

[0309] Compound 5d (5.00 g, 15.96 mmol), compound 6a (16.39 g, 61.38 mmol), and potassium carbonate (11.03 g, 79.79 mmol) were added sequentially to a mixed solution of acetonitrile (25 mL) and water (25 mL). The mixture was stirred at 25°C for 8 h. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 5), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain compound 6b (3.00 g, yield: 52%). LCMS: 364.1 [M+H] + .

[0310] Step 2: 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine hydrochloride (6c)

[0311] Compound 6b (600.00 mg, 1.651 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (10 mL, 4 mol / L). The mixture was stirred at 25°C for 1 h. After the reaction was complete, the mixture was dried under reduced pressure to obtain compound 6c (450 mg, yield: 91%). LCMS: 264.0 [M+H] + .

[0312] Step 3: 1-(3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 6)

[0313] Compound 1f (200 mg, 0.96 mmol), N,N-diisopropylethylamine (371 mg, 2.87 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (546 mg, 1.42 mmol) were added sequentially to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition, the mixture was stirred at 25°C under nitrogen protection for 1 h. Then, compound 6c (286 mg, 0.96 mmol) was added and stirred at 25°C for 8 h. After the reaction was completed, water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (40 mL×5), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. The crude product was separated and purified by preparative liquid chromatography (mobile phase: acetonitrile and 0.5% formic acid aqueous solution) to give compound 6 (70 mg, yield: 16%). LCMS: 455.08 [M+H] + . 1H NMR (500MHz, d-DMSO) δ13.23–12.89(m,1H),7.39–7.10(m,3H),4.92–4.45(m,4H),3.75–3. 50(m,2H),3.26–3.00(m,2H),2.85–2.51(m,3H),2.18–1.99(m,3H),1.85–1.50(m,4H)ppm.

[0314] Example 7

[0315] 1-(3-(4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 7)

[0316] Step 1: tert-Butyl 4-(2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (7b)

[0317] In a 100 mL pressure bottle, compound 5d (1.60 g, 5.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), cooled to 0°C, and sodium hydroxide (410 mg, 10.21 mmol, purity: 60%) was added. After the addition, the mixture was stirred for 30 minutes. Compound 7a (3.35 g, 12.89 mmol) was then added and stirred at 25°C for 8 hours. After completion, the reaction was quenched with water (60 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated brine (120 mL × 5), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 7b (1.80 g, yield: 72%). LCMS: 442.0, 444.0 [M+H] + .

[0318] Step 2: tert-Butyl 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine-1-carboxylate (7c)

[0319] Compound 7b (600 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0°C under nitrogen, and ethylmagnesium bromide (3.7 mL, 3.66 mmol, 1 mol / L) was added. The mixture was stirred at 25°C for 8 h. After completion of the reaction, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel thin layer chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 7c (250 mg, yield: 52%). LCMS: 394.1 [M+H] + .

[0320] Step 3: 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine hydrochloride (7d)

[0321] Compound 7c (250 mg, 0.64 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (5 mL, 4 mol / L). The mixture was stirred at 25°C for 1 h. After the reaction was complete, the mixture was dried under reduced pressure to give compound 7d (209 mg). LCMS: 294.0 [M+H] + Step 4: 1-(3-(4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 7)

[0322] Compound 7d (209 mg, 0.63 mmol), compound 1f (199 mg, 0.95 mmol), N,N-diisopropylethylamine (410 mg, 3.17 mmol), and butylphosphonic anhydride (913 mg, 1.27 mmol, 50% ethyl acetate solution) were added sequentially to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition, the mixture was stirred at 25°C under nitrogen protection for 8 h. After the reaction was completed, methanol was added to quench the reaction. The mixture was then directly separated and purified by preparative liquid chromatography (neutral, mobile phase acetonitrile and water) to obtain compound 7 (150 mg, yield: 48%). LCMS: 485.1 [M+H] + . 1H NMR(500MHz,d-DMSO)δ13.16–12.88(m,1H),7.50–7.35(m,1H),7.34–7.25(m,1H),4.90–4.50(m,4H) ,3.72–3.55(m,2H),3.30–3.05(m,2H),2.90–2.55(m,3H),2.15–2.00(m,3H),1.85–1.51(m,4H)ppm.

[0323] Example 8

[0324] 1-(3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 8)

[0325] Step 1: tert-Butyl 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine-1-carboxylate (8a)

[0326] Compound 7b (250 mg, 0.508 mmol) and cesium fluoride (231 mg, 1.52 mmol) were added sequentially to a solution of dimethyl sulfoxide (5 mL) and stirred at 120°C for 8 h. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 5), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford compound 8a (200 mg, yield: 95%). LCMS: 414.04 [M+H] + .

[0327] Step 2: 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine hydrochloride (8b)

[0328] Compound 8a (200 mg, 0.48 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (5 mL, 4 mol / L). The mixture was stirred at 25°C for 1 h. After the reaction was complete, the mixture was dried under reduced pressure to give compound 8b (169 mg). LCMS: 314.0 [M+H] + Step 3: 1-(3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 8)

[0329] Compound 8b (169 mg, 0.48 mmol), compound 1f (152 mg, 0.75 mmol), N,N-diisopropylethylamine (312 mg, 2.42 mmol), and butylphosphonic anhydride (3.60 g, 5.0 mmol, 50% ethyl acetate solution) were added sequentially to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition, the mixture was stirred at 25°C under nitrogen for 8 h. After the reaction was completed, methanol was added to quench the reaction. The mixture was then directly isolated and purified by preparative liquid chromatography (neutral, mobile phase acetonitrile and water) to obtain compound 8 (80 mg, yield: 33%). LC-MS: 505.1 [M+H] + . 1 H NMR(500MHz,d-DMSO)δ7.52–7.43(m,1H),7.38–7.30(m,1H),7.13–6.89(m,1H),4.82–4.41(m,4H), 3.72–3.56(m,2H),3.16–2.96(m,2H),2.91–2.54(m,3H),2.15–2.04(m,3H),1.85–1.51(m,4H)ppm.

[0330] Example 9

[0331] 1-(3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one

[0332] Step 1: tert-Butyl 4-(2-amino-3,4-difluorophenyl)piperidine-1-carboxylate (9b)

[0333] In a 100 mL three-necked flask, compound 9a (200 mg, 0.96 mmol), compound 1b (760 mg, 2.88 mmol), sodium iodide (720 mg, 4.81 mmol), potassium carbonate (600 mg, 4.33 mmol), bis(boronic acid)-pinacol ester (1.1 g, 4.33 mmol), and (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (117 mg, 0.24 mmol) were dissolved in anhydrous N,N-dimethylacetamide (10 mL). The reaction liquid was then nitrogen-purified three times and heated to 60°C, where the temperature was maintained for 6 hours. After the reaction was complete, the reaction solution was poured directly into water (50 mL), followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in petroleum ether (10 mL) and stirred at room temperature for 30 minutes. A large amount of solid precipitated, which was filtered, collected, and dried under vacuum to obtain compound 9b (600 mg, yield: 80%) as an off-white solid. LCMS: 313.4 [M+H] + .

[0334] Step 2: tert-Butyl 4-(3,4-difluoro-2-iodophenyl)piperidine-1-carboxylate (9c)

[0335] In a 50 mL round-bottom flask, cuprous iodide (731 mg, 3.84 mmol) and tert-butyl nitrite (400 mg, 3.84 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at room temperature for 5 minutes. The reaction solution was then heated directly to 60°C. At this temperature, a solution of compound 9b (600 mg, 1.92 mmol) in acetonitrile (1 mL) was added dropwise, and the temperature was maintained for 30 minutes. After the reaction was completed, the reaction solution was cooled directly to room temperature, poured into water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 9c (500 mg, 49.2% yield) as an off-white solid. LCMS: 424.2 [M+H] + .

[0336] Step 3: tert-Butyl 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine-1-carboxylate (9d)

[0337] In a 30 mL microwave tube, compound 9c (500 mg, 1.18 mmol), silver trifluoromethylthioate (700 mg, 3.54 mmol), cuprous iodide (450 mg, 2.36 mmol), bipyridine (370 mg, 2.36 mmol), and N-methylpyrrolidone (10 mL) were added sequentially. Under nitrogen protection, the mixture was microwaved at 150°C for 1 hour. After completion of the reaction, the reaction solution was poured directly into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (50 mL × 3) and saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography afforded compound 9d (189 mg, yield: 40.26%) as a colorless oil. LCMS: 398.4 [M+H] + .

[0338] Step 4: 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine (9e)

[0339] In a 50 mL round-bottom flask, compound 9d (180 mg, 0.45 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid / ethyl acetate solution (4 M, 10 mL) was slowly added dropwise under an ice bath. The reaction was maintained at this temperature for 2 hours. The reaction solution was then concentrated to dryness to obtain compound 9e (136 mg) as an off-white solid. LCMS: 298.0 [M+H] + .

[0340] Step 5: 1-(3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 9)

[0341] In a 50 mL round-bottom flask, compound 1f (94 mg, 0.45 mmol) and triethylamine (123 mg, 1.22 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The reaction solution was then cooled to 0°C and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) was added. The temperature was maintained for 15 minutes, followed by the addition of compound 9e (136 mg, 0.34 mmol) and the temperature was maintained for 2 hours. After completion of the reaction, the reaction solution was poured directly into water (50 mL) and extracted with ethyl acetate (30 × 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative liquid chromatography was then performed to obtain compound 9 (30 mg, 15% yield) as a white solid. LCMS: 489.1 [M+H] + . 1H NMR(500MHz,DMSO)δ7.75–7.70(m,1H),7.45–7.43(m,1H),4.65–4.60(m,4H),3.69–3.54 (m,4H),2.70–2.68(m,2H),2.58–2.55(m,1H),2.11–2.09(m,3H),1.79–1.56(m,4H)ppm.

[0342] Example 10

[0343] 1-(3-(4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 10)

[0344] Step 1: tert-Butyl 4-(2-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (10a)

[0345] In a 100 mL round-bottom flask, compound 9c (3 g, 7.09 mmol), 2-ethylhexyl 3-mercaptopropionate (4.87 g, 22.3 mmol), potassium carbonate (2.94 g, 21.27 mmol) and 1,4-dioxane (45 mL) were added in sequence, and finally 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (0.82 g, 1.42 mmol) and tris(dibenzylideneacetone)dipalladium (0.65 g, 0.71 mmol) were added in sequence. After replacing the air with nitrogen three times, the mixture was reacted at 100 °C for 6 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the filtrate for dilution, and the mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain crude compound 10a (4.58 g) as a yellow oil. LCMS: 514.2 [M+H] + Step 2: tert-Butyl 4-(3,4-difluoro-2-mercaptophenyl)piperidine-1-carboxylate (10b)

[0346] Compound 10a (4.58 g, 8.92 mmol) and anhydrous tetrahydrofuran (50 mL) were added sequentially to a 100 mL round-bottom flask. Sodium ethoxide (0.61 g, 8.92 mmol) was added portionwise at 0°C and allowed to react for 30 min. The reaction was quenched by adding 2 M potassium bisulfate solution at 0°C to adjust the pH to 5. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain Compound 10b (2.2 g, yield: 68%) as a yellow oil. LCMS: 330.1 [M+H] + .

[0347] Step 3: tert-Butyl 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (10c)

[0348] To a 100 mL round-bottom flask, compound 10b (500 mg, 1.52 mmol), potassium hydroxide (426 mg, 7.59 mmol), acetonitrile (5 mL), and water (5 mL) were added sequentially. A solution of diethyl bromofluoromethylphosphonate (2.03 g, 7.60 mmol) in acetonitrile (5 mL) was added dropwise at -20°C. The mixture was allowed to react at -20°C for 1 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 10c (454 mg, yield: 72%) as a yellow oil. LCMS: 380.1 [M+H] + .

[0349] Step 4: 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine hydrochloride (10d)

[0350] In a 50 mL round-bottom flask, compound 10c (454 mg, 1.20 mmol) was dissolved in ethyl acetate (2 mL). 4 mol ethyl acetate hydrochloride (10 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 h. The reaction solution was concentrated under reduced pressure to afford compound 10d (378 mg) as an off-white solid. LCMS: 280.1 [M+H] + .

[0351] Step 5: 1-(3-(4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 10)

[0352] In a 25 mL round-bottom flask, compound 1f (86 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (0.28 mL, 1.58 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (157 mg, 0.41 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 30 min. Finally, compound 10d (100 mg, 0.32 mmol) was added and the reaction was carried out at room temperature for 3 h. The reaction was complete after TLC detection, and water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain an off-white solid compound 10 (18 mg, yield: 12%). LCMS: 471.1 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.32–7.26(m,1H),7.11–7.04(m,1H),6.87(t,J=57.0 Hz,1H),5.03–4.59(m,4H),4.54–4.01(m,1H),3.93–3.74(m,1H),3.70–3.66 (m,1H),3.65–3.58(m,1H),3.26–2.89(m,2H),2.85(t,J=5.3Hz,1H),2.69(t ,J=5.3Hz,1H),2.23–2.16(m,3H),1.89–1.78(m,2H),1.72–1.62(m,2H)ppm.

[0353] Example 11

[0354] 1-(3-(4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one

[0355] Step 1: tert-Butyl 4-(2-((2-bromo-1,1,2,2-tetrafluoroethyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (11a)

[0356] In a 100 mL three-necked flask, compound 10b (5.0 g, 15.18 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL). The reaction solution was then cooled to 0°C and sodium hydride (910 mg, 22.77 mmol) was added. The mixture was allowed to react at room temperature for 15 minutes. The reaction solution was then cooled to 0°C again and 1,2-dibromo-1,1,2,2-tetrafluoroethane (11.83 g, 45.54 mmol) was added dropwise. The temperature was maintained for 2 hours. The reaction solution was poured directly into 200 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 10%) to obtain compound 11a (6.0 g, yield: 78%) as a colorless oil. LC-MS: 509.3, 511.3 [M+H] + .

[0357] Step 2: tert-Butyl 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine-1-carboxylate (11b)

[0358] In a 100mL round-bottom flask, ethylmagnesium bromide (17.7mL, 17.71mmol) was added dropwise to anhydrous tetrahydrofuran (40mL). The reaction mixture was then cooled to 0°C under nitrogen and a solution of compound 11a (3.0g, 5.9mmol) in tetrahydrofuran (10mL) was quickly added dropwise. The temperature was maintained for 15 minutes. After the reaction, the reaction mixture was poured into 200mL of ice water and extracted with ethyl acetate (50mL x 3). 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 (ethyl acetate / petroleum ether = 0% to 10%) to obtain compound 11b (1.5g, 62% yield) as a colorless oil. LCMS: 410.4 [M+H] + .

[0359] Step 3: 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine (11c)

[0360] In a 100 mL round-bottom flask, compound 11b (1.5 g, 3.66 mmol) was dissolved in anhydrous dioxane (5 mL). A hydrochloric acid / dioxane solution (20 mL) was then added and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to dryness to obtain a crude off-white solid compound 11c (1.1 g). LCMS: 310.0 [M+H] + .

[0361] Step 4: 1-(3-(4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 11)

[0362] In a 50 mL round-bottom flask, compound 11c (100 mg, 0.29 mmol) and compound 1f (73 mg, 0.35 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (112 mg, 0.87 mmol) was then added. The reaction solution was then cooled to 0°C and a 50% solution of n-butylphosphonic anhydride in ethyl acetate (312 mg, 0.43 mmol) was added. The temperature was maintained for 1 hour. The reaction solution was poured directly into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by preparative liquid chromatography afforded compound 11 (50 mg, 35% yield) as a white solid. LCMS: 501.1 [M+H] + . 1 H NMR(500MHz,DMSO)δ12.88(s,1H),7.60–7.55(m,1H),7.35–7.33(m,1H),4.85–4.56(m,4H),3.67–3.53(m ,3H),3.20–3.10(m,1H),2.84–2.58(m,3H),2.11–2.09(m,3H),1.85–1.70(m,2H),1.67–1.55(m,2H)ppm.

[0363] Example 12

[0364] 1-(3-(4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 12)

[0365] Step 1: tert-Butyl 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine-1-carboxylate (12a)

[0366] In a 100 mL round-bottom flask, compound 11a (3.0 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). The reaction mixture was then cooled to 0°C under nitrogen and ethylmagnesium bromide (5.9 mL, 5.9 mmol) was added dropwise. The temperature was maintained for 15 minutes. The reaction mixture was poured into 200 mL of ice water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed 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 (ethyl acetate / petroleum ether = 0% to 10%) to obtain compound 12a (0.6 g, yield: 24%) as a colorless oil. LCMS: 30.4 [M+H] + .

[0367] Step 2: 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine (12b)

[0368] In a 100 mL round-bottom flask, compound 12a (600 mg, 1.4 mmol) was dissolved in anhydrous dioxane (2 mL). A hydrochloric acid / dioxane solution (10 mL) was then added and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was concentrated to dryness to obtain crude compound 12b (460 mg) as an off-white solid. LCMS: 330.1 [M+H] + .

[0369] Step 3: 1-(3-(4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 12)

[0370] In a 50 mL round-bottom flask, compound 12b (100 mg, 0.30 mmol) and compound 1f (68 mg, 0.33 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (106 mg, 0.82 mmol) was then added. The reaction solution was then cooled to 0°C and a 50% solution of n-butylphosphonic anhydride in ethyl acetate (295 mg, 0.41 mmol) was added. The reaction was maintained at this temperature for 1 hour. The reaction solution was poured directly into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. Pre-HPLC separation yielded compound 12 (34 mg, 25% yield) as a white solid. LCMS: 521.1 [M+H] + . 1H NMR(500MHz,DMSO)δ12.89(s,1H),7.70–7.68(m,1H),7.43–7.40(m,1H),6.95–6.73(m,1H),4.85–4.54(m ,4H),3.68–3.52(m,3H),3.18–3.04(m,1H),2.77–2.57(m,3H),2.11–2.08(m,3H),1.74–1.61(m,4H)ppm.

[0371] Example 13

[0372] 1-(3-(4-(3,4-difluoro-2-((perfluoroethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one

[0373] Step 1: tert-Butyl 4-(3,4-difluoro-2-(tosylthio)phenyl)piperidine-1-carboxylate (13a)

[0374] In a 100 mL three-necked flask, compound 10b (100 mg, 0.3 mmol) was dissolved in anhydrous acetonitrile (10 mL), followed by the addition of p-methylbenzenesulfonylhydrazine (85 mg, 0.46 mmol) and sodium iodide (23 mg, 0.15 mmol). A 75% aqueous solution of tert-butyl peroxide (91 mg, 0.76 mmol) was added dropwise at room temperature and the reaction was maintained at this temperature for 1 hour. The reaction solution was directly poured into 200 mL of water, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether: 0% to 10%) to obtain compound 13a (80 mg, yield: 55%) as a colorless oil. LCMS: 384.1 [M+H] + .

[0375] Step 2: tert-Butyl 4-(3,4-difluoro-2-((perfluoroethyl)thio)phenyl)piperidine-1-carboxylate (13b)

[0376] In a 100 mL round-bottom flask, compound 13a (210 mg, 0.43 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 mL). Sodium acetate (107 mg, 1.3 mmol) and trimethyl(perfluoroethyl)silane (250 mg, 1.3 mmol) were then added sequentially at room temperature and the reaction was maintained at this temperature for 1 hour. The reaction solution was poured into ice water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. Purification by silica gel column chromatography (ethyl acetate / petroleum ether: 0% to 10%) afforded compound 13b (130 mg, yield: 67%) as a colorless oil. LCMS: 448.1 [M+H] + .

[0377] Step 3: 4-(3,4-difluoro-2-((perfluoroethyl)thio)phenyl)piperidine (13c)

[0378] In a 100 mL round-bottom flask, compound 13b (130 mg, 0.3 mmol) was dissolved in anhydrous dioxane (2 mL). A hydrochloric acid / dioxane solution (10 mL, 4 mol / L) was then added and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was concentrated to afford compound 13c (100 mg) as an off-white solid. LCMS: 348.1 [M+H] + .

[0379] Step 4: 1-(3-(4-(3,4-difluoro-2-((perfluoroethyl)thio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 13)

[0380] In a 50 mL round-bottom flask, compound 13c (100 mg, 0.29 mmol) and compound 1f (65 mg, 0.31 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (101 mg, 0.78 mmol). The reaction solution was then cooled to 0°C, and a 50% solution of n-butylphosphonic anhydride in ethyl acetate (281 mg, 0.39 mmol) was added. The reaction was maintained at this temperature for 1 hour. The reaction solution was poured directly into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative liquid chromatography separation and purification afforded compound 13 as a white solid (20 mg, yield: 14%). LCMS: 539.1 [M+H] + . 1H NMR (400MHz, d-DMSO) δ12.93(s,1H),7.79–7.68(m,1H),7.49–7.40(m,1H),4.86–4.60(m,4H),3.70–3.68( m,2H),3.54–3.46(m,1H),3.18–3.12(m,1H),2.80–2.58(m,3H),2.12–2.10(m,3H),1.75–1.63(m,4H)ppm.

[0381] Example 14

[0382] 2-(6-(1-(6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorophenyl)-2,2-difluoroacetonitrile

[0383] Step 1: tert-Butyl 4-(2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-3,4-difluorophenyl)piperidine-1-carboxylate (14a)

[0384] In a 50 mL round-bottom flask, compound 9c (300 mg, 0.71 mmol) was dissolved in dimethyl sulfoxide (20 mL), followed by the addition of ethyl 2-bromo-2,2-difluoroacetate (173 mg, 0.85 mmol) and copper powder (90 mg, 1.42 mmol). Under nitrogen protection, the reaction solution was heated to 55°C for 6 hours. The reaction solution was directly poured into 100 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether: 0% to 10%) to obtain compound 14a (120 mg, yield: 40%) as a colorless oil. LCMS: 420.2 [M+H] + .

[0385] Step 2: tert-Butyl 4-(2-(2-(2-amino-1,1-difluoro-2-oxoethyl)-3,4-difluorophenyl)piperidine-1-carboxylate (14b)

[0386] In a 100 mL round-bottom flask, compound 14a (120 mg, 0.28 mmol) was dissolved in ammonia / methanol solution (10 mL, 7 M) and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to dryness to obtain crude product 14b (110 mg) as a colorless oil. LCMS: 391.1 [M+H] + .

[0387] Step 3: 2-(2,3-difluoro-6-(piperidin-4-yl)phenyl)-2,2-difluoroacetamide (14c)

[0388] In a 100 mL round-bottom flask, compound 14b (110 mg, 0.28 mmol) was dissolved in anhydrous dioxane (2 mL). A hydrochloric acid / dioxane solution (10 mL) was then added and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to dryness to obtain crude product 14c (100 mg) as an off-white solid. LCMS: 291.1 [M+H] + .

[0389] Step 4: 2-(6-(1-(6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorophenyl)-2,2-difluoroacetamide (14d)

[0390] In a 50 mL round-bottom flask, compound 14c (100 mg, 0.31 mmol) and compound 1f (77 mg, 0.37 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (119 mg, 0.92 mmol). The reaction solution was then cooled to 0°C, and a 50% T4P ethyl acetate solution (330 mg, 0.46 mmol) was added. The reaction was maintained at this temperature for 1 hour. The reaction solution was directly poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane: 0%-10%) afforded compound 14d (50 mg, yield: 35%) as a white solid. LCMS: 482.2 [M+H] + .

[0391] Step 5: 2-(6-(1-(6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorophenyl)-2,2-difluoroacetonitrile (Compound 14)

[0392] In a 50 mL round-bottom flask, compound 14d (50 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (5 mL). The reaction solution was then cooled to 0°C and pyridine (33 mg, 0.42 mmol) and trifluoroacetic anhydride (65 mg, 0.31 mmol) were added dropwise. The temperature was maintained for 1 hour. The reaction solution was diluted directly with dichloromethane (100 mL), then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative liquid chromatography separation and purification afforded compound 14 (20 mg, yield: 42%) as an off-white solid. LCMS: 464.2 [M+H] + . 1H NMR(500MHz,DMSO)δ12.89(s,1H),7.74–7.84(m,1H),7.56–7.51(m,1H),4.85–4.59(m,4H),3.6 8–3.62(m,2H),3.25–3.19(m,2H),2.81–2.57(m,3H),2.11–2.09(m,3H),1.79–1.70(m,4H)ppm.

[0393] Example 15

[0394] 1-(3-(4-(3-(pentafluoro-λ 6 -sulfonyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 15)

[0395] Step 1: 4-(3-(pentafluoro-λ 6 -sulfonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (15b)

[0396] In a 100 mL round-bottom flask, compound 15a (500 mg, 1.77 mmol), compound 1b (560 mg, 2.12 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (86 mg, 0.18 mmol), sodium iodide (529 mg, 3.53 mmol), potassium carbonate (439 mg, 3.18 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (807 mg, 3.18 mmol) were added in sequence, and finally N,N-dimethylacetamide (20 mL) was added. The air was replaced with nitrogen three times, and the reaction was carried out at 60 °C for 11 h. The mixture was filtered through celite, quenched with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with water (20 mL × 2). Finally, the organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15b as a colorless oil (484 mg, yield: 39%). LCMS: 388.1 [M+H] + .

[0397] Step 2: 4-(3-(pentafluoro-λ 6 -sulfonyl)phenyl)piperidine hydrochloride (15c)

[0398] In a 50 mL round-bottom flask, compound 15b (480 mg, 1.24 mmol) was dissolved in ethyl acetate (1 mL). 4 mol ethyl acetate hydrochloride (5 mL) was added dropwise at 0°C, and the mixture was stirred at 0°C for 8 h. The reaction solution was concentrated under reduced pressure to afford compound 15c (397 mg, yield: 99%) as a yellow solid. LCMS: 288.1 [M+H] + .

[0399] Step 3: 1-(3-(4-(3-(pentafluoro-λ 6 -sulfonyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 15)

[0400] In a 25 mL round-bottom flask, compound 1f (193.9 mg, 0.93 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (299.4 mg, 2.32 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (352.35 mg, 0.93 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 30 min. Finally, compound 15c (150 mg, 0.46 mmol) was added and the reaction was carried out at room temperature for 11 h. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain an off-white solid compound 15 (45 mg, yield: 19%). LCMS: 479.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.61–7.55(m,2H),7.42–7.37(m,1H),7.36–7.32(m,1H),4.31–4.16(m,2H ),3.72–3.63(m,2H),3.35–3.27(m,2H),2.87–2.75(m,2H),2.75–2.68(m,1H),1.48(s,9H)ppm.

[0401] Example 16

[0402] 1-(3-(4-(2-(methylthio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 16)

[0403] Step 1: tert-Butyl 4-(2-aminophenyl)piperidine-1-carboxylate (16b)

[0404] In a 500 mL round-bottom flask, compound 16a (5 g, 23.98 mmol), compound 1b (7.60 g, 28.77 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (1.17 g, 2.40 mmol), sodium iodide (7.19 g, 47.97 mmol), potassium carbonate (5.96 g, 43.16 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (10.96 g, 43.16 mmol) were added in sequence, and finally N,N-dimethylacetamide (100 mL) was added. The air was replaced with nitrogen three times, and the reaction was carried out at 60 °C for 8 h. The mixture was filtered through celite, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with water (50 mL × 2). Finally, the organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 16b as a yellow oil (2.56 g, yield: 39%). LCMS: 277.2 [M+H] + .

[0405] Step 2: tert-Butyl 4-(2-iodophenyl)piperidine-1-carboxylate (16c)

[0406] To a 100 mL round-bottom flask, cuprous iodide (2.76 g, 14.49 mmol), tert-butyl nitrite (1.49 g, 14.49 mmol), and acetonitrile (30 mL) were added sequentially. The mixture was heated to 65°C, and compound 16b (2 g, 7.24 mmol) in acetonitrile (10 mL) was added dropwise to the reaction mixture. The mixture was reacted at 65°C for 3 h. The mixture was filtered through celite, concentrated under reduced pressure, and diluted with ethyl acetate (30 mL). The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 16c (0.96 g, yield: 33%) as a yellow oil. LCMS: 388.1 [M+H] + .

[0407] Step 3: tert-Butyl 4-(2-(methylthio)phenyl)piperidine-1-carboxylate (16d)

[0408] In a 100 mL round-bottom flask, compound 16c (476 mg, 1.23 mmol), cuprous iodide (281 mg, 1.48 mmol), and 1,10-phenanthroline (222 mg, 1.23 mmol) were sequentially added to dimethyl sulfoxide (5 mL), followed by triethylenediamine (276 mg, 2.46 mmol). The reaction was stirred at 170°C for 3 h in a microwave reactor. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 16d (366 mg, yield: 60%) as a yellow oil. LCMS: 308.2 [M+H] + .

[0409] Step 4: 4-(2-(methylthio)phenyl)piperidine hydrochloride (16e)

[0410] In a 50 mL round-bottom flask, compound 16d (366 mg, 1.19 mmol) was dissolved in dichloromethane (1 mL). 4 M 1,4-dioxane hydrochloride solution (5 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 h. The reaction solution was concentrated under reduced pressure to obtain compound 16e (300 mg) as an off-white solid. LCMS: 208.1 [M+1] + .

[0411] Step 5: 1-(3-(4-(2-(methylthio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 16)

[0412] In a 25 mL round-bottom flask, compound 16e (290 mg, 1.19 mmol) and compound 1f (573 mg, 2.74 mmol) were dissolved in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (923 mg, 7.14 mmol) and butylphosphonic anhydride (50% ethyl acetate solution) (644 mg, 0.89 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 1.5 h. Water (5 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 16 (150 mg, yield: 31%) as an off-white solid. LCMS: 399.2 [M+1] + . 1H NMR(500MHz)δ7.25–7.19(m,2H),7.17–7.11(m,2H),4.92–4.58(m,4H),3.84(s,1H),3.66(t,J=5.4Hz,1H) ,3.33–2.80(m,5H),2.69(s,1H),2.47(s,3H),2.21–2.17(m,3H),1.99–1.91(m,2H),1.73–1.62(m,2H)ppm.

[0413] Example 17

[0414] 6-((1-(6-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorobenzenesulfonamide)(Compound 17)

[0415] Step 1: tert-Butyl-4-[(2-(phenylthio)-3,4-difluorophenyl)piperidin-1-carboxyl]acetic acid (17a)

[0416] In a 100 mL round-bottom flask, compound 9c (423 mg, 1.0 mmol), benzyl mercaptan (248 mg, 2.0 mmol), and N,N-diisopropylethylamine (259 mg, 2.0 mmol) were dissolved in 1,4-dioxane (50 mL). Tris(dibenzylideneacetone)palladium (92 mg, 0.1 mmol) and Xantphos (116 mg, 0.2 mmol) were added and heated to 100°C for 8 h. The solid was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 200:1 to 10:1) to obtain compound 17a (0.35 g, yield: 84%) as a yellow solid. LCMS: 420.2 [M+1] + Step 2: 4-(2-(Benzylthio)-3,4-difluorophenyl)piperidine (17b)

[0417] In a 100 mL round-bottom flask, compound 17a (350 mg, 0.83 mmol) was dissolved in DCM (5 mL). A hydrochloric acid / 1,4-dioxane solution (3 mL, 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, and the mixture was slurried with petroleum ether, filtered, and dried to obtain compound 17b (245 mg, yield: 92%) as a yellow solid. LCMS: 320.1 [M+H] +Step 3: 1,1'-[(3-(4-(2-(phenylmethylthio)-3,4-difluorophenyl)piperidin-1-carboxyl)-4,7-dihydro-1H-pyrazolo[3,4-c]pyridine-1,6(5H)-diyl)ethan-1-one](17c)

[0418] In a 50 mL round-bottom flask, compound 1f (251 mg, 1.2 mmol) was dissolved in DMF (4 mL). Triethylamine (0.60 mL, 3.0 mmol) was then added and the mixture was allowed to react on ice for 2 min. HATU (380 mg, 1.0 mmol) was then added and allowed to react on ice for 2 min. Compound 17b (245 mg, 0.77 mmol) was then added and allowed to react at room temperature for 2 h. The reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated to obtain the crude product, which was then separated using a C18 reverse phase column (acetonitrile / water: 0-100%) to afford compound 17c (389 mg, 85% yield) as an off-white solid. LCMS: 553.2 [M+H] + .

[0419] Step 4: 6-(1-(1,6-diacetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorobenzenesulfonyl chloride (17d)

[0420] In a 100 mL round-bottom flask, compound 17c (380 mg, 0.69 mmol) was dissolved in acetic acid / water (v / v, 3 / 1, 15 mL) and placed in an ice bath. Chlorosuccinamide (275 mg, 2.07 mmol) was then added and the mixture was allowed to react in an ice bath for 30 min. 100 mL of water was then added, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was collected and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 20:1-2:1) to afford compound 17d (236.8 mg, yield: 65%) as an off-white solid. LCMS: 529.2 [M+H] + Step 5: 6-((1-(6-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)piperidin-4-yl)-2,3-difluorobenzenesulfonamide)(Compound 17)

[0421] In a 100 mL round-bottom flask, compound 17d (236 mg, 0.45 mmol) was dissolved in DCM (15 mL) and placed in an ice bath. A 7.0 mol methanolic amine solution (1 mL) was then added and the mixture was allowed to react in an ice bath for 30 min. Water (100 mL) was then added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was collected and concentrated to obtain the crude product. The crude product was separated on a C18 reverse phase column (acetonitrile / water: 0-100%) to afford compound 17 (45 mg, 22% yield) as an off-white solid. LCMS: 468.2 [M+H] + . 1 H NMR (500MHz, d-DMSO) δ12.89(s,1H),7.97(s,2H),7.56-7.68(m,1H),7.44–7.30(m,1H),4.93–4.47(m,4H),4.04–3.87( m,1H),3.73–3.56(m,2H),3.10(s,1H),2.84–2.53(m,3H),2.14–2.04(m,3H),1.89–1.70(m,2H),1.69–1.51(m,2H)ppm.

[0422] Example 18

[0423] 1-(3-(4-(2-(dimethylphosphino)-3,4-difluorophenyl)piperidin-1-carboxyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 18)

[0424] Step 1: tert-Butyl 4-(2-(dimethylphosphoryl)-3,4-difluorophenyl)piperidine-1-carboxylate (18a)

[0425] In a 100 mL round-bottom flask, compound 9c (423 mg, 1.0 mmol), dimethylphosphine oxide (117 mg, 1.5 mmol), and potassium phosphate (318 mg, 1.5 mmol) were dissolved in 1,4-dioxane (10 mL). Finally, tris(dibenzylideneacetone)palladium (92 mg, 0.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg, 0.2 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 silica gel column chromatography (petroleum ether:ethyl acetate = 200:1-10:1) to afford compound 18a (80 mg, yield: 21%) as a white solid. LCMS: 374.2 [M+H] + .

[0426] Step 2: (2,3-difluoro-6-(piperidin-4-yl)phenyl)dimethylphosphine oxide (18b)

[0427] In a 100 mL round-bottom flask, compound 18a (80 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL). 1 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 18b as a white solid (55 mg, yield: 95%). LCMS: 273.2 [M+1] + .

[0428] Step 3: 1-(3-(4-(2-(dimethylphosphino)-3,4-difluorophenyl)piperidin-1-carboxyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 18)

[0429] In a 50 mL round-bottom flask, compound 1f (65 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (0.2 mL, 1.0 mmol) was then added and the mixture was allowed to react on ice for 2 min. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.3 mmol) was then added and the mixture was allowed to react on ice for 2 min. Compound 18b (55 mg, 0.21 mmol) was then added and the mixture was allowed to react at room temperature for 2 h. The reaction was quenched by adding water and extracted with ethyl acetate (10 mL x 3). The organic phase was collected and concentrated to obtain the crude product, which was then separated using a C18 reverse phase column (acetonitrile / water: 0-100%) to afford compound 18 (25 mg, 26% yield) as an off-white solid. LCMS: 465.2 [M+H] + . 1 H NMR (500MHz, d-DMSO) δ13.22–12.66(m,1H),7.64–7.49(m,1H),7.38–7.26(m,1H),4.81–4.40(m,5H),3. 72–3.58(m,2H),3.05(s,1H),2.75–2.53(m,3H),2.13–2.05(m,3H),1.89–1.73(m,8H),1.58(s,2H)ppm.

[0430] Example 19

[0431] 1-(3-(4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidin-1-carboxyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 19)

[0432] Step 1: tert-Butyl 4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidine-1-carboxylate (19a)

[0433] In a 100 mL round-bottom flask, compound 10b (400 mg, 1.21 mmol), cyclopropylboronic acid (430 mg, 5.0 mmol), cesium carbonate (406 mg, 1.25 mmol), and 2,2'-bipyridine (195 mg, 1.25 mmol) were dissolved in 1,2-dichloroethane (10 mL). Finally, copper acetate (227 mg, 1.25 mmol) was added and the mixture was heated to 70°C under air for 8 h. The solid was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 200:1 to 10:1) to obtain compound 19a (363 mg, yield: 78.7%) as a white solid. LCMS: 370.2 [M+1] + .

[0434] Step 2: 4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidine (19b)

[0435] In a 50 mL round-bottom flask, compound 19a (360 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 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 by adding saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 19b (230 mg, 88% yield) as a colorless oily solid. LCMS: 270.1 [M+1] + .

[0436] Step 3: 1-(3-(4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidin-1-carboxyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 19)

[0437] In a 50 mL round-bottom flask, compound 1f (209 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Triethylamine (227 mg, 2.25 mmol) was then added and the mixture was allowed to react on ice for 2 min. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol) was then added and allowed to react on ice for 2 min. Compound 19b (122 mg, 0.5 mmol) was then added and allowed to react at room temperature for 2 h. The reaction was quenched by adding water and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated to obtain the crude product, which was then separated using a C18 reverse phase column (acetonitrile / water: 0-100%) to afford compound 19 (240 mg, 70% yield) as an off-white solid. LCMS: 461.2 [M+1] + . 1 H NMR(400MHz,d-DMSO)δ13.36–12.41(m,1H),7.49–7.31(m,1H),7.27–7.13(m,1H),4 .77–4.49(m,3H),3.73–3.56(m,2H),3.51–3.42(m,1H),3.42–3.29(m,1H),3.23–3. 05(m,1H),2.95–2.74(m,1H),2.73–2.55(m,2H),2.40–2.31(m,1H),2.14–2.07(m,3 H),1.81–1.65(m,2H),1.65–1.49(m,2H),0.96–0.87(m,2H),0.65–0.55(m,2H)ppm.

[0438] Example 20

[0439] 1-(3-(4-(2-(ethylthio)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 20)

[0440] Step 1: tert-Butyl 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine-1-carboxylate (20a)

[0441] In a 25 mL round-bottom flask, compound 10b (500 mg, 1.52 mmol) and anhydrous tetrahydrofuran (5 mL) were added sequentially. After stirring at 0°C for 30 min, iodoethane (237 mg, 1.52 mmol) was added and stirred at 0°C for 15 min. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 20a (465 mg, yield: 84%) as a colorless oil. LCMS: 358.2 [M+H] + .

[0442] Step 2: 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine hydrochloride (20b)

[0443] In a 50 mL round-bottom flask, compound 20a (465 mg, 1.30 mmol) was dissolved in ethyl acetate (1 mL). 4 M hydrochloric acid in ethyl acetate (5 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 h. The reaction solution was concentrated under reduced pressure to obtain compound 20b (343 mg, yield: 90%) as an off-white solid. LCMS: 258.1 [M+H] + .

[0444] Step 3: 1-(3-(4-(2-(ethylthio)-3,4-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Compound 20)

[0445] In a 25 mL round-bottom flask, compound 1f (142 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.30 mL, 1.70 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (259 mg, 0.68 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 30 min, and finally 20b (100 mg, 0.34 mmol) was added. The mixture was allowed to react at room temperature for 2.5 h. The reaction was quenched by the addition of water (5 mL) and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was isolated and purified by silica gel column chromatography to afford compound 20 (65 mg, 42% yield) as an off-white solid. LCMS: 449.2 [M+H] + . 1H NMR (500MHz, d-DMSO) δ13.19–12.79 (m, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.24–7. 17(m,1H),4.96–4.39(m,4H),3.71–3.52(m,3H),3.22–3.04(m,1H),2.90–2. 85(m,2H),2.84–2.71(m,1H),2.70–2.65(m,1H),2.64–2.51(m,1H),2.11–2 .06(m,3H),1.79–1.65(m,2H),1.63–1.51(m,2H),1.13(t,J=7.3Hz,3H)ppm.

[0446] Biological activity test

[0447] Biological Test Example 1: Compounds inhibit RBP4-TTR complex formation

[0448] The ability of the compounds of the present invention to inhibit 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 in each well was measured using a Varioskan LUX microplate reader (Thermo Fisher), and the 665 / 615 ratio was calculated. The wells without compound (0 nM) were taken as 100%, and 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 Calculation results are shown in Table 1.

[0449] Biological test example 2: Radioligand binding test

[0450] Radioligand binding was used to detect the inhibitory ability of the compounds of the present invention on RBP4-retinol binding. The test compound was prepared into a 10mM storage stock solution using DMSO, and then the stock solution was further diluted to different test concentrations (1μM starting, 3-fold dilution, 8 concentrations, 2 repetitions) using binding buffer (0.01M PBS, pH 7.2, containing 0.1% BSA, 0.5% CHAPS, 1mM EDTA). 1μL of the above-mentioned compounds at different concentrations were respectively added to a 384-well plate (Perkin Elmer, Proxiplate), 2μL of 50nM RBP4-biotin (MCE) protein was added, and incubated at room temperature for 30min; then 2μL of 30nM 3 H Retinol, incubated at room temperature for 3 hours. 5 μL streptomycin SPA beads were added to each well and incubated at room temperature for 10 minutes. MicroBeta 2 readings were taken. The addition of 1 μM retinol was used as a blank control, and the absence of compound was taken as 100%. The binding inhibition rate (%) of each well was calculated. Graphpad Prism 8.0 software was used for data processing and curve fitting (nonlinear fitting, 4 parameters), and IC was calculated. 50 Calculate and perform IC 50 Calculation results are shown in Table 1.

[0451] Table 1

[0452] The test results show that the compound of this example has strong inhibitory activity on the formation of RBP4-TTR complex and the binding of RBP4-retinol.

[0453] 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 phenylpiperidine compound having a structure as represented by formula (0), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure represented by formula (0); in, R 1 Selected from hydrogen, deuterium, cyano, nitro, cycloalkyl, heterocyclic, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 5 are each independently selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl, and when R 1 When it is hydrogen, R 2 ~R 5 At least one of them is deuterium, hydroxyl, nitro, amino, -SF5, alkoxy, carboxyl, thiol, cyano or cycloalkyl; Or, R 1 ~R 5 Connect at any ortho position to form a carbocyclic group or a heterocyclic group; R a is selected from amino, alkyl, -NH-alkyl, -NH-cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 7 ~R 9 are each independently 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 ~R 13 are each independently 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 13 and R a 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.

2. The compound according to claim 1, wherein R 1 ~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 a Selected from amino, C 1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; 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 9 are each independently 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 ~R 13 are each independently 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 13 and R a 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.

3. The compound according to claim 1 or 2, 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 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane; Or, R 1 ~R 5 Connected at any ortho position to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen heterocyclic group; R a is selected from amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-isopropyl, -NH-n-butyl, -NH-tert-butyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl or piperazinyl; 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 9 are each independently 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 ~R 13 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

4. The compound according to any one of claims 1 to 3, wherein the compound has a structure represented by formula (I): In formula (I), R 1 ~R 5 has the same meaning as in any one of claims 1 to 3; Preferably, R 4 and R 5 At least one of is hydrogen; Preferably, R 4 and R 5 All are hydrogen.

5. The compound according to any one of claims 1 to 4, wherein the compound has a structure represented by formula (II): R 1 Selected from deuterium, cyano, nitro, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, -NR 7 R 8 、-NR 9 (C=O)R 6 、-NR 9 (C=O)OR 10 、-NR 9 (C=O)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(C=O)R 6 、-O(C=O)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 、-P(=O)R 12 R 13 ; R 2 ~R 3 Each independently selected from hydrogen, deuterium, hydroxyl, nitro, amino, -SF5, C 1-6 Alkoxy, carboxyl, mercapto, cyano, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, or C 1-6 alkyl halide; Or, R 1 and R 2 connected to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen-containing heterocyclic group; or, R 2 and R 3 connected to form a 4-6 membered carbocyclic group or a 4-6 membered oxygen-containing heterocyclic group; R 6 ~R 13 The definition is the same as that in claim 2 or 3.

6. The compound according to any one of claims 1 to 5, wherein R 1 Selected from: cyano, nitro, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, -OR 10 、-C(O)NR 7 R 8 、-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 7 ~R 9 are each independently selected from hydrogen, deuterium, cyano or C 1-6 alkyl; R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl or C 3-8 Halogenated cycloalkyl; R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl or C 3-8 Cycloalkyl; R 12 ~R 13 are each independently selected from hydrogen, deuterium or C 1-6 alkyl; R 1 、R 7 ~R 13 C in 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl and C 1-9 The heterocyclic group 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.

7. The compound according to any one of claims 1 to 6, wherein R 1 Selected from the group consisting of: -CN、-CF2CN、-NO2、-S-CH3、-S-CH2CH3、-S-CF3、-S-CF2H、-S-CF2CF3、-S-CF2CF2H、-S-CF2CF2CF3、-C(=NH)NH2、-C(=O)NH2、-OCH3、-O-CF3、-O-CF2H、-O-CF2CF3、-O-CF2CF2H、-O-CF2CF2CF3、 Preferably, R 1 Selected from the group consisting of: -S-CH3, -S-CH2CH3, -S-CF3, -S-CF2H, -S-CF2CF2H, -O-CF3, -O-CF2H, -O-CF2CF2H, and / or, R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl or C 3-8 Halogenated cycloalkyl; Preferably, R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane; Preferably, R 2 and R 3 are each independently selected from hydrogen, deuterium or halogen; Preferably, R 2 and R 3 All are F.

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 characterized by excessive accumulation of lipofuscin in the retina; Preferably, the retinol binding protein 4-related disease is age-related macular degeneration, dry (atrophic) age-related macular degeneration, fundus yellow spot disease (Stargardt disease), vitelliform macular degeneration (Best disease) or macular dystrophy similar to Stargardt disease.

11. A method for inhibiting RBP4-TTR complex formation in a cell, comprising contacting the cell with an effective amount of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9. 12 . A method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 .

13. A method for inhibiting RBP4-TTR complex formation in the serum of a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9.

14. A method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9.

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