AAK1 inhibitor and application thereof

Abstract

The invention relates to an amine derivative with AAK1 inhibitory activity as shown in a formula I, and an isotope form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug and a polymorphic substance of the amine derivative, and describes a preparation method of the amine derivative and application of the amine derivative in preparation of drugs for related diseases mediated by AAK1 activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a compound capable of inhibiting ligand-associated protein kinase 1, a preparation method and a composition thereof, and use of the compound in preparing medicines. Background Art

[0002] Neuropathic pain is a painful state caused by neuronal lesions and can be divided into peripheral neuropathic syndrome and central neuropathic syndrome (Deng Fengjian, Li Zheng. Journal of Shenyang Pharmaceutical University, 2021, 38(04): 439-447). Central neuropathic pain, such as multiple sclerosis or spinal cord injury, is the result of central lesions or diseases; peripheral neuropathic pain is caused by peripheral nerve dysfunction or damage, including diabetes or herpes infection, which lead to diabetic peripheral neuropathy and post-herpetic neuropathy, respectively. Diabetic peripheral neuropathy is one of the most common complications of diabetes, one of the main symptoms of which is diabetic pain, accounting for 10-20% of all diabetic patients. At present, the mechanism of diabetic pain is not clearly understood and the clinical treatment effect is not ideal. There is an urgent need to develop new treatment methods.

[0003] Herpes zoster is an infectious skin disease caused by the reactivation of varicella-zoster virus (VZV) that has long been dormant in the dorsal root ganglia of the spinal cord or cranial nerve ganglia (Wen Xiaowen, Li Minzhi. Inner Mongolia Journal of Traditional Chinese Medicine, 2021, 40(01):148-150; Xia Tianbao. PLA Medical College, 2016). Risk factors for VZV reactivation include: advanced age, trauma, HIV infection, immunosuppression caused by malignant tumors, systemic diseases (such as diabetes, kidney disease, fever, hypertension), etc. After the blisters are cleared, some patients will still feel the pain of herpes zoster for a long time because the damaged nerve fibers in the skin send confused or exaggerated pain information to the brain, which is called postherpetic neuralgia (Guo Rui, Ma Ruijuan, et al. Ningxia Medical Journal, 2022, 44(01):14-17+6).

[0004] Neuropathic pain seriously affects the quality of life of patients with chronic diseases and also imposes a significant burden on the medical system. Currently, the most common treatments for neurological diseases include tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin and opioids. However, these drugs not only have limited efficacy, but also produce adverse reactions and side effects such as dizziness, drowsiness and dependence.

[0005] Adaptor-associated kinase 1 (AAK1) is an inhibitor of neuregulin-1 / ErbB4 signaling and a member of the Arkl / Prkl family of serine / threonine kinases. It is responsible for regulating clathrin-mediated endocytosis and is ubiquitous in the central nervous system (CNS) (Xin Xin, Wang Yue, Zhang Lele, et al. European Journal of Medicinal Chemistry, 2023, 248; Qi Xiang, Jiang Songwei, et al. Acta Pharmaceutica Sinica, 2022, 57(07): 1991-2002). AAK1 mRNA exists in two splicing forms, short and long, of which the long chain is dominant and is highly expressed in the brain and heart. Studies have shown that gene silencing or treatment with kinase inhibitors can lead to the loss of AAK1 expression, resulting in enhanced neurite hyperplasia induced by neuregulin-1, which can be used to treat schizophrenia, Parkinson's disease, neuropathic pain and Alzheimer's disease, etc. (Abdel-Magid Ahmed F. ACS medicinal chemistry letters, 2017, 8 (6); Fu Xue. 1. Study on the expression of AAK1 in the Aβ1-42-induced Alzheimer's disease mouse model; 2. Reliability and validity test of the Chinese version of the Baylor Severe Mental State Examination Scale [D]. Chongqing Medical University, 2018). Inhibition of AAK1 in the central nervous system, especially in the spinal cord, was found to be a relevant site for achieving anti-nociceptive effects (Luo Guanglin, Chen Ling, Kostich Walter A, et al. Journal of medicinal chemistry, 2022. 65, 6, 4534-4564; Martinez-Gualda B, Schols D, De Jonghe S. Expert Opin Ther Pat. 2021 Oct; 31(10): 911-936).

[0006] AAK1 plays an important role in neuropathic pain and many other human diseases, including viral invasion, Alzheimer's disease, Parkinson's syndrome, etc. Therefore, targeting AAK1 is a promising therapeutic strategy for controlling diseases. In recent years, a large number of studies on AAK1 inhibitors have been conducted to improve the efficacy and selectivity of AAK1 kinase. According to the chemical structure, there are mainly the following categories: imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, biaryl analogs, conformationally restricted biaryl analogs, etc. However, most compounds with AAK1 inhibitory activity cannot be well performed in animal models due to poor PK performance or weak BBB penetration. Currently, only BMS-986176 / LX-9211 has entered clinical trials. In addition, in order to develop drugs targeting CNS targets, drugs should have better hERG characteristics and avoid dose-related brain toxicity. Summary of the invention

[0007] The purpose of the present invention is to provide a novel small molecule compound with AAK1 inhibitory activity, which can be used to prepare drugs for treating schizophrenia, Parkinson's disease, neuropathic pain, Alzheimer's disease and other diseases mediated by AAK1 activity.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0009] The first aspect of the present invention provides a compound of formula I or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph,

[0010]

[0011] in,

[0012] A is selected from one of the following structures:

[0013]

[0014] Q is selected from one of the following structures:

[0015]

[0016]

[0017] X is O or NH;

[0018] R 1 , R 2 are independently selected from substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C2-10 Alkenyl and C 2-10 one of the alkynyl groups; or, R 1 With R 2 Forming substituted or unsubstituted C 3-10 Carbocyclic, substituted or unsubstituted C containing O or S 3-8 One of a carboheterocycle, a substituted or unsubstituted spirocycle, a substituted or unsubstituted spiroheterocycle containing O or S, a substituted or unsubstituted fused carbocycle, a substituted or unsubstituted fused heterocycle containing O or S, and a bridged carboheterocycle having at least one N as a heteroatom.

[0019] The above substitution may be one or more hydrogens replaced by a substituent, and the substituent may be selected from deuterium, halogen, C 2-6 One or more of the alkyl groups.

[0020] Furthermore, the R 1 , R 2 Each independently selected from C 1-10 One of the alkyl groups, such as methyl, ethyl, propyl, butyl, isobutyl, etc.; or, R 1 With R 2 Form C 3-10 Carbocyclic, fluorine-substituted C 3-10 Carbocyclic, C containing O or S 3-8 A carbon heterocycle.

[0021] More preferably, in the structure of formula I Select one of the following structures:

[0022]

[0023] Furthermore, the compound represented by formula I is a compound represented by the following structural formula I-1 to formula I-57:

[0024]

[0025]

[0026]

[0027]

[0028]

[0029] The second aspect of the present invention provides a pharmaceutical composition, comprising one or more of the compound represented by formula I described in the first aspect, its isotopic form, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs.

[0030] Furthermore, in the pharmaceutical composition, the compound represented by any of the above formula I or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph is used in combination with other drugs.

[0031] The third aspect of the present invention provides a use of the compound represented by formula I described in the first aspect or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph or the pharmaceutical composition described in the second aspect in the preparation of AAK1 inhibitors.

[0032] Furthermore, the AAK1 inhibitor is administered orally, parenterally, intravenously or transdermally.

[0033] The fourth aspect of the present invention provides a use of the compound of formula I described in the first aspect or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph or the pharmaceutical composition described in the second aspect in the preparation of a drug for treating diseases mediated by AAK1 activity.

[0034] Furthermore, the disorders mediated by AAK1 activity include schizophrenia, Parkinson's disease, Alzheimer's disease and neuropathic pain, including but not limited to diabetic peripheral neuropathy and herpes zoster neuralgia.

[0035] Furthermore, the drug is administered orally, parenterally, intravenously or transdermally.

[0036] Furthermore, in the drug, the compound represented by any one of the above formula I or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph is used in combination with other drugs.

[0037] As used herein, the following definitions and terms shall apply unless otherwise indicated.

[0038] "R" and "S", as terms for describing isomers, are descriptors of the stereochemical configuration of an asymmetrically substituted carbon atom. The designation of an asymmetrically substituted carbon atom as "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rules, which are well known to those skilled in the art and are described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (lUPAC) Rules of Organic Nomenclature.

[0039] The term C used here i-j means that the part has ij carbon atoms. For example, "C 1-10"Alkyl" means an alkyl unit having any number of carbon atoms between 1 and 10.

[0040] As used herein, "alkyl" refers to a fully saturated straight chain, branched alkane radical. In certain embodiments, the alkyl contains 1-6 carbon atoms. In certain embodiments, the alkyl contains 1-4 carbon atoms. In certain embodiments, the alkyl contains 1-3 carbon atoms. In other embodiments, the alkyl contains 2-3 carbon atoms, and in other embodiments, the alkyl contains 1-2 carbon atoms. The non-limiting examples of exemplary alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, n-octyl, etc. In addition, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each ring having 3 to 10 carbon atoms.

[0041] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-10 Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0042] The term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which may be linear or branched, or a combination thereof. 2-10 The alkenyl group includes ethenyl, propenyl, 2-methyl-1-propenyl and the like.

[0043] In addition, the "spirocycle" described in the present invention refers to a polycyclic group in which one carbon atom (spiro atom) is shared between rings, and may contain 0 or more double or triple bonds, and the "spiroheterocycle" is a spirocycle containing one or more heteroatoms, including but not limited to O, S, N, etc.; the "fused carbocycle" described in the present invention refers to a polycyclic group in which two adjacent atoms are shared between rings, and may contain 0 or more double or triple bonds, and the "fused heterocycle" is a fused ring containing one or more heteroatoms, including but not limited to O, S, N, etc.

[0044] Unless otherwise indicated, the term "halogen" or "halogen element" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl. For example, "haloC 1-4 The term "alkyl" refers to, but is not limited to, trifluoromethyl, 2,2,2-trifluoromethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0045] Optical isomers, diastereomers, geometric isomers and tautomers: Some compounds of Formula I may contain one or more ring systems and may therefore exist as cis and trans isomers. The present invention is intended to encompass all such cis and trans isomers. Olefinic double bonds are included and, unless otherwise specified, are meant to include both E and Z geometric isomers.

[0046] Any enantiomer of a compound of formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0047] In addition, the compounds of formula I may also include a series of stable isotope labeled analogs. For example, one or more protons in the compounds of formula I may be replaced by deuterium atoms to provide deuterated analogs with improved pharmacological activity.

[0048] "Pharmaceutically acceptable salts" refer to acid or base salts of the compounds of the invention which have the desired pharmacological activity and are neither biologically desirable nor otherwise desirable. Salts can be formed with acids including, but not limited to, acetic acid, adipic acid, benzoate, citric acid, camphoric acid, camphorsulfonate, dichloroate, dodecyl sulfate, ethanesulfonate, fumarate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, oxalate.

[0049] The term "AAK1 activity-mediated" disorder refers to any disease or other deleterious condition in which AAK1 or a mutant thereof is known to play a role.

[0050] By means of the above technical solution, the present invention has at least the following advantages:

[0051] The present invention provides a novel amine derivative with AAK1 inhibitory activity, which has high AAK1 inhibitory activity and low cardiotoxicity, and can be used to treat AAK1 activity-mediated diseases, such as schizophrenia, Parkinson's disease, neuropathic pain, Alzheimer's disease, etc. In addition, this novel AAK1 inhibitor shows good tolerability in animal models, has high safety and a larger therapeutic window. DETAILED DESCRIPTION

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0053] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0054] In the following examples of the present application, the synthesis methods of the reaction raw materials or reaction intermediates used are as follows:

[0055] The synthesis of intermediates AA-1 to AA-3 is carried out according to the synthesis method shown in the following reaction scheme 1:

[0056]

[0057] The preparation process of intermediate AA-1 is as follows:

[0058] At 0°C, thionyl chloride (1 mL) was added dropwise to a solution of 1-aminocyclohexane-1-carboxylic acid (500 mg, 3.5 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours and the reaction progress was monitored by thin layer chromatography (TLC). After the reaction was completed, methanol was removed in vacuo. The residue was mixed with water and the pH of the aqueous solution was adjusted to 9 with a saturated Na2CO3 solution. The solution was then extracted with DCM (2 × 10 mL). The organic phases were combined, dried over Na2SO4 and filtered. The solvent was removed in vacuo to obtain 350 mg (yield 64%) of crude product 2.

[0059] LiAlH4 (72 mg, 1.9 mmol) was suspended in THF and cooled to 0° C. Compound 2 (100 mg, 0.64 mmol) was added to the reaction mixture in batches, the solution temperature was raised to room temperature and stirred for 2 hours; the reaction mixture was then poured into ice water and extracted 3 times with ethyl acetate; the organic extract was dried (Na2SO4) and concentrated to give the crude product AA-1 (50 mg, 62% yield).

[0060] LCMS(ESI):130.5[M+H] + .

[0061] Preparation of intermediate AA-2:

[0062]

[0063] Using 4-aminotetrahydro-2H-pyran-4-carboxylic acid as a starting material, the intermediate AA-2 was prepared according to the synthetic method shown in reaction scheme 1.

[0064] LCMS(ESI):132.3[M+H] + .

[0065] Preparation of intermediate AA-3:

[0066]

[0067] Using 1-amino-4,4-difluorocyclohexane-1-carboxylic acid as a starting material, the intermediate AA-3 was prepared according to the synthetic method shown in reaction scheme 1.

[0068] LCMS(ESI):166.4[M+H] + .

[0069] Preparation of intermediate AA-4:

[0070]

[0071] LiAlH4 (1.37 g, 36 mmol) was suspended in THF (30 mL) and cooled to 0°C. 1-Aminocyclohexane-1-carbonitrile (1.5 g, 12 mmol) was added to the system in batches; the mixture was warmed to room temperature and stirred for 1 hour to terminate the reaction; the reaction mixture was poured into ice water and extracted with ethyl acetate 3 times. The organic extract was dried and concentrated to give a crude product AA-4 (1.0 g, 65% yield).

[0072] LCMS(ESI):129.3[M+H] + .

[0073] Preparation of intermediate Q-1:

[0074]

[0075] At 0 ℃, 6-bromo-3-fluoropyridine carboxaldehyde (1.0 g, 4.9 mmol) was dissolved in DCM (10 mL) solution, DAST (1.58 g, 9.8 mmol) was added, the reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature and continued to stir for 2 hours. The reactant was poured into an ice-cold 1N NaOH solution, the organic layer was separated and the aqueous layer was extracted with DCM (2x). The combined DCM layers were passed through Na2SO4 and were dried and concentrated under reduced pressure to obtain 5-bromo-3-(difluoromethyl)-2-fluoropyridine Q-1 (675 mg, 3.0 mmol, 61% yield).

[0076] 1 H NMR (400MHz, CHCl3-d) δ7.62(ddt,J=8.7,3.5,0.9Hz,1H),7.43(t,J=8.8Hz,1H),6.71(t,J=53.3Hz,1H).

[0077] Preparation of intermediate A-1:

[0078]

[0079] Pd(dppf)Cl2 (87 mg, 0.12 mmol), KOAc (705 mg, 7.2 mmol), 4-bromo-2-(difluoromethyl)pyridine (500 mg, 2.4 mmol) and bis(pinacol)diboron (914 mg, 3.6 mmol) were dissolved in a dioxane (5 mL) solution and degassed 3 times. The mixture was heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, and the remaining solid was dissolved in a mixture of methanol and DCM. Filtered and concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel column to obtain the target product A-1 (700 mg, 2.2 mmol, yield 92%).

[0080] LCMS(ESI):254.1[M+H] + .

[0081] Example 1

[0082] 1-(((2-(Difluoromethyl)-6-(isoxazol-4-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-1)

[0083] The compound is prepared from intermediates Q-1 and AA-1 according to the synthetic method shown in the following reaction scheme 2:

[0084]

[0085] The specific preparation process is as follows:

[0086] At 0°C, compound AA-1 (1.1 g, 8.5 mmol) was dissolved in DMF (20 mL) in a 50 mL round-bottom flask, NaH (1.0 g, 25.5 mmol) was added to the mixture and stirred for 20 minutes, and compound Q-1 (2.1 g, 9.4 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product D-1.

[0087] 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.8Hz,1H),7.66(d,J=8.9Hz,1H),7.15(t,J=53.4Hz,1H),3.82(s,2H),1.41(s,10H).

[0088] LCMS(ESI):335.05[M+H] + .

[0089] Intermediate D-1 (300 mg, 0.9 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoxazole (1.4 mmol) were dissolved in 1,4-dioxane (5 mL), Pd(dppf)Cl2 (33 mg, 0.05 mmol) and Cs2CO3 (878 mg, 2.7 mmol) were added to the system, and the mixture was stirred at 100 ° C for 4 hours under N2 atmosphere. The mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate (20 mL x3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. Purification by column chromatography gave the target compound I-1.

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.51(d,J=9.0Hz,1H),7.42(d,J=8.9Hz,1H),7.3 5-6.90(m,2H),4.07(s,2H),1.85-1.77(m,2H),1.65-1.58(m,4H),1.54-1.46(m,4H).

[0091] LCMS(ESI):324.25[M+H] + .

[0092] Example 2

[0093] 1-(((2-(difluoromethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-2)

[0094]

[0095] The compound is prepared from intermediate D-1 and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole according to reaction route 2. The product is characterized, and the characterization results are as follows:

[0096] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.65(m,2H),7.22(t,J=53.8Hz,1H),3.90(s,2H),2.54(s,3H),2.36(s,3H),1.67-1.42(m,10H).

[0097] LCMS(ESI):352.35[M+H] + .

[0098] Example 3

[0099] 1-(((2-(Difluoromethyl)-6-(thiazol-5-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-4)

[0100]

[0101] The compound was prepared from intermediate D-1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole according to reaction route 2. The product was characterized, and the characterization results are as follows:

[0102] 1 H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.54 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.8 2(d,J=8.8Hz,1H),7.34(t,J=53.5Hz,1H),4.06(s,2H),1.73-1.39(m,10H).

[0103] LCMS(ESI):340.40[M+H] + .

[0104] Example 4

[0105] 1-(((6-(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)methyl)cyclohexan-1-amine (I-6)

[0106]

[0107] The compound was prepared from intermediate D-1 and pyridin-4-ylboronic acid according to reaction route 2. The product was characterized, and the characterization results are as follows:

[0108] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.1Hz,2H),8.30(d,J=8.8Hz,1H),8.03(d,J=5.1Hz ,2H),7.84(d,J=8.9Hz,1H),7.35(t,J=53.6Hz,1H),4.04(s,2H),1.66-1.41(m,10H).

[0109] LCMS(ESI):334.2[M+H] + .

[0110] Example 5

[0111] 1-(((6-(difluoromethyl)-[2,3'-bipyridyl]-5-yl)oxy)methyl)cyclohexan-1-amine (I-7)

[0112]

[0113] The compound was prepared from intermediate D-1 and pyridin-3-ylboronic acid according to reaction route 2. The product was characterized, and the characterization results are as follows:

[0114] 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.2Hz,1H),8.61(d,J=4.1Hz,1H),8.40(d,J=8.0Hz,1H),8.23(d,J=8.6Hz,1 H),7.82(d,J=8.7Hz,1H),7.52(dd,J=8.0,4.8Hz,1H),7.34(t,J=53.6Hz,1H),4.03(s,2H),1.70-1.40(m,10H).

[0115] LCMS(ESI):334.2[M+H] + .

[0116] Example 6

[0117] 2-((1-aminocyclohexyl)methoxy)-5-(pyridin-4-yl)benzonitrile (I-13)

[0118] The compound is prepared according to the synthetic method shown in the following reaction scheme:

[0119]

[0120] The starting material 5-bromo-2-fluorobenzonitrile is first reacted with the intermediate AA-1 to obtain the intermediate D-2, and then the intermediate D-2 is subjected to a standard Suzuki reaction with pyridin-4-ylboronic acid to obtain compound I-13.

[0121] 1 H NMR (400MHz, DMSO-d6) δ8.66-8.59(m,2H),8.28(d,J=2.4Hz,1H),8.14(dd,J=8.9,2. 5Hz,1H),7.80-7.72(m,2H),7.43(d,J=9.0Hz,1H),4.10(s,2H),1.76-1.40(m,10H).

[0122] LCMS(ESI):308.50[M+H] + .

[0123] Example 7

[0124] 2-((1-aminocyclohexyl)methoxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile (I-14)

[0125] The compound is prepared according to the synthetic method shown in the following reaction scheme:

[0126]

[0127] The starting material 5-bromo-2-fluorobenzonitrile is first reacted with the intermediate AA-1 to obtain the intermediate D-2, and then the intermediate D-2 is subjected to a standard Suzuki reaction with (2-(difluoromethyl)pyridin-4-yl)boronic acid to obtain compound I-14.

[0128] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=5.2Hz,1H),8.42(d,J=2.4Hz,1H),8.36(s,2H),8.26(dd,J=8.9,2.4Hz,1H),8.10(s,1H),7.98(d ,J=5.3Hz,1H),7.51(d,J=9.0Hz,1H),7.00(t,J=54.8Hz,1H),4.40(s,2H),1.94-1.86(m,2H),1.77-1.63(m,4H),1.58-1.43(m,4H).

[0129] LCMS(ESI):358.65[M+H] + .

[0130] Example 8

[0131] 1-(((2-(difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-5)

[0132] The compound is prepared by the synthesis method shown in the following reaction scheme 3:

[0133]

[0134] At 0°C, compound 7 (750 mg, 3.4 mmol) was dissolved in DCM (15 mL), TFA (387 mg, 3.4 mmol) and (Boc)2O (1.11 g, 5.1 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was transferred to a separatory funnel containing water (10 mL) and extracted with DCM (2×10 mL), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain intermediate 8.

[0135] Standard Suzuki reaction of intermediate D-1 with intermediate 8 affords intermediate 9, and then removal of the Boc-protected intermediate 9 using trifluoroacetic acid in DCM affords the desired product 1-5.

[0136] 1 H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.8Hz,1H),7.54(d,J=8.7Hz,1H),7.42-7.23(m,1H),4.12(s,2H),2.33(s,6H),1.79-1.37(m,10H).

[0137] LCMS(ESI):351.3[M+H] + .

[0138] Example 9

[0139] 1-(((2-(Difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-3)

[0140]

[0141] The compound is prepared according to the similar synthetic steps of reaction scheme 3, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the starting material, and the Boc-protected intermediate is subjected to standard Suzuki reaction with intermediate D-1, and then trifluoroacetic acid in DCM solution is used to remove the Boc-protected compound to obtain the desired compound I-3.

[0142] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,2H),7.82(d,J=8.8Hz,1H),7.66(d,J=8.8Hz,1H),7.34-7.07(m,1H),3.90(s,2H),1.69-1.39(m,10H).

[0143] LCMS(ESI):323.2[M+H] + .

[0144] Example 10

[0145] N-((1-aminocyclohexyl)methyl)-6-(difluoromethyl)-[2,4'-bipyridyl]-5-amine (I-8)

[0146] The compound is prepared by the synthesis method shown in the following reaction scheme 4:

[0147]

[0148] In a 50 mL round-bottom flask, compound AA-4 (400 mg, 3.13 mmol) was dissolved in DMF (15 mL) at 0°C, DBU (951 mg, 6.2 mmol) was added to the mixture and stirred for 20 minutes, compound Q-1 (675 mg, 2.98 mmol) was added to the mixture and stirred at 100°C for 16 hours. The reaction was quenched with water and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a crude product 10. LCMS (ESI): 335.3 [M+H]+.

[0149] Intermediate 10 is then subjected to standard Suzuki reaction with pyridin-4-ylboronic acid to yield the desired compound 1-8.

[0150] 1 H NMR (400MHz, CHCl3-d) δ8.62-8.57(m,2H),8.06(d,J=8.8Hz,1H),7.96-7.90(m,2H),7.31(d,J=8.9Hz,1H),7.04(t,J =53.9Hz,1H),6.21(t,J=6.0Hz,1H),3.37-3.35(m,2H),3.21(q,J=6.5Hz,2H),2.46-2.41(m,2H),1.74-1.50(m,8H).

[0151] LCMS (ESI): 333.4 [M+H]+.

[0152] Embodiment 11

[0153] 1-(((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)methyl)-4,4-difluorocyclohexane-1-amine (I-9)

[0154]

[0155] The compound uses intermediate Q-1 and intermediate AA-3 as starting materials, synthesizes the intermediate according to the synthesis steps described in reaction scheme 2, and then performs a standard Suzuki reaction with intermediate A-1 to generate the desired product I-9. The product is characterized, and the characterization results are as follows:

[0156] 1H NMR (400MHz, DMSO-d6) δ8.79(d,J=5.2Hz,1H),8.41(d,J=8.8Hz,1H),8.32(s,1H),8.22(d,J=4.5Hz,1H),7.8 1(d,J=8.8Hz,1H),7.42-6.88(m,2H),3.98(s,2H),2.28-2.08(m,2H),1.94-1.82(m,3H),1.69-1.61(m,4H).

[0157] LCMS(ESI):420.5[M+H] + .

[0158] Example 12

[0159] 4-(((6-(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)methyl)tetrahydro-2H-pyran-4-amine (I-10)

[0160]

[0161] The compound uses compound Q-1 and intermediate AA-2 as starting materials, synthesizes the intermediate according to the synthesis steps described in reaction scheme 2, and then the intermediate is subjected to a standard Suzuki reaction with pyridin-4-ylboronic acid to generate the desired product I-10. The product is characterized, and the characterization results are as follows:

[0162] 1 H NMR (400MHz, DMSO-d6) δ8.72-8.65(m,2H),8.30(d,J=8.8Hz,1H),8.07-8.00(m,2H),7.80(d,J=8.8Hz,1H),7. 27(t,J=53.6Hz,1H),3.96(s,2H),3.81-3.72(m,2H),3.69-3.58(m,2H),1.76-1.64(m,2H),1.47-1.36(m,2H).

[0163] LCMS(ESI):336.30[M+H] + .

[0164] Example 13

[0165] 1-(((6-(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)methyl)-4,4-difluorocyclohexyl-1-amine (I-11)

[0166]

[0167] The compound uses compound Q-1 and intermediate AA-3 as starting materials, synthesizes the intermediate according to the synthesis steps described in reaction scheme 2, and then the intermediate is subjected to a standard Suzuki reaction with pyridin-4-ylboronic acid to generate the desired product I-11. The product is characterized, and the characterization results are as follows:

[0168] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.7Hz,2H),8.31(d,J=8.8Hz,1H),8.03(d,J=5.9Hz,2H),7.80(d,J=8 .8Hz,1H),7.28(t,J=53.6Hz,1H),4.00(s,2H),2.31-2.09(m,2H),2.01-1.83(m,2H),1.80-1.59(m,4H).

[0169] LCMS(ESI):370.3[M+H] + .

[0170] Embodiment 14

[0171] 2-((1-amino-4,4-difluorocyclohexyl)methoxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile (I-15)

[0172]

[0173] The compound is prepared by using compound 6 and intermediate AA-3 as starting materials, synthesizing the intermediate according to the synthesis steps described in reaction scheme 2, and then subjecting the intermediate to a standard Suzuki reaction with intermediate A-1 to generate the desired product I-15. The product is characterized, and the characterization results are as follows:

[0174] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=5.2Hz,1H),8.38(d,J=2.4Hz,1H),8.22(dd,J=8.9,2.5Hz,1H),8.07(s,1H),7.95(d,J=5.4Hz,1H),7 .40(d,J=9.0Hz,1H),6.99(t,J=54.8Hz,1H),4.02(s,2H),2.26-2.11(m,2H),1.96-1.84(m,2H),1.81-1.68(m,2H),1.66-1.58(m,2H).

[0175] LCMS(ESI):394.3[M+H] + .

[0176] Embodiment 15

[0177] 1-(((2-(Difluoromethyl)-6-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)pyridin-3-yl)oxy)methyl)cyclohexan-1-amine (I-19)

[0178] The compound is prepared by the synthesis method shown in the following reaction scheme 5:

[0179]

[0180] A solution of Pd(OAc)2 (216 mg, 1.3 mmol), Xphos (621 mg, 1.3 mmol), Cs2CO3 (12.7 g, 39 mmol), a mixture of compound 11 (2.0 g, 13.0 mmol) and bis(pinacol)diboron (6.6 g, 26.0 mmol) in dioxane (40 mL) was degassed 3 times by vacuum purging, and the reaction mixture was heated at 100°C for 2 hours. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate, the organic layer was washed 3 times with water and dried with Na2SO4, the organic layer was filtered and concentrated under reduced pressure to obtain the desired solid product A-2. LCMS (ESI): 244.4 [M+H] + .

[0181] Intermediate A-2 and intermediate D-1 were subjected to a standard Suzuki reaction to generate the desired product I-15. The product was characterized, and the characterization results were as follows:

[0182] 1 H NMR(400MHz,CHCl3-d)δ8.42(d,J=5.2Hz,1H),7.70(d,J=8.7Hz,1H),7.43-7.36(m,2H),6.93(t,J=54.1H z,1H),3.94(s,2H),3.22(t,J=7.4Hz,2H),3.07(t,J=7.7Hz,2H),2.18-2.08(m,2H),1.70-1.45(m,10H).

[0183] LCMS(ESI):374.6[M+H] + .

[0184] Example 16

[0185] 1-(((2-(difluoromethyl)-6-(7-fluoro-6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)pyridin-3-yl)oxy)methyl)cyclohexane-1-amine (I-20)

[0186] The compound is prepared by the synthesis method shown in the following reaction scheme 6:

[0187]

[0188] Compound 12 (600 mg, 3.55 mmol) was dissolved in DCM (15 mL) at 0°C, DAST (743 mg, 4.62 mmol) was added, and the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the mixture was poured into 1N NaOH solution, the organic layer was separated and the aqueous layer was extracted with DCM (2x), and the combined DCM layer was dried over Na2SO4 and concentrated under reduced pressure to obtain compound 13 (480 mg, 2.8 mmol, 79% yield). LCMS (ESI): 173.3 [M+H] + .

[0189] Intermediate 13 (550 mg, 3.2 mmol) and bis(pinacol)diboron (1.63 g, 6.4 mmol) were subjected to Suzuki reaction to synthesize intermediate A-3. Intermediate A-3 and intermediate D-1 were then subjected to standard Suzuki reaction to produce the desired compound I-20. The product was characterized, and the characterization results are as follows:

[0190] 1 H NMR (400MHz, CHCl3-d) δ8.63(d,J=5.1Hz,1H),7.76(d,J=8.7Hz,1H),7.59(dd,J=5.1,1.8Hz,1H),7.43(d,J=8.7Hz,1 H),7.05(t,J=54.1Hz,1H),6.10-5.85(m,1H),4.01(s,2H),3.51-3.20(m,2H),2.55-2.35(m,2H),1.76-1.39(m,10H).

[0191] LCMS(ESI):392.5[M+H] + .

[0192] Embodiment 17

[0193] 1-(((6-(7,7-difluoro-6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)methyl)cyclohexane-1-amine (I-21)

[0194] The compound is prepared by the synthesis method shown in the following reaction scheme 7:

[0195]

[0196] Manganese oxide (2.6 g, 29.4 mmol) was added in batches to a DCM (10 mL) solution of compound 14 (500 mg, 2.9 mmol), and the mixture was stirred at room temperature for 16 hours, filtered through celite, and the solvent was evaporated to obtain compound 15 (400 mg, yield 82%). LCMS (ESI): 169.2 [M+H] + .

[0197] DAST (867 mg, 5.4 mmol) was added to a solution of compound 15 (300 mg, 1.8 mmol) in DCM (5 mL) at 0°C, and the reaction was stirred at 0°C for 4 days. After the reaction was completed, the reactant was poured into 1N NaOH solution, the organic layer was separated and the aqueous layer was extracted with DCM (2x), and the crude product was purified by silica gel column chromatography to obtain the target product 16 (130 mg, yield 38%). LCMS (ESI): 191.4 [M+H] + .

[0198] Intermediate 16 (100 mg, 0.5 mmol) and bis(pinacol)diboron (269 g, 1.1 mmol) were subjected to Suzuki reaction to synthesize intermediate A-4. Intermediate A-4 and intermediate D-1 were subjected to standard Suzuki reaction to obtain the desired compound I-21. The product was characterized, and the characterization results are as follows:

[0199] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=5.1Hz,1H),8.20(d,J=8.8Hz,1H),7.98(d,J=5.1Hz,1H),7.87(d,J=8. 9Hz,1H),7.35(t,J=53.6Hz,1H),4.02(s,2H),3.42-3.36(m,2H),2.74-2.59(m,2H),1.69-1.41(m,10H).

[0200] LCMS(ESI):410.4[M+H] + .

[0201] Embodiment 18

[0202] (S)-1-((2-(difluoromethyl)-6-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (I-22)

[0203] The compound is prepared by the synthesis method shown in the following reaction scheme 8:

[0204]

[0205] LiAlH4 (786 mg, 20.7 mmol) was dissolved in THF and cooled to 0°C, compound 17 (1.0 g, 6.9 mmol) was added to the reaction mixture in batches, the system was warmed to room temperature and stirred for 1 hour, then the reaction mixture was poured into ice water and extracted with ethyl acetate 3 times, the extracted organic matter was dried and concentrated to obtain a crude product AA-5 (800 mg, 89% yield). LCMS (ESI): 132.3 [M+H] + .

[0206] In a 50 mL round-bottom flask, compound AA-5 (1.5 g, 11.4 mmol) was dissolved in DMF (20 mL) at 0 ° C, NaH (1.4 g, 34.3 mmol) was added to the mixture and stirred for 20 minutes, compound Q-1 (3.1 g, 13.7 mmol) was added to the mixture and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water and extracted with EtOAc, the organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure to obtain a crude product D-3. LCMS (ESI): 338.2 [M + H] + .

[0207] Compounds A-2 and D-3 were subjected to a standard Suzuki reaction to obtain the desired compound I-22. The product was characterized, and the characterization results are as follows:

[0208] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=5.2Hz,1H),8.04(d,J=8.7Hz,1H),7.80(d,J=8.8Hz,1H),7.54(d,J=5.3Hz,1H),7.32(t,J=53.7Hz,1H),4.03(s,2 H),3.22(t,J=7.4Hz,2H),2.97(t,J=7.7Hz,2H),2.13–2.00(m,2H),1.86- 1.75(m,1H),1.61-1.43(m,2H),1.25(s,3H),0.93(dd,J=14.9,6.6Hz,6H).

[0209] LCMS(ESI):376.5[M+H] + .

[0210] Embodiment 19

[0211] (S)-1-((3-(difluoromethyl)-5-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine (I-23)

[0212]

[0213] Intermediate Q-3 was prepared using 5-bromo-2-fluoronicotinaldehyde as the starting material according to the preparation method of intermediate Q-1. LCMS (ESI): 226.8 [M+H] + .

[0214] The intermediate Q-3 prepared was substituted for the intermediate Q-1 in the above reaction scheme 8 to prepare the target product I-23. The product was characterized, and the characterization results are as follows:

[0215] 1 H NMR (400MHz, DMSO-d6) δ8.54(d,J=2.4Hz,1H),8.38(d,J=5.2Hz,1H),8.14(d,J=2.4Hz,1H),7.51-7.19(m,2H),4.26(s,2H),3.02(t,J= 7.3Hz,2H),2.97(t,J=7.6Hz,2H),2.11-1.99(m,2H),1.86-1.74(m,1H),1.59-1.42(m,2H),1.23(s,3H),0.92(dd,J=12.8,6.6Hz,6H).

[0216] LCMS(ESI):376.4[M+H] + .

[0217] Embodiment 20

[0218] (S)-1-((6-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)-2-ethynylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (I-24)

[0219]

[0220] The specific preparation process is as follows:

[0221] To a solution of 5-bromo-2-fluorobenzaldehyde (100 mg, 0.50 mmol) in anhydrous MeOH (5 mL), K2CO3 (138 mg, 1 mmol) was added, and diazophosphonate (230 mg, 0.55 mmol) was added under stirring at room temperature, stirred for 2 hours, and monitored by TLC until the starting material was completely consumed. The reaction was quenched by adding DCM and water, the aqueous phase was extracted with DCM, the organic phases were combined, washed with brine, and dried over Na2SO4. The crude product was purified by silica gel column chromatography to obtain compound Q-2. LCMS (ESI): 199.7 [M + H] + .

[0222] The intermediate Q-2 prepared was substituted for the intermediate Q-1 in the above reaction scheme 8 to prepare the target product I-24. The product was characterized, and the characterization results are as follows:

[0223] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=5.3Hz,1H),7.85(d,J=8.8Hz,1H),7.66(d,J=8.8Hz,1H),7.48(d,J=5.3Hz,1H),4.53(s,1H),3.99-3.90(m,2H) ,3.17(t,J=7.4Hz,2H),2.96(t,J=7.7Hz,2H),2.11-2.01(m,2H),1.87-1 .75(m,1H),1.56-1.44(m,2H),1.22(s,3H),0.94(dd,J=6.6,4.4Hz,6H).

[0224] LCMS(ESI):350.4[M+H] + .

[0225] Embodiment 21

[0226] (S)-5-((2-amino-2,4-dimethylpentyl)oxy)-2-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)benzonitrile (I-25)

[0227]

[0228] The intermediate Q-1 in the above reaction scheme 8 is replaced by 2-bromo-5-fluorobenzonitrile to prepare the target product I-25. The product is characterized, and the characterization results are as follows:

[0229] 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=5.2Hz,1H),7.63(d,J=2.6Hz,1H),7.55(d,J=8.6Hz,1H),7.42(dd,J=8.7,2.6Hz,1H),7.16(d,J=5.1Hz,1H),4.00(s ,2H),3.00(t,J=7.6Hz,2H),2.84(t,J=7.4Hz,2H),2.10-2.01(m,2H),1.87 -1.76(m,1H),1.60-1.46(m,2H),1.26(s,3H),0.94(dd,J=12.2,6.6Hz,6H).

[0230] LCMS(ESI):350.4[M+H]+ .

[0231] Embodiment 22

[0232] (S)-1-((6-(6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)-2-ethynylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (I-26)

[0233]

[0234] The intermediate Q-1 in the above reaction scheme 8 is replaced by 5-bromo-2-fluorobenzonitrile to prepare the target product I-26. The product is characterized, and the characterization results are as follows:

[0235] 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=5.3Hz,1H),7.96(d,J=2.4Hz,1H),7.85(d d,J=8.8,2.4Hz,1H),7.35(d,J=8.9Hz,1H),7.22(d,J=5.2Hz,1H),3.97-3.8 9(m,2H),3.01(t,J=7.3Hz,2H),2.96(t,J=7.6Hz,2H),2.08-1.99(m,2H),1. 87-1.75(m,1H),1.50-1.38(m,2H),1.16(s,3H),0.93(dd,J=6.6,3.5Hz,6H).

[0236] LCMS(ESI):350.3[M+H] + .

[0237] Embodiments 23 to 29

[0238] Compounds I-28, I-30, I-32, I-33, I-34, I-38, and I-39 were prepared by the synthesis method shown in the following reaction scheme 9:

[0239]

[0240] Compound I-28: (S)-1-((2-(difluoromethyl)-6-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0241]

[0242] Compound 28 and D-3 were used as starting materials and the desired compound I-29 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0243] 1 H NMR(400MHz,DMSO-d6)δ7.87(d,J=8.8Hz,1H),7.75-7.67(m,2H),7.45(s,1H),7.28(t,J=53.7Hz,1H) ,3.96-3.87(m,5H),1.85-1.73(m,1H),1.53-1.39(m,2H),1.18(s,3H),0.92(dd,J=12.4,6.6Hz,6H).

[0244] LCMS(ESI):339.0[M+H] + .

[0245] Compound I-30: (S)-1-((2-(difluoromethyl)-6-(thieno[3,2-b]pyridin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0246]

[0247] Compound 30 and D-3 were used as starting materials and the desired compound I-30 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0248] LCMS(ESI):392.3[M+H] + .

[0249] Compound I-32: (S)-1-((2-(difluoromethyl)-6-(furan[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0250]

[0251] Compound 32 and D-3 were used as starting materials and the desired compound I-32 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0252] LCMS(ESI):376.4[M+H] + .

[0253] Compound I-33: (S)-1-((2-(difluoromethyl)-6-(furan[3,2-b]pyridin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0254]

[0255] Compound 33 and D-3 were used as starting materials and the desired compound I-33 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0256] LCMS(ESI):376.2[M+H] + .

[0257] Compound I-34: (S)-1-((2-(difluoromethyl)-6-(thieno[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0258]

[0259] Compound 34 and D-3 were used as starting materials and the desired compound I-34 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0260] LCMS(ESI):392.1[M+H] + .

[0261] Compound I-38: (S)-1-((2-(difluoromethyl)-6-(thieno[2,3-d]pyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0262]

[0263] Compound 38 and D-3 were used as starting materials and the desired compound I-38 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0264] LCMS(ESI):393.2[M+H] + .

[0265] Compound I-39: (S)-1-((2-(difluoromethyl)-6-(thieno[3,2-d]pyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0266]

[0267] Compound 39 and D-3 were used as starting materials and the desired compound I-39 was obtained by standard Suzuki reaction. The product was characterized and the characterization results are as follows:

[0268] LCMS(ESI):393.3[M+H] + .

[0269] Embodiments 30 to 36

[0270] Compounds I-29, I-31, I-35, I-36, I-37, I-40, and I-41 were prepared by the synthesis method shown in the following reaction scheme 10:

[0271]

[0272] Compound I-29: (S)-1-((2-(difluoromethyl)-6-(1H-pyrrolo[3,2-b]pyridin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0273]

[0274] Using compound 29 and D-3 as starting materials, intermediate D-29 was prepared by standard Suzuki reaction, and compound D-29 was subjected to SEM deprotection with TFA to obtain target compound I-29. The product was characterized, and the characterization results are as follows:

[0275] LCMS(ESI):375.4[M+H] + .

[0276] Compound I-31: (S)-1-((2-(difluoromethyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0277]

[0278] Using compound 31 and D-3 as starting materials, intermediate D-31 was prepared by standard Suzuki reaction, and compound D-31 was subjected to SEM deprotection with TFA to obtain target compound I-31. The product was characterized, and the characterization results are as follows:

[0279] LCMS(ESI):389.1[M+H] + .

[0280] Compound I-35: (S)-1-((2-(difluoromethyl)-6-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0281]

[0282] Using compound 35 and D-3 as starting materials, intermediate D-35 was prepared by standard Suzuki reaction, and compound D-35 was subjected to SEM deprotection with TFA to obtain target compound I-35. The product was characterized, and the characterization results are as follows:

[0283] LCMS(ESI):393.1[M+H] + .

[0284] Compound I-36: (S)-1-((2-(difluoromethyl)-6-(6-fluoro-1H-pyrrolo[3,2-b]pyridin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0285]

[0286] Using compound 36 and D-3 as starting materials, intermediate D-36 was prepared by standard Suzuki reaction, and compound D-36 was subjected to SEM deprotection with TFA to obtain target compound I-36. The product was characterized, and the characterization results are as follows:

[0287] LCMS(ESI):393.2[M+H] + .

[0288] Compound I-37: (S)-1-((2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0289]

[0290] Using compound 37 and D-3 as starting materials, intermediate D-37 was prepared by standard Suzuki reaction, and compound D-37 was subjected to SEM deprotection with TFA to obtain target compound I-37. The product was characterized, and the characterization results are as follows:

[0291] LCMS(ESI):375.2[M+H] + .

[0292] Compound I-40: (S)-1-((2-(difluoromethyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0293]

[0294] Using compound 40 and D-3 as starting materials, intermediate D-40 was prepared by standard Suzuki reaction, and compound D-40 was subjected to SEM deprotection with TFA to obtain target compound I-40. The product was characterized, and the characterization results are as follows:

[0295] LCMS(ESI):376.4[M+H] + .

[0296] Compound I-41: (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

[0297]

[0298] Using compound 41 and D-3 as starting materials, intermediate D-41 was prepared by standard Suzuki reaction, and compound D-41 was subjected to SEM deprotection with TFA to obtain target compound I-41. The product was characterized, and the characterization results are as follows:

[0299] LCMS(ESI):393.3[M+H] + .

[0300] Embodiment 37

[0301] (S)-1-((5-(2-(difluoromethyl)pyridin-4-yl)-4-methylthiazol-2-yl)oxy)-2,4-dimethylpentan-2-amine (I-42)

[0302]

[0303] The target product I-42 was prepared by replacing the intermediate Q-1 in the above reaction scheme 8 with 5-bromo-2-fluoro-4-methylthiazole. The product was characterized, and the characterization results are as follows:

[0304] LCMS(ESI):356.3[M+H] + .

[0305] Embodiment 38

[0306] (S)-1-((6-(difluoromethyl)-2'-vinyl-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentane-2-amine (I-43)

[0307] The compound is prepared according to the synthetic method shown in the following reaction scheme:

[0308]

[0309] Compound 42 (3.8 g, 21 mmol) and Lindlar catalyst (500 mg) were placed in a reactor, methanol solvent was added, and the reaction was carried out under a hydrogen environment for 16 hours. TLC detected that the raw material completely disappeared. The product was washed with brine, the aqueous phase was extracted with DCM, and the organic phases were combined and dried over Na2SO4. The crude product was purified by silica gel column chromatography to obtain compound 43 (2.8 g, yield 72.4%).

[0310] Pd(dppf)Cl2 (278 mg, 0.3 mmol), KOAc (2 g, 20.5 mmol), 43 (1.3 g, 6.8 mmol) and bis(pinacol)diboron (2.6 g, 10.2 mmol) were dissolved in a dioxane (20 mL) solution and degassed three times. The mixture was heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, and the remaining solid was dissolved in a mixture of methanol and DCM. Filtration and concentration under reduced pressure gave a crude product, which was purified by silica gel column to give the target product 44 (1.5 g, yield 95.5%).

[0311] Using compound 44 and D-3 as starting materials, the target compound I-43 (350 mg, yield 14.3%) was obtained by standard Suzuki reaction. The product was characterized, and the characterization results are as follows:

[0312] 1 H NMR(400MHz,Chloroform-d)δ8.52(d,J=5.1Hz,1H),7.75(s,1H),7.65(d,J=8.6Hz,1H ),7.52(dd,J=5.2,1.6Hz,1H),7.35(s,1H),7.27–7.21(m,1H),6.79(dd,J=17.4,10.8 Hz,1H),6.22(d,J=17.5Hz,1H),5.46(d,J=10.8Hz,1H),4.16(d,J=9.6Hz,1H),3.97(d ,J=9.5Hz,1H),1.70(s,3H),1.38(s,3H),0.87(d,J=5.9Hz,4H),0.82(d,J=5.9Hz,4H).

[0313] LCMS(ESI):362.1[M+H] + .

[0314] Embodiment 39

[0315] (S)-1-((6-(difluoromethyl)-2'-ethynyl-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentane-2-amine (I-44)

[0316] The compound is prepared according to the synthetic method shown in the following reaction scheme:

[0317]

[0318] Compound 45 (22 g, 110 mmol), compound 46 (15.9 g, 160 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2 mmol) were dissolved in triethylamine (200 mL), and cuprous iodide (206 mg, 1 mmol) was added. Under nitrogen protection, the mixture was stirred at 80 degrees Celsius for overnight reaction. TLC showed that the reaction was complete and the target product was obtained. After the reaction was completed, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1) to obtain the target product compound 47 (17 g, yield 70.0%).

[0319] Compound 47 (7 g, 31.8 mmol) and NH4Cl (8.4 g, 159 mmol) were dissolved in 100 ml of 90% ethanol aqueous solution, and then iron powder (8.9 g, 159 mmol) was added. After reacting for 7 hours, the reaction mixture was filtered through a diatomaceous earth pad, the filter pad was washed with ethanol, the filtrate was concentrated under reduced pressure, and the residue was azeotroped with benzene twice to obtain a crude product 48 (5 g, yield 82.8%).

[0320] NaNO2 (5.4 g, 78.9 mmol), TMSBr (12 g, 78.9 mmol) and benzyltriethylammonium bromide (1.2 g, 5.3 mmol) were dissolved in DMF (100 mL) at 0 degrees Celsius, and then compound 48 (5 g, 26.3 mmol) was added. The reaction mixture was stirred for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with water and then with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. Purification by silica gel flash column chromatography using petroleum ether / ethyl acetate (7:3) as eluent gave the target product 49 (650 mg, yield 3.3%).

[0321] Pd(dppf)Cl2 (160 mg, 0.2 mmol), KOAc (576 mg, 5.88 mmol), 49 (500 mg, 1.96 mmol) and bis(pinacol)diboron (996 mg, 3.92 mmol) were dissolved in a dioxane (5 mL) solution and degassed three times. The mixture was heated to 90 °C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, and the remaining solid was dissolved in a mixture of methanol and DCM. Filter and concentrate under reduced pressure to obtain a crude product, and the crude mixture was purified by a silica gel column to obtain the target product 50 (550 mg, 93%). Using compound 50 and D-3 as starting materials, product 51 was obtained by standard Suzuki reaction, and then TBAF was used to remove the TMS protective agent to finally obtain the target compound I-43 (45 mg, total yield 6.4%). The product was characterized, and the characterization results are as follows:

[0322] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=5.3Hz,1H),8.37(d,J=8.8Hz,1H),8.20(d,J=1.7Hz,1H),8.07(dd,J=5.3,1.8Hz,1H ),7.80(d,J=8.8Hz,1H),4.41(s,1H),3.92(s,2H),1.80(m,1H),1.57(m,1H),1.15(s,3H),0.92(dd,J=9.2,6.7Hz,6H).

[0323] LCMS(ESI):360.3[M+H] + .

[0324] Embodiment 40

[0325] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2-methylpent-4-yn-2-amine (I-45)

[0326] The compound is prepared according to the synthetic method shown in the following reaction scheme:

[0327]

[0328] The synthesis method of compound 56 is obtained by the synthesis route of reference (J.Org.Chem.2012,77,3099-3114). LiAlH4 (216 mg, 5.7 mmol) was suspended in THF and cooled to 0°C, followed by adding compound 56 (300 mg, 1.92 mmol) in batches. After the reaction mixture was warmed to room temperature and stirred for 2 hours, it was poured into ice water and extracted 3 times with ethyl acetate. The combined organic phase was dried over Na2SO4 and concentrated to give a crude product 57 (150 mg).

[0329] At 0°C, compound 57 (1.1 g, 8.5 mmol) was dissolved in DMF (20 mL) in a 50 mL round-bottom flask, NaH (1.0 g, 25.5 mmol) was added to the mixture and stirred for 20 minutes, compound Q-1 (2.1 g, 9.4 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product 58.

[0330] Compound 58 (300 mg, 0.9 mmol) and compound A-1 were dissolved in 1,4-dioxane (5 mL), Pd(dppf)Cl2 (33 mg, 0.05 mmol) and Cs2CO3 (878 mg, 2.7 mmol) were added to the system, and the mixture was stirred at 100 ° C for 4 hours under N2 atmosphere. The mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. Purification by column chromatography gave the target compound I-45 (165 mg, 51% yield). The product was characterized, and the characterization results are as follows:

[0331] LCMS(ESI):368.13[M+H] + .

[0332] Test Example 1

[0333] The biological activity of some of the target compounds synthesized in Examples 1 to 40 was tested, and LX9211 was used as a control sample to test their in vitro inhibitory activity against AAK1. The specific operation was as follows:

[0334] Add the compound (dissolved in DMSO) to a 384-well plate. Add 5 μL of enzyme (ICE, Cat#E2209T-H11H) working solution to the 384-well assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min. Add 5 μL of substrate (ATP and substrate) working solution to initiate the reaction and incubate at 25°C for 120 min. Add 5 μL of ADP-Glo ​​(Promega, Cat#V9101) working solution to start the reaction and incubate at 25°C for 40 min. Add 10 μL of Detection working solution to start the reaction and incubate at 25°C for 40 min. Use a MicroplateReader (BMG, PHERAstar FSX) to read the relative luminescence units and calculate the IC of AAK1 inhibitory activity. 50 The test results are shown in Table 1 below:

[0335] Table 1 In vitro inhibition test IC of different compounds on AAK1 50 Test Results

[0336]

[0337]

[0338] According to the above-mentioned AAK1 in vitro inhibition test IC50 test results, the novel amine derivatives provided in the embodiments of the present invention have high inhibitory activity against AAK1, among which compounds I-6, I-13, I-14, I-23, I-26, I-43, and I-44 have better inhibitory activity against AAK1 than LX9211 or are equivalent to LX9211.

[0339] Test Example 2

[0340] hERG safety evaluation was performed on some of the compounds synthesized in Examples 1 to 40 above, and the specific operation was as follows:

[0341] HEK293 cells (Invitrogen, Cat#K1236) were positioned in the ideal position and approached the cell surface using fine control of the manipulator. Gentle suction was applied through the side port of the electrode to form a gigahertz seal. The morphology of the entire cell was obtained by repeated, short, and strong suction until the membrane patch ruptured. The hERG current was first stimulated by depolarization, then inactivated, and the inactivated tail current was observed. The hERG current amplitude was determined by the maximum tail current. The cells were vector-controlled to establish a baseline. Once the hERG current was found to be stable for 5 minutes, the working solution was applied. In the presence of the test compound, the hERG current was recorded for about 5 minutes to reach steady state, and then 5 scans were captured. In a dose-response experiment, 5 doses of the test compound were cumulatively applied to the cells from low to high concentrations. The hERG post-current measurement was performed with the highest concentration of the test compound as an internal low control to normalize the percentage inhibition. Peak currents were extracted from the raw data using PatchMaster or Clampfit software. GraphpadPrism 8.0 was used to draw the dose response curve of the % inhibition effect on the concentration of the test compound, and the curve was fitted into a sigmoid dose response curve with a variable slope. The IC value of the compound for the inhibitory activity of hERG channel was calculated. 50 The test results are shown in Table 2 below:

[0342] Table 2 In vitro inhibition test IC of different compounds on hERG channel 50 Test Results

[0343] Compound <![CDATA[IC 50 (μM)]]> I-6 14.504 I-9 11.677 I-15 9.074 I-22 11.557 I-26 8.059 I-43 1.523 I-44 3.612 *LX9211 1.4

[0344] *Reference J. Med. Chem. 2022, 65, 4457-4480.

[0345] As shown in Table 2, the IC values ​​of the compounds prepared in the present invention for the in vitro inhibition of hERG channels are 50 The value is significantly greater than that of LX9211, that is, it has lower inhibitory activity on the hERG channel, indicating that the compound of the present invention has less cardiotoxicity and higher safety, thus meeting the needs of pharmaceutical use.

[0346] Test Example 3

[0347] The pharmacokinetics of some of the compounds synthesized in Examples 1 to 40 above in rats were studied, and the specific operation was as follows:

[0348] Experimental animals: SD male rats (purchased from SPF Experimental Animal Technology Co., Ltd.), age: 6-8 weeks, weight: 180-300 grams.

[0349] Administration: intravenous (1 mg / kg); PO (10 mg / kg).

[0350] Blood collection time points: IV (0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h); PO (0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h).

[0351] All blood samples were transferred into plastic microcentrifuge tubes containing anticoagulants, centrifuged at 4000g, 4°C for 5 min, and the supernatant was transferred into microcentrifuge tubes without anticoagulants. The plasma was stored in a refrigerator at -75±15°C. LC-MS / MS analysis was performed after pretreatment. Pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software. The test results are shown in Table 3 below:

[0352] Table 3 Pharmacokinetic parameters of different compounds in rats

[0353]

[0354] *: Reference J. Med. Chem. 2022, 65, 4457-4480.

[0355] Experimental results show that the novel amine derivatives provided by the present invention have a high exposure amount and good drugability when administered intravenously or orally.

[0356] In summary, the novel amine derivatives provided by the present invention have high inhibitory activity against AAK1, low inhibitory activity against hERG potassium channels and good drugability, and have extremely high application value in the preparation of drugs for preventing and / or treating diseases mediated by AAK1 activity in vivo.

[0357] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A compound of formula I or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, in, A is selected from one of the following structures: Q is selected from one of the following structures: X is O or NH; R 1 , R 2 are independently selected from substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C 2-10 Alkenyl and C 2-10 one of the alkynyl groups; or, R 1 With R 2 Forming substituted or unsubstituted C 3-10 Carbocyclic, substituted or unsubstituted C containing O or S 3-8 One of a carboheterocycle, a substituted or unsubstituted spirocycle, a substituted or unsubstituted spiroheterocycle containing O or S, a substituted or unsubstituted fused carbocycle, a substituted or unsubstituted fused heterocycle containing O or S, and a bridged carboheterocycle having at least one N as a heteroatom.

2. The compound of formula I according to claim 1 or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: The R 1 , R 2 Each independently selected from C 1-10 One of the alkyl groups, or R 1 With R 2 Form C 3-10 Carbocyclic, fluorine-substituted C 3-10 Carbocyclic, C containing O or S 3-8 A carbon heterocycle.

3. The compound of formula I according to claim 1 or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: In the structure of formula I Select one of the following structures:

4. The compound of formula I according to claim 1 or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: The compound represented by the formula I is a compound represented by the following structural formula I-1 to formula I-43:

5. A pharmaceutical composition, characterized in that The invention relates to a compound represented by formula (I) as described in any one of claims 1 to 4, and one or more of its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs.

6. Use of a compound of formula (I) according to any one of claims 1 to 4 or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or the pharmaceutical composition according to claim 5 in the preparation of an AAK1 inhibitor.

7. The use according to claim 6, characterized in that: The AAK1 inhibitor is administered orally, parenterally, intravenously or transdermally.

8. Use of a compound of formula (I) according to any one of claims 1 to 4 or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, and the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating a disease mediated by AAK1 activity.

9. The use according to claim 8, characterized in that: Conditions mediated by AAK1 activity include schizophrenia, Parkinson's disease, Alzheimer's disease, and neuropathic pain, including but not limited to diabetic peripheral neuropathy and herpes zoster neuralgia.

10. The use according to claim 8, characterized in that: The drug is administered orally, parenterally, intravenously or transdermally.

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