AAK1 inhibitor and application thereof in medicine

Abstract

The invention relates to a connexin-related kinase 1 (AAK1) inhibitor of a compound shown in a general formula (I), a preparation method thereof and application of the connexin-related kinase 1 (AAK1) inhibitor in medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to adhesion molecule-associated kinase 1 (AAK1) inhibitors, methods for preparing the same and their use in medicine. BACKGROUND

[0002] AAK1 is a member of the Arkl / Prkl family of serine / threonine kinases and has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a, which inhibits AAK1 kinase activity, resulted in an enhancement of neuregulin-1-induced neurite hyperbranching. These treatments resulted in increased expression of ErbB4 and increased accumulation of ErbB4 in or near the plasma membrane. SNPs in NRG1 and ErbB4 have been associated with multiple endophenotypes of schizophrenia. Neuregulin 1 and ErbB4 KO mouse models have shown schizophrenia-related morphological changes and behavioral phenotypes. These results suggest that inhibition of AAK1 activity can be useful in the treatment of schizophrenia, cognitive deficit in schizophrenia, Parkinson’s disease, neuropathic pain, bipolar disorder, and Alzheimer’s disease. In addition, reduction of AAK1 protein using RNA interference-mediated gene silencing, treatment with the kinase inhibitor sunitinib, a potent AAK1 inhibitor, and overexpression of a Mu2 (AAK1 substrate) phosphorylation site mutant all resulted in a decrease in HCV virion assembly. Further, studies suggest that AAK1 activity can be useful in the treatment of schizophrenia, cognitive deficit in schizophrenia, Parkinson’s disease, neuropathic pain, bipolar disorder, and Alzheimer’s disease. Currently, Lexion Pharmaceutical’s LX9211 is in clinical stage, and there is no marketed drug of the related target point at present, so it is necessary to study it to meet the clinical needs. SUMMARY

[0003] The technical problem to be solved by the present application is to provide a novel AAK1 inhibitor with excellent activity for treating and / or preventing diseases mediated by AAK1, or an antiviral drug.

[0004] To solve the above technical problems, the technical solutions provided by the present application are as follows:

[0005] A compound shown in formula I, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:

[0006]

[0007] wherein ring A is selected from C 6-18 aryl or 5-18 membered heteroaryl, the preceding C 6-18 aryl or 5-18 membered heteroaryl can be optionally further substituted by one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0008] ring B is selected from

[0009] wherein "*" represents the point of attachment to the structure and "**" indicates the point of attachment to ring A;

[0010] the preceding ring B can be optionally substituted by one or more substituents selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2;

[0011] each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0012] R1is selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0013] R2is selected from H, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 alkoxy or C 1-6 haloalkoxy;

[0014] R3is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0015] m is selected from 1 or 2;

[0016] and the compound of Formula I is not:

[0017] Preferably, in the foregoing Formula I, ring B is selected from

[0018] Preferably, the compound of Formula II, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0019]

[0020] wherein ring A is selected from C 6-18 aryl or 5-18 membered heteroaryl, the foregoing C 6-18 aryl or 5-18 membered heteroaryl can be optionally substituted with one or more R a each R a is independently selected from H, oxo, hydroxyl, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0021] R1is selected from H, oxo, hydroxyl, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0022] R2is selected from H, hydroxyl, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0023] R3is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0024] m is selected from 1 or 2;

[0025] X1 is selected from N or CR4;

[0026] X2 is selected from N or CR5;

[0027] X3 is selected from N or CR6;

[0028] X4 is selected from N or CR7;

[0029] R4, R5, R6, and R7 are each independently selected from H, cyano, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) b 2. Nitro group, -C 0-3 Alkylene-C(=O)R b -C 0-3 Alkylene-C(=O)OR b or -C 0-3 Alkylene-C(=O)N(R) b )2, each R b Each is independently selected from H, hydroxyl, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0030] Preferably, the compounds are those represented by formulas (IIA), (IIB), and (IIC), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts:

[0031]

[0032] Among them, ring A is selected from C. 6-18 Aryl or 5-18 heteroaryl, wherein C 6-18 Aryl or 5-18 heteroaryl groups may be optionally replaced by one or more R groups. a Replaced; each R a Each group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0033] R1 is selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy or C 1-6 Halogenated alkoxy groups;

[0034] R2 is selected from H, hydroxyl, amino, cyano, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0035] R3 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0036] m is selected from 1 or 2;

[0037] R4, R5, R6, and R7 are each independently selected from H, cyano, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) b 2. Nitro group, -C 0-3 Alkylene-C(=O)R b -C 0-3 Alkylene-C(=O)OR b or -C 0-3 Alkylene-C(=O)N(R) b )2, each R b Each is independently selected from H, hydroxyl, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0038] Preferably, it is a compound of formula (IIA-1), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0039]

[0040] Ring A is selected from pyrazolyl groups, which may optionally be surrounded by one or more R groups. a Replaced; each R a Each group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0041] R1is selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0042] R2is selected from H, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0043] R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0044] R4, R5, R6, R7are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

[0045] Preferred is a compound of formula (IIB-1), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0046]

[0047] said ring A is selected from pyrazolyl, which can be optionally substituted with one or more R a ; each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.haloalkyl, C

[0048] R1is selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0049] R2is selected from H, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0050] R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0051] R4, R5, R6are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

[0052] Preferred is a compound of Formula (IIC-1), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0053]

[0054] Ring A is selected from pyrazolyl, which pyrazolyl can be optionally substituted with one or more R a ; each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 alkyl, C 1-6 haloalkyl, C

[0055] R1is selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0056] R2is selected from H, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0057] R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0058] R4, R5, R7are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

[0059] Preferred is a compound represented by Formula (IIA-2), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0060]

[0061] Ring A is selected from and Ring A can be optionally substituted with one or more R a ; each R aEach group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0062] R1 is selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0063] R2 is selected from H, hydroxyl, amino, cyano, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0064] R3 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0065] R4, R5, R6, and R7 are each independently selected from H, cyano, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) b 2. Nitro group, -C 0-3 Alkylene-C(=O)R b -C 0-3 Alkylene-C(=O)OR b or -C 0-3 Alkylene-C(=O)N(R) b )2, each R b Each is independently selected from H, hydroxyl, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0066] Preferably, it is a compound of formula (IIB-2), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0067]

[0068] Among them, ring A is selected from Furthermore, ring A can be arbitrarily assigned to one or more R. a Replaced; each R a Each group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0069] R1 is selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0070] R2 is selected from H, hydroxyl, amino, cyano, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0071] R3 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0072] R4, R5, and R6 are each independently selected from H, cyano, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) b 2. Nitro group, -C 0-3 Alkylene-C(=O)R b -C 0-3 Alkylene-C(=O)OR b or -C 0-3 Alkylene-C(=O)N(R) b )2, each R b Each is independently selected from H, hydroxyl, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0073] Preferably, it is a compound of formula (IIC-2), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0074]

[0075] Among them, ring A is selected from Furthermore, ring A can be arbitrarily assigned to one or more R. a Replaced; each R a Each group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0076] R1 is selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0077] R2 is selected from H, hydroxyl, amino, cyano, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0078] R3 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0079] R4, R5, and R7 are each independently selected from H, cyano, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) b 2. Nitro group, -C 0-3 Alkylene-C(=O)R b -C 0-3 Alkylene-C(=O)OR b or -C 0-3 Alkylene-C(=O)N(R) b )2, each R b Each is independently selected from H, hydroxyl, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0080] In some embodiments, R5 is selected from H, hydroxyl, halogen, cyano, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -C(=O)NH2, -C(=O)CH3, -C(=O)OH, -C(=O)N(H)CH3, -N(CH3)2, -C(=O)N(CH3)2 or -C(=O)OCH3.

[0081] In some embodiments, R6 is selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -C(=O)NH2, -C(=O)CH3, -C(=O)OH, -C(=O)N(H)CH3, -N(CH3)2, -C(=O)N(CH3)2 or -C(=O)OCH3.

[0082] In some embodiments, R7 is selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -N(CH3)2.

[0083] In some embodiments, ring A is selected from 5-18-membered heteroaryl groups, preferably 5-12-membered heteroaryl groups.

[0084] In some implementations, ring A is selected from...

[0085]

[0086] The ring A is optionally further divided by one or more R. a The R that was replaced a Each group is independently selected from H, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0087] In some embodiments, R1 is selected from H, oxo, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0088] In some embodiments, the R2 is selected from H, cyano, halogen, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0089] In some implementations, R3 is selected from H and C. 1-6 Alkyl, halogen or C 1-6 Halogenated alkyl groups.

[0090] The present invention also provides a compound having the following structure, or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0091]

[0092]

[0093]

[0094]

[0095] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts.

[0096] On the other hand, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts.

[0097] In another aspect, the present invention provides the use of compounds of formula (I) as described above, or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts or pharmaceutical compositions thereof, in the preparation of medicaments, said medicaments for treating and / or preventing diseases mediated by AAK1, or antiviral medicaments.

[0098] The present invention also provides a treatment for a disease or symptom, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I) as described above or a stereoisomer, tautomer, deuterated compound or pharmaceutical salt thereof, wherein the disease or symptom is an AAK1-mediated disease or a virus-induced disease, wherein the AAK1-mediated disease is selected from Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia, and wherein the virus-induced disease is a coronavirus, rabies virus or dengue virus.

[0099] The present invention also provides a method for treating a disease or symptom, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I) as described above or a stereoisomer, tautomer, deuterated compound or pharmaceutical salt thereof, wherein the disease or symptom is an AAK1-mediated disease or a virus-induced disease, the disease being treated and / or prevented is an AAK1-mediated disease, the pain is neuropathic pain, and further, the neuropathic pain is fibromyalgia or peripheral neuropathy.

[0100] Furthermore, the muscular dystrophy is selected from: myotonic dystrophy, Duchenne muscular dystrophy, Beck muscular dystrophy, limb girdle muscular dystrophy, facial scapular muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, peripheral muscular dystrophy, or Edwin muscular dystrophy.

[0101]

Terminology Explanation

[0102] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0103] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0104] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0105] The term "alkylene" refers to a divalent alkyl linking group. Formally, an alkylene group refers to an alkane where two CH bonds are replaced by alkylene groups at the junction with the rest of the compound. Similarly, C... 1-3 The "C" in alkylene 1-3 "" refers to alkylene compounds containing 1, 2, or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene, or 1,2-isopropylene.

[0106] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0107] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0108] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0109] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0110] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 aryl, more preferably aryl is C 6-10Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0111] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0112] When the number of a linking group is 0, for example, -(CH2)0- indicates that the linking group is a bond.

[0113] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0114] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0115] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0116] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0117] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0118] When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0119] Replacing the compound shown in formula (I) with a heavier isotope (e.g., deuterium) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0120] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0121] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0122] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0123] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0124] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0125] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0126] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0127] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0128] 1) This invention provides a novel compound molecule, all of which possess excellent AAK1 kinase inhibitory activity;

[0129] 2) Compared with the control compound LX9211, the compound of the present invention has a lower ability to inhibit HepG2 proliferation and less toxicity at the cellular level;

[0130] 3) Some compounds of this invention have better analgesic activity than LX9211. Attached Figure Description

[0131] Figure 1 The pain threshold (Mean ± SEM, N = 3) in DPNP-induced rats after a single dose of LX9211 (3 mg / kg) and compound 20 (1, 3 mg / kg).

[0132] One-way ANOVA was used to compare each treatment group with the normal group. ▲, P<0.05, ▲▲, P<0.01, ▲▲▲, P<0.001; *, P<0.05, **, P<0.01, ***, P<0.001.

[0133] Figure 2 The thermal pain threshold (Mean ± SEM, N = 4) in rats modeled by a single dose of LX9211 (10 mg / kg) and compound 53 (3 mg / kg) via CCI was determined.

[0134] One-way ANOVA was used to compare each treatment group with the sham group. ▲, P<0.05, ▲▲, P<0.01, ▲▲▲, P<0.001; *, P<0.05, **, P<0.01, ***, P<0.001. Detailed Implementation

[0135] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0136] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0137] The following abbreviations were used in the examples:

[0138] TosMIC: refers to the reagent p-toluenesulfonylisocyanate; XPhos: refers to the reagent 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; HCl / EA: refers to the reagent hydrochloric acid in ethyl acetate solution; TMEDA: refers to the reagent N,N,N',N'-tetramethylethylenediamine; m-CPBA: refers to the reagent m-chloroperoxybenzoic acid; DAST: refers to the reagent diethylaminosulfur trifluoride; DCM: refers to the reagent dichloromethane; EA: refers to the reagent ethyl acetate; PE: refers to the reagent petroleum ether; TEA: refers to the reagent triethylamine; Tol: refers to the reagent toluene; Boc: refers to the group tert-butyloxycarbonyl; Bn: refers to the group benzyl; THP: refers to the group tetrahydropyranyl;

[0139] The (S)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester used in the embodiments of the present invention was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., with a purity of 97%; the (R)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., with a purity of 95%.

[0140] Synthesis of intermediate M1: tert-butyl 2-isobutylpiperazine-1-carboxylic acid

[0141]

[0142] Step 1: Synthesis of 2-chloroacetylleucine methyl ester (M1-2)

[0143] DL-leucine methyl ester (36.33 g, 200 mmol), sodium bicarbonate (33.6 g, 400 mmol), and 80 mL of water were added to the reaction flask. Chloroacetyl chloride (22.6 g, 200 mmol) was dissolved in 80 mL of toluene and slowly added dropwise to the reaction flask. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 to 5 hours, monitored by TLC. Once the starting material was completely converted, the reaction was quenched with 100 mL of water and extracted twice with ethyl acetate (100 mL each time). The organic phases were combined and concentrated under vacuum to obtain crude 2-chloroacetylleucine methyl ester (42.28 g), which was used directly in the next reaction step.

[0144] Step 2: Synthesis of 1-benzyl-3-isobutylpiperazine-2,5-dione (M1-3)

[0145] 42.28 g of 2-chloroacetylleucine methyl ester, 200 mL of methanol, and 57.85 g (572.1 mmol) of triethylamine were added sequentially to the reaction flask. Then, benzylamine (24.52 g, 228.8 mmol) was dissolved in 180 mL of methanol and slowly added dropwise to the reaction flask. After the addition was complete, the temperature was raised to 70 °C, and the reaction was allowed to proceed for 18 to 20 hours. The reaction was monitored by TLC. After complete conversion of the starting material, the methanol was removed by vacuum concentration. Then, 100 mL of water was added, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, and the mixture was concentrated under vacuum to obtain a crude solid product (63 g). The crude product was slurried with 200 mL of petroleum ether and 5 mL of ethyl acetate, filtered, and the filter cake was collected to obtain 27.0 g of 1-benzyl-3-isobutylpiperazine-2,5-dione. The two-step yield was 37.4%.

[0146] MS(m / z): 261.1 [M+H] + .

[0147] Step 3: Synthesis of 1-benzyl-3-isobutylpiperazine (M1-4)

[0148] Lithium aluminum hydride (6.0 g, 40.0 mmol) and 500 mL tetrahydrofuran were added to the reaction flask, and the temperature was raised to 70 °C. Then, 1-benzyl-3-isobutylpiperazine-2,5-dione (27.0 g, 277.0 mmol) was dissolved in 300 mL tetrahydrofuran and slowly added dropwise to the reaction flask. After the addition was complete, the reaction solution was cooled to room temperature and the reaction was continued for 18 to 20 hours, monitored by TLC. When the starting material was completely converted, the reaction solution was slowly poured into 1.5 L of saturated sodium sulfate solution to quench the reaction, filtered, and 100 mL of water was added to the filtrate. The solution was extracted with ethyl acetate (twice, 100 mL each time). The organic phases were combined and concentrated under vacuum to obtain crude 1-benzyl-3-isobutylpiperazine (22.5 g), which was directly used in the next reaction step.

[0149] Step 4: Synthesis of 4-benzyl-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (M1-5)

[0150] 1-Benzyl-3-isobutylpiperazine (22.5 g), Boc anhydride (25.4 g, 116.2 mmol), and 120 mL of methanol were added to a reaction flask. The reaction was carried out at room temperature for 18 to 20 hours, and the reaction was monitored by TLC. After the starting material was completely converted, the methanol was removed by vacuum concentration, 100 mL of water was added, and the mixture was extracted with ethyl acetate (twice, 100 mL each time). The organic phases were combined, and the resulting organic phase was concentrated under vacuum and purified by column chromatography (pure dichloromethane) to obtain 4-benzyl-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (13.3 g), with a yield of 53.5%.

[0151] MS(m / z): 333.2 [M+H] + .

[0152] Step 5: Synthesis of 2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (M1)

[0153] 13.3 g (40.0 mmol) of 4-benzyl-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 10% Pd / C (1.33 f, 1.22 mmol), and 220 mL of methanol were added to a reaction flask. The mixture was purged three times with hydrogen, and then reacted at room temperature for 18 to 20 hours. The reaction was monitored by LC-MS. When the M1-5 content was less than 1%, the methanol was removed by vacuum concentration, 200 mL of ethyl acetate was added, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated to give 9.1 g (93.9%) of 2-isobutylpiperazine-1-carboxylic acid tert-butyl ester.

[0154] MS(m / z): 243.2 [M+H] + .

[0155] 1H NMR (400MHz, DMSO-d6) δ4.09(s,1H),3.85(s,1H),2.96-2.65(m,5H),1.65-1.62(m,2H),1.52-1.43(m,11H),0.93-0.92(m,6H).

[0156] In the following examples, the preparative liquid chromatography was performed on a Waters Prep 150 preparative liquid chromatography system using one of the following methods.

[0157] Method A:

[0158] Sunfire Prep C18 column (19*100mm-5μm); mobile phase: A=ACN, mobile phase B=0.1% formic acid aqueous solution; operation: 10-50% mobile phase A for 4.0 min, then 90% mobile phase A for 2 min, then 10% mobile phase A for 2 min; flow rate = 15 mL / min; λ = 254 nm; column oven = 25℃.

[0159] Method B:

[0160] Sunfire Prep C18 column (19*100mm-5μm); mobile phase: A=ACN, mobile phase B=0.1% trifluoroacetic acid aqueous solution; operation: 10-50% mobile phase A for 4.0 min, then 90% mobile phase A for 2 min, then 10% mobile phase A for 2 min; flow rate = 15 mL / min; λ = 254 nm; column oven = 25℃.

[0161] Method C:

[0162] Xbridge BEH Shield Rp18 (10*150mm-5μm); Mobile phase: A=ACN, B=10mM NH4HCO3 solution in water; Operation: 50-90% mobile phase A for 5.0 min, then 95% mobile phase A for 2 min, then 50% mobile phase A for 1 min; Flow rate = 8 mL / min; λ = 254 nm; Column oven = 25℃.

[0163] Example 1: Synthesis of 3-isobutyl-1-(4-(pyridin-4-yl)phenyl)piperazine (compound 1)

[0164]

[0165] The synthetic route for compound 1 is as follows:

[0166]

[0167] Step 1: Synthesis of 4-(4-bromophenyl)pyridine (1-2)

[0168] 1,4-Dibromobenzene (708 mg, 3 mmol), 4-pyridineboronic acid (184 mg, 1.5 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (76 mg, 0.105 mmol) were dissolved in 20 mL of dioxane. Cesium carbonate (1.46 g, 4.5 mmol) was dissolved in 5 mL of water and added to the system. The reaction was carried out at 100 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was filtered with diatomaceous earth, the filter residue was washed with methanol, and the resulting organic phase was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 4-(4-bromophenyl)pyridine (117 mg), in 33% yield.

[0169] MS (m / z): 233.9 [M+H] + .

[0170] Step 2: Synthesis of tert-butyl 2-isobutyl-4-(4-(pyridin-4-yl)phenyl)piperazine-1-carboxylic acid (1-3)

[0171] 4-(4-bromophenyl)pyridine (117 mg, 0.5 mmol), intermediate M1 (121 mg, 0.5 mmol), tris(dibenzylacetone)palladium (23 mg, 0.025 mmol), XPhos (26 mg, 0.055 mmol), and cesium carbonate (489 mg, 1.5 mmol) dissolved in 10 mL of toluene were added to a reaction flask. The mixture was heated to 105 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the solid was removed by filtration, and the filter cake was washed with methanol. The filtrate was evaporated to dryness and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give tert-butyl 2-isobutyl-4-(4-(pyridin-4-yl)phenyl)piperazine-1-carboxylic acid (158 mg), in 80% yield.

[0172] MS (m / z): 396.2 [M+H] + .

[0173] Step 3: Synthesis of 3-isobutyl-1-(4-(pyridin-4-yl)phenyl)piperazine (compound 1)

[0174] 158 mg (0.4 mmol) of 2-isobutyl-4-(4-(pyridin-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester and 20 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. After the reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness, and purified by preparative liquid chromatography (Method A) to obtain the target compound 3-isobutyl-1-(4-(pyridin-4-yl)phenyl)piperazine (113 mg), with a yield of 96%.

[0175] MS (m / z): 296.2 [M+H] + .

[0176] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=5.2Hz,2H),7.69(d,J=8.6Hz,2H),7.66-7.57(m,2H),7.04(d,J=8.6Hz,2H),3.65(d,J=11.6Hz,2H),3.00 (d,J=11.8Hz,1H),2.83-2.65(m,3H),2.36(t,J=11.2Hz,1H),1.79(dt,J=13.2,6.8Hz,1H),1.31-1.21(m,2H),0.90(dd,J=6.6,4.6Hz,6H).

[0177] Example 2: Synthesis of 5-(4-(3-isobutylpiperazin-1-yl)phenyl)oxazole (compound 2)

[0178]

[0179] The synthetic route for compound 2 is as follows:

[0180]

[0181] Step 1: Synthesis of 5-(4-bromophenyl)oxazole (2-2)

[0182] p-Toluenesulfonylmethylisocyanate (1.1 g, 5.4 mmol) was suspended in 20 mL of methanol, and p-bromobenzaldehyde (1 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.7 mmol) were added. After the addition was complete, the mixture was heated to reflux for 4 h under nitrogen protection. After the reaction was complete, the solvent was removed under vacuum, and the resulting solid was washed with water and recrystallized in ethanol to give compound 5-(4-bromophenyl)oxazole (0.92 g), with a yield of 84%.

[0183] MS (m / z): 233.9 [M+H] + .

[0184] Step 2: Synthesis of tert-butyl-2-isobutyl-4-(4-(oxazol-5-yl)phenyl)piperazine-1-carboxylate (2-3)

[0185] 5-(4-bromophenyl)oxazole (67 mg, 0.3 mmol), intermediate M1 (73 mg, 0.39 mmol), cesium carbonate (294 mg, 0.9 mmol), XPhos (16 mg, 0.033 mmol), and 15 mL of toluene were added to a reaction flask. After purging with nitrogen, tris(dibenzylacetone)dipalladium (14 mg, 0.015 mmol) was added. The mixture was heated at 105 °C and stirred for 16 h, with TLC monitoring the reaction progress. After the reaction was complete, diatomaceous earth was added for filtration, and the filter residue was washed with dichloromethane. The resulting organic phase was concentrated under vacuum to obtain a brown crude product. The product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain tert-butyl-2-isobutyl-4-(4-(oxazol-5-yl)phenyl)piperazine-1-carboxylic acid ester (70 mg), in 60% yield.

[0186] MS (m / z): 386.2 [M+H] + .

[0187] Step 3: Synthesis of 5-(4-(3-isobutylpiperazin-1-yl)phenyl)oxazole (2)

[0188] 70 mg (0.18 mmol) of tert-butyl-2-isobutyl-4-(4-(oxazol-5-yl)phenyl)piperazine-1-carboxylic acid ester was added to a reaction flask, followed by 10 mL of HCl / EA. The mixture was stirred at room temperature for 4 h, and the reaction progress was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under vacuum and purified by preparative liquid chromatography (Method C) to obtain the target compound 5-(4-(3-isobutylpiperazine-1-yl)phenyl)oxazole (50 mg), with a yield of 96%.

[0189] MS (m / z): 286.2 [M+H] + .

[0190] 1 H NMR (400MHz, DMSO-d6) δ9.80-9.46(m,1H),8.36(s,1H),7.59(d,J=7.2Hz,2H),7.10(d,J=7.4Hz,2H),3.84(d,J=12.4Hz,2H),3.27(s,2 H),3.14(d,J=11.0Hz,2H),2.90(t,J=11.8Hz,1H),1.96-1.79(m,1H),1.61-1.52(m,2H),1.22(d,J=7.2Hz,1H),0.91(t,J=6.2Hz,6H).

[0191] Example 3: Synthesis of 3-isobutyl-1-(4-(2-methylpyridin-4-yl)phenyl)piperazine (compound 3)

[0192]

[0193] The synthesis steps of compound 3 are as follows:

[0194]

[0195] Referring to steps 1 to 3 of Example 1, only 4-pyridineboronic acid in step 1 was replaced with 2-methylpyridineboronic acid ester to obtain the target compound 3-isobutyl-1-(4-(2-methylpyridin-4-yl)phenyl)piperazine (80 mg), with a three-step yield of 36%.

[0196] MS (m / z): 310.2 [M+H] + .

[0197] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=6.4Hz,1H),8.27(s,1H),8.17(d,J=6.4Hz,1H),8.01(d,J=8.4Hz,2H),7.21(d,J=8.6Hz,2H),4.05(d,J=13.2 Hz,2H),3.34-3.28(m,2H),3.17-3.13(m,2H),3.06-3.00(m,1H),2.74( s,3H),1.91(t,J=6.6Hz,2H),1.59-1.52(m,1H),0.93(t,J=6.4Hz,6H).

[0198] Example 4: Synthesis of 1-(4-(1H-imidazol-1-yl)phenyl)-3-isobutylpiperazine (compound 4)

[0199]

[0200] The synthesis steps of compound 4 are as follows:

[0201]

[0202] Step 1: Synthesis of 1-(4-bromophenyl)-1H-imidazolium (4-1):

[0203] Imidazole (0.35 g, 5.1 mmol), 1,4-dibromobenzene (1.0 g, 4.3 mmol), and TMEDA (0.2 g, 1.7 mmol) were dissolved in 10 mL of dimethyl sulfoxide. After purging with nitrogen, Cu₂O (0.12 g, 0.86 mmol) and potassium phosphate (1.8 g, 8.6 mmol) were added. After the addition was complete, the mixture was refluxed under nitrogen protection for 16 h, and the reaction progress was monitored by TLC. When the reaction was complete, the solid was removed by filtration, the filter residue was washed with dichloromethane, and the resulting organic phase was concentrated under vacuum to give a white solid. The obtained solid was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 1-(4-bromophenyl)-1H-imidazole (0.85 g), in 85% yield.

[0204] MS(m / z): 223.0 [M+H] + .

[0205] Step 2: Synthesis of tert-butyl 4-(4-(1H-imidazol-1-yl)phenyl)-2-isobutylpiperazine-1-carboxylate (4-2)

[0206] 1-(4-bromophenyl)-1H imidazole (97.2 mg, 0.44 mmol), intermediate M1 (106 mg, 0.44 mmol), cesium carbonate (430 mg, 1.3 mmol), XPhos (23 mg, 0.048 mmol), and 15 mL of toluene were added to a reaction flask. After purging with nitrogen, tris(dibenzylacetone)dipalladium (20 mg, 0.022 mmol) was added. The mixture was heated at 105 °C and stirred for 16 h. The reaction progress was monitored by TLC. After the reaction was completed, the solid was removed by filtration, the filter residue was washed with dichloromethane, and the resulting organic phase was concentrated under vacuum to obtain a brown crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain tert-butyl 4-(4-(1H-imidazol-1-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid ester (70 mg), with a yield of 42%.

[0207] MS (m / z): 385.2 [M+H] + .

[0208] Step 3: Synthesis of 1-(4-(1H-imidazol-1-yl)phenyl)-3-isobutylpiperazine (4)

[0209] 70 mg (0.18 mmol) of 4-(4-(1H-imidazol-1-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid ester was added to a reaction flask, followed by 10 mL of HCl / EA solution. The mixture was stirred at room temperature for 4 h, and the reaction progress was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under vacuum and purified by preparative liquid chromatography (Method A) to obtain the target compound 5-(4-(3-isobutylpiperazine-1-yl)phenyl)oxazole (55 mg), with a yield of 95%.

[0210] MS (m / z): 285.2 [M+H] + .

[0211] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.22(d,J=1.8Hz,1H),7.88(t,J=1.8Hz,1H),7.68(d,J=8.8Hz,2H),7.23(d,J=8.8Hz,2H),3.90(d, J=13.0Hz,2H),3.24-3.11(m,5H),2.95(dd,J=13.4,10.6Hz,1H),1.92(dt,J=13.4,6.8Hz,1H),1.67-1.50(m,2H),0.93(t,J=7.0Hz,6H).

[0212] Example 5: Synthesis of 1-(4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 5)

[0213]

[0214] The synthesis steps of compound 5 are as follows:

[0215]

[0216] Referring to steps 1 to 3 of Example 1, only 4-pyridineboronic acid in step 1 is replaced with (1H-pyrazole-4-yl)boronic acid to obtain the target compound 1-(4-(1H-pyrazole-4-yl)phenyl)-3-isobutylpiperazine (113 mg), with a three-step yield of 25%.

[0217] MS (m / z): 285.2 [M+H] + .

[0218] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=5.2Hz,2H),7.69(d,J=8.4Hz,2H),7.66-7.57(m,2H),7.04(d,J=8.6Hz,2H),3.65(d,J=11.6Hz,2H) ,3.00(d,J=11.8Hz,1H),2.83-2.65(m,3H),2.36(t,J=11.2Hz,1H),1.91-1.84(m,1H),1.31-1.21(m,2H),0.90(dd,J=6.6,4.8Hz,6H).

[0219] Example 6: Synthesis of 2-isobutyl-1-(3-(pyridin-4-yl)phenyl)piperazine (compound 6)

[0220]

[0221] The synthesis steps of compound 6 are as follows:

[0222]

[0223] Referring to steps 1 to 3 of Example 1, only 4-pyridineboronic acid in step 1 was replaced with 3-pyridineboronic acid to obtain the target compound 2-isobutyl-1-(3-(pyridin-4-yl)phenyl)piperazine (113 mg), with a three-step yield of 26%.

[0224] MS (m / z): 296.2 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=5.4Hz,2H),7.69(d,J=8.2Hz,2H),7.66-7.57(m,2H),7.04(d,J=8.6Hz,2H),3.65(d,J=11.6Hz,2H) ,3.00(d,J=11.8Hz,1H),2.83-2.65(m,3H),2.36(t,J=11.2Hz,1H),1.97-1.89(m,1H),1.31-1.21(m,2H),0.90(dd,J=6.6,4.8Hz,6H).

[0226] Example 7: Synthesis of 3-isobutyl-1-(4-(2-methoxypyridin-4-yl)phenyl)piperazine (compound 7)

[0227]

[0228] The synthesis steps of compound 7 are as follows:

[0229]

[0230] Referring to steps 1 to 3 of Example 1, only 4-pyridineboronic acid in step 1 is replaced with (2-methoxypyridine-4-yl)boronic acid to obtain the target compound 3-isobutyl-1-(4-(2-methoxypyridine-4-yl)phenyl)piperazine (80 mg), with a three-step yield of 37%.

[0231] MS (m / z): 326.2 [M+H] + .

[0232] 1H NMR (400MHz, DMSO-d6) δ9.59(d,J=10.6Hz,1H),9.47(d,J=10.8Hz,1H),8.20(d,J=5.6 Hz,1H),7.80(d,J=8.4Hz,2H),7.42(d,J=5.6Hz,1H),7.23(s,1H),7.13(d,J=8.4Hz,2H ),3.97(s,3H),3.94(s,2H),3.31(d,J=11.6Hz,1H),3.23-3.12(m,2H),2.95(dd,J=13. 4,10.6Hz,1H),1.90(dt,J=13.4,6.6Hz,1H),1.63-1.49(m,2H),0.93(t,J=6.4Hz,6H).

[0233] Example 8: Synthesis of 3-isobutyl-1-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 8)

[0234]

[0235] The synthesis steps of compound 8 are as follows:

[0236]

[0237] Step 1: Synthesis of 4-(4-bromo-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (8-2)

[0238] 1-Bromo-4-iodo-2-toluene (250 mg, 0.84 mmol), intermediate M1 (160 mg, 0.67 mmol), tris(dibenzylacetone)dipalladium (38 mg, 0.042 mmol), XPhos (44 mg, 0.092 mmol), and cesium carbonate (410 mg, 1.26 mmol) were added to a reaction flask and dissolved in 10 mL of toluene. The mixture was heated to 110 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the solid was removed by filtration, and the filter cake was washed with methanol. The filtrate was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound 4-(4-bromo-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (100 mg), yield 30%.

[0239] MS(m / z): 411.2 [M+H] + .

[0240] Step 2: Synthesis of 4-(4-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (8-3)

[0241] 4-(4-bromo-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.24 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (103 mg, 0.48 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (35 mg, 0.048 mmol) were dissolved in 20 mL of dioxane. Cesium carbonate (237 mg, 0.73 mmol) was dissolved in 5 mL of water and added to the reaction system. The reaction was carried out at 105 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the mixture was extracted with an ethyl acetate / water system, the organic phases were combined, dried with anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 4-(4-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (60 mg), yield 50%.

[0242] MS (m / z): 499.2 [M+H] + .

[0243] Step 3: Synthesis of 3-isobutyl-1-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)piperazine (8)

[0244] 60 mg (0.12 mmol) of 4-(4-(1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)-3-methylphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester and 20 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 3 h. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the target compound 3-isobutyl-1-(3-methyl-4-(1H-pyrazole-4-yl)phenyl)piperazine (35 mg) was obtained by separation and purification by preparative liquid chromatography (Method A), with a yield of 97%.

[0245] MS (m / z): 299.2 [M+H] + .

[0246] 1H NMR (600MHz, DMSO-d6) δ9.55(s,1H),7.97(s,1H),7.90(d,J=2.2Hz,1H),7.29(d,J=8.4Hz,1H),6.96(d,J=2.6Hz,1H),6.91(dd,J=8.0,2.2Hz,1H), 6.45(d,J=2.2Hz,1H),3.77(d,J=11.8Hz,1H),3.33-3.29(m,1H),3.17(s, 4H), 2.34 (s, 2H), 1.91 (s, 3H), 1.23 (s, 2H), 0.93 (dd, J = 10.4, 6.4Hz, 6H).

[0247] Example 9: Synthesis of 1-(3-ethyl-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 9)

[0248]

[0249] The synthesis steps of compound 9 are as follows:

[0250]

[0251] Step 1: Synthesis of 4-(4-bromo-2-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (9-2)

[0252] Add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (140 mg, 0.52 mmol), 4-bromo-2-ethyl-1-iodobenzene (180 mg, 0.57 mmol), cesium carbonate (0.56 g, 1.72 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (79 mg, 0.109 mmol), 16 mL of dioxane, and 4 mL of water to the reaction flask. React at 105 °C for 16 h under nitrogen protection, and monitor the reaction progress by TLC. After the reaction was completed, the mixture was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 4-(4-bromo-2-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg), with a yield of 53%.

[0253] MS (m / z): 335.1 [M+H] + .

[0254] Step 2: Synthesis of 4-(3-ethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (9-3)

[0255] 4-(4-bromo-2-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (65 mg, 0.19 mmol), intermediate M1 (47 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (14 mg, 0.015 mmol), XPhos (13 mg, 0.028 mmol), and cesium carbonate (120 mg, 0.37 mmol) were added to a reaction flask, followed by 20 mL of anhydrous toluene. The reaction was carried out at 110 °C for 16 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 4-(3-ethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (60 mg), yield 63%.

[0256] MS (m / z): 497.2 [M+H] + .

[0257] Step 3: Synthesis of 1-(3-ethyl-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (9)

[0258] 60 mg (0.12 mmol) of 4-(3-ethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester was added to a reaction flask along with 20 mL of HCl / EA solution. The mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under vacuum, and the target compound 1-(3-ethyl-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (35 mg) was obtained by preparative liquid chromatography (Method A), with a yield of 95%.

[0259] MS (m / z): 313.2 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6) δ7.67(s,2H),7.17(d,J=8.4Hz,1H),6.89(d,J=2.6Hz ,1H),6.83(dd,J=8.4,2.8Hz,1H),3.72(d,J=12.0Hz,2H),3.28-3.19(m,3H), 3.13-3.07(m,1H),2.93(td,J=12.2,2.8Hz,1H),2.64(q,J=7.8Hz,2H),1.89- 1.80(m,1H),1.51-1.43(m,2H),1.11(t,J=7.6Hz,3H),0.93(t,J=5.6Hz,6H).

[0261] Example 10: Synthesis of 3-isobutyl-1-(3-cyano-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 10)

[0262]

[0263] The synthesis steps of compound 10 are as follows:

[0264]

[0265] Referring to steps 1 to 3 in Example 8, only 4-bromo-2-methyl-1-iodobenzene in step 1 was replaced with 1-bromo-2-cyano-4-iodobenzene, thus obtaining the target compound 3-isobutyl-1-(3-cyano-4-(1H-pyrazol-4-yl)phenyl)piperazine (32 mg), with a three-step yield of 23%.

[0266] MS (m / z): 310.2 [M+H] + .

[0267] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,2H),8.06(s,2H),7.60(d,J=8.8Hz,1H),7.48(d,J=2.6Hz,1H),7.38(dd,J=8.8,2.8Hz,1H),3.89(t,J=10. 6Hz,2H),3.34-3.26(m,2H),3.17-3.07(m,2H),2.86(dd,J=13.4,10.8Hz,1H),1.94-1.88(m,1H),1.60-1.47(m,2H),0.93(t,J=6.6Hz,6H).

[0268] Example 11: Synthesis of 3-isobutyl-1-(3-hydroxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 11)

[0269]

[0270] The synthesis steps of compound 11 are as follows:

[0271]

[0272] Step 1: Synthesis of 4-(4-bromo-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (11-2)

[0273] 1-Bromo-2-methoxy-4-iodobenzene (261 mg, 0.84 mmol), intermediate M1 (160 mg, 0.67 mmol), tris(dibenzylacetone)dipalladium (38 mg, 0.042 mmol), XPhos (44 mg, 0.092 mmol), and cesium carbonate (410 mg, 1.26 mmol) dissolved in 10 mL of toluene were added to a reaction flask. The mixture was heated to 110 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the solid was removed by filtration, and the filter cake was washed with methanol. The filtrate was evaporated to dryness and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 4-(4-bromo-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (197 mg), yield 55%.

[0274] MS (m / z): 427.2 [M+H] + .

[0275] Step 2: Synthesis of 4-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (11-3)

[0276] 4-(4-bromo-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (102 mg, 0.24 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (103 mg, 0.48 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (35 mg, 0.048 mmol) were dissolved in 20 mL of dioxane. Cesium carbonate (237 mg, 0.73 mmol) was dissolved in 5 mL of water and added to the reaction system. The reaction was carried out at 105 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the mixture was extracted with an ethyl acetate / water system, the organic phases were combined, dried with anhydrous sodium sulfate, concentrated under vacuum, and purified by preparative liquid chromatography (Method B) to obtain compound 4-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (45 mg), with a yield of 45%.

[0277] MS (m / z): 415.2 [M+H] + .

[0278] Step 3: Synthesis of 3-isobutyl-1-(3-hydroxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (11)

[0279] 50 mg (0.12 mmol) of 4-(3-methoxy-4-(1H-pyrazole-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester and 20 mL of dichloromethane were added to a reaction flask, and 0.5 mL of BBr3 was added dropwise at room temperature. After the reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness, and the target compound 3-isobutyl-1-(3-hydroxy-4-(1H-pyrazole-4-yl)phenyl)piperazine (32 mg) was obtained by preparative liquid chromatography (Method B) with a yield of 94%.

[0280] MS (m / z): 301.2 [M+H] + .

[0281] 1 H NMR (600MHz, DMSO-d6) δ9.54(s,1H),7.94(s,1H),7.41(d,J=8.8Hz,1H),6.50(d,J=7.2Hz,2H),3.68-3.60(m,2H),3.37-3.34(m,2H),3.22-3.16(m ,2H),2.70(dd,J=13.2,10.4Hz,1H),1.80(dt,J=13.6,6.8Hz,1H),1.48( td,J=7.2,3.2Hz,2H),1.24(d,J=5.2Hz,1H),0.94(dd,J=8.4,6.6Hz,6H).

[0282] Example 12: Synthesis of 3-isobutyl-1-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 12)

[0283]

[0284] The synthesis steps of compound 12 are as follows:

[0285]

[0286] Referring to steps 1 to 3 in Example 8, only the -methyl-1-iodobenzene in step 1 is replaced with 1-bromo-2-methoxy-4-iodobenzene, thus obtaining the target compound 3-isobutyl-1-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (35 mg), with a three-step yield of 22%.

[0287] MS (m / z): 315.2 [M+H] + .

[0288] 1H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 7.90 (s, 2H), 7.42 (d, J = 8.4Hz, 1H), 6.59 (d, J = 2.4Hz,

[0289] 1H),6.53(dd,J=8.4,2.2Hz,1H),3.85(s,3H),3.60(d,J=11.2Hz,2H),3.06(s,1H),2.91(d,J=11.6Hz,2H),2.70(t, J=11.2Hz,1H),2.39(t,J=11.0Hz,1H),1.82(dt,J=13.4,6.8Hz,1H),1.36-1.25(m,2H),0.91(dd,J=6.6,1.4Hz,6H).

[0290] Example 13: Synthesis of 1-(3-(difluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 13)

[0291]

[0292] The synthesis steps of compound 13 are as follows:

[0293]

[0294] Referring to steps 1 to 3 in Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 was replaced with 4-bromo-1-iodo-2-(difluoromethoxy)benzene, thus obtaining the target compound 1-(3-(difluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (35 mg), with a three-step yield of 26%.

[0295] MS (m / z): 351.2 [M+H] + .

[0296] 1H NMR (400MHz, DMSO-d6) δ8.54(d,J=1.6Hz,1H),7.98(dd,J=3.4,1.8Hz,1H),7.55(d ,J=7.8Hz,1H),6.65-6.54(m,2H),3.56-3.42(m,3H),3.29(dd,J=12.2,4.2Hz,1H) ,3.15-3.10(m,1H),3.02-2.93(m,1H),2.90-2.85(m,1H),1.96(dt,J=6.0,2.8Hz, 1H), 1.68-1.50 (m, 2H), 1.38 (dt, J=13.4, 7.6Hz, 1H), 0.93 (dd, J=6.6, 0.6Hz, 6H).

[0297] Example 14: Synthesis of 3-isobutyl-1-(3-ethoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 14)

[0298]

[0299] The synthesis steps of compound 14 are as follows:

[0300]

[0301] Referring to steps 1 to 3 in Example 8, only 4-bromo-2-methyl-1-iodobenzene in step 1 was replaced with 1-bromo-2-ethoxy-4-iodobenzene, thus obtaining the target compound 3-isobutyl-1-(3-ethoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (17 mg), with a three-step yield of 11%.

[0302] MS (m / z): 329.2 [M+H] + .

[0303] 1H NMR (400MHz, DMSO-d6) δ7.95(s,2H),7.46(d,J=8.4Hz,1H),6.62(d,J=2.2Hz,1H),6.57(dd ,J=8.4,2.4Hz,1H),4.11(q,J=6.8Hz,2H),3.73(dd,J=13.2,3.0Hz,2H),3.27-3.17(m,2H), 3.09(td,J=12.2,3.0Hz,1H),2.95(td,J=12.4,2.8Hz,1H),2.70(dd,J=13.0,10.4Hz,1H),1 .93-1.84(m,1H),1.48(q,J=6.8Hz,2H),1.42(t,J=6.8Hz,3H),0.93(dd,J=6.6,4.8Hz,6H).

[0304] Example 15: Synthesis of 3-isobutyl-1-(3-isopropoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 15)

[0305]

[0306] The synthesis steps of compound 15 are as follows:

[0307]

[0308] Referring to steps 1 to 3 in Example 8, only 4-bromo-2-methyl-1-iodobenzene in step 1 was replaced with 1-bromo-2-isopropoxy-4-iodobenzene, thus obtaining the target compound 3-isobutyl-1-(3-isopropoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (35 mg), with a three-step yield of 26%.

[0309] MS (m / z): 343.2 [M+H] + .

[0310] 1H NMR (400MHz, DMSO-d6) δ9.52(d,J=9.8Hz,1H),9.44(s,1H),8.17(s,2H),7.51(d,J=8.4Hz, 1H),6.70(d,J=2.4Hz,1H),6.62(dd,J=8.6,2.2Hz,1H),4.81-4.75(m,1H),3.79(d,J=12.8 Hz,2H),3.30(d,J=10.2Hz,2H),3.13(q,J=13.0,11.8Hz,2H),2.88(dd,J=13.2,10.6Hz,1H ),1.94-1.82(m,1H),1.62-1.48(m,2H),1.32(dd,J=6.0,1.8Hz,6H),0.93(t,J=7.0Hz,6H).

[0311] Example 16: Synthesis of 1-(3-(trifluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 16)

[0312]

[0313] The synthesis steps of compound 16 are as follows:

[0314]

[0315] Referring to steps 1 to 3 of Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 was replaced with 4-bromo-1-iodo-2-(trifluoromethoxy)benzene, thus obtaining the target compound 1-(3-(trifluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (35 mg), with a three-step yield of 28%.

[0316] MS (m / z): 369.2 [M+H] + .

[0317] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=1.6Hz,1H),7.93(dd,J=3.4,1.8Hz,1H),7.53(d,J =7.8Hz,1H),6.68(d,J=1.8Hz,1H),6.54(dd,J=7.8,2.0Hz,1H),3.52-3.38(m,3H),3. 28(dd,J=12.4,4.0Hz,1H),3.15-3.10(m,1H),3.03-2.85(m,2H),1.92(dt,J=6.0,2.8 Hz,1H),1.66-1.47(m,2H),1.34(dt,J=13.4,7.6Hz,1H),0.91(dd,J=6.8,0.6Hz,6H).

[0318] Example 17: Synthesis of 1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (compound 17)

[0319]

[0320] The synthesis steps of compound 17 are as follows:

[0321]

[0322] Referring to steps 1 to 3 in Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 was replaced with 5-bromo-2-iodopyridine to obtain the target compound 1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (20 mg), with a three-step yield of 13%.

[0323] MS (m / z): 286.1 [M+H] + .

[0324] 1 HNMR (400MHz, DMSO-d6) δ8.45-8.18(m,3H),8.06(s,2H),7.54(d,J=8.6Hz,1H),7.38(dd,J=8.6,3.0Hz,1H),3.69(d,J=12.2Hz, 2H),3.30-2.92(m,3H),2.85(t,J=11.8Hz,1H),2.57(t,J=11.4Hz,1H),1.88-1.79(m,1H),1.45-1.23(m,2H),1.02-0.78(m,6H).

[0325] Example 18: Synthesis of (1-(4-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (compound 18)

[0326]

[0327] The synthesis steps of compound 18 are as follows:

[0328]

[0329] Referring to steps 1 to 3 of Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 is replaced with 5-bromo-4-(difluoromethyl)-2-iodopyridine to obtain the target compound (1-(4-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (16 mg), with a three-step yield of 4%).

[0330] MS (m / z): 336.2 [M+H] + .

[0331] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.30(s,1H),8.23(s,2H),7.82(s,1H),7.20(t,J=54.4Hz,1H),3.08-2 .93(m,6H),2.67-2.58(m,1H),1.70(dt,J=13.4,6.8Hz,1H),1.40-1.34(m,2H),0.88(dd,J=6.6,3.2Hz,6H).

[0332] Example 19: Synthesis of 3-isobutyl-1-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine (compound 19)

[0333]

[0334] The synthetic steps of compound 19 are as follows:

[0335]

[0336] Referring to the synthesis steps in Example 12, only the (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid in step 2 was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol, yielding the target compound 3-isobutyl-1-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine (20 mg), with a three-step yield of 11%.

[0337] MS (m / z): 329.2 [M+H] + .

[0338] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.95(s,1H),7.76(s,1H),7.39(d,J=8.4Hz,1H) ,6.59(d,J=2.2Hz,1H),6.54(dd,J=8.4,2.2Hz,1H),3.85(d,J=4.4Hz,6H),3.67-3.5 9(m,2H),3.14-3.08(m,1H),3.01-2.88(m,2H),2.75(td,J=11.8,3.0Hz,1H),2.45(d d,J=12.2,10.2Hz,1H),1.86--1.77(m,1H),1.42-1.27(m,2H),0.91(d,J=6.4Hz,6H).

[0339] Example 20: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (compound 20)

[0340]

[0341] The synthesis steps of compound 20 are as follows:

[0342]

[0343] Step 1: Synthesis of 2-bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (20-1)

[0344] 2-Bromo-5-iodobenzonitrile (200 mg, 0.65 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (271 mg, 0.98 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (48 mg, 0.065 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (636 mg, 1.95 mmol) was dissolved in 1 mL of water and added to the reaction system. The reaction was carried out at 100 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the compound 2-bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (130 mg) was obtained by vacuum concentration and separation and purification by column chromatography (petroleum ether: ethyl acetate = 6:1), with a yield of 60%.

[0345] MS(m / z): 332.1 [M+H] +.

[0346] Step 2: Synthesis of 4-(2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (20-2)

[0347] 2-Bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (110 mg, 0.33 mmol), intermediate M1 (80 mg, 0.33 mmol), tris(dibenzylacetone)dipalladium (25 mg, 0.027 mmol), XPhos (24 mg, 0.049 mmol), and cesium carbonate (216 mg, 0.66 mmol) dissolved in 10 mL of toluene were added to the reaction flask. The mixture was heated to 110 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (130 mg), yield 80%.

[0348] MS (m / z): 494.3 [M+H] + .

[0349] Step 3: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (20)

[0350] 4-(2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.22 mmol), 2 mL of HCl / EA solution, and 5 mL of dichloromethane were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the target compound 2-(3-isobutylpiperazine-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (51 mg) was purified by preparative liquid chromatography (Method A) in a yield of 74%.

[0351] MS (m / z): 310.2 [M+H] + .

[0352] 1H NMR (600MHz, DMSO-d6) δ8.26 (s, 1H), 8.10 (s, 2H), 7.99 (d, J = 2.2Hz, 1H), 7.83 (dd, J=8.6,2.2Hz,1H),7.16(d,J=8.6Hz,1H),3.46(d,J=11.6Hz,1H),3.36(d,J=11.4Hz ,1H),3.12(d,J=12.2Hz,1H),3.02-2.93(m,2H),2.87(td,J=11.6,2.6Hz,1H),2.5 6-2.51(m,1H),1.78-1.72(m,1H),1.36-1.26(m,2H),0.91(dd,J=12.2,6.4Hz,6H).

[0353] Example 21: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(1H-pyrazol-5-yl)phenol (compound 21)

[0354]

[0355] The synthesis steps of compound 21 are as follows:

[0356]

[0357] Step 1: Synthesis of 5-(4-bromo-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (21-2)

[0358] 4-Bromo-1-iodo-2-methoxybenzene (250 mg, 0.798 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (210 mg, 0.798 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (57 mg, 0.08 mmol), and 10 mL of dioxane were added to the reaction flask. Cesium carbonate (0.52 g, 1.6 mmol) was dissolved in 2 mL of water and added to the reaction system. The mixture was purged with nitrogen and stirred at 110 °C for 8 h. The compound 5-(4-bromo-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (140 mg) was obtained by column chromatography (petroleum ether: ethyl acetate = 6:1), with a yield of 52%.

[0359] MS(m / z): 337.0 [M+H] + .

[0360] Step 2: Synthesis of 2-isobutyl-4-(3-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (21-3)

[0361] 5-(4-bromo-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg, 0.296 mmol), intermediate M1 (70 mg, 0.296 mmol), tris(dibenzylacetone)dipalladium (14 mg, 0.014 mmol), XPhos (29 mg, 0.058 mmol), and cesium carbonate (193 mg, 0.593 mmol) were added to the reaction flask and dissolved in toluene. The reaction was carried out under nitrogen protection and heated to 110 °C for 12 h. The reaction was monitored by LC-MS. After the reaction was complete, the solid was removed by filtration, and the filtrate was dried by rotary evaporation and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 2-isobutyl-4-(3-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (90 mg), yield 61%.

[0362] MS(m / z): 499.0 [M+H] + .

[0363] Step 3: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(1H-pyrazol-5-yl)phenol (21)

[0364] 0.15 g (0.3 mmol) of 2-isobutyl-4-(3-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was added to a reaction flask and dissolved in 5 mL of dichloromethane. BBr3 (0.23 g, 0.9 mmol) was then added dropwise, and the mixture was heated to 40 °C and reacted for 16 h. After the reaction was complete, the solvent was concentrated under vacuum, and the solution was purified by preparative liquid chromatography (Method B) to obtain the target compound 5-(3-isobutylpiperazine-1-yl)-2-(1H-pyrazole-5-yl)phenol (37 mg), with a yield of 28%.

[0365] MS (m / z): 301.2 [M+H] + .

[0366] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.81(d,J=2.4Hz,1H),7.56(d,J=8.6Hz,1H),6.73 (d,J=2.2Hz,1H),6.56(dd,J=8.6,2.4Hz,1H),6.51(d,J=2.4Hz,1H),3.76(dd,J=12.8,4. 2Hz,2H),3.30-3.21(m,2H),3.12(td,J=12.2,3.2Hz,1H),2.98-2.91(m,1H),2.70(dd,J= 13.2,10.4Hz,1H),1.88-1.81(m,1H),1.46(t,J=7.0Hz,2H),0.92(dd,J=6.6,4.0Hz,6H).

[0367] Example 22: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(1H-pyrazol-4-yl)aniline (compound 22)

[0368]

[0369] The synthesis steps of compound 22 are as follows:

[0370]

[0371] Referring to steps 1 to 3 in Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 was replaced with tert-butyl (5-bromo-2-iodophenyl)carbamate to obtain the target compound 5-(3-isobutylpiperazin-1-yl)-2-(1H-pyrazole-4-yl)aniline (30 mg), with a three-step yield of 28%.

[0372] MS (m / z): 300.2 [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.84 (d, J = 10.8Hz, 1H), 7.86 (s, 2H), 7 .28(d,J=8.6Hz,1H),6.83-6.72(m,2H),3.73(t,J=11.6Hz,2H),3.39(d,J= 12.8Hz,2H),3.22(d,J=11.2Hz,1H),3.04-2.90(m,1H),2.75(dd,J=13.2,1 0.4Hz,1H),1.83-1.79(m,1H),1.49(t,J=7.2Hz,2H),0.94(t,J=6.4Hz,6H).

[0374] Example 23: Synthesis of 1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 23)

[0375]

[0376] The synthesis steps of compound 23 are as follows:

[0377]

[0378] Step 1: Synthesis of 4-(4-bromo-3-(difluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (23-2)

[0379] 1-Bromo-2-(difluoromethyl)-4-iodobenzene (190 mg, 0.57 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (159 mg, 0.57 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (42 mg, 0.057 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (373 mg, 1.14 mmol) was dissolved in 1 mL of water and added to the system. The mixture was refluxed at 105 °C for 12 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the compound 4-(4-bromo-3-(difluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (120 mg) was obtained by vacuum concentration and separation and purification by column chromatography (petroleum ether: ethyl acetate = 4:1), with a yield of 59%.

[0380] MS(m / z): 357.0 [M+H] + .

[0381] Step 2: Synthesis of 4-(2-(difluoromethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (23-3)

[0382] 4-(4-bromo-3-(difluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (120 mg, 0.336 mmol), intermediate M1 (82 mg, 0.336 mmol), tris(dibenzylacetone)dipalladium (25 mg, 0.027 mmol), XPhos (24 mg, 0.05 mmol), and cesium carbonate (328 mg, 1.01 mmol) dissolved in 5 mL of toluene were added to the reaction flask. The mixture was heated to 110 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was evaporated to dryness and then purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(2-(difluoromethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (60 mg), yield 41%.

[0383] MS (m / z): 519.3 [M+H] + .

[0384] Step 3: Synthesis of 1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (23)

[0385] A solution of 60 mg (0.116 mmol) of 4-(2-(difluoromethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester in dichloromethane (5 mL) and 0.5 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the target compound 1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (25 mg) was purified by preparative liquid chromatography (Method A) to obtain the target compound 1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (25 mg), with a yield of 64%.

[0386] MS (m / z): 335.2 [M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.09(s,2H),7.79-7.71(m,2H),7.28(d,J=8.0Hz,1H),7.19(t,J=56.0Hz,1 H),3.04-2.75(m,6H),2.45(d,J=10.4Hz,1H),1.72-1.65(m,1H),1.33-1.17(m,2H),0.88(dd,J=6.6,3.8Hz,6H).

[0388] Example 24: Synthesis of 5-(3-isobutylpiperazin-1-yl)-N,N-dimethyl-2-(1H-pyrazol-4-yl)aniline (compound 24)

[0389]

[0390] The synthesis steps of compound 24 are as follows:

[0391]

[0392] Referring to steps 1 to 3 of Example 9, only 4-bromo-2-ethyl-1-iodobenzene in step 1 was replaced with 5-bromo-2-iodo-N,N-dimethylaniline, thus obtaining the target compound 5-(3-isobutylpiperazin-1-yl)-N,N-dimethyl-2-(1H-pyrazol-4-yl)aniline (28 mg), with a three-step yield of 36%.

[0393] MS (m / z): 328.3 [M+H] + .

[0394] 1 H NMR(600MHz,DMSO-d6)δ9.25(d,J=11.0Hz,1H),9.09(d,J=11.8Hz,1H),,7.93(s,2H) ,7.30(d,J=8.4Hz,1H),7.05(s,1H),6.89(d,J=8.6Hz,1H),3.85(d,J=13.0Hz,2H),3 .41-3.30(m,2H),3.21(q,J=11.4Hz,1H),3.08-3.01(m,1H),2.90-2.81(m,6H),2.79 -2.77(m,1H),1.90-1.83(m,1H),1.52(t,J=7.0Hz,2H),0.94(dd,J=11.4,6.6Hz,6H).

[0395] Example 25: Synthesis of 5-(4-(3-isobutylpiperazin-1-yl)-2-methoxyphenyl)isoxazole (compound 25)

[0396]

[0397] The synthesis steps of compound 25 are as follows:

[0398]

[0399] Step 1: Synthesis of (Z)-1-(4-bromo-2-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one (25-2)

[0400] 1-(4-bromo-2-methoxyphenyl)ethane-1-one (500 mg, 2.20 mmol) and 1,1-dimethoxy-N,N-dimethylmethylamine (391 mg, 3.30 mmol) were dissolved in 3 mL of xylene, and the mixture was reacted in a microwave reactor at 160 °C for 55 minutes. After the reaction was completed, the solvent was concentrated under vacuum, and the compound (Z)-1-(4-bromo-2-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one (390 mg) was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) in 63% yield.

[0401] MS(m / z): 284.1 [M+H] + .

[0402] Step 2: Synthesis of (Z)-4-(4-(3-(dimethylamino)acryloyl)-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (25-3)

[0403] (Z)-1-(4-bromo-2-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one (200 mg, 0.70 mmol), intermediate M1 (190 mg, 0.70 mmol), tris(dibenzylacetone)dipalladium (60 mg, 0.057 mmol), XPhos (56 mg, 0.105 mmol), and cesium carbonate (770 mg, 2.10 mmol) dissolved in 5 mL toluene were added to a reaction flask. The reaction was carried out at 110 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, the compound (S,Z)-4-(4-(3-(dimethylamino)acryloyl)-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (162 mg) was purified by column chromatography (petroleum ether:ethyl acetate = 4:1), with a yield of 57%.

[0404] MS (m / z): 446.3 [M+H] + .

[0405] Step 3: Synthesis of 2-isobutyl-4-(4-(isoxazo-5-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (25-4)

[0406] (Z)-4-(4-(3-(dimethylamino)acryloyl)-3-methoxyphenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) and hydroxylamine hydrochloride (52 mg, 0.72 mmol) were added to a reaction flask, followed by 10 mL of ethanol. The reaction was carried out at 78 °C for 5 hours. After the reaction was completed by TLC monitoring, the mixture was extracted and the reaction solution was evaporated to dryness to give compound 2-isobutyl-4-(4-(isoxazol-5-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (140 mg), with a yield of 86%.

[0407] MS (m / z): 416.2 [M+H] + .

[0408] Step 4: Synthesis of 5-(4-(3-isobutylpiperazin-1-yl)-2-methoxyphenyl)isoxazole (25)

[0409] 140 mg (0.33 mmol) of 2-isobutyl-4-(4-(isooxazol-5-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, 5 mL of dichloromethane, and 1.5 mL of HCl / EA solution were added to a reaction flask. The reaction was carried out at room temperature for 16 h, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was evaporated to dryness, and the target compound 5-(4-(3-isobutylpiperazine-1-yl)-2-methoxyphenyl)isooxazole (62 mg) was purified by preparative liquid chromatography (Method A) in 60% yield.

[0410] MS (m / z): 316.2 [M+H] + .

[0411] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=1.8Hz,1H),8.31(s,1H),7.68(d,J=8.6Hz,1H),6.67(dd,J=8.8,2.2Hz,1H),6.64-6.61(m,2H),3.93(s,3H), 3.82-3.75(m,2H),3.15-3.08(m,1H),2.96-2.81(m,3H),2.59-2.54(m, 1H),1.87-1.78(m,1H),1.38-1.28(m,2H),0.91(dd,J=6.6,1.6Hz,6H).

[0412] Example 26: Synthesis of 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (compound 26)

[0413]

[0414] The synthesis steps of compound 26 are as follows:

[0415]

[0416] Referring to steps 1 to 3 in Example 8, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 4-pyridineboronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (30 mg), with a three-step yield of 16%.

[0417] MS (m / z): 310.2 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.87(d,J=6.2Hz,2H),8.09-8.01(m,2H),7.38(d,J=8.2Hz,1H),7.07-7.02(m,2H),3.95(d,J=13.8Hz,2 H),3.35-3.29(m,2H),3.21-3.14(m,2H),2.94(dd,J=13.6,10.6Hz,1H),2.38(s,3H),1.91(s,1H),1.60-1.46(m,2H),0.94(t,J=6.8Hz,6H).

[0419] Example 27: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(pyridin-4-yl)phenol (compound 27)

[0420]

[0421] The synthesis steps of compound 27 are as follows:

[0422]

[0423] Referring to steps 1 to 3 of Example 11, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 4-pyridineboronic acid, thus obtaining the target compound 5-(3-isobutylpiperazin-1-yl)-2-(pyridine-4-yl)phenol (35 mg), with a three-step yield of 31%.

[0424] MS(m / z): 312.2 [M+H] + .

[0425] 1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.98(s,1H),8.79-8.72(m,2H),8.37-8.31(m,2H),7. 67(d,J=9.0Hz,1H),6.74(dd,J=9.0,2.6Hz,1H),6.61(d,J=2.4Hz,1H),3.90(dd,J=14.6,4 .4Hz,2H),3.40(td,J=17.4,17.0,8.2Hz,2H),3.20(d,J=9.4Hz,2H),2.97(dd,J=13.8,10. 4Hz, 1H), 1.84 (dt, J=13.4, 6.6Hz, 1H), 1.53 (t, J=7.0Hz, 2H), 0.94 (dd, J=6.4, 5.2Hz, 6H).

[0426] Example 28: Synthesis of compound 3-isobutyl-1-(3-methoxy-4-(pyridin-4-yl)phenyl)piperazine (compound 28)

[0427]

[0428] The synthesis steps of compound 28 are as follows:

[0429]

[0430] Referring to the synthesis steps in Example 12, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 4-pyridineboronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methoxy-4-(pyridine-4-yl)phenyl)piperazine (10 mg), with a three-step yield of 7%.

[0431] MS (m / z): 326.3 [M+H] + .

[0432] 1 H NMR(600MHz,DMSO-d6)δ9.83(s,1H),8.73(s,2H),8.13(s,2H),7.58(s,1H),6.74(d,J=42.2Hz,2H),4.03( s,2H),3.90(s,3H),3.12(d,J=35.2Hz,4H),1.93(s,1H),1.56(d,J=63.8Hz,2H),1.18(s,1H),0.91(s,6H).

[0433] Example 29: Synthesis of 2-isobutyl-4-(4-(pyridin-4-yl)-3-(difluoromethoxy)phenyl)piperazine (compound 29)

[0434]

[0435] The synthetic route for compound 29 is as follows:

[0436]

[0437] Referring to the synthesis steps in Example 13, only 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with 4-pyridineboronic acid, thus obtaining the target compound 2-isobutyl-4-(4-(pyridin-4-yl)-3-(difluoromethoxy)phenyl)piperazine (80 mg), with a three-step yield of 50%.

[0438] MS (m / z): 362.2 [M+H] + .

[0439] 1 H NMR(400MHz,DMSO-d6)δ8.62-8.53(m,2H),8.18(s,1H),7.49-7.40(m,2H),7.24( t,J=72.0Hz,1H),6.99(dd,J=8.8,2.4Hz,1H),6.85(d,J=2.4Hz,1H),3.78(dd,J= 12.6,3.2Hz,2H),3.17(d,J=12.0Hz,1H),3.03-2.88(m,3H),2.61(dd,J=12.6,10 .4Hz,1H),1.88-1.79(m,1H),1.38(td,J=7.0,3.8Hz,2H),0.92(d,J=6.4Hz,6H).

[0440] Example 30: Synthesis of 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (compound 30)

[0441]

[0442] The synthesis steps of compound 30 are as follows:

[0443]

[0444] Referring to steps 1 to 3 in Example 8, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 is replaced with (2-methylpyridin-4-yl)boronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (15 mg), with a three-step yield of 10%.

[0445] MS (m / z): 324.2 [M+H] + .

[0446] 1 H NMR (400MHz, DMSO-d6) δ9.71(d,J=10.2Hz,1H),9.56(d,J=10.6Hz,1H),8.71(d,J=6.2 Hz,1H),7.94(d,J=1.8Hz,1H),7.86(dd,J=6.2,1.8Hz,1H),7.36(d,J=8.4Hz,1H),7.04 (d,J=9.4Hz,2H),3.94(d,J=12.8Hz,2H),3.34-3.08(m,4H),2.97(dd,J=13.6,10.6Hz ,1H),2.77(s,3H),2.38(s,3H),1.91(s,1H),1.65-1.47(m,2H),0.93(t,J=6.8Hz,6H).

[0447] Example 31: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(2-methylpyridin-4-yl)phenol (compound 31)

[0448]

[0449] The synthesis steps of compound 31 are as follows:

[0450]

[0451] Referring to steps 1 to 3 of Example 11, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with (2-methylpyridin-4-yl)boronic acid, thus obtaining the target compound 5-(3-isobutylpiperazin-1-yl)-2-(2-methylpyridin-4-yl)phenol (37 mg), with a three-step yield of 30%.

[0452] MS (m / z): 326.2 [M+H] + .

[0453] 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),9.74(d,J=10.2Hz,1H),9.56(d,J=10.4Hz,1H),8. 57(d,J=6.2Hz,1H),8.16(d,J=6.8Hz,2H),7.62(d,J=9.4Hz,1H),6.76-6.66(m,2H),3.85 (t,J=10.8Hz,2H),3.28(dt,J=25.2,12.8Hz,3H),3.15(d,J=15.0Hz,1H),3.01(dd,J=13. 4,10.6Hz,1H),2.72(s,3H),1.93-1.80(m,1H),1.63-1.49(m,2H),0.93(t,J=6.2Hz,6H).

[0454] Example 32: Synthesis of 3-isobutyl-1-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)piperazine (compound 32)

[0455]

[0456] The synthesis steps of compound 32 are as follows:

[0457]

[0458] Referring to the synthesis steps in Example 12, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with (2-methylpyridin-4-yl)boronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)piperazine (35 mg), with a three-step yield of 30%.

[0459] MS (m / z): 340.2 [M+H] + .

[0460] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=6.2Hz,1H),8.10-8.01(m,2H),7.60(d,J=8.8Hz,1H),6.79(dd,J=8.8,2.2Hz,1H),6.72(d,J=2.2Hz,1H),4.09 -4.01(m,2H),3.91(s,3H),3.30(d,J=12.4Hz,3H),3.17-3.01(m,2H),2 .73(s,3H),1.97-1.89(m,1H),1.65-1.51(m,2H),0.93(t,J=6.8Hz,6H).

[0461] Example 33: Synthesis of 1-(3-(difluoromethoxy)-4-(2-methylpyridin-4-yl)phenyl)-3-isobutylpiperazine (compound 33)

[0462]

[0463] The synthesis steps of compound 33 are as follows:

[0464]

[0465] Referring to the synthesis steps in Example 13, only the 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with (2-methylpyridin-4-yl)boronic acid, thus obtaining the target compound 1-(3-(difluoromethoxy)-4-(2-methylpyridin-4-yl)phenyl)-3-isobutylpiperazine (80 mg), with a three-step yield of 50%.

[0466] MS (m / z): 376.2 [M+H] + .

[0467] 1 H NMR(400MHz,DMSO-d6)δ8.62-8.53(m,2H),8.18(s,1H),7.49-7.40(m,2H),7.24(t, J=72.0Hz,1H),6.99(dd,J=8.8,2.4Hz,1H),6.85(d,J=2.4Hz,1H),3.78(dd,J=12.6, 3.2Hz,2H),3.17(d,J=12.0Hz,1H),3.03-2.88(m,3H),2.72(s,3H),2.61(dd,J=12.8 ,10.4Hz,1H),1.88-1.79(m,1H),1.38(td,J=7.0,3.6Hz,2H),0.92(d,J=6.6Hz,6H).

[0468] Example 34: Synthesis of 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (compound 34)

[0469]

[0470] The synthetic steps of compound 34 are as follows:

[0471]

[0472] Referring to steps 1 to 3 in Example 8, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 3-pyridineboronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methyl-4-(pyridin-3-yl)phenyl)piperazine (25 mg), with a three-step yield of 18%.

[0473] MS (m / z): 310.2 [M+H] + .

[0474] 1 H NMR(600MHz,DMSO-d6)δ9.62(d,J=10.6Hz,1H),8.94(d,J=2.0Hz,1H),8.87(d,J=5.6 Hz,1H),8.59(d,J=8.0Hz,1H),8.10(dd,J=8.2,5.6Hz,1H),7.29(d,J=8.4Hz,1H),7.0 8-6.98(m,2H),3.89(t,J=11.0Hz,2H),3.35-3.07(m,4H),2.95(dd,J=13.4,10.6Hz, 1H),2.29(s,3H),1.95-1.88(m,1H),1.64-1.52(m,2H),0.93(dd,J=11.0,6.4Hz,6H).

[0475] Example 35: Synthesis of 5-(3-isobutylpiperazin-1-yl)-2-(pyridin-3-yl)phenol (compound 35)

[0476]

[0477] The synthesis steps of compound 35 are as follows:

[0478]

[0479] Referring to steps 1 to 3 of Example 11, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 3-pyridineboronic acid, thus obtaining the target compound 5-(3-isobutylpiperazin-1-yl)-2-(pyridine-3-yl)phenol (35 mg), with a three-step yield of 31%.

[0480] MS(m / z): 312.2 [M+H] + .

[0481] 1H NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.65(dd,J=4.8,1.7Hz,1H),8.59(d,J=2.1Hz,1H),7.83(dt,J=8.2,1 .8Hz,1H),7.48(d,J=7.7Hz,1H),7.38(dd,J=8.3,4.8Hz,1H),6.47(dd,J=7.7,1.8Hz,1H),6.26(d,J=2.0H z,1H),3.54-3.43(m,3H),3.30-3.21(m,2H),2.98(ddt,J=12.5,5.1,3.0Hz,1H),2.87(ddt,J=12.5,5.1,3 .0Hz,1H),1.94(dt,J=6.0,2.8Hz,1H),1.69-1.50(m,2H),1.42-1.33(m,1H),0.91(dd,J=6.7,0.6Hz,6H).

[0482] Example 36: Synthesis of 3-isobutyl-1-(3-methoxy-4-(pyridin-3-yl)phenyl)piperazine (compound 36)

[0483]

[0484] The synthesis steps of compound 36 are as follows:

[0485]

[0486] Referring to the synthesis steps in Example 12, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 3-pyridineboronic acid, thus obtaining the target compound 3-isobutyl-1-(3-methoxy-4-(pyridin-3-yl)phenyl)piperazine (12 mg), with a three-step yield of 6%.

[0487] MS (m / z): 326.3 [M+H] + .

[0488] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.44(d,J=4.8Hz,1H),8.31(s,1H),7.83(d,J= 7.8Hz,1H),7.38(t,J=6.2Hz,1H),7.21(d,J=8.2Hz,1H),6.67-6.59(m,2H),3.79(s ,3H),3.69(t,J=9.8Hz,2H),3.08(d,J=11.6Hz,1H),2.90(s,2H),2.77(s,1H),2.44 (d,J=10.8Hz,1H),1.87-1.77(m,1H),1.32(q,J=8.2Hz,2H),0.91(d,J=6.2Hz,6H).

[0489] Example 37: Synthesis of 2-isobutyl-4-(4-(pyridin-3-yl)-3-(difluoromethoxy)phenyl)piperazine (compound 37)

[0490]

[0491] The synthetic steps of compound 37 are as follows:

[0492]

[0493] Referring to the synthesis steps in Example 13, only 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with 3-pyridineboronic acid, thus obtaining the target compound 2-isobutyl-4-(4-(pyridin-3-yl)-3-(difluoromethoxy)phenyl)piperazine (80 mg), with a three-step yield of 50%.

[0494] MS (m / z): 362.2 [M+H] + .

[0495] 1H NMR (400MHz, DMSO-d6) δ8.64(d,J=2.2Hz,1H),8.52(dd,J=4.6,1.8Hz,1H),8.22(s,1H),7.84(dt,J=7.8 ,2.0Hz,1H),7.45(dd,J=7.8,4.6Hz,1H),7.38(d,J=8.6Hz,1H),7.23(t,J=72.0Hz,1H),6.99(dd,J=8.6, 2.4Hz,1H),6.87(d,J=2.4Hz,1H),3.78(dd,J=12.2,3.2Hz,2H),3.20(d,J=11.4Hz,1H),3.11-2.91(m,3 H),2.65(dd,J=12.6,10.2Hz,1H),1.89-1.82(m,1H),1.41(q,J=6.8Hz,2H),0.92(dd,J=6.4,2.0Hz,6H).

[0496] Example 38: Synthesis of 2-isobutyl-4-(4-(pyridin-4-yl)-3-(trifluoromethoxy)phenyl)piperazine (compound 38)

[0497]

[0498] The synthesis steps of compound 38 are as follows:

[0499]

[0500] Referring to the synthesis method in Example 16, only 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with 4-pyridineboronic acid, thus obtaining the target compound 2-isobutyl-4-(4-(pyridin-4-yl)-3-(trifluoromethoxy)phenyl)piperazine (80 mg), with a three-step yield of 36%.

[0501] MS (m / z): 380.2 [M+H] + .

[0502] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=5.4Hz,2H),7.51-7.43(m,3H),7.10(dd,J=8.8,2.6Hz,1H),6.98(s,1H),3.71(dd,J=12.4,3.4Hz, 2H),3.05(d,J=10.8Hz,1H),2.88-2.75(m,3H),2.51-2.42(m,2H),1.86-1.78(m,1H),1.33-1.22(m,2H),0.90(dd,J=6.6,3.4Hz,6H).

[0503] Example 39: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)phenol (compound 39)

[0504]

[0505] The synthetic steps of compound 39 are as follows:

[0506]

[0507] 80 mg (0.25 mmol) of 2-isobutyl-4-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester and 3 mL of dichloromethane were added to a reaction flask, followed by the dropwise addition of 1 mL of BBr3. The mixture was heated to reflux for 16 h. After the reaction reached equilibrium as monitored by LC-MS, the reaction mixture was evaporated to dryness and purified by preparative liquid chromatography (Method B) to obtain the target compound 2-(3-isobutylpiperazine-1-yl)-5-(1H-pyrazole-4-yl)phenol (20 mg), with a yield of 27%.

[0508] MS (m / z): 301.2 [M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d6) δ8.43-8.29(m,1H),7.87(s,2H),7.04-6.94(m,2H),6.87(d,J=8.0Hz,1H),3.25(d,J=11.2Hz,1H),3.12-2.96(m,1 H),3.04(d,J=18.8Hz,3H),2.67(t,J=10.2Hz,1H)),2.35(t,J=10.6Hz,1H),1.76-1.68(m,1H),1.37-1.24(m,2H),0.90(d,J=6.4Hz,6H).

[0510] Example 40: Synthesis of 3-isobutyl-1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 40)

[0511]

[0512] The synthesis steps of compound 40 are as follows:

[0513]

[0514] Step 1: Synthesis of 4-(4-bromo-2-methoxyphenyl)-1-methyl-1H-pyrazole (40-1)

[0515] 4-Bromo-1-iodo-3-methoxybenzene (400 mg, 1.28 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (534 mg, 1.92 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (94 mg, 0.128 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (1.25 g, 3.84 mmol) was dissolved in 1 mL of water and added to the reaction system. The reaction was carried out at 105 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 4-(4-bromo-2-methoxyphenyl)-1-methyl-1H-pyrazole (220 mg), yield 51%.

[0516] MS (m / z): 337.1 [M+H] + .

[0517] Step 2: Synthesis of 2-isobutyl-4-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (40-2)

[0518] 4-(4-bromo-2-methoxyphenyl)-1-methyl-1H-pyrazole (220 mg, 0.65 mmol), intermediate M1 (158 mg, 0.65 mmol), tris(dibenzylacetone)dipalladium (48 mg, 0.05 mmol), XPhos (47 mg, 0.098 mmol), cesium carbonate (425 mg, 1.31 mmol), and 5 mL of toluene were added to a reaction flask. The mixture was heated to 110 °C and reacted for 16 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 2-isobutyl-4-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (200 mg), yield 62%.

[0519] MS (m / z): 499.1 [M+H] + .

[0520] Step 3: Synthesis of 3-isobutyl-1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (40)

[0521] 180 mg (0.36 mmol) of 2-isobutyl-4-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester, 3 mL of dichloromethane, and 2 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 5 h. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the target compound 3-isobutyl-1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperazine (7 mg) was purified by preparative liquid chromatography (Method A) in a yield of 24%.

[0522] MS (m / z): 315.2 [M+H] + .

[0523] 1H NMR (600MHz, DMSO-d6) δ8.33 (s, 1H), 7.99 (s, 2H), 7.15 (d, J = 1.8Hz, 1H), 7.10 (dd ,J=8.0,1.8Hz,1H),6.86(d,J=8.0Hz,1H),3.84(s,3H),3.34(d,J=11.4Hz,1H),3 .27(d,J=11.4Hz,1H),3.12-2.97(m,3H),2.70(td,J=11.4,2.6Hz,1H),2.38(t,J =10.6Hz,1H),1.77-1.69(m,1H),1.37-1.30(m,2H),0.91(dd,J=6.6,1.8Hz,6H).

[0524] Example 41: Synthesis of 1-(2-(difluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 41)

[0525]

[0526] The synthesis steps of compound 41 are as follows:

[0527]

[0528] Referring to the synthesis steps in Example 13, only the 4-bromo-1-iodo-2-(difluoromethoxy)benzene in step 1 was replaced with 1-bromo-2-(difluoromethoxy)-4-iodobenzene, thus obtaining the target compound 1-(2-(difluoromethoxy)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (47 mg), with a three-step yield of 11%.

[0529] MS (m / z): 351.2 [M+H] + .

[0530] 1H NMR (400MHz, DMSO-d6) δ8.25(s,1H),8.04(s,2H),7.45(dd,J=8.2,2.0Hz,1H),7.37(d,J=2. 0Hz,1H),7.09(d,J=8.2Hz,1H),3.34(dt,J=11.6,2.4Hz,1H),3.26-3.22(m,1H),3.18(dt,J =12.2,2.6Hz,1H),3.13-3.09(m,1H),3.02(td,J=11.8,3.2Hz,1H),2.87(td,J=11.6,2.6Hz ,1H),2.55-2.52(m,1H),1.77-1.69(m,1H),1.43-1.33(m,2H),0.90(dd,J=6.6,3.0Hz,6H).

[0531] Example 42: Synthesis of 2-(2-(difluoromethyl)pyridin-4-yl)-5-(3-isobutylpiperazin-1-yl)phenol (compound 42)

[0532]

[0533] The synthesis steps of compound 42 are as follows:

[0534]

[0535] Referring to steps 1 to 3 of Example 11, only the (1-(tert-butoxycarbonyl)-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with (2-(difluoromethyl)pyridin-4-yl)boronic acid, thus obtaining the target compound 2-(2-(difluoromethyl)pyridin-4-yl)-5-(3-isobutylpiperazin-1-yl)phenol (6 mg), with a three-step yield of 4%.

[0536] MS (m / z): 362.2 [M+H] + .

[0537] 1H NMR(400MHz,DMSO-d6)δ8.59(d,J=5.2Hz,1H),8.24(s,1H),7.92(s,1H),7.75(d,J=5.2Hz,1H), 7.37(d,J=8.8Hz,1H),6.95(t,J=55.2Hz,1H),6.58(dd,J=8.8,2.4Hz,1H),6.52(d,J=2.6Hz,1H) ,3.60(d,J=11.8Hz,2H),3.09(d,J=12.2Hz,1H),2.88(t,J=8.2Hz,2H),2.78-2.70(m,1H),2.49- 2.41(m,1H),1.82-1.42(dt,J=13.4,6.6Hz,1H),1.34-1.24(m,2H),0.92(dd,J=6.6,2.4Hz,6H).

[0538] Example 43: Synthesis of 1-(4-(2-(difluoromethyl)pyridin-4-yl)-3-methoxyphenyl)-3-isobutylpiperazine (compound 43)

[0539]

[0540] The synthesis steps of compound 43 are as follows:

[0541]

[0542] Referring to steps 1 to 3 of Example 40, only 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with (2-(difluoromethyl)pyridin-4-yl)boronic acid, thus obtaining the target compound 1-(4-(2-(difluoromethyl)pyridin-4-yl)-3-methoxyphenyl)-3-isobutylpiperazine (14 mg), with a three-step yield of 11%.

[0543] MS (m / z): 376.2 [M+H] + .

[0544] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=5.2Hz,1H),8.30(s,1H),7.79(d,J=1.2Hz,1H),7.67 (d,J=5.2Hz,1H),7.35(d,J=8.8Hz,1H),6.95(t,J=55.2Hz,1H),6.66-6.61(m,2H),3.8 3(s,3H),3.73-3.67(m,2H),3.03(dt,J=11.6,2.4Hz,1H),2.85-2.68(m,3H),2.41(dd, J=12.0,10.2Hz,1H),1.87-1.77(m,1H),1.29-1.22(m,2H),0.91(dd,J=6.6,4.2Hz,6H).

[0545] Example 44: Synthesis of 1-(2-(difluoromethyl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 44)

[0546]

[0547] The synthesis steps of compound 44 are as follows:

[0548]

[0549] Step 1: Synthesis of 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (44-2)

[0550] 4-Bromo-2-(difluoromethyl)-1-iodobenzene (700 mg, 2.11 mmol), intermediate M1 (510 mg, 2.11 mmol), tris(dibenzylacetone)dipalladium (19 mg, 0.84 mmol), BINAP (105 mg, 0.17 mmol), and cesium carbonate (1.37 g, 4.22 mmol) were dissolved in 10 mL of toluene. The mixture was heated to 110 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (670 mg), with a yield of 72%.

[0551] MS (m / z): 447.3 [M+H] + .

[0552] Step 2: Synthesis of 4-(3-(difluoromethyl)-4-(-3-isobutylpiperazin-1-yl)phenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (44-3)

[0553] 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.315 mmol), (1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazol-4-yl)boronic acid (76 mg, 0.315 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (23 mg, 0.032 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (204 mg, 0.63 mmol) was dissolved in 1 mL of water and added to the reaction system. The mixture was heated to 105 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(3-(difluoromethyl)-4-(-3-isobutylpiperazin-1-yl)phenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (140 mg), with a yield of 79%.

[0554] MS (m / z): 463.3 [M+H] + .

[0555] Step 3: Synthesis of 1-(2-(difluoromethyl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (44)

[0556] 4-(3-(difluoromethyl)-4-(-3-isobutylpiperazin-1-yl)phenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (140 mg, 0.303 mmol), 5 mL of dichloromethane, and 2.5 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the target compound 1-(2-(difluoromethyl)-4-(3,5-dimethyl-1H-pyrazole-4-yl)phenyl)-3-isobutylpiperazine (75 mg) was purified by preparative liquid chromatography (Method A) with a yield of 68%.

[0557] MS(m / z): 363.2 [M+H] + .

[0558] 1H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.44(d,J=8.8Hz,2H),7.35(d,J=4.6Hz,1H),7.33-7.07(m,1H) ,3.11-2.81(m,6H),2.19(s,6H),1.71-1.66(m,1H),1.34-1.22(m,2H),0.88(dd,J=6.6,3.2Hz,6H).

[0559] Example 45: Synthesis of 4-(3-(difluoromethyl)-4-(3-isobutylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (compound 45)

[0560]

[0561] The synthesis steps of compound 45 are as follows:

[0562]

[0563] Referring to steps 1 to 3 of the synthesis scheme in Example 44, only the (1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazole-4-yl)boronic acid in step 2 was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine to obtain the target compound 4-(3-(difluoromethyl)-4-(3-isobutylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (55 mg), with a three-step yield of 20%.

[0564] MS (m / z): 385.2 [M+H] + .

[0565] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.47-8.20(m,2H),8.00-7.84(m,2 H),7.63-7.52(m,1H),7.46(d,J=8.6Hz,1H),7.42-7.07(m,2H),6.56(d,J =3.2Hz,1H),3.17-2.94(m,5H),2.90(d,J=10.0Hz,1H),2.57(t,J=10.8H z,1H),1.73-1.67(m,1H),1.36-1.21(m,2H),0.89(dd,J=6.6,3.8Hz,6H).

[0566] Example 46: Synthesis of 1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-3-isobutylpiperazine (compound 46)

[0567]

[0568] The synthetic steps of compound 46 are as follows:

[0569]

[0570] Referring to steps 1 to 3 of the synthesis scheme in Example 44, simply replacing (1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazol-4-yl)boronic acid in step 2 with (2-(difluoromethyl)pyridin-4-yl)boronic acid yields the target compound 1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-3-isobutylpiperazine (30 mg), with a three-step yield of 27%.

[0571] MS (m / z): 396.2 [M+H] + .

[0572] 1 H NMR(400MHz,DMSO-d6)δ8.74(d,J=5.2Hz,1H),8.07-7.98(m,3H),7.93(dd,J=5.2,1 .8Hz,1H),7.43(d,J=8.4Hz,1H),7.12(dt,J=85.4,54.8Hz,2H),3.12-2.95(m,5H), 2.89(td,J=11.0,3.2Hz,1H),2.61-2.53(m,1H),1.70(dt,J=13.4,6.6Hz,1H),1.33 (dt,J=13.8,6.8Hz,1H),1.24(dd,J=12.0,5.2Hz,1H),0.89(dd,J=6.6,3.8Hz,6H).

[0573] Example 47: Synthesis of 1-(2-(difluoromethyl)-3-fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 47)

[0574]

[0575] The synthetic steps of compound 47 are as follows:

[0576]

[0577] Referring to steps 1 to 3 of the synthesis scheme in Example 23, simply replacing (1-bromo-2-(difluoromethyl)-4-iodobenzene in step 1 with 1-bromo-2-(difluoromethyl)-3-fluoro-4-iodobenzene yields the target compound 1-(2-(difluoromethyl)-3-fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (85 mg), with a three-step yield of 25%.

[0578] MS (m / z): 353.2 [M+H] + .

[0579] 1 H NMR(400MHz, DMSO-d6)δ8.29(s,1H),8.06(d,J=1.8Hz,2H),7.87(t,J=8.4Hz,1H),7.40-7.08(m,2H),3.14- 2.81(m,6H),2.57(dd,J=11.8,9.8Hz,1H),1.75-1.65(m,1H),1.3-1.22(m,2H),0.89(dd,J=6.6,2.8Hz,6H).

[0580] The synthetic route for compound 1-bromo-2-(difluoromethyl)-3-fluoro-4-iodobenzene is as follows:

[0581]

[0582] 0.3 g (0.92 mmol) of 6-bromo-2-fluoro-3-iodobenzaldehyde and 10 mL of dichloromethane were added to a reaction flask. DAST (443 mg, 2.74 mmol) was slowly added at 0 °C. After stirring for 30 minutes, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC. When the reaction was basically complete, 20 mL of water was added to quench the reaction. The mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined and concentrated under vacuum to give 300 mg of compound 1-bromo-2-(difluoromethyl)-3-fluoro-4-iodobenzaldehyde, with a yield of 93%.

[0583] MS (m / z): 350.8 [M+H] + .

[0584] Example 48: Synthesis of 3-(3-(difluoromethyl)-4-(3-isobutylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (compound 48)

[0585]

[0586] The synthesis steps of compound 48 are as follows:

[0587]

[0588] Step 1: Synthesis of 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (44-2)

[0589] 4-Bromo-2-(difluoromethyl)-1-iodobenzene (700 mg, 2.11 mmol), intermediate M1 (510 mg, 2.11 mmol), palladium acetate (19 mg, 0.84 mmol), BINAP (105 mg, 0.17 mmol), and cesium carbonate (1.37 g, 4.22 mmol) were dissolved in 10 mL of toluene. The mixture was heated to 110 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (670 mg), with a yield of 72%.

[0590] MS (m / z): 447.3 [M+H] + .

[0591] Step 2: Synthesis of 4-(4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (48-1)

[0592] 4-(4-bromo-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.224 mmol), 1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine (84 mg, 0.250 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (17 mg, 0.023 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (219 mg, 0.670 mmol) was dissolved in 1 mL of water and added to the reaction system. The mixture was heated to 105 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (115 mg), yield 89%.

[0593] MS (m / z): 575.1 [M+H] + .

[0594] Step 3: Synthesis of 4-(2-(difluoromethyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (48-2)

[0595] 4-(4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (115 mg, 0.20 mmol) was dissolved in 2 mL of dimethyl sulfoxide, and then 1 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added. The reaction was carried out at room temperature for 5 hours under an oxygen atmosphere. After the reaction was monitored by TLC until complete, 5 mL of water was added, and the mixture was extracted with ethyl acetate (3 times, 5 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness to give compound 4-(2-(difluoromethyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80 mg), yield 82%.

[0596] MS (m / z): 485.3 [M+H] + .

[0597] Step 4: Synthesis of 3-(3-(difluoromethyl)-4-(3-isobutylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (48)

[0598] 80 mg (0.165 mmol) of 4-(2-(difluoromethyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester and 5 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. After the reaction was completed by TLC monitoring, the target compound 3-(3-(difluoromethyl)-4-(3-isobutylpiperazine-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg) was purified by preparative liquid chromatography (Method A) in a yield of 79%.

[0599] MS (m / z): 385.3 [M+H] + .

[0600] 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.33-8.26(m,2H),8.21(dd,J=8.0,1.6Hz,1H),7.93(d,J=2.0Hz,1H),7.90-7.83(m,2H),7.42-7.10(m ,3H),3.14-2.93(m,5H),2.88(td,J=11.2,3.0Hz,1H),2.63-2.53(m,1H),1.73-1.65(m,1H),1.38-1.23(m,2H),0.89(dd,J=6.6,2.8Hz,6H).

[0601] Example 49: Synthesis of 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (compound 49)

[0602]

[0603] The synthetic steps of compound 49 are as follows:

[0604]

[0605] Referring to steps 1 to 3 of the synthesis scheme in Example 44, simply replacing 4-bromo-2-(difluoromethyl)-1-iodobenzene in step 1 with 5-bromo-2-iodobenzonitrile yields the target compound 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (32 mg), with a three-step yield of 20%.

[0606] MS (m / z): 338.2 [M+H] + .

[0607] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.59(d,J=2.2Hz,1H),7.51(dd,J=8.6,2.2Hz,1H),7.21(d,J=8.4Hz,1H),3.55-3.36(m,2 H),3.17-2.89(m,4H),2.58(t,J=10.8Hz,1H),2.18(s,6H),1.81-1.70(m,1H),1.35-1.26(m,2H),0.91(dd,J=8.2,6.6Hz,6H).

[0608] Example 50: Synthesis of (5-(2-(difluoromethyl)pyridin-4-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (compound 50)

[0609]

[0610] The synthesis steps of compound 50 are as follows:

[0611]

[0612] Referring to the synthesis scheme of Example 49, simply replacing (1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazol-4-yl)boronic acid in step 2 with (2-(difluoromethyl)pyridin-4-yl)boronic acid yields the target compound (5-(2-(difluoromethyl)pyridin-4-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (29 mg), with a three-step yield of 22%.

[0613] MS(m / z): 371.2 [M+H] + .

[0614] 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=5.2Hz,1H),8.32(d,J=2.4Hz,1H),8.25(s,1H),8.11(dd,J=8.8 ,2.4Hz,1H),8.06(d,J=1.8Hz,1H),7.94(dd,J=5.2,1.8Hz,1H),7.27(d,J=8.8Hz,1H),6.99(t,J=5 4.8Hz,1H),3.62(dt,J=11.8,2.4Hz,1H),3.56-3.48(m,1H),3.12-3.03(m,1H),2.97-2.88(m,3H) ,2.58(dd,J=11.8,10.0Hz,1H),1.81-1.71(m,1H),1.34-1.21(m,2H),0.91(dd,J=9.6,6.4Hz,6H).

[0615] Example 51: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound 51)

[0616]

[0617] The synthesis steps of compound 51 are as follows:

[0618]

[0619] Referring to steps 1 to 4 of the synthesis scheme in Example 48, simply replacing 4-bromo-2-(difluoromethyl)-1-iodobenzene in step 1 with 5-bromo-2-iodobenzonitrile yields the target compound 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (48 mg), with a three-step yield of 39%.

[0620] MS (m / z): 360.2 [M+H] + .

[0621] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.33-8.26(m,3H),8.07-7.92(m,3H), 7.25(d,J=8.6Hz,1H),7.17(dd,J=7.8,4.6Hz,1H),3.52(d,J=11.8Hz,1H),3. 40(d,J=10.8Hz,1H),3.16(d,J=11.4Hz,1H),3.08-2.87(m,3H),2.59(t,J=10 .8Hz,1H),1.80-1.71(m,1H),1.40-1.29(m,2H),0.92(dd,J=8.4,6.5Hz,6H).

[0622] Example 52: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzonitrile (compound 52)

[0623]

[0624] The synthesis steps of compound 52 are as follows:

[0625]

[0626] Referring to the synthesis scheme of Example 49, by simply replacing (1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazole-4-yl)boronic acid in step 2 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine, the target compound 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzonitrile (40 mg) was obtained, with a three-step yield of 20%.

[0627] MS (m / z): 360.3 [M+H] + .

[0628] 1H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 8.27 (d, J = 4.8Hz, 2H), 8.11-7.92 (m, 2 H),7.56(d,J=3.4Hz,1H),7.25(dd,J=41.4,6.6Hz,2H),6.62(d,J=3.2Hz,1H) ,3.53(dd,J=45.2,9.4Hz,2H),3.09(s,1H),3.01-2.84(m,3H),2.57(t,J=10 .6Hz,1H),1.87-1.65(m,1H),1.33-1.25(m,2H),0.91(dd,J=9.8,6.2Hz,6H).

[0629] Example 53: Synthesis of 1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (compound 53)

[0630]

[0631] The synthesis steps of compound 53 are as follows:

[0632]

[0633] Step 1: Synthesis of 4-(6-chloro-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (53-2)

[0634] 3-Bromo-6-chloro-2-(difluoromethyl)pyridine (600 mg, 2.49 mmol), intermediate M1 (604 mg, 2.49 mmol), palladium acetate (24 mg, 0.0996 mmol), BINAP (124 mg, 0.1992 mmol), and cesium carbonate (2.34 g, 47 mmol) were dissolved in 20 mL of toluene. The mixture was heated to 110 °C and reacted for 16 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(6-chloro-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (110 mg), yield 12%.

[0635] MS (m / z): 404.2 [M+H] + .

[0636] Step 2: Synthesis of 4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (53-3)

[0637] 4-(6-chloro-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (110 mg, 273 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (76 mg, 273 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (20 mg, 0273 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (178 mg, 546 mmol) was dissolved in 1 mL of water and then added to the reaction system. The mixture was heated to 105 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (140 mg), yield 96%.

[0638] MS (m / z): 520.3 [M+H] + .

[0639] Step 3: Synthesis of 1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (53)

[0640] 140 mg (0.27 mmol) of 4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 5 mL of dichloromethane, and 2 mL of HCl / dioxane solution were added to a reaction flask, and the reaction was carried out at room temperature for 6 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method A) to obtain the target compound 1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (62 mg), with a yield of 69%.

[0641] MS (m / z): 336.1 [M+H] + .

[0642] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.17(s,2H),7.85-7.73(m,2H),7.20(t,J=54.2Hz,1H),3.10-2.82 (m,6H),2.59-2.53(m,1H),1.70(dt,J=13.4,6.8Hz,1H),1.36-1.21(m,2H),0.89(dd,J=6.6,3.2Hz,6H).

[0643] Example 54: Synthesis of 1-(6-(difluoromethyl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)-3-isobutylpiperazine (compound 54)

[0644]

[0645] The synthesis steps of compound 54 are as follows:

[0646]

[0647] Step 1: Synthesis of 4-(5-bromo-6-(difluoromethyl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (54-1)

[0648] 3-Bromo-6-chloro-2-(difluoromethyl)pyridine (420 mg, 1.04 mmol), intermediate M1 (422 mg, 1.74 mmol), palladium acetate (17 mg, 0.076 mmol), BINAP (87 mg, 0.14 mmol), and cesium carbonate (1.70 g, 5.24 mmol) were dissolved in 20 mL of toluene. The mixture was heated to 110 °C and reacted for 16 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(5-bromo-6-(difluoromethyl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (62 mg), yield 13%.

[0649] MS (m / z): 448.2 [M+H] + .

[0650] Step 2: Synthesis of 4-(6-(difluoromethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (54-2)

[0651] 4-(5-bromo-6-(difluoromethyl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (62 mg, 0.139 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (38 mg, 0.136 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 0.014 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (93 mg, 0.285 mmol) was dissolved in 1 mL of water and added to the reaction system. The mixture was heated to 105 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(6-(difluoromethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (50 mg), yield 69%.

[0652] MS (m / z): 520.3 [M+H] + .

[0653] Step 3: Synthesis of 1-(6-(difluoromethyl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)-3-isobutylpiperazine (54)

[0654] 4-(6-(difluoromethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.096 mmol), 5 mL of dichloromethane, and 2 mL of HCl / dioxane solution were added to a reaction flask, and the reaction was carried out at room temperature for 6 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method A) to obtain the target compound 1-(6-(difluoromethyl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)-3-isobutylpiperazine (14 mg), yield 44%.

[0655] MS (m / z): 336.2 [M+H] + .

[0656] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.75(s,2H),7.68(d,J=8.8Hz,1H),7.07(d,J=8.8Hz,1H),6.78(t,J=54.4Hz,1H),4.24(dd,J=24 .8,12.6Hz,2H),3.14-2.77(m,4H),2.61(dd,J=12.6,10.2Hz,1H),1.83-1.75(m,1H),1.37-1.26(m,2H),0.91(dd,J=6.6,3.6Hz,6H).

[0657] Example 55: Synthesis of 2-fluoro-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (compound 55)

[0658]

[0659] The synthesis steps of compound 55 are as follows:

[0660]

[0661] Referring to steps 1 to 3 of the synthesis scheme in Example 20, simply replacing 2-bromo-5-iodobenzonitrile in step 1 with 1-bromo-2-cyano-3-fluoro-4-iodobenzene yields the target compound 2-fluoro-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (34 mg), with a three-step yield of 12%.

[0662] MS (m / z): 328.2 [M+H] + .

[0663] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),8.05(d,J=1.8Hz,2H),7.93(t,J=8.8Hz,1H),7.01(d,J=8.8Hz,1H),3.55(dt,J=11.8,2.6Hz,1H),3.45(d,J=8 .6Hz,1H),3.13-3.04(m,1H),2.99-2.86(m,3H),2.57(dd,J=12.0,10.0H z,1H),1.79-1.72(m,1H),1.35-1.22(m,2H),0.91(dd,J=8.8,6.4Hz,6H).

[0664] The synthetic route for compound 1-bromo-2-cyano-3-fluoro-4-iodobenzene is as follows:

[0665]

[0666] 0.4 g (1.20 mmol) of 6-bromo-2-fluoro-3-iodobenzaldehyde and 5 mL of trifluoroacetic acid were added to a reaction flask. Hydroxylamine hydrochloride (256 mg, 3.6 mmol) was slowly added at 0 °C, followed by reaction at 70 °C for 10 hours. The reaction was monitored by TLC. When the reaction was substantially complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 12:1) to give compound 1-bromo-2-cyano-3-fluoro-4-iodobenzene (260 mg), in 67% yield.

[0667] MS (m / z): 325.8 [M+H] + .

[0668] Example 56: Synthesis of (1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)-3-isobutylpiperazine (compound 56)

[0669]

[0670] The synthesis steps of compound 56 are as follows:

[0671]

[0672] Step 1: Synthesis of (4-(4-bromo-2-(trifluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (56-2)

[0673] Intermediate M1 (0.3 g, 1.24 mmol), 4-bromo-1-iodo-2-(trifluoromethyl)benzene (0.39 g, 1.11 mmol), Pd(OAc)2 (0.028 g, 0.123 mmol), BINAP (0.154 g, 0.247 mmol), cesium carbonate (0.807 g, 2.48 mmol), and 20 mL of toluene were added to a reaction flask. The reaction was carried out at 110 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound (4-(4-bromo-2-(trifluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (70 mg), yield 12%).

[0674] MS (m / z): 465.2 [M+H] + .

[0675] Step 2: Synthesis of 2-isobutyl-4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (56-3)

[0676] Add (4-(4-bromo-2-(trifluoromethyl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (0.07 g, 0.15 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (0.042 g, 0.15 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 0.015 mmol), carbon to the reaction flask. Cesium acid (0.147 g, 0.451 mmol), 10 mL of dioxane, and 2 mL of water were reacted at 100 °C for 12 h under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain tert-butyl 2-isobutyl-4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid (50 mg), yield 62%.

[0677] MS (m / z): 537.2 [M+H] + .

[0678] Step 3: Synthesis of (1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)-3-isobutylpiperazine (56)

[0679] 80 mg (0.093 mmol) of 2-isobutyl-4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 20 mL of a 4M dioxane solution of hydrogen chloride. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was concentrated under vacuum, and the target compound (1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)-3-isobutylpiperazine (40 mg) was obtained by preparative liquid chromatography (Method A), with a yield of 76%.

[0680] MS (m / z): 353.2 [M+H] + .

[0681] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.14(s,2H),7.94-7.77(m,2H),7.48(d,J=8.2Hz,1H),3.22- 2.74(m,6H),2.56(t,J=10.0Hz,1H),1.67-1.60(m,1H),1.41-1.19(m,2H),0.86(d,J=6.2Hz,6H).

[0682] Example 57: Synthesis of methyl 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazole-4-yl)benzoate (compound 57)

[0683]

[0684] The synthesis steps of compound 57 are as follows:

[0685]

[0686] Referring to steps 1 to 3 of the synthesis scheme in Example 53, simply replacing 3-bromo-6-chloro-2-(difluoromethyl)pyridine in step 1 with methyl 5-bromo-2-iodobenzoate yields the target compound methyl 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazole-4-yl)benzoate (30 mg), with a three-step yield of 16%.

[0687] MS (m / z): 343.3 [M+H] + .

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.02(s,2H),7.78(d,J=2.2Hz,1H),7.68(dd,J=8.4,2.2Hz,1H),7.10(d,J=8.4Hz,1H),3.82(s,3H),3 .20-3.02(m,3H),2.99-2.75(m,3H),2.46(dd,J=11.6,9.8Hz,1H),1.70(dt,J=13.4,6.6Hz,1H),1.35-1.20(m,2H),0.90(t,J=7.0Hz,6H).

[0689] Example 58: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzoic acid (compound 58)

[0690]

[0691] The synthesis steps of compound 58 are as follows:

[0692]

[0693] Referring to steps 1 to 3 of the synthesis scheme in Example 53, simply replacing 3-bromo-6-chloro-2-(difluoromethyl)pyridine with 5-bromo-2-iodobenzoic acid in step 1 yields the target compound 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazole-4-yl)benzoic acid (24 mg), with a three-step yield of 15%.

[0694] MS (m / z): 329.2 [M+H] + .

[0695] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),8.15(d,J=2.2Hz,1H),8.12(s,2H),7.86(dd,J=8.4,2.4Hz,1H),7.60(d,J=8.4Hz,1H),3.11(dt,J=12.4,2.6H z,1H),3.05-2.95(m,3H),2.92-2.82(m,2H),2.69(t,J=10.6Hz,1H),1.7 2(dt,J=13.4,6.8Hz,1H),1.35-1.15(m,2H),0.88(dd,J=6.6,5.0Hz,6H).

[0696] Example 59: Synthesis of 1-(2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)phenyl)ethane-1-one (compound 59)

[0697]

[0698] The synthesis steps of compound 59 are as follows:

[0699]

[0700] Step 1: Synthesis of (4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (59-2)

[0701] 1-Bromo-2-chloro-4-iodobenzene (500 mg, 1.59 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (440 mg, 1.59 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (115 mg, 0.159 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (1.03 g, 3.17 mmol) was dissolved in 1 mL of water and added to the reaction system. The reaction was carried out at 105 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound (4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (360 mg), yield 67%).

[0702] MS(m / z): 341.2 [M+H] + .

[0703] Step 2: Synthesis of 4-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (59-3)

[0704] (4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (320 mg, 0.94 mmol), intermediate M1 (274 mg, 1.13 mmol), tris(dibenzylacetone)palladium (69 mg, 0.075 mmol), Xantphos (82 mg, 0.14 mmol), and cesium carbonate (917 mg, 2.82 mmol) were dissolved in 5 mL of toluene. The reaction was carried out at 110 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (300 mg), yield 64%.

[0705] MS (m / z): 503.2 [M+H] + .

[0706] Step 3: Synthesis of 4-(2-(1-ethoxyvinyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (59-4)

[0707] 4-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.44 mmol), tributyl(1-ethoxyvinyl)tin (240 mg, 0.66 mmol), tridibenzylacetone dipalladium (30 mg, 0.032 mmol), tricyclohexylphosphine (19 mg, 0.066 mmol), and cesium carbonate (286 mg, 0.88 mmol) were dissolved in 5 mL of dioxane and reacted at 130 °C for 16 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(2-(1-ethoxyvinyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (40 mg), yield 17%.

[0708] MS (m / z): 539.2 [M+H] + .

[0709] Step 4: Synthesis of 1-(2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)phenyl)ethane-1-one (59)

[0710] 4-(2-(1-ethoxyvinyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.074 mmol), 5 mL of dichloromethane, and 0.5 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 8 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method B) to obtain the target compound 1-(2-(3-isobutylpiperazine-1-yl)-5-(1H-pyrazole-4-yl)phenyl)ethane-1-one (2 mg), yield 10%.

[0711] MS (m / z): 327.2 [M+H] + .

[0712] 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.03(s,2H),7.67(dd,J=8.4,2.2Hz,1 H),7.53(d,J=2.4Hz,1H),7.13(d,J=8.4Hz,1H),3.07-2.97(m,3H),2.96-2 .86(m,2H),2.76(dd,J=12.0,9.2Hz,1H),2.61(s,3H),2.43(dd,J=11.8,9. 8Hz,1H),1.74-1.63(m,1H),1.32-1.17(m,2H),0.89(dd,J=6.6,4.4Hz,6H).

[0713] Example 60: Synthesis of 2-(3-isobutylpiperazin-1-yl)-N-methyl-5-(1H-pyrazol-4-yl)benzamide (compound 60)

[0714]

[0715] The synthesis steps of compound 60 are as follows:

[0716]

[0717] Referring to steps 1 to 3 of the synthesis scheme in Example 53, simply replacing 3-bromo-6-chloro-2-(difluoromethyl)pyridine in step 1 with 5-bromo-2-iodo-N-methylbenzamide yields the target compound 2-(3-isobutylpiperazin-1-yl)-N-methyl-5-(1H-pyrazole-4-yl)benzamide (12 mg), with a three-step yield of 3%.

[0718] MS (m / z): 342.3 [M+H] + .

[0719] 1 H NMR (400MHz, DMSO-d6) δ8.84(q,J=4.6Hz,1H),8.31(s,1H),8.02(s,2H),7.82(d,J=2.2Hz,1H),7.63(dd,J=8.2,2.2Hz,1H),7.14(d,J=8.4Hz,1H ),3.14-2.93(m,5H),2.83(d,J=4.6Hz,3H),2.44(t,J=10.6Hz,1H),1.69 (dt,J=13.4,6.6Hz,1H),1.35-1.20(m,2H),0.90(dd,J=6.6,3.8Hz,6H).

[0720] Example 61: Synthesis of 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (compound 61)

[0721]

[0722] The synthesis steps of compound 61 are as follows:

[0723]

[0724] Step 1: Synthesis of 2-(1,3-dioxaindol-2-yl)-4-methylpentanoic acid (61-2)

[0725] Leucine (1.31 g, 10.0 mmol), phthalic anhydride (1.55 g, 10.5 mmol), triethylamine (303 mg, 3.0 mmol), and 50 mL of toluene were added to a reaction flask. The reaction was carried out at 110 °C for 5 hours under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, 20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (3 times, 20 mL each time). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to give compound 2-(1,3-dioxanedol-2-yl)-4-methylpentanoic acid (3.35 g), with a yield of 90%.

[0726] MS(m / z): 262.1 [M+H] + .

[0727] Step 2: Synthesis of N-(4-bromo-2-cyanophenyl)-2-(1,3-dioxoisoindoline-2-yl)-4-methylpentanamide (61-3)

[0728] 2-(1,3-dioxaindol-2-yl)-4-methylpentanoic acid (1.58 g, 8.0 mmol) and 2-amino-5-bromobenzonitrile (2.09 g, 8.0 mmol) were dissolved in 10 mL of pyridine, cooled to 0 °C, and then 5 mL of POCl3 was added dropwise. The mixture was then allowed to react at room temperature for 0.5 h, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound N-(4-bromo-2-cyanophenyl)-2-(1,3-dioxaisoindololin-2-yl)-4-methylpentanamide (1.40 g), with a yield of 39%.

[0729] MS (m / z): 440.41 [M+H] + .

[0730] Step 3: Synthesis of 2-amino-N-(4-bromo-2-cyanophenyl)-4-methylpentanamide (61-4)

[0731] N-(4-bromo-2-cyanophenyl)-2-(1,3-dioxoisoindoline-2-yl)-4-methylpentanamide (1.40 g, 3.19 mmol), 80% hydrazine hydrate (1.99 g, 31.9 mmol), and 30 mL of ethanol were added to a reaction flask. The mixture was refluxed under nitrogen protection for 8 h, and the reaction was monitored by LC-MS. After the reaction was completed, the solid was removed by filtration, and the filtrate was concentrated under vacuum. The filtrate was then purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 2-amino-N-(4-bromo-2-cyanophenyl)-4-methylpentanamide (300 mg), with a yield of 30%.

[0732] MS(m / z): 310.1 [M+H] + .

[0733] Step 4: Synthesis of 5-bromo-2-(4-isobutyl-5-oxoimidazolidine-1-yl)benzonitrile (61-5)

[0734] 2-Amino-N-(4-bromo-2-cyanophenyl)-4-methylpentanamide (300 mg, 0.97 mmol), paraformaldehyde (58 mg, 1.94 mmol), sodium bicarbonate (163 mg, 1.94 mmol), and 10 mL of acetonitrile were added to a reaction flask. The reaction was carried out at 70 °C for 3 h, and the reaction was monitored by LC-MS. When the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 5-bromo-2-(4-isobutyl-5-oxoimidazolidine-1-yl)benzonitrile (240 mg), yield 75%.

[0735] MS(m / z): 322.1 [M+H] + .

[0736] Step 5: Synthesis of 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (61-6)

[0737] 5-Bromo-2-(4-isobutyl-5-oxoimidazolidine-1-yl)benzonitrile (230 mg, 0.71 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (217.2 mg, 0.78 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (52 mg, 0.07 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (463 mg, 1.42 mmol) was dissolved in 1 mL of water and added to the reaction system. The reaction was carried out at 100 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (260 mg), with a yield of 93%.

[0738] MS (m / z): 394.2 [M+H] + .

[0739] Step 6: Synthesis of 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (61)

[0740] 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (260.0 mg, 0.66 mmol) and 4 mL of HCl / EA solution were added to a reaction flask, and the reaction was carried out at room temperature for 6 h. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method C) to obtain the target compound 2-(4-isobutyl-5-oxoimidazolidine-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (153 mg), with a yield of 75%.

[0741] MS(m / z): 310.1 [M+H] + .

[0742] 1H NMR (400MHz, DMSO-d6) δ8.28-8.11(m,3H),8.00(dd,J=8.5,2.1Hz,1H),7.49(d,J=8.5Hz,1H),4.78-4.59(m,2H),3.48(dd,J=10.1,4 .1Hz,1H),1.94-1.79(m,1H),1.57(ddd,J=13.0,8.6,4.0Hz,1H),1.47(ddd,J=13.7,10.1,5.5Hz,1H),0.95(dd,J=13.2,6.6Hz,6H).

[0743] Example 62: Synthesis of 2-(3-isobutylpiperazin-1-yl)-N,N-dimethyl-5-(1H-pyrazol-4-yl)benzamide (compound 62)

[0744]

[0745] The synthesis steps of compound 62 are as follows:

[0746]

[0747] Referring to steps 1 to 3 of the synthesis scheme in Example 53, simply replacing 3-bromo-6-chloro-2-(difluoromethyl)pyridine in step 1 with 5-bromo-2-iodo-N,N-dimethylbenzamide yields the target compound 2-(3-isobutylpiperazin-1-yl)-N,N-dimethyl-5-(1H-pyrazole-4-yl)benzamide (44 mg), with a three-step yield of 15%.

[0748] MS (m / z): 356.3 [M+H] + .

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.03(s,2H),7.58(dd,J=8.4,2.2Hz,1H),7.39(d,J=2.4Hz,1H),7.04(t,J=7.8Hz,1H),3.37-3 .11(m,2H),3.00(s,3H),2.98-2.83(m,2H),2.79(s,3H),2.69(s,3H),1.79-1.57(m,1H),1.39-1.16(m,2H),0.89(t,J=7.2Hz,6H).

[0750] Example 63: Synthesis of 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzamide (compound 63)

[0751]

[0752] The synthesis steps of compound 63 are as follows:

[0753]

[0754] 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazole-4-yl)benzonitrile (80 mg, 0.16 mmol, compound 20) and 5 mL of phosphorus oxychloride solution were added to a reaction flask. Water was slowly added dropwise until the solution stopped bubbling. The reaction was heated at 70 °C for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was evaporated to dryness and purified by preparative liquid chromatography (Method A) to obtain the target compound 2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazole-4-yl)benzamide (21 mg), with a yield of 25%.

[0755] MS (m / z): 328.2 [M+H] + .

[0756] 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=10.8Hz,1H),8.68(d,J=10.8Hz,1H),8.04( d,J=4.2Hz,2H),7.80(d,J=2.2Hz,1H),7.69-7.55(m,2H),7.15(d,J=8.4Hz,1 H),3.35(td,J=32.6,15.8Hz,5H),3.04-2.95(m,1H),2.74(dd,J=12.6,10.4H z,1H),1.78-1.65(m,1H),1.45(t,J=7.2Hz,2H),0.93(dd,J=6.4,2.4Hz,6H).

[0757] Example 64: Synthesis of 2-(3-isobutyl-4-methylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (compound 64)

[0758]

[0759] The synthesis steps of compound 64 are as follows:

[0760]

[0761] Referring to steps 1 to 3 of the synthesis scheme in Example 20, only replacing 2-isobutylpiperazine-1-carboxylic acid tert-butyl ester in step 2 with 2-isobutyl-N-methylpiperazine yields the target compound 2-(3-isobutyl-4-methylpiperazine-1-yl)-5-(1H-pyrazole-4-yl)benzonitrile (71 mg), with a three-step yield of 15%.

[0762] MS(m / z): 324.1 [M+H] + .

[0763] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.40-7.96(m,3H),7.88(dd,J=8.6,2.2Hz,1H),7.26(d,J=8.6Hz,1H),3. 75-3.43(m,3H),3.34(s,3H),2.98(s,1H),2.83(s,3H),1.84-1.64(m,2H),1.51(s,1H),0.95(d,J=5.6Hz,6H).

[0764] Example 65: Synthesis of 1-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 65)

[0765]

[0766] The synthesis steps of compound 65 are as follows:

[0767]

[0768] Referring to steps 1 to 3 of the synthesis scheme in Example 20, simply replacing 2-bromo-5-iodobenzonitrile in step 1 with 4-bromo-2-fluoro-1-iodobenzene yields the target compound 1-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (101 mg), with a three-step yield of 33%.

[0769] MS (m / z): 303.2 [M+H] + .

[0770] 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),9.33(s,1H),7.95(s,2H),7.58(t,J=8.8Hz,1H),6.98-6.84(m,2H),3.87-3.78(m,2H) ,3.30(s,2H),3.22-3.01(m,2H),2.83(dd,J=13.4,10.6Hz,1H),1.93-1.84(m,1H),1.59-1.46(m,2H),0.93(t,J=6.4Hz,6H).

[0771] Example 66: Synthesis of 5-(6-(difluoromethyl)pyridin-3-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (compound 66)

[0772]

[0773] The synthesis steps of compound 66 are as follows:

[0774]

[0775] Referring to steps 1 to 3 of Example 20, only 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole in step 1 was replaced with (6-(difluoromethyl)pyridin-3-yl)boronic acid, thus obtaining the target compound 5-(6-(difluoromethyl)pyridin-3-yl)-2-(3-isobutylpiperazin-1-yl)benzonitrile (39 mg), with a three-step yield of 20%.

[0776] MS(m / z): 371.2 [M+H] + .

[0777] 1H NMR(400MHz, DMSO-d6)δ9.04(d,J=2.2Hz,1H),8.32(dd,J=8.2,2.4Hz,1H),8.23(d,J=2.4Hz,2H), 8.05(dd,J=8.8,2.4Hz,1H),7.78(d,J=8.2Hz,1H),7.32(d,J=8.8Hz,1H),7.02(t,J=55.0Hz,1H),3 .67-3.59(m,1H),3.52(d,J=8.6Hz,1H),3.19(dd,J=8.8,2.4Hz,1H),3.05(dd,J=28.0,7.8Hz,3H) ,2.68(dd,J=12.2,10.2Hz,1H),1.81-1.72(m,1H),1.42-1.29(m,2H),0.92(dd,J=7.8,6.6Hz,6H).

[0778] Example 67: Synthesis of 3-isobutyl-1-(2-methyl-6-(1H-pyrazol-4-yl)pyridin-3-yl)piperazine (compound 67)

[0779]

[0780] The synthesis steps of compound 67 are as follows:

[0781]

[0782] Referring to steps 1 to 3 of the synthesis scheme in Example 56, simply replacing 4-bromo-1-iodo-2-(trifluoromethyl)benzene in step 1 with 3-bromo-6-chloro-2-methylpyridine yields the target compound 3-isobutyl-1-(2-methyl-6-(1H-pyrazol-4-yl)pyridin-3-yl)piperazine (25 mg), with a three-step yield of 5%.

[0783] MS (m / z): 300.2 [M+H] + .

[0784] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.06(s,2H),7.49-7.33(m,2H),3.09-2.94(m,5H),2.71(t,J=10.4Hz,1H),2 .45(s,3H),2.40(d,J=10.8Hz,1H),1.74(dt,J=13.2,6.6Hz,1H),1.39-1.22(m,2H),0.89(dd,J=6.6,1.8Hz,6H).

[0785] Example 68: Synthesis of 4-fluoro-2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (compound 68)

[0786]

[0787] The synthesis steps of compound 68 are as follows:

[0788]

[0789] Referring to steps 1 to 3 of Example 56, only the 4-bromo-1-iodo-2-(trifluoromethyl)benzene in step 1 is replaced with 5-bromo-4-fluoro-2-iodobenzonitrile, thus obtaining the target compound 4-fluoro-2-(3-isobutylpiperazin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (20 mg), with a three-step yield of 10%.

[0790] MS (m / z): 328.2 [M+H] + .

[0791] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.17(d,J=8.6Hz,1H),8.08(s,2H),7.07(d,J=13.4Hz,1H),3.52-3.48(m,1H),3.44-3.35(m ,1H),3.11-3.01(m,1H),2.94-2.76(m,3H),2.49-2.42(m,1H),1.80-1.70(m,1H),1.34-1.16(m,2H),0.90(dd,J=8.8,6.4Hz,6H).

[0792] The synthetic route for compound 5-bromo-4-fluoro-2-iodobenzonitrile is as follows:

[0793]

[0794] 1-Bromo-2-fluoro-4-iodo-5-toluene (2 g, 6.4 mmol), tert-butyl nitrite (1.97 g, 19.1 mmol), palladium acetate (70 mg, 0.32 mmol), and NHPI (3.12 g, 19.1 mmol) dissolved in 30 mL of acetonitrile were added to a reaction flask. The mixture was heated to 70 °C under nitrogen protection and reacted for 24 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 5-bromo-4-fluoro-2-iodobenzonitrile (700 mg), yield 34%.

[0795] MS(m / z): 325.8[M+H]+.

[0796] Example 69: Synthesis of 3-isobutyl-1-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)piperazine (compound 69)

[0797]

[0798] The synthesis steps of compound 69 are as follows:

[0799]

[0800] Referring to steps 1 to 3 of the synthesis scheme in Example 20, simply replacing 2-bromo-5-iodobenzonitrile in step 1 with 1-bromo-4-iodo-2-toluene yields the target compound 3-isobutyl-1-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)piperazine (22 mg), with a three-step yield of 11%.

[0801] MS (m / z): 299.3 [M+H] + .

[0802] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.95(s,2H),7.49-7.32(m,2H),6.97(d,J=8.2Hz,1H),3.08(d,J=10.4Hz,5H),2.77- 2.64(m,1H),2.40(t,J=11.0Hz,1H),2.26(s,3H),1.72(dt,J=13.2,6.6Hz,1H),1.38-1.23(m,2H),0.89(d,J=6.4Hz,6H).

[0803] Example 70: Synthesis of 1-(3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (compound 70)

[0804]

[0805] The synthetic steps of compound 70 are as follows:

[0806]

[0807] Referring to steps 1 to 3 of the synthesis scheme in Example 20, simply replacing 2-bromo-5-iodobenzonitrile in step 1 with 4-bromo-2-(difluoromethyl)-1-iodobenzene yields the target compound 1-(3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3-isobutylpiperazine (84 mg), with a three-step yield of 48%.

[0808] MS (m / z): 335.2 [M+H] + .

[0809] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),7.73(s,2H),7.37(d,J=8.4Hz,1H),7.19(d,J=8.8Hz, 2H),6.92(t,J=54.8Hz,1H),3.75(dd,J=12.8,3.0Hz,2H),3.22(dt,J=12.4,2.8Hz,1H),3.1 6-3.11(m,1H),3.04(td,J=12.0,3.0Hz,1H),2.91(td,J=12.2,2.8Hz,1H),2.64(dd,J=12. 6,10.4Hz,1H),1.88-1.80(m,1H),1.43(td,J=7.0,2.8Hz,2H),0.92(dd,J=6.6,2.8Hz,6H).

[0810] Example 71: Synthesis of 3-(3-isobutylpiperazin-1-yl)-6-(1H-pyrazol-4-yl)pyridinenitrile (compound 71)

[0811]

[0812] The synthetic steps of compound 71 are as follows:

[0813]

[0814] Referring to steps 1 to 3 of the synthesis scheme in Example 20, simply replacing 2-bromo-5-iodobenzonitrile in step 1 with 3-bromo-6-iodopyridinium yields the target compound 3-(3-isobutylpiperazin-1-yl)-6-(1H-pyrazol-4-yl)pyridinium (55 mg), with a three-step yield of 18%.

[0815] MS(m / z): 311.0 [M+H] + .

[0816] 1H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.19(s,2H),7.92(d,J=8.8Hz,1H),7.68(d,J=8.8Hz,1H),3.51(dt,J=11.8,2.6Hz,1H),3.41(d,J=8.4Hz,1H) ,3.14(dd,J=9.0,2.6Hz,1H),3.07-2.89(m,3H),2.62(dd,J=12.0,10.0H z,1H),1.81-1.71(m,1H),1.38-1.23(m,2H),0.91(dd,J=7.8,6.6Hz,6H).

[0817] The synthetic route for compound 3-bromo-6-iodopyridinium is as follows:

[0818]

[0819] Step 1: Synthesis of 5-bromo-2-iodopyridine-1-oxide

[0820] In a reaction flask, 5-bromo-2-iodopyridine (2.84 g, 10.00 mmol) was dissolved in 40.0 mL of dichloromethane. The mixture was cooled to 0 °C in an ice bath, and then m-CPBA (3.45 g, 20.00 mmol) was added. The mixture was then transferred to 50 °C and reacted for 12 h. After the reaction was basically completed by TLC monitoring, the solid was removed by filtration. The filtrate was washed with 30 mL of saturated NaHCO3, and the aqueous phase was back-extracted with DCM (3 times, 30 mL each time). The combined organic phases were dried and evaporated to dryness to obtain compound 5-bromo-2-iodopyridine-1-oxide (1.50 g), with a yield of 50%.

[0821] MS (m / z): 299.9 [M+H] + .

[0822] Step 2: Synthesis of 3-bromo-6-iodopyridinium

[0823] In a reaction flask, 5-bromo-2-iodopyridine-1-oxide (1.50 g, 5.00 mmol), TMSCN (1.98 g, 20.00 mmol), and triethylamine (1.52 g, 15.0 mmol) were dissolved in 20 mL of acetonitrile. The reaction was carried out at 85 °C for 10 h, and the reaction was monitored by LC-MS. When the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 3-bromo-6-iodopyridine nitrile (510.0 mg), with a yield of 33%.

[0824] MS (m / z): 308.8 [M+H] + .

[0825] Example 72: Synthesis of 2-hydroxy-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (compound 72)

[0826]

[0827] The synthetic route for compound 72 is as follows:

[0828]

[0829] Step 1: Synthesis of 6-bromo-2-hydroxy-3-iodobenzonitrile (72-2)

[0830] 2-Bromo-6-hydroxybenzonitrile (396 mg, 2.00 mmol) was dissolved in a mixed solvent of 0.4 mL H₂SO₄ and 16 mL water, followed by the addition of KI (299 mg, 1.38 mmol) and KIO₃ (132.7 mg, 0.62 mmol). The reaction was carried out at room temperature for 16 h. After the reaction was completed by TLC monitoring, the mixture was extracted with dichloromethane, and the organic phases were combined and concentrated under vacuum. The organic phases were then purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 6-bromo-2-hydroxy-3-iodobenzonitrile (188 mg), with a yield of 29%.

[0831] MS (m / z): 321.8 [MH] - .

[0832] Step 2: Synthesis of 2-(benzyloxy)-6-bromo-3-iodobenzonitrile (72-3)

[0833] 6-Bromo-2-hydroxy-3-iodobenzonitrile (120 mg, 0.37 mmol), BnBr (95 mg, 0.55 mmol), and potassium carbonate (77 mg, 0.55 mmol) were dissolved in 10 mL of acetonitrile and reacted at 50 °C for 3 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2-(benzyloxy)-6-bromo-3-iodobenzonitrile (188 mg), in 100% yield.

[0834] MS (m / z): 414.2 [M+H] + .

[0835] Step 3: Synthesis of 2-(benzyloxy)-6-bromo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (72-4)

[0836] 2-(benzyloxy)-6-bromo-3-iodobenzonitrile (90 mg, 0.23 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (63 mg, 0.23 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (17 mg, 0.02 mmol) were dissolved in 5 mL of dioxane. Cesium carbonate (147 mg, 0.45 mmol) was dissolved in 1 mL of water and added to the reaction system. The reaction was carried out at 100 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 2-(benzyloxy)-6-bromo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (70 mg), yield 70%.

[0837] MS (m / z): 438.1 [M+H] + .

[0838] Step 4: Synthesis of 4-(3-(benzyloxy)-2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (72-5)

[0839] 2-(benzyloxy)-6-bromo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (190 mg, 0.43 mmol), intermediate M1 (113 mg, 0.47 mmol), tris(dibenzylacetone)palladium (39 mg, 0.04 mmol), XPhos (41 mg, 0.09 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in 10 mL of toluene. The mixture was heated to 110 °C under nitrogen protection and reacted for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4-(3-(benzyloxy)-2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (160 mg), yield 62%.

[0840] MS (m / z): 600.3 [M+H] + .

[0841] Step 5: Synthesis of 2-(benzyloxy)-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (72-6)

[0842] 160 mg (0.27 mmol) of 4-(3-(benzyloxy)-2-cyano-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester was dissolved in 4 mL of dichloromethane, followed by the addition of 4 mL of HCl / dioxane solution. The reaction was carried out at room temperature for 6 h. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under vacuum to give compound 2-(benzyloxy)-6-(3-isobutylpiperazine-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (112 mg), with a yield of 100%.

[0843] MS (m / z): 416.2 [M+H] + .

[0844] Step 6: Synthesis of 2-hydroxy-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazol-4-yl)benzonitrile (72)

[0845] 112 mg (0.27 mmol) of 2-(benzyloxy)-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazole-4-yl)benzonitrile (1H-2-yl) was dissolved in 410 mL of methanol, followed by the addition of 20 mg of Pd(OH)₂ / C and one drop of acetic acid. The reaction was carried out at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method B) to obtain the target compound 2-hydroxy-6-(3-isobutylpiperazin-1-yl)-3-(1H-pyrazole-4-yl)benzonitrile (36 mg), with a yield of 41%.

[0846] MS (m / z): 326.1 [M+H] + .

[0847] 1 H NMR (600MHz, DMSO-d6) δ8.00(s,2H),7.51(d,J=8.2Hz,1H),6.31(d,J=8.2Hz,1H),3.40(d,J=11.8Hz,1H),3.30-3.24(m,1H),3.10-3.04(m,1H ),2.97-2.90(m,2H),2.75(td,J=11.6,2.8Hz,1H),2.40(t,J=10.8Hz,1H),1.73-1.66(m,1H),1.31-1.21(m,2H),0.87(dd,J=15.2,6.6Hz,6H).

[0848] Example 73: Synthesis of 3-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (compound 73)

[0849]

[0850] The synthetic route for compound 73 is as follows:

[0851]

[0852] Step 1: Synthesis of 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-2)

[0853] 6-Bromo-3-fluoropyridinecarboxaldehyde (100 mg, 0.49 mmol), 2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (154 mg, 0.64 mmol), DIPEA (253 mg, 1.96 mmol), and 10 mL of acetonitrile were added to a reaction flask. The mixture was heated to 80 °C and reacted overnight. The reaction was monitored by LC-MS. When the reaction was substantially complete, the reaction solution was concentrated under vacuum to give compound 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg), yield 96%.

[0854] MS (m / z): 426.1 [M+H] + .

[0855] Step 2: Synthesis of 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-3)

[0856] 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.47 mmol) and 10 mL of DCM were added to a reaction flask. After cooling the reaction to 0 °C, DAST (228 mg, 1.41 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for three hours, and the reaction was monitored by LC-MS. When the reaction was substantially complete, the reaction solution was concentrated under vacuum to obtain compound 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (240 mg), with a yield of 98%.

[0857] MS (m / z): 448.1 [M+H] + .

[0858] Step 3: Synthesis of 4-(6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-4)

[0859] Add 80 mg (0.18 mmol) of 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 60 mg (0.18 mmol) of 1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg (0.018 mmol)) and 5 mL of 1,4-dioxane to the reaction flask. Then, dissolve 1 mL of cesium carbonate (118 mg (0.36 mmol) in water and slowly add it dropwise to the reaction system. After the addition is complete, the reaction is heated to 105 °C under nitrogen protection and reacted overnight. The reaction is monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-(6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80 mg), yield 77%.

[0860] MS (m / z): 576.2 [M+H] + .

[0861] Step 4: Synthesis of 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-5)

[0862] 4-(6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) and 2 mL of DMSO were added to a reaction flask, followed by 1 mL of (1 M) potassium tert-butoxide tetrahydrofuran solution. The reaction was carried out at room temperature under an oxygen atmosphere for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, 5 mL of water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (10 mL each time, twice). The organic phases were combined. Subsequently, the organic phase was concentrated under vacuum to give compound 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (65 mg), yield 96%.

[0863] MS (m / z): 486.2 [M+H] + .

[0864] Step 5: Synthesis of 3-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (73)

[0865] 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (65 mg, 0.134 mmol), 5 mL of dichloromethane, and 1 mL of HCl / dioxane solution were added to a reaction flask. The reaction was carried out overnight at room temperature, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was concentrated under vacuum, and the compound 3-(6-(difluoromethyl)-5-(3-isobutylpiperazine-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (65 mg) was obtained by preparative liquid chromatography (Method B), with a yield of 18%.

[0866] MS (m / z): 386.2 [M+H] + .

[0867] 1 H NMR (600MHz, DMSO-d6) δ12.09(d,J=2.8Hz,1H),8.85(dd,J=8.0,1.6Hz,1H),8.31(d,J=2. 8Hz,1H),8.29(dd,J=4.6,1.6Hz,1H),8.06(d,J=8.6Hz,1H),7.81(d,J=8.6Hz,1H),7.34(t ,J=54.2Hz,1H),7.21(dd,J=7.8,4.6Hz,1H),3.30-3.20(m,3H),3.16-3.05(m,3H),2.84(d d,J=12.4,10.1Hz,1H),1.76-1.69(m,1H),1.52-1.41(m,2H),0.91(dd,J=6.4,1.4Hz,6H).

[0868] Example 74: Synthesis of 4-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (compound 74)

[0869]

[0870] The synthetic route for compound 74 is as follows:

[0871]

[0872] Step 1: Synthesis of 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-2)

[0873] 6-Bromo-3-fluoropyridinecarboxaldehyde (100 mg, 0.49 mmol), intermediate M1 (154 mg, 0.64 mmol), DIPEA (253 mg, 1.96 mmol), and 10 mL of acetonitrile were added to a reaction flask. The mixture was heated to 80 °C and reacted for 16 h, with the reaction monitored by LC-MS. After the reaction was substantially complete, the mixture was concentrated under vacuum to give 200 mg of 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, with a yield of 96%.

[0874] MS (m / z): 426.1 [M+H] + .

[0875] Step 2: Synthesis of 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (73-3)

[0876] 4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.47 mmol) and 10 mL of DCM were added to a reaction flask. The reaction was cooled to 0 °C, and then DAST (228 mg, 1.41 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for three hours, and the reaction was monitored by LC-MS. When the reaction was substantially complete, the mixture was concentrated under vacuum to give 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg), with a yield of 98%.

[0877] MS (m / z): 448.1 [M+H] + .

[0878] Step 3: Synthesis of 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (74-1)

[0879] Add 80 mg (0.18 mmol) of 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine (44 mg, 0.18 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 0.018 mmol), and 5 mL of 1,4-dioxane to the reaction flask. Dissolve 118 mg (0.36 mmol) of cesium carbonate in 1 mL of water and slowly add it dropwise to the reaction solution. The reaction was carried out at 105 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (MeOH:DCM = 10:1) to obtain tert-butyl 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid (37 mg), yield 42%.

[0880] MS (m / z): 486.2 [M+H] + .

[0881] Step 4: Synthesis of 4-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (74)

[0882] 37 mg (0.076 mmol) of 4-(2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 5 mL of dichloromethane, and 0.5 mL of HCl / dioxane solution were added to a reaction flask, and the reaction was carried out overnight at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method B) to obtain compound 4-(6-(difluoromethyl)-5-(3-isobutylpiperazine-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (5.5 mg), yield 19%.

[0883] MS (m / z): 386.2 [M+H] + .

[0884] 1H NMR(600MHz,DMSO-d6)δ11.80(s,1H),8.33(d,J=5.0Hz,1H),8.25(d,J=8.6Hz,1H),7 .88(d,J=8.6Hz,1H),7.61(d,J=5.0Hz,1H),7.59(t,J=3.0Hz,1H),7.30(t,J=54.0Hz, 1H),7.14(dd,J=3.4,1.8Hz,1H),3.15-3.02(m,5H),2.97-2.90(m,1H),2.62(t,J=11 .0Hz,1H),1.72(dt,J=13.6,6.8Hz,1H),1.31(d,J=6.8Hz,2H),0.91(t,J=6.4Hz,6H).

[0885] Example 75: Synthesis of 6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)-[2,4'-bipyridine]-2'(1'H)-one (compound 76)

[0886]

[0887] The synthetic route for compound 76 is as follows:

[0888]

[0889] Referring to steps 1 to 3 and 5 of the synthetic scheme in Example 73, only 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrrolo[2,3-b]pyridine in step 3 was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine-2(1H)-one to obtain the target compound 6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)-[2,4'-bipyridine]-2'(1'H)-one (5.5 mg), with a four-step yield of 48%.

[0890] MS(m / z): 363.2 [M+H] + .

[0891] 1H NMR (600MHz, DMSO-d6) δ11.79(s,1H),8.75(d,J=10.8Hz,1H),8.20(d,J=8.6Hz,1H),7.91(d,J=8.6Hz,1H),7.50(d ,J=6.8Hz,1H),7.31(t,J=53.6Hz,1H),7.03(d,J=1.8Hz,1H),6.89(dd,J=6.8,1.8Hz,1H),3.50(d,J=8.8Hz,1H),3 .42(dt,J=12.6,2.6Hz,1H),3.39-3.32(m,1H),3.31-3.26(m,1H),3.25-3.19(m,1H),3.12(td,J=12.8,12.2,2.8H z,1H),2.90(dd,J=12.8,10.2Hz,1H),1.70(dt,J=13.4,6.6Hz,1H),1.49-1.44(m,2H),0.92(dd,J=6.4,3.0Hz,6H).

[0892] Example 76: Synthesis of (R)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (compound 80)

[0893]

[0894] The synthetic route for compound 80 is as follows:

[0895]

[0896] Step 1: Synthesis of (R)-4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80-2)

[0897] 6-Bromo-3-fluoropyridinecarboxaldehyde (100 mg, 0.49 mmol), (R)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (154 mg, 0.64 mmol), DIPEA (253 mg, 1.96 mmol), and 10 mL of acetonitrile were added to a reaction flask. The mixture was heated to 80 °C and reacted for 16 h. The reaction was monitored by LC-MS. When the reaction was substantially complete, the reaction solution was concentrated under vacuum to give compound (R)-4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg), with a yield of 96%.

[0898] MS (m / z): 426.1 [M+H] + .

[0899] Step 2: Synthesis of (R)-4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80-3)

[0900] (R)-4-(6-bromo-2-formylpyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.47 mmol) and 10 mL of DCM were added to a reaction flask. The reaction was cooled to 0 °C, and then DAST (228 mg, 1.41 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for three hours, and the reaction was monitored by LC-MS. When the reaction was substantially complete, the reaction solution was concentrated under vacuum to obtain compound (R)-4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (127 mg), with a yield of 60%.

[0901] MS (m / z): 448.1 [M+H] + .

[0902] Step 3: Synthesis of (2R)-4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80-4)

[0903] Add (R)-4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (80.0 mg, 0.18 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (50.0 mg, 0.18 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (13.0 mg, 0.018 mmol), and 5 mL of 1,4-dioxane to the reaction flask. Then, dissolve cesium carbonate (118.0 mg, 0.36 mmol) in 1 mL of water and slowly add it dropwise to the reaction flask. After the addition is complete, heat to 100 °C under nitrogen protection and react overnight. Monitor the reaction by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound (2R)-4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (38 mg), yield 41%.

[0904] MS (m / z): 520.2 [M+H] + .

[0905] Step 4: Synthesis of (R)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (80)

[0906] (2R)-4-(2-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester (38 mg, 0.07 mmol), 5 mL of dichloromethane, and 1 mL of HCl / dioxane solution were added to a reaction flask, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under vacuum, and the compound (R)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (15.0 mg) was obtained by preparative liquid chromatography (Method B), with a yield of 61% and ee = 99.36%.

[0907] MS (m / z): 336.1 [M+H] + .

[0908] 1 H NMR(600MHz,DMSO-d6)δ9.47(d,J=10.8Hz,1H),9.26(d,J=10.8Hz,1H),8.19(s,2H), 7.86(d,J=8.6Hz,1H),7.80(d,J=8.6Hz,1H),7.28(t,J=54.0Hz,1H),3.49-3.43(m,1 H),3.34(dt,J=12.4,2.8Hz,1H),3.31-3.25(m,1H),3.17-3.13(m,2H),2.90(dd,J=1 2.7,10.2Hz,1H),1.75-1.68(m,1H),1.57-1.47(m,2H),0.91(dd,J=6.6,4.4Hz,6H).

[0909] Example 77: Synthesis of (S)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (compound 81)

[0910]

[0911] The synthetic route for compound 81 is as follows:

[0912]

[0913] Referring to steps 1 to 4 of the synthesis scheme in Example 76, simply replacing (R)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester with (S)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester in step 1 yields compound (S)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (58 mg), with a four-step yield of 15% and ee = 93.74%.

[0914] The obtained compound (ee = 93.74%) was chirally resolved using a Gilson GX-271 preparative liquid chromatography system. The resolution method was a YMC CHIRAL ART Amylose-C column (50*250mm-10μm); mobile phase: A = n-hexane + 0.1% diethylamine, mobile phase B = ethanol; operation: 70% mobile phase A; flow rate = 24mL / min; λ = 210 / 254nm; column temperature = 25℃; circulation time = 60min, and the fraction with a retention time of 24min was collected for separation. After separation, the fraction was concentrated and dried under vacuum to obtain the target compound (S)-1-(2-(difluoromethyl)-6-(1H-pyrazol-4-yl)pyridin-3-yl)-3-isobutylpiperazine (42mg), yield 72%, ee = 99.88%.

[0915] MS (m / z): 336.1 [M+H] + .

[0916] 1 H NMR(600MHz,DMSO-d6)δ13.09(s,1H),8.14(s,2H),7.81(d,J=8.6Hz,1H),7.7 3(d,J=8.6Hz,1H),7.17(t,J=54.3Hz,1H),2.98(dt,J=12.0,3.0Hz,1H),2.95 -2.84(m,4H),2.76(dd,J=10.8,3.2Hz,1H),2.43(t,J=10.8Hz,1H),1.76-1.6 5(m,1H),1.30-1.22(m,2H),1.17(dt,J=13.6,6.8Hz,1H),0.91-0.83(m,6H).

[0917] Example 78: Synthesis of 4-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-3-amine (compound 101)

[0918]

[0919] The synthetic route for compound 101 is as follows:

[0920]

[0921] Step 1: Synthesis of N-(4-bromo-1H-pyrazol-3-yl)acetamide (101-2)

[0922] 4-Bromo-1H-pyrazole-3-amine (1.0 g, 6.17 mmol), K₂CO₃ (3.0 g, 21.61 mmol), and 20 mL of acetonitrile were added to a reaction flask, and the mixture was cooled to 0 °C in an ice bath. Acetyl chloride (1.45 g, 18.52 mmol) was then added dropwise to the reaction flask. After the addition was complete, the reaction system was heated to 80 °C and reacted for 3 h, monitored by LC-MS. When the reaction was essentially complete, the reaction solution was concentrated under vacuum and subjected to column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain the product N-(4-bromo-1H-pyrazole-3-yl)acetamide (1.23 g), with a yield of 95%.

[0923] MS(m / z): 204.1 [M+H] + .

[0924] Step 2: Synthesis of (N-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetamide (101-3)

[0925] N-(4-bromo-1H-pyrazol-3-yl)acetamide (1.23 g, 6.03 mmol), 15 mL of 2,6-dihydropyran, and then 3 drops of trifluoroacetic acid were added to a reaction flask. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by LC-MS. When the reaction was basically completed, the reaction solution was concentrated under vacuum and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to give the product (N-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetamide (1.70 g), yield 95%).

[0926] MS(m / z): 288.1 [M+H] + .

[0927] Step 3: Synthesis of N-(1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-3-yl)acetamide (101-4)

[0928] Add (N-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetamide (1.5 g, 5.21 mmol), pinacol diboronate (1.45 g, 5.73 mmol), potassium acetate (1.53 g, 15.63 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.38 g, 0.52 mmol), and 10 mL of 1,4-dioxane to the reaction flask. Under nitrogen protection, heat the reaction solution to 80 °C and react for 6 h. Monitor the reaction by LC-MS. After the reaction is complete, concentrate the reaction solution under vacuum to obtain the crude product, which is then directly transferred to the next step.

[0929] MS (m / z): 336.2 [M+H] + .

[0930] Step 4: Synthesis of tert-butyl 4-(6-(3-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylate (101-5)

[0931] Add 0.3 g (0.67 mmol) of 4-(6-bromo-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 0.27 g (0.80 mmol) of N-(1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-3-yl)acetamide, 50.0 mg (0.07 mmol) of 1,1-bis(diphenylphosphine)ferrocene palladium dichloride, and 8 mL of 1,4-dioxane to the reaction flask. Then dissolve 0.44 g (1.34 mmol) in 1 mL of water and add it to the reaction flask. Under nitrogen protection, heat the reaction solution to 100 °C and react for 12 h. Monitor the reaction by LC-MS. After the reaction was complete, the reaction solution was concentrated under vacuum and subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to give the product tert-butyl 4-(6-(3-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylate (0.2 g), with a yield of 52%.

[0932] MS (m / z): 577.3 [M+H] + .

[0933] Step 5: Synthesis of 4-(6-(difluoromethyl)-5-(3-isobutylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-3-amine (101)

[0934] 0.2 g (0.34 mmol) of 4-(6-(3-acetamido-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester, 10 mL of ethanol, 10 mL of 2M HCl solution, and the reaction was carried out at 60 °C for 6 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by preparative liquid chromatography (Method B) to obtain compound 4-(6-(difluoromethyl)-5-(3-isobutylpiperazine-1-yl)pyridin-2-yl)-1H-pyrazol-3-amine (45.0 mg), yield 20%.

[0935] MS (m / z): 351.2 [M+H] + .

[0936] 1 H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.94(s,1H),7.70(s,2H),7.21(t,J=54.4Hz,1H),5.98(s,2H),3.08-2. 96(m,3H),2.93-2.80(m,3H),2.54(s,1H),1.71-1.67(m,1H),1.30-1.24(m,2H),0.88(dd,J=6.6,4.8Hz,6H).

[0937] Comparative Example 1: Synthesis of (S)-2',6-bisdifluoromethyl-5-(3-isobutylpiperazin-1-yl)-2,4'-bipyridine

[0938]

[0939] The synthetic route of compound 1 in Comparative Example 1 is as follows:

[0940]

[0941] Referring to steps 1 to 4 of the synthesis scheme in Example 76, replacing 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole with (2-(difluoromethyl)pyridin-4-yl)boronic acid yields compound (S)-2',6-bisdifluoromethyl-5-(3-isobutylpiperazin-1-yl)-2,4'-bipyridine (30 mg), with a four-step yield of 12% and ee = 98.72%.

[0942] MS (m / z): 397.2 [M+H] + .

[0943] 1H NMR (600MHz, DMSO-d6) δ8.58(d,J=5.4Hz,1H),7.89-7.85(m,1H),7.72(d,J=8.2Hz,1H),7.70-7.66m,1H),7.40-7.33 (m,2H),3.54-3.44(m,3H),3.30-3.10(m,2H),3.03-1.99(m,2H),1.97-1.91(m,1H),1.69-1.50(m,2H),1.39-1.35(m 1H),0.91(d,J=6.7,6H).

[0944] Biological experiments

[0945] Example 1: ADP-Glo ​​assay for detecting the inhibitory effect of a compound on AAK1 kinase activity.

[0946] Preparation of kinase buffer

[0947]

[0948] The test compound was dissolved in DMSO (MP Biomedicals, 196055) to prepare a 10 mM stock solution. The compound was then diluted 200-fold with DMSO to the highest concentration gradient, followed by 3-fold serial dilutions until eight concentration gradients were achieved. The series of compounds were then diluted 5-fold with 1× kinase buffer and added to 384-well plates (SPLlifescience, 32384) (1 μL / well). AAK1 recombinant human protein (Invitrogen, A30967) was prepared to a 2.5-fold final concentration with 1× kinase buffer and added to 384-well plates (2 μL / well). ATP (Promega, V915A) and AAK1 substrate (KR-18) (GL) were then added. Biochem (929398) prepared a 2.5-fold final concentration mixed solution using 1× kinase buffer and added it to a 384-well plate (2 μL / well). The 384-well plate was centrifuged at 1000 rpm for 1 min using a centrifuge (Hunan Xiangyi, TDZ5-WS) and the catalytic reaction was allowed to proceed for 4 h. Then, 5 μL of ADP-Glo ​​was added. TM After adding the reagent (Promega, V912A), centrifuge at 1000 rpm for 1 min, incubate at room temperature for 60 min to terminate the kinase reaction and consume the remaining ATP. Then add 10 μL of kinase assay (Promega, V9101), centrifuge at 1000 rpm for 1 min, incubate at room temperature for 30 min, and place in a multi-functional microplate reader (TECAN, SPARK) to detect the luminescence signal.

[0949]

[0950] Fit curves and calculate IC using GraphPad 9.0 50 The values, a, b, c, and d in the table below, represent the IC values ​​of compounds. 50 The value range, i.e., a≤50nM, 50 <b≤100nM、100<c≤500nM、500nM<d。

[0951] Table 1. Inhibitory activity of AAK1 kinase

[0952] Compound No. IC 50 ]]> Compound 10 a Compound 11 a Compound 12 b Compound 20 a Compound 23 a Compound 41 a Compound 47 a Compound 52 b Compound 53 a Compound 55 a Compound 56 a Compound 57 b Compound 60 b Compound 64 a Compound 67 a Compound 68 a Compound 69 a Compound 71 a Compound 74 a Compound 75 a Compound 80 a Compound 81 a Compound 101 a Comparative Example 1 d Control Compound LX9211 a

[0953] Example 2: Evaluation of the toxicity of the compound to human liver cancer cells.

[0954] Human hepatocellular carcinoma cells HepG2 were cultured in DMEM medium (gibco, C11995500BT) containing 10% FBS. When the cells were in good growth condition, they were seeded into 96-well plates at a density of 4000 cells / well and 100 μL / well and incubated overnight at 37°C in a 5% CO2 incubator.

[0955] Add serially diluted test compound or DMSO (MP Biomedicals, 196055) to each well. Set up a blank control with uninoculated cells and culture medium. Incubate at 37°C, 5% CO2 for 72 hours. Following the SRB (BioBio, BB-4208-1000T) instructions, remove the 96-well plate from the culture medium. Carefully add 50 μL of fixative to the surface of the culture medium, let stand for 5 minutes, then place in a 4°C freezer for 1 hour. Discard the fixative. Wash each well once with 100 μL of washing buffer, then wash three times with pure water. Dry at room temperature. Add 50 μL of staining solution to each well, stain at room temperature with shaking in the dark for 15 minutes, then discard the staining solution. Add 100 μL of washing solution D to each well, wash 5–10 times until the staining solution is removed, and dry at room temperature. Add 100 μL of dissolving solution to each well, shake at room temperature with shaking in the dark for 5 minutes. Measure the absorbance at 515 nm using a microplate reader (TECAN, SPARK). The results are shown in Table 3.

[0956]

[0957] The structure of the reference compound LX9211 is as follows:

[0958]

[0959] LX9211 was prepared according to Example 123 of the reference patent CN106458994B.

[0960] Table 3. Inhibitory activity of the tested compounds against HepG2 cells at 10 μM.

[0961] Compound No. Inhibition Rate (%) Control Compound LX9211 90.86 Compound 11 48.67 Compound 20 60.46 Compound 53 49.67 Compound 55 44.00 Compound 57 50.30 Compound 58 60.17

[0962] Experimental results show that, compared with the control compound LX9211, the compound of the present invention has a lower ability to inhibit HepG2 proliferation and less toxicity at the cellular level.

[0963] Example 3: Evaluation of the mechanical analgesia effect of the compound on diabetic peripheral neuropathy pain (DPNP) rats.

[0964] SD rats were purchased from Zhejiang Vitonlihua Laboratory Animal Technology Co., Ltd. The rats were acclimatized for one week before the model was established. The specific establishment method is as follows:

[0965] 1. Measure the blood glucose level of rats and perform mechanical pain threshold test before modeling. Animals with normal blood glucose level (blood glucose level <10 mmol / L) and normal mechanical pain threshold (selected 15g < mechanical pain threshold <50g) were grouped according to the mechanical pain threshold before modeling, into normal control group and model rat group.

[0966] 2. Rats were fasted for 12 hours but allowed free access to water. The model rats were then induced to develop diabetes by a single intraperitoneal injection of streptozotocin (STZ) 60 mg / kg. The Normal group was given an equal volume of citrate-sodium citrate buffer (pH 4.2).

[0967] 3. One week after STZ injection, blood glucose was measured from the tail vein of rats 2 hours after a meal, and mechanical pain threshold was tested after modeling.

[0968] 4. Successful model establishment criteria: blood glucose level greater than 16 mmol / L, and mechanical pain threshold significantly reduced after modeling compared to before modeling (P<0.05).

[0969] Rats were randomly divided into four groups (n=3 per group) according to their mechanical pain threshold after modeling: model group, LX9211 group (3 mg / kg), compound 20 group (1 mg / kg), and compound 20 group (3 mg / kg). The analgesic efficacy was evaluated against the normal group (N=3). The normal group and model group were given an equal volume of solvent (pure water), while the LX9211 group (3 mg / kg), compound 20 group (1 mg / kg), and compound 20 group (3 mg / kg) were given equal volumes of the corresponding drug concentrations. The mechanical pain threshold of the rats was tested at 1.5, 3.5, and 5.5 hours after drug administration.

[0970] Results and Discussion: See below for results. Figure 1At 1.5, 3.5, and 5.5 hours after a single dose, compared with the Model group, 3 mg / kg LX9211 and 1 and 3 mg / kg compound 20 effectively increased the pain threshold in DPNP-induced rats. 1 mg / kg compound 20 showed superior analgesic efficacy compared to 3 mg / kg LX9211 at all time points and maintained significant analgesic efficacy from 3.5 to 5.5 hours post-drug administration, achieving the mechanical pain threshold level of the Normal group. In contrast, the efficacy of 3 mg / kg compound 20 tended to stabilize within the 1.5 to 5.5 hour post-drug administration range, with a faster onset of action than 3 mg / kg LX9211 at 1.5 hours and a faster efficacy from 1.5 to 5.5 hours post-drug administration. These data indicate that compound 20 has superior analgesic activity compared to LX9211.

[0971] Example 4: Evaluation of the compound's thermal analgesia effect on rats with chronic sciatic nerve compression injury (CCI).

[0972] SD rats purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. were used to establish the model after one week of acclimatization. The specific establishment method is as follows:

[0973] 1. Disinfect surgical instruments and 5-0 sutures.

[0974] 2. The experimental animals were anesthetized and placed in a prone position on the operating table.

[0975] 3. Shave the fur from the outer side of one hind limb to the femur area of ​​the animal, and disinfect with iodine solution.

[0976] 4. Incise the skin, separate the fascia, bluntly dissect the biceps femoris muscle to expose the sciatic nerve, and gently dissect the sciatic nerve at the main trunk anterior to the trigeminal branch of the sciatic nerve.

[0977] 5. Gently ligate the sciatic nerve four times with 5-0 sutures, each 1 mm apart. The tightness of the ligation should be such that the calf muscle or toes twitch slightly when the first ligation is tightened. Four rats were randomly selected as the sham-operated group, in which only the sciatic nerve was exposed without ligation.

[0978] 6. Suture the muscles, subcutaneous tissue, and skin in sequence, clean the wound, and disinfect it with iodine solution.

[0979] 7. The hallmark of successful model establishment: a significant reduction in the pain threshold.

[0980] On day 7 after modeling, the paw heat pain response time of the model rats was measured. Rats with stable heat pain response times were randomly divided into three groups of four each: the model group, the LX9211 group (10 mg / kg), and the compound 53 group (3 mg / kg). The analgesic efficacy of the compound 53 was evaluated in comparison to the sham-operated group (N=4). The sham-operated group and the model group received the same volume of solvent, while the LX9211 group and the compound 53 group (3 mg / kg) received the same volume of the corresponding drug concentration. The heat pain response time was measured at 1.5, 3.5, and 5.5 hours after administration. Positive reactions included licking paws, stomping feet, jumping, and escaping the hot plate.

[0981] Results and Discussion: See below for results. Figure 2 At 1.5, 3.5, and 5.5 hours after a single administration, compared with the model group, both 10 mg / kg LX9211 and 3 mg / kg compound 53 effectively increased the thermal pain response time in CCI rats, indicating an increase in the thermal pain threshold. The analgesic efficacy of 10 mg / kg LX9211 reached its peak at 3.5 hours post-administration, after which the efficacy declined. In contrast, the analgesic efficacy of 3 mg / kg compound 53 reached its peak at 1.5 hours post-administration, and its efficacy remained stable between 1.5 and 5.5 hours, demonstrating superior efficacy compared to LX9211 during this period. These data indicate that compound 53 exhibits superior analgesic activity compared to LX9211.

Claims

1. A compound of Formula I: or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof. wherein said ring A is selected from C 6-18 aryl or 5-18 membered heteroaryl, said C 6-18 aryl or 5-18 membered heteroaryl can be optionally further substituted by one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said ring B is selected from wherein "*" represents the point of attachment to the the point of attachment to the structure and "**" represents the point of attachment to ring A; said ring B is optionally substituted with one or more substituents selected from the group consisting of H, cyano, hydroxy, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2; each R is independently selected from H, hydroxyl, C b each R is independently selected from H, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; the m is selected from 1 or 2; and the compound represented by formula I is not:

2. The compound of claim 1, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein, In the formula I, ring B is selected from 3. The compound of claim 2, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. the compound is a compound of Formula II: or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof. wherein ring A is selected from C 6-18 aryl or 5-18 membered heteroaryl, said C 6-18 aryl or 5-18 membered heteroaryl can be optionally substituted with one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; the m is selected from 1 or 2; the X1is selected from N or CR4; the X2is selected from N or CR5; the X3is selected from N or CR6; the X4is selected from N or CR7; R4, R5, R6, R7are each independently selected from the group consisting of H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

4. The compound of claim 3, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. the compound is selected from a compound of Formula (IIA), (IIB), or (IIC), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt of Formula (IIA), (IIB), (IIC), wherein ring A is selected from C 6-18 aryl or 5-18 membered heteroaryl, said C 6-18 aryl or 5-18 membered heteroaryl can be optionally substituted with one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; the m is selected from 1 or 2; R4, R5, R6, R7are each independently selected from the group consisting of H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

5. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein, when the compound is a compound of Formula IIA-1, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, said ring A is selected from pyrazolyl, which can be optionally substituted with one or more R a each R a each independently selected from H, oxo, hydroxy, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R6, R7are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

6. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein, when the compound is a compound of Formula IIB-1, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, said ring A is selected from pyrazolyl, which can be optionally substituted with one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R6are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

7. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein, when the compound is a compound of Formula IIC-1, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, said ring A is selected from pyrazolyl, which can be optionally substituted with one or more R a each R a each independently selected from H, oxo, hydroxy, amino, cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R7are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

8. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein, when the compound is a compound of Formula IIA-2, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, said ring A is selected from and ring A can be optionally substituted with one or more R a each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R6, R7are each independently selected from the group consisting of H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

9. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein, the compound is a compound of Formula IIB-2, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from and ring A can be optionally substituted with one or more R a ; each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R6are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

10. The compound of any one of claims 1-4, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein, the compound is a compound of Formula IIC-2, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from and ring A can be optionally substituted with one or more R a ; each R a is independently selected from H, oxo, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R1is selected from H, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; said R2is selected from H, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; said R3is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R4, R5, R7are each independently selected from H, cyano, hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R b )2, nitro, -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , or -C 0-3 alkylene-C(=O)N(R b )2, each R b is independently selected from H, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

11. A compound of Formula I: or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof. or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition, characterized by, The pharmaceutical composition contains a therapeutically effective amount of a compound of any one of claims 1-11 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof.

13. Use of a compound of any one of claims 1-11 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 12 in the manufacture of a medicament for the treatment and / or prevention of a disease mediated by AAK1, or a disease caused by viral infection.

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