Nitrogen heterocyclic compounds as AAK1 inhibitors

Abstract

The present invention relates to the use of nitrogen-containing heterocyclic compounds that inhibit connexin-related kinase 1 (AAK1 kinase) activity, or pharmaceutically acceptable salts thereof, in drugs for treating or preventing diseases or disorders mediated by AAK1 activity. Specifically, the present invention provides compounds represented by formula I, their stereoisomers, or pharmaceutically acceptable salts, where the definitions of each group are as described in the specification. The compounds of the present invention have relatively high AAK1 inhibitory activity. TIFF2026515688000043.tif45170

Description

Technical Field

[0001] The present invention belongs to the field of drugs, and specifically relates to nitrogen-containing heterocyclic compounds capable of inhibiting the activity of adaptor associated kinase 1 (AAK1), compositions of the above compounds, and their use in the preparation of drugs for treating diseases or disorders mediated by the activity of adaptor associated kinase 1.

Background Art

[0002] Adaptor associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two splice forms called short form and long form. The long form is dominant and highly expressed in the brain and heart (Henderson and Conner, Mol. Biol (Cell 2007, 18, 2698-2706). AAK1 is abundant in synaptosomal preparations and co-localizes with endocytosis structures in cultured cells. AAK1 regulates clatherin-coated endocytosis, a crucial process in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 binds to the AP2 complex, a heterotetramer that links the receptor cargo to the clatherin coating. When clatherin binds to AAK1, AAK1 kinase activity is stimulated (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J Cell Biol 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, thereby promoting the binding of mu-2 to the tyrosine-containing sorting motif on the cargo receptor (Ricotta et.al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Although phosphorylation of mu2 is not essential for receptor uptake, it improves the efficiency of internalization (Motely et.al., Mol. Bio. Cell. 2006, 17, 5298-5308).

[0003] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. RNA interference-mediated gene silencing, or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity), leads to the loss of AAK1 expression and enhanced neuregulin-1-induced neurite outgrowth. These treatments increase ErbB4 expression and lead to increased accumulation of ErbB4 within or near the cell membrane (Kuai et al., Chemistry and Biology 2011, 18, 891-906). NRG1 and ErbB4 are considered to be susceptibility genes (putative) (Buonanno, Brain Res. Bull 2010, 83, 122-131). SNPs in both genes are associated with multiple endophenotypes of schizophrenia (Greenwood et., Am.J. Psychiatry 2011, 168, 930-946). Neuroregulin 1 and ErbB4 knockout mouse models have shown morphological changes and behavioral phenotypes associated with schizophrenia (Jaaro-Peled et., Schizophrenia Bulletin 2010, 36, 301-313; Wenet). (al., Proc. Natl. Acad. Sci. USA. 2010, 107, 1211-1216). Furthermore, single nucleotide polymorphisms in the intron of the AAK1 gene are associated with the age of onset of Parkinson's disease (Latou relle et. al., BMC Med. Genet. 2009, 10, 98). Our results suggest that inhibiting AAK1 activity may be effective in treating schizophrenia, cognitive deficits within schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease.

[0004] Many AAK1 inhibitor compounds are disclosed in literature such as CN106458994A, CN108290843A, and WO2023284838A, and the compound BMS-986176 / LX-9211, which inhibits AAK1 activity, is disclosed in J. Med. Chem. 2022, 65, 4457-4480. [Overview of the project] [Problems that the invention aims to solve]

[0005] As a result of extensive research, the inventors have discovered that the compounds provided by the present invention, their stereoisomers, or pharmaceutically acceptable salts possess potent AAK1 inhibitory activity, overcoming the shortcomings of AAK1 inhibitory activity in the prior art. The nitrogen-containing heterocyclic compounds provided by the present invention exhibit excellent inhibitory activity against AAK1. [Means for solving the problem]

[0006] The present invention solves the above technical problems by the following technical solutions.

[0007] In one embodiment, the present invention provides a compound represented by formula I, its stereoisomers, or pharmaceutically acceptable salts. [ka] (Here, X1, X2, and X3 are each independently selected from N or CR2. Ring A is, [ka] Selected from, R1, R2, and R3 are independently hydrogen, amino, -CO2H, halogen, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carbamoyl, and C. 1~6 alkyl, deuterated C 1~6Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy, deuterated C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, hydroxy C 1~6 Alkyl, C 3~6 Selected from 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from cycloalkyl, N, S, O R4, R5, and R6 are each independently hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkenyl, fluoromethyl, difluoromethyl, trifluoromethyl, C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, deuterated C 1~6 Alkyl, deuterated C 1~6 Alkoxy, C 3~6 Cycloalkyl, hydroxy C 1~6 Selected from 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from cycloalkyl, N, S, O Alternatively, R4 and R5, together with the carbon atoms to which they are attached, form C 3~6 Selected from 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from cycloalkyl, N, S, O or form a double bond n is selected from 0, 1, 2, 3, 4; when n is greater than 1, R1 may be the same or different.) As a preferred technical solution, R1 is selected from hydrogen, fluorine, chlorine, -CO2H, cyano, methoxy, methyl, difluoromethyl, trifluoromethyl, carbamoyl.

[0008] As a preferred technical solution, R2 is selected from hydrogen, methyl, cyano, difluoromethyl, trifluoromethyl, cyclopropyl.

[0009] As a preferred technical solution, R3 is selected from methyl, and R4, R5, and R6 are each independently selected from 4-6 membered heterocycloalkyls containing 1-3 heteroatoms selected from hydrogen, methyl, halogen, alkenyl, N, S, and O.

[0010] A preferred technical solution is that R4 and R5, together with the carbon atoms they link to, form a 4-6 membered heterocycloalkyl group or a double bond containing 1-3 heteroatoms selected from N, S, and O.

[0011] As a preferred technical solution, [ka] The following elements are selected: [ka]

[0012] In a second aspect, the present invention provides a compound represented by formula I-1, its stereoisomers, or pharmaceutically acceptable salts. [ka] (Here, R1, R2, ring A, n, R4, R5, R6, X1, X2, and X3 are as defined above.)

[0013] In a third aspect, the present invention provides a compound represented by formula I-2, its stereoisomers, or pharmaceutically acceptable salts. [ka] (Here, X1, X2, X3, R1, R2, ring A, and n are as defined above.)

[0014] In a fourth aspect, the present invention provides compounds represented by formulas I-3, I-4, I-5, I-6, I-7, and I-8, stereoisomers thereof, or pharmaceutically acceptable salts thereof. [ka] (Here, R1, ring A, and n are as defined above.)

[0015] As a preferred technical solution, the compounds provided by the present invention include, but are not limited to, the following compounds. [ka] [ka]

[0016] In a fifth aspect, the present invention provides a pharmaceutical composition comprising a compound of any of the technical solutions described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] The present invention also provides the use of compounds, stereoisomers thereof, or pharmaceutically acceptable salts or pharmaceutical compositions of any of the aforementioned technical solutions in the preparation of drugs for treating diseases or disorders mediated by connexin-related kinase 1 activity.

[0018] As a preferred technical solution, the disease or disorder is selected from Alzheimer's disease, bipolar disorder, Parkinson's disease, schizophrenia, diabetic peripheral neuropathy, and postherpetic neuralgia. ru.

[0019] The dosages of the compounds described in this invention, their stereoisomers, or pharmaceutically acceptable salts are all calculated in the form of free bases.

[0020] The inventors have found that such compounds are high-performance AAK1 inhibitors, possessing extremely high AAK1 inhibitory activity, and can be used in the preparation of drugs to prevent and / or treat AAK1-mediated diseases or disorders, including Alzheimer's disease, bipolar disorder, Parkinson's disease, schizophrenia, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, or peripheral neuropathy. The present invention is completed based on these findings.

[0021] Details of the invention The following describes various aspects and features of the present invention.

[0022] All references made herein are incorporated herein by whole-length reference, and in the event of any conflict between the meaning expressed in these references and the meaning expressed herein, the meaning expressed herein shall prevail. Furthermore, various terms and phrases used herein have general meanings known to those skilled in the art. Nevertheless, the present invention intends to provide more detailed explanations and interpretations of these terms and phrases herein. In the event of any conflict between the known meanings of any terms and phrases mentioned herein and the meaning expressed herein shall prevail. The following are definitions of various terms used herein, and these definitions apply to terms used throughout this specification unless otherwise specified.

[0023] The compounds according to the present invention may exist in the form of tautomers, in which case the present invention includes all tautomers.

[0024] The compounds of the present invention have a chiral center, and compounds of the present invention containing chiral substituted atoms can be separated into an optically active form or a racemic form. Those skilled in the art know how to produce the optically active form, such as by racemic separation or synthesis from optically active starting materials. Unless otherwise specified, the present invention includes all chiral isomers, diastereomers, and racemics. Methods for preparing the compounds of the present invention and their intermediates are part of the present invention. All tautomers of the compounds of the present invention are also part of the present invention.

[0025] The singular forms “a,” “one kind,” and “the” include plural referents unless the context clearly indicates otherwise.

[0026] As used herein, the terms “any” or “optionally” mean that the event or situation described thereafter may or may not occur, and this description includes both the event or situation occurring and not occurring. For example, “optionally substituted alkyl” refers to both the event or situation where the alkyl may be substituted and the alkyl group is not substituted.

[0027] The term “substituted” refers to a moiety having a substituent that replaces hydrogen on one or more carbons of the main chain. It is understood that “substituted” or “substituted by” includes the implicit condition that such substitution is consistent with the acceptable valences of the substituted atom and the substituent, and that a stable compound is obtained by this substitution that is not spontaneously converted, for example, by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all acceptable substituents of organic compounds. In a broad sense, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Acceptable substituents may be one or more of the same or different substituents for a suitable organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have any acceptable substituent of the organic compounds described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, alkyl, alkoxy, amino, cyano, heteroaryl, heterocyclyl, etc. Those skilled in the art will understand that the substituent itself may be substituted if appropriate. In a broad sense, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Acceptable substituents may be one or more of the same or different substituents for a suitable organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have any acceptable substituent of the organic compounds described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, alkyl, alkoxy, amino, cyano, heteroaryl, heterocyclyl, etc. Those skilled in the art will understand that the substituent itself may be substituted if appropriate.

[0028] As used herein, terms such as "halogen" and "halogenated" refer to fluorine, chlorine, bromine, or iodine, and more particularly to fluorine, chlorine, and bromine, with fluorine and chlorine being particularly preferred.

[0029] C x~y The term "group" refers to a group containing x to y carbon atoms, for example, "C 1~6 "Alkyl" refers to alkyl groups containing 1 to 6 carbon atoms.

[0030] As used herein, the term "alkyl" refers to a linear or branched alkyl group having a specific number of carbon atoms, and may include its subgroups. For example, when "C1-C6 alkyl" is mentioned, it may include subrange groups represented by C1-C4 alkyl, C1-C3 alkyl, C2-C6 alkyl, C2-C4 alkyl, etc., as well as specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0031] "Halogenated C 1~6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms in which one or more hydrogen atoms are substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine), and the upper limit of the number of halogen substituents is equal to the total number of hydrogen atoms that can be substituted in the alkyl group. The number of halogen substituents is not particularly limited and is any integer from 1 up to the upper limit, preferably 1 to 5 halogen substituents, 1 to 3 halogen substituents, 1 to 2 halogen substituents, or 1 halogen substituent. If the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens, including, but not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0032] "Hydroxyalkyl" refers to an alkyl group substituted with hydroxyl, and alkyl is defined as described above.

[0033] The term "alkoxy" is a conventional expression referring to an alkyl group linked to the rest of a molecule via one oxygen atom, or an alkyl group containing an oxygen atom. Examples of such groups include methoxy, ethoxy, or propoxy.

[0034] The term "alkyl halide" refers to the alkyl group defined above, which is linked to the rest of the molecule via a halogenated bond. For example, C 1~6 Alkyl halides refer to alkyl groups having 1 to 6 carbon atoms, or 1 to 3 carbon atoms, linked to the rest of the molecule via halogenated bonds. Preferred alkyl halides include, but are not limited to, -CH2Cl, -CHCl2, and -CF3.

[0035] "Halogenated alkoxy" refers to -O-halogenated alkoxy, and is not particularly limited to -O-halogenated C 1~8 Alkyl, preferably -O-halogenated C 1~6 Alkyl, more preferably -O-halogenated C 1~4 Alkyl, more preferably -O-halogen C 1~2 It is alkyl. The upper limit of the number of halogen substituents is equal to the total number of hydrogens that can be substituted by the substituents. No special consideration is given to this limitation. The number of halogen substituents is any integer from 1 up to the upper limit, preferably 1 to 5 halogen substituents, 1 to 3 halogen substituents, 1 to 2 halogen substituents, and 1 halogen substituent. If the number of halogen substituents is greater than 1, they may be substituted by the same or different halogens, and non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, etc.

[0036] "Cycloalkyl" refers to a substituted or unsubstituted, saturated or partially unsaturated non-aromatic hydrocarbon ring, which may be monocyclic, dicyclic, or polycyclic. The dicyclic or polycyclic rings may be parallel rings, spirocyclic rings, or bridging rings. Unless otherwise specified, they usually have 3 to 20 carbon atoms. In the case of monocyclic cycloalkyls, the number of carbon atoms is preferably 3 to 15, more preferably 3 to 10, more preferably 3 to 8, even more preferably 3 to 6, and still more preferably 3 to 4. In the case of bicyclic or polycyclic cycloalkyls, the number of carbon atoms is preferably 4 to 12, more preferably 4 to 11, more preferably 5 to 11, even more preferably 6 to 11, and still more preferably 6 to 10. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl. [ka] It includes.

[0037] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, it mainly contains 2 to 18 carbon atoms (e.g., 2 to 8, 2 to 6, 2 to 4) and includes, but is not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, and 2-hexenyl. Alkenyls may be further substituted with any group.

[0038] A "heterocycloalkyl" refers to a substituted or unsubstituted, saturated or partially unsaturated non-aromatic ring containing at least one heteroatom. Unless otherwise specified, heterocycloalkyls are 3- to 20-membered rings; for monocyclic heterocycloalkyls, preferably 3- to 15 members, preferably 3-10 members, more preferably 3-8 members, and even more preferably 3-6 members; and for bicyclic or polycyclic heterocycloalkyls, preferably 4- to 12 members, preferably 4-11 members, more preferably 5-11 members, even more preferably 6-11 members, and even more preferably 6-10 members. Heterocycloalkyls can be monocyclic, bicyclic, or polycyclic. The ring can be a bridging ring, a parallel ring, or a spiro ring, where the heteroatom is selected from N, S, O, P, Si heteroatoms and their oxidation states. When a heterocycloalkyl is bicyclic or polycyclic, at least one ring contains at least one heteroatom and may be a bicyclic or polycyclic ring formed by a ring containing a heteroatom and a ring not containing a heteroatom, and when linked to other groups, the linkage point may be a heteroatom or a carbon atom. Non-limiting examples include azetidinyl, morpholinyl, piperadinyl, piperidinyl, tetrahydropyranil, oxetanyl, pyranil, and azepinyl. This includes azocyclohexenyl, oxolenyl, and others.

[0039] "Deuterium" refers to an isotope of hydrogen (H).

[0040] As used herein, the term "cyano" refers to a group in which a carbon atom is triple-bonded to a nitrogen atom.

[0041] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other terms, mean -OH.

[0042] A "pharmaceutically acceptable salt" refers to a compound of the present invention that retains the biological efficacy and characteristics of a free acid or free base, and in which the free acid is mixed with a non-toxic inorganic base or organic base, or the free base is mixed with a non-toxic inorganic acid or organic acid. It is a non-toxic salt formed by the reaction of an inorganic acid or organic acid.

[0043] "Pharmaceutical composition" means a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts, cocrystals, deuterated compounds, and other components, the other components of which include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0044] "Stereoisomers" refer to isomers that are produced by differences in the spatial arrangement of atoms within a molecule, and include cis-trans isomers, enantiomers, and conformational isomers.

[0045] A "solubilized product" refers to a compound of the present invention, or a salt thereof, bonded to a stoichiometric or non-stoichiometric amount of solvent by non-covalent intermolecular bonds. If the solvent is water, it is a hydrate.

[0046] A "cocrystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a cocrystal-forming agent (CCF) via hydrogen bonds or other non-covalent bonds. Both API and CCF are solids in their pure state, and there is a fixed stoichiometric ratio between each component. Cocrystals are multicomponent crystals, including bicomponent eutectic crystals formed between two neutral solids and multicomponent eutectic crystals formed between a neutral solid and a salt or solvate.

[0047] The term "disease" refers to the physical condition of a subject related to a disease described in the present invention. Examples include Alzheimer's disease, bipolar disorder, Kinson's disease, schizophrenia, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, or peripheral neuropathy-related disorders as described in the present invention.

[0048] A "carrier" refers to a system that can deliver a drug to a target organ without causing significant irritation to the living body, without impairing the biological activity and properties of the administered compound, by altering the drug's delivery route and distribution within the body, and controlling the drug's release rate. Non-limited examples include liposomes and nanoparticles.

[0049] The compound of the present invention, or a pharmaceutical composition containing the same, can be administered in unit dosage form, and the route of administration may be orally, intravenously, intramuscularly, intravenously, by drip infusion, subcutaneously, enterally (such as through the nasal cavity, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum), or parenterally.

[0050] The dosage form can be liquid, solid, or semi-solid. Liquid dosage forms include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and complex emulsions), suspensions, and injectables (vial injections, powder injections, and infusions). These include eye drops, nasal drops, lotions, and topical preparations.Solid dosage forms include tablets (including regular tablets, enteric-coated tablets, lozenge tablets, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, pellet tablets, drops, suppositories, films, patches, aerosols (powdered aerosols), and sprays.Semi-solid dosage forms include ointments, gels, and pastes.

[0051] The drug or pharmaceutical composition of the present invention can be administered by any known method of administration to achieve the purpose of drug administration and to enhance the therapeutic effect.

[0052] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic agents or symptomatic treatments. If the compounds of the present invention have a synergistic effect with other therapeutic agents, the dosage may need to be adjusted according to the actual situation. [Effects of the Invention]

[0053] Beneficial technical effects The inventors unexpectedly discovered that the compounds of the present invention possess unexpectedly superior AKK1 inhibitory activity, with IC50 or EC50 values ​​equivalent to or lower than those of the positive control BMS-986176 / LX-9211. The present invention provides novel AKK1 inhibitory compounds with novel structures and potent activity that have excellent potential for application in the prevention and / or treatment of AKK1 inhibition-related conditions such as Alzheimer's disease, bipolar disorder, Kinson's disease, schizophrenia, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and peripheral neuropathy. [Brief explanation of the drawing]

[0054] [Figure 1] This shows the effect of a single oral forced administration (ig) of compound 26 on the pain threshold of peripheral neuropathy in diabetic rats. [Modes for carrying out the invention]

[0055] The following examples are intended to help those skilled in the art better understand the technical solutions of the present invention and do not limit the invention in any way.

[0056] In all the following examples, standard procedures and methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (Celsius). The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS).

[0057] The structure of the compounds of the present invention is confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is expressed in parts per million (ppm). NMR was measured using a Bruker avance-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0058] For the liquid phase portion of the LC-MS measurement, ACQUITY UPLC ultra-high pressure liquid chromatography is used, and for the mass spectrometry portion, Xevo G2-S Qtof mass spectrometer is used.

[0059] The starting materials used in the examples of this invention are known and can be purchased commercially, or they can be synthesized using or in accordance with methods known in the art.

[0060] Those skilled in the art can refer to WO2017059085, WO2017059080, and WO201 The compounds of the present invention can be prepared by combining the literature in 5153720 with known organic synthesis techniques. The starting materials are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from normal commercial channels, and suppliers include companies such as Shanghai Pharmaceutical Co., Ltd. and Nanjing Chemical Co., Ltd.

[0061] Example 1: Synthesis of (R)-1-{[2-(difluoromethyl)-6-(pyrazolo[1,5-a]pyrimidine-7-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (Compound 1)

[0062] [ka] Step 1: 1H-pyrazole-5-amine (6.0 g, 72 mmol, 1.0 eq) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (14.2 g, 100.8 mmol, 1.4 eq) were added to sodium ethoxide (60 mL, 20 wt%) and reacted at 80°C for 3 hours. After the reaction was complete, the mixture was cooled to 0°C, filtered, and the filter cake was dissolved in water and washed three times with dichloromethane. The aqueous phase was then adjusted to weak acidity using acetic acid, cooled to 0°C, precipitated the solid, filtered, and dried to obtain a white solid pyrazolo[1,5-a]pyrimidine-7(6H)-one (5.8 g, 43.0 mmol, yield 59.7%). LC-MS (TOF MS ES) + )m / z [M+H] +: 136.04. 1 H NMR (400 MHz, DMSO) δ 12.08 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 5.93 (d, J = 7.9 Hz, 1H), 5.81 (d, J = 2.0 Hz, 1H).

[0063] Step 2: Pyrazolo[1,5-a]pyrimidine-7(6H)-one (2.0 g, 14.8 mmol, 1.0 eq) and potassium carbonate (6.12 g, 44.4 mmol, 3.0 eq) were added to acetonitrile solution, followed by the addition of phosphorus oxybromide (12.7 g, 44.40 mmol, 3.0 eq), and the reaction was carried out at 80°C for 5 hours. After the reaction was complete, the reaction mixture was poured into ice water, and then saturated sodium bicarbonate solution was added to neutralize the phosphorus oxybromide. The aqueous phase was extracted three times with ethyl acetate, and the organic phase was concentrated together. Separation and purification were performed using a normal-phase column (ethyl acetate / petroleum ether, ethyl acetate %=25%) to obtain a yellow solid 7-bromopyrazolo[1,5-a]pyrimidine (800 mg, 4.06 mmol, yield 27.4%). LCMS (TOF MS ES) + )m / z [M+H] + : 197.96. 1 H NMR (400 MHz, DMSO) δ 9.08 (d, J = 7.1 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H).

[0064] Step 3: Dissolve (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (200 mg, 0.59 mmol, 1.0 eq) and bis(pinacorato)diborone (299 mg, 1.18 mmol, 2.0 eq) in 1,4-dioxane (12 mL), then add potassium acetate (173.7 mg, 1.77 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) di Chloride (43.2 mg, 0.059 mmol, 0.1 eq) was added sequentially, and the reaction was carried out at 80°C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated. The filtrate was then separated and purified by reverse-phase column chromatography (water / acetonitrile, acetonitrile %=3-5%) to obtain a white oily substance, (R)-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}boric acid (35 mg, 0.11 mmol, yield 17.5%). LCMS (TOF MS) ES + )m / z [M+H] + : 303.16. 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 6.9 Hz, 2H), 7.90 - 7.53 (m, 2H), 7.27 (m, J = 53.7, 10.9 Hz, 1H), 3.95 (s, 2H), 1.79 (m, J = 11.6, 6.1 Hz, 1H), 1.57 - 1.40 (m, 2H), 1.31 (s, 3H), 0.92 (m, J = 14.7, 6.6, 3.4 Hz, 6H).

[0065] Step 4: Dissolve (R)-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}boric acid (25 mg, 0.082 mmol, 1.0 eq) and 7-bromopyrazolo[1,5-a]pyrimidine (16.48 mg, 0.082 mmol, 1.0 eq) in 2 mL of 1,4-dioxane, and then add sodium carbonate (35 mg, 0.33 mmol, 4.0 eq) and [1,1'-bis(diphenylphosphinol)] Erocenepalladium(II) dichloride (6.05 mg, 0.008 mmol, 0.1 eq) was added, the system was substituted twice with nitrogen, and the reaction was carried out at 120°C for 6 hours. After the reaction was complete, (R)-1-{[2-(difluoromethyl)-6-(pyrazolo[1,5-a]pyrimidine-7-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (1.4 mg, 0.003 mmol, yield 5.6%) was obtained as a white solid by reverse-phase fractionation. LCMS (TOF MS ES) + )m / z [M+H] + : 376. 1 H NMR (400 MHz, methanol-d4) δ 8.99 - 8.91 (m, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.52 (s, 2H), 8.18 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.26 - 6.95 (m, 1H), 6.74 (m, J = 2.3, 0.9 Hz, 1H), 4.24 - 4.09 (m, 2H), 1.85 (m, J = 12.6, 6.3 Hz, 1H), 1.75 (m, J = 14.3, 5.7 Hz, 1H), 1.63 (m, J = 14.2, 5.5 Hz, 1H), 1.41 (s, 3H), 1.02 (m, J = 14.9, 6.6 Hz, 6H).

[0066] Example 2: Synthesis of (R)-1-{[2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (Compound 2)

[0067] [ka]

[0068] Step 1: D-alanine (43 g, 428.90 mmol, 1.0 eq) and sodium carbonate (153.55 g, 1448.70 mmol, 3.8 eq) were dissolved in purified water (540 mL). Benzyl chloroformate (93.90 g, 550.50 mmol, 1.3 eq) was slowly added dropwise at 0°C, and the mixture was reacted at room temperature for 16 hours. After the reaction was complete, water (1 L) and ethyl acetate (1 L) were added for extraction and liquid-liquid separation. The aqueous phase was adjusted to pH 2 with 4 mol / L dilute hydrochloric acid, then ethyl acetate (1 L) was added for extraction and liquid-liquid separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a white solid [(benzyloxy)carbonyl]-D-alanine (55 g, yield 51.40%). LC-MS (TOF MS ES) + )m / z [M+H] + : 224.08. 1 1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.41 - 7.24 (m, 5H), 5.02 (s, 2H), 4.05 - 3.99 (m, 1H), 1.26 (d, J = 7.3 Hz, 3H).

[0069] Step 2: Compound [(benzyloxy)carbonyl]-D-alanine (55 g, 246.40 mmol, 1.0 eq) and benzaldehyde dimethyl acetal (45 g, 295.68 mmol, 1.2 eq) were dissolved in tetrahydrofuran (400 mL), and thionyl chloride (35.20 g, 295.68 mmol, 1.2 eq) was slowly added dropwise at 0°C. After reacting at 0°C for half an hour, zinc chloride (40.30 g, 295.68 mmol, 1.2 eq) was added and the mixture was reacted at 0°C for 4 hours. After the reaction was complete, the reaction solution was diluted with 1000 ml of water, extracted three times with ethyl acetate (500 mL), and the ethyl acetate phase was washed twice with water (800 mL). Next, it was washed once with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a pale yellow oily substance, (4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (38 g, 49.54% yield). LCMS (TOF MS ES) + )m / z [M+H] + : 312.12. 1 H NMR (400 MHz, DMSO) δ 7.53 - 7.41 (m, 5H), 7.41 - 7.18 (m, 5H), 6.58 (s, 1H), 5.06 (d, J = 26.7 Hz, 2H), 4.56 (q, J = 7.0 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H).

[0070] Step 3: (4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (38 g, 122.2 mmol, 1.0 eq) and 3-bromo-2-methyl-1-propene (20 g, 152.6 mmol, 1.25 eq) were dissolved in tetrahydrofuran, and lithium bis(trimethylsilyl)amide (183.07 mL, 183.07 mmol, 1.5 eq) was added dropwise at -78°C under nitrogen protection, and the mixture was reacted for 3 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (15 mL) was added dropwise under an ice bath, and then... Extraction with ethyl acetate and water was performed, followed by liquid-liquid separation. The organic layer was collected and washed twice with water and once with saturated brine. Separation was performed by normal-phase column chromatography, and when the ethyl acetate content reached 6%, a clear oily substance, benzyl(4R)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (19 g, yield 43.20%), was obtained. LC-MS (TOF MS ES) + )m / z [M+H] + : 366.16. 1 H NMR (400 MHz, DMSO) δ 7.45 (m, J = 11.4, 5.9 Hz, 7H), 7.19 (m, J = 14.6, 7.2 Hz, 2H), 6.79 (d, J = 7.3 Hz, 1H), 6.45 (d, J = 26.5 Hz, 1H), 5.21 - 5.07 (m, 1H), 5.03 - 4.85 (m, 2H), 4.74 - 4.54 (m, 1H), 3.20 - 2.85 (m, 1H), 2.42 (m, J = 13.8, 8.9 Hz, 1H), 1.82 - 1.56 (m, 6H).

[0071] Step 4: Benzyl(4R)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (19 g, 52 mmol, 1.0 eq) was dissolved in tetrahydrofuran, then lithium hydroxide hydrate (2.4 g, 57.20 mmol, 1.1 eq) was dissolved in water and added dropwise to the reaction system at °C. The reaction was then allowed to proceed at room temperature for 16 hours. After the reaction was complete, the solution was extracted with ethyl acetate and water, and the aqueous phase was adjusted to pH 5-6. The solution was then extracted with ethyl acetate and water again and separated, and the organic phase was concentrated to obtain a clear oily substance, (R)-2-[(benzyloxycarbonyl)amino]-2,4-dimethylpenta-4-enoic acid (9.0 g, yield 42.10%). LCMS (TOF MS ES) + )m / z [M+H] + : 278. 1 1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 7.35 - 7.17 (m, 5H), 4.96 (d, J = 3.7 Hz, 2H), 4.78 (dd, J = 2.7, 1.5 Hz, 1H), 4.63 (d, J = 2.5 Hz, 1H), 2.63 - 2.36 (m, 2H), 1.61 (s, 3H), 1.26 (s, 3H).

[0072] Step 5: Dissolve (R)-2-[(benzyloxycarbonyl)amino]-2,4-dimethylpenta-4-enoic acid (9.0 g, 32.5 mmol, 1.0 eq) and triethylamine (4.9 g, 48.75 mmol, 1.5 eq) in THF (30 mL), and under nitrogen protection, add isobutyl chloroformate (5.3 g, 39 mmol, 1.2 eq) dropwise to the system at -15°C. After reacting at this temperature for 0.5 hours, filter and retain the filtrate. Add an aqueous solution of sodium borohydride to the filtrate at 0°C and react at room temperature for 10 minutes. After the reaction was complete, water was added to quench the sodium borohydride, and the mixture was extracted with ethyl acetate and water. After liquid-liquid extraction, the organic phase was concentrated and separated by normal-phase column chromatography. When the ethyl acetate content reached 30%, the desired product was obtained and concentrated to yield the clear oily substance benzyl(R)-(1-hydroxy-2,4-dimethylpenta-4-en-2-yl)carbamate (3.8 g, yield 44.46%). LC-MS (TOF MS ES) + )m / z [M+H] + :264 / 265. 1 H NMR (400 MHz, DMSO) δ 7.42 - 7.25 (m, 5H), 6.73 (s, 1H), 5.07 - 4.91 (m, 2H), 4.79 (m, J = 3.0, 1.6 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.64 (d, J = 2.7 Hz, 1H), 3.46 - 3.32 (m, 2H), 2.47 (s, 1H), 2.21 (d, J = 13.2 Hz, 1H), 1.68 (s, 3H), 1.10 (s, 3H).

[0073] Step 6: Dissolve compound benzyl(R)-(1-hydroxy-2,4-dimethylpenta-4-en-2-yl)carbamate (1.5 g, 5.70 mmol) in methanol (20.0 mL), add palladium-carbon (150 mg, 10%), and under hydrogen protection... The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, diatomaceous earth was added and the mixture was filtered. The filtrate was concentrated, and then water (100 mL) and ethyl acetate (100 mL) were added for extraction and liquid-liquid separation to separate the organic phase. Each phase was then washed twice with water (100 mL), followed by one wash with saturated sodium chloride solution (100 mL). Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain the white solid product (R)-2-amino-2,4-dimethylpenta-1-ol (620 mg, yield 82.90%). LC-MS (TOF MS ES) + )m / z [M+H] + : 132.

[0074] Step 7: Compound (R)-2-amino-2,4-dimethylpenta-1-ol (80 mg, 4.42 mmol, 1.0 eq) was added to tetrahydrofuran (30.0 mL), then t-potassium butoxide (1.24 g, 11.05 mmol, 2.5 eq) and 6-bromo-2-(difluoromethyl)-3-fluoropyridine (1.49 g, 6.63 mmol, 1.5 eq) were added, and the mixture was reacted at 93°C for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by normal-phase column chromatography to obtain the brown oily product (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (926 mg, yield 62.11%). LCMS (TOF MS ES) + )m / z [M+H] + : 337 / 339. 1 H NMR (400 MHz, DMSO) δ 7.79 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.16 (t, J = 53.4 Hz, 1H), 3.81 (s, 2H), 1.79 (m, J = 12.7, 6.3 Hz, 1H), 1.68 (s, 2H), 1.10 (s, 3H), 0.92 (m, J = 8.4, 6.6 Hz, 6H).

[0075] Step 8: (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (40 mg, 0.12 mmol, 1.0 eq), 7-azaindole-3-boronic acid pinacol ester (28.95 mg, 0.12 mmol, 1.0 eq), sodium carbonate (50 mg, 0.48 mmol, 4.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (8 (R)-1-{[2-(difluoromethyl)-6-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (8.60 mg, yield 19.32%) was obtained as a white solid by LCMS (TOF MS ES). + )m / z [M+H] + : 375.2. 1 H NMR (400 MHz, MeOD) δ 8.95 (m, J = 8.0, 1.7 Hz, 1H), 8.55 (s, 1H), 8.29 (d, J = 4.7 Hz, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.34 - 7.03 (m, 2H), 4.29 - 4.23 (m, 1H), 4.21 - 4.14 (m, 1H), 1.95 - 1.83 (m, 2H), 1.77 - 1.67 (m, 1H), 1.53 (d, J = 1.7 Hz, 3H), 1.08 (m, J = 15.5, 6.5, 1.8 Hz, 6H).

[0076] Example 16: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine trifluoroacetate (compound 16)

[0077] [ka]

[0078] Step 1: Synthesis of 3-iodo-4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine Compound 4-methoxy-7-azaindol (200 mg, 1.35 mmol, 1.0 eq) and potassium hydroxide (189 mg, 3.37 mmol, 2.5 eq) were added to N,N-dimethylformamide (3.0 mL). Elemental iodine (360 mg, 1.42 mmol, 1.05 eq) was dissolved in N,N-dimethylformamide (2.0 mL), and then slowly added to the above system. The mixture was reacted at room temperature for 45 minutes. Subsequently, an additional potassium hydroxide (189 mg, 3.37 mmol, 2.5 eq) was added, and the mixture was reacted for 10 minutes. Finally, p-toluenesulfonyl chloride (540 mg, 2.83 mmol, 2.1 eq) was added, and the mixture was reacted at room temperature for 2.5 hours. After the reaction was complete, the solution was injected into water (20 mL) to precipitate the solid, filtered, and the filtered cake was washed with water (10 mL) and ethyl acetate (20 mL), respectively. The filtered cake was collected and dried to obtain a yellow solid of 3-iodo-4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (360 mg, yield 62.28%). LCMS (TOF MS ES+) m / z [M+H]+: 428.9760. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 5.7 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.90 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 5.7 Hz, 1H), 3.94 (s, 3H), 2.36 (s, 3H).

[0079] Step 2: Synthesis of (4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)boric acid 3-Iodo-4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (310 mg, 0.72 mmol, 1.0 eq), pinacorborane (463 mg, 3.62 mmol, 5.0 eq), triethylamine (366 mg, 3.62 mmol, 5.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (52 mg, 0.072 mmol, 0.10 eq) was added to 1,4-dioxane (3.0 mL) and reacted at 120°C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and reverse-phase fractionation was performed using a C18 column to obtain a yellow solid (4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)boric acid (150 mg, yield 59.86%). LCMS (TOF MS ES+) m / z [M+H]+: 347.1177. 1 1H NMR (400 MHz, DMSO) δ 8.28 (d, J = 5.7 Hz, 1H), 8.04 - 7.98 (m, 3H), 7.86 (s, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 5.7 Hz, 1H), 4.02 (s, 3H).

[0080] Step 3: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (4-Methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)boric acid (100 mg, 0.29 mmol, 1.0 eq), (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylphenyl 97.41 mg, 0.29 mmol, 1.0 eq of thontan-2-amine, 122.50 mg, 1.06 mmol, 4.0 eq of sodium carbonate, and 21.14 mg, 0.029 mmol, 0.10 eq of [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride were added to 1,4-dioxane (3.0 mL) and reacted at 120°C for 8 hours under nitrogen protection. After the reaction was complete, the mixture was filtered. After filtering and concentrating the filtrate, the brown oily product (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (150 mg, yield 92.95%) was obtained by normal-phase column chromatography (dichloromethane:methanol = 12:1). LCMS (TOF MS ES+) m / z [M+H]+: 559.2274. 1 H NMR (400 MHz, DMSO) δ 8.37 - 8.29 (m, 1H), 8.07 (d, J = 8.0 Hz, 2H), 8.03 - 7.97 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 - 7.08 (m, 1H), 7.04 - 6.97 (m, 1H), 4.12 - 3.98 (m, 2H), 3.91 (d, J = 2.2 Hz, 3H), 2.37 (s, 3H), 2.00 (d, J = 2.2 Hz, 2H), 1.81 (d, J = 7.5 Hz, 1H), 1.18 - 1.16 (m, 3H), 0.95 (ddd, J = 9.0, 6.9, 2.1 Hz, 6H).

[0081] Step 4: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine trifluoroacetate (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (150 mg, 0.27 mmol, 1.0 eq) was added to a hydrogen chloride-dioxane solution (5.0 mL, 4.0 mol / L) and reacted at 60°C for 16 hours. After the reaction was complete, the solution was filtered directly, and the filtration cake was washed with a mixed solvent (petroleum ether:ethyl acetate = 5:1, 20 mL) to remove impurities. The filtration cake was collected and reversed-phase fractionated by C18 column chromatography (formic acid system) to obtain the white solid (S)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine trifluoroacetate (6.2 mg, yield 4.26%). LCMS (TOF MS ES+) m / z [M+H]+: 391.2328. 1 H NMR (400 MHz, DMSO) δ 12.12 (s, 1H), 8.23 ​​(d, J = 5.6 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.61 - 7.30 (m, 1H), 6.85 (d, J = 5.7 Hz, 1H), 4.25 - 4.11 (m, 2H), 3.98 (s, 3H), 1.89 - 1.71 (m, 2H), 1.61 (dd, J = 14.1, 5.3 Hz, 1H), 1.40 (s, 3H), 1.04 - 0.90 (m, 6H).

[0082] Example 17: Synthesis of (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (Compound 17)

[0083] [ka]

[0084] Step 1: Synthesis of [(benzyloxy)carbonyl]-L-alanine L-alanine (50 g, 561.15 mmol, 1.0 eq) and sodium carbonate (118.72 g, 1122.96 mmol, 2.0 eq) were dissolved in water (540 mL). Next, benzyl chloroformate (105.36 g, 550.50 mmol, 1.10 eq) was added to 1,4-dioxane (83 mL), and benzyl chloroformate (105.36 g, 550.50 mmol, 1.10 eq) was slowly added dropwise at 0°C. The mixture was reacted at 0°C for 0.5 hours, and then at room temperature for 16 hours. After the reaction was complete, water (500 mL) and ethyl acetate (750 mL) were added for extraction, and the mixture was separated twice. The aqueous phase was adjusted to pH 2-4 with 4 mol / L dilute hydrochloric acid, and then ethyl acetate (1 L) was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain a white solid [(benzyloxy)carbonyl]-L-alanine (101.00 g, yield 80.62%). 1 H NMR (400 MHz, DMSO) δ 12.52 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.44 - 7.16 (m, 65H), 5.02 (s, 2H), 4.07 - 3.94 (m, 1H), 1.28 - 1.13 (m, 3H).

[0085] Step 2: Synthesis of (4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester The compounds [(benzyloxy)carbonyl]-L-alanine (101 g, 452.71 mmol, 1.0 eq) and benzaldehyde dimethyl acetal (72.29 g, 475.37 mmol, 1.05 eq) were dissolved in tetrahydrofuran (500 mL), and thionyl chloride (64.62 g, 543.24 mmol, 1.2 eq) was slowly added at 0°C. After half an hour of reaction, zinc chloride (74.04 g, 543.26 mmol, 1.2 eq) was added, and the reaction was continued at 0°C for 4 hours. After the reaction was complete, the reaction solution was diluted with water (1 L), extracted three times with ethyl acetate (500 mL), and the ethyl acetate phase was washed twice with water (800 mL). Next, the mixture was washed once with saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the mixture was obtained by normal-phase column chromatography to obtain a pale yellow oily substance, (4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (80.7 g, yield 57.29%). 1 H NMR (400 MHz, DMSO) δ 7.49 - 7.36 (m, 6H), 7.36 - 7.24 (m, 4H), 6.54 (s, 1H), 5.16 - 4.84 (m, 2H), 4.52 (q, J = 7.0 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H).

[0086] Step 3: Synthesis of (4R)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (80.7g, 259.5 mmol, 1.0eq) and 3-bromo-2 -Methyl-1-propene (42.5 g, 324.1 mmol, 1.25 eq) was dissolved in tetrahydrofuran (500 mL), and under nitrogen protection, lithium bis(trimethylsilyl)amide (388 mL, 389.1 mmol, 1.5 eq) was added dropwise over 15 minutes at -78°C, and the mixture was reacted for 3 hours. After the reaction was complete, saturated aqueous ammonium chloride (25 mL) was added dropwise under an ice bath, and then the mixture was extracted with ethyl acetate and water and separated. The organic layer was collected and washed twice with water and once with saturated brine. Separation was performed by normal-phase column chromatography, and when the ethyl acetate content reached 6%, the product was eluted and concentrated to obtain a clear oily benzyl(4R)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (40.76 g, yield 43.03%). LCMS(ESI)[M+H]+:366. 1 H NMR (400 MHz, DMSO) δ 7.47 - 7.32 (m, 7H), 7.16 (m, J = 14.6, 7.2 Hz, 2H), 6.76 (d, J = 7.3 Hz, 1H), 6.49 - 6.33 (m, 1H), 5.16 - 5.04 (m, 1H), 4.98 - 4.83 (m, 2H), 4.70 - 4.51 (m, 1H), 3.16 - 2.78 (m, 1H), 2.39 (dd, J = 13.8, 8.5 Hz, 1H), 1.76 - 1.50 (m, 6H).

[0087] Step 4: Synthesis of (R)-2-[(benzyloxycarbonyl)amino]-2,4-dimethylpenta-4-enoic acid Benzyl(4R)-4-methyl-4-(2-methylallyl)-5-oxo-2-phenyloxazolidine-3-carboxylate benzyl ester (16.72 g, 45.8 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), and then lithium hydroxide hydrate (2.88 g, 68.67 mmol, 1.15 eq) was dissolved in water (100 mL). This mixture was added dropwise to the reaction system at 0°C, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the aqueous phase was adjusted to pH 5-6. The mixture was then extracted with ethyl acetate and water three times, and the organic phase was concentrated to obtain a clear oily substance, (R)-2-[(benzyloxycarbonyl)amino]-2,4-dimethylpenta-4-enoic acid (6.84 g, yield 53.91%). LCMS(ESI)[M+H]+:278. 1 H NMR (400 MHz, DMSO) δ12.59 (s, 1H), 7.35 - 7.19 (m, 5H), 4.95 (s, 2H), 4.75 (dd, J = 2.7, 1.5 Hz, 1H), 4.63 - 4.58 (m, 1H), 2.56 (d, J = 13.4 Hz, 1H), 2.44 - 2.40 (m, 1H), 1.59 (s, 3H), 1.26 (s, 3H).

[0088] Step 5: Synthesis of (R)-(1-hydroxy-2,4-dimethylpenta-4-en-2-yl)carbamate (R)-2-((benzyloxy)carbonyl)amino)-2,4-dimethylpenta-4-enoic acid (6.8 g, 24.5 mmol, 1.0 eq) and triethylamine (3.71 g, 36.7 mmol, 1.5 eq) were dissolved in tetrahydrofuran (25 mL). Under nitrogen protection, isobutyl chloroformate (4.02 g, 24.3 mmol, 1.2 eq) was added dropwise to the system at -15 °C, and the reaction was allowed to proceed at this temperature for 0.5 hours. The mixture was then filtered, and the filtrate was retained. At 0 °C, a solution of sodium borohydride (3.7 g, 98.08 mmol, 4.0 eq) in water (15 mL) was added to the filtrate, and the reaction was allowed to proceed at room temperature for 10 minutes. After the reaction was complete, water was added to quench the sodium borohydride, and the mixture was extracted with ethyl acetate and water. After liquid-liquid extraction, the organic phase was concentrated and separated by normal-phase column chromatography. When the ethyl acetate content reached 23%, the desired product was eluted and concentrated to obtain the clear oily benzyl(R)-(1-hydroxy-2,4-dimethylpenta-4-en-2-yl)carbamate (4.26 g, yield 66.01%). LCMS(ESI)[M+H]+:264. 1 H NMR (400 MHz, DMSO) δ 7.37 - 7.22 (m, 5H), 6.66 (s, 1H), 5.01 - 4.88 (m, 2H), 4.76 (m, J = 3.0, 1.5 Hz, 1H), 4.70 - 4.58 (m, 2H), 3.43 - 3.31 (m, 2H), 2.44 (s, 1H), 2.18 (d, J = 13.2 Hz, 1H), 1.65 (s, 3H), 1.08 (s, 3H).

[0089] Step 6: Synthesis of (R)-2-amino-2,4-dimethylpenta-1-ol Benzyl(R)-(1-hydroxy-2,4-dimethylpenta-4-en-2-yl)carbamate (2.0 g, 7.6 mmol, 1.0 eq) was added to methanol (25 mL), followed by the addition of Pd / C (0.2 g, 10% wt). The mixture was reacted at room temperature under a hydrogen atmosphere for 14 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain the yellow oily substance (R)-2-amino-2,4-dimethylpenta-1-ol (1.06 g, crude). This was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 3.07 (s, 2H), 1.79 - 1.67 (m, 1H), 1.28 - 1.08 (m, 2H), 0.97 - 0.74 (m, 9H).

[0090] Step 7: Synthesis of (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine Compound (R)-2-amino-2,4-dimethylpenta-1-ol (200 mg, crude) was added to tetrahydrofuran (4 mL), then t-potassium butoxide (4.0 g, 11.05 mmol, 2.5 eq) and 6-bromo-2-(difluoromethyl)-3-fluoropyridine (350 mg, 1.55 mmol, 1.0 eq) were added, and the mixture was reacted at 80°C for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain the brown oily liquid (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (255 mg, crude product). This was used directly in the next step without further purification. LCMS (TOF MS ES+) m / z [M + H] + : 337. 1H NMR (400 MHz, DMSO) δ 7.75 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.38 - 6.78 (m, 1H), 3.80 (s, 2H), 2.02 - 1.59 (m, 2H), 1.48 - 1.26 (m, 2H), 1.21 (d, J = 8.7 Hz, 1H), 1.08 (s, 3H), 0.89 (dd, J = 8.7, 6.6 Hz, 6H).

[0091] Step 8: Synthesis of (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (R)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (255 mg, crude product), (4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)boric acid (261 mg, 0.756 mmol, 1.0 eq), sodium carbonate (320.58 mg, 3.02 mmol, 4.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (55.4 mg, 0.07 56 mmol, 0.1 eq) was added to 1,4-dioxane (10 mL) and reacted at 120°C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 19:1) to obtain the brown solid product (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (364 mg, yield 86.23%). LCMS (TOF MS ES+) m / z [M+H]+: 559. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J = 5.6 Hz, 1H), 8.13 - 7.96 (m, 3H), 7.93 (d, J = 10.9 Hz, 3H), 7.64 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.29 - 6.98 (m, 1H), 6.95 (d, J = 5.7 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 2.32 (s, 3H), 1.42 - 1.31 (m, 2H), 1.19 (d, J = 5.5 Hz, 1H), 1.10 (s, 3H), 0.89 (t, J = 7.1 Hz, 6H).

[0092] Step 9: Synthesis of (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-ylpyridine-3-yloxy)-2,4-dimethylpenta-2-amine (177 mg, 0.44 mmol, 1.0 eq) was added to a hydrogen chloride-dioxane solution (3.5 mL, 4.0 mol / L), reacted at 60°C for 1 hour, and then reacted at room temperature for 16 hours. After the reaction was complete, the insoluble solid was precipitated, filtered, and the filtrate was concentrated. The solid and filtrate were dissolved in methanol (3 mL) to prepare the white solid (R)-1-{[2-(difluoromethyl)-6-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (16.1 mg, yield 12.56%). LCMS (TOF MS ES+) m / z [M + H] + :405.2290. 1H NMR (400 MHz, DMSO)δ 11.91 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.29 - 6.87 (m, 1H), 6.73 (d, J = 5.7 Hz, 1H), 3.91 (s, 3H), 3.77 (s, 2H), 1.78 (m, J = 6.4 Hz, 1H), 1.41 - 1.30 (m, 2H), 1.09 (s, 3H), 0.90 (t, J (= 6.7 Hz, 6H).

[0093] Example 26: Synthesis of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl)oxy)-2,4-dimethylpentan-2-amine (Compound 26)

[0094] [ka]

[0095] Step 1: Add 5-fluoro-1H-pyrrolo[2,3-b]pyridine (600 mg, 4.4 mmol, 1.0 eq) and potassium hydroxide (616.0 mg, 11.0 mmol, 2.5 eq) to N,N-dimethylformamide (5 mL). Slowly add iodine solution (586.7 mg, 4.62 mmol, 1.05 eq) dissolved in N,N-dimethylformamide (5 mL) to the system and react for 45 minutes. Replenish with potassium hydroxide (616.0 mg, 11.0 mmol, 2.5 eq) to continue the reaction for 5 minutes. Then, slowly add p-toluenesulfonyl chloride solution (1.76 g, 9.24 mmol, 2.1 eq) dissolved in N,N-dimethylformamide (3 mL) to the system and react at room temperature for 3 hours. After the reaction was complete, the system was poured into water (50 mL), stirred for 10 minutes, and then filtered directly. The filter cake was washed with water (20 mL) and ethyl acetate (20 mL), and dried to obtain the yellow solid product 5-fluoro-3-iodo-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (957 mg, 69.75%).

[0096] Step 2: 6-bromo-3-fluoropyridine aldehyde (20 g, 98.04 mmol, 1.0 eq) was dissolved in super-dried dichloromethane (200 mL), and diethylaminosulfur trifluoride (27.2 mL, 196.08 mmol, 2.0 eq) was added dropwise to the system at -20°C and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was complete, the system was poured into cold saturated sodium bicarbonate aqueous solution (200 mL) and quenched, and dichloromethane (200 mL) was added for extraction and liquid-liquid separation. The organic phase was collected, washed twice with water (250 mL), dried and concentrated to obtain a red solid, and then decolorized by adding silica gel to a suction filtration funnel to obtain white crystalline 6-bromo-2-(difluoromethyl)-3-fluoropyridine (19.0 g, yield 85.75%). LCMS (TOF MS ES+) m / z [M+H]+: 225.94. 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 6.7 Hz, 2H), 7.33-6.78 (m, 1H).

[0097] Step 3: Compound (S)-2-amino-2,4-dimethylpenta-1-ol (17.74 g, 135 mmol, 1 eq) was added to tetrahydrofuran (450 mL), then t-butoxide potassium (37.87 g, 337.5 mmol, 2.5 eq) and 6-bromo-2-(difluoromethyl)-3-fluoropyridine (36.61 g, 162 mmol, 1.2 eq) were added, and the mixture was reacted at 93°C for 2 hours. After the reaction was complete, the filtrate was filtered, concentrated, and purified by normal-phase column chromatography (dichloromethane:methanol = 95:5). Further purification was performed by reverse-phase column chromatography until the ratio of acetonitrile to water (1‰ formic acid) reached 13:87. The desired product was then eluted and concentrated to obtain a pale yellow oily product, (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (11.80 g, 25.88%). LCMS (TOF MS ES+) m / z [M + H] + : 337 / 339. 1 H NMR (400 MHz, DMSO) δ 7.79 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.16 (t, J = 53.4 Hz, 1H), 3.81 (s, 2H), 1.79 (m, J = 12.7, 6.3 Hz, 1H), 1.38 - 1.34 (m, 2H), 1.10 (s, 3H), 0.92 (m, J = 8.4, 6.6 Hz, 6H).

[0098] Step 4: Compound (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (450 mg, 1.35 mmol, 1.0 eq) and bis(pinacorato)diborone (405 mg, 1.59 mmol, 1.2 eq) were dissolved in 1,4-dioxane (15.0 mL), and then potassium acetate (393 mg, 4.02 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (58.5 mg, 0.08 mmol, 0.06 eq) were added, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was complete... The solution was filtered to obtain the crude product, filtrate (S)-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}boric acid (4.8 mL). Then, 5-fluoro-3-iodo-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (588 mg, 1.35 mmol, 1.0 eq), [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (99.0 mg, 0.135 mmol, 0.1 eq), and sodium carbonate (426 mg, 4.02 mmol, 3.0 eq) were added to the above solution and reacted at 90°C for 4 hours under nitrogen protection. After the reaction was complete, the diatomaceous earth was filtered, the filtrate was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 15:1) to obtain the brown solid product (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (260.7 mg, 35.75%). 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.71 (dd, J = 9.3, 2.9 Hz, 1H), 8.48 (dd, J = 2.9, 1.2 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.9 Hz, 1H), 7.50 - 7.17 (m, 3H), 3.95 (s, 2H), 2.37 (s, 3H), 1.82 (dt, J = 12.7, 6.3 Hz, 1H), 1.43 - 1.39 (m, 2H), 1.33 (d, J = 9.8 Hz, 1H), 1.22 - 1.17 (m, 1H), 1.14 (s, 3H), 0.94 (dd, J = 8.7, 6.6 Hz, 6H).

[0099] Step 5: (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (476 mg, 1.21 mmol, 1.0 eq) was added to a hydrogen chloride-dioxane solution (3 mL, 4.0 mol / L) and reacted at 60°C for 16 hours. After the reaction was complete, the solution was filtered directly, and the filtered cake was washed with a mixed solvent (petroleum ether:ethyl acetate = 5:1, 20 mL) to remove impurities. The filtered cake was collected and dried under reduced pressure to obtain the final product, (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine trihydrochloride (246 mg, yield 40.46%). LCMS (TOF MS ES+) m / z [M + H] + : 393.19. 1 H NMR (400 MHz, DMSO) δ 12.22 (d, J = 2.9 Hz, 1H), 8.59 (dd, J = 9.9, 2.9 Hz, 1H), 8.39 (d, J = 2.9 Hz, 4H), 8.29 (dd, J = 2.9, 1.5 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.81 - 7.46 (m, 2H), 4.25 - 4.13 (m, 2H), 1.86 - 1.72 (m, 2H), 1.62 (dd, J = 14.0, 5.3 Hz, 1H), 1.39 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.4 Hz (3H).

[0100] Step 6: (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine trihydrochloride (100 mg, Dissolve 0.2 mmol (1.0 eq) in tetrahydrofuran (1 mL), and hydroxylate the resulting solution. It was added to a 1 mL aqueous solution of sodium (24 mg, 0.6 mmol, 3 eq). The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, it was directly isolated to obtain a white solid (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (31.7 mg, yield 40.56%). LCMS (TOF MS ES+) m / z [M+H]+: 393.19.

[0101] Example 28: Synthesis of (S)-1-{[2-(difluoromethyl)-6-[5-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]pyridine-3-yl]oxy}-2,4-dimethylpentane-2-amine formate (Compound 28)

[0102] [ka]

[0103] Step 1: Synthesis of 7-azaindole-5-carboxaldehyde 5-Bromo-7-azaindole (5 g, 25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL) and, under nitrogen protection, at -78°C, n-butyllithium (21 mL, 2.5 mol / L, 2.1 eq) was slowly added dropwise, and the mixture was reacted at -78°C for 40 minutes. At this temperature, ultra-dried N,N-dimethylformamide (5 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, water (200 mL) and ethyl acetate (200 mL) were added for extraction and liquid-liquid separation. The organic phase was washed three times with water (150 mL), dried over anhydrous sodium sulfate, and then purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 2:3) to obtain a yellow solid 7-azaindole-5-carboxaldehyde (2.4 g, yield 64.43%). LCMS (TOF MS ES+) m / z [M+H]+: 147. 1 H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 10.11 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H).

[0104] Step 2: Synthesis of 3-iodine-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde Compound 7-azaindol-5-carboxaldehyde (2.4 g, 16.42 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (25 mL), and N-iodosuccinimide (3.69 g, 16.42 mmol, 1.0 eq) was slowly added at 0°C. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), extracted with water (200 mL), washed three times, then washed once with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the yellow solid 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (4.0 g, 89.55% yield). LCMS(TOF MS ES+)m / z [M+H]+: 272.94. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.17 (s, 1H), 8.81 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.94 (d, J (= 2.5 Hz, 1H).

[0105] Step 3: 5-Formyl-3-iodine-1H-pyrrolo[2,3-b]pyridine-1- Synthesis of t-butyl carboxylates 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (2 g, 7.35 mmol, 1.0 eq) and triethylamine (3.06 mL, 22.06 mmol, 3.0 eq) were dissolved in dichloromethane (25 mL), and 4-dimethylaminopyridine (45 mg, 0.37 mmol, 0.05 eq) and di-t-butyl dicarbonate (1.76 g, 8.09 mmol, 1.1 eq) were added at 0°C. The mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was collected and washed twice with water and once with saturated brine. After drying with anhydrous sodium sulfate and filtration, the solution was separated by normal-phase column chromatography. When the ethyl acetate content reached 20%, a white solid 5-formyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (1.7 g, yield 62.16%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 373. 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 8.20 (s, 1H), 1.64 (s, 9H).

[0106] Step 4: Synthesis of 5-(difluoromethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester 5-Formyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (1.0 g, 2.69 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), and diethylaminosulfur trifluoride (866 mg, 5.38 mmol, 2.0 eq) was slowly added dropwise under 0°C conditions. The mixture was then reacted at room temperature for 5 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water, the organic phase was washed three times with water, then once with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column (petroleum ether:ethyl acetate = 4:1) to obtain a pale yellow solid of 5-(difluoromethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (750 mg, yield 70.69%). LCMS (TOF MS ES+) m / z [M+H]+: 395. 1 H NMR (400 MHz, DMSO) δ 8.69 - 8.64 (m, 1H), 8.17 (s, 1H), 8.00 (dt, J = 2.2, 1.2 Hz, 1H), 7.47 - 7.14 (m, 1H), 1.63 (s, 9H).

[0107] Step 5: Synthesis of 5-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester Compounds 5-(difluoromethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (750 mg, 1.90 mmol, 1.0 eq), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (414 mg, 3.23 mmol, 1.7 eq), and triethylamine (963 mg, 9.51 mmol, 5.0 eq) were added to 1,4-dioxane (10.0 mL), and finally, tetrakis(triphenylphosphine)palladium (220 g, 0.19 mmol, 0.1 eq) was added, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was complete, the filtrate was filtered, concentrated, and purified by normal-phase column chromatography to obtain the yellow solid product 5-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (115 mg, yield 15.33%). LCMS (TOF MS ES+) m / z [M+H]+: 395. 1 H NMR (400 MHz, DMSO) δ 8.63 (m, J = 1.5 Hz, 1H), 8.33 - 8.26 (m, 1H), 8.10 (s, 1H), 7.46 - 7.11 (m, 1H), 1.62 (s, 9H), 1.33 (s, 12H).

[0108] Step 6: Synthesis of (S)-3-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}-5-(difluoromethyl ester)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (85 mg, 0.25 mmol, 1.0 eq), 5-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (100 mg, 0.25 mmol, 1.0 eq), sodium carbonate (107 mg, 1.00 mmol, 4.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocempara Dium(II) dichloride (18 mg, 0.025 mmol, 0.10 eq) was added to 1,4-dioxane (5.0 mL) and reacted at 120°C for 8 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and purified by reverse-phase C18 column to obtain the yellow solid product (S)-3-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}-5-(difluoromethyl ester)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (45 mg, yield 33.83%). LCMS (TOF MS ES+) m / z [M+H]+: 525.24. 1 H NMR (400 MHz, DMSO) δ 9.21 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 8.66 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.49 - 7.16 (m, 2H), 3.91 (s, 2H), 1.82 (dd, J = 12.7, 6.3 Hz, 1H), 1.69 (s, 9H), 1.50 - 1.38 (m, 2H), 1.16 (s, 3H), 0.95 (dd, J = 9.1, 6.6 Hz, 6H).

[0109] Step 7: Synthesis of (S)-1-{[2-(Difluoromethyl)-6-[5-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl]oxy}-2,4-dimethylpentan-2-amine formate (S)-3-{5-[(2-Amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridin-2-yl}-5-(difluoromethyl ester)-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid t-butyl ester (45 mg, 0.086 mmol, 1.0 eq) was added to a hydrogen chloride-dioxane solution (3.0 mL, 4.0 mol / L), and the reaction was carried out at room temperature for 2 hours. After completion of the reaction, it was directly concentrated and separated by C18 reverse phase (formic acid system) to obtain the formate of the final product (S)-1-{[2-(difluoromethyl)-6-[5-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl]oxy}-2,4-dimethylpentan-2-amine (32.3 mg, yield 80.03%). LCMS (TOF MS ES+) m / z [M+H]+: 425.2298。 1 H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 9.08 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.52 - 7.10 (m, 2H), 3.97 (s, 2H), 1.83 (m, J = 12.7, 6.4 Hz, 1H), 1.51 (m, J = 14.1, 5.6 Hz, 2H), 1.23 (s, 3H), 0.95 (dd, J = 12.6, 6.6 Hz, 6H)。

[0110] Example 43: Synthesis of (S)-1-{[2-(Difluoromethyl)-6-(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentan-2-amine (Compound 43)

[0111] [ka]

[0112] Step 1: Synthesis of 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine 5-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.48 mmol, 1.0 eq), 6-bromo-2-(difluoromethyl)-3-fluoropyridine (108 mg, 0.48 mmol, 1.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (35 mg, 0.048 mmol, 0.1 eq) was added to a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL) and reacted at 90°C for 4 hours. After the reaction was complete, it was cooled and extracted three times with ethyl acetate (10 mL). The organic phase was concentrated and purified by normal phase (PE:EA = 3:1) to obtain a yellow solid 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (135 mg, yield 64.6%). LCMS (TOF MS ES+) m / z [M+H]+: 436.1. 1 H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.72 (dd, J = 9.2, 2.8 Hz, 1H), 8.50 (m, J = 5.9, 4.1 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.38 - 7.21 (m, 1H), 2.37 (s, 3H).

[0113] Step 2: Synthesis of 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (135 mg, 0.31 mmol, 1.0 eq), sodium hydroxide (49.6 mg, 1.24 mmol, 4.0 eq), and methyl iodide (49.6 mg, 0.93 mmol, 3.0 eq) were added to dichloromethane (5 mL), and the mixture was then heated to 40°C and reacted for 16 hours. After the reaction was complete, the mother liquor was concentrated and purified by normal phase (PE:EA = 4:1) to obtain a yellow solid 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (65.0 mg, yield 71.0%). LCMS(TOF MS ES+)m / z [M+H]+: 296.1H NMR (400 MHz, DMSO) δ 8.64 (dd, J = 9.7, 2.8 Hz, 1H), 8.53 (s, 1H), 8.44-8.34 (m, 1H), 8.12 (dd, J = 8.9, 3.7 Hz, 1H), 7.97 (t, J = 9.5 Hz, 1H), 7.49 - 7.16 (m, 1H), 3.92 (s, 3H).

[0114] Step 3: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine 3-[6-(difluoromethyl)-5-fluoropyridine-2-yl]-5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (88 mg, 0.22 mmol, 1 (S)-2-amino-2,4-dimethylpenta-1-ol (29 mg, 0.22 mmol, 1.0 eq) and (S)-2-amino-2,4-dimethylpenta-1-ol (29 mg, 0.22 mmol, 1.0 eq) were added to tetrahydrofuran (2 mL), then t-butoxide potassium (74 mg, 0.66 mmol, 3.0 eq) was added, and the mixture was reacted at 90°C for 4 hours. After the reaction was complete, the mixture was filtered, the mother liquor was concentrated, and then preparatively purified to obtain a white solid (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethylpenta-2-amine (6.9 mg, yield 7.8%). LCMS(TOF MS ES+)m / z [M+H]+: 407.20. 1H NMR (400 MHz, DMSO) 1H NMR (400 MHz, DMSO) δ 8.60 (dd, J = 9.8, 2.8 Hz, 1H), 8.38 (s, 1H), 8.33 (dd, J = 2.9, 1.5 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40-7.09 (m, 1H), 3.88 (s, 3H), 3.81 (s, 2H), 1.80 (m, J = 12.6, 6.2 Hz, 1H), 1.38 (dd, J = 5.5, 2.4 Hz, 2H), 1.11 (s, 3H), 0.92 (t, J = 7.0 Hz, 6H).

[0115] Example 44: Synthesis of (S)-1-{[6-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (compound 44)

[0116] [ka]

[0117] Step 1: Synthesis of 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine Compounds 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.0g, 4.35 mmol, 1.0eq), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2g, 17.2 mmol, 4.0eq), [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (159mg, 0.217 mmol, 0.05eq), and triethylamine (2.19 (g, 2.17 mmol, 5 eq) was added to 1,4-dioxane (10 mL) and reacted at 120°C for 1 hour under nitrogen protection. After the reaction was complete, insoluble matter was removed by filtration, and the filtrate was separated and purified by reverse-phase column chromatography to obtain a white solid 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (155 mg, yield 12.7%). LCMS(ESI)[M+H]+:279. 1 H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (s, J = 7.8, 1.6 Hz, 1H), 7.68 (s, 1H), 1.39 (s, 12H).

[0118] Step 2: Synthesis of (S)-1-{[6-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine 5-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.180 mmol, 1.0 eq), (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (60.4 mg, 0.180 mmol, 1.0 eq) are dissolved in 1,4-dioxane (2 mL), and then [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (13.2 mg, (0.018 mmol, 0.05 eq) and sodium carbonate (57.2 mg, 0.54 mmol, 3.0 eq) were added, and the mixture was reacted at 120°C for 2 hours under nitrogen protection. After the reaction was complete, excess solid was removed by filtration, and the filtrate was concentrated to prepare the off-white solid (S)-1-{[6-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (4.3 mg, yield 5.8%). LCMS(ESI)[M+H]+: 409.19.1H NMR (400 MHz, DMSO-d6) δ 12.32 (d, J = 2.9 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.11 (s, 2H), 7.79 (d, J = 9.0 Hz, 1H), 7.71 - 7.41 (m, 1H), 4.25 - 4.13 (m, 2H), 1.89 - 1.72 (m, 2H), 1.61 (dd, J = 14.1, 5.3 Hz, 1H), 1.40 (s, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H).

[0119] Example 45: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethyl-2-amylamine diformate (Compound 45)

[0120] [ka]

[0121] Step 1: Synthesis of 5-methyl-1H-pyrrole[2,3-b]pyridine Compound 5-bromo-1H-pyrrole[2,3-b]pyridine (11.0 g, 33.7 mmol, 1.0 eq) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (197.3 mg, 0.27 mmol, 0.008 eq) were added to toluene (100 mL) and heated to 100 °C under nitrogen protection. Methylmagnesium chloride (3 M, 28.2 mL, 2.5 eq) was then added dropwise to the reaction system, and the reaction was sustained for 2 hours. After the reaction was complete, the reaction mixture was concentrated directly, extracted with water and ethyl acetate, and separated by liquid-liquid separation. The organic phase was concentrated, separated by normal-phase column (PE:EA = 4:1), and concentrated to obtain a colorless oily product, 5-methyl-1H-pyrrole[2,3-b]pyridine (4.0 g, yield 53.95%). LCMS(ESI)[M+H]+:133.

[0122] Step 2: Synthesis of 3-iodo-5-methyl-1H-pyrrole[2,3-b]pyridine 5-methyl-1H-pyrrole[2,3-b]pyridine (4.0 g, 30.26 mmol, 1.0 eq) and iodine (3.84 g, 15.13 mmol, 0.5 eq) were dissolved in N,N-dimethylformamide (30 mL), and potassium hydroxide (8.56 g, 151.3 mmol, 5 eq) was added in batches. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into ice water to produce a yellow solid. The mixture was filtered, the filtered cake was collected and dried to obtain 3.0 g of the yellow crude product 3-iodo-5-methyl-1H-pyrrole[2,3-b]pyridine. LCMS(ESI)[M+H]+:259.

[0123] Step 3: Synthesis of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole[2,3-b]pyridine 3-iodo-5-methyl-1H-pyrrole[2,3-b]pyridine (3.0g, 11.64 mmol, 1.0eq), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.5g, 58.2 mmol, 5.0eq), triethylamine (5.96g, 58.2 mmol, 5.0eq), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (852mg, 1 0.164 mmol (0.1 eq) was added to 1,4-dioxane (15 mL) and reacted at 120°C for 2 hours under nitrogen protection. The diatomaceous earth was filtered, concentrated, separated and purified by normal phase, and concentrated again to obtain the yellow solid 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole[2,3-b]pyridine (2.0 g). LCMS(ESI)[M+H]+:259. 1 H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 7.9, 2.0 Hz, 1H), 7.93 (s, 2H), 7.72 (d, J = 2.3 Hz, 1H), 1.30 (s, 3H), 1.07 (s, 12H).

[0124] Step 4: Synthesis of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester Dissolve 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.384 mmol, 1 eq) in dichloromethane (5 mL), and add di-t-butyl dicarbonate (110 mg, 0.504 mmol, 1.3 eq), triethylamine (78.4 mg, 0.775 mmol, 2.0 eq), and DMAP (4.7 mg, 0.038 mmol, 0.1 eq) sequentially at 0°C. The reaction was maintained at °C for 1 hour. After the reaction was complete, water (10 mL) was added to dilute the mixture, and it was extracted three times with 20 mL of dichloromethane. The organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by TLC preparative plate (PE:EA = 2:1) to obtain 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (81 mg, yield: 58.4%), a yellow oily substance. LCMS(ESI)[M+H]+:359.

[0125] Step 5: Synthesis of (S)-3-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester Dissolve 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (81 mg, 0.226 mmol, 1.0 eq) and (S)-1-{[6-bromo-2-(difluoromethyl)pyridine-3-yl]oxy}-2,4-dimethylpentan-2-amine (75.8 mg, 0.226 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and water (0.5 mL), and then 1,1'-bis(diphenylphosphinol) Ferrocene palladium(II) dichloride (16.8 mg, 0.023 mmol, 0.1 eq) and cesium carbonate (222.3 mg, 0.678 mmol, 3.0 eq) were added, and the mixture was reacted at 80°C for 2 hours under nitrogen protection. After the reaction was complete, the diatomaceous earth was filtered, and the filtrate was concentrated and obtained by reverse-phase column chromatography (50% acetonitrile) to obtain the off-white solid (S)-3-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (33 mg, crude). This was used directly in the next step without further purification. LCMS(ESI)[M+H]+:489.

[0126] Step 6: Synthesis of (S)-1-{[2-(difluoromethyl)-6-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethyl-2-amylamine diformate Compound (S)-3-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridine-2-yl}-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate t-butyl ester (33 mg, crude) was added to dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the organic phase was concentrated and purified by preparative fractionation to obtain the white solid (S)-1-{[2-(difluoromethyl)-6-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-3-yl]oxy}-2,4-dimethyl-2-amylamine diformate (9.3 mg, yield 35.4%). LCMS(ESI)[M+H]+: 389.21. 1 H NMR (400 MHz, DMSO) δ 11.92 (d, J = 2.9 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.13 (s, 2H), 8.06 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.66-7.36 (m, 1H), 4.73 (s, 2H), 4.21-4.10 (m, 2H), 2.42 (s, 3H), 1.87-1.69 (m, 2H), 1.60 (dd, J = 14.1, 5.3 Hz, 1H), 1.38 (s, 3H), 1.00-0.89 (m, 6H).

[0127] Example 46: Synthesis of (S)-1-{[3-(difluoromethyl)-5-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine formate (compound 46)

[0128] Step 1: Synthesis of (S)-1-{[5-bromo-3-(difluoromethyl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine Compound (S)-2-amino-2,4-dimethylpenta-1-ol (275 mg, 2.10 mmol, 0.95 eq) was added to tetrahydrofuran (6.0 mL), then t-butoxide potassium (620 mg, 5.53 mmol, 2.5 eq) and 5-bromo-3-(difluoromethyl)-2-fluoropyridine (500 mg, 2.21 mmol, 1.0 eq) were added, and the mixture was reacted at 93°C for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the yellow oily product (S)-1-{[5-bromo-3-(difluoromethyl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine (200 mg, yield 26.85%). LCMS(TOF MS ES+)m / z [M+H]+: 337 / 339.1H NMR (400 MHz, DMSO) δ 8.49 - 8.43 (m, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.31 - 7.00 (m, 1H), 4.04 (d, J = 1.7 Hz, 2H), 1.79 (m, J = 12.8, 6.4 Hz, 1H), 1.6 0 (s, 2H), 1.35 (m, J = 5.8, 3.4 Hz, 2H), 1.09 (s, 3H), 0.90 (d, J = 6.7 Hz, 6H).

[0129] Step 2: Synthesis of (S)-1-{[3-(difluoromethyl)-5-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine formate (S)-1-{[5-bromo-3-(difluoromethyl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine (80 mg, 0.24 mmol, 1.0 eq), 7-azaindole-3-boronic acid pinacol ester (57.91 mg, 0.24 mmol, 1.0 eq), sodium carbonate (100 mg, 0.95 mmol, 4.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (17.56 mg (0.024 mmol, 0.10 eq) was added to 1,4-dioxane (3.0 mL) and reacted at 120°C for 8 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was separated by reverse-phase C18 column chromatography (formic acid system) to obtain the white solid (S)-1-{[3-(difluoromethyl)-5-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2-yl]oxy}-2,4-dimethylpentan-2-amine formate (6.0 mg, yield 6.02%). LC-MS (TOF MS ES+) m / z [M+H]+: 375 / 376. 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.44-8.36 (m, 1H), 8.31 (dd, J = 4.7, 1.4 Hz, 1H), 8.27 (dd, J = 8.0, 1.6 Hz, 2H), 8.02 (s, 1H), 7.55-7.24 (m, 1H), 7.20 (dd, J = 8.0, 4.6 Hz, 1H), 4.28 (s, 2H), 1.81 (m, J = 16.6, 8.2 Hz, 1H), 1.65-1.48 (m, 2H), 1.28 (s, 3H), 0.94 (dd, J = 14.3, 6.6 Hz, 6H).

[0130] Example 47: Synthesis of (S)-1-{4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(trifluoromethyl)phenoxy}-2,4-dimethylpentan-2-amine (Compound 47)

[0131] [ka]

[0132] Step 1: Synthesis of (S)-1-[4-bromo-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine Compound (S)-2-amino-2,4-dimethylpenta-1-ol (200 mg, 1.52 mmol, 0.95 eq) was added to tetrahydrofuran (5.0 mL), then t-potassium butoxide (450 mg, 4.0 mmol, 2.5 eq) and 5-bromo-2-fluorobenzotrifluoride (390 mg, 1.60 mmol, 1.0 eq) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 3:1) to produce a colorless oil. (S)-1-[4-bromo-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine (240 mg, yield 44.50%) was obtained. LC-MS (TOF MS ES+) m / z [M+H]+: 354 / 356. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 2.5 Hz, 1H), 7.57 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 3.82 - 3.68 (m, 2H), 1.85-1.68 (m, J = 6.4 Hz, 1H), 1.47 (dd, J = 5.7, 4.0 Hz, 2H), 1.22 (s, 3H), 0.96 (dd, J = 9.9, 6.7 Hz, 6H).

[0133] Step 2: Synthesis of (S)-1-{4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(trifluoromethyl)phenoxy}-2,4-dimethylpentan-2-amine (S)-1-[4-bromo-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine (92 mg, 0.26 mmol, 1.0 eq), 7-azaindole-3-boronic acid pinacol ester (63 mg, 0.26 mmol, 1.0 eq), sodium carbonate (110 mg, 1.04 mmol, 4.0 eq), and [1,1'-bis(diphenylphosphino)]ferrocenepalladium(II) dichloride (19 mg, 0. (0.26 mmol, 0.10 eq) was added to 1,4-dioxane (3.0 mL) and reacted at 120°C for 8 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was separated by reverse-phase C18 column chromatography (sodium bicarbonate system) to obtain a brown solid (S)-1-{4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(trifluoromethyl)phenoxy}-2,4-dimethylpentan-2-amine (3.1 mg, yield 3.05%). LCMS (TOF MS ES+)m / z [M+H]+: 392.2213.1H NMR (400 MHz, MeOD) δ 8.30-8.25(m, 2H), 7.93-7.85 (m, 2H), 7.68 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 7.8, 5.0 Hz, 1H), 4.01-3.90 (m, 2H), 1.90 - 1.80 (m, 1H), 1.58 (m, J = 14.2, 5.5 Hz, 2H), 1.29 (s, 3H), 1.02 (t, J = 7.0 Hz, 6H).

[0134] The compounds in Table 1 are obtained by referring to the methods of Examples 1 and 2. [Table 1-1]

[0135] [Table 1-2]

[0136] [Table 1-3]

[0137] Experimental Example 1: Testing the binding ability of the compound of the present invention to the AAK1 protein. Experimental objective: To detect the binding ability of compounds to the AAK1 protein using the CETSA experimental method. Background and Principle: The CETSA experiment is a molecular detection method that measures the affinity between a drug and a target protein. Its principle is that when a drug binds to a target protein, its structure becomes more stable. When a candidate drug is co-incubated with a target protein, the candidate drug becomes AAK If a candidate drug is an inhibitor, it can bind to AAK1. When the sample is heat-treated, the AAK1 protein becomes more stable, making it easier to detect in Western blotting experiments. On the other hand, the stability of the AAK1 protein decreases further after heating, and the amount of protein detected also decreases. This is used to evaluate the ability of a drug to bind to its target protein and to screen for AAK1 protein inhibitors. Specific experimental process: AAK1 (30-330) protein expression: The AAK1 sequence (residues 30-330) was cloned into a pET24N vector containing an n-terminal (His) 6x tag and a tobacco etch virus (TEV) protease cleavage site. The constructed vector was transformed into E. coli BL21 (DE3), cultured with shaking until the OD reached 0.6, then 1 mM IPTG was added and cultured at 12°C for 16 hours. Cells were collected, sonicated, and the supernatant was collected by centrifugation. The protein was purified by Ni-NTA, and the protein concentration and purity were measured after dialysis.

[0138] CETSA sample preparation: Samples were incubated for 30 minutes using the candidate drug, control drug, and control reagent, respectively, and then heated at approximately 10 set temperatures for each group. The samples were allowed to return to room temperature, centrifuged at 20,000 g, and the supernatant was collected. Protein samples were denatured by heating them at 100°C for 10 minutes using sample buffer. After the samples returned to room temperature, Western blot detection was performed on the samples. The protein loading amount was controlled to 20 ug. After determining the mutation temperature, compound concentration gradients were generally set to 9, samples were incubated, and Western blot detection was performed as described above. Protein electrophoresis: The voltage of the concentration gel was set to 60 V, and the voltage of the separation gel was set to 120 V. After electrophoresis was completed, electrotransformation was started. The electrotransformation conditions were set to 250 mA for 2 hours. The samples were blocked with 5% BSA for 1 hour, a specific primary antibody was added, and the mixture was incubated overnight at 4°C on a shaker. The samples were then washed four times with TBST for 2.5 minutes each. The secondary antibody was incubated for 1 hour at room temperature on a shaker, washed four times with TBST for 2.5 minutes each, and developed using ECL. The expression levels of the AAK1 protein were detected in different groups and at each temperature. Western blot bands were converted and processed using ImageJ and GraphPad software to calculate EC50. EC50 stands for 50% of maximal effect concentration, and refers to the concentration of a drug that can produce an effect in 50% of individuals. Bristol-Myers Squibb's AAK1 inhibitor BMS-986176 / LX-9211 was used as the positive reference compound, and its preparation method is described in Example 123 of Patent Document CN106458994A. The structure of BMS-986176 / LX-9211 is as follows:

[0139] [ka]

[0140] The test results are shown in Table 2 below. The EC50 values ​​of each compound are classified according to the following explanation. A "+" indicates that the EC50 value is greater than 1 μM. "++" indicates that the EC50 value is less than 1 μM and greater than 100 nM. "+++" indicates that the EC50 value is less than 100 nM and greater than 10 nM. "++++" indicates that the EC50 value is less than 10 nM.

[0141] [Table 2]

[0142] The experimental results show that the compound of the present invention has the ability to strongly bind to the AAK1 protein kinase functional domain, and that its in vitro binding ability is equivalent to or better than that of the positive control compound BMS-986176. This indicates that the compound of the present invention is promising as an AAK1 protein inhibitor.

[0143] Experimental Example 2: Measurement of the effect of the compound of the present invention on AP2M1 phosphorylation in cells Experimental Objective: The objective of this test is to examine the effect of the compound on AP2M1 phosphorylation in cells. Background and Principle: Adapter-related kinase 1 (AAK1), also known as AP2-related kinase 1, is a 104 kDa serine / threonine kinase. AAK1 interacts with the adapter protein 2 (AP2) complex and enhances its binding affinity to specific tyrosine or dileucine-based sorting signals of certain membrane receptors by phosphorylating threonine residues within the AP2 (AP2M1) microsubunit. By detecting intracellular AP2M1 phosphorylation levels, we evaluate the inhibitory effects of compounds on AAK1 and screen candidate compounds. Specific experimental process: 293T cells were inoculated into T25 cells, and confluence was allowed to reach 60%-80% by day 2. On day 2, each T25 cell was transfected using lip2000 transfection reagent. Plasmid (AAK1 / HA / pIRES 1μg and Flag / AP2MI / pcDNA) Cotransfection was performed using 15 μg (16 μg). On day 3, the cells were digested and resuspended, centrifuged at 1000 rpm for 5 minutes, and 450 μl / well was placed in a 24-well plate, 2 × 10⁶. 5 Cells were inoculated into each well. The test compound was gradient diluted, 50 μl was added to each well and mixed uniformly, and incubated at 37°C for 3 hours. DMSO was used as a control, and a non-transfection plasmid was used as a blank control. After incubation, cells were collected, washed twice with PBS, and lysed on ice for 30 minutes using a cell lysate containing the protease inhibitor PMSF. The concentration of the protein sample was measured using a BCA kit. Protein electrophoresis: The voltage of the concentrating gel was set to 60 V, and the voltage of the separation gel was set to 120 V. After electrophoresis, electrotransformation was started. The conditions for electrotransformation were set to 250 mA for 2 hours. The samples were blocked with 5% BSA for 1 hour, the specific primary antibody anti-p-AP2M1 was added, and the mixture was incubated overnight at 4°C on a shaker. The samples were then washed four times with TBST for 2.5 minutes each, and the secondary antibody was incubated for 1 hour at room temperature on a shaker. The samples were washed four times with TBST for 2.5 minutes each, and the mixture was developed using ECL to detect the expression level of p-AP2M1. Western blot bands were converted and processed using ImageJ and GraphPad software to calculate EC50. IC50 (half maximal inhibitory concentration) refers to the half-inhibitory concentration of the antagonist being measured. It represents half the amount of a drug or substance (inhibitor) that inhibits a particular biological process (or substances such as enzymes, cell receptors, or microorganisms involved in this process). The compound BMS-986176 was used as the positive reference compound.

[0144] The test results are shown in Table 3 below. The IC50 values ​​of each compound are classified according to the following explanation. A "+" indicates that the EC50 value is greater than 1 μM. "++" indicates that the EC50 value is less than 1 μM and greater than 100 nM. "+++" indicates that the EC50 value is less than 100 nM and greater than 10 nM. "++++" indicates that the EC50 value is less than 10 nM. The test results are shown in Table 3 below.

[0145] [Table 3]

[0146] The results indicate that the compound of the present invention inhibits intracellular AP2M1 phosphorylation levels, reaching nM levels with IC50 values ​​equivalent to or higher than those of the positive drug. This potent inhibitory effect has significant therapeutic implications for the treatment of disorders or diseases associated with AAK1 inhibition.

[0147] Experimental Example 3: Testing the effect of the compound of the present invention on the function of AAK1 kinase. Experimental Objective: The objective of this test is to examine the effect of the compound on AAK1 kinase function. Background and Principle: AAK1 phosphorylates the threonine residue of the AP2 (AP2M1) microsubunit. In this process, ATP supplies phosphate and produces ADP. Therefore, the capacity of AAK1 kinase can be evaluated by detecting the amount of ADP produced. Specific experimental process: AAK1 (30-330) protein expression: The AAK1 sequence (residues 30-330) was cloned into a pET24N vector containing an n-terminal (His) 6x tag and a tobacco etch virus (TEV) protease cleavage site. The constructed vector was transformed into E. coli BL21 (DE3), cultured with shaking until the OD reached 0.6, then 1 mM IPTG was added and cultured at 12°C for 16 hours. Cells were collected, sonicated, and the supernatant was collected by centrifugation. The protein was purified by Ni-NTA, and the protein concentration and purity were measured after dialysis. AAK1 kinase experiment: Purified AAK1 protein was added to the control buffer (20 mM Tris, pH 7.80, 10 mM MgCl2, 1 mM DTT, 0.01% Tween20), and the substrate (Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP) and the test compound were added. The final concentrations of each reagent in the system were 3.5 nM for AAK1, 1.5 μM for Aha-KEEQSQITSQVTGQIGWR-NH2, and 22 μM for ATP. The reaction mixture was incubated in a metal bath at 25°C for 3 hours, and the reaction was stopped by adding 1% SDS. The amount of ADP produced was detected by HPLC. The IC50 was calculated by processing with GraphPad software and the compound was screened by comparison with the positive reagent BMS-986176. The test results are shown in Table 4 below.

[0148] [Table 4]

[0149] The results indicate that the compounds of the present invention exhibit very strong inhibitory activity against the function of AAK1 protein kinase, with IC50 values ​​reaching nM levels equivalent to or lower than those of the positive drug. This potent inhibitory activity has significant therapeutic implications for the treatment of disorders or diseases associated with AAK1 inhibition.

[0150] Experimental Example 4: In vitro pharmacokinetic study of the compound of the present invention in SD rats Experimental Objective: The objective of this experiment is to test the pharmacokinetics of compounds in SD rats. Background and Principles: Non-clinical pharmacokinetic studies use in vivo, in vitro, and in vitro research methods in animals to elucidate the patterns of drug kinetic changes in the body, obtain basic pharmacokinetic parameters, and clarify the processes and characteristics of drug absorption, distribution, metabolism, and excretion. Non-clinical pharmacokinetic studies play a crucial role in the evaluation process of new drug research and development. In pharmacodynamic and toxicological evaluations, drug or active metabolite concentration data and associated pharmacokinetic parameters can serve as the basis for generating, determining, or explaining the magnitude of efficacy or toxicity, and can provide the basis for the drug's effect (efficacy or toxicity) on target organs. Specific experimental process: (1) Preparation of test sample: Solvent: PEG300 40%, Tween80 15%, ethanol 10%, water 35%, prepared on the day of administration. (2) Experimental animals: 18 male SD rats, SPF grade. (3) Experimental design:

[0151] [Table 5]

[0152] (4) Method of administration: Before administration, measure the body weight, calculate the dosage based on the body weight, and administer orally by intravenous or intragastric administration. (5) Blood collection time: After administration, IV: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h; PO: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. Blood was collected from the jugular vein, and approximately 0.2 mL was taken for each sample. K2-EDTA was used as an anticoagulant, and the sample was placed on ice after collection. (6) Processing of plasma samples: After blood collection, place the blood sample on ice and separate the plasma by centrifugation within one hour (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Store the plasma sample in a freezer at -80°C until analysis. (7) Results Analysis: Using Phoenix WinNonlin7.0, pharmacokinetic parameters are calculated based on blood drug concentration data at various time points, and parameters such as AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, along with their mean and standard deviations, are provided. The experimental results are shown in Table 6 below.

[0153] [Table 6]

[0154] Experimental conclusion: Pharmacokinetic data of compound 26 in SD rats showed that, compared to the positive control, the half-life and peak duration of compound 26 were similar, but the peak concentration and in vivo exposure were approximately four times higher. In short, the pharmacokinetic data of compound 26 in rats were significantly superior to that of BMS-986176.

[0155] Experimental Example 5: The efficacy of the compound of the present invention against diabetic peripheral neuropathy (DPNP) in SD rats Efficacy testing Experimental Objective: The objective of this experiment is to investigate the analgesic effect of the test substance on diabetic peripheral neuropathy (DPNP) in streptozotocin (STZ)-induced diabetic rats, and the blood-brain distribution associated with the efficacy of the compound, by single forced oral administration (ig.). Experimental Method: After the acclimatization period of the experimental rats, the plantar basal pain threshold was measured using the von Frey method (UP-Down method) before modeling. Subsequently, the remaining rats, excluding the blank control group, were fasted for 16 hours and given free access to water. Then, streptozotocin (65 mg / kg, 2 mL / kg) was administered intraperitoneally to construct the model. One week after modeling, blood was collected from the tip of the tail and blood glucose levels were examined after a 4-hour fast. Rats were diagnosed with diabetes if their blood glucose level exceeded 16.7 mmol / L. After successful modeling, the von Frey method (UP-Down method) was used to measure the plantar basal pain threshold of rats, which is the basal pain threshold before drug administration. According to the pain threshold, the rats were evenly divided into a blank group, a model group, a positive control 1 mg / kg group, a compound 26 (0.5 mg / kg) group, and a compound 26 (1 mg / kg) group. The next day, the solvent or the corresponding drug was administered, and the pain threshold of the affected foot of the rats was measured with von Frey filaments 2 h, 3 h, 4 h, 5 h, and 6 h after administration. The increase rate of the pain threshold of the test substance against neuropathic pain in diabetic rats was calculated, and the time-effect relationship was observed. After the experiment, 1-3 rats in each group of G3-G5 groups were collected, and plasma and brain tissues were examined. Experimental results: The results are shown in Table 7, Table 8, Table 9, and Figure 1 of the specification. Before modeling, the basal pain sensation threshold of rats in each group was 15 g. After modeling, the pain sensation threshold of rats in other groups except the blank control group decreased to about 7.0 g, showing a statistically significant difference compared with the blank control group (p < 0.01).

[0156]

Table 7

[0157]

Table 8

[0158]

Table 9

[0159] Experimental Conclusions: In experiments on the analgesic effect of this test substance on peripheral neuropathy in diabetic rats, (1) after administration of test substance BMS-986176 (1 mg / kg), compound 26 (0.5 mg / kg), and compound 26 (1 mg / kg), the pain threshold of the model animals was significantly increased 2 hours later, and the duration of analgesia was maintained up to 4 hours after administration. (2) Both the analgesic effect and duration of compound 26 were superior to the positive control BMS-986176. (3) This compound has better brain penetration than the positive control BMS-986176.

Claims

1. The compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt. 【Chemistry 1】 (Here, X １ , X ２ , X ３ These are, independently, N or CR ２ Selected from, Ring A is, 【Chemistry 2】 Selected from, R １ 、R ２ 、R ３ are each independently selected from hydrogen, amino, -CO ２ H, halogen, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, formylamino, C １～６ alkyl, deuterated C １～６ alkyl, halogenated C １～６ alkyl, C １～６ alkoxy, deuterated C １～６ alkoxy, halogenated C １～６ alkoxy, hydroxy C １～６ alkyl, C ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O R ４ , R ５ , R ６ These are, independently, hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkenyl, fluoromethyl, difluoromethyl, trifluoromethyl, and C. １～６ Alkyl, halogenated C １～６ Alkyl, C １～６ Alkoxy, C halogenated １～６ Alkoxy, deuterated C １～６ Alkyl, deuterated C １～６ Alkoxy, C ３～６ Cycloalkyl, hydroxy C １～６ Selected from 4-6 membered heterocycloalkyls containing 1-3 heteroatoms selected from alkyl, N, S, and O, Alternatively, R ４ and R ５ Each of these is linked to a carbon atom, along with C ３～６ A cycloalkyl, a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, or forming a double bond, n is selected from 0, 1, 2, 3, 4, and if n is greater than 1, R １ They may be the same or they may be different.

2. R １ It is hydrogen, fluorine, chlorine, -CO ２ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from H, cyano, methoxy, methyl, difluoromethyl, trifluoromethyl, and formylamino.

3. R ２ The compound according to claim 1, its stereoisomer, or pharmaceutical is selected from hydrogen, methyl, methoxy, cyano, difluoromethyl, trifluoromethyl, and cyclopropyl. A generally acceptable salt.

4. R ３ is a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from methyl.

5. R ４ , R ５ , R ６ The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt, wherein each is independently selected from a 4-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from hydrogen, methyl, halogen, alkenyl, N, S, and O.

6. R ４ , R ５ The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt, wherein each carbon atom contains one to three heteroatoms selected from N, S, and O, together with the carbon atoms to which it is linked, forming a 4- to 6-membered heterocycloalkyl group or a double bond. 【Request Item 7】 【Chemistry 3】 is a compound according to any one of claims 4 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from the following groups. 【Chemistry 4】

8. The compound represented by formula (I-1), its stereoisomer, or a pharmaceutically acceptable salt. 【Transformation 5】 (Here, R １ , ring A, n, R ４ , R ５ , R ６ , X １ , X ２ , X ３ (This is as defined in claim 1.)

9. The compound represented by formula (I-2), its stereoisomer, or a pharmaceutically acceptable salt. 【Transformation 6】 (Here, X １ , X ２ , X ３ , R １ (Ring A, n is as defined in claim 1.)

10. Compounds represented by formulas (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), their stereoisomers, or pharmaceutically acceptable salts. 【Transformation 7】 (Here, R １ (Ring A, n is as defined in claim 1.)

11. The compound is a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from the following structures. 【Chemistry 8-1】 【Chemistry 8-2】

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a drug for treating a disease or disorder mediated by connexin-related kinase 1 activity, wherein the disease or disorder is preferably selected from Alzheimer's disease, bipolar disorder, Parkinson's disease, schizophrenia, diabetic peripheral neuropathy, and postherpetic neuralgia.

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