Method for preparing benzofuran derivatives

Abstract

Method for preparing benzofuran derivatives. Specifically, the present invention relates to a method for preparing benzofuran derivatives represented by formula I, which has a greatly improved yield and good applicability. [Formula 1] TIFF2024537339000039.tif31168

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application Publication No. 2021112061010 (filing date: October 15, 2021). This application cites the full text of the above-mentioned Chinese patent application.

[0002] The present disclosure relates to a method for preparing benzofuran derivatives, which is in the field of pharmaceutics. [Background technology]

[0003] Lymphoma is a malignant tumor originating from the lymphocytic blood-producing system. Based on the tumor cells, it is classified into two types: non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). In Asian regions, 90% of patients have NHL, which pathologically mainly involves different levels of lymphocyte, histiocytic, or reticulocyte differentiation. Based on the natural history of NHL, it can be classified into three clinical types: highly infiltrative lymphoma, infiltrative lymphoma, and indolent lymphoma. Based on the origin of various lymphocytes, it can be classified as follows; B-cell lymphoma, T-cell lymphoma, and NK (natural killer) cell lymphoma. The main function of B cells is to secrete various antibodies to help defend the body against various exogenous insults.

[0004] The histone methyltransferase encoded by the EZH2 gene is a catalytic component of polycomb repressive complex 2 (PRC2). In cancer tissues, the expression level of EZH2 is abnormally high compared to normal tissues, while the expression level of EZH2 is highest in advanced cancers or those with poor prognosis. In some types of cancer, overexpression of EZH2 occurs simultaneously with amplification of the EZH2 gene. In a number of si / shRNA experiments, it has been found that reducing the expression of EZH2 in tumor cell lines inhibits tumor cell proliferation, migration, and invasion or angiogenesis, and leads to apoptosis.

[0005] An EZH2 inhibitor is provided in WO2017084494A having the following structure: [ka]

[0006] Although WO2019091450A also discloses a method for preparing the aforementioned compounds, the present disclosure provides a method for preparing a pharma- ceutically acceptable salt of the compound, which is designed to simplify the preparation process and reduce production costs. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2017084494A Brochure [Patent Document 2] International Publication No. 2019091450A Brochure Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides a process for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula VI with a compound of formula VII. [ka] [In the formula, R 1 are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R A is replaced by R Ais selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, and alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally selected from one or more R B is replaced by R B is selected from halogen, hydroxy, cyano, amino, and nitro; n is selected from 1 or 2; X is selected from halogen.

[0009] In an optional embodiment, the process for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof comprises reacting a compound of formula VI with a compound of formula VII under the action of a condensing agent.

[0010] In an optional embodiment, the condensing agent is selected from N,N-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (4-PPY), 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), 2-(7-azabenzotriazole)-N,N',N',N'-tetramethylurea hexafluorophosphate (HATU), and O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU).

[0011] In an optional embodiment, the condensing agent is selected from a combination of EDCI and HOBT.

[0012] In an optional embodiment, the compound of formula V or a pharma- ceutically acceptable salt thereof is prepared and reacted in a basic environment.

[0013] In an optional embodiment, the method for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof comprises a basic environment selected from the group consisting of triethylamine, pyridine, and N,N-diisopropylethylamine (DIPEA).

[0014] In an optional embodiment, in the method for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof in the present disclosure, the reaction solvent is selected from N,N-dimethylformamide (DMF) or dichloromethane.

[0015] In an optional embodiment, the method for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof includes reacting compound 1 with 3-(aminomethyl)-4,6-lutidin-2(1H)-one to obtain compound 2. [ka]

[0016] In yet another aspect of the present disclosure, there is provided a method for preparing a compound of formula III or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula V with a compound of formula IV. [ka] [In the formula, Ring A is selected from cycloalkyl and heterocycloalkyl; R 7 is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from one or more R C It is replaced with RC is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; m is selected from 0, 1, 2, 3, 4, 5, or 6; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are each as defined in the compound of formula V.

[0017] In an optional embodiment, in the process for preparing a compound of formula III or a pharma- ceutically acceptable salt thereof, a compound of formula V is reacted with a compound of formula IV in the presence of a palladium catalyst and a phosphine ligand catalyst.

[0018] In an optional embodiment, the palladium catalyst is bis(dibenzylideneacetone)palladium (Pd(dba)2).

[0019] In an optional embodiment, the phosphine ligand catalyst is R-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthalene (BINAP).

[0020] In an optional embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is reacted in a basic environment.

[0021] In an optional embodiment, the process for preparing the compound of formula III or a pharma- ceutically acceptable salt thereof comprises a basic environment selected from potassium tert-butanol (tBuOK) and / or sodium tert-butanol (tBuONa).

[0022] In an optional embodiment, the method for preparing a compound of formula III or a pharma- ceutically acceptable salt thereof includes reacting compound 2 with 4-aminotetrahydropyran to obtain compound 3. [ka]

[0023] In an optional embodiment, the method for preparing a compound of formula III or a pharma- ceutically acceptable salt thereof obtained in the present disclosure further comprises the steps in the method for preparing a compound of formula V or a pharma- ceutically acceptable salt thereof described above.

[0024] In yet another aspect of the disclosure, there is provided a process for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula III with a compound of formula II. [ka] [In the formula, R 8 is alkyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n, and m are each as defined in the compound of formula III.

[0025] In an optional embodiment, the process for preparing the compound of formula I or a pharma- ceutically acceptable salt thereof is carried out in a mildly acidic environment.

[0026] In an optional embodiment, in the process for preparing a compound of Formula I or a pharma- ceutically acceptable salt thereof, a weakly acidic environment is provided by acetic acid.

[0027] In an optional embodiment, in the process for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof, a compound of formula III is reacted with a compound of formula II in the presence of a reducing agent.

[0028] In an optional embodiment, the reducing agent is selected from sodium borohydride or sodium cyanoborohydride.

[0029] In an optional embodiment, the method for preparing a compound of formula I or a pharma- ceutically acceptable salt thereof includes reacting compound 3 with acetaldehyde to give compound 4. [ka]

[0030] In an optional embodiment, the method for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof, provided in the present disclosure further comprises the steps in the above-mentioned method for preparing a compound of formula V, or a pharma- ceutically acceptable salt thereof, and / or the steps in the above-mentioned method for preparing a compound of formula III, or a pharma- ceutically acceptable salt thereof.

[0031] In an optional embodiment, the present disclosure provides a process for preparing a compound of formula I or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) reacting a compound of formula I with a soluble salt thereof; [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n, and m are as defined above.]

[0032] In an optional embodiment, the method for preparing a compound of formula I or a pharma- ceutically acceptable salt thereof provided in the present disclosure includes the steps of: [ka]

[0033] In yet another aspect of the present disclosure, there is provided a compound of formula III, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n, and m are as defined above.]

[0034] In an optional embodiment, the compound of formula III provided herein or a pharma- ceutically acceptable salt thereof is as follows: [ka]

[0035] In yet another aspect of the present disclosure, there is provided a compound of formula V, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and m are as defined above.]

[0036] In an optional embodiment, the compound of formula V obtained according to the present disclosure, or a pharma- ceutically acceptable salt thereof, is as follows: [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Unless otherwise specified, terms used in the specification and claims have the following meanings.

[0038] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight or branched groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 carbon atoms. Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-hexyl, n-octyl, n-heptyl, isooctyl, decyl, undecyl, dodecyl, and the various branched isomers thereof.

[0039] The term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon substituent having a cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptidyl, cycloheptidyl, cyclooctyl, and the like. Polycycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0040] The term "heterocycloalkyl" refers to an alkyl group in which one or more ring atoms are nitrogen, oxygen, or S(O). m(where m is an integer 0-2) (excluding rings in which a portion of the ring is -OO-, -OS-, or -SS- and the remaining ring atoms are carbon) refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms. It is preferred that it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms. It is more preferred that it contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms. It is more preferred that it contains 5 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, high piperazinyl, etc. Polycyclic heterocyclyl groups include spirocyclic, fused ring, and bridged ring heterocyclyl groups.

[0041] Heterocyclyl rings may be fused to aryl, heteroaryl, or cycloalkyl rings where the ring attached to the parent structure is a heterocyclyl group, non-limiting examples include: [ka]

[0042] The term "aryl" refers to all-carbon monocyclic or fused polycyclic groups having a conjugated pi-electron system (i.e., rings sharing adjacent pairs of carbon atoms), preferably 6 to 10 members, such as phenyl and naphthyl. Aryl rings may be fused to heteroaryl, heterocyclyl, or cycloalkyl rings, where the ring attached to the parent structure is an aryl ring, non-limiting examples include: [ka]

[0043] Aryl groups may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from one or more of the following substituents: halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, and heterocyclyl.

[0044] The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5-10 membered, such as: furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazolyl, and the like. Heteroaryl rings may be fused to aryl, heterocyclyl, or cycloalkyl rings, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include: [ka]

[0045] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from one or more of the following substituents: halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0046] The term "haloalkyl" refers to an alkyl substituted with one or more halogens, where alkyl is as defined above. The term "hydroxyl" refers to an -OH group.

[0047] The term "hydroxyalkyl" refers to an alkyl substituted with a hydroxyl group, where the alkyl group is as defined above.

[0048] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] The term "amino" refers to --NH.sub.2.

[0050] The term "cyano" refers to --CN.

[0051] The term "nitro" refers to --NO2.

[0052] The term "oxo" refers to =O.

[0053] In the chemical structures of the compounds described in this disclosure, [ka] represents an unspecified configuration, i.e., when chiral isomers are present in a chemical structure, the bond [ka] is the configuration [ka] or both of the following configurations: [ka] In the chemical structures of the compounds described in this disclosure, the bond [ka] does not specify a configuration, ie, it can have the Z or E configuration, or both.

[0054] The compounds and intermediates of the present disclosure may also exist in various tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of various energies that can tautomerize through a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include tautomerization via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactimide isomerization. An example of lactam-lactimide equilibrium is shown below between A and B. [ka]

[0055] All compounds in this disclosure can be designated as Type A or Type B. All tautomeric forms are within the scope of this disclosure. Tautomerism is not excluded from the naming of the compounds.

[0056] Pharmaceutically acceptable salts of the present disclosure include, but are not limited to, solvates in solvents including, but not limited to, water, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, n-propanol, 2-butanone, propylene glycol monomethyl ether, n-heptane, cyclohexane, and n-hexane.

[0057] The term "optional" or "optionally" means that the event or circumstance described thereafter can or must occur, but rather that the statement containing the event or circumstance may or may not occur in a given setting. For example, the statement "optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and includes situations in which the heterocyclic group is substituted with an alkyl group and situations in which the heterocyclic group is not substituted with an alkyl group.

[0058] The term "substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are replaced independently with the respective number of substituents. It goes without saying that the substituents are present only where they are chemically possible, and the skilled person can determine (experimentally or theoretically) possible or unlikely substitutions without too much difficulty. For example, amino or hydroxyl groups with free hydrogens can be unstable if they are attached to carbon atoms with unsaturated (e.g. ethylenically) bonds.

[0059] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts, or prodrugs thereof with other chemical components, as well as other components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism to facilitate absorption of the active ingredient, thereby exerting biological activity. The "purity" or "content" described in this disclosure is determined by detection by HPLC, and the structural analysis data of the compound is obtained by analysis of the nuclear magnetic resonance spectrum. The reactants used in this disclosure can be purchased through commercial routes. EXAMPLES

[0060] Hereinafter, the present disclosure will be described in more detail with reference to embodiments, but these embodiments are only used to illustrate the technical solutions of the present disclosure, and the substance and scope of the present disclosure are not limited thereto.

[0061] The structures of the compounds of the present disclosure have been determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (shifts) R are within the range of 10 -6 The concentrations are expressed in ppm. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0062] For the MS measurements, a FINNIGAN LCQ Ad(ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) was used.

[0063] HPLC was measured using a WATER e2695-2489 high performance liquid chromatograph.

[0064] Known starting materials of the present disclosure can be synthesized using or according to methods known to those skilled in the art, or can be purchased commercially, for example from companies such as BEPHARM.

[0065] Method for preparing compound 4 of embodiment 1 [ka] Step 1. Synthesis of compound 2 4L of DMF, 500g of the compound of formula 1, and 800g of DIPEA were added in this order into a reaction vessel. After stirring, 335.5g of HOBt, 476g of EDCI, and 257.5g of 3-(aminomethyl)-4,6-lutidin-2(1H)-one were added in this order, followed by 1L of DMF. It was heated to an internal temperature of 40°C and stirred until the reaction was complete. Water was added to precipitate the solid, which was then stirred and filtered by shaking. After washing with water and drying, the compound of formula 2 (580g) was obtained in 94% yield. [ka]

[0066] Step 2. Synthesis of compound 3 0.46g of Pd(dba)2 and 2.0g of BINAP were weighed. They were mixed thoroughly and then added to the reaction vessel. Then, vacuum-N2 replacement was performed and 20.0g of the compound of formula 2, 11.52g of tBuONa and 3.2g of tBuOLi were added. Under N2 protection, 200mL of 1,4-dioxane was added, followed by 8.08g of 4-aminotetrahydropyran. With stirring, the temperature was raised to 100°C and the reaction was refluxed for 24 hours to complete the reaction, and then work-up was started.

[0067] Water was added to quench the reaction solution and DCM was used to wash the aqueous phase. The organic phase was discarded and the aqueous phase was kept. DCM was then added to the aqueous phase for extraction, the aqueous phase was discarded and the organic phase was kept. Aqueous NaHSO3 was added and the internal temperature was raised to 30-40°C. After stirring for 1 hour, the separated solution was allowed to settle. The organic phase was separated. After drying, vacuum filtration and dehydration, crude compound of formula 3 was obtained.

[0068] MTBE was added, stirred, refluxed and plowed. Later, n-heptane was added and cooled to crystallize. The mother liquor was shaken and filtered, and the filter cake was washed with n-heptane. After drying, the compound of formula 3 (17.3 g) was obtained with a yield of 83%. [ka]

[0069] Step 3. Synthesis of compound 4 50 mL of DCM was added to the reaction vessel, and 5.0 g of the compound of formula 3 was added while stirring. It was dissolved and the temperature was lowered to 0-10°C. 2.11 g of acetaldehyde and 0.576 g of acetic acid were added in this order and stirred for 0.5 hours. Then 6.31 kg of sodium borohydride acetate was added, and the temperature was gradually raised to 25°C under N2 protection to complete the reaction. Water, NaOH were added, the liquid phase was separated, saturated sodium bicarbonate solution was added for washing, dried, filtered, and spin-dried. Methyl tert-butyl ether was added to the vessel, and after stirring to dissolve, it was heated to reflux. n-Heptane was added dropwise, cooled to crystallize, and filtered to obtain crude compound of formula 4 (5.0 g) in 95% yield. [ka]

Claims

1. A process for preparing a compound of formula V, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula VI, or a pharmaceutically acceptable salt thereof, with a compound of formula VII, or a pharmaceutically acceptable salt thereof. 【Chemical 1】 [In the formula, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; n is selected from 1 or 2; X is a halogen.

2. 10. A process for preparing the compound of formula V or a pharmaceutically acceptable salt thereof according to claim 1, comprising reacting compound 1 or a pharmaceutically acceptable salt thereof with 3-(aminomethyl)-4,6-lutidin-2(1H)-one to obtain compound 2 or a pharmaceutically acceptable salt thereof. 【Chemistry 2】

3. A process for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula V or a pharmaceutically acceptable salt thereof with a compound of formula IV or a pharmaceutically acceptable salt thereof. 【Chemistry 3】 [In the formula, Ring A is selected from cycloalkyl and heterocycloalkyl; R ７ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from one or more R Ｃ wherein R Ｃ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; m is selected from 0, 1, 2, 3, 4, 5, or 6; Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; n is selected from 1 or 2; X is a halogen.

4. 4. A process for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 3, comprising reacting compound 2 or a pharmaceutically acceptable salt thereof with 4-aminotetrahydropyran to obtain compound 3 or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 5. A method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 3 or 4, comprising reacting a compound of formula VI or a pharmaceutically acceptable salt thereof with a compound of formula VII or a pharmaceutically acceptable salt thereof to prepare a compound of formula V or a pharmaceutically acceptable salt thereof. 【Chemistry 5】 [In the formula, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; n is selected from 1 or 2; X is a halogen.

6. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula III, or a pharmaceutically acceptable salt thereof, with a compound of formula II, or a pharmaceutically acceptable salt thereof. 【Chemistry 6】 [In the formula, R ８ is alkyl, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; Ring A is selected from cycloalkyl and heterocycloalkyl; R ７ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from one or more R Ｃ wherein R Ｃ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; m is selected from 0, 1, 2, 3, 4, 5 or 6; n is selected from 1 or 2.

7. 7. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, comprising reacting compound 3 or a pharmaceutically acceptable salt thereof with acetaldehyde to obtain compound 4 or a pharmaceutically acceptable salt thereof. 【Chemistry 7】 8. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6 or 7, comprising reacting a compound of formula VII or a pharmaceutically acceptable salt thereof with formula VI or a pharmaceutically acceptable salt thereof to prepare a compound of formula V or a pharmaceutically acceptable salt thereof: 【Chemistry 8】 The method further comprises reacting a compound of formula V, or a pharmaceutically acceptable salt thereof, with a compound of formula IV, or a pharmaceutically acceptable salt thereof, to prepare a compound of formula III, or a pharmaceutically acceptable salt thereof. 【Chemistry 9】 [In the formula, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; Ring A is selected from cycloalkyl and heterocycloalkyl; R ７ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from one or more R Ｃ wherein R Ｃ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; m is selected from 0, 1, 2, 3, 4, 5, or 6; n is selected from 1 or 2; X is a halogen.

9. 9. A process for preparing the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, comprising: reacting compound 1, or a pharmaceutically acceptable salt thereof, with 3-(aminomethyl)-4,6-lutidin-2(1H)-one to prepare compound 2, or a pharmaceutically acceptable salt thereof; reacting compound 2, or a pharmaceutically acceptable salt thereof, with 4-aminotetrahydropyran to prepare compound 3, or a pharmaceutically acceptable salt thereof; and reacting compound 3, or a pharmaceutically acceptable salt thereof, with acetaldehyde to prepare compound 4, or a pharmaceutically acceptable salt thereof. 【Chemistry 10】

10. A compound of formula III: or a pharmaceutically acceptable salt thereof. 【Chemistry 11】 [In the formula, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; Ring A is selected from cycloalkyl and heterocycloalkyl; R ７ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from one or more R Ｃ wherein R Ｃ is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; m is selected from 0, 1, 2, 3, 4, 5, or 6; n is selected from 1 or 2.

11. 11. The compound of formula III according to claim 10, wherein: or a pharmaceutically acceptable salt thereof. 【Chemistry 12】

12. A compound of formula V: or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 [In the formula, Each R １ are the same or different and each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ａ wherein R Ａ is selected from halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, and heterocycloalkyl, wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally selected from one or more R Ｂ wherein R Ｂ is selected from halogen, hydroxy, cyano, amino, and nitro; n is selected from 1 or 2; X is a halogen.

13. 13. The compound of formula V according to claim 12, wherein: or a pharmaceutically acceptable salt thereof. 【Chemistry 14】

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof prepared by the method of claim 6 or 7, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. A process for preparing a compound of formula V or a pharmaceutically acceptable salt thereof according to claim 1, comprising: R 1 is alkyl substituted with R A , wherein said R A is heterocycloalkyl; R 2 , R 4 and R 6 are each independently alkyl; R 3 and R 5 are hydrogen; n is 1, The method wherein X is bromine.

16. A process for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 3, comprising: R 1 is alkyl substituted with R A , wherein said R A is heterocycloalkyl; R 2 , R 4 and R 6 are each independently alkyl; R 3 and R 5 are hydrogen; n is 1, Ring A is heterocycloalkyl; The method wherein m is 0.

17. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, comprising: R 1 is alkyl substituted with R A , wherein said R A is heterocycloalkyl; R 2 , R 4 and R 6 are each independently alkyl; R 3 and R 5 are hydrogen; R 8 is alkyl; n is 1, Ring A is heterocycloalkyl; The method wherein m is 0.

18. A process for preparing a compound of formula V or a pharmaceutically acceptable salt thereof according to claim 1, comprising:

1. A method comprising reacting a compound of Formula VI or a pharmaceutically acceptable salt thereof with a compound of Formula VII or a pharmaceutically acceptable salt thereof in the presence of a condensing agent selected from N,N-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (4-PPY), 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), or a combination thereof.

19. The method for preparing a compound of formula V or a pharmaceutically acceptable salt thereof according to claim 18, wherein the condensing agent is a combination of EDCI and HOBT.

20. A process for preparing a compound of formula V or a pharmaceutically acceptable salt thereof according to claim 1, comprising: A process comprising reacting a compound of formula VI, or a pharmaceutically acceptable salt thereof, with a compound of formula VII, or a pharmaceutically acceptable salt thereof, in the presence of a base.

21. The method for preparing a compound of formula V or a pharmaceutically acceptable salt thereof according to claim 20, wherein the base is N,N-diisopropylethylamine (DIPEA).

22. A process for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 3, comprising: A process comprising reacting a compound of formula V, or a pharmaceutically acceptable salt thereof, with a compound of formula IV, or a pharmaceutically acceptable salt thereof, in the presence of a palladium catalyst and a phosphine ligand.

23. The method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 22, wherein the palladium catalyst is bis(dibenzylideneacetone)palladium (Pd(dba) 2 ) and the phosphine ligand is R-(+)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (BINAP).

24. A process for preparing a compound of formula III or a pharmaceutically acceptable salt thereof according to claim 3, comprising: A process comprising reacting a compound of formula V, or a pharmaceutically acceptable salt thereof, with a compound of formula IV, or a pharmaceutically acceptable salt thereof, in the presence of a base.

25. The method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof of claim 24, wherein the salt is a combination of tBuONa and tBuOLi.

26. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, comprising: A process comprising reacting a compound of formula III, or a pharmaceutically acceptable salt thereof, with a compound of formula II, or a pharmaceutically acceptable salt thereof, in the presence of acetic acid.

27. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 26, comprising: A process comprising reacting a compound of formula III, or a pharmaceutically acceptable salt thereof, with a compound of formula II, or a pharmaceutically acceptable salt thereof, in the presence of a reducing agent.

28. The method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 27, wherein the reducing agent is sodium borohydride acetate.

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