Pyrimidine compounds, methods for their preparation, and their medical use

Abstract

Pyrimidine compounds, methods for preparing them, and their medical uses are disclosed. Specifically, compounds represented by general formula (SI), methods for preparing them, pharmaceutical compositions containing the compounds, and their use as ubiquitin-specific protease 1 (USP1) inhibitors, particularly for the treatment or prevention of cancer, are disclosed. The definitions of the groups in general formula (SI) are the same as those in the specification. JPEG2026523087000394.jpg25170

Description

[Technical Field]

[0001] The present invention relates to a class of compounds having inhibitory activity against USP1, compositions comprising the same, and their use in the preparation of pharmaceuticals for the treatment of USP1 enzyme-related diseases. Specifically, the present invention relates to compounds of formula (SI), or pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers thereof. [Background technology]

[0002] Ubiquitination, as a dynamic and reversible process, involves a family of deubiquitinating enzymes (DUBs). Humans possess approximately 100 DUBs, which can be divided into the cysteine ​​protease family and the metalloproteinase family. Among these, the cysteine ​​protease family primarily includes ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), Machado-Josephine domain proteases (MJDs), MINDY proteases (MINDY), and ovarian tumor domain proteases (OTUs). The USP family is the largest family of known deubiquitinating enzymes, with over 50 types encoded by human genes. USPs play a role in various physiological functions, such as cell cycle, signal transduction, DNA damage repair, chromosomal translocation, and gene transcription, by regulating protease substrates.

[0003] USP1 belongs to the USP subfamily of DUB and does not exhibit significant activity on its own. However, by binding with UAF1 to form a heterodimer complex (USP1 / UAF1), USP1 acquires full enzymatic activity and can modulate cellular targets in numerous cancer-related pathways. For example, the USP1 / UAF1 complex prevents excessive repair of proliferating cell nuclear antigen (PCNA) monoubiquitinated by the major protein during damage overcome synthesis (TLS) by enabling deubiquitination of the major protein-mediated monoubiquitinated Fanconi anemia complement D2 (FANCD2) in the Fanconi anemia (FA) pathway, thereby preventing improper TLS repair in cells and ensuring genomic stability. These two DNA damage response (DDR) pathways are important pathways for repairing DNA damage induced by DNA crosslinking agents, such as cisplatin, mitomycin, and ultraviolet light. USP1 also interacts with ID proteins and can stabilize their expression within cells through deubiquitination. For example, in osteosarcoma cells, USP1 can deubiquitinate ID1, ID2, and ID3, promoting cell proliferation, and inhibition of USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. In addition, some studies demonstrate that USP1 is closely associated with the development of resistance to various drugs used for tumor treatment. For example, in non-small cell lung cancer (NSCLC) cells resistant to cisplatin, USP1 is highly expressed, and knockdown of USP1 can significantly increase the sensitivity of cells to cisplatin. In breast cancer cells, USP1 is highly expressed, promoting breast cancer cell proliferation and is closely associated with a poor prognosis of breast cancer.As reported in the literature (J. Med. Chem. 2014, 57, pp. 8099-8110, "Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1 / UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer"), compounds such as ML323, which are USP1 inhibitors, can be used for nonsmall cell lung cancer. As reported in the literature (Cui SZ, Lei ZY, Gua nT-P et al., "Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy." Cancer Sci. 2020; pp. 00:1-15), USP1 inhibitors are being used as promising therapeutic agents for prostate cancer. In summary, USP1 is expected to be a hot target for the treatment of various cancers and other diseases. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] J. Med. Chem. 2014, 57, pp. 8099-8110, Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1 / UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer [Non-Patent Document 2] Cui S-Z, Lei Z-Y, Guan T-P, et al., Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020; 00:1-15 pages

Summary of the Invention

Means for Solving the Problems

[0005] The present invention relates to a compound of formula (I'),

Chemical Formula

Chemical Formula

[0006] In some embodiments, the compound of formula (I') is of formula (I) [ka] [In the formula, ring A, ring B, L, R a , R b The compound is such that R2-R5 and n are as defined in formula (I').

[0007] In some embodiments, R2 consists of H atom, -OH, -CN, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 2~6 Alkinyl, -C 1~6 Alkylene-C 6~10 Ariel, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~6 Selected from the group consisting of cycloalkyls and 5-7 membered heterocyclines, C 1~6 Alkyl or -C 1~6 Alkylene-C 6~10 The aryl is optionally replaced by one or more R1s, where R1 is as defined in formula (I'), Preferably, R2 is selected from the group consisting of H atom, -CN, methyl, triduteriomethyl, ethinyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy, and hydroxy. and / or R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl-O-, 5-7 membered heterocyclyl and -C 1~6 Alkylene-C(O)-OC 1~6 Selected from the group consisting of alkyl groups, C 1~6 Hydroxyalkyl and 5-7 membered heterocyclyl each independently have one or more C 1~6 It is sometimes substituted with alkyl groups. Preferably, R3 is H atom, methoxy, cyclopropyl-O-, trifluoromethyl, Cl atom, -CN, isopropoxy, ethynyl, difluoromethoxy, morpholinyl, [ka] -OH, [ka] F atom, hydroxymethyl and [ka] Selected from the group consisting of, and / or R4 consists of H atoms, -OH, -COOH, -NH2, -CN, halogens, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl groups, Preferably, a compound of formula (I) or (I') is provided, wherein R4 is a hydrogen atom.

[0008] In some embodiments, the compound of formula (I') or (I) is of formula (II) [ka] [In the formula, ring C is, [ka] Selected from the group consisting of, Each existing R6 is independently H or C 1~ It is either a C6 alkyl group, or two R6 atoms together with the atom to which they are bonded, C 3~8 Forming cycloalkyl or 3-8 membered heterocyclines, Ring A, Ring B, L, R a , R b R4, R5 and n are as defined in formula (I'), especially, R4 consists of H atoms, -OH, -COOH, -NH2, -CN, halogens, and C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 It is a compound selected from the group consisting of hydroxyalkyl groups, preferably in which R4 is a H atom.

[0009] In some embodiments, the compound of formula (I') is the compound of formula (III) [ka] [In the formula, ring D is, [ka] Selected from the group consisting of, Each of the above bases is independently and optionally substituted by one or more R1s. R, R a , R bR1, R2, R5 and n are as defined in formula (I'), Specifically, R2 consists of an H atom, -OH, and C. 1~6 Alkyl, C 2~6 Alkinyl, -C 1~6 Alkylene-C 6~10 Ariel, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl, C 1~6 Alkyl or C 1~6 Alkyl-C 6~10 The aryl is optionally replaced by one or more R1, where R1 is as defined in formula (I'), Preferably, R2 is an H atom or [ka] It is.

[0010] In some embodiments, Ring A and Ring B are independently phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, pentacyclooctanyl, isoindolinonyl, imidazo[1,2-a]pyradinyl, piperidine-2,6-dionyl, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, morpholini A selection is made from the group consisting of R1, naphthyl, pyrrolyl, pyrazinyl, pyridadinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indolinonyl, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, and cubanyl, wherein ring A and ring B are each independently and optionally substituted with one or more R1, and R1 is as defined in formula (I'), L is a chemical bond, -O-, -OC 1~6 Alkylene and -C 1~6Selected from the group consisting of alkylene-O-, in particular, [ka] but, [ka] A group consisting of is selected, where ring A and ring B are each independently and optionally substituted with one or more R1, and R1 is as defined in formula (I'), More specifically, [ka] but, [ka] [ka] A compound of formula (I'), (I), (II), or (III) is provided, selected from the group consisting of the following.

[0011] In some embodiments, R is C 6~10 C condensed with aryl or 5-6 member heteroaryl 6~10 It is aryl, and each of the above groups is independently oxo, C 1~6 Alkyl, -OC 1~6 Alkylene-OC 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkyl groups. Specifically, R is [ka] And, R2 consists of H atom, -OH, and C 1~6 Alkyl, C 2~6 Alkinyl, -C 1~6 Alkylene-C 6~10 Ariel, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl groups, preferably, R2 is a H atom. R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl groups, preferably R3 is methoxy, R4 consists of H atoms, -OH, -COOH, -NH2, -CN, halogens, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl groups, preferably R4 is a H atom, Alternatively, a compound of formula (I') is provided, wherein R3 and R4, together with the atom to which they are bonded, form a ring D, and ring D is a 5-7 member heteroaryl or 5-7 member heterocyclyl, preferably furanyl.

[0012] In some embodiments, R5 is C 6~10 C is condensed with aryl, 5-6 member heteroaryl, and 5-6 member heterocyclyl. 6~10 C condensed with aryl and 5-6 member heteroaryls 6~10 Selected from the group consisting of aryls, preferably selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indolinyl and isoxazolyl, C 6~10 C is condensed with aryl, 5-6 member heteroaryl, and 5-6 member heterocyclyl. 6~10 C condensed with aryl and 5-6 member heteroaryls 6~10 Each aryl group independently consists of -OH, -COOH, -NH2, -CN, halogen, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl and C 3~6 Optionally substituted with one or more substituents selected from the group consisting of cycloalkyl compounds, Specifically, R5 is, [ka] A compound of formula (I'), (I), (II), or (III) is provided, selected from the group consisting of the following.

[0013] In some embodiments, compounds of formula (I'), (I), (II), or (III) are provided, where n is 0 or 1.

[0014] In some embodiments, R a and R b These are, independently, H atom, -CN, and C. 1~6 Selected from the group consisting of alkyl, -OH, and halogen, Preferably, R a and R b This provides compounds of formula (I'), (I), (II), or (III), each independently comprising either a hydrogen atom or a -CN atom.

[0015] Typical compounds of formula (I) or (I') of the present invention include, but are not limited to, the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes.

[0016] The present invention also provides a method for preparing a compound of formula (I'), [ka] The step of reacting a compound of formula (IA) with a compound of formula (IB') to obtain a compound of formula (I'), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. R, R a , R b , step R2~R5 and n are as defined in equation (I'), or [ka] The step involves reacting a compound of formula (IC') with a compound of formula (ID) to obtain a compound of formula (I'), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. R, R a , R b , step R2~R5 and n are as defined in equation (I'), or [ka] The step of reacting a compound of formula (IE) with a compound of formula (IB') to obtain a compound of formula (IF'), and then deprotecting the compound of formula (IF') to obtain a compound of formula (I'), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Y is a hydroxy protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl, and ethoxyethyl. R2 is hydroxyl, R, R a , R b , step R3~R5 and n are as defined in formula (I'), or [ka] The step involves reacting a compound of formula (IG') with a compound of formula (ID) to obtain a compound of formula (IH'), and then deprotecting the compound of formula (IH') to obtain a compound of formula (I'), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Y is a hydroxy protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl, and ethoxyethyl. R2 is hydroxyl, R, R a , R b , step R3~R5 and n are as defined in formula (I'), or [ka] The step of reacting a compound of formula (IC') with a compound of formula (IJ) to obtain a compound of formula (I'), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. R, R a , R b The step in which R2~R5 and n are as defined by equation (I'). This provides a method that includes [something].

[0017] The present invention also provides a method for preparing a compound of formula (I), [ka] The step of reacting a compound of formula (IA) with a compound of formula (IB) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, L, R a , R b , step R2~R5 and n are as defined in equation (I'), or [ka] The step of reacting a compound of formula (IC) with a compound of formula (ID) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, L, R a , R b , step R2~R5 and n are as defined in equation (I'), or [ka] The steps include reacting a compound of formula (IE) with a compound of formula (IB) to obtain a compound of formula (IF), and deprotecting the compound of formula (IF) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Y is a hydroxy protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl, and ethoxyethyl. R2 is hydroxyl, Ring A, Ring B, L, R a , R b , step R3~R5 and n are as defined in formula (I'), or [ka] The step of reacting a compound of formula (IG) with a compound of formula (ID) to obtain a compound of formula (IH), and then deprotecting the compound of formula (IH) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Y is a hydroxy protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl, and ethoxyethyl. R2 is hydroxyl, Ring A, Ring B, L, R a , R b , step R3~R5 and n are as defined in formula (I'), or [ka] The step of reacting a compound of formula (IC) with a compound of formula (IJ) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, L, R a , R b The present invention provides a method that includes the step of having R2 to R5 and n as defined by formula (I').

[0018] This invention relates to the compound of formula (SI) [ka] or its pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers. [In the formula, Ring A and Ring B are independent of each other, C 6~10 Aryl, 5-10 member heteroaryl, C 3~8Selected from the group consisting of cycloalkyls and 3- to 8-membered heterocyclines, ring A and ring B are each independently optionally substituted with one or more R1 groups. Ring E is C 6~10 C is condensed with aryl, 5-6 member heteroaryl, and 5-6 member heterocyclyl. 6~10 C condensed with aryl and 5-6 member heteroaryls 6~10 Selected from the group consisting of aryls, ring E is optionally substituted with one or more R1s. L represents a chemical bond, -O-, -S-, -C 1~6 Alkylene-,-OC 1~6 Alkylene-,-C 1~6 Alkylene-O-,-SC 1~6 Alkylene- and -C 1~6 Selected from the group consisting of alkylene-S-, R a and R b These are, independently, H atom, -CN, and C. 1~6 alkyl, -OH, halogen, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Selected from the group consisting of haloalkoxys, or R a and R b They come together, oxo, C 3~8 Forming a cycloalkyl or 3-8 membered heterocycline, C 1~6 The alkyl group may be substituted with one or more R1 groups. R2 consists of H atom, -OH, -CN, and C. 1~6 Alkyl, -C 1~6 Alkylene-C 6~10 Ariel, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 member heteroaryl, C3~8 Selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclines, C 1~6 Alkyl or -C 1~6 Alkylene-C 6~10 The aryl is optionally replaced by one or more R1s. R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, -SC 1~6 Alkyl, -S(O)-C 1~6 Alkyl, -S(O)2-C 1~6 Alkyl, phosphoryl, phosphonyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 member heteroaryl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-O-, 3-8 membered heterocyclyl and -C 1~6 Alkylene-C(O)-OC 1~6 Selected from the group consisting of alkyl groups, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 member heteroaryl, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines are each independently optionally substituted with one or more R1 groups. R4 consists of H atoms, -OH, -COOH, -NH2, -CN, halogens, and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C6~10 Aryl, 5-10 member heteroaryl, C 3~8 Selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclines, In each of the R1 present, independently, there is a D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, and C. 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 member heteroaryl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-O-, 3-8 membered heterocyclyl, -OC 1~6 Alkylene-OC 1~6 Selected from the group consisting of alkyl groups, C 6~10 Aryl, 5-10 member heteroaryl, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines are, independently of each other, a D atom, -OH, -COOH, -NH2, -CN, halogen, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy and C 1~6 Optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl groups, [n is an integer between 0 and 8].

[0019] In some embodiments, ring B is C 6~10 It is an aryl or 5-6 member heteroaryl, where ring B is optionally substituted with one or more R1s, and R1 is as defined in formula (SI). in particular, Ring B is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, piperazinyl, naphthyl, pyrrolyl, pyridadinyl, triazolyl, tetrazolyl, and furanyl, and ring B is optionally substituted with one or more R1, where R1 is as defined in formula (SI), More specifically, A compound of formula (SI) is provided, wherein ring B is imidazolyl, and ring B is optionally substituted with one or more R1, where R1 is as defined in formula (SI).

[0020] In some embodiments, the compound of formula (SI) is of formula (SII) [ka] [In the formula, In each existing R 1a These are independently D atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-6 member heteroaryl, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, C 3~6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, In each existing R 1b These are independently D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-6 member heteroaryl, C3~6 Cycloalkyl, C 3~6 Halocycloalkyl, C 3~6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, R 1c H atom, D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-6 member heteroaryl, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, C 3~6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, R 1d H atom, D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-6 member heteroaryl, C 3~6 Cycloalkyl, C 3~6 Halocycloalkyl, C 3~6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, m is 0, 1, or 2. p is 0, 1, or 2. Ring A, Ring E, R a , R b It is a compound of the formula (SI) [where R2-R4 and n are as defined by formula (SI)].

[0021] In some embodiments, Ring A is C 6~10 Ariel, C3~8 Selected from the group consisting of cycloalkyls and 3- to 8-membered heterocyclines, ring A is optionally substituted with one or more R1s, where R1 is as defined in formula (SI), in particular, Ring A is selected from the group consisting of phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, cubanil, piperidyl, pyranil, pyrrolidinyl, piperazinyl, and morpholinil, and Ring A is one or more R 1b It is replaced in some cases, R 1b This is as defined in equation (SII), More specifically, Ring A is selected from the group consisting of phenyl, cyclohexyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, and cubanyl, and ring A has one or more R 1b It is replaced in some cases, R 1b Compounds of formula (SI) or (SII) are provided, wherein the compound is as defined in formula (SII).

[0022] In some embodiments, [ka] but, [ka] A compound of formula (SI) or (SII) is provided, selected from the group consisting of the following.

[0023] In some embodiments, Ring E is C 6~10 It is an aryl or 5-6 member heteroaryl, in which the ring E is optionally substituted with one or more R1s, where R1 is as defined in formula (SI), in particular, Ring E is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, and isoxazolyl, and ring E is one R1c and one R 1d It is replaced in some cases, R 1c and R 1d This is as defined in equation (SII), More specifically, Ring E is selected from the group consisting of pyridinyl, pyrimidinyl, and imidazolyl, and ring E is one R 1c and one R 1d It is replaced in some cases, R 1c and R 1d However, as stipulated in (SII), More specifically, [ka] but, [ka] A compound of formula (SI) or (SII) is provided, selected from the group consisting of the following.

[0024] In some embodiments, n is either 0 or 1, and / or R a and R b However, each is independent of the H atom, -CN, and C. 1~6 Selected from the group consisting of alkyl, -OH, and halogen, Preferably, R a and R b However, each is independent of the H atom or C 1~6 It is alkyl, Comfortable, R a and R b Both are H atoms, or R a is an H atom, and R b Compounds of formula (SI) or (SII) are provided, wherein the compound is methyl.

[0025] In some embodiments, R2 consists of H atom, -OH, -CN, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C2~6 Alkinyl, -C 1~6 Alkylene-C 6~10 Ariel, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~6 Selected from the group consisting of cycloalkyl and 5-7 membered heterocyclyl, Preferably, R2 is selected from the group consisting of H atom, -CN, methyl, and triduteriomethyl. and / or R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~6 Cycloalkyl-O-, 5-7 membered heterocyclyl and -C 1~6 Alkylene-C(O)-OC 1~6 Selected from the group consisting of alkyl groups, Preferably, R3 is methoxy or cyclopropyl-O-, and / or R4 consists of H atoms, -OH, -COOH, -NH2, -CN, halogens, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 Selected from the group consisting of hydroxyalkyl groups, Preferably, a compound of formula (SI) or (SII) is provided, wherein R4 is a hydrogen atom.

[0026] In some embodiments, rings A, B, E, L, R a , R b R2~R4, R 1a , R 1b , R 1c , R 1dCompounds of formula (SI) or (SII) are provided, wherein m, n, and p are each independently the corresponding groups in compounds S1 to S51.

[0027] Typical compounds of the formula (SI) or (SII) of the present invention include, but are not limited to, the following compounds: [ka] [ka] Includes.

[0028] The present invention is a method for preparing a compound of formula (SI), [ka] The step of reacting a compound of formula (SIA) with a compound of formula (SIB) to obtain a compound of formula (SI), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, L, R a , R b The step in which R2~R4 and n are as defined by formula (SI). or [ka] The step of reacting a compound of formula (SIA) with a compound of formula (SIC) to obtain a compound of formula (SI), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, L, R a , R b The step in which R2~R4 and n are as defined by formula (SI). We also provide methods that include this.

[0029] The present invention also provides a method for preparing a compound of formula (SII), [ka] The step of reacting a compound of formula (SIIA) with a compound of formula (SIIB) to obtain a compound of formula (SII), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, R a , R b R2~R4, R 1a , R 1b , R 1c , R 1d Steps where m, n and p are as defined in formula (SII), or [ka] The step involves reacting a compound of formula (SIIA) with a compound of formula (SIIC) to obtain a compound of formula (SII), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, R a , R b R2~R4, R 1a , R 1b , R 1c , R 1d Steps where m, n, and p are as defined in formula (SII) This provides a method that includes [something].

[0030] The present invention also provides a pharmaceutical composition comprising at least one compound of formula (I'), (I), (II), (III), (SI), or (SII), and one or more pharmaceutically acceptable excipients.

[0031] The present invention relates to the use of compounds of formula (I'), (I), (II), (III), (SI), or (SII), or pharmaceutical compositions containing the same, in the preparation of pharmaceuticals for treating or preventing diseases or conditions associated with inhibition of ubiquitin-specific protease 1 (USP1).

[0032] The present invention specifically relates to the use of compounds of formula (I'), (I), (II), (III), (SI), or (SII) or pharmaceutical compositions containing the same in the preparation of pharmaceuticals for treating or preventing cancer selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

[0033] The present invention relates to compounds of formula (I'), (I), (II), (III), (SI), or (SII) or pharmaceutical compositions containing the same, for use as pharmaceuticals.

[0034] The present invention relates to compounds of formula (I'), (I), (II), (III), (SI), or (SII) or pharmaceutical compositions containing the same, for use in the treatment or prevention of diseases or conditions associated with inhibition of ubiquitin-specific protease 1 (USP1).

[0035] The present invention relates specifically to compounds of formula (I'), (I), (II), (III), (SI), or (SII) or pharmaceutical compositions containing the same, for use in the treatment or prevention of cancers selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

[0036] The present invention relates to a method for treating or preventing a disease or condition associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising the step of administering a therapeutically effective amount of a compound of formula (I'), (I), (II), (III), (SI), or (SII) or a pharmaceutical composition containing the same to a patient in need.

[0037] The present invention also relates to a method for treating or preventing cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (I'), (I), (II), (III), (SI), or (SII) or a pharmaceutical composition containing the same to a patient in need, wherein the cancer is specifically selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

[0038] The pharmaceutical composition of the present invention may be in various conventional dosage forms, such as tablets, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile aqueous solutions for injection, sterile oil-in-water microemulsions for injection, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0039] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's overall health, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of elimination, and concomitant drug use. In addition, the optimal treatment, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt thereof, can be determined according to conventional treatment regimens.

[0040] Definition of Terms Unless otherwise specified, the following terms and phrases used herein are intended to have the meanings set forth below. Certain terms or phrases without a specific definition should not be considered ambiguous or unclear, but should be understood according to their ordinary meaning.

[0041] The term "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, with a reasonable benefit / risk ratio, and without excessive toxicity, irritation, allergic reactions or other problems or complications.

[0042] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention having a specific substituent and a salt of the compound of the present invention prepared from a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts (inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid), and organic acid salts (organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid), as well as salts of amino acids (e.g., arginine) and salts of organic acids, such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted into any base addition salt or acid addition salt.

[0043] The term "isomer" refers to a compound that has the same composition and molecular weight but different physical and / or chemical properties. Structural differences can be in the stereoconfiguration (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compound of formula (I) may have one or more chiral carbon atoms and may exist as a racemate, a racemic mixture, and as individual enantiomers or diastereomers.

[0044] The phrase "depending on the circumstances" or "depending on the circumstances" means that the event or situation described below may occur, but is not necessarily required to occur, and such description includes the circumstances under which the event or situation may occur, as well as the circumstances under which the event or situation may not occur.

[0045] The term "solvate" refers to a complex of variable stoichiometric amounts formed by a solute and a solvent. For the purposes of this application, such a solvent cannot interfere with the biological activity of the solute. Examples of suitable solvents, but not limited to, include water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally called hydrates. Hydrates include compositions containing a stoichiometric amount of water and compositions containing a variable amount of water.

[0046] As used herein, the terms “disease,” “disorder,” or “condition” refer to a condition requiring and / or desired treatment, a pathological condition or functional impairment and / or abnormality that may manifest in the form of specific signs, symptoms, and / or functional impairments. The compounds of the present invention inhibit the USP1 protein and are useful for treating diseases and conditions such as proliferative disorders in which inhibition of the USP1 protein is beneficial.

[0047] "USP1" and "ubiquitin-specific processing protease 1" refer to any natural polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses the unprocessed "full-length" USP1 polypeptide as well as any form of USP1 produced from intracellular processing (e.g., removal of signal peptides). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allele variants. The USP1 polypeptides described herein may be isolated from various sources, e.g., human tissue types or other sources, or prepared by recombinant or synthetic methods.

[0048] The terms “cancer” and “tumor” refer to or describe a physiological condition in which a population of cells within a mammal is characterized by uncontrolled cell growth. The terms encompass solid tumors and hematological / lymphatic cancers. Examples of cancer include, but are not limited to, cancers with defects in DNA damage repair pathways. Other examples of cancer include, but are not limited to, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer (including triple-negative breast cancer). Cancer can also be BRCA1 or BRCA2 wild-type. Cancer can also be BRCA1 or BRCA2 mutant. Cancer can also be PARP inhibitor-resistant or refractory cancer, or PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0049] In the structure of a compound, if any of the variable elements (e.g., R) appear more than once, their definitions are independent in each case. For example, if a group is substituted with 0 to 2 R's, the group can be substituted with up to 2 R's depending on the case, and R has an independent choice in each case.

[0050] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 1~10 Alkyl, more preferably C 1~6This refers to alkyl groups. Examples of alkyl groups, but not limited to these, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, and 2,4-dimethylbutyl. Examples include methylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0051] The term "alkenyl" refers to a monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located anywhere within the alkenyl. The alkenyl is preferably C 2~5 These are alkenyls. Examples of alkenyls, though not limited to these, include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3, and -CH2-C(CH3)=CH2.

[0052] The term "alkynyl" refers to a monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located anywhere within the alkynyl. The alkynyl is preferably C 2~5These are alkynyls. Examples of alkynyls, though not limited to these, include -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0053] The term "cycloalkyl" encompasses two categories: conventional cycloalkyls and heterostructured cycloalkyls.

[0054] Conventional cycloalkyls are aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 3~12 Conventional cycloalkyl, more preferably C 3~10 Conventional cycloalkyl groups, more preferably C 3~8 Conventional cycloalkyl groups, most preferably C 3~6 This refers to conventional cycloalkyl groups. Conventional cycloalkyl groups may contain one or more double or triple bonds.

[0055] Conventional cycloalkyls may be monocyclic cycloalkyls, and examples of monocyclic cycloalkyls, though not limited to these, include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Conventional cycloalkyls may also be polycyclic cycloalkyls (e.g., bicycloalkyls, tricycloalkyls, tetracycloalkyls, and pentacycloalkyls). Examples of polycyclic cycloalkyls include spirocycloalkyls, condensed cycloalkyls, and crosslinked cycloalkyls.

[0056] The term "spirocycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spirocycloalkyl, preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. A spirocycloalkyl may be a monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl, preferably a monospirocycloalkyl, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. Examples of spirocycloalkyls, but not limited to these, include: [ka] These are some examples.

[0057] The term "condensed cycloalkyl" refers to 5-20 member (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 member) condensed cycloalkyls, preferably 6-14 member condensed cycloalkyls, more preferably 7-10 member condensed cycloalkyls. A condensed cycloalkyl is bicyclic, tricyclic, tetracyclic, pentacyclic, or more condensed cycloalkyl, preferably bicyclic or tricyclic condensed cycloalkyls, and more preferably 5-member / 5-member or 5-member / 6-member condensed cycloalkyls. Examples of condensed cycloalkyls, but not limited to these, include: [ka] These are some examples.

[0058] The term "crosslinked cycloalkyl" refers to 5-20 member (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 member) crosslinked cycloalkyls, preferably 6-14 member crosslinked cycloalkyls, more preferably 7-10 member crosslinked cycloalkyls. Crosslinked cycloalkyls are bicyclic, tricyclic, tetracyclic, pentacyclic, or more crosslinked cycloalkyls, preferably bicyclic, tricyclic, or tetracyclic crosslinked cycloalkyls, more preferably bicyclic or tricyclic crosslinked cycloalkyls. Examples of crosslinked cycloalkyls, but not limited to these, include: [ka] These are some examples.

[0059] The term "heterostructured cycloalkyl" includes monocyclic cycloalkyls, spirocycloalkyls, condensed cycloalkyls, and cross-linked cycloalkyls condensed with any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional heterocyclyls, where the bond site is located at the corresponding conventional cycloalkyl (see monocyclic cycloalkyl, spirocycloalkyl, condensed cycloalkyl, or cross-linked cycloalkyl). Examples of heterostructured cycloalkyls, but not limited to these: [ka] These are some examples.

[0060] The term "heterocyclyl" encompasses two categories: conventional heterocyclyls and heterostructured heterocyclyls.

[0061] Conventional heterocyclyls are aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, wherein one or more ring atoms are replaced by one or more elements selected from the group consisting of N, O, S, S(O), and S(O)2, and this replacement does not form -OO-, -OS-, or -SS-. Conventional heterocyclyls are preferably C 3~12 A conventional heterocycline in which 1 to 4 atoms (e.g., 1, 2, 3, and 4) are heteroatoms, more preferably C 3~8 A conventional heterocycline in which 1 to 3 atoms (e.g., 1, 2, and 3) are heteroatoms, most preferably C 5~7 This is a conventional heterocycline, in which 1-2 or 1-3 atoms are heteroatoms.

[0062] Conventional heterocyclils may also be monocyclic heterocyclils, and examples of monocyclic heterocyclils, though not limited to these, include oxetanil, 3-pyrrolinil, pyrrolidinil, imidazolidinil, tetrahydrofuranil, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, homopiperazinil, and pyranil, preferably 1,2,5-oxadiazolyl, pyranil, or morpholinil. Conventional heterocyclils may also be polycyclic heterocyclils, and examples of polycyclic heterocyclils include spiroheterocyclils, condensed heterocyclils, and cross-linked heterocyclils.

[0063] The term “spiroheterocyclil” refers to spiroheterocyclils with 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 members), preferably 6 to 14 member spiroheterocyclils, more preferably 7 to 10 member spiroheterocyclils. A spiroheterocyclil is a monospiroheterocyclil, dispiroheterocyclil, or polyspiroheterocyclil, preferably a monospiroheterocyclil or dispiroheterocyclil, more preferably a 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclil. Examples of spiroheterocyclils, but not limited to these, include: [ka] These are some examples.

[0064] The term "condensed heterocyclyl" refers to 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) condensed heterocyclyls, preferably 6- to 14-membered condensed heterocyclyls, and more preferably 7- to 10-membered condensed heterocyclyls. A condensed heterocyclyl is bicyclic, tricyclic, tetracyclic, pentacyclic, or more. A condensed heterocyclyl is preferably a bicyclic or tricyclic condensed heterocyclyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic condensed heterocyclyl. Examples of condensed heterocyclyls, but not limited to these, include: [ka] These are some examples.

[0065] The term "crosslinked heterocyclil" refers to 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) crosslinked heterocyclils, preferably 6- to 14-membered crosslinked heterocyclils, more preferably 7- to 10-membered crosslinked heterocyclils. A crosslinked heterocyclil may be bicyclic, tricyclic, tetracyclic, pentacyclic, or more crosslinked heterocyclils, preferably bicyclic, tricyclic, or tetracyclic crosslinked heterocyclils, more preferably bicyclic or tricyclic crosslinked heterocyclils. Examples of crosslinked heterocyclils, but not limited to these, include: [ka] These are some examples.

[0066] The term "heterostructured heterocyclil" includes monocyclic heterocyclils, spiroheterocyclils, condensed heterocyclils, and cross-linked heterocyclils condensed with any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional cycloalkyls, where the bond site is located on the corresponding conventional heterocyclil (see monocyclic heterocyclil, spiroheterocyclil, condensed heterocyclil, or cross-linked heterocyclil). Examples of heterostructured heterocyclils, but not limited to these: [ka] These are some examples.

[0067] The term "aryl" encompasses two categories: conventional aryls and heterostructured aryls.

[0068] Conventional aryls are aromatic hydrocarbon groups with 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 members), preferably C 6~10 This refers to conventional aryls, more preferably phenyls, naphthyls, phenanthryls, or anthracennyls.

[0069] The term "heterostructured aryl" includes conventional aryls condensed with any one selected from the group consisting of conventional heteroaryls, conventional heterocyclyls, and conventional cycloalkyls, where the bond site is located on the conventional aryl. Examples of heterostructured aryls, but not limited to these: [ka] These are some examples.

[0070] The term "heteroaryl" encompasses two categories: conventional heteroaryls and heterostructured heteroaryls.

[0071] Conventional heteroaryls refer to aromatic hydrocarbon groups with 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 members), in which 1 to 4 carbon atoms (e.g., 1, 2, 3, and 4) are replaced by heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5 to 10, including 1 to 3 heteroatoms (e.g., 1, 2, and 3). More preferably, the number of ring atoms is 5 or 6, including 1 to 2 heteroatoms. Examples of conventional heteroaryls, but not limited to these, include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0072] The term "heterostructured heteroaryl" includes conventional heteroaryls condensed with any one selected from the group consisting of conventional aryls, conventional cycloalkyls, and conventional heterocyclyls, where the bond site is located on the conventional heteroaryl. Examples of heterostructured heteroaryls, but not limited to these, include: [ka] These are some examples.

[0073] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, where "alkyl" and "cycloalkyl" are defined above. Examples of alkoxys, but not limited to these, include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0074] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogens, where the alkyl group is as defined above.

[0075] The term "haloalkoxy" refers to an alkoxy compound substituted with one or more halogens, where the alkoxy is as defined above.

[0076] The term "hydroxy" refers to the -OH group.

[0077] The term "halogen" refers to the -F, -Cl, -Br, or -I group.

[0078] The term "amino" refers to the -NH2 group.

[0079] The term "cyano" refers to the -CN group.

[0080] The term "nitro" refers to the -NO2 group.

[0081] The term "oxo" refers to the =O group.

[0082] The term "carboxy" refers to the -C(=O)OH group.

[0083] The term "thiol" refers to the -SH group.

[0084] The term "alkoxycarbonyl" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl groups, where alkyl and cycloalkyl are as defined above.

[0085] The term "acyl" refers to the -C(=O)R group (wherein R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl).

[0086] The term "protecting group for hydroxyl" refers to a group introduced on a hydroxyl group to block or protect it while a reaction is occurring with other functional groups of the compound, and which is easily removed. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl.

[0087] symbol" [ka] " refers to a connection point.

[0088] The term "stereoisomer" refers to isomers that have the same structure but differ in the arrangement of atoms in space. Stereoiomers include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, atrop isomers, conformational isomers, and mixtures thereof (e.g., racemates and mixtures of diastereomers). Substituents in the compounds of the present invention may have additional asymmetric atoms. All of these stereoisomers and mixtures thereof are within the scope of the present invention. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Isomers of the compound of the present invention can be prepared by asymmetric synthesis or by chiral auxiliary groups. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereoisomer salt can be formed from it using a suitable optically active acid or base, and then the diastereoisomer can be divided by conventional methods known in the art to obtain the pure isomer. In addition, the division of enantiomers and diastereomers is usually achieved by chromatography.

[0089] In the chemical structure of the compound of the present invention, the bond " [ka] " represents an unspecified stereoconfiguration, that is, when chiral isomers exist in the chemical structure, the bond " [ka] "teeth," [ka] " or " [ka] It may be " or " [ka] "and" [ka] It can contain both configurations of Z and E. For every carbon-carbon double bond, even if only one configuration is named, it can contain both Z and E configurations.

[0090] The compounds and intermediates of the present invention may also exist in different tautomerized forms, and all such forms are included within the scope of the present invention. The terms “tautomer” or “tautomerized form” refer to structural isomers with different energies that can be interconverted over a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, and lactam-lactoimide isomerization.

[0091] The compounds of the present invention include all suitable isotopic substitutes for the compound. The term "isotopic substitute" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic weight. Examples of isotopes that can be incorporated into the compounds of the present invention include stable and radioactive isotopes such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (Tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I,131 I, preferably containing deuterium.

[0092] As used herein, the singular forms "a," "an," and "the" include multiple references unless the context explicitly indicates otherwise, and vice versa.

[0093] The term "approximately" applies to parameters such as pH, concentration, and temperature, indicating that the parameters may vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will recognize, the numbers are generally given for illustrative purposes only, and not for limiting purposes. [Modes for carrying out the invention]

[0094] The present invention has been described in more detail through the following examples, but this does not mean to impose any adverse limitations on the invention. The literature of the present invention describes the invention in detail and also discloses specific embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the invention without departing from the spirit and scope of the invention.

[0095] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. The present invention provides typical or preferred reaction conditions for reactants, such as reaction temperature, time, solvent, pressure, and molar ratio. However, other reaction conditions may also be employed unless specifically specified. Optimal conditions may vary depending on the use of specific reactants or solvents, but optimized steps and conditions for the reaction can be determined under normal circumstances.

[0096] In addition, in the present invention, certain protecting groups can be used to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and the conditions for their protection or deprotection are already well known to those skilled in the art.

[0097] The isolation and purification of compounds and intermediates are carried out by appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific methods to be used can be found in the examples described in this invention. Naturally, other similar isolation and purification methods can also be used. These can be characterized using conventional methods (including physical constants and spectral data).

[0098] The purity analysis method is as follows: A Kinetex EVO C18 (50 × 4.6 mm, 5 μm, 100 Å) chromatography column was used, acetonitrile-water was used as the mobile phase for gradient elution, the flow rate was 1.5 mL / min, and the detection wavelength was 220 nm.

[0099] Mass spectroscopy (MS) is determined using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole type) mass spectrum graph (manufacturer: Agilent) (photodiode array detector).

[0100] The compound's structure was determined by hydrogen nuclear magnetic resonance, and the instrument model was WNMR-I-400MHz.

[0101] Preparative liquid chromatography is performed using an Agilent 1260 Infinity II high-performance liquid chromatograph (manufacturer: Agilent). The chromatography column is Daisogel C18 10μm 100A (30mm × 250mm), and the mobile phase is acetonitrile / water.

[0102] GF254 silica gel plates manufactured by Qingdao Haiyang Chemical are used for thin-layer chromatography (TLC). The specification for the silica gel plates used is 0.20 mm to 0.25 mm for thin-layer chromatography for reaction monitoring, and 0.5 mm for thin-layer chromatography for separation and purification.

[0103] For silica gel column chromatography, silica gel of 100-200 mesh, 200-300 mesh, and 300-400 mesh manufactured by Qingdao Haiyang Chemical Co., Ltd. is used as the support.

[0104] The known starting materials of the present invention can be prepared by methods known in the art, or they can be purchased from Wanghua Mall, Beijing Ouhe Technology, Sigma, J & K Scientific, Yishiming, Shanghai Shuya Chemical, Shanghai Innochem Science & Technology, Energy Chemical, Shanghai Bide Pharmatech, and others.

[0105] Unless otherwise specifically stated in the examples, all reactions are carried out under a nitrogen atmosphere.

[0106] A nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of approximately 1 liter.

[0107] The reaction solvent, organic solvent, or inert solvent is described as a solvent that does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, and N-methylpyrrolidone (NMP).

[0108] Unless otherwise specifically stated in the examples, "solution" refers to an aqueous solution.

[0109] The chemical reactions described in this invention are generally carried out under standard pressure. The reaction time and conditions are, for example, between -78°C and 200°C at 1 atmosphere, and are completed within approximately 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, i.e., 20°C to 30°C.

[0110] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar to or equivalent to those described herein can be applied to the methods of the present invention.

[0111] Unless otherwise specified, the mixing ratio of different solvents is given as a volume ratio.

[0112] The synthesis of general intermediates, including the A series, AA series, B series, BB series, C series, D series, SA series, SB series, SC series, and further synthesized intermediate series, is described below.

[0113] Synthesis of common intermediate A1 (2-(2-isopropylphenyl)-5-methoxypyrimidine-4-amine)

[0114] [ka]

[0115] 2-Chloro-5-methoxypyrimidine-4-amine (compound A1-1, 5.0 g, 31.3 mmol, 1.00 equivalent), (2-isopropylphenyl)boric acid (compound A1-2, 6.7 g, 40.7 mmol, 1.30 equivalent, purchased from Bide Pharmatech), potassium carbonate (13.0 g, 94.0 mmol, 3.00 equivalent), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (2.3 g, 3.13 mmol, 0.10 equivalent) were sequentially added to dioxane (50.0 mL) and water (12.5 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 16 hours. Then, ethyl acetate (500.0 mL) was added, the resulting mixture was stirred for 10 minutes, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound A1 (4.9 g, yield 63.3%, purity 98.2%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.32-7.36 (m, 3H), 7.16-7.19 (m, 1H), 6.71 (s, 2H), 3.87 (s, 3H), 3.44-3.50 (m, 1H), 1.12 (d, J = 7.20 Hz, 6H); LC-MS: m / z = 244.2 (M+H) + .

[0116] Synthesis of general intermediate A2 (4'-cyclopropyl-5,6'-dimethoxy-N-methyl-[2,5'-bipyrimidine]-4-amine)

[0117] [ka]

[0118] Step 1: Synthesis of compound A2-3 (6-cyclopropylpyrimidine-4-ol) Compound A2-1 (200.0 g, 1.4 mol, 1.00 equivalent) and compound A2-2 (292.0 g, 2.81 mol, 2.00 equivalent) were sequentially added to methanol (1.2 L), and a solution of sodium methoxide in methanol (5.4 M, 1.3 L, 5.00 equivalent) was gradually added at 0°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 13 hours. Then, glacial acetic acid was added at 0°C to adjust the pH to 7-8. The resulting mixture was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound A2-3 (90.3 g). LC-MS: m / z = 137.1 (M + H) + .

[0119] Step 2: Synthesis of compound A2-4 (4-chloro-6-cyclopropylpyrimidine) Compound A2-3 (40.0 g, 293.0 mmol, 1.00 equivalent) was gradually added to phosphorus oxychloride (180.0 mL). After the addition was complete, the reaction mixture was heated to 60°C and stirred for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. The crude product was dissolved in ethyl acetate (400.0 mL) and water (400.0 mL) and stirred for 5 minutes. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (400.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain compound A2-4 (11.0 g). LC-MS: m / z = 155.0 (M+H) + .

[0120] Step 3: Synthesis of compound A2-5 (5-bromo-4-chloro-6-cyclopropylpyrimidine) Compound A2-4 (11.0 g, 71.1 mmol, 1.00 equivalent) was dissolved in methanol (150.0 mL), and bromine (34.1 g, 213.0 mmol, 3.00 equivalent) was slowly added at -60°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 2 hours. Then, saturated sodium bicarbonate solution (200.0 mL) and water (100.0 mL) were added at 0°C, the resulting mixture was stirred for 5 minutes, and extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain compound A2-5 (7.8 g). 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 2.56 - 2.62 (m, 1H), 1.23 - 1.26 (m, 2H), 1.16 - 1.21 (m, 2H); LC-MS: m / z = 232.9 (M+H) + .

[0121] Step 4: Synthesis of compound A2-6 (5-bromo-4-cyclopropyl-6-methoxypyrimidine) Compound A2-5 (7.8 g, 33.4 mmol, 1.00 equivalent) was dissolved in methanol (240.0 mL), and sodium methoxide (18.0 g, 100.0 mmol, 3.00 equivalent) was added at 0°C. After the addition was complete, the reaction mixture was heated to 30°C and stirred for 1 hour. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound A2-6 (7.3 g). LC-MS: m / z = 228.9 (M + H) + .

[0122] Step 5: Synthesis of Compound A2-7 ((4-Cyclopropyl-6-methoxypyrimidine-5-yl)boronic acid) Compound A2-6 (10.3 g, 44.9 mmol, 1.00 equivalent) and triisopropyl borate (11.8 g, 62.9 mmol, 1.40 equivalent) were dissolved in tetrahydrofuran (30.0 mL) and toluene (90.0 mL), and n-butyllithium (2.5 M, 25.1 mL, 1.40 equivalent) was added dropwise at -70°C. After the addition was complete, the reaction mixture was stirred at -70°C for 3 hours. Next, 1N hydrochloric acid solution (50.0 mL) was added dropwise at -70°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 0.5 hours. Next, saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, and the resulting mixture was extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound A2-7 (6.9 g). 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.45 (s, 2H), 3.84 (s, 3H), 1.88 - 1.92 (m, 2H), 0.93 - 1.01 (m, 4H).

[0123] Step 6: Synthesis of Intermediate A2 Compound A2-8 (1.2 g, 6.9 mmol, 1.0 equivalent), 1,1'-bis(diphenylphosphin)ferrocene palladium dichloride (505.0 mg, 0.7 mmol, 0.10 equivalent), and potassium carbonate (2.9 g, 20.7 mmol, 3.00 equivalent) were sequentially added to dioxane (100.0 mL) and water (25.0 mL), and the resulting mixture was purged three times with nitrogen. Compound A2-7 (1.6 g, 8.3 mmol, 1.20 equivalent), dissolved in N,N-dimethylformamide (10.0 mL), was added dropwise at 100°C under a nitrogen atmosphere. After the addition was complete, the reaction was carried out at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was then concentrated under vacuum, followed by the addition of water (60.0 mL), and the resulting mixture was extracted twice with ethyl acetate (40.0 mL). The organic layers were combined, washed twice with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~10 / 1) to obtain compound A2 (100.0 mg, 348 μmol, yield 5.0%, purity 100%) as a white solid. LC-MS: m / z = 288.0 (M+H) + .

[0124] Synthesis of common intermediate A3 (4-chloro-2-(2-isopropylphenyl)-5-nitropyrimidine)

[0125] [ka]

[0126] Step 1: Synthesis of compound A3-3 (2-(2-isopropylphenyl)-4-methoxy-5-nitropyrimidine) Compound A3-2 (3.3g, 17.4 mmol, 1.00 equivalent), compound A3-1 (5.7g, 34.8 mmol, 2.00 equivalent), 1,1'-bis(diphenylphosphin)ferrocene palladium dichloride (1.3g, 1.7 mmol, 0.10 equivalent), and potassium carbonate (4.8g, 34.8 mmol, 2.00 equivalent) were dissolved in dioxane (30.0 mL) and water (7.0 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was then concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound A3-3 (3.2g). LC-MS: m / z = 274.1 (M + H) + .

[0127] Step 2: Synthesis of compound A3-4 (2-(2-isopropylphenyl)-5-nitropyrimidine-4-ol) Compound A3-3 (2.0 g, 7.3 mmol, 1.00 equivalent) was dissolved in dioxane (30.0 mL), and hydrobromic acid and glacial acetic acid (6 M, 15.0 mL, 12.30 equivalents) were added. After the addition was complete, the reaction mixture was heated to 50°C and stirred for 1 hour. The reaction mixture was then concentrated under vacuum to obtain crude compound A3-4 (2.0 g). This was used directly in the next step. LC-MS: m / z = 260.0 (M + H) + .

[0128] Step 3: Synthesis of Intermediate A3 Compound A3-4 (2.0 g, 6.8 mmol, 1.00 equivalent) was added to phosphorus oxychloride (18.0 mL) and reacted at 90°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1-30 / 1) to obtain compound A3 (1.0 g, 3.59 mmol, yield 53.1%, purity 99.8%) as a pale yellow oily substance. LC-MS: m / z = 278.1 (M + H) + .

[0129] Synthesis of common intermediate A4 (2-(2-isopropylphenyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0130] [ka]

[0131] Step 1: Synthesis of compound A4-2 (2-chloro-5-(trifluoromethyl)pyrimidine-4-amine) Compound A4-1 (18.7 g, 86.2 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and aqueous ammonia (15.1 g, 129 mmol, 30.0% purity, 1.50 equivalent) was added at 0°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 16 hours. Then, water (30.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound A4-2 (1.73 g). 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.95 (s, 2H); LC-MS: m / z = 197.9 (M+H) + .

[0132] Step 2: Synthesis of Intermediate A4 Compound A4-2 (1.15 g, 5.77 mmol, 1.00 equivalent), compound A4-3 (1.14 g, 6.92 mmol, 1.20 equivalent), potassium carbonate (2.39 g, 17.3 mmol, 3.00 equivalent), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (422 mg, 577 μmol, 0.10 equivalent) were sequentially added to dimethyl sulfoxide (12.0 mL) and water (2.5 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was then concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC to obtain compound A4 (200 mg, 711 μmol, yield 12.3%, purity 100%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.41 - 7.44 (m, 3H), 7.22 - 7.26 (m, 1H), 3.41 - 3.45 (m, 1H), 3.30 (s, 2H), 1.16 (dd, J1= 7.2Hz, J2= 13.2Hz, 6H); LC-MS: m / z = 282.1 (M+H) + .

[0133] Synthesis of the common intermediate A5 (2-(2-isopropylphenyl)-5-methoxy-N-methylpyrimidine-4-amine)

[0134] [ka]

[0135] Step 1: Synthesis of compound A5-2 (2-chloro-5-methoxy-N-methylpyrimidine-4-amine) Compound A5-1 (10.0 g, 55.9 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (100.0 mL), and methylamine (2.0 M aqueous methylamine solution, 54.5 mL, 1.95 equivalents) was added at 0°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 2 hours. Water (200.0 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound A5-2 (9.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 5.48 (s, 1H), 3.86 (s, 3H), 3.05 (d, J = 4.00 Hz, 3H); LC-MS: m / z = 173.9 (M+H) + .

[0136] Step 2: Synthesis of Intermediate A5 Compound A5-2 (3.0 g, 17.3 mmol, 1.00 equivalent), Compound A5-3 (3.7 g, 22.5 mmol, 1.3 equivalent), potassium carbonate (7.2 g, 51.8 mmol, 3.00 equivalent), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.3 g, 1.7 mmol, 0.10 equivalent) were sequentially added to dioxane (30.0 mL) and water (7.5 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 16 hours. Subsequently, ethyl acetate (500.0 mL) was added and the mixture was stirred for 10 minutes. The resulting mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound A5 (4.3 g, 16.3 mmol, yield 94.4%, purity 96.9%) as a brown oily substance. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.56 (d, J = 7.60 Hz, 1H), 7.33-7.41 (m, 2H), 7.23-7.25 (m, 1H), 5.29 (s, 1H), 3.92 (s, 3H), 3.53-3.60 (m, 1H), 3.07 (d, J = 5.20 Hz, 3H), 1.25-1.29 (m, 6H); LC-MS: m / z = 258.0 (M+H) + .

[0137] Synthesis of general intermediate A6 (2-(2-isopropylphenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0138] [ka]

[0139] Step 1: Synthesis of compound A6-2 (4-amino-2-chloropyrimidine-5-ol) Compound A6-1 (15.6 g, 97.8 mmol, 1.00 equivalent) was dissolved in dichloromethane (1.5 L), and boron tribromide (367.0 g, 1.5 mol, 15.0 equivalent) was slowly added at 0°C. After the addition was complete, the reaction mixture was heated to 20°C and stirred for 96 hours. Then, methanol (1.0 L) was slowly added at 0°C to quench the reaction. The reaction mixture was concentrated under vacuum to obtain the crude product. Dichloromethane (200.0 mL) was added, the resulting mixture was stirred for 5 minutes, and filtered to obtain a filter cake. The filter cake was dissolved in water (200.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. The resulting mixture was filtered to obtain a filter cake. This was washed twice with water (50.0 mL), concentrated under vacuum to obtain compound A6-2 (12.9 g). 1H NMR (400 MHz, DMSO) δ 10.0 (d, J = 10.0 Hz, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.07 (s, 2H); LC-MS: m / z = 145.9 (M+H) + .

[0140] Step 2: Synthesis of compound A6-4 (2-chloro-5-(2-chloroethoxy)pyrimidine-4-amine) Compound A6-2 (19.0 g, 130 mmol, 1.00 equivalent), compound A6-3 (28.1 g, 196 mmol, 16.2 mL, 1.50 equivalent), and potassium carbonate (54.1 g, 392 mmol, 3.00 equivalent) were sequentially added to N,N-dimethylformamide (200.0 mL), and the mixture was reacted at 20°C for 16 hours to obtain the crude product compound A6-4 (27.2 g). This reaction solution was used directly in the next step. LC-MS: m / z = 207.8 (M + H) + .

[0141] Step 3: Synthesis of compound A6-5 (2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine) The reaction solution of compound A6-4 (27.2 g) was heated to 100°C, stirred for 16 hours, and filtered to obtain the filtrate. Water (800.0 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with ethyl acetate (300.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. Methyl tert-butyl ether (1000.0 mL) was added, and the resulting mixture was stirred for 30 minutes and filtered to obtain the filter cake. This was concentrated under vacuum to obtain compound A6-5 (3.4 g). 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 9.60 Hz, 1H), 7.63 (d, J = 18.8 Hz, 1H), 4.10-4.34 (m, 2H), 3.43-3.46 (m, 2H);LC-MS: m / z = 171.9 (M+H) + .

[0142] Step 4: Synthesis of Intermediate A6 Compound A6-5 (1.5 g, 8.74 mmol, 1.00 equivalent), compound A6-6 (1.4 g, 8.74 mmol, 1.00 equivalent), potassium carbonate (3.6 g, 26.2 mmol, 3.00 equivalent), and 1,1'-bis(diphenylphosphin)ferrocenepalladium dichloride (640.0 mg, 874 μmol, 0.10 equivalent) were sequentially added to N,N-dimethylformamide (15.0 mL) and water (3.8 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Kromasil Eternity XT 250×80mm×10μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 28%~58%, 21 min) to obtain compound A6 (1.37g, 5.27 mmol, yield 60.3%, purity 98.3%) as a brown solid. 1 H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.73-7.83 (m, 1H), 7.54-7.73 (m, 1H), 7.31-7.36 (m, 2H), 7.16-7.20 (m, 1H), 4.16-4.18 (m, 2H), 3.43-3.48 (m, 3H), 1.12-1.23 (m, 6H); LC-MS: m / z = 456.0 (M+H) + .

[0143] Synthesis of common intermediate A7 (2-(2-isopropylphenyl)-6H-pyrimido[5,4-b][1,4]oxazine-7(8H)-one)

[0144] [ka]

[0145] Step 1: Synthesis of compound A7-2 (2-chloro-6H-pyrimido[5,4-b][1,4]oxazine-7(8H)-one) Compound A6-2 (4.00 g, 27.4 mmol, 1.00 equivalent), compound A7-1 (4.66 g, 41.2 mmol, 3.28 mL, 1.50 equivalent), and potassium carbonate (11.4 g, 82.4 mmol, 3.00 equivalent) were sequentially added to N,N-dimethylformamide (50.0 mL) and reacted at 30°C for 3 hours. Water (150.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed three times with saturated brine (70.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-5 / 1) to obtain compound A7-2 (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 12.00 (s, 1H), 8.18 - 8.23 ​​(m, 1H), 4.77 - 4.78 (m, 2H); LC-MS: m / z = 185.9 (M+H) + .

[0146] Step 2: Synthesis of Intermediate A7 Compound A7-2 (500.0 mg, 2.69 mmol, 1.00 equivalent), compound A7-3 (574.1 mg, 3.50 mmol, 1.30 equivalent), aqueous potassium phosphate solution (1.5 M, 5.39 mL, 3.00 equivalent), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (231.1 mg, 269 μmol, 0.100 equivalent) were sequentially added to tetrahydrofuran (25.0 mL). The resulting mixture was purged three times with nitrogen and stirred under a nitrogen atmosphere at 60°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75×30mm×3μm; mobile phase: water (HCl)~ACN; B%: 28%~48%, 8 min) to obtain A7 (90.0 mg, 334 μmol, yield 12.4%) as a white solid. LC-MS: m / z=270.1(M+H) + .

[0147] Synthesis of the general intermediate A8 (2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0148] [ka]

[0149] Compound A6-5 (1.50 g, 8.74 mmol, 1.00 equivalent), compound A2-7 (1.70 g, 8.74 mmol, 1.00 equivalent), potassium carbonate (3.62 g, 26.2 mmol, 3.00 equivalent), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (640 mg, 874 μmol, 0.10 equivalent) were sequentially added to a mixed solvent of N,N-dimethylformamide (15.0 mL) and water (3.75 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Waters Xbridge BEH C18 250×50mm×10μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 10%~35%, 20 min) to obtain compound A8 (414 mg, 1.45 mmol, yield 16.6%, purity 100%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 4.17-4.19 (m, 2H), 3.82 (s, 3H), 3.47-3.49 (m, 2H), 1.67-1.71 (m, 1H), 0.99-1.01 (m, 2H), 0.88-0.90 (m, 2H); LC-MS: m / z = 286.0 (M+H) + .

[0150] Synthesis of common intermediate A9 (4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[0151] [ka]

[0152] Step 1: Synthesis of compound A9-2 (2-chloro-5-methoxy-N,N-bis(4-methoxybenzyl)pyrimidine-4-amine) Compound A9-1 (6.0 g, 37.6 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (60.0 mL), and sodium hydride (3.31 g, 82.7 mmol, 60% purity, 2.20 equivalents) was added gradually at 0°C. After the addition was complete, the resulting mixture was stirred at 5°C for 30 minutes. 4-methoxybenzyl chloride (12.9 g, 82.7 mmol, 2.20 equivalents) was added, and the mixture was stirred at 5°C for 12 hours. Then, saturated aqueous ammonium chloride solution (40.0 mL) was added at 0°C to quench the reaction. Water (150.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (70.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound A9-2 (10.3g). LC-MS: m / z = 400.2 (M + H) + .

[0153] Step 2: Synthesis of compound A9-3 (4'-cyclopropyl-5,6'-dimethoxy-N,N-bis(4-methoxybenzyl)-[2,5'-bipyrimidine]-4-amine) Compound A9-2 (2.0 g, 5.00 mmol, 1.00 equivalent), compound A2-7 (1.46 g, 7.50 mmol, 1.50 equivalent), aqueous potassium phosphate solution (1.5 M, 10.0 mL, 3.00 equivalent), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (430 mg, 500 μmol, 0.100 equivalent) were sequentially added to tetrahydrofuran (40.0 mL). The resulting mixture was purged three times with nitrogen and stirred under a nitrogen atmosphere at 80°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (FA) ~ ACN]; B%: 35% ~ 65%, 21 min) to obtain A9-3 (0.9 g). LC-MS: m / z = 514.3 (M + H) + .

[0154] Step 3: Synthesis of Intermediate A9 Compound A9-3 (900 mg, 1.75 mmol, 1.00 equivalent) was added to trifluoroacetic acid (10.0 mL), heated to 90°C, and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and saturated sodium bicarbonate solution (10.0 mL) was added to adjust the pH to 8. The resulting mixture was extracted three times with ethyl acetate (20.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain A9 (300.0 mg, yield 62.5%, purity 100%) as a white solid. LC-MS: m / z = 274.1 (M + H) + .

[0155] Synthesis of the common intermediate A10 (2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6H-pyrimido[5,4-b][1,4]oxazine-7(8H)-one)

[0156] [ka]

[0157] Compounds A7-2 (600 mg, 3.23 mmol, 1.00 equivalent), A2-7 (940 mg, 4.85 mmol, 1.50 equivalent), aqueous potassium phosphate solution (1.5 M, 6.47 mL, 3.00 equivalent), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (417 mg, 485 μmol, 0.150 equivalent) were sequentially added to tetrahydrofuran (10.0 mL). The resulting mixture was purged three times with nitrogen and stirred under a nitrogen atmosphere at 80°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Phenomenex luna C18 150×40mm×15μm; mobile phase: [water (TFA)-ACN]; B%: 10%~40%, 10 min) to obtain intermediate A10 (60.0 mg, 0.2 mmol, yield 6.2%, purity 100%). LC-MS: m / z = 300.1 (M+H) + .

[0158] Synthesis of the common intermediate AA3 (1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole)

[0159] [ka]

[0160] Step 1: Synthesis of compound AA3-2 (7-bromo-1-methyl-1H-indole) 7-Bromoindole (compound AA3-1, 15.0 g, 76.5 mmol, 1.00 equivalent) was dissolved in THF (150 mL), and NaH (4.59 g, 115 mmol, 60% purity, 1.50 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was heated to room temperature (25°C) and stirred for 1.5 hours. Then, potassium iodide (14.1 g, 99.5 mmol, 6.19 mL, 1.30 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to room temperature (25°C) and stirred for 12 hours. The reaction was quenched by adding 60 mL of ice water at 0°C, and the resulting mixture was extracted three times with ethyl acetate (70.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound AA3-2 (16.5 g, crude product) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6Hz, 1H), 7.39 - 7.41 (m, 1H), 7.01 - 7.02 (m, 1H), 6.94 - 6.98 (m, 1H), 6.50 - 6.51 (m, 1H), 4.18 (s, 3H); LC-MS: m / z = 212.0 (M+H) + .

[0161] Step 2: Synthesis of intermediate AA3 Compound AA3-2 (4.00 g, 19.0 mmol, 1.00 equivalent), bis(pinacolato)diborone (9.67 g, 38.1 mmol, 2.00 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (1.39 g, 1.90 mmol, 0.100 equivalent), and potassium acetate (3.74 g, 38.1 mmol, 2.00 equivalent) were dissolved in dioxane (40.0 mL) and stirred at an external temperature of 95°C for 12 hours. Then, water (80.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain intermediate AA3 (2.47 g, 9.45 mmol, yield 49.6%, purity 98.4%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0Hz, 1H), 7.70 (d, J = 6.0Hz, 1H), 7.11 - 7.15 (m, 1H), 7.03 - 7.04 (m, 1H), 6.51 - 6.52 (m, 1H), 4.00 (s, 3H), 1.43 - 1.50 (m, 12H); LC-MS: m / z = 258.1 (M+H) + .

[0162] Synthesis of the common intermediate AA4 ((1-methylindoline-7-yl)boronic acid)

[0163] [ka]

[0164] Step 1: Synthesis of compound AA4-1 (7-bromo-1-methylindole) Compound AA3-2 (6.70 g, 31.8 mmol, 1.00 equivalent) was added to acetic acid (50.0 mL), followed by sodium borohydride cyanohydride (16.0 g, 255 mmol, 8.00 equivalent) at 10°C. The mixture was stirred at 20°C for 12 hours. A 1 M aqueous sodium hydroxide solution was added to adjust the pH to approximately 8, and the resulting mixture was extracted three times with dichloromethane (60 mL). The organic layers were combined, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This filtrate was concentrated under vacuum to obtain compound AA4-1 (8.00 g, crude product) as a brown oily substance. LC-MS: m / z = 212.1 (M + H) + .

[0165] Step 2: Synthesis of intermediate AA4 Compound AA4-1 (500 mg, 2.36 mmol, 1.00 equivalent) and triisopropyl borate (576 mg, 3.06 mmol, 704 μL, 1.30 equivalent) were added to tetrahydrofuran (10.0 mL), and n-butyllithium (2.5 M, 1.23 mL, 1.30 equivalent) was added dropwise at -78°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Then, saturated aqueous ammonium chloride solution (20 mL) was added dropwise at 0°C to quench the reaction. Water (30.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (15 mL). The organic layers were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to obtain intermediate AA4 (120 mg, 588.45 μmol, yield 24.96%, purity 86.8%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1H), 7.02 (d, J = 6.8Hz, 2H), 6.52 - 6.60 (m, 2H), 3.24 (t, J = 8.0Hz, 2H), 2.84 (t, J = 8.0Hz, 2H), 2.76(s, 3H); LC-MS: m / z = 178.1 (M+H) + .

[0166] Synthesis of the common intermediate AA5 ((1-isopropyl-4-methyl-1H-imidazole-5-yl)boronic acid)

[0167] [ka]

[0168] Step 1: Synthesis of compound AA5-2 (5-bromo-1-isopropyl-4-methyl-1H-imidazole) 4-Methyl-5-bromoimidazole (AA5-1, 40.0 g, 248 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (800 mL), and sodium hydride (7.15 g, 178 mmol, 60% purity, 0.720 equivalents) was gradually added at -15°C. After the addition was complete, the resulting mixture was stirred at -15°C for 30 minutes. 2-iodopropane (42.2 g, 248 mmol, 24.8 mL, 1.00 equivalent) was added, and the resulting mixture was stirred at 0°C for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (100 mL). Water (800.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (500 mL). The organic layers were combined, washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound AA5-2 (7.00 g, 34.4 mmol, yield 46.6%) as a brown oily substance. 1 H NMR (400MHz, CDCl3) δ 7.56 (s, 1H), 4.32 - 4.39 (m, 1H), 2.20 (s, 3H), 1.47 (d, J = 4.4 Hz, 6H); LC-MS: m / z = 203.0 (M+H) + .

[0169] Step 2: Synthesis of intermediate AA5 Compound AA5-2 (7.00 g, 34.5 mmol, 1.00 equivalent) and triisopropyl borate (32.4 g, 172 mmol, 39.6 mL, 5.00 equivalent) were added to tetrahydrofuran (150.0 mL), and n-butyllithium (2.50 M, 27.6 mL, 2.00 equivalent) was added dropwise at -78°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Then, saturated aqueous ammonium chloride solution (200 mL) was added dropwise at 0°C to quench the reaction. Water (300.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (300 mL). The organic layers were combined, washed twice with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound AA5 (6.5 g, crude product) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.22 - 8.26 (m, 2H), 8.20 (s, 1H), 5.12 (s, 1H),2.30 (s, 3H), 1.37 - 1.39 (m, 6H); LC-MS: m / z = 169.1 (M+H) + .

[0170] Synthesis of the common intermediate AA6 (2-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0171] [ka]

[0172] Step 1: Synthesis of compound AA6-2 (2-bromopyridine-3-yltrifluoromethanesulfonate) 5-Bromo-3-hydroxypyridine (compound AA6-1, 1.0 g, 7.72 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (2.76 g, 7.72 mmol, purchased from Bide Pharmatech), and triethylamine (1.1 mL, 8.1 mmol) were sequentially added to dichloromethane (20 mL). The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere, then heated to 25°C and stirred for 1.5 hours. The reaction mixture was washed once with 1 M sodium hydroxide (100 mL), twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound AA6-2 (2.8 g, crude product) as a pale yellow oil. LC-MS: m / z = 305.9 (M + H) + .

[0173] Step 2: Synthesis of compound AA6-3 (2-cyclopropylpyridine-3-yltrifluoromethanesulfonate) Compound AA6-2 (2.5 g), tetrakis(triphenylphosphine)palladium (199 mg), and cyclopropyl zinc chloride (0.4 M THF solution, 23 mL) were sequentially added to tetrahydrofuran (15 mL). The resulting mixture was stirred under a nitrogen atmosphere at 70 °C for 3 hours and then cooled to room temperature. Saturated aqueous sodium bicarbonate (60 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound AA6-3 (1.5 g) as a colorless, transparent oil. LC-MS: m / z = 268.1 (M + H) + .

[0174] Step 3: Synthesis of intermediate AA6 Compound AA6-3 (0.5 g), bis(pinacolato)diborone (0.57 g), potassium carbonate (0.525 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (0.156 g) were added to dioxane (80 mL). The resulting mixture was stirred at 100 °C for 20 hours and then cooled to room temperature. Ethyl acetate (200 mL) was added, and the resulting mixture was washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound AA6 (0.2 g) as a white solid.

[0175] Synthesis of the common intermediate AA7 (2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0176] [ka]

[0177] Step 1: Synthesis of compound AA7-2 (2-isopropylpyridine-3-yltrifluoromethanesulfonate) 2-Isopropylpyridine-3-ol (compound AA7-1, 3.00 g, 21.8 mmol, 1.00 equivalent) was added to pyridine (30.0 mL), followed by the addition of trifluoromethanesulfonic anhydride (6.17 g, 21.8 mmol, 3.61 mL, 1.00 equivalent) at 0°C, and the mixture was stirred at 15°C for 2 hours. Water (30 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (60 mL). The organic layers were combined, washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound AA7-2 (3.62 g, crude product) as a yellow oil. 1H NMR (400MHz, CDCl3) δ 8.59 (t, J = 3.6 Hz, 1H), 7.55 - 7.58 (m, 1H), 7.21 - 7.24 (m, 1H), 3.39 - 3.46 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 270.2 (M+H) + .

[0178] Step 2: Synthesis of Compound AA7 Compound AA7-2 (3.62 g, 13.4 mmol, 1.00 equivalent), bis(pinacolato)diborone (6.83 g, 26.8 mmol, 2.00 equivalent), potassium acetate (2.64 g, 26.8 mmol, 2.00 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (983 mg, 1.34 mmol, 0.100 equivalent) were sequentially added to dioxane (60.0 mL). The resulting mixture was stirred at 100 °C for 20 hours and then cooled to room temperature. Ethyl acetate (300 mL) was added, and the resulting mixture was washed three times with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound AA7 (2.00 g, 8.09 mmol, yield 60.2%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 8.60 (dd, J1= 2.0Hz, J2= 3.2Hz, 1H), 7.99 (dd, J1= 2.0Hz, J2= 5.2Hz, 1H), 7.07 (dd, J1= 4.8Hz, J2= 2.8Hz, 1H), 3.71 - 3.78 (m, 1H), 1.35 (s, 12H), 1.24 - 1.28 (m, 6H).

[0179] Common intermediate AA8 ((2-(dimethylamino)phenyl)boronic acid) Intermediate AA8 was purchased from Bide Pharmatech.

[0180] [ka]

[0181] Synthesis of the common intermediate AA9 (4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0182] [ka]

[0183] Step 1: Synthesis of compound AA9-2 (4-chloro-1-isopropyl-1H-pyrazole) Compound AA9-1 (50.00 g, 487.70 mmol, 1.00 equivalent), 2-iodopropane (124.36 g, 731.55 mmol, 73.15 mL, 1.50 equivalent), and cesium carbonate (317.80 g, 975.40 mmol, 2.00 equivalent) were added to acetonitrile (500.00 mL) and stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was then filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound AA9-2 (45.00 g, 306.53 mmol, yield 62.85%, purity 98.50%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.41-7.40 (m, 2H), 4.46 - 4.41(m, 1H), 1.48 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 144.0 (M+H) + .

[0184] Step 2: Synthesis of intermediate AA9 Compound AA9-2 (10 g, 69.16 mmol, 1 equivalent) was dissolved in anhydrous tetrahydrofuran (100 mL), and n-butyllithium (2.5 M, 33.19 mL, 1.2 equivalents) was added dropwise at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 1 hour. Isopropyl pinacollyl borate (15.44 g, 82.99 mmol, 16.93 mL, 1.2 equivalents) was added at -78°C, and the resulting mixture was heated to 25°C and stirred for 2 hours. Then, saturated aqueous ammonium chloride solution (100 mL) was added at 0°C to quench the reaction. Water (200 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (60.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Welch Ultimate XB-CN 250×70×10 μm; mobile phase: [hexane-ethanol]; B%: 1%~1%, 15 min) to obtain compound AA9 (6.5 g, 18.33 mmol, yield 26.51%, purity 76.3%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 7.45 (s, 1H), 5.07 - 5.00(m, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.36 (s, 12H); LC-MS: m / z = 271.2 (M+H) + .

[0185] Common intermediate AA10 ((2-cyclopropylphenyl)boronic acid) Intermediate AA10 was purchased from Bide Pharmatech.

[0186] [ka]

[0187] Synthesis of the common intermediate AA11 ((1-isopropyl-4-methoxy-1H-pyrazole-5-yl)boronic acid)

[0188] [ka]

[0189] Step 1: Synthesis of compound AA11-2 (1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole) 4-Pyrazolyl pinacolyl borate (compound AA11-1, 130 g, 669 mmol, 1.00 equivalent) was dissolved in N,N-dimethylformamide (114 g, 669 mmol, 67.0 mL, 1.00 equivalent). 2-iodopropane (114 g, 669 mmol, 67.0 mL, 1.00 equivalent) and cesium carbonate (327 g, 1.00 mol, 1.50 equivalent) were added, and the mixture was stirred at an external temperature of 90°C for 12 hours. The reaction mixture was then filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound AA11-2 (120 g, 508 mmol, yield 75.9%) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ 7.74 (m, 2H), 4.46 - 4.53 (m, 1H), 1.48 (d, J = 6.8Hz, 6H), 1.29 (s, 12H); LC-MS: m / z = 237.1 (M+H) + .

[0190] Step 2: Synthesis of compound AA11-3 (1-isopropyl-1H-pyrazole-4-ol) Compound AA11-2 (60.0 g, 254 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (600 mL), followed by the addition of aqueous sodium hydroxide solution (2.50 M, 203 mL, 2.00 equivalent) and hydrogen peroxide (72.0 g, 635 mmol, 61.0 mL, 30.0% purity, 2.50 equivalent). The mixture was stirred at 25°C for 3 hours. 1 M aqueous hydrochloric acid was added to adjust the pH to approximately 2. Anhydrous sodium sulfite (50.0 g) was then added at 0°C to quench the reaction. The resulting mixture was concentrated under vacuum to remove the tetrahydrofuran and extracted three times with dichloromethane / methanol = 10 / 1 (1500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound AA11-3 (17.5 g, 138 mmol, yield 54.6%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ7.12 (s, 1H), 7.09 (d, J = 0.8 Hz, 1H), 4.32 - 4.39 (m, 1H), 1.43 (s, 3H), 1.41 (s, 3H).

[0191] Step 3: Synthesis of compound AA11-4 (1-isopropyl-4-methoxy-1H-pyrazole) Compound AA11-3 (17.5 g, 139 mmol, 1.00 equivalent) was dissolved in N,N-dimethylformamide (350 mL), followed by the addition of cesium carbonate (67.8 g, 208 mmol, 1.50 equivalent) and iodomethane (29.5 g, 208 mmol, 13.0 mL, 1.50 equivalent). The mixture was stirred at room temperature (25 °C) for 3 hours. Then, water (1000 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (600 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound AA11-4 (12.3 g, 87.7 mmol, yield 63.3%) as a pale yellow solid.1 H NMR (400MHz, CDCl3) δ 7.17 (s, 1H), 7.05 (d, J = 0.8 Hz, 1H), 4.30 - 4.36 (m, 1H), 3.70 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H).

[0192] Step 4: Synthesis of Compound AA11 Compound AA11-4 (1.00 g, 7.13 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (15.0 mL). n-butyllithium (2.50 M, 4.28 mL, 1.50 equivalent) was added dropwise under a nitrogen atmosphere at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 1 hour. Next, isopropyl pinacollyl borate (2.01 g, 10.8 mmol, 2.2 mL, 1.50 equivalent) was added at -70°C. The resulting mixture was stirred at -70°C for 1 hour, then heated to 25°C and stirred for 12 hours. Next, saturated aqueous ammonium chloride solution (20.0 mL) was added at 0°C, and the resulting mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was ground in petroleum ether (20.00 mL) for 15 minutes to obtain intermediate AA11 (200 mg, 1.09 mmol, yield 15.2%) as an off-white solid. LC-MS: m / z = 185.2 (M + H) + .

[0193] Synthesis of the common intermediate AA12 ((1-cyclopropyl-4-methoxy-1H-pyrazole-5-yl)boronic acid)

[0194] [ka]

[0195] Step 1: Synthesis of compound AA12-2 (1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole) Compound AA12-1 (19.0 g, 102 mmol, 1.00 equivalent) was dissolved in dioxane (250 mL), and then bis(pinacolato)diborone (36.1 g, 142 mmol, 1.40 equivalent), potassium acetate (39.9 g, 406 mmol, 4.00 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (4.15 g, 5.08 mmol, 0.05 equivalent) were added sequentially. The mixture was stirred under a nitrogen atmosphere at 85°C for 12 hours. Then, water (800 mL) and ethyl acetate (500 mL) were added, and the resulting mixture was filtered to obtain a filtrate. This was extracted three times with ethyl acetate (500 mL). The organic layers were combined, washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 0) to obtain compound AA12-2 (4.40 g) as a pale yellow oily substance. 1 LC-MS: m / z = 235.1 (M+H) + .

[0196] Step 2: Synthesis of compound AA12-3 (1-cyclopropyl-1H-pyrazole-4-ol) Compound AA12-2 (3.30 g, 14.1 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (43.0 mL), followed by the addition of aqueous sodium hydroxide solution (2.50 M, 11.3 mL, 2.00 equivalent) and hydrogen peroxide (5.84 g, 51.5 mmol, 4.95 mL, 30.0% purity, 3.65 equivalent). The mixture was stirred at 25°C for 3 hours. 1 M aqueous hydrochloric acid solution was added to adjust the pH to approximately 2. Anhydrous sodium sulfite (50.0 g) was then added at 0°C to quench the reaction. The resulting mixture was concentrated under vacuum to remove tetrahydrofuran and extracted three times with dichloromethane / methanol = 10 / 1 (150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound AA12-3 (0.980 g, crude product) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 7.12 (d, J = 3.6Hz, 2H), 3.46 - 3.48 (m, 1H), 0.95 - 0.96 (m, 2H), 0.94 - 0.95 (m, 2H).

[0197] Step 3: Synthesis of compound AA12-4 (1-cyclopropyl-4-methoxy-1H-pyrazole) Compound AA12-3 (0.980 g, 7.89 mmol, 1.00 equivalent) was dissolved in N,N-dimethylformamide (19.5 mL), followed by the addition of cesium carbonate (3.86 g, 11.8 mmol, 1.50 equivalent) and iodomethane (1.68 g, 11.8 mmol, 737 μL, 1.50 equivalent). The mixture was stirred at room temperature (25°C) for 3 hours. Then, water (10.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 2) to obtain compound AA12-4 (0.460 g, 3.33 mmol, yield 42.2%) as a pale yellow solid.1 LC-MS: m / z = 139.2 (M+H) + .

[0198] Step 4: Synthesis of intermediate AA12 Compound AA12-4 (0.300 g, 2.17 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (8.50 mL), and n-butyllithium (2.50 M, 1.74 mL, 2.00 equivalent) was added dropwise under a nitrogen atmosphere at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 1 hour. Next, isopropyl pinacollyl borate (808 mg, 4.34 mmol, 886 μL, 2.00 equivalent) was added at -70°C, and the resulting mixture was stirred at -70°C for 1 hour, then heated to 25°C and stirred for 12 hours. Next, saturated aqueous ammonium chloride solution (30.0 mL) was added at 0°C, and the resulting mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (chromatography column: Waters Xbridge C18 150×50mm×10μm; mobile phase: [water (NH4HCO3)~ACN]; B%: 3%~33%, 10 min) to obtain compound AA12 (0.400g, crude product) as a pale yellow oily substance. LC-MS: m / z=183.1(M+H) + .

[0199] Synthesis of the common intermediate AA13 ((5-isopropyl-3-methylisoxazole-4-yl)boronic acid)

[0200] [ka]

[0201] Step 1: Synthesis of compound AA13-2 (5-isopropyl-3-methylisoxazole) Isobutyrylacetone (compound AA13-1, 2.00 g, 15.6 mmol, 1.00 equivalent) and hydroxylamine hydrochloride (1.36 g, 19.6 mmol, 1.25 equivalents) were sequentially added to ethanol (10.0 mL) and stirred at 130°C for 10 minutes. Dichloromethane (100 mL) was added, and the resulting mixture was washed twice with saturated brine (50.0 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound AA13-2 and compound AA13-2a (total 4.80 g, crude product) as a colorless, transparent liquid. Compound AA13-2: 1 H NMR (400MHz, CDCl3) δ 5.76 (s, 1H), 3.04 - 2.97 (m,1H), 2.35 (s, 3H), 1.28 - 1.23 (m, 6H).

[0202] Step 2: Synthesis of compound AA13-3 (4-bromo-5-isopropyl-3-methylisoxazole) Compounds AA13-2 and AA13-2a (3.50 g, 28.0 mmol, 1.00 equivalent) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N-bromosuccinimide (7.94 g, 44.6 mmol, 1.59 equivalent). The mixture was stirred at 25°C for 15 hours. Ethyl acetate (250 mL) was added, and the resulting mixture was washed once with saturated sodium thiosulfate (100 mL) and three times with saturated brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound AA13-3 and compound AA13-3a (5.24 g, crude product) as a pale yellow oil. Compound AA13-3: 1 H NMR (400MHz, CDCl3) δ 3.20 - 3.13 (m, 1H), 2.24 (s, 3H), 1.33 - 1.30 (m, 6H); LC-MS: m / z = 203.9 (M+H) + .

[0203] Step 3: Synthesis of Compound AA13 Compounds AA13-3 and AA13-3a (3.00 g, 14.7 mmol, 1.00 equivalent) and triisopropyl borate (3.59 g, 19.1 mmol, 4.39 mL, 1.30 equivalent) were dissolved in tetrahydrofuran (30.0 mL), and n-butyllithium (2.5 M, 7.64 mL, 1.30 equivalent) was added dropwise at -70°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Water (10.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (chromatography column: Phenomenex luna C18 250×80mm×10μm; mobile phase: [water (FA)~ACN]; B%: 20%~50%, 20 min) to obtain compound AA13 (470 mg, 2.73 mmol, yield 18.5%, purity 98.0%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 3.83 - 3.76 (m, 1H), 2.49 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H); LC-MS: m / z = 170.1 (M+H) + .

[0204] Synthesis of the common intermediate AA14 (4-chloro-1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0205] [ka]

[0206] Step 1: Synthesis of compound AA14-2 (4-chloro-1-cyclopropyl-1H-pyrazole) 4-chloropyrazole (compound AA14-1, 10.0 g, 97.54 mmol, 1.0 equivalent), cyclopropyl bromide (21.2 g, 175.57 mmol, 1.8 equivalents), and cesium carbonate (63 g, 195.08 mmol, 2.0 equivalents) were sequentially added to dioxane (50 mL), and the mixture was stirred at an external temperature of 140 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 2) to obtain compound AA14-2 (6.4 g) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8 Hz, 1H), 1.13 - 1.05 (m, 2H), 1.05 - 0.95 (m, 2H). LC-MS: m / z = 143.1 (M+H)+.

[0207] Step 2: Synthesis of intermediate AA14 Compound AA14-2 (8.3 g, 58.21 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (100 mL), and lithium diisopropylamide (58 mL, 116.42 mmol, 2.0 equivalents) was added dropwise under a nitrogen atmosphere at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 1 hour. Isopropyl pinacollyl borate (17.3 g, 93.14 mmol, 1.6 equivalents) was added, and the resulting mixture was stirred at -70°C for 1 hour, then heated to 25°C and stirred for 2 hours. Next, water (100 mL) was added to quench the reaction, and the resulting mixture was extracted three times with dichloromethane (200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the intermediate AA14 (4.2 g) as a colorless and transparent oily substance. 1H NMR (400MHz, CDCl3) δ 7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8 Hz, 1H), 1.13 - 1.05 (m, 2H), 1.05 - 0.95 (m, 2H).

[0208] Common intermediate AA15 ((4-cyclopropylpyrimidine-5-yl)boronic acid) Intermediate AA15 was purchased from Leyan Reagents.

[0209] [ka]

[0210] Synthesis of the common intermediate AA16 (1-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0211] [ka]

[0212] Following the same steps as for intermediate AA14, intermediate AA16 (2.9 g) was obtained using 4-methylpyrazole (compound AA16-1) as the starting material. 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 4.03 (td, J = 7.5, 3.8 Hz, 1H), 2.15 (s, 3H), 1.35 (s, 12H), 1.12 - 1.01 (m, 2H), 0.99 - 0.89 (m, 2H).

[0213] Synthesis of the common intermediate AA17 (1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0214] [ka]

[0215] Following the same steps as for intermediate AA14, intermediate AA17 (4.1 g) was obtained using 4-methylpyrazole (compound AA16-1) as the starting material. 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 4.94-4.98 (m, 1H), 2.12 (s, 3H), 1.34 (d, J = 6.6 Hz, 6H), 1.29 (s, 12H).

[0216] Synthesis of common intermediate B1 (3-(4-(chloromethyl)piperidine-1-yl)pyridine)

[0217] [ka]

[0218] Step 1: Synthesis of compound B1-3 (ethyl 1-(pyridine-3-yl)piperidine-4-carboxylate) Compound B1-1 (6.4 g, 40.7 mmol, 1.28 equivalents), Compound B1-2 (5.0 g, 31.8 mmol, 1.00 equivalent), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (1.1 g, 1.91 mmol, 0.06 equivalents), cesium carbonate (13.9 g, 42.90 mmol, 1.35 equivalents), and tris(dibenzylideneacetone)dipalladium (582.0 mg, 0.6 mmol, 0.02 equivalents) were sequentially added to anhydrous dioxane (50.0 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to obtain compound B1-3 (3.2 g). 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.12 - 7.19 (m, 2H), 4.11 - 4.17 (m, 2H), 3.60 - 3.65 (m, 2H), 2.80 - 2.86 (m, 2H), 2.39 - 2.48 (m, 2H), 2.00 - 2.04 (m, 2H), 1.83 - 1.87 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H); LC-MS: m / z =235.1 (M+H) + .

[0219] Step 2: Synthesis of Compound B1-4 ((1-(pyridine-3-yl)piperidine-4-yl)methanol) Compound B1-3 (2.0 g, 8.5 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum tetrahydrogen (356.0 mg, 9.4 mmol, 1.10 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Then, water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) were added at 0°C. After the addition was complete, the resulting mixture was stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the resulting mixture was stirred for 5 minutes, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain crude compound B1-4 (1.2 g). This was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 4.4 Hz, 1H), 7.19 - 7.21 (m, 1H), 7.12 - 7.16 (m, 1H), 3.71 - 3.74 (m, 2H), 3.53 - 3.55 (m, 2H), 2.73 - 2.80 (m, 2H), 2.60 (s, 1H), 1.86 - 1.89 (m, 2H), 1.67 - 1.70 (m, 1H), 1.25 - 1.44 (m, 2H); LC-MS: m / z = 193.2 (M+H) + .

[0220] Step 3: Synthesis of Intermediate B1 Compound B1-4 (0.5 g, 2.6 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (3.1 g, 26.0 mmol, 10.0 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B1 (520 mg, 2.31 mmol, yield 88.9%, purity 93.7%) as a pale yellow solid. LC-MS: m / z = 211.2 (M + H) + .

[0221] Synthesis of common intermediate B2 (4-(4-(chloromethyl)piperidine-1-yl)pyridine)

[0222] [ka]

[0223] Step 1: Synthesis of compound B2-3 (ethyl 1-(pyridine-4-yl)piperidine-4-carboxylate) Compound B2-1 (5.0 g, 33.3 mmol, 1.00 equivalent), compound B2-2 (5.2 g, 33.3 mmol, 1.00 equivalent), and triethylamine (10.1 g, 100.0 mmol, 3.00 equivalent) were added to ethanol (50.0 mL), and the mixture was heated to 100°C and stirred for 16 hours. Then, water (50.0 mL) was added at 25°C, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound B2-3 (2.7 g). 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 5.2 Hz, 2H), 6.65 (d, J = 5.6 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.82 (d, J = 13.2 Hz, 2H), 2.96 (d, J = LC-MS: m / z =235.2 (M+H) + .

[0224] Step 2: Synthesis of Compound B2-4 ((1-(pyridine-4-yl)piperidine-4-yl)methanol) Compound B2-3 (1.7 g, 7.3 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (302.0 mg, 8.0 mmol, 1.10 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Sodium hydroxide aqueous solution (0.25 M, 2 mL) was added at 0°C, and the resulting mixture was stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the resulting mixture was stirred for 5 minutes, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain the crude product compound B2-4 (1.1 g). This was used directly in the next step.1 H NMR (400 MHz, CDCl3) δ 8.25 (t, J = 1.6 Hz, 2H), 6.67 (t, J = 1.2 Hz, 2H), 3.92 (d, J = 16.0 Hz, 2H), 3.55 (d, J = 2.4 Hz, 2H), 2.84 - 2.90 (m, 2H), 1.78 - 1.87 (m, 3H), 1.30 - 1.37 (m, 2H); LC-MS: m / z = 193.0 (M+H) + .

[0225] Step 3: Synthesis of Compound B2 Compound B2-4 (500.0 mg, 2.60 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (2.5 g, 20.8 mmol, 8.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B2 (530 mg, 2.52 mmol, yield 96.7%) as a white solid. LC-MS: m / z = 193.0 (M + H) + .

[0226] Synthesis of the common intermediate B3 (3-(4-(chloromethyl)phenyl)pyridine)

[0227] [ka]

[0228] Step 1: Synthesis of compound B3-3 ((4-(pyridine-3-yl)phenyl)methanol) Compound B3-1 (3.0 g, 18.9 mmol, 1.00 equivalent), Compound B3-2 (3.8 g, 24.6 mmol, 1.30 equivalent), sodium carbonate (14.8 g, 140.0 mmol, 7.40 equivalent), and tetrakis(triphenylphosphine)palladium (2.2 g, 1.89 mmol, 0.10 equivalent) were sequentially added to a mixed solvent of toluene (15.0 mL), water (15.0 mL), and ethanol (3.0 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound B3-3 (2.3 g). 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 7.87 - 7.90 (m, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.36 - 7.39 (m, 1H), 4.78 (s, 2H), 1.96 - 2.06 (m, 1H); LC-MS: m / z = 186.1 (M+H) + .

[0229] Step 2: Synthesis of Intermediate B3 Compound B3-3 (1.0 g, 5.4 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (6.4 g, 53.9 mmol, 10.0 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B3 (1.1 g, 5.35 mmol, 99.1% yield) as a white solid. LC-MS: m / z = 204.0 (M + H) + .

[0230] Synthesis of the common intermediate B4 (4-(4-(chloromethyl)phenyl)pyridine)

[0231] [ka]

[0232] Compound B4-1 (250.0 mg, 1.4 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (802.0 mg, 6.8 mmol, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B4 (260 mg, 1.28 mmol, yield 94.5%) as a white solid. LC-MS: m / z = 204.0 (M + H) + .

[0233] Synthesis of the common intermediate B5 (5-(4-(chloromethyl)phenyl)-2-methylpyridine)

[0234] [ka]

[0235] Step 1: Synthesis of Compound B5-3 ((4-(6-methylpyridine-3-yl)phenyl)methanol) Compound B5-1 (3.0 g, 17.4 mmol, 1.00 equivalent), Compound B5-2 (3.5 g, 22.6 mmol, 1.30 equivalent), sodium carbonate (13.6 g, 129.0 mmol, 7.40 equivalent), and tetrakis(triphenylphosphine)palladium (2.0 g, 1.74 mmol, 0.10 equivalent) were sequentially added to a mixed solvent of toluene (15.0 mL), water (15.0 mL), and ethanol (3.00 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound B5-3 (3.0 g). 1H NMR (400 MHz, CDCl3) δ 8.59 - 8.63 (m, 1H), 7.76 - 7.78 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 4.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 2.61 (s, 3H), 2.33 - 2.37 (m, 1H); LC-MS: m / z = 200.1 (M+H) + .

[0236] Step 2: Synthesis of Intermediate B5 Compound B5-3 (0.5 g, 2.5 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (1.5 g, 12.5 mmol, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B5 (530 mg, 2.43 mmol, yield 97.0%) as a white solid. LC-MS: m / z = 218.1 (M + H) + .

[0237] Synthesis of the common intermediate B6 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0238] [ka]

[0239] Step 1: Synthesis of compound B6-3 (methyl 4-(4-(trifluoromethyl)-1H-imidazole-2-yl)benzoate) Compound B6-2 (7.2 g, 26.8 mmol, 1.10 equivalents) and sodium acetate (2.2 g, 27.3 mmol, 1.12 equivalents) were dissolved in water (8.0 mL) and stirred at 100°C for 1 hour. Compound B6-1 (4.0 g, 24.4 mmol, 1.00 equivalent) was dissolved in methanol (80.0 mL) and aqueous ammonia (22.0 mL) was added at 25°C. After the addition was complete, the resulting mixture was stirred at 25°C for 40 minutes, heated to 100°C, and stirred for 2 hours. Then, water (60.0 mL) was added to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (80.0 mL). The organic layers were combined, washed twice with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound B6-3 (4.5g). 1 HNMR (400 MHz, CDCl3) δ 13.4 (s, 1H), 8.10 - 8.12 (m, 2H), 8.04 - 8.06 (m, 2H), 7.99 (s, 1H), 3.87 (s, 3H); LC-MS: m / z = 271.0 (M+H) + .

[0240] Step 2: Synthesis of compound B6-4 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzoate) Compound B6-3 (2.5 g, 9.3 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and sodium hydride (444.1 mg, 11.1 mmol, 1.20 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Then, iodomethane (6.8 g, 48.1 mmol, 5.20 equivalent) was added. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. Then, ice water (20.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound B6-4 (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4Hz, 2H), 7.99 (s, 1H), 7.90 (d, J = 8.4Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H); LC-MS: m / z =285.1 (M+H) + .

[0241] Step 3: Synthesis of Compound B6-5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methanol) Compound B6-4 (0.6 g, 2.1 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum hydride (88.1 mg, 2.32 mmol, 1.10 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) were added at 0°C, and the resulting mixture was stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the resulting mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain crude product B6-5 (505.4 mg). This was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.30 - 5.33 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H); LC-MS: m / z = 257.1 (M+H) + .

[0242] Step 4: Synthesis of Intermediate B6 Compound B6-5 (500.0 mg, 2.0 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (1.9 g, 15.6 mmol, 8.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B6 (523 mg, 1.90 mmol, yield 97.6%) as a brown solid. LC-MS: m / z = 275.1 (M + H) + .

[0243] Synthesis of common intermediate B7 (2-(4-(chloromethyl)cyclohexyl)pyrimidine)

[0244] [ka]

[0245] Step 1: Synthesis of compound B7-3 (ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-ene-1-carboxylate) Compound B7-1 (10.0 g, 33.1 mmol, 1.00 equivalent), Compound B7-2 (9.2 g, 36.4 mmol, 1.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (1.4 g, 1.7 mmol, 0.05 equivalent), and potassium acetate (9.8 g, 99.3 mmol, 3.00 equivalent) were sequentially added to dioxane (80.0 mL). The resulting mixture was purged three times with nitrogen and stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (200.0 mL) was then added, and the resulting mixture was extracted three times with ethyl acetate (70.0 mL). The organic layers were combined, washed twice with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 30 / 1) to obtain compound B7-3 (4.5 g). 1 H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 4.12-4.17 (m, 2H), 2.50-2.51 (m, 1H), 2.26-2.35 (m, 3H), 2.01-2.05 (m, 2H), 1.58-1.63 (m, 1H), 1.27-1.28 (m, 15H); LC-MS: m / z = 281.1 (M+H) + .

[0246] Step 2: Synthesis of compound B7-5 (ethyl 4-(pyrimidine-2-yl)cyclohexa-3-ene-1-carboxylate) Compound B7-3 (4.9 g, 17.3 mmol, 1.10 equivalents), Compound B7-4 (2.5 g, 15.7 mmol, 1.00 equivalent), sodium carbonate (5.0 g, 47.2 mmol, 3.00 equivalents), and tetrakis(triphenylphosphine)palladium (1.8 g, 1.6 mmol, 0.10 equivalents) were sequentially added to dioxane (50.0 mL) and water (12.5 mL). The resulting mixture was purged three times with nitrogen and stirred under a nitrogen atmosphere at 90°C for 20 hours. Then, water (100.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound B7-5 (3.1 g). 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.80 Hz, 2H), 7.28-7.29 (m, 1H), 7.07-7.10 (m, 1H), 4.12-4.20 (m, 2H), 2.82-2.83 (m, 1H), 2.58-2.63 (m, 1H), 2.55-2.58 (m, 3H), 2.04-2.21 (m, 1H), 1.81-1.84 (m, 1H), 1.23-1.30 (m, 3H); LC-MS: m / z = 233.1 (M+H) + .

[0247] Step 3: Synthesis of Compound B7-6 (Ethyl 4-(Pyrimidine-2-yl)cyclohexane-1-carboxylate) Compound B7-5 (3.0 g, 13.1 mmol, 1.00 equivalent) and wet palladium-supported carbon (1.4 g, 1.3 mmol, purity 10.0%, 0.10 equivalent) were sequentially added to ethanol (90.0 mL) and stirred at 25°C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound B7-6 (2.1 g). 1H NMR (400 MHz, CDCl3) δ 8.64-8.66 (m, 2H), 7.07-7.12 (m, 1H), 4.10-4.15 (m, 2H), 2.95-2.97 (m, 1H), 2.59-2.61 (m, 1H), 2.10-2.15 LC-MS: m / z = 235.1 (M+H) + .

[0248] Step 4: Synthesis of Compound B7-7 ((4-(pyrimidine-2-yl)cyclohexyl)methanol) Compound B7-6 (500.0 mg, 2.1 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and diisobutylaluminum hydride (1.0 M, 3.20 equivalents) was added at -65°C. After the addition was complete, the resulting mixture was reacted at -65°C for 0.5 hours, then heated to 20°C and stirred for 1 hour. Next, saturated aqueous ammonium chloride solution (20.0 mL) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 1 hour. The reaction mixture was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain crude compound B7-7 (263.5 mg). This was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.80 Hz, 2H), 7.11-7.14 (m, 1H), 3.64 (d, J = 7.20 Hz, 2H), 3.04-3.08 (m, 1H), 2.05-2.08 (m, 2H), 1.83-1.85 (m, 3H), 1.64-1.69 (m, 4H), 1.14-1.26 (m, 1H); LC-MS: m / z = 193.0 (M+H) + .

[0249] Step 5: Synthesis of Intermediate B7 Compound B7-7 (263.0 mg, 1.4 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (814.0 mg, 6.8 mmol, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound B7 (300 mg, crude product) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.79-8.98 (m, 2H), 7.17-7.25 (m, 1H), 3.59-3.76 (m, 1H), 3.26-3.47 (m, 2H), 2.05-2.37 (m, 2H), 1.73-1.88 (m, 4H), 1.47-1.56 (m, 1H), 1.45-1.47 (m, 1H), 1.27-1.45 (m, 1H); LC-MS: m / z = 211.2 (M+H) + .

[0250] Synthesis of the common intermediate B8 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine)

[0251] [ka]

[0252] Intermediate B6 (700.0 mg, 2.55 mmol, 1.00 equivalent) and aqueous ammonia (27.3 g, 233.0 mmol, 30% purity, 91.70 equivalents) were added to dioxane (15.0 mL), and the resulting mixture was reacted in a sealed tube at 50°C for 12 hours. The reaction solution was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain B8 (580 mg, 1.99 mmol, yield 78.0%, HCl) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.76 (m, 3H), 7.63 - 7.65 (m, 2H), 4.22 (s, 2H), 3.80 (s, 3H); LC-MS: m / z = 256.0 (M+H) + .

[0253] Synthesis of common intermediate B9 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0254] [ka]

[0255] Following the synthesis of intermediate B6, and without changing any other experimental conditions, general intermediate B9 was obtained by using an equimolar amount of B9-1 instead of B6-1. Compound B9 (330.0 mg, crude product) was finally obtained as a white solid. LC-MS: m / z = 281.0 (M + H) + .

[0256] Synthesis of common intermediate B10 (2-(4-(chloromethyl)phenyl)pyridine)

[0257] [ka]

[0258] Step 1: Synthesis of compound B10-3 ((4-(pyridine-2-yl)phenyl)methanol) Compound B10-1 (10.0 g, 63.3 mmol, 6.02 mL, 1.00 equivalent), compound B10-2 (12.5 g, 82.3 mmol, 1.30 equivalent), tetrakis(triphenylphosphine)palladium (7.31 g, 6.33 mmol, 0.100 equivalent), and sodium carbonate (49.6 g, 468 mmol, 7.40 equivalent) were sequentially added to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B10-3 (9.63 g). 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J=4.4Hz, 1H), 7.75 - 7.95 (m, 2H), 7.70 - 7.74 (m, 2H), 7.42 - 7.44 (m, 2H), 7.22 - 7.25 (m, 1H), 4.73 (s, 2H), 2.70 (s, 1H); LC-MS: m / z = 186.2 (M+H) + .

[0259] Step 2: Synthesis of Intermediate B10 Compound B10-3 (1.0 g, 5.40 mmol, 1.00 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain B10 (1.1 g, crude product) as a white solid. LC-MS: m / z = 204.1 (M + H) + .

[0260] Synthesis of common intermediate B11 (2-(4-(chloromethyl)piperidine-1-yl)pyridine)

[0261] [ka]

[0262] Step 1: Synthesis of compound B11-3 (ethyl 1-(pyridine-2-yl)piperidine-4-carboxylate) Compound B11-1 (20.8 g, 132 mmol, 20.4 mL, 1.00 equivalent), compound B11-2 (15.0 g, 132.0 mmol, 1.00 equivalent), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 equivalent) were dissolved in DMSO (50.0 mL), and the resulting mixture was reacted at 120-150°C for 16 hours. The reaction mixture was cooled to quench the reaction. Water (50 mL) was added at room temperature to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (60.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to obtain compound B11-32 (6.0 g, yield 19.4%, purity 100%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.17 - 8.19 (m, 1H), 7.44 - 7.48 (m, 1H), 6.66 (d, J=8.4Hz, 1H), 6.59 - 6.61 (m, 1H), 4.21 - 4.24 (m, 2H), 4.13 LC-MS: m / z =235.2(M+H) + .

[0263] Step 2: Synthesis of Compound B11-4 ((1-(pyridine-2-yl)piperidine-4-yl)methanol) Compound B11-3 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL), and lithium aluminum hydride (LiAlH4, 1.07 g, 28.2 mmol, 1.10 equivalents) was carefully added at 0°C. The resulting mixture was then stirred at room temperature for 16 hours. Additional lithium aluminum hydride (LiAlH4, 486 mg, 12.8 mmol, 0.500 equivalents) was added, and the resulting mixture was stirred for a further 6 hours. The reaction was quenched by carefully adding H2O (20.0 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (60.0 mL × 3). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:1) to obtain compound B11-4 (1.20 g, yield 23.8%, purity 97.8%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J=3.6Hz, 1H), 7.43 - 7.48 (m, 1H), 6.67 (d, J=8.8Hz, 1H), 6.58 - 6.59 (m, 1H),4.33 (d, J=12.8Hz, 2H), 3.54 (d, J=6.0Hz, 2H), 2.81 - 2.88 (m, 2H), 1.77 - 1.86 (m, 2H), 1.73 - 1.76 (m, 1H), 1.55 (s, 1H), 1.28 - 1.35 (m, 2H). LC-MS: m / z =193.2(M+H) + .

[0264] Step 3: Synthesis of Intermediate B11 Compound B11-4 (1.20 g, 6.24 mmol, 1.00 equivalent) was dissolved in dichloromethane (12.0 mL), and thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain compound B11 (1.57 g, crude product) as a white solid. LC-MS: m / z = 211.1.

[0265] Synthesis of the common intermediate B12 (2-((1r,4r)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0266] [ka]

[0267] Step 1: Synthesis of compound B12-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B12-1 (33.0 g, 242.0 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Next, iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 equivalent) was added. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 5 hours. Saturated aqueous ammonium chloride solution (30.0 mL) was added at 0°C to quench the reaction. Water (30.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B12-2 (21.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M+H) + .

[0268] Step 2: Synthesis of compound B12-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B12-2 (16.8 g, 111.0 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equivalent) was added dropwise at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 30 minutes. Next, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equivalent) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction mixture. After the addition was complete, the resulting mixture was reacted at -70°C for 1 hour, heated to 20°C, and stirred for 3 hours. Saturated aqueous ammonium chloride solution (200.0 mL) was added at 0°C to quench the reaction. Water (300.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain compound B12-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0269] Step 3: Synthesis of compound B12-5 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexa-3-ene-1-carboxylate) Compound B12-3 (7.0 g, 31.9 mmol, 1.00 equivalent), Compound B12-4 (9.0 g, 31.9 mmol, 1.00 equivalent), potassium phosphate (20.3 g, 95.8 mmol, 3.00 equivalent), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.3 g, 1.6 mmol, 0.05 equivalent), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 equivalent) were successively added to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C for 5 hours under a nitrogen atmosphere. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to obtain compound B12-5 (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 6.05 (d, J = 2.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.61 (s, 3H), 2.50 - 2.67 (m, 5H), 2.13 - 2.14 (m, 1H), 1.86 - 1.89 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); LC-MS: m / z = 337.2 (M+H) + .

[0270] Step 4: Synthesis of compound B12-6 (ethyl(1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexane-1-formate) Compound B12-5 (1.9 g, 5.6 mmol, 1.00 equivalent), sodium acetate (925.0 mg, 11.2 mmol, 2.00 equivalent), and wet palladium-supported carbon (0.5 g, 1.4 mmol, purity 10.0%, 0.25 equivalent) were sequentially added to ethanol (30.0 mL). The resulting mixture was reacted at 50°C for 5 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3) ~ ​​ACN]; B%: 34% ~ 64%, 10 min) to obtain compound B12-6 (0.3 g). 1 H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 4.15(q, J = 6.8 Hz, 2H), 3.64(s, 3H), 2.60 - 2.65 (m, 1H), 2.41 - 2.44 (m, 1H), 2.12 - 2.15 (m, LC-MS: m / z = 305.0 (M+H) + .

[0271] Step 5: Synthesis of compound B12-7 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexyl)methanol) Compound B12-6 (0.6 g, 2.0 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 0.5 hours, then heated to 20°C and stirred for 12 hours. Next, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 30 minutes, followed by the addition of tetrahydrofuran (10.0 mL), and the mixture was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain crude compound B12-7 (0.5 g). This was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 2.59 - 2.65 (m, 1H), 1.95 - 1.98 (m, 4H), 1.77 - 1.80 (m, 3H), 1.07 - 1.17 (m, 2H); LC-MS: m / z = 263.1 (M+H) + .

[0272] Step 6: Synthesis of Intermediate B12 Compound B12-7 (500.0 mg, 1.9 mmol, 1.00 equivalent) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 24 hours. The reaction mixture was concentrated under vacuum to obtain compound B12 (550 mg, 1.36 mmol, yield 71.5%, HCl) as a pale yellow solid. LC-MS: m / z = 281.0 (M + H) + .

[0273] Synthesis of general intermediate B13 (4-(chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine hydrochloride)

[0274] [ka]

[0275] Step 1: Synthesis of compound B13-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B13-1 (33.0 g, 242 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Then, iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 equivalent) was added. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Then, ice water (200.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (200.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B13-2 (21.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M+H) + .

[0276] Step 2: Synthesis of compound B13-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B13-2 (16.8 g, 111 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equivalent) was added dropwise at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 30 minutes. Next, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equivalent) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction mixture. After the addition was complete, the resulting mixture was reacted at -70°C for 1 hour, heated to 20°C, and stirred for 3 hours. Saturated aqueous ammonium chloride solution (200.0 mL) was added at 0°C to quench the reaction. Water (300.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain compound B13-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0277] Step 3: Synthesis of compound B13-5 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-carboxylate) Compound B13-3 (7.0 g, 31.9 mmol, 1.00 equivalent), Compound B13-4 (7.54 g, 47.9 mmol, 7.39 mL, 1.50 equivalent), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 equivalent), and sodium iodide (479 mg, 3.20 mmol, 0.100 equivalent) were sequentially added to N,N-dimethylformamide (70.0 mL), and the resulting mixture was reacted at 130°C for 72 hours. Water (350 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to obtain compound B13-5 (2.2 g). 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J = 7.2Hz, 2H), 3.45 (s, 3H), 3.24 - 3.28 (m, 2H), 2.90 - 2.97 (m, 2H), 2.40 - 2.45 (m, 1H), 2.02 - 2.06 (m, 2H), 1.85 - 1.88 (m, 2H), 1.28 (t, J = 8.0Hz, 2H); LC-MS: m / z = 340.1 (M+H) + .

[0278] Step 4: Synthesis of compound B13-6 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-carboxylate) Compound B13-5 (2.2 g, 6.48 mmol, 1.00 equivalent), sodium acetate (1.06 g, 12.9 mmol, 2.00 equivalent), and wet palladium-supported carbon (0.5 g, 1.94 mmol, purity 10.0%, 0.300 equivalent) were sequentially added to ethanol (40.0 mL). The resulting mixture was reacted under a hydrogen atmosphere (15 psi) at 50°C for 36 hours. The reaction solution was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound B13-6 (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.15 (q, J = 7.2Hz, 2H), 3.52 (s, 3H), 3.25 - 3.29 (m, 2H), 2.92 - 2.98 (m, 2H), 2.40 - 2.45 (m, 1H), 2.01 - 2.05 (m, 2H), 1.85 - 1.89 (m, 2H), 1.28 (t, J = 6.8Hz, 3H); LC-MS: m / z = 306.1 (M+H) + .

[0279] Step 5: Synthesis of compound B13-7 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methanol) Compound B13-6 (1.2 g, 3.93 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 0.5 hours, then heated to 20°C and stirred for 12 hours. Next, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 30 minutes, followed by the addition of tetrahydrofuran (10.0 mL), and the mixture was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product compound B13-7 (1.0 g). This was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 3.57 (d, J = 6.4Hz, 2H), 3.51 (s, 3H), 3.27 - 3.30 (m, 2H), 2.90 - 2.96 (m, 2H), 1.84 - 1.87 (m, 2H), 1.65 - 1.70 (m, 1H), 1.39 - 1.42(m, 2H); LC-MS: m / z = 264.1 (M+H) + .

[0280] Step 6: Synthesis of Intermediate B13 Compound B13-7 (1.0 g, 3.80 mmol, 1.00 equivalent) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 24 hours. The reaction mixture was concentrated under vacuum to obtain compound B13 (1.1 g, 3.46 mmol, yield 91.0%, HCl) as a brown solid. LC-MS: m / z = 282.1 (M + H) + .

[0281] Synthesis of common intermediate B14 (2-(5-(chloromethyl)furan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0282] [ka]

[0283] Step 1: Synthesis of compound B14-3 (5-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)furan-2-carboaldehyde) Compounds B14-2 (400 mg, 1.83 mmol, 1.00 equivalent), B14-1 (255 mg, 1.83 mmol, 1.00 equivalent), methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (71.2 mg, 91.3 μmol, 0.0500 equivalents), and potassium phosphate (1.16 g, 5.48 mmol, 3.00 equivalents) were sequentially added to n-butanol (3.0 mL) and water (0.5 mL). The resulting mixture was purged three times with nitrogen and reacted under a nitrogen atmosphere at 60°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: Phenomenex C18 75×30mm×3μm; mobile phase: [water (FA)~ACN]; B%: 22%~52%, 7 min) to obtain compound B14-3 (60.0 mg). 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.37 (d, J = 3.6Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 3.6 Hz, 1H), 4.07 (s, 3H); LC-MS: m / z = 245.2 (M+H)+.

[0284] Step 2: Synthesis of compound B14-4 ((5-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)furan-2-yl)methanol) Compound B14-3 (60.0 mg, 245 μmol, 1.00 equivalent) was dissolved in methanol (1.0 mL), followed by the addition of sodium borohydride (90.0 mg, 2.38 mmol, 9.68 equivalents). The resulting mixture was stirred at 15°C for 30 minutes. Then, saturated aqueous ammonium chloride solution (10.0 mL) was added at 0°C, followed by the addition of water (20.0 mL). The resulting mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This filtrate was concentrated under vacuum to obtain compound B14-4 (50.0 mg). 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 6.92 (d, J = 3.2Hz, 1H), 6.42 (d, J = 3.2Hz, 1H), 4.70 (s, 2H), 3.93 (s, 3H); LC-MS: m / z = 247.1 (M+H) + .

[0285] Step 3: Synthesis of Intermediate B14 Compound B14-4 (50.0 mg, 203 μmol, 1.00 equivalent) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (1.2 g, 10.1 mmol, 50.0 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and reacted for 24 hours. The reaction solution was concentrated under vacuum to obtain compound B14 (45 mg, crude product) as a pale yellow oily substance. LC-MS: m / z = 265.1 (M + H) + .

[0286] Synthesis of the common intermediate B15 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0287] [ka]

[0288] Step 1: Synthesis of compound B15-3 ((4-(imidazo[1,2-a]pyrazine-8-yl)phenyl)methanol) Compound B15-1 (9.6 g, 62.5 mmol, 1.00 equivalent), Compound B15-2 (12.4 g, 81.3 mmol, 1.30 equivalent), Tetrakis(triphenylphosphine)palladium (7.2 g, 6.25 mmol, 0.10 equivalent), and sodium carbonate (49.0 g, 463 mmol, 7.40 equivalent) were sequentially added to a mixed solvent of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound B15-3 (12.7 g). LC-MS: m / z = 226.2(M+H) + .

[0289] Step 2: Synthesis of Intermediate B15 Compound B15-3 (6.0 g, 26.6 mmol, 1.00 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (15.9 g, 133 mmol, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain compound B15 (7.3 g, 26.2 mmol, yield 98.2%, HCl) as an off-white solid. LC-MS: m / z = 244.1 (M + H) + .

[0290] Synthesis of general intermediate B16 ((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0291] [ka]

[0292] Step 1: Synthesis of compound B16-3 (methyl 4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octane-1-carboxylate) Compound B16-1 (25.0 g, 118 mmol, 1.00 equivalent), Compound B16-2 (20.8 g, 141 mmol, 1.20 equivalent), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 equivalent), and silver nitrate (4.01 g, 23.6 mmol, 0.20 equivalent) were sequentially added to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL). The resulting mixture was reacted at 20°C for 16 hours, followed by the addition of dichloromethane (250.0 mL). The mixture was filtered to obtain the filtrate, which was washed three times with water (100.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered to obtain the filtrate. This filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (alkaline conditions, NH3·H2O / MeCN / H2O) to obtain compound B16-3 (7.5g). 1 H NMR (400 MHz, CDCl3) δ 8.81 (s, , 1H), 7.85 (dd, J1= 4.0Hz, J2= 4.0Hz, 1H), 7.37 (d, J = 4.0Hz, 1H), 3.69 (s, 3H), 1.96 (s, 12H).

[0293] Step 2: Synthesis of compound B16-4 ((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methanol) Compound B16-3 (2.5 g, 7.98 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (50.0 mL), and lithium aluminum hydride (908 mg, 23.9 mmol, 3.00 equivalent) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C, the resulting mixture was stirred for 10 minutes, and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound B16-4 (2.3 g). LC-MS: m / z = 286.1 (M + H) + .

[0294] Step 3: Synthesis of Intermediate B16 Compound B16-4 (1.6 g, 5.61 mmol, 1.00 equivalent) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 equivalent) were added to pyridine (25.0 mL), and the resulting mixture was reacted at 20°C for 12 hours. The reaction solution was concentrated under vacuum. Water (10.0 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with dichloromethane (5.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain compound B16 (1.5 g, 3.38 mmol, yield 60.2%, purity 98.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.84-7.79 (m, 3H), 7.38 (m, 3H), 3.72 (s, 2H), 2.47 (s, 3H), 1.93-1.89 (m, 6H), 1.57-1.54 (m, 6H); LC-MS: m / z = 440.2 (M+H) + .

[0295] Synthesis of common intermediate B17 (1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0296] [ka]

[0297] Step 1: Synthesis of compound B17-2 (methyl 4-hydrazinyl benzoate) Compound B17-1 (15.0 g, 90.32 mmol, 1.0 equivalent) was dissolved in 25.0 mL of 37% hydrochloric acid aqueous solution, followed by the addition of sodium nitrite (6.2 g, 90.32 mmol, 1.0 equivalent) dissolved in 10.0 mL of water at 0°C. After the addition was complete, the resulting mixture was stirred for 10 minutes. Next, 75.0 mL of 37% hydrochloric acid aqueous solution dissolved in 85.6 g, 451.62 mmol, 5.0 equivalents was added dropwise at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 2 hours. The reaction mixture was filtered to obtain a filter cake. This was washed three times with ethyl acetate (50.0 mL) and concentrated under vacuum to obtain compound B17-2 (16.5 g). LC-MS: m / z = 167.1 (M + H) + .

[0298] Step 2: Synthesis of compound B17-4 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzoate) Compound B17-2 (5 g, 24.75 mmol, 1.0 equivalent) and Compound B17-3 (3.8 g, 24.75 mmol, 1.0 equivalent) were added to hexafluoroisopropanol (25.0 mL). Triethylamine (5.0 g, 49.50 mmol, 2.0 equivalent) dissolved in hexafluoroisopropanol (25.0 mL) was added dropwise at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 1 hour. Then, water (10 mL) was added, and the resulting mixture was extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound B17-4 (5.3 g). LC-MS: m / z = 285.0 (M + H) + .

[0299] Step 3: Synthesis of Compound B17-5 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methanol) Compound B17-4 (5.3 g, 18.65 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (100.0 mL), and lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 equivalents) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 6 hours. Then, ice water (50.0 mL) was added at 0°C, the resulting mixture was stirred for 10 minutes, and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 2) to obtain compound B17-5 (3.6 g). LC-MS: m / z = 257.1 (M + H) + .

[0300] Step 4: Synthesis of Intermediate B17 Compound B17-5 (1.0 g, 3.91 mmol, 1.0 equivalent) was dissolved in dichloroethane (25.0 mL), and thionyl chloride (1.4 g, 11.73 mmol, 5.2 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was concentrated under vacuum to obtain compound B17 (1.0 g, 3.64 mmol, yield 93.1%, purity 96.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H), 6.47 (s, 1H), 4.64 (s, 2H), 2.37 (s, 3H); LC-MS: m / z = 275.1 (M+H) + .

[0301] Common intermediate BB1 ​​(2-chloro-5-methoxy-N-methylpyrimidine-4-amine) Intermediate BB1 ​​was purchased from Leyan Reagents.

[0302] [ka]

[0303] Common intermediate BB2 (2-chloro-5-methoxypyrimidine-4-amine) Intermediate BB2 was purchased from Leyan Reagents.

[0304] [ka]

[0305] Common intermediate BB3 (2-chloro-5-isopropoxy-N-methylpyrimidine-4-amine)

[0306] [ka]

[0307] Step 1: Synthesis of compound BB3-2 (2,4-dichloro-5-isopropoxypyrimidine) 2,4-Dichloro-5-isopropylpyrimidine (compound BB3-1, 0.5 g, 2.41 mmol, 1.00 equivalent) was added to phosphorus oxychloride (5.0 mL) and refluxed under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to remove the phosphorus oxychloride. Ice water (100.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain compound BB3-2 (551.0 mg, crude product) as a pale yellow oily substance. LC-MS: m / z = 207.1 (M + H) + .

[0308] Step 2: Synthesis of intermediate BB3 Compound BB3-2 (100 mg, 0.48 mmol, 1.00 equivalent), methylamine hydrochloride (97.8 mg, 1.45 mmol, 3.00 equivalent), and cesium carbonate (472.4 mg, 1.45 mmol, 3.00 equivalent) were sequentially added to N,N-dimethylformamide (2.0 mL), and the resulting mixture was stirred at 60°C for 6 hours. Ethyl acetate (15.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain intermediate BB3 (38.8 mg, 0.19 mmol, yield 40.1%). LC-MS: m / z = 202.1 (M + H) + .

[0309] Common intermediate BB4 (2-chloro-5-isopropoxypyrimidine-4-amine)

[0310] [ka]

[0311] Compound BB3-2 (100 mg, 0.48 mmol, 1.00 equivalent) and aqueous ammonia (1.68 g, 48.0 mmol, 30% purity, 100.0 equivalents) were added to dioxane (3.0 mL). The resulting mixture was reacted in a sealed tube at 50°C for 12 hours. The reaction solution was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain the intermediate BB4 (27.3 mg, 0.15 mmol, yield 30.3%) as a white solid. LC-MS: m / z = 188.2 (M + H) + .

[0312] Common intermediate BB12 (2-chloro-5-(trifluoromethyl)pyrimidine-4-amine) Intermediate BB12 was purchased from Bide Pharmatech.

[0313] [ka]

[0314] Synthesis of the common intermediate BB13 (2-chlorofl[3,2-d]pyrimidine-4-amine)

[0315] [ka]

[0316] 2,4-Dichloroflou[3,2-d]pyrimidine (compound BB13-1, 5.0 g, 26.46 mmol, 1.00 equivalent) and aqueous ammonia (30.9 g, 264.6 mmol, 30% purity, 100.0 equivalent) were added to dioxane (100.0 mL). The resulting mixture was reacted in a sealed tube at 50°C for 12 hours. The reaction solution was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound BB13 (3.2 g, 18.87 mmol, yield 71.3%) as a white solid. LC-MS: m / z = 170.1 (M + H) + .

[0317] Synthesis of the common intermediate BB14 (2-chloropyrido[3,2-d]pyrimidine-4-amine)

[0318] [ka]

[0319] Following the same steps as for intermediate BB13, intermediate BB14 (1.1 g, 6.09 mmol, yield 40.6%) was used as the starting material to obtain 2,4-dichloropyrido[3,2-d]pyrimidine (BB14-1, 3.0 g, 15.0 mmol, 1.00 equivalent). LC-MS: m / z = 181.0 (M + H) + .

[0320] Common intermediate BB15 (2,5-dichloropyrimidine-4-amine) Intermediate BB15 was purchased from Bide Pharmatech.

[0321] [ka]

[0322] Synthesis of the common intermediate BB16 (2-chloro-5-fluoro-N-methylpyrimidine-4-amine)

[0323] [ka]

[0324] 2,4-Dichloro-5-fluoropyrimidine (compound BB16-1, 3.0 g, 18.07 mmol, 1.00 equivalent), methylamine hydrochloride (3.66 g, 54.23 mmol, 3.00 equivalent), and cesium carbonate (23.55 g, 72.28 mmol, 4.00 equivalent) were sequentially added to N,N-dimethylformamide (500.0 mL), and the resulting mixture was stirred at 60°C for 6 hours. Ethyl acetate (1000.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound BB16 (1.1 g, 6.81 mmol, yield 37.7%). LC-MS: m / z = 162.0 (M+H) + .

[0325] Synthesis of the common intermediate BB16-D3 (2-chloro-5-fluoro-N-(methyl-D3)pyrimidine-4-amine)

[0326] [ka]

[0327] Following the same steps as for intermediate BB16, 2,4-dichloro-5-fluoropyrimidine (BB16-1, 3.0 g, 18.07 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate BB16-D3 (1.47 g, 8.93 mmol, yield 49.4%). LC-MS: m / z = 165.1 (M + H) + .

[0328] Common intermediate BB17 (4-amino-2-chloropyrimidine-5-carbonitride) Intermediate BB17 was purchased from Bide Pharmatech.

[0329] [ka]

[0330] Synthesis of the common intermediate BB18 (2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine)

[0331] [ka]

[0332] Compound 2,4-dichloro-5-iodopyrimidine (BB18-1, 1.0 g, 3.6 mmol, 1.00 equivalent), bis(triphenylphosphine)dichloride palladium (256 mg, 0.3 mmol, 0.1 equivalent), cuprous iodide (139 mg, 0.7 mmol, 0.2 equivalent), trimethylethynylsilane (700 mg, 7.2 mmol, 2.0 equivalent), and triethylamine (1.1 g, 10.9 mmol, 3.0 equivalent) were sequentially added to tetrahydrofuran (15 mL). The reaction mixture was stirred at 40°C for 3 hours and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound BB18 (590 mg, 2.4 mmol) as a white solid. 1 HNMR (400MHz, DMSO) δ 8.97 - 8.89 (m, 1H), 0.28 (s, 9H).

[0333] Synthesis of the common intermediate BB19 (2-chloro-5-(difluoromethoxy)pyrimidine-4-amine)

[0334] [ka]

[0335] Step 1: Synthesis of compound BB19-2 (2,4-dichloro-5-(difluoromethoxy)pyrimidine) 2,4-Dichloropyrimidine-5-ol (compound BB19-1, 3.40 g, 20.6 mmol, 1.00 equivalent) and potassium hydroxide (13.3 g, 237 mmol, 11.5 equivalents) were sequentially added to acetonitrile (60.0 mL) and water (60.0 mL), and diethyl bromofluoromethylphosphonate (9.35 g, 35.0 mmol, 1.70 equivalents) was added dropwise. After the addition was complete, the resulting mixture was stirred at 25°C for 1.5 hours. The reaction was quenched by adding saturated aqueous citric acid solution (10.0 mL), and water (10.0 mL) was added. The resulting mixture was extracted three times with ethyl acetate (40 mL). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to obtain intermediate BB19-2 (3.70 g, 17.2 mmol, yield 83.5%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 8.53 (s, 1H), 6.84 - 6.49 (t, J =70.8 Hz, 1H); LC-MS: m / z = 215.0 (M+H) + .

[0336] Step 2: Synthesis of intermediate BB19 Following the same steps as for intermediate BB13, compound BB19-2 (500.0 mg, 2.33 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate BB19 (298.5 mg, 1.53 mmol, yield 65.5%). LC-MS: m / z = 196.1 (M + H) + .

[0337] Common intermediate BB21 (4-(2,4-dichloropyrimidine-5-yl)morpholine) Intermediate BB21 was purchased from Bide Pharmatech.

[0338] [ka]

[0339] Synthesis of the common intermediate BB22 (2,4-dichloro-5-(4-methylpiperazin-1-yl)pyrimidine)

[0340] [ka]

[0341] Step 1: Synthesis of compound BB22-2 (5-(4-methylpiperazin-1-yl)pyrimidine-2,4(1H,3H)-dione) 5-Bromouracil (BB22-1, 5.0 g, 26.18 mmol, 1.00 equivalent) was dissolved in pyridine (25 mL), and N-methylpiperazine (3.9 g, 39.2 mmol, 1.5 equivalent) was added. The resulting mixture was heated to 110°C, stirred for 4 hours, and then cooled to room temperature. The resulting mixture was concentrated under vacuum to obtain the crude product. This was ground with ethyl acetate (50 mL). The resulting mixture was filtered to obtain a solid. This was concentrated under vacuum to obtain compound BB22-2 (5.1 g, 24.26 mmol, yield 92.7%) as a brown solid. LC-MS: m / z = 211.1 (M + H) + .

[0342] Step 2: Synthesis of compound BB22 BB22-2 (5.0 g, 23.8 mmol, 1.0 equivalent) was added to phosphorus oxychloride (200 mL), and the mixture was stirred at 90°C for 16 hours. The resulting mixture was cooled to room temperature and concentrated under vacuum. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 7, and the resulting mixture was extracted three times with dichloromethane (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain the intermediate BB22 (1.3 g, 5.26 mmol, yield 22.1%, purity 97.8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 3.16 - 3.05 (m, 4H), 2.50 - 2.42 (m, 4H), 2.24 (s, 3H); LC-MS: m / z =247.1 (M+H) + .

[0343] Common intermediate BB24 (2,4-dichloropyrimidine-5-ol) Intermediate BB24 was purchased from Bide Pharmatech.

[0344] [ka]

[0345] Common intermediate BB35 ((2,4-dichloropyrimidine-5-yl)methanol) Intermediate BB35 was purchased from Bide Pharmatech.

[0346] [ka]

[0347] Synthesis of the common intermediate BB36 (2-chloro-5-(methoxymethyl)-N-methylpyrimidine-4-amine)

[0348] [ka]

[0349] Following the same steps as for intermediate BB16, 2,4-dichloro-5-(methoxymethyl)pyrimidine (BB36-1, 2.9 g, 15.0 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate BB36 (1.89 g, 10.07 mmol, yield 67.2%). LC-MS: m / z = 188.1 (M + H) + .

[0350] Synthesis of the common intermediate BB41 (methyl 2-(2,4-dichloropyrimidine-5-yl)acetate)

[0351] [ka]

[0352] Step 1: Synthesis of compound BB41-2 (dimethyl 2-formyl succinate) Dimethyl succinate (compound BB41-1, 200 g, 1.37 mol, 179 mL, 1.00 equivalent), ethyl formate (203 g, 2.74 mol, 220 mL, 2.00 equivalent), and sodium methoxide (259 g, 1.44 mol, purity 30.0%, 1.05 equivalent) were sequentially added to tetrahydrofuran (850 mL), and the resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then concentrated under vacuum to obtain the crude product. This was washed twice with petroleum ether (400 mL). 1 M hydrochloric acid was added to adjust the pH to approximately 6, and the resulting mixture was extracted three times with methyl tert-butyl ether (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound BB41-2 (70.0 g, 402 mmol, yield 29.4%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.69 (m, 1H), 4.03-3.58 (m, 1H), 3.57-3.56 (m, 6H), 1.17-1.10 (m, 1H), 1.07-1.03, (m, 1H).

[0353] Step 2: Synthesis of compound BB41-3 (2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidine-5-yl)acetic acid) Compound BB41-2 (60.0 g, 345 mmol, 1.00 equivalent) was dissolved in methanol (525 mL) and sodium methoxide (124 g, 689 mmol, purity 30.0%, 2.00 equivalent), and thiourea (26.2 g, 345 mmol, 1.00 equivalent) was added. The resulting mixture was stirred at 100°C for 12 hours and filtered to obtain a filter cake. 1 M hydrochloric acid aqueous solution (600 mL) was added, and the resulting mixture was stirred at 0°C for 30 minutes. The resulting mixture was filtered to obtain a filter cake. This was washed twice with water (100 mL) to obtain compound BB41-3 (30.0 g, 161 mmol, yield 46.8%, purity 100%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 12.5 (s, 1H), 12.3-12.2 (m, 2H), 7.42 (s, 1H), 3.20 (s, 2H).

[0354] Step 3: Synthesis of compound BB41-4 (methyl 2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidine-5-yl)acetate) Compound BB41-3 (15.0 g, 80.6 mmol, 1.00 equivalent) was dissolved in methanol (100 mL), and concentrated sulfuric acid (23.7 g, 242 mmol, 12.9 mL, 3.00 equivalent) was added. The resulting mixture was stirred at 80°C for 12 hours, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound BB41-4 (13.0 g, 64.9 mmol, yield 80.6%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 12.5 (s, 1H), 12.3(s, 1H), 7.40-7.60 (m, 1H), 3.59 (s, 3H), 3.30 (s, 2H).

[0355] Step 4: Synthesis of intermediate BB41 Compound BB41-3 (12.0 g, 59.9 mmol, 1.00 equivalent) was dissolved in phosphorus oxychloride (158 g, 1.03 mol, 96.0 mL, 17.2 equivalents) and stirred at 110°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 20°C and ice water (50.0 mL) was added. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 7, and the resulting mixture was extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed three times with saturated brine (35.0 mL), filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound BB41 (3.60 g, 15.7 mmol, yield 26.2%, purity 96.4%) as a pale yellow oily substance. LC-MS: m / z = 220.9(M+H) + .

[0356] Synthesis of the common intermediate BB42 (2-chloro-5-methoxy-N-(propa-2-in-1-yl)pyrimidine-4-amine)

[0357] [ka]

[0358] Following the same steps as for intermediate BB16, intermediate BB42 (140.8 mg, 0.71 mmol, yield 25.6%) was obtained using 2,4-dichloro-5-methoxypyrimidine (BB42-1, 500 mg, 2.79 mmol, 1.00 equivalent) and propargylamine (153.7 mg, 2.79 mmol, 1.00 equivalent) as starting materials. LC-MS: m / z = 198.2 (M + H) + .

[0359] Synthesis of the common intermediate BB43 (2-chloro-5-methoxy-N-(tetrahydrofuran-3-yl)pyrimidine-4-amine)

[0360] [ka]

[0361] Following the same steps as for intermediate BB16, intermediate BB43 (910.5 mg, 3.96 mmol, yield 59.2%) was obtained using 2,4-dichloro-5-methoxypyrimidine (BB42-1, 1.2 g, 6.7 mmol, 1.00 equivalent) and 3-aminotetrahydrofuran (584.0 mg, 6.7 mmol, 1.00 equivalent) as starting materials. LC-MS: m / z = 230.2 (M + H) + .

[0362] Synthesis of the common intermediate BB44 (2-chloro-N-cyclopropyl-5-methoxypyrimidine-4-amine)

[0363] [ka]

[0364] Following the same steps as for intermediate BB16, 2,4-dichloro-5-methoxypyrimidine (BB42-1, 0.8 g, 4.47 mmol, 1.00 equivalent) and cyclopropylamine (255.2 mg, 4.47 mmol, 1.00 equivalent) were used as starting materials to obtain intermediate BB44 (556.3 mg, 2.79 mmol, yield 62.3%). LC-MS: m / z = 200.1 (M + H) + .

[0365] Synthesis of the common intermediate BB45 (N-(2-chloro-5-methoxypyrimidine-4-yl)-O-methylhydroxylamine)

[0366] [ka]

[0367] Following the same steps as for intermediate BB16, 2,4-dichloro-5-methoxypyrimidine (compound BB45-1, 500 mg, 2.8 mmol, 1.0 equivalent) and methoxyamine hydrochloride (352 mg, 4.2 mmol, 1.5 equivalents) were used as starting materials to obtain intermediate BB45 (490.0 mg, 2.58 mmol, yield 92.3%). LC-MS: m / z = 190.1 (M + H) + .

[0368] Synthesis of the common intermediate C2(2-(4-(chloromethyl)cyclohexyl)pyridine)

[0369] [ka]

[0370] Step 1: Synthesis of compound C2-2 (ethyl 4-(pyridine-2-yl)cyclohexa-3-ene-1-carboxylate) 2-Bromopyridine (C2-1, 15.0 g, 94.9 mmol, 9.04 mL, 1.00 equivalent), 1-Ethoxycarbonylcyclohexa-3-ene-4-pinacollylborate (26.9 g, 94.9 mmol, 99.0% purity, 1.00 equivalent), potassium carbonate (39.4 g, 284 mmol, 3.00 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.95 g, 9.49 mmol, 0.10 equivalent) were successively added to water (50.0 mL) and dioxane (200 mL), and the resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. Then, water (30.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound C2-2 (9.00 g, 38.9 mmol, yield 41.0%) as a colorless, transparent oil. 1H NMR (400 MHz, CDCl3) δ 8.54 - 8.55 (m, 1H), 7.60 - 7.64 (m, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.10 - 7.13 (m, 1H), 6.66 - 6.68 (m, 1H), 4.11 - 4.20 (m, 2H), 2.62 - 2.72 (m, 5H), 2.50 - 2.53 (m, 1H), 1.79 - 1.87 (m, 1H), 1.25 - 1.29 (m, 3H); LC-MS: m / z = 232.0 (M+H) + .

[0371] Step 2: Synthesis of compound C2-3 (ethyl 4-(pyridine-2-yl)cyclohexane-1-carboxylate) Compound C2-2 (9.00 g, 38.9 mmol, 1.00 equivalent) was dissolved in methanol (288.0 mL), and palladium-supported carbon (4.14 g, 3.89 mmol, 10% purity, 0.10 equivalent) was added under a nitrogen atmosphere. The resulting mixture was purged three times with hydrogen and stirred at 25°C for 16 hours under a hydrogen atmosphere (15 Psi). The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C2-3 (8.13 g, 34.9 mmol, yield 89.6%) as a colorless, transparent oil. 1 H NMR (400 MHz, CDCl3) δ 8.51 - 8.54 (m, 1H), 7.58 - 7.62 (m, 1H), 7.09 - 7.14 (m, 2H), 4.14 - 4.20 (m, 2H), 2.67 - 2.78 (m, 1H), 2.22 - 2.25 (m, 3H), 1.62 - 1.87 (m, 6H), 1.26 - 1.29 (m, 3H); LC-MS: m / z = 234.0 (M+H) + .

[0372] Step 3: Synthesis of compound C2-4 ((4-(pyridine-2-yl)cyclohexyl)methanol) Compound C2-3 (8.13 g, 34.8 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (300.0 mL), and diisobutylaluminum hydride (1 M, 112 mL, 3.20 equivalents) was added dropwise at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 30 minutes, heated to 25°C, and stirred for 1 hour. Water (100 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (300 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C2-4 (4.80 g, 25.1 mmol, yield 72.0%) as a colorless, transparent oil. 1 H NMR (400 MHz, CDCl3) δ 8.54 - 8.55 (m, 1H), 7.59 - 7.63 (m, 1H), 7.10 - 7.20 (m, 2H), 3.52 - 3.71 (m, 2H), 2.80 - 2.85(m, 1H), 1.67 - 1.84 (m, 8H), 1.15 - 1.23 (m, 1H); LC-MS: m / z = 192.0 (M+H) + .

[0373] Step 4: Compound C2 Compound C2-4 (800 mg, 4.18 mmol, 1.00 equivalent) was dissolved in dichloromethane (16.0 mL), and thionyl chloride (2.49 g, 20.9 mmol, 1.52 mL, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C2 (900 mg, crude product) as a white solid. LC-MS: m / z = 210.0 (M + H) + .

[0374] Synthesis of the common intermediate C3(2-(4-(chloromethyl)phenyl)pyridine)

[0375] [ka]

[0376] Step 1: Synthesis of compound C3-2 ((4-(pyridine-2-yl)phenyl)methanol) Compounds 2-bromopyridine (C3-1, 10.0 g, 63.3 mmol, 6.02 mL, 1.00 equivalent), 2-(4-hydroxymethylphenyl)pyridine (12.5 g, 82.3 mmol, 1.30 equivalent), tetrakis(triphenylphosphine)palladium (7.31 g, 6.33 mmol, 0.100 equivalent), and sodium carbonate (49.6 g, 468 mmol, 7.40 equivalent) were sequentially added to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound C3-2 (9.63 g) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J=4.4Hz, 1H), 7.75 - 7.95 (m, 2H), 7.70 - 7.74 (m, 2H), 7.42 - 7.44 (m, 2H), 7.22 - 7.25 (m, 1H), 4.73 (s, 2H), 2.70 (s, 1H); LC-MS: m / z = 186.2 (M+H) + .

[0377] Step 2: Synthesis of intermediate C3 Compound C3-2 (1.0 g, 5.40 mmol, 1.00 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C3 (1.1 g, crude product) as a white solid. LC-MS: m / z = 204.1 (M + H) + .

[0378] Synthesis of the common intermediate C4(4-(chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine)

[0379] [ka]

[0380] Step 1: Synthesis of compound C4-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound 4-(trifluoromethyl)-1H-imidazole (compound C4-1, 33.0 g, 242 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Then, iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 equivalent) was added. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Then, ice water (200.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (200.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound C4-2 (21.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M+H) + .

[0381] Step 2: Synthesis of compound C4-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound C4-2 (16.8 g, 111 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equivalent) was added dropwise at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 30 minutes. Next, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equivalent) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction mixture. After the addition was complete, the resulting mixture was reacted at -70°C for 1 hour, heated to 20°C, and stirred for 3 hours. Saturated aqueous ammonium chloride solution (200.0 mL) was added at 0°C to quench the reaction. Water (300.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain compound C4-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0382] Step 3: Synthesis of compound C4-4 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-carboxylate) Compound C4-3 (7.0 g, 31.9 mmol, 1.00 equivalent), ethyl 4-piperidinyl carboxylate (7.54 g, 47.9 mmol, 7.39 mL, 1.50 equivalent), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 equivalent), and sodium iodide (479 mg, 3.20 mmol, 0.100 equivalent) were sequentially added to N,N-dimethylformamide (70.0 mL), and the resulting mixture was reacted at 130°C for 72 hours. Water (350 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to obtain compound C4-4 (2.2 g).1 H NMR (400 MHz, CDCl3) δ 4.17 (q, J = 7.2Hz, 2H), 3.45 (s, 3H), 3.24 - 3.28 (m, 2H), 2.90 - 2.97 (m, 2H), 2.40 - 2.45 (m, 1H), 2.02 - 2.06 (m, 2H), 1.85 - 1.88 (m, 2H), 1.28 (t, J = 8.0Hz, 2H); LC-MS: m / z = 340.1 (M+H) + .

[0383] Step 4: Synthesis of compound C4-5 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-carboxylate) Compound C4-4 (2.2 g, 6.48 mmol, 1.00 equivalent), sodium acetate (1.06 g, 12.9 mmol, 2.00 equivalent), and wet palladium-supported carbon (0.5 g, 1.94 mmol, purity 10.0%, 0.300 equivalent) were sequentially added to ethanol (40.0 mL). The resulting mixture was reacted under a hydrogen atmosphere (15 psi) at 50°C for 36 hours. The reaction solution was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C4-5 (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.15 (q, J = 7.2Hz, 2H), 3.52 (s, 3H), 3.25 - 3.29 (m, 2H), 2.92 - 2.98 (m, 2H), 2.40 - 2.45 (m, 1H), 2.01 - 2.05 (m, 2H), 1.85 - 1.89 (m, 2H), 1.28 (t, J = 6.8Hz, 3H); LC-MS: m / z = 306.1 (M+H) + .

[0384] Step 5: Synthesis of compound C4-6 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methanol) Compound C4-5 (1.2 g, 3.93 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 0.5 hours, then heated to 20°C and stirred for 12 hours. Next, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 30 minutes, followed by the addition of tetrahydrofuran (10.0 mL), and the mixture was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain compound C4-6 (1.0 g, crude product). This was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 3.57 (d, J = 6.4Hz, 2H), 3.51 (s, 3H), 3.27 - 3.30 (m, 2H), 2.90 - 2.96 (m, 2H), 1.84 - 1.87 (m, 2H), 1.65 - 1.70 (m, 1H), 1.39 - 1.42(m, 2H); LC-MS: m / z = 264.1 (M+H) + .

[0385] Step 6: Synthesis of intermediate C4 Compound C4-6 (1.0 g, 3.80 mmol, 1.00 equivalent) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 24 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C4 (1.1 g, 3.46 mmol, yield 91.0%, HCl) as a brown solid. LC-MS: m / z = 282.1 (M + H) + .

[0386] Synthesis of the common intermediate C5(2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0387] [ka]

[0388] Step 1: Synthesis of compound C5-2 (methyl 4-(4-(trifluoromethyl)-1H-imidazole-2-yl)benzoate) 1,1-Dibromo-3,3,3-trifluoroacetone (7.2 g, 26.8 mmol, 1.10 equivalents) and sodium acetate (2.2 g, 27.3 mmol, 1.12 equivalents) were dissolved in water (8.0 mL), and the resulting mixture was stirred at 100°C for 1 hour. Methyl p-formylbenzoate (C5-1, 4.0 g, 24.4 mmol, 1.00 equivalent) was dissolved in methanol (80.0 mL), and aqueous ammonia (22.0 mL) was added at 25°C. After the addition was complete, the resulting mixture was reacted at 25°C for 40 minutes, heated to 100°C, and stirred for 2 hours. Then, water (60.0 mL) was added to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (80.0 mL). The organic layers were combined, washed twice with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain compound C5-2 (4.5 g). 1 H NMR (400 MHz, CDCl3) δ 13.4 (s, 1H), 8.10 - 8.12 (m, 2H), 8.04 - 8.06 (m, 2H), 7.99 (s, 1H), 3.87 (s, 3H); LC-MS: m / z = 271.0 (M+H) + .

[0389] Step 2: Synthesis of compound C5-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzoate) Compound C5-2 (2.5 g, 9.3 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and sodium hydride (444.1 mg, 11.1 mmol, 1.20 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Then, iodomethane (6.8 g, 48.1 mmol, 5.20 equivalent) was added. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. Then, ice water (20.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound C5-3 (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4Hz, 2H), 7.99 (s, 1H), 7.90 (d, J = 8.4Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H); LC-MS: m / z =285.1 (M+H) + .

[0390] Step 3: Synthesis of compound C5-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methanol) Compound C5-3 (0.6 g, 2.1 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum hydride (88.1 mg, 2.32 mmol, 1.10 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 4 hours. Water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) were added at 0°C, and the resulting mixture was stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the resulting mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain crude product C5-4 (505.4 mg). This was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.30 - 5.33 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H); LC-MS: m / z = 257.1 (M+H)+.

[0391] Step 4: Synthesis of intermediate C5 Compound C5-4 (500.0 mg, 2.0 mmol, 1.00 equivalent) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (1.9 g, 15.6 mmol, 8.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum to obtain compound C5 (523 mg, 1.90 mmol, yield 97.6%) as a brown solid. 1 LC-MS: m / z = 275.1 (M+H) + .

[0392] Synthesis of the common intermediate C6 (2-(4-(chloromethyl)piperidine-1-yl)pyridine)

[0393] [ka]

[0394] Step 1: Synthesis of compound C6-2 (ethyl 1-(pyridine-2-yl)piperidine-4-carboxylate) Ethylpiperidine-4-carboxylate (compound C6-1, 20.8 g, 132 mmol, 20.4 mL, 1.00 equivalent), 2-chloropyridine (15.0 g, 132.0 mmol, 1.00 equivalent), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 equivalent) were dissolved in dimethyl sulfoxide (50.0 mL), and the resulting mixture was reacted at 130°C for 16 hours. The reaction was stopped by cooling the reaction mixture. The reaction was quenched by adding water (50 mL) at room temperature, and the resulting mixture was extracted three times with ethyl acetate (60.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C6-2 (6.0 g, yield 19.4%, purity 100%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.17 - 8.19 (m, 1H), 7.44 - 7.48 (m, 1H), 6.66 (d, J=8.4Hz, 1H), 6.59 - 6.61 (m, 1H), 4.21 - 4.24 (m, 2H), 4.13 LC-MS: m / z = 235.2(M+H) + .

[0395] Step 2: Synthesis of compound C6-3 ((1-(pyridine-2-yl)piperidine-4-yl)methanol) Compound C6-2 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL), and lithium aluminum hydride (1.07 g, 28.2 mmol, 1.10 equivalents) was added gradually at 0°C. The resulting mixture was heated to room temperature and stirred for 16 hours. Additional lithium aluminum hydride (486 mg, 12.8 mmol, 0.500 equivalents) was added, and the resulting mixture was stirred for a further 6 hours. Water (20.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (60.0 mL). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C6-3 (1.20 g, yield 23.8%, purity 97.8%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J=3.6Hz, 1H), 7.43 - 7.48 (m, 1H), 6.67 (d, J=8.8Hz, 1H), 6.58 - 6.59 (m, 1H),4.33 (d, J=12.8Hz, 2H), 3.54 (d, J=6.0Hz, 2H), 2.81 - 2.88 (m, 2H), 1.77 - 1.86 (m, 2H), 1.73 - 1.76 (m, 1H), 1.55 (s, 1H), 1.28 - 1.35 (m, 2H). LC-MS: m / z =193.2(M+H) + .

[0396] Step 3: Synthesis of intermediate C6 Compound C6-3 (1.20 g, 6.24 mmol, 1.00 equivalent) was dissolved in dichloromethane (12.0 mL), and thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C6 (1.57 g, crude product) as a white solid. LC-MS: m / z = 211.1.

[0397] Synthesis of the common intermediate C7(2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0398] [ka]

[0399] Following the synthesis of intermediate C5, and without changing other experimental conditions, general intermediate C7 was obtained by using an equimolar amount of methyl 5-formylthiophene-2-carboxylate (compound C7-1) instead of compound C5-1. Intermediate C7 (330.0 mg, crude product) was finally obtained as a white solid. LC-MS: m / z = 281.0 (M + H) + .

[0400] Synthesis of the common intermediate C9(2-((1R,4R)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0401] [ka]

[0402] Step 1: Synthesis of compound C9-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) 4-(trifluoromethyl)-1H-imidazole (compound C9-1, 33.0 g, 242.0 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 equivalent) was added little by little at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Next, iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 equivalent) was added. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 5 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (30.0 mL) at 0°C. Water (30.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound C9-2 (21.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M+H) + .

[0403] Step 2: Synthesis of compound C9-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound C9-2 (16.8 g, 111.0 mmol, 1.00 equivalent) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equivalent) was added dropwise at -70°C. After the addition was complete, the resulting mixture was stirred at -70°C for 30 minutes. Next, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equivalent) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction mixture. After the addition was complete, the resulting mixture was reacted at -70°C for 1 hour, heated to 20°C, and stirred for 3 hours. Saturated aqueous ammonium chloride solution (200.0 mL) was added at 0°C to quench the reaction. Water (300.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain compound C9-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0404] Step 3: Synthesis of compound C9-4 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexa-3-ene-1-carboxylate) Compound C9-3 (7.0g, 31.9mmol, 1.00 equivalent), 1-Ethoxycarbonylcyclohexa-3-ene-4-pinacolylborate (8.94g, 31.9mmol, 1.00 equivalent), potassium phosphate (20.3g, 95.8mmol, 3.00 equivalent), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1') Palladium(II) (1.3 g, 1.6 mmol, 0.05 equivalents) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 equivalents) were sequentially added to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 5 hours. The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% FA) to obtain compound C9-4 (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 6.05 (d, J = 2.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H).3.61 (s, 3H), 2.50 - 2.67 (m, 5H), 2.13 - 2.14 (m, 1H), 1.86 - 1.89 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); LC-MS: m / z = 337.2 (M+H) + .

[0405] Step 4: Synthesis of compound C9-5 (ethyl(1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexane-1-carboxylate) Compound C9-4 (1.9 g, 5.6 mmol, 1.00 equivalent), sodium acetate (925.0 mg, 11.2 mmol, 2.00 equivalent), and wet palladium-supported carbon (0.5 g, 1.4 mmol, purity 10.0%, 0.25 equivalent) were sequentially added to ethanol (30.0 mL), and the resulting mixture was reacted at 50°C for 5 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered to obtain the filtrate, which was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (column: water Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3) ~ ​​ACN]; B%: 34% ~ 64%, 10 min) to obtain compound C9-5 (0.3 g). 1 H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 4.15(q, J = 6.8 Hz, 2H), 3.64(s, 3H), 2.60 - 2.65 (m, 1H), 2.41 - 2.44 (m, 1H), 2.12 - 2.15 (m, LC-MS: m / z = 305.0 (M+H) + .

[0406] Step 5: Synthesis of compound C9-6(((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexyl)methanol) Compound C9-5 (0.6 g, 2.0 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 0.5 hours, then heated to 20°C and stirred for 12 hours. Next, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 30 minutes, followed by the addition of tetrahydrofuran (10.0 mL), and the mixture was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain crude compound C9-6 (0.5 g). This was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 2.59 - 2.65 (m, 1H), 1.95 - 1.98 (m, 4H), 1.77 - 1.80 (m, 3H), 1.07 - 1.17 (m, 2H); LC-MS: m / z = 263.1 (M+H)+.

[0407] Step 6: Synthesis of intermediate C9 Compound C9-6 (500.0 mg, 1.9 mmol, 1.00 equivalent) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 24 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C9 (550 mg, 1.36 mmol, yield 71.5%) as a pale yellow solid. LC-MS: m / z = 281.0 (M + H) + .

[0408] Synthesis of the common intermediate C11(1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0409] [ka]

[0410] Step 1: Synthesis of compound C11-2 (methyl 4-hydrazinyl benzoate) Compound C11-1 (15.0 g, 90.32 mmol, 1.0 equivalent) was dissolved in 25.0 mL of 37% hydrochloric acid aqueous solution, and sodium nitrite (6.2 g, 90.32 mmol, 1.0 equivalent) dissolved in 10.0 mL of water was added at 0°C. After the addition was complete, the resulting mixture was stirred for 10 minutes. Then, tin chloride (85.6 g, 451.62 mmol, 5.0 equivalent) dissolved in 75.0 mL of 37% hydrochloric acid aqueous solution was added dropwise at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 2 hours. The reaction mixture was filtered to obtain a filter cake. This was washed three times with ethyl acetate (50.0 mL) and concentrated under vacuum to obtain compound C11-2 (16.5 g). LC-MS: m / z = 167.1 (M + H) + .

[0411] Step 2: Synthesis of compound C11-3 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzoate) Compound C11-2 (5 g, 24.75 mmol, 1.0 equivalent) and 1,1,1-trifluoro-2,4-pentanedione (3.8 g, 24.75 mmol, 1.0 equivalent) were added to hexafluoroisopropanol (25.0 mL), and triethylamine (5.0 g, 49.50 mmol, 2.0 equivalent) dissolved in hexafluoroisopropanol (25.0 mL) was added dropwise at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 1 hour. Then, water (10 mL) was added, and the resulting mixture was extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C11-3 (5.3g). LC-MS: m / z = 285.0 (M + H) + .

[0412] Step 3: Synthesis of compound C11-4 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methanol) Compound C11-3 (5.3 g, 18.65 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (100.0 mL), and lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 equivalents) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 6 hours. Then, ice water (50.0 mL) was added at 0°C, the resulting mixture was stirred for 10 minutes, and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 2) to obtain compound C11-4 (3.6 g). LC-MS: m / z = 257.1 (M+H) + .

[0413] Step 4: Synthesis of intermediate C11 Compound C11-4 (1.0 g, 3.91 mmol, 1.0 equivalent) was dissolved in dichloroethane (25.0 mL), and thionyl chloride (1.4 g, 11.73 mmol, 5.2 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C11 (1.0 g, 3.64 mmol, yield 93.1%, purity 96.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H), 6.47 (s, 1H), 4.64 (s, 2H), 2.37 (s, 3H); LC-MS: m / z = 275.1 (M+H) + .

[0414] Synthesis of the common intermediate C12(8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0415] [ka]

[0416] Step 1: Synthesis of compound C12-2 ((4-(imidazo[1,2-a]pyrazine-8-yl)phenyl)methanol) 8-Chloroimidazo[1,2-A]pyrazine (compound C12-1, 9.6 g, 62.5 mmol, 1.00 equivalent), 4-hydroxymethylphenylboronic acid (12.4 g, 81.3 mmol, 1.30 equivalent), tetrakis(triphenylphosphine)palladium (7.2 g, 6.25 mmol, 0.10 equivalent), and sodium carbonate (49.0 g, 463 mmol, 7.40 equivalent) were sequentially added to a mixed solvent of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The resulting mixture was purged three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound C12-2 (12.7 g). LC-MS: m / z = 226.2 (M + H) + .

[0417] Step 2: Synthesis of intermediate C12 Compound C12-2 (6.0 g, 26.6 mmol, 1.00 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (15.9 g, 133 mmol, 5.00 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C12 (7.3 g, 26.2 mmol, yield 98.2%, HCl) as an off-white solid. LC-MS: m / z = 244.1(M+H)+.

[0418] Synthesis of the common intermediate C13(2-(4-(chloromethyl)phenyl)-5-(trifluoromethyl)pyridine)

[0419] [ka]

[0420] Following the same steps as for intermediate C3, 2-bromo-5-(trifluoromethyl)pyridine (compound C13-1) was used as the starting material to obtain intermediate C13 (2.0 g). LC-MS: m / z = 272.0 (M + H) + .

[0421] Synthesis of the common intermediate C14(2-(4-(chloromethyl)phenyl)-5-methylpyridine)

[0422] [ka]

[0423] Following the same steps as for intermediate C3, 2-bromo-5-methylpyridine (compound C14-1) was used as the starting material to obtain intermediate C14 (10.0 g). LC-MS: m / z = 218.0 (M + H) + .

[0424] Synthesis of the common intermediate C19 ((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0425] [ka]

[0426] Step 1: Synthesis of compound C19-2 (methyl 4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octane-1-carboxylate) Monomethyl hydrogen bicyclo[2.2.2]octane-1,4-dicarbonoxylate (compound C19-1, 25.0 g, 118 mmol, 1.00 equivalent), 3-(trifluoromethyl)pyridine (20.8 g, 141 mmol, 1.20 equivalent), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 equivalent), and silver nitrate (4.01 g, 23.6 mmol, 0.20 equivalent) were sequentially added to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL), and the resulting mixture was reacted at 20°C for 16 hours. Dichloromethane (250.0 mL) was added, and the resulting mixture was filtered to obtain a filtrate. This was washed three times with water (100.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (purification conditions: NH3·H2O / MeCN / H2O) to obtain compound C19-2 (7.5g). 1 H NMR (400 MHz, CDCl3) δ 8.81 (s, , 1H), 7.85 (dd, J1= 4.0Hz, J2= 4.0Hz, 1H), 7.37 (d, J = 4.0Hz, 1H), 3.69 (s, 3H), 1.96 (s, 12H).

[0427] Step 2: Synthesis of compound C19-3 ((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methanol) Compound C19-2 (2.5 g, 7.98 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (50.0 mL), and lithium aluminum hydride (908 mg, 23.9 mmol, 3.00 equivalent) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C, the resulting mixture was stirred for 10 minutes, and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C19-3 (2.3 g) as a white solid. LC-MS: m / z = 286.1 (M + H) + .

[0428] Step 3: Synthesis of intermediate C19 Compound C19-3 (1.6 g, 5.61 mmol, 1.00 equivalent) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 equivalent) were added to pyridine (25.0 mL), and the resulting mixture was reacted at 20°C for 12 hours. The reaction mixture was concentrated under vacuum. Water (10.0 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with dichloromethane (5.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain intermediate C19 (1.5 g, 3.38 mmol, yield 60.2%, purity 98.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.84-7.79 (m, 3H), 7.38 (m, 3H), 3.72 (s, 2H), 2.47 (s, 3H), 1.93-1.89 (m, 6H), 1.57-1.54 (m, 6H); LC-MS: m / z = 440.2 (M+H) + .

[0429] Synthesis of the common intermediate C25 (6-(chloromethyl)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one)

[0430] [ka]

[0431] Step 1: Synthesis of compound C25-2 (methyl 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate) 2-Methyl-1-oxo-3,4-dihydroisoquinoline-6-carbonitrile (compound C25-1, 500 mg, 2.69 mmol, 1 equivalent) was dissolved in hydrochloric acid in methanol (4 M, 6.71 mL, 10 equivalents), and the mixture was stirred at 70°C for 3 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (FA) to obtain compound C25-2 (0.16 g, 715.21 μmol, yield 26.64%, purity 98%) as a white solid. LC-MS: m / z = 220.2 (M + H) + .

[0432] Step 2: Synthesis of compound C25-3 (6-(hydroxymethyl)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one) Compound C25-2 (75 mg, 342.10 μmol, 1 equivalent) was dissolved in tetrahydrofuran (4 mL), and lithium borohydride (2 M, 1 mL, 5.85 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was stirred at 25°C for 3 hours. Then, hydrochloric acid (2 mL, 1 M) was added three times for quenching, and the resulting mixture was extracted three times with ethyl acetate (15.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain compound C25-3 (50 mg, crude product) as a white solid. LC-MS: m / z = 192.2 (M + H) + .

[0433] Step 3: Synthesis of intermediate C25 Compound C25-3 (50 mg, 261.47 μmol, 1 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (155.54 mg, 1.31 mmol, 94.84 μL, 5 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain intermediate C25 (50 mg, 238.47 μmol, yield 91.20%) as an off-white solid. LC-MS: m / z = 210.0 (M + H) + .

[0434] Synthesis of the common intermediate C26 (6-(chloromethyl)-2-isopropyl-3,4-dihydroisoquinoline-1(2H)-one)

[0435] [ka]

[0436] Step 1: Synthesis of compound C26-2 (6-bromo-2-isopropyl-3,4-dihydroisoquinoline-1(2H)-one) 6-Bromo-3,4-dihydro-2H-isoquinoline-1-one (compound C26-1, 500 mg, 2.69 mmol, 1 equivalent) was dissolved in tetrahydrofuran (40 mL), followed by the addition of sodium hydride (1.06 g, 26.54 mmol, 60% purity, 1.5 equivalents) at 0°C. The resulting mixture was stirred for 30 minutes. 2-iodopropane (6.02 g, 35.39 mmol, 3.54 mL, 2 equivalents) was added dropwise at 0°C. After the addition was complete, the resulting mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours. Water (30 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to obtain compound C26-2 (1.7 g, 6.19 mmol, yield 35.01%, purity 97.7%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.4Hz, 1H), 7.47-7.45 (m, 1H), 7.33 (s, 1H), 5.09-5.03(m, 1H), 3.42 (t, J1=6.4Hz, J2=6.8Hz, 2H), 2.91 (t, J1=6.8Hz, J2=6.4Hz, 2H), 1.19 (d, J=6.8Hz, 6H); LC-MS: m / z = 268.0 (M+H)+.

[0437] Step 2: Synthesis of compound C26-3 (2-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitride) Compound C26-2 (2.6 g, 9.70 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of zinc cyanide (797.00 mg, 6.79 mmol, 430.81 μL, 0.7 equivalents) and tetrakis(triphenylphosphine)palladium (1.12 g, 969.61 μmol, 0.1 equivalents). The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 12 hours. Water (30 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound C26-3 (1.9 g, 8.84 mmol, yield 91.18%, purity 99.7%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.4Hz, 1H), 7.64-7.62 (m, 1H), 7.50 (s,1H), 5.11-5.04(m, 1H), 3.48(t, J1=6.4Hz, J2=6.4Hz, 2H), 2.99(t, J1=6.4Hz, J2=6.4Hz, 2H), 1.22 (d, J=6.8Hz, 6H); LC-MS: m / z = 215.1 (M+H) + .

[0438] Steps 3-5: Synthesis of intermediate C26 Following the same steps as for intermediate C25, compound C26-3 was used as the starting material to obtain intermediate C26 (433.4 mg, 1.82 mmol, yield 45.1%). LC-MS: m / z = 238.2 (M + H) + .

[0439] Synthesis of the common intermediate C27(2-((4-(chloromethyl)phenoxy)methyl)pyridine)

[0440] [ka]

[0441] Following the same steps as for intermediate C28, intermediate C27 (800.7 mg, crude product, pale yellow oily substance) was obtained using 4-hydroxybenzonitrile (compound C27-1) and 2-(bromomethyl)pyridine hydrobromide as starting materials. LC-MS: m / z = 234.0 (M + H) + .

[0442] Synthesis of the common intermediate C28 (1-(chloromethyl)-4-(2-ethoxyethoxy)benzene)

[0443] [ka]

[0444] Step 1: Synthesis of compound C28-2 (4-(2-ethoxyethoxy)benzonitrile) 4-Hydroxybenzonitrile (compound C28-1, 4.00 g, 33.6 mmol, 1.00 equivalent), 2-bromoethyl ethyl ether (10.0 g, 65.4 mmol, 7.35 mL, 1.95 equivalent), and potassium carbonate (9.28 g, 67.2 mmol, 2.00 equivalent) were sequentially added to acetonitrile (142 mL), and the resulting mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. Water (30.0 mL) was added, and the pH was adjusted to approximately 5 with 1N HCl aqueous solution. The resulting mixture was extracted three times with dichloromethane (50.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to obtain compound C28-2 (6.69 g, crude product) as a pale yellow oily substance. 1H NMR (400MHz, DMSO) δ 7.75 (dd, J1= 1.6Hz, J2= 6.8Hz, 2H), 7.11 (d, J = 8.8Hz, 2H), 4.16 - 4.19 (m, 2H), 3.69 - 3.71 (m, 2H), 3.46 - 3.51 (m, 2H), 1.11 (t, J = 7.0Hz, 3H).

[0445] Step 2: Synthesis of compound C28-3 (methyl 4-(2-ethoxyethoxy)benzoate) Compound C28-2 (2.00 g, 10.5 mmol, 1.00 equivalent) was dissolved in HCl / MeOH (4 M, 105 mL, 40.0 equivalents), and the resulting mixture was stirred at 80°C for 36 hours and concentrated under vacuum to obtain the crude product. Water (20.0 mL) was added, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C28-3 (1.46 g, 6.51 mmol, yield 62.3%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 7.99 (d, J = 8.4Hz, 2H), 6.95 (d, J = 8.8Hz, 2H), 4.17 - 4.19 (m, 2H), 3.89 (s, 3H), 3.81 - 3.83 (m, 2H), 3.59 - 3.64 (m, 2H), 1.26 (t, J = 7.0Hz, 3H); LC-MS: m / z = 225.3 (M+H) + .

[0446] Step 3: Synthesis of compound C28-4 ((4-(2-ethoxyethoxy)phenyl)methanol) Compound C28-3 (0.700 g, 3.12 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (7.00 mL), and lithium aluminum hydride (237 mg, 6.24 mmol, 2.00 equivalent) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C, the resulting mixture was stirred for 10 minutes, and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound C28-4 (0.62 g, crude product) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ 7.28 - 7.29 (m, 2H), 6.90 - 6.94 (m, 2H), 4.61 (s, 2H), 4.11 - 4.14 (m, 2H), 3.78 - 3.81 (m, 2H), 3.59 - 3.64 (m, 2H), 1.25 (t, J = 7.0Hz, 3H).

[0447] Step 4: Synthesis of intermediate C28 Compound C28-4 (0.560 g, 2.85 mmol, 1.00 equivalent) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (2.46 g, 20.7 mmol, 1.50 mL, 7.25 equivalents) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain compound C28 (0.60 g, crude product) as a pale yellow oily substance. 1 H NMR (400MHz, DMSO) δ 7.35 - 7.37 (m, 2H), 6.93 - 6.95 (m, 2H), 4.73 (s, 2H), 4.08 - 4.10 (m, 2H), 3.68 - 3.70 (m, 2H), 3.48 - 3.53 (m, 2H), 1.13 (t, J = 7.0Hz, 3H); LC-MS: m / z = 215.0 (M+H) + .

[0448] Synthesis of the common intermediate C29 (1-(chloromethyl)-4-(3-methoxycyclobutoxy)benzene)

[0449] [ka]

[0450] Step 1: Synthesis of compound C29-2 (4-(3-methoxycyclobutoxy)benzaldehyde) 4-(3-methoxycyclobutoxy)benzonitrile (compound C29-1, 0.560 g, 2.85 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (6.50 mL), and diisobutylaluminum hydride (1 M, 7.75 mL, 2.50 equivalents) was added dropwise at 0°C. After the addition was complete, the resulting mixture was stirred at 25°C for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (20.0 mL) dropwise at 0°C, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This was concentrated under vacuum to obtain compound C29-2 (0.65 g, crude product) as a pale yellow oily substance. 1 H NMR (400MHz, DMSO) δ 9.87 (s, 1H), 7.85 - 7.87 (m, 2H), 7.04 - 7.06 (m, 2H), 4.50 - 4.54 (m, 1H), 4.07 - 4.10 (m, 1H), 3.61 - 3.67 (m, 3H), 2.90 - 2.92 (m, 2H), 1.91 - 1.96 (m, 2H).

[0451] Step 2: Synthesis of compound C29-3 ((4-(3-methoxycyclobutoxy)phenyl)methanol) Compound C29-2 (0.65 g, 3.15 mmol, 1.00 equivalent) was dissolved in methanol (6.00 mL), and sodium borohydride (0.210 g, 5.55 mmol, 1.76 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 2 hours. Water (10.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 2) to obtain compound C29-3 (0.12 g, crude product) as a pale yellow oily substance. 1 H NMR (400MHz, DMSO) δ 7.22 - 7.24 (m, 2H), 6.77 - 6.79 (m, 2H), 4.28 - 4.32 (m, 1H), 3.73 (s, 2H), 3.65 - 3.68 (m, 1H), 3.28 (s, 3H), 2.86 - 2.91 (m, 2H), 2.05 - 2.16 (m, 2H).

[0452] Step 3: Synthesis of Compound C29 Compound C29-3 (0.12 g, 576 μmol, 1.00 equivalent) was dissolved in dichloromethane (3.0 mL), and thionyl chloride (686 mg, 5.76 mmol, 418 μL, 10.0 equivalent) was added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain compound C29 (0.120 g, 529 μmol, yield 91.9%) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 7.28 - 7.29 (m, 1H), 7.25 - 7.27 (m, 1H), 6.80 - 6.83 (m, 2H), 4.62 (s, 2H), 4.30 - 4.33 (m, 1H), 3.65 - 3.69 (m, 1H), 3.28 (s, 3H), 2.87 - 2.91 (m, 2H), 2.05 - 2.16 (m, 2H); LC-MS: m / z = 227.1 (M+H) + .

[0453] Synthesis of the common intermediate C30(2-(4-(chloromethyl)-3-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0454] [ka]

[0455] Step 1: Synthesis of compound C30-2 (methyl 4-(dibromomethyl)-2-methoxybenzoate) Methyl 2-methoxy-4-methylbenzoate (compound C30-1, 5.00 g, 27.8 mmol, 1.00 equivalent) was added to tetrachloromethane (75.0 mL), and N-bromosuccinimide (10.9 g, 61.0 mmol, 2.20 equivalents) was gradually added at room temperature. After the addition was complete, the resulting mixture was heated to 85°C and stirred for 12 hours. The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C30-2 (6.50 g, 19.2 mmol, yield 69.3%) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ 7.77 (d, J = 8.0Hz, 1H), 7.21 (d, J = 1.6Hz, 1H), 7.13 (dd, J1= 1.8Hz, J2= 8.2Hz, 1H), 6.62 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H).

[0456] Step 2: Synthesis of compound C30-3 (methyl 4-formyl-2-methoxybenzoate) Compound C30-2 (5.00 g, 14.8 mmol, 1.00 equivalent) was dissolved in acetone (60.0 mL), and silver nitrate (7.57 g, 44.6 mmol, 3.01 equivalents) and water (15.0 mL) were added. The resulting mixture was stirred at 20°C for 3 hours and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C30-3 (2.60 g, 13.4 mmol, yield 90.5%) as a colorless, transparent oil. 1 H NMR δ 10.0 (s, 1H), 7.89 - 7.91 (m, 1H), 7.48 - 7.50 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H).

[0457] Steps 3-6: Synthesis of intermediate C30 For steps 3-6, following the same steps as for intermediate C5, C30-3 was used as the starting material to obtain intermediate C30 (320 mg, 938 μmol, 75.0% yield, white solid). LC-MS: m / z = 305.1 (M + H) + .

[0458] Synthesis of the common intermediate C31(2-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0459] [ka]

[0460] Following the same steps as for intermediate C30, intermediate C31 (450 mg, white solid) was obtained using methyl 3-methoxy-4-methylbenzoate (compound C31-1) as the starting material. LC-MS: m / z = 305.1 (M + H) + .

[0461] Synthesis of the common intermediate C32(1-(4-(chloromethyl)-3-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0462] [ka]

[0463] Following the same steps as for intermediate C11, methyl 2-methoxy-4-aminobenzoic acid (compound C32-1) was used as the starting material to obtain intermediate C32 (1.18 g, 3.87 mmol, yield 88.5%, white solid). LC-MS: m / z = 305.1 (M + H) + .

[0464] Synthesis of the common intermediate C33(1-(4-(chloromethyl)-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0465] [ka]

[0466] Following the same steps as for intermediate C11, methyl 4-amino-3-methoxybenzoate (compound C33-1) was used as the starting material to obtain intermediate C33 (796.0 mg, 2.61 mmol, yield 79.6%, white solid). LC-MS: m / z = 305.0 (M + H) + .

[0467] Synthesis of the common intermediate C35 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0468] [ka]

[0469] Step 1: Synthesis of compound C35-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound 4-(trifluoromethyl)-1H-imidazole (compound C35-1, 26 g, 0.19 mol) and potassium carbonate (105.5 g, 0.76 mol, 4.0 equivalents) were added to acetonitrile (390 mL), and the resulting mixture was stirred at 0°C for 30 minutes. Iodomethane (32.6 g, 0.23 mol, 1.2 equivalents) was added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under vacuum to obtain the crude product. Water (260 mL) was added, and the resulting mixture was stirred for 10 minutes and extracted three times with ethyl acetate (200 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C35-2 (26 g, crude product). LC-MS: m / z = 151.0 (M + H) + .

[0470] Step 2: Synthesis of compound C35-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)bicyclo[2.2.2]octane-1-carboxylate) Compound C35-2 (14.75 g, 98.3 mmol) and monomethyl hydrogen bicyclo[2.2.2]octane-1,4-dicarbonoxylate (25 g, 117.9 mmol, 1.2 equivalents) were dissolved in dichloromethane (295 mL) and water (295 mL). Subsequently, silver nitrate (6.0 g, 35.4 mmol, 0.3 equivalents) and ammonium persulfate (44.9 g, 78.7 mmol, 2.0 equivalents) were added, and the resulting mixture was stirred at 25°C for 16 hours. The reaction solution was filtered through diatomaceous earth and washed twice with dichloromethane (100 mL). The organic layer was separated, and the aqueous layer was extracted three times with dichloromethane (200 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C35-3 (35.2 g, crude product) as a yellow oily substance. 1H NMR (400MHz, CDCl3) 7.09 - 7.08 (m, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 2.07 - 2.03 (m, 6H), 1.93 - 1.89 (m, 6H); LC-MS: m / z = 317.2 (M+H) + .

[0471] Step 3: Synthesis of compound C35-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)bicyclo[2.2.2]octan-1-yl)methanol) Compound C35-3 (35.2 g, 111.4 mmol) was dissolved in tetrahydrofuran (180.0 mL), and lithium aluminum hydride (2.5 M, 111.4 mL, 278.5 mmol, 2.5 equivalents) was slowly added at 0°C. After the addition was complete, the resulting mixture was heated to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C, and the resulting mixture was stirred for 10 minutes and extracted three times with ethyl acetate (500.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound C35-4 (25.1 g, crude product) as a yellow oily substance. LC-MS: m / z = 289.1 (M + H) + .

[0472] Step 4: Synthesis of Compound C35 Compound C35-4 (25.1 g, 87.2 mmol), p-toluenesulfonyl chloride (33.2 g, 174.4 mmol, 2.0 equivalents), and 4-dimethylaminopyridine (32.0 g, 261.6 mmol, 3.0 equivalents) were sequentially added to dichloromethane (251 mL), and the resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was washed twice with water (100 mL), and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0 to 0 / 1) to obtain intermediate C35 (10.0 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 2.46 (s, 3H), 1.95 - 1.86 (m, 6H), 1.49 - 1.37 (m, 6H); LC-MS: m / z = 443.3 (M+H) + .

[0473] Synthesis of the common intermediate C48(2-(4-(chloromethyl)phenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole)

[0474] [ka]

[0475] Step 1: Synthesis of compound C48-2 ((2-(4-bromophenyl)-1H-imidazole-4-yl)methanol) 4-Bromobenzimidohydrochloride (compound C48-1, 17.8 g, 75.36 mmol), 1,3-dihydroxyacetone dimer (15 g, 83.26 mmol, 1.1 equivalents), ammonium chloride (20 g, 374 mmol, 5 equivalents), and sodium hydroxide (3 g, 75.36 mmol, 1 equivalent) were sequentially added to aqueous ammonia (500 mL). The resulting mixture was stirred at an external temperature of 80°C for 2 hours. The reaction solution was cooled to room temperature and filtered to obtain a solid. This was concentrated under vacuum to obtain compound C48-2 (15 g, crude product) as a white solid. LC-MS: m / z = 252.6 (M + H) + .

[0476] Step 2: Synthesis of compound C48-3 (2-(4-bromophenyl)-1H-imidazole-4-carboaldehyde) Compound C48-2 (14 g, 55.56 mmol) was dissolved in tetrahydrofuran (300 mL), and manganese dioxide (48 g, 555.6 mmol, 10 equivalents) was added. The mixture was stirred at an external temperature of 60°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was obtained. This filtrate was concentrated under vacuum to obtain compound C48-3 (11.1 g, crude product) as a white solid. LC-MS: m / z = 250.8 (M + H) + .

[0477] Step 3: Synthesis of compound C48-4 (2-(4-bromophenyl)-1-methyl-1H-imidazole-4-carboaldehyde) Compound C48-3 (11.1 g, 44.4 mmol), iodomethane (8.2 g, 57.7 mmol, 1.3 equivalents), and potassium carbonate (24.6 g, 177.6 mmol, 4 equivalents) were added to N,N-dimethylformamide (120 mL). The reaction mixture was stirred at an external temperature of 45°C for 3 hours, filtered, and the filtrate was obtained. Water (1000 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain compound C48-4 and compound C48-4a (6.8 g in total) as white solids. LC-MS: m / z = 265.0 (M + H) + .

[0478] Step 4: Synthesis of compound C48-5 (2-(4-bromophenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole) Compounds C48-4 and C48-4a (6.7 g, 25.38 mmol) were dissolved in anhydrous dichloromethane (200 mL), and diethylaminosulfur trifluoride (41 g, 253.8 mmol, 10 equivalents) was slowly added dropwise at 0°C. After the addition was complete, the resulting mixture was stirred at room temperature (25°C) for 5 hours. The reaction mixture was then slowly added to a saturated aqueous solution of sodium bicarbonate and extracted three times with dichloromethane (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain compounds C48-5 and C48-5a (4.1 g) as white solids. LC-MS: m / z = 286.9 (M + H) + .

[0479] Step 5: Synthesis of compound C48-6 (ethyl 4-(4-(difluoromethyl)-1-methyl-1H-imidazole-2-yl)benzoate) Compounds C48-5 and C48-5a (800 mg, 2.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (1.36 g, 1.68 mmol, 0.6 equivalents), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (730 mg, 1.26 mmol, 0.45 equivalents), and triethylamine (1.42 g, 14 mmol, 5 equivalents) were sequentially added to anhydrous ethanol (32 mL). The resulting mixture was stirred under a carbon monoxide atmosphere (double-layer balloon, 25 psi) at an external temperature of 85 °C for 20 hours. Then, EA (100 mL) was added, and the resulting mixture was stirred for 10 minutes. The mixture was then filtered to obtain the filtrate. The filtrate was mixed with silica gel and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C48-6 and compound C48-6a (630 mg). LC-MS: m / z = 281.1 (M + H) + .

[0480] Step 6: Synthesis of compound C48-7 ((4-(4-(difluoromethyl)-1-methyl-1H-imidazole-2-yl)phenyl)methanol) Compounds C48-6 and C48-6a (630 mg) were dissolved in anhydrous THF (7 mL), and a solution of lithium aluminum hydride in THF (2.5 M, 2 mL) was added dropwise at 0°C. After the addition was complete, the resulting mixture was self-heated to room temperature (25°C) and stirred for 2 hours. Water (10 mL) was added at 0°C to quench the reaction, and the pH was adjusted to approximately 5 with 1 M hydrochloric acid aqueous solution. The resulting mixture was extracted three times (50 mL) with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude compounds C48-7 and C48-7a (500 mg). LC-MS: m / z = 239.1 (M + H) + .

[0481] Step 7: Synthesis of intermediate C48 Compounds C48-7 and C48-7a (500 mg) were dissolved in anhydrous dichloromethane (5 mL), and thionyl chloride (1.5 mL) was added. The resulting mixture was stirred at room temperature (25°C) for 1.5 hours. The reaction mixture was then concentrated directly under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound C48 (130 mg). LC-MS: m / z = 257.1 (M + H) + .

[0482] Synthesis of the common intermediate C49(2-(chloromethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)pyridine)

[0483] [ka]

[0484] Following the same steps as for intermediate C5, methyl 5-formylpyridine-2-carboxylate (compound C49-1) was used as the starting material to obtain intermediate C49 (2.0 g). LC-MS: m / z = 276.0 (M + H) + .

[0485] Synthesis of the common intermediate C57(2-(4-(chloromethyl)phenyl)-1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole)

[0486] [ka]

[0487] Following the same steps as for intermediate C5, methyl p-formylbenzoate (compound C5-1) was used as the starting material to obtain intermediate C57 (1.83 g). LC-MS: m / z = 301.2 (M + H) + .

[0488] Synthesis of the common intermediate C58(2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole)

[0489] [ka]

[0490] Following the same steps as for intermediate C5, methyl p-formylbenzoate (compound C5-1) was used as the starting material to obtain intermediate C58 (0.6 g). 1 LC-MS: m / z = 303.1 (M+H) + .

[0491] Synthesis of the common intermediate C59(2-(4-(chloromethyl)phenyl)-1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole)

[0492] [ka]

[0493] Following the same steps as for intermediate C5, methyl p-formylbenzoate (compound C5-1) was used as the starting material to obtain intermediate C59 (0.6 g). LC-MS: m / z = 293.1 (M + H) + .

[0494] Synthesis of the common intermediate D5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine)

[0495] [ka]

[0496] Following the same steps as for intermediate BB13, compound C5 (0.2 g, 0.73 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate D5 (0.16 g, 0.63 mmol, yield 85.9%). 1 LC-MS: m / z = 256.0 (M+H) + .

[0497] Synthesis of the common intermediate D11 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methaneamine)

[0498] [ka]

[0499] Following the same steps as for intermediate BB13, compound C11 (2.2 g, 8.03 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate D11 (1.59 g, 6.23 mmol, yield 77.6%). 1H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.47 (m, 4H), 6.76 (s, 1H), 3.84 (s, 2H), 2.35 (s, 3H); LC-MS: m / z = 256.1 (M+H) + .

[0500] Synthesis of the common intermediate D58 ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methanamine)

[0501] [ka]

[0502] Following the same steps as for intermediate BB13, compound C58 (1.5 g, 4.95 mmol, 1.00 equivalent) was used as the starting material to obtain intermediate D58 (0.98 g, 3.46 mmol, 69.9% yield). LC-MS: m / z = 284.3 (M + H) + .

[0503] Synthesis of intermediate BB1C2 (2-chloro-5-methoxy-N-methyl-N-((4-(pyridine-2-yl)cyclohexyl)methyl)pyrimidine-4-amine)

[0504] [ka]

[0505] Compound BB1 (500.0 mg, 2.89 mmol, 1.00 equivalent), compound C2 (634.4 mg, 3.04 mmol, 1.05 equivalent), and cesium carbonate (3.77 g, 11.56 mmol, 4.0 equivalent) were sequentially added to N,N-dimethylformamide (10.0 mL), and the resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to 25°C. Ethyl acetate (100.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 2) to obtain the intermediate BB1C2 (910.3 mg, 2.63 mmol, yield 91.0%) as a pale yellow solid. LC-MS: m / z = 347.2(M+H) + .

[0506] Synthesis of intermediate BB1C3 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridine-2-yl)benzyl)pyrimidine-4-amine)

[0507] [ka]

[0508] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C3 were used as starting materials to obtain intermediate BB1C3 (689.9 mg, 2.03 mmol, yield 87.5%, pale yellow solid). LC-MS: m / z = 341.2 (M + H) + .

[0509] Synthesis of intermediate BB1C4(2-chloro-5-methoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0510] [ka]

[0511] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C4 were used as starting materials to obtain intermediate BB1C4 (352.5 mg, 0.843 mmol, yield 69.5%, pale yellow solid). LC-MS: m / z = 419.2 (M + H) + .

[0512] Synthesis of intermediate BB1C5 (2-chloro-5-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0513] [ka]

[0514] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C5 were used as starting materials to obtain intermediate BB1C5 (2.39 g, 5.81 mmol, yield 81.6%, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.90 (m, 2H), 7.80 - 7.72 (m, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.98 (s, 2H), 3.18 (s, 3H), 2.92 (s, 3H), 2.76 (d, J = 0.6 Hz, 3H); LC-MS: m / z = 412.1 (M+H) + .

[0515] Synthesis of intermediate BB1C6 (2-chloro-5-methoxy-N-methyl-N-(1-(pyridine-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0516] [ka]

[0517] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C6 were used as starting materials to obtain intermediate BB1C6 (169.7 mg, 0.49 mmol, yield 59.9%, pale yellow solid). LC-MS: m / z = 348.2 (M + H) + .

[0518] Synthesis of intermediate BB1C11 (2-chloro-5-methoxy-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)pyrimidine-4-amine)

[0519] [ka]

[0520] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C11 were used as starting materials to obtain intermediate BB1C11 (3.31 g, 8.04 mmol, yield 73.2%, off-white solid). LC-MS: m / z = 412.8 (M + H) + .

[0521] Synthesis of intermediate BB2C2 (2-chloro-5-methoxy-N-((4-(pyridine-2-yl)cyclohexyl)methyl)pyrimidine-4-amine)

[0522] [ka]

[0523] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C2 were used as starting materials to obtain intermediate BB2C2 (134.1 mg, 0.40 mmol, yield 46.6%, pale yellow oily substance). LC-MS: m / z = 333.1 (M + H) + .

[0524] Synthesis of intermediate BB2C3 (2-chloro-5-methoxy-N-(4-(pyridine-2-yl)benzyl)pyrimidine-4-amine)

[0525] [ka]

[0526] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C3 were used as starting materials to obtain intermediate BB2C3 (255.5 mg, 0.78 mmol, yield 87.7%, pale yellow solid). LC-MS: m / z = 327.0 (M + H) + .

[0527] Synthesis of intermediate BB2C4(2-chloro-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0528] [ka]

[0529] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C4 were used as starting materials to obtain intermediate BB2C4 (98.8 mg, 0.24 mmol, yield 39.2%, pale yellow solid). LC-MS: m / z = 405.1 (M + H) + .

[0530] Synthesis of intermediate BB2C5(2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0531] [ka]

[0532] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C5 were used as starting materials to obtain intermediate BB2C5 (18.9 g, 47.60 mmol, yield 69.8%, pale yellow solid). 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.62 (m, 2H), 7.57 (s, 1H), 7.42 - 7.44 (m, 2H), 7.27 - 7.31 (m, 1H), 5.82 (s, 1H), 4.73 - 4.74 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H); LC-MS: m / z = 398.6 (M+H) + .

[0533] Synthesis of intermediate BB2C6(2-chloro-5-methoxy-N-((1-(pyridine-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0534] [ka]

[0535] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C6 were used as starting materials to obtain intermediate BB2C6 (100.6 mg, 0.30 mmol, yield 35.3%, pale yellow solid). LC-MS: m / z = 344.1 (M + H) + .

[0536] Synthesis of intermediate BB2C9(2-chloro-5-methoxy-N-(((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cyclohexyl)methyl)pyrimidine-4-amine)

[0537] [ka]

[0538] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C9 were used as starting materials to obtain intermediate BB2C9 (31.1 mg, 0.077 mmol, yield 13.2%, pale yellow solid). LC-MS: m / z = 404.2 (M + H) + .

[0539] Synthesis of intermediate BB2C11 (2-chloro-5-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)pyrimidine-4-amine

[0540] [ka]

[0541] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C11 were used as starting materials to obtain intermediate BB2C11 (5.6 g, 14.10 mmol, yield 77.8%, white solid). 1 H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 - 7.47 (m, 4H), 6.47 - 6.49 (m, 1H), 5.76 (s, 1H), 4.75 - 4.82 (m, 2H), 3.90 (s, 3H), 2.36 (s, 3H); LC-MS: m / z = 398.0 (M+H) + .

[0542] Synthesis of intermediate BB2C12(2-chloro-N-(4-(imidazo[1,2-a]pyrazine-8-yl)benzyl)-5-methoxypyrimidine-4-amine)

[0543] [ka]

[0544] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C12 were used as starting materials to obtain intermediate BB2C12 (130.3 mg, 0.36 mmol, yield 88.2%, pale yellow solid). 1H NMR (400 MHz, DMSO) δ 8.71 (d, J = 8.4 Hz, 2H), 8.60 (d, J = 4.4 Hz, 1H), 8.19 - 8.21 (m, 2H), 7.99 (d, J = 4.4 Hz, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 4.61 (d, J = 4.4 Hz, 2H), 3.88 (s, 3H); LC-MS: m / z = 367.0 (M+H) + .

[0545] Synthesis of intermediate BB2C13 (2-chloro-5-methoxy-N-(4-(5-(trifluoromethyl)pyridine-2-yl)benzyl)pyrimidine-4-amine)

[0546] [ka]

[0547] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C13 were used as starting materials to obtain intermediate BB2C13 (455.1 mg, 1.16 mmol, yield 69.9%, pale yellow solid). LC-MS: m / z = 395.0 (M + H) + .

[0548] Synthesis of intermediate BB2C14 (2-chloro-5-methoxy-N-(4-(5-methylpyridine-2-yl)benzyl)pyrimidine-4-amine)

[0549] [ka]

[0550] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C14 were used as starting materials to obtain intermediate BB2C14 (173.45 mg, 0.51 mmol, 90.3% yield, pale yellow solid). LC-MS: m / z = 341.1 (M + H) + .

[0551] Synthesis of intermediate BB2C19(2-chloro-5-methoxy-N-((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidine-4-amine)

[0552] [ka]

[0553] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C19 were used as starting materials to obtain intermediate BB2C19 (281.3 mg, 0.66 mmol, yield 35.6%, pale yellow solid). LC-MS: m / z = 427.3 (M + H) + .

[0554] Synthesis of intermediate BB2C26(6-((2-chloro-5-methoxypyrimidine-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinoline-1(2H)-one)

[0555] [ka]

[0556] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C26 were used as starting materials to obtain intermediate BB2C26 (379.2 mg, 1.05 mmol, yield 82.0%, pale yellow solid). LC-MS: m / z = 361.1 (M + H) + .

[0557] Synthesis of intermediate BB2C27 (2-chloro-5-methoxy-N-(4-(pyridine-2-ylmethoxy)benzyl)pyrimidine-4-amine)

[0558] [ka]

[0559] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C27 were used as starting materials to obtain intermediate BB2C27 (268.5 mg, 0.61 mmol, yield 93.6%, pale yellow solid). 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.8Hz, 1H), 7.72 - 7.76 (m, 1H), 7.72 - 7.75 (m, 2H), 7.29 (s, 1H), 7.24 - 7.25 (m, 1H), 6.99 (d, J = LC-MS: m / z = 357.0 (M+H) + .

[0560] Synthesis of intermediate BB2C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)-5-methoxypyrimidine-4-amine)

[0561] [ka]

[0562] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C28 were used as starting materials to obtain intermediate BB2C28 (316.9 mg, 0.94 mmol, yield 78.8%, white solid). 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.24 - 7.29 (m, 2H), 6.89 - 6.94 (m, 2H), 5.61 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.10 - 4.14 (m, LC-MS: m / z = 338.1 (M+H) + .

[0563] Synthesis of intermediate BB2C30 (2-chloro-5-methoxy-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0564] [ka]

[0565] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C30 were used as starting materials to obtain intermediate BB2C30 (662.0 mg, 1.55 mmol, yield 86.7%, pale yellow solid). LC-MS: m / z = 428.0 (M + H) + .

[0566] Synthesis of intermediate BB2C31 (2-chloro-5-methoxy-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0567] [ka]

[0568] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C31 were used as starting materials to obtain intermediate BB2C31 (337.4 mg, 0.79 mmol, yield 93.9%, white solid). LC-MS: m / z = 428.1 (M + H) + .

[0569] Synthesis of intermediate BB2C33 (2-chloro-5-methoxy-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)pyrimidine-4-amine

[0570] [ka]

[0571] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C33 were used as starting materials to obtain intermediate BB2C33 (3.02 g, 2.66 mmol, yield 88.3%, white solid). LC-MS: m / z = 428.0 (M + H) + .

[0572] Synthesis of intermediate BB2C35(2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidine-4-amine)

[0573] [ka]

[0574] Compound BB2 (1.0 g, 6.29 mmol, 1.00 equivalent), compound C35 (2.78 g, 6.29 mmol, 1.0 equivalent), and cesium carbonate (10.2 g, 31.45 mmol, 5.0 equivalents) were sequentially added to N,N-dimethylformamide (20.0 mL), and the resulting mixture was stirred at 130°C for 36 hours. The reaction mixture was cooled to 25°C. Dichloromethane (100.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0 to 0 / 1) to obtain the intermediate BB2C35 (1.03 g, 2.41 mmol, yield 38.3%) as a white solid. LC-MS: m / z = 430.1 (M+H) + .

[0575] Synthesis of intermediate BB2C48(2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazole-2-yl)benzyl)-5-methoxypyrimidine-4-amine)

[0576] [ka]

[0577] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C48 were used as starting materials to obtain intermediate BB2C48 (371.5 mg, 0.98 mmol, 77.5% yield, white solid). LC-MS: m / z = 380.3 (M + H) + .

[0578] Synthesis of intermediate BB2C58(2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-methoxypyrimidine-4-amine)

[0579] [ka]

[0580] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C58 were used as starting materials to obtain intermediate BB2C58 (357.1 mg, 0.84 mmol, yield 97.0%, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.15 (m, 2H), 7.75 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 4.63 (d, J = 6.3 Hz, 2H), 4.56 - 4.38 (m, 1H), 3.90 (s, 3H), 1.42 (d, J = 6.6 Hz, 6H); LC-MS: m / z = 426.1 (M+H) + .

[0581] Synthesis of intermediate BB2C59(2-chloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-methoxypyrimidine-4-amine)

[0582] [ka]

[0583] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C59 were used as starting materials to obtain intermediate BB2C59 (91.3 mg, 0.22 mmol, yield 78.8%, white solid). LC-MS: m / z = 426.1 (M + H) + .

[0584] Synthesis of intermediate BB3C4(2-chloro-5-isopropoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0585] [ka]

[0586] Following the same steps as for intermediate BB2C35, intermediate BB3 and compound C4 were used as starting materials to obtain intermediate BB3C4 (178.5 mg, 0.40 mmol, yield 28.7%, white solid). LC-MS: m / z = 447.3 (M + H) + .

[0587] Synthesis of intermediate BB3C5 (2-chloro-5-isopropoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0588] [ka]

[0589] Following the same steps as for intermediate BB1C2, intermediate BB3 and compound C5 were used as starting materials to obtain intermediate BB3C5 (2.1 g, 4.78 mmol, yield 86.4%, white solid). LC-MS: m / z = 440.2 (M + H) + .

[0590] Synthesis of intermediate BB4C4(2-chloro-5-isopropoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0591] [ka]

[0592] Following the same steps as for intermediate BB2C35, intermediate BB4 and compound C4 were used as starting materials to obtain intermediate BB4C4 (159.9 mg, 0.37 mmol, yield 39.6%, white solid). LC-MS: m / z = 433.2 (M + H) + .

[0593] Synthesis of intermediate BB4C5 (2-chloro-5-isopropoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0594] [ka]

[0595] Following the same steps as for intermediate BB1C2, intermediate BB4 and compound C5 were used as starting materials to obtain intermediate BB4C5 (2.03 g, 4.78 mmol, yield 86.4%, white solid). LC-MS: m / z = 426.1 (M + H) + .

[0596] Synthesis of intermediate BB4C19 (2-chloro-5-isopropoxy-N-((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidine-4-amine)

[0597] [ka]

[0598] Following the same steps as for intermediate BB1C2, intermediate BB4 and compound C19 were used as starting materials to obtain intermediate BB4C19 (349.7 mg, 0.77 mmol, yield 83.2%, white solid). LC-MS: m / z = 455.2 (M + H) + .

[0599] Synthesis of intermediate BB12C2(2-chloro-N-((4-(pyridine-2-yl)cyclohexyl)methyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0600] [ka]

[0601] Following the same steps as for intermediate BB2C35, intermediate BB12 and compound C2 were used as starting materials to obtain intermediate BB12C2 (51.8 mg, 0.14 mmol, yield 35.4%, white solid). LC-MS: m / z = 371.1 (M + H) + .

[0602] Synthesis of intermediate BB12C3 (2-chloro-N-(4-(pyridine-2-yl)benzyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0603] [ka]

[0604] Following the same steps as for intermediate BB1C2, intermediate BB12 and compound C3 were used as starting materials to obtain intermediate BB12C3 (396.8 mg, 1.09 mmol, yield 76.6%, pale yellow solid). LC-MS: m / z = 365.0 (M + H) + .

[0605] Synthesis of intermediate BB12C4(2-chloro-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0606] [ka]

[0607] Following the same steps as for intermediate BB2C35, intermediates BB12 and C4 were used as starting materials to obtain intermediate BB12C4 (53.1 mg, 0.12 mmol, yield 21.1%, pale yellow oily substance). LC-MS: m / z = 443.0 (M + H) + .

[0608] Synthesis of intermediate BB12C5(2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0609] [ka]

[0610] Following the same steps as for intermediate BB1C2, intermediate BB12 and compound C5 were used as starting materials to obtain intermediate BB12C5 (248.0 mg, 0.57 mmol, yield 88.8%, pale yellow solid). LC-MS: m / z = 436.1 (M + H) + .

[0611] Synthesis of intermediate BB12C6(2-chloro-N-((1-(pyridine-2-yl)piperidine-4-yl)methyl)-5-(trifluoromethyl)pyrimidine-4-amine)

[0612] [ka]

[0613] Following the same steps as for intermediate BB2C35, intermediate BB12 and compound C6 were used as starting materials to obtain intermediate BB12C6 (29.7 mg, 0.08 mmol, yield 18.0%, pale yellow oily substance). LC-MS: m / z = 372.3 (M + H) + .

[0614] Synthesis of intermediate BB13C3 (2-chloro-N-(4-(pyridine-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0615] [ka]

[0616] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C3 were used as starting materials to obtain intermediate BB13C3 (1.19 g, 3.55 mmol, yield 89.4%, pale yellow solid). LC-MS: m / z = 337.1 (M + H) + .

[0617] Synthesis of intermediate BB13C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0618] [ka]

[0619] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C5 were used as starting materials to obtain intermediate BB13C5 (761.1 mg, 1.87 mmol, yield 76.7%, pale yellow solid). 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.29-8.33 (m, 1H), 7.90-7.94 (m, 1H), 7.67-7.72 (m, 2H), 7.46-7.52 (m, 2H), 6.96-7.00 (m, 1H), 4.74 (s, 2H), 3.77 (s, 3H); C-MS: m / z = 407.9 (M+H) + .

[0620] Synthesis of intermediate BB13C7(2-chloro-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)thiophen-2-yl)methyl)flo[3,2-d]pyrimidine-4-amine)

[0621] [ka]

[0622] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C7 were used as starting materials to obtain intermediate BB13C7 (342.6 mg, 0.83 mmol, yield 56.9%, white solid). LC-MS: m / z = 414.0 (M + H) + .

[0623] Synthesis of intermediate BB13C11 (2-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0624] [ka]

[0625] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C11 were used as starting materials to obtain intermediate BB13C11 (4.23 g, 10.39 mmol, yield 76.9%, pale yellow solid). LC-MS: m / z = 408.0 (M + H) + .

[0626] Synthesis of intermediate BB13C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazine-8-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0627] [ka]

[0628] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C12 were used as starting materials to obtain intermediate BB13C12 (458.8 mg, 1.22 mmol, yield 88.7%, white solid). 1 H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.74 (d, J = 8.4Hz, 2H), 8.60 (d, J = 4.4Hz, 1H), 8.27 - 8.31 (m, 1H), 8.21 (s, 1H), 7.99 (d, J = LC-MS: m / z = 377.1 (M+H) + .

[0629] Synthesis of intermediate BB13C19 (2-chloro-N-((4-(5-(trifluoromethyl)pyridine-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)flo[3,2-d]pyrimidine-4-amine)

[0630] [ka]

[0631] Following the same steps as for intermediate BB2C35, intermediate BB13 and compound C19 were used as starting materials to obtain intermediate BB13C19 (383.8 mg, 0.88 mmol, yield 22.3%, pale yellow oily substance). LC-MS: m / z = 437.0 (M + H) + .

[0632] Synthesis of intermediate BB13C25(6-(((2-chlorofl[3,2-d]pyrimidine-4-yl)amino)methyl)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one)

[0633] [ka]

[0634] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C25 were used as starting materials to obtain intermediate BB13C25 (195.0 mg, 0.57 mmol, yield 90.4%, white solid). 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.30 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.24 (s, 1H), 6.97 (d, J=2.0Hz, 1H), 4.69 (s, 2H),3.52 (t, J1=6.4Hz, J2=6.8Hz, 2H), 3.00 (s, 3H), 2.95 (t, J1=6.4Hz, J2=6.8Hz, 2H); LC-MS: m / z = 343.2 (M+H) + .

[0635] Synthesis of intermediate BB13C26(6-(((2-chlorofl[3,2-d]pyrimidine-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinoline-1(2H)-one)

[0636] [ka]

[0637] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C26 were used as starting materials to obtain intermediate BB13C26 (233.1 mg, 0.63 mmol, yield 82.6%, pale yellow solid). LC-MS: m / z = 371.2 (M + H)+ .

[0638] Synthesis of intermediate BB13C27 (2-chloro-N-(4-(pyridine-2-ylmethoxy)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0639] [ka]

[0640] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C27 were used as starting materials to obtain intermediate BB13C27 (256.3 mg, 0.70 mmol, yield 66.8%, pale yellow solid). LC-MS: m / z = 366.9 (M + H) + .

[0641] Synthesis of intermediate BB13C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0642] [ka]

[0643] Following the same steps as for intermediate BB1C2, intermediates BB13 and C28 were used as starting materials to obtain intermediate BB13C28 (118.0 mg, 0.34 mmol, yield 84.5%, pale yellow solid). LC-MS: m / z = 348.2 (M + H) + .

[0644] Synthesis of intermediate BB13C29 (2-chloro-N-(4-(3-methoxycyclobutoxy)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0645] [ka]

[0646] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C29 were used as starting materials to obtain intermediate BB13C29 (244.2 mg, 0.68 mmol, yield 93.5%, pale yellow solid). LC-MS: m / z = 360.2 (M + H) + .

[0647] Synthesis of intermediate BB13C30 (2-chloro-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0648] [ka]

[0649] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C30 were used as starting materials to obtain intermediate BB13C30 (292.9 mg, 0.67 mmol, yield 78.8%, white solid). LC-MS: m / z = 438.1 (M + H) + .

[0650] Synthesis of intermediate BB13C31 (2-chloro-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0651] [ka]

[0652] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C31 were used as starting materials to obtain intermediate BB13C31 (214.2 mg, 0.49 mmol, yield 73.9%, white solid). LC-MS: m / z = 438.0 (M + H) + .

[0653] Synthesis of intermediate BB13C32 (2-chloro-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0654] [ka]

[0655] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C32 were used as starting materials to obtain intermediate BB13C32 (100.5 mg, 0.23 mmol, 70.0% yield, white solid). LC-MS: m / z = 438.0 (M + H) + .

[0656] Synthesis of intermediate BB13C33 (2-chloro-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0657] [ka]

[0658] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C33 were used as starting materials to obtain intermediate BB13C33 (257.6 mg, 0.59 mmol, yield 84.2%, pale yellow solid). LC-MS: m / z = 437.9 (M + H) + .

[0659] Synthesis of intermediate BB13C35(2-chloro-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)flo[3,2-d]pyrimidine-4-amine)

[0660] [ka]

[0661] Following the same steps as for intermediate BB2C35, intermediate BB13 and compound C35 were used as starting materials to obtain intermediate BB13C35 (48.3 mg, 0.11 mmol, yield 28.8%, white solid). LC-MS: m / z = 440.2 (M + H) + .

[0662] Synthesis of intermediate BB13C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazole-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0663] [ka]

[0664] Following the same steps as for intermediate BB1C2, intermediates BB13 and C48 were used as starting materials to obtain intermediate BB13C48 (886.2 mg, 2.28 mmol, yield 77.9%, white solid). LC-MS: m / z = 390.1 (M + H) + .

[0665] Synthesis of intermediate BB14C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrido[3,2-d]pyrimidine-4-amine)

[0666] [ka]

[0667] Following the same steps as for intermediate BB1C2, intermediate BB14 and compound C5 were used as starting materials to obtain intermediate BB14C5 (1.22 g, 2.92 mmol, yield 93.3%, pale yellow solid). LC-MS: m / z = 419.1 (M + H) + .

[0668] Synthesis of intermediate BB15C5(2,5-dichloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0669] [ka]

[0670] Following the same steps as for intermediate BB1C2, intermediate BB15 and compound C5 were used as starting materials to obtain intermediate BB15C5 (398.7 mg, 0.99 mmol, yield 80.4%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.87 - 7.68 (m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 5.00 (s, 2H), 3.21 (s, 3H); LC-MS: m / z = 402.0 (M+H) + .

[0671] Synthesis of intermediate BB15C59 (2,5-dichloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0672] [ka]

[0673] Following the same steps as for intermediate BB1C2, intermediate BB15 and compound C59 were used as starting materials to obtain intermediate BB15C59 (124.0 mg, 0.30 mmol, yield 58.9%, white solid). LC-MS: m / z = 420.0 (M + H) + .

[0674] Synthesis of intermediate BB16C58(2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-N-methylpyrimidine-4-amine)

[0675] [ka]

[0676] Following the same steps as for intermediate BB1C2, intermediate BB16 and compound C58 were used as starting materials to obtain intermediate BB16C58 (6.66 g, 16.69 mmol, yield 93.3%, pale yellow solid). LC-MS: m / z = 428.2 (M + H) + .

[0677] Synthesis of intermediate BB16-D3C57(2-chloro-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-fluoro-N-(methyl-d3)pyrimidine-4-amine)

[0678] [ka]

[0679] Following the same steps as for intermediate BB1C2, intermediate BB16-D3 and compound C57 were used as starting materials to obtain intermediate BB16-D3C57 (1.33 g, 3.10 mmol, yield 89.8%, off-white solid). LC-MS: m / z = 429.3 (M + H) + .

[0680] Synthesis of intermediate BB16-D3C58(2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-N-(methyl-d3)pyrimidine-4-amine)

[0681] [ka]

[0682] Following the same steps as for intermediate BB1C2, intermediate BB16-D3 and compound C58 were used as starting materials to obtain intermediate BB16-D3C58 (1.54 g, 3.57 mmol, yield 79.6%, off-white solid). LC-MS: m / z = 431.1 (M + H) + .

[0683] Synthesis of intermediate BB16-D3C59(2-chloro-5-fluoro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-N-(methyl-D3)pyrimidine-4-amine)

[0684] [ka]

[0685] Following the same steps as for intermediate BB1C2, intermediate BB16-D3 and compound C59 were used as starting materials to obtain intermediate BB16-D3C59 (874.2 mg, 2.08 mmol, yield 84.1%, yellow solid). LC-MS: m / z = 421.1 (M + H) + .

[0686] Synthesis of intermediate BB17C5(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)pyrimidine-5-carbonitrile)

[0687] [ka]

[0688] Following the same steps as for intermediate BB1C2, intermediate BB17 and compound C5 were used as starting materials to obtain intermediate BB17C5 (149.0 mg, 0.38 mmol, 48.7% yield, off-white solid). LC-MS: m / z = 393.0 (M + H) + .

[0689] Synthesis of intermediate BB19C4(2-chloro-5-(difluoromethoxy)-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)piperidine-4-yl)methyl)pyrimidine-4-amine)

[0690] [ka]

[0691] Following the same steps as for intermediate BB2C35, intermediate BB19 and compound C4 were used as starting materials to obtain intermediate BB19C4 (44.0 mg, 0.10 mmol, yield 17.7%, colorless, transparent oil). LC-MS: m / z = 441.0 (M + H) + .

[0692] Synthesis of intermediate BB19C5(2-chloro-5-(difluoromethoxy)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0693] [ka]

[0694] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C5 were used as starting materials to obtain intermediate BB19C5 (1.03 g, 2.33 mmol, yield 82.2%, white solid). LC-MS: m / z = 434.0 (M + H) + .

[0695] Synthesis of intermediate BB19C11(2-chloro-5-(difluoromethoxy)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)pyrimidine-4-amine)

[0696] [ka]

[0697] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C11 were used as starting materials to obtain intermediate BB19C11 (545.7 mg, 1.26 mmol, yield 77.3%, white solid). LC-MS: m / z = 434.2 (M + H) + .

[0698] Synthesis of intermediate BB19C30 (2-chloro-5-(difluoromethoxy)-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0699] [ka]

[0700] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C30 were used as starting materials to obtain intermediate BB19C30 (546.4 mg, 1.18 mmol, yield 66.5%, off-white solid). LC-MS: m / z = 464.0 (M + H) + .

[0701] Synthesis of intermediate BB36C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-(methoxymethyl)-N-methylpyrimidine-4-amine)

[0702] [ka]

[0703] Following the same steps as for intermediate BB1C2, intermediate BB36 and compound C58 were used as starting materials to obtain intermediate BB36C58 (382.0 mg, 0.84 mmol, yield 69.3%, colorless, transparent oil). LC-MS: m / z = 454.0 (M + H) + .

[0704] Synthesis of intermediate BB42C5(2-chloro-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-N-(propa-2-in-1-yl)pyrimidine-4-amine)

[0705] [ka]

[0706] Following the same steps as for intermediate BB1C2, intermediate BB42 and compound C5 were used as starting materials to obtain intermediate BB42C5 (332.6 mg, 0.76 mmol, 44.5% yield, off-white solid). LC-MS: m / z = 436.2 (M + H) + .

[0707] Synthesis of intermediate BB43C5(2-chloro-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-N-(tetrahydrofuran-2-yl)pyrimidine-4-amine)

[0708] [ka]

[0709] Following the same steps as for intermediate BB1C2, intermediate BB43 and compound C5 were used as starting materials to obtain intermediate BB43C5 (101.1 mg, 0.22 mmol, yield 37.3%, white solid). LC-MS: m / z = 468.1 (M + H) + .

[0710] Synthesis of intermediate BB44C5(2-chloro-N-cyclopropyl-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0711] [ka]

[0712] Following the same steps as for intermediate BB1C2, intermediate BB44 and compound C5 were used as starting materials to obtain intermediate BB44C5 (258.3 mg, 0.59 mol, yield 74.8%, pale yellow solid). LC-MS: m / z = 438.1 (M + H) + .

[0713] Synthesis of intermediate BB45C5(N-(2-chloro-5-methoxypyrimidine-4-yl)-O-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)hydroxylamine)

[0714] [ka]

[0715] Compound BB45 (250 mg, 1.3 mmol, 1.0 equivalent), compound C5 (392 mg, 1.43 mmol, 1.1 equivalent), and potassium carbonate (548 mg, 4.0 mmol, 3.0 equivalent) were sequentially added to dimethyl sulfoxide (5.0 mL), and the resulting mixture was stirred at 85°C for 1 hour. The reaction mixture was cooled to 25°C. Ethyl acetate (20.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain the intermediate BB45C5 (160.5 mg, 0.38 mmol, yield 28.9%) as a pale yellow oily substance. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.96 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.68 (s, 3H); LC-MS: m / z = 428.1 (M+H) + .

[0716] Synthesis of intermediate BB18D5 (2-chloro-5-ethynyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrimidine-4-amine)

[0717] [ka]

[0718] 2-(2,4-dichloropyrimidine-5-yl)ethynyl-trimethylsilane (compound BB18-1, 2.2 g, 8.16 mmol, 1.00 equivalent), compound D5 (2.19 g, 8.57 mmol, 1.05 equivalent), and potassium carbonate (4.51 g, 32.64 mmol, 4.0 equivalent) were sequentially added to N,N-dimethylformamide (40.0 mL), and the resulting mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C. Ethyl acetate (100.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the intermediate BB18D5 (2.24 g, 5.73 mmol, yield 70.2%) as a white solid. LC-MS: m / z = 392.2 (M + H) + .

[0719] Synthesis of intermediate BB21D5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-morpholinopyrimidine-4-amine)

[0720] [ka]

[0721] Following the same steps as for intermediate BB18D5, intermediate BB21 and compound D5 were used as starting materials to obtain intermediate BB21D5 (880.0 mg, 1.95 mmol, yield 88.6%, white solid). LC-MS: m / z = 453.1 (M + H) + .

[0722] Synthesis of intermediate BB22D5(2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-5-(4-methylpiperazine-1-yl)pyrimidine-4-amine)

[0723] [ka]

[0724] Following the same steps as for intermediate BB18D5, intermediate BB22 and compound D5 were used as starting materials to obtain intermediate BB22D5 (441.9 mg, 0.95 mmol, yield 87.4%, off-white solid). LC-MS: m / z = 466.2 (M + H) + .

[0725] Synthesis of intermediate BB24D5(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)pyrimidine-5-ol)

[0726] [ka]

[0727] Following the same steps as for intermediate BB18D5, intermediate BB24 and compound D5 were used as starting materials to obtain intermediate BB24D5 (26.8 mg, 0.07 mmol, yield 22.8%, pale yellow solid). LC-MS: m / z = 384.1 (M + H) + .

[0728] Synthesis of intermediate BB24D11(2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzyl)amino)pyrimidine-5-ol)

[0729] [ka]

[0730] Following the same steps as for intermediate BB18D5, intermediates BB24 and D11 were used as starting materials to obtain intermediate BB24D11 (115.1 mg, 0.3 mmol, yield 83.0%, white solid). LC-MS: m / z = 384.2 (M + H) + .

[0731] Synthesis of intermediate BB35D5 ((2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)pyrimidine-5-yl)methanol)

[0732] [ka]

[0733] Following the same steps as for intermediate BB18D5, intermediate BB35 and compound D5 were used as starting materials to obtain intermediate BB35D5 (333.8 mg, 1.86 mmol, yield 55.6%, colorless, transparent oil). LC-MS: m / z = 398.1 (M + H) + .

[0734] Synthesis of intermediate BB41C5 (methyl 2-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)pyrimidine-5-yl)acetate)

[0735] [ka]

[0736] Following the same steps as for intermediate BB18D5, intermediate BB41 and compound D5 were used as starting materials to obtain intermediate BB41D5 (133.9 mg, 0.30 mmol, yield 69.9%, pale yellow solid). LC-MS: m / z = 440.2 (M + H) + . [Examples]

[0737] (Example 1) Synthesis of Compound 1 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-(4-(pyridine-2-yl)benzyl)pyrimidine-4-amine)

[0738] [ka]

[0739] Compound A5 (100 mg, 389 μmol, 1.00 equivalent) was dissolved in tetrahydrofuran (2.5 mL), and sodium hydride (62.2 mg, 1.55 mmol, 60.0% purity, 4.00 equivalent) was gradually added at 0°C. After the addition was complete, the resulting mixture was reacted at 0°C for 30 minutes. Next, compound B10 (95.0 mg, 466 μmol, 1.20 equivalent) was added. After the addition was complete, the resulting mixture was heated to 25°C and stirred for 12 hours. Then, ice water (2.0 mL) was added at 0°C to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and a filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75×30mm×3μm; mobile phase: water (HCl)~ACN; B%: 15%~35%, 8 min) to obtain compound 1 (136 mg, 277 μmol, yield 71.3%, HCl) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 4.40 Hz, 1H), 8.40 (s, 1H), 8.18-8.19 (m, 3H), 7.80 (s, 1H), 7.65 (s, 1H), 7.43-7.46 (m, 6H), 5.09-5.21 (m, 2H), 3.85-3.94 (m, 3H), 3.54 (s, 1H), 3.26-3.34 (m, 3H), 1.01-1.23 (m, 6H); LC-MS: m / z = 425.2 (M+H) + .

[0740] Different common intermediates A and B were used together with cesium carbonate, sodium hydride, or potassium carbonate, and the following compounds were obtained according to the preparation method for compound 1.

[0741] [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E] [Table 1F] [Table 1G] [Table 1H] [Table 1I]

[0742] (Example 32) Synthesis of compound 32 (2-(2-isopropylphenyl)-N-(4-(pyridine-2-yl)benzyl)flo[3,2-d]pyrimidine-4-amine)

[0743] [ka]

[0744] Step 1: Synthesis of Compound 32-3 Compound 32-1 (200.0 mg, 1.09 mmol, 1.00 equivalent), Compound 32-2 (205.0 mg, 1.09 mmol, 1.00 equivalent), and cesium carbonate (1.1 g, 3.27 mmol, 3 equivalents) were sequentially added to N,N-dimethylformamide (4.0 mL), and the resulting mixture was stirred at 60°C for 1 hour. Ethyl acetate (30.0 mL) was added, and the resulting mixture was stirred for 5 minutes. The mixture was filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~2 / 1) to obtain Compound 32-3 (360.9 mg). LC-MS: m / z = 337.0 (M+H) + .

[0745] Step 2: Synthesis of Compound 32 Compound 32-3 (100.0 mg, 0.3 mmol, 1.00 equivalent), Compound 32-4 (97.7 mg, 0.6 mmol, 2.00 equivalent), potassium phosphate (191.0 mg, 0.9 mmol, 3.00 equivalent), and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.03 mmol, 0.10 equivalent) were sequentially added to dioxane (2.0 mL) and water (0.4 mL). The resulting mixture was purged three times with nitrogen and stirred at 90°C under a nitrogen atmosphere for 16 hours. Water (10.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (20.0 mL). The organic layers were combined, washed twice with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound 32 (87.5 mg, 0.21 mmol, yield 69.4%, purity 98.6%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 8.03 - 7.95 (m, 2H), 7.58 - 7.48 (m, 5H), 7.47 - 7.42 (m, 1H), 7.40 - 7.33 (m, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.93 (d, J = 6.0 Hz, 2H), 3.29 - 3.22 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 421.2 (M+H) + .

[0746] The reaction conditions for Step 1 were set to cesium carbonate, sodium hydride, or potassium carbonate, and the reaction conditions for Step 2 were set to Pd(PPh3)4 / K3PO4 or XPhos-Pd-G2 / XPhos / K3PO4. The following compounds were obtained according to the preparation method for compound 32.

[0747] [Table 2A] [Table 2B] [Table 2C] [Table 2D] [Table 2E]

[0748] (Example 61) Synthesis of compound 61(2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-((4-(pyridine-2-yl)cyclohexyl)methyl)pyrimidine-4-amine)

[0749] [ka]

[0750] Compound BB1C2 (125.0 mg, 0.36 mmol, 1.00 equivalent), Compound A1-2 (118.1 mg, 0.72 mmol, 2.00 equivalent), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G2, 56.58 mg, 0.072 mmol, 0.20 equivalents) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 68.65 mg, 0.144 mmol, 0.40 equivalents) and potassium phosphate (229.3 mg, 1.08 mmol, 3.00 equivalents) were sequentially added to dioxane (2.5 mL) and water (0.5 mL). The resulting mixture was purged three times with nitrogen and stirred at 95°C under a nitrogen atmosphere for 16 hours. Water (15.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 61 (93.5 mg, 0.22 mmol, yield 60.3%, purity 97.3%) as a white solid. LC-MS: m / z = 431.2 (M + H) + .

[0751] Using intermediates A series, AA series, BBC series, or A series, AA series, BBD series as starting materials, XPhos-Pd-G2 / XPhos / K3PO4 was used as the reaction reagent, and dioxane and water were used as solvents to obtain the following compounds according to the preparation method for compound 61.

[0752] [Table 3-1] [Table 3-2] [Table 3-3] Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 [Table 3-38] [Table 3-39] [Table 3-40] [Table 3-41] [Table 3-42]

[0753] (Example 204) Synthesis of compound 204 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)hydroxylamine)

[0754] [ka]

[0755] Step 1: Synthesis of compound BB46-2 (O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidine-4-yl)hydroxylamine) Compound 2,4-dichloro-5-fluoropyrimidine (compound BB46-1, 1.0 g, 5.6 mmol, 1.0 equivalent), O-(tert-butyldimethylsilyl)hydroxylamine (0.9 g, 6.2 mmol, 1.1 equivalent), and N,N-diisopropylethylamine (2.1 g, 16.8 mmol, 3.0 equivalent) were sequentially added to dioxane (20 mL), and the resulting mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain compound BB46-2 (430.2 mg, 1.49 mmol, yield 26.6%) as a pale yellow oily substance. LC-MS: m / z = 290.0 (M+H) + .

[0756] Step 2: Synthesis of compound BB46-2C5(O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidine-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)hydroxylamine) Following the same steps as for intermediate BB1C2, intermediate BB46-2 (430 mg, 1.5 mmol, 1.0 equivalent) and compound C5 (452 ​​mg, 1.65 mmol, 1.1 equivalent) were used as starting materials to obtain intermediate BB46-2C5 (506.8 mg, 0.96 mmol, yield 64.1%, pale yellow solid). LC-MS: m / z = 528.3 (M + H) + .

[0757] Step 3: Synthesis of compound A2-7BB46-2C5(O-(tert-butyldimethylsilyl)-N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)hydroxylamine) Following the same steps as for compound A1-2BB1C2, intermediate BB46-2 (486.0 mg, 0.9 mmol, 1.0 equivalent) and compound A2-7 (262.1 mg, 1.35 mmol, 1.5 equivalent) were used as starting materials to obtain intermediate A2-7BB46-2C5 (323.3 mg, 0.50 mmol, yield 56.0%, yellow solid). LC-MS: m / z = 642.3 (M + H) + .

[0758] Step 4: Synthesis of Compound 204 Intermediate A2-7BB46-2C5 (323.0 mg, 0.5 mmol, 1.0 equivalent) was dissolved in 4 M hydrochloric acid solution in methanol, and the mixture was stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate solution (30.0 mL) was added, and the resulting mixture was extracted three times with dichloromethane (20.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~1 / 2) to obtain compound 204 (109.9 mg, 0.21 mmol, yield 41.7%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 9.51 (s, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.75 - 7.57 (m, 2H), 7.56 - 7.41 (m, 2H), 4.87 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 1.62 (dt, J = 8.1, 3.5 Hz, 1H), 0.99 (dq, J = 5.9, 3.5 Hz, 2H), 0.84 (dq, J = 10.0, 3.4 Hz, 2H); LC-MS: m / z = 528.3 (M+H) + .

[0759] (Example 205) Synthesis of compound 205 (N-(2-(1-cyclopropyl-4-methyl-1H-pyrazole-5-yl)-5-methoxypyrimidine-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)hydroxylamine)

[0760] [ka]

[0761] Following the same steps as for compound 204, compound 205 (37.2 mg, 0.074 mmol, yield 66.9%, white solid) was obtained using intermediate BB46-2 and compound AA16 as starting materials. LC-MS: m / z = 500.3 (M + H) + .

[0762] (Example 206) Synthesis of compound 206 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)cyanamide)

[0763] [ka]

[0764] Compound 29 (50 mg, 0.092 mmol, 1.0 equivalent) was dissolved in N,N-dimethylformamide (1.0 mL), and sodium hydride (60% content, 36.8 mg, 0.92 mmol, 10 equivalents) was added gradually at 0°C. The reaction mixture was heated to 25°C by natural heating and stirred for 1 hour. Cyanogen bromide (48.7 mg, 0.46 mmol, 5 equivalents) was added, and the resulting mixture was stirred at room temperature (25°C) for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound 206 (6.7 mg, 0.0125 mmol, yield 13.6%) as a pale white solid. 11H NMR (400MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 5.39 (d, J = 6.3 LC-MS: m / z = 537.2 (M+H) + .

[0765] (Example 207) Synthesis of compound 207 (2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-5-methoxy-N-methyl-N-[[4-[1-methyl-4-(trifluoromethyl)imidazole-2-yl]cubane-1-yl]methyl]pyrimidine-4-amine)

[0766] [ka]

[0767] Step 1: Synthesis of compound 207-2 (methyl(2R,3R,4S,5S)-4-(hydroxymethyl)cubane-1-carboxylate) Compound (1S,2R,3R,8S)-4-(methoxycarbonyl)cubane-1-carboxylic acid (207-1, 10.0 g, 48.5 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (300 mL). A 10 M solution of boranedimethyl sulfide in tetrahydrofuran (5.82 mL, 1.20 equivalents) was added at 20°C, and the resulting mixture was stirred at 50°C for 13 hours. Methanol (300 mL) was slowly added at 0°C to quench the reaction, and the resulting mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound 207-2 (11.0 g, crude product) as a white solid. 1H NMR (400MHz, CDCl3) δ 4.15 - 4.13 (m, 3H), 3.89 - 3.87 (m, 3H), 3.77 - 3.75 (m, 2H), 3.70 (s, 3H).

[0768] Step 2: Synthesis of compound 207-3 (methyl(2R,3R,4S,5S)-4-formylcubane-1-carboxylate) Compound 207-2 (11.0 g, 57.2 mmol, 1.00 equivalent) was dissolved in dichloromethane (150 mL), followed by the addition of dess-martin periodinane (DMP, 29.1 g, 68.6 mmol, 21.2 mL, 1.20 equivalent) at 0°C. The resulting mixture was stirred at 0°C for 2 hours. Saturated aqueous sodium bicarbonate (100 mL) was added, and the resulting mixture was extracted three times with dichloromethane (150 mL). The organic layers were combined, washed twice with saturated brine (120 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain compound 207-3 (5.8 g, 30.5 mmol, yield 53.3%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 9.75 (s, 1H), 4.38 - 4.36 (m, 3H), 4.27 - 4.25 (m, 3H), 3.72 (s, 3H).

[0769] Step 3: Synthesis of compound 207-4 (methyl(2R,3R,4S,5S)-4-(4-(trifluoromethyl)-1H-imidazole-2-yl)cubane-1-carboxylate) Sodium acetate (5.25 g, 64.0 mmol, 2.1 equivalents) was dissolved in water (25.0 mL), and 1,1-dibromo-3,3,3-trifluoroacetone (9.05 g, 33.5 mmol, 1.1 equivalents) was added at 20°C. The reaction mixture was heated to 100°C and stirred for 1 hour. Compound 207-3 (5.8 g, 30.5 mmol, 1.0 equivalent) was dissolved in methanol (65.0 mL), and aqueous ammonia (25.0 mL) was added at 20°C. After the addition was complete, the resulting mixture was stirred at 20°C for 11 hours. The reaction mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound 207-4 (6.0 g, 18.5 mmol, yield 60.8%) as a white solid. LC-MS: m / z = 297.0 (M + H) + .

[0770] Step 4: Synthesis of compound 207-5 (methyl(2R,3R,4S,5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cubane-1-carboxylate) Compound 207-4 (4.5 g, 15.2 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (40.0 mL), and sodium hydride (911 mg, 22.7 mmol, 60% content, 1.50 equivalents) was added gradually at 0°C. After the addition was complete, the resulting mixture was stirred at 20°C for 30 minutes. Iodomethane (2.16 g, 15.2 mmol, 945 μL, 1.0 equivalent) was added, and the resulting mixture was reacted at 20°C for 2 hours. Saturated aqueous ammonium chloride solution (50.0 mL) was added at 0°C to quench the reaction. Water (100 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (70.0 mL). The organic layers were combined, washed twice with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by reverse-phase chromatography HPLC (0.1% FA) to obtain compound 207-5 (1.6 g, 4.95 mmol, yield 32.5%) as a white solid. 1H NMR (400MHz, CD3OD) δ 7.54 (d, J = 1.2 Hz, 1H), 4.45 - 4.42 (m, 3H), 4.32 - 4.30 (m, 3H), 3.73 (s, 3H), 3.66 (s, 3H);LC-MS: m / z = 311.1 (M+H) + .

[0771] Step 5: Synthesis of compound 207-6 ((2R,3R,4S,5S)-N-methyl-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cubane-1-carboxamide) Compound 207-5 (120 mg, 386.76 mmol, 1 equivalent) was dissolved in ethanol (24.0 mL), and a solution of methylamine in ethanol (16.51 g, 159.48 mmol, 30% content, 412.35 equivalents) was added at 25°C. The resulting mixture was stirred at 70°C for 12 hours under pressure of 50 Psi. The reaction mixture was cooled to room temperature, and ice water (15.0 mL) was added. The resulting mixture was concentrated under vacuum to remove the ethanol, and extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was obtained. This filtrate was concentrated under vacuum to obtain compound 207-6 (0.11 g, crude product) as a white solid. LC-MS: m / z = 310.1 (M + H) + .

[0772] Step 6: Synthesis of compound 207-7(N-methyl-1-((2R,3R,4S,5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cubane-1-yl)methylamine) Compound 207-6 (0.1 g, 323.33 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10.0 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (2.5 mmol, 387.99 μL, 3 equivalents) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, then heated to 50°C and stirred for 3 hours. Sodium sulfate decahydrate (1.0 g) was added at 0°C, and the resulting mixture was stirred for 30 minutes, followed by the addition of tetrahydrofuran (5.0 mL) and stirring for 5 minutes. The resulting mixture was filtered to obtain the filtrate. This was concentrated under vacuum to obtain compound 207-7 (86 mg, crude product) as a white solid. LC-MS: m / z = 296.3 (M + H) + .

[0773] Step 7: Synthesis of compound 207-8 (2-chloro-5-methoxy-N-methyl-N-[[4-[1-methyl-4-(trifluoromethyl)imidazole-2-yl]cubane-1-yl]methyl]pyrimidine-4-amine) Compound 207-7 (40 mg, 135.45 mmol, 1 equivalent), N,N-diisopropylethylamine (70.03 mg, 541.82 mmol, 94.37 μL, 4 equivalents), and 2,4-dichloro-5-methoxypyrimidine (38.80 mg, 216.73 mmol, 1.6 equivalents) were sequentially added to dioxane (2.0 mL), and the resulting mixture was stirred at an external temperature of 60°C for 8 hours. The reaction mixture was cooled to room temperature. Water (10.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, washed twice with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound 207-8 (32.0 mg, 73.09 mmol, yield 53.96%) as a white solid. LC-MS: m / z = 438.2 (M+H) + .

[0774] Step 8: Synthesis of compound 207 (4'-cyclopropyl-5,6'-dimethoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)cubane-1-yl)methyl)-[2,5'-bipyrimidine]-4-amine) Following the same steps as for compound 61, compound 207 (2.66 mg, 4.32 mmol, yield 7.56%, white solid) was obtained using compound 207-8 (25.0 mg, 57.10 mmol, 1 equivalent) and intermediate A2-7 (22.15 mg, 114.20 mmol, 2.0 equivalents) as starting materials. LC-MS: m / z = 552.3 (M + H) + .

[0775] (Example 208) Synthesis of compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)amino...

Claims

1. Compounds of formula (SI), 【Chemistry 1】 or its pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers. [In the formula, Ring A and Ring B are independent of each other, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Selected from the group consisting of cycloalkyls and 3- to 8-membered heterocyclines, ring A and ring B each independently contain one or more R 1 It is sometimes replaced by, Ring E is C 6～10 C is condensed with aryl, 5-6 member heteroaryl, and 5-6 member heterocyclyl. 6～10 C condensed with aryls and 5-6 member heteroaryls 6～10 Selected from the group consisting of aryls, ring E is one or more R 1 It is sometimes replaced by, L is selected from the group consisting of a chemical bond, -O-, -S-, -C 1～6 alkylene-, -O-C 1～6 alkylene-, -C 1～6 alkylene-O-, -S-C 1～6 alkylene- and -C 1～6 alkylene-S-, R a and R b These are, independently, H atom, -CN, and C. 1～6 alkyl, -OH, halogen, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Hydroxyalkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Selected from the group consisting of haloalkoxys, or R a and R b They come together, oxo, C 3～8 Forming a cycloalkyl or 3-8 membered heterocycline, C 1～6 Alkyl is one or more R 1 It is sometimes replaced by, R 2 This consists of H atom, -OH, -CN, and C. 1～6 Alkyl, -C 1～6 Alkylene-C 6～10 Ariel, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Selected from the group consisting of cycloalkyls and 3- to 8-membered heterocyclines, C 1～6 Alkyl or -C 1～6 Alkylene-C 6～10 A aryl is one or more R 1 It is sometimes replaced by; R 3 These are H atoms, -OH, -COOH, -NH 2 -CN, halogen, C 1～6 Alkyl, -SC 1～6 Alkyl, -S(O)-C 1～6 Alkyl, -S(O) 2 -C 1～6 Alkyl, phosphoryl, phosphonyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Cycloalkyl, C 3～8 Cycloalkyl-O-, 3- to 8-membered heterocyclyl and -C 1～6 Alkylene-C(O)-OC 1～6 Selected from the group consisting of alkyl groups, -NH 2 , C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Cycloalkyls and 3- to 8-membered heterocyclines each independently contain one or more R 1 It is sometimes replaced by, R 4 These are H atoms, -OH, -COOH, -NH 2 -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclines, R in each of the existences 1 is, independently, a D atom, -OH, -COOH, -NH 2 , -CN, oxo, halogen, C 1～6 alkyl, C 2～6 alkynyl, C 1～6 haloalkyl, C 1～6 alkoxy, C 1～6 deuterated alkoxy, C 1～6 haloalkoxy, C 1～6 hydroxyalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl, C 3～8 cycloalkyl-O-, 3- to 8-membered heterocyclyl, -O-C 1～6 alkylene-O-C 1～6 is selected from the group consisting of alkyl, and C 6～10 aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of a D atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 alkyl, C 1～6 haloalkyl, C 1～6 alkoxy, C 1～6 haloalkoxy and C 1～6 hydroxyalkyl, and are optionally substituted n is an integer between 0 and 8.

2. Ring B is C 6～10 It is an aryl or a 5-6 member heteroaryl, and ring B is one or more R 1 It is replaced in some cases, R 1 This is as defined in claim 1, in particular, Ring B is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, piperazinyl, naphthyl, pyrrolyl, pyridadinyl, triazolyl, tetrazolyl, and furanyl, and ring B is one or more R 1 It is replaced in some cases, R 1 This is as defined in claim 1, More specifically, Ring B is imidazolyl, and ring B is one or more R 1 It is replaced in some cases, R 1 The compound according to claim 1, wherein the compound is as defined in claim 1.

3. Compounds of formula (SII) 【Chemistry 2】 [In the formula, In each existing R 1a These are independently D atom, -OH, -COOH, -NH 2 -CN, halogen, C 1～6 Alkyl, C 2～6 Alkinyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Deuterated alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-6 member heteroaryl, C 3～6 Cycloalkyl, C 3～6 Halocycloalkyl, C 3～6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, In each existing R 1b These are independently D atom, -OH, -COOH, -NH 2 -CN, oxo, halogen, C 1～6 Alkyl, C 2～6 Alkinyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Deuterated alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-6 member heteroaryl, C 3～6 Cycloalkyl, C 3～6 Halocycloalkyl, C 3～6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, R 1c These are H atoms, D atoms, -OH, -COOH, -NH 2 -CN, oxo, halogen, C 1～6 Alkyl, C 2～6 Alkinyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Deuterated alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-6 member heteroaryl, C 3～6 Cycloalkyl, C 3～6 Halocycloalkyl, C 3～6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, R 1d These are H atoms, D atoms, -OH, -COOH, -NH 2 -CN, oxo, halogen, C 1～6 Alkyl, C 2～6 Alkinyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Deuterated alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-6 member heteroaryl, C 3～6 Cycloalkyl, C 3～6 Halocycloalkyl, C 3～6 Selected from the group consisting of cycloalkyl-O- and 5- to 7-membered heterocyclines, m is 0, 1, or 2. p is 0, 1, or 2. Ring A, Ring E, R a , R b , R 2 ~R 4 The compound according to claim 1 or 2, wherein n is as defined in claim 1.

4. Ring A is C 6～10 Ariel, C 3～8 Selected from the group consisting of cycloalkyls and 3- to 8-membered heterocyclines, ring A has one or more R 1 It is replaced in some cases, R 1 This is as defined in claim 1, in particular, Ring A is selected from the group consisting of phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, cubanil, piperidyl, pyranil, pyrrolidinyl, piperazinyl, and morpholinil, and ring A is one or more R 1b It is replaced in some cases, R 1b This is as defined in claim 3, More specifically, Ring A is selected from the group consisting of phenyl, cyclohexyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, and cubanyl, and ring A is one or more R 1b It is replaced in some cases, R 1b The compound according to any one of claims 1 to 3, wherein the compound is as defined in claim 3. 【Request Item 5】 【Chemistry 3】 but, 【Chemistry 4】 A compound according to any one of claims 1 to 4, selected from the group consisting of the following.

6. Ring E is C 6～10 It is an aryl or 5-6 member heteroaryl with one or more rings E and R 1 It is replaced in some cases, R 1 This is as defined in claim 1, in particular, Ring E is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, and isoxazolyl, and ring E is one R 1c and one R 1d It is replaced in some cases, R 1c and R 1d This is as defined in claim 3, More specifically, Ring E is selected from the group consisting of pyridinyl, pyrimidinyl, and imidazolyl, and ring E is one R 1c and one R 1d It is replaced in some cases, R 1c and R 1d This is as defined in claim 3, More specifically, 【Transformation 5】 but, 【Transformation 6】 A compound according to any one of claims 1 to 5, selected from the group consisting of the following:

7. n is either 0 or 1, and / or R a and R b However, each is independent of the H atom, -CN, and C. 1～6 Selected from the group consisting of alkyl, -OH, and halogen, Preferably, R a and R b However, each is independent of the H atom or C 1～6 It is alkyl, Comfortable, R a and R b Both are H atoms, or R a is an H atom, and R b The compound according to any one of claims 1 to 6, wherein is methyl.

8. R 2 However, H atom, -OH, -CN, C 1～6 Alkyl, C 1～6 Alkyl deuterated, C 2～6 Alkinyl, -C 1～6 Alkylene-C 6～10 Ariel, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～6 Selected from the group consisting of cycloalkyl and 5- to 7-membered heterocyclines, Preferably, R 2 However, selected from the group consisting of H atoms, -CN, methyl, and triduteriomethyl, and / or R 3 However, H atom, -OH, -COOH, -NH 2 -CN, halogen, C 1～6 Alkyl, C 2～6 Alkinyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～6 Cycloalkyl-O-, 5-7 membered heterocyclyl and -C 1～6 Alkylene-C(O)-OC 1～6 Selected from the group consisting of alkyl groups, Preferably, R 3 is methoxy or cyclopropyl-O-, and / or R 4 However, H atom, -OH, -COOH, -NH 2 -CN, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy and C 1～6 Selected from the group consisting of hydroxyalkyl groups, Preferably, R 4 The compound according to any one of claims 1 to 7, wherein is a hydrogen atom. 【Request Item 9】 【Chemistry 7A】 【Chem. 7B】 【Chem.7C】 A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. A method for preparing the compound described in claim 1, 【Transformation 8】 The step of reacting a compound of formula (SIA) with a compound of formula (SIB) to obtain a compound of formula (SI), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, L, R a , R b , R 2 ~R 4 and the step in which n is as defined in claim 1, or 【Chemistry 9】 The step involves reacting a compound of formula (SIA) with a compound of formula (SIC) to obtain a compound of formula (SI), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, L, R a , R b , R 2 ~R 4 and the step where n is as defined in claim 1. Methods that include...

11. The compound of formula (SI) is the compound of formula (SII), and the method is, 【Chemistry 10】 The step of reacting a compound of formula (SIIA) with a compound of formula (SIIB) to obtain a compound of formula (SII), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, R a , R b , R 2 ~R 4 , R 1a , R 1b , R 1c , R 1d The steps are as defined in claim 3, or 【Chemistry 11】 The step involves reacting a compound of formula (SIIA) with a compound of formula (SIIC) to obtain a compound of formula (SII), X is a leaving group selected from the group consisting of halogens, sulfonates, boronic acids, and borates. Ring A, Ring B, Ring E, R a , R b , R 2 ~R 4 , R 1a , R 1b , R 1c , R 1d Steps where m, n, and p are as defined in claim 3. The method according to claim 10, including the method described in claim 10.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and one or more pharmaceutically acceptable excipients.

13. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 12 in the preparation of a pharmaceutical for treating or preventing a disease or condition associated with inhibition of ubiquitin-specific protease 1 (USP1).

14. The use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 12 in the preparation of a pharmaceutical for treating or preventing cancer, Specifically, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

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