Pyrimidine compounds, processes for preparing same, and pharmaceutical uses thereof

Abstract

Provided are compounds of general formula (I'), processes for their preparation, pharmaceutical compositions containing them, and their use as ubiquitin-specific protease 1 (USP1) inhibitors, in particular in the treatment or prevention of cancer. JPEG2025515319000346.jpg36170

Description

[Technical Field]

[0001] The present invention relates to compounds having USP1 inhibitory activity, compositions thereof, and their use in the preparation of medicaments for treating USP1 enzyme-related diseases. In particular, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof: [Background technology]

[0002] Ubiquitination is a dynamic and reversible process involving the deubiquitinating enzyme (DUB) family. Approximately 100 DUBs exist in the human body, which can be divided into the cysteine ​​protease family and the metalloprotease family. Among these, the cysteine ​​protease family primarily includes ubiquitin-specific proteases (USPs), ubiquitin carboxyl-terminal hydrolases (UCHs), Machado Josephin domain proteases (MJDs), MINDY proteases (MINDYs), and ovarian tumor domain proteases (OTUs). The USP family is the largest known deubiquitinating enzyme family, with over 50 members encoded by human genes. By regulating substrate proteases, the USP family plays a role in various physiological functions, such as cell cycle, signal transduction, DNA damage repair, chromosomal translocation, and gene transcription.

[0003] USP1 belongs to the USP subfamily of DUBs. Although USP1 does not possess significant activity by itself, it acquires full enzymatic activity after binding to UAF1 to form a heterodimeric complex (USP1 / UAF1), thereby regulating cellular targets in numerous pathways related to cancer. For example, the USP1 / UAF1 complex deubiquitinates monoubiquitinated proliferating cell nuclear antigen (PCNA), a key protein in the translesion synthesis (TLS) process, thereby preventing excessive repair of the TLS process. It also deubiquitinates monoubiquitinated Fanconi anemia complementation group D2 (FAND2), a key protein in the Fanconi anemia (FA) pathway, thereby preventing cells from performing inappropriate TLS repair, thereby ensuring genome stability. These two DNA damage response (DDR) pathways are the primary pathways for repairing DNA damage induced by DNA cross-linking agents, such as cisplatin, mitomycin, and ultraviolet light. USP1 also interacts with ID proteins and stabilizes their expression in cells through deubiquitination. For example, in osteosarcoma cells, USP1 deubiquitinates ID1, ID2, and ID3, promoting cell proliferation. Inhibition of USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. In addition, experiments have shown that USP1 is closely related to the development of drug resistance to various tumor treatment drugs. For example, USP1 expression is high in cisplatin-resistant non-small cell lung cancer (NSCLC) cells, and knockdown of USP1 significantly enhances the sensitivity of these cells to cisplatin. High expression of USP1 in breast cancer cells promotes breast cancer cell proliferation and is closely associated with poor prognosis.A literature study (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 Non-Small Cell Lung Cancer) has reported that USP1 inhibitors, such as the ML323 compound, can be used to treat non-small cell lung cancer. Another literature study (Cui SZ, Lei ZY, Guan TP et al., Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020; 00:1-15) has reported that USP1 inhibitors can be used as promising drugs against prostate cancer. In summary, USP1 is expected to become 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 SZ, Lei ZY, Gua nT-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 problem]

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

[0006] [ka]

[0007] or a pharmaceutically acceptable salt, hydrate, solvate, isotopic substitute or stereoisomer thereof [In the formula, R is C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 C fused with aryl, 5-10 membered heteroaryl 6~10 aryl, and

[0008] [ka]

[0009] wherein each of the above groups is independently optionally substituted with one or more R1; Ring A and ring B each independently represent C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 and R1 is selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclyl, wherein ring A and ring B are each independently optionally substituted with one or more R1; L is 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 alkylene-S-; R a and R b are each independently a H atom, -CN, or C 1~6 Alkyl, -OH, halogen, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxy, or R a and R b Together, Oxo, C 3~8 forming a cycloalkyl or a 3- to 8-membered heterocyclyl; R2 is H atom, -OH, -CN, C 1~6 Alkyl, -C 1~6 Alkyl-C 6~10 Aryl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 heterocyclyl; 1~6 Alkyl and -C 1~6 Alkyl-C 6~10 each aryl is optionally substituted with one or more R1; 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, C2~6 Alkenyl, C 2~6 Alkynyl, 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, 3- to 8-membered heterocyclyl and -C 1~6 Alkylene-C(O)-OC 1~6 alkyl, -NH2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 and 3- to 8-membered heterocyclyl are each independently optionally substituted by one or more R1; R4 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 heterocyclyl; or R2 and R3 together with the atoms to which they are attached form a ring C, wherein ring C is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, wherein the heteroatom of the 5- to 7-membered heteroaryl or the 5- to 7-membered heterocyclyl is O or N, and wherein the 5- to 7-membered heterocyclyl is selected from the group consisting of morpholinyl, 3-morpholinonyl, pyrrolidinyl, 2-oxazolidinonyl, and 2-pyrrolidinonyl, and ring C is optionally substituted with one or more R1; or R3 and R4 together with the atoms to which they are attached form a ring D, wherein ring D is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, and ring D is optionally substituted with one or more R1; R5 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, C fused with 5- to 10-membered heteroaryl 6~10 C fused with aryl, 3-8 membered heterocyclyl 6~10 Aryl, C 3~8 selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 and 3- to 8-membered heterocyclyl are each independently optionally substituted by one or more R1; R1 in each occurrence is independently a D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, C 1~6 Alkyl, C 2~6 Alkynyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl and -OC 1~6 Alkylene-OC 1~6 alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently selected from D atom, —OH, —COOH, —NH, —CN, halogen, 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; and n is an integer from 0 to 8.

[0010] In some embodiments, the compound of formula (I') has formula (I):

[0011] [ka]

[0012] [In the formula, ring A, ring B, L, R a , R b , R2 to R5 and n are as defined in formula (I').

[0013] In some embodiments, in the compound of Formula (I') or (I): R2 is H atom, -OH, -CN, C 1~6 Alkyl, C 2~6 Alkynyl, -C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C1~6 Hydroxyalkyl, C 3~6 selected from the group consisting of cycloalkyl and 5- to 7-membered heterocyclyl; 1~6 Alkyl and -C 1~6 Alkyl-C 6~10 Each aryl is optionally substituted with one or more R1, where R1 is as defined in formula (I'); Preferably, R2 is selected from the group consisting of an H atom, -CN, methyl, trideuteriomethyl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy and hydroxy; R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, 5- to 7-membered heterocyclyl and -C 1~6 Alkylene-C(O)-OC 1~6 alkyl, C 1~6 The hydroxyalkyl and 5- to 7-membered heterocyclyl each independently represent one or more C 1~6 optionally substituted with alkyl; Preferably, R3 is an H atom, methoxy, trifluoromethyl, Cl atom, -CN, isopropoxy, ethynyl, difluoromethoxy, morpholinyl,

[0014] [ka]

[0015] -OH,

[0016] [ka]

[0017] F atoms, hydroxymethyl and

[0018] [ka]

[0019] is selected from the group consisting of R4 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 hydroxyalkyl; Preferably, R4 is an H atom.

[0020] In some embodiments, the compound of formula (I') or (I) has formula (II):

[0021] [ka]

[0022] wherein ring C is

[0023] [ka]

[0024] is selected from the group consisting of R6 in each occurrence is independently H or C 1~6 alkyl, or two R6 together with the atoms to which they are attached form C 3~8 forming a cycloalkyl or a 3- to 8-membered heterocyclyl; Ring A, Ring B, L, R a , R b , R4, R5 and n are as defined in formula (I'), especially, R4 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C1~6 Haloalkoxy and C 1~6 hydroxyalkyl, preferably R4 is an H atom.

[0025] In some embodiments, the compound of formula (I') is a compound of formula (III):

[0026] [ka]

[0027] wherein ring D is

[0028] [ka]

[0029] is selected from the group consisting of each of the above groups is independently optionally substituted with one or more R1; R, R a , R b , R1, R2, R5 and n are as defined in formula (I'), In particular, R2 is an H atom, -OH, C 1~6 Alkyl, C 2~6 Alkynyl, -C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 hydroxyalkyl, C 1~6 Alkyl or -C 1~6 Alkyl-C 6~10 Each aryl is optionally substituted with one or more R1, where R1 is as defined in formula (I'); Preferably, R2 is a H atom or

[0030] [ka]

[0031] is] is.

[0032] In some embodiments, in the compound of Formula (I'), (I), (II) or (III): Ring A and ring B each independently represent 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]pyrazinyl, piperidine-2,6-dionyl, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, or morpholinyl. wherein R is selected from the group consisting of aryl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indolinonyl, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, and cubanyl; wherein Ring A and Ring B are each independently optionally substituted with one or more R, wherein R is as defined in formula (I'); L is a chemical bond, -O-, -OC 1~6 Alkylene- and -C 1~6 alkylene-O-; especially,

[0033] [ka]

[0034] teeth,

[0035] [ka]

[0036] wherein ring A and ring B are each independently optionally substituted with one or more R1, wherein R1 is as defined in formula (I'); More particularly,

[0037] [ka]

[0038] teeth,

[0039] [ka]

[0040] [ka]

[0041] is selected from the group consisting of:

[0042] In some embodiments, in the compound of Formula (I'), R is C 6~10 C fused with aryl or 5-6 membered heteroaryl 6~10 aryl, each of which independently represents oxo, C 1~6 Alkyl and -OC 1~6 Alkylene-OC 1~6 optionally substituted with one or more substituents selected from the group consisting of alkyl; In particular, R is

[0043] [ka]

[0044] and R2 is H atom, -OH, C 1~6 Alkyl, C 2~6 Alkynyl, -C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkoxy, C1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 hydroxyalkyl, preferably R2 is an H atom; R3 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 hydroxyalkyl, preferably R3 is methoxy; R4 is H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy and C 1~6 hydroxyalkyl, preferably R4 is an H atom or Alternatively, R3 and R4 together with the atoms to which they are attached form ring D, and ring D is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, preferably furanyl.

[0045] In some embodiments, in the compound of Formula (I'), (I), (II) or (III): R5 is C 6~10 C fused with aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl 6~10 C fused with aryl and 5-6 membered heteroaryl 6~10 aryl, preferably selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indolinyl and isoxazolyl; 6~10 C fused with aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl 6~10 C fused with aryl and 5-6 membered heteroaryl 6~10 Aryl is independently -OH, -COOH, -NH2, -CN, halogen, C 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, 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; In particular, R5

[0046] [ka]

[0047] is selected from the group consisting of:

[0048] In some embodiments, n is 0 or 1 in the compound of Formula (I'), (I), (II) or (III).

[0049] In some embodiments, in the compound of Formula (I'), (I), (II), or (III), R a and R b are each independently a H atom, -CN, or C 1~6 selected from the group consisting of alkyl, —OH, and halogen; Preferably, R a and R b are each independently an H atom or —CN.

[0050] Exemplary compounds of formula (I) or (I') of the present invention include, but are not limited to, the following compounds:

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] Includes.

[0062] The present invention also provides a method for preparing a compound of formula (I'), comprising the following steps:

[0063] [ka]

[0064] 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 halogen, sulfonate, boronic acid, and borate; R, R a , R b , R2 to R5 and n are as defined in formula (I'), or

[0065] [ka]

[0066] 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 halogen, sulfonate, boronic acid, and borate; R, R a , R b , R2 to R5 and n are as defined in formula (I'), or

[0067] [ka]

[0068] 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 halogen, sulfonate, boronic acid, and borate; 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 hydroxy; R, R a , R b , R3 to R5 and n are as defined in formula (I'), or

[0069] [ka]

[0070] reacting a compound of formula (IG') with a compound of formula (ID) to obtain a compound of formula (IH'), and deprotecting the compound of formula (IH') to obtain a compound of formula (I'); X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, and borate; 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 hydroxy; R, R a , R b , R3 to R5 and n are as defined in formula (I'), or

[0071] [ka]

[0072] 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 halogen, sulfonate, boronic acid, and borate; R, R a , R b wherein R2 to R5 and n are as defined in formula (I'). The present invention provides a method comprising:

[0073] The present invention provides a process for preparing a compound of formula (I), comprising the following steps:

[0074] [ka]

[0075] 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 halogen, sulfonate, boronic acid, and borate; Ring A, Ring B, L, R a , R b , R2 to R5 and n are as defined in formula (I'), or

[0076] [ka]

[0077] 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 halogen, sulfonate, boronic acid, and borate; Ring A, Ring B, L, R a , R b , R2 to R5 and n are as defined in formula (I'), or

[0078] [ka]

[0079] 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 halogen, sulfonate, boronic acid, and borate; 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 hydroxy; Ring A, Ring B, L, R a , R b, R3 to R5 and n are as defined in formula (I'), or

[0080] [ka]

[0081] reacting a compound of formula (IG) with a compound of formula (ID) to obtain a compound of formula (IH), and deprotecting the compound of formula (IH) to obtain a compound of formula (I), X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, and borate; 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 hydroxy; Ring A, Ring B, L, R a , R b , R3 to R5 and n are as defined in formula (I'), or

[0082] [ka]

[0083] 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 halogen, sulfonate, boronic acid, and borate; Ring A, Ring B, L, R a , R b wherein R2 to R5 and n are as defined in formula (I'). Also provided is a method comprising:

[0084] The present invention also provides pharmaceutical compositions comprising at least one compound of formula (I'), (I), (II) or (III), and one or more pharmaceutically acceptable excipients.

[0085] The present invention relates to the use of a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising the same in the preparation of a medicament for treating or preventing a disease or condition associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0086] The present invention relates to the use of a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising the same in the preparation of a medicament for treating or preventing cancer, particularly when 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.

[0087] The present invention relates to a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising same for use as a medicament.

[0088] The present invention relates to a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising same for use in the treatment or prevention of diseases or conditions associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0089] The present invention relates to a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising the same for use in the treatment or prevention of cancer, in particular, a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising the same, wherein 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.

[0090] 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 to a patient in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (II) or (III) or a pharmaceutical composition comprising same.

[0091] The present invention 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) or (III) or a pharmaceutical composition comprising same to a patient in need thereof, particularly wherein 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.

[0092] The pharmaceutical compositions of the present invention can be in a variety of 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 methods.

[0093] It is well known to those skilled in the art that the dosage of a drug depends on various factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's general health condition, the patient's behavior, the patient's diet, the administration time, the administration route, the excretion rate, concomitant drug use, etc. In addition, the optimal treatment, e.g., the treatment mode, the daily dose of the compound or the type of pharmaceutically acceptable salt thereof, can be verified according to conventional treatment regimens.

[0094] Definition of Terms Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings: Any particular term or phrase not specifically defined is not to be considered vague or indefinite and is to be understood in accordance with its ordinary meaning.

[0095] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0096] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound of the present invention having a specific substituent and a relatively non-toxic acid or base. When a 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 in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a 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 in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts (inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.) and organic acid salts (organic acids include, for example, 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, methanesulfonic acid, etc.), as well as salts of amino acids (e.g., arginine, etc.) 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 or acid addition salt.

[0097] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural difference can be in configuration (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0098] The term "optionally" or "optionally" means that the subsequently described event or aspect may, but need not, occur, and that such description includes circumstances in which the event or aspect occurs or circumstances in which the event or aspect does not occur.

[0099] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For purposes of this application, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0100] As used herein, the terms "disease" or "disorder" or "condition" refer to a condition for which treatment is necessary and / or desirable, and refer to disorders and / or abnormalities generally considered to be pathological conditions or functions, which may manifest themselves in the form of specific signs, symptoms, and / or dysfunctions. The compounds of the present invention inhibit the USP1 protein and are useful for treating diseases and conditions, such as proliferative disorders, for which inhibition of the USP1 protein would be beneficial.

[0101] "USP1" and "ubiquitin-specific processing protease 1" refer to any naturally occurring polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses unprocessed "full-length" USP1 polypeptides as well as all forms of USP1 generated by intracellular processing (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein can be isolated from various sources, e.g., human tissue types or from another source, or prepared by recombinant or synthetic methods.

[0102] The terms "cancer" and "tumor" refer to or describe a physiological condition in a mammal in which a population of cells is characterized by unregulated cell growth. The terms include solid cancers and hematologic / 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). The cancer can be BRCA1 or BRCA2 wild-type. The cancer can also be BRCA1 or BRCA2 mutant. The cancer can also be PARP inhibitor-resistant or refractory cancer, or PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0103] When any variable (e.g., R) occurs more than one time in the structures of compounds, its definition is independent at each occurrence. For example, if a group is substituted with 0 to 2 R, the group may also be optionally substituted with up to 2 R, and R has an independent option at each occurrence.

[0104] 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. Alkyl is preferably C 1~10 alkyl, more preferably C 1~6 Examples of alkyl include, but are not limited to, 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, 2,4-dimethylbutyl, 2,4-dimethylpentyl, 2,5-dimethylbutyl, 2,6-dimethylbutyl, 2,7-dimethylbutyl, 2,8-dimethylbutyl, 2,9-dimethylbutyl, 2,10-dimethylbutyl, 2,11-dimethylbutyl, 2,12-dimethylbutyl, 2,13-dimethylbutyl, 2,14-dimethylbutyl, 2,15-dimethylbutyl, 2,16-dimethylbutyl, 2,17-dimethylbutyl, 2,18-dimethylbutyl, 2,19 ... Examples of alkyl ethers include ethylpentyl, 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.

[0105] The term "alkenyl" refers to a linear or branched 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, which may be located anywhere within the alkenyl. Alkenyl is preferably C 2~5 Examples of alkenyl include, but are not limited to, -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.

[0106] The term "alkynyl" refers to a linear or branched 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, which may be located anywhere within the alkynyl. Alkynyl is preferably C 2~5 Examples of alkynyl include, but are not limited to, -C≡CH, -C≡C-CH, -CH-C≡CH, -C≡C-CH-CH, -CH-CH-C≡CH, -CH(CH)C≡CH, and -CH-C≡C-CH.

[0107] The term "cycloalkyl" encompasses two categories: conventional cycloalkyls and heterostructured cycloalkyls.

[0108] Conventional cycloalkyl refers to an aliphatic saturated or partially unsaturated monovalent cyclic hydrocarbon group 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. Conventional cycloalkyl is preferably C 3~12 is a conventional cycloalkyl of the formula C, more preferably C 3~10 and more preferably C 3~8 is a conventional cycloalkyl of the formula C, most preferably C 3~6 A conventional cycloalkyl optionally contains one or more double or triple bonds.

[0109] Conventional cycloalkyls can be monocyclic cycloalkyls. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Conventional cycloalkyls can also be polycyclic cycloalkyls (e.g., bicycloalkyl, tricycloalkyl, tetracycloalkyl, and pentacycloalkyl). Polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0110] 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. The spirocycloalkyl is preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. The spirocycloalkyl can be a monospirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, and the spirocycloalkyl is 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 include, but are not limited to:

[0111] [ka]

[0112] Examples include:

[0113] The term "fused cycloalkyl" 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) fused cycloalkyl. The fused cycloalkyl is preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl. The fused cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher fused cycloalkyl, and the fused cycloalkyl is preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered, or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyls include, but are not limited to:

[0114] [ka]

[0115] Examples include:

[0116] The term "bridged cycloalkyl" 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) bridged cycloalkyl. The bridged cycloalkyl is preferably a 6- to 14-membered bridged cycloalkyl, more preferably a 7- to 10-membered bridged cycloalkyl. The bridged cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic or higher bridged cycloalkyl, and the bridged cycloalkyl is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyls include, but are not limited to:

[0117] [ka]

[0118] Examples include:

[0119] The term "heterostructured cycloalkyl" includes monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls fused to any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional heterocyclyls, where the point of attachment is at the corresponding conventional cycloalkyl (see monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, or bridged cycloalkyls). Examples of heterostructured cycloalkyls include, but are not limited to:

[0120] [ka]

[0121] Examples include:

[0122] The term "heterocyclyl" encompasses two categories, one being conventional heterocyclyl and the other being heterostructured heterocyclyl.

[0123] Conventional heterocyclyl refers to an aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon group 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, in which 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 the replacements do not form -OO-, -OS-, or -SS-. Conventional heterocyclyl is preferably C 3~12 and a conventional heterocyclyl of the formula: 3~8 and conventional heterocyclyl, in which 1 to 3 (e.g., 1, 2, and 3) atoms are heteroatoms, most preferably C 5~7 and a conventional heterocyclyl in which 1 to 2 or 1 to 3 atoms are heteroatoms.

[0124] Conventional heterocyclyls can be monocyclic heterocyclyls. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Conventional heterocyclyls can also be polycyclic heterocyclyls. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0125] The term "spiroheterocyclyl" 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) spiroheterocyclyl. The spiroheterocyclyl is preferably a 6- to 14-membered spiroheterocyclyl, more preferably a 7- to 10-membered spiroheterocyclyl. The spiroheterocyclyl can be a monospiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl, and the spiroheterocyclyl is preferably a monospiroheterocyclyl or a dispiroheterocyclyl, more preferably a 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Examples of spiroheterocyclyl include, but are not limited to:

[0126] [ka]

[0127] Examples include:

[0128] The term "fused heterocyclyl" 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) fused heterocyclyl. The fused heterocyclyl is preferably a 6- to 14-membered fused heterocyclyl, more preferably a 7- to 10-membered fused heterocyclyl. The fused heterocyclyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher fused heterocyclyl, and is preferably a bicyclic or tricyclic fused heterocyclyl, more preferably a 5-membered / 5-membered, or 5-membered / 6-membered, bicyclic fused heterocyclyl. Examples of fused heterocyclyls include, but are not limited to:

[0129] [ka]

[0130] Examples include:

[0131] The term "bridged heterocyclyl" refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) bridged heterocyclyl. The bridged heterocyclyl is preferably a 6- to 14-membered bridged heterocyclyl, more preferably a 7- to 10-membered bridged heterocyclyl. The bridged heterocyclyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic or higher bridged heterocyclyl, and is preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Examples of bridged heterocyclyls include, but are not limited to:

[0132] [ka]

[0133] Examples include:

[0134] The term "heterostructured heterocyclyl" includes monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl fused to any one selected from the group consisting of conventional aryl, conventional heteroaryl, and conventional cycloalkyl, where the point of attachment is on the corresponding conventional heterocyclyl (see monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl, or bridged heterocyclyl). Examples of heterostructured heterocyclyl include, but are not limited to:

[0135] [ka]

[0136] Examples include:

[0137] The term "aryl" encompasses two categories: conventional aryls and heterostructured aryls.

[0138] Conventional aryl refers to a 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group. Conventional aryl is preferably C 6~10 It is a conventional aryl, more preferably phenyl, naphthyl, phenanthryl or anthracenyl.

[0139] The term "heterostructured aryl" includes a conventional aryl fused to any one selected from the group consisting of a conventional heteroaryl, a conventional heterocyclyl, and a conventional cycloalkyl, where the point of attachment is on the conventional aryl. Examples of heterostructured aryls include, but are not limited to:

[0140] [ka]

[0141] Examples include:

[0142] The term "heteroaryl" encompasses two categories: conventional heteroaryls and heterostructured heteroaryls.

[0143] Conventional heteroaryl refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group in which 1 to 4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, and N. Preferably, the number of ring atoms is 5 to 10, including 1 to 3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, including 1 to 2 heteroatoms. Examples of conventional heteroaryl include, but are not limited to, 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.

[0144] The term "heterostructured heteroaryl" includes a conventional heteroaryl fused to any one selected from the group consisting of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclyl, where the point of attachment is on the conventional heteroaryl. Examples of heterostructured heteroaryls include, but are not limited to:

[0145] [ka]

[0146] Examples include:

[0147] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, where "alkyl" and "cycloalkyl" are defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0148] The term "haloalkyl" refers to alkyl substituted with one or more halogens, where alkyl is as defined above.

[0149] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0150] The term "hydroxy" refers to the group --OH.

[0151] The term "halogen" refers to a -F, -Cl, -Br or -I group.

[0152] The term "amino" refers to the group --NH.sub.2.

[0153] The term "cyano" refers to the group --CN.

[0154] The term "nitro" refers to the group --NO.sub.2.

[0155] The term "oxo" refers to the group =O.

[0156] The term "carboxy" refers to the group -C(=O)OH.

[0157] The term "thiol" refers to the group --SH.

[0158] The term "alkoxycarbonyl" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0159] The term "acyl" refers to the group -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0160] The term "hydroxy protecting group" refers to a group that is installed on a hydroxy and used to block or protect the hydroxy while being easily removed and reacting with other functional groups in the compound. 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, p-nitrobenzoyl, and the like.

[0161] symbol"

[0162] [ka]

[0163] " refers to the point of attachment.

[0164] The term "stereoisomer" refers to isomers that have the same constitution but differ in the arrangement of atoms in space. Stereoisomers include cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present invention can have additional asymmetric atoms. All of these stereoisomers and mixtures thereof are included 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 compounds of the present invention can be prepared by asymmetric synthesis or chiral auxiliaries, or, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, diastereoisomeric salts can be formed therefrom with an appropriate optically active acid or base, and the diastereoisomers can then be separated by conventional methods known in the art to give the pure isomers. Additionally, resolution of enantiomers and diastereomers is commonly achieved by chromatography.

[0165] In the chemical structures of the compounds described in this invention, the bond "

[0166] [ka]

[0167] " indicates an unspecified configuration, i.e., if chiral isomers exist in the chemical structure, the bond "

[0168] [ka]

[0169] "teeth,"

[0170] [ka]

[0171] " or "

[0172] [ka]

[0173] " or "

[0174] [ka]

[0175] "and"

[0176] [ka]

[0177] For all carbon-carbon double bonds, both the Z and E configurations are included, even if only one configuration is named.

[0178] The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted via 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, lactam-lactam isomerization.

[0179] The compounds of the present invention include all suitable isotopic substitutes of the compounds. The term "isotopic substitute" refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as: 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 and 131 I, etc., preferably containing deuterium.

[0180] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0181] The term "about" applies to parameters such as pH, concentration, temperature, etc., and it is intended that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As one of skill in the art will recognize, where a parameter is not critical, numbers are generally given for purposes of illustration only and not limitation. DETAILED DESCRIPTION OF THE INVENTION

[0182] The present invention is described in detail below by way of example, but is not intended to limit the invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.

[0183] The compounds of the present invention are prepared by using convenient starting materials and general preparation procedures. The present invention provides typical or preferred reaction conditions of reactants, such as reaction temperature, time, solvent, pressure, and molar ratio. However, unless otherwise specified, other reaction conditions can also be adopted. Although optimal conditions may vary depending on the use of specific reactants or solvents, the optimization steps and conditions of the reaction can be determined under normal circumstances.

[0184] In addition, certain protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are well known to those skilled in the art.

[0185] Isolation and purification of compounds and intermediates can be carried out according to specific needs by suitable methods and steps, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. The specific methods used can be referenced to the examples described in the present invention. Of course, other similar isolation and purification methods can also be used. They can be characterized using conventional methods (including physical constants and spectral data).

[0186] The purity analysis method is as follows: a Kinetex EVO C18 (50 × 4.6 mm, 5 μm, 100 Å) chromatography column is used, acetonitrile-water is used as the mobile phase for gradient elution, the flow rate is 1.5 mL / min, and the detection wavelength is 220 nm.

[0187] MS was determined by LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole type) mass spectrograph (manufacturer: Agilent) (photodiode array detector).

[0188] The structure of the compound was identified by hydrogen nuclear magnetic resonance, and the instrument model was WNMR-I-400MHz.

[0189] Preparative liquid chromatography was performed on an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent). The chromatography column was Daisogel C18 10 μm 100A (30 mm×250 mm) and the mobile phase was acetonitrile / water.

[0190] GF254 silica gel plates from Qingdao Haiyang Chemical Company were used for thin-layer silica gel chromatography (TLC). The dimensions of the silica gel plates used for TLC were 0.20 mm to 0.25 mm, and the dimensions of the silica gel plates used for product purification were 0.5 mm.

[0191] Silica gel of 100-200 mesh, 200-300 mesh or 300-400 mesh from Qingdao Haiyang Chemical Company is used as the carrier for gel column chromatography.

[0192] The known starting materials of the present invention can be prepared by methods known in the art or can be purchased from Wanghua Mall Co., Ltd., Beijing Ouhe Technology Co., Ltd., Sigma Co., Ltd., J & K Scientific Co., Ltd., Yishiming Co., Ltd., Shanghai Shuya Chemical Co., Ltd., Shanghai Innochem Science & Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Bide Pharmatech Co., Ltd., etc.

[0193] Unless otherwise stated, reactions are carried out under a nitrogen atmosphere.

[0194] Nitrogen atmosphere means that the reaction flask is equipped with a nitrogen balloon (approximately 1 L).

[0195] Reaction solvents, organic solvents or inert solvents are each expressed as solvents used that do not participate in the reaction under the reaction conditions described, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, N-methylpyrrolidone (NMP).

[0196] Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0197] The chemical reactions described in this invention are generally carried out under standard pressure. The reaction times and conditions are, for example, between -78°C and 200°C at 1 atmosphere, and are completed within about 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.

[0198] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0199] Unless otherwise stated, the mixing ratios of different solvents are by volume.

[0200] The following introduces the synthesis of common intermediates including the A series, AA series, B series, BB series, C series, D series, and BBC series, as well as the BBD series, which is further synthesized from the BB series and C series or D series.

[0201] Synthesis of General Intermediate A1 (2-(2-Isopropylphenyl)-5-methoxypyrimidin-4-amine)

[0202] [ka]

[0203] 2-Chloro-5-methoxypyrimidin-4-amine (Compound A1-1, 5.0 g, 31.3 mmol, 1.00 equiv.), (2-isopropylphenyl)boronic acid (Compound A1-2, 6.7 g, 40.7 mmol, 1.30 equiv., purchased from Bide Pharmatech), potassium carbonate (13.0 g, 94.0 mmol, 3.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (2.3 g, 3.13 mmol, 0.10 equiv.) were sequentially added to dioxane (50.0 mL) and water (12.5 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 16 hours. Ethyl acetate (500.0 mL) was then added, and the resulting mixture was stirred for 10 minutes and filtered. The resulting filtrate was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH H O) to give compound A1 (4.9 g, 63.3% yield, 98.2% purity) 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) + .

[0204] Synthesis of general intermediate A2 (4'-cyclopropyl-5,6'-dimethoxy-N-methyl-[2,5'-bipyrimidine]-4-amine)

[0205] [ka]

[0206] Step 1: Synthesis of compound A2-3 (6-cyclopropylpyrimidin-4-ol) Compound A2-1 (200.0 g, 1.4 mol, 1.00 eq) and compound A2-2 (292.0 g, 2.81 mol, 2.00 eq) were added sequentially to methanol (1.2 L), and a solution of sodium methoxide in methanol (5.4 M, 1.3 L, 5.00 eq) was added portionwise at 0 °C. After the addition was complete, the reaction mixture was heated to 20 °C and stirred for 13 h. Then, glacial acetic acid was added at 0 °C to adjust the pH to 7-8. The resulting mixture was concentrated under vacuum to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound A2-3 (90.3 g). LC-MS: m / z = 137.1 (M+H). + .

[0207] Step 2: Synthesis of compound A2-4 (4-chloro-6-cyclopropylpyrimidine) Compound A2-3 (40.0 g, 293.0 mmol, 1.00 equiv) was added portionwise to phosphorus oxychloride (180.0 mL). After the addition was complete, the reaction was heated to 60° C. and stirred for 2 hours. The reaction mixture was concentrated in vacuo to give 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 give the filtrate. The filtrate was concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give compound A2-4 (11.0 g). LC-MS: m / z = 155.0 (M+H). + .

[0208] Step 3: Synthesis of compound A2-5 (5-bromo-4-chloro-6-cyclopropylpyrimidine) Compound A2-4 (11.0 g, 71.1 mmol, 1.00 equiv) was dissolved in methanol (150.0 mL) and bromine (34.1 g, 213.0 mmol, 3.00 equiv) was slowly added at -60 °C. After the addition was complete, the reaction mixture was heated to 20 °C and stirred for 2 h. Saturated sodium bicarbonate solution (200.0 mL) and water (100.0 mL) were then added at 0 °C. The resulting mixture was stirred for 5 min 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 to 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) + .

[0209] Step 4: Synthesis of compound A2-6 (5-bromo-4-cyclopropyl-6-methoxypyrimidine) Compound A2-5 (7.8 g, 33.4 mmol, 1.00 equiv.) was dissolved in methanol (240 mL) and sodium methoxide (18.0 g, 100.0 mmol, 3.00 equiv.) was added at 0 °C. After the addition was complete, the reaction mixture was heated to 30 °C and stirred for 1 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give compound A2-6 (7.3 g). LC-MS: m / z = 228.9 (M+H). + .

[0210] Step 5: Synthesis of compound A2-7 ((4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid) Compound A2-6 (10.3 g, 44.9 mmol, 1.00 equiv.) and triisopropyl borate (11.8 g, 62.9 mmol, 1.40 equiv.) were dissolved in tetrahydrofuran (30.0 mL) and toluene (90.0 mL), and n-butyllithium (2.5 M, 25.1 mL, 1.40 equiv.) was added dropwise at −70°C. After the addition was complete, the reaction was stirred at −70°C for 3 h. Then, 1N hydrochloric acid solution (50.0 mL) was added dropwise at −70°C. After the addition was complete, the reaction was heated to 20°C and stirred for 0.5 h. Saturated aqueous sodium bicarbonate solution was then 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, and filtered to obtain the filtrate. It was concentrated in vacuo to give 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).

[0211] Step 6: Synthesis of intermediate A2 Compound A2-8 (1.2 g, 6.9 mmol, 1.0 equiv.), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (505.0 mg, 0.7 mmol, 0.10 equiv.), and potassium carbonate (2.9 g, 20.7 mmol, 3.00 equiv.) were added sequentially to dioxane (100.0 mL) and water (25.0 mL), and the resulting mixture was purged with nitrogen three times. Compound A2-7 (1.6 g, 8.3 mmol, 1.20 equiv.) 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 mixture was reacted 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 a filtrate. The filtrate was concentrated in vacuo to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 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). + .

[0212] Synthesis of general intermediate A3 (4-chloro-2-(2-isopropylphenyl)-5-nitropyrimidine)

[0213] [ka]

[0214] Step 1: Synthesis of compound A3-3 (2-(2-isopropylphenyl)-4-methoxy-5-nitropyrimidine) Compound A3-2 (3.3 g, 17.4 mmol, 1.00 equiv.), compound A3-1 (5.7 g, 34.8 mmol, 2.00 equiv.), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1.3 g, 1.7 mmol, 0.10 equiv.), and potassium carbonate (4.8 g, 34.8 mmol, 2.00 equiv.) were dissolved in dioxane (30.0 mL) and water (7.0 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was then concentrated under vacuum to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give compound A3-3 (3.2 g). LC-MS: m / z = 274.1 (M+H). + .

[0215] Step 2: Synthesis of compound A3-4 (2-(2-isopropylphenyl)-5-nitropyrimidin-4-ol) Compound A3-3 (2.0 g, 7.3 mmol, 1.00 equiv) was dissolved in dioxane (30.0 mL), and hydrobromic acid and glacial acetic acid (6 M, 15.0 mL, 12.30 equiv) were added. After the addition was complete, the reaction was heated to 50° C. and stirred for 1 h. The reaction was then concentrated in vacuo to give crude compound A3-4 (2.0 g), which was used directly in the next step. LC-MS: m / z=260.0 (M+H). + .

[0216] Step 3: Synthesis of intermediate A3 Compound A3-4 (2.0 g, 6.8 mmol, 1.00 equivalents) was added to phosphorus oxychloride (18.0 mL) and reacted at 90° C. for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to give compound A3 (1.0 g, 3.59 mmol, yield 53.1%, purity 99.8%) as a pale yellow oil. LC-MS: m / z = 278.1 (M+H). + .

[0217] Synthesis of general intermediate A4 (2-(2-isopropylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0218] [ka]

[0219] Step 1: Synthesis of compound A4-2 (2-chloro-5-(trifluoromethyl)pyrimidin-4-amine) Compound A4-1 (18.7 g, 86.2 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (20.0 mL), and aqueous ammonia (15.1 g, 129 mmol, 30.0% purity, 1.50 equiv.) was added at 0 °C. After the addition was complete, the reaction mixture was heated to 20 °C and stirred for 16 h. Water (30.0 mL) was then 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) + .

[0220] Step 2: Synthesis of intermediate A4 Compound A4-2 (1.15 g, 5.77 mmol, 1.00 equiv.), compound A4-3 (1.14 g, 6.92 mmol, 1.20 equiv.), potassium carbonate (2.39 g, 17.3 mmol, 3.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (422 mg, 577 μmol, 0.10 equiv.) were sequentially added to dimethyl sulfoxide (12.0 mL) and water (2.5 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give compound A4 (200 mg, 711 μmol, 12.3% yield, 100% purity) 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) + .

[0221] Synthesis of General Intermediate A5 (2-(2-Isopropylphenyl)-5-methoxy-N-methylpyrimidin-4-amine)

[0222] [ka]

[0223] Step 1: Synthesis of compound A5-2 (2-chloro-5-methoxy-N-methylpyrimidin-4-amine) Compound A5-1 (10.0 g, 55.9 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (100.0 mL), and methylamine (2.0 M aqueous methylamine solution, 54.5 mL, 1.95 equiv.) 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, and filtered to obtain the filtrate, which was concentrated in vacuo 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) + .

[0224] Step 2: Synthesis of intermediate A5 Compound A5-2 (3.0 g, 17.3 mmol, 1.00 equiv.), compound A5-3 (3.7 g, 22.5 mmol, 1.3 equiv.), potassium carbonate (7.2 g, 51.8 mmol, 3.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.3 g, 1.7 mmol, 0.10 equiv.) were sequentially added to dioxane (30.0 mL) and water (7.5 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 16 hours. Subsequently, ethyl acetate (500.0 mL) was added and stirred for 10 minutes. The resulting mixture was filtered to obtain the filtrate, which was concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to give compound A5 (4.3 g, 16.3 mmol, 94.4% yield, 96.9% purity) as a brown oil. 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) + .

[0225] Synthesis of General Intermediate A6 (2-(2-Isopropylphenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0226] [ka]

[0227] Step 1: Synthesis of compound A6-2 (4-amino-2-chloropyrimidin-5-ol) Compound A6-1 (15.6 g, 97.8 mmol, 1.00 equiv.) was dissolved in dichloromethane (1.5 L) and boron tribromide (367.0 g, 1.5 mol, 15.0 equiv.) was added slowly at 0 °C. After the addition was complete, the reaction was heated to 20 °C and stirred for 96 hours. Methanol (1.0 L) was then added slowly at 0 °C to quench the reaction. The reaction was concentrated in vacuo to give the crude product. Dichloromethane (200 mL) was added, and the resulting mixture was stirred for 5 minutes and filtered to give a filter cake. The filter cake was dissolved in water (200 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. The resulting mixture was filtered to give a filter cake. This was washed twice with water (50 mL) and concentrated in vacuo to give 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) + .

[0228] Step 2: Synthesis of compound A6-4 (2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine) Compound A6-2 (19.0 g, 130 mmol, 1.00 equiv.), compound A6-3 (28.1 g, 196 mmol, 16.2 mL, 1.50 equiv.), and potassium carbonate (54.1 g, 392 mmol, 3.00 equiv.) were added sequentially to N,N-dimethylformamide (200.0 mL) and reacted at 20 °C for 16 hours to give crude product compound A6-4 (27.2 g). This reaction mixture was used directly in the next step. LC-MS: m / z = 207.8 (M+H). + .

[0229] Step 3: Synthesis of compound A6-5 (2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine) The reaction mixture of compound A6-4 (27.2 g) was heated to 100 °C, stirred for 16 hours, and filtered to obtain a filtrate. Water (800 mL) was added, and the resulting mixture was stirred for 5 minutes and extracted three times with ethyl acetate (300 mL). The organic layers were combined, washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. This was concentrated in vacuo to obtain a crude product. Methyl tert-butyl ether (1000 mL) was added, and the resulting mixture was stirred for 30 minutes and filtered to obtain a filter cake. This was concentrated in vacuo 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) + .

[0230] Step 4: Synthesis of intermediate A6 Compound A6-5 (1.5 g, 8.74 mmol, 1.00 equiv.), compound A6-6 (1.4 g, 8.74 mmol, 1.00 equiv.), potassium carbonate (3.6 g, 26.2 mmol, 3.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (640.0 mg, 874 μmol, 0.10 equiv.) were added sequentially to N,N-dimethylformamide (15.0 mL) and water (3.8 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: Kromasil Eternity XT 250 × 80 mm × 10 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 28% to 58%, 21 min) to obtain compound A6 (1.37 g, 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) + .

[0231] Synthesis of General Intermediate A7 (2-(2-isopropylphenyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0232] [ka]

[0233] Step 1: Synthesis of compound A7-2 (2-chloro-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one) Compound A6-2 (4.00 g, 27.4 mmol, 1.00 equiv.), compound A7-1 (4.66 g, 41.2 mmol, 3.28 mL, 1.50 equiv.), and potassium carbonate (11.4 g, 82.4 mmol, 3.00 equiv.) were added sequentially to N,N-dimethylformamide (50.0 mL) and reacted at 30 °C for 3 h. 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 give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-5 / 1) to give 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) + .

[0234] Step 2: Synthesis of intermediate A7 Compound A7-2 (500.0 mg, 2.69 mmol, 1.00 equiv.), compound A7-3 (574.1 mg, 3.50 mmol, 1.30 equiv.), aqueous potassium phosphate solution (1.5 M, 5.39 mL, 3.00 equiv.), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonato)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (231.1 mg, 269 μmol, 0.100 equiv.) were added sequentially to tetrahydrofuran (25.0 mL). The resulting mixture was purged with nitrogen three times and stirred under a nitrogen atmosphere at 60 °C for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: water (HCl) to ACN; B%: 28% to 48%, 8 min) to give A7 (90.0 mg, 334 μmol, 12.4% yield) as a white solid. LC-MS: m / z = 270.1 (M+H). + .

[0235] Synthesis of General Intermediate A8 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0236] [ka]

[0237] Compound A6-5 (1.50 g, 8.74 mmol, 1.00 equiv.), compound A2-7 (1.70 g, 8.74 mmol, 1.00 equiv.), potassium carbonate (3.62 g, 26.2 mmol, 3.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (640 mg, 874 μmol, 0.10 equiv.) were added sequentially to a mixture of N,N-dimethylformamide (15.0 mL) and water (3.75 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 × 50 mm × 10 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 10% to 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) + .

[0238] Synthesis of general intermediate A9 (4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[0239] [ka]

[0240] Step 1: Synthesis of compound A9-2 (2-chloro-5-methoxy-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine) Compound A9-1 (6.0 g, 37.6 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (60.0 mL), and sodium hydride (3.31 g, 82.7 mmol, 60% purity, 2.20 equiv.) was added portionwise 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 equiv.) was added, and the mixture was stirred at 5° C. for 12 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (40.0 mL) at 0° C. 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 in vacuo 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 (10.3 g). LC-MS: m / z = 400.2 (M+H) + .

[0241] 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 equiv.), compound A2-7 (1.46 g, 7.50 mmol, 1.50 equiv.), aqueous potassium phosphate solution (1.5 M, 10.0 mL, 3.00 equiv.), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonato)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (430 mg, 500 μmol, 0.100 equiv.) were added sequentially to tetrahydrofuran (40.0 mL). The resulting mixture was purged with nitrogen three times and stirred at 80 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (FA) to ACN]; B%: 35% to 65%, 21 min) to give A9-3 (0.9 g). LC-MS: m / z = 514.3 (M+H). + .

[0242] Step 3: Synthesis of intermediate A9 Compound A9-3 (900 mg, 1.75 mmol, 1.00 equiv) was added to trifluoroacetic acid (10.0 mL), heated to 90 °C, and stirred for 12 hours. The reaction mixture was concentrated in vacuo, and saturated aqueous sodium bicarbonate (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 in vacuo to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain A9 (300.0 mg, 62.5% yield, 100% purity) as a white solid. LC-MS: m / z = 274.1 (M+H). + .

[0243] Synthesis of General Intermediate A10 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0244] [ka]

[0245] Compound A7-2 (600 mg, 3.23 mmol, 1.00 equiv.), A2-7 (940 mg, 4.85 mmol, 1.50 equiv.), aqueous potassium phosphate solution (1.5 M, 6.47 mL, 3.00 equiv.), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonato)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (417 mg, 485 μmol, 0.150 equiv.) were added sequentially to tetrahydrofuran (10.0 mL). The resulting mixture was purged with nitrogen three times and stirred under a nitrogen atmosphere at 80 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 40 mm x 15 μm; mobile phase: [water (TFA)-ACN]; B%: 10% to 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). + .

[0246] Synthesis of general intermediate AA3 (1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole)

[0247] [ka]

[0248] 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 equiv.) was dissolved in THF (150 mL), and NaH (4.59 g, 115 mmol, 60% purity, 1.50 equiv.) was added portionwise at 0°C. After the addition was complete, the resulting mixture was heated to room temperature (25°C) and stirred for 1.5 hours. Potassium iodide (14.1 g, 99.5 mmol, 6.19 mL, 1.30 equiv.) was then 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 the addition of 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, and filtered to obtain the filtrate. It was concentrated in vacuo to give 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) + .

[0249] Step 2: Synthesis of intermediate AA3 Compound AA3-2 (4.00 g, 19.0 mmol, 1.00 equiv.), bis(pinacolato)diboron (9.67 g, 38.1 mmol, 2.00 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (1.39 g, 1.90 mmol, 0.100 equiv.), and potassium acetate (3.74 g, 38.1 mmol, 2.00 equiv.) were dissolved in dioxane (40.0 mL) and stirred at an external temperature of 95 °C for 12 hours. Water (80.0 mL) was then 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 in vacuo 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) + .

[0250] Synthesis of general intermediate AA4 ((1-methylindolin-7-yl)boronic acid)

[0251] [ka]

[0252] Step 1: Synthesis of compound AA4-1 (7-bromo-1-methylindole) Compound AA3-2 (6.70 g, 31.8 mmol, 1.00 equiv.) was added to acetic acid (50.0 mL), followed by the addition of sodium cyanoborohydride (16.0 g, 255 mmol, 8.00 equiv.) at 10° C., and the mixture was stirred at 20° C. for 12 hours. 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 was concentrated under vacuum to give compound AA4-1 (8.00 g, crude product) as a brown oil. LC-MS: m / z=212.1 (M+H). + .

[0253] Step 2: Synthesis of intermediate AA4 Compound AA4-1 (500 mg, 2.36 mmol, 1.00 equiv.) and triisopropyl borate (576 mg, 3.06 mmol, 704 μL, 1.30 equiv.) were added to tetrahydrofuran (10.0 mL), and n-butyllithium (2.5 M, 1.23 mL, 1.30 equiv.) was added dropwise at −78° C. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 4 hours. The reaction was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (20 mL) at 0° C. 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 in vacuo to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to give intermediate AA4 (120 mg, 588.45 μmol, 24.96% yield, 86.8% purity) 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) + .

[0254] Synthesis of general intermediate AA5 ((1-isopropyl-4-methyl-1H-imidazol-5-yl)boronic acid)

[0255] [ka]

[0256] 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 equiv) was dissolved in tetrahydrofuran (800 mL), and sodium hydride (7.15 g, 178 mmol, 60% purity, 0.720 equiv) was added portionwise 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 equiv) was added, and the resulting mixture was stirred at 0° C. for 3 hours. The reaction was quenched by the addition of 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, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH H O) to give compound AA5-2 (7.00 g, 34.4 mmol, 46.6% yield) as a brown oil. 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) + .

[0257] Step 2: Synthesis of intermediate AA5 Compound AA5-2 (7.00 g, 34.5 mmol, 1.00 equiv.) and triisopropyl borate (32.4 g, 172 mmol, 39.6 mL, 5.00 equiv.) were added to tetrahydrofuran (150.0 mL), and n-butyllithium (2.50 M, 27.6 mL, 2.00 equiv.) was added dropwise at −78° C. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 4 hours. The reaction was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (200 mL) at 0° C. 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, and filtered to obtain the filtrate, which was concentrated in vacuo to give compound AA5 (6.5 g, crude product) as a yellow solid. 1 LC-MS: m / z = 169.1 (M+H) + .

[0258] Synthesis of general intermediate AA6 (2-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0259] [ka]

[0260] Step 1: Synthesis of compound AA6-2 (2-bromopyridin-3-yl trifluoromethanesulfonate) 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 added sequentially 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 a filtrate. The filtrate was concentrated in vacuo to give compound AA6-2 (2.8 g, crude product) as a pale yellow oil. LC-MS: m / z=305.9 (M+H). + .

[0261] Step 2: Synthesis of compound AA6-3 (2-cyclopropylpyridin-3-yl trifluoromethanesulfonate) Compound AA6-2 (2.5 g), tetrakis(triphenylphosphine)palladium (199 mg), and cyclopropylzinc chloride (0.4 M THF solution, 23 mL) were added sequentially to tetrahydrofuran (15 mL). The resulting mixture was stirred at 70 °C for 3 hours under a nitrogen atmosphere and 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). + .

[0262] Step 3: Synthesis of intermediate AA6 Compound AA6-3 (0.5 g), bis(pinacolato)diboron (0.57 g), potassium carbonate (0.525 g), and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (0.156 g) were added to dioxane (80 mL). The resulting mixture was stirred at 100 °C for 20 hours and 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.

[0263] Synthesis of general intermediate AA7 (2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0264] [ka]

[0265] Step 1: Synthesis of compound AA7-2 (2-isopropylpyridin-3-yl trifluoromethanesulfonate) 2-Isopropylpyridin-3-ol (compound AA7-1, 3.00 g, 21.8 mmol, 1.00 equiv.) 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 equiv.) at 0° C. and stirring 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, and filtered to obtain the filtrate, which was concentrated in vacuo to give 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) + .

[0266] Step 2: Synthesis of compound AA7 Compound AA7-2 (3.62 g, 13.4 mmol, 1.00 equiv.), bis(pinacolato)diboron (6.83 g, 26.8 mmol, 2.00 equiv.), potassium acetate (2.64 g, 26.8 mmol, 2.00 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (983 mg, 1.34 mmol, 0.100 equiv.) were added sequentially to dioxane (60.0 mL). The resulting mixture was stirred at 100 °C for 20 hours and 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 in vacuo 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 oil. 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).

[0267] General Intermediate AA8 ((2-(dimethylamino)phenyl)boronic acid) Intermediate AA8 was purchased from Bide Pharmatech.

[0268] [ka]

[0269] Synthesis of general intermediate AA9 (4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0270] [ka]

[0271] Step 1: Synthesis of compound AA9-2 (4-chloro-1-isopropyl-1H-pyrazole) Compound AA9-1 (50.00 g, 487.70 mmol, 1.00 equiv.), 2-iodopropane (124.36 g, 731.55 mmol, 73.15 mL, 1.50 equiv.), and cesium carbonate (317.80 g, 975.40 mmol, 2.00 equiv.) were added to acetonitrile (500.00 mL) and stirred at 80 °C for 2 h under a N2 atmosphere. The reaction mixture was then filtered to obtain the filtrate. The filtrate was concentrated in vacuo 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 oil. 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) + .

[0272] Step 2: Synthesis of intermediate AA9 Compound AA9-2 (10 g, 69.16 mmol, 1 equiv.) was dissolved in anhydrous tetrahydrofuran (100 mL), and n-butyllithium (2.5 M, 33.19 mL, 1.2 equiv.) was added dropwise at 0 °C. After the addition was complete, the resulting mixture was heated to 25 °C and stirred for 1 h. Isopropyl pinacolyl borate (15.44 g, 82.99 mmol, 16.93 mL, 1.2 equiv.) was added at -78 °C, and the resulting mixture was heated to 25 °C and stirred for 2 h. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (100 mL) at 0 °C. Water (200 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed twice with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Welch Ultimate XB-CN 250 × 70 × 10 μm; mobile phase: [hexane-ethanol]; B%: 1% to 1%, 15 min) to give compound AA9 (6.5 g, 18.33 mmol, yield 26.51%, purity 76.3%) as a pale yellow oil. 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) + .

[0273] General Intermediate AA10 ((2-Cyclopropylphenyl)boronic Acid) Intermediate AA10 was purchased from Bide Pharmatech.

[0274] [ka]

[0275] Synthesis of general intermediate AA11 ((1-isopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0276] [ka]

[0277] 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 equiv.) was dissolved in N,N-dimethylformamide (114 g, 669 mmol, 67.0 mL, 1.00 equiv.). 2-Iodopropane (114 g, 669 mmol, 67.0 mL, 1.00 equiv.) and cesium carbonate (327 g, 1.00 mol, 1.50 equiv.) were added, and the mixture was stirred at an external temperature of 90 °C for 12 h. 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 0 / 1) to obtain compound AA11-2 (120 g, 508 mmol, 75.9% yield) as a colorless, clear 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) + .

[0278] Step 2: Synthesis of compound AA11-3 (1-isopropyl-1H-pyrazol-4-ol) Compound AA11-2 (60.0 g, 254 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (600 mL), followed by the addition of aqueous sodium hydroxide (2.50 M, 203 mL, 2.00 equiv.) and hydrogen peroxide (72.0 g, 635 mmol, 61.0 mL, 30.0% purity, 2.50 equiv.). 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 tetrahydrofuran and extracted three times with dichloromethane / methanol = 10 / 1 (1500 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 AA11-3 (17.5 g, 138 mmol, yield 54.6%) as a pale yellow oil. 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).

[0279] Step 3: Synthesis of compound AA11-4 (1-isopropyl-4-methoxy-1H-pyrazole) Compound AA11-3 (17.5 g, 139 mmol, 1.00 equiv.) was dissolved in N,N-dimethylformamide (350 mL), followed by the addition of cesium carbonate (67.8 g, 208 mmol, 1.50 equiv.) and iodomethane (29.5 g, 208 mmol, 13.0 mL, 1.50 equiv.). The mixture was stirred at room temperature (25 °C) for 3 h. Water (1000 mL) was then 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, 63.3% yield) 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).

[0280] Step 4: Synthesis of compound AA11 Compound AA11-4 (1.00 g, 7.13 mmol, 1.00 equiv) was dissolved in anhydrous tetrahydrofuran (15.0 mL). n-Butyllithium (2.50 M, 4.28 mL, 1.50 equiv) 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 h. Isopropyl pinacolyl borate (2.01 g, 10.8 mmol, 2.2 mL, 1.50 equiv) was then added at −70° C. The resulting mixture was stirred at −70° C. for 1 h, heated to 25° C., and stirred for 12 h. Saturated aqueous ammonium chloride solution (20.0 mL) was then 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 triturated with petroleum ether (20.00 mL) for 15 min to give intermediate AA11 (200 mg, 1.09 mmol, 15.2% yield) as an off-white solid. LC-MS: m / z=185.2 (M+H). + .

[0281] Synthesis of general intermediate AA12 ((1-cyclopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0282] [ka]

[0283] 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 equiv.) was dissolved in dioxane (250 mL), followed by the sequential addition of bis(pinacolato)diboron (36.1 g, 142 mmol, 1.40 equiv.), potassium acetate (39.9 g, 406 mmol, 4.00 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (4.15 g, 5.08 mmol, 0.05 equiv.). The mixture was stirred at 85 °C for 12 hours under a nitrogen atmosphere. Water (800 mL) and ethyl acetate (500 mL) were then added, and the resulting mixture was filtered to obtain the 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, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 0) to give compound AA12-2 (4.40 g) as a pale yellow oil. 1 LC-MS: m / z = 235.1 (M+H) + .

[0284] Step 2: Synthesis of compound AA12-3 (1-cyclopropyl-1H-pyrazol-4-ol) Compound AA12-2 (3.30 g, 14.1 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (43.0 mL), followed by the addition of aqueous sodium hydroxide (2.50 M, 11.3 mL, 2.00 equiv.) and hydrogen peroxide (5.84 g, 51.5 mmol, 4.95 mL, 30.0% purity, 3.65 equiv.). 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 tetrahydrofuran and extracted three times with dichloromethane / methanol = 10 / 1 (150 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 AA12-3 (0.980 g, crude product) as a pale yellow oil. 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).

[0285] Step 3: Synthesis of compound AA12-4 (1-cyclopropyl-4-methoxy-1H-pyrazole) Compound AA12-3 (0.980 g, 7.89 mmol, 1.00 equiv.) was dissolved in N,N-dimethylformamide (19.5 mL), followed by the addition of cesium carbonate (3.86 g, 11.8 mmol, 1.50 equiv.) and iodomethane (1.68 g, 11.8 mmol, 737 μL, 1.50 equiv.). The mixture was stirred at room temperature (25 °C) for 3 h. Water (10 mL) was then added, and the resulting mixture was extracted three times with ethyl acetate (10 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, 42.2% yield) as a pale yellow solid.1 LC-MS: m / z = 139.2 (M+H) + .

[0286] Step 4: Synthesis of intermediate AA12 Compound AA12-4 (0.300 g, 2.17 mmol, 1.00 equiv) was dissolved in anhydrous tetrahydrofuran (8.50 mL), and n-butyllithium (2.50 M, 1.74 mL, 2.00 equiv) was added dropwise at −70° C. under a nitrogen atmosphere. After the addition was complete, the resulting mixture was stirred at −70° C. for 1 h. Isopropyl pinacolyl borate (808 mg, 4.34 mmol, 886 μL, 2.00 equiv) was then added at −70° C., and the resulting mixture was stirred at −70° C. for 1 h, heated to 25° C., and stirred for 12 h. Saturated aqueous ammonium chloride solution (30.0 mL) was then 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 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3) to ACN]; B%: 3% to 33%, 10 min) to give compound AA12 (0.400 g, crude product) as a pale yellow oil. LC-MS: m / z = 183.1 (M+H). + .

[0287] Synthesis of general intermediate AA13 ((5-isopropyl-3-methylisoxazol-4-yl)boronic acid)

[0288] [ka]

[0289] Step 1: Synthesis of compound AA13-2 (5-isopropyl-3-methylisoxazole) Isobutyrylacetone (compound AA13-1, 2.00 g, 15.6 mmol, 1.00 equivalents) and hydroxylamine hydrochloride (1.36 g, 19.6 mmol, 1.25 equivalents) were added sequentially 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 (4.80 g total, crude product) as a colorless, clear 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).

[0290] Step 2: Synthesis of compound AA13-3 (4-bromo-5-isopropyl-3-methylisoxazole) Compound AA13-2 and compound AA13-2a (3.50 g, 28.0 mmol, 1.00 equivalents) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N-bromosuccinimide (7.94 g, 44.6 mmol, 1.59 equivalents). 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 a filtrate. The filtrate 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) + .

[0291] Step 3: Synthesis of compound AA13 Compound AA13-3, compound AA13-3a (3.00 g, 14.7 mmol, 1.00 equiv.), and triisopropyl borate (3.59 g, 19.1 mmol, 4.39 mL, 1.30 equiv.) were dissolved in tetrahydrofuran (30.0 mL), and n-butyllithium (2.5 M, 7.64 mL, 1.30 equiv.) 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 in vacuo to obtain the crude product. This was purified by preparative HPLC (chromatography column: Phenomenex luna C18 250 × 80 mm × 10 μm; mobile phase: [water (FA) to ACN]; B%: 20% to 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) + .

[0292] Synthesis of general intermediate AA14 (4-chloro-1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0293] [ka]

[0294] 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 equiv.), cyclopropyl bromide (21.2 g, 175.57 mmol, 1.8 equiv.), and cesium carbonate (63 g, 195.08 mmol, 2.0 equiv.) were added sequentially to dioxane (50 mL) and stirred at an external temperature of 140 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to give compound AA14-2 (6.4 g) as a pale yellow oil. 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)+.

[0295] Step 2: Synthesis of intermediate AA14 Compound AA14-2 (8.3 g, 58.21 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (100 mL), and lithium diisopropylamide (58 mL, 116.42 mmol, 2.0 equiv.) was added dropwise at −70° C. under a nitrogen atmosphere. After the addition was complete, the resulting mixture was stirred at −70° C. for 1 hour. Isopropyl pinacolyl borate (17.3 g, 93.14 mmol, 1.6 equiv.) was added, and the resulting mixture was stirred at −70° C. for 1 hour, heated to 25° C., and stirred for 2 hours. Water (100 mL) was then 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 in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give intermediate AA14 (4.2 g) as a colorless and transparent oil. 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).

[0296] General Intermediate AA15 ((4-Cyclopropylpyrimidin-5-yl)boronic Acid) Intermediate AA15 was purchased from Leyan Reagents.

[0297] [ka]

[0298] Synthesis of general intermediate AA16 (1-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0299] [ka]

[0300] Following the same steps as for intermediate AA14, using 4-methylpyrazole (compound AA16-1) as the starting material, intermediate AA16 (2.9 g) was obtained. 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).

[0301] Synthesis of general intermediate AA17 (1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0302] [ka]

[0303] Following the same steps as for intermediate AA14, using 4-methylpyrazole (compound AA16-1) as the starting material, intermediate AA17 (4.1 g) was obtained. 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).

[0304] Synthesis of General Intermediate B1 (3-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0305] [ka]

[0306] Step 1: Synthesis of compound B1-3 (ethyl 1-(pyridin-3-yl)piperidine-4-carboxylate) Compound B1-1 (6.4 g, 40.7 mmol, 1.28 equiv.), compound B1-2 (5.0 g, 31.8 mmol, 1.00 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.1 g, 1.91 mmol, 0.06 equiv.), cesium carbonate (13.9 g, 42.90 mmol, 1.35 equiv.), and tris(dibenzylideneacetone)dipalladium (582.0 mg, 0.6 mmol, 0.02 equiv.) were added sequentially to anhydrous dioxane (50.0 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% FA) to give 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) + .

[0307] Step 2: Synthesis of compound B1-4 ((1-(pyridin-3-yl)piperidin-4-yl)methanol) Compound B1-3 (2.0 g, 8.5 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum tetrahydride (356.0 mg, 9.4 mmol, 1.10 equiv.) 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 then 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 and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain crude compound B1-4 (1.2 g), which 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) + .

[0308] Step 3: Synthesis of intermediate B1 Compound B1-4 (0.5 g, 2.6 mmol, 1.00 equiv.) was dissolved in dichloromethane (5.0 mL) and thionyl chloride (3.1 g, 26.0 mmol, 10.0 equiv.) 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 in vacuo to give compound B1 (520 mg, 2.31 mmol, 88.9% yield, 93.7% purity) as a pale yellow solid. LC-MS: m / z=211.2 (M+H). + .

[0309] Synthesis of General Intermediate B2 (4-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0310] [ka]

[0311] Step 1: Synthesis of compound B2-3 (ethyl 1-(pyridin-4-yl)piperidine-4-carboxylate) Compound B2-1 (5.0 g, 33.3 mmol, 1.00 equiv.), compound B2-2 (5.2 g, 33.3 mmol, 1.00 equiv.), and triethylamine (10.1 g, 100.0 mmol, 3.00 equiv.) were added to ethanol (50.0 mL), and the mixture was heated to 100 °C and stirred for 16 h. Water (50.0 mL) was then 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) + .

[0312] Step 2: Synthesis of compound B2-4 ((1-(pyridin-4-yl)piperidin-4-yl)methanol) Compound B2-3 (1.7 g, 7.3 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (302.0 mg, 8.0 mmol, 1.10 equiv.) was added at 0° C. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 4 hours. Aqueous sodium hydroxide 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 and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain crude compound B2-4 (1.1 g), which 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) + .

[0313] Step 3: Synthesis of compound B2 Compound B2-4 (500.0 mg, 2.60 mmol, 1.00 equiv) was dissolved in dichloromethane (5.0 mL) and thionyl chloride (2.5 g, 20.8 mmol, 8.00 equiv) 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 in vacuo to give compound B2 (530 mg, 2.52 mmol, 96.7% yield) as a white solid. LC-MS: m / z=193.0 (M+H). + .

[0314] Synthesis of General Intermediate B3 (3-(4-(chloromethyl)phenyl)pyridine)

[0315] [ka]

[0316] Step 1: Synthesis of compound B3-3 ((4-(pyridin-3-yl)phenyl)methanol) Compound B3-1 (3.0 g, 18.9 mmol, 1.00 equiv.), compound B3-2 (3.8 g, 24.6 mmol, 1.30 equiv.), sodium carbonate (14.8 g, 140.0 mmol, 7.40 equiv.), and tetrakis(triphenylphosphine)palladium (2.2 g, 1.89 mmol, 0.10 equiv.) were sequentially added to a mixture of toluene (15.0 mL), water (15.0 mL), and ethanol (3.0 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to give 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) + .

[0317] Step 2: Synthesis of intermediate B3 Compound B3-3 (1.0 g, 5.4 mmol, 1.00 equiv.) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (6.4 g, 53.9 mmol, 10.0 equiv.) 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 in vacuo to give compound B3 (1.1 g, 5.35 mmol, 99.1% yield) as a white solid. LC-MS: m / z=204.0 (M+H). + .

[0318] Synthesis of general intermediate B4 (4-(4-(chloromethyl)phenyl)pyridine)

[0319] [ka]

[0320] Compound B4-1 (250.0 mg, 1.4 mmol, 1.00 equiv.) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (802.0 mg, 6.8 mmol, 5.00 equiv.) 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 in vacuo to give compound B4 (260 mg, 1.28 mmol, 94.5% yield) as a white solid. LC-MS: m / z=204.0 (M+H). + .

[0321] Synthesis of General Intermediate B5 (5-(4-(chloromethyl)phenyl)-2-methylpyridine)

[0322] [ka]

[0323] Step 1: Synthesis of compound B5-3 ((4-(6-methylpyridin-3-yl)phenyl)methanol) Compound B5-1 (3.0 g, 17.4 mmol, 1.00 equiv.), compound B5-2 (3.5 g, 22.6 mmol, 1.30 equiv.), sodium carbonate (13.6 g, 129.0 mmol, 7.40 equiv.), and tetrakis(triphenylphosphine)palladium (2.0 g, 1.74 mmol, 0.10 equiv.) were added sequentially to a mixture of toluene (15.0 mL), water (15.0 mL), and ethanol (3.00 mL). The resulting mixture was purged with nitrogen three times and reacted at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to give 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) + .

[0324] Step 2: Synthesis of intermediate B5 Compound B5-3 (0.5 g, 2.5 mmol, 1.00 equiv.) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (1.5 g, 12.5 mmol, 5.00 equiv.) 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 in vacuo to give compound B5 (530 mg, 2.43 mmol, 97.0% yield) as a white solid. LC-MS: m / z=218.1 (M+H). + .

[0325] Synthesis of General Intermediate B6 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0326] [ka]

[0327] Step 1: Synthesis of compound B6-3 (methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate) Compound B6-2 (7.2 g, 26.8 mmol, 1.10 equiv.) and sodium acetate (2.2 g, 27.3 mmol, 1.12 equiv.) 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 equiv.) 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. Water (60.0 mL) was then 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 in vacuo 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 (4.5 g). 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) + .

[0328] Step 2: Synthesis of compound B6-4 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate) Compound B6-3 (2.5 g, 9.3 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (20.0 mL), and sodium hydride (444.1 mg, 11.1 mmol, 1.20 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was reacted at 0 °C for 30 minutes. Iodomethane (6.8 g, 48.1 mmol, 5.20 equiv) was then added. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 15 hours. Ice water (20.0 mL) was then 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 a filtrate. The filtrate was concentrated under vacuum to obtain a 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) + .

[0329] Step 3: Synthesis of Compound B6-5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol) Compound B6-4 (0.6 g, 2.1 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum hydride (88.1 mg, 2.32 mmol, 1.10 equiv) 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 a filtrate. The filtrate was concentrated under vacuum to obtain crude product B6-5 (505.4 mg), which 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) + .

[0330] Step 4: Synthesis of intermediate B6 Compound B6-5 (500.0 mg, 2.0 mmol, 1.00 equiv) was dissolved in dichloromethane (5.0 mL) and thionyl chloride (1.9 g, 15.6 mmol, 8.00 equiv) 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 in vacuo to give compound B6 (523 mg, 1.90 mmol, 97.6% yield) as a brown solid. LC-MS: m / z=275.1 (M+H). + .

[0331] Synthesis of General Intermediate B7 (2-(4-(chloromethyl)cyclohexyl)pyrimidine)

[0332] [ka]

[0333] Step 1: Synthesis of compound B7-3 (ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate) Compound B7-1 (10.0 g, 33.1 mmol, 1.00 equiv.), compound B7-2 (9.2 g, 36.4 mmol, 1.10 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (1.4 g, 1.7 mmol, 0.05 equiv.), and potassium acetate (9.8 g, 99.3 mmol, 3.00 equiv.) were added sequentially to dioxane (80.0 mL). The resulting mixture was purged with nitrogen three times 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 a filtrate. The filtrate was concentrated in vacuo to obtain a 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) + .

[0334] Step 2: Synthesis of compound B7-5 (ethyl 4-(pyrimidin-2-yl)cyclohex-3-ene-1-carboxylate) Compound B7-3 (4.9 g, 17.3 mmol, 1.10 equiv.), compound B7-4 (2.5 g, 15.7 mmol, 1.00 equiv.), sodium carbonate (5.0 g, 47.2 mmol, 3.00 equiv.), and tetrakis(triphenylphosphine)palladium (1.8 g, 1.6 mmol, 0.10 equiv.) were added sequentially to dioxane (50.0 mL) and water (12.5 mL). The resulting mixture was purged with nitrogen three times and stirred at 90 °C under a nitrogen atmosphere for 20 hours. Water (100.0 mL) was then 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 a filtrate. The filtrate was concentrated in vacuo to obtain a 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) + .

[0335] Step 3: Synthesis of compound B7-6 (ethyl 4-(pyrimidin-2-yl)cyclohexane-1-carboxylate) Compound B7-5 (3.0 g, 13.1 mmol, 1.00 equiv.) and wet palladium on carbon (1.4 g, 1.3 mmol, 10.0% purity, 0.10 equiv.) were added sequentially to ethanol (90.0 mL) and stirred under a hydrogen atmosphere at 25 °C for 16 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 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) + .

[0336] Step 4: Synthesis of compound B7-7 ((4-(pyrimidin-2-yl)cyclohexyl)methanol) Compound B7-6 (500.0 mg, 2.1 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (20.0 mL), and diisobutylaluminum hydride (1.0 M, 3.20 equiv) was added at −65° C. After the addition was complete, the resulting mixture was reacted at −65° C. for 0.5 hours, heated to 20° C., and stirred for 1 hour. Saturated aqueous ammonium chloride solution (20.0 mL) was then 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 a filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain crude compound B7-7 (263.5 mg), which 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) + .

[0337] Step 5: Synthesis of Intermediate B7 Compound B7-7 (263.0 mg, 1.4 mmol, 1.00 equiv) was dissolved in dichloromethane (5.0 mL) and thionyl chloride (814.0 mg, 6.8 mmol, 5.00 equiv) 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 in vacuo to give compound B7 (300 mg, crude) as a pale yellow oil. 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) + .

[0338] Synthesis of General Intermediate B8 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0339] [ka]

[0340] Intermediate B6 (700.0 mg, 2.55 mmol, 1.00 equiv) and aqueous ammonia (27.3 g, 233.0 mmol, 30% purity, 91.70 equiv) were added to dioxane (15.0 mL), and the resulting mixture was reacted in a sealed tube at 50 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to give B8 (580 mg, 1.99 mmol, 78.0% yield, 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) + .

[0341] Synthesis of General Intermediate B9 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0342] [ka]

[0343] General intermediate B9 was obtained by following the synthesis of intermediate B6 and using an equimolar amount of B9-1 instead of B6-1, with other experimental conditions remaining unchanged. Compound B9 (330.0 mg, crude product) was finally obtained as a white solid. LC-MS: m / z=281.0 (M+H). + .

[0344] Synthesis of General Intermediate B10 (2-(4-(chloromethyl)phenyl)pyridine)

[0345] [ka]

[0346] Step 1: Synthesis of compound B10-3 ((4-(pyridin-2-yl)phenyl)methanol) Compound B10-1 (10.0 g, 63.3 mmol, 6.02 mL, 1.00 equiv.), compound B10-2 (12.5 g, 82.3 mmol, 1.30 equiv.), tetrakis(triphenylphosphine)palladium (7.31 g, 6.33 mmol, 0.100 equiv.), and sodium carbonate (49.6 g, 468 mmol, 7.40 equiv.) were added sequentially to a mixture of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated in vacuo 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) + .

[0347] Step 2: Synthesis of intermediate B10 Compound B10-3 (1.0 g, 5.40 mmol, 1.00 equiv) was dissolved in dichloromethane (10.0 mL) and thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 12 h. The reaction was concentrated in vacuo to give B10 (1.1 g, crude product) as a white solid. LC-MS: m / z = 204.1 (M+H). + .

[0348] Synthesis of General Intermediate B11 (2-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0349] [ka]

[0350] Step 1: Synthesis of compound B11-3 (ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate) Compound B11-1 (20.8 g, 132 mmol, 20.4 mL, 1.00 equiv.), compound B12-2 (15.0 g, 132.0 mmol, 1.00 equiv.), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 equiv.) were dissolved in DMSO (50.0 mL), and the resulting mixture was reacted at 120-150 °C for 16 h. The reaction was quenched by cooling. 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, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to obtain compound B12-2 (6.0 g, yield 19.4%, purity 100%) as a yellow oil. 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) + .

[0351] Step 2: Synthesis of compound B11-4 ((1-(pyridin-2-yl)piperidin-4-yl)methanol) Compound B11-3 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL), and lithium aluminum hydride (LiAlH, 1.07 g, 28.2 mmol, 1.10 equiv.) was carefully added at 0 °C. The resulting mixture was then stirred at room temperature for 16 h. Additional lithium aluminum hydride (LiAlH, 486 mg, 12.8 mmol, 0.500 equiv.) was added, and the resulting mixture was further stirred for 6 h. HO (20.0 mL) was carefully added at 0 °C to quench the reaction. 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 in vacuo 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 oil. 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) + .

[0352] Step 3: Synthesis of intermediate B11 Compound B11-4 (1.20 g, 6.24 mmol, 1.00 equiv) was dissolved in dichloromethane (12.0 mL) and thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 12 h. The reaction was concentrated in vacuo to give compound B11 (1.57 g, crude) as a white solid. LC-MS: m / z = 211.1.

[0353] Synthesis of general intermediate B12 (2-((1r,4r)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0354] [ka]

[0355] Step 1: Synthesis of compound B12-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B12-1 (33.0 g, 242.0 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 equiv) was added portionwise at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 30 minutes. Iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 equiv) was then added. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 5 hours. The reaction was quenched by the addition of 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 a filtrate. The filtrate was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH H O) to give 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) + .

[0356] 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 equiv) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equiv) was added dropwise at −70° C. After the addition was complete, the resulting mixture was stirred at −70° C. for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equiv) 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. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200.0 mL) at 0° C. 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound B12-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0357] Step 3: Synthesis of compound B12-5 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-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 added sequentially to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL). The resulting mixture was purged with nitrogen three times and stirred under a nitrogen atmosphere at 100°C for 5 hours. The reaction mixture was filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain a 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) + .

[0358] Step 4: Synthesis of compound B12-6 (ethyl (1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-formate) Compound B12-5 (1.9 g, 5.6 mmol, 1.00 equiv.), sodium acetate (925.0 mg, 11.2 mmol, 2.00 equiv.), and wet palladium on carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 equiv.) were added sequentially to ethanol (30.0 mL), and the resulting mixture was reacted at 50 °C under a hydrogen atmosphere (15 psi) for 5 hours. The reaction mixture was filtered to obtain a filtrate, which was then 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) to ACN]; B%: 34% to 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) + .

[0359] Step 5: Synthesis of compound B12-7 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol) Compound B12-6 (0.6 g, 2.0 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 equiv.) was added at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 0.5 hours, heated to 20° C., and stirred for 12 hours. Sodium sulfate decahydrate (0.5 g) was then 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 filtration to obtain a filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain crude compound B12-7 (0.5 g), which 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) + .

[0360] Step 6: Synthesis of intermediate B12 Compound B12-7 (500.0 mg, 1.9 mmol, 1.00 equiv) was dissolved in dichloromethane (2.0 mL) and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equiv) 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 was concentrated in vacuo to give compound B12 (550 mg, 1.36 mmol, 71.5% yield, HCl) as a pale yellow solid. LC-MS: m / z=281.0 (M+H). + .

[0361] Synthesis of General Intermediate B13 (4-(chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine Hydrochloride)

[0362] [ka]

[0363] Step 1: Synthesis of compound B13-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole) Compound B13-1 (33.0 g, 242 mmol, 1.00 equivalents) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 equivalents) was added portionwise at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 30 minutes. Iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 equivalents) was then added. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 4 hours. Ice water (200.0 mL) was then 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, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to give 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) + .

[0364] 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 equiv) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equiv) was added dropwise at −70° C. After the addition was complete, the resulting mixture was stirred at −70° C. for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equiv) 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. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200.0 mL) at 0° C. 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound B13-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0365] Step 3: Synthesis of compound B13-5 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate) Compound B13-3 (7.0 g, 31.9 mmol, 1.00 equiv.), compound B13-4 (7.54 g, 47.9 mmol, 7.39 mL, 1.50 equiv.), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 equiv.), and sodium iodide (479 mg, 3.20 mmol, 0.100 equiv.) were added sequentially 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, and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain a crude product. This was purified by reverse-phase HPLC (0.1% FA) to give 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) + .

[0366] Step 4: Synthesis of compound B13-6 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate) Compound B13-5 (2.2 g, 6.48 mmol, 1.00 equiv.), sodium acetate (1.06 g, 12.9 mmol, 2.00 equiv.), and wet palladium on carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 equiv.) were added sequentially to ethanol (40.0 mL), and the resulting mixture was reacted under a hydrogen atmosphere (15 psi) at 50 °C for 36 hours. The reaction mixture was filtered to obtain a filtrate, which 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) + .

[0367] Step 5: Synthesis of compound B13-7 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol) Compound B13-6 (1.2 g, 3.93 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 equiv.) was added at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 0.5 hours, heated to 20° C., and stirred for 12 hours. Sodium sulfate decahydrate (0.5 g) was then 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 filtration to obtain a filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain the crude product, compound B13-7 (1.0 g), which 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) + .

[0368] Step 6: Synthesis of intermediate B13 Compound B13-7 (1.0 g, 3.80 mmol, 1.00 equiv) was dissolved in dichloromethane (2.0 mL) and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equiv) 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 was concentrated in vacuo to give compound B13 (1.1 g, 3.46 mmol, 91.0% yield, HCl) as a brown solid. LC-MS: m / z=282.1 (M+H). + .

[0369] Synthesis of general intermediate B14 (2-(5-(chloromethyl)furan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0370] [ka]

[0371] Step 1: Synthesis of compound B14-3 (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)furan-2-carbaldehyde) Compound B14-2 (400 mg, 1.83 mmol, 1.00 equiv.), B14-1 (255 mg, 1.83 mmol, 1.00 equiv.), methanesulfonato(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 equiv.), and potassium phosphate (1.16 g, 5.48 mmol, 3.00 equiv.) were added sequentially to n-butanol (3.0 mL) and water (0.5 mL). The resulting mixture was purged with nitrogen three times and reacted at 60 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: [water (FA) to ACN]; B%: 22% to 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)+.

[0372] Step 2: Synthesis of compound B14-4 ((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)furan-2-yl)methanol) Compound B14-3 (60.0 mg, 245 μmol, 1.00 equiv) was dissolved in methanol (1.0 mL), followed by the addition of sodium borohydride (90.0 mg, 2.38 mmol, 9.68 equiv), and the resulting mixture was stirred at 15° C. for 30 minutes. Saturated aqueous ammonium chloride solution (10.0 mL) was then added at 0° C., water (20.0 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 a filtrate. This was concentrated in vacuo 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) + .

[0373] Step 3: Synthesis of intermediate B14 Compound B14-4 (50.0 mg, 203 μmol, 1.00 equiv.) was dissolved in dichloromethane (2.0 mL), and thionyl chloride (1.2 g, 10.1 mmol, 50.0 equiv.) 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 mixture was concentrated in vacuo to give compound B14 (45 mg, crude product) as a pale yellow oil. LC-MS: m / z=265.1 (M+H). + .

[0374] Synthesis of General Intermediate B15 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0375] [ka]

[0376] Step 1: Synthesis of compound B15-3 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol) Compound B15-1 (9.6 g, 62.5 mmol, 1.00 equiv.), compound B15-2 (12.4 g, 81.3 mmol, 1.30 equiv.), tetrakis(triphenylphosphine)palladium (7.2 g, 6.25 mmol, 0.10 equiv.), and sodium carbonate (49.0 g, 463 mmol, 7.40 equiv.) were added sequentially to a mixture of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered to obtain the filtrate, which was concentrated in vacuo 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) + .

[0377] Step 2: Synthesis of intermediate B15 Compound B15-3 (6.0 g, 26.6 mmol, 1.00 equiv.) was dissolved in dichloromethane (10.0 mL) and thionyl chloride (15.9 g, 133 mmol, 5.00 equiv.) 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 was concentrated in vacuo to give compound B15 (7.3 g, 26.2 mmol, 98.2% yield, HCl) as an off-white solid. LC-MS: m / z=244.1 (M+H). + .

[0378] Synthesis of general intermediate B16 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0379] [ka]

[0380] Step 1: Synthesis of compound B16-3 (methyl 4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate) Compound B16-1 (25.0 g, 118 mmol, 1.00 equivalents), compound B16-2 (20.8 g, 141 mmol, 1.20 equivalents), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 equivalents), and silver nitrate (4.01 g, 23.6 mmol, 0.20 equivalents) were added sequentially to a mixed solvent of dichloromethane (750 mL) and water (750 mL). The resulting mixture was reacted at 20° C. for 16 hours, followed by the addition of dichloromethane (250 mL) and filtration to obtain a filtrate. This was washed three times with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered to obtain a filtrate. This was concentrated under vacuum to obtain a crude product. The crude product was purified by preparative HPLC (alkaline condition, NH3·H2O / MeCN / H2O) to give compound B16-3 (7.5 g). 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).

[0381] Step 2: Synthesis of compound B16-4 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol) Compound B16-3 (2.5 g, 7.98 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (50.0 mL), and lithium aluminum hydride (908 mg, 23.9 mmol, 3.00 equiv.) was added slowly at 0° C. After the addition was complete, the resulting mixture was heated to 20° C. and stirred for 3 hours. Ice water (50.0 mL) was then added at 0° C., and 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 a filtrate. The filtrate was concentrated under vacuum to obtain compound B16-4 (2.3 g). LC-MS: m / z=286.1 (M+H). + .

[0382] Step 3: Synthesis of intermediate B16 Compound B16-4 (1.6 g, 5.61 mmol, 1.00 equiv.) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 equiv.) 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, and filtered to obtain the filtrate, which 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 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) + .

[0383] Synthesis of general intermediate B17 (1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0384] [ka]

[0385] Step 1: Synthesis of compound B17-2 (methyl 4-hydrazinylbenzoate) Compound B17-1 (15.0 g, 90.32 mmol, 1.0 equiv) was dissolved in 37% aqueous hydrochloric acid (25.0 mL), followed by the addition of sodium nitrite (6.2 g, 90.32 mmol, 1.0 equiv) dissolved in water (10.0 mL) 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 equiv) dissolved in 37% aqueous hydrochloric acid (75.0 mL) 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, which 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). + .

[0386] Step 2: Synthesis of compound B17-4 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-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. Water (10 mL) was then added, and the resulting mixture 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 a filtrate. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound B17-4 (5.3 g). LC-MS: m / z = 285.0 (M+H). + .

[0387] Step 3: Synthesis of compound B17-5 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol) Compound B17-4 (5.3 g, 18.65 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (100.0 mL), and lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 equiv.) was added slowly at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 6 hours. Ice water (50.0 mL) was then added at 0 °C, and 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 a filtrate. The filtrate was concentrated under vacuum to obtain a 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). + .

[0388] Step 4: Synthesis of intermediate B17 Compound B17-5 (1.0 g, 3.91 mmol, 1.0 equiv) was dissolved in dichloroethane (25.0 mL) and thionyl chloride (1.4 g, 11.73 mmol, 5.2 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was concentrated in vacuo to give compound B17 (1.0 g, 3.64 mmol, 93.1% yield, 96.9% purity) 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) + .

[0389] General Intermediate BB1 ​​(2-chloro-5-methoxy-N-methylpyrimidin-4-amine) Intermediate BB1 ​​was purchased from Leyan Reagents.

[0390] [ka]

[0391] General Intermediate BB2 (2-Chloro-5-methoxypyrimidin-4-amine) Intermediate BB2 was purchased from Leyan Reagents.

[0392] [ka]

[0393] General Intermediate BB3 (2-chloro-5-isopropoxy-N-methylpyrimidin-4-amine)

[0394] [ka]

[0395] 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 equiv.) was added to phosphorus oxychloride (5.0 mL) and refluxed under nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove 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 in vacuo to give compound BB3-2 (551.0 mg, crude product) as a pale yellow oil. LC-MS: m / z = 207.1 (M+H). + .

[0396] Step 2: Synthesis of intermediate BB3 Compound BB3-2 (100 mg, 0.48 mmol, 1.00 equiv.), methylamine hydrochloride (97.8 mg, 1.45 mmol, 3.00 equiv.), and cesium carbonate (472.4 mg, 1.45 mmol, 3.00 equiv.) were added sequentially to N,N-dimethylformamide (2.0 mL), and the resulting mixture was stirred at 60 °C for 6 h. Ethyl acetate (15.0 mL) was added, and the resulting mixture was stirred for 5 min 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 intermediate BB3 (38.8 mg, 0.19 mmol, 40.1% yield). LC-MS: m / z = 202.1 (M+H). + .

[0397] General Intermediate BB4 (2-chloro-5-isopropoxypyrimidin-4-amine)

[0398] [ka]

[0399] Compound BB3-2 (100 mg, 0.48 mmol, 1.00 equiv.) and aqueous ammonia (1.68 g, 48.0 mmol, 30% purity, 100.0 equiv.) were added to dioxane (3.0 mL), and the resulting mixture was reacted in a sealed tube at 50 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to give intermediate BB4 (27.3 mg, 0.15 mmol, 30.3% yield) as a white solid. LC-MS: m / z = 188.2 (M+H). + .

[0400] General Intermediate BB12 (2-chloro-5-(trifluoromethyl)pyrimidin-4-amine) Intermediate BB12 was purchased from Bide Pharmatech.

[0401] [ka]

[0402] Synthesis of general intermediate BB13 (2-chlorofuro[3,2-d]pyrimidin-4-amine)

[0403] [ka]

[0404] 2,4-Dichlorofuro[3,2-d]pyrimidine (compound BB13-1, 5.0 g, 26.46 mmol, 1.00 equiv.) and aqueous ammonia (30.9 g, 264.6 mmol, 30% purity, 100.0 equiv.) were added to dioxane (100.0 mL), and the resulting mixture was reacted in a sealed tube at 50 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to give compound BB13 (3.2 g, 18.87 mmol, 71.3% yield) as a white solid. LC-MS: m / z = 170.1 (M+H). + .

[0405] Synthesis of general intermediate BB14 (2-chloropyrido[3,2-d]pyrimidin-4-amine)

[0406] [ka]

[0407] Following the same steps as for intermediate BB13, intermediate BB14 (1.1 g, 6.09 mmol, 40.6% yield) was used as the starting material to give 2,4-dichloropyrido[3,2-d]pyrimidine (BB14-1, 3.0 g, 15.0 mmol, 1.00 equiv.). LC-MS: m / z = 181.0 (M+H). + .

[0408] General Intermediate BB15 (2,5-Dichloropyrimidin-4-amine) Intermediate BB15 was purchased from Bide Pharmatech.

[0409] [ka]

[0410] Synthesis of general intermediate BB16 (2-chloro-5-fluoro-N-methylpyrimidin-4-amine)

[0411] [ka]

[0412] 2,4-Dichloro-5-fluoropyrimidine (compound BB16-1, 3.0 g, 18.07 mmol, 1.00 equiv.), methylamine hydrochloride (3.66 g, 54.23 mmol, 3.00 equiv.), and cesium carbonate (23.55 g, 72.28 mmol, 4.00 equiv.) were added sequentially to N,N-dimethylformamide (500 mL), and the resulting mixture was stirred at 60 °C for 6 h. Ethyl acetate (1000 mL) was added, and the resulting mixture was stirred for 5 min 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 BB16 (1.1 g, 6.81 mmol, 37.7% yield). LC-MS: m / z = 162.0 (M+H). + .

[0413] Synthesis of general intermediate BB16-D3 (2-chloro-5-fluoro-N-(methyl-D3)pyrimidin-4-amine)

[0414] [ka]

[0415] Following the same steps as for intermediate BB16, using 2,4-dichloro-5-fluoropyrimidine (BB16-1, 3.0 g, 18.07 mmol, 1.00 equiv.) as the starting material, intermediate BB16-D3 (1.47 g, 8.93 mmol, 49.4% yield) was obtained. LC-MS: m / z = 165.1 (M+H). + .

[0416] General Intermediate BB17 (4-Amino-2-chloropyrimidine-5-carbonitrile) Intermediate BB17 was purchased from Bide Pharmatech.

[0417] [ka]

[0418] Synthesis of general intermediate BB18 (2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine)

[0419] [ka]

[0420] Compound 2,4-dichloro-5-iodopyrimidine (BB18-1, 1.0 g, 3.6 mmol, 1.00 equiv.), bis(triphenylphosphine)palladium dichloride (256 mg, 0.3 mmol, 0.1 equiv.), cuprous iodide (139 mg, 0.7 mmol, 0.2 equiv.), trimethylethynylsilane (700 mg, 7.2 mmol, 2.0 equiv.), and triethylamine (1.1 g, 10.9 mmol, 3.0 equiv.) were added sequentially to tetrahydrofuran (15 mL). The reaction mixture was stirred at 40 °C for 3 h and concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 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).

[0421] Synthesis of general intermediate BB19 (2-chloro-5-(difluoromethoxy)pyrimidin-4-amine)

[0422] [ka]

[0423] Step 1: Synthesis of compound BB19-2 (2,4-dichloro-5-(difluoromethoxy)pyrimidine) 2,4-Dichloropyrimidin-5-ol (compound BB19-1, 3.40 g, 20.6 mmol, 1.00 equiv.) and potassium hydroxide (13.3 g, 237 mmol, 11.5 equiv.) were added sequentially to acetonitrile (60.0 mL) and water (60.0 mL), and diethyl bromofluoromethylphosphonate (9.35 g, 35.0 mmol, 1.70 equiv.) was added dropwise. After the addition was complete, the resulting mixture was stirred at 25° C. for 1.5 hours. Saturated aqueous citric acid solution (10.0 mL) was added to quench the reaction, 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 in vacuo 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 oil. 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) + .

[0424] 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 equiv) was used as the starting material to give intermediate BB19 (298.5 mg, 1.53 mmol, 65.5% yield). LC-MS: m / z = 196.1 (M+H). + .

[0425] General Intermediate BB21 (4-(2,4-Dichloropyrimidin-5-yl)morpholine) Intermediate BB21 was purchased from Bide Pharmatech.

[0426] [ka]

[0427] Synthesis of general intermediate BB22 (2,4-dichloro-5-(4-methylpiperazin-1-yl)pyrimidine)

[0428] [ka]

[0429] 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 equiv.) was dissolved in pyridine (25 mL) and N-methylpiperazine (3.9 g, 39.2 mmol, 1.5 equiv.) 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 in vacuo to give the crude product, which was triturated with ethyl acetate (50 mL). The resulting mixture was filtered to give a solid, which was concentrated in vacuo to give compound BB22-2 (5.1 g, 24.26 mmol, 92.7% yield) as a brown solid. LC-MS: m / z=211.1 (M+H). + .

[0430] Step 2: Synthesis of compound BB22 BB22-2 (5.0 g, 23.8 mmol, 1.0 equiv.) was added to phosphorus oxychloride (200 mL), and the mixture was stirred at 90 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated in vacuo. Saturated aqueous sodium bicarbonate 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 in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain intermediate BB22 (1.3 g, 5.26 mmol, 22.1% yield, 97.8% purity) as a yellow solid. 1 LC-MS: m / z =247.1 (M+H) + .

[0431] General Intermediate BB24 (2,4-Dichloropyrimidin-5-ol) Intermediate BB24 was purchased from Bide Pharmatech.

[0432] [ka]

[0433] General Intermediate BB35 ((2,4-Dichloropyrimidin-5-yl)methanol) Intermediate BB35 was purchased from Bide Pharmatech.

[0434] [ka]

[0435] Synthesis of general intermediate BB36 (2-chloro-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0436] [ka]

[0437] Following the same steps as for intermediate BB16, using 2,4-dichloro-5-(methoxymethyl)pyrimidine (BB36-1, 2.9 g, 15.0 mmol, 1.00 equiv.) as the starting material, intermediate BB36 (1.89 g, 10.07 mmol, 67.2% yield) was obtained. LC-MS: m / z = 188.1 (M+H). + .

[0438] Synthesis of general intermediate BB41 (methyl 2-(2,4-dichloropyrimidin-5-yl)acetate)

[0439] [ka]

[0440] Step 1: Synthesis of compound BB41-2 (dimethyl 2-formylsuccinate) Dimethyl succinate (compound BB41-1, 200 g, 1.37 mol, 179 mL, 1.00 equiv.), ethyl formate (203 g, 2.74 mol, 220 mL, 2.00 equiv.), and sodium methoxide (259 g, 1.44 mol, 30.0% purity, 1.05 equiv.) were added sequentially 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 give the crude product, which 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 give the filtrate, which was concentrated under vacuum to give compound BB41-2 (70.0 g, 402 mmol, 29.4% yield) 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).

[0441] Step 2: Synthesis of compound BB41-3 (2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetic acid) Compound BB41-2 (60.0 g, 345 mmol, 1.00 equiv.) was dissolved in methanol (525 mL) and sodium methoxide (124 g, 689 mmol, 30.0% purity, 2.00 equiv.), and thiourea (26.2 g, 345 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at 100 °C for 12 hours and filtered to obtain a filter cake. 1 M aqueous hydrochloric acid (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, 46.8% yield, 100% purity) 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).

[0442] Step 3: Synthesis of compound BB41-4 (methyl 2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetate) Compound BB41-3 (15.0 g, 80.6 mmol, 1.00 equiv.) was dissolved in methanol (100 mL) and concentrated sulfuric acid (23.7 g, 242 mmol, 12.9 mL, 3.00 equiv.) was added. The resulting mixture was stirred at 80 °C for 12 hours and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain compound BB41-4 (13.0 g, 64.9 mmol, 80.6% yield) 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).

[0443] Step 4: Synthesis of intermediate BB41 Compound BB41-3 (12.0 g, 59.9 mmol, 1.00 equiv.) was dissolved in phosphorus oxychloride (158 g, 1.03 mol, 96.0 mL, 17.2 equiv.) 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 combined organic layers were washed three times with saturated brine (35.0 mL), 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 BB41 (3.60 g, 15.7 mmol, yield 26.2%, purity 96.4%) as a pale yellow oil. LC-MS: m / z=220.9 (M+H) + .

[0444] Synthesis of general intermediate BB42 (2-chloro-5-methoxy-N-(prop-2-yn-1-yl)pyrimidin-4-amine)

[0445] [ka]

[0446] Following the same steps as for intermediate BB16, using 2,4-dichloro-5-methoxypyrimidine (BB42-1, 500 mg, 2.79 mmol, 1.00 equiv.) and propargylamine (153.7 mg, 2.79 mmol, 1.00 equiv.) as starting materials, intermediate BB42 (140.8 mg, 0.71 mmol, 25.6% yield) was obtained. LC-MS: m / z = 198.2 (M+H). + .

[0447] Synthesis of general intermediate BB43 (2-chloro-5-methoxy-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine)

[0448] [ka]

[0449] Following the same steps as for intermediate BB16, using 2,4-dichloro-5-methoxypyrimidine (BB42-1, 1.2 g, 6.7 mmol, 1.00 equiv.) and 3-aminotetrahydrofuran (584.0 mg, 6.7 mmol, 1.00 equiv.) as starting materials, intermediate BB43 (910.5 mg, 3.96 mmol, 59.2% yield) was obtained. LC-MS: m / z = 230.2 (M+H). + .

[0450] Synthesis of general intermediate BB44 (2-chloro-N-cyclopropyl-5-methoxypyrimidin-4-amine)

[0451] [ka]

[0452] Following the same steps as for intermediate BB16, using 2,4-dichloro-5-methoxypyrimidine (BB42-1, 0.8 g, 4.47 mmol, 1.00 equiv.) and cyclopropylamine (255.2 mg, 4.47 mmol, 1.00 equiv.) as starting materials, intermediate BB44 (556.3 mg, 2.79 mmol, 62.3% yield) was obtained. LC-MS: m / z = 200.1 (M+H). + .

[0453] Synthesis of general intermediate BB45 (N-(2-chloro-5-methoxypyrimidin-4-yl)-O-methylhydroxylamine)

[0454] [ka]

[0455] Following the same steps as for intermediate BB16, 2,4-dichloro-5-methoxypyrimidine (compound BB45-1, 500 mg, 2.8 mmol, 1.0 equiv.) and methoxyamine hydrochloride (352 mg, 4.2 mmol, 1.5 equiv.) were used as starting materials to obtain intermediate BB45 (490.0 mg, 2.58 mmol, 92.3% yield). LC-MS: m / z = 190.1 (M+H). + .

[0456] Synthesis of general intermediate C2 (2-(4-(chloromethyl)cyclohexyl)pyridine)

[0457] [ka]

[0458] Step 1: Synthesis of compound C2-2 (ethyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate) 2-Bromopyridine (C2-1, 15.0 g, 94.9 mmol, 9.04 mL, 1.00 equiv.), 1-ethoxycarbonylcyclohex-3-ene-4-pinacolylborate (26.9 g, 94.9 mmol, 99.0% purity, 1.00 equiv.), potassium carbonate (39.4 g, 284 mmol, 3.00 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.95 g, 9.49 mmol, 0.10 equiv.) were added sequentially to water (50.0 mL) and dioxane (200 mL), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. Water (30.0 mL) was then 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound C2-2 (9.00 g, 38.9 mmol, 41.0% yield) as a colorless, clear 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) + .

[0459] Step 2: Synthesis of compound C2-3 (ethyl 4-(pyridin-2-yl)cyclohexane-1-carboxylate) Compound C2-2 (9.00 g, 38.9 mmol, 1.00 equiv.) was dissolved in methanol (288.0 mL), and palladium on carbon (4.14 g, 3.89 mmol, 10% purity, 0.10 equiv.) was added under a nitrogen atmosphere. The resulting mixture was purged with hydrogen three times and stirred under a hydrogen atmosphere (15 Psi) at 25 °C for 16 h. The reaction mixture was filtered to obtain the filtrate, which was concentrated in vacuo to give compound C2-3 (8.13 g, 34.9 mmol, 89.6% yield) as a colorless, clear 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) + .

[0460] Step 3: Synthesis of compound C2-4 ((4-(pyridin-2-yl)cyclohexyl)methanol) Compound C2-3 (8.13 g, 34.8 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (300.0 mL), and diisobutylaluminum hydride (1 M, 112 mL, 3.20 equiv.) 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 in vacuo 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) + .

[0461] Step 4: Compound C2 Compound C2-4 (800 mg, 4.18 mmol, 1.00 equiv) was dissolved in dichloromethane (16.0 mL) and thionyl chloride (2.49 g, 20.9 mmol, 1.52 mL, 5.00 equiv) 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 was concentrated in vacuo to give intermediate C2 (900 mg, crude) as a white solid. LC-MS: m / z=210.0 (M+H). + .

[0462] Synthesis of general intermediate C3 (2-(4-(chloromethyl)phenyl)pyridine)

[0463] [ka]

[0464] Step 1: Synthesis of compound C3-2 ((4-(pyridin-2-yl)phenyl)methanol) Compound 2-bromopyridine (C3-1, 10.0 g, 63.3 mmol, 6.02 mL, 1.00 equiv.), 2-(4-hydroxymethylphenyl)pyridine (12.5 g, 82.3 mmol, 1.30 equiv.), tetrakis(triphenylphosphine)palladium (7.31 g, 6.33 mmol, 0.100 equiv.), and sodium carbonate (49.6 g, 468 mmol, 7.40 equiv.) were added sequentially to a mixture of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The resulting mixture was purged with nitrogen three times 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 in vacuo to obtain the crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to give compound C3-2 (9.63 g) as a pale yellow oil. 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) + .

[0465] Step 2: Synthesis of intermediate C3 Compound C3-2 (1.0 g, 5.40 mmol, 1.00 equiv) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 12 h. The reaction was concentrated in vacuo to give intermediate C3 (1.1 g, crude product) as a white solid. LC-MS: m / z = 204.1 (M+H). + .

[0466] Synthesis of general intermediate C4 (4-(chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine)

[0467] [ka]

[0468] 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 equivalents) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 equivalents) was added portionwise at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 30 minutes. Iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 equivalents) was then added. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 4 hours. Ice water (200.0 mL) was then 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, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by reverse-phase HPLC (0.1% NH3·H2O) to give 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) + .

[0469] 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 equiv) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equiv) was added dropwise at −70°C. After the addition was complete, the resulting mixture was stirred at −70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equiv) 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. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200.0 mL) at 0°C. 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound C4-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0470] Step 3: Synthesis of compound C4-4 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate) Compound C4-3 (7.0 g, 31.9 mmol, 1.00 equiv.), ethyl 4-piperidinylcarboxylate (7.54 g, 47.9 mmol, 7.39 mL, 1.50 equiv.), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 equiv.), and sodium iodide (479 mg, 3.20 mmol, 0.100 equiv.) were added sequentially to N,N-dimethylformamide (70.0 mL), and the resulting mixture was reacted at 130 °C for 72 h. Water (350 mL) was added, and the resulting mixture was stirred for 5 min and 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 in vacuo to obtain the crude product. This was purified by reverse-phase HPLC (0.1% FA) to give 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) + .

[0471] Step 4: Synthesis of compound C4-5 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate) Compound C4-4 (2.2 g, 6.48 mmol, 1.00 equiv.), sodium acetate (1.06 g, 12.9 mmol, 2.00 equiv.), and wet palladium on carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 equiv.) were added sequentially to ethanol (40.0 mL), and the resulting mixture was reacted under a hydrogen atmosphere (15 psi) at 50 °C for 36 hours. The reaction mixture was filtered to obtain the filtrate, which 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) + .

[0472] Step 5: Synthesis of compound C4-6 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol) Compound C4-5 (1.2 g, 3.93 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was reacted at 0 °C for 0.5 h, heated to 20 °C, and stirred for 12 h. Sodium sulfate decahydrate (0.5 g) was then added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 30 min, followed by the addition of tetrahydrofuran (10.0 mL) and filtration to obtain a filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain compound C4-6 (1.0 g, crude product), which 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) + .

[0473] Step 6: Synthesis of intermediate C4 Compound C4-6 (1.0 g, 3.80 mmol, 1.00 equiv) was dissolved in dichloromethane (2.0 mL) and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 24 h. The reaction was concentrated in vacuo to give intermediate C4 (1.1 g, 3.46 mmol, 91.0% yield, HCl) as a brown solid. LC-MS: m / z = 282.1 (M+H). + .

[0474] Synthesis of General Intermediate C5 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0475] [ka]

[0476] Step 1: Synthesis of compound C5-2 (methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate) 1,1-Dibromo-3,3,3-trifluoroacetone (7.2 g, 26.8 mmol, 1.10 equiv.) and sodium acetate (2.2 g, 27.3 mmol, 1.12 equiv.) were dissolved in water (8.0 mL), and the resulting mixture was stirred at 100 °C for 1 hour. Compound methyl p-formylbenzoate (C5-1, 4.0 g, 24.4 mmol, 1.00 equiv.) 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. Water (60.0 mL) was then 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound C5-2 (4.5 g). 1 LC-MS: m / z = 271.0 (M+H) + .

[0477] Step 2: Synthesis of compound C5-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate) Compound C5-2 (2.5 g, 9.3 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (20.0 mL), and sodium hydride (444.1 mg, 11.1 mmol, 1.20 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was reacted at 0 °C for 30 minutes. Iodomethane (6.8 g, 48.1 mmol, 5.20 equiv) was then added. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 15 hours. Ice water (20.0 mL) was then 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 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) + .

[0478] Step 3: Synthesis of compound C5-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol) Compound C5-3 (0.6 g, 2.1 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum hydride (88.1 mg, 2.32 mmol, 1.10 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 25 °C and stirred for 4 h. Water (1.6 mL) and aqueous sodium hydroxide (1 M, 0.4 mL) were added at 0 °C, and the resulting mixture was stirred at 0 °C for 0.5 h. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the resulting mixture was filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain crude product C5-4 (505.4 mg), which 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)+.

[0479] Step 4: Synthesis of intermediate C5 Compound C5-4 (500.0 mg, 2.0 mmol, 1.00 equiv) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (1.9 g, 15.6 mmol, 8.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 15 h. The reaction mixture was concentrated in vacuo to give compound C5 (523 mg, 1.90 mmol, 97.6% yield) as a brown solid. 1 LC-MS: m / z = 275.1 (M+H) + .

[0480] Synthesis of general intermediate C6 (2-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0481] [ka]

[0482] Step 1: Synthesis of compound C6-2 (ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate) Ethyl piperidine-4-carboxylate (compound C6-1, 20.8 g, 132 mmol, 20.4 mL, 1.00 equiv.), 2-chloropyridine (15.0 g, 132.0 mmol, 1.00 equiv.), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 equiv.) were dissolved in dimethyl sulfoxide (50.0 mL), and the resulting mixture was reacted at 130 °C for 16 hours. The reaction was cooled to stop 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, and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain a 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 oil. 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) + .

[0483] Step 2: Synthesis of compound C6-3 ((1-(pyridin-2-yl)piperidin-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 equiv) was added portionwise at 0 °C. The resulting mixture was heated to room temperature and stirred for 16 h. Additional lithium aluminum hydride (486 mg, 12.8 mmol, 0.500 equiv) was added, and the resulting mixture was further stirred for 6 h. 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 in vacuo 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 oil. 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) + .

[0484] Step 3: Synthesis of intermediate C6 Compound C6-3 (1.20 g, 6.24 mmol, 1.00 equiv) was dissolved in dichloromethane (12.0 mL), and thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 12 h. The reaction was concentrated in vacuo to give intermediate C6 (1.57 g, crude) as a white solid. LC-MS: m / z = 211.1.

[0485] Synthesis of general intermediate C7 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0486] [ka]

[0487] General intermediate C7 was obtained by following the synthesis of intermediate C5 and using an equimolar amount of methyl 5-formylthiophene-2-carboxylate (compound C7-1) instead of compound C5-1, with other experimental conditions remaining unchanged. Intermediate C7 (330.0 mg, crude product) was finally obtained as a white solid. LC-MS: m / z=281.0 (M+H). + .

[0488] Synthesis of general intermediate C9 (2-((1R,4R)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0489] [ka]

[0490] 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 equiv.) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 equiv.) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was reacted at 0 °C for 30 minutes. Iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 equiv.) was then added. After the addition was complete, the resulting mixture was heated to 25 °C and stirred for 5 hours. The reaction was quenched by the addition of 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 combined organic layers were washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to give a filtrate. The filtrate was concentrated in vacuo to give the crude product, which was purified by reverse-phase HPLC (0.1% NH H O) to give 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) + .

[0491] 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 equiv) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyllithium (2.5 M, 44.7 mL, 1.00 equiv) was added dropwise at −70°C. After the addition was complete, the resulting mixture was stirred at −70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 equiv) 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. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200.0 mL) at 0°C. 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 a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound C9-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0492] Step 3: Synthesis of compound C9-4 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-3-ene-1-carboxylate) Compound C9-3 (7.0 g, 31.9 mmol, 1.00 equivalent), 1-ethoxycarbonylcyclohex-3-ene-4-pinacolylborate (8.94 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 equiv.) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 equiv.) were added sequentially to a mixture of dioxane (70.0 mL) and water (10.0 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 5 hours. The reaction mixture was filtered to obtain the filtrate, which was concentrated in vacuo 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) + .

[0493] Step 4: Synthesis of compound C9-5 (ethyl (1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-carboxylate) Compound C9-4 (1.9 g, 5.6 mmol, 1.00 equiv.), sodium acetate (925.0 mg, 11.2 mmol, 2.00 equiv.), and wet palladium on carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 equiv.) were added sequentially to ethanol (30.0 mL), and the resulting mixture was reacted at 50 °C under a hydrogen atmosphere (15 psi) for 5 h. The reaction mixture was filtered to obtain a filtrate, which was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (column: water Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3) to ACN]; B%: 34% to 64%, 10 min) to give 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) + .

[0494] Step 5: Synthesis of compound C9-6 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol) Compound C9-5 (0.6 g, 2.0 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was reacted at 0 °C for 0.5 h, heated to 20 °C, and stirred for 12 h. Sodium sulfate decahydrate (0.5 g) was then added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 30 min, followed by the addition of tetrahydrofuran (10.0 mL) and filtration to obtain a filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain crude compound C9-6 (0.5 g), which 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)+.

[0495] Step 6: Synthesis of intermediate C9 Compound C9-6 (500.0 mg, 1.9 mmol, 1.00 equiv) was dissolved in dichloromethane (2.0 mL) and thionyl chloride (4.5 g, 38.1 mmol, 20.0 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 24 h. The reaction was concentrated in vacuo to give intermediate C9 (550 mg, 1.36 mmol, 71.5% yield) as a pale yellow solid. LC-MS: m / z = 281.0 (M+H). + .

[0496] Synthesis of general intermediate C11 (1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0497] [ka]

[0498] Step 1: Synthesis of compound C11-2 (methyl 4-hydrazinylbenzoate) Compound C11-1 (15.0 g, 90.32 mmol, 1.0 equiv.) was dissolved in 37% aqueous hydrochloric acid (25.0 mL), and sodium nitrite (6.2 g, 90.32 mmol, 1.0 equiv.) dissolved in water (10.0 mL) 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 equiv.) dissolved in 37% aqueous hydrochloric acid (75.0 mL) 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, which 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). + .

[0499] Step 2: Synthesis of compound C11-3 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate) Compound C11-2 (5 g, 24.75 mmol, 1.0 equiv.) and 1,1,1-trifluoro-2,4-pentanedione (3.8 g, 24.75 mmol, 1.0 equiv.) were added to hexafluoroisopropanol (25.0 mL), and triethylamine (5.0 g, 49.50 mmol, 2.0 equiv.) 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 h. Water (10 mL) was then added, and the resulting mixture 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. The filtrate was concentrated in vacuo 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 (5.3 g). LC-MS: m / z = 285.0 (M+H) + .

[0500] Step 3: Synthesis of compound C11-4 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol) Compound C11-3 (5.3 g, 18.65 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (100.0 mL), and lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 equiv.) was added slowly at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 6 h. Ice water (50.0 mL) was then added at 0 °C, and the resulting mixture was stirred for 10 min 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 to 1 / 2) to obtain compound C11-4 (3.6 g). LC-MS: m / z = 257.1 (M+H). + .

[0501] Step 4: Synthesis of intermediate C11 Compound C11-4 (1.0 g, 3.91 mmol, 1.0 equiv) was dissolved in dichloroethane (25.0 mL), and thionyl chloride (1.4 g, 11.73 mmol, 5.2 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was concentrated in vacuo to give intermediate C11 (1.0 g, 3.64 mmol, 93.1% yield, 96.9% purity) 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) + .

[0502] Synthesis of the general intermediate C12 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0503] [ka]

[0504] Step 1: Synthesis of compound C12-2 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol) 8-Chlorimidazo[1,2-A]pyrazine (compound C12-1, 9.6 g, 62.5 mmol, 1.00 equiv.), 4-hydroxymethylphenylboronic acid (12.4 g, 81.3 mmol, 1.30 equiv.), tetrakis(triphenylphosphine)palladium (7.2 g, 6.25 mmol, 0.10 equiv.), and sodium carbonate (49.0 g, 463 mmol, 7.40 equiv.) were added sequentially to a mixture of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The resulting mixture was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered to obtain the filtrate, which was concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH H O) to give compound C12-2 (12.7 g). LC-MS: m / z = 226.2 (M+H). + .

[0505] Step 2: Synthesis of intermediate C12 Compound C12-2 (6.0 g, 26.6 mmol, 1.00 equiv) was dissolved in dichloromethane (10.0 mL) and thionyl chloride (15.9 g, 133 mmol, 5.00 equiv) was added at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 12 h. The reaction was concentrated in vacuo to give intermediate C12 (7.3 g, 26.2 mmol, 98.2% yield, HCl) as an off-white solid. LC-MS: m / z = 244.1 (M+H)+.

[0506] Synthesis of general intermediate C13 (2-(4-(chloromethyl)phenyl)-5-(trifluoromethyl)pyridine)

[0507] [ka]

[0508] Following the same steps as for Intermediate C3, 2-bromo-5-(trifluoromethyl)pyridine (compound C13-1) was used as the starting material to give Intermediate C13 (2.0 g). LC-MS: m / z=272.0 (M+H). + .

[0509] Synthesis of the general intermediate C14 (2-(4-(chloromethyl)phenyl)-5-methylpyridine)

[0510] [ka]

[0511] Following the same steps as for Intermediate C3, 2-bromo-5-methylpyridine (compound C14-1) was used as the starting material to give Intermediate C14 (10.0 g). LC-MS: m / z=218.0 (M+H). + .

[0512] Synthesis of general intermediate C19 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0513] [ka]

[0514] Step 1: Synthesis of compound C19-2 (methyl 4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate) Monomethyl hydrogen bicyclo[2.2.2]octane-1,4-dicarboxylate (Compound C19-1, 25.0 g, 118 mmol, 1.00 equiv.), 3-(trifluoromethyl)pyridine (20.8 g, 141 mmol, 1.20 equiv.), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 equiv.), and silver nitrate (4.01 g, 23.6 mmol, 0.20 equiv.) were added sequentially to a mixture of dichloromethane (750 mL) and water (750 mL), and the resulting mixture was reacted at 20 °C for 16 hours. Dichloromethane (250 mL) was added, and the resulting mixture was filtered to obtain a filtrate. This was washed three times with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (purification conditions, NH H O / MeCN / H O) to give compound C19-2 (7.5 g). 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).

[0515] Step 2: Synthesis of compound C19-3 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol) Compound C19-2 (2.5 g, 7.98 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (50.0 mL), and lithium aluminum hydride (908 mg, 23.9 mmol, 3.00 equiv) was added slowly at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 3 hours. Ice water (50.0 mL) was then added at 0 °C, and 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 compound C19-3 (2.3 g) as a white solid. LC-MS: m / z = 286.1 (M+H). + .

[0516] Step 3: Synthesis of intermediate C19 Compound C19-3 (1.6 g, 5.61 mmol, 1.00 equiv.) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 equiv.) were added to pyridine (25.0 mL), and the resulting mixture was reacted at 20 °C for 12 hours. The reaction mixture was concentrated in vacuo. 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, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo 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) + .

[0517] Synthesis of general intermediate C25 (6-(chloromethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0518] [ka]

[0519] 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 equiv.) was dissolved in hydrochloric acid in methanol (4 M, 6.71 mL, 10 equiv.), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (FA) to give compound C25-2 (0.16 g, 715.21 μmol, 26.64% yield, 98% purity) as a white solid. LC-MS: m / z=220.2 (M+H). + .

[0520] Step 2: Synthesis of compound C25-3 (6-(hydroxymethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one) Compound C25-2 (75 mg, 342.10 μmol, 1 equiv.) was dissolved in tetrahydrofuran (4 mL), and lithium borohydride (2 M, 1 mL, 5.85 equiv.) 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 to quench, 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 give compound C25-3 (50 mg, crude product) as a white solid. LC-MS: m / z=192.2 (M+H). + .

[0521] Step 3: Synthesis of intermediate C25 Compound C25-3 (50 mg, 261.47 μmol, 1 equiv.) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (155.54 mg, 1.31 mmol, 94.84 μL, 5 equiv.) 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 was concentrated in vacuo to give intermediate C25 (50 mg, 238.47 μmol, 91.20% yield) as an off-white solid. LC-MS: m / z=210.0 (M+H). + .

[0522] Synthesis of general intermediate C26 (6-(chloromethyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0523] [ka]

[0524] Step 1: Synthesis of compound C26-2 (6-bromo-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one) 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (compound C26-1, 500 mg, 2.69 mmol, 1 equiv.) was dissolved in tetrahydrofuran (40 mL), followed by the addition of sodium hydride (1.06 g, 26.54 mmol, 60% purity, 1.5 equiv.) at 0° C., and the resulting mixture was stirred for 30 minutes. 2-Iodopropane (6.02 g, 35.39 mmol, 3.54 mL, 2 equiv.) was added dropwise at 0° C. After the addition was complete, the resulting mixture was stirred at 25° C. under a nitrogen atmosphere 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 in vacuo 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 oil. 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)+.

[0525] Step 2: Synthesis of compound C26-3 (2-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile) Compound C26-2 (2.6 g, 9.70 mmol, 1 equiv.) 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 equiv.) and tetrakis(triphenylphosphine)palladium (1.12 g, 969.61 μmol, 0.1 equiv.), and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere 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 in vacuo 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) + .

[0526] 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 give intermediate C26 (433.4 mg, 1.82 mmol, 45.1% yield). LC-MS: m / z=238.2 (M+H). + .

[0527] Synthesis of general intermediate C27 (2-((4-(chloromethyl)phenoxy)methyl)pyridine)

[0528] [ka]

[0529] Following the same steps as for intermediate C28, using 4-hydroxybenzonitrile (compound C27-1) and 2-(bromomethyl)pyridine hydrobromide as starting materials, intermediate C27 (800.7 mg, crude product, pale yellow oil) was obtained. LC-MS: m / z=234.0 (M+H). + .

[0530] Synthesis of general intermediate C28 (1-(chloromethyl)-4-(2-ethoxyethoxy)benzene)

[0531] [ka]

[0532] Step 1: Synthesis of compound C28-2 (4-(2-ethoxyethoxy)benzonitrile) 4-Hydroxybenzonitrile (compound C28-1, 4.00 g, 33.6 mmol, 1.00 equiv.), 2-bromoethyl ethyl ether (10.0 g, 65.4 mmol, 7.35 mL, 1.95 equiv.), and potassium carbonate (9.28 g, 67.2 mmol, 2.00 equiv.) were added sequentially to acetonitrile (142 mL), and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. Water (30.0 mL) was added, and the pH was adjusted to about 5 with 1N aqueous HCl. 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 give the filtrate. The filtrate was concentrated in vacuo to give 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 oil. 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).

[0533] Step 2: Synthesis of compound C28-3 (methyl 4-(2-ethoxyethoxy)benzoate) Compound C28-2 (2.00 g, 10.5 mmol, 1.00 equiv) was dissolved in HCl / MeOH (4 M, 105 mL, 40 equiv). The resulting mixture was stirred at 80 °C for 36 h and concentrated in vacuo to give the crude product. Water (20 mL) was added, and the pH was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with ethyl acetate (50 mL). The combined organic layers were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered to give the filtrate. The filtrate was concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound C28-3 (1.46 g, 6.51 mmol, 62.3% yield) as a pale yellow oil. 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) + .

[0534] Step 3: Synthesis of compound C28-4 ((4-(2-ethoxyethoxy)phenyl)methanol) Compound C28-3 (0.700 g, 3.12 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (7.00 mL), and lithium aluminum hydride (237 mg, 6.24 mmol, 2.00 equiv) was added slowly at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 3 hours. Ice water (50.0 mL) was then added at 0 °C, and 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, which was concentrated in vacuo to obtain compound C28-4 (0.62 g, crude product) as a colorless, clear 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).

[0535] Step 4: Synthesis of intermediate C28 Compound C28-4 (0.560 g, 2.85 mmol, 1.00 equiv) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (2.46 g, 20.7 mmol, 1.50 mL, 7.25 equiv) 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 in vacuo to give compound C28 (0.60 g, crude product) as a pale yellow oil. 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) + .

[0536] Synthesis of general intermediate C29 (1-(chloromethyl)-4-(3-methoxycyclobutoxy)benzene)

[0537] [ka]

[0538] 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 equiv.) was dissolved in tetrahydrofuran (6.50 mL), and diisobutylaluminum hydride (1 M, 7.75 mL, 2.50 equiv.) was added dropwise at 0° C. After the addition was complete, the resulting mixture was stirred at 25° C. for 2 hours. Saturated aqueous ammonium chloride solution (20.0 mL) was added dropwise at 0° C. to quench the reaction, 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, which was concentrated in vacuo to obtain compound C29-2 (0.65 g, crude product) as a pale yellow oil. 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).

[0539] Step 2: Synthesis of compound C29-3 ((4-(3-methoxycyclobutoxy)phenyl)methanol) Compound C29-2 (0.65 g, 3.15 mmol, 1.00 equiv) was dissolved in methanol (6.00 mL), and sodium borohydride (0.210 g, 5.55 mmol, 1.76 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was heated to 25 °C and stirred for 2 h. 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 in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to obtain compound C29-3 (0.12 g, crude product) as a pale yellow oil. 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).

[0540] Step 3: Synthesis of compound C29 Compound C29-3 (0.12 g, 576 μmol, 1.00 equiv) was dissolved in dichloromethane (3.0 mL), and thionyl chloride (686 mg, 5.76 mmol, 418 μL, 10.0 equiv) 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 in vacuo to give compound C29 (0.120 g, 529 μmol, 91.9% yield) as a pale yellow oil. 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) + .

[0541] Synthesis of general intermediate C30 (2-(4-(chloromethyl)-3-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0542] [ka]

[0543] 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 equiv.) was added to tetrachloromethane (75.0 mL), and N-bromosuccinimide (10.9 g, 61.0 mmol, 2.20 equiv.) was added portionwise at room temperature. After the addition was complete, the resulting mixture was heated to 85 °C and stirred for 12 h. The reaction mixture was filtered to obtain the filtrate, which was concentrated in vacuo 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, 69.3% yield) as a colorless, clear 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).

[0544] Step 2: Synthesis of compound C30-3 (methyl 4-formyl-2-methoxybenzoate) Compound C30-2 (5.00 g, 14.8 mmol, 1.00 equiv.) was dissolved in acetone (60.0 mL), and silver nitrate (7.57 g, 44.6 mmol, 3.01 equiv.) and water (15.0 mL) were added. The resulting mixture was stirred at 20 °C for 3 h and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain a 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, 90.5% yield) 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).

[0545] Steps 3-6: Synthesis of intermediate C30 For steps 3-6, the same steps as for intermediate C5 were followed, using C30-3 as the starting material, to give intermediate C30 (320 mg, 938 μmol, 75.0% yield, white solid). LC-MS: m / z = 305.1 (M+H). + .

[0546] Synthesis of general intermediate C31 (2-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0547] [ka]

[0548] Following the same steps as for intermediate C30, using methyl 3-methoxy-4-methylbenzoate (compound C31-1) as the starting material, intermediate C31 (450 mg, white solid) was obtained. LC-MS: m / z=305.1 (M+H). + .

[0549] Synthesis of general intermediate C32 (1-(4-(chloromethyl)-3-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0550] [ka]

[0551] Following the same steps as for intermediate C11, using methyl 2-methoxy-4-aminobenzoate (compound C32-1) as the starting material, intermediate C32 (1.18 g, 3.87 mmol, 88.5% yield, white solid) was obtained. LC-MS: m / z = 305.1 (M+H). + .

[0552] Synthesis of general intermediate C33 (1-(4-(chloromethyl)-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0553] [ka]

[0554] Following the same steps as for intermediate C11, using methyl 4-amino-3-methoxybenzoate (compound C33-1) as the starting material, intermediate C33 (796.0 mg, 2.61 mmol, 79.6% yield, white solid) was obtained. LC-MS: m / z = 305.0 (M+H). + .

[0555] General Intermediate C35 (Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0556] [ka]

[0557] 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 in vacuo to give 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 give the filtrate, which was concentrated in vacuo to give compound C35-2 (26 g, crude product). LC-MS: m / z = 151.0 (M+H). + .

[0558] Step 2: Synthesis of compound C35-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-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-dicarboxylate (25 g, 117.9 mmol, 1.2 equiv.) were dissolved in dichloromethane (295 mL) and water (295 mL). Silver nitrate (6.0 g, 35.4 mmol, 0.3 equiv.) and ammonium persulfate (44.9 g, 78.7 mmol, 2.0 equiv.) were then added, and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture 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. It was concentrated in vacuo to give compound C35-3 (35.2 g, crude product) as a yellow oil. 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) + .

[0559] Step 3: Synthesis of compound C35-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-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 equiv.) was added slowly at 0 °C. After the addition was complete, the resulting mixture was heated to 20 °C and stirred for 3 h. Then, ice water (50.0 mL) was added at 0 °C, and the resulting mixture was stirred for 10 min 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. It was concentrated under vacuum to obtain compound C35-4 (25.1 g, crude product) as a yellow oil. LC-MS: m / z = 289.1 (M+H). + .

[0560] 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 equiv.), and 4-dimethylaminopyridine (32.0 g, 261.6 mmol, 3.0 equiv.) were added sequentially to dichloromethane (251 mL), and the resulting mixture was stirred at 25 °C for 16 h. 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) + .

[0561] Synthesis of general intermediate C48 (2-(4-(chloromethyl)phenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole)

[0562] [ka]

[0563] Step 1: Synthesis of compound C48-2 ((2-(4-bromophenyl)-1H-imidazol-4-yl)methanol) 4-Bromobenzimidamide hydrochloride (compound C48-1, 17.8 g, 75.36 mmol), 1,3-dihydroxyacetone dimer (15 g, 83.26 mmol, 1.1 eq), ammonium chloride (20 g, 374 mmol, 5 eq), and sodium hydroxide (3 g, 75.36 mmol, 1 eq) were added sequentially to aqueous ammonia (500 mL), and the resulting mixture was stirred at an external temperature of 80 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered to obtain a solid. It 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). + .

[0564] Step 2: Synthesis of compound C48-3 (2-(4-bromophenyl)-1H-imidazole-4-carbaldehyde) 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 and filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain compound C48-3 (11.1 g, crude product) as a white solid. LC-MS: m / z=250.8 (M+H). + .

[0565] Step 3: Synthesis of compound C48-4 (2-(4-bromophenyl)-1-methyl-1H-imidazole-4-carbaldehyde) Compound C48-3 (11.1 g, 44.4 mmol), iodomethane (8.2 g, 57.7 mmol, 1.3 equiv.), and potassium carbonate (24.6 g, 177.6 mmol, 4 equiv.) were added to N,N-dimethylformamide (120 mL). The reaction mixture was stirred at an external temperature of 45 °C for 3 hours and filtered to obtain the filtrate. 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 to 1 / 1) to obtain compound C48-4 and compound C48-4a (6.8 g in total) as a white solid. LC-MS: m / z = 265.0 (M+H). + .

[0566] Step 4: Synthesis of compound C48-5 (2-(4-bromophenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole) Compound C48-4 and compound 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 saturated aqueous 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 to 1 / 1) to obtain compounds C48-5 and C48-5a (4.1 g) as a white solid. LC-MS: m / z = 286.9 (M+H). + .

[0567] Step 5: Synthesis of compound C48-6 (ethyl 4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzoate) Compounds C48-5 and C48-5a (800 mg, 2.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.36 g, 1.68 mmol, 0.6 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (730 mg, 1.26 mmol, 0.45 equiv.), and triethylamine (1.42 g, 14 mmol, 5 equiv.) were added sequentially to absolute ethanol (32 mL), and the resulting mixture was stirred under a carbon monoxide atmosphere (double-walled balloon, 25 psi) at an external temperature of 85 °C for 20 h. EA (100 mL) was then added, and the resulting mixture was stirred for 10 min and 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). + .

[0568] Step 6: Synthesis of compound C48-7 ((4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)phenyl)methanol) Compound C48-6 and compound 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 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 about 5 with 1 M aqueous hydrochloric acid. The resulting mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give crude compound C48-7 and compound C48-7a (500 mg). LC-MS: m / z = 239.1 (M+H). + .

[0569] Step 7: Synthesis of intermediate C48 Compound C48-7 and compound 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 directly 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 C48 (130 mg). LC-MS: m / z = 257.1 (M+H). + .

[0570] Synthesis of general intermediate C49 (2-(chloromethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine)

[0571] [ka]

[0572] Following the same steps as for Intermediate C5, using methyl 5-formylpyridine-2-carboxylate (compound C49-1) as the starting material, Intermediate C49 (2.0 g) was obtained. LC-MS: m / z=276.0 (M+H). + .

[0573] Synthesis of general intermediate C57 (2-(4-(chloromethyl)phenyl)-1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole)

[0574] [ka]

[0575] Following the same steps as for Intermediate C5, using methyl p-formylbenzoate (compound C5-1) as the starting material, Intermediate C57 (1.83 g) was obtained. LC-MS: m / z = 301.2 (M+H). + .

[0576] Synthesis of general intermediate C58 (2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole)

[0577] [ka]

[0578] Following the same steps as for intermediate C5, intermediate C58 (0.6 g) was obtained using methyl p-formylbenzoate (compound C5-1) as the starting material. 1 LC-MS: m / z = 303.1 (M+H) + .

[0579] Synthesis of general intermediate C59 (2-(4-(chloromethyl)phenyl)-1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole)

[0580] [ka]

[0581] Following the same steps as for Intermediate C5, using methyl p-formylbenzoate (compound C5-1) as the starting material, Intermediate C59 (0.6 g) was obtained. LC-MS: m / z = 293.1 (M+H). + .

[0582] Synthesis of general intermediate D5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0583] [ka]

[0584] Following the same steps as for intermediate BB13, intermediate D5 (0.16 g, 0.63 mmol, 85.9% yield) was obtained using compound C5 (0.2 g, 0.73 mmol, 1.00 equiv) as the starting material. 1 LC-MS: m / z = 256.0 (M+H) + .

[0585] Synthesis of general intermediate D11 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine)

[0586] [ka]

[0587] Following the same steps as for intermediate BB13, compound C11 (2.2 g, 8.03 mmol, 1.00 equiv) was used as the starting material to give intermediate D11 (1.59 g, 6.23 mmol, 77.6% yield). 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) + .

[0588] Synthesis of general intermediate D58 ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0589] [ka]

[0590] Following the same steps as for intermediate BB13, compound C58 (1.5 g, 4.95 mmol, 1.00 equiv.) was used as the starting material to give intermediate D58 (0.98 g, 3.46 mmol, 69.9% yield). LC-MS: m / z = 284.3 (M+H). + .

[0591] Synthesis of intermediate BB1C2 (2-chloro-5-methoxy-N-methyl-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0592] [ka]

[0593] Compound BB1 (500.0 mg, 2.89 mmol, 1.00 equiv.), compound C2 (634.4 mg, 3.04 mmol, 1.05 equiv.), and cesium carbonate (3.77 g, 11.56 mmol, 4.0 equiv.) were added sequentially to N,N-dimethylformamide (10.0 mL), and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to 25 °C. Ethyl acetate (100.0 mL) was added, and the resulting mixture was stirred for 5 min and filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to obtain intermediate BB1C2 (910.3 mg, 2.63 mmol, 91.0% yield) as a pale yellow solid. LC-MS: m / z=347.2 (M+H) + .

[0594] Synthesis of intermediate BB1C3 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0595] [ka]

[0596] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C3 were used as starting materials to give intermediate BB1C3 (689.9 mg, 2.03 mmol, 87.5% yield, pale yellow solid). LC-MS: m / z=341.2 (M+H). + .

[0597] Synthesis of intermediate BB1C4 (2-chloro-5-methoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0598] [ka]

[0599] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C4 were used as starting materials to give intermediate BB1C4 (352.5 mg, 0.843 mmol, 69.5% yield, pale yellow solid). LC-MS: m / z=419.2 (M+H). + .

[0600] Synthesis of intermediate BB1C5 (2-chloro-5-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0601] [ka]

[0602] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C5 were used as starting materials to give intermediate BB1C5 (2.39 g, 5.81 mmol, 81.6% yield, 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) + .

[0603] Synthesis of intermediate BB1C6 (2-chloro-5-methoxy-N-methyl-N-(1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0604] [ka]

[0605] Following the same steps as for intermediate BB1C2, intermediate BB1 ​​and compound C6 were used as starting materials to give intermediate BB1C6 (169.7 mg, 0.49 mmol, 59.9% yield, pale yellow solid). LC-MS: m / z=348.2 (M+H). + .

[0606] Synthesis of intermediate BB1C11 (2-chloro-5-methoxy-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0607] [ka]

[0608] Following the same steps as for intermediate BB1C2, using intermediate BB1 ​​and compound C11 as starting materials, intermediate BB1C11 (3.31 g, 8.04 mmol, 73.2% yield, off-white solid) was obtained. LC-MS: m / z=412.8 (M+H). + .

[0609] Synthesis of intermediate BB2C2 (2-chloro-5-methoxy-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0610] [ka]

[0611] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C2 were used as starting materials to give intermediate BB2C2 (134.1 mg, 0.40 mmol, 46.6% yield, pale yellow oil). LC-MS: m / z=333.1 (M+H). + .

[0612] Synthesis of intermediate BB2C3 (2-chloro-5-methoxy-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0613] [ka]

[0614] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C3 were used as starting materials to give intermediate BB2C3 (255.5 mg, 0.78 mmol, 87.7% yield, pale yellow solid). LC-MS: m / z = 327.0 (M+H). + .

[0615] Synthesis of intermediate BB2C4 (2-chloro-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0616] [ka]

[0617] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C4 were used as starting materials to give intermediate BB2C4 (98.8 mg, 0.24 mmol, 39.2% yield, pale yellow solid). LC-MS: m / z = 405.1 (M+H). + .

[0618] Synthesis of intermediate BB2C5 (2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0619] [ka]

[0620] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C5 were used as starting materials to give intermediate BB2C5 (18.9 g, 47.60 mmol, 69.8% yield, 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) + .

[0621] Synthesis of intermediate BB2C6 (2-chloro-5-methoxy-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0622] [ka]

[0623] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C6 were used as starting materials to give intermediate BB2C6 (100.6 mg, 0.30 mmol, 35.3% yield, pale yellow solid). LC-MS: m / z = 344.1 (M+H). + .

[0624] Synthesis of intermediate BB2C9 (2-chloro-5-methoxy-N-(((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0625] [ka]

[0626] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C9 were used as starting materials to give intermediate BB2C9 (31.1 mg, 0.077 mmol, 13.2% yield, pale yellow solid). LC-MS: m / z=404.2 (M+H). + .

[0627] Synthesis of intermediate BB2C11 (2-chloro-5-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0628] [ka]

[0629] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C11 were used as starting materials to give intermediate BB2C11 (5.6 g, 14.10 mmol, 77.8% yield, 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) + .

[0630] Synthesis of intermediate BB2C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0631] [ka]

[0632] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C12 were used as starting materials to give intermediate BB2C12 (130.3 mg, 0.36 mmol, 88.2% yield, 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) + .

[0633] Synthesis of intermediate BB2C13 (2-chloro-5-methoxy-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0634] [ka]

[0635] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C13 were used as starting materials to give intermediate BB2C13 (455.1 mg, 1.16 mmol, 69.9% yield, pale yellow solid). LC-MS: m / z=395.0 (M+H). + .

[0636] Synthesis of intermediate BB2C14 (2-chloro-5-methoxy-N-(4-(5-methylpyridin-2-yl)benzyl)pyrimidin-4-amine)

[0637] [ka]

[0638] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C14 were used as starting materials to give intermediate BB2C14 (173.45 mg, 0.51 mmol, 90.3% yield, pale yellow solid). LC-MS: m / z=341.1 (M+H). + .

[0639] Synthesis of intermediate BB2C19 (2-chloro-5-methoxy-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidin-4-amine)

[0640] [ka]

[0641] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C19 were used as starting materials to give intermediate BB2C19 (281.3 mg, 0.66 mmol, 35.6% yield, pale yellow solid). LC-MS: m / z=427.3 (M+H). + .

[0642] Synthesis of intermediate BB2C26 (6-((2-chloro-5-methoxypyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0643] [ka]

[0644] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C26 were used as starting materials to give intermediate BB2C26 (379.2 mg, 1.05 mmol, 82.0% yield, pale yellow solid). LC-MS: m / z=361.1 (M+H). + .

[0645] Synthesis of intermediate BB2C27 (2-chloro-5-methoxy-N-(4-(pyridin-2-ylmethoxy)benzyl)pyrimidin-4-amine)

[0646] [ka]

[0647] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C27 were used as starting materials to give intermediate BB2C27 (268.5 mg, 0.61 mmol, 93.6% yield, 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) + .

[0648] Synthesis of intermediate BB2C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)-5-methoxypyrimidin-4-amine)

[0649] [ka]

[0650] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C28 were used as starting materials to give intermediate BB2C28 (316.9 mg, 0.94 mmol, 78.8% yield, 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) + .

[0651] Synthesis of intermediate BB2C30 (2-chloro-5-methoxy-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0652] [ka]

[0653] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C30 were used as starting materials to give intermediate BB2C30 (662.0 mg, 1.55 mmol, 86.7% yield, pale yellow solid). LC-MS: m / z = 428.0 (M+H). + .

[0654] Synthesis of intermediate BB2C31 (2-chloro-5-methoxy-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0655] [ka]

[0656] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C31 were used as starting materials to give intermediate BB2C31 (337.4 mg, 0.79 mmol, 93.9% yield, white solid). LC-MS: m / z=428.1 (M+H). + .

[0657] Synthesis of intermediate BB2C33 (2-chloro-5-methoxy-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0658] [ka]

[0659] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C33 were used as starting materials to give intermediate BB2C33 (3.02 g, 2.66 mmol, 88.3% yield, white solid). LC-MS: m / z=428.0 (M+H). + .

[0660] Synthesis of intermediate BB2C35 (2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidin-4-amine)

[0661] [ka]

[0662] Compound BB2 (1.0 g, 6.29 mmol, 1.00 equiv.), compound C35 (2.78 g, 6.29 mmol, 1.0 equiv.), and cesium carbonate (10.2 g, 31.45 mmol, 5.0 equiv.) were added sequentially 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 and filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0 to 0 / 1) to give intermediate BB2C35 (1.03 g, 2.41 mmol, 38.3% yield) as a white solid. LC-MS: m / z = 430.1 (M+H). + .

[0663] Synthesis of intermediate BB2C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0664] [ka]

[0665] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C48 were used as starting materials to give intermediate BB2C48 (371.5 mg, 0.98 mmol, 77.5% yield, white solid). LC-MS: m / z=380.3 (M+H). + .

[0666] Synthesis of intermediate BB2C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0667] [ka]

[0668] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C58 were used as starting materials to give intermediate BB2C58 (357.1 mg, 0.84 mmol, 97.0% yield, 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) + .

[0669] Synthesis of intermediate BB2C59 (2-chloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0670] [ka]

[0671] Following the same steps as for intermediate BB1C2, intermediate BB2 and compound C59 were used as starting materials to give intermediate BB2C59 (91.3 mg, 0.22 mmol, 78.8% yield, white solid). LC-MS: m / z=426.1 (M+H). + .

[0672] Synthesis of intermediate BB3C4 (2-chloro-5-isopropoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0673] [ka]

[0674] Following the same steps as for intermediate BB2C35, intermediate BB3 and compound C4 were used as starting materials to give intermediate BB3C4 (178.5 mg, 0.40 mmol, 28.7% yield, white solid). LC-MS: m / z=447.3 (M+H). + .

[0675] Synthesis of intermediate BB3C5 (2-chloro-5-isopropoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0676] [ka]

[0677] Following the same steps as for intermediate BB1C2, intermediate BB3 and compound C5 were used as starting materials to give intermediate BB3C5 (2.1 g, 4.78 mmol, 86.4% yield, white solid). LC-MS: m / z=440.2 (M+H). + .

[0678] Synthesis of intermediate BB4C4 (2-chloro-5-isopropoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0679] [ka]

[0680] Following the same steps as for intermediate BB2C35, intermediate BB4 and compound C4 were used as starting materials to give intermediate BB4C4 (159.9 mg, 0.37 mmol, 39.6% yield, white solid). LC-MS: m / z=433.2 (M+H). + .

[0681] Synthesis of intermediate BB4C5 (2-chloro-5-isopropoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0682] [ka]

[0683] Following the same steps as for intermediate BB1C2, intermediate BB4 and compound C5 were used as starting materials to give intermediate BB4C5 (2.03 g, 4.78 mmol, 86.4% yield, white solid). LC-MS: m / z=426.1 (M+H). + .

[0684] Synthesis of intermediate BB4C19 (2-chloro-5-isopropoxy-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidin-4-amine)

[0685] [ka]

[0686] Following the same steps as for intermediate BB1C2, intermediate BB4 and compound C19 were used as starting materials to give intermediate BB4C19 (349.7 mg, 0.77 mmol, 83.2% yield, white solid). LC-MS: m / z=455.2 (M+H). + .

[0687] Synthesis of intermediate BB12C2 (2-chloro-N-((4-(pyridin-2-yl)cyclohexyl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0688] [ka]

[0689] Following the same steps as for intermediate BB2C35, intermediate BB12 and compound C2 were used as starting materials to give intermediate BB12C2 (51.8 mg, 0.14 mmol, 35.4% yield, white solid). LC-MS: m / z = 371.1 (M+H). + .

[0690] Synthesis of intermediate BB12C3 (2-chloro-N-(4-(pyridin-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0691] [ka]

[0692] Following the same steps as for intermediate BB1C2, intermediate BB12 and compound C3 were used as starting materials to give intermediate BB12C3 (396.8 mg, 1.09 mmol, 76.6% yield, pale yellow solid). LC-MS: m / z = 365.0 (M+H). + .

[0693] Synthesis of intermediate BB12C4 (2-chloro-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0694] [ka]

[0695] Following the same steps as for intermediate BB2C35, using intermediates BB12 and C4 as starting materials, intermediate BB12C4 (53.1 mg, 0.12 mmol, 21.1% yield, pale yellow oil) was obtained. LC-MS: m / z=443.0 (M+H). + .

[0696] Synthesis of intermediate BB12C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0697] [ka]

[0698] Following the same steps as for intermediate BB1C2, intermediate BB12 and compound C5 were used as starting materials to give intermediate BB12C5 (248.0 mg, 0.57 mmol, 88.8% yield, pale yellow solid). LC-MS: m / z = 436.1 (M+H). + .

[0699] Synthesis of intermediate BB12C6 (2-chloro-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0700] [ka]

[0701] Following the same steps as for intermediate BB2C35, intermediate BB12 and compound C6 were used as starting materials to give intermediate BB12C6 (29.7 mg, 0.08 mmol, 18.0% yield, pale yellow oil). LC-MS: m / z=372.3 (M+H). + .

[0702] Synthesis of intermediate BB13C3 (2-chloro-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0703] [ka]

[0704] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C3 were used as starting materials to give intermediate BB13C3 (1.19 g, 3.55 mmol, 89.4% yield, pale yellow solid). LC-MS: m / z = 337.1 (M+H). + .

[0705] Synthesis of intermediate BB13C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0706] [ka]

[0707] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C5 were used as starting materials to give intermediate BB13C5 (761.1 mg, 1.87 mmol, 76.7% yield, 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) + .

[0708] Synthesis of intermediate BB13C7 (2-chloro-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)furo[3,2-d]pyrimidin-4-amine)

[0709] [ka]

[0710] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C7 were used as starting materials to give intermediate BB13C7 (342.6 mg, 0.83 mmol, 56.9% yield, white solid). LC-MS: m / z = 414.0 (M+H). + .

[0711] Synthesis of intermediate BB13C11 (2-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0712] [ka]

[0713] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C11 were used as starting materials to give intermediate BB13C11 (4.23 g, 10.39 mmol, 76.9% yield, pale yellow solid). LC-MS: m / z=408.0 (M+H). + .

[0714] Synthesis of intermediate BB13C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0715] [ka]

[0716] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C12 were used as starting materials to give intermediate BB13C12 (458.8 mg, 1.22 mmol, 88.7% yield, 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) + .

[0717] Synthesis of intermediate BB13C19 (2-chloro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)furo[3,2-d]pyrimidin-4-amine)

[0718] [ka]

[0719] Following the same steps as for intermediate BB2C35, intermediate BB13 and compound C19 were used as starting materials to give intermediate BB13C19 (383.8 mg, 0.88 mmol, 22.3% yield, pale yellow oil). LC-MS: m / z=437.0 (M+H). + .

[0720] Synthesis of intermediate BB13C25 (6-(((2-chlorofuro[3,2-d]pyrimidin-4-yl)amino)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0721] [ka]

[0722] 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, 90.4% yield, 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) + .

[0723] Synthesis of intermediate BB13C26 (6-(((2-chlorofuro[3,2-d]pyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0724] [ka]

[0725] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C26 were used as starting materials to give intermediate BB13C26 (233.1 mg, 0.63 mmol, 82.6% yield, pale yellow solid). LC-MS: m / z = 371.2 (M+H).+ .

[0726] Synthesis of intermediate BB13C27 (2-chloro-N-(4-(pyridin-2-ylmethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0727] [ka]

[0728] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C27 were used as starting materials to give intermediate BB13C27 (256.3 mg, 0.70 mmol, 66.8% yield, pale yellow solid). LC-MS: m / z=366.9 (M+H). + .

[0729] Synthesis of intermediate BB13C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0730] [ka]

[0731] Following the same steps as for intermediate BB1C2, intermediates BB13 and C28 were used as starting materials to give intermediate BB13C28 (118.0 mg, 0.34 mmol, 84.5% yield, pale yellow solid). LC-MS: m / z=348.2 (M+H). + .

[0732] Synthesis of intermediate BB13C29 (2-chloro-N-(4-(3-methoxycyclobutoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0733] [ka]

[0734] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C29 were used as starting materials to give intermediate BB13C29 (244.2 mg, 0.68 mmol, 93.5% yield, pale yellow solid). LC-MS: m / z=360.2 (M+H). + .

[0735] Synthesis of intermediate BB13C30 (2-chloro-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0736] [ka]

[0737] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C30 were used as starting materials to give intermediate BB13C30 (292.9 mg, 0.67 mmol, 78.8% yield, white solid). LC-MS: m / z=438.1 (M+H). + .

[0738] Synthesis of intermediate BB13C31 (2-chloro-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0739] [ka]

[0740] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C31 were used as starting materials to give intermediate BB13C31 (214.2 mg, 0.49 mmol, 73.9% yield, white solid). LC-MS: m / z=438.0 (M+H). + .

[0741] Synthesis of intermediate BB13C32 (2-chloro-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0742] [ka]

[0743] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C32 were used as starting materials to give intermediate BB13C32 (100.5 mg, 0.23 mmol, 70.0% yield, white solid). LC-MS: m / z=438.0 (M+H). + .

[0744] Synthesis of intermediate BB13C33 (2-chloro-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0745] [ka]

[0746] Following the same steps as for intermediate BB1C2, intermediate BB13 and compound C33 were used as starting materials to give intermediate BB13C33 (257.6 mg, 0.59 mmol, 84.2% yield, pale yellow solid). LC-MS: m / z = 437.9 (M+H). + .

[0747] Synthesis of intermediate BB13C35 (2-chloro-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)furo[3,2-d]pyrimidin-4-amine)

[0748] [ka]

[0749] Following the same steps as for intermediate BB2C35, intermediate BB13 and compound C35 were used as starting materials to give intermediate BB13C35 (48.3 mg, 0.11 mmol, 28.8% yield, white solid). LC-MS: m / z=440.2 (M+H). + .

[0750] Synthesis of intermediate BB13C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0751] [ka]

[0752] Following the same steps as for intermediate BB1C2, using intermediates BB13 and C48 as starting materials, intermediate BB13C48 (886.2 mg, 2.28 mmol, 77.9% yield, white solid) was obtained. LC-MS: m / z=390.1 (M+H). + .

[0753] Synthesis of intermediate BB14C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidin-4-amine)

[0754] [ka]

[0755] Following the same steps as for intermediate BB1C2, intermediate BB14 and compound C5 were used as starting materials to give intermediate BB14C5 (1.22 g, 2.92 mmol, 93.3% yield, pale yellow solid). LC-MS: m / z=419.1 (M+H). + .

[0756] Synthesis of intermediate BB15C5 (2,5-dichloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0757] [ka]

[0758] Following the same steps as for intermediate BB1C2, intermediate BB15 and compound C5 were used as starting materials to give intermediate BB15C5 (398.7 mg, 0.99 mmol, 80.4% yield, 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) + .

[0759] Synthesis of intermediate BB15C59 (2,5-dichloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0760] [ka]

[0761] Following the same steps as for intermediate BB1C2, intermediate BB15 and compound C59 were used as starting materials to give intermediate BB15C59 (124.0 mg, 0.30 mmol, 58.9% yield, white solid). LC-MS: m / z=420.0 (M+H). + .

[0762] Synthesis of intermediate BB16C58 (2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyrimidin-4-amine)

[0763] [ka]

[0764] Following the same steps as for intermediate BB1C2, intermediate BB16 and compound C58 were used as starting materials to give intermediate BB16C58 (6.66 g, 16.69 mmol, 93.3% yield, pale yellow solid). LC-MS: m / z = 428.2 (M+H). + .

[0765] Synthesis of intermediate BB16-D3C57 (2-chloro-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-fluoro-N-(methyl-d3)pyrimidin-4-amine)

[0766] [ka]

[0767] Following the same steps as for intermediate BB1C2, intermediate BB16-D3 and compound C57 were used as starting materials to give intermediate BB16-D3C57 (1.33 g, 3.10 mmol, 89.8% yield, off-white solid). LC-MS: m / z = 429.3 (M+H). + .

[0768] Synthesis of intermediate BB16-D3C58 (2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(methyl-d3)pyrimidin-4-amine)

[0769] [ka]

[0770] Following the same steps as for intermediate BB1C2, intermediate BB16-D3 and compound C58 were used as starting materials to give intermediate BB16-D3C58 (1.54 g, 3.57 mmol, 79.6% yield, off-white solid). LC-MS: m / z = 431.1 (M+H). + .

[0771] Synthesis of intermediate BB16-D3C59 (2-chloro-5-fluoro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(methyl-D3)pyrimidin-4-amine)

[0772] [ka]

[0773] 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, 84.1% yield, yellow solid). LC-MS: m / z = 421.1 (M+H). + .

[0774] Synthesis of intermediate BB17C5 (2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carbonitrile)

[0775] [ka]

[0776] Following the same steps as for intermediate BB1C2, intermediate BB17 and compound C5 were used as starting materials to give intermediate BB17C5 (149.0 mg, 0.38 mmol, 48.7% yield, off-white solid). LC-MS: m / z=393.0 (M+H). + .

[0777] Synthesis of intermediate BB19C4 (2-chloro-5-(difluoromethoxy)-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0778] [ka]

[0779] Following the same steps as in Example 1, intermediate BB2C35, intermediate BB19, and compound C4 were used as starting materials to obtain intermediate BB19C4 (44.0 mg, 0.10 mmol, 17.7% yield, clear, colorless oil). LC-MS: m / z = 441.0 (M+H). + .

[0780] Synthesis of intermediate BB19C5 (2-chloro-5-(difluoromethoxy)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0781] [ka]

[0782] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C5 were used as starting materials to give intermediate BB19C5 (1.03 g, 2.33 mmol, 82.2% yield, white solid). LC-MS: m / z=434.0 (M+H). + .

[0783] Synthesis of intermediate BB19C11 (2-chloro-5-(difluoromethoxy)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0784] [ka]

[0785] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C11 were used as starting materials to give intermediate BB19C11 (545.7 mg, 1.26 mmol, 77.3% yield, white solid). LC-MS: m / z=434.2 (M+H). + .

[0786] Synthesis of intermediate BB19C30 (2-chloro-5-(difluoromethoxy)-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0787] [ka]

[0788] Following the same steps as for intermediate BB1C2, intermediate BB19 and compound C30 were used as starting materials to give intermediate BB19C30 (546.4 mg, 1.18 mmol, 66.5% yield, off-white solid). LC-MS: m / z=464.0 (M+H). + .

[0789] Synthesis of intermediate BB36C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0790] [ka]

[0791] Following the same steps as for intermediate BB1C2, intermediate BB36 and compound C58 were used as starting materials to give intermediate BB36C58 (382.0 mg, 0.84 mmol, 69.3% yield, clear colorless oil). LC-MS: m / z=454.0 (M+H). + .

[0792] Synthesis of intermediate BB42C5 (2-chloro-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(prop-2-yn-1-yl)pyrimidin-4-amine)

[0793] [ka]

[0794] Following the same steps as for intermediate BB1C2, intermediate BB42 and compound C5 were used as starting materials to give intermediate BB42C5 (332.6 mg, 0.76 mmol, 44.5% yield, off-white solid). LC-MS: m / z=436.2 (M+H). + .

[0795] Synthesis of intermediate BB43C5 (2-chloro-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(tetrahydrofuran-2-yl)pyrimidin-4-amine)

[0796] [ka]

[0797] Following the same steps as for intermediate BB1C2, intermediate BB43 and compound C5 were used as starting materials to give intermediate BB43C5 (101.1 mg, 0.22 mmol, 37.3% yield, white solid). LC-MS: m / z = 468.1 (M+H). + .

[0798] Synthesis of intermediate BB44C5 (2-chloro-N-cyclopropyl-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0799] [ka]

[0800] Following the same steps as for intermediate BB1C2, intermediate BB44 and compound C5 were used as starting materials to give intermediate BB44C5 (258.3 mg, 0.59 mol, 74.8% yield, pale yellow solid). LC-MS: m / z = 438.1 (M+H). + .

[0801] Synthesis of intermediate BB45C5 (N-(2-chloro-5-methoxypyrimidin-4-yl)-O-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[0802] [ka]

[0803] Compound BB45 (250 mg, 1.3 mmol, 1.0 equiv.), compound C5 (392 mg, 1.43 mmol, 1.1 equiv.), and potassium carbonate (548 mg, 4.0 mmol, 3.0 equiv.) were added sequentially to dimethyl sulfoxide (5.0 mL), and the resulting mixture was stirred at 85 °C for 1 h. The reaction mixture was cooled to 25 °C. Ethyl acetate (20.0 mL) was added, and the resulting mixture was stirred for 5 min and filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain intermediate BB45C5 (160.5 mg, 0.38 mmol, 28.9% yield) as a pale yellow oil. 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) + .

[0804] Synthesis of intermediate BB18D5 (2-chloro-5-ethynyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0805] [ka]

[0806] 2-(2,4-Dichloropyrimidin-5-yl)ethynyl-trimethylsilane (compound BB18-1, 2.2 g, 8.16 mmol, 1.00 equiv.), compound D5 (2.19 g, 8.57 mmol, 1.05 equiv.), and potassium carbonate (4.51 g, 32.64 mmol, 4.0 equiv.) were added sequentially 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 and filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give intermediate BB18D5 (2.24 g, 5.73 mmol, 70.2% yield) as a white solid. LC-MS: m / z = 392.2 (M+H) + .

[0807] Synthesis of intermediate BB21D5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-morpholinopyrimidin-4-amine)

[0808] [ka]

[0809] Following the same steps as for intermediate BB18D5, intermediate BB21 and compound D5 were used as starting materials to give intermediate BB21D5 (880.0 mg, 1.95 mmol, 88.6% yield, white solid). LC-MS: m / z=453.1 (M+H). + .

[0810] Synthesis of intermediate BB22D5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(4-methylpiperazin-1-yl)pyrimidin-4-amine)

[0811] [ka]

[0812] Following the same steps as for intermediate BB18D5, intermediate BB22 and compound D5 were used as starting materials to give intermediate BB22D5 (441.9 mg, 0.95 mmol, 87.4% yield, off-white solid). LC-MS: m / z=466.2 (M+H). + .

[0813] Synthesis of intermediate BB24D5 (2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-ol)

[0814] [ka]

[0815] Following the same steps as for intermediate BB18D5, intermediate BB24 and compound D5 were used as starting materials to give intermediate BB24D5 (26.8 mg, 0.07 mmol, 22.8% yield, pale yellow solid). LC-MS: m / z=384.1 (M+H). + .

[0816] Synthesis of intermediate BB24D11 (2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)amino)pyrimidin-5-ol)

[0817] [ka]

[0818] Following the same steps as for intermediate BB18D5, using intermediates BB24 and D11 as starting materials, intermediate BB24D11 (115.1 mg, 0.3 mmol, 83.0% yield, white solid) was obtained. LC-MS: m / z=384.2 (M+H). + .

[0819] Synthesis of intermediate BB35D5 ((2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)methanol)

[0820] [ka]

[0821] Following the same steps as for intermediate BB18D5, intermediate BB35 and compound D5 were used as starting materials to give intermediate BB35D5 (333.8 mg, 1.86 mmol, 55.6% yield, clear colorless oil). LC-MS: m / z=398.1 (M+H). + .

[0822] Synthesis of intermediate BB41C5 (methyl 2-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)acetate)

[0823] [ka]

[0824] Following the same steps as for intermediate BB18D5, intermediate BB41 and compound D5 were used as starting materials to give intermediate BB41D5 (133.9 mg, 0.30 mmol, 69.9% yield, pale yellow solid). LC-MS: m / z=440.2 (M+H). + . [Example]

[0825] Example 1 Synthesis of Compound 1 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0826] [ka]

[0827] Compound A5 (100 mg, 389 μmol, 1.00 equivalents) was dissolved in tetrahydrofuran (2.5 mL), and sodium hydride (62.2 mg, 1.55 mmol, 60.0% purity, 4.00 equivalents) was added portionwise at 0° C. After the addition was complete, the resulting mixture was reacted at 0° C. for 30 minutes. Compound B10 (95.0 mg, 466 μmol, 1.20 equivalents) was then added. After the addition was complete, the resulting mixture was heated to 25° C. and stirred for 12 hours. Ice water (2.0 mL) was then 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, and filtered to obtain a filtrate. The filtrate was concentrated under vacuum to obtain a crude product. This was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: water (HCl) to ACN; B%: 15% to 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) + .

[0828] The following compounds were obtained according to the method for preparing compound 1 using different general intermediates A and B together with cesium carbonate or sodium hydride or potassium carbonate.

[0829] [Table 1A]

[0830] [Table 1B]

[0831] [Table 1C]

[0832] [Table 1D]

[0833] [Table 1E]

[0834] [Table 1F]

[0835] [Table 1G]

[0836] [Table 1H]

[0837] [Table 1I]

[0838] Example 32 Synthesis of Compound 32 (2-(2-isopropylphenyl)-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0839] [ka]

[0840] Step 1: Synthesis of compound 32-3 Compound 32-1 (200.0 mg, 1.09 mmol, 1.00 equiv.), compound 32-2 (205.0 mg, 1.09 mmol, 1.00 equiv.), and cesium carbonate (1.1 g, 3.27 mmol, 3 equiv.) were added sequentially to N,N-dimethylformamide (4.0 mL), and the resulting mixture was stirred at 60 °C for 1 h. Ethyl acetate (30.0 mL) was added, and the resulting mixture was stirred for 5 min 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 32-3 (360.9 mg). LC-MS: m / z = 337.0 (M+H). + .

[0841] Step 2: Synthesis of compound 32 Compound 32-3 (100.0 mg, 0.3 mmol, 1.00 equiv.), compound 32-4 (97.7 mg, 0.6 mmol, 2.00 equiv.), potassium phosphate (191.0 mg, 0.9 mmol, 3.00 equiv.), and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.03 mmol, 0.10 equiv.) were added sequentially to dioxane (2.0 mL) and water (0.4 mL). The resulting mixture was purged with nitrogen three times and stirred at 90 °C under a nitrogen atmosphere for 16 h. 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 in vacuo 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) + .

[0842] The following compounds were obtained according to the preparation method of Compound 32, using cesium carbonate, sodium hydride, or potassium carbonate as the reaction conditions for Step 1 and Pd(PPh3)4 / K3PO4 or XPhos-Pd-G2 / XPhos / K3PO4 as the reaction conditions for Step 2.

[0843] [Table 2A]

[0844] [Table 2B]

[0845] [Table 2C]

[0846] [Table 2D]

[0847] [Table 2E]

[0848] Example 61 Synthesis of Compound 61 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0849] [ka]

[0850] Compound BB1C2 (125.0 mg, 0.36 mmol, 1.00 equivalents), compound A1-2 (118.1 mg, 0.72 mmol, 2.00 equivalents), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, To a solution of 2.5 mL of dioxane and 0.5 mL of water was added 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 56.58 mg, 0.072 mmol, 0.20 equiv.), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 68.65 mg, 0.144 mmol, 0.40 equiv.), and potassium phosphate (229.3 mg, 1.08 mmol, 3.00 equiv.) in dioxane (2.5 mL) and water (0.5 mL) sequentially. The resulting mixture was purged with nitrogen three times and stirred at 95°C under a nitrogen atmosphere for 16 hours. Water (15 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to give the filtrate. The filtrate was concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 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). + .

[0851] The following compounds were obtained according to the preparation method of compound 61 using intermediates A series, AA series, BBC series or A series, AA series, BBD series as starting materials, XPhos-Pd-G2 / XPhos / K3PO4 as reaction reagents, and dioxane and water as solvents.

[0852] [Table 3-1]

[0853] [Table 3-2]

[0854]

Table 3-3

[0855]

Table 3-4

[0856]

Table 3-5

[0857]

Table 3-6

[0858]

Table 3-7

[0859]

Table 3-8

[0860] Table 3-9

[0861] Table 3-10

[0862] Table 3-11

[0863] Table 3-12

[0864] Table 3-13

[0865] Table 3-14

[0866]

Table 3-15

[0867]

Table 3-16

[0868]

Table 3-17

[0869]

Table 3-18

[0870]

Table 3-19

[0871]

Table 3-20

[0872]

Table 3-21

[0873]

Table 3-22

[0874]

Table 3-23

[0875]

Table 3-24

[0876]

Table 3-25

[0877]

Table 3-26

[0878]

Table 3-27

[0879]

Table 3-28

[0880]

Table 3-29

[0881]

Table 3-30

[0882]

Table 3-31

[0883] Table 3-32

[0884] Table 3-33

[0885] [Table 3-34]

[0886] [Table 3-35]

[0887] [Table 3-36]

[0888] [Table 3-37]

[0889] [Table 3-38]

[0890] [Table 3-39]

[0891] [Table 3-40]

[0892] [Table 3-41]

[0893] [Table 3-42]

[0894] (Example 204) Synthesis of Compound 204 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[0895] [ka]

[0896] Step 1: Synthesis of compound BB46-2 (O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)hydroxylamine) Compound 2,4-dichloro-5-fluoropyrimidine (compound BB46-1, 1.0 g, 5.6 mmol, 1.0 equiv.), O-(tert-butyldimethylsilyl)hydroxylamine (0.9 g, 6.2 mmol, 1.1 equiv.), and N,N-diisopropylethylamine (2.1 g, 16.8 mmol, 3.0 equiv.) were added sequentially to dioxane (20 mL), and the resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound BB46-2 (430.2 mg, 1.49 mmol, 26.6% yield) as a pale yellow oil. LC-MS: m / z = 290.0 (M+H). + .

[0897] Step 2: Synthesis of compound BB46-2C5 (O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine) Following the same steps as for intermediate BB1C2, intermediate BB46-2 (430 mg, 1.5 mmol, 1.0 equiv.) and compound C5 (452 ​​mg, 1.65 mmol, 1.1 equiv.) were used as starting materials to give intermediate BB46-2C5 (506.8 mg, 0.96 mmol, 64.1% yield, pale yellow solid). LC-MS: m / z = 528.3 (M+H). + .

[0898] Step 3: Synthesis of compound A2-7BB46-2C5 (O-(tert-butyldimethylsilyl)-N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine) Following the same steps as for compound A1-2BB1C2, intermediate BB46-2 (486.0 mg, 0.9 mmol, 1.0 equiv.) and compound A2-7 (262.1 mg, 1.35 mmol, 1.5 equiv.) were used as starting materials to obtain intermediate A2-7BB46-2C5 (323.3 mg, 0.50 mmol, 56.0% yield, yellow solid). LC-MS: m / z = 642.3 (M+H). + .

[0899] Step 4: Synthesis of Compound 204 Intermediate A2-7BB46-2C5 (323.0 mg, 0.5 mmol, 1.0 equiv) was dissolved in 4 M hydrochloric acid in methanol, and the mixture was stirred at 25 °C for 1 h. Saturated aqueous sodium bicarbonate (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 in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to obtain compound 204 (109.9 mg, 0.21 mmol, 41.7% yield) as a white solid. 1H 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) + .

[0900] (Example 205) Synthesis of Compound 205 (N-(2-(1-cyclopropyl-4-methyl-1H-pyrazol-5-yl)-5-methoxypyrimidin-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[0901] [ka]

[0902] Following the same steps as for compound 204, using intermediate BB46-2 and compound AA16 as starting materials, compound 205 (37.2 mg, 0.074 mmol, 66.9% yield, white solid) was obtained. LC-MS: m / z=500.3 (M+H). + .

[0903] (Example 206) Synthesis of Compound 206 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)cyanamide)

[0904] [ka]

[0905] Compound 29 (50 mg, 0.092 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (1.0 mL) and sodium hydride (60% content, 36.8 mg, 0.92 mmol, 10 equiv) was added portionwise at 0 °C. The reaction mixture was allowed to warm to 25 °C by natural heating and stirred for 1 h. Cyanogen bromide (48.7 mg, 0.46 mmol, 5 equiv) was added, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 206 (6.7 mg, 0.0125 mmol, 13.6% yield) as a pale white solid. 1 H 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) + .

[0906] (Example 207) Synthesis of Compound 207 (2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-methoxy-N-methyl-N-[[4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]cuban-1-yl]methyl]pyrimidin-4-amine)

[0907] [ka]

[0908] 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 equiv.) was dissolved in tetrahydrofuran (300 mL). A 10 M solution of borane dimethyl sulfide in tetrahydrofuran (5.82 mL, 1.20 equiv.) 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. The resulting mixture was filtered to obtain a filtrate. The filtrate was concentrated in vacuo to obtain compound 207-2 (11.0 g, crude product) as a white solid. 1 H 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).

[0909] 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 equiv.) 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 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. Saturated aqueous sodium bicarbonate (100 mL) was added, and the resulting mixture was extracted three times with dichloromethane (150 mL). The combined organic layers were 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 to 3 / 1) to obtain compound 207-3 (5.8 g, 30.5 mmol, 53.3% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ 9.75 (s, 1H), 4.38 - 4.36 (m, 3H), 4.27 - 4.25 (m, 3H), 3.72 (s, 3H).

[0910] Step 3: Synthesis of compound 207-4 (methyl (2R,3R,4S,5S)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylate) Sodium acetate (5.25 g, 64.0 mmol, 2.1 equiv) was dissolved in water (25.0 mL), and 1,1-dibromo-3,3,3-trifluoroacetone (9.05 g, 33.5 mmol, 1.1 equiv) 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 equiv) 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, which was concentrated under vacuum to give compound 207-4 (6.0 g, 18.5 mmol, 60.8% yield) as a white solid. LC-MS: m / z=297.0 (M+H). + .

[0911] Step 4: Synthesis of compound 207-5 (methyl (2R,3R,4S,5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylate) Compound 207-4 (4.5 g, 15.2 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (40.0 mL), and sodium hydride (911 mg, 22.7 mmol, 60% content, 1.50 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was stirred at 20 °C for 30 min. Iodomethane (2.16 g, 15.2 mmol, 945 μL, 1.0 equiv) was added, and the resulting mixture was reacted at 20 °C for 2 h. 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, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. This was purified by reverse phase chromatography HPLC (0.1% FA) to give compound 207-5 (1.6 g, 4.95 mmol, 32.5% yield) as a white solid. 1 LC-MS: m / z = 311.1 (M+H) + .

[0912] Step 5: Synthesis of compound 207-6 ((2R,3R,4S,5S)-N-methyl-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide) Compound 207-5 (120 mg, 386.76 mmol, 1 equiv.) was dissolved in ethanol (24.0 mL), and a solution of methylamine in ethanol (16.51 g, 159.48 mmol, 30% content, 412.35 equiv.) was added at 25° C. The resulting mixture was stirred at 70° C. under 50 Psi pressure for 12 hours. The reaction mixture was cooled to room temperature, and ice water (15.0 mL) was added. The resulting mixture was concentrated in vacuo to remove ethanol and 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, which was concentrated in vacuo to give compound 207-6 (0.11 g, crude product) as a white solid. LC-MS: m / z=310.1 (M+H). + .

[0913] Step 6: Synthesis of compound 207-7 (N-methyl-1-((2R,3R,4S,5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methylamine) Compound 207-6 (0.1 g, 323.33 mmol, 1 equiv.) was dissolved in tetrahydrofuran (10.0 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (2.5 mmol, 387.99 μL, 3 equiv.) 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, which 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). + .

[0914] Step 7: Synthesis of compound 207-8 (2-chloro-5-methoxy-N-methyl-N-[[4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]cuban-1-yl]methyl]pyrimidin-4-amine) Compound 207-7 (40 mg, 135.45 mmol, 1 equiv.), N,N-diisopropylethylamine (70.03 mg, 541.82 mmol, 94.37 μL, 4 equiv.), and 2,4-dichloro-5-methoxypyrimidine (38.80 mg, 216.73 mmol, 1.6 equiv.) were added sequentially 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 in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 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) + .

[0915] Step 8: Synthesis of Compound 207 (4'-cyclopropyl-5,6'-dimethoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine) Following the same steps as for compound 61, compound 207-8 (25.0 mg, 57.10 mmol, 1 eq) and intermediate A2-7 (22.15 mg, 114.20 mmol, 2.0 eq) were used as starting materials to give compound 207 (2.66 mg, 4.32 mmol, 7.56% yield, white solid). LC-MS: m / z = 552.3 (M+H). + .

[0916] (Example 208) Synthesis of Compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[0917] [ka]

[0918] Step 1: Synthesis of compound 208-1 (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde) Compound C5-4 (1.0 g, 3.91 mmol, 1.0 equiv.) and manganese dioxide (3.4 g, 39.1 mmol, 10.0 equiv.) were added sequentially to tetrahydrofuran (30.0 mL), and the resulting mixture was stirred at an external temperature of 45 °C for 16 h. 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 1 / 1) to obtain compound 208-1 (823.1 mg, 3.24 mmol, 82.8% yield) as a white solid. LC-MS: m / z = 255.1 (M+H). + .

[0919] Step 2: Synthesis of compound 208-2 (2-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile) Compound 208-1 (400.0 mg, 1.57 mmol, 1.0 equiv.), trimethylsilyl cyanide (203.0 mg, 2.05 mmol, 1.3 equiv.), and 1-octyl-3-methylimidazolium hexafluorophosphate (3.21 g, 9.42 mmol, 6.0 equiv.) were added sequentially to tetrahydrofuran (8.0 mL), and the resulting mixture was stirred at an external temperature of 35 °C for 16 h. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 208-2 (303.3 mg, 1.08 mmol, 68.7% yield) as a colorless, clear oil. LC-MS: m / z = 282.2 (M+H). + .

[0920] Step 3: Synthesis of compound 208-3 (2-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile) Compound 208-2 (300.0 mg, 1.07 mmol, 1.00 equiv) was dissolved in dichloromethane (6.0 mL), and thionyl chloride (635.0 mg, 5.33 mmol, 5.00 equiv) was added at 0° C. After the addition was complete, the resulting mixture was heated to room temperature (25° C.) and stirred for 4 hours. The reaction mixture was concentrated in vacuo to give compound 208-3 (288.8 mg, crude product) as a colorless, clear oil. LC-MS: m / z=300.2 (M+H). + .

[0921] Step 4: Synthesis of compound 208-4 (2-((2-chloro-5-methoxypyrimidin-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile) Compound 208-3 (260.0 mg, 0.87 mmol, 1.0 equiv.), 2-chloro-4-amino-5-methoxypyrimidine (415.3 mg, 2.61 mmol, 3.0 equiv.), and pyridine (206.4 mg, 2.61 mmol, 3.0 equiv.) were added sequentially to toluene (5.2 mL), and the resulting mixture was reacted at 140 °C for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 208-4 (96.0 mg, 0.23 mmol, 26.1% yield) as a pale yellow solid. LC-MS: m / z = 423.1 (M+H). + .

[0922] Step 5: Synthesis of Compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile) Compound 208-4 (90.0 mg, 0.21 mmol, 1.00 equiv.), compound A2-7 (83.4 mg, 0.43 mmol, 2.0 equiv.), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos-Pd-G2, 33.8 mg, 0.043 mmol, 0.20 equiv.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 41.0 mg, 0.086 mmol, 0.40 equiv.), and sodium bicarbonate (72.2 mg, 0.86 mmol, 4.0 equiv.) were added sequentially to dioxane (2.0 mL) and water (0.4 mL). The resulting mixture was purged with nitrogen three times and stirred under a nitrogen atmosphere at 95°C for 16 hours. 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 in vacuo to obtain the crude product. This was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 208 (38.2 mg, 0.071 mmol, 33.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 7.92 - 7.89 (m, 2H), 7.86 - 7.81 (m, 2H), 7.53 (s, 1H),7.09 (s, LC-MS: m / z = 537.2 (M+H) + .

[0923] (Example 209) Synthesis of Compound 209 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)pyrimidin-4-amine)

[0924] [ka]

[0925] Step 1: Synthesis of compound 209-2 ((1,4-dioxaspiro[4.5]decane-8,8-diyl)bis(methylene)bis(4-methylbenzenesulfonate)) Compound 209-1 ([8-(hydroxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanol, 50.0 g, 247 mmol, 1.00 equivalents) and p-toluenesulfonyl chloride (104 g, 544 mmol, 2.20 equivalents) were added sequentially to pyridine (250 mL), and the resulting mixture was stirred at 25° C. for 12 hours. Ethyl acetate (500 mL) was added, and the resulting mixture was washed three times with 10% aqueous citric acid solution (500 mL) and once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was triturated with ethanol (500.0 mL) for 1 h and filtered to give compound 209-2 (116.0 g, 227.0 mmol, 91.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.40 Hz, 4H), 7.36 (d, J = 8.00 Hz, 4H), 3.89 (s, 4H), 3.84 (s, 4H), 2.47 (s, 6H), 1.49 (s, 8H).

[0926] Step 2: Synthesis of compound 209-3 ((4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)) Compound 209-2 (116 g, 227 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (1000 mL), followed by the addition of 1 M hydrochloric acid (579 mL, 2.55 equiv.), and the resulting mixture was stirred at 70 °C for 12 hours. Saturated brine (200 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (1000 mL). The organic layers were combined, washed twice with saturated brine (400 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated in vacuo to give compound 209-3 (110 g, crude product) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.00 Hz, 4H), 7.48 (d, J = 8.40 Hz, 4H), 3.98 (s, 4H), 2.46 (d, J = 27.6 Hz, 6H), 2.15 - 2.11 (t, J = 7.20 Hz, 4H), 1.62 - 1.54 (m, 4H); LC-MS: m / z = 467.1 (M+H) + .

[0927] Step 3: Synthesis of compound 209-4 ((4-hydroxy-4-vinylcyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)) Compound 209-3 (55.0 g, 118 mmol, 1.00 equiv.) was dissolved in tetrahydrofuran (500 mL), and a 1 M solution of vinylmagnesium bromide in tetrahydrofuran (236 mL, 2.00 equiv.) was added dropwise slowly at −70° C. After the addition was complete, the resulting mixture was stirred at −70° C. for 2 hours. Saturated aqueous ammonium chloride solution (300 mL) was added at 0° C. to quench the reaction. The resulting mixture was concentrated in vacuo to remove the solvent. Water (100 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated in vacuo to give compound 209-4 (100 g, crude product) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J1= 8.0 Hz, J2= 12.8 Hz, 4H), 7.36 (t, J = 8.0 Hz, 4H), 5.84 (dd, J1= 10.8 Hz, J2= 17.2 Hz, 1H), 5.17 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 3.92 (s, 2H), 3.76 (s, 2H), 2.46 (d, J = 1.60 Hz, 6H), 1.56-1.26 (m, 8H).

[0928] Step 4: Synthesis of compound 209-5 ((1-vinyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl-4-methylbenzenesulfonate) Compound 209-4 (30.0 g, 60.7 mmol, 1.00 equiv) was dissolved in ethylene glycol dimethyl ether (500 mL), and sodium hydride (4.85 g, 121 mmol, 60% content, 2.00 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was stirred at 0 °C for 30 minutes, heated to 110 °C, and stirred for 16 hours. Saturated aqueous ammonium chloride solution (400 mL) was added at 0 °C to quench the reaction, and water (500 mL) was added. The resulting mixture was concentrated in vacuo to remove the organic solvent and extracted three times with ethyl acetate (600 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated in vacuo to give compound 209-5 (27.4 g, crude product) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 8.00 Hz, 2H), 5.85 - 5.76 (m, 1H), 5.15- 5.11 (t, J = 1.60 Hz, 1H), 5.04 - 5.00 (d, J1= 1.60 Hz, J2= 11.2 Hz, 1H), 3.69 (d, J = 6.80 Hz, 4H), 2.46 (s, 3H), 1.90 - 1.86 (m, 2H), 1.72 - 1.65 (m, 4H), 1.52 - 1.51 (m, 2H).

[0929] Step 5: Synthesis of compound 209-6 ((1-formyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl-4-methylbenzenesulfonate) Compound 209-5 (4.00 g, 12.4 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (80.0 mL), and sodium periodate (7.96 g, 37.2 mmol, 2.06 mL, 3.00 equiv) was added at 0 °C. Potassium osmate (1.14 g, 3.10 mmol, 0.250 equiv) dissolved in water (16.0 mL) was added, and the resulting mixture was stirred at 20 °C for 12 h and filtered to obtain a filtrate. The filtrate was washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. This was concentrated in vacuo to give 209-6 (4.0 g, crude product) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.77 - 7.74 (m, 2H), 7.37 - 7.34 (m, 2H), 3.74 - 3.67 (m, 4H), 2.46 (s, 3H),1.91 1.49 (m, 8H).

[0930] Step 6: Synthesis of compound 209-7 ((1-(4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl-4-methylbenzenesulfonate) 3,3-Dibromo-1,1,1-trifluoropropan-2-one (3.99 g, 14.8 mmol, 1.20 equiv.) and sodium acetate (2.12 g, 25.9 mmol, 2.10 equiv.) were added sequentially to water (8.0 mL), and the resulting mixture was stirred at 100 °C for 1 h. Compound 209-6 (4.00 g, 12.3 mmol, 1.00 equiv.) was dissolved in aqueous ammonia (11.5 g, 98.7 mmol, 12.7 mL, 30.0% content, 8.0 equiv.), and methanol (40.0 mL) was added at 25 °C. After the addition was complete, the resulting mixture was stirred at 25 °C for 5 h. Water (100 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (180 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under vacuum to give the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 209-7 (2.2 g, 5.05 mmol, yield 41.0%) as a white solid. LC-MS: m / z = 431.2 (M+H). + .

[0931] Step 7: Synthesis of compound 209-8 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl-4-methylbenzenesulfonate) Compound 209-7 (2.20 g, 5.11 mmol, 1.00 equiv) was dissolved in tetrahydrofuran (30.0 mL), and sodium hydride (307 mg, 7.67 mmol, 60.0% content, 1.50 equiv) was added portionwise at 0 °C. After the addition was complete, the resulting mixture was stirred at 0 °C for 30 minutes. Iodomethane (725 mg, 5.11 mmol, 1.0 equiv) was added, and the resulting mixture was heated to 25 °C and reacted for 2 hours. Ice water (30.0 mL) was added at 0 °C to quench the reaction. Water (20.0 mL) was added, and the resulting mixture was extracted three times with ethyl acetate (150 mL). The organic layers were combined, washed twice with saturated brine (60.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. This was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (TFA) to ACN]; gradient: 45% to 75%) to obtain compound 209-8 (1.5 g, 3.37 mmol, yield 66.0%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.2 Hz, 1H), 3.81 (s, 5H), 3.73 (s, 2H), 2.47 (s, LC-MS: m / z = 445.3 (M+H) + .

[0932] Step 8: Synthesis of compound 209-9 (2-chloro-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)pyrimidin-4-amine) Compound 209-8 (1.0 g, 2.25 mmol, 1.0 equiv.), compound BB2 (716.0 mg, 4.50 mmol, 2.0 equiv.), sodium iodide (1.01 g, 6.75 mmol, 3.0 equiv.), and cesium carbonate (3.67 g, 11.25 mmol, 5.0 equiv.) were added sequentially to N,N-dimethylformamide (20.0 mL), and the mixture was stirred at 130 °C for 24 hours. The reaction mixture was cooled to 25 °C. Dichloromethane (100.0 mL) was added, and the resulting mixture was stirred for 5 minutes and filtered to obtain the filtrate. The filtrate was washed three times with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0 to 0 / 1) to obtain compound 209-9 (135.6 mg, 0.31 mmol, 14.0% yield) as a white solid. LC-MS: m / z = 432.3 (M+H). + .

[0933] Step 9: Synthesis of compound 209 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)pyrimidin-4-amine) Compound 209-9 (40.0 mg, 92.6 μmol, 1.00 equivalents), compound AA9 (75.2 mg, 277.8 μmol, 3.00 equivalents), and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphino](methanesulfonato)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (Xphos Pd G4 (16.0 mg, 18.52 μmol, 0.2 equiv.), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos, 17.7 mg, 37.04 μmol, 0.4 equiv.), and potassium phosphate (78.6 mg, 370.4 μmol, 4 equiv.) were added sequentially to dioxane (0.8 mL) and water (0.16 mL), and the resulting mixture was stirred at an external temperature of 95 °C for 16 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column; mobile phase: [water (FA) to ACN]; gradient: 61% to 91%) to give compound 209 (16.6 mg, 30.8 μmol, 33.3% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.55 (s, 1H),7.13 (s, 1H), 6.01-5.88 (m, 1H), 5.32 - 5.26 (m, 1H), 4.27 (s, 2H), 4.01 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 2.39 - 2.31 (m, 2H), 2.29 - 2.21 (m, 2H), 1.97 - 1.91 (m, 2H), 1.83 - 1.76 (m, 2H), 1.51 (s, 3H), 1.49 (s, 3H); LC-MS: m / z =540.3 (M+H) + .

[0934] (Example 210) Synthesis of Compound 210 (4'-cyclopropyl-5,6'-dimethoxy-N-(1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-[2,5'-bipyrimidin]-4-amine)

[0935] [ka]

[0936] Following the same steps as for compound 209, compound 209-9 (50.0 mg, 0.116 mmol, 1 equiv.) and intermediate A2-7 (67.4 mg, 0.348 mmol, 3.0 equiv.) were used as starting materials to obtain compound 210 (7.8 mg, 0.0143 mmol, 12.3% yield, white solid). 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.91 (s, 1H),7.11 (s, 1H), 5.58 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.87 (s, 2H), 3.83 (s, LC-MS: m / z = 546.3 (M+H) +.。

[0937] Example 211 Synthesis of Compound 211 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-5-methoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)pyrimidin-4-amine)

[0938] [ka]

[0939] Following the same steps as for compound 209, compound 209-8 (300.0 mg, 0.675 mmol, 1 equiv.) and intermediate BB-1 (351.5 mg, 2.02 mmol, 3.0 equiv.) were used as starting materials to give compound 211 (44.3 mg, 0.08 mmol, 18.9% yield, pale yellow solid). LC-MS: m / z = 554.2 (M+H). + .

[0940] Example 212 Synthesis of Compound 212 (4'-cyclopropyl-5,6'-dimethoxy-N-methyl-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-[2,5'-bipyrimidin]-4-amine)

[0941] [ka]

[0942] Following the same ste...

Claims

1. A compound of formula (I'), 【Chemistry 1】 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopic substitute, or stereoisomer thereof. [In the formula, R is C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 C fused to aryl, 5- to 10-membered heteroaryl 6～10 Aryl, and 【Chemistry 2】 each of the above groups is independently selected from the group consisting of one or more R 1 and optionally replaced by Ring A and ring B each independently represent C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 cycloalkyl and 3- to 8-membered heterocyclyl, and ring A and ring B are each independently selected from the group consisting of one or more R 1 and optionally replaced by L is 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 alkylene-S-; R a and R b are each independently a H atom, -CN, or C 1～6 Alkyl, -OH, halogen, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Hydroxyalkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 1～6 haloalkoxy or R a and R b Together, Oxo, C 3～8 forming a cycloalkyl or 3- to 8-membered heterocyclyl; R 2 is H atom, -OH, -CN, C 1～6 Alkyl, -C 1～6 Alkyl-C 6～10 Aryl, C 2～6 Alkenyl, C 2～6 Alkynyl, 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 is selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclyl; 1～6 Alkyl and -C 1～6 Alkyl-C 6～10 Each aryl is one or more R 1 and optionally replaced by R 3 is H atom, -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 Alkenyl, C 2～6 Alkynyl, 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, 3- to 8-membered heterocyclyl and -C 1～6 Alkylene-C(O)-OC 1～6 alkyl, -NH 2 , C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 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 and 3- to 8-membered heterocyclyl each independently represent one or more R 1 and optionally replaced by R 4 is H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 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 heterocyclyl; Or R 2 and R 3 together with the atoms to which they are attached form a ring C, wherein ring C is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, the heteroatom of the 5- to 7-membered heteroaryl or the 5- to 7-membered heterocyclyl is O or N, and further wherein the 5- to 7-membered heterocyclyl is selected from the group consisting of morpholinyl, 3-morpholinonyl, pyrrolidinyl, 2-oxazolidinonyl, and 2-pyrrolidinonyl, and ring C is selected from one or more R 1 or possibly replaced by Or R 3 and R 4 together with the atoms to which they are attached form a ring D, where ring D is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, and ring D is one or more R 1 and optionally replaced by R 5 is C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C fused to 5- to 10-membered heteroaryl 6～10 C fused to aryl, 3- to 8-membered heterocyclyl 6～10 Aryl, C 3～8 is selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclyl; 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 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 and 3- to 8-membered heterocyclyl each independently represent one or more R 1 and optionally replaced by R in each of the existing 1 are independently D atoms, -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 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl and -OC 1～6 Alkylene-OC 1～6 alkyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 3～8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently 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 Optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; n is an integer from 0 to 8.

2. Formula (I) 【Chemistry 3】 [In the formula, ring A, ring B, L, R a , R b , R 2 ~R 5 and n is as defined in claim 1.

3. R 2 H atom, -OH, -CN, C 1～6 Alkyl, C 2～6 Alkynyl, -C 1～6 Alkyl-C 6～10 Aryl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～6 cycloalkyl and 5- to 7-membered heterocyclyl; 1～6 Alkyl and -C 1～6 Alkyl-C 6～10 Each aryl is one or more R 1 is optionally replaced by R 1 is as defined in claim 1, Preferably, R 2 is selected from the group consisting of H atom, -CN, methyl, trideuteriomethyl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy and hydroxy; R 3 H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, 5- to 7-membered heterocyclyl and -C 1～6 Alkylene-C(O)-OC 1～6 alkyl, C 1～6 Hydroxyalkyl and 5- to 7-membered heterocyclyl each independently represent one or more C 1～6 is optionally substituted with alkyl; Preferably, R 3 is H atom, methoxy, trifluoromethyl, Cl atom, -CN, isopropoxy, ethynyl, difluoromethoxy, morpholinyl, 【Chemistry 4】 -OH, 【Chemistry 5】 F atom, hydroxymethyl and 【Chemistry 6】 is selected from the group consisting of R 4 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 hydroxyalkyl; Preferably, R 4 The compound according to claim 1 or 2, wherein is a H atom.

4. Formula (II) 【Chemistry 7】 [In the formula, ring C is 【Chemistry 8】 is selected from the group consisting of R in each of the existing 6 are independently H or C 1～6 alkyl or two R 6 together with the atoms to which they are attached, C 3～8 forming a cycloalkyl or 3- to 8-membered heterocyclyl; Ring A, Ring B, L, R a , R b , R 4 , R 5 and n is as defined in claim 1, especially, R 4 is 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 hydroxyalkyl, preferably R 4 is a H atom.

5. Formula (III) 【Chemistry 9】 [In the formula, ring D is 【Chemistry 10】 is selected from the group consisting of Each of the above groups may independently be one or more R 1 and optionally replaced by R, R a , R b , R 1 , R 2 , R 5 and n is as defined in claim 1, In particular, R 2 is H atom, -OH, C 1～6 Alkyl, C 2～6 Alkynyl, -C 1～6 Alkyl-C 6～10 Aryl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy and C 1～6 hydroxyalkyl; 1～6 Alkyl or -C 1～6 Alkyl-C 6～10 Each aryl may be one or more R 1 is optionally replaced by R 1 is as defined in claim 1, Preferably, R 2 is a H atom or 【Chemistry 11】 The compound of claim 1, wherein

6. Ring A and ring B each independently represent phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, pentacyclooctanyl, isoindolinyl, imidazo[1,2-a]pyrazinyl, piperidine-2,6-dionyl, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, or pyrrolidinyl. ring A and ring B are each independently selected from the group consisting of one or more R 1 is optionally replaced by R 1 is as defined in claim 1, L is a chemical bond, -O-, -OC 1～6 Alkylene- and -C 1～6 alkylene-O-; especially, 【Chemistry 12】 but, 【Chemistry 13】 wherein ring A and ring B each independently represent one or more R 1 is optionally replaced by R 1 is as defined in claim 1, More particularly, 【Chemistry 14】 but, 【Chemical 15A】 【Chemistry 15B】 6. The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. R is C 6～10 C fused with aryl or 5- to 6-membered heteroaryl 6～10 aryl, each of the above groups being independently oxo, C 1～6 Alkyl and -OC 1～6 Alkylene-OC 1～6 and optionally substituted with one or more substituents selected from the group consisting of alkyl, In particular, R is 【Chemistry 16】 and R 2 H atom, -OH, C 1～6 Alkyl, C 2～6 Alkynyl, -C 1～6 Alkyl-C 6～10 Aryl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy and C 1～6 hydroxyalkyl, preferably R 2 is a H atom, R 3 H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy and C 1～6 hydroxyalkyl, preferably R 3 is methoxy, R 4 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 hydroxyalkyl, preferably R 4 is a H atom or Or R 3 and R 4 together with the atoms to which they are attached form Ring D, and Ring D is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclyl, preferably furanyl.

8. R 5 But, C 6～10 C fused to aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl 6～10 C fused with aryl and 5- to 6-membered heteroaryl 6～10 aryl, preferably selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indolinyl and isoxazolyl; 6～10 C fused to aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl 6～10 C fused with aryl and 5- to 6-membered heteroaryl 6～10 Aryl is, independently, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl and C 3～6 cycloalkyl; In particular, R 5 but, 【Chemistry 17】 8. The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. n is 0 or 1, R a and R b are independently H atoms, -CN, C 1～6 is selected from the group consisting of alkyl, -OH and halogen; Preferably, R a and R b The compound according to any one of claims 1 to 8, wherein each is independently an H atom or -CN.

10. 【Chemical 18A】 【Chemistry 18B】 【Chemical 18C】 【Chemistry 18D】 【Chemistry 18E】 【Chemical 18F】 【18G】 【18H】 【Chemical 18I】 【Chemical 18J】 10. The compound according to any one of claims 1 to 9, selected from the group consisting of:

11. Follow these steps: 【Chemistry 19】 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 , R 2 ~R 5 and n is as defined in claim 1, or 【Chemistry 20】 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 , R 2 ~R 5 and n is as defined in claim 1, or 【Chemistry 21】 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; R 2 is hydroxy, R, R a , R b , R 3 ~R 5 and n is as defined in claim 1, or 【Chemical 22】 reacting a compound of formula (IG') with a compound of formula (ID) to obtain a compound of formula (IH') and 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; R 2 is hydroxy, R, R a , R b , R 3 ~R 5 and n is as defined in claim 1, or 【Chemistry 23】 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 , R 2 ~R 5 and n is as defined in claim 1.

2. A method for preparing the compound of claim 1, comprising:

12. The compound of formula (I') is a compound of formula (I), and the process comprises the steps of: 【Chemistry 24】 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 , R 2 ~R 5 and n is as defined in claim 1, or 【Chemistry 25】 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 , R 2 ~R 5 and n is as defined in claim 1, or 【Chemistry 26】 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; R 2 is hydroxy, Ring A, Ring B, L, R a , R b , R 3 ~R 5 and n is as defined in claim 1, or 【Chemical 27】 reacting a compound of formula (IG) with a compound of formula (ID) to obtain a compound of formula (IH) and 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; R 2 is hydroxy, Ring A, Ring B, L, R a , R b , R 3 ~R 5 and n is as defined in claim 1, or 【Chemistry 28】 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 , R 2 ~R 5 and n is as defined in claim 1.

12. The method of claim 11, comprising:

13. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and one or more pharma- ceutically acceptable excipients.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 13 in the preparation of a medicament for the treatment or prevention of a disease or condition associated with the inhibition of ubiquitin-specific protease 1 (USP1).

15. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating or preventing cancer, comprising In particular, the use wherein 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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