Pyrimidine compound, preparation method therefor and medical use thereof

Abstract

Disclosed are a pyrimidine compound, a preparation method therefor and a medical use thereof. Specifically, disclosed are a compound represented by the general formula (SI), a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof as a ubiquitin-specific protease 1 (USP1) inhibitor, particularly a use thereof for treating or preventing cancer. The definitions of the groups in the general formula (SI) are the same as those in the description.

Description

Pyrimidine compounds, preparation methods and medical uses thereof Technical Field

[0001] The present invention relates to compounds and compositions having USP1 inhibitory effects, as well as their use in the preparation and treatment of drugs for USP1 enzyme-related diseases. Specifically, the present invention relates to compounds represented by general formula (SI) or pharmaceutically acceptable salts, hydrates, solvates, isotope-substituted compounds, or stereoisomers thereof. Background Art

[0002] Ubiquitination is a dynamic, reversible process involving the deubiquitinating enzyme (DUB) family. Approximately 100 DUBs exist in humans, classified as cysteine ​​proteases and metalloproteases. 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 oncodomain proteases (OTUs). The USP family is the largest known family of deubiquitinating enzymes, with over 50 encoded by human genes. These enzymes play a role in various physiological functions, including cell cycle regulation, signal transduction, DNA damage repair, chromosomal translocations, and gene transcription, by regulating substrate proteases.

[0003] USP1 belongs to the USP subfamily of DUBs. While inactive on its own, it acquires full enzymatic activity upon binding to UAF1 to form a heterodimeric complex (USP1 / UAF1), regulating cellular targets in multiple cancer-related pathways. For example, the USP1 / UAF1 complex deubiquitinates proliferating cell nuclear antigen (PCNA), a key protein in the translesion synthesis (TLS) process, to prevent excessive repair. It also deubiquitinates Fanconi anemia complementation group D2 (FAND2), a key protein in the Fanconi anemia (FA) pathway, to block inappropriate TLS repair in cells, thereby ensuring genomic stability. These two DNA damage response (DDR) pathways are key for repairing DNA damage induced by DNA cross-linking agents such as cisplatin, mitomycin, and ultraviolet radiation. USP1 also interacts with proteins such as ID, stabilizing their expression in cells through deubiquitination. For example, in osteosarcoma cells, USP1 can deubiquitinate ID1, ID2, and ID3, promoting cell proliferation. Inhibiting USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. Furthermore, studies have confirmed that USP1 is closely associated with the development of resistance to various tumor therapeutic drugs. For example, in cisplatin-resistant non-small cell lung cancer (NSCLC) cells, USP1 expression is high, and knocking down USP1 can significantly enhance the cells' sensitivity to cisplatin. In breast cancer cells, USP1 is highly expressed, promoting cell proliferation and being closely associated with a poor prognosis in breast cancer. A report (J. Med. Chem. 2014, 57, 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) reported that compounds such as the USP1 inhibitor ML323 could be used in non-small cell lung cancer. A report (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.) reported that USP1 inhibitors are potential therapeutic drugs for prostate cancer. In summary, USP1 is expected to become a popular target for the treatment of various cancers and other diseases.

[0004] Summary of the Invention

[0005] The present invention provides a compound represented by general formula (I'),

[0006] or a pharmaceutically acceptable salt, hydrate, solvate, isotope-substituted product or stereoisomer thereof,

[0007] in,

[0008] R is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, C fused to 5-10 membered heteroaryl 6-10 Aryl and The above groups are each independently optionally substituted by one or more R1;

[0009] Ring A and Ring B are each independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, and Ring A and Ring B are each independently optionally substituted by one or more R1;

[0010] L is selected from chemical bonds, -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-;

[0011] R a and R b Each independently selected from H atoms, -CN, C 1-6 Alkyl, -OH, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form an oxo group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 1-6 Alkyl is optionally substituted with one or more R1;

[0012] R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, -C 1-6 Alkylene-C 6-10 Aryl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkylene-C 6-10 Aryl is optionally substituted with one or more R1;

[0013] R3 is selected from the group consisting of H atoms, -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, phosphite, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with one or more R1;

[0014] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups;

[0015] Alternatively, R2 and R3 together with the atoms to which they are attached form a ring C, wherein the ring C is a 5-7 membered heteroaryl or a 5-7 membered heterocyclyl, wherein the heteroatom in the 5-7 membered heteroaryl or the 5-7 membered heterocyclyl is O or N, further wherein the 5-7 membered heterocyclyl is selected from morpholinyl, 3-morpholinonyl, pyrrolidinyl, 2-oxazolidinonyl and 2-pyrrolidinonyl, and the ring C is optionally substituted with one or more R1;

[0016] Alternatively, R3 and R4 together with the atoms to which they are attached form ring D, said ring D being a 5-7 membered heteroaryl or a 5-7 membered heterocyclyl, and said ring D being optionally substituted with one or more R1;

[0017] R5 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryl, C fused to 3-8 membered heterocyclic group 6-10 Aryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with one or more R1;

[0018] R1 is independently selected at each occurrence from a D atom, -OH, -COOH, -NH2, -CN, an oxo group, a halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups are each independently optionally selected from D atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of the hydroxyalkyl group; and

[0019] n is an integer between 0 and 8.

[0020] In some embodiments, the compound represented by general formula (I') is a compound represented by general formula (I),

[0021] Among them, ring A, ring B, L, R a 、R b , R2 to R5 and n are as defined in the general formula (I').

[0022] In some embodiments, in the compound represented by general formula (I') or (I),

[0023] R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl and 5-7 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkylene-C 6-10 The aryl group is optionally substituted with one or more R1, R1 being as defined in the general formula (I');

[0024] Preferably, R2 is selected from the group consisting of an H atom, -CN, a methyl group, a trideuterated methyl group, an ethynyl group, a propynyl group, a tetrahydrofuranyl group, a cyclopropyl group, a methoxy group, and a hydroxyl group;

[0025] and / or

[0026] R3 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl-O-, 5-7 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the C 1-6 The hydroxyalkyl and 5-7 membered heterocyclic groups are each independently optionally substituted with one or more C 1-6 Alkyl substitution;

[0027] Preferably, R3 is selected from H atom, methoxy, cyclopropyl-O-, trifluoromethyl, Cl atom, -CN, isopropoxy, ethynyl, difluoromethoxy, morpholinyl, -OH, F atoms, hydroxymethyl and

[0028] and / or

[0029] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0030] Preferably, R4 is a H atom.

[0031] In some embodiments, the compound represented by formula (I') or (I) is a compound represented by formula (II),

[0032] wherein ring C is selected from

[0033] R6 is independently H or C1-C6 alkyl at each occurrence, or two R6 together with the atoms to which they are attached form C 3-8 cycloalkyl or 3-8 membered heterocyclyl; and

[0034] Ring A, Ring B, L, R a 、R b , R4, R5 and n are as defined in formula (I');

[0035] In particular,

[0036] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably R4 is a H atom.

[0037] In some embodiments, the compound represented by general formula (I') is a compound represented by general formula (III),

[0038] wherein ring D is selected from The above groups are each independently optionally substituted with one or more R1; and

[0039] R, R a 、R b , R1, R2, R5 and n are as defined in formula (I');

[0040] In particular, R2 is selected from H atoms, -OH, C 1-6 Alkyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl or C 1-6 Alkyl-C 6-10 The aryl group is optionally substituted with one or more R1, R1 being as defined in the general formula (I');

[0041] Preferably, R2 is an H atom or

[0042] In some embodiments, in the compound represented by formula (I'), (I), (II) or (III),

[0043] Ring A and Ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, pentacyclooctanyl, isoindolinone, imidazo[1,2-a]pyrazinyl, piperidine-2,6-dione, thienyl, furanyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, morpholin ... linyl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolyl, indolinonyl, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl and cubanyl, and ring A and ring B are each independently optionally substituted with one or more R1, R1 is as defined in the general formula (I');

[0044] L is selected from chemical bonds, -O-, -OC 1-6 Alkylene- and -C 1-6 Alkylene-O-;

[0045] In particular, Selected from and Ring A and Ring B are each independently optionally substituted by one or more R1, R1 being as defined in the general formula (I');

[0046] More specifically, Selected from

[0047] In some embodiments, in the compound represented by general formula (I'),

[0048] R is C 6-10 Aryl or C fused with 5-6 membered heteroaryl 6-10 Aryl, the above groups are each independently optionally selected from oxo, C 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 The alkyl group is substituted with one or more substituents;

[0049] In particular, R is

[0050] R2 is selected from H atoms, -OH, C 1-6 Alkyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C1-6 Hydroxyalkyl; preferably, R2 is an H atom;

[0051] R3 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl; preferably, R3 is methoxy;

[0052] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R4 is an H atom;

[0053] Alternatively, R3 and R4 together with the atoms to which they are attached form a ring D, said ring D being a 5-7 membered heteroaryl or a 5-7 membered heterocyclyl, preferably a furyl.

[0054] In some embodiments, in the compound represented by formula (I'), (I), (II) or (III),

[0055] R5 is selected from C 6-10 Aryl, 5-6 membered heteroaryl, C 6-10 Aryl and C fused to 5-6 membered heteroaryl 6-10 Aryl, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indolyl and isoxazolyl, said C 6-10 Aryl, 5-6 membered heteroaryl, C 6-10 Aryl and C fused to 5-6 membered heteroaryl 6-10 Each aryl group is independently optionally selected from -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-6 The cycloalkyl group is substituted with one or more substituents;

[0056] In particular, R5 is selected from

[0057] In some embodiments, in the compound represented by Formula (I'), (I), (II) or (III), n is 0 or 1.

[0058] In some embodiments, in the compounds represented by formula (I'), (I), (II) or (III), R a and R b Each independently selected from H atoms, -CN, C 1-6 Alkyl, -OH and halogen;

[0059] Preferably, R a and R b Each is independently a H atom or -CN.

[0060] Typical compounds of the general formula (I) or (I') of the present invention include but are not limited to the following compounds:

[0061] The present invention also provides a method for preparing the compound represented by general formula (I'), which comprises:

[0062] The compound represented by the general formula (IA) reacts with the compound represented by the general formula (IB') to obtain the compound represented by the general formula (I');

[0063] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0064] R, R a 、R b , R2 to R5 and n are as defined in the general formula (I');

[0065] or

[0066] The compound represented by the general formula (IC') reacts with the compound represented by the general formula (ID) to obtain the compound represented by the general formula (I');

[0067] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0068] R, R a 、R b , R2 to R5 and n are as defined in the general formula (I');

[0069] or

[0070] The compound represented by the general formula (IE) reacts with the compound represented by the general formula (IB') to obtain the compound represented by the general formula (IF'), and the compound represented by the general formula (IF') is deprotected to obtain the compound represented by the general formula (I');

[0071] X is a leaving group selected from halogen, sulfonate, boronic acid and borate;

[0072] Y is a hydroxyl protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0073] R2 is a hydroxyl group;

[0074] R, R a 、R b , R3 to R5 and n are as defined in the general formula (I');

[0075] or

[0076] The compound represented by the general formula (IG') reacts with the compound represented by the general formula (ID) to obtain the compound represented by the general formula (IH'), and the compound represented by the general formula (IH') is deprotected to obtain the compound represented by the general formula (I');

[0077] X is a leaving group selected from halogen, sulfonate, boronic acid and borate;

[0078] Y is a hydroxyl protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0079] R2 is a hydroxyl group;

[0080] R, R a 、R b , R3 to R5 and n are as defined in the general formula (I');

[0081] or

[0082] The compound represented by the general formula (IC') reacts with the compound represented by the general formula (IJ) to obtain the compound represented by the general formula (I');

[0083] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0084] R, R a 、R b, R2 to R5 and n are as defined in the general formula (I').

[0085] The present invention also provides a method for preparing the compound represented by general formula (I), which comprises:

[0086] The compound represented by general formula (IA) reacts with the compound represented by general formula (IB) to obtain the compound represented by general formula (I);

[0087] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0088] Ring A, Ring B, L, R a 、R b , R2 to R5 and n are as defined in the general formula (I');

[0089] or

[0090] The compound represented by the general formula (IC) reacts with the compound represented by the general formula (ID) to obtain the compound represented by the general formula (I);

[0091] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0092] Ring A, Ring B, L, R a 、R b , R2 to R5 and n are as defined in the general formula (I');

[0093] or

[0094] The compound represented by general formula (IE) reacts with the compound represented by general formula (IB) to obtain the compound represented by general formula (IF), and the compound represented by general formula (IF) is deprotected to obtain the compound represented by general formula (I);

[0095] X is a leaving group selected from halogen, sulfonate, boronic acid and borate;

[0096] Y is a hydroxyl protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0097] R2 is a hydroxyl group;

[0098] Ring A, Ring B, L, R a 、R b , R3 to R5 and n are as defined in the general formula (I');

[0099] The compound represented by the general formula (IG) reacts with the compound represented by the general formula (ID) to obtain the compound represented by the general formula (IH), and the compound represented by the general formula (IH) is deprotected to obtain the compound represented by the general formula (I);

[0100] X is a leaving group selected from halogen, sulfonate, boronic acid and borate;

[0101] Y is a hydroxyl protecting group selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0102] R2 is a hydroxyl group;

[0103] Ring A, Ring B, L, R a 、R b , R3 to R5 and n are as defined in the general formula (I');

[0104] or

[0105] The compound represented by general formula (IC) reacts with the compound represented by general formula (IJ) to obtain the compound represented by general formula (I);

[0106] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0107] Ring A, Ring B, L, R a 、R b , R2 to R5 and n are as defined in the general formula (I').

[0108] The present invention also provides a compound represented by general formula (SI),

[0109] or a pharmaceutically acceptable salt, hydrate, solvate, isotope-substituted product or stereoisomer thereof,

[0110] in,

[0111] Ring A and Ring B are each independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, and Ring A and Ring B are each independently optionally substituted by one or more R1;

[0112] Ring E is selected from C 6-10 Aryl, 5-6 membered heteroaryl, C 6-10 Aryl and C fused to 5-6 membered heteroaryl 6-10 aryl, and ring E is optionally substituted with one or more R1;

[0113] L is selected from chemical bonds, -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-;

[0114] R a and R b Each independently selected from H atoms, -CN, C 1-6 Alkyl, -OH, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R a and R b Together they form an oxo group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 1-6 Alkyl is optionally substituted with one or more R1;

[0115] R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, -C 1-6 Alkylene-C 6-10 Aryl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkylene-C 6-10 Aryl is optionally substituted with one or more R1;

[0116] R3 is selected from the group consisting of H atoms, -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, phosphite, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with one or more R1;

[0117] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups;

[0118] R1 is independently selected at each occurrence from a D atom, -OH, -COOH, -NH2, -CN, an oxo group, a halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups are each independently optionally selected from D atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of the hydroxyalkyl group; and

[0119] n is an integer between 0 and 8.

[0120] In some embodiments, in the compound represented by formula (SI), ring B is C 6-10 aryl or 5-6 membered heteroaryl, and ring B is optionally substituted by one or more R1, R1 is as defined in the general formula (SI);

[0121] In particular,

[0122] Ring B is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, piperazinyl, naphthyl, pyrrolyl, pyridazinyl, triazolyl, tetrazolyl and furanyl, and is optionally substituted with one or more R1, R1 being as defined in Formula (SI);

[0123] More specifically,

[0124] Ring B is imidazolyl, and Ring B is optionally substituted by one or more R1, R1 being as defined in the general formula (SI).

[0125] In some embodiments, the compound represented by general formula (SI) is a compound represented by general formula (SII),

[0126] in,

[0127] R 1a is independently selected at each occurrence from D atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl;

[0128] R 1b is independently selected at each occurrence from a D atom, -OH, -COOH, -NH2, -CN, an oxo group, a halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl;

[0129] R 1c Selected from H atoms, D atoms, -OH, -COOH, -NH2, -CN, oxo groups, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl;

[0130] R 1d Selected from H atoms, D atoms, -OH, -COOH, -NH2, -CN, oxo groups, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl;

[0131] m is 0, 1, or 2;

[0132] p is 0, 1, or 2;

[0133] Ring A, Ring E, R a 、R b , R2 to R4 and n are as defined in the general formula (SI).

[0134] In some embodiments, in the compound represented by formula (SI) or (SII),

[0135] Ring A is selected from C6-10 Aryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, and Ring A is optionally substituted by one or more R1, R1 is as defined in the general formula (SI);

[0136] In particular,

[0137] Ring A is selected from phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, cubanyl, piperidinyl, pyranyl, pyrrolidinyl, piperazinyl and morpholinyl, and ring A is optionally substituted by one or two R 1b Replacement, R 1b As defined in formula (SII);

[0138] More specifically,

[0139] Ring A is selected from phenyl, cyclohexyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl and cubanyl, and ring A is optionally substituted by one or two R 1b Replacement, R 1b As defined in general formula (SII).

[0140] In some embodiments, in the compound represented by formula (SI) or (SII),

[0141] Selected from

[0142] In some embodiments, in the compound represented by formula (SI) or (SII),

[0143] Ring E is C 6-10 aryl or 5-6 membered heteroaryl, and ring E is optionally substituted by one or more R1, R1 is as defined in the general formula (SI);

[0144] In particular,

[0145] Ring E is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl and isoxazolyl, and ring E is optionally replaced by one R 1c and an R 1d Replacement, R 1c and R 1d As defined in formula (SII);

[0146] More specifically,

[0147] Ring E is selected from pyridyl, pyrimidinyl and imidazolyl, and ring E is optionally substituted by one R 1c and an R 1d Replacement, R 1cand R 1d As defined in formula (SII);

[0148] Even more specifically,

[0149] Selected from

[0150] In some embodiments, in the compound represented by formula (SI) or (SII),

[0151] n is 0 or 1;

[0152] and / or

[0153] R a and R b Each independently selected from H atoms, -CN, C 1-6 Alkyl, -OH and halogen;

[0154] Preferably, R a and R b Each independently is a H atom or a C 1-6 alkyl;

[0155] More preferably, R a and R b are all H atoms, or R a is an H atom and R b It is a methyl group.

[0156] In some embodiments, in the compound represented by formula (SI) or (SII),

[0157] R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl and 5-7 membered heterocyclic groups,

[0158] Preferably, R2 is selected from H atom, -CN, methyl and trideuterated methyl;

[0159] and / or

[0160] R3 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl-O-, 5-7 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 alkyl;

[0161] Preferably, R3 is methoxy or cyclopropyl-O-;

[0162] and / or

[0163] R4 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0164] Preferably, R4 is a H atom.

[0165] In some embodiments, in the compound represented by formula (SI) or (SII), ring A, ring B, ring E, L, R a 、R b , R2 to R4, R 1a 、R 1b 、R 1c 、R 1d , m, n and p are each independently the corresponding groups in compounds S1-S51.

[0166] Typical compounds of the present invention represented by general formula (SI) or (SII) include but are not limited to the following compounds:

[0167] The present invention also provides a method for preparing a compound represented by general formula (SI), the method comprising:

[0168] The compound represented by the general formula (SIA) reacts with the compound represented by the general formula (SIB) to obtain the compound represented by the general formula (SI);

[0169] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0170] Ring A, Ring B, Ring E, L, R a 、R b , R2 to R4 and n are as defined in formula (SI);

[0171] or

[0172] The compound represented by the general formula (SIA) reacts with the compound represented by the general formula (SIC) to obtain the compound represented by the general formula (SI);

[0173] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0174] Ring A, Ring B, Ring E, L, R a 、R b , R2 to R4 and n are as defined in the general formula (SI).

[0175] The present invention also provides a method for preparing a compound represented by general formula (SII), the method comprising:

[0176] The compound represented by the general formula (SIIA) reacts with the compound represented by the general formula (SIIB) to obtain the compound represented by the general formula (SII);

[0177] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0178] Ring A, Ring B, Ring E, R a 、R b , R2 to R4, R 1a 、R 1b 、R 1c 、R 1d , m, n and p are as defined in formula (SII);

[0179] The compound represented by the general formula (SIIA) reacts with the compound represented by the general formula (SIIC) to obtain the compound represented by the general formula (SII);

[0180] X is a leaving group selected from halogen, sulfonate, boronic acid, and borate; and

[0181] Ring A, Ring B, Ring E, R a 、R b , R2 to R4, R 1a 、R 1b 、R 1c 、R 1d , m, n and p are as defined in the general formula (SII).

[0182] The present invention also provides a pharmaceutical composition comprising at least one compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) and one or more pharmaceutically acceptable excipients.

[0183] The present invention relates to the use of a compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) or a pharmaceutical composition containing the same in the preparation of a drug for treating or preventing diseases or conditions associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0184] The present invention relates to the use of a compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) or a pharmaceutical composition containing the same in the preparation of a medicament for treating or preventing cancer, particularly, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer and breast cancer.

[0185] The present invention relates to compounds represented by general formula (I'), (I), (II), (III), (SI) or (SII) or pharmaceutical compositions containing the same, which can be used as medicines.

[0186] The present invention relates to compounds represented by general formula (I'), (I), (II), (III), (SI) or (SII) or pharmaceutical compositions containing the same, which are used for treating or preventing diseases or conditions associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0187] The present invention relates to a compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) or a pharmaceutical composition comprising the same, which is used for treating or preventing cancer, particularly, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer and breast cancer.

[0188] 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 administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) or a pharmaceutical composition comprising the same.

[0189] The present invention relates to a method for treating or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I'), (I), (II), (III), (SI) or (SII) or a pharmaceutical composition comprising the same, particularly, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer and breast cancer.

[0190] The pharmaceutical composition of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oil suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile injectable aqueous solutions, sterile injectable oil-in-water microemulsions, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0191] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0192] Definition of terms

[0193] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0194] 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0195] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat 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 the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0196] The term "isomer" refers to compounds having the same composition and molecular weight but different physical and / or chemical properties. The structural differences may lie in the configuration (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). In terms of stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0197] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0198] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of this application 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 commonly referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0199] As used herein, the term "disease" or "disorder" or "condition" refers to a condition for which treatment is needed and / or desired and represents a disorder and / or abnormality generally considered a pathological condition or function, and which may manifest in the form of specific signs, symptoms, and / or dysfunction. The compounds of the present invention inhibit USP1 protein and are useful in treating diseases and conditions such as proliferative diseases, in which inhibition of USP1 protein would provide a benefit.

[0200] "USP1" and "ubiquitin-specific processing protease 1" refer to any naturally occurring polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses "full-length," unprocessed USP1 polypeptides as well as any form of USP1 resulting from 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 a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.

[0201] The terms "cancer" and "tumor" refer to or describe the physiological condition in a mammalian cell population characterized by unregulated cell growth. The terms encompass solid cancers and blood / lymphoid 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 a PARP inhibitor-resistant or refractory cancer, or a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0202] When any variable (e.g., R) occurs more than once in a compound's structure, its definition at each occurrence is independent. For example, if a group is substituted with 0-2 R, then the group may be optionally substituted with up to 2 R, and each occurrence of R is independently selectable.

[0203] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 1-10 Alkyl, more preferably C 1-6Alkyl. Examples of alkyl groups 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-dimethylpentyl, 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.

[0204] 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, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, preferably C 2-5 Alkenyl. Examples of alkenyl groups 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.

[0205] 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, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, preferably C 2-5 Alkynyl. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0206] The term "cycloalkyl" includes two types, one is a conventional cycloalkyl group and the other is a heterostructure cycloalkyl group.

[0207] 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, preferably C 3-12 Conventional cycloalkyl, more preferably C 3-10 Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl, most preferably C 3-6Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0208] Conventional cycloalkyl groups can be monocyclic alkyl groups, and examples of monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Conventional cycloalkyl groups can also be polycyclic alkyl groups (e.g., bicyclic alkyl groups, tricyclic alkyl groups, tetracyclic alkyl groups, and pentacyclic alkyl groups), and polycyclic alkyl groups include spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0209] The term "spirocycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spirocycloalkyl, preferably a 6-14 membered spirocycloalkyl, more preferably a 7-10 membered spirocycloalkyl. The spirocycloalkyl may be a monospirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, preferably a monospirocycloalkyl, more preferably a 4 membered / 4 membered, 4 membered / 5 membered, 4 membered / 6 membered, 5 membered / 5 membered, or 5 membered / 6 membered monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0210] The term "fused cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused cycloalkyl, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher ring fused cycloalkyl, 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:

[0211] The term "bridged cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) bridged cycloalkyl group, preferably a 6-14 membered bridged cycloalkyl group, more preferably a 7-10 membered bridged cycloalkyl group. The bridged cycloalkyl group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Examples of bridged cycloalkyl groups include, but are not limited to:

[0212] The term "heterocyclic alkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl fused to any one of conventional aryl, conventional heteroaryl and conventional heterocyclic groups, and the connection point is located on the corresponding conventional cycloalkyl (referring to monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cycloalkyl). Examples of heterocyclic alkyl groups include, but are not limited to:

[0213] The term "heterocyclic group" includes two types, one is a conventional heterocyclic group and the other is a heterostructure heterocyclic group.

[0214] Conventional heterocyclic groups refer to aliphatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, wherein one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O), and S(O)2, and the substitution does not form -OO-, -OS-, or -SS-; preferably C 3-12 Conventional heterocyclic groups, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, C 3-8 Conventional heterocyclic groups, wherein 1 to 3 (e.g. 1, 2 and 3) are heteroatoms; most preferably C 5-7 Conventional heterocyclic groups, wherein 1-2 or 1-3 are heteroatoms.

[0215] Conventional heterocyclic groups can be monocyclic heterocyclic groups. Examples of monocyclic heterocyclic groups 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 heterocyclic groups can also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0216] The term "spiroheterocyclyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spiroheterocyclyl, preferably a 6-14 membered spiroheterocyclyl, more preferably a 7-10 membered spiroheterocyclyl. The spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a bispiroheterocyclyl, 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 spiroheterocyclyls include, but are not limited to:

[0217] The term "fused heterocyclic group" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused heterocyclic group, preferably a 6-14 membered fused heterocyclic group, more preferably a 7-10 membered fused heterocyclic group. The fused heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of fused heterocyclic groups include, but are not limited to:

[0218] The term "bridged heterocyclic group" refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) bridged heterocyclic group, preferably a 6-14 membered bridged heterocyclic group, more preferably a 7-10 membered bridged heterocyclic group. The bridged heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Examples of bridged heterocyclic groups include, but are not limited to:

[0219] The term "heterocyclic group" includes monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups fused to any one of conventional aryl groups, conventional heteroaryl groups and conventional cycloalkyl groups, and the connection point is located on the corresponding conventional heterocyclic group (referring to monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups). Examples of heterocyclic groups include, but are not limited to:

[0220] The term "aryl" includes two types, one is a conventional aryl group and the other is a heterostructure aryl group.

[0221] Conventional aryl refers to a 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon group, preferably a C 6-10 Conventional aryl groups are more preferably phenyl, naphthyl, phenanthrenyl or anthracenyl.

[0222] The term "heteroaryl" includes a conventional aryl fused to any one of conventional heteroaryl, conventional heterocyclyl and conventional cycloalkyl, with the attachment point being located on the conventional aryl. Examples of heteroaryl groups include, but are not limited to:

[0223] The term "heteroaryl" includes two types, one is a conventional heteroaryl and the other is a heterostructural heteroaryl.

[0224] Conventional heteroaryl refers to 1-4 (e.g., 1, 2, 3, and 4) carbon atoms in a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon group replaced with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, wherein 1-3 (e.g., 1, 2, and 3) heteroatoms are contained. More preferably, the number of ring atoms is 5 or 6, wherein 1-2 heteroatoms are contained. Examples of conventional heteroaryl include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0225] The term "heteroaryl" includes a conventional heteroaryl fused to any one of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclic group, with the point of attachment being located on the conventional heteroaryl. Examples of heteroaryl groups include, but are not limited to:

[0226] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0227] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0228] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0229] The term "hydroxy" refers to -OH.

[0230] The term "halogen" refers to -F, -Cl, -Br or -I.

[0231] The term "amino" refers to -NH2.

[0232] The term "cyano" refers to -CN.

[0233] The term "nitro" refers to -NO2.

[0234] The term "oxo" refers to =0.

[0235] The term "carboxyl" refers to -C(=O)OH.

[0236] The term "mercapto" refers to -SH.

[0237] The term "ester group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0238] The term "acyl" refers to -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0239] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of 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, etc.

[0240] symbol Refers to the attachment site.

[0241] The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. These 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). Additional asymmetric atoms may be present in the substituents in the compounds of the present invention. 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. An isomer of a compound of the present invention can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0242] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0243] 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 of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations.

[0244] The compounds of the present invention include all suitable isotopic substitutions of the compounds thereof. The term "isotopic substitution" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0245] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0246] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustrative purposes only and are not limiting. DETAILED DESCRIPTION

[0247] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0248] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0249] In addition, some protecting groups may be used in the present invention to protect certain functional groups to avoid unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are already widely known to those skilled in the art.

[0250] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0251] Purity analysis was performed using Kinetex EVO C18 (50 × 4.6 mm, 5 μm, ) column, acetonitrile-water was used as the mobile phase for gradient elution, the flow rate was 1.5 mL / min, and the detection wavelength was 220 nm.

[0252] MS was measured using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0253] The structure of the compound was confirmed by hydrogen spectrum using WNMR-I-400MHz.

[0254] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0255] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0256] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0257] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, etc.

[0258] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0259] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 L.

[0260] The reaction solvent, organic solvent or inert solvent is each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP).

[0261] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0262] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0263] Unless otherwise defined, all professional 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.

[0264] Unless otherwise specified, the mixing ratios of different solvents are by volume.

[0265] The following introduces the synthesis of common intermediates, including A series, AA series, B series, BB series, C series, D series, SA series, SB series, SC series and further synthesized intermediate series.

[0266] Synthesis of General Intermediate A1 (2-(2-isopropylphenyl)-5-methoxypyrimidin-4-amine)

[0267] 2-Chloro-5-methoxypyrimidin-4-amine (Compound A1-1, 5.0 g, 31.3 mmol, 1.00 eq), (2-isopropylphenyl)boric acid (Compound A1-2, 6.7 g, 40.7 mmol, 1.30 eq, purchased from Bidex Pharmaceuticals), potassium carbonate (13.0 g, 94.0 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (2.3 g, 3.13 mmol, 0.10 eq) were added to dioxane (50.0 mL) and water (12.5 mL) in sequence, and the mixture was replaced with nitrogen three times. The reaction was carried out at 100°C under nitrogen protection for 16 hours. Then, ethyl acetate (500.0 mL) was added and stirred for 10 minutes. The filtrate was filtered and concentrated in vacuo to obtain a crude product, which was purified by reverse phase HPLC (0.1% NH3·H2O) to give a light yellow solid compound A1 (4.9 g, 63.3% yield, 98.2% purity). 1 H NMR(400MHz,DMSO)δ7.93(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=7.20Hz,6H); LC-MS:m / z=244.2(M+H) + .

[0268] Synthesis of Universal Intermediate A2 (4'-Cyclopropyl-5,6'-dimethoxy-N-methyl-[2,5'-bipyrimidinyl]-4-amine)

[0269] Step 1: Synthesis of compound A2-3 (6-cyclopropylpyrimidin-4-ol)

[0270] 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). Sodium methoxide methanol solution (5.4 M, 1.3 L, 5.00 eq) was added portionwise at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 13 hours. Then, glacial acetic acid was added at 0°C to adjust the pH to 7-8. The mixture 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 obtain compound A2-3 (90.3 g). LC-MS: m / z = 137.1 (M+H) + .

[0271] Step 2: Synthesis of compound A2-4 (4-chloro-6-cyclopropylpyrimidine)

[0272] Compound A2-3 (40.0 g, 293.0 mmol, 1.00 eq) was added portionwise to phosphorus oxychloride (180.0 mL). After the addition was complete, the temperature was raised to 60°C and stirred for 2 hours. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was dissolved in ethyl acetate (400.0 mL) and water (400.0 mL) and stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (400.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain 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 = 20 / 1-1 / 1) to obtain compound A2-4 (11.0 g). LC-MS: m / z = 155.0 (M+H) + .

[0273] Step 3: Synthesis of compound A2-5 (5-bromo-4-chloro-6-cyclopropylpyrimidine)

[0274] Compound A2-4 (11.0 g, 71.1 mmol, 1.00 eq) was dissolved in methanol (150.0 mL). Bromine (34.1 g, 213.0 mmol, 3.00 eq) was slowly added at -60°C. After the addition was complete, the temperature was raised to 20°C and stirred for 2 hours. Then, saturated sodium bicarbonate solution (200.0 mL) and water (100.0 mL) were added at 0°C and stirred for 5 minutes. The mixture was extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which 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 (400MHz, CDCl3) δ8.61 (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) + .

[0275] Step 4: Synthesis of compound A2-6 (5-bromo-4-cyclopropyl-6-methoxypyrimidine)

[0276] Compound A2-5 (7.8 g, 33.4 mmol, 1.00 eq) was dissolved in methanol (240.0 mL). Sodium methoxide (18.0 g, 100.0 mmol, 3.00 eq) was added at 0°C. After the addition, the temperature was raised to 30°C and stirred for 1 hour. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain compound A2-6 (7.3 g). LC-MS: m / z = 228.9 (M+H) + .

[0277] Step 5: Synthesis of compound A2-7 ((4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid)

[0278] Compound A2-6 (10.3 g, 44.9 mmol, 1.00 eq) and triisopropyl borate (11.8 g, 62.9 mmol, 1.40 eq) were dissolved in tetrahydrofuran (30.0 mL) and toluene (90.0 mL). n-Butyl lithium (2.5 M, 25.1 mL, 1.40 eq) was added dropwise at -70°C and stirred at -70°C for 3 hours. Then, 1N hydrochloric acid solution (50.0 mL) was added dropwise at -70°C. After the addition was complete, the temperature was raised to 20°C and stirred for 0.5 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain compound A2-7 (6.9 g). 1 H NMR (400MHz, CDCl3) δ8.52(s,1H),8.45(s,2H),3.84(s,3H),1.88-1.92(m,2H),0.93-1.01(m,4H).

[0279] Step 6: Synthesis of Intermediate A2

[0280] Compound A2-8 (1.2 g, 6.9 mmol, 1.0 eq), 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (505.0 mg, 0.7 mmol, 0.10 eq), and potassium carbonate (2.9 g, 20.7 mmol, 3.00 eq) were added to dioxane (100.0 mL) and water (25.0 mL) in sequence, and the nitrogen atmosphere was replaced three times. Compound A2-7 (1.6 g, 8.3 mmol, 1.20 eq) dissolved in N,N-dimethylformamide (10.0 mL) was added dropwise under a nitrogen atmosphere at 100°C. After the addition, the mixture was reacted at 100°C for 2 hours under nitrogen protection. The reaction mixture was then concentrated in vacuo, added with water (60.0 mL), and extracted twice with ethyl acetate (40.0 mL). The organic layers were combined, washed twice with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was then concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-10 / 1) to obtain Compound A2 (100.0 mg, 348 μmol, 5.0% yield, 100% purity) as a white solid. LC-MS: m / z = 288.0 (M+H) + .

[0281] Synthesis of General Intermediate A3 (4-chloro-2-(2-isopropylphenyl)-5-nitropyrimidine)

[0282] Step 1: Synthesis of compound A3-3 (2-(2-isopropylphenyl)-4-methoxy-5-nitropyrimidine)

[0283] Compound A3-2 (3.3 g, 17.4 mmol, 1.00 eq), compound A3-1 (5.7 g, 34.8 mmol, 2.00 eq), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (1.3 g, 1.7 mmol, 0.10 eq), and potassium carbonate (4.8 g, 34.8 mmol, 2.00 eq) were dissolved in dioxane (30.0 mL) and water (7.0 mL). The atmosphere was replaced with nitrogen three times and the mixture was reacted at 100°C under nitrogen protection for 12 hours. The reaction solution was then concentrated in vacuo to obtain a crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain compound A3-3 (3.2 g). LC-MS: m / z = 274.1 (M+H) + .

[0284] Step 2: Synthesis of compound A3-4 (2-(2-isopropylphenyl)-5-nitropyrimidin-4-ol)

[0285] Compound A3-3 (2.0 g, 7.3 mmol, 1.00 eq) was dissolved in dioxane (30.0 mL), and hydrobromic acid and glacial acetic acid (6 M, 15.0 mL, 12.30 eq) were added. After the addition was complete, the temperature was raised to 50°C and stirred for 1 hour. The reaction solution was then concentrated in vacuo to obtain crude compound A3-4 (2.0 g), which was used directly in the next reaction. LC-MS: m / z = 260.0 (M+H) + .

[0286] Step 3: Synthesis of Intermediate A3

[0287] Compound A3-4 (2.0 g, 6.8 mmol, 1.00 eq) was added to phosphorus oxychloride (18.0 mL) and reacted at 90°C for 2 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to obtain compound A3 (1.0 g, 3.59 mmol, 53.1% yield, 99.8% purity) as a pale yellow oil. LC-MS: m / z = 278.1 (M+H) + .

[0288] Synthesis of Universal Intermediate A4 (2-(2-isopropylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0289] Step 1: Synthesis of compound A4-2 (2-chloro-5-(trifluoromethyl)pyrimidin-4-amine)

[0290] Compound A4-1 (18.7 g, 86.2 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Aqueous ammonia (15.1 g, 129 mmol, 30.0% purity, 1.50 eq) was added at 0°C. After complete addition, the temperature was raised to 20°C and stirred for 16 hours. Water (30.0 mL) was then added, and the 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, which was then 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 (400MHz, DMSO) δ8.56 (s, 1H), 7.95 (s, 2H); LC-MS: m / z=197.9 (M+H) + .

[0291] Step 2: Synthesis of Intermediate A4

[0292] Compound A4-2 (1.15 g, 5.77 mmol, 1.00 eq), compound A4-3 (1.14 g, 6.92 mmol, 1.20 eq), potassium carbonate (2.39 g, 17.3 mmol, 3.00 eq), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (422 mg, 577 μmol, 0.10 eq) were added sequentially to dimethyl sulfoxide (12.0 mL) and water (2.5 mL). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 12 hours. The reaction solution was then concentrated in vacuo to obtain a crude product, which was then purified by preparative HPLC to afford Compound A4 (200 mg, 711 μmol, 12.3% yield, 100% purity) as a pale yellow oil. 1 H NMR(400MHz,DMSO)δ8.57(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) + .

[0293] Synthesis of General Intermediate A5 (2-(2-isopropylphenyl)-5-methoxy-N-methylpyrimidin-4-amine)

[0294] Step 1: Synthesis of compound A5-2 (2-chloro-5-methoxy-N-methylpyrimidin-4-amine)

[0295] Compound A5-1 (10.0 g, 55.9 mmol, 1.00 eq) was dissolved in tetrahydrofuran (100.0 mL), and methylamine (2.0 M aqueous methylamine solution, 54.5 mL, 1.95 eq) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 2 hours. Water (200.0 mL) was added and stirred for 5 minutes. The mixture was extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain compound A5-2 (9.0 g). 1 H NMR (400MHz, CDCl3) δ7.50 (s, 1H), 5.48 (s, 1H), 3.86 (s, 3H), 3.05 (d, J = 4.00Hz, 3H); LC-MS: m / z = 173.9 (M+H) + .

[0296] Step 2: Synthesis of Intermediate A5

[0297] Compound A5-2 (3.0 g, 17.3 mmol, 1.00 eq), compound A5-3 (3.7 g, 22.5 mmol, 1.3 eq), potassium carbonate (7.2 g, 51.8 mmol, 3.00 eq), and 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (1.3 g, 1.7 mmol, 0.10 eq) were added sequentially to dioxane (30.0 mL) and water (7.5 mL). The atmosphere was replaced with nitrogen three times and the mixture was reacted at 100°C for 16 hours. Ethyl acetate (500.0 mL) was then added and stirred for 10 minutes. The filtrate was filtered and concentrated in vacuo to obtain the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to afford Compound A5 (4.3 g, 16.3 mmol, 94.4% yield, 96.9% purity) as a brown oil. 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.56 (d, J = 7.60Hz, 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=5.20Hz,3H),1.25-1.29(m,6H); LC-MS:m / z=258.0(M+H) + .

[0298] Synthesis of General Intermediate A6 (2-(2-isopropylphenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0299] Step 1: Synthesis of compound A6-2 (4-amino-2-chloropyrimidin-5-ol)

[0300] Compound A6-1 (15.6 g, 97.8 mmol, 1.00 eq) was dissolved in dichloromethane (1.5 L). Boron tribromide (367.0 g, 1.5 mol, 15.0 eq) was slowly added at 0°C. After complete addition, the temperature was raised to 20°C and stirred for 96 hours. Methanol (1.0 L) was then slowly added at 0°C to quench the reaction. The reaction solution was concentrated in vacuo to obtain the crude product. Dichloromethane (200.0 mL) was added and stirred for 5 minutes. The mixture was filtered to obtain a filter cake. The filter cake was dissolved in water (200.0 mL) and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The filter cake was filtered to obtain the filter cake. The filter cake was washed twice with water (50.0 mL) and concentrated in vacuo to obtain compound A6-2 (12.9 g). 1 H NMR (400MHz, DMSO) δ10.0 (d, J = 10.0Hz, 1H), 7.47 (d, J = 15.6Hz, 1H), 7.07 (s, 2H); LC-MS: m / z = 145.9 (M + H) + .

[0301] Step 2: Synthesis of compound A6-4 (2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine)

[0302] Compound A6-2 (19.0 g, 130 mmol, 1.00 eq), compound A6-3 (28.1 g, 196 mmol, 16.2 mL, 1.50 eq), and potassium carbonate (54.1 g, 392 mmol, 3.00 eq) were added sequentially to N,N-dimethylformamide (200.0 mL). The mixture was reacted at 20°C for 16 hours to obtain crude compound A6-4 (27.2 g). The reaction solution was used directly in the next step. LC-MS: m / z = 207.8 (M+H) + .

[0303] Step 3: Synthesis of compound A6-5 (2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0304] The reaction solution of compound A6-4 (27.2 g) was heated to 100° C. and stirred for 16 hours. The reaction solution was filtered to obtain a filtrate, and water (800.0 mL) was added and stirred for 5 minutes. The mixture was extracted three times with ethyl acetate (300.0 mL). The organic layers were combined, washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain a crude product. Methyl tert-butyl ether (1000.0 mL) was added and stirred for 30 minutes. The filter cake was filtered and concentrated in vacuo to obtain compound A6-5 (3.4 g). 1H NMR (400MHz, CDCl3) δ8.33 (d, J = 9.60Hz, 1H), 7.63 (d, J = 18.8Hz, 1H), 4.10-4.34 (m, 2H), 3.43-3.46 (m, 2H); LC-MS: m / z = 171.9 (M+H) + .

[0305] Step 4: Synthesis of Intermediate A6

[0306] Compound A6-5 (1.5 g, 8.74 mmol, 1.00 eq), compound A6-6 (1.4 g, 8.74 mmol, 1.00 eq), potassium carbonate (3.6 g, 26.2 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (640.0 mg, 874 μmol, 0.10 eq) were added to N,N-dimethylformamide (15.0 mL) and water (3.8 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Kromasil Eternity XT The mixture was purified by HPLC (250×80mm×10μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 28%-58%, 21min) to give brown solid compound A6 (1.37g, 5.27mmol, 60.3% yield, 98.3% purity). 1 H NMR(400MHz,DMSO)δ7.86(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) + .

[0307] Synthesis of General Intermediate A7 (2-(2-isopropylphenyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0308] Step 1: Synthesis of compound A7-2 (2-chloro-6-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0309] Compound A6-2 (4.00 g, 27.4 mmol, 1.00 eq), compound A7-1 (4.66 g, 41.2 mmol, 3.28 mL, 1.50 eq), and potassium carbonate (11.4 g, 82.4 mmol, 3.00 eq) were added sequentially to N,N-dimethylformamide (50.0 mL), reacted at 30°C for 3 hours, added with water (150.0 mL), and extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed three times with saturated brine (70.0 mL), and dried over anhydrous sodium sulfate. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-5 / 1) to obtain compound A7-2 (1.1 g). 1 H NMR (400MHz, CDCl3) δ12.00 (s, 1H), 8.18-8.23 (m, 1H), 4.77-4.78 (m, 2H); LC-MS: m / z = 185.9 (M+H) + .

[0310] Step 2: Synthesis of Intermediate A7

[0311] Compound A7-2 (500.0 mg, 2.69 mmol, 1.00 eq), compound A7-3 (574.1 mg, 3.50 mmol, 1.30 eq), potassium phosphate aqueous solution (1.5 M, 5.39 mL, 3.00 eq) and (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (231.1 mg, 269 μmol, 0.100 eq) were added to tetrahydrofuran (25.0 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 60°C for 12 hours under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: 3_Phenomenex Luna C18 A7 (90.0 mg, 334 μmol, 12.4% yield) was obtained by purification using a 75×30 mm×3 μm column; mobile phase: [water (HCl)-ACN]; B%: 28%-48%, 8 min). LC-MS: m / z = 270.1 (M+H) + .

[0312] Synthesis of Universal Intermediate A8 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0313] Compound A6-5 (1.50 g, 8.74 mmol, 1.00 eq), compound A2-7 (1.70 g, 8.74 mmol, 1.00 eq), potassium carbonate (3.62 g, 26.2 mmol, 3.00 eq), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (640 mg, 874 μmol, 0.10 eq) were added sequentially to a mixed solvent of N,N-dimethylformamide (15.0 mL) and water (3.75 mL). The mixture was replaced with nitrogen three times and stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 The mixture was purified by HPLC (250×50mm×10μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 10%-35%, 20min) to give compound A8 as a white solid (414 mg, 1.45 mmol, 16.6% yield, 100% purity). 1 H NMR(400MHz,DMSO)δ8.59(s,1H),7.94(s,1H),7.87(s,1H),4.17-4.19(m,2H),3.82(s,3H),3.4 7-3.49(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) + .

[0314] Synthesis of Universal Intermediate A9 (4'-Cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidinyl]-4-amine)

[0315] Step 1: Synthesis of compound A9-2 (2-chloro-5-methoxy-N, N-bis(4-methoxybenzyl)pyrimidin-4-amine)

[0316] Compound A9-1 (6.0 g, 37.6 mmol, 1.00 eq) was dissolved in tetrahydrofuran (60.0 mL). Sodium hydride (3.31 g, 82.7 mmol, 60% purity, 2.20 eq) was added portionwise at 0°C. After complete addition, the mixture was stirred at 5°C for 30 minutes. 4-Methoxybenzyl chloride (12.9 g, 82.7 mmol, 2.20 eq) was added and stirred at 5°C for 12 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (40.0 mL) at 0°C. The mixture was then extracted three times with water (150.0 mL) and ethyl acetate (70.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was then concentrated in vacuo to obtain the crude product, which was then 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).+ .

[0317] Step 2: Synthesis of compound A9-3 (4'-cyclopropyl-5,6'-dimethoxy-N,N-bis(4-methoxybenzyl)-[2,5'-bipyrimidine]-4-amine)

[0318] Compound A9-2 (2.0 g, 5.00 mmol, 1.00 eq), compound A2-7 (1.46 g, 7.50 mmol, 1.50 eq), potassium phosphate aqueous solution (1.5 M, 10.0 mL, 3.00 eq), (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (430 mg, 500 μmol, 0.100 eq) were added to tetrahydrofuran (40.0 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex luna C18 (250×70 mm, 10 μm); mobile phase: [water (FA)-ACN]; B%: 35%-65%, 21 min) to obtain A9-3 (0.9 g). LC-MS: m / z=514.3 (M+H) + .

[0319] Step 3: Synthesis of Intermediate A9

[0320] Compound A9-3 (900 mg, 1.75 mmol, 1.00 eq) was added to trifluoroacetic acid (10.0 mL), heated to 90°C, and stirred for 12 hours. The reaction solution was concentrated in vacuo, and saturated aqueous sodium bicarbonate (10.0 mL) was added to adjust the pH to 8. The 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, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain A9 as a white solid (300.0 mg, 62.5% yield, 100% purity). LC-MS: m / z = 274.1 (M+H) + .

[0321] Synthesis of Universal Intermediate A10 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0322] Compound A7-2 (600 mg, 3.23 mmol, 1.00 eq), A2-7 (940 mg, 4.85 mmol, 1.50 eq), potassium phosphate aqueous solution (1.5 M, 6.47 mL, 3.00 eq), (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (417 mg, 485 μmol, 0.150 eq) were added to tetrahydrofuran (10.0 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex luna C18 The intermediate A10 (60.0 mg, 0.2 mmol, 6.2% yield, 100% purity) was purified using a 150×40 mm×15 μm column; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 10 min). LC-MS: m / z = 300.1 (M+H) + .

[0323] Synthesis of Universal Intermediate AA3 (1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole)

[0324] Step 1: Synthesis of compound AA3-2 (7-bromo-1-methyl-1H-indole)

[0325] 7-Bromoindole (Compound AA3-1, 15.0 g, 76.5 mmol, 1.00 eq) was dissolved in THF (150 mL). NaH (4.59 g, 115 mmol, 60% purity, 1.50 eq) was added portionwise at 0°C. After complete addition, the mixture was warmed to 25°C and stirred for 1.5 hours. Potassium iodide (14.1 g, 99.5 mmol, 6.19 mL, 1.30 eq) was then added at 0°C. After complete addition, the mixture was warmed to 25°C and stirred for 12 hours. The reaction was quenched by the addition of 60 mL of ice water at 0°C. The 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 the filtrate was filtered and concentrated in vacuo to afford Compound AA3-2 (16.5 g, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.59 (d, J = 7.6Hz, 1H), 7.39-7.41 (m, 1H), 7.01-7.02 (m, 1 H),6.94-6.98(m,1H),6.50-6.51(m,1H),4.18(s,3H); LC-MS: m / z=212.0(M+H) + .

[0326] Step 2: Synthesis of intermediate AA3

[0327] Compound AA3-2 (4.00 g, 19.0 mmol, 1.00 eq), pinacol diboron (9.67 g, 38.1 mmol, 2.00 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.39 g, 1.90 mmol, 0.100 eq) and potassium acetate (3.74 g, 38.1 mmol, 2.00 eq) were dissolved in dioxane (40.0 mL) and stirred at an external temperature of 95°C for 12 hours. Then, water (80.0 mL) was added, and the mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (50.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain a white solid intermediate AA3 (2.47 g, 9.45 mmol, 49.6% yield, 98.4% purity). 1 H NMR(400MHz, CDCl3)δ7.75(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) + .

[0328] Synthesis of Universal Intermediate AA4 ((1-Methylindol-7-yl)boronic Acid)

[0329] Step 1: Synthesis of compound AA4-1 (7-bromo-1-methylindole)

[0330] Compound AA3-2 (6.70 g, 31.8 mmol, 1.00 eq) was added to acetic acid (50.0 mL), and sodium cyanoborohydride (16.0 g, 255 mmol, 8.00 eq) was added at 10°C. The mixture was stirred at 20°C for 12 hours, and a 1 M aqueous sodium hydroxide solution was added to adjust the pH to approximately 8. The 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 the filtrate was filtered. The mixture was concentrated in vacuo to obtain compound AA4-1 (8.00 g, crude product) as a brown oil. LC-MS: m / z = 212.1 (M+H) + .

[0331] Step 2: Synthesis of intermediate AA4

[0332] Compound AA4-1 (500 mg, 2.36 mmol, 1.00 eq) and triisopropyl borate (576 mg, 3.06 mmol, 704 μL, 1.30 eq) were added to tetrahydrofuran (10.0 mL). n-Butyl lithium (2.5 M, 1.23 mL, 1.30 eq) was added dropwise at -78°C. After complete addition, the mixture was heated to 25°C and stirred for 4 hours. Saturated aqueous ammonium chloride (20 mL) was then added dropwise at 0°C to quench the reaction. The mixture was then extracted three times with water (30.0 mL) and 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, which was purified by reverse-phase HPLC (0.1% FA) to afford intermediate AA4 (120 mg, 588.45 μmol, 24.96% yield, 86.8% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.06 (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) + .

[0333] Synthesis of Universal Intermediate AA5 ((1-Isopropyl-4-methyl-1H-imidazol-5-yl)boronic acid)

[0334] Step 1: Synthesis of compound AA5-2 (5-bromo-1-isopropyl-4-methyl-1H-imidazole)

[0335] 4-Methyl-5-bromoimidazole (AA5-1, 40.0 g, 248 mmol, 1.00 eq) was dissolved in tetrahydrofuran (800 mL), and sodium hydride (7.15 g, 178 mmol, 60% purity, 0.720 eq) was added in batches at -15°C. After the addition, the mixture was stirred at -15°C for 30 minutes. 2-Iodopropane (42.2 g, 248 mmol, 24.8 mL, 1.00 eq) was added and stirred at 0°C for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (100 mL), and water (800.0 mL) was added. The mixture was extracted three times with ethyl acetate (500 mL). The organic layers were combined, washed twice with saturated brine (500 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by reverse phase HPLC (0.1% NH3·H2O) to obtain compound AA5-2 (7.00 g, 34.4 mmol, 46.6% yield) as a brown oil. 1H NMR (400MHz, CDCl3) δ7.56 (s, 1H), 4.32-4.39 (m, 1H), 2.20 (s, 3H), 1.47 (d, J = 4.4Hz, 6H); LC-MS: m / z = 203.0 (M+H) + .

[0336] Step 2: Synthesis of intermediate AA5

[0337] Compound AA5-2 (7.00 g, 34.5 mmol, 1.00 eq) and triisopropyl borate (32.4 g, 172 mmol, 39.6 mL, 5.00 eq) were added to tetrahydrofuran (150.0 mL). n-Butyl lithium (2.50 M, 27.6 mL, 2.00 eq) was added dropwise at -78°C. After the addition, the temperature was raised to 25°C and stirred for 4 hours. Then, saturated aqueous ammonium chloride (200 mL) was added dropwise at 0°C to quench the reaction. The mixture was extracted three times with water (300.0 mL) and ethyl acetate (300 mL). The organic layers were combined, washed twice with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated in vacuo to obtain compound AA5 (6.5 g, crude) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.22-8.26(m,2H),8.20(s,1H),5.12(s,1H),2.30(s,3H),1.37-1.39(m,6H); LC-MS: m / z=169.1(M+H) + .

[0338] Synthesis of Universal Intermediate AA6 (2-Cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0339] Step 1: Synthesis of compound AA6-2 (2-bromopyridin-3-yl trifluoromethanesulfonate)

[0340] 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 Bidex Pharmaceuticals), and triethylamine (1.1 mL, 8.1 mmol) were added sequentially to dichloromethane (20 mL). The mixture was stirred at 0°C under nitrogen for 1 hour, then heated to 25°C and stirred for 1.5 hours. The mixture was washed once with 1M sodium hydroxide (100 mL) and twice with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain Compound AA6-2 (2.8 g, crude product) as a pale yellow oil. LC-MS: m / z = 305.9 (M+H) + .

[0341] Step 2: Synthesis of compound AA6-3 (2-cyclopropylpyridin-3-yl trifluoromethanesulfonate)

[0342] Compound AA6-2 (2.5 g), tetrakis(triphenylphosphine)palladium (199 mg), and cyclopropylzinc chloride (0.4 M THF solution, 23 mL) were added to tetrahydrofuran (15 mL) in sequence. The mixture was stirred at 70°C under nitrogen for 3 hours. The mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (60 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product 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) + .

[0343] Step 3: Synthesis of intermediate AA6

[0344] Compound AA6-3 (0.5 g), pinacol diboron (0.57 g), potassium carbonate (0.525 g) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (0.156 g) were added to dioxane (80 mL), stirred at 100°C for 20 hours, cooled to room temperature, added ethyl acetate (200 mL), washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product 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.

[0345] Synthesis of Universal Intermediate AA7 (2-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0346] Step 1: Synthesis of compound AA7-2 (2-isopropylpyridin-3-yl trifluoromethanesulfonate)

[0347] 2-Isopropylpyridin-3-ol (compound AA7-1, 3.00 g, 21.8 mmol, 1.00 eq) was added to pyridine (30.0 mL), and trifluoromethanesulfonic anhydride (6.17 g, 21.8 mmol, 3.61 mL, 1.00 eq) was added at 0°C. The mixture was stirred at 15°C for 2 hours, and water (30 mL) was added. The 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 the filtrate was filtered. The mixture was concentrated in vacuo to obtain compound AA7-2 (3.62 g, crude product) as a yellow oil. 1H NMR (400MHz, CDCl3) δ8.59 (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 = 6.8Hz, 6H); LC-MS: m / z = 270.2 (M+H) + .

[0348] Step 2: Synthesis of Compound AA7

[0349] Compound AA7-2 (3.62 g, 13.4 mmol, 1.00 eq), pinacol diboron (6.83 g, 26.8 mmol, 2.00 eq), potassium acetate (2.64 g, 26.8 mmol, 2.00 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (983 mg, 1.34 mmol, 0.100 eq) were added to dioxane (60.0 mL) in sequence, stirred at 100 ° C for 20 hours, cooled to room temperature, added ethyl acetate (300 mL), 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, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound AA7 (2.00 g, 8.09 mmol, 60.2% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ8.60 (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).

[0350] Universal intermediate AA8 ((2-(dimethylamino)phenyl)boronic acid)

[0351] Intermediate AA8 was purchased from Bidex Pharmaceuticals.

[0352] Synthesis of Universal Intermediate AA9 (4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0353] Step 1: Synthesis of compound AA9-2 (4-chloro-1-isopropyl-1H-pyrazole)

[0354] Compound AA9-1 (50.00 g, 487.70 mmol, 1.00 eq), 2-iodopropane (124.36 g, 731.55 mmol, 73.15 mL, 1.50 eq), and cesium carbonate (317.80 g, 975.40 mmol, 2.00 eq) were added to acetonitrile (500.00 mL) and stirred at 80°C under N2 protection for 2 hours. The filtrate was then filtered and concentrated in vacuo to obtain the crude product, which 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, 62.85% yield, 98.50% purity) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.41-7.40 (m, 2H), 4.46-4.41 (m, 1H), 1.48 (d, J = 6.8Hz, 6H); LC-MS: m / z = 144.0 (M+H) + .

[0355] Step 2: Synthesis of intermediate AA9

[0356] Compound AA9-2 (10 g, 69.16 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (100 mL), and n-butyl lithium (2.5 M, 33.19 mL, 1.2 eq) was added dropwise at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1 hour. Isopropyl pinacol borate (15.44 g, 82.99 mmol, 16.93 mL, 1.2 eq) was added at -78°C, and the temperature was raised to 25°C and stirred for 2 hours. Then, saturated aqueous ammonium chloride solution (100 mL) was added at 0°C to quench the reaction, water (200 mL) was added, and the mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (60.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product, which was purified by prep-HPLC (chromatographic column: Welch Ultimate XB-CN 250×70×10 μm; mobile phase: [hexane-ethanol]; B%: 1%-1%, 15 min) to obtain compound AA9 (6.5 g, 18.33 mmol, 26.51% yield, 76.3% purity) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.45 (s, 1H), 5.07–5.00 (m, 1H), 1.46 (d, J = 6.8Hz, 6H), 1.36 (s, 12H); LC-MS: m / z = 271.2 (M+H) + .

[0357] General intermediate AA10 ((2-cyclopropylphenyl)boronic acid)

[0358] The intermediate AA10 was purchased from Bidex Pharmaceuticals.

[0359] Synthesis of Universal Intermediate AA11 ((1-Isopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0360] Step 1: Synthesis of compound AA11-2 (1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0361] 4-Pyrazoleboronic acid pinacol ester (Compound AA11-1, 130 g, 669 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (114 g, 669 mmol, 67.0 mL, 1.00 eq). 2-Iodopropane (114 g, 669 mmol, 67.0 mL, 1.00 eq) and cesium carbonate (327 g, 1.00 mol, 1.50 eq) were added, and the mixture was stirred at 90°C for 12 hours. The filtrate was then filtered and concentrated in vacuo to obtain the crude product. The crude product 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, transparent oil. 1 H NMR (400MHz, CDCl3) δ7.74 (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) + .

[0362] Step 2: Synthesis of compound AA11-3 (1-isopropyl-1H-pyrazol-4-ol)

[0363] Compound AA11-2 (60.0 g, 254 mmol, 1.00 eq) was dissolved in tetrahydrofuran (600 mL), and aqueous sodium hydroxide solution (2.50 M, 203 mL, 2.00 eq) and hydrogen peroxide (72.0 g, 635 mmol, 61.0 mL, 30.0% purity, 2.50 eq) were added. The mixture was stirred at 25 °C for 3 hours, and 1 M aqueous hydrochloric acid solution was added to adjust the pH to about 2. Then, anhydrous sodium sulfite (50.0 g) was added at 0°C to quench the reaction, and the tetrahydrofuran was removed by vacuum concentration. The mixture was 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, which was concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound AA11-3 (17.5 g, 138 mmol, 54.6% yield) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.12 (s, 1H), 7.09 (d, J = 0.8Hz, 1H), 4.32-4.39 (m, 1H), 1.43 (s, 3H), 1.41 (s, 3H).

[0364] Step 3: Synthesis of compound AA11-4 (1-isopropyl-4-methoxy-1H-pyrazole)

[0365] Compound AA11-3 (17.5 g, 139 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (350 mL), and cesium carbonate (67.8 g, 208 mmol, 1.50 eq) and iodomethane (29.5 g, 208 mmol, 13.0 mL, 1.50 eq) were added. The mixture was stirred at room temperature (25°C) for 3 hours. Water (1000 mL) was then added, and the 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 in vacuo to obtain the crude product, which 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) δ7.17 (s, 1H), 7.05 (d, J = 0.8Hz, 1H), 4.30-4.36 (m, 1H), 3.70 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H).

[0366] Step 4: Synthesis of compound AA11

[0367] Compound AA11-4 (1.00 g, 7.13 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (15.0 mL). n-Butyl lithium (2.50 M, 4.28 mL, 1.50 eq) was added dropwise under nitrogen at -70°C. The mixture was stirred at -70°C for 1 hour. Isopropyl pinacol borate (2.01 g, 10.8 mmol, 2.2 mL, 1.50 eq) was then added at -70°C. The mixture was stirred at -70°C for 1 hour, then warmed to 25°C and stirred for 12 hours. Saturated aqueous ammonium chloride (20.0 mL) was added at 0°C, and the 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 in vacuo to afford the crude product, which was then slurried with petroleum ether (20.00 mL) for 15 minutes to afford intermediate AA11 (200 mg, 1.09 mmol, 15.2% yield) as an off-white solid. LC-MS: m / z=185.2 (M+H) + .

[0368] Synthesis of Universal Intermediate AA12 ((1-cyclopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0369] Step 1: Synthesis of compound AA12-2 (1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0370] Compound AA12-1 (19.0 g, 102 mmol, 1.00 eq) was dissolved in dioxane (250 mL), and pinacol diboron (36.1 g, 142 mmol, 1.40 eq), potassium acetate (39.9 g, 406 mmol, 4.00 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.15 g, 5.08 mmol, 0.05 eq) were added in sequence. The mixture was stirred at 85 ° C for 12 hours under nitrogen protection. Then, water (800 mL) and ethyl acetate (500 mL) were added, and the filtrate was filtered. The mixture was extracted three times with ethyl acetate (500 mL). The organic layers were combined, washed twice with saturated brine (500 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 0) to obtain compound AA12-2 (4.40 g) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J = 3.2Hz, 2H), 3.50-3.60 (m, 1H), 1.32 (s, 12H), 1.09-1.12 (m, 2H), 1.01-1.04 (m, 2H); LC-MS: m / z = 235.1 (M+H) + .

[0371] Step 2: Synthesis of compound AA12-3 (1-cyclopropyl-1H-pyrazol-4-ol)

[0372] Compound AA12-2 (3.30 g, 14.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (43.0 mL). Aqueous sodium hydroxide (2.50 M, 11.3 mL, 2.00 eq) and hydrogen peroxide (5.84 g, 51.5 mmol, 4.95 mL, 30.0% purity, 3.65 eq) were added and stirred at 25°C for 3 hours. 1 M aqueous hydrochloric acid was added to adjust the pH to approximately 2. The reaction was then quenched by the addition of anhydrous sodium sulfite (50.0 g) at 0°C. The tetrahydrofuran was removed by vacuum concentration, and the mixture was 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 then concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound AA12-3 (0.980 g, crude) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.12 (d, J = 3.6Hz, 2H), 3.46-3.48 (m, 1H), 0.95-0.96 (m, 2H), 0.94-0.95 (m, 2H).

[0373] Step 3: Synthesis of compound AA12-4 (1-cyclopropyl-4-methoxy-1H-pyrazole)

[0374] Compound AA12-3 (0.980 g, 7.89 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (19.5 mL), and cesium carbonate (3.86 g, 11.8 mmol, 1.50 eq) and iodomethane (1.68 g, 11.8 mmol, 737 μL, 1.50 eq) were added. The mixture was stirred at room temperature (25°C) for 3 hours. Water (10.0 mL) was then added, and the 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 in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to obtain compound AA12-4 (0.460 g, 3.33 mmol, 42.2% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.21(s,1H),7.13(s,1H),3.74(s,3H),3.49-3.53(m,1H),1.08-1.09(m,2H),0.96-0.99(m,2H); LC-MS: m / z=139.2(M+H) + .

[0375] Step 4: Synthesis of intermediate AA12

[0376] Compound AA12-4 (0.300 g, 2.17 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (8.50 mL), and n-butyl lithium (2.50 M, 1.74 mL, 2.00 eq) was added dropwise at -70 ° C under nitrogen protection. After the addition, the mixture was stirred at -70 ° C for 1 hour. Then, isopropyl pinacol borate (808 mg, 4.34 mmol, 886 μL, 2.00 eq) was added at -70 ° C, stirred at -70 ° C for 1 hour, and then the temperature was raised to 25 ° C and stirred for 12 hours. Then, saturated aqueous ammonium chloride (30.0 mL) was added at 0°C, and the mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 3%-33%, 10 min) to obtain compound AA12 (0.400 g, crude) as a pale yellow oil. LC-MS: m / z = 183.1 (M+H) + .

[0377] Synthesis of Universal Intermediate AA13 ((5-isopropyl-3-methylisoxazol-4-yl)boronic acid)

[0378] Step 1: Synthesis of compound AA13-2 (5-isopropyl-3-methylisoxazole)

[0379] Isobutyrylacetone (Compound AA13-1, 2.00 g, 15.6 mmol, 1.00 eq) and hydroxylamine hydrochloride (1.36 g, 19.6 mmol, 1.25 eq) were added to ethanol (10.0 mL) in sequence, stirred at 130°C for 10 minutes, and dichloromethane (100 mL) was added. The mixture was washed twice with saturated brine (50.0 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain colorless transparent liquid Compound AA13-2 and Compound AA13-2a (4.80 g, crude product in total). Compound AA13-2 1 H NMR (400MHz, CDCl3) δ5.76 (s, 1H), 3.04-2.97 (m, 1H), 2.35 (s, 3H), 1.28-1.23 (m, 6H).

[0380] Step 2: Synthesis of compound AA13-3 (4-bromo-5-isopropyl-3-methylisoxazole)

[0381] Compound AA13-2 and compound AA13-2a (3.50 g, 28.0 mmol, 1.00 eq) were dissolved in N, N-dimethylformamide (15 mL), N-bromosuccinimide (7.94 g, 44.6 mmol, 1.59 eq) was added, and stirred at 25 ° C for 15 hours. Ethyl acetate (250 mL) was added, and the 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 the filtrate was filtered and concentrated in vacuo to obtain light yellow oily compound AA13-3 and compound AA13-3a (5.24 g, crude product). 1 H NMR (400MHz, CDCl3) δ3.20-3.13(m,1H),2.24(s,3H),1.33-1.30(m,6H); LC-MS: m / z=203.9(M+H) + .

[0382] Step 3: Synthesis of compound AA13

[0383] Compound AA13-3 and compound AA13-3a (3.00 g, 14.7 mmol, 1.00 eq) and triisopropyl borate (3.59 g, 19.1 mmol, 4.39 mL, 1.30 eq) were dissolved in tetrahydrofuran (30.0 mL). n-Butyl lithium (2.5 M, 7.64 mL, 1.30 eq) was added dropwise at -70 °C. After the addition, the temperature was raised to 25 °C and stirred for 4 hours. Water (10.0 mL) was added at 0 °C to quench the reaction. The reaction was extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product was purified by prep-HPLC (chromatographic column: Phenomenex luna C18 The mixture was purified by HPLC (250×80mm×10μm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 20min) to give compound AA13 (470mg, 2.73mmol, 18.5% yield, 98.0% purity) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.83-3.76(m,1H),2.49(s,3H),1.38(s,3H),1.36(s,3H); LC-MS: m / z=170.1(M+H) + .

[0384] Synthesis of Universal Intermediate AA14 (4-chloro-1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0385] Step 1: Synthesis of compound AA14-2 (4-chloro-1-cyclopropyl-1H-pyrazole)

[0386] 4-Chloropyrazole (compound AA14-1, 10.0 g, 97.54 mmol, 1.0 eq), cyclopropane bromide (21.2 g, 175.57 mmol, 1.8 eq) and cesium carbonate (63 g, 195.08 mmol, 2.0 eq) were added to dioxane (50 mL) in sequence, stirred at an external temperature of 140 ° C for 16 hours, cooled to room temperature, and concentrated in vacuo 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 AA14-2 (6.4 g) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8Hz, 1H), 1.13–1.05 (m, 2H), 1.05–0.95 (m, 2H). LC-MS: m / z=143.1(M+H)+.

[0387] Step 2: Synthesis of intermediate AA14

[0388] Compound AA14-2 (8.3 g, 58.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL). Lithium diisopropylamide (58 mL, 116.42 mmol, 2.0 eq) was added dropwise under nitrogen at -70°C. After the addition was complete, the mixture was stirred at -70°C for 1 hour. Isopropyl pinacol borate (17.3 g, 93.14 mmol, 1.6 eq) was added, and the mixture was stirred at -70°C for 1 hour. The mixture was then warmed to 25°C and stirred for 2 hours. The reaction was quenched by the addition of water (100 mL). The mixture was extracted three times with dichloromethane (200 mL). The organic layers were combined, 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 / ethyl acetate = 1 / 0 to 1 / 1) to obtain intermediate AA14 (4.2 g) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8Hz, 1H), 1.13–1.05 (m, 2H), 1.05–0.95 (m, 2H).

[0389] Universal Intermediate AA15 ((4-cyclopropylpyrimidin-5-yl)boronic acid)

[0390] Intermediate AA15 was purchased from Leyan Reagents.

[0391] Synthesis of Universal Intermediate AA16 (1-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0392] Intermediate AA16 (2.9 g) was prepared from 4-methylpyrazole (Compound AA16-1) by the same procedure as Intermediate AA14. 1 H NMR (400MHz, DMSO-d6) δ7.24(s,1H),4.03(td,J=7.5,3.8Hz,1H),2.15(s,3H),1.35(s,12H),1.12–1.01(m,2H),0.99–0.89(m,2H).

[0393] Synthesis of Universal Intermediate AA17 (1-Isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0394] Intermediate AA17 (4.1 g) was prepared from 4-methylpyrazole (Compound AA16-1) by the same procedure as Intermediate AA14. 1 H NMR (400MHz, DMSO-d6) δ7.27 (s, 1H), 4.94-4.98 (m, 1H), 2.12 (s, 3H), 1.34 (d, J = 6.6Hz, 6H), 1.29 (s, 12H).

[0395] Synthesis of Universal Intermediate B1 (3-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0396] Step 1: Synthesis of compound B1-3 (ethyl 1-(pyridin-3-yl)piperidine-4-carboxylate)

[0397] Compound B1-1 (6.4 g, 40.7 mmol, 1.28 eq), compound B1-2 (5.0 g, 31.8 mmol, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.1 g, 1.91 mmol, 0.06 eq), cesium carbonate (13.9 g, 42.90 mmol, 1.35 eq), and tris(dibenzylideneacetone)dipalladium (582.0 mg, 0.6 mmol, 0.02 eq) were added sequentially to anhydrous dioxane (50.0 mL), and the mixture was replaced with nitrogen three times. The reaction was carried out at 100 ° C. under nitrogen protection for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by reverse phase HPLC (0.1% FA) to obtain compound B1-3 (3.2 g). 1H NMR (400MHz, CDCl3) δ8.29(d,J=1.6Hz,1H),8.05(d,J=3.2Hz,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=7.2Hz,3H); LC-MS:m / z=235.1(M+H) + .

[0398] Step 2: Synthesis of Compound B1-4 ((1-(pyridin-3-yl)piperidin-4-yl)methanol)

[0399] Compound B1-3 (2.0 g, 8.5 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum tetrahydride (356.0 mg, 9.4 mmol, 1.10 eq) was added at 0°C. After the addition was complete, the temperature was raised to 25°C and stirred for 4 hours. Then, water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) were added at 0°C. After the addition was complete, the temperature was stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the mixture was stirred for 5 minutes. The filtrate was filtered and concentrated in vacuo to obtain crude compound B1-4 (1.2 g), which was used directly in the next reaction. 1 H NMR(400MHz, CDCl3) δ8.29(d,J=2.8Hz,1H),8.03(d,J=4.4Hz,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) + .

[0400] Step 3: Synthesis of Intermediate B1

[0401] Compound B1-4 (0.5 g, 2.6 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (3.1 g, 26.0 mmol, 10.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain a pale yellow solid, Compound B1 (520 mg, 2.31 mmol, 88.9% yield, 93.7% purity). LC-MS: m / z = 211.2 (M+H)+ .

[0402] Synthesis of Universal Intermediate B2 (4-(4-(Chloromethyl)piperidin-1-yl)pyridine)

[0403] Step 1: Synthesis of compound B2-3 (ethyl 1-(pyridin-4-yl)piperidine-4-carboxylate)

[0404] Compound B2-1 (5.0 g, 33.3 mmol, 1.00 eq), compound B2-2 (5.2 g, 33.3 mmol, 1.00 eq), and triethylamine (10.1 g, 100.0 mmol, 3.00 eq) were added to ethanol (50.0 mL), heated to 100°C, and stirred for 16 hours. Then, water (50.0 mL) was added at 25°C, and the 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 the crude product. The crude product 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 (400MHz, CDCl3) δ8.25(d,J=5.2Hz,2H),6.65(d,J=5.6Hz,2H),4.15(q,J=7.2Hz,2H),3.82(d,J=13.2Hz,2H),2.96(d ,J=11.6Hz,2H),2.51-2.58(m,1H),1.99-2.02(m,2H),1.77-1.84(m,2H),1.27(d,J=7.2Hz,3H); LC-MS:m / z=235.2(M+H) + .

[0405] Step 2: Synthesis of compound B2-4 ((1-(pyridin-4-yl)piperidin-4-yl)methanol)

[0406] Compound B2-3 (1.7 g, 7.3 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum tetrahydride (302.0 mg, 8.0 mmol, 1.10 eq) was added at 0°C. After the addition, the temperature was raised to 25°C and stirred for 4 hours. Aqueous sodium hydroxide solution (0.25 M, 2 mL) was added at 0°C and stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added and stirred for 5 minutes. The filtrate was filtered and concentrated in vacuo to obtain a crude compound B2-4 (1.1 g), which was used directly in the next step. 1H NMR (400MHz, CDCl3) δ8.25(t,J=1.6Hz,2H),6.67(t,J=1.2Hz,2H),3.92(d,J=16.0Hz,2H),3.55( d,J=2.4Hz,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) + .

[0407] Step 3: Synthesis of Compound B2

[0408] Compound B2-4 (500.0 mg, 2.60 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (2.5 g, 20.8 mmol, 8.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain compound B2 (530 mg, 2.52 mmol, 96.7% yield) as a white solid. LC-MS: m / z = 193.0 (M+H) + .

[0409] Synthesis of General Intermediate B3 (3-(4-(chloromethyl)phenyl)pyridine)

[0410] Step 1: Synthesis of Compound B3-3 ((4-(pyridin-3-yl)phenyl)methanol)

[0411] Compound B3-1 (3.0 g, 18.9 mmol, 1.00 eq), compound B3-2 (3.8 g, 24.6 mmol, 1.30 eq), sodium carbonate (14.8 g, 140.0 mmol, 7.40 eq), and tetrakistriphenylphosphine palladium (2.2 g, 1.89 mmol, 0.10 eq) were added sequentially to a mixed solvent of toluene (15.0 mL), water (15.0 mL) and ethanol (3.0 mL), and the mixture was replaced with nitrogen three times. The mixture was reacted at 100° C. under nitrogen protection for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by reverse phase HPLC (0.1% NH 3 · H 2 O) to obtain compound B3-3 (2.3 g). 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 8.59 (d, J = 4.8Hz, 1H), 7.87-7.90 (m, 1H), 7.59 (d, J = 8.0Hz, 2H) ,7.50(d,J=8.0Hz,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) + .

[0412] Step 2: Synthesis of Intermediate B3

[0413] Compound B3-3 (1.0 g, 5.4 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (6.4 g, 53.9 mmol, 10.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain compound B3 (1.1 g, 5.35 mmol, 99.1% yield) as a white solid. LC-MS: m / z = 204.0 (M+H) + .

[0414] Synthesis of General Intermediate B4 (4-(4-(chloromethyl)phenyl)pyridine)

[0415] Compound B4-1 (250.0 mg, 1.4 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (802.0 mg, 6.8 mmol, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain compound B4 (260 mg, 1.28 mmol, 94.5% yield) as a white solid. LC-MS: m / z = 204.0 (M+H) + .

[0416] Synthesis of General Intermediate B5 (5-(4-(chloromethyl)phenyl)-2-methylpyridine)

[0417] Step 1: Synthesis of compound B5-3 ((4-(6-methylpyridin-3-yl)phenyl)methanol)

[0418] Compound B5-1 (3.0 g, 17.4 mmol, 1.00 eq), compound B5-2 (3.5 g, 22.6 mmol, 1.30 eq), sodium carbonate (13.6 g, 129.0 mmol, 7.40 eq), and tetrakistriphenylphosphine palladium (2.0 g, 1.74 mmol, 0.10 eq) were added sequentially to a mixed solvent of toluene (15.0 mL), water (15.0 mL) and ethanol (3.00 mL), and the mixture was replaced with nitrogen three times. The mixture was reacted at 100° C. under nitrogen protection for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by reverse phase HPLC (0.1% NH 3 · H 2 O) to obtain compound B5-3 (3.0 g). 1H NMR (400MHz, CDCl3) δ8.59-8.63(m,1H),7.76-7.78(m,1H),7.54(d,J=8.0Hz,2H),7.47(t,J=4.0H z,2H),7.22(d,J=8.0Hz,1H),4.76(s,2H),2.61(s,3H),2.33-2.37(m,1H); LC-MS: m / z=200.1(M+H) + .

[0419] Step 2: Synthesis of Intermediate B5

[0420] Compound B5-3 (0.5 g, 2.5 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (1.5 g, 12.5 mmol, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain compound B5 (530 mg, 2.43 mmol, 97.0% yield) as a white solid. LC-MS: m / z = 218.1 (M+H) + .

[0421] Synthesis of General Intermediate B6 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0422] Step 1: Synthesis of compound B6-3 (methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0423] Compound B6-2 (7.2 g, 26.8 mmol, 1.10 eq) and sodium acetate (2.2 g, 27.3 mmol, 1.12 eq) 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 eq) dissolved in methanol (80.0 mL) and aqueous ammonia (22.0 mL) was added at 25°C. After the addition, the mixture was reacted at 25°C for 40 minutes, then heated to 100°C and stirred for 2 hours. The reaction was then quenched by the addition of water (60.0 mL) and 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, which 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 (400MHz, CDCl3) δ13.4 (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)+ .

[0424] Step 2: Synthesis of compound B6-4 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0425] Compound B6-3 (2.5 g, 9.3 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Sodium hydride (444.1 mg, 11.1 mmol, 1.20 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 30 minutes. Iodomethane (6.8 g, 48.1 mmol, 5.20 eq) was then added. The mixture was heated to 20°C and stirred for 15 hours. The reaction was quenched by the addition of ice water (20.0 mL) at 0°C. The 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 in vacuo to obtain the crude product, which 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 (400MHz, CDCl3) δ8.07 (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) + .

[0426] Step 3: Synthesis of compound B6-5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol)

[0427] Compound B6-4 (0.6 g, 2.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum tetrahydride (88.1 mg, 2.32 mmol, 1.10 eq) was added at 0°C. After the addition, the temperature was raised 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 stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the filtrate was filtered. The crude product was concentrated in vacuo to obtain a crude product B6-5 (505.4 mg), which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8.0Hz, 2H) ,5.30-5.33(m,1H),4.58(d,J=5.6Hz,2H),3.78(s,3H); LC-MS:m / z=257.1(M+H) + .

[0428] Step 4: Synthesis of Intermediate B6

[0429] Compound B6-5 (500.0 mg, 2.0 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (1.9 g, 15.6 mmol, 8.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction mixture was concentrated in vacuo to obtain a brown solid compound B6 (523 mg, 1.90 mmol, 97.6% yield). LC-MS: m / z = 275.1 (M+H) + .

[0430] Synthesis of Universal Intermediate B7 (2-(4-(chloromethyl)cyclohexyl)pyrimidine)

[0431] 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)

[0432] Compound B7-1 (10.0 g, 33.1 mmol, 1.00 eq), compound B7-2 (9.2 g, 36.4 mmol, 1.10 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.4 g, 1.7 mmol, 0.05 eq), and potassium acetate (9.8 g, 99.3 mmol, 3.00 eq) were added to dioxane (80.0 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 80°C for 2 hours under nitrogen protection. Then, water (200.0 mL) was added, and the mixture was extracted three times with ethyl acetate (70.0 mL). The organic layers were combined, washed twice with saturated brine (100.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-30 / 1) to obtain compound B7-3 (4.5 g). 1 H NMR(400MHz, CDCl3)δ6.55(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) + .

[0433] Step 2: Synthesis of compound B7-5 (ethyl 4-(pyrimidin-2-yl)cyclohex-3-ene-1-carboxylate)

[0434] Compound B7-3 (4.9 g, 17.3 mmol, 1.10 eq), compound B7-4 (2.5 g, 15.7 mmol, 1.00 eq), sodium carbonate (5.0 g, 47.2 mmol, 3.00 eq), and tetrakistriphenylphosphine palladium (1.8 g, 1.6 mmol, 0.10 eq) were added sequentially to dioxane (50.0 mL) and water (12.5 mL). The mixture was purged with nitrogen three times and stirred at 90°C under nitrogen for 20 hours. Water (100.0 mL) was then added and the 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, 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 0 / 1) to obtain compound B7-5 (3.1 g). 1 H NMR (400MHz, CDCl3) δ8.67 (d, J = 4.80Hz, 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) + .

[0435] Step 3: Synthesis of compound B7-6 (ethyl 4-(pyrimidin-2-yl)cyclohexane-1-carboxylate)

[0436] Compound B7-5 (3.0 g, 13.1 mmol, 1.00 eq) and wet palladium carbon (1.4 g, 1.3 mmol, 10.0% purity, 0.10 eq) were added to ethanol (90.0 mL) in sequence, stirred under a hydrogen atmosphere at 25 ° C for 16 hours, and the filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound B7-6 (2.1 g). 1 H NMR (400MHz, CDCl3) δ8.64-8.66(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 (m,3H),1.98-2.02(m,1H),1.90-1.98(m,1H),1.67-1.68(m,2H),1.26-1.68(m,1H),1.21-1.26(m,3H); LC-MS: m / z=235.1(M+H)+ .

[0437] Step 4: Synthesis of Compound B7-7 ((4-(pyrimidin-2-yl)cyclohexyl)methanol)

[0438] Compound B7-6 (500.0 mg, 2.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Diisobutylaluminum hydride (1.0 M, 3.20 eq) was added at -65°C. After the addition, the mixture was reacted at -65°C for 0.5 hours, then the temperature was raised to 20°C and stirred for 1 hour. Subsequently, saturated aqueous ammonium chloride solution (20.0 mL) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 1 hour. The filtrate was filtered to obtain the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and the filtrate was filtered to obtain the crude product, compound B7-7 (263.5 mg), which was used directly in the next reaction. 1 H NMR(400MHz, CDCl3) δ8.69(d,J=4.80Hz,2H),7.11-7.14(m,1H),3.64(d,J=7.20Hz,2H),3.04-3.08(m,1 H),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) + .

[0439] Step 5: Synthesis of Intermediate B7

[0440] Compound B7-7 (263.0 mg, 1.4 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (814.0 mg, 6.8 mmol, 5.00 eq) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction solution was concentrated in vacuo to obtain compound B7 (300 mg, crude product) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ8.79-8.98(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) + .

[0441] Synthesis of General Intermediate B8 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0442] Intermediate B6 (700.0 mg, 2.55 mmol, 1.00 eq) and aqueous ammonia (27.3 g, 233.0 mmol, 30% purity, 91.70 eq) were added to dioxane (15.0 mL), sealed and reacted at 50°C for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain a white solid B8 (580 mg, 1.99 mmol, 78.0% yield, HCl). 1 H NMR (400MHz, CDCl3) δ7.73-7.76(m,3H),7.63-7.65(m,2H),4.22(s,2H),3.80(s,3H); LC-MS: m / z=256.0(M+H) + .

[0443] Synthesis of Universal Intermediate B9 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0444] The synthesis of universal intermediate B9 was carried out according to the synthesis of intermediate B6, except that B6-1 was replaced with an equal molar amount of B9-1, and all other experimental conditions remained unchanged. Compound B9 (330.0 mg, crude) was obtained as a white solid. LC-MS: m / z = 281.0 (M+H) + .

[0445] Synthesis of General Intermediate B10 (2-(4-(chloromethyl)phenyl)pyridine)

[0446] Step 1: Synthesis of compound B10-3 ((4-(pyridin-2-yl)phenyl)methanol)

[0447] Compound B10-1 (10.0 g, 63.3 mmol, 6.02 mL, 1.00 eq), compound B10-2 (12.5 g, 82.3 mmol, 1.30 eq), tetrakistriphenylphosphine palladium (7.31 g, 6.33 mmol, 0.100 eq), and sodium carbonate (49.6 g, 468 mmol, 7.40 eq) were added sequentially to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The mixture was replaced with nitrogen three times and stirred at 100° C. for 12 hours under nitrogen protection. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by reverse phase HPLC (0.1% NH 3 · H 2 O) to obtain compound B10-3 (9.63 g). 1H NMR (400MHz, CDCl3) δ8.67 (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) + .

[0448] Step 2: Synthesis of Intermediate B10

[0449] Compound B10-3 (1.0 g, 5.40 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 eq) was added at 0°C. After addition, the mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to obtain a white solid B10 (1.1 g, crude product). LC-MS: m / z = 204.1 (M+H) + .

[0450] Synthesis of Universal Intermediate B11 (2-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0451] Step 1: Synthesis of compound B11-3 (ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate)

[0452] Compound B11-1 (20.8 g, 132 mmol, 20.4 mL, 1.00 eq), compound B11-2 (15.0 g, 132.0 mmol, 1.00 eq), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 eq) were dissolved in DMSO (50.0 mL) and reacted at 120-150°C for 16 h. The reaction was stopped by cooling and quenched by adding water (50 mL) at room temperature. The 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, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to obtain compound B11-32 (6.0 g, yield 19.4%, purity 100%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ8.17-8.19(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,2 H),4.13-4.18(m,2H),2.92-2.99(m,2H),2.52-2.53(m,1H),1.98-2.02(m,2H),1.75-1.79(m,2H),1.25-1.28(m,3H). LC-MS:m / z=235.2(M+H) + .

[0453] Step 2: Synthesis of compound B11-4 ((1-(pyridin-2-yl)piperidin-4-yl)methanol)

[0454] Compound B11-3 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL). Lithium aluminum tetrahydride (LiAlH4, 1.07 g, 28.2 mmol, 1.10 eq) was carefully added at 0°C, and the mixture was stirred at room temperature for 16 h. Additional lithium aluminum tetrahydride (LiAlH4, 486 mg, 12.8 mmol, 0.500 eq) was added, and stirring was continued for 6 h. The reaction was quenched by the careful addition of H2O (20.0 mL) at 0°C. The mixture was extracted with ethyl acetate (60.0 mL x 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, which 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 (400MHz, CDCl3) δ8.18(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=12.8 Hz, 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) + .

[0455] Step 3: Synthesis of Intermediate B11

[0456] Compound B11-4 (1.20 g, 6.24 mmol, 1.00 eq) was dissolved in dichloromethane (12.0 mL). Thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 eq) was added at 0°C. After addition, the mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to afford Compound B11 (1.57 g, crude) as a white solid. LC-MS: m / z = 211.1.

[0457] Synthesis of Universal Intermediate B12 (2-((1r, 4r)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0458] Step 1: Synthesis of compound B12-2 (1-methyl-4-(trifluoromethyl)-1H imidazole)

[0459] Compound B12-1 (33.0 g, 242.0 mmol, 1.00 eq) was dissolved in tetrahydrofuran (330.0 mL). Sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 30 minutes. Iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 eq) was then added. The temperature was raised to 25°C and stirred for 5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30.0 mL) at 0°C. Water (30.0 mL) was added and the 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 the filtrate was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B12-2 (21.0 g). 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z=151.1 (M+H) + .

[0460] Step 2: Synthesis of compound B12-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H imidazole)

[0461] Compound B12-2 (16.8 g, 111.0 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyl lithium (2.5 M, 44.7 mL, 1.00 eq) was added dropwise at -70°C. After the addition, the mixture was stirred at -70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction solution. After the addition, the mixture was reacted at -70°C for 1 hour, then heated to 20°C and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200.0 mL) at 0°C. Water (300.0 mL) was added and the mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-20 / 1) to obtain compound B12-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0462] Step 3: Synthesis of compound B12-5 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-3-ene-1-carboxylate)

[0463] Compound B12-3 (7.0 g, 31.9 mmol, 1.00 eq), compound B12-4 (9.0 g, 31.9 mmol, 1.00 eq), potassium phosphate (20.3 g, 95.8 mmol, 3.00 eq), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.3 g, 1.6 mmol) were added to the mixture. , 0.05eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 eq) were added sequentially to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL), replaced with nitrogen three times, stirred at 100 ° C for 5 hours under nitrogen protection, the reaction liquid was filtered to obtain a filtrate, and vacuum concentrated to obtain a crude product, which was purified by reverse phase HPLC (0.1% FA) to obtain compound B12-5 (1.9 g). 1 H NMR (400MHz, CDCl3) δ6.05 (d, J = 2.0Hz, 1H), 4.18 (q, J = 7.2Hz, 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=7.2Hz,3H); LC-MS: m / z=337.2(M+H) + .

[0464] Step 4: Synthesis of compound B12-6 (ethyl (1R, 4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-carboxylate)

[0465] Compound B12-5 (1.9 g, 5.6 mmol, 1.00 eq), sodium acetate (925.0 mg, 11.2 mmol, 2.00 eq) and wet palladium carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 eq) were added to ethanol (30.0 mL) in sequence, and the mixture was reacted at 50°C under a hydrogen atmosphere (15 psi) for 5 hours. The reaction solution was filtered to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 10 min) to obtain compound B12-6 (0.3 g). 1 H NMR (400MHz, CDCl3) δ7.13 (s, 1H), 4.15 (q, J = 6.8Hz, 2H), 3.64 (s, 3H), 2.60-2.65 (m, 1H), 2.41-2.44 (m, 1H), 2.12-2 .15(m,2H),1.97-1.98(m,2H),1.77-1.80(m,2H),1.54-1.59(m,2H),1.27(t,J=8.8Hz,3H); LC-MS:m / z=305.0(M+H) + .

[0466] Step 5: Synthesis of compound B12-7 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol)

[0467] Compound B12-6 (0.6 g, 2.0 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL). Lithium aluminum tetrahydride (224.0 mg, 5.9 mmol, 3.00 eq) was added at 0°C. After the addition was complete, the mixture was reacted at 0°C for 0.5 hours, then the temperature was raised to 20°C and stirred for 12 hours. Then, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 30 minutes. Tetrahydrofuran (10.0 mL) was added and the filtrate was filtered. The organic layer was separated, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain crude compound B12-7 (0.5 g), which was used directly in the next reaction. 1H NMR (400MHz, CDCl3) δ7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6Hz, 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) + .

[0468] Step 6: Synthesis of Intermediate B12

[0469] Compound B12-7 (500.0 mg, 1.9 mmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL). Thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 24 hours. The reaction mixture was concentrated in vacuo to obtain a light yellow solid compound B12 (550 mg, 1.36 mmol, 71.5% yield, HCl). LC-MS: m / z = 281.0 (M+H) + .

[0470] Synthesis of Universal Intermediate B13 (4-(Chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine hydrochloride)

[0471] Step 1: Synthesis of compound B13-2 (1-methyl-4-(trifluoromethyl)-1H imidazole)

[0472] Compound B13-1 (33.0 g, 242 mmol, 1.00 eq) was dissolved in tetrahydrofuran (330.0 mL). Sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 30 minutes. Iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 eq) was then added. After the addition was complete, the mixture was heated to 25°C and stirred for 4 hours. The reaction was quenched by the addition of ice water (200.0 mL) at 0°C. The mixture was extracted three times with ethyl acetate (200.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B13-2 (21.0 g). 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z=151.1 (M+H) + .

[0473] Step 2: Synthesis of compound B13-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H imidazole)

[0474] Compound B13-2 (16.8 g, 111 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyl lithium (2.5 M, 44.7 mL, 1.00 eq) was added dropwise at -70°C. After the addition, the mixture was stirred at -70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction solution. After the addition, the mixture was reacted at -70°C for 1 hour, then heated to 20°C and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200.0 mL) at 0°C. Water (300.0 mL) was added and the mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-20 / 1) to obtain compound B13-3 (12.0 g). LC-MS: m / z = 219.0 (M+H) + .

[0475] Step 3: Synthesis of compound B13-5 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0476] Compound B13-3 (7.0 g, 31.9 mmol, 1.00 eq), compound B13-4 (7.54 g, 47.9 mmol, 7.39 mL, 1.50 eq), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 eq) and sodium iodide (479 mg, 3.20 mmol, 0.100 eq) were added to N,N-dimethylformamide (70.0 mL) in sequence, reacted at 130 ° C for 72 hours, added water (350 mL) and stirred for 5 minutes, extracted three times with ethyl acetate (100 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product was purified by reverse phase HPLC (0.1% FA) to obtain compound B13-5 (2.2 g). 1 H NMR (400MHz, CDCl3) δ4.17 (q, J = 7.2Hz, 2H), 3.45 (s, 3H), 3.24-3.28 (m, 2H), 2.90-2.97 (m, 2H), 2.4 0-2.45(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)+ .

[0477] Step 4: Synthesis of compound B13-6 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0478] Compound B13-5 (2.2 g, 6.48 mmol, 1.00 eq), sodium acetate (1.06 g, 12.9 mmol, 2.00 eq) and wet palladium carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 eq) were added to ethanol (40.0 mL) in sequence, and the mixture was reacted under a hydrogen atmosphere (15 psi) at 50°C for 36 hours. The reaction solution was filtered to obtain a filtrate, which was then concentrated in vacuo to obtain compound B13-6 (1.9 g). 1 H NMR (400MHz, CDCl3) δ7.02(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) + .

[0479] Step 5: Synthesis of compound B13-7 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol)

[0480] Compound B13-6 (1.2 g, 3.93 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Lithium aluminum tetrahydride (447 mg, 11.8 mmol, 3.00 eq) was added at 0°C. After addition, the mixture was reacted at 0°C for 0.5 hours, then heated to 20°C and stirred for 12 hours. Sodium sulfate decahydrate (0.5 g) was then added at 0°C. After addition, the mixture was heated to 20°C and stirred for 30 minutes. Tetrahydrofuran (10.0 mL) was added and 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 in vacuo to obtain compound B13-7 (1.0 g). The crude product was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.01 (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) + .

[0481] Step 6: Synthesis of Intermediate B13

[0482] Compound B13-7 (1.0 g, 3.80 mmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL). Thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 24 hours. The reaction mixture was concentrated in vacuo to obtain a brown solid compound B13 (1.1 g, 3.46 mmol, 91.0% yield, HCl). LC-MS: m / z = 282.1 (M+H) + .

[0483] Synthesis of Universal Intermediate B14 (2-(5-(chloromethyl)furan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0484] Step 1: Synthesis of compound B14-3 (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)furan-2-carbaldehyde)

[0485] Compound B14-2 (400 mg, 1.83 mmol, 1.00 eq), B14-1 (255 mg, 1.83 mmol, 1.00 eq), methanesulfonic acid (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 eq), potassium phosphate (1.16 g, 5.48 mmol, 3.00 eq) were added to n-butanol (3.0 mL) and water (0.5 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 60°C under nitrogen protection for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex C18 The mixture was purified by centrifugation at 4 °C for 1 hr (75 × 30 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 7 min) to obtain compound B14-3 (60.0 mg). 1 H NMR (400MHz, CDCl3) δ9.70 (s, 1H), 7.37 (d, J = 3.6Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 3.6Hz, 1H), 4.07 (s, 3H); LC-MS: m / z = 245.2 (M + H) +.

[0486] Step 2: Synthesis of compound B14-4 ((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)furan-2-yl)methanol)

[0487] Compound B14-3 (60.0 mg, 245 μmol, 1.00 eq) was dissolved in methanol (1.0 mL), and sodium borohydride (90.0 mg, 2.38 mmol, 9.68 eq) was added. The mixture was stirred at 15°C for 30 minutes. Saturated aqueous ammonium chloride solution (10.0 mL) was added at 0°C, and water (20.0 mL) was added. The mixture was extracted three times with ethyl acetate (10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. The mixture was concentrated in vacuo to obtain compound B14-4 (50.0 mg). 1 H NMR (400MHz, CDCl3) δ7.25 (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) + .

[0488] Step 3: Synthesis of Intermediate B14

[0489] Compound B14-4 (50.0 mg, 203 μmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL). Thionyl chloride (1.2 g, 10.1 mmol, 50.0 eq) was added at 0°C. After addition, the temperature was raised to 25°C and the mixture was reacted for 24 hours. The reaction solution was concentrated in vacuo to obtain compound B14 (45 mg, crude) as a pale yellow oil. LC-MS: m / z = 265.1 (M+H) + .

[0490] Synthesis of General Intermediate B15 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0491] Step 1: Synthesis of compound B15-3 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol)

[0492] Compound B15-1 (9.6 g, 62.5 mmol, 1.00 eq), compound B15-2 (12.4 g, 81.3 mmol, 1.30 eq), tetrakistriphenylphosphine palladium (7.2 g, 6.25 mmol, 0.10 eq), and sodium carbonate (49.0 g, 463 mmol, 7.40 eq) were added sequentially to a mixed solvent of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. The filtrate was filtered and concentrated in vacuo to obtain the crude product, which 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) + .

[0493] Step 2: Synthesis of Intermediate B15

[0494] Compound B15-3 (6.0 g, 26.6 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (15.9 g, 133 mmol, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to obtain an off-white solid compound B15 (7.3 g, 26.2 mmol, 98.2% yield, HCl). LC-MS: m / z = 244.1 (M+H) + .

[0495] Synthesis of General Intermediate B16 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0496] Step 1: Synthesis of compound B16-3 (methyl 4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate)

[0497] Compound B16-1 (25.0 g, 118 mmol, 1.00 eq), compound B16-2 (20.8 g, 141 mmol, 1.20 eq), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 eq) and silver nitrate (4.01 g, 23.6 mmol, 0.20 eq) were added sequentially to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL), and the mixture was reacted at 20°C for 16 hours. Dichloromethane (250.0 mL) was added, the mixture was filtered to obtain a filtrate, and the mixture was washed three times with water (100.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (basic conditions, NH3·H2O / MeCN / H2O) to obtain compound B16-3 (7.5 g). 1 H NMR (400MHz, CDCl3) δ8.81(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).

[0498] Step 2: Synthesis of compound B16-4 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol)

[0499] Compound B16-3 (2.5 g, 7.98 mmol, 1.00 eq) was dissolved in tetrahydrofuran (50.0 mL). Lithium aluminum tetrahydride (908 mg, 23.9 mmol, 3.00 eq) was slowly added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C and stirred for 10 minutes. Extraction was performed three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain compound B16-4 (2.3 g). LC-MS: m / z = 286.1 (M+H) + .

[0500] Step 3: Synthesis of intermediate B16

[0501] Compound B16-4 (1.6 g, 5.61 mmol, 1.00 eq) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 eq) were added to pyridine (25.0 mL), reacted at 20°C for 12 hours, concentrated in vacuo, added with water (10.0 mL) and stirred for 5 minutes, extracted three times with dichloromethane (5.0 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain compound B16 (1.5 g, 3.38 mmol, 60.2% yield, 98.9% purity) as a white solid. 1 H NMR(400MHz, CDCl3)δ8.79(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) + .

[0502] Synthesis of Universal Intermediate B17 (1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0503] Step 1: Synthesis of compound B17-2 (methyl 4-hydrazinobenzoate)

[0504] Compound B17-1 (15.0 g, 90.32 mmol, 1.0 eq) was dissolved in 37% aqueous hydrochloric acid (25.0 mL). Sodium nitrite (6.2 g, 90.32 mmol, 1.0 eq) dissolved in water (10.0 mL) was added at 0°C and stirred for 10 minutes. Then, tin chloride (85.6 g, 451.62 mmol, 5.0 eq) dissolved in 37% aqueous hydrochloric acid (75.0 mL) was added dropwise at 0°C. After addition, the temperature was raised to 25°C and stirred for 2 hours. The filter cake was filtered and washed three times with ethyl acetate (50.0 mL). The mixture was concentrated in vacuo to obtain compound B17-2 (16.5 g). LC-MS: m / z = 167.1 (M+H) + .

[0505] Step 2: Synthesis of compound B17-4 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate)

[0506] Compound B17-2 (5 g, 24.75 mmol, 1.0 eq) and compound B17-3 (3.8 g, 24.75 mmol, 1.0 eq) were added to hexafluoroisopropanol (25.0 mL). Triethylamine (5.0 g, 49.50 mmol, 2.0 eq) dissolved in hexafluoroisopropanol (25.0 mL) was added dropwise at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1 hour. Water (10 mL) was then added and the mixture was extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound B17-4 (5.3 g). LC-MS: m / z = 285.0 (M+H) + .

[0507] Step 3: Synthesis of compound B17-5 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol)

[0508] Compound B17-4 (5.3 g, 18.65 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100.0 mL). Lithium aluminum tetrahydride (1.9 g, 46.64 mmol, 2.5 eq) was slowly added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 6 hours. Ice water (50.0 mL) was then added at 0°C and stirred for 10 minutes. Extraction was performed 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, which was then 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) +.

[0509] Step 4: Synthesis of Intermediate B17

[0510] Compound B17-5 (1.0 g, 3.91 mmol, 1.0 eq) was dissolved in dichloroethane (25.0 mL), and thionyl chloride (1.4 g, 11.73 mmol, 5.2 eq) was added at 0°C. After the addition, the temperature was raised to 50°C and stirred for 2 hours. The reaction solution was concentrated in vacuo to obtain compound B17 (1.0 g, 3.64 mmol, 93.1% yield, 96.9% purity) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.53 (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) + .

[0511] General intermediate BB1 ​​(2-chloro-5-methoxy-N-methylpyrimidin-4-amine)

[0512] The intermediate BB1 ​​was purchased from Leyan Reagent.

[0513] Universal intermediate BB2 (2-chloro-5-methoxypyrimidin-4-amine)

[0514] The intermediate BB2 was purchased from Leyan Reagent.

[0515] Universal intermediate BB3 (2-chloro-5-isopropoxy-N-methylpyrimidin-4-amine)

[0516] Step 1: Synthesis of compound BB3-2 (2,4-dichloro-5-isopropoxypyrimidine)

[0517] 2,4-Dichloro-5-isopropylpyrimidine (Compound BB3-1, 0.5 g, 2.41 mmol, 1.00 eq) was added to phosphorus oxychloride (5.0 mL) and refluxed under nitrogen for 4 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to remove the phosphorus oxychloride. Ice water (100.0 mL) was added and extracted three times with ethyl acetate (100.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain Compound BB3-2 (551.0 mg, crude product) as a pale yellow oil. LC-MS: m / z = 207.1 (M+H) + .

[0518] Step 2: Synthesis of intermediate BB3

[0519] Compound BB3-2 (100 mg, 0.48 mmol, 1.00 eq), methylamine hydrochloride (97.8 mg, 1.45 mmol, 3.00 eq), and cesium carbonate (472.4 mg, 1.45 mmol, 3.00 eq) were added to N,N-dimethylformamide (2.0 mL) in sequence and stirred at 60°C for 6 hours. Ethyl acetate (15.0 mL) was added and stirred for 5 minutes. The filtrate was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain intermediate BB3 (38.8 mg, 0.19 mmol, 40.1% yield). LC-MS: m / z = 202.1 (M+H) + .

[0520] Universal intermediate BB4 (2-chloro-5-isopropoxypyrimidin-4-amine)

[0521] Compound BB3-2 (100 mg, 0.48 mmol, 1.00 eq) and aqueous ammonia (1.68 g, 48.0 mmol, 30% purity, 100.0 eq) were added to dioxane (3.0 mL). The mixture was sealed and reacted at 50°C for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was then purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain the intermediate BB4 (27.3 mg, 0.15 mmol, 30.3% yield) as a white solid. LC-MS: m / z = 188.2 (M+H) + .

[0522] Universal intermediate BB12 (2-chloro-5-(trifluoromethyl)pyrimidin-4-amine)

[0523] The intermediate BB12 was purchased from Bid Pharmaceuticals.

[0524] Synthesis of universal intermediate BB13 (2-chlorofuro[3,2-d]pyrimidin-4-amine)

[0525] 2,4-Dichlorofuro[3,2-D]pyrimidine (compound BB13-1, 5.0 g, 26.46 mmol, 1.00 eq) and aqueous ammonia (30.9 g, 264.6 mmol, 30% purity, 100.0 eq) were added to dioxane (100.0 mL). The mixture was sealed and reacted at 50°C for 12 hours. The reaction solution was concentrated in vacuo to obtain the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound BB13 (3.2 g, 18.87 mmol, 71.3% yield) as a white solid. LC-MS: m / z = 170.1 (M+H) + .

[0526] Synthesis of universal intermediate BB14 (2-chloropyridone[3,2-d]pyrimidin-4-amine)

[0527] Intermediate BB14 (1.1 g, 6.09 mmol, 40.6% yield) was prepared using the same procedure as intermediate BB13, starting from 2,4-dichloropyrido[3,2-d]pyrimidine (BB14-1, 3.0 g, 15.0 mmol, 1.00 eq). LC-MS: m / z = 181.0 (M+H) + .

[0528] General intermediate BB15 (2,5-dichloropyrimidin-4-amine)

[0529] The intermediate BB15 was purchased from Bid Pharmaceuticals.

[0530] Synthesis of universal intermediate BB16 (2-chloro-5-fluoro-N-methylpyrimidin-4-amine)

[0531] 2,4-Dichloro-5-fluoropyrimidine (compound BB16-1, 3.0 g, 18.07 mmol, 1.00 eq), methylamine hydrochloride (3.66 g, 54.23 mmol, 3.00 eq), and cesium carbonate (23.55 g, 72.28 mmol, 4.00 eq) were added to N,N-dimethylformamide (500.0 mL) in sequence and stirred at 60°C for 6 hours. Ethyl acetate (1000.0 mL) was added and stirred for 5 minutes. The filtrate was filtered and concentrated in vacuo to obtain the crude product. The crude product 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) + .

[0532] Synthesis of universal intermediate BB16-D3 (2-chloro-5-fluoro-N-(methyl-D3)pyrimidin-4-amine)

[0533] Intermediate BB16-D3 (1.47 g, 8.93 mmol, 49.4% yield) was prepared using the same procedure as intermediate BB16, starting from 2,4-dichloro-5-fluoropyrimidine (BB16-1, 3.0 g, 18.07 mmol, 1.00 eq). LC-MS: m / z = 165.1 (M+H) + .

[0534] Universal intermediate BB17 (4-amino-2-chloropyrimidine-5-carbonitrile)

[0535] The intermediate BB17 was purchased from Bid Biopharm.

[0536] Synthesis of the universal intermediate BB18 (2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine)

[0537] Compound 2,4-dichloro-5-iodopyrimidine (BB18-1, 1.0 g, 3.6 mmol, 1.00 eq), bistriphenylphosphine palladium dichloride (256 mg, 0.3 mmol, 0.1 eq), cuprous iodide (139 mg, 0.7 mmol, 0.2 eq), trimethylethynylsilane (700 mg, 7.2 mmol, 2.0 eq) and triethylamine (1.1 g, 10.9 mmol, 3.0 eq) were added to tetrahydrofuran (15 mL) in sequence, and the reaction was stirred at 40°C for 3 hours. The mixture was concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound BB18 (590 mg, 2.4 mmol) as a white solid. 1 HNMR(400MHz,DMSO)δ8.97–8.89(m,1H),0.28(s,9H).

[0538] Synthesis of universal intermediate BB19 (2-chloro-5-(difluoromethoxy)pyrimidin-4-amine)

[0539] Step 1: Synthesis of compound BB19-2 (2,4-dichloro-5-(difluoromethoxy)pyrimidine)

[0540] 2,4-Dichloropyrimidin-5-ol (compound BB19-1, 3.40 g, 20.6 mmol, 1.00 eq) and potassium hydroxide (13.3 g, 237 mmol, 11.5 eq) were added to acetonitrile (60.0 mL) and water (60.0 mL) in sequence, and diethyl bromofluoromethylphosphonate (9.35 g, 35.0 mmol, 1.70 eq) was added dropwise. After the addition was completed, the mixture was stirred at 25°C for 1.5 hours and saturated lemon water was added. The reaction was quenched with aqueous solution (10.0 mL), and water (10.0 mL) was added. The mixture was extracted three times with ethyl acetate (40 mL). The organic layers were combined, washed twice with saturated brine (20.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-2 / 1) to give the intermediate BB19-2 (3.70 g, 17.2 mmol, 83.5% yield) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ8.53 (s, 1H), 6.84-6.49 (t, J = 70.8Hz, 1H); LC-MS: m / z = 215.0 (M+H) + .

[0541] Step 2: Synthesis of intermediate BB19

[0542] Intermediate BB19 (298.5 mg, 1.53 mmol, 65.5% yield) was prepared from compound BB19-2 (500.0 mg, 2.33 mmol, 1.00 eq) following the same procedure as intermediate BB13. LC-MS: m / z = 196.1 (M+H) + .

[0543] Universal intermediate BB21 (4-(2,4-dichloropyrimidin-5-yl)morpholine)

[0544] The intermediate BB21 was purchased from Bid Biopharm.

[0545] Synthesis of Universal Intermediate BB22 (2,4-Dichloro-5-(4-methylpiperazin-1-yl)pyrimidine)

[0546] Step 1: Synthesis of compound BB22-2 (5-(4-methylpiperazin-1-yl)pyrimidine-2,4(1H,3H)-dione)

[0547] 5-Bromouracil (BB22-1, 5.0 g, 26.18 mmol, 1.00 eq) was dissolved in pyridine (25 mL), and N-methylpiperazine (3.9 g, 39.2 mmol, 1.5 eq) was added. The mixture was heated to 110°C and stirred for 4 hours. The mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was slurried with ethyl acetate (50 mL) and filtered to obtain the solid. The solid was concentrated in vacuo to obtain the brown solid compound BB22-2 (5.1 g, 24.26 mmol, 92.7% yield). LC-MS: m / z = 211.1 (M+H) + .

[0548] Step 2: Synthesis of compound BB22

[0549] BB22-2 (5.0 g, 23.8 mmol, 1.0 eq) was added to phosphorus oxychloride (200 mL), stirred at 90°C for 16 hours, cooled to room temperature, concentrated in vacuo, and the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate solution. The 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, which was concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain the intermediate BB22 (1.3 g, 5.26 mmol, 22.1% yield, 97.8% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 3.16–3.05 (m, 4H), 2.50–2.42 (m, 4H), 2.24 (s, 3H); LC-MS: m / z=247.1 (M+H) + .

[0550] General intermediate BB24 (2,4-dichloropyrimidin-5-ol)

[0551] The intermediate BB24 was purchased from Bidex Pharmaceuticals.

[0552] Universal intermediate BB35 ((2,4-dichloropyrimidin-5-yl)methanol)

[0553] The intermediate BB35 was purchased from Bidex Pharmaceuticals.

[0554] Synthesis of universal intermediate BB36 (2-chloro-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0555] Intermediate BB36 (1.89 g, 10.07 mmol, 67.2% yield) was prepared using the same procedure as intermediate BB16, starting from 2,4-dichloro-5-(methoxymethyl)pyrimidine (BB36-1, 2.9 g, 15.0 mmol, 1.00 eq). LC-MS: m / z = 188.1 (M+H) + .

[0556] Synthesis of Universal Intermediate BB41 (Methyl 2-(2,4-dichloropyrimidin-5-yl)acetate)

[0557] Step 1: Synthesis of compound BB41-2 (dimethyl 2-formylsuccinate)

[0558] Dimethyl succinate (compound BB41-1, 200 g, 1.37 mol, 179 mL, 1.00 eq), ethyl formate (203 g, 2.74 mol, 220 mL, 2.00 eq), and sodium methoxide (259 g, 1.44 mol, 30.0% purity, 1.05 eq) were added sequentially to tetrahydrofuran (850 mL) and stirred at 25°C for 12 hours. The reaction mixture was then concentrated in vacuo to afford the crude product, which was then washed twice with petroleum ether (400 mL), adjusted to pH 6 with 1 M hydrochloric acid, and extracted three times with methyl tert-butyl ether (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was then concentrated in vacuo to afford compound BB41-2 (70.0 g, 402 mmol, 29.4% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.69(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).

[0559] Step 2: Synthesis of compound BB41-3 (2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetic acid)

[0560] Compound BB41-2 (60.0 g, 345 mmol, 1.00 eq) was dissolved in methanol (525 mL), and sodium methoxide (124 g, 689 mmol, 30.0% purity, 2.00 eq) and thiourea (26.2 g, 345 mmol, 1.00 eq) were added. The mixture was stirred at 100°C for 12 hours, filtered to obtain a filter cake, and 1 M aqueous hydrochloric acid solution (600 mL) was added. The mixture was stirred at 0°C for 30 minutes, filtered to obtain a filter cake, and washed with water (100 mL) twice to obtain a white solid compound BB41-3 (30.0 g, 161 mmol, 46.8% yield, 100% purity). 1 H NMR (400MHz, CDCl3) δ12.5(s,1H),12.3-12.2(m,2H),7.42(s,1H),3.20(s,2H).

[0561] Step 3: Synthesis of compound BB41-4 (methyl 2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetate)

[0562] Compound BB41-3 (15.0 g, 80.6 mmol, 1.00 eq) was dissolved in methanol (100 mL), and concentrated sulfuric acid (23.7 g, 242 mmol, 12.9 mL, 3.00 eq) was added. The mixture was stirred at 80°C for 12 hours, filtered, and 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) δ12.5(s,1H),12.3(s,1H),7.40-7.60(m,1H),3.59(s,3H),3.30(s,2H).

[0563] Step 4: Synthesis of intermediate BB41

[0564] Compound BB41-3 (12.0 g, 59.9 mmol, 1.00 eq) was dissolved in phosphorus oxychloride (158 g, 1.03 mol, 96.0 mL, 17.2 eq) and stirred at 110°C under nitrogen for 12 hours. The mixture was cooled to 20°C, ice water (50.0 mL) was added, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate (30 mL). The organic layers were combined and washed three times with saturated brine (35.0 mL). The filtrate was filtered and 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 BB41 (3.60 g, 15.7 mmol, 26.2% yield, 96.4% purity) as a light yellow oil. LC-MS: m / z = 220.9 (M+H) + .

[0565] Synthesis of universal intermediate BB42 (2-chloro-5-methoxy-N-(prop-2-yn-1-yl)pyrimidin-4-amine)

[0566] Intermediate BB42 (140.8 mg, 0.71 mmol, 25.6% yield) was prepared using the same procedure as intermediate BB16, starting from 2,4-dichloro-5-methoxypyrimidine (BB42-1, 500 mg, 2.79 mmol, 1.00 eq) and propargylamine (153.7 mg, 2.79 mmol, 1.00 eq). LC-MS: m / z = 198.2 (M+H) + .

[0567] Synthesis of universal intermediate BB43 (2-chloro-5-methoxy-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine)

[0568] Intermediate BB43 (910.5 mg, 3.96 mmol, 59.2% yield) was prepared using the same procedure as Intermediate BB16, starting from 2,4-dichloro-5-methoxypyrimidine (BB42-1, 1.2 g, 6.7 mmol, 1.00 eq) and 3-aminotetrahydrofuran (584.0 mg, 6.7 mmol, 1.00 eq). LC-MS: m / z = 230.2 (M+H) + .

[0569] Synthesis of universal intermediate BB44 (2-chloro-N-cyclopropyl-5-methoxypyrimidin-4-amine)

[0570] Intermediate BB44 (556.3 mg, 2.79 mmol, 62.3% yield) was prepared using the same procedure as intermediate BB16, starting from 2,4-dichloro-5-methoxypyrimidine (BB42-1, 0.8 g, 4.47 mmol, 1.00 eq) and cyclopropylamine (255.2 mg, 4.47 mmol, 1.00 eq). LC-MS: m / z = 200.1 (M+H) + .

[0571] Synthesis of Universal Intermediate BB45 (N-(2-chloro-5-methoxypyrimidin-4-yl)-O-methylhydroxylamine)

[0572] Intermediate BB45 (490.0 mg, 2.58 mmol, 92.3% yield) was prepared using the same procedure as Intermediate BB16, starting from 2,4-dichloro-5-methoxypyrimidine (compound BB45-1, 500 mg, 2.8 mmol, 1.0 eq) and methoxyamine hydrochloride (352 mg, 4.2 mmol, 1.5 eq). LC-MS: m / z = 190.1 (M+H) + .

[0573] Synthesis of Universal Intermediate C2 (2-(4-(Chloromethyl)cyclohexyl)pyridine)

[0574] Step 1: Synthesis of compound C2-2 (ethyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate)

[0575] 2-Bromopyridine (C2-1, 15.0 g, 94.9 mmol, 9.04 mL, 1.00 eq), 1-ethoxycarbonylcyclohex-3-ene-4-boronic acid pinacol ester (26.9 g, 94.9 mmol, 99.0% purity, 1.00 eq), potassium carbonate (39.4 g, 284 mmol, 3.00 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.95 g, 9.49 mmol, 0.10 eq) were added to water (50.0 mL) and dioxane (200 mL) in sequence and stirred at 100 °C under nitrogen for 16 hours. Then, water (30.0 mL) was added, and the mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound C2-2 (9.00 g, 38.9 mmol, 41.0% yield) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ8.54-8.55(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) + .

[0576] Step 2: Synthesis of compound C2-3 (ethyl 4-(pyridin-2-yl)cyclohexane-1-carboxylate)

[0577] Compound C2-2 (9.00 g, 38.9 mmol, 1.00 eq) was dissolved in methanol (288.0 mL), and palladium carbon (4.14 g, 3.89 mmol, 10% purity, 0.10 eq) was added under a nitrogen atmosphere. The mixture was replaced with hydrogen three times, and the mixture was stirred at 25°C under a hydrogen atmosphere (15 Psi) for 16 hours. The filtrate was filtered and concentrated in vacuo to obtain compound C2-3 (8.13 g, 34.9 mmol, 89.6% yield) as a colorless transparent oil. 1H NMR (400MHz, CDCl3) δ8.51-8.54(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) + .

[0578] Step 3: Synthesis of Compound C2-4 ((4-(pyridin-2-yl)cyclohexyl)methanol)

[0579] Compound C2-3 (8.13 g, 34.8 mmol, 1.00 eq) was dissolved in tetrahydrofuran (300.0 mL), and diisobutylaluminum hydride (1 M, 112 mL, 3.20 eq) was added dropwise at -70°C. After the addition, the 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 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, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound C2-4 (4.80 g, 25.1 mmol, 72.0% yield) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ8.54-8.55(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) + .

[0580] Step 4: Synthesis of Compound C2

[0581] Compound C2-4 (800 mg, 4.18 mmol, 1.00 eq) was dissolved in dichloromethane (16.0 mL). Thionyl chloride (2.49 g, 20.9 mmol, 1.52 mL, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to obtain intermediate C2 (900 mg, crude product) as a white solid. LC-MS: m / z = 210.0 (M+H) + .

[0582] Synthesis of General Intermediate C3 (2-(4-(Chloromethyl)phenyl)pyridine)

[0583] Step 1: Synthesis of compound C3-2 ((4-(pyridin-2-yl)phenyl)methanol)

[0584] Compound 2-bromopyridine (C3-1, 10.0 g, 63.3 mmol, 6.02 mL, 1.00 eq), 2-(4-hydroxymethylphenyl)pyridine (12.5 g, 82.3 mmol, 1.30 eq), tetrakistriphenylphosphine palladium (7.31 g, 6.33 mmol, 0.100 eq), and sodium carbonate (49.6 g, 468 mmol, 7.40 eq) were added sequentially to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The mixture was replaced with nitrogen three times and stirred at 100°C for 12 hours under nitrogen protection. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by reverse phase HPLC (0.1% NH3·H2O) to obtain compound C3-2 (9.63 g) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ8.67 (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) + .

[0585] Step 2: Synthesis of intermediate C3

[0586] Compound C3-2 (1.0 g, 5.40 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to obtain intermediate C3 (1.1 g, crude product) as a white solid. LC-MS: m / z = 204.1 (M+H) + .

[0587] Synthesis of Universal Intermediate C4 (4-(Chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine)

[0588] Step 1: Synthesis of compound C4-2 (1-methyl-4-(trifluoromethyl)-1H imidazole)

[0589] Compound 4-(trifluoromethyl)-1H-imidazole (compound C4-1, 33.0 g, 242 mmol, 1.00 eq) was dissolved in tetrahydrofuran (330.0 mL). Sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 30 minutes after the addition was complete. Then, iodomethane (34.4 g, 242 mmol, 15.1 mL, 1.00 eq) was added. After the addition was complete, the temperature was raised to 25°C and stirred for 4 hours. The reaction was quenched by the addition of ice water (200.0 mL) at 0°C. The mixture was extracted three times with ethyl acetate (200.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound C4-2 (21.0 g). 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z=151.1 (M+H) + .

[0590] Step 2: Synthesis of compound C4-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H imidazole)

[0591] Compound C4-2 (16.8 g, 111 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyl lithium (2.5 M, 44.7 mL, 1.00 eq) was added dropwise at -70°C. After the addition, the mixture was stirred at -70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction solution. After addition, the mixture was reacted at -70°C for 1 hour, then heated to 20°C and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200.0 mL) at 0°C. Water (300.0 mL) was added and the mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-20 / 1) to obtain compound C4-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0592] Step 3: Synthesis of compound C4-4 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0593] Compound C4-3 (7.0 g, 31.9 mmol, 1.00 eq), ethyl 4-piperidinic acid ester (7.54 g, 47.9 mmol, 7.39 mL, 1.50 eq), N,N-diisopropylethylamine (16.5 g, 127 mmol, 22.2 mL, 4.00 eq) and sodium iodide (479 mg, 3.20 mmol, 0.100 eq) were added to N,N-dimethylformamide (70.0 mL) in sequence, and the mixture was reacted at 130° C. for 72 hours. Water (350 mL) was added and stirred for 5 minutes. The mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product was purified by reverse phase HPLC (0.1% FA) to obtain compound C4-4 (2.2 g). 1 H NMR (400MHz, CDCl3) δ4.17 (q, J = 7.2Hz, 2H), 3.45 (s, 3H), 3.24-3.28 (m, 2H), 2.90-2.97 (m, 2H), 2.4 0-2.45(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) + .

[0594] Step 4: Synthesis of compound C4-5 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0595] Compound C4-4 (2.2 g, 6.48 mmol, 1.00 eq), sodium acetate (1.06 g, 12.9 mmol, 2.00 eq) and wet palladium carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 eq) were added to ethanol (40.0 mL) in sequence, and the mixture was reacted under a hydrogen atmosphere (15 psi) at 50°C for 36 hours. The reaction solution was filtered to obtain a filtrate, which was then concentrated in vacuo to obtain compound C4-5 (1.9 g). 1 H NMR (400MHz, CDCl3) δ7.02(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) + .

[0596] Step 5: Synthesis of compound C4-6 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol)

[0597] Compound C4-5 (1.2 g, 3.93 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Lithium aluminum tetrahydride (447 mg, 11.8 mmol, 3.00 eq) was added at 0°C. After addition, the mixture was allowed to react at 0°C for 0.5 hours, then the temperature was raised to 20°C and stirred for 12 hours. Then, sodium sulfate decahydrate (0.5 g) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 30 minutes. Tetrahydrofuran (10.0 mL) was added and the filtrate was filtered. The organic layer was separated, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain compound C4-6 (1.0 g, crude product), which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.01 (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) + .

[0598] Step 6: Synthesis of intermediate C4

[0599] Compound C4-6 (1.0 g, 3.80 mmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL). Thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 24 hours. The reaction mixture was concentrated in vacuo to obtain intermediate C4 (1.1 g, 3.46 mmol, 91.0% yield, HCl) as a brown solid. LC-MS: m / z = 282.1 (M+H) + .

[0600] Synthesis of General Intermediate C5 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0601] Step 1: Synthesis of compound C5-2 (methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0602] Dissolve 1,1-dibromo-3,3,3-trifluoroacetone (7.2 g, 26.8 mmol, 1.10 eq) and sodium acetate (2.2 g, 27.3 mmol, 1.12 eq) in water (8.0 mL) and stir at 100°C for 1 hour. Add methyl p-formylbenzoate (C5-1, 4.0 g, 24.4 mmol, 1.00 eq) dissolved in methanol (80.0 mL) and aqueous ammonia (22.0 mL) at 25°C. After addition, react at 25°C for 40 minutes, then heat to 100°C and stir for 2 hours. Then, water (60.0 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (80.0 mL). The organic layers were combined, washed twice with saturated brine (80.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain compound C5-2 (4.5 g). 1 H NMR (400MHz, CDCl3) δ13.4 (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) + .

[0603] Step 2: Synthesis of compound C5-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0604] Compound C5-2 (2.5 g, 9.3 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Sodium hydride (444.1 mg, 11.1 mmol, 1.20 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 30 minutes after the addition was complete. Then, iodomethane (6.8 g, 48.1 mmol, 5.20 eq) was added. After the addition was complete, the temperature was raised to 20°C and stirred for 15 hours. The reaction was then quenched by the addition of ice water (20.0 mL) at 0°C. The 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 in vacuo to obtain the crude product, which 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 (400MHz, CDCl3) δ8.07 (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) + .

[0605] Step 3: Synthesis of compound C5-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol)

[0606] Compound C5-3 (0.6 g, 2.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (6.0 mL), and lithium aluminum tetrahydride (88.1 mg, 2.32 mmol, 1.10 eq) was added at 0°C. After the addition, the temperature was raised 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 stirred at 0°C for 0.5 hours. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, the filtrate was filtered, and vacuum concentrated to obtain a crude product C5-4 (505.4 mg), which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8.0Hz, 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)+.

[0607] Step 4: Synthesis of intermediate C5

[0608] Compound C5-4 (500.0 mg, 2.0 mmol, 1.00 eq) was dissolved in dichloromethane (5.0 mL). Thionyl chloride (1.9 g, 15.6 mmol, 8.00 eq) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 15 hours. The reaction solution was concentrated in vacuo to obtain a brown solid compound C5 (523 mg, 1.90 mmol, 97.6% yield). 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=1.4Hz,1H),7.74(d,J=8.2Hz,2H),7.58(d,J=8.1Hz,2H),4.84(s,2H),3.80(s,3H); LC-MS: m / z=275.1(M+H) + .

[0609] Synthesis of Universal Intermediate C6 (2-(4-(Chloromethyl)piperidin-1-yl)pyridine)

[0610] Step 1: Synthesis of compound C6-2 (ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate)

[0611] Ethyl 4-piperidinate (Compound C6-1, 20.8 g, 132 mmol, 20.4 mL, 1.00 eq), 2-chloropyridine (15.0 g, 132.0 mmol, 1.00 eq), and triethylamine (26.7 g, 264 mmol, 36.8 mL, 2.00 eq) were dissolved in dimethyl sulfoxide (50.0 mL) and reacted at 130°C for 16 hours. The reaction was stopped by cooling and quenched by adding water (50 mL) at room temperature. The 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, which 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 (400MHz, CDCl3) δ8.17-8.19(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,2 H),4.13-4.18(m,2H),2.92-2.99(m,2H),2.52-2.53(m,1H),1.98-2.02(m,2H),1.75-1.79(m,2H),1.25-1.28(m,3H). LC-MS:m / z=235.2(M+H) + .

[0612] Step 2: Synthesis of compound C6-3 ((1-(pyridin-2-yl)piperidin-4-yl)methanol)

[0613] Compound C6-2 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL). Lithium aluminum hydride (1.07 g, 28.2 mmol, 1.10 eq) was added portionwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 h. Lithium aluminum hydride (486 mg, 12.8 mmol, 0.500 eq) was then added and stirring continued for 6 h. The reaction was quenched by the addition of water (20.0 mL) at 0°C and 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, which 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. 1H NMR (400MHz, CDCl3) δ8.18(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=12.8 Hz, 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) + .

[0614] Step 3: Synthesis of intermediate C6

[0615] Compound C6-3 (1.20 g, 6.24 mmol, 1.00 eq) was dissolved in dichloromethane (12.0 mL). Thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 eq) was added at 0°C. After addition, the mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to afford intermediate C6 (1.57 g, crude) as a white solid. LC-MS: m / z = 211.1.

[0616] Synthesis of Universal Intermediate C7 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0617] The synthesis of general intermediate C7 was carried out according to the synthesis of intermediate C5, except that compound C5-1 was replaced with an equal amount of methyl 5-formylthiophene-2-carboxylate (compound C7-1). Other experimental conditions remained unchanged, and white solid intermediate C7 (330.0 mg, crude product) was obtained. LC-MS: m / z = 281.0 (M+H) + .

[0618] Synthesis of Universal Intermediate C9 (2-((1R, 4R)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0619] Step 1: Synthesis of compound C9-2 (1-methyl-4-(trifluoromethyl)-1H imidazole)

[0620] 4-(Trifluoromethyl)-1H-imidazole (Compound C9-1, 33.0 g, 242.0 mmol, 1.00 eq) was dissolved in tetrahydrofuran (330.0 mL), and sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 eq) was added in portions at 0°C. After the addition, the mixture was reacted at 0°C for 30 minutes. Then, iodomethane (34.4 g, 242.0 mmol, 15.1 mL, 1.00 eq) was added, and the temperature was raised to 25 ° C. and stirred for 5 hours. Saturated aqueous ammonium chloride solution (30.0 mL) was added at 0 ° C. to quench the reaction, and water (30.0 mL) was added. The 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 crude product was purified by reverse phase HPLC (0.1% NH3·H2O) to obtain compound C9-2 (21.0 g). 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z=151.1 (M+H) + .

[0621] Step 2: Synthesis of compound C9-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H imidazole)

[0622] Compound C9-2 (16.8 g, 111.0 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (370.0 mL), and n-butyl lithium (2.5 M, 44.7 mL, 1.00 eq) was added dropwise at -70°C. After the addition, the mixture was stirred at -70°C for 30 minutes. Then, hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) was added dropwise to the reaction solution. After addition, the mixture was reacted at -70°C for 1 hour, then heated to 20°C and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200.0 mL) at 0°C. Water (300.0 mL) was added and the mixture was extracted three times with ethyl acetate (150.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-20 / 1) to obtain compound C9-3 (12.0 g). LC-MS: m / z = 219.0 (M+H). + .

[0623] Step 3: Synthesis of compound C9-4 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-3-ene-1-carboxylate)

[0624] Compound C9-3 (7.0 g, 31.9 mmol, 1.00 eq), 1-ethoxycarbonylcyclohex-3-ene-4-boronic acid pinacol ester (8.94 g, 31.9 mmol, 1.00 eq), potassium phosphate (20.3 g, 95.8 mmol, 3.00 eq), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.3 g, To a mixed solvent of dioxane (70.0 mL) and water (10.0 mL) were added 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 eq), and the mixture was replaced with nitrogen three times. The mixture was stirred at 100°C for 5 hours under nitrogen protection. The reaction solution was filtered to obtain a filtrate, which was concentrated in vacuo to obtain a 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 (400MHz, CDCl3) δ6.05 (d, J = 2.0Hz, 1H), 4.18 (q, J = 7.2Hz, 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=7.2Hz,3H); LC-MS: m / z=337.2(M+H) + .

[0625] Step 4: Synthesis of compound C9-5 (ethyl (1R, 4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-carboxylate)

[0626] Compound C9-4 (1.9 g, 5.6 mmol, 1.00 eq), sodium acetate (925.0 mg, 11.2 mmol, 2.00 eq) and wet palladium carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 eq) were added to ethanol (30.0 mL) in sequence, and the mixture was reacted at 50°C under a hydrogen atmosphere (15 psi) for 5 hours. The reaction solution was filtered to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (column: water Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 10 min) to obtain compound C9-5 (0.3 g). 1H NMR (400MHz, CDCl3) δ7.13 (s, 1H), 4.15 (q, J = 6.8Hz, 2H), 3.64 (s, 3H), 2.60-2.65 (m, 1 H),2.41-2.44(m,1H),2.12-2.15(m,2H),1.97-1.98(m,2H),1.77-1.80(m,2H),1.54- 1.59(m,2H),1.27(t,J=8.8Hz,3H); LC-MS: m / z=305.0(M+H) + .

[0627] Step 5: Synthesis of compound C9-6 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol)

[0628] Compound C9-5 (0.6 g, 2.0 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL). Lithium aluminum tetrahydride (224.0 mg, 5.9 mmol, 3.00 eq) was added at 0°C. After the addition was complete, the mixture was reacted at 0°C for 0.5 hours, then the temperature was raised to 20°C and stirred for 12 hours. Then, sodium sulfate decahydrate (0.5 g) was added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 30 minutes. Tetrahydrofuran (10.0 mL) was added and the filtrate was filtered. The organic layer was separated, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain crude compound C9-6 (0.5 g), which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6Hz, 2H), 2.59-2.65 (m, 1 H), 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)+.

[0629] Step 6: Synthesis of intermediate C9

[0630] Compound C9-6 (500.0 mg, 1.9 mmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL). Thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 24 hours. The reaction mixture was concentrated in vacuo to obtain a light yellow solid intermediate C9 (550 mg, 1.36 mmol, 71.5% yield). LC-MS: m / z = 281.0 (M+H) + .

[0631] Synthesis of Universal Intermediate C11 (1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0632] Step 1: Synthesis of compound C11-2 (methyl 4-hydrazinobenzoate)

[0633] Compound C11-1 (15.0 g, 90.32 mmol, 1.0 eq) was dissolved in 37% aqueous hydrochloric acid (25.0 mL). Sodium nitrite (6.2 g, 90.32 mmol, 1.0 eq) dissolved in water (10.0 mL) was added at 0°C and stirred for 10 minutes. Then, tin chloride (85.6 g, 451.62 mmol, 5.0 eq) dissolved in 37% aqueous hydrochloric acid (75.0 mL) was added dropwise at 0°C. After addition, the temperature was raised to 25°C and stirred for 2 hours. The filter cake was filtered and washed three times with ethyl acetate (50.0 mL). The mixture was concentrated in vacuo to afford compound C11-2 (16.5 g). LC-MS: m / z = 167.1 (M+H) + .

[0634] Step 2: Synthesis of compound C11-3 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate)

[0635] Compound C11-2 (5 g, 24.75 mmol, 1.0 eq) and 1,1,1-trifluoro-2,4-pentanedione (3.8 g, 24.75 mmol, 1.0 eq) were added to hexafluoroisopropanol (25.0 mL). Triethylamine (5.0 g, 49.50 mmol, 2.0 eq) dissolved in hexafluoroisopropanol (25.0 mL) was added dropwise at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1 hour. Water (10 mL) was then added and the mixture was extracted three times with dichloromethane (200.0 mL). The organic layers were combined, washed twice with saturated brine (200.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was then 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) + .

[0636] Step 3: Synthesis of compound C11-4 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol)

[0637] Compound C11-3 (5.3 g, 18.65 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100.0 mL). Lithium aluminum tetrahydride (1.9 g, 46.64 mmol, 2.5 eq) was slowly added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 6 hours. Ice water (50.0 mL) was then added at 0°C and stirred for 10 minutes. Extraction was performed 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, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 2) to obtain compound C11-4 (3.6 g). LC-MS: m / z = 257.1 (M+H). + .

[0638] Step 4: Synthesis of intermediate C11

[0639] Compound C11-4 (1.0 g, 3.91 mmol, 1.0 eq) was dissolved in dichloroethane (25.0 mL), and thionyl chloride (1.4 g, 11.73 mmol, 5.2 eq) was added at 0°C. After the addition, the temperature was raised to 50°C and stirred for 2 hours. The reaction solution was concentrated in vacuo to obtain a white solid intermediate C11 (1.0 g, 3.64 mmol, 93.1% yield, 96.9% purity). 1 H NMR (400MHz, CDCl3) δ7.53 (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) + .

[0640] Synthesis of General Intermediate C12 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0641] Step 1: Synthesis of compound C12-2 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol)

[0642] 8-Chloromidazo[1,2-A]pyrazine (Compound C12-1, 9.6 g, 62.5 mmol, 1.00 eq), 4-hydroxymethylphenylboronic acid (12.4 g, 81.3 mmol, 1.30 eq), tetrakistriphenylphosphine palladium (7.2 g, 6.25 mmol, 0.10 eq), and sodium carbonate (49.0 g, 463 mmol, 7.40 eq) were added sequentially to a mixed solvent of toluene (48.0 mL), water (48.0 mL), and ethanol (9.6 mL). The mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. The filtrate was filtered and concentrated in vacuo to obtain the crude product, which was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound C12-2 (12.7 g). LC-MS: m / z = 226.2 (M+H). + .

[0643] Step 2: Synthesis of intermediate C12

[0644] Compound C12-2 (6.0 g, 26.6 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (15.9 g, 133 mmol, 5.00 eq) was added at 0°C. After addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to afford 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)+.

[0645] Synthesis of Universal Intermediate C13 (2-(4-(chloromethyl)phenyl)-5-(trifluoromethyl)pyridine)

[0646] Intermediate C13 (2.0 g) was prepared using the same procedure as Intermediate C3 using 2-bromo-5-(trifluoromethyl) (Compound C13-1)pyridine as starting material. LC-MS: m / z = 272.0 (M+H) + .

[0647] Synthesis of General Intermediate C14 (2-(4-(Chloromethyl)phenyl)-5-methylpyridine)

[0648] Intermediate C14 (10.0 g) was prepared using 2-bromo-5-methylpyridine (Compound C14-1) in the same manner as Intermediate C3. LC-MS: m / z = 218.0 (M+H) + .

[0649] Synthesis of Universal Intermediate C19 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0650] Step 1: Synthesis of compound C19-2 (methyl 4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate)

[0651] Bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylic acid monomethyl ester (Compound C19-1, 25.0 g, 118 mmol, 1.00 eq), 3-(trifluoromethyl)pyridine (20.8 g, 141 mmol, 1.20 eq), ammonium persulfate (26.9 g, 118 mmol, 25.6 mL, 1.00 eq) and silver nitrate (4.01 g, 23.6 mmol, 0.20 eq) were added sequentially. The reaction mixture was added to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL), and the reaction was carried out at 20°C for 16 hours. Dichloromethane (250.0 mL) was added, and the filtrate was filtered. The filtrate was washed three times with water (100.0 mL). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was filtered. The product was concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (purification conditions, NH3.H2O / MeCN / H2O) to obtain compound C19-2 (7.5 g). 1 H NMR (400MHz, CDCl3) δ8.81(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).

[0652] Step 2: Synthesis of compound C19-3 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol)

[0653] Compound C19-2 (2.5 g, 7.98 mmol, 1.00 eq) was dissolved in tetrahydrofuran (50.0 mL). Lithium aluminum tetrahydride (908 mg, 23.9 mmol, 3.00 eq) was slowly added at 0°C. After complete addition, the temperature was raised to 20°C and stirred for 3 hours. Ice water (50.0 mL) was then added at 0°C and stirred for 10 minutes. Extraction was performed three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. Concentration in vacuo afforded compound C19-3 (2.3 g) as a white solid. LC-MS: m / z = 286.1 (M+H) + .

[0654] Step 3: Synthesis of intermediate C19

[0655] Compound C19-3 (1.6 g, 5.61 mmol, 1.00 eq) and p-toluenesulfonyl chloride (1.28 g, 6.73 mmol, 1.20 eq) were added to pyridine (25.0 mL), reacted at 20°C for 12 hours, concentrated in vacuo, added with water (10.0 mL) and stirred for 5 minutes, extracted three times with dichloromethane (5.0 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain white solid intermediate C19 (1.5 g, 3.38 mmol, 60.2% yield, 98.9% purity). 1 H NMR(400MHz, CDCl3)δ8.79(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) + .

[0656] Synthesis of General Intermediate C25 (6-(Chloromethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0657] Step 1: Synthesis of compound C25-2 (methyl 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate)

[0658] 2-Methyl-1-oxo-3,4-dihydroisoquinoline-6-carbonitrile (Compound C25-1, 500 mg, 2.69 mmol, 1 eq) was dissolved in methanolic hydrochloric acid (4 M, 6.71 mL, 10 eq) and stirred at 70°C for 3 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was then purified by prep-HPLC (FA) to obtain Compound C25-2 as a white solid (0.16 g, 715.21 μmol, 26.64% yield, 98% purity). LC-MS: m / z = 220.2 (M+H) + .

[0659] Step 2: Synthesis of compound C25-3 (6-(hydroxymethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0660] Compound C25-2 (75 mg, 342.10 μmol, 1 eq) was dissolved in tetrahydrofuran (4 mL). Lithium borohydride (2 M, 1 mL, 5.85 eq) was added at 0°C and stirred at 25°C for 3 hours. The mixture was then quenched three times with hydrochloric acid (2 mL, 1 M) and extracted three times with ethyl acetate (15.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford compound C25-3 (50 mg, crude) as a white solid. LC-MS: m / z = 192.2 (M+H) + .

[0661] Step 3: Synthesis of intermediate C25

[0662] Compound C25-3 (50 mg, 261.47 μmol, 1 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (155.54 mg, 1.31 mmol, 94.84 μL, 5 eq) was added at 0°C. After addition, the mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to obtain intermediate C25 (50 mg, 238.47 μmol, 91.20% yield) as an off-white solid. LC-MS: m / z = 210.0 (M+H) + .

[0663] Synthesis of General Intermediate C26 (6-(Chloromethyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0664] 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 eq) was dissolved in tetrahydrofuran (40 mL), sodium hydride (1.06 g, 26.54 mmol, 60% purity, 1.5 eq) was added at 0°C, stirred for 30 minutes, and 2-iodopropane (6.02 g, 35. After the addition, the mixture was stirred at 25°C for 2 hours under nitrogen protection. The reaction was quenched by adding water (30 mL) at 0°C and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and 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 / 0-1 / 2) to obtain compound C26-2 (1.7 g, 6.19 mmol, 35.01% yield, 97.7% purity) as a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.94 (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)+.

[0665] Step 2: Synthesis of compound C26-3 (2-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile)

[0666] Compound C26-2 (2.6 g, 9.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL), and zinc cyanide (797.00 mg, 6.79 mmol, 430.81 μL, 0.7 eq) and tetrakis(triphenylphosphine)palladium (1.12 g, 969.61 μmol, 0.1 eq) were added. The mixture was stirred at 80°C under nitrogen for 12 hours. Water (30 mL) was added, and the 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, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound C26-3 (1.9 g, 8.84 mmol, 91.18% yield, 99.7% purity) as a white solid. 1 H NMR(400MHz, CDCl3)δ8.19(d,J=8.4Hz,1H),7.64-7.62(m,1H),7.50(s,1H),5.11-5.04(m,1H),3.48(t,J 1=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) + .

[0667] Steps 3-5: Synthesis of intermediate C26

[0668] Intermediate C26 (433.4 mg, 1.82 mmol, 45.1% yield) was prepared using compound C26-3 as the starting material according to the same procedure as intermediate C25. LC-MS: m / z = 238.2 (M+H) + .

[0669] Synthesis of Universal Intermediate C27 (2-((4-(chloromethyl)phenoxy)methyl)pyridine)

[0670] Using 4-hydroxybenzonitrile (compound C27-1) and 2-(bromomethyl)pyridine hydrobromide as starting materials, the pale yellow oily intermediate C27 (800.7 mg, crude product) was prepared according to the same procedure as intermediate C28. LC-MS: m / z = 234.0 (M+H) + .

[0671] Synthesis of Universal Intermediate C28 (1-(Chloromethyl)-4-(2-ethoxyethoxy)benzene)

[0672] Step 1: Synthesis of compound C28-2 (4-(2-ethoxyethoxy)benzonitrile)

[0673] 4-Hydroxybenzonitrile (compound C28-1, 4.00 g, 33.6 mmol, 1.00 eq), 2-bromoethyl ethyl ether (10.0 g, 65.4 mmol, 7.35 mL, 1.95 eq) and potassium carbonate (9.28 g, 67.2 mmol, 2.00 eq) were added to acetonitrile (142 mL) in sequence and stirred at 80°C for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product. Water (30.0 mL) was added and the pH was adjusted to about 5 with 1N HCl aqueous solution. The product was extracted three times with dichloromethane (50.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-2 / 1) to obtain compound C28-2 (6.69 g, crude product) as a light yellow oil. 1 H NMR (400MHz, DMSO) δ7.75 (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).

[0674] Step 2: Synthesis of compound C28-3 (methyl 4-(2-ethoxyethoxy)benzoate)

[0675] Compound C28-2 (2.00 g, 10.5 mmol, 1.00 eq) was dissolved in HCl / MeOH (4 M, 105 mL, 40.0 eq), stirred at 80°C for 36 hours, and concentrated in vacuo to obtain a crude product. Water (20.0 mL) was added, and the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate solution. The product was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound C28-3 (1.46 g, 6.51 mmol, 62.3% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.99(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) + .

[0676] Step 3: Synthesis of compound C28-4 ((4-(2-ethoxyethoxy)phenyl)methanol)

[0677] Compound C28-3 (0.700 g, 3.12 mmol, 1.00 eq) was dissolved in tetrahydrofuran (7.00 mL). Lithium aluminum tetrahydride (237 mg, 6.24 mmol, 2.00 eq) was slowly added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 3 hours. Then, ice water (50.0 mL) was added at 0°C and stirred for 10 minutes. Extraction was performed three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain compound C28-4 (0.62 g, crude product) as a colorless, transparent oil. 1 H NMR (400MHz, CDCl3) δ7.28-7.29(m,2H),6.90-6.94(m,2H),4.61(s,2H),4.1 1-4.14(m,2H),3.78-3.81(m,2H),3.59-3.64(m,2H),1.25(t,J=7.0Hz,3H).

[0678] Step 4: Synthesis of intermediate C28

[0679] Compound C28-4 (0.560 g, 2.85 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL), and thionyl chloride (2.46 g, 20.7 mmol, 1.50 mL, 7.25 eq) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction solution was concentrated in vacuo to obtain compound C28 (0.60 g, crude product) as a light yellow oil. 1 H NMR (400MHz, DMSO) δ7.35-7.37(m,2H),6.93-6.95(m,2H),4.73(s,2H),4.08-4.10(m,2 H),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) + .

[0680] Synthesis of Universal Intermediate C29 (1-(Chloromethyl)-4-(3-methoxycyclobutyloxy)benzene)

[0681] Step 1: Synthesis of compound C29-2 (4-(3-methoxycyclobutyloxy)benzaldehyde)

[0682] 4-(3-Methoxycyclobutyloxy)benzonitrile (compound C29-1, 0.560 g, 2.85 mmol, 1.00 eq) was dissolved in tetrahydrofuran (6.50 mL), and diisobutylaluminum hydride (1 M, 7.75 mL, 2.50 eq) was added dropwise at 0°C. After the addition, the 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. The mixture was extracted three times with ethyl acetate (50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain compound C29-2 (0.65 g, crude product) as a light yellow oil. 1 H NMR(400MHz,DMSO)δ9.87(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).

[0683] Step 2: Synthesis of compound C29-3 ((4-(3-methoxycyclobutyloxy)phenyl)methanol)

[0684] Compound C29-2 (0.65 g, 3.15 mmol, 1.00 eq) was dissolved in methanol (6.00 mL), and sodium borohydride (0.210 g, 5.55 mmol, 1.76 eq) was added in portions at 0°C. After the addition, the temperature was raised to 25°C and stirred for 2 hours. Water (10.0 mL) was added, and the 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 a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 2) to obtain compound C29-3 (0.12 g, crude product) as a light yellow oil. 1 H NMR (400MHz, DMSO) δ7.22-7.24(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).

[0685] Step 3: Synthesis of compound C29

[0686] Compound C29-3 (0.12 g, 576 μmol, 1.00 eq) was dissolved in dichloromethane (3.0 mL). Thionyl chloride (686 mg, 5.76 mmol, 418 μL, 10.0 eq) was added at 0°C. After the addition, the temperature was raised to 20°C and stirred for 12 hours. The reaction solution was concentrated in vacuo to obtain compound C29 (0.120 g, 529 μmol, 91.9% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.28-7.29(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) + .

[0687] Synthesis of Universal Intermediate C30 (2-(4-(chloromethyl)-3-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0688] Step 1: Synthesis of compound C30-2 (methyl 4-(dibromomethyl)-2-methoxybenzoate)

[0689] Methyl 2-methoxy-4-methylbenzoate (compound C30-1, 5.00 g, 27.8 mmol, 1.00 eq) was added to carbon tetrachloride (75.0 mL), and N-bromosuccinimide (10.9 g, 61.0 mmol, 2.20 eq) was added in batches at room temperature. After the addition, the temperature was raised to 85°C and stirred for 12 hours. The filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound C30-2 (6.50 g, 19.2 mmol, 69.3% yield) as a colorless transparent oil. 1 H NMR (400MHz, CDCl3) δ7.77 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.13 (dd, J1 = 1.8 Hz, J2 = 8.2 Hz, 1H), 6.62 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H).

[0690] Step 2: Synthesis of compound C30-3 (methyl 4-formyl-2-methoxybenzoate)

[0691] Compound C30-2 (5.00 g, 14.8 mmol, 1.00 eq) was dissolved in acetone (60.0 mL), and silver nitrate (7.57 g, 44.6 mmol, 3.01 eq) and water (15.0 mL) were added. The mixture was stirred at 20°C for 3 hours, and the filtrate was filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain a colorless, transparent oily compound C30-3 (2.60 g, 13.4 mmol, 90.5% yield). 1 H NMRδ10.0(s,1H),7.89-7.91(m,1H),7.48-7.50(m,2H),3.98(s,3H),3.93(s,3H).

[0692] Steps 3-6: Synthesis of intermediate C30

[0693] In the synthesis of steps 3 to 6, C30-3 was used as the starting material and the same procedure as for intermediate C5 was followed to prepare intermediate C30 (320 mg, 938 μmol, 75.0% yield) as a white solid. LC-MS: m / z = 305.1 (M+H) + .

[0694] Synthesis of General Intermediate C31 (2-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0695] Using methyl 3-methoxy-4-methylbenzoate (Compound C31-1) as the starting material, the white solid intermediate C31 (450 mg) was prepared according to the same procedure as intermediate C30. LC-MS: m / z = 305.1 (M+H) + .

[0696] Synthesis of Universal Intermediate C32 (1-(4-(chloromethyl)-3-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0697] Using methyl 2-methoxy-4-aminobenzoate (Compound C32-1) as starting material, the white solid intermediate C32 (1.18 g, 3.87 mmol, 88.5% yield) was prepared according to the same procedure as intermediate C11. LC-MS: m / z = 305.1 (M+H) + .

[0698] Synthesis of Universal Intermediate C33 (1-(4-(chloromethyl)-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0699] Using methyl 4-amino-3-methoxybenzoate (Compound C33-1) as starting material, the white solid intermediate C33 (796.0 mg, 2.61 mmol, 79.6% yield) was prepared according to the same procedure as intermediate C11. LC-MS: m / z = 305.0 (M+H) + .

[0700] Synthesis of Universal Intermediate C35 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0701] Step 1: Synthesis of compound C35-2 (1-methyl-4-(trifluoromethyl)-1H imidazole)

[0702] Compound 4-(trifluoromethyl)-1H-imidazole (compound C35-1, 26 g, 0.19 mol) and potassium carbonate (105.5 g, 0.76 mol, 4.0 eq) were added to acetonitrile (390 mL) and stirred at 0°C for 30 minutes. Methyl iodide (32.6 g, 0.23 mol, 1.2 eq) was added dropwise and stirred at room temperature for 16 hours. The reaction solution was then concentrated in vacuo to obtain a crude product. Water (260 mL) was added and stirred for 10 minutes. The product was extracted three times with ethyl acetate (200 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was then concentrated in vacuo to obtain compound C35-2 (26 g, crude product). LC-MS: m / z = 151.0 (M+H) + .

[0703] Step 2: Synthesis of compound C35-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate)

[0704] Compound C35-2 (14.75 g, 98.3 mmol) and bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylic acid monomethyl ester (25 g, 117.9 mmol, 1.2 eq) were dissolved in dichloromethane (295 mL) and water (295 mL), and silver nitrate (6.0 g, 35.4 mmol, 0.3 eq.) and ammonium persulfate (44.9 g, 78.7 mmol, 2.0 eq.) were added. The mixture was stirred at 25°C for 16 hours, filtered through celite, washed twice with dichloromethane (100 mL), and the organic layer was separated. 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 the filtrate was filtered. The mixture was concentrated in vacuo to obtain compound C35-3 (35.2 g, crude product) as a yellow oil. 1 H 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) + .

[0705] Step 3: Synthesis of compound C35-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanol)

[0706] Compound C35-3 (35.2 g, 111.4 mmol) was dissolved in tetrahydrofuran (180.0 mL). Lithium aluminum tetrahydride (2.5 M, 111.4 mL, 278.5 mmol, 2.5 eq) was slowly added at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 3 hours. Ice water (50.0 mL) was then added at 0°C and stirred for 10 minutes. The mixture was extracted three times with ethyl acetate (500.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered. The filtrate was concentrated in vacuo to obtain compound C35-4 (25.1 g, crude product) as a yellow oil. LC-MS: m / z = 289.1 (M+H) + .

[0707] Step 4: Synthesis of compound C35

[0708] Compound C35-4 (25.1 g, 87.2 mmol), p-toluenesulfonyl chloride (33.2 g, 174.4 mmol, 2.0 eq) and 4-dimethylaminopyridine (32.0 g, 261.6 mmol, 3.0 eq) were added to dichloromethane (251 mL) in sequence, and the reaction was stirred at 25°C for 16 hours. The mixture was washed twice with water (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0-0 / 1) to obtain white solid intermediate C35 (10.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=8.2Hz,2H),7.67(s,1H),7.52(d,J=8.0Hz,2H),3.77(s,3 H),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) + .

[0709] Synthesis of Universal Intermediate C48 (2-(4-(chloromethyl)phenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole)

[0710] Step 1: Synthesis of compound C48-2 ((2-(4-bromophenyl)-1H-imidazol-4-yl)methanol)

[0711] 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 to aqueous ammonia (500 mL) in sequence. The mixture was stirred at 80°C for 2 hours, cooled to room temperature, and filtered to obtain a solid. The solid was then concentrated in vacuo to obtain Compound C48-2 (15 g, crude) as a white solid. LC-MS: m / z = 252.6 (M+H) + .

[0712] Step 2: Synthesis of compound C48-3 (2-(4-bromophenyl)-1H-imidazole-4-carbaldehyde)

[0713] Compound C48-2 (14 g, 55.56 mmol) was dissolved in tetrahydrofuran (300 mL), and manganese dioxide (48 g, 555.6 mmol, 10 eq) was added. The mixture was stirred at 60°C for 16 hours, cooled to room temperature, and the filtrate was filtered and 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) + .

[0714] Step 3: Synthesis of compound C48-4 (2-(4-bromophenyl)-1-methyl-1H-imidazole-4-carbaldehyde)

[0715] Compound C48-3 (11.1 g, 44.4 mmol), iodomethane (8.2 g, 57.7 mmol, 1.3 eq), and potassium carbonate (24.6 g, 177.6 mmol, 4 eq) were added to N,N-dimethylformamide (120 mL) and stirred at an external temperature of 45°C for 3 hours. The filtrate was filtered and extracted three times with water (1000 mL) and ethyl acetate (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and 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 obtain compounds C48-4 and C48-4a (total 6.8 g) as white solids. LC-MS: m / z = 265.0 (M+H) + .

[0716] Step 4: Synthesis of compound C48-5 (2-(4-bromophenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole)

[0717] Compounds C48-4 and C48-4a (6.7 g, 25.38 mmol) were dissolved in anhydrous dichloromethane (200 mL). Diethylaminosulfur trifluoride (41 g, 253.8 mmol, 10 eq) was slowly added dropwise at 0°C. After complete addition, the mixture was stirred at room temperature for 5 hours at 25°C. The reaction solution was then slowly added to a saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to afford compounds C48-5 and C48-5a (4.1 g) as white solids. LC-MS: m / z = 286.9 (M+H) + .

[0718] Step 5: Synthesis of compound C48-6 (ethyl 4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzoate)

[0719] Compounds C48-5 and C48-5a (800 mg, 2.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.36 g, 1.68 mmol, 0.6 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (730 mg, 1.26 mmol, 0.45 eq), and triethylamine (1.42 g, 14 mmol, 5 eq) were added sequentially to anhydrous ethanol (32 mL). The mixture was stirred at 85°C under a carbon monoxide atmosphere (double-layer balloon, 25 psi) for 20 hours. EA (100 mL) was then added and stirred for 10 minutes. The filtrate was filtered, silica gel was added, and the mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compounds C48-6 and C48-6a (630 mg). LC-MS: m / z=281.1 (M+H) + .

[0720] Step 6: Synthesis of compound C48-7 ((4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)phenyl)methanol)

[0721] Compound C48-6 and compound C48-6a (630 mg) were dissolved in anhydrous THF (7 mL). A 2.5 M THF solution of lithium aluminum tetrahydride (2 mL) was added dropwise at 0°C. After the addition, the 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. The pH was then adjusted to approximately 5 with a 1 M aqueous hydrochloric acid solution. The mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain crude compound C48-7 and compound C48-7a (500 mg). LC-MS: m / z = 239.1 (M+H). + .

[0722] Step 7: Synthesis of Intermediate C48

[0723] 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 mixture was stirred at room temperature (25°C) for 1.5 hours. The reaction solution was then concentrated in vacuo to obtain a crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound C48 (130 mg). LC-MS: m / z = 257.1 (M+H) + .

[0724] Synthesis of Universal Intermediate C49 (2-(Chloromethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine)

[0725] Intermediate C49 (2.0 g) was prepared using methyl 5-formylpyridine-2-carboxylate (Compound C49-1) as the starting material, following the same procedure as Intermediate C5. LC-MS: m / z = 276.0 (M+H) + .

[0726] Synthesis of Universal Intermediate C57 (2-(4-(chloromethyl)phenyl)-1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole)

[0727] Intermediate C57 (1.83 g) was prepared using methyl p-formylbenzoate (Compound C5-1) as the starting material, following the same procedure as Intermediate C5. LC-MS: m / z = 301.2 (M+H) + .

[0728] Synthesis of General Intermediate C58 (2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole)

[0729] Intermediate C58 (0.6 g) was prepared using methyl p-formylbenzoate (Compound C5-1) as starting material by the same procedure as Intermediate C5. 1 H NMR (400MHz, DMSO-d6) δ8.22 (s, 1H), 7.61-7.64 (m, 4H), 4.88 (d, J = 2.4Hz, 2H), 4.50-4.55 (m, 1H), 1.44 (d, J = 6.6Hz, 6H); LC-MS: m / z = 303.1 (M+H) + .

[0730] Synthesis of Universal Intermediate C59 (2-(4-(chloromethyl)phenyl)-1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole)

[0731] Intermediate C59 (0.6 g) was prepared using methyl p-formylbenzoate (Compound C5-1) as the starting material, following the same procedure as Intermediate C5. LC-MS: m / z = 293.1 (M+H) + .

[0732] Synthesis of Universal Intermediate D5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0733] Intermediate D5 (0.16 g, 0.63 mmol, 85.9% yield) was prepared from compound C5 (0.2 g, 0.73 mmol, 1.00 eq) according to the same procedure as intermediate BB13. 1 H NMR (400MHz, DMSO-d6) δ7.92(t,J=1.4Hz,1H),7.75–7.61(m,2H),7.50(d,J=8.0Hz,2H),3.83(s,2H),3.80(s,3H); LC-MS: m / z=256.0(M+H) + .

[0734] Synthesis of Universal Intermediate D11 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine)

[0735] Intermediate D11 (1.59 g, 6.23 mmol, 77.6% yield) was prepared from compound C11 (2.2 g, 8.03 mmol, 1.00 eq) according to the same procedure as intermediate BB13. 1 H NMR (400MHz, DMSO-d6) δ7.60–7.47(m,4H),6.76(s,1H),3.84(s,2H),2.35(s,3H); LC-MS: m / z=256.1(M+H) + .

[0736] Synthesis of Universal Intermediate D58 ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0737] Intermediate D58 (0.98 g, 3.46 mmol, 69.9% yield) was prepared using compound C58 (1.5 g, 4.95 mmol, 1.00 eq) in the same manner as intermediate BB13. LC-MS: m / z = 284.3 (M+H) + .

[0738] Synthesis of intermediate BB1C2 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0739] Compound BB1 (500.0 mg, 2.89 mmol, 1.00 eq), compound C2 (634.4 mg, 3.04 mmol, 1.05 eq), and cesium carbonate (3.77 g, 11.56 mmol, 4.0 eq) were added to N,N-dimethylformamide (10.0 mL) in sequence and stirred at 80°C for 2 hours. The mixture was cooled to 25°C, and ethyl acetate (100.0 mL) was added and stirred for 5 minutes. The filtrate was filtered and washed three times with saturated brine (100.0 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 / ethyl acetate = 1 / 0-1 / 2) to obtain the intermediate BB1C2 (910.3 mg, 2.63 mmol, 91.0% yield) as a pale yellow solid. LC-MS: m / z = 347.2 (M+H) + .

[0740] Synthesis of intermediate BB1C3 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0741] Using intermediate BB1 ​​and compound C3 as starting materials, the pale yellow solid intermediate BB1C3 (689.9 mg, 2.03 mmol, 87.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 341.2 (M+H) + .

[0742] 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)

[0743] Using intermediate BB1 ​​and compound C4 as starting materials, the pale yellow solid intermediate BB1C4 (352.5 mg, 0.843 mmol, 69.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 419.2 (M+H)+ .

[0744] Synthesis of intermediate BB1C5 (2-chloro-5-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0745] Using intermediate BB1 ​​and compound C5 as raw materials, the pale yellow solid intermediate BB1C5 (2.39 g, 5.81 mmol, 81.6% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz,DMSO-d6)δ8.03–7.90(m,2H),7.80–7.72(m,2H),7.41(d,J=8.3Hz,2H), 4.98(s,2H),3.18(s,3H),2.92(s,3H),2.76(d,J=0.6Hz,3H); LC-MS: m / z=412.1(M+H) + .

[0746] Synthesis of intermediate BB1C6 (2-chloro-5-methoxy-N-methyl-N-(1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0747] Using intermediate BB1 ​​and compound C6 as starting materials, the pale yellow solid intermediate BB1C6 (169.7 mg, 0.49 mmol, 59.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 348.2 (M+H) + .

[0748] Synthesis of intermediate BB1C11 (2-chloro-5-methoxy-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0749] Using intermediate BB1 ​​and compound C11 as starting materials, the off-white solid intermediate BB1C11 (3.31 g, 8.04 mmol, 73.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 412.8 (M+H) + .

[0750] Synthesis of intermediate BB2C2 (2-chloro-5-methoxy-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0751] Using intermediate BB2 and compound C2 as starting materials, the pale yellow oily intermediate BB2C2 (134.1 mg, 0.40 mmol, 46.6% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 333.1 (M+H) + .

[0752] Synthesis of intermediate BB2C3 (2-chloro-5-methoxy-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0753] Using intermediate BB2 and compound C3 as starting materials, the pale yellow solid intermediate BB2C3 (255.5 mg, 0.78 mmol, 87.7% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 327.0 (M+H) + .

[0754] 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)

[0755] Using intermediate BB2 and compound C4 as starting materials, the pale yellow solid intermediate BB2C4 (98.8 mg, 0.24 mmol, 39.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 405.1 (M+H) + .

[0756] Synthesis of intermediate BB2C5 (2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0757] Using intermediate BB2 and compound C5 as raw materials, the pale yellow solid intermediate BB2C5 (18.9 g, 47.60 mmol, 69.8% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR (400MHz, CDCl3) δ7.60-7.62(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) + .

[0758] Synthesis of intermediate BB2C6 (2-chloro-5-methoxy-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0759] Using intermediate BB2 and compound C6 as starting materials, the pale yellow solid intermediate BB1C6 (100.6 mg, 0.30 mmol, 35.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 344.1 (M+H) + .

[0760] 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)

[0761] Using intermediate BB2 and compound C9 as starting materials, the pale yellow solid intermediate BB2C9 (31.1 mg, 0.077 mmol, 13.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 404.2 (M+H) + .

[0762] Synthesis of intermediate BB2C11 (2-chloro-5-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0763] Using intermediate BB2 and compound C11 as raw materials, the white solid intermediate BB2C11 (5.6 g, 14.10 mmol, 77.8% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz, CDCl3)δ7.49(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) + .

[0764] Synthesis of intermediate BB2C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0765] Using intermediate BB2 and compound C12 as raw materials, the pale yellow solid intermediate BB2C12 (130.3 mg, 0.36 mmol, 88.2% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR (400MHz, DMSO) δ8.71(d,J=8.4Hz,2H),8.60(d,J=4.4Hz,1H),8.19-8.21(m,2H),7.99(d,J=4.4Hz,1H), 7.87(s,1H),7.72(s,1H),7.46(d,J=8.4Hz,2H),4.61(d,J=4.4Hz,2H),3.88(s,3H); LC-MS: m / z=367.0(M+H) + .

[0766] Synthesis of intermediate BB2C13 (2-chloro-5-methoxy-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0767] Using intermediate BB2 and compound C13 as starting materials, the pale yellow solid intermediate BB2C13 (455.1 mg, 1.16 mmol, 69.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 395.0 (M+H) + .

[0768] Synthesis of intermediate BB2C14 (2-chloro-5-methoxy-N-(4-(5-methylpyridin-2-yl)benzyl)pyrimidin-4-amine)

[0769] Using intermediate BB2 and compound C14 as starting materials, the pale yellow solid intermediate BB2C14 (173.45 mg, 0.51 mmol, 90.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 341.1 (M+H) + .

[0770] 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)

[0771] Using intermediate BB2 and compound C19 as starting materials, the pale yellow solid intermediate BB2C19 (281.3 mg, 0.66 mmol, 35.6% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 427.3 (M+H) + .

[0772] Synthesis of Intermediate BB2C26 (6-((2-chloro-5-methoxypyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0773] Using intermediate BB2 and compound C26 as starting materials, the pale yellow solid intermediate BB2C26 (379.2 mg, 1.05 mmol, 82.0% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 361.1 (M+H) + .

[0774] Synthesis of intermediate BB2C27 (2-chloro-5-methoxy-N-(4-(pyridin-2-ylmethoxy)benzyl)pyrimidin-4-amine)

[0775] Using intermediate BB2 and compound C27 as raw materials, the pale yellow solid intermediate BB2C27 (268.5 mg, 0.61 mmol, 93.6% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz, CDCl3)δ8.62(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,1 H),6.99(d,J=8.4Hz,2H),5.61(s,1H),5.23(s,2H),4.60(d,J=5.6Hz,2H),3.85(s,3H); LC-MS: m / z=357.0(M+H) + .

[0776] Synthesis of intermediate BB2C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)-5-methoxypyrimidin-4-amine)

[0777] Using intermediate BB2 and compound C28 as raw materials, the white solid intermediate BB2C28 (316.9 mg, 0.94 mmol, 78.8% yield) was prepared according to the same procedure as intermediate BB1C2. 1H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 7.24-7.29 (m, 2H), 6.89-6.94 (m, 2H), 5.61 (s, 1H), 4.59 (d, J = 5.6Hz, 2H), 4.1 0-4.14(m,2H),3.84(s,3H),3.76-3.81(m,2H),3.60-3.62(m,2H),1.25(t,J=6.8Hz,3H); LC-MS: m / z=338.1(M+H) + .

[0778] Synthesis of intermediate BB2C30 (2-chloro-5-methoxy-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0779] Using intermediate BB2 and compound C30 as starting materials, the pale yellow solid intermediate BB2C30 (662.0 mg, 1.55 mmol, 86.7% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 428.0 (M+H) + .

[0780] Synthesis of intermediate BB2C31 (2-chloro-5-methoxy-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0781] Using intermediate BB2 and compound C31 as starting materials, the white solid intermediate BB2C31 (337.4 mg, 0.79 mmol, 93.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 428.1 (M+H) + .

[0782] Synthesis of intermediate BB2C33 (2-chloro-5-methoxy-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0783] Using intermediate BB2 and compound C33 as starting materials, the white solid intermediate BB2C33 (3.02 g, 2.66 mmol, 88.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 428.0 (M+H) + .

[0784] 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)

[0785] Compound BB2 (1.0 g, 6.29 mmol, 1.00 eq), compound C35 (2.78 g, 6.29 mmol, 1.0 eq), and cesium carbonate (10.2 g, 31.45 mmol, 5.0 eq) were added to N,N-dimethylformamide (20.0 mL) in sequence and stirred at 130°C for 36 hours. The mixture was cooled to 25°C, and dichloromethane (100.0 mL) was added and stirred for 5 minutes. The filtrate was filtered and 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 the intermediate BB2C35 (1.03 g, 2.41 mmol, 38.3% yield) as a white solid. LC-MS: m / z = 430.1 (M+H) + .

[0786] Synthesis of intermediate BB2C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0787] Using intermediate BB2 and compound C48 as starting materials, the white solid intermediate BB2C48 (371.5 mg, 0.98 mmol, 77.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 380.3 (M+H) + .

[0788] Synthesis of intermediate BB2C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0789] Using intermediate BB2 and compound C58 as raw materials, the pale yellow solid intermediate BB2C58 (357.1 mg, 0.84 mmol, 97.0% yield) was prepared according to the same procedure as intermediate BB1C2. 1H NMR (400MHz, DMSO-d6) δ8.31–8.15(m,2H),7.75(s,1H),7.54(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H), 4.63(d,J=6.3Hz,2H),4.56–4.38(m,1H),3.90(s,3H),1.42(d,J=6.6Hz,6H); LC-MS: m / z=426.1(M+H) + .

[0790] Synthesis of intermediate BB2C59 (2-chloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0791] Using intermediate BB2 and compound C59 as starting materials, the white solid intermediate BB2C59 (91.3 mg, 0.22 mmol, 78.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 426.1 (M+H) + .

[0792] 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)

[0793] Using intermediate BB3 and compound C4 as starting materials, the white solid intermediate BB3C4 (178.5 mg, 0.40 mmol, 28.7% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 447.3 (M+H) + .

[0794] Synthesis of intermediate BB3C5 (2-chloro-5-isopropoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0795] Using intermediates BB3 and C5 as starting materials, the white solid intermediate BB3C5 (2.1 g, 4.78 mmol, 86.4% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 440.2 (M+H) + .

[0796] 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)

[0797] Using intermediate BB4 and compound C4 as starting materials, the white solid intermediate BB4C4 (159.9 mg, 0.37 mmol, 39.6% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 433.2 (M+H) + .

[0798] Synthesis of intermediate BB4C5 (2-chloro-5-isopropoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0799] Using intermediate BB4 and compound C5 as starting materials, the white solid intermediate BB4C5 (2.03 g, 4.78 mmol, 86.4% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 426.1 (M+H) + .

[0800] 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)

[0801] Using intermediate BB4 and compound C19 as starting materials, the white solid intermediate BB4C19 (349.7 mg, 0.77 mmol, 83.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 455.2 (M+H) + .

[0802] Synthesis of intermediate BB12C2 (2-chloro-N-((4-(pyridin-2-yl)cyclohexyl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0803] Using intermediate BB12 and compound C2 as starting materials, the white solid intermediate BB12C2 (51.8 mg, 0.14 mmol, 35.4% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 371.1 (M+H) + .

[0804] Synthesis of intermediate BB12C3 (2-chloro-N-(4-(pyridin-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0805] Using intermediate BB12 and compound C3 as starting materials, the pale yellow solid intermediate BB12C3 (396.8 mg, 1.09 mmol, 76.6% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 365.0 (M+H) + .

[0806] 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)

[0807] Using intermediates BB12 and C4 as starting materials, the pale yellow oily intermediate BB12C4 (53.1 mg, 0.12 mmol, 21.1% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 443.0 (M+H) + .

[0808] Synthesis of intermediate BB12C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0809] Using intermediate BB12 and compound C5 as starting materials, the pale yellow solid intermediate BB12C5 (248.0 mg, 0.57 mmol, 88.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 436.1 (M+H) + .

[0810] Synthesis of intermediate BB12C6 (2-chloro-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0811] Using intermediate BB12 and compound C6 as starting materials, the pale yellow oily intermediate BB12C6 (29.7 mg, 0.08 mmol, 18.0% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 372.3 (M+H) + .

[0812] Synthesis of Intermediate BB13C3 (2-chloro-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0813] Using intermediate BB13 and compound C3 as starting materials, the pale yellow solid intermediate BB13C3 (1.19 g, 3.55 mmol, 89.4% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 337.1 (M+H) + .

[0814] Synthesis of intermediate BB13C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0815] Using intermediate BB13 and compound C5 as starting materials, the pale yellow solid intermediate BB13C5 (761.1 mg, 1.87 mmol, 76.7% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz,DMSO)δ9.00(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) + .

[0816] 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)

[0817] Using intermediate BB13 and compound C7 as starting materials, the white solid intermediate BB13C7 (342.6 mg, 0.83 mmol, 56.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 414.0 (M+H) + .

[0818] Synthesis of intermediate BB13C11 (2-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0819] Using intermediate BB13 and compound C11 as starting materials, the pale yellow solid intermediate BB13C11 (4.23 g, 10.39 mmol, 76.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 408.0 (M+H) + .

[0820] Synthesis of intermediate BB13C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0821] Using intermediate BB13 and compound C12 as raw materials, the white solid intermediate BB13C12 (458.8 mg, 1.22 mmol, 88.7% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz, DMSO)δ9.07(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=8.4Hz,1H),7.87(s,1H),7.53(d,J=8.0Hz,2H),6.93-6.98(m,1H),4.76(s,2H); LC-MS: m / z=377.1(M+H) + .

[0822] Synthesis of Intermediate BB13C19 (2-chloro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)furo[3,2-d]pyrimidin-4-amine)

[0823] Using intermediate BB13 and compound C19 as starting materials, the pale yellow oily intermediate BB13C19 (383.8 mg, 0.88 mmol, 22.3% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 437.0 (M+H) + .

[0824] Synthesis of Intermediate BB13C25 (6-(((2-chlorofurfuryl[3,2-d]pyrimidin-4-yl)amino)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0825] Using intermediate BB13 and compound C25 as raw materials, the white solid intermediate BB13C25 (195.0 mg, 0.57 mmol, 90.4% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR (400MHz, DMSO) δ8.94(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,2 H), 3.00 (s, 3H), 2.95 (t, J1=6.4Hz, J2=6.8Hz, 2H); LC-MS: m / z=343.2(M+H) + .

[0826] Synthesis of Intermediate BB13C26 (6-(((2-chlorofurfuryl[3,2-d]pyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0827] Using intermediate BB13 and compound C26 as starting materials, the pale yellow solid intermediate BB13C26 (233.1 mg, 0.63 mmol, 82.6% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 371.2 (M+H) + .

[0828] Synthesis of Intermediate BB13C27 (2-chloro-N-(4-(pyridin-2-ylmethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0829] Using intermediate BB13 and compound C27 as starting materials, the pale yellow solid intermediate BB13C27 (256.3 mg, 0.70 mmol, 66.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 366.9 (M+H) + .

[0830] Synthesis of Intermediate BB13C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0831] Using intermediates BB13 and C28 as starting materials, the pale yellow solid intermediate BB13C28 (118.0 mg, 0.34 mmol, 84.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 348.2 (M+H) + .

[0832] Synthesis of Intermediate BB13C29 (2-chloro-N-(4-(3-methoxycyclobutyloxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0833] Using intermediate BB13 and compound C29 as starting materials, the pale yellow solid intermediate BB13C29 (244.2 mg, 0.68 mmol, 93.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 360.2 (M+H) + .

[0834] 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)

[0835] Using intermediate BB13 and compound C30 as starting materials, the white solid intermediate BB13C30 (292.9 mg, 0.67 mmol, 78.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 438.1 (M+H) + .

[0836] 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)

[0837] Using intermediate BB13 and compound C31 as starting materials, the white solid intermediate BB13C31 (214.2 mg, 0.49 mmol, 73.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 438.0 (M+H) + .

[0838] 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)

[0839] Using intermediate BB13 and compound C32 as starting materials, the white solid intermediate BB13C32 (100.5 mg, 0.23 mmol, 70.0% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 438.0 (M+H) + .

[0840] 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)

[0841] Using intermediate BB13 and compound C33 as starting materials, the pale yellow solid intermediate BB13C33 (257.6 mg, 0.59 mmol, 84.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 437.9 (M+H) + .

[0842] 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)

[0843] Using intermediate BB13 and compound C35 as starting materials, the white solid intermediate BB13C35 (48.3 mg, 0.11 mmol, 28.8% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 440.2 (M+H) + .

[0844] Synthesis of Intermediate BB13C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0845] Using intermediates BB13 and C48 as starting materials, the white solid intermediate BB13C48 (886.2 mg, 2.28 mmol, 77.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 390.1 (M+H) + .

[0846] Synthesis of intermediate BB14C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidin-4-amine)

[0847] Using intermediate BB14 and compound C5 as starting materials, the pale yellow solid intermediate BB14C5 (1.22 g, 2.92 mmol, 93.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 419.1 (M+H) + .

[0848] Synthesis of intermediate BB15C5 (2,5-dichloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0849] Using intermediate BB15 and compound C5 as starting materials, the white solid intermediate BB15C5 (398.7 mg, 0.99 mmol, 80.4% yield) was prepared according to the same procedure as intermediate BB1C2. 1 H NMR(400MHz, DMSO-d6)δ8.60(s,1H),7.96(d,J=1.3Hz,1H),7.87–7.68(m,2H),7.45(d,J=8.3Hz,2H),5.00(s,2H),3.21(s,3H); LC-MS: m / z=402.0(M+H) + .

[0850] Synthesis of intermediate BB15C59 (2,5-dichloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0851] Using intermediate BB15 and compound C59 as starting materials, the white solid intermediate BB15C59 (124.0 mg, 0.30 mmol, 58.9% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 420.0 (M+H) + .

[0852] Synthesis of intermediate BB16C58 (2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyrimidin-4-amine)

[0853] Using intermediate BB16 and compound C58 as starting materials, the pale yellow solid intermediate BB16C58 (6.66 g, 16.69 mmol, 93.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 428.2 (M+H) + .

[0854] 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)

[0855] Using intermediate BB16-D3 and compound C57 as starting materials, the off-white solid intermediate BB16-D3C57 (1.33 g, 3.10 mmol, 89.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 429.3 (M+H) + .

[0856] 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)

[0857] Using intermediate BB16-D3 and compound C58 as starting materials, the off-white solid intermediate BB16-D3C58 (1.54 g, 3.57 mmol, 79.6% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 431.1 (M+H) + .

[0858] 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)

[0859] Using intermediate BB16-D3 and compound C59 as starting materials, the yellow solid intermediate BB16-D3C59 (874.2 mg, 2.08 mmol, 84.1% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 421.1 (M+H) + .

[0860] Synthesis of intermediate BB17C5 (2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carbonitrile)

[0861] Using intermediate BB17 and compound C5 as starting materials, the off-white solid intermediate BB17C5 (149.0 mg, 0.38 mmol, 48.7% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 393.0 (M+H) + .

[0862] 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)

[0863] Using intermediate BB19 and compound C4 as starting materials, the colorless, transparent oily intermediate BB19C4 (44.0 mg, 0.10 mmol, 17.7% yield) was prepared according to the same procedure as intermediate BB2C35. LC-MS: m / z = 441.0 (M+H) + .

[0864] Synthesis of intermediate BB19C5 (2-chloro-5-(difluoromethoxy)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0865] Using intermediate BB19 and compound C5 as starting materials, the white solid intermediate BB19C5 (1.03 g, 2.33 mmol, 82.2% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 434.0 (M+H) + .

[0866] Synthesis of intermediate BB19C11 (2-chloro-5-(difluoromethoxy)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0867] Using intermediate BB19 and compound C11 as starting materials, the white solid intermediate BB19C11 (545.7 mg, 1.26 mmol, 77.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 434.2 (M+H) + .

[0868] Synthesis of intermediate BB19C30 (2-chloro-5-(difluoromethoxy)-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0869] Using intermediate BB19 and compound C30 as starting materials, the off-white solid intermediate BB19C30 (546.4 mg, 1.18 mmol, 66.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 464.0 (M+H) + .

[0870] Synthesis of intermediate BB36C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0871] Using intermediate BB36 and compound C58 as starting materials, the same procedure as for intermediate BB1C2 was followed to prepare intermediate BB36C58 (382.0 mg, 0.84 mmol, 69.3% yield) as a colorless, transparent oil. LC-MS: m / z = 454.0 (M+H) + .

[0872] 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)

[0873] Using intermediate BB42 and compound C5 as starting materials, the off-white solid intermediate BB42C5 (332.6 mg, 0.76 mmol, 44.5% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 436.2 (M+H) + .

[0874] 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)

[0875] Using intermediate BB43 and compound C5 as starting materials, the white solid intermediate BB43C5 (101.1 mg, 0.22 mmol, 37.3% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 468.1 (M+H) + .

[0876] Synthesis of intermediate BB44C5 (2-chloro-N-cyclopropyl-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0877] Using intermediate BB44 and compound C5 as starting materials, the pale yellow solid intermediate BB44C5 (258.3 mg, 0.59 mol, 74.8% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 438.1 (M+H)+ .

[0878] 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)

[0879] Compound BB45 (250 mg, 1.3 mmol, 1.0 eq), compound C5 (392 mg, 1.43 mmol, 1.1 eq) and potassium carbonate (548 mg, 4.0 mmol, 3.0 eq) were added to dimethyl sulfoxide (5.0 mL) in sequence, stirred at 85°C for 1 hour, cooled to 25°C, added ethyl acetate (20.0 mL), stirred for 5 minutes, 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. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain the intermediate BB45C5 (160.5 mg, 0.38 mmol, 28.9% yield) as a light yellow oil. 1 H NMR(400MHz, DMSO-d6)δ8.18(s,1H),7.96(d,J=1.5Hz,1H),7.77–7.71(m,2H),7.51(d,J =8.2Hz,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) + .

[0880] Synthesis of intermediate BB18D5 (2-chloro-5-ethynyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0881] 2-(2,4-Dichloropyrimidin-5-yl)ethynyl-trimethylsilane (compound BB18-1, 2.2 g, 8.16 mmol, 1.00 eq), compound D5 (2.19 g, 8.57 mmol, 1.05 eq) and potassium carbonate (4.51 g, 32.64 mmol, 4.0 eq) were added to N,N-dimethylformamide (40.0 mL) in sequence, stirred at 50°C for 2 hours, cooled to 25°C, and ethyl acetate (100.0 mL) was added. The mixture was stirred for 5 minutes and filtered to obtain a filtrate. The filtrate was washed three times with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a white solid intermediate BB18D5 (2.24 g, 5.73 mmol, 70.2% yield). LC-MS: m / z=392.2 (M+H) + .

[0882] Synthesis of intermediate BB21D5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-morpholinopyrimidin-4-amine)

[0883] Using intermediate BB21 and compound D5 as starting materials, the white solid intermediate BB21D5 (880.0 mg, 1.95 mmol, 88.6% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 453.1 (M+H) + .

[0884] 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)

[0885] Using intermediate BB22 and compound D5 as starting materials, the off-white solid intermediate BB22D5 (441.9 mg, 0.95 mmol, 87.4% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 466.2 (M+H) + .

[0886] Synthesis of intermediate BB24D5 (2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-ol)

[0887] Using intermediate BB24 and compound D5 as starting materials, the pale yellow solid intermediate BB24D5 (26.8 mg, 0.07 mmol, 22.8% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 384.1 (M+H) + .

[0888] Synthesis of intermediate BB24D11 (2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)amino)pyrimidin-5-ol)

[0889] Using intermediates BB24 and D11 as starting materials, the white solid intermediate BB24D11 (115.1 mg, 0.3 mmol, 83.0% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 384.2 (M+H) + .

[0890] Synthesis of intermediate BB35D5 ((2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)methanol)

[0891] Using intermediate BB35 and compound D5 as starting materials, the colorless, transparent oily intermediate BB35D5 (333.8 mg, 1.86 mmol, 55.6% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 398.1 (M+H) + .

[0892] Synthesis of intermediate BB41C5 (methyl 2-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)acetate)

[0893] Using intermediate BB41 and compound D5 as starting materials, the pale yellow solid intermediate BB41D5 (133.9 mg, 0.30 mmol, 69.9% yield) was prepared according to the same procedure as intermediate BB18D5. LC-MS: m / z = 440.2 (M+H) + .

[0894] Example 1: Synthesis of Compound 1 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0895] Compound A5 (100 mg, 389 μmol, 1.00 eq) was dissolved in tetrahydrofuran (2.5 mL), and sodium hydride (62.2 mg, 1.55 mmol, 60.0% purity, 4.00 eq) was added portionwise at 0°C. After the addition, the mixture was reacted at 0°C for 30 minutes. Then, compound B10 (95.0 mg, 466 μmol, 1.20 eq) was added, and the temperature was raised to 25 ° C. and stirred for 12 hours. Then, ice water (2.0 mL) was added at 0 ° C. to quench the reaction, and the 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 in vacuo to obtain the crude product, which was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (HCl)-ACN]; B%: 15%-35%, 8 min) to obtain a light yellow solid compound 1 (136 mg, 277 μmol, 71.3% yield, HCl). 1 H NMR (400MHz, CDCl3) δ8.91 (d, J = 4.40Hz, 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) + .

[0896] The following compounds are prepared by reference to the preparation method of compound 1, using different general intermediates A, B and cesium carbonate or sodium hydride or potassium carbonate:

[0897] Example 32: Synthesis of Compound 32 (2-(2-isopropylphenyl)-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0898] Step 1: Synthesis of compound 32-3

[0899] Compound 32-1 (200.0 mg, 1.09 mmol, 1.00 eq), compound 32-2 (205.0 mg, 1.09 mmol, 1.00 eq), and cesium carbonate (1.1 g, 3.27 mmol, 3 eq) were added sequentially to N,N-dimethylformamide (4.0 mL), stirred at 60°C for 1 hour, ethyl acetate (30.0 mL) was added, stirred for 5 minutes, and the filtrate was filtered to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-2 / 1) to obtain compound 32-3 (360.9 mg). LC-MS: m / z = 337.0 (M+H) + .

[0900] Step 2: Synthesis of compound 32

[0901] Compound 32-3 (100.0 mg, 0.3 mmol, 1.00 eq), compound 32-4 (97.7 mg, 0.6 mmol, 2.00 eq), potassium phosphate (191.0 mg, 0.9 mmol, 3.00 eq), tetrakistriphenylphosphine palladium (34.7 mg, 0.03 mmol, 0.10 eq) were added to dioxane (2.0 mL) and water (0.4 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 90°C for 16 hours, water (10.0 mL) was added, and the mixture was extracted three times with ethyl acetate (20.0 mL). The organic layers were combined, washed twice with saturated brine (10.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give compound 32 (87.5 mg, 0.21 mmol, 69.4% yield, 98.6% purity) as a white solid. 1 H NMR (400MHz, DMSO) δ10.05(s,1H),8.71(d,J=4.9Hz,1H),8.59(d,J=2.2Hz,1H),8.06(d,J=8.0Hz,2H),8.03–7.95(m,2H),7.58–7.48(m,5H),7.4 7–7.42(m,1H),7.40–7.33(m,1H),7.20(d,J=2.2Hz,1H),4.93(d,J=6.0H z,2H),3.29–3.22(m,1H),1.07(d,J=6.8Hz,6H); LC-MS: m / z=421.2(M+H) + .

[0902] The following compounds were prepared by the preparation method of reference compound 32, wherein the reaction conditions of step 1 are cesium carbonate or sodium hydride or potassium carbonate, and the reaction conditions of step 2 are Pd(PPh3)4 / K3PO4 or XPhos-Pd-G2 / XPhos / K3PO4

[0903] Example 61: Synthesis of Compound 61 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0904] Compound BB1C2 (125.0 mg, 0.36 mmol, 1.00 eq), compound A1-2 (118.1 mg, 0.72 mmol, 2.00 eq), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, 56.58 mg, 0.072 mmol, 0.20 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 68.65 mg, 0.144 mmol, 0.40 eq) and Potassium phosphate (229.3 mg, 1.08 mmol, 3.00 eq) was added to dioxane (2.5 mL) and water (0.5 mL). The mixture was replaced with nitrogen three times and stirred at 95°C for 16 hours. Water (15.0 mL) was added and extracted three times with ethyl acetate (30.0 mL). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain Compound 61 (93.5 mg, 0.22 mmol, 60.3% yield, 97.3% purity) as a white solid. LC-MS: m / z = 431.2 (M+H) + .

[0905] The following compounds were prepared according to the preparation method of compound 61, using intermediates A series, AA series, BBC series or A series, AA series, BBD series as reaction raw materials, XPhos-Pd-G2 / XPhos / K3PO4 as reaction reagents, and dioxane and water as solvents:

[0906] Example 204: Compound 204 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-

[0907] Synthesis of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine

[0908] Step 1: Synthesis of compound BB46-2 (O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)hydroxylamine)

[0909] Compound 2,4-dichloro-5-fluoropyrimidine (compound BB46-1, 1.0 g, 5.6 mmol, 1.0 eq), O-(tert-butyldimethylsilyl)hydroxylamine (0.9 g, 6.2 mmol, 1.1 eq), and N,N-diisopropylethylamine (2.1 g, 16.8 mmol, 3.0 eq) were added to dioxane (20 mL) in sequence. The mixture was stirred at 80°C for 4 hours, cooled to room temperature, and the filtrate was filtered and 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 BB46-2 (430.2 mg, 1.49 mmol, 26.6% yield) as a light yellow oil. LC-MS: m / z = 290.0 (M+H) + .

[0910] 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)

[0911] Using intermediate BB46-2 (430 mg, 1.5 mmol, 1.0 eq) and compound C5 (452 ​​mg, 1.65 mmol, 1.1 eq) as starting materials, the pale yellow solid intermediate BB46-2C5 (506.8 mg, 0.96 mmol, 64.1% yield) was prepared according to the same procedure as intermediate BB1C2. LC-MS: m / z = 528.3 (M+H) + .

[0912] Step 3: Synthesis of compound A2-7BB46-2C5 (O-(tert-butyldimethylsilyl)-N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidinyl]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[0913] Using intermediate BB46-2 (486.0 mg, 0.9 mmol, 1.0 eq) and compound A2-7 (262.1 mg, 1.35 mmol, 1.5 eq) as starting materials, the yellow solid intermediate A2-7BB46-2C5 (323.3 mg, 0.50 mmol, 56.0% yield) was prepared according to the same procedure as compound A1-2BB1C2. LC-MS: m / z = 642.3 (M+H) + .

[0914] Step 4: Synthesis of compound 204

[0915] Intermediate A2-7BB46-2C5 (323.0 mg, 0.5 mmol, 1.0 eq) was dissolved in 4 M methanolic hydrochloric acid solution and stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate solution (30.0 mL) was added and extracted three times with dichloromethane (20.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 2) to obtain compound 204 (109.9 mg, 0.21 mmol, 41.7% yield) as a white solid. 1H NMR(400MHz, DMSO-d6)δ9.51(s,1H),8.62(s,1H),8.28(s,1H),7.92(d,J=1.4Hz,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=8.1,3.5Hz,1H),0.99(dq, J=5.9, 3.5Hz, 2H), 0.84 (dq, J=10.0, 3.4Hz, 2H); LC-MS: m / z=528.3(M+H) + .

[0916] 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)

[0917] Using intermediate BB46-2 and compound AA16 as starting materials, white solid compound 205 (37.2 mg, 0.074 mmol, 66.9% yield) was prepared according to the same procedure as compound 204. LC-MS: m / z = 500.3 (M+H) + .

[0918] Example 206: Synthesis of Compound 206 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidinyl]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)cyanamide)

[0919] Compound 29 (50 mg, 0.092 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (1.0 mL). Sodium hydride (60% content, 36.8 mg, 0.92 mmol, 10 eq) was added portionwise at 0°C. The temperature was naturally raised to 25°C and the mixture was stirred for 1 hour. Cyanogen bromide (48.7 mg, 0.46 mmol, 5 eq) was added and the mixture was stirred at room temperature at 25°C for 2 hours. The mixture 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 0 / 1) to obtain compound 206 (6.7 mg, 0.0125 mmol, 13.6% yield) as a pale white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.96(s,1H),7.92(s,1H),7.60(d,J=7.8Hz,2H),7.40(d,J=7.8Hz,2H),5.39(d,J=6.3Hz,2 H),3.93(s,3H),3.81(s,3H),3.70(s,3H),1.68(tt,J=8.2,4.8Hz,1H),0.96(s,2H),0.78-0.73(m,2H); LC-MS: m / z=537.2(M+H) + .

[0920] 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)

[0921] Step 1: Synthesis of compound 207-2 ((2R, 3R, 4S, 5S)-4-(hydroxymethyl)cubane-1-carboxylic acid methyl ester)

[0922] Compound (1S, 2R, 3R, 8S)-4-(methoxycarbonyl)cubane-1-carboxylic acid (207-1, 10.0 g, 48.5 mmol, 1.00 eq) was dissolved in tetrahydrofuran (300 mL), and 10 M borane dimethyl sulfide tetrahydrofuran solution (5.82 mL, 1.20 eq) was added at 20 ° C. The reaction was stirred at 50 ° C for 13 hours. Methanol (300 mL) was slowly added at 0 ° C to quench the reaction. The filtrate was filtered and concentrated in vacuo to obtain white solid compound 207-2 (11.0 g, crude product). 1 H NMR (400MHz, CDCl3) δ4.15-4.13(m,3H), 3.89-3.87(m,3H), 3.77-3.75(m,2H), 3.70(s,3H).

[0923] Step 2: Synthesis of compound 207-3 ((2R, 3R, 4S, 5S)-4-formylcubane-1-carboxylic acid methyl ester)

[0924] Compound 207-2 (11.0 g, 57.2 mmol, 1.00 eq) was dissolved in dichloromethane (150 mL), and Dess-Martin periodinane (DMP, 29.1 g, 68.6 mmol, 21.2 mL, 1.20 eq) was added at 0°C. The mixture was stirred at 0°C for 2 hours, and saturated aqueous sodium bicarbonate solution (100 mL) was added. The mixture was extracted three times with dichloromethane (150 mL). The organic layers were combined, washed twice with saturated brine (120 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain compound 207-3 (5.8 g, 30.5 mmol, 53.3% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ9.75 (s, 1H), 4.38-4.36 (m, 3H), 4.27-4.25 (m, 3H), 3.72 (s, 3H).

[0925] Step 3: Synthesis of compound 207-4 ((2R, 3R, 4S, 5S)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylic acid methyl ester)

[0926] Sodium acetate (5.25 g, 64.0 mmol, 2.1 eq) was dissolved in water (25.0 mL). 1,1-Dibromo-3,3,3-trifluoroacetone (9.05 g, 33.5 mmol, 1.1 eq) was added at 20°C. The temperature was raised to 100°C and stirred for 1 hour. Compound 207-3 (5.8 g, 30.5 mmol, 1.0 eq) dissolved in methanol (65.0 mL) and aqueous ammonia (25.0 mL) was added at 20°C. After the addition was complete, the mixture was stirred at 20°C for 11 hours. The reaction solution was filtered to obtain the filtrate, which was concentrated in vacuo to obtain compound 207-4 (6.0 g, 18.5 mmol, 60.8% yield) as a white solid. LC-MS: m / z = 297.0 (M+H) + .

[0927] Step 4: Synthesis of compound 207-5 ((2R, 3R, 4S, 5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylic acid methyl ester)

[0928] Compound 207-4 (4.5 g, 15.2 mmol, 1.0 eq) was dissolved in tetrahydrofuran (40.0 mL). Sodium hydride (911 mg, 22.7 mmol, 60% content, 1.50 eq) was added portionwise at 0°C. After the addition, the mixture was stirred at 20°C for 30 minutes. Iodomethane (2.16 g, 15.2 mmol, 945 μL, 1.0 eq) was added and the mixture was reacted at 20°C for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (50.0 mL) at 0°C. Water (100 mL) was added and the 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, which was purified by reverse phase HPLC (0.1% FA) to obtain compound 207-5 (1.6 g, 4.95 mmol, 32.5% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.54 (d, J = 1.2Hz, 1H), 4.45-4.42 (m, 3H), 4.32-4.30 (m, 3H), 3.73 (s, 3H), 3.66 (s, 3H); LC-MS: m / z = 311.1 (M+H) + .

[0929] 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)

[0930] Compound 207-5 (120 mg, 386.76 mmol, 1 eq) was dissolved in ethanol (24.0 mL). Methylamine ethanol solution (16.51 g, 159.48 mmol, 30% content, 412.35 eq) was added at 25°C. The mixture was stirred at 70°C and 50 psi for 12 hours. The mixture was cooled to room temperature, ice water (15.0 mL) was added, and the mixture was concentrated in vacuo to remove ethanol. The 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 compound 207-6 (0.11 g, crude product) as a white solid. LC-MS: m / z = 310.1 (M+H) + .

[0931] 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)methanamine)

[0932] Compound 207-6 (0.1 g, 323.33 mmol, 1 eq) was dissolved in tetrahydrofuran (10.0 mL). Lithium aluminum hydride tetrahydrofuran solution (2.5 mmol, 387.99 μL, 3 eq) was added at 0°C. The 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 stirred for 30 minutes. Tetrahydrofuran (5.0 mL) was added and stirred for 5 minutes. The filtrate was filtered and concentrated in vacuo to obtain compound 207-7 (86 mg, crude) as a white solid. LC-MS: m / z = 296.3 (M+H) + .

[0933] 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)

[0934] Compound 207-7 (40 mg, 135.45 mmol, 1 eq), N,N-diisopropylethylamine (70.03 mg, 541.82 mmol, 94.37 μL, 4 eq) and 2,4-dichloro-5-methoxypyrimidine (38.80 mg, 216.73 mmol, 1.6 eq) were added to dioxane (2.0 mL) in sequence, and the reaction was stirred at an external temperature of 60°C for 8 hours. After cooling to room temperature, water (10.0 mL) was added, and the 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, which 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, 53.96% yield) as a white solid. LC-MS: m / z=438.2 (M+H) + .

[0935] 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'-bipyrimidinyl]-4-amine)

[0936] 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 and the same procedure as for compound 61 was followed to prepare compound 207 (2.66 mg, 4.32 mmol, 7.56% yield) as a white solid. LC-MS: m / z = 552.3 (M+H) + .

[0937] Example 208: Synthesis of Compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidinyl]-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[0938] Step 1: Synthesis of compound 208-1 (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde)

[0939] Compound C5-4 (1.0 g, 3.91 mmol, 1.0 eq) and manganese dioxide (3.4 g, 39.1 mmol, 10.0 eq) were added to tetrahydrofuran (30.0 mL) in sequence and stirred at 45°C for 16 hours. The filtrate was filtered and 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 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) + .

[0940] Step 2: Synthesis of compound 208-2 (2-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[0941] Compound 208-1 (400.0 mg, 1.57 mmol, 1.0 eq), trimethylsilyl cyanide (203.0 mg, 2.05 mmol, 1.3 eq), and 1-octyl-3-methylimidazolium hexafluorophosphate (3.21 g, 9.42 mmol, 6.0 eq) were added to tetrahydrofuran (8.0 mL) in sequence. The mixture was stirred at 35°C for 16 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 208-2 (303.3 mg, 1.08 mmol, 68.7% yield) as a colorless, transparent oil. LC-MS: m / z = 282.2 (M+H) + .

[0942] Step 3: Synthesis of compound 208-3 (2-chloro-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[0943] Compound 208-2 (300.0 mg, 1.07 mmol, 1.00 eq) was dissolved in dichloromethane (6.0 mL). Thionyl chloride (635.0 mg, 5.33 mmol, 5.00 eq) was added at 0°C. After the addition, the mixture was heated to room temperature (25°C) and stirred for 4 hours. The reaction mixture was concentrated in vacuo to obtain compound 208-3 (288.8 mg, crude product) as a colorless, transparent oil. LC-MS: m / z = 300.2 (M+H) + .

[0944] 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)

[0945] Compound 208-3 (260.0 mg, 0.87 mmol, 1.0 eq), 2-chloro-4-amino-5-methoxypyrimidine (415.3 mg, 2.61 mmol, 3.0 eq), and pyridine (206.4 mg, 2.61 mmol, 3.0 eq) were added to toluene (5.2 mL) in sequence and reacted in a microwave oven at 140°C for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a light yellow solid compound 208-4 (96.0 mg, 0.23 mmol, 26.1% yield). LC-MS: m / z = 423.1 (M+H) + .

[0946] Step 5: Synthesis of Compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidinyl]-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[0947] Compound 208-4 (90.0 mg, 0.21 mmol, 1.00 eq), compound A2-7 (83.4 mg, 0.43 mmol, 2.0 eq), 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 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 41.0 mg, 0.086 mmol, 0.40 eq) were sequentially added. ) and sodium bicarbonate (72.2 mg, 0.86 mmol, 4.0 eq) were added to dioxane (2.0 mL) and water (0.4 mL), and the mixture was replaced with nitrogen three times. The mixture was stirred at 95°C under nitrogen protection for 16 hours, and water (10.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL) three times. 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, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain white solid compound 208 (38.2 mg, 0.071 mmol, 33.9% yield). 1 H NMR(400MHz,DMSO-d6)δ8.70(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,1H),3.98(s,3H),3.88(s,3H),3.83(s,3H),1.84-1.80(m,1H),1.18–0.82(m,4H); LC-MS: m / z=537.2(M+H) + .

[0948] 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]oct-4-yl)methyl)pyrimidin-4-amine)

[0949] Step 1: Synthesis of compound 209-2 ((1,4-dioxyaspirino[4.5]decane-8,8-diyl)bis(methylene)bis(4-methylbenzenesulfonate))

[0950] Compound 209-1 ([8-(Hydroxymethyl)-1,4-dioxyaspirino[4.5]dec-8-yl]methanol, 50.0 g, 247 mmol, 1.00 eq) and p-toluenesulfonyl chloride (104 g, 544 mmol, 2.20 eq) were added to pyridine (250.0 mL) in sequence, and the reaction was stirred at 25°C for 12 hours. Ethyl acetate (500.0 mL) was added, and the mixture was washed three times with 10% aqueous citric acid solution (500.0 mL) and once with saturated brine (500.0 mL). The mixture was dried over anhydrous sodium sulfate and filtered to obtain the filtrate. The filtrate was concentrated in vacuo to obtain the crude product. The crude product was slurried with ethanol (500.0 mL) for 1 hour and filtered to obtain compound 209-2 as a white solid (116.0 g, 227.0 mmol, 91.9% yield). 1 H NMR (400MHz, CDCl3) δ7.73 (d, J = 8.40Hz, 4H), 7.36 (d, J = 8.00Hz, 4H), 3.89 (s, 4H), 3.84 (s, 4H), 2.47 (s, 6H), 1.49 (s, 8H).

[0951] Step 2: Synthesis of compound 209-3 ((4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate))

[0952] Compound 209-2 (116 g, 227 mmol, 1.00 eq) was dissolved in tetrahydrofuran (1000 mL), 1 M hydrochloric acid (579 mL, 2.55 eq) was added, and the mixture was stirred at 70°C for 12 hours. Saturated brine (200 mL) was added, and the 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 the filtrate was filtered. The mixture was concentrated in vacuo to obtain compound 209-3 (110 g, crude product) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.00Hz,4H),7.48(d,J=8.40Hz,4H),3.98(s,4H),2.46( d, J=27.6Hz, 6H), 2.15-2.11 (t, J=7.20Hz, 4H), 1.62-1.54 (m, 4H); LC-MS: m / z=467.1 (M+H) + .

[0953] Step 3: Synthesis of compound 209-4 ((4-hydroxy-4-vinylcyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate))

[0954] Compound 209-3 (55.0 g, 118 mmol, 1.00 eq) was dissolved in tetrahydrofuran (500 mL), and 1 M vinylmagnesium bromide tetrahydrofuran solution (236 mL, 2.00 eq) was slowly added dropwise at -70°C. After the addition was completed, stirring was continued at -70°C for 2 hours. Saturated aqueous ammonium chloride solution (300 mL) was added at 0°C to quench the reaction. The solvent was removed by vacuum concentration, and water (100 mL) was added. The 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 obtain compound 209-4 (100 g, crude product) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.74 (dd, J1=8.0Hz, J2=12.8Hz, 4H), 7.36 (t, J=8.0Hz, 4H), 5.84 (dd, J1=10.8Hz, J2=17.2Hz, 1H) ,5.17(d,J=17.2Hz,1H),5.04(d,J=10.8Hz,1H),3.92(s,2H),3.76(s,2H),2.46(d,J=1.60Hz,6H),1.56-1.26(m,8H).

[0955] Step 4: Synthesis of compound 209-5 ((1-vinyl-2-oxabicyclo[2.2.2]oct-4-yl)methyl-4-methylbenzenesulfonate)

[0956] Compound 209-4 (30.0 g, 60.7 mmol, 1.00 eq) was dissolved in ethylene glycol dimethyl ether (500 mL), and sodium hydride (4.85 g, 121 mmol, 60% content, 2.00 eq) was added in portions at 0°C. After the addition, the reaction was stirred at 0°C for 30 minutes, the temperature was raised to 110°C and stirred for 16 hours, and a saturated aqueous ammonium chloride solution (400 mL) was added at 0°C to quench the reaction. Water (500 mL) was added and the organic solvent was removed by vacuum concentration. The mixture was 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 obtain a light yellow solid compound 209-5 (27.4 g, crude product). 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.00Hz,2H),7.36(d,J=8.00Hz,2H),5.85-5.76(m,1H),5.15-5.11(t,J=1.60Hz,1H),5.04-5.0 0(d,J1=1.60Hz,J2=11.2Hz,1H),3.69(d,J=6.80Hz,4H),2.46(s,3H),1.90-1.86(m,2H),1.72-1.65(m,4H),1.52-1.51(m,2H);

[0957] Step 5: Synthesis of compound 209-6 ((1-formyl-2-oxabicyclo[2.2.2]oct-4-yl)methyl-4-methylbenzenesulfonate)

[0958] Compound 209-5 (4.00 g, 12.4 mmol, 1.00 eq) was dissolved in tetrahydrofuran (80.0 mL), and sodium periodate (7.96 g, 37.2 mmol, 2.06 mL, 3.00 eq) was added at 0°C, followed by potassium osmate (1.14 g, 3.10 mmol, 0.250 eq) dissolved in water (16.0 mL). The mixture was stirred at 20°C for 12 hours, filtered to obtain the filtrate, washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain 209-6 (4.0 g, crude product) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ9.53(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).

[0959] Step 6: Synthesis of compound 209-7 ((1-(4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl-4-methylbenzenesulfonate)

[0960] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (3.99 g, 14.8 mmol, 1.20 eq) and sodium acetate (2.12 g, 25.9 mmol, 2.10 eq) were added to water (8.0 mL) in sequence and stirred at 100 °C for 1 hour. Compound 209 dissolved in ammonia water (11.5 g, 98.7 mmol, 12.7 mL, 30.0% content, 8.0 eq) and methanol (40.0 mL) was added at 25 °C. -6 (4.00 g, 12.3 mmol, 1.00 eq) was added and stirred at 25°C for 5 hours. Water (100 mL) was added and 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 in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain white solid compound 209-7 (2.2 g, 5.05 mmol, 41.0% yield). LC-MS: m / z = 431.2 (M+H) + .

[0961] Step 7: Synthesis of compound 209-8 ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl-4-methylbenzenesulfonate)

[0962] Compound 209-7 (2.20 g, 5.11 mmol, 1.00 eq) was dissolved in tetrahydrofuran (30.0 mL), and sodium hydride (307 mg, 7.67 mmol, 60.0% content, 1.50 eq) was added in batches at 0°C. After the addition, the mixture was stirred at 0°C for 30 minutes. Iodomethane (725 mg, 5.11 mmol, 1.0 eq) was added, and the temperature was raised to 25°C 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 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. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 The mixture was purified by HPLC (150×40mm×15μm; mobile phase: [water (TFA)-ACN]; gradient: 45%-75%) to give compound 209-8 (1.5 g, 3.37 mmol, 66.0% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.4Hz,2H),7.37(d,J=8.0Hz,2H),7.11(d,J=1.2Hz,1H),3.81(s,5H),3.73(s,2H) ,2.47(s,3H),2.28-2.22(m,2H),2.19-2.13(m,2H),1.78-1.71(m,2H),1.62-1.55(m,2H); LC-MS: m / z=445.3(M+H) + .

[0963] 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)

[0964] Compound 209-8 (1.0 g, 2.25 mmol, 1.0 eq), compound BB2 (716.0 mg, 4.50 mmol, 2.0 eq), sodium iodide (1.01 g, 6.75 mmol, 3.0 eq) and cesium carbonate (3.67 g, 11.25 mmol, 5.0 eq) were added to N,N-dimethylformamide (20.0 mL) in sequence, stirred at 130 ° C for 24 hours, cooled to 25 ° C, added with dichloromethane (100.0 mL), stirred for 5 minutes, and filtered to obtain a filtrate. The filtrate was washed three times with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0-0 / 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) + .

[0965] 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)

[0966] Compound 209-9 (40.0 mg, 92.6 μmol, 1.00 eq), compound AA9 (75.2 mg, 277.8 μmol, 3.00 eq), (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (Xphos Pd G4, 16.0 mg, 18.52 μmol, 0.2 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos, 17.7 mg, 37.04 μmol, 0.4 eq) and potassium phosphate (78.6 mg, 370.4 μmol, 4 eq) were added to dioxane (0.8 mL) and water (0.16 mL), and the reaction was stirred at an external temperature of 95°C for 16 hours. The reaction solution was concentrated in vacuo to obtain the crude product, which was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; gradient: 61%-91%) to obtain compound 209 (16.6 mg, 30.8 μmol, 33.3% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ8.21(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) + .

[0967] 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'-bipyrimidine]-4-amine)

[0968] White solid compound 210 (7.8 mg, 0.0143 mmol, 12.3% yield) was prepared using compound 209-9 (50.0 mg, 0.116 mmol, 1 eq) and intermediate A2-7 (67.4 mg, 0.348 mmol, 3.0 eq) as starting materials according to the same procedure as compound 209. 1 H NMR (400MHz, CDCl3) δ8.63(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,3H ),3.43(d,J=6.4Hz,2H),2.29-2.21(m,4H),1.82-1.71(m,5H),1.23-1.21(m,2H),0.94-0.91(m,2H); LC-MS: m / z=546.3(M+H) + .

[0969] 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]oct-4-yl)methyl)pyrimidin-4-amine)

[0970] Compound 209-8 (300.0 mg, 0.675 mmol, 1 eq) and intermediate BB-1 (351.5 mg, 2.02 mmol, 3.0 eq) were used as starting materials and the same procedure as for compound 209 was followed to prepare compound 211 (44.3 mg, 0.08 mmol, 18.9% yield) as a pale yellow solid. LC-MS: m / z = 554.2 (M+H) + .

[0971] 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]oct-4-yl)methyl)-[2,5'-bipyrimidine]-4-amine)

[0972] Compound 211-1 (30.0 mg, 0.067 mmol, 1 eq) and intermediate A2-7 (39.2 mg, 0.20 mmol, 3.0 eq) were used as starting materials and the same procedure as for compound 209 was followed to prepare compound 212 (5.7 mg, 0.01 mmol, 15.2% yield) as a white solid. LC-MS: m / z = 560.3 (M+H) + .

[0973] Example 213: Synthesis of Compound 213 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-N-((1-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl)-5-methoxypyrimidin-4-amine)

[0974] Compound 209-7 (1.0 g, 2.32 mmol, 1 eq) and cyclopropyl bromide (843.2 mg, 6.97 mmol, 3.0 eq) were used as starting materials and the same procedure as for compound 209 was followed to prepare compound 213 (11.6 mg, 0.02 mmol, 17.2% yield) as a white solid. LC-MS: m / z = 566.3 (M+H) + .

[0975] Example 214: Synthesis of Compound 214 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-N-((1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl)-5-methoxypyrimidin-4-amine)

[0976] Compound 209-7 (1.0 g, 2.32 mmol, 1 eq) and isopropyl iodide (1.18 g, 6.97 mmol, 3.0 eq) were used as starting materials and the same procedure as for compound 209 was followed to prepare compound 214 (10.4 mg, 0.018 mmol, 20.4% yield) as a white solid. LC-MS: m / z = 568.4 (M+H) + .

[0977] Example 215: Synthesis of Compound 215 (4'-cyclopropyl-5,6'-dimethoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-[2,5'-bipyrimidine]-4-amine)

[0978] White solid compound 215 (7.77 mg, 14.0 μM, 11.9% yield) was prepared using compound 207-5 (500 mg, 1.61 mmol, 1.0 eq) and 7 M ammonia methanol (40.0 mL, 173 eq) as starting materials according to the same procedure as compound 207. 1 H NMR (400MHz, CDCl3) δ8.61 (s, 1H), 7.87 (s, 1H), 7.19 (s, 1H), 5.46 (t, J = 6.4Hz, 1H), 4.31-4.28 (m, 3H), 3.97-3.95 (m, 6H), 3.9 3(s,3H),3.85(d,J=6.0Hz,2H),3.58(s,3H),1.81-1.75(m,1H),1.21-1.17(m,2H),0.92-0.87(m,2H); LC-MS: m / z=538.3(M+H) + .

[0979] Example 216: Synthesis of Compound 216 (4'-cyclopropyl-N-((4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[0980] Compound 207-4 (200 mg, 0.68 mmol, 1.0 eq) and cyclopropyl bromide (246.8 mg, 2.04 mmol, 3.0 eq) were used as starting materials and the same procedure as for compound 207 was followed to prepare compound 216 (2.5 mg, 4.45 μmol, 10.5% yield) as a white solid. LC-MS: m / z = 564.2 (M+H) + .

[0981] Example 217: Synthesis of Compound 217 (4'-cyclopropyl-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[0982] Compound 207-4 (600 mg, 2.03 mmol, 1.0 eq) and isopropyl iodide (1.04 g, 6.09 mmol, 3.0 eq) were used as starting materials to prepare compound 217 (10.5 mg, 0.019 mmol, 13.8% yield) as a white solid following the same procedure as compound 207. LC-MS: m / z = 566.3 (M+H) + .

[0983] Synthesis of the universal intermediate SA2 ((4-cyclopropyl-6-(methoxy-D3)pyrimidin-5-yl)boronic acid)

[0984] Intermediate SA2 (5.8 g, 34.4 mmol, 78.5% yield) was prepared using compound A2-5 as starting material according to the same procedure as intermediate A2-7. 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.33(s,2H),1.84-1.75(m,1H),1.20-1.13(m,2H),0.91-0.87(m,2H); LC-MS: m / z=198.0(M+H) + .

[0985] Synthesis of universal intermediate SA4 ((4-methoxy-6-(trifluoromethyl)pyrimidin-5-yl)boronic acid)

[0986] Intermediate SA4 (2.4 g, 10.8 mmol, 57.1% yield) was prepared from 5-bromo-4-chloro-6-trifluoromethylpyrimidine (compound SA4-1) according to the same procedure as intermediate A2-7. 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 4.01 (s, 3H); LC-MS: m / z=223.0 (M+H) + .

[0987] Synthesis of General Intermediate SA5 ((4-(2-fluorocyclopropyl)-6-methoxypyrimidin-5-yl)boronic acid)

[0988] Step 1: Synthesis of compound SA5-2 (5-bromo-6-(2-fluorocyclopropyl)pyrimidin-4-ol)

[0989] 5-Bromo-4-chloropyrimidine (compound SA5-1, 4.0 g, 20.68 mol) was added to acetonitrile (60.0 mL) and water (45.0 mL), and 2-fluorocyclopropanecarboxylic acid (6.46 g, 62.04 mmol) and silver nitrate (7.03 g, 41.36 mmol) were added. Ammonium persulfate (9.44 g, 41.36 mmol) dissolved in water (15.0 mL) was added dropwise under nitrogen protection at 80°C with stirring. After completion, the reaction was stirred at 80°C for 16 hours, cooled to room temperature, and extracted three times with water (150.0 mL) and ethyl acetate (100.0 mL). The organic layers were combined, washed twice with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo 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 SA5-2 (1.4 g, 6.0 mol, 29.1% yield) as a light yellow oil. LC-MS: m / z = 233.0 (M+H) + .

[0990] Steps 2-4: Synthesis of intermediate SA5

[0991] Intermediate SA5 (354.7 mg, 1.67 mmol, 39.9% yield) was prepared using compound SA5-2 as the starting material according to the same procedure as intermediate A2-7. 1 H NMR (400MHz, CDCl3) δ8.79(s,1H),6.10–5.91(m,1H),4.02(s,3H),3.19–3.23(m,1H),1.23–1.49(m,2H); LC-MS: m / z=213.1(M+H) + .

[0992] Synthesis of the universal intermediate SA6 ((4-cyclopropyloxy-6-methylpyrimidin-5-yl)boronic acid)

[0993] Step 1: Synthesis of compound SA6-2 (5-bromo-4-cyclopropyloxy-6-methylpyrimidine)

[0994] 5-Bromo-4-chloro-6-methylpyrimidine (compound SA6-1,...

Claims

1. A compound represented by the general formula (SI), or a pharmaceutically acceptable salt, hydrate, solvate, isotope-substituted product or stereoisomer thereof, in, Ring A and Ring B are each independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, and Ring A and Ring B are each independently optionally substituted by one or more R1; Ring E is selected from C 6-10 Aryl, 5-6 membered heteroaryl, C 6-10 Aryl and C fused to 5-6 membered heteroaryl 6-10 Aryl, and Ring E is optionally substituted with one or more R1; L is selected from 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 Each independently selected from H atoms, -CN, 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, C 1-6 Haloalkoxy; or R a and R b Together they form an oxo group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-6 The alkyl group is optionally substituted with one or more R1; R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, -C 1-6 Alkylene-C 6-10 Aryl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl or -C 1-6 Alkylene-C 6-10 Aryl is optionally substituted with one or more R1; R3 is selected from the group consisting of H atoms, -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, phosphite, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, wherein the -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted by one or more R1; R4 is selected from H atoms, -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 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group; R1 is independently selected at each occurrence from a D atom, -OH, -COOH, -NH2, -CN, oxo, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclic group, -OC 1-6 Alkylene-OC 1-6 Alkyl, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups are each independently optionally selected from D atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of the hydroxyalkyl group; and n is an integer between 0 and 8.

2. The compound according to claim 1, wherein Ring B is C 6-10 aryl or 5-6 membered heteroaryl, and Ring B is optionally substituted by one or more R1, R1 is as defined in claim 1; In particular, Ring B is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, piperazinyl, naphthyl, pyrrolyl, pyridazinyl, triazolyl, tetrazolyl and furanyl, and Ring B is optionally substituted with one or more R1, R1 is as defined in claim 1; More specifically, Ring B is imidazolyl, and Ring B is optionally substituted by one or more R1, R1 being as defined in claim 1.

3. The compound according to claim 1 or 2, which is a compound represented by general formula (SII), in, R 1a is independently selected at each occurrence from D atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl; R 1b is independently selected at each occurrence from a D atom, -OH, -COOH, -NH2, -CN, an oxo group, a halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl; R 1c Selected from H atoms, D atoms, -OH, -COOH, -NH2, -CN, oxo groups, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl; R 1d Selected from H atoms, D atoms, -OH, -COOH, -NH2, -CN, oxo groups, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl-O- and 5-7 membered heterocyclyl; m is 0, 1 or 2; p is 0, 1, or 2; Ring A, Ring E, R a , R b , R2 to R4 and n are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, wherein Ring A is selected from C 6-10 Aryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, and Ring A is optionally substituted by one or more R1, R1 is as defined in claim 1; In particular, Ring A is selected from phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, cubanyl, piperidinyl, pyranyl, pyrrolidinyl, piperazinyl and morpholinyl, and ring A is optionally substituted by one or two R 1b Replacement, R 1b As defined in claim 3; More specifically, Ring A is selected from phenyl, cyclohexyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl and cubanyl, and ring A is optionally substituted by one or two R 1b Replacement, R 1b As defined in claim 3.

5. The compound according to any one of claims 1 to 4, wherein Selected from 6. The compound according to any one of claims 1 to 5, wherein Ring E is C 6-10 aryl or 5-6 membered heteroaryl, and ring E is optionally substituted by one or more R1, R1 is as defined in claim 1; In particular, Ring E is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl and isoxazolyl, and ring E is optionally substituted by one R 1c and an R 1d Replacement, R 1c and R 1d As defined in claim 3; More specifically, Ring E is selected from pyridyl, pyrimidinyl and imidazolyl, and ring E is optionally substituted by one R 1c and an R 1d Replacement, R 1c and R 1d As defined in claim 3; Even more specifically, Selected from 7. The compound according to any one of claims 1 to 6, wherein n is 0 or 1; and / or R a and R b Each independently selected from H atoms, -CN, C 1-6 Alkyl, -OH and halogen; Preferably, R a and R b Each independently is a H atom or a C 1-6 alkyl; More preferably, R a and R b are all H atoms, or R a is an H atom and R b It is methyl.

8. The compound according to any one of claims 1 to 7, wherein R2 is selected from H atoms, -OH, -CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl and 5-7 membered heterocyclic group, Preferably, R2 is selected from H atom, -CN, methyl and trideuterated methyl; and / or R3 is selected from the group consisting of H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl-O-, 5-7 membered heterocyclic group and -C 1-6 Alkylene-C(O)-OC 1-6 alkyl; Preferably, R3 is methoxy or cyclopropyl-O-; and / or R4 is selected from H atoms, -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 a H atom.

9. A compound according to any one of claims 1 to 8, selected from 10. A method for preparing the compound according to claim 1, the method comprising: The compound represented by the general formula (SIA) reacts with the compound represented by the general formula (SIB) to obtain the compound represented by the general formula (SI); X is a leaving group selected from halogen, sulfonate, boronic acid and borate; and Ring A, Ring B, Ring E, L, R a , R b , R2 to R4 and n are as defined in claim 1; or The compound represented by the general formula (SIA) reacts with the compound represented by the general formula (SIC) to obtain the compound represented by the general formula (SI); X is a leaving group selected from halogen, sulfonate, boronic acid and borate; and Ring A, Ring B, Ring E, L, R a , R b , R2 to R4 and n are as defined in claim 1.

11. The method according to claim 10, wherein the compound represented by general formula (SI) is a compound represented by general formula (SII), and the method comprises: The compound represented by the general formula (SIIA) reacts with the compound represented by the general formula (SIIB) to obtain the compound represented by the general formula (SII); X is a leaving group selected from halogen, sulfonate, boronic acid and borate; and Ring A, Ring B, Ring E, R a , R b , R2 to R4, R 1a , R 1b , R 1c , R 1d , m, n and p are as defined in claim 3; The compound represented by the general formula (SIIA) reacts with the compound represented by the general formula (SIIC) to obtain the compound represented by the general formula (SII); X is a leaving group selected from halogen, sulfonate, boronic acid and borate; and Ring A, Ring B, Ring E, R a , R b , R2 to R4, R 1a , R 1b , R 1c , R 1d , m, n and p are as defined in claim 3.

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

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

14. Use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating or preventing cancer, In particular, 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.

Images