Pyrimidine compounds, preparation methods thereof and pharmaceutical uses thereof

Abstract

The present invention discloses pyrimidine compounds, a preparation method thereof and a pharmaceutical use thereof. Specifically, the present invention discloses a compound represented by the general formula (I'), a preparation method thereof, a pharmaceutical composition containing the same, and a use thereof as a ubiquitin-specific protease 1 (USP1) inhibitor, in particular a use thereof for treating or preventing cancer. The definitions of the groups in the general formula (I') are the same as those in the specification.

Description

Technical Field

[0001] The present invention relates to a class of compounds having USP1 inhibitory activity and their compositions, and their use in the preparation of drugs for treating diseases related to USP1 enzyme. Specifically, it relates to the compounds of formula (I) and their pharmaceutically acceptable salts. Background Art

[0002] Ubiquitination is a dynamic and reversible process involving the deubiquitinating enzyme (DUB) family. There are approximately 100 DUBs in the human body, which can be divided into the cysteine protease family and the metalloprotease family. Among them, the cysteine protease family mainly includes ubiquitin-specific proteases (USPs), ubiquitin carboxyl-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs), MINDY proteases (MINDYs), and ovarian cancer domain proteases (OTUs). The USPs family is the largest family among the known deubiquitinating enzymes, with more than 50 encoded by human genes. It plays a role in various physiological functions such as the cell cycle, signal transduction, DNA damage repair, chromosomal translocation, and gene transcription by regulating substrate proteases.

[0003] USP1 belongs to the USP subfamily of DUBs. It has no significant activity on its own, but acquires full enzymatic activity after 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 monoubiquitinated proliferating cell nuclear antigen (PCNA), a key protein in the translesion synthesis (TLS) process, to prevent its overrepair, and deubiquitinates monoubiquitinated Fanconi anemia complementation group D2 (FAND2), a key protein in the Fanconi anemia (FA) pathway, to block improper TLS repair by cells, thereby ensuring genomic stability, etc. These two DNA damage response (DDR) pathways are key pathways for repairing DNA damage induced by DNA crosslinking agents such as cisplatin, mitomycin, and ultraviolet radiation. USP1 can also interact with ID proteins, etc., and stabilize the expression of ID proteins, etc. in cells through deubiquitination. For example, in osteosarcoma cells, USP1 can deubiquitinate ID1, ID2, and ID3, promoting cell proliferation, and inhibiting USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. In addition, studies have confirmed that USP1 is closely related to the generation of resistance to various tumor therapeutic drugs. For example, in non-small cell lung cancer (NSCLC) cells with cisplatin resistance, the expression level of USP1 is high, and knocking down USP1 can significantly enhance the sensitivity of cells to cisplatin; in breast cancer cells, USP1 is highly expressed, promoting the proliferation of breast cancer cells and being closely related to poor prognosis of breast cancer. The literature (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) reports that compounds such as the USP1 inhibitor ML323 can be used for non-small cell lung cancer; the literature (Cui S-Z, Lei Z-Y, Guan T-P, et al. Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020; 00:1–15.) reports that USP1 inhibitors are potential therapeutic drugs for prostate cancer. In summary, USP1 is expected to become a popular target for treating various cancers and other diseases. Summary of the Invention

[0004] The present invention provides a compound represented by the general formula (I’),

[0005]

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

[0007] wherein,

[0008] R is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, aryl fused with a 5- to 10-membered heteroaryl, C 6-10 aryl and each of the above groups is independently optionally substituted by one or more R1;

[0009] Ring A and Ring B are each independently selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group, and Ring A and Ring B are each independently optionally substituted by one or more R1;

[0010] L is selected from a chemical bond, -O-, -S-, -C 1-6 alkylene-, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -S-C 1-6 alkylene- and -C 1-6 alkylene-S-;

[0011] R a and R b are each independently selected from an H atom, -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 form an oxo group, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group;

[0012] R2 is selected from an H atom, -OH, -CN, C 1-6 alkyl, -C 1-6Alkyl-C 6-10 Aryl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1-6 Alkyl or -C 1-6 Alkyl-C 6-10 The aryl is optionally substituted by one or more R1;

[0013] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, -S-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, phosphoryl, phosphonous, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and -C 1-6 Alkylene-C(O)-O-C 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 Haloalkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The cycloalkyl and 3-8 membered heterocyclic group are each independently optionally substituted by one or more R1;

[0014] R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclic group;

[0015] Alternatively, R2 and R3 together with the atoms to which they are attached form a ring C, which is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclic group, and the heteroatom in the 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group is O or N. Further, the 5- to 7-membered heterocyclic group is selected from morpholinyl, 3-morpholinone, pyrrolidinyl, 2-oxazolidinone, and 2-pyrrolidinone, and the ring C is optionally substituted by one or more R1;

[0016] Alternatively, R3 and R4 together with the atoms to which they are attached form a ring D, which is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclic group, and the ring D is optionally substituted by 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 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C-fused 6-10 with a 5- to 10-membered heteroaryl, C-fused 6-10 with a 3- to 8-membered heterocyclic group, aryl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclic group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclic group are each independently optionally substituted by one or more R1;

[0018] R1, in each occurrence, is independently selected from a D atom, -OH, -COOH, -NH2, -CN, oxo group, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, -O-C 1-6Alkylene-O-C 1-6 alkyl, wherein said C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group are each independently optionally substituted with one or more substituents selected from D atom, -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 hydroxyalkyl; and

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

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

[0021]

[0022] wherein, ring A, ring B, L, R a , R b , R2 to R5 and n are as defined in the general formula (I').

[0023] In some embodiments, in the compound represented by the general formula (I') or (I),

[0024] R2 is selected from H atom, -OH, -CN, C 1-6 alkyl, C 2-6 alkynyl, -C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 5- to 7-membered heterocyclic group, wherein said C 1-6 alkyl or -C 1-6 alkyl-C 6-10 aryl is optionally substituted with one or more R1, and R1 is as defined in the general formula (I');

[0025] Preferably, R2 is selected from H atom, -CN, methyl, trideuteriomethyl, ethynyl, propynyl, tetrahydrofuranyl, cyclopropyl, methoxy and hydroxy;

[0026] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C1-6 haloalkoxy, C 1-6 hydroxyalkyl, 5- to 7-membered heterocyclic group, and -C 1-6 alkylene-C(O)-O-C 1-6 alkyl, wherein said C 1-6 hydroxyalkyl and 5- to 7-membered heterocyclic group are each independently optionally substituted with one or more C 1-6 alkyl;

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

[0028] R4 is selected from an H atom, -OH, -COOH, -NH2, -CN, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl;

[0029] Preferably, R4 is an H atom.

[0030] In some embodiments, the compound represented by the general formula (I') or (I) is the compound represented by the general formula (II),

[0031]

[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 a C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group; and

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

[0035] In particular,

[0036] R4 is selected from an H atom, -OH, -COOH, -NH2, -CN, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; preferably R4 is an H atom.

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

[0038]

[0039] wherein ring D is selected from each of the above groups is independently optionally substituted by one or more R1; and

[0040] R, R a 、R b 、R1, R2, R5 and n are as defined in general formula (I');

[0041] In particular, R2 is selected from an H atom, -OH, C 1-6 alkyl, C 2-6 alkynyl, -C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl, wherein the C 1-6 alkyl or C 1-6 alkyl-C 6-10 aryl is optionally substituted by one or more R1, and R1 is as defined in general formula (I');

[0042] Preferably, R2 is an H atom or

[0043] In some embodiments, in the compounds represented by general formula (I'), (I), (II) or (III),

[0044] ring A and ring B are each independently selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, bicyclo[2.2.2]octyl, 2-oxabicyclo[2.2.2]octyl, pentacyclooctyl, isoindolinone, imidazo[1,2-a]pyrazinyl, piperidine-2,6-dione, thiophenyl, furyl, cyclopentyl, pyranyl, pyrrolidinyl, piperazinyl, morpholinyl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indolinone, pyrido[3,2-d]pyrimidinyl, pteridinyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-d]pyrimidinyl and cubyl, and ring A and ring B are each independently optionally substituted by one or more R1, and R1 is as defined in general formula (I');

[0045] L is selected from a chemical bond, -O-, -O-C 1-6 alkylene- and -C 1-6Alkylene-O-;

[0046] In particular, selected from

[0047]

[0048] and each of ring A and ring B is independently optionally substituted by one or more R1, where R1 is as defined in general formula (I');

[0049] More particularly, selected from,

[0050]

[0051] In some embodiments, in the compounds of general formula (I'),

[0052] R is C 6-10 aryl or C 6-10 aryl fused to a 5- or 6-membered heteroaryl, each of the above groups being independently optionally substituted by one or more substituents selected from oxo group, C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkyl;

[0053] In particular, R is

[0054] R2 is selected from H atom, -OH, C 1-6 alkyl, C 2-6 alkynyl, -C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably, R2 is H atom;

[0055] R3 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably, R3 is methoxy;

[0056] R4 is selected from H atom, -OH, -COOH, -NH2, -CN, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R4 is an H atom;

[0057] Alternatively, R3 and R4 together with the atoms to which they are attached form a ring D, and the ring D is a 5- to 7-membered heteroaryl or a 5- to 7-membered heterocyclic group, preferably a furyl group.

[0058] In some embodiments, in the compounds represented by the general formula (I'), (I), (II) or (III),

[0059] R5 is selected from C 6-10 Aryl, 5- to 6-membered heteroaryl, C fused with a 5- to 6-membered heterocyclic group 6-10 Aryl and C fused with a 5- to 6-membered heteroaryl 6-10 Aryl, preferably selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, indolinyl and isoxazolyl, and the C 6-10 Aryl, 5- to 6-membered heteroaryl, C fused with a 5- to 6-membered heterocyclic group 6-10 Aryl and C fused with a 5- to 6-membered heteroaryl 6-10 Aryl is each independently optionally substituted with one or more substituents selected from -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and C 3-6 Cycloalkyl;

[0060] In particular, R5 is selected from

[0061] In some embodiments, in the compounds represented by the general formula (I'), (I), (II) or (III), n is 0 or 1.

[0062] In some embodiments, in the compounds represented by the general formula (I'), (I), (II) or (III), R a and R b are each independently selected from an H atom, -CN, C 1-6 Alkyl, -OH and halogen;

[0063] Preferably, R a and R b are each independently an H atom or -CN.

[0064] Typical compounds of general formula (I) or general formula (I') of the present invention include, but are not limited to, the following compounds:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] The present invention also provides a method for preparing the compound represented by general formula (I'), the method comprising:

[0075]

[0076] Reacting the compound represented by general formula (IA) with the compound represented by general formula (IB') to obtain the compound represented by general formula (I');

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

[0078] R, R a , R b , R2 to R5 and n are as defined in general formula (I');

[0079] Or

[0080]

[0081] Reacting the compound represented by general formula (IC') with the compound represented by general formula (ID) to obtain the compound represented by general formula (I');

[0082] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and

[0083] R, R a , R b , R2 to R5 and n are as defined in general formula (I');

[0084] Or

[0085]

[0086] 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’);

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

[0088] Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0089] R2 is a hydroxyl group;

[0090] R, R a 、R b 、R3 to R5 and n are as defined in the general formula (I’);

[0091] Or

[0092]

[0093] 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’);

[0094] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate;

[0095] Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0096] R2 is a hydroxyl group;

[0097] R, R a 、R b 、R3 to R5 and n are as defined in the general formula (I’);

[0098] Or

[0099]

[0100] 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’);

[0101] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and

[0102] R, R a , R b , R2 to R5 and n are as defined in the general formula (I').

[0103] The present invention also provides a method for preparing the compound shown in the general formula (I), and the method includes:

[0104]

[0105] The compound shown in the general formula (IA) reacts with the compound shown in the general formula (IB) to obtain the compound shown in the general formula (I);

[0106] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric 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] Or

[0109]

[0110] The compound shown in the general formula (IC) reacts with the compound shown in the general formula (ID) to obtain the compound shown in the general formula (I);

[0111] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and

[0112] Ring A, ring B, L, R a , R b , R2 to R5 and n are as defined in the general formula (I');

[0113] Or

[0114]

[0115] The compound shown in the general formula (IE) reacts with the compound shown in the general formula (IB) to obtain the compound shown in the general formula (IF), and the compound shown in the general formula (IF) is deprotected to obtain the compound shown in the general formula (I);

[0116] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate;

[0117] Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0118] R2 is a hydroxyl group;

[0119] Ring A, Ring B, L, R a , R b , R3 to R5 and n are as defined in general formula (I');

[0120]

[0121] The compound represented by general formula (IG) reacts with the compound represented by general formula (ID) to obtain the compound represented by general formula (IH), and the compound represented by general formula (IH) is deprotected to obtain the compound represented by general formula (I);

[0122] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate;

[0123] Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl;

[0124] R2 is a hydroxyl group;

[0125] Ring A, Ring B, L, R a , R b , R3 to R5 and n are as defined in general formula (I');

[0126] Or

[0127]

[0128] 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);

[0129] X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and

[0130] Ring A, Ring B, L, R a , R b , R2 to R5 and n are as defined in general formula (I').

[0131] The present invention also provides a pharmaceutical composition, which contains at least one compound represented by general formula (I'), (I), (II) or (III) and one or more pharmaceutically acceptable excipients.

[0132] The present invention relates to the use of a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same in the preparation of a drug for treating or preventing diseases or disorders related to the inhibition of ubiquitin-specific protease 1 (USP1).

[0133] The present invention relates to the use of a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same in the preparation of a medicament for treating or preventing cancer. In particular, 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.

[0134] The present invention relates to a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same, which is used as a medicament.

[0135] The present invention relates to a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same, which is used for treating or preventing a disease or disorder associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0136] The present invention relates to a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same, which is used for treating or preventing cancer. In particular, 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.

[0137] The present invention relates to a method for treating or preventing a disease or disorder associated with the inhibition of ubiquitin-specific protease 1 (USP1), which comprises administering to a patient in need a therapeutically effective amount of a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same.

[0138] The present invention relates to a method for treating or preventing cancer, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by general formula (I'), (I), (II) or (III) or a pharmaceutical composition containing the same. In particular, 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.

[0139] The pharmaceutical composition of the present invention can be various conventional dosage forms, such as tablets, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile injectable aqueous solutions, sterile water-in-oil microemulsions, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0140] 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 dosage of the compound or the type of pharmaceutically acceptable salt, can be verified according to traditional treatment regimens.

[0141] Term Definitions

[0142] 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 indefinite or unclear in the absence of a specific definition, but should be understood in its ordinary meaning.

[0143] 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 humans and animals, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0144] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; also included are salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0145] 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 constitution (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). In the case of stereoisomers, the compounds of general formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers.

[0146] The term "optionally" or "optionally" means that the subsequently described event or condition may but need not occur, and the description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0147] The term "solvate" refers to a variable stoichiometric complex 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 generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0148] As used herein, the terms "disease" or "disorder" or "condition" refer to a disorder that requires and / or is amenable to treatment and denotes a disorder or abnormality of a physiological function that is generally regarded as pathological and / or a dysfunction, and which may manifest in the form of specific signs, symptoms, and / or dysfunctions. The compounds of the present invention inhibit the USP1 protein and can be used to treat diseases and disorders such as proliferative diseases, where inhibition of the USP1 protein would provide a benefit.

[0149] "USP1" and "ubiquitin-specific processing protease 1" refer to any native polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses "full-length" unprocessed USP1 polypeptides as well as any form of USP1 obtained by intracellular processing (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.

[0150] The terms "cancer" and "tumor" refer to or describe a physiological disorder in a mammalian body characterized by unregulated cell growth of a cell population. The terms encompass solid cancers and blood / lymph cancers. Examples of cancers include, but are not limited to, cancers defective in DNA damage repair pathways. Other examples of cancers 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). A cancer can be wild-type for BRCA1 or BRCA2. A cancer can also be mutant for BRCA1 or BRCA2. A cancer can also be a PARP inhibitor-resistant or refractory cancer, or a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0151] When any variable (e.g., R) appears more than once in the structure of a compound, its definition is independent in each case. For example, if a group is substituted with 0 - 2 R's, the group can optionally be substituted with up to 2 R's, and each R in each case has independent options.

[0152] The term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group having 1 - 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 1-6 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-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.

[0153] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having 2 - 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 can be located at any position within the alkenyl, preferably C 2-5Alkenyl. Examples of alkenyl include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3, and -CH2-C(CH3)=CH2.

[0154] The term "alkynyl" refers to a straight-chain 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 can be located at any position within the alkynyl group, preferably C 2-5 Alkynyl. Examples of alkynyl 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.

[0155] The term "cycloalkyl" includes two categories, one is a conventional cycloalkyl and the other is a heterostructure cycloalkyl.

[0156] Conventional cycloalkyl refers to an aliphatic saturated or partially unsaturated monovalent cycloalkyl 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, further preferably C 3-8 Conventional cycloalkyl, most preferably C 3-6 Conventional cycloalkyl. The conventional cycloalkyl optionally contains one or more double bonds or triple bonds.

[0157] Conventional cycloalkyl can be a monocycloalkyl group. Examples of monocycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Conventional cycloalkyl can also be a polycycloalkyl group (e.g., bicycloalkyl, tricycloalkyl, tetracycloalkyl, and pentacycloalkyl), and polycycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0158] The term "spirocycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spirocycloalkyl group, preferably a 6- to 14-membered spirocycloalkyl group, more preferably a 7- to 10-membered spirocycloalkyl group. The spirocycloalkyl group can be a monospirocycloalkyl group, a dispirocycloalkyl group, or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group, more preferably a 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl group. Examples of spirocycloalkyl include, but are not limited to:

[0159]

[0160] The term "fused cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) fused cycloalkyl, preferably a 6- to 14-membered fused cycloalkyl, and more preferably a 7- to 10-membered fused cycloalkyl. The fused cycloalkyl can be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of the fused cycloalkyl include, but are not limited to:

[0161]

[0162] The term "bridged cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) bridged cycloalkyl, preferably a 6- to 14-membered bridged cycloalkyl, and more preferably a 7- to 10-membered bridged cycloalkyl. The bridged cycloalkyl can be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, and more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of the bridged cycloalkyl include, but are not limited to:

[0163]

[0164] The term "hetero-structured cycloalkyl" includes a monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl fused to any one selected from a conventional aryl, conventional heteroaryl, and conventional heterocyclic group, and the connection site is located on the corresponding conventional cycloalkyl (referring to a monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, or bridged cycloalkyl). Examples of the hetero-structured cycloalkyl include, but are not limited to:

[0165]

[0166] The term "heterocyclic group" includes two categories, one is a conventional heterocyclic group, and the other is a hetero-structured heterocyclic group.

[0167] The conventional heterocyclic group refers to an aliphatic saturated or partially unsaturated monovalent cycloalkyl group having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, and one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O), and S(O)2, and after substitution, -O-O-, -O-S-, or -S-S- is not formed; preferably a C 3-12 conventional heterocyclic group in which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably a C 3-8 conventional heterocyclic group in which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; most preferably a C5-7 A conventional heterocyclic group, where 1-2 or 1-3 of them are heteroatoms.

[0168] The conventional heterocyclic group can be a monocyclic heterocyclic group. Examples of the monocyclic heterocyclic group include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Preferably, it is 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. The conventional heterocyclic group can also be a polycyclic heterocyclic group, which includes spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0169] The term "spiro heterocyclic group" refers to a 5-20 membered (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spiro heterocyclic group, preferably a 6-14 membered spiro heterocyclic group, and more preferably a 7-10 membered spiro heterocyclic group. The spiro heterocyclic group can be a monospiro heterocyclic group, a bispiro heterocyclic group, or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group or a bispiro heterocyclic group, and 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 monospiro heterocyclic group. Examples of the spiro heterocyclic group include, but are not limited to:

[0170]

[0171] The term "fused heterocyclic group" refers to a 5-20 membered (such as 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, and more preferably a 7-10 membered fused heterocyclic group. The fused heterocyclic group can be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of the fused heterocyclic group include, but are not limited to:

[0172]

[0173] The term "bridged heterocyclic group" refers to a 5-14 membered (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) bridged heterocyclic group, preferably a 6-14 membered bridged heterocyclic group, and more preferably a 7-10 membered bridged heterocyclic group. The bridged heterocyclic group can be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Examples of the bridged heterocyclic group include, but are not limited to:

[0174]

[0175] The term "hetero-structured heterocyclic group" includes monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups fused to any one selected from conventional aryl groups, conventional heteroaryl groups, and conventional cycloalkyl groups, and the connecting site is located on the corresponding conventional heterocyclic group (referring to the monocyclic heterocyclic group, spiro heterocyclic group, fused heterocyclic group, or bridged heterocyclic group). Examples of hetero-structured heterocyclic groups include, but are not limited to:

[0176]

[0177] The term "aryl group" includes two categories, one is a conventional aryl group, and the other is a hetero-structured aryl group.

[0178] Conventional aryl groups refer to aromatic hydrocarbon groups with 6-14 members (such as 6, 7, 8, 9, 10, 11, 12, 13, and 14 members), preferably C 6-10 conventional aryl groups, more preferably phenyl, naphthyl, phenanthryl, or anthryl.

[0179] The term "hetero-structured aryl group" includes conventional aryl groups fused to any one selected from conventional heteroaryl groups, conventional heterocyclic groups, and conventional cycloalkyl groups, and the connecting site is located on the conventional aryl group. Examples of hetero-structured aryl groups include, but are not limited to:

[0180]

[0181] The term "heteroaryl group" includes two categories, one is a conventional heteroaryl group, and the other is a hetero-structured heteroaryl group.

[0182] Conventional heteroaryl groups refer to those in which 1-4 (such as 1, 2, 3, and 4) carbon atoms in a 5-14 member (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 member) aromatic hydrocarbon group are replaced by heteroatoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, among which there are 1-3 (such as 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, among which there are 1-2 heteroatoms. Examples of conventional heteroaryl groups 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.

[0183] The term "hetero-structured heteroaryl group" includes conventional heteroaryl groups fused to any one selected from conventional aryl groups, conventional cycloalkyl groups, and conventional heterocyclic groups, and the connecting site is located on the conventional heteroaryl group. Examples of hetero-structured heteroaryl groups include, but are not limited to:

[0184]

[0185] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, where "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.

[0186] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, where alkyl is as defined above.

[0187] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogen atoms, where alkoxy is as defined above.

[0188] The term "hydroxy" refers to -OH.

[0189] The term "halogen" refers to -F, -Cl, -Br, or -I.

[0190] The term "amino" refers to -NH2.

[0191] The term "cyano" refers to -CN.

[0192] The term "nitro" refers to -NO2.

[0193] The term "oxo" refers to =O.

[0194] The term "carboxy" refers to -C(=O)OH.

[0195] The term "mercapto" refers to -SH.

[0196] The term "ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where alkyl and cycloalkyl are as defined above.

[0197] The term "acyl" refers to -C(=O)R, where R is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0198] The term "hydroxy protecting group" refers to a group that is easily removable and introduced onto a hydroxy group to block or protect the hydroxy group during reactions on other functional groups of a 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.

[0199] The symbol refers to the attachment site.

[0200] The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis- and trans- (or Z- and E-) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the compounds of the present invention may have additional asymmetric atoms. All such stereoisomers and their mixtures 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 certain compound of the present invention can be prepared by asymmetric synthesis or chiral auxiliaries, 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 diastereomeric salts with an appropriate optically active acid or base, and then separating the diastereomers by conventional methods known in the art to obtain the pure isomer. In addition, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

[0201] In the chemical structure of the compounds described in the present invention, the bond represents an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond can be or or contain both and two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-form and the E-form are included.

[0202] 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 called prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization.

[0203] The compounds of the present invention include all suitable isotopic substitutes of the compounds. The term "isotopic substitute" refers to a compound in which at least one atom is replaced 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, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C,13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I etc., preferably deuterium.

[0204] As used herein, the singular forms "a", "an", and "the" include plural references, and vice versa, unless the context clearly indicates otherwise.

[0205] When the term "about" is applied to parameters 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 the parameter is not critical, numbers are usually given for illustrative purposes only and not for limitation. Detailed Description of the Invention

[0206] The present invention will be described in detail below by way of examples, but this does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0207] The compounds of the present invention are prepared using convenient starting materials and general preparation steps. The present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. The optimized conditions may vary depending on the specific reactants or solvents used, but in general, the reaction optimization steps and conditions can be determined.

[0208] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are well known to those skilled in the art.

[0209] The separation and purification of the compounds and intermediates are carried out by appropriate methods and steps according to specific requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. The specific usage methods can be referred to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. They can be characterized by conventional methods (including physical constants and spectroscopic data).

[0210] The purity analysis method is as follows: Use a Kinetex EVO C18 (50×4.6mm, 5μm, ) chromatographic column, and use acetonitrile-water as the mobile phase for gradient elution. The flow rate is 1.5 mL / min, and the detection wavelength is 220 nm.

[0211] The determination of MS is carried out using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0212] The structure of the compound is determined by 1H NMR, and the equipment model is WNMR-I-400MHz.

[0213] Preparative liquid chromatography uses an Agilent 1260 Infinity II high-performance liquid chromatograph (manufacturer: Agilent). The chromatographic column is Daisogel C18 10μm 100A (30mm×250mm), and the mobile phase is acetonitrile / water.

[0214] Thin-layer chromatography (TLC) uses a GF254 silica gel plate from Qingdao Marine Chemical Industry. The silica gel plate used for reaction monitoring by thin-layer chromatography has a specification of 0.20 mm - 0.25 mm, and the silica gel plate used for separation and purification by thin-layer chromatography has a specification of 0.5 mm.

[0215] Silica gel column chromatography uses silica gel with 100 - 200 mesh, 200 - 300 mesh, and 300 - 400 mesh from Qingdao Marine Silica Gel as the carrier.

[0216] The known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from companies such as ChemNet Mall, Beijing Coupling, Sigma, J&K Scientific, Yishiming, Shanghai Shuya, Shanghai Aladdin, Energy Chemical, and Shanghai Bide.

[0217] Unless otherwise specified in the examples, the reactions are all carried out under a nitrogen atmosphere.

[0218] The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.

[0219] The reaction solvent, organic solvent or inert solvent is each described as the solvent used not participating in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, N-methylpyrrolidone (NMP).

[0220] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0221] The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere pressure and completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0222] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present invention.

[0223] Unless otherwise specified, the mixing ratio of different solvents is by volume.

[0224] The synthesis of general intermediates is introduced separately below, including Series A, Series AA, Series B, Series BB, Series C, Series D, and Series BBC and Series BBD further synthesized from Series BB and Series C or Series D.

[0225] Synthesis of general intermediate A1 (2-(2-isopropylphenyl)-5-methoxypyrimidin-4-amine)

[0226]

[0227] 2-Chloro-5-methoxypyrimidin-4-amine (Compound A1-1, 5.0 g, 31.3 mmol, 1.00 eq), (2-isopropylphenyl)boronic acid (Compound A1-2, 6.7 g, 40.7 mmol, 1.30 eq, purchased from Bidepharm), potassium carbonate (13.0 g, 94.0 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (2.3 g, 3.13 mmol, 0.10 eq) were successively added to dioxane (50.0 mL) and water (12.5 mL). After purging with nitrogen 3 times, the reaction was carried out under nitrogen protection at 100°C for 16 hours. Then, ethyl acetate (500.0 mL) was added and stirred for 10 minutes. The filtrate was obtained by filtration and concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain a pale yellow solid compound A1 (4.9 g, 63.3% yield, 98.2% purity). 11H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.32 - 7.36 (m, 3H), 7.16 - 7.19 (m, 1H), 6.71 (s, 2H), 3.87 (s, 3H), 3.44 - 3.50 (m, 1H), 1.12 (d, J = 7.20 Hz, 6H); LC-MS: m / z = 244.2 (M + H) + 。

[0228] Synthesis of General Intermediate A2 (4'-Cyclopropyl-5,6'-dimethoxy-N-methyl-[2,5'-bipyrimidine]-4-amine)

[0229]

[0230] Step 1: Synthesis of Compound A2-3 (6-Cyclopropylpyrimidin-4-ol)

[0231] 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 successively added to methanol (1.2 L). Sodium methoxide in methanol solution (5.4 M, 1.3 L, 5.00 eq) was added portionwise at 0 °C. After addition, the temperature was raised to 20 °C and the mixture was stirred for 13 hours. Then, glacial acetic acid was added at 0 °C to adjust the pH to 7 - 8, and 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 - 1 / 1) to obtain Compound A2-3 (90.3 g). LC-MS: m / z = 137.1 (M + H) + 。

[0232] Step 2: Synthesis of Compound A2-4 (4-Chloro-6-cyclopropylpyrimidine)

[0233] Compound A2-3 (40.0 g, 293.0 mmol, 1.00 eq) was added portionwise to phosphorus oxychloride (180.0 mL). After addition, the temperature was raised to 60 °C and the mixture was stirred for 2 hours. The reaction mixture 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), stirred for 5 minutes, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (400.0 mL). The combined organic layers were 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 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) + 。

[0234] Step 3: Synthesis of Compound A2-5 (5-Bromo-4-chloro-6-cyclopropylpyrimidine)

[0235] Dissolve compound A2-4 (11.0 g, 71.1 mmol, 1.00 eq) in methanol (150.0 mL). Slowly add bromine (34.1 g, 213.0 mmol, 3.00 eq) at -60 °C. After addition, warm the mixture to 20 °C and stir for 2 hours. Then, add saturated sodium bicarbonate solution (200.0 mL) and water (100.0 mL) at 0 °C, stir for 5 minutes, extract with dichloromethane (200.0 mL) three times, combine the organic layers, wash with saturated brine (200.0 mL) twice, dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate under vacuum to get the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain compound A2-5 (7.8 g). 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 2.56 - 2.62 (m, 1H), 1.23 - 1.26 (m, 2H), 1.16 - 1.21 (m, 2H); LC-MS: m / z = 232.9 (M + H) + 。

[0236] Step 4: Synthesis of compound A2-6 (5-bromo-4-cyclopropyl-6-methoxypyrimidine)

[0237] Dissolve compound A2-5 (7.8 g, 33.4 mmol, 1.00 eq) in methanol (240.0 mL). Add sodium methoxide (18.0 g, 100.0 mmol, 3.00 eq) at 0 °C. After addition, warm the mixture to 30 °C and stir for 1 hour. Concentrate the reaction solution under vacuum to get the crude product, and purify the crude product 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) + 。

[0238] Step 5: Synthesis of compound A2-7 ((4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid)

[0239] 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-Butyllithium (2.5 M, 25.1 mL, 1.40 eq) was added dropwise at -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 3 hours. Then, 1 N hydrochloric acid solution (50.0 mL) was added dropwise at -70 °C. After the addition, the temperature was raised to 20 °C and stirred for 0.5 hour. Then, saturated aqueous sodium bicarbonate was added to adjust the pH to 7 - 8. The mixture was extracted with ethyl acetate (100.0 mL) three times. The organic layers were combined, washed with saturated brine (100.0 mL) three times, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain compound A2-7 (6.9 g). 1 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.45 (s, 2H), 3.84 (s, 3H), 1.88 - 1.92 (m, 2H), 0.93 - 1.01 (m, 4H).

[0240] Step 6: Synthesis of Intermediate A2

[0241] Compound A2-8 (1.2 g, 6.9 mmol, 1.0 eq), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (505.0 mg, 0.7 mmol, 0.10 eq), and potassium carbonate (2.9 g, 20.7 mmol, 3.00 eq) were successively added to dioxane (100.0 mL) and water (25.0 mL). The mixture was purged with nitrogen 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 was complete, the reaction was carried out at 100 °C under nitrogen protection for 2 hours. Then, the reaction solution was concentrated in vacuo, water (60.0 mL) was added, and the mixture was extracted with ethyl acetate (40.0 mL) twice. The organic layers were combined, washed with saturated brine (40.0 mL) twice, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to obtain white solid compound A2 (100.0 mg, 348 μmol, 5.0% yield, 100% purity). LC-MS: m / z = 288.0 (M + H) + 。

[0242] Synthesis of General Intermediate A3 (4-Chloro-2-(2-isopropylphenyl)-5-nitropyrimidine)

[0243]

[0244] Step 1: Synthesis of Compound A3-3 (2-(2-Isopropylphenyl)-4-methoxy-5-nitropyrimidine)

[0245] Dissolve 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(diphenylphosphino)ferrocene palladium dichloride (1.3 g, 1.7 mmol, 0.10 eq), and potassium carbonate (4.8 g, 34.8 mmol, 2.00 eq) in dioxane (30.0 mL) and water (7.0 mL). Replace the air with nitrogen three times and react under nitrogen protection at 100 °C for 12 hours. Then, concentrate the reaction solution under vacuum to obtain a crude product, and purify the crude product 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) + 。

[0246] Step 2: Synthesis of Compound A3-4 (2-(2-Isopropylphenyl)-5-nitropyrimidin-4-ol)

[0247] Dissolve Compound A3-3 (2.0 g, 7.3 mmol, 1.00 eq) in dioxane (30.0 mL), add hydrobromic acid in acetic acid (6 M, 15.0 mL, 12.30 eq). After addition, raise the temperature to 50 °C and stir for 1 hour. Then, concentrate the reaction solution under vacuum to obtain the crude product of Compound A3-4 (2.0 g), and the crude product is directly used for the next step reaction. LC-MS: m / z = 260.0 (M+H) + 。

[0248] Step 3: Synthesis of Intermediate A3

[0249] Add Compound A3-4 (2.0 g, 6.8 mmol, 1.00 eq) to phosphorus oxychloride (18.0 mL), react at 90 °C for 2 hours, concentrate the reaction solution under vacuum to obtain a crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1 - 30 / 1) to obtain a pale yellow oily compound A3 (1.0 g, 3.59 mmol, 53.1% yield, 99.8% purity). LC-MS: m / z = 278.1 (M+H) + 。

[0250] Synthesis of General Intermediate A4 (2-(2-Isopropylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0251]

[0252] Step 1: Synthesis of Compound A4-2 (2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine)

[0253] Compound A4-1 (18.7 g, 86.2 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Ammonia water (15.1 g, 129 mmol, 30.0% purity, 1.50 eq) was added at 0 °C. After the addition, the temperature was raised to 20 °C and the reaction was stirred for 16 hours. Then, water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL) three times. The organic layers were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain compound A4-2 (1.73 g). 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.95 (s, 2H); LC-MS: m / z = 197.9 (M + H) + 。

[0254] Step 2: Synthesis of intermediate A4

[0255] 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(diphenylphosphino)ferrocene dichloropalladium (422 mg, 577 μmol, 0.10 eq) were successively added to dimethyl sulfoxide (12.0 mL) and water (2.5 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 12 hours under nitrogen protection. Then, the reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC to obtain a pale yellow oily compound A4 (200 mg, 711 μmol, 12.3% yield, 100% purity). 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.41 - 7.44 (m, 3H), 7.22 - 7.26 (m, 1H), 3.41 - 3.45 (m, 1H), 3.30 (s, 2H), 1.16 (dd, J1 = 7.2 Hz, J2 = 13.2 Hz, 6H); LC-MS: m / z = 282.1 (M + H) + 。

[0256] Synthesis of general intermediate A5 (2-(2-isopropylphenyl)-5-methoxy-N-methylpyrimidin-4-amine)

[0257]

[0258] Step 1: Synthesis of compound A5-2 (2-chloro-5-methoxy-N-methylpyrimidin-4-amine)

[0259] Dissolve compound A5-1 (10.0 g, 55.9 mmol, 1.00 eq) in tetrahydrofuran (100.0 mL). Add methylamine (2.0 M aqueous methylamine solution, 54.5 mL, 1.95 eq) at 0 °C. After addition, warm the mixture to 20 °C and stir for 2 hours. Add water (200.0 mL) and stir for 5 minutes. Extract with ethyl acetate (100.0 mL) three times. Combine the organic layers, dry over anhydrous sodium sulfate, filter to obtain a filtrate, and concentrate in vacuo to obtain compound A5-2 (9.0 g). 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 5.48 (s, 1H), 3.86 (s, 3H), 3.05 (d, J = 4.00 Hz, 3H); LC-MS: m / z = 173.9 (M + H) + 。

[0260] Step 2: Synthesis of intermediate A5

[0261] Add 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(diphenylphosphino)ferrocene dichloropalladium (1.3 g, 1.7 mmol, 0.10 eq) successively into dioxane (30.0 mL) and water (7.5 mL). Replace the air with nitrogen three times and react at 100 °C under nitrogen protection for 16 hours. Then, add ethyl acetate (500.0 mL) and stir for 10 minutes. Filter to obtain a filtrate, and concentrate in vacuo to obtain a crude product. The crude product is purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound A5 as a brown oil (4.3 g, 16.3 mmol, 94.4% yield, 96.9% purity). 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.56 (d, J = 7.60 Hz, 1H), 7.33 - 7.41 (m, 2H), 7.23 - 7.25 (m, 1H), 5.29 (s, 1H), 3.92 (s, 3H), 3.53 - 3.60 (m, 1H), 3.07 (d, J = 5.20 Hz, 3H), 1.25 - 1.29 (m, 6H); LC-MS: m / z = 258.0 (M + H) + 。

[0262] Synthesis of general intermediate A6 (2-(2-isopropylphenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0263]

[0264] Step 1: Synthesis of Compound A6-2 (4-Amino-2-chloropyrimidin-5-ol)

[0265] Dissolve Compound A6-1 (15.6 g, 97.8 mmol, 1.00 eq) in dichloromethane (1.5 L), and slowly add boron tribromide (367.0 g, 1.5 mol, 15.0 eq) at 0 °C. After addition, warm the reaction mixture to 20 °C and stir for 96 hours. Then, slowly add methanol (1.0 L) to quench the reaction at 0 °C. The reaction solution is concentrated in vacuo to obtain a crude product. Add dichloromethane (200.0 mL) and stir for 5 minutes, then filter to obtain a filter cake. Dissolve the filter cake in water (200.0 mL), adjust the pH to 7 with saturated aqueous sodium bicarbonate solution, filter by suction to obtain a filter cake, wash the filter cake with water (50.0 mL) twice, and concentrate in vacuo to obtain Compound A6-2 (12.9 g). 1 H NMR (400 MHz, DMSO) δ 10.0 (d, J = 10.0 Hz, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.07 (s, 2H); LC-MS: m / z = 145.9 (M + H) + 。

[0266] Step 2: Synthesis of Compound A6-4 (2-Chloro-5-(2-chloroethoxy)pyrimidin-4-amine)

[0267] Add 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) to N,N-dimethylformamide (200.0 mL) in sequence, and react at 20 °C for 16 hours to obtain a crude product of Compound A6-4 (27.2 g). The reaction solution is directly used for the next step. LC-MS: m / z = 207.8 (M + H) + 。

[0268] Step 3: Synthesis of Compound A6-5 (2-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0269] Heat the reaction solution of Compound A6-4 (27.2 g) to 100 °C and stir for 16 hours. Filter the reaction solution to obtain a filtrate, add water (800.0 mL) and stir for 5 minutes, extract with ethyl acetate (300.0 mL) three times, combine the organic layers, wash with saturated brine (100.0 mL) three times, dry over anhydrous sodium sulfate, filter to obtain a filtrate, concentrate in vacuo to obtain a crude product, add methyl tert-butyl ether (1000.0 mL) and stir for 30 minutes, filter by suction to obtain a filter cake, and concentrate the filter cake in vacuo to obtain Compound A6-5 (3.4 g). 11H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 9.60 Hz, 1H), 7.63 (d, J = 18.8 Hz, 1H), 4.10 - 4.34 (m, 2H), 3.43 - 3.46 (m, 2H); LC-MS: m / z = 171.9 (M + H) + 。

[0270] Step 4: Synthesis of Intermediate A6

[0271] 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)ferrocene dichloropalladium (640.0 mg, 874 μmol, 0.10 eq) were successively added to N,N-dimethylformamide (15.0 mL) and water (3.8 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C under nitrogen protection for 16 h. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Kromasil EternityXT 250×80 mm×10 μm; mobile phase: [water (ammonium hydroxide v / v) - ACN]; B%: 28% - 58%, 21 min) to obtain brown solid compound A6 (1.37 g, 5.27 mmol, 60.3% yield, 98.3% purity). 1 1H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.73 - 7.83 (m, 1H), 7.54 - 7.73 (m, 1H), 7.31 - 7.36 (m, 2H), 7.16 - 7.20 (m, 1H), 4.16 - 4.18 (m, 2H), 3.43 - 3.48 (m, 3H), 1.12 - 1.23 (m, 6H); LC-MS: m / z = 456.0 (M + H) + 。

[0272] Synthesis of General Intermediate A7 (2-(2-Isopropylphenyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0273]

[0274] Step 1: Synthesis of Compound A7-2 (2-Chloro-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0275] 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 successively added to N,N-dimethylformamide (50.0 mL). The reaction was carried out at 30 °C for 3 hours. Water (150.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, washed three times with saturated brine (70.0 mL), dried over anhydrous sodium sulfate, and 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 = 20 / 1 - 5 / 1) to obtain compound A7-2 (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 12.00 (s, 1H), 8.18 - 8.23 (m, 1H), 4.77 - 4.78 (m, 2H); LC-MS: m / z = 185.9 (M + H) + 。

[0276] Step 2: Synthesis of Intermediate A7

[0277] Compound A7-2 (500.0 mg, 2.69 mmol, 1.00 eq), compound A7-3 (574.1 mg, 3.50 mmol, 1.30 eq), aqueous potassium phosphate 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](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (231.1 mg, 269 μmol, 0.100 eq) were successively added to tetrahydrofuran (25.0 mL). The mixture was purged with nitrogen three times and stirred at 60 °C under nitrogen protection for 12 hours. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (HCl)-ACN]; B%: 28% - 48%, 8 min) to obtain white solid A7 (90.0 mg, 334 μmol, 12.4% yield). LC-MS: m / z = 270.1 (M + H) + 。

[0278] Synthesis of General Intermediate A8 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine)

[0279]

[0280] 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(diphenylphosphino)ferrocene dichloropalladium (640 mg, 874 μmol, 0.10 eq) were successively added to a mixed solvent of N,N-dimethylformamide (15.0 mL) and water (3.75 mL). The mixture was purged with nitrogen three times and stirred at 100 °C under nitrogen protection for 16 hours. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 10%-35%, 20 min) to obtain white solid compound A8 (414 mg, 1.45 mmol, 16.6% yield, 100% purity). 1 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 4.17 - 4.19 (m, 2H), 3.82 (s, 3H), 3.47 - 3.49 (m, 2H), 1.67 - 1.71 (m, 1H), 0.99 - 1.01 (m, 2H), 0.88 - 0.90 (m, 2H); LC-MS: m / z = 286.0 (M + H) + 。

[0281] Synthesis of General Intermediate A9 (4'-Cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[0282]

[0283] Step 1: Synthesis of Compound A9-2 (2-Chloro-5-methoxy-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine)

[0284] 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 the 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 the mixture was stirred at 5 °C for 12 hours. Then, the reaction was quenched by adding saturated ammonium chloride aqueous solution (40.0 mL) at 0 °C. Water (150.0 mL) was added, and the mixture was extracted with ethyl acetate (70.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 - 1 / 1) to obtain Compound A9-2 (10.3 g). LC-MS: m / z = 400.2 (M+H) + 。

[0285] Step 2: Synthesis of Compound A9-3 (4'-cyclopropyl-5,6'-dimethoxy-N,N-bis(4-methoxybenzyl)-[2,5'-bipyrimidine]-4-amine)

[0286] Compound A9-2 (2.0 g, 5.00 mmol, 1.00 eq), Compound A2-7 (1.46 g, 7.50 mmol, 1.50 eq), aqueous potassium phosphate 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 successively added to tetrahydrofuran (40.0 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under vacuum to obtain a crude product. The crude product 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) + 。

[0287] Step 3: Synthesis of Intermediate A9

[0288] Compound A9-3 (900 mg, 1.75 mmol, 1.00 eq) was added to trifluoroacetic acid (10.0 mL). The temperature was raised to 90 °C and stirred for 12 hours. The reaction solution was concentrated under vacuum. Saturated aqueous sodium bicarbonate (10.0 mL) was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (20.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated under vacuum to obtain a crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain white solid A9 (300.0 mg, 62.5% yield, 100% purity). LC-MS: m / z = 274.1 (M+H) + 。

[0289] Synthesis of general intermediate A10 (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one)

[0290]

[0291] Compound A7-2 (600 mg, 3.23 mmol, 1.00 eq), A2-7 (940 mg, 4.85 mmol, 1.50 eq), aqueous potassium phosphate (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 successively added to tetrahydrofuran (10.0 mL). The mixture was purged with nitrogen three times and stirred at 80 °C under nitrogen protection for 12 hours. The reaction solution was concentrated under vacuum to obtain a crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 10 min) to obtain intermediate A10 (60.0 mg, 0.2 mmol, 6.2% yield, 100% purity). LC-MS: m / z = 300.1 (M+H) + 。

[0292] Synthesis of general intermediate AA3 (1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole)

[0293]

[0294] Step 1: Synthesis of compound AA3-2 (7-bromo-1-methyl-1H-indole)

[0295] Dissolve 7-bromoindole (Compound AA3-1, 15.0 g, 76.5 mmol, 1.00 eq) in THF (150 mL). Add NaH (4.59 g, 115 mmol, purity 60%, 1.50 eq) portionwise at 0 °C. After addition, warm to room temperature (25 °C) and stir for 1.5 h. Then, add potassium iodide (14.1 g, 99.5 mmol, 6.19 mL, 1.30 eq) at 0 °C. After addition, warm to room temperature (25 °C) and stir for 12 h. Quench the reaction with 60 mL of ice water at 0 °C. Extract with ethyl acetate (70.0 mL) three times. Combine the organic layers, wash with saturated brine (100.0 mL) three times, dry over anhydrous sodium sulfate, filter to obtain a filtrate, and concentrate in vacuo to obtain yellow solid Compound AA3-2 (16.5 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 1H), 7.39 - 7.41 (m, 1H), 7.01 - 7.02 (m, 1H), 6.94 - 6.98 (m, 1H), 6.50 - 6.51 (m, 1H), 4.18 (s, 3H); LC-MS: m / z = 212.0 (M + H) + 。

[0296] Step 2: Synthesis of Intermediate AA3

[0297] Dissolve Compound AA3-2 (4.00 g, 19.0 mmol, 1.00 eq), bis(pinacolato)diboron (9.67 g, 38.1 mmol, 2.00 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.39 g, 1.90 mmol, 0.100 eq) and potassium acetate (3.74 g, 38.1 mmol, 2.00 eq) in dioxane (40.0 mL). Stir the reaction at an external temperature of 95 °C for 12 h. Then, add water (80.0 mL). Extract with ethyl acetate (50.0 mL) three times. Combine the organic layers, wash with saturated brine (50.0 mL) twice, dry over anhydrous sodium sulfate, filter to obtain a filtrate, and concentrate in vacuo to obtain a crude product. The crude product is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain white solid Intermediate AA3 (2.47 g, 9.45 mmol, 49.6% yield, 98.4% purity). 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 6.0 Hz, 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) + 。

[0298] Synthesis of General Intermediate AA4 ((1-Methylindol-7-yl)boronic Acid)

[0299]

[0300] Step 1: Synthesis of Compound AA4-1 (7-Bromo-1-methylindole)

[0301] Add compound AA3-2 (6.70 g, 31.8 mmol, 1.00 eq) to acetic acid (50.0 mL). Add sodium cyanoborohydride (16.0 g, 255 mmol, 8.00 eq) at 10 °C. Stir at 20 °C for 12 hours. Add 1 M aqueous sodium hydroxide solution to adjust the pH to about 8. Extract with dichloromethane (60 mL) three times. Combine the organic layers, wash with saturated brine (50 mL) twice, dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain a brown oily compound AA4-1 (8.00 g, crude product). LC-MS: m / z = 212.1 (M+H) + 。

[0302] Step 2: Synthesis of Intermediate AA4

[0303] Add compound AA4-1 (500 mg, 2.36 mmol, 1.00 eq) and triisopropyl borate (576 mg, 3.06 mmol, 704 μL, 1.30 eq) to tetrahydrofuran (10.0 mL). Dropwise add n-butyllithium (2.5 M, 1.23 mL, 1.30 eq) at -78 °C. After addition, warm to 25 °C and stir for 4 hours. Then, dropwise add saturated ammonium chloride aqueous solution (20 mL) to quench the reaction at 0 °C. Add water (30.0 mL), extract with ethyl acetate (15 mL) three times. Combine the organic layers, wash with saturated brine (20 mL) twice, dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain the crude product. The crude product is purified by reverse-phase HPLC (0.1% FA) to obtain a white solid intermediate AA4 (120 mg, 588.45 μmol, 24.96% yield, 86.8% purity). 1 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.02 (d, J = 6.8 Hz, 2H), 6.52 - 6.60 (m, 2H), 3.24 (t, J = 8.0 Hz, 2H), 2.84 (t, J = 8.0 Hz, 2H), 2.76 (s, 3H); LC-MS: m / z = 178.1 (M+H) + 。

[0304] Synthesis of General Intermediate AA5 ((1-Isopropyl-4-methyl-1H-imidazol-5-yl)boronic Acid)

[0305]

[0306] Step 1: Synthesis of Compound AA5-2 (5-Bromo-1-isopropyl-4-methyl-1H-imidazole)

[0307] Dissolve 4-methyl-5-bromoimidazole (AA5-1, 40.0 g, 248 mmol, 1.00 eq) in tetrahydrofuran (800 mL). Add sodium hydride (7.15 g, 178 mmol, 60% purity, 0.720 eq) portionwise at -15 °C. After addition, stir at -15 °C for 30 minutes. Add 2-iodopropane (42.2 g, 248 mmol, 24.8 mL, 1.00 eq). Stir at 0 °C for 3 hours. Quench the reaction by adding saturated ammonium chloride aqueous solution (100 mL). Add water (800.0 mL). Extract with ethyl acetate (500 mL) three times. Combine the organic layers, wash twice with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to get the crude product. Purify the crude product by reverse-phase HPLC (0.1% NH3·H2O) to obtain the brown oily compound AA5-2 (7.00 g, 34.4 mmol, 46.6% yield). 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 4.32 - 4.39 (m, 1H), 2.20 (s, 3H), 1.47 (d, J = 4.4 Hz, 6H); LC-MS: m / z = 203.0 (M + H) + 。

[0308] Step 2: Synthesis of Intermediate AA5

[0309] Add 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) to tetrahydrofuran (150.0 mL). Dropwise add n-butyllithium (2.50 M, 27.6 mL, 2.00 eq) at -78 °C. After addition, warm to 25 °C and stir for 4 hours. Then, quench the reaction by dropwise adding saturated ammonium chloride aqueous solution (200 mL) at 0 °C. Add water (300.0 mL). Extract with ethyl acetate (300 mL) three times. Combine the organic layers, wash twice with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the yellow solid compound AA5 (6.5 g, crude product). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.26 (m, 2H), 8.20 (s, 1H), 5.12 (s, 1H), 2.30 (s, 3H), 1.37 - 1.39 (m, 6H); LC-MS: m / z = 169.1 (M + H) + 。

[0310] Synthesis of General Intermediate AA6 (2-Cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0311]

[0312] Step 1: Synthesis of Compound AA6-2 (2-Bromopyridin-3-yl Trifluoromethanesulfonate)

[0313] 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 Bidepharm), and triethylamine (1.1 mL, 8.1 mmol) were successively added to dichloromethane (20 mL). The mixture was stirred at 0 °C under nitrogen protection for 1 hour, then warmed to 25 °C and stirred for 1.5 hours. It was washed once with 1 M sodium hydroxide (100 mL) and twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a pale yellow oily compound AA6-2 (2.8 g, crude product). LC-MS: m / z = 305.9 (M+H) + 。

[0314] Step 2: Synthesis of Compound AA6-3 (2-Cyclopropylpyridin-3-yl Trifluoromethanesulfonate)

[0315] Compound AA6-2 (2.5 g), tetrakis(triphenylphosphine)palladium (199 mg), and cyclopropylzinc chloride (0.4 M THF solution, 23 mL) were successively added to tetrahydrofuran (15 mL). The mixture was stirred at 70 °C under nitrogen protection for 3 hours, cooled to room temperature, saturated aqueous sodium bicarbonate solution (60 mL) was added, and the mixture was extracted 3 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 give a colorless transparent oily compound AA6-3 (1.5 g). LC-MS: m / z = 268.1 (M+H) + 。

[0316] Step 3: Synthesis of Intermediate AA6

[0317] Compound AA6-3 (0.5 g), bis(pinacolato)diboron (0.57 g), potassium carbonate (0.525 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.156 g) were added to dioxane (80 mL). The mixture was stirred at 100 °C for 20 h, cooled to room temperature, ethyl acetate (200 mL) was added, and the mixture was washed three times with saturated brine (100 mL), 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain white solid compound AA6 (0.2 g).

[0318] Synthesis of general intermediate AA7 (2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)

[0319]

[0320] Step 1: Synthesis of compound AA7-2 (2-isopropylpyridin-3-yl trifluoromethanesulfonate)

[0321] 2-Isopropylpyridin-3-ol (compound AA7-1, 3.00 g, 21.8 mmol, 1.00 eq) was added to pyridine (30.0 mL). Trifluoromethanesulfonic anhydride (6.17 g, 21.8 mmol, 3.61 mL, 1.00 eq) was added at 0 °C, and the mixture was stirred at 15 °C for 2 h. Water (30 mL) was added, and 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, filtered to obtain a filtrate, and concentrated in vacuo to obtain yellow oily compound AA7-2 (3.62 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 8.59 (t, J = 3.6 Hz, 1H), 7.55 - 7.58 (m, 1H), 7.21 - 7.24 (m, 1H), 3.39 - 3.46 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 270.2 (M + H) + 。

[0322] Step 2: Synthesis of compound AA7

[0323] Compound AA7-2 (3.62 g, 13.4 mmol, 1.00 eq) was successively added to dioxane (60.0 mL) along with bis(pinacolato)diboron (6.83 g, 26.8 mmol, 2.00 eq), potassium acetate (2.64 g, 26.8 mmol, 2.00 eq), and dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (983 mg, 1.34 mmol, 0.100 eq). The mixture was stirred at 100 °C for 20 h, cooled to room temperature, ethyl acetate (300 mL) was added, and it was washed three times with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to give the pale yellow oily compound AA7 (2.00 g, 8.09 mmol, 60.2% yield). 1 H NMR (400 MHz, CDCl3) δ 8.60 (dd, J1 = 2.0 Hz, J2 = 3.2 Hz, 1H), 7.99 (dd, J1 = 2.0 Hz, J2 = 5.2 Hz, 1H), 7.07 (dd, J1 = 4.8 Hz, J2 = 2.8 Hz, 1H), 3.71 - 3.78 (m, 1H), 1.35 (s, 12H), 1.24 - 1.28 (m, 6H).

[0324] General intermediate AA8 ((2-(dimethylamino)phenyl)boronic acid)

[0325] Intermediate AA8 was purchased from Bidepharm.

[0326]

[0327] Synthesis of general intermediate AA9 (4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0328]

[0329] Step 1: Synthesis of compound AA9-2 (4-chloro-1-isopropyl-1H-pyrazole)

[0330] 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 the mixture was stirred at 80 °C for 2 hours under N2 protection. Then, it was filtered by suction to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 5 / 1) to obtain a pale yellow oily compound AA9-2 (45.00 g, 306.53 mmol, 62.85% yield, 98.50% purity). 1 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.40 (m, 2H), 4.46 - 4.41 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 144.0 (M+H) + 。

[0331] Step 2: Synthesis of intermediate AA9

[0332] Compound AA9-2 (10 g, 69.16 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (100 mL). n-Butyllithium (2.5 M, 33.19 mL, 1.2 eq) was added dropwise at 0 °C. After addition, the temperature was raised to 25 °C and stirred for 1 hour. Isopropyl alcohol pinacol borate (15.44 g, 82.99 mmol, 16.93 mL, 1.2 eq) was added at -78 °C, and then the temperature was raised to 25 °C and stirred for 2 hours. Then, the reaction was quenched by adding saturated ammonium chloride aqueous solution (100 mL) at 0 °C. Water (200 mL) was added, and the mixture was extracted 3 times with ethyl acetate (50.0 mL). The organic layers were combined, washed twice with saturated brine (60.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, concentrated in vacuo to obtain a crude product. The crude product 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 a pale yellow oily compound AA9 (6.5 g, 18.33 mmol, 26.51% yield, 76.3% purity). 1 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 5.07–5.00 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.36 (s, 12H); LC-MS: m / z = 271.2 (M+H) + 。

[0333] General intermediate AA10 ((2-cyclopropylphenyl)boronic acid)

[0334] The intermediate AA10 was purchased from Bidepharm.

[0335]

[0336] Synthesis of the general intermediate AA11 ((1-Isopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0337]

[0338] Step 1: Synthesis of compound AA11-2 (1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0339] Dissolve 4-pyrazoleboronic acid pinacol ester (compound AA11-1, 130 g, 669 mmol, 1.00 eq) in N,N-dimethylformamide (114 g, 669 mmol, 67.0 mL, 1.00 eq), add 2-iodopropane (114 g, 669 mmol, 67.0 mL, 1.00 eq) and cesium carbonate (327 g, 1.00 mol, 1.50 eq), and stir at an external temperature of 90 °C for 12 hours. Then, perform suction filtration to obtain the filtrate, concentrate it under vacuum to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain the colorless transparent oily compound AA11-2 (120 g, 508 mmol, 75.9% yield). 1 H NMR (400 MHz, CDCl3) δ 7.74 (m, 2H), 4.46 - 4.53 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H), 1.29 (s, 12H); LC-MS: m / z = 237.1 (M + H) + 。

[0340] Step 2: Synthesis of compound AA11-3 (1-Isopropyl-1H-pyrazol-4-ol)

[0341] Compound AA11-2 (60.0 g, 254 mmol, 1.00 eq) was dissolved in tetrahydrofuran (600 mL), and an 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 the pH was adjusted to about 2 with 1 M aqueous hydrochloric acid. Then, anhydrous sodium sulfite (50.0 g) was added at 0 °C to quench the reaction. Tetrahydrofuran was removed by vacuum concentration. The residue was extracted three times with dichloromethane / methanol = 10 / 1 (1500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 give a pale yellow oily compound AA11-3 (17.5 g, 138 mmol, 54.6% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 7.09 (d, J = 0.8 Hz, 1H), 4.32 - 4.39 (m, 1H), 1.43 (s, 3H), 1.41 (s, 3H).

[0342] Step 3: Synthesis of compound AA11-4 (1-isopropyl-4-methoxy-1H-pyrazole)

[0343] 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 methyl iodide (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. Then, water (1000 mL) was added, and the mixture was extracted three times with ethyl acetate (600 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and 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 give a pale yellow solid compound AA11-4 (12.3 g, 87.7 mmol, 63.3% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 7.05 (d, J = 0.8 Hz, 1H), 4.30 - 4.36 (m, 1H), 3.70 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H).

[0344] Step 4: Synthesis of compound AA11

[0345] Compound AA11-4 (1.00 g, 7.13 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (15.0 mL). Under nitrogen protection, n-butyllithium (2.50 M, 4.28 mL, 1.50 eq) was added dropwise at -70 °C. After the addition, the mixture was stirred at -70 °C for 1 hour. Then, isopropyl alcohol pinacol borate (2.01 g, 10.8 mmol, 2.2 mL, 1.50 eq) was added at -70 °C, and the mixture was stirred at -70 °C for 1 hour and then warmed to 25 °C and stirred for 12 hours. Then, saturated ammonium chloride aqueous solution (20.0 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (100 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated in vacuo to obtain a crude product. The crude product was slurried with petroleum ether (20.00 mL) for 15 minutes to obtain an off-white solid intermediate AA11 (200 mg, 1.09 mmol, 15.2% yield). LC-MS: m / z = 185.2 (M+H) + 。

[0346] Synthesis of general intermediate AA12 ((1-cyclopropyl-4-methoxy-1H-pyrazol-5-yl)boronic acid)

[0347]

[0348] Step 1: Synthesis of compound AA12-2 (1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0349] Compound AA12-1 (19.0 g, 102 mmol, 1.00 eq) was dissolved in dioxane (250 mL). Bis(pinacolato)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(II) dichloromethane complex (4.15 g, 5.08 mmol, 0.05 eq) were added successively. 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 mixture was filtered to obtain a filtrate. The filtrate was extracted with ethyl acetate (500 mL) three times. The organic layers were combined, washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, 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 a pale yellow oily compound AA12-2 (4.40 g). 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 3.2 Hz, 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)+ 。

[0350] Step 2: Synthesis of Compound AA12-3 (1-cyclopropyl-1H-pyrazol-4-ol)

[0351] Dissolve Compound AA12-2 (3.30 g, 14.1 mmol, 1.00 eq) in tetrahydrofuran (43.0 mL), add aqueous sodium hydroxide solution (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), stir at 25 °C for 3 hours, and adjust the pH to about 2 with 1 M aqueous hydrochloric acid. Then, add anhydrous sodium sulfite (50.0 g) to quench the reaction at 0 °C, concentrate under vacuum to remove tetrahydrofuran, extract 3 times with dichloromethane / methanol = 10 / 1 (150 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, concentrate under vacuum to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain the pale yellow oily compound AA12-3 (0.980 g, crude product). 1 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 3.6 Hz, 2H), 3.46 - 3.48 (m, 1H), 0.95 - 0.96 (m, 2H), 0.94 - 0.95 (m, 2H).

[0352] Step 3: Synthesis of Compound AA12-4 (1-cyclopropyl-4-methoxy-1H-pyrazole)

[0353] Dissolve Compound AA12-3 (0.980 g, 7.89 mmol, 1.00 eq) in N,N-dimethylformamide (19.5 mL), add cesium carbonate (3.86 g, 11.8 mmol, 1.50 eq) and methyl iodide (1.68 g, 11.8 mmol, 737 μL, 1.50 eq), and stir at room temperature (25 °C) for 3 hours. Then, add water (10.0 mL), extract 3 times with ethyl acetate (10.0 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, concentrate under vacuum to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2) to obtain the pale yellow solid compound AA12-4 (0.460 g, 3.33 mmol, 42.2% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.21 (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) + 。

[0354] Step 4: Synthesis of Intermediate AA12

[0355] Dissolve compound AA12-4 (0.300 g, 2.17 mmol, 1.00 eq) in anhydrous tetrahydrofuran (8.50 mL). Under nitrogen protection, add n-butyllithium (2.50 M, 1.74 mL, 2.00 eq) dropwise at -70 °C. After addition, stir at -70 °C for 1 hour, then add isopropylpinacol borate (808 mg, 4.34 mmol, 886 μL, 2.00 eq) at -70 °C and stir at -70 °C for 1 hour. Then, warm up to 25 °C and stir for 12 hours. Subsequently, add saturated ammonium chloride aqueous solution (30.0 mL) at 0 °C, extract with ethyl acetate (10.0 mL) three times, combine the organic layers, dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the crude product, and purify the crude product by prep-HPLC (chromatographic column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 3%-33%, 10 min) to obtain a pale yellow oily compound AA12 (0.400 g, crude product). LC-MS: m / z = 183.1 (M+H) + 。

[0356] Synthesis of General Intermediate AA13 ((5-isopropyl-3-methylisoxazol-4-yl)boronic acid)

[0357]

[0358] Step 1: Synthesis of Compound AA13-2 (5-isopropyl-3-methylisoxazole)

[0359] Successively add 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) to ethanol (10.0 mL), stir at 130 °C for 10 minutes, add dichloromethane (100 mL), wash with saturated brine (50.0 mL) twice, separate the organic layer, dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain a colorless transparent liquid compound AA13-2 and compound AA13-2a (total 4.80 g, crude product). The 1 1H NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 3.04 - 2.97 (m, 1H), 2.35 (s, 3H), 1.28 - 1.23 (m, 6H).

[0360] Step 2: Synthesis of Compound AA13-3 (4-bromo-5-isopropyl-3-methylisoxazole)

[0361] Dissolve compound AA13-2 and compound AA13-2a (3.50 g, 28.0 mmol, 1.00 eq) in N,N-dimethylformamide (15 mL), add N-bromosuccinimide (7.94 g, 44.6 mmol, 1.59 eq), stir at 25 °C for 15 h, add ethyl acetate (250 mL), wash once with saturated sodium thiosulfate (100 mL) and three times with saturated brine (200 mL). Separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, and concentrate in vacuo to obtain the yellowish oily compound AA13-3 and compound AA13-3a (5.24 g, crude product). For compound AA13-3, 1 1H NMR (400 MHz, CDCl3) δ 3.20 - 3.13 (m, 1H), 2.24 (s, 3H), 1.33 - 1.30 (m, 6H); LC-MS: m / z = 203.9 (M + H) + 。

[0362] Step 3: Synthesis of compound AA13

[0363] Dissolve 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) in tetrahydrofuran (30.0 mL), add n-butyllithium (2.5 M, 7.64 mL, 1.30 eq) dropwise at -70 °C. After addition, warm to 25 °C and stir for 4 h. Quench the reaction by adding water (10.0 mL) at 0 °C, extract three times with ethyl acetate (30.0 mL). Combine the organic layers, dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain the crude product. The crude product is purified by prep-HPLC (column: Phenomenex luna C18 250×80 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 20% - 50%, 20 min) to obtain the white solid compound AA13 (470 mg, 2.73 mmol, 18.5% yield, 98.0% purity). 1 1H NMR (400 MHz, CDCl3) δ 3.83 - 3.76 (m, 1H), 2.49 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H); LC-MS: m / z = 170.1 (M + H) + 。

[0364] Synthesis of general intermediate AA14 (4-chloro-1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0365]

[0366] Step 1: Synthesis of Compound AA14-2 (4-chloro-1-cyclopropyl-1H-pyrazole)

[0367] 4-Chloropyrazole (Compound AA14-1, 10.0 g, 97.54 mmol, 1.0 eq), bromocyclopropane (21.2 g, 175.57 mmol, 1.8 eq) and cesium carbonate (63 g, 195.08 mmol, 2.0 eq) were successively added to dioxane (50 mL). The mixture was stirred at an external temperature of 140 °C for 16 hours, cooled to room temperature, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2) to obtain a pale yellow oily compound AA14-2 (6.4 g). 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8 Hz, 1H), 1.13–1.05 (m, 2H), 1.05–0.95 (m, 2H). LC-MS: m / z = 143.1 (M+H)+.

[0368] Step 2: Synthesis of Intermediate AA14

[0369] Compound AA14-2 (8.3 g, 58.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL). Diisopropylamine lithium (58 mL, 116.42 mmol, 2.0 eq) was added dropwise at -70 °C under nitrogen protection. After the addition was completed, the mixture was stirred at -70 °C for 1 hour. Isopropyl alcohol pinacol borate (17.3 g, 93.14 mmol, 1.6 eq) was added, and the mixture was stirred at -70 °C for 1 hour, then warmed to 25 °C and stirred for 2 hours. Then, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum 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 intermediate AA14 (4.2 g). 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.37 (s, 1H), 3.54 (tt, J = 7.3, 3.8 Hz, 1H), 1.13–1.05 (m, 2H), 1.05–0.95 (m, 2H).

[0370] General Intermediate AA15 ((4-cyclopropylpyrimidin-5-yl)boronic acid)

[0371] Intermediate AA15 was purchased from Leyan Reagent.

[0372]

[0373] Synthesis of General Intermediate AA16 (1-Cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0374]

[0375] Using 4-methylpyrazole (Compound AA16-1) as the raw material, Intermediate AA16 (2.9 g) was prepared according to the same steps as Intermediate AA14. 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 4.03 (td, J = 7.5, 3.8 Hz, 1H), 2.15 (s, 3H), 1.35 (s, 12H), 1.12–1.01 (m, 2H), 0.99–0.89 (m, 2H).

[0376] Synthesis of General Intermediate AA17 (1-Isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

[0377]

[0378] Using 4-methylpyrazole (Compound AA16-1) as the raw material, Intermediate AA17 (4.1 g) was prepared according to the same steps as Intermediate AA14. 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 4.94 - 4.98 (m, 1H), 2.12 (s, 3H), 1.34 (d, J = 6.6 Hz, 6H), 1.29 (s, 12H).

[0379] Synthesis of General Intermediate B1 (3-(4-(Chloromethyl)piperidin-1-yl)pyridine)

[0380]

[0381] Step 1: Synthesis of Compound B1-3 (Ethyl 1-(pyridin-3-yl)piperidine-4-carboxylate)

[0382] 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(0) (582.0 mg, 0.6 mmol, 0.02 eq) were successively added to anhydrous dioxane (50.0 mL). The mixture was purged with nitrogen three times and then reacted at 100 °C for 12 h under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by reverse-phase HPLC (0.1% FA) to give compound B1-3 (3.2 g). 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.12 - 7.19 (m, 2H), 4.11 - 4.17 (m, 2H), 3.60 - 3.65 (m, 2H), 2.80 - 2.86 (m, 2H), 2.39 - 2.48 (m, 2H), 2.00 - 2.04 (m, 2H), 1.83 - 1.87 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H); LC-MS: m / z = 235.1 (M + H) + 。

[0383] Step 2: Synthesis of compound B1-4 ((1-(pyridin-3-yl)piperidin-4-yl)methanol)

[0384] Compound B1-3 (2.0 g, 8.5 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). Lithium aluminum hydride (356.0 mg, 9.4 mmol, 1.10 eq) was added at 0 °C. After addition, the temperature was raised to 25 °C and the mixture was stirred for 4 h. Then, water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) were added at 0 °C. After addition, the mixture was stirred at 0 °C for 0.5 h. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added, and the mixture was stirred for 5 min. The filtrate was obtained by filtration and concentrated in vacuo to obtain crude compound B1-4 (1.2 g), which was directly used in the next step of the reaction. 11H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 4.4 Hz, 1H), 7.19 - 7.21 (m, 1H), 7.12 - 7.16 (m, 1H), 3.71 - 3.74 (m, 2H), 3.53 - 3.55 (m, 2H), 2.73 - 2.80 (m, 2H), 2.60 (s, 1H), 1.86 - 1.89 (m, 2H), 1.67 - 1.70 (m, 1H), 1.25 - 1.44 (m, 2H); LC-MS: m / z = 193.2 (M + H) + 。

[0385] Step 3: Synthesis of Intermediate B1

[0386] A solution of compound B1-4 (0.5 g, 2.6 mmol, 1.00 eq) in dichloromethane (5.0 mL) was added with thionyl chloride (3.1 g, 26.0 mmol, 10.0 eq) at 0 °C. After addition, the temperature was raised to 20 °C and stirred for 15 h. The reaction solution 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) + 。

[0387] Synthesis of General Intermediate B2 (4-(4-(Chloromethyl)piperidin-1-yl)pyridine)

[0388]

[0389] Step 1: Synthesis of Compound B2-3 (Ethyl 1-(pyridin-4-yl)piperidine-4-carboxylate)

[0390] 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). The temperature was raised to 100 °C and stirred for 16 h. Then, water (50.0 mL) was added at 25 °C, and the mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain compound B2-3 (2.7 g). 11H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 5.2 Hz, 2H), 6.65 (d, J = 5.6 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.82 (d, J = 13.2 Hz, 2H), 2.96 (d, J = 11.6 Hz, 2H), 2.51 - 2.58 (m, 1H), 1.99 - 2.02 (m, 2H), 1.77 - 1.84 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H); LC-MS: m / z = 235.2 (M + H) + 。

[0391] Step 2: Synthesis of Compound B2-4 ((1-(pyridin-4-yl)piperidin-4-yl)methanol)

[0392] Dissolve Compound B2-3 (1.7 g, 7.3 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL). Add lithium aluminum hydride (302.0 mg, 8.0 mmol, 1.10 eq) at 0 °C. After addition, warm the reaction mixture to 25 °C and stir for 4 hours. Add aqueous sodium hydroxide solution (0.25 M, 2 mL) at 0 °C, stir at 0 °C for 0.5 hour, add tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g), stir for 5 minutes, filter to obtain the filtrate, and concentrate it in vacuo to obtain the crude product of Compound B2-4 (1.1 g). The crude product is directly used in the next step of the reaction. 1 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J = 1.6 Hz, 2H), 6.67 (t, J = 1.2 Hz, 2H), 3.92 (d, J = 16.0 Hz, 2H), 3.55 (d, J = 2.4 Hz, 2H), 2.84 - 2.90 (m, 2H), 1.78 - 1.87 (m, 3H), 1.30 - 1.37 (m, 2H); LC-MS: m / z = 193.0 (M + H) + 。

[0393] Step 3: Synthesis of Compound B2

[0394] Dissolve Compound B2-4 (500.0 mg, 2.60 mmol, 1.00 eq) in dichloromethane (5.0 mL). Add thionyl chloride (2.5 g, 20.8 mmol, 8.00 eq) at 0 °C. After addition, warm the reaction mixture to 20 °C and stir for 15 hours. Concentrate the reaction solution in vacuo to obtain the white solid Compound B2 (530 mg, 2.52 mmol, 96.7% yield). LC-MS: m / z = 193.0 (M + H) + 。

[0395] Synthesis of General Intermediate B3 (3-(4-(chloromethyl)phenyl)pyridine)

[0396]

[0397] Step 1: Synthesis of Compound B3-3 ((4-(pyridin-3-yl)phenyl)methanol)

[0398] 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 tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.89 mmol, 0.10 eq) were successively added to a mixed solvent of toluene (15.0 mL), water (15.0 mL), and ethanol (3.0 mL). The mixture was purged with nitrogen three times and then reacted under nitrogen protection at 100 °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 Compound B3-3 (2.3 g). 1 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 7.87 - 7.90 (m, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.36 - 7.39 (m, 1H), 4.78 (s, 2H), 1.96 - 2.06 (m, 1H); LC-MS: m / z = 186.1 (M + H) + 。

[0399] Step 2: Synthesis of Intermediate B3

[0400] 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 the mixture was stirred for 15 hours. The reaction solution was concentrated in vacuo to obtain a white solid compound B3 (1.1 g, 5.35 mmol, 99.1% yield). LC-MS: m / z = 204.0 (M + H) + 。

[0401] Synthesis of General Intermediate B4 (4-(4-(chloromethyl)phenyl)pyridine)

[0402]

[0403] 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 h. The reaction solution was concentrated in vacuo to obtain white solid compound B4 (260 mg, 1.28 mmol, 94.5% yield). LC-MS: m / z = 204.0 (M+H) + 。

[0404] Synthesis of General Intermediate B5 (5-(4-(Chloromethyl)phenyl)-2-methylpyridine)

[0405]

[0406] Step 1: Synthesis of Compound B5-3 ((4-(6-Methylpyridin-3-yl)phenyl)methanol)

[0407] 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 tetrakis(triphenylphosphine)palladium (2.0 g, 1.74 mmol, 0.10 eq) were successively added to a mixed solvent of toluene (15.0 mL), water (15.0 mL), and ethanol (3.00 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 12 h under nitrogen protection. 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 compound B5-3 (3.0 g). 1 1H NMR (400 MHz, CDCl3) δ 8.59 - 8.63 (m, 1H), 7.76 - 7.78 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 4.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 2.61 (s, 3H), 2.33 - 2.37 (m, 1H); LC-MS: m / z = 200.1 (M+H) + 。

[0408] Step 2: Synthesis of Intermediate B5

[0409] A solution of compound B5-3 (0.5 g, 2.5 mmol, 1.00 eq) in dichloromethane (5.0 mL) was added with thionyl chloride (1.5 g, 12.5 mmol, 5.00 eq) 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 white solid compound B5 (530 mg, 2.43 mmol, 97.0% yield). LC-MS: m / z = 218.1 (M+H) + 。

[0410] Synthesis of general intermediate B6 (2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0411]

[0412] Step 1: Synthesis of compound B6-3 (methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0413] 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. At 25 °C, compound B6-1 (4.0 g, 24.4 mmol, 1.00 eq) dissolved in methanol (80.0 mL) and ammonia water (22.0 mL) was added. After the addition, the reaction was carried out at 25 °C for 40 minutes and then stirred at 100 °C for 2 hours. Then, water (60.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (80.0 mL) three times. The organic layers were combined, washed twice with saturated brine (80.0 mL), 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain compound B6-3 (4.5 g). 1 HNMR (400 MHz, CDCl3) δ 13.4 (s, 1H), 8.10 - 8.12 (m, 2H), 8.04 - 8.06 (m, 2H), 7.99 (s, 1H), 3.87 (s, 3H); LC-MS: m / z = 271.0 (M+H) + 。

[0414] Step 2: Synthesis of compound B6-4 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0415] 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. After the addition, the reaction was carried out at 0 °C for 30 minutes. Then, methyl iodide (6.8 g, 48.1 mmol, 5.20 eq) was added. After the addition, the temperature was raised to 20 °C and stirred for 15 hours. Then, ice water (20.0 mL) was added at 0 °C to quench the reaction. The mixture was extracted with ethyl acetate (30.0 mL) three times. The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain compound B6-4 (1.1 g). 1 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.99 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H); LC-MS: m / z = 285.1 (M + H) + 。

[0416] Step 3: Synthesis of compound B6-5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol)

[0417] Compound B6-4 (0.6 g, 2.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (6.0 mL). Lithium aluminum hydride (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. The mixture was stirred at 0 °C for 0.5 hour. Tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g) were added. The mixture was filtered to obtain a filtrate, and concentrated in vacuo to give crude product B6-5 (505.4 mg). The crude product was directly used in the next step of the reaction. 1 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.30 - 5.33 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H); LC-MS: m / z = 257.1 (M + H) + 。

[0418] Step 4: Synthesis of intermediate B6

[0419] A solution of compound B6-5 (500.0 mg, 2.0 mmol, 1.00 eq) in dichloromethane (5.0 mL) was added with thionyl chloride (1.9 g, 15.6 mmol, 8.00 eq) at 0 °C. After the addition, the temperature was raised to 20 °C and stirred for 15 hours. The reaction solution was concentrated under vacuum to obtain a brown solid compound B6 (523 mg, 1.90 mmol, 97.6% yield). LC-MS: m / z = 275.1 (M+H) + 。

[0420] Synthesis of General Intermediate B7 (2-(4-(Chloromethyl)cyclohexyl)pyrimidine)

[0421]

[0422] 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)

[0423] 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 successively added to dioxane (80.0 mL). After purging with nitrogen three times, the mixture was stirred at 80 °C under nitrogen protection for 2 hours. Then, water (200.0 mL) was added, and the mixture was extracted with ethyl acetate (70.0 mL) three times. The organic layers were combined, washed twice with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated under vacuum 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 1H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 4.12 - 4.17 (m, 2H), 2.50 - 2.51 (m, 1H), 2.26 - 2.35 (m, 3H), 2.01 - 2.05 (m, 2H), 1.58 - 1.63 (m, 1H), 1.27 - 1.28 (m, 15H); LC-MS: m / z = 281.1 (M+H) + 。

[0424] Step 2: Synthesis of Compound B7-5 (Ethyl 4-(pyrimidin-2-yl)cyclohex-3-ene-1-carboxylate)

[0425] 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 tetrakis(triphenylphosphine)palladium (1.8 g, 1.6 mmol, 0.10 eq) were successively added to dioxane (50.0 mL) and water (12.5 mL). The mixture was purged with nitrogen three times and stirred at 90 °C for 20 h under nitrogen protection. Then, water (100.0 mL) was 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, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain compound B7-5 (3.1 g). 1 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.80 Hz, 2H), 7.28 - 7.29 (m, 1H), 7.07 - 7.10 (m, 1H), 4.12 - 4.20 (m, 2H), 2.82 - 2.83 (m, 1H), 2.58 - 2.63 (m, 1H), 2.55 - 2.58 (m, 3H), 2.04 - 2.21 (m, 1H), 1.81 - 1.84 (m, 1H), 1.23 - 1.30 (m, 3H); LC-MS: m / z = 233.1 (M + H) + 。

[0426] Step 3: Synthesis of compound B7-6 (ethyl 4-(pyrimidin-2-yl)cyclohexane-1-carboxylate)

[0427] Compound B7-5 (3.0 g, 13.1 mmol, 1.00 eq) and wet palladium on carbon (1.4 g, 1.3 mmol, 10.0% purity, 0.10 eq) were successively added to ethanol (90.0 mL). The mixture was stirred at 25 °C in a hydrogen atmosphere for 16 h, filtered by suction to obtain a filtrate, and concentrated in vacuo to give 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 1H NMR (400 MHz, CDCl3) δ 8.64 - 8.66 (m, 2H), 7.07 - 7.12 (m, 1H), 4.10 - 4.15 (m, 2H), 2.95 - 2.97 (m, 1H), 2.59 - 2.61 (m, 1H), 2.10 - 2.15 (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)+ 。

[0428] Step 4: Synthesis of Compound B7-7 ((4-(Pyrimidin-2-yl)cyclohexyl)methanol)

[0429] Dissolve Compound B7-6 (500.0 mg, 2.1 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL), add diisobutylaluminum hydride (1.0 M, 3.20 eq) at -65 °C. After addition, react at -65 °C for 0.5 h, then warm to 20 °C and stir for 1 h. Then, add saturated aqueous ammonium chloride solution (20.0 mL) at 0 °C. After addition, warm to 20 °C and stir for 1 h. Filter to obtain the filtrate, separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, and concentrate in vacuo to obtain the crude Compound B7-7 (263.5 mg). The crude product is directly used for the next reaction. 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.80 Hz, 2H), 7.11 - 7.14 (m, 1H), 3.64 (d, J = 7.20 Hz, 2H), 3.04 - 3.08 (m, 1H), 2.05 - 2.08 (m, 2H), 1.83 - 1.85 (m, 3H), 1.64 - 1.69 (m, 4H), 1.14 - 1.26 (m, 1H); LC-MS: m / z = 193.0 (M + H) + 。

[0430] Step 5: Synthesis of Intermediate B7

[0431] Dissolve Compound B7-7 (263.0 mg, 1.4 mmol, 1.00 eq) in dichloromethane (5.0 mL), add thionyl chloride (814.0 mg, 6.8 mmol, 5.00 eq) at 0 °C. After addition, warm to 20 °C and stir for 15 h. Concentrate the reaction solution in vacuo to obtain the light yellow oily Compound B7 (300 mg, crude product). 1 H NMR (400 MHz, CDCl3) δ 8.79 - 8.98 (m, 2H), 7.17 - 7.25 (m, 1H), 3.59 - 3.76 (m, 1H), 3.26 - 3.47 (m, 2H), 2.05 - 2.37 (m, 2H), 1.73 - 1.88 (m, 4H), 1.47 - 1.56 (m, 1H), 1.45 - 1.47 (m, 1H), 1.27 - 1.45 (m, 1H); LC-MS: m / z = 211.2 (M + H) + 。

[0432] Synthesis of General Intermediate B8 ((4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0433]

[0434] Intermediate B6 (700.0 mg, 2.55 mmol, 1.00 eq) and ammonia water (27.3 g, 233.0 mmol, 30% purity, 91.70 eq) were added to dioxane (15.0 mL). The reaction was carried out in a sealed tube at 50 °C for 12 hours. The reaction solution was concentrated under vacuum to obtain a crude product, and the crude product was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to obtain white solid B8 (580 mg, 1.99 mmol, 78.0% yield, HCl). 1 HNMR (400 MHz, CDCl₃) δ 7.73 - 7.76 (m, 3H), 7.63 - 7.65 (m, 2H), 4.22 (s, 2H), 3.80 (s, 3H); LC-MS: m / z = 256.0 (M + H) + 。

[0435] Synthesis of general intermediate B9 (2-(5-(chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0436]

[0437] For the synthesis of general intermediate B9, the specific operation refers to the synthesis of intermediate B6. Replace B6-1 with an equimolar amount of B9-1, and keep other experimental conditions unchanged. Finally, white solid compound B9 (330.0 mg, crude product) was obtained. LC-MS: m / z = 281.0 (M + H) + 。

[0438] Synthesis of general intermediate B10 (2-(4-(chloromethyl)phenyl)pyridine)

[0439]

[0440] Step 1: Synthesis of compound B10-3 ((4-(pyridin-2-yl)phenyl)methanol)

[0441] 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), tetrakis(triphenylphosphine)palladium (7.31 g, 6.33 mmol, 0.100 eq), and sodium carbonate (49.6 g, 468 mmol, 7.40 eq) were successively added to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C under nitrogen protection for 12 hours. The mixture was filtered by suction 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% NH₃·H₂O) to obtain compound B10-3 (9.63 g). 1 ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 4.4 Hz, 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) + 。

[0442] Step 2: Synthesis of intermediate B10

[0443] A solution of compound B10-3 (1.0 g, 5.40 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added with thionyl chloride (3.2 g, 27.0 mmol, 1.96 mL, 5.00 eq) 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 white solid B10 (1.1 g, crude product). LC-MS: m / z = 204.1 (M+H) + 。

[0444] Synthesis of general intermediate B11 (2-(4-(chloromethyl)piperidin-1-yl)pyridine)

[0445]

[0446] Step 1: Synthesis of compound B11-3 (ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate)

[0447] Compound B11-1 (20.8 g, 132 mmol, 20.4 mL, 1.00 eq), compound B12-2 (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 the reaction was carried out at 120 - 150 °C for 16 h. The temperature was lowered, the reaction was stopped, water (50 ml) was added at room temperature to quench the reaction, and the mixture was extracted with ethyl acetate (60.0 mL) three times. The organic layers were combined, washed twice with saturated brine (30.0 mL), 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 silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a yellow oily compound B12-2 (6.0 g, yield 19.4%, purity 100%). 1 1H NMR (400 MHz, CDCl3) δ 8.17 - 8.19 (m, 1H), 7.44 - 7.48 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.59 - 6.61 (m, 1H), 4.21 - 4.24 (m, 2H), 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) + 。

[0448] Step 2: Synthesis of compound B11-4 ((1-(pyridin-2-yl)piperidin-4-yl)methanol)

[0449] Compound B11-3 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL), and lithium aluminum hydride (LiAlH4, 1.07 g, 28.2 mmol, 1.10 eq) was carefully added at 0 °C, and then the mixture was stirred at room temperature for 16 h. Lithium aluminum hydride (LiAlH4, (486 mg, 12.8 mmol, 0.500 eq)) was added, and stirring was continued for 6 hours. Water (20.0 mL) was carefully added at 0 °C to quench the reaction. The mixture was extracted with ethyl acetate (60.0 mL × 3). The organic layers were combined, washed twice with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a yellow oily compound B11-4 (1.20 g, yield 23.8%, purity 97.8%). 11H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.6 Hz, 1H), 7.43 - 7.48 (m, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.58 - 6.59 (m, 1H), 4.33 (d, J = 12.8 Hz, 2H), 3.54 (d, J = 6.0 Hz, 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) + 。

[0450] Step 3: Synthesis of Intermediate B11

[0451] Dissolve compound B11-4 (1.20 g, 6.24 mmol, 1.00 eq) in dichloromethane (12.0 mL). Add thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 eq) at 0 °C. After addition, warm the reaction mixture to 20 °C and stir for 12 hours. Concentrate the reaction solution under vacuum to obtain a white solid compound B11 (1.57 g, crude product). LC-MS: m / z = 211.1.

[0452] Synthesis of General Intermediate B12 (2 - ((1r,4r)-4-(chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0453]

[0454] Step 1: Synthesis of Compound B12-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0455] Dissolve compound B12-1 (33.0 g, 242.0 mmol, 1.00 eq) in tetrahydrofuran (330.0 mL). Add sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 eq) portionwise at 0 °C. After addition, stir the reaction mixture at 0 °C for 30 minutes. Then, add methyl iodide (34.4 g, 242.0 mmol, 15.1 mL, 1.00 eq). After addition, warm the reaction mixture to 25 °C and stir for 5 hours. Quench the reaction by adding saturated ammonium chloride aqueous solution (30.0 mL) at 0 °C. Add water (30.0 mL), extract with ethyl acetate (30.0 mL) three times. Combine the organic layers, wash with saturated brine (30.0 mL) twice, dry over anhydrous sodium sulfate, filter to obtain a filtrate, and concentrate the filtrate under vacuum to obtain a crude product. The crude product is purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain compound B12-2 (21.0 g). 11H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M+H) + 。

[0456] Step 2: Synthesis of Compound B12-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0457] Dissolve Compound B12-2 (16.8 g, 111.0 mmol, 1.00 eq) in anhydrous tetrahydrofuran (370.0 mL), add n-butyllithium (2.5 M, 44.7 mL, 1.00 eq) dropwise at -70 °C, and stir at -70 °C for 30 minutes after addition. Then, add hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) dropwise to the reaction solution, react at -70 °C for 1 hour after addition, warm up to 20 °C and stir for 3 hours, quench the reaction by adding saturated ammonium chloride aqueous solution (200.0 mL) at 0 °C, add water (300.0 mL), extract with ethyl acetate (150.0 mL) three times, combine the organic layers, wash twice with saturated brine (200.0 mL), dry over anhydrous sodium sulfate, filter to obtain a filtrate, concentrate in vacuo to obtain a crude product, and purify the crude product 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) + 。

[0458] Step 3: Synthesis of Compound B12-5 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-3-ene-1-carboxylate)

[0459] Add 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, 0.05 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 eq) to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL) in sequence, displace with nitrogen three times, stir at 100 °C under nitrogen protection for 5 hours, filter the reaction solution to obtain a filtrate, concentrate in vacuo to obtain a crude product, and purify the crude product by reverse-phase HPLC (0.1% FA) to obtain Compound B12-5 (1.9 g). 11H NMR (400 MHz, CDCl3) δ 6.05 (d, J = 2.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.61 (s, 3H), 2.50 - 2.67 (m, 5H), 2.13 - 2.14 (m, 1H), 1.86 - 1.89 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); LC-MS: m / z = 337.2 (M + H) + 。

[0460] Step 4: Synthesis of compound B12-6 ((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-carboxylic acid ethyl ester)

[0461] 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 on carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 eq) were successively added to ethanol (30.0 mL). The reaction was carried out at 50 °C for 5 h under a hydrogen atmosphere (15 psi). 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 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 4.15 (q, J = 6.8 Hz, 2H), 3.64 (s, 3H), 2.60 - 2.65 (m, 1H), 2.41 - 2.44 (m, 1H), 2.12 - 2.15 (m, 2H), 1.97 - 1.98 (m, 2H), 1.77 - 1.80 (m, 2H), 1.54 - 1.59 (m, 2H), 1.27 (t, J = 8.8 Hz, 3H); LC-MS: m / z = 305.0 (M + H) + 。

[0462] Step 5: Synthesis of compound B12-7 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol)

[0463] Dissolve compound B12-6 (0.6 g, 2.0 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL). Add lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 eq) at 0 °C. After addition, react at 0 °C for 0.5 h, then warm to 20 °C and stir for 12 h. Then, add sodium sulfate decahydrate (0.5 g) at 0 °C. After addition, warm to 20 °C and stir for 30 min. Add tetrahydrofuran (10.0 mL), filter to obtain the filtrate, separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, and concentrate in vacuo to obtain the crude compound B12-7 (0.5 g). The crude product is directly used for the next reaction. 1 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 2.59 - 2.65 (m, 1H), 1.95 - 1.98 (m, 4H), 1.77 - 1.80 (m, 3H), 1.07 - 1.17 (m, 2H); LC-MS: m / z = 263.1 (M + H) + 。

[0464] Step 6: Synthesis of Intermediate B12

[0465] Dissolve compound B12-7 (500.0 mg, 1.9 mmol, 1.00 eq) in dichloromethane (2.0 mL). Add thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) at 0 °C. After addition, warm to 20 °C and stir for 24 h. Concentrate the reaction solution in vacuo to obtain the pale yellow solid compound B12 (550 mg, 1.36 mmol, 71.5% yield, HCl). LC-MS: m / z = 281.0 (M + H) + 。

[0466] Synthesis of General Intermediate B13 (4-(Chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine Hydrochloride)

[0467]

[0468] Step 1: Synthesis of Compound B13-2 (1-Methyl-4-(trifluoromethyl)-1H-imidazole)

[0469] 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. After the addition, the reaction was carried out at 0 °C for 30 minutes. Then, methyl iodide (34.4 g, 242 mmol, 15.1 mL, 1.00 eq) was added. After the addition, the temperature was raised to 25 °C and stirred for 4 hours. Then, ice water (200.0 mL) was added at 0 °C to quench the reaction. The mixture was extracted with ethyl acetate (200.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to give compound B13-2 (21.0 g). 1 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M + H) + 。

[0470] Step 2: Synthesis of compound B13-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0471] Compound B13-2 (16.8 g, 111 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (370.0 mL). n-Butyllithium (2.5 M, 44.7 mL, 1.00 eq) was added dropwise at -70 °C. After the addition, the reaction 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 reaction was carried out at -70 °C for 1 hour, the temperature was raised to 20 °C and stirred for 3 hours. Saturated ammonium chloride aqueous solution (200.0 mL) was added at 0 °C to quench the reaction. Water (300.0 mL) was added, and the mixture was extracted with ethyl acetate (150.0 mL) three times. The organic layers were combined, washed with saturated brine (200.0 mL) twice, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 20 / 1) to give compound B13-3 (12.0 g). LC-MS: m / z = 219.0 (M + H) + 。

[0472] Step 3: Synthesis of compound B13-5 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0473] 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 successively added to N,N-dimethylformamide (70.0 mL). The reaction was carried out at 130 °C for 72 hours. Water (350 mL) was added and stirred for 5 minutes. The mixture was extracted with ethyl acetate (100 mL) three times. The organic layers were combined, 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 reverse-phase HPLC (0.1% FA) to obtain compound B13-5 (2.2 g). 1 H NMR (400 MHz, CDCl3) δ 4.17 (q, J = 7.2 Hz, 2H), 3.45 (s, 3H), 3.24 - 3.28 (m, 2H), 2.90 - 2.97 (m, 2H), 2.40 - 2.45 (m, 1H), 2.02 - 2.06 (m, 2H), 1.85 - 1.88 (m, 2H), 1.28 (t, J = 8.0 Hz, 2H); LC-MS: m / z = 340.1 (M + H) + 。

[0474] Step 4: Synthesis of compound B13-6 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0475] 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 on carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 eq) were successively added to ethanol (40.0 mL). The reaction was carried out at 50 °C for 36 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered to obtain a filtrate, and concentrated in vacuo to obtain compound B13-6 (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.15 (q, J = 7.2 Hz, 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 = 6.8 Hz, 3H); LC-MS: m / z = 306.1 (M + H) + 。

[0476] Step 5: Synthesis of Compound B13-7 ((1-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol)

[0477] Dissolve Compound B13-6 (1.2 g, 3.93 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL). Add lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 eq) at 0 °C. After addition, react at 0 °C for 0.5 h, then warm to 20 °C and stir for 12 h. Then, add sodium sulfate decahydrate (0.5 g) at 0 °C. After addition, warm to 20 °C and stir for 30 min. Add tetrahydrofuran (10.0 mL), filter to obtain the filtrate, separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, and concentrate in vacuo to obtain Compound B13-7 (1.0 g). The crude product is directly used in the next step of the reaction. 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 3.57 (d, J = 6.4 Hz, 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) + 。

[0478] Step 6: Synthesis of Intermediate B13

[0479] Dissolve Compound B13-7 (1.0 g, 3.80 mmol, 1.00 eq) in dichloromethane (2.0 mL). Add thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) at 0 °C. After addition, warm to 20 °C and stir for 24 h. Concentrate the reaction solution 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) + 。

[0480] Synthesis of General Intermediate B14 (2-(5-(Chloromethyl)furan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0481]

[0482] Step 1: Synthesis of Compound B14-3 (5-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)furan-2-carbaldehyde)

[0483] Compound B14-2 (400 mg, 1.83 mmol, 1.00 eq), B14-1 (255 mg, 1.83 mmol, 1.00 eq), (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (71.2 mg, 91.3 μmol, 0.0500 eq), and potassium phosphate (1.16 g, 5.48 mmol, 3.00 eq) were successively added to n-butanol (3.0 mL) and water (0.5 mL). The mixture was purged with nitrogen three times and then reacted at 60 °C for 12 h under nitrogen protection. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 7 min) to obtain compound B14-3 (60.0 mg). 1 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.37 (d, J = 3.6 Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 3.6 Hz, 1H), 4.07 (s, 3H); LC-MS: m / z = 245.2 (M+H)+.

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

[0485] Compound B14-3 (60.0 mg, 245 μmol, 1.00 eq) was dissolved in methanol (1.0 mL), sodium borohydride (90.0 mg, 2.38 mmol, 9.68 eq) was added, and the mixture was stirred at 15 °C for 30 min. An aqueous saturated ammonium chloride solution (10.0 mL) was added at 0 °C, followed by water (20.0 mL). The mixture was extracted with ethyl acetate (10.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain compound B14-4 (50.0 mg). 1 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.70 (s, 2H), 3.93 (s, 3H); LC-MS: m / z = 247.1 (M+H) + 。

[0486] Step 3: Synthesis of intermediate B14

[0487] 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 the addition, the temperature was raised to 25 °C and the reaction was carried out for 24 hours. The reaction solution was concentrated in vacuo to obtain crude compound B14 (45 mg) as a pale yellow oil. LC-MS: m / z = 265.1 (M+H) + 。

[0488] Synthesis of general intermediate B15 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0489]

[0490] Step 1: Synthesis of compound B15-3 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol)

[0491] Compound B15-1 (9.6 g, 62.5 mmol, 1.00 eq), compound B15-2 (12.4 g, 81.3 mmol, 1.30 eq), tetrakis(triphenylphosphine)palladium (7.2 g, 6.25 mmol, 0.10 eq), and sodium carbonate (49.0 g, 463 mmol, 7.40 eq) were successively added 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 under nitrogen protection for 12 hours. The mixture 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% NH3·H2O) to obtain compound B15-3 (12.7 g). LC-MS: m / z = 226.2 (M+H) + 。

[0492] Step 2: Synthesis of intermediate B15

[0493] 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 the addition, the temperature was raised to 20 °C and the mixture was stirred for 12 hours. The reaction solution was concentrated in vacuo to obtain compound B15 (7.3 g, 26.2 mmol, 98.2% yield, HCl) as an off-white solid. LC-MS: m / z = 244.1 (M+H) + 。

[0494] Synthesis of general intermediate B16 ((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0495]

[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 successively added to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL). The reaction was carried out at 20 °C for 16 h. Dichloromethane (250.0 mL) was added, and the mixture was filtered to obtain a filtrate, which was washed 3 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 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.85 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1H), 7.37 (d, J = 4.0 Hz, 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 hydride (908 mg, 23.9 mmol, 3.00 eq) was slowly added at 0 °C. After the addition, the temperature was raised to 20 °C and stirred for 3 h. Then, ice water (50.0 mL) was added at 0 °C and stirred for 10 min. The mixture was extracted 3 times with ethyl acetate (50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered to obtain a filtrate, 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), and the reaction was carried out at 20 °C for 12 h. After vacuum concentration, water (10.0 mL) was added and stirred for 5 min. The mixture was extracted with dichloromethane (5.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain white solid compound B16 (1.5 g, 3.38 mmol, 60.2% yield, 98.9% purity). 1 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.84 - 7.79 (m, 3H), 7.38 (m, 3H), 3.72 (s, 2H), 2.47 (s, 3H), 1.93 - 1.89 (m, 6H), 1.57 - 1.54 (m, 6H); LC-MS: m / z = 440.2 (M + H) + 。

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

[0503]

[0504] Step 1: Synthesis of Compound B17-2 (methyl 4-hydrazinobenzoate)

[0505] Compound B17-1 (15.0 g, 90.32 mmol, 1.0 eq) was dissolved in 37% aqueous hydrochloric acid (25.0 mL), and sodium nitrite (6.2 g, 90.32 mmol, 1.0 eq) dissolved in water (10.0 mL) was added at 0 °C. After addition, the mixture was stirred for 10 min. Then, stannous 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 h. The mixture was filtered to obtain a filter cake, and the filter cake was washed with ethyl acetate (50.0 mL) three times. The filtrate was concentrated in vacuo to obtain compound B17-2 (16.5 g). LC-MS: m / z = 167.1 (M + H) + 。

[0506] Step 2: Synthesis of Compound B17-4 (methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate)

[0507] 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 addition, the temperature was raised to 25 °C and stirred for 1 hour. Then, water (10 mL) was added, and the mixture was extracted with dichloromethane (200.0 mL) three times. The organic layers were combined, washed twice with saturated brine (200.0 mL), 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain compound B17-4 (5.3 g). LC-MS: m / z = 285.0 (M+H) + 。

[0508] Step 3: Synthesis of compound B17-5 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol)

[0509] Compound B17-4 (5.3 g, 18.65 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100.0 mL). Lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 eq) was slowly added at 0 °C. After addition, the temperature was raised to 20 °C and stirred for 6 hours. Then, ice water (50.0 mL) was added at 0 °C and stirred for 10 minutes. The mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, 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 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) + 。

[0510] Step 4: Synthesis of intermediate B17

[0511] Compound B17-5 (1.0 g, 3.91 mmol, 1.0 eq) was dissolved in dichloroethane (25.0 mL). Thionyl chloride (1.4 g, 11.73 mmol, 5.2 eq) was added at 0 °C. After addition, the temperature was raised to 50 °C and stirred for 2 hours. The reaction solution was concentrated in vacuo to obtain white solid compound B17 (1.0 g, 3.64 mmol, 93.1% yield, 96.9% purity). 1 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 4.64 (s, 2H), 2.37 (s, 3H); LC-MS: m / z = 275.1 (M+H) + 。

[0512] General intermediate BB1 (2-chloro-5-methoxy-N-methylpyrimidin-4-amine)

[0513] Intermediate BB1 was purchased from Leyan Reagent Co., Ltd.

[0514]

[0515] General intermediate BB2 (2-chloro-5-methoxypyrimidin-4-amine)

[0516] Intermediate BB2 was purchased from Leyan Reagent Co., Ltd.

[0517]

[0518] General intermediate BB3 (2-chloro-5-isopropoxy-N-methylpyrimidin-4-amine)

[0519]

[0520] Step 1: Synthesis of compound BB3-2 (2,4-dichloro-5-isopropoxypyrimidine)

[0521] 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 the mixture was refluxed for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, and phosphorus oxychloride was removed by vacuum concentration. Ice water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a pale yellow oily compound BB3-2 (551.0 mg, crude product). LC-MS: m / z = 207.1 (M+H) + 。

[0522] Step 2: Synthesis of intermediate BB3

[0523] 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 successively added to N,N-dimethylformamide (2.0 mL), and the mixture was stirred at 60 °C for 6 hours. Ethyl acetate (15.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by filtration 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 intermediate BB3 (38.8 mg, 0.19 mmol, 40.1% yield). LC-MS: m / z = 202.1 (M+H) + 。

[0524] General intermediate BB4 (2-chloro-5-isopropoxypyrimidin-4-amine)

[0525]

[0526] Compound BB3-2 (100 mg, 0.48 mmol, 1.00 eq) and ammonia water (1.68 g, 48.0 mmol, 30% purity, 100.0 eq) were added to dioxane (3.0 mL). The reaction was carried out in a sealed tube at 50 °C for 12 hours. The reaction solution was concentrated under vacuum to obtain a crude product, and the crude product was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to obtain the white solid intermediate BB4 (27.3 mg, 0.15 mmol, 30.3% yield). LC-MS: m / z = 188.2 (M+H) + 。

[0527] General intermediate BB12 (2-chloro-5-(trifluoromethyl)pyrimidin-4-amine)

[0528] Intermediate BB12 was purchased from Bidepharm.

[0529]

[0530] Synthesis of general intermediate BB13 (2-chlorofuro[3,2-d]pyrimidin-4-amine)

[0531]

[0532] 2,4-Dichlorofuro[3,2-D]pyrimidine (Compound BB13-1, 5.0 g, 26.46 mmol, 1.00 eq) and ammonia water (30.9 g, 264.6 mmol, 30% purity, 100.0 eq) were added to dioxane (100.0 mL). The reaction was carried out in a sealed tube at 50 °C for 12 hours. The reaction solution was concentrated under vacuum to obtain a crude product, and the crude product was purified by reverse-phase HPLC (0.1% NH₃·H₂O) to obtain the white solid compound BB13 (3.2 g, 18.87 mmol, 71.3% yield). LC-MS: m / z = 170.1 (M+H) + 。

[0533] Synthesis of general intermediate BB14 (2-chloropyridone[3,2-d]pyrimidin-4-amine)

[0534]

[0535] Using 2,4-dichloropyrido[3,2-d]pyrimidine (BB14-1, 3.0 g, 15.0 mmol, 1.00 eq) as the raw material, intermediate BB14 (1.1 g, 6.09 mmol, 40.6% yield) was prepared according to the same procedure as intermediate BB13. LC-MS: m / z = 181.0 (M+H) + 。

[0536] General intermediate BB15 (2,5-dichloropyrimidin-4-amine)

[0537] Intermediate BB15 was purchased from Bide Pharmatech Ltd.

[0538]

[0539] Synthesis of general intermediate BB16 (2-chloro-5-fluoro-N-methylpyrimidin-4-amine)

[0540]

[0541] 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 successively added to N,N-dimethylformamide (500.0 mL). The mixture was stirred at 60 °C for 6 hours, ethyl acetate (1000.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by suction filtration and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to give Compound BB16 (1.1 g, 6.81 mmol, 37.7% yield). LC-MS: m / z = 162.0 (M+H) + 。

[0542] Synthesis of general intermediate BB16-D3 (2-chloro-5-fluoro-N-(methyl-D3)pyrimidin-4-amine)

[0543]

[0544] Using 2,4-dichloro-5-fluoropyrimidine (BB16-1, 3.0 g, 18.07 mmol, 1.00 eq) as the raw material, intermediate BB16-D3 (1.47 g, 8.93 mmol, 49.4% yield) was prepared according to the same procedure as intermediate BB16. LC-MS: m / z = 165.1 (M+H) + 。

[0545] General intermediate BB17 (4-amino-2-chloropyrimidine-5-carbonitrile)

[0546] The intermediate BB17 was purchased from Bidepharm.

[0547]

[0548] Synthesis of general intermediate BB18 (2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine)

[0549]

[0550] Compound 2,4-dichloro-5-iodopyrimidine (BB18-1, 1.0 g, 3.6 mmol, 1.00 eq), bis(triphenylphosphine)palladium(II) dichloride (256 mg, 0.3 mmol, 0.1 eq), copper(I) iodide (139 mg, 0.7 mmol, 0.2 eq), trimethylsilylacetylene (700 mg, 7.2 mmol, 2.0 eq) and triethylamine (1.1 g, 10.9 mmol, 3.0 eq) were successively added to tetrahydrofuran (15 mL), and the mixture was stirred at 40 °C for 3 h. The mixture was concentrated under vacuum to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain a white solid compound BB18 (590 mg, 2.4 mmol). 1 HNMR (400 MHz, DMSO) δ 8.97–8.89 (m, 1H), 0.28 (s, 9H).

[0551] Synthesis of general intermediate BB19 (2-chloro-5-(difluoromethoxy)pyrimidin-4-amine)

[0552]

[0553] Step 1: Synthesis of compound BB19-2 (2,4-dichloro-5-(difluoromethoxy)pyrimidine)

[0554] 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 successively added to acetonitrile (60.0 mL) and water (60.0 mL). Diethyl bromofluoromethylphosphonate (9.35 g, 35.0 mmol, 1.70 eq) was added dropwise. After the addition was complete, the mixture was stirred at 25 °C for 1.5 h. The reaction was quenched by adding saturated lemon aqueous solution (10.0 mL), water (10.0 mL) was added, and the mixture was extracted 3 times with ethyl acetate (40 mL). The organic layers were combined, washed 2 times with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1) to obtain a pale yellow oily intermediate BB19-2 (3.70 g, 17.2 mmol, 83.5% yield). 11H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 6.84 - 6.49 (t, J = 70.8 Hz, 1H); LC-MS: m / z = 215.0 (M + H) + 。

[0555] Step 2: Synthesis of intermediate BB19

[0556] Using compound BB19-2 (500.0 mg, 2.33 mmol, 1.00 eq) as the raw material, intermediate BB19 (298.5 mg, 1.53 mmol, 65.5% yield) was prepared according to the same procedure as intermediate BB13. LC-MS: m / z = 196.1 (M + H) + 。

[0557] General intermediate BB21 (4-(2,4-dichloropyrimidin-5-yl)morpholine)

[0558] Intermediate BB21 was purchased from Bidepharm.

[0559]

[0560] Synthesis of general intermediate BB22 (2,4-dichloro-5-(4-methylpiperazin-1-yl)pyrimidine)

[0561]

[0562] Step 1: Synthesis of compound BB22-2 (5-(4-methylpiperazin-1-yl)pyrimidine-2,4(1H,3H)-dione)

[0563] 5-Bromouracil (BB22-1, 5.0 g, 26.18 mmol, 1.00 eq) was dissolved in pyridine (25 mL), N-methylpiperazine (3.9 g, 39.2 mmol, 1.5 eq) was added, the temperature was raised to 110 °C, and the mixture was stirred for 4 hours. Then it was cooled to room temperature, concentrated in vacuo to obtain the crude product, triturated with ethyl acetate (50 mL), filtered to obtain the solid, and 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) + 。

[0564] Step 2: Synthesis of compound BB22

[0565] BB22-2 (5.0 g, 23.8 mmol, 1.0 eq) was added to phosphorus oxychloride (200 mL), and the mixture was stirred at 90 °C for 16 h. After cooling to room temperature, it was concentrated under vacuum. The pH was adjusted to about 7 with saturated aqueous sodium bicarbonate, and the mixture was extracted with dichloromethane (300 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain a yellow solid intermediate BB22 (1.3 g, 5.26 mmol, 22.1% yield, 97.8% purity). 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 3.16–3.05 (m, 4H), 2.50–2.42 (m, 4H), 2.24 (s, 3H); LC-MS: m / z = 247.1 (M+H) + 。

[0566] General intermediate BB24 (2,4-dichloropyrimidin-5-ol)

[0567] Intermediate BB24 was purchased from Bide Pharmatech.

[0568]

[0569] General intermediate BB35 ((2,4-dichloropyrimidin-5-yl)methanol)

[0570] Intermediate BB35 was purchased from Bide Pharmatech.

[0571]

[0572] Synthesis of general intermediate BB36 (2-chloro-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0573]

[0574] Using 2,4-dichloro-5-(methoxymethyl)pyrimidine (BB36-1, 2.9 g, 15.0 mmol, 1.00 eq) as the raw material, intermediate BB36 (1.89 g, 10.07 mmol, 67.2% yield) was prepared according to the same procedure as intermediate BB16. LC-MS: m / z = 188.1 (M+H) + 。

[0575] Synthesis of general intermediate BB41 (methyl 2-(2,4-dichloropyrimidin-5-yl)acetate)

[0576]

[0577] Step 1: Synthesis of Compound BB41-2 (Dimethyl 2-formylsuccinate)

[0578] 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 successively added to tetrahydrofuran (850 mL), and the mixture was stirred at 25 °C for 12 hours. Then, the reaction solution was concentrated in vacuo to obtain a crude product. The crude product was washed twice with petroleum ether (400 mL), the pH was adjusted to about 6 with 1 M hydrochloric acid, and the mixture was extracted three times with methyl tert-butyl ether (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain Compound BB41-2 as a yellow oil (70.0 g, 402 mmol, 29.4% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.69 (m, 1H), 4.03 - 3.58 (m, 1H), 3.57 - 3.56 (m, 6H), 1.17 - 1.10 (m, 1H), 1.07 - 1.03, (m, 1H).

[0579] Step 2: Synthesis of Compound BB41-3 (2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetic acid)

[0580] 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, and the filter cake was obtained by filtration. 1 M hydrochloric acid aqueous solution (600 mL) was added, and the mixture was stirred at 0 °C for 30 minutes. The filter cake was obtained by filtration and washed twice with water (100 mL) to obtain Compound BB41-3 as a white solid (30.0 g, 161 mmol, 46.8% yield, 100% purity). 1 1H NMR (400 MHz, CDCl3) δ 12.5 (s, 1H), 12.3 - 12.2 (m, 2H), 7.42 (s, 1H), 3.20 (s, 2H).

[0581] Step 3: Synthesis of Compound BB41-4 (Methyl 2-(6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidin-5-yl)acetate)

[0582] Compound BB41-3 (15.0 g, 80.6 mmol, 1.00 eq) was dissolved in methanol (100 mL), concentrated sulfuric acid (23.7 g, 242 mmol, 12.9 mL, 3.00 eq) was added, and the mixture was stirred at 80 °C for 12 hours. The filtrate was obtained by filtration, and the white solid compound BB41-4 (13.0 g, 64.9 mmol, 80.6% yield) was obtained by vacuum concentration. 1 1H NMR (400 MHz, CDCl3) δ 12.5 (s, 1H), 12.3 (s, 1H), 7.40 - 7.60 (m, 1H), 3.59 (s, 3H), 3.30 (s, 2H).

[0583] Step 4: Synthesis of Intermediate BB41

[0584] 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 the mixture was stirred at 110 °C for 12 hours under nitrogen protection. After cooling to 20 °C, ice water (50.0 mL) was added, and the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate solution. The mixture was extracted 3 times with ethyl acetate (30 mL), the organic layers were combined, washed 3 times with saturated brine (35.0 mL), and the filtrate was obtained by suction filtration. The crude product was obtained by vacuum concentration, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain the pale yellow oily compound BB41 (3.60 g, 15.7 mmol, 26.2% yield, 96.4% purity). LC-MS: m / z = 220.9 (M + H) + 。

[0585] Synthesis of General Intermediate BB42 (2-chloro-5-methoxy-N-(prop-2-yn-1-yl)pyrimidin-4-amine)

[0586]

[0587] Using 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) as raw materials, Intermediate BB42 (140.8 mg, 0.71 mmol, 25.6% yield) was prepared according to the same steps as Intermediate BB16. LC-MS: m / z = 198.2 (M + H) + 。

[0588] Synthesis of General Intermediate BB43 (2-chloro-5-methoxy-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine)

[0589]

[0590] Using 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) as starting materials, intermediate BB43 (910.5 mg, 3.96 mmol, 59.2% yield) was prepared according to the same procedure as for intermediate BB16. LC-MS: m / z = 230.2 (M+H) + 。

[0591] Synthesis of general intermediate BB44 (2-chloro-N-cyclopropyl-5-methoxypyrimidin-4-amine)

[0592]

[0593] Using 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) as starting materials, intermediate BB44 (556.3 mg, 2.79 mmol, 62.3% yield) was prepared according to the same procedure as for intermediate BB16. LC-MS: m / z = 200.1 (M+H) + 。

[0594] Synthesis of general intermediate BB45 (N-(2-chloro-5-methoxypyrimidin-4-yl)-O-methylhydroxylamine)

[0595]

[0596] Using 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) as starting materials, intermediate BB45 (490.0 mg, 2.58 mmol, 92.3% yield) was prepared according to the same procedure as for intermediate BB16. LC-MS: m / z = 190.1 (M+H) + 。

[0597] Synthesis of general intermediate C2 (2-(4-(chloromethyl)cyclohexyl)pyridine)

[0598]

[0599] Step 1: Synthesis of compound C2-2 (ethyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate)

[0600] 2-Bromopyridine (C2-1, 15.0 g, 94.9 mmol, 9.04 mL, 1.00 eq) was added successively to 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] dichloropalladium (6.95 g, 9.49 mmol, 0.10 eq) in water (50.0 mL) and dioxane (200 mL). The mixture was stirred at 100 °C for 16 h under nitrogen protection. Then, water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (100 mL) three times. The organic layers were combined, washed twice with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to give a colorless transparent oily compound C2-2 (9.00 g, 38.9 mmol, 41.0% yield). 1 H NMR (400 MHz, CDCl3) δ 8.54 - 8.55 (m, 1H), 7.60 - 7.64 (m, 1H), 7.37 (d, J = 8.8 Hz, 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) + 。

[0601] Step 2: Synthesis of compound C2-3 (ethyl 4-(pyridin-2-yl)cyclohexanecarboxylate)

[0602] Compound C2-2 (9.00 g, 38.9 mmol, 1.00 eq) was dissolved in methanol (288.0 mL). Palladium on carbon (4.14 g, 3.89 mmol, 10% purity, 0.10 eq) was added under a nitrogen atmosphere, and the mixture was purged with hydrogen three times. The mixture was then stirred at 25 °C for 16 h under a hydrogen atmosphere (15 Psi), filtered to obtain a filtrate, and concentrated in vacuo to give a colorless transparent oily compound C2-3 (8.13 g, 34.9 mmol, 89.6% yield). 11H NMR (400 MHz, CDCl3) δ 8.51 - 8.54 (m, 1H), 7.58 - 7.62 (m, 1H), 7.09 - 7.14 (m, 2H), 4.14 - 4.20 (m, 2H), 2.67 - 2.78 (m, 1H), 2.22 - 2.25 (m, 3H), 1.62 - 1.87 (m, 6H), 1.26 - 1.29 (m, 3H); LC-MS: m / z = 234.0 (M + H) + 。

[0603] Step 3: Synthesis of compound C2-4 ((4-(pyridin-2-yl)cyclohexyl)methanol)

[0604] Dissolve compound C2-3 (8.13 g, 34.8 mmol, 1.00 eq) in tetrahydrofuran (300.0 mL), add diisobutylaluminum hydride (1 M, 112 mL, 3.20 eq) dropwise at -70 °C. After addition, stir at -70 °C for 30 minutes, then warm to 25 °C and stir for 1 hour. Quench the reaction by adding water (100 mL) at 0 °C. Extract with ethyl acetate (300 mL) three times, combine the organic layers, wash twice with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to get the crude product. The crude product is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain colorless transparent oily compound C2-4 (4.80 g, 25.1 mmol, 72.0% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.54 - 8.55 (m, 1H), 7.59 - 7.63 (m, 1H), 7.10 - 7.20 (m, 2H), 3.52 - 3.71 (m, 2H), 2.80 - 2.85 (m, 1H), 1.67 - 1.84 (m, 8H), 1.15 - 1.23 (m, 1H); LC-MS: m / z = 192.0 (M + H) + 。

[0605] Step 4: Synthesis of compound C2

[0606] Dissolve compound C2-4 (800 mg, 4.18 mmol, 1.00 eq) in dichloromethane (16.0 mL), add thionyl chloride (2.49 g, 20.9 mmol, 1.52 mL, 5.00 eq) at 0 °C. After addition, warm to 20 °C and stir for 12 hours. Concentrate the reaction mixture in vacuo to obtain white solid intermediate C2 (900 mg, crude product). LC-MS: m / z = 210.0 (M + H) + 。

[0607] Synthesis of general intermediate C3 (2-(4-(chloromethyl)phenyl)pyridine)

[0608]

[0609] Step 1: Synthesis of Compound C3-2 ((4-(pyridin-2-yl)phenyl)methanol)

[0610] 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), tetrakis(triphenylphosphine)palladium(0) (7.31 g, 6.33 mmol, 0.100 eq), and sodium carbonate (49.6 g, 468 mmol, 7.40 eq) were successively added to a mixed solvent of toluene (50.0 mL), water (50.0 mL), and ethanol (10.0 mL). The mixture was purged with nitrogen three times and stirred at 100 °C for 12 hours under nitrogen protection. The mixture 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% NH3·H2O) to obtain a pale yellow oily compound C3-2 (9.63 g). 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.4 Hz, 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) + 。

[0611] Step 2: Synthesis of Intermediate C3

[0612] 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 a white solid intermediate C3 (1.1 g, crude product). LC-MS: m / z = 204.1 (M + H) + 。

[0613] Synthesis of General Intermediate C4 (4-(chloromethyl)-1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine)

[0614]

[0615] Step 1: Synthesis of Compound C4-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0616] Dissolve 4-(trifluoromethyl)-1H-imidazole (Compound C4-1, 33.0 g, 242 mmol, 1.00 eq) in tetrahydrofuran (330.0 mL). Add sodium hydride (9.70 g, 242 mmol, 60.0% purity, 1.00 eq) portionwise at 0 °C. After addition, stir the reaction mixture at 0 °C for 30 minutes. Then, add methyl iodide (34.4 g, 242 mmol, 15.1 mL, 1.00 eq). After addition, warm the reaction mixture to 25 °C and stir for 4 hours. Then, quench the reaction by adding ice water (200.0 mL) at 0 °C. Extract with ethyl acetate (200.0 mL) three times. Combine the organic layers, dry over anhydrous sodium sulfate, filter by suction to obtain a filtrate, and concentrate the filtrate under vacuum to obtain a crude product. The crude product is purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound C4-2 (21.0 g). 1 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M + H) + 。

[0617] Step 2: Synthesis of Compound C4-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0618] Dissolve Compound C4-2 (16.8 g, 111 mmol, 1.00 eq) in anhydrous tetrahydrofuran (370.0 mL). Add n-butyllithium (2.5 M, 44.7 mL, 1.00 eq) dropwise at -70 °C. After addition, stir the reaction mixture at -70 °C for 30 minutes. Then, add hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) dropwise to the reaction solution. After addition, stir the reaction mixture at -70 °C for 1 hour, warm the reaction mixture to 20 °C and stir for 3 hours, quench the reaction by adding saturated ammonium chloride aqueous solution (200.0 mL) at 0 °C, add water (300.0 mL), extract with ethyl acetate (150.0 mL) three times, wash the combined organic layers with saturated brine (200.0 mL) twice, dry over anhydrous sodium sulfate, filter to obtain a filtrate, and concentrate the filtrate under vacuum to obtain a crude product. The crude product is 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) + 。

[0619] Step 3: Synthesis of Compound C4-4 (ethyl 1-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0620] Compound C4-3 (7.0 g, 31.9 mmol, 1.00 eq), ethyl 4-piperidinecarboxylate (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 successively added to N,N-dimethylformamide (70.0 mL). The reaction was carried out at 130 °C for 72 h. Water (350 mL) was added and stirred for 5 min. The mixture was extracted with ethyl acetate (100 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by reverse-phase HPLC (0.1% FA) to obtain compound C4-4 (2.2 g). 1 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J = 7.2 Hz, 2H), 3.45 (s, 3H), 3.24 - 3.28 (m, 2H), 2.90 - 2.97 (m, 2H), 2.40 - 2.45 (m, 1H), 2.02 - 2.06 (m, 2H), 1.85 - 1.88 (m, 2H), 1.28 (t, J = 8.0 Hz, 2H); LC-MS: m / z = 340.1 (M + H) + .

[0621] Step 4: Synthesis of compound C4-5 (ethyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate)

[0622] 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 on carbon (0.5 g, 1.94 mmol, 10.0% purity, 0.300 eq) were successively added to ethanol (40.0 mL). The reaction was carried out at 50 °C for 36 h under a hydrogen atmosphere (15 psi). The reaction mixture was filtered to obtain a filtrate, and concentrated in vacuo to give compound C4-5 (1.9 g). 1 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.15 (q, J = 7.2 Hz, 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 = 6.8 Hz, 3H); LC-MS: m / z = 306.1 (M + H) + .

[0623] Step 5: Synthesis of Compound C4-6 ((1-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanol)

[0624] Dissolve Compound C4-5 (1.2 g, 3.93 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL). Add lithium aluminum hydride (447 mg, 11.8 mmol, 3.00 eq) at 0 °C. After addition, react at 0 °C for 0.5 h, then warm to 20 °C and stir for 12 h. Then, add sodium sulfate decahydrate (0.5 g) at 0 °C. After addition, warm to 20 °C and stir for 30 min. Add tetrahydrofuran (10.0 mL), filter to obtain the filtrate, separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain the filtrate, and concentrate in vacuo to obtain Compound C4-6 (1.0 g, crude product). The crude product is directly used for the next reaction. 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 3.57 (d, J = 6.4 Hz, 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) + 。

[0625] Step 6: Synthesis of Intermediate C4

[0626] Dissolve Compound C4-6 (1.0 g, 3.80 mmol, 1.00 eq) in dichloromethane (2.0 mL). Add thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) at 0 °C. After addition, warm to 20 °C and stir for 24 h. Concentrate the reaction solution in vacuo to obtain the brown solid Intermediate C4 (1.1 g, 3.46 mmol, 91.0% yield, HCl). LC-MS: m / z = 282.1 (M + H) + 。

[0627] Synthesis of General Intermediate C5 (2-(4-(Chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0628]

[0629] Step 1: Synthesis of Compound C5-2 (Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0630] 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), stir at 100 °C for 1 hour, and add methyl 4-formylbenzoate (C5-1, 4.0 g, 24.4 mmol, 1.00 eq) dissolved in methanol (80.0 mL) and ammonia water (22.0 mL) at 25 °C. After the addition, react at 25 °C for 40 minutes, then raise the temperature to 100 °C and stir for 2 hours. Then, add water (60.0 mL) to quench the reaction, extract with ethyl acetate (80.0 mL) three times, combine the organic layers, wash twice with saturated brine (80.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain compound C5-2 (4.5 g). 1 1H NMR (400 MHz, CDCl3) δ 13.4 (s, 1H), 8.10 - 8.12 (m, 2H), 8.04 - 8.06 (m, 2H), 7.99 (s, 1H), 3.87 (s, 3H); LC-MS: m / z = 271.0 (M + H) + 。

[0631] Step 2: Synthesis of compound C5-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate)

[0632] Dissolve compound C5-2 (2.5 g, 9.3 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL), add sodium hydride (444.1 mg, 11.1 mmol, 1.20 eq) portionwise at 0 °C. After the addition, react at 0 °C for 30 minutes. Then, add methyl iodide (6.8 g, 48.1 mmol, 5.20 eq). After the addition, raise the temperature to 20 °C and stir for 15 hours. Then, add ice water (20.0 mL) at 0 °C to quench the reaction, extract with ethyl acetate (30.0 mL) three times, combine the organic layers, wash twice with saturated brine (30.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain compound C5-3 (1.1 g). 1 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.99 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H); LC-MS: m / z = 285.1 (M + H) + 。

[0633] Step 3: Synthesis of Compound C5-4 ((4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol)

[0634] Dissolve Compound C5-3 (0.6 g, 2.1 mmol, 1.00 eq) in tetrahydrofuran (6.0 mL). Add lithium aluminum hydride (88.1 mg, 2.32 mmol, 1.10 eq) at 0 °C. After addition, warm the mixture to 25 °C and stir for 4 hours. Add water (1.6 mL) and aqueous sodium hydroxide solution (1 M, 0.4 mL) at 0 °C, stir at 0 °C for 0.5 hour, add tetrahydrofuran (10.0 mL) and anhydrous sodium sulfate (1.0 g), filter to obtain the filtrate, and concentrate it under vacuum to get the crude product C5-4 (505.4 mg). The crude product is directly used in the next step of the reaction. 1 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.30 - 5.33 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H); LC-MS: m / z = 257.1 (M + H)+.

[0635] Step 4: Synthesis of Intermediate C5

[0636] Dissolve Compound C5-4 (500.0 mg, 2.0 mmol, 1.00 eq) in dichloromethane (5.0 mL). Add thionyl chloride (1.9 g, 15.6 mmol, 8.00 eq) at 0 °C. After addition, warm the mixture to 20 °C and stir for 15 hours. Concentrate the reaction mixture under vacuum to obtain a brown solid compound C5 (523 mg, 1.90 mmol, 97.6% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 4.84 (s, 2H), 3.80 (s, 3H); LC-MS: m / z = 275.1 (M + H) + 。

[0637] Synthesis of General Intermediate C6 (2-(4-(Chloromethyl)piperidin-1-yl)pyridine)

[0638]

[0639] Step 1: Synthesis of Compound C6-2 (Ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate)

[0640] Ethyl 4-piperidinecarboxylate (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 the reaction was carried out at 130 °C for 16 hours. The temperature was lowered, the reaction was stopped, water (50 ml) was added at room temperature to quench the reaction, and the mixture was extracted with ethyl acetate (60.0 mL) three times. The organic layers were combined, washed twice with saturated brine (30.0 mL), 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain Compound C6-2 as a yellow oil (6.0 g, yield 19.4%, purity 100%). 1 H NMR (400 MHz, CDCl3) δ 8.17 - 8.19 (m, 1H), 7.44 - 7.48 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.59 - 6.61 (m, 1H), 4.21 - 4.24 (m, 2H), 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) + 。

[0641] Step 2: Synthesis of Compound C6-3 ((1-(pyridin-2-yl)piperidin-4-yl)methanol)

[0642] Compound C6-2 (6.00 g, 25.6 mmol) was dissolved in THF (60.0 mL), and lithium aluminum hydride (1.07 g, 28.2 mmol, 1.10 eq) was added portionwise at 0 °C. The mixture was warmed to room temperature and stirred for 16 h, then additional lithium aluminum hydride (486 mg, 12.8 mmol, 0.500 eq) was added and stirring was continued for 6 hours. Water (20.0 mL) was added at 0 °C to quench the reaction, and the mixture was extracted with ethyl acetate (60.0 mL) three times. The organic layers were combined, washed twice with saturated brine (20.0 mL), 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain Compound C6-3 as a yellow oil (1.20 g, yield 23.8%, purity 97.8%). 11H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.6 Hz, 1H), 7.43 - 7.48 (m, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.58 - 6.59 (m, 1H), 4.33 (d, J = 12.8 Hz, 2H), 3.54 (d, J = 6.0 Hz, 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) + 。

[0643] Step 3: Synthesis of Intermediate C6

[0644] Dissolve compound C6-3 (1.20 g, 6.24 mmol, 1.00 eq) in dichloromethane (12.0 mL). Add thionyl chloride (3.71 g, 31.2 mmol, 2.26 mL, 5.00 eq) at 0 °C. After addition, warm the reaction mixture to 20 °C and stir for 12 h. Concentrate the reaction solution under vacuum to obtain white solid Intermediate C6 (1.57 g, crude product). LC-MS: m / z = 211.1

[0645] Synthesis of General Intermediate C7 (2-(5-(Chloromethyl)thiophen-2-yl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0646]

[0647] For the synthesis of General Intermediate C7, refer to the synthesis of Intermediate C5 for specific operations. Replace compound C5-1 with an equimolar amount of methyl 5-formylthiophene-2-carboxylate (Compound C7-1), and keep other experimental conditions unchanged. Finally, obtain white solid Intermediate C7 (330.0 mg, crude product). LC-MS: m / z = 281.0 (M + H) + 。

[0648] Synthesis of General Intermediate C9 (2-((1R,4R)-4-(Chloromethyl)cyclohexyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0649]

[0650] Step 1: Synthesis of Compound C9-2 (1-Methyl-4-(trifluoromethyl)-1H-imidazole)

[0651] Dissolve 4-(trifluoromethyl)-1H-imidazole (Compound C9-1, 33.0 g, 242.0 mmol, 1.00 eq) in tetrahydrofuran (330.0 mL). Add sodium hydride (9.7 g, 242.0 mmol, 60.0% purity, 1.00 eq) portionwise at 0 °C. After addition, react at 0 °C for 30 minutes. Then, add methyl iodide (34.4 g, 242.0 mmol, 15.1 mL, 1.00 eq). After addition, warm the reaction mixture to 25 °C and stir for 5 hours. Quench the reaction by adding saturated ammonium chloride aqueous solution (30.0 mL) at 0 °C. Add water (30.0 mL), and extract with ethyl acetate (30.0 mL) three times. Combine the organic layers, wash twice with saturated brine (30.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain the crude product. The crude product is purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain Compound C9-2 (21.0 g). 1 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.24 (s, 1H), 3.75 (s, 3H); LC-MS: m / z = 151.1 (M + H) + 。

[0652] Step 2: Synthesis of Compound C9-3 (2,5-dichloro-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0653] Dissolve Compound C9-2 (16.8 g, 111.0 mmol, 1.00 eq) in anhydrous tetrahydrofuran (370.0 mL). Add n-butyllithium (2.5 M, 44.7 mL, 1.00 eq) dropwise at -70 °C. After addition, stir at -70 °C for 30 minutes. Then, add hexachloroethane (15.9 g, 67.0 mmol, 0.60 eq) dissolved in anhydrous tetrahydrofuran (60.0 mL) dropwise to the reaction mixture. After addition, react at -70 °C for 1 hour, warm to 20 °C and stir for 3 hours. Quench the reaction by adding saturated ammonium chloride aqueous solution (200.0 mL) at 0 °C. Add water (300.0 mL), and extract with ethyl acetate (150.0 mL) three times. Combine the organic layers, wash twice with saturated brine (200.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain the crude product. The crude product is 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) + 。

[0654] Step 3: Synthesis of Compound C9-4 (ethyl 4-(5-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohex-3-ene-1-carboxylate)

[0655] 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, 1.6 mmol, 0.05 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.9 g, 12.4 mmol, 0.39 eq) were successively added to a mixed solvent of dioxane (70.0 mL) and water (10.0 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C under nitrogen protection for 5 hours. The reaction solution was filtered to obtain a filtrate, which was concentrated in vacuo to give a crude product. The crude product was purified by reverse-phase HPLC (0.1% FA) to obtain Compound C9-4 (1.9 g). 1 1H NMR (400 MHz, CDCl3) δ 6.05 (d, J = 2.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.61 (s, 3H), 2.50 - 2.67 (m, 5H), 2.13 - 2.14 (m, 1H), 1.86 - 1.89 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); LC-MS: m / z = 337.2 (M + H) + 。

[0656] Step 4: Synthesis of Compound C9-5 ((1R,4R)-ethyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexane-1-carboxylate)

[0657] 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 on carbon (0.5 g, 1.4 mmol, 10.0% purity, 0.25 eq) were successively added to ethanol (30.0 mL). The reaction was carried out 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 give 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 C9-5 (0.3 g). 11H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 4.15 (q, J = 6.8 Hz, 2H), 3.64 (s, 3H), 2.60 - 2.65 (m, 1H), 2.41 - 2.44 (m, 1H), 2.12 - 2.15 (m, 2H), 1.97 - 1.98 (m, 2H), 1.77 - 1.80 (m, 2H), 1.54 - 1.59 (m, 2H), 1.27 (t, J = 8.8 Hz, 3H); LC-MS: m / z = 305.0 (M+H) + 。

[0658] Step 5: Synthesis of Compound C9-6 (((1R,4R)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cyclohexyl)methanol)

[0659] Dissolve Compound C9-5 (0.6 g, 2.0 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL). Add lithium aluminum hydride (224.0 mg, 5.9 mmol, 3.00 eq) at 0 °C. After addition, react at 0 °C for 0.5 h, then warm to 20 °C and stir for 12 h. Then, add sodium sulfate decahydrate (0.5 g) at 0 °C. After addition, warm to 20 °C and stir for 30 min. Add tetrahydrofuran (10.0 mL), filter to obtain a filtrate, separate the organic layer, dry over anhydrous sodium sulfate, filter by suction to obtain a filtrate, and concentrate in vacuo to obtain the crude product of Compound C9-6 (0.5 g). The crude product is directly used for the next reaction. 1 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 3.63 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 2.59 - 2.65 (m, 1H), 1.95 - 1.98 (m, 4H), 1.77 - 1.80 (m, 3H), 1.07 - 1.17 (m, 2H); LC-MS: m / z = 263.1 (M+H)+.

[0660] Step 6: Synthesis of Intermediate C9

[0661] Dissolve Compound C9-6 (500.0 mg, 1.9 mmol, 1.00 eq) in dichloromethane (2.0 mL). Add thionyl chloride (4.5 g, 38.1 mmol, 20.0 eq) at 0 °C. After addition, warm to 20 °C and stir for 24 h. Concentrate the reaction solution in vacuo to obtain a pale yellow solid of Intermediate C9 (550 mg, 1.36 mmol, 71.5% yield). LC-MS: m / z = 281.0 (M+H) + 。

[0662] Synthesis of General Intermediate C11 (1-(4-(Chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0663]

[0664] Step 1: Synthesis of Compound C11-2 (Methyl 4-hydrazinobenzoate)

[0665] Dissolve Compound C11-1 (15.0 g, 90.32 mmol, 1.0 eq) in 37% aqueous hydrochloric acid (25.0 mL). Add sodium nitrite (6.2 g, 90.32 mmol, 1.0 eq) dissolved in water (10.0 mL) at 0 °C. After addition, stir for 10 minutes. Then, dropwise add stannous chloride (85.6 g, 451.62 mmol, 5.0 eq) dissolved in 37% aqueous hydrochloric acid (75.0 mL) at 0 °C. After addition, warm the temperature to 25 °C and stir for 2 hours. Filter to obtain the filter cake, wash the filter cake 3 times with ethyl acetate (50.0 mL), and concentrate under vacuum to obtain Compound C11-2 (16.5 g). LC-MS: m / z = 167.1 (M+H) + 。

[0666] Step 2: Synthesis of Compound C11-3 (Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate)

[0667] Add 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) to hexafluoroisopropanol (25.0 mL). Dropwise add triethylamine (5.0 g, 49.50 mmol, 2.0 eq) dissolved in hexafluoroisopropanol (25.0 mL) at 0 °C. After addition, warm the temperature to 25 °C and stir for 1 hour. Then, add water (10 mL), extract 3 times with dichloromethane (200.0 mL), combine the organic layers, wash 2 times with saturated brine (200.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate under vacuum to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain Compound C11-3 (5.3 g). LC-MS: m / z = 285.0 (M+H) + 。

[0668] Step 3: Synthesis of Compound C11-4 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol)

[0669] Compound C11-3 (5.3 g, 18.65 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100.0 mL). Lithium aluminum hydride (1.9 g, 46.64 mmol, 2.5 eq) was slowly added at 0 °C. After the addition, the temperature was raised to 20 °C and stirred for 6 hours. Then, ice water (50.0 mL) was added at 0 °C and stirred for 10 minutes. The mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, 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 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) + 。

[0670] Step 4: Synthesis of Intermediate C11

[0671] Compound C11-4 (1.0 g, 3.91 mmol, 1.0 eq) was dissolved in dichloroethane (25.0 mL). 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 (400 MHz, CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 4.64 (s, 2H), 2.37 (s, 3H); LC-MS: m / z = 275.1 (M+H) + 。

[0672] Synthesis of General Intermediate C12 (8-(4-(chloromethyl)phenyl)imidazo[1,2-a]pyrazine)

[0673]

[0674] Step 1: Synthesis of Compound C12-2 ((4-(imidazo[1,2-a]pyrazin-8-yl)phenyl)methanol)

[0675] 8-Chloroimidazo[1,2-a]pyrazine (Compound C12-1, 9.6 g, 62.5 mmol, 1.00 eq), 4-(Hydroxymethyl)phenylboronic acid (12.4 g, 81.3 mmol, 1.30 eq), tetrakis(triphenylphosphine)palladium(0) (7.2 g, 6.25 mmol, 0.10 eq), and sodium carbonate (49.0 g, 463 mmol, 7.40 eq) were successively added 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 under nitrogen protection for 12 hours. The mixture was filtered by suction 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% NH3·H2O) to obtain Compound C12-2 (12.7 g). LC-MS: m / z = 226.2 (M+H) + 。

[0676] Step 2: Synthesis of Intermediate C12

[0677] A solution of Compound C12-2 (6.0 g, 26.6 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added with thionyl chloride (15.9 g, 133 mmol, 5.00 eq) 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 an off-white solid Intermediate C12 (7.3 g, 26.2 mmol, 98.2% yield, HCl). LC-MS: m / z = 244.1 (M+H)+.

[0678] Synthesis of General Intermediate C13 (2-(4-(Chloromethyl)phenyl)-5-(trifluoromethyl)pyridine)

[0679]

[0680] Using 2-bromo-5-(trifluoromethyl)pyridine (Compound C13-1) as a raw material, Intermediate C13 (2.0 g) was prepared according to the same steps as Intermediate C3. LC-MS: m / z = 272.0 (M+H) + 。

[0681] Synthesis of General Intermediate C14 (2-(4-(Chloromethyl)phenyl)-5-methylpyridine)

[0682]

[0683] Using 2-bromo-5-methylpyridine (Compound C14-1) as a raw material, Intermediate C14 (10.0 g) was prepared according to the same steps as Intermediate C3. LC-MS: m / z = 218.0 (M+H) + 。

[0684] Synthesis of General Intermediate C19 ((4-(5-(Trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0685]

[0686] Step 1: Synthesis of Compound C19-2 (Methyl 4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate)

[0687] Monomethyl bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylate (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 successively added to a mixed solvent of dichloromethane (750.0 mL) and water (750.0 mL). The reaction was carried out at 20 °C for 16 hours. Dichloromethane (250.0 mL) was added, and the mixture was filtered to obtain a filtrate, which was washed 3 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 (purification conditions, NH3.H2O / MeCN / H2O) to obtain Compound C19-2 (7.5 g). 1 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.85 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1H), 7.37 (d, J = 4.0 Hz, 1H), 3.69 (s, 3H), 1.96 (s, 12H).

[0688] Step 2: Synthesis of Compound C19-3 ((4-(5-(Trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol)

[0689] Compound C19-2 (2.5 g, 7.98 mmol, 1.00 eq) was dissolved in tetrahydrofuran (50.0 mL). Lithium aluminum hydride (908 mg, 23.9 mmol, 3.00 eq) was slowly added at 0 °C. After addition, 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. The mixture was extracted 3 times with ethyl acetate (50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain a white solid Compound C19-3 (2.3 g). LC-MS: m / z = 286.1 (M+H) + 。

[0690] Step 3: Synthesis of Intermediate C19

[0691] 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). The reaction was carried out at 20 °C for 12 hours. After vacuum concentration, water (10.0 mL) was added and stirred for 5 minutes. The mixture was extracted with dichloromethane (5.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1) to obtain a white solid intermediate C19 (1.5 g, 3.38 mmol, 60.2% yield, 98.9% purity). 1 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.84 - 7.79 (m, 3H), 7.38 (m, 3H), 3.72 (s, 2H), 2.47 (s, 3H), 1.93 - 1.89 (m, 6H), 1.57 - 1.54 (m, 6H); LC-MS: m / z = 440.2 (M + H) + 。

[0692] Synthesis of general intermediate C25 (6-(chloromethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0693]

[0694] Step 1: Synthesis of compound C25-2 (methyl 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate)

[0695] 2-Methyl-1-oxo-3,4-dihydroisoquinoline-6-carbonitrile (compound C25-1, 500 mg, 2.69 mmol, 1 eq) was dissolved in hydrochloric acid in methanol (4 M, 6.71 mL, 10 eq). The mixture was stirred at 70 °C for 3 hours. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (FA) to obtain a white solid compound C25-2 (0.16 g, 715.21 μmol, 26.64% yield, 98% purity). LC-MS: m / z = 220.2 (M + H) + 。

[0696] Step 2: Synthesis of compound C25-3 (6-(hydroxymethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0697] 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. After the addition, the reaction mixture was stirred at 25 °C for 3 hours. Then, hydrochloric acid (2 mL, 1 M) was added for quenching three times, and the mixture was extracted with ethyl acetate (15.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a white solid compound C25-3 (50 mg, crude product). LC-MS: m / z = 192.2 (M+H) + .

[0698] Step 3: Synthesis of Intermediate C25

[0699] 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 the addition, the reaction mixture was heated to 20 °C and stirred for 12 hours. The reaction solution was concentrated in vacuo to obtain an off-white solid Intermediate C25 (50 mg, 238.47 μmol, 91.20% yield). LC-MS: m / z = 210.0 (M+H) + .

[0700] Synthesis of General Intermediate C26 (6-(Chloromethyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0701]

[0702] Step 1: Synthesis of Compound C26-2 (6-Bromo-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0703] 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, and the mixture was stirred for 30 minutes. 2-Iodopropane (6.02 g, 35.39 mmol, 3.54 mL, 2 eq) was added dropwise at 0 °C. After the addition, the reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. Water (30 mL) was added at 0 °C to quench the reaction. The mixture was extracted with ethyl acetate (50 mL) three times. The organic layers were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2) to obtain a pale yellow oily compound C26-2 (1.7 g, 6.19 mmol, 35.01% yield, 97.7% purity). 11H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.33 (s, 1H), 5.09 - 5.03 (m, 1H), 3.42 (t, J1 = 6.4 Hz, J2 = 6.8 Hz, 2H), 2.91 (t, J1 = 6.8 Hz, J2 = 6.4 Hz, 2H), 1.19 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 268.0 (M + H)+.

[0704] Step 2: Synthesis of Compound C26-3 (2-Isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile)

[0705] Dissolve Compound C26-2 (2.6 g, 9.70 mmol, 1 eq) in N,N-dimethylformamide (30 mL), add 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), stir at 80 °C for 12 h under nitrogen protection, add water (30 mL), extract with ethyl acetate (20 mL) three times, combine the organic layers, dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain the white solid Compound C26-3 (1.9 g, 8.84 mmol, 91.18% yield, 99.7% purity). 1 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.64 - 7.62 (m, 1H), 7.50 (s, 1H), 5.11 - 5.04 (m, 1H), 3.48 (t, J1 = 6.4 Hz, J2 = 6.4 Hz, 2H), 2.99 (t, J1 = 6.4 Hz, J2 = 6.4 Hz, 2H), 1.22 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 215.1 (M + H) + 。

[0706] Steps 3 - 5: Synthesis of Intermediate C26

[0707] Using Compound C26-3 as the raw material, Intermediate C26 (433.4 mg, 1.82 mmol, 45.1% yield) was prepared according to the same steps as Intermediate C25. LC-MS: m / z = 238.2 (M + H) + 。

[0708] Synthesis of General Intermediate C27 (2-((4-(Chloromethyl)phenoxy)methyl)pyridine)

[0709]

[0710] Using 4-hydroxybenzonitrile (Compound C27-1) and 2-(bromomethyl)pyridine hydrobromide as raw materials, the pale yellow oily intermediate C27 (800.7 mg, crude product) was prepared according to the same steps as intermediate C28. LC-MS: m / z = 234.0 (M+H) + 。

[0711] Synthesis of General Intermediate C28 (1-(chloromethyl)-4-(2-ethoxyethoxy)benzene)

[0712]

[0713] Step 1: Synthesis of Compound C28-2 (4-(2-ethoxyethoxy)benzonitrile)

[0714] 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 successively added to acetonitrile (142 mL), and the mixture was 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 mixture was extracted 3 times with dichloromethane (50.0 mL). The organic layers were combined, washed 2 times with saturated brine (30.0 mL), 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1) to obtain a pale yellow oily compound C28-2 (6.69 g, crude product). 1 H NMR (400 MHz, DMSO) δ 7.75 (dd, J1 = 1.6 Hz, J2 = 6.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 4.16 - 4.19 (m, 2H), 3.69 - 3.71 (m, 2H), 3.46 - 3.51 (m, 2H), 1.11 (t, J = 7.0 Hz, 3H).

[0715] Step 2: Synthesis of Compound C28-3 (methyl 4-(2-ethoxyethoxy)benzoate)

[0716] Compound C28-2 (2.00 g, 10.5 mmol, 1.00 eq) was dissolved in HCl / MeOH (4 M, 105 mL, 40.0 eq), and stirred at 80 °C for 36 h. The mixture was concentrated in vacuo to obtain the crude product. Water (20.0 mL) was added, and the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, washed twice with saturated brine (30.0 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 the pale yellow oily compound C28-3 (1.46 g, 6.51 mmol, 62.3% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 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 = 7.0 Hz, 3H); LC-MS: m / z = 225.3 (M+H) + 。

[0717] Step 3: Synthesis of compound C28-4 ((4-(2-ethoxyethoxy)phenyl)methanol)

[0718] Compound C28-3 (0.700 g, 3.12 mmol, 1.00 eq) was dissolved in tetrahydrofuran (7.00 mL). Lithium aluminum hydride (237 mg, 6.24 mmol, 2.00 eq) was slowly added at 0 °C. After addition, the temperature was raised to 20 °C and stirred for 3 h. Then, ice water (50.0 mL) was added at 0 °C and stirred for 10 min. The mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated in vacuo to obtain the colorless transparent oily compound C28-4 (0.62 g, crude product). 1 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.29 (m, 2H), 6.90 - 6.94 (m, 2H), 4.61 (s, 2H), 4.11 - 4.14 (m, 2H), 3.78 - 3.81 (m, 2H), 3.59 - 3.64 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H);

[0719] Step 4: Synthesis of intermediate C28

[0720] Compound C28-4 (0.560 g, 2.85 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (2.46 g, 20.7 mmol, 1.50 mL, 7.25 eq) was added at 0 °C. After addition, the temperature was raised to 20 °C and stirred for 12 h. The reaction solution was concentrated in vacuo to obtain crude compound C28 as a pale yellow oil (0.60 g). 1 1H NMR (400 MHz, DMSO) δ 7.35 - 7.37 (m, 2H), 6.93 - 6.95 (m, 2H), 4.73 (s, 2H), 4.08 - 4.10 (m, 2H), 3.68 - 3.70 (m, 2H), 3.48 - 3.53 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); LC-MS: m / z = 215.0 (M + H) + .

[0721] Synthesis of general intermediate C29 (1-(chloromethyl)-4-(3-methoxycyclobutoxy)benzene)

[0722]

[0723] Step 1: Synthesis of compound C29-2 (4-(3-methoxycyclobutoxy)benzaldehyde)

[0724] 4-(3-Methoxycyclobutoxy)benzonitrile (compound C29-1, 0.560 g, 2.85 mmol, 1.00 eq) was dissolved in tetrahydrofuran (6.50 mL). Diisobutylaluminum hydride (1 M, 7.75 mL, 2.50 eq) was added dropwise at 0 °C. After addition, the mixture was stirred at 25 °C for 2 h. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (20.0 mL) at 0 °C. The mixture was extracted with ethyl acetate (50.0 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain crude compound C29-2 as a pale yellow oil (0.65 g). 1 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 7.85 - 7.87 (m, 2H), 7.04 - 7.06 (m, 2H), 4.50 - 4.54 (m, 1H), 4.07 - 4.10 (m, 1H), 3.61 - 3.67 (m, 3H), 2.90 - 2.92 (m, 2H), 1.91 - 1.96 (m, 2H).

[0725] Step 2: Synthesis of compound C29-3 ((4-(3-methoxycyclobutoxy)phenyl)methanol)

[0726] Compound C29-2 (0.65 g, 3.15 mmol, 1.00 eq) was dissolved in methanol (6.00 mL). Sodium borohydride (0.210 g, 5.55 mmol, 1.76 eq) was added portionwise at 0 °C. After addition, the temperature was raised to 25 °C and stirred for 2 h. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2) to obtain a pale yellow oily compound C29-3 (0.12 g, crude product). 1 1H NMR (400 MHz, DMSO) δ 7.22 - 7.24 (m, 2H), 6.77 - 6.79 (m, 2H), 4.28 - 4.32 (m, 1H), 3.73 (s, 2H), 3.65 - 3.68 (m, 1H), 3.28 (s, 3H), 2.86 - 2.91 (m, 2H), 2.05 - 2.16 (m, 2H).

[0727] Step 3: Synthesis of compound C29

[0728] A solution of compound C29-3 (0.12 g, 576 μmol, 1.00 eq) in dichloromethane (3.0 mL) was added thionyl chloride (686 mg, 5.76 mmol, 418 μL, 10.0 eq) at 0 °C. After addition, the temperature was raised to 20 °C and stirred for 12 h. The reaction mixture was concentrated in vacuo to obtain a pale yellow oily compound C29 (0.120 g, 529 μmol, 91.9% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.29 (m, 1H), 7.25 - 7.27 (m, 1H), 6.80 - 6.83 (m, 2H), 4.62 (s, 2H), 4.30 - 4.33 (m, 1H), 3.65 - 3.69 (m, 1H), 3.28 (s, 3H), 2.87 - 2.91 (m, 2H), 2.05 - 2.16 (m, 2H); LC-MS: m / z = 227.1 (M + H) + 。

[0729] Synthesis of general intermediate C30 (2-(4-(chloromethyl)-3-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0730]

[0731] Step 1: Synthesis of compound C30-2 (methyl 4-(dibromomethyl)-2-methoxybenzoate)

[0732] 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). N-Bromosuccinimide (10.9 g, 61.0 mmol, 2.20 eq) was added portionwise at room temperature. After addition, the temperature was raised to 85 °C and stirred for 12 hours. The mixture was filtered to obtain a filtrate, which was concentrated under vacuum to give 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 C30-2 (6.50 g, 19.2 mmol, 69.3% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.77 (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).

[0733] Step 2: Synthesis of Compound C30-3 (methyl 4-formyl-2-methoxybenzoate)

[0734] Compound C30-2 (5.00 g, 14.8 mmol, 1.00 eq) was dissolved in acetone (60.0 mL). 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, filtered to obtain a filtrate, which was concentrated under vacuum to give 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 1H NMR δ 10.0 (s, 1H), 7.89 - 7.91 (m, 1H), 7.48 - 7.50 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H).

[0735] Steps 3 - 6: Synthesis of Intermediate C30

[0736] For the synthesis of Steps 3 - 6, using C30-3 as the starting material, the white solid intermediate C30 (320 mg, 938 μmol, 75.0% yield) was prepared according to the same steps as Intermediate C5. LC-MS: m / z = 305.1 (M + H) + 。

[0737] Synthesis of General Intermediate C31 (2-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0738]

[0739] Using methyl 3-methoxy-4-methylbenzoate (Compound C31-1) as the raw material, the white solid intermediate C31 (450 mg) was prepared according to the same steps as those for Intermediate C30. LC-MS: m / z = 305.1 (M+H) + 。

[0740] Synthesis of General Intermediate C32 (1-(4-(chloromethyl)-3-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0741]

[0742] Using methyl 2-methoxy-4-aminobenzoate (Compound C32-1) as the raw material, the white solid intermediate C32 (1.18 g, 3.87 mmol, 88.5% yield) was prepared according to the same steps as those for Intermediate C11. LC-MS: m / z = 305.1 (M+H) + 。

[0743] Synthesis of General Intermediate C33 (1-(4-(chloromethyl)-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole)

[0744]

[0745] Using methyl 4-amino-3-methoxybenzoate (Compound C33-1) as the raw material, the white solid intermediate C33 (796.0 mg, 2.61 mmol, 79.6% yield) was prepared according to the same steps as those for Intermediate C11. LC-MS: m / z = 305.0 (M+H) + 。

[0746] Synthesis of General Intermediate C35 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl-4-methylbenzenesulfonate)

[0747]

[0748] Step 1: Synthesis of Compound C35-2 (1-methyl-4-(trifluoromethyl)-1H-imidazole)

[0749] The 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). The mixture was stirred at 0 °C for 30 minutes, and then iodomethane (32.6 g, 0.23 mol, 1.2 eq) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 16 hours. Then, the reaction solution was concentrated under vacuum to obtain a crude product, which was added to water (260 mL) and stirred for 10 minutes. The mixture was extracted with ethyl acetate (200 mL) three times. The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated under vacuum to obtain Compound C35-2 (26 g, crude product). LC-MS: m / z = 151.0 (M+H) + 。

[0750] Step 2: Synthesis of Compound C35-3 (methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate)

[0751] Compound C35-2 (14.75 g, 98.3 mmol) and monomethyl bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylate (25 g, 117.9 mmol, 1.2 eq) were dissolved in dichloromethane (295 mL) and water (295 mL). Then, 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 diatomaceous earth, washed twice with dichloromethane (100 mL). The organic layer was separated, and the aqueous layer was extracted three times with dichloromethane (200 mL). The organic layers were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated under vacuum to obtain Compound C35-3 as a yellow oily substance (35.2 g, crude product). 1 1H NMR (400 MHz, CDCl3) δ 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) + 。

[0752] Step 3: Synthesis of Compound C35-4 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanol)

[0753] Compound C35-3 (35.2 g, 111.4 mmol) was dissolved in tetrahydrofuran (180.0 mL). Lithium aluminum hydride (2.5 M, 111.4 mL, 278.5 mmol, 2.5 eq) was slowly added at 0 °C. After the addition, 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. The mixture was extracted with ethyl acetate (500.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a yellow oily compound C35-4 (25.1 g, crude product). LC-MS: m / z = 289.1 (M+H) + 。

[0754] Step 4: Synthesis of Compound C35

[0755] 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 successively added to dichloromethane (251 mL). The mixture was stirred at 25 °C for 16 hours, washed with water (100 mL) twice, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / dichloromethane = 1 / 0 - 0 / 1) to obtain a white solid intermediate C35 (10.0 g). 1 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 2.46 (s, 3H), 1.95–1.86 (m, 6H), 1.49–1.37 (m, 6H); LC-MS: m / z = 443.3 (M+H) + 。

[0756] Synthesis of General Intermediate C48 (2-(4-(Chloromethyl)phenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole)

[0757]

[0758] Step 1: Synthesis of Compound C48-2 ((2-(4-Bromophenyl)-1H-imidazol-4-yl)methanol)

[0759] 4-Bromobenzamidine 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 successively added to ammonia water (500 mL). The mixture was stirred at an external temperature of 80 °C for 2 hours, cooled to room temperature, and filtered to obtain a solid. The solid was concentrated in vacuo to obtain a white solid compound C48-2 (15 g, crude product). LC-MS: m / z = 252.6 (M+H) + 。

[0760] Step 2: Synthesis of Compound C48-3 (2-(4-bromophenyl)-1H-imidazole-4-carbaldehyde)

[0761] Compound C48-2 (14 g, 55.56 mmol) was dissolved in tetrahydrofuran (300 mL), manganese dioxide (48 g, 555.6 mmol, 10 eq) was added, and the mixture was stirred at an external temperature of 60 °C for 16 hours. After cooling to room temperature, the mixture was filtered to obtain a filtrate, which was concentrated in vacuo to obtain a white solid compound C48-3 (11.1 g, crude product). LC-MS: m / z = 250.8 (M+H) + 。

[0762] Step 3: Synthesis of Compound C48-4 (2-(4-bromophenyl)-1-methyl-1H-imidazole-4-carbaldehyde)

[0763] Compound C48-3 (11.1 g, 44.4 mmol), methyl iodide (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). The mixture was stirred at an external temperature of 45 °C for 3 hours, filtered to obtain a filtrate, 1000 mL of water was added, and the mixture was extracted 3 times with 500 mL of ethyl acetate. 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 a white solid compound C48-4 and compound C48-4a (total 6.8 g). LC-MS: m / z = 265.0 (M+H) + 。

[0764] Step 4: Synthesis of Compound C48-5 (2-(4-bromophenyl)-4-(difluoromethyl)-1-methyl-1H-imidazole) Dissolve Compound C48-4 and Compound C48-4a (6.7 g, 25.38 mmol) in anhydrous dichloromethane (200 mL). Slowly add diethylaminosulfur trifluoride (41 g, 253.8 mmol, 10 eq) dropwise at 0 °C. After addition, stir at room temperature (25 °C) for 5 hours. Then, slowly add the reaction solution to saturated aqueous sodium bicarbonate. Extract with dichloromethane (500 mL) three times. Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain the crude product. The crude product is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain the white solid compounds C48-5 and C48-5a (4.1 g). LC-MS: m / z = 286.9 (M+H) + 。

[0765] Step 5: Synthesis of Compound C48-6 (Ethyl 4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzoate)

[0766] Add Compound 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) successively into anhydrous ethanol (32 mL). Stir the reaction under a carbon monoxide (double-layer balloon, 25 psi) atmosphere at an external temperature of 85 °C for 20 hours. Then, add EA (100 mL), stir for 10 minutes, filter by suction to obtain the filtrate, add silica gel for sample mixing, and purify by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain Compound C48-6 and Compound C48-6a (630 mg). LC-MS: m / z = 281.1 (M+H) + 。

[0767] Step 6: Synthesis of Compound C48-7 ((4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)phenyl)methanol)

[0768] Dissolve compound C48-6 and compound C48-6a (630 mg) in anhydrous THF (7 mL), add dropwise a THF solution of lithium aluminum hydride (2.5 M, 2 mL) at 0 °C. After addition, the mixture heats up spontaneously to room temperature (25 °C) and is stirred for 2 hours. Quench the reaction by adding water (10 mL) at 0 °C, then adjust the pH to about 5 with 1 M aqueous hydrochloric acid. Extract with dichloromethane (50 mL) three times, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain the crude products of compound C48-7 and compound C48-7a (500 mg). LC-MS: m / z = 239.1 (M+H) + 。

[0769] Step 7: Synthesis of Intermediate C48

[0770] Dissolve compound C48-7 and compound C48-7a (500 mg) in anhydrous dichloromethane (5 mL), add thionyl chloride (1.5 mL), and stir the reaction at room temperature (25 °C) for 1.5 hours. Then, directly concentrate the reaction solution in vacuo to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain compound C48 (130 mg). LC-MS: m / z = 257.1 (M+H) + 。

[0771] Synthesis of General Intermediate C49 (2-(Chloromethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine)

[0772]

[0773] Using methyl 5-formylpyridine-2-carboxylate (Compound C49-1) as the raw material, Intermediate C49 (2.0 g) was prepared according to the same steps as Intermediate C5. LC-MS: m / z = 276.0 (M+H) + 。

[0774] Synthesis of General Intermediate C57 (2-(4-(Chloromethyl)phenyl)-1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole)

[0775]

[0776] Using methyl 4-formylbenzoate (Compound C5-1) as the raw material, Intermediate C57 (1.83 g) was prepared according to the same steps as Intermediate C5. LC-MS: m / z = 301.2 (M+H) + 。

[0777] Synthesis of General Intermediate C58 (2-(4-(Chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole)

[0778]

[0779] Using methyl 4-formylbenzoate (Compound C5-1) as the raw material, Intermediate C58 (0.6 g) was prepared according to the same steps as Intermediate C5. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.61 - 7.64 (m, 4H), 4.88 (d, J = 2.4 Hz, 2H), 4.50 - 4.55 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H); LC-MS: m / z = 303.1 (M + H) + 。

[0780] Synthesis of General Intermediate C59 (2-(4-(chloromethyl)phenyl)-1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazole)

[0781]

[0782] Using methyl 4-formylbenzoate (Compound C5-1) as the raw material, Intermediate C59 (0.6 g) was prepared according to the same steps as Intermediate C5. LC-MS: m / z = 293.1 (M + H) + 。

[0783] Synthesis of General Intermediate D5 ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0784]

[0785] Using Compound C5 (0.2 g, 0.73 mmol, 1.00 eq) as the raw material, Intermediate D5 (0.16 g, 0.63 mmol, 85.9% yield) was prepared according to the same steps as Intermediate BB13. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J = 1.4 Hz, 1H), 7.75–7.61 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 3.83 (s, 2H), 3.80 (s, 3H); LC-MS: m / z = 256.0 (M + H) + 。

[0786] Synthesis of General Intermediate D11 ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine)

[0787]

[0788] Using compound C11 (2.2 g, 8.03 mmol, 1.00 eq) as the starting material, intermediate D11 (1.59 g, 6.23 mmol, 77.6% yield) was prepared according to the same procedure as for intermediate BB13. 1 H NMR (400 MHz, DMSO-d6) δ 7.60–7.47 (m, 4H), 6.76 (s, 1H), 3.84 (s, 2H), 2.35 (s, 3H); LC-MS: m / z = 256.1 (M+H) + 。

[0789] Synthesis of general intermediate D58 ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine)

[0790]

[0791] Using compound C58 (1.5 g, 4.95 mmol, 1.00 eq) as the starting material, intermediate D58 (0.98 g, 3.46 mmol, 69.9% yield) was prepared according to the same procedure as for intermediate BB13. LC-MS: m / z = 284.3 (M+H) + 。

[0792] Synthesis of intermediate BB1C2 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0793]

[0794] 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 successively added to N,N-dimethylformamide (10.0 mL). The mixture was stirred at 80 °C for 2 hours, cooled to 25 °C, ethyl acetate (100.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by filtration, washed 3 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 pale yellow solid intermediate BB1C2 (910.3 mg, 2.63 mmol, 91.0% yield). LC-MS: m / z = 347.2 (M+H) + 。

[0795] Synthesis of intermediate BB1C3 (2-chloro-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0796]

[0797] Using intermediate BB1 and compound C3 as raw materials, the pale yellow solid intermediate BB1C3 (689.9 mg, 2.03 mmol, 87.5% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 341.2 (M+H) + 。

[0798] 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)

[0799]

[0800] Using intermediate BB1 and compound C4 as raw materials, the pale yellow solid intermediate BB1C4 (352.5 mg, 0.843 mmol, 69.5% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 419.2 (M+H) + 。

[0801] Synthesis of intermediate BB1C5 (2-chloro-5-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0802]

[0803] 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 steps as intermediate BB1C2. 1 H NMR (400 MHz, DMSO-d6) δ 8.03–7.90 (m, 2H), 7.80–7.72 (m, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.98 (s, 2H), 3.18 (s, 3H), 2.92 (s, 3H), 2.76 (d, J = 0.6 Hz, 3H); LC-MS: m / z = 412.1 (M+H) + 。

[0804] Synthesis of intermediate BB1C6 (2-chloro-5-methoxy-N-methyl-N-(1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine)

[0805]

[0806] Using intermediate BB1 and compound C6 as starting materials, a pale yellow solid intermediate BB1C6 (169.7 mg, 0.49 mmol, 59.9% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 348.2 (M+H) + 。

[0807] Synthesis of intermediate BB1C11 (2-chloro-5-methoxy-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0808]

[0809] Using intermediate BB1 and compound C11 as starting materials, a grayish-white solid intermediate BB1C11 (3.31 g, 8.04 mmol, 73.2% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 412.8 (M+H) + 。

[0810] Synthesis of intermediate BB2C2 (2-chloro-5-methoxy-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[0811]

[0812] Using intermediate BB2 and compound C2 as starting materials, a pale yellow oily intermediate BB2C2 (134.1 mg, 0.40 mmol, 46.6% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 333.1 (M+H) + 。

[0813] Synthesis of intermediate BB2C3 (2-chloro-5-methoxy-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0814]

[0815] Using intermediate BB2 and compound C3 as starting materials, a pale yellow solid intermediate BB2C3 (255.5 mg, 0.78 mmol, 87.7% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 327.0 (M+H) + 。

[0816] 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)

[0817]

[0818] Using intermediate BB2 and compound C4 as starting materials, a pale yellow solid intermediate BB2C4 (98.8 mg, 0.24 mmol, 39.2% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 405.1 (M+H) + 。

[0819] Synthesis of intermediate BB2C5 (2-chloro-5-methoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine))

[0820]

[0821] Using intermediate BB2 and compound C5 as starting materials, a pale yellow solid intermediate BB2C5 (18.9 g, 47.60 mmol, 69.8% yield) was prepared according to the same procedure as for intermediate BB1C2. 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.62 (m, 2H), 7.57 (s, 1H), 7.42 - 7.44 (m, 2H), 7.27 - 7.31 (m, 1H), 5.82 (s, 1H), 4.73 - 4.74 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H); LC-MS: m / z = 398.6 (M+H) + 。

[0822] Synthesis of intermediate BB2C6 (2-chloro-5-methoxy-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidin-4-amine))

[0823]

[0824] Using intermediate BB2 and compound C6 as starting materials, a pale yellow solid intermediate BB1C6 (100.6 mg, 0.30 mmol, 35.3% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 344.1 (M+H) + 。

[0825] 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))

[0826]

[0827] Using intermediate BB2 and compound C9 as raw materials, a pale yellow solid intermediate BB2C9 (31.1 mg, 0.077 mmol, 13.2% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 404.2 (M+H) + 。

[0828] Synthesis of intermediate BB2C11 (2-chloro-5-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0829]

[0830] Using intermediate BB2 and compound C11 as raw materials, a white solid intermediate BB2C11 (5.6 g, 14.10 mmol, 77.8% yield) was prepared according to the same steps as intermediate BB1C2. 1 H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 - 7.47 (m, 4H), 6.47 - 6.49 (m, 1H), 5.76 (s, 1H), 4.75 - 4.82 (m, 2H), 3.90 (s, 3H), 2.36 (s, 3H); LC-MS: m / z = 398.0 (M+H) + 。

[0831] Synthesis of intermediate BB2C12 (2-chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0832]

[0833] Using intermediate BB2 and compound C12 as raw materials, a pale yellow solid intermediate BB2C12 (130.3 mg, 0.36 mmol, 88.2% yield) was prepared according to the same steps as intermediate BB1C2. 1 H NMR (400 MHz, DMSO) δ 8.71 (d, J = 8.4 Hz, 2H), 8.60 (d, J = 4.4 Hz, 1H), 8.19 - 8.21 (m, 2H), 7.99 (d, J = 4.4 Hz, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 4.61 (d, J = 4.4 Hz, 2H), 3.88 (s, 3H); LC-MS: m / z = 367.0 (M+H) + 。

[0834] Synthesis of Intermediate BB2C13 (2-Chloro-5-methoxy-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzyl)pyrimidin-4-amine)

[0835]

[0836] Using intermediate BB2 and compound C13 as starting materials, a pale yellow solid intermediate BB2C13 (455.1 mg, 1.16 mmol, 69.9% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 395.0 (M+H) + 。

[0837] Synthesis of Intermediate BB2C14 (2-Chloro-5-methoxy-N-(4-(5-methylpyridin-2-yl)benzyl)pyrimidin-4-amine)

[0838]

[0839] Using intermediate BB2 and compound C14 as starting materials, a pale yellow solid intermediate BB2C14 (173.45 mg, 0.51 mmol, 90.3% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 341.1 (M+H) + 。

[0840] 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)

[0841]

[0842] Using intermediate BB2 and compound C19 as starting materials, a pale yellow solid intermediate BB2C19 (281.3 mg, 0.66 mmol, 35.6% yield) was prepared according to the same procedure as for intermediate BB1C2. LC-MS: m / z = 427.3 (M+H) + 。

[0843] Synthesis of Intermediate BB2C26 (6-((2-Chloro-5-methoxypyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0844]

[0845] Using intermediate BB2 and compound C26 as raw materials, a light yellow solid intermediate BB2C26 (379.2 mg, 1.05 mmol, 82.0% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 361.1 (M+H) + 。

[0846] Synthesis of intermediate BB2C27 (2-chloro-5-methoxy-N-(4-(pyridin-2-ylmethoxy)benzyl)pyrimidin-4-amine)

[0847]

[0848] Using intermediate BB2 and compound C27 as raw materials, a light yellow solid intermediate BB2C27 (268.5 mg, 0.61 mmol, 93.6% yield) was prepared according to the same steps as intermediate BB1C2. 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.8 Hz, 1H), 7.72 - 7.76 (m, 1H), 7.72 - 7.75 (m, 2H), 7.29 (s, 1H), 7.24 - 7.25 (m, 1H), 6.99 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H), 5.23 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H); LC-MS: m / z = 357.0 (M+H) + 。

[0849] Synthesis of intermediate BB2C28 (2-chloro-N-(4-(2-ethoxyethoxy)benzyl)-5-methoxypyrimidin-4-amine)

[0850]

[0851] Using intermediate BB2 and compound C28 as raw materials, a white solid intermediate BB2C28 (316.9 mg, 0.94 mmol, 78.8% yield) was prepared according to the same steps as intermediate BB1C2. 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.24 - 7.29 (m, 2H), 6.89 - 6.94 (m, 2H), 5.61 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.10 - 4.14 (m, 2H), 3.84 (s, 3H), 3.76 - 3.81 (m, 2H), 3.60 - 3.62 (m, 2H), 1.25 (t, J = 6.8 Hz, 3H); LC-MS: m / z = 338.1 (M+H) + 。

[0852] Synthesis of Intermediate BB2C30 (2-chloro-5-methoxy-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0853]

[0854] Using Intermediate BB2 and Compound C30 as raw materials, a light yellow solid Intermediate BB2C30 (662.0 mg, 1.55 mmol, 86.7% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 428.0 (M+H) + 。

[0855] Synthesis of Intermediate BB2C31 (2-chloro-5-methoxy-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0856]

[0857] Using Intermediate BB2 and Compound C31 as raw materials, a white solid Intermediate BB2C31 (337.4 mg, 0.79 mmol, 93.9% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 428.1 (M+H) + 。

[0858] Synthesis of Intermediate BB2C33 (2-chloro-5-methoxy-N-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0859]

[0860] Using Intermediate BB2 and Compound C33 as raw materials, a white solid Intermediate BB2C33 (3.02 g, 2.66 mmol, 88.3% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 428.0 (M+H) + 。

[0861] 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)

[0862]

[0863] 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 successively added to N,N-dimethylformamide (20.0 mL). The mixture was stirred at 130 °C for 36 h, cooled to 25 °C, dichloromethane (100.0 mL) was added, and the mixture was stirred for 5 min. The filtrate was obtained by suction filtration, washed 3 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 - 0 / 1) to obtain the white solid intermediate BB2C35 (1.03 g, 2.41 mmol, 38.3% yield). LC-MS: m / z = 430.1 (M+H) + 。

[0864] Synthesis of intermediate BB2C48 (2-chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0865]

[0866] Using intermediate BB2 and compound C48 as raw 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) + 。

[0867] Synthesis of intermediate BB2C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0868]

[0869] 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. 1 H NMR (400 MHz, DMSO-d6) δ 8.31–8.15 (m, 2H), 7.75 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 4.63 (d, J = 6.3 Hz, 2H), 4.56–4.38 (m, 1H), 3.90 (s, 3H), 1.42 (d, J = 6.6 Hz, 6H); LC-MS: m / z = 426.1 (M+H) + 。

[0870] Synthesis of Intermediate BB2C59 (2-chloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methoxypyrimidin-4-amine)

[0871]

[0872] Using Intermediate BB2 and Compound C59 as raw materials, white solid Intermediate BB2C59 (91.3 mg, 0.22 mmol, 78.8% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 426.1 (M+H) + 。

[0873] 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)

[0874]

[0875] Using Intermediate BB3 and Compound C4 as raw materials, white solid Intermediate BB3C4 (178.5 mg, 0.40 mmol, 28.7% yield) was prepared according to the same steps as Intermediate BB2C35. LC-MS: m / z = 447.3 (M+H) + 。

[0876] Synthesis of Intermediate BB3C5 (2-chloro-5-isopropoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0877]

[0878] Using Intermediate BB3 and C5 as raw materials, white solid Intermediate BB3C5 (2.1 g, 4.78 mmol, 86.4% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 440.2 (M+H) + 。

[0879] 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)

[0880]

[0881] Using intermediate BB4 and compound C4 as raw materials, the white solid intermediate BB4C4 (159.9 mg, 0.37 mmol, 39.6% yield) was prepared according to the same steps as intermediate BB2C35. LC-MS: m / z = 433.2 (M+H) + 。

[0882] Synthesis of intermediate BB4C5 (2-chloro-5-isopropoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0883]

[0884] Using intermediate BB4 and compound C5 as raw materials, the white solid intermediate BB4C5 (2.03 g, 4.78 mmol, 86.4% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 426.1 (M+H) + 。

[0885] 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)

[0886]

[0887] Using intermediate BB4 and compound C19 as raw materials, the white solid intermediate BB4C19 (349.7 mg, 0.77 mmol, 83.2% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 455.2 (M+H) + 。

[0888] Synthesis of intermediate BB12C2 (2-chloro-N-((4-(pyridin-2-yl)cyclohexyl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0889]

[0890] Using intermediate BB12 and compound C2 as raw materials, the white solid intermediate BB12C2 (51.8 mg, 0.14 mmol, 35.4% yield) was prepared according to the same steps as intermediate BB2C35. LC-MS: m / z = 371.1 (M+H) + 。

[0891] Synthesis of intermediate BB12C3 (2-chloro-N-(4-(pyridin-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0892]

[0893] Using intermediate BB12 and compound C3 as raw materials, a pale yellow solid intermediate BB12C3 (396.8 mg, 1.09 mmol, 76.6% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 365.0 (M+H) + 。

[0894] 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)

[0895]

[0896] Using intermediate BB12 and C4 as raw materials, a pale yellow oily intermediate BB12C4 (53.1 mg, 0.12 mmol, 21.1% yield) was prepared according to the same steps as intermediate BB2C35. LC-MS: m / z = 443.0 (M+H) + 。

[0897] Synthesis of intermediate BB12C5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0898]

[0899] Using intermediate BB12 and compound C5 as raw materials, a pale yellow solid intermediate BB12C5 (248.0 mg, 0.57 mmol, 88.8% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 436.1 (M+H) + 。

[0900] Synthesis of intermediate BB12C6 (2-chloro-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-4-amine)

[0901]

[0902] Using intermediate BB12 and compound C6 as raw materials, a pale yellow oily intermediate BB12C6 (29.7 mg, 0.08 mmol, 18.0% yield) was prepared according to the same steps as intermediate BB2C35. LC-MS: m / z = 372.3 (M+H) + 。

[0903] Synthesis of Intermediate BB13C3 (2-Chloro-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0904]

[0905] Using Intermediate BB13 and Compound C3 as raw materials, the light yellow solid Intermediate BB13C3 (1.19 g, 3.55 mmol, 89.4% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 337.1 (M+H) + 。

[0906] Synthesis of Intermediate BB13C5 (2-Chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0907]

[0908] Using Intermediate BB13 and Compound C5 as raw materials, the light yellow solid Intermediate BB13C5 (761.1 mg, 1.87 mmol, 76.7% yield) was prepared according to the same steps as Intermediate BB1C2. 1 H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.29 - 8.33 (m, 1H), 7.90 - 7.94 (m, 1H), 7.67 - 7.72 (m, 2H), 7.46 - 7.52 (m, 2H), 6.96 - 7.00 (m, 1H), 4.74 (s, 2H), 3.77 (s, 3H); C-MS: m / z = 407.9 (M+H) + 。

[0909] 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)

[0910]

[0911] Using Intermediate BB13 and Compound C7 as raw materials, the white solid Intermediate BB13C7 (342.6 mg, 0.83 mmol, 56.9% yield) was prepared according to the same steps as Intermediate BB1C2. LC-MS: m / z = 414.0 (M+H) + 。

[0912] Synthesis of Intermediate BB13C11 (2-Chloro-N-(4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0913]

[0914] Using Intermediate BB13 and Compound C11 as starting materials, following the same procedure as for Intermediate BB1C2, a pale yellow solid Intermediate BB13C11 (4.23 g, 10.39 mmol, 76.9% yield) was prepared. LC-MS: m / z = 408.0 (M+H) + 。

[0915] Synthesis of Intermediate BB13C12 (2-Chloro-N-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0916]

[0917] Using Intermediate BB13 and Compound C12 as starting materials, following the same procedure as for Intermediate BB1C2, a white solid Intermediate BB13C12 (458.8 mg, 1.22 mmol, 88.7% yield) was prepared. 1 H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.74 (d, J = 8.4 Hz, 2H), 8.60 (d, J = 4.4 Hz, 1H), 8.27–8.31 (m, 1H), 8.21 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 6.93 - 6.98 (m, 1H), 4.76 (s, 2H); LC-MS: m / z = 377.1 (M+H) + 。

[0918] Synthesis of Intermediate BB13C19 (2-Chloro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)furo[3,2-d]pyrimidin-4-amine)

[0919]

[0920] Using Intermediate BB13 and Compound C19 as starting materials, following the same procedure as for Intermediate BB2C35, a pale yellow oily Intermediate BB13C19 (383.8 mg, 0.88 mmol, 22.3% yield) was prepared. LC-MS: m / z = 437.0 (M+H) + 。

[0921] Synthesis of Intermediate BB13C25 (6-(((2-chlorofuro[3,2-d]pyrimidin-4-yl)amino)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one)

[0922]

[0923] 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 steps as intermediate BB1C2. 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.30 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.69 (s, 2H), 3.52 (t, J1 = 6.4 Hz, J2 = 6.8 Hz, 2H), 3.00 (s, 3H), 2.95 (t, J1 = 6.4 Hz, J2 = 6.8 Hz, 2H); LC-MS: m / z = 343.2 (M+H) + 。

[0924] Synthesis of Intermediate BB13C26 (6-(((2-chlorofuro[3,2-d]pyrimidin-4-yl)amino)methyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one)

[0925]

[0926] Using intermediate BB13 and compound C26 as raw materials, the light yellow solid intermediate BB13C26 (233.1 mg, 0.63 mmol, 82.6% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 371.2 (M+H) + 。

[0927] Synthesis of Intermediate BB13C27 (2-chloro-N-(4-(pyridin-2-ylmethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0928]

[0929] Using intermediate BB13 and compound C27 as raw materials, the light yellow solid intermediate BB13C27 (256.3 mg, 0.70 mmol, 66.8% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 366.9 (M+H) + 。

[0930] Synthesis of Intermediate BB13C28 (2-Chloro-N-(4-(2-ethoxyethoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0931]

[0932] Using Intermediate BB13 and C28 as starting materials, following the same procedure as for Intermediate BB1C2, a pale yellow solid Intermediate BB13C28 (118.0 mg, 0.34 mmol, 84.5% yield) was prepared. LC-MS: m / z = 348.2 (M+H) + 。

[0933] Synthesis of Intermediate BB13C29 (2-Chloro-N-(4-(3-methoxycyclobutoxy)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0934]

[0935] Using Intermediate BB13 and Compound C29 as starting materials, following the same procedure as for Intermediate BB1C2, a pale yellow solid Intermediate BB13C29 (244.2 mg, 0.68 mmol, 93.5% yield) was prepared. LC-MS: m / z = 360.2 (M+H) + 。

[0936] 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)

[0937]

[0938] Using Intermediate BB13 and Compound C30 as starting materials, following the same procedure as for Intermediate BB1C2, a white solid Intermediate BB13C30 (292.9 mg, 0.67 mmol, 78.8% yield) was prepared. LC-MS: m / z = 438.1 (M+H) + 。

[0939] 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)

[0940]

[0941] Using intermediate BB13 and compound C31 as raw materials, white solid intermediate BB13C31 (214.2 mg, 0.49 mmol, 73.9% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 438.0 (M+H) + 。

[0942] 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)

[0943]

[0944] Using intermediate BB13 and compound C32 as raw materials, white solid intermediate BB13C32 (100.5 mg, 0.23 mmol, 70.0% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 438.0 (M+H) + 。

[0945] 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)

[0946]

[0947] Using intermediate BB13 and compound C33 as raw materials, light yellow solid intermediate BB13C33 (257.6 mg, 0.59 mmol, 84.2% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 437.9 (M+H) + 。

[0948] 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)

[0949]

[0950] Using intermediate BB13 and compound C35 as raw materials, white solid intermediate BB13C35 (48.3 mg, 0.11 mmol, 28.8% yield) was prepared according to the same steps as intermediate BB2C35. LC-MS: m / z = 440.2 (M+H) + 。

[0951] Synthesis of Intermediate BB13C48 (2-Chloro-N-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[0952]

[0953] Using Intermediate 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) + 。

[0954] Synthesis of Intermediate BB14C5 (2-Chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidin-4-amine)

[0955]

[0956] 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) + 。

[0957] Synthesis of Intermediate BB15C5 (2,5-Dichloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0958]

[0959] 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 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.87–7.68 (m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 5.00 (s, 2H), 3.21 (s, 3H); LC-MS: m / z = 402.0 (M+H) + 。

[0960] Synthesis of Intermediate BB15C59 (2,5-Dichloro-N-(4-(1-(fluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0961]

[0962] Using intermediate BB15 and compound C59 as raw materials, the white solid intermediate BB15C59 (124.0 mg, 0.30 mmol, 58.9% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 420.0 (M+H) + 。

[0963] Synthesis of intermediate BB16C58 (2-chloro-5-fluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyrimidin-4-amine)

[0964]

[0965] Using intermediate BB16 and compound C58 as raw materials, the light yellow solid intermediate BB16C58 (6.66 g, 16.69 mmol, 93.3% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 428.2 (M+H) + 。

[0966] 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)

[0967]

[0968] Using intermediate BB16-D3 and compound C57 as raw materials, the off-white solid intermediate BB16-D3C57 (1.33 g, 3.10 mmol, 89.8% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 429.3 (M+H) + 。

[0969] 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)

[0970]

[0971] Using intermediate BB16-D3 and compound C58 as raw materials, the off-white solid intermediate BB16-D3C58 (1.54 g, 3.57 mmol, 79.6% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 431.1 (M+H)+ .

[0972] 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)

[0973]

[0974] 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) + .

[0975] Synthesis of Intermediate BB17C5 (2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carbonitrile)

[0976]

[0977] 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) + .

[0978] 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)

[0979]

[0980] 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) + .

[0981] Synthesis of Intermediate BB19C5 (2-Chloro-5-(difluoromethoxy)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0982]

[0983] Using intermediate BB19 and compound C5 as raw materials, white solid intermediate BB19C5 (1.03 g, 2.33 mmol, 82.2% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 434.0 (M+H) + 。

[0984] Synthesis of intermediate BB19C11 (2-chloro-5-(difluoromethoxy)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidin-4-amine)

[0985]

[0986] Using intermediate BB19 and compound C11 as raw materials, white solid intermediate BB19C11 (545.7 mg, 1.26 mmol, 77.3% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 434.2 (M+H) + 。

[0987] Synthesis of intermediate BB19C30 (2-chloro-5-(difluoromethoxy)-N-(2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[0988]

[0989] Using intermediate BB19 and compound C30 as raw materials, off-white solid intermediate BB19C30 (546.4 mg, 1.18 mmol, 66.5% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 464.0 (M+H) + 。

[0990] Synthesis of intermediate BB36C58 (2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(methoxymethyl)-N-methylpyrimidin-4-amine)

[0991]

[0992] Using intermediate BB36 and compound C58 as raw materials, colorless transparent oily intermediate BB36C58 (382.0 mg, 0.84 mmol, 69.3% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 454.0 (M+H) + 。

[0993] 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)

[0994]

[0995] Using intermediate BB42 and compound C5 as raw materials, the off-white solid intermediate BB42C5 (332.6 mg, 0.76 mmol, 44.5% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 436.2 (M+H) + 。

[0996] 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)

[0997]

[0998] Using intermediate BB43 and compound C5 as raw materials, the white solid intermediate BB43C5 (101.1 mg, 0.22 mmol, 37.3% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 468.1 (M+H) + 。

[0999] Synthesis of Intermediate BB44C5 (2-chloro-N-cyclopropyl-5-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[1000]

[1001] Using intermediate BB44 and compound C5 as raw materials, the pale yellow solid intermediate BB44C5 (258.3 mg, 0.59 mol, 74.8% yield) was prepared according to the same steps as intermediate BB1C2. LC-MS: m / z = 438.1 (M+H) + 。

[1002] 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)

[1003]

[1004] 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 successively added to dimethyl sulfoxide (5.0 mL). The mixture was stirred at 85 °C for 1 hour, cooled to 25 °C, ethyl acetate (20.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by suction filtration, washed 3 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 as a pale yellow oil (160.5 mg, 0.38 mmol, 28.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.77–7.71 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.96 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.68 (s, 3H); LC-MS: m / z = 428.1 (M + H) + 。

[1005] Synthesis of intermediate BB18D5 (2-chloro-5-ethynyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidin-4-amine)

[1006]

[1007] 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 successively added to N,N-dimethylformamide (40.0 mL). The mixture was stirred at 50 °C for 2 hours, cooled to 25 °C, ethyl acetate (100.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by suction filtration, washed 3 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 - 0 / 1) to obtain the intermediate BB18D5 as a white solid (2.24 g, 5.73 mmol, 70.2% yield). LC-MS: m / z = 392.2 (M + H) + 。

[1008] Synthesis of intermediate BB21D5 (2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-morpholinopyrimidin-4-amine)

[1009]

[1010] Using intermediate BB21 and compound D5 as raw materials, white solid intermediate BB21D5 (880.0 mg, 1.95 mmol, 88.6% yield) was prepared according to the same steps as intermediate BB18D5. LC-MS: m / z = 453.1 (M+H) + 。

[1011] 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)

[1012]

[1013] Using intermediate BB22 and compound D5 as raw materials, off-white solid intermediate BB22D5 (441.9 mg, 0.95 mmol, 87.4% yield) was prepared according to the same steps as intermediate BB18D5. LC-MS: m / z = 466.2 (M+H) + 。

[1014] Synthesis of intermediate BB24D5 (2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-ol)

[1015]

[1016] Using intermediate BB24 and compound D5 as raw materials, pale yellow solid intermediate BB24D5 (26.8 mg, 0.07 mmol, 22.8% yield) was prepared according to the same steps as intermediate BB18D5. LC-MS: m / z = 384.1 (M+H) + 。

[1017] Synthesis of intermediate BB24D11 (2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)amino)pyrimidin-5-ol)

[1018]

[1019] Using intermediate BB24 and D11 as raw materials, white solid intermediate BB24D11 (115.1 mg, 0.3 mmol, 83.0% yield) was prepared according to the same steps as intermediate BB18D5. LC-MS: m / z = 384.2 (M+H) + 。

[1020] Synthesis of Intermediate BB35D5 ((2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)methanol)

[1021]

[1022] Using Intermediate BB35 and Compound D5 as starting materials, Intermediate BB35D5 (333.8 mg, 1.86 mmol, 55.6% yield) as a colorless transparent oil was prepared according to the same procedure as Intermediate BB18D5. LC-MS: m / z = 398.1 (M+H) + 。

[1023] Synthesis of Intermediate BB41C5 (methyl 2-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)acetate)

[1024]

[1025] Using Intermediate BB41 and Compound D5 as starting materials, Intermediate BB41D5 (133.9 mg, 0.30 mmol, 69.9% yield) as a pale yellow solid was prepared according to the same procedure as Intermediate BB18D5. LC-MS: m / z = 440.2 (M+H) + 。

[1026] Example 1: Synthesis of Compound 1 (2-(2-isopropylphenyl)-5-methoxy-N-methyl-N-(4-(pyridin-2-yl)benzyl)pyrimidin-4-amine)

[1027]

[1028] Compound A5 (100 mg, 389 μmol, 1.00 eq) was dissolved in tetrahydrofuran (2.5 mL). Sodium hydride (62.2 mg, 1.55 mmol, 60.0% purity, 4.00 eq) was added portionwise at 0 °C. After addition, the reaction was carried out at 0 °C for 30 minutes. Then, Compound B10 (95.0 mg, 466 μmol, 1.20 eq) was added. After addition, the temperature was raised to 25 °C and stirred for 12 hours. Then, the reaction was quenched by adding ice water (2.0 mL) at 0 °C. The mixture was extracted with ethyl acetate (10.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a crude product. The crude product 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 Compound 1 (136 mg, 277 μmol, 71.3% yield, HCl) as a pale yellow solid.1 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 4.40 Hz, 1H), 8.40 (s, 1H), 8.18 - 8.19 (m, 3H), 7.80 (s, 1H), 7.65 (s, 1H), 7.43 - 7.46 (m, 6H), 5.09 - 5.21 (m, 2H), 3.85 - 3.94 (m, 3H), 3.54 (s, 1H), 3.26 - 3.34 (m, 3H), 1.01 - 1.23 (m, 6H); LC-MS: m / z = 425.2 (M + H) + 。

[1029] The following compounds were prepared by referring to the preparation method of Reference Compound 1, using different general intermediates A, B, and cesium carbonate or sodium hydride or potassium carbonate:

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038] Example 32: Synthesis of Compound 32 (2-(2-Isopropylphenyl)-N-(4-(pyridin-2-yl)benzyl)furo[3,2-d]pyrimidin-4-amine)

[1039]

[1040] Step 1: Synthesis of Compound 32-3

[1041] 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 successively added to N,N-dimethylformamide (4.0 mL). The mixture was stirred at 60 °C for 1 hour, ethyl acetate (30.0 mL) was added, and the mixture was stirred for 5 minutes. The filtrate was obtained by suction filtration 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 obtain compound 32-3 (360.9 mg). LC-MS: m / z = 337.0 (M+H) + 。

[1042] Step 2: Synthesis of compound 32

[1043] 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), and tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol, 0.10 eq) were successively added to dioxane (2.0 mL) and water (0.4 mL). The mixture was purged with nitrogen three times and stirred at 90 °C for 16 hours under nitrogen protection. 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), 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 white solid compound 32 (87.5 mg, 0.21 mmol, 69.4% yield, 98.6% purity). 1 1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 8.03–7.95 (m, 2H), 7.58–7.48 (m, 5H), 7.47–7.42 (m, 1H), 7.40–7.33 (m, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.93 (d, J = 6.0 Hz, 2H), 3.29–3.22 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H); LC-MS: m / z = 421.2 (M+H) + 。

[1044] The following compounds were prepared according to the preparation method of reference compound 32, wherein the reaction conditions for step 1 were cesium carbonate, sodium hydride or potassium carbonate, and the reaction conditions for step 2 were Pd(PPh3)4 / K3PO4 or XPhos-Pd-G2 / XPhos / K3PO4

[1045]

[1046]

[1047]

[1048]

[1049]

[1050] Example 61: Synthesis of Compound 61 (2-(2-Isopropylphenyl)-5-methoxy-N-methyl-N-((4-(pyridin-2-yl)cyclohexyl)methyl)pyrimidin-4-amine)

[1051]

[1052] 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) were successively added to dioxane (2.5 mL) and water (0.5 mL). After purging with nitrogen three times, the mixture was stirred at 95 °C under nitrogen protection for 16 hours. Water (15.0 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 (20.0 mL), 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain white solid compound 61 (93.5 mg, 0.22 mmol, 60.3% yield, 97.3% purity). LC-MS: m / z = 431.2 (M+H) + 。

[1053] The following compounds are prepared according to the preparation method of Compound 61, using Series A, AA, BBC or Series A, AA, BBD of intermediates as reaction raw materials, XPhos-Pd-G2 / XPhos / K3PO4 as reaction reagents, and dioxane and water as solvents:

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087] Example 204: Synthesis of Compound 204 (N-(4'-Cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[1088]

[1089] Step 1: Synthesis of Compound BB46-2 (O-(tert-butyldimethylsilyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)hydroxylamine)

[1090] 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 successively added to dioxane (20 mL), and the mixture was stirred at 80 °C for 4 hours, cooled to room temperature, filtered to obtain a filtrate, 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 pale yellow oily compound BB46-2 (430.2 mg, 1.49 mmol, 26.6% yield). LC-MS: m / z = 290.0 (M+H) + 。

[1091] 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)

[1092] Using intermediate BB46-2 (430 mg, 1.5 mmol, 1.0 eq) and compound C5 (452 mg, 1.65 mmol, 1.1 eq) as raw materials, a pale yellow solid intermediate BB46-2C5 (506.8 mg, 0.96 mmol, 64.1% yield) was prepared according to the same procedure as that of intermediate BB1C2. LC-MS: m / z = 528.3 (M+H) + 。

[1093] Step 3: Synthesis of Compound A2-7BB46-2C5 (O-(tert-butyldimethylsilyl)-N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydroxylamine)

[1094] 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 raw materials, a yellow solid intermediate A2-7BB46-2C5 (323.3 mg, 0.50 mmol, 56.0% yield) was prepared according to the same procedure as that of compound A1-2BB1C2. LC-MS: m / z = 642.3 (M+H) + 。

[1095] Step 4: Synthesis of Compound 204

[1096] Dissolve intermediate A2-7BB46-2C5 (323.0 mg, 0.5 mmol, 1.0 eq) in 4M hydrochloric acid methanol solution, stir at 25 °C for 1 hour, add saturated sodium bicarbonate aqueous solution (30.0 mL), extract with dichloromethane (20.0 mL) for 3 times, combine the organic layers, dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate in vacuo to obtain the crude product, and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2) to obtain white solid compound 204 (109.9 mg, 0.21 mmol, 41.7% yield). 11H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.75–7.57 (m, 2H), 7.56–7.41 (m, 2H), 4.87 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 1.62 (dt, J = 8.1, 3.5 Hz, 1H), 0.99 (dq, J = 5.9, 3.5 Hz, 2H), 0.84 (dq, J = 10.0, 3.4 Hz, 2H); LC-MS: m / z = 528.3 (M+H) + 。

[1097] 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)

[1098]

[1099] 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) + 。

[1100] Example 206: Synthesis of Compound 206 (N-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)cyanamide)

[1101]

[1102] 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 mixture was allowed to warm to 25 °C and stirred for 1 hour. Cyanogen bromide (48.7 mg, 0.46 mmol, 5 eq) was added and the mixture was stirred at 25 °C for 2 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 - 0 / 1) to give a pale white solid compound 206 (6.7 mg, 0.0125 mmol, 13.6% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 11H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 5.39 (d, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.70 (s, 3H), 1.68 (tt, J = 8.2, 4.8 Hz, 1H), 0.96 (s, 2H), 0.78 - 0.73 (m, 2H); LC-MS: m / z = 537.2 (M + H) + 。

[1103] Example 207: Synthesis of Compound 207 (2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methoxy-N-methyl-N-[[4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]cubane-1-yl]methyl]pyrimidin-4-amine)

[1104]

[1105] Step 1: Synthesis of Compound 207-2 ((2R, 3R, 4S, 5S)-4-(Hydroxymethyl)cubane-1-carboxylic acid methyl ester)

[1106] Dissolve compound (1S, 2R, 3R, 8S)-4-(Methoxycarbonyl)cubane-1-carboxylic acid (207-1, 10.0 g, 48.5 mmol, 1.00 eq) in tetrahydrofuran (300 mL). Add 10 M borane dimethyl sulfide tetrahydrofuran solution (5.82 mL, 1.20 eq) at 20 °C and stir the reaction at 50 °C for 13 hours. Slowly add methanol (300 mL) to quench the reaction at 0 °C. Filter by suction to obtain the filtrate, and concentrate it under vacuum to obtain white solid compound 207-2 (11.0 g, crude product). 1 1H NMR (400 MHz, CDCl3) δ 4.15 - 4.13 (m, 3H), 3.89 - 3.87 (m, 3H), 3.77 - 3.75 (m, 2H), 3.70 (s, 3H).

[1107] Step 2: Synthesis of Compound 207-3 ((2R, 3R, 4S, 5S)-4-Formylcubane-1-carboxylic acid methyl ester)

[1108] Compound 207-2 (11.0 g, 57.2 mmol, 1.00 eq) was dissolved in dichloromethane (150 mL). Dess-Martin periodinane (DMP, 29.1 g, 68.6 mmol, 21.2 mL, 1.20 eq) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with dichloromethane (150 mL) three times. The organic layers were combined, washed twice with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and 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 - 3 / 1) to obtain white solid compound 207-3 (5.8 g, 30.5 mmol, 53.3% yield). 1 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 4.38 - 4.36 (m, 3H), 4.27 - 4.25 (m, 3H), 3.72 (s, 3H);

[1109] Step 3: Synthesis of compound 207-4 ((2R,3R,4S,5S)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylic acid methyl ester)

[1110] 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, and the mixture was heated to 100 °C and stirred for 1 h. Compound 207-3 (5.8 g, 30.5 mmol, 1.0 eq) dissolved in methanol (65.0 mL) and ammonia water (25.0 mL) was added at 20 °C. After addition, the reaction mixture was stirred at 20 °C for 11 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo to obtain white solid compound 207-4 (6.0 g, 18.5 mmol, 60.8% yield). LC-MS: m / z = 297.0 (M + H) + 。

[1111] 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)

[1112] 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 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 reaction was carried out at 20 °C for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (50.0 mL) at 0 °C. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (70.0 mL) three times. The organic layers were combined, washed twice with saturated brine (80.0 mL), 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 reverse-phase chromatography HPLC (0.1% FA) to obtain white solid compound 207-5 (1.6 g, 4.95 mmol, 32.5% yield). 1 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J = 1.2 Hz, 1H), 4.45 - 4.42 (m, 3H), 4.32 - 4.30 (m, 3H), 3.73 (s, 3H), 3.66 (s, 3H); LC-MS: m / z = 311.1 (M + H) + 。

[1113] 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)

[1114] 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 reaction was stirred at 70 °C and

[1115] 50 Psi for 12 hours. After cooling to room temperature, ice water (15.0 mL) was added, and ethanol was removed by concentration in vacuo. The mixture was extracted with ethyl acetate (30.0 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to obtain white solid compound 207-6 (0.11 g, crude product). LC-MS: m / z = 310.1 (M + H) + 。

[1116] Step 6: Synthesis of compound 207-7 (N-methyl-1-((2R,3R,4S,5S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-yl)methanamine)

[1117] Compound 207-6 (0.1 g, 323.33 mmol, 1 eq) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum hydride tetrahydrofuran solution (2.5 mmol, 387.99 μL, 3 eq) was added at 0°C, 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 vacuum concentrated to obtain white solid compound 207-7 (86 mg, crude product). LC-MS: m / z=296.3 (M+H) + .

[1118] 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)

[1119] 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 ethyl acetate (10.0 mL) was used for extraction three times. The organic layers were combined, washed twice with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and the filtrate was filtered to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain a white solid compound 207-8 (32.0 mg, 73.09 mmol, 53.96% yield). LC-MS: m / z=438.2 (M+H) + .

[1120] 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'-bipyrimidine]-4-amine)

[1121] 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 raw materials and the white solid compound 207 (2.66 mg, 4.32 mmol, 7.56% yield) was prepared according to the same procedure as compound 61. LC-MS: m / z=552.3 (M+H) + .

[1122] Example 208: Synthesis of Compound 208 (2 - ((4'-cyclopropyl - 5,6'-dimethoxy - [2,5'-bipyrimidine]-4 - yl)amino)-2-(4-(1 - methyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)acetonitrile))

[1123]

[1124] Step 1: Synthesis of Compound 208 - 1 (4-(1 - methyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzaldehyde)

[1125] 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 successively added to tetrahydrofuran (30.0 mL). The reaction was stirred at an external temperature of 45 °C for 16 hours. The filtrate was obtained by filtration 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 white solid compound 208 - 1 (823.1 mg, 3.24 mmol, 82.8% yield). LC - MS: m / z = 255.1 (M + H) + 。

[1126] Step 2: Synthesis of Compound 208 - 2 (2 - hydroxy - 2-(4-(1 - methyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)acetonitrile)

[1127] 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 successively added to tetrahydrofuran (8.0 mL). The reaction was stirred at an external temperature of 35 °C for 16 hours. 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 = 1 / 0 - 0 / 1) to obtain a colorless transparent oily compound 208 - 2 (303.3 mg, 1.08 mmol, 68.7% yield). LC - MS: m / z = 282.2 (M + H) + 。

[1128] Step 3: Synthesis of Compound 208 - 3 (2 - chloro - 2-(4-(1 - methyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)acetonitrile)

[1129] A solution of compound 208-2 (300.0 mg, 1.07 mmol, 1.00 eq) in dichloromethane (6.0 mL) was added with thionyl chloride (635.0 mg, 5.33 mmol, 5.00 eq) at 0 °C. After the addition, the temperature was raised to 25 °C and stirred for 4 hours. The reaction solution 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) + 。

[1130] 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)

[1131] 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 successively added to toluene (5.2 mL). The mixture was reacted by microwave at 140 °C for 1 hour, 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 - 0 / 1) to obtain compound 208-4 (96.0 mg, 0.23 mmol, 26.1% yield) as a pale yellow solid. LC-MS: m / z = 423.1 (M+H) + 。

[1132] Step 5: Synthesis of compound 208 (2-((4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-yl)amino)-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile)

[1133] 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) and sodium bicarbonate (72.2 mg, 0.86 mmol, 4.0 eq) were successively added to dioxane (2.0 mL) and water (0.4 mL). After purging with nitrogen three times, the mixture was stirred at 95 °C for 16 h under nitrogen protection. 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, filtered to obtain a filtrate, 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 white solid compound 208 (38.2 mg, 0.071 mmol, 33.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 7.92–7.89 (m, 2H), 7.86–7.81 (m, 2H), 7.53 (s, 1H), 7.09 (s, 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) + 。

[1134] Example 209: Synthesis of compound 209 (2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-5-methoxy-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)pyrimidin-4-amine)

[1135]

[1136] Step 1: Synthesis of compound 209-2 ((1,4-dioxaspiro[4.5]dec-8,8-diyl)bis(methylene) bis(4-methylbenzenesulfonate))

[1137] Compound 209-1 ([8-(hydroxymethyl)-1,4-dioxaspiro[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 successively added to pyridine (250.0 mL). The reaction was stirred at 25 °C for 12 hours. Ethyl acetate (500.0 mL) was added, and it was washed 3 times with 10% aqueous citric acid solution (500.0 mL) and once with saturated brine (500.0 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated in vacuo to obtain a crude product. The crude product was slurried in ethanol (500.0 mL) for 1 hour, filtered by suction to obtain white solid compound 209-2 (116.0 g, 227.0 mmol, 91.9% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.40 Hz, 4H), 7.36 (d, J = 8.00 Hz, 4H), 3.89 (s, 4H), 3.84 (s, 4H), 2.47 (s, 6H), 1.49 (s, 8H).

[1138] Step 2: Synthesis of compound 209-3 ((4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate))

[1139] 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 it was extracted 3 times with ethyl acetate (1000 mL). The organic layers were combined, washed 2 times with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered by suction to obtain a filtrate, and concentrated in vacuo to obtain white solid compound 209-3 (110 g, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.00 Hz, 4H), 7.48 (d, J = 8.40 Hz, 4H), 3.98 (s, 4H), 2.46 (d, J = 27.6 Hz, 6H), 2.15 - 2.11 (t, J = 7.20 Hz, 4H), 1.62 - 1.54 (m, 4H); LC-MS: m / z = 467.1 (M + H) + 。

[1140] Step 3: Synthesis of compound 209-4 ((4-hydroxy-4-vinylcyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate))

[1141] Compound 209-3 (55.0 g, 118 mmol, 1.00 eq) was dissolved in tetrahydrofuran (500 mL). A 1 M solution of vinylmagnesium bromide in tetrahydrofuran (236 mL, 2.00 eq) was slowly added dropwise at -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (300 mL) at 0 °C. The solvent was removed by vacuum concentration. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give yellow solid Compound 209-4 (100 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J1 = 8.0 Hz, J2 = 12.8 Hz, 4H), 7.36 (t, J = 8.0 Hz, 4H), 5.84 (dd, J1 = 10.8 Hz, J2 = 17.2 Hz, 1H), 5.17 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 3.92 (s, 2H), 3.76 (s, 2H), 2.46 (d, J = 1.60 Hz, 6H), 1.56 - 1.26 (m, 8H).

[1142] Step 4: Synthesis of Compound 209-5 ((1-Vinyl-2-oxabicyclo[2.2.2]oct-4-yl)methyl 4-methylbenzenesulfonate)

[1143] Compound 209-4 (30.0 g, 60.7 mmol, 1.00 eq) was dissolved in ethylene glycol dimethyl ether (500 mL). Sodium hydride (4.85 g, 121 mmol, 60% content, 2.00 eq) was added portionwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes, then heated to 110 °C and stirred for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (400 mL) at 0 °C. Water (500 mL) was added, and the organic solvent was removed by vacuum concentration. The mixture was extracted with ethyl acetate (600 mL) three times. The combined organic layers were washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated in vacuo to give pale yellow solid Compound 209-5 (27.4 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 8.00 Hz, 2H), 5.85 - 5.76 (m, 1H), 5.15 - 5.11 (t, J = 1.60 Hz, 1H), 5.04 - 5.00 (d, J1 = 1.60 Hz, J2 = 11.2 Hz, 1H), 3.69 (d, J = 6.80 Hz, 4H), 2.46 (s, 3H), 1.90 - 1.86 (m, 2H), 1.72 - 1.65 (m, 4H), 1.52 - 1.51 (m, 2H);

[1144] Step 5: Synthesis of Compound 209-6 ((1-Formyl-2-oxabicyclo[2.2.2]oct-4-yl)methyl 4-methylbenzenesulfonate)

[1145] Dissolve Compound 209-5 (4.00 g, 12.4 mmol, 1.00 eq) in tetrahydrofuran (80.0 mL). Add sodium periodate (7.96 g, 37.2 mmol, 2.06 mL, 3.00 eq) at 0 °C, and then add potassium osmate (1.14 g, 3.10 mmol, 0.250 eq) dissolved in water (16.0 mL). Stir the reaction at 20 °C for 12 hours, filter to obtain the filtrate, wash it 3 times with saturated brine (100 mL), dry it over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate it under vacuum to obtain yellow oily 209-6 (4.0 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.77 - 7.74 (m, 2H), 7.37 - 7.34 (m, 2H), 3.74 - 3.67 (m, 4H), 2.46 (s, 3H), 1.91 1.49 (m, 8H).

[1146] 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)

[1147] Add 3,3-Dibromo-1,1,1-trifluoropropan-2-one (3.99 g, 14.8 mmol, 1.20 eq) and sodium acetate (2.12 g, 25.9 mmol, 2.10 eq) to water (8.0 mL) in sequence, stir at 100 °C for 1 hour. Add Compound 209-6 (4.00 g, 12.3 mmol, 1.00 eq) dissolved in ammonia water (11.5 g, 98.7 mmol, 12.7 mL, 30.0% content, 8.0 eq) and methanol (40.0 mL) at 25 °C. After addition, stir the reaction at 25 °C for 5 hours, add water (100 mL), extract it 3 times with ethyl acetate (180 mL), combine the organic layers, dry it over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate it under vacuum to obtain the crude product. The crude product is 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) + 。

[1148] 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)

[1149] Dissolve Compound 209-7 (2.20 g, 5.11 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL). Add sodium hydride (307 mg, 7.67 mmol, 60.0% content, 1.50 eq) portionwise at 0 °C. After addition, stir the reaction at 0 °C for 30 minutes. Add iodomethane (725 mg, 5.11 mmol, 1.0 eq), and warm the reaction to 25 °C for 2 hours. Quench the reaction by adding ice water (30.0 mL) at 0 °C. Add water (20.0 mL), and extract with ethyl acetate (150 mL) three times. Combine the organic layers, wash twice with saturated brine (60.0 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, and concentrate in vacuo to obtain the crude product. The crude product is purified by prep-HPLC (column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: [water (TFA)-ACN]; gradient: 45%-75%) to obtain white solid Compound 209-8 (1.5 g, 3.37 mmol, 66.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.2 Hz, 1H), 3.81 (s, 5H), 3.73 (s, 2H), 2.47 (s, 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) + 。

[1150] 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]oct-4-yl)methyl)pyrimidin-4-amine)

[1151] 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 successively added to N,N-dimethylformamide (20.0 mL). The mixture was stirred at 130 °C for 24 h, cooled to 25 °C, dichloromethane (100.0 mL) was added, and the mixture was stirred for 5 min. The filtrate was obtained by suction filtration, washed 3 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 - 0 / 1) to obtain white solid compound 209-9 (135.6 mg, 0.31 mmol, 14.0% yield). LC-MS: m / z = 432.3 (M+H) + 。

[1152] 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)

[1153] 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](methanesulfonate)[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 successively added to dioxane (0.8 mL) and water (0.16 mL). The mixture was stirred at an external temperature of 95 °C for 16 h. The reaction solution was concentrated in vacuo to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; gradient: 61% - 91%) to obtain white solid compound 209 (16.6 mg, 30.8 μmol, 33.3% yield). 11H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.55 (s, 1H), 7.13 (s, 1H), 6.01 - 5.88 (m, 1H), 5.32 - 5.26 (m, 1H), 4.27 (s, 2H), 4.01 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 2.39 - 2.31 (m, 2H), 2.29 - 2.21 (m, 2H), 1.97 - 1.91 (m, 2H), 1.83 - 1.76 (m, 2H), 1.51 (s, 3H), 1.49 (s, 3H); LC-MS: m / z = 540.3 (M + H) + 。

[1154] 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]oct-4-yl)methyl)-[2,5'-bipyrimidin]-4-amine)

[1155]

[1156] 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, Compound 210 (7.8 mg, 0.0143 mmol, 12.3% yield), a white solid, was prepared according to the same procedure as for Compound 209. 1 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.11 (s, 1H), 5.58 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.87 (s, 2H), 3.83 (s, 3H), 3.43 (d, J = 6.4 Hz, 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) + 。

[1157] 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)

[1158]

[1159] Using compound 209-8 (300.0 mg, 0.675 mmol, 1 eq) and intermediate BB-1 (351.5 mg, 2.02 mmol, 3.0 eq) as raw materials, a pale yellow solid compound 211 (44.3 mg, 0.08 mmol, 18.9% yield) was prepared according to the same procedure as compound 209. LC-MS: m / z = 554.2 (M+H) + 。

[1160] 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)

[1161]

[1162] Using compound 211-1 (30.0 mg, 0.067 mmol, 1 eq) and intermediate A2-7 (39.2 mg, 0.20 mmol, 3.0 eq) as raw materials, a white solid compound 212 (5.7 mg, 0.01 mmol, 15.2% yield) was prepared according to the same procedure as compound 209. LC-MS: m / z = 560.3 (M+H) + 。

[1163] 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)

[1164]

[1165] Using compound 209-7 (1.0 g, 2.32 mmol, 1 eq) and cyclopropyl bromide (843.2 mg, 6.97 mmol, 3.0 eq) as raw materials, a white solid compound 213 (11.6 mg, 0.02 mmol, 17.2% yield) was prepared according to the same procedure as compound 209. LC-MS: m / z = 566.3 (M+H) + 。

[1166] 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)

[1167]

[1168] Using Compound 209-7 (1.0 g, 2.32 mmol, 1 eq) and isopropyl iodide (1.18 g, 6.97 mmol, 3.0 eq) as starting materials, Compound 214, a white solid (10.4 mg, 0.018 mmol, 20.4% yield), was prepared according to the same procedure as for Compound 209. LC-MS: m / z = 568.4 (M+H) + 。

[1169] Example 215: Synthesis of Compound 215 (4'-cyclopropyl-5,6'-dimethoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine)

[1170]

[1171] Using Compound 207-5 (500 mg, 1.61 mmol, 1.0 eq) and 7M ammonia in methanol (40.0 mL, 173 eq) as starting materials, Compound 215, a white solid (7.77 mg, 14.0 μM, 11.9% yield), was prepared according to the same procedure as for Compound 207. LC-MS: m / z = 538.3 (M+H) + 。

[1172] Example 216: Synthesis of Compound 216 (4'-cyclopropyl-N-((4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-yl)methyl)-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-amine)

[1173]

[1174] Using Compound 207-4 (200 mg, 0.68 mmol, 1.0 eq) and cyclopropyl bromide (246.8 mg, 2.04 mmol, 3.0 eq) as starting materials, Compound 216, a white solid (2.5 mg, 4.45 μmol, 10.5% yield), was prepared according to the same procedure as for Compound 207. LC-MS: m / z = 564.2 (M+H) + 。

[1175] Example 217: Synthesis of Compound 217 (4'-Cyclopropyl-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-yl)methyl)-5,6'-dimethoxy-[2,5'-bipyrimidine]-4-amine)

[1176]

[1177] Using Compound 207-4 (600 mg, 2.03 mmol, 1.0 eq) and isopropyl iodide (1.04 g, 6.09 mmol, 3.0 eq) as starting materials, white solid Compound 217 (10.5 mg, 0.019 mmol, 13.8% yield) was prepared according to the same procedure as for Compound 207. LC-MS: m / z = 566.3 (M+H) + 。

[1178] Test Example 1: In Vitro USP1 Kinase Inhibitory Activity

[1179] Experimental Purpose: To screen the inhibitory activity of compounds against USP1 kinase by fluorescence detection using a 384-well plate

[1180] Experimental Materials: Recombinant human His6-USP1 / His6-UAF1 complex protein (R&D, catalog number: E-568-050), ubiquitin rhodamine 110 protein (Ub-Rho) (R&D, catalog number: U-555-050), 384-well plate (Perkin Elmer, catalog number: 6007279); all compounds were dissolved in 100% DMSO to prepare a 50 mM stock solution

[1181] Experimental Method:

[1182] 1) Preparation of 1× assay buffer: Prepare 1× assay buffer (modified Tris buffer);

[1183] 2) Compound dilution: Transfer the compounds to the assay plate by Echo. The final ratio of DMSO is 1%;

[1184] 3) Preparation of enzyme solution: Add recombinant human His6-USP1 / His6-UAF1 complex protein to 1× assay buffer to prepare the enzyme solution;

[1185] 4) Preparation of substrate solution: Add ubiquitin rhodamine 110 protein CF (Ub-Rho) to 1× assay buffer to prepare the substrate solution;

[1186] 5) Transfer 10 μL of the enzyme solution to the assay plate, and add 10 μL of 1× assay buffer to the control wells;

[1187] 6) Incubate at room temperature for 1 h

[1188] 7) Start the reaction by adding 10 μL of substrate solution to each well, centrifuge for 30 s, and shake for 30 s;

[1189] 8) Read the plate with Envision after 30 minutes, and set the parameters as excitation light 480 nm and emission light 540 nm;

[1190] 9) Collect and summarize the data;

[1191] 10) Curve fitting: Fit the data in Excel,

[1192] Inhibition rate formula: Percent inhibition = (Maximum value - Signal value) / (Maximum value - Minimum value) × 100; Fit the data in XL-Fit,

[1193] Half-maximal inhibitory concentration formula: Percent inhibition = Minimum concentration + (Maximum concentration - Minimum concentration) / (1 + (Half-maximal inhibitory concentration / Compound concentration) 斜率 );

[1194] Half-maximal inhibitory concentration, hereinafter referred to as IC 50 .

[1195] Test example 2: Cell viability CTG experiment

[1196] 1. Purpose: To screen for inhibitors of USP1 by CTG detection method using a 96-well plate.

[1197] 2. Materials:

[1198] The cells used are MDA-MB-436 (manufacturer: Nanjing Kebai Biotechnology Co., Ltd.), and the culture medium is DMEM.

[1199] CTG (CellTiter- Glow cell viability assay) (Promega, catalog number: G7572)

[1200] 96-well plate (Corning, catalog number: 3610)

[1201] 3. Compounds:

[1202] All compounds are dissolved in 100% DMSO to form a 50 mM stock solution.

[1203] 4. Experimental method:

[1204] ① Seeding:

[1205] Seed the cells to be tested into a 96-well plate at a certain density, 200 μL per well, and add 200 μL of cell culture medium to the blank well. Place the seeded cell plate in a 37 °C incubator.

[1206] ② Compound dilution:

[1207] Dilute the compound with 100% DMSO to different concentrations, with the final proportion of DMSO being 4%.

[1208] ③ Adding the compound:

[1209] Add the compound prepared in ② to the cell plate in ①, 10 μL per well. Place the cell plate with the added compound in an incubator at 37 °C and continue culturing for 7 days before detection.

[1210] ④ Detection:

[1211] Mix the substrate and buffer of the CTG reagent evenly. Take out the cell plate with the added compound in ③ from the incubator and let it stand at room temperature for 30 min to equilibrate. Discard the culture medium containing the drug in the cell plate, add 100 μL of PBS and 50 μL of CTG reagent to each well, mix and shake for 3 min, and then incubate at room temperature for 10 min. Use a BIotek microplate reader for detection, with the parameter set to 567 CPM.

[1212] 5. Curve fitting

[1213] Same as that in enzymology.

[1214] The IC 50 value of the USP1 kinase inhibitory activity of the compound of the present invention and the cell IC 50 data are shown as follows:

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221] In addition, in some embodiments, the compounds of the present invention have good pharmacokinetic properties and good CYP (cytochrome P450), hERG, PPB (plasma protein binding), and LM (liver microsome metabolic stability) properties. Moreover, the compounds of the present invention show good anti-tumor activity in the MDA-MB-436 or MX-1 models in mice.

Claims

1. A compound represented by the general formula (II), Among them, The loop C is R6 is independently H or C1-C6 alkyl at each occurrence; and Ring A is selected from phenyl, naphthyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, bicyclo[2.2.2]octyl, cyclopentyl, pyrrolidinyl, and piperazinyl; Ring B is selected from pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, and tetrazolyl, and ring B is optionally substituted by one or more R1; L is a chemical bond; R a and R b are both H atoms; R4 is an H atom; R5 is selected from phenyl and pyrimidinyl, wherein the phenyl and pyrimidinyl are each independently substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl; R1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-8 cycloalkyl at each occurrence; and n is 1.

2. The compound according to claim 1, wherein R6 is H at each occurrence; Ring A is selected from phenyl, piperidinyl, cyclohexyl, cyclopropyl, cyclobutyl, bicyclo[2.2.2]octyl, cyclopentyl, pyrrolidinyl, and piperazinyl; Ring B is selected from pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrrolyl, pyrazinyl, and pyridazinyl, and ring B is substituted by one or more R1; R5 is selected from R1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; and n is 1.

3. The compound according to claim 1, wherein, Selected from And ring B is substituted by one or more R1, where R1 is as defined in claim 1.

4. The compound according to claim 3, wherein selected from 5. A compound represented by the general formula (II), which is selected from 6. A compound represented by the general formula (III), Among them, The ring D is R is selected from Ring A is selected from phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, furyl, pyranyl, naphthyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, and tetrazolyl, Ring B is selected from pyrimidinyl, imidazolyl, pyrazolyl, pyrrolyl, pyrazinyl, pyridazinyl, triazolyl, and tetrazolyl, and ring A and ring B are each independently optionally substituted by one or more R1; L is a chemical bond; R a and R b are both H atoms; R2 is an H atom; R5 is selected from pyrimidinyl and pyrazolyl, wherein the pyrimidinyl and pyrazolyl are each independently substituted by one or more R1; R1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-8 cycloalkyl at each occurrence; and n is 1.

7. The compound according to claim 6, wherein, Ring A is selected from phenyl and thienyl, and ring B is selected from imidazolyl and pyrazolyl.

8. The compound according to claim 6, wherein, selected from and each of ring A and ring B is independently optionally substituted with one or more R1s, wherein R1 is as defined in claim 6.

9. The compound according to claim 6, wherein Selected from 10. The compound according to claim 6, wherein selected from 11. The compound according to claim 6, wherein R5 is selected from pyrimidinyl and pyrazolyl, which are each independently optionally substituted by one or more substituents selected from F, Br, Cl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl.

12. The compound according to claim 11, wherein R5 is selected from 13. The compound according to any one of claims 6-12, which is selected from 14. A method for preparing the compound according to claim 1, the method comprising: reacting a compound represented by the general formula (IIA) with a compound represented by the general formula (IB) to obtain a compound represented by the general formula (II); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid, and borate; and Ring A, Ring B, Ring C, L, R a , R b , R4, R5 and n are as defined in claim 1; or reacting a compound represented by the general formula (IIC) with a compound represented by the general formula (ID) to obtain a compound represented by the general formula (II); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid, and borate; and Ring A, Ring B, Ring C, L, R a , R b , R4, R5 and n are as defined in claim 1; or reacting a compound represented by the general formula (IIC) with a compound represented by the general formula (IJ) to obtain a compound represented by the general formula (II); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid, and borate; and Ring A, Ring B, Ring C, L, R a , R b , R4, R5, and n are as defined in claim 1.

15. A method for preparing the compound according to claim 6, the method comprising: reacting the compound represented by general formula (IIIA) with the compound represented by general formula (IB’) to obtain the compound represented by general formula (III); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and Ring D, R, R a , R b , R2, R5 and n are as defined in claim 6; or reacting the compound represented by general formula (IIIC) with the compound represented by general formula (ID) to obtain the compound represented by general formula (III); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and Rings D, R, R a , R b , R2, R5 and n are as defined in claim 6; or reacting the compound represented by general formula (IIIE) with the compound represented by general formula (IB’) to obtain the compound represented by general formula (IIIF), and deprotecting the compound represented by general formula (IIIF) to obtain the compound represented by general formula (III); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl; R2 is hydroxyl; Rings D, R, R a , R b , R2, R5 and n are as defined in claim 6; or reacting the compound represented by general formula (IIIG) with the compound represented by general formula (ID) to obtain the compound represented by general formula (IIIH), and deprotecting the compound represented by general formula (IIIH) to obtain the compound represented by general formula (III); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; Y is a hydroxyl protecting group, and the hydroxyl protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, benzyl, methoxymethyl and ethoxyethyl; R2 is hydroxyl; Rings D, R, R a , R b , R2, R5 and n are as defined in claim 6; or reacting the compound represented by general formula (IIIC) with the compound represented by general formula (IJ) to obtain the compound represented by general formula (III); X is a leaving group, and the leaving group is selected from halogen, sulfonate, boric acid and borate; and Ring D, R, R a , R b , R2, R5 and n are as defined in claim 6.

16. A pharmaceutical composition, the pharmaceutical composition containing the compound according to any one of claims 1-13 and one or more pharmaceutically acceptable excipients.

17. Use of the compound according to any one of claims 1-13 or the pharmaceutical composition according to claim 16 in the preparation of a drug for treating or preventing a disease or disorder associated with the inhibition of ubiquitin-specific protease 1.

18. Use of the compound according to any one of claims 1-13 or the pharmaceutical composition according to claim 16 in the preparation of a drug for treating or preventing cancer.

19. The use according to claim 18, wherein the cancer is selected from lung cancer, non-small cell lung cancer, colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer and breast cancer.

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