Azacycloalkane Menin-MLL protein inhibitor as well as pharmaceutical composition and application thereof

Abstract

The invention provides azacycloalkane compounds as shown in a formula I and a formula II, pharmaceutically acceptable salts, hydrates, isomers, prodrugs or a mixture of the salts, the hydrates, the isomers and the prodrugs, a pharmaceutical composition containing the azacycloalkane compounds, and application of the azacycloalkane compounds to preparation of drugs for preventing, relieving or treating related diseases caused by Menin-MLL protein interaction.

Description

Technical Field

[0001] This invention relates to diazonium alkylene Menin-MLL protein inhibitors, pharmaceutical compositions containing the same, and their use in the preparation of medicaments for the prevention, relief, or treatment of diseases caused by Menin-MLL protein interactions. Background Technology

[0002] MLL (Mixed Lineage Leukemia) protein is a histone methyltransferase, also known as KMT2A (Histone-lysine N-methyltransferase 2A). MLL rearrangement (MLL-r) leukemia is caused by a translocation at the 11q23 chromosomal locus containing the gene encoding KMT2A. This chromosomal translocation is known to produce more than 60 oncogenic fusion proteins—formed by the fusion of the N-terminus of MLL with various different proteins, among which the MLL-AF4 / 9 fusion mutation is the most malignant. MLL-r leukemia accounts for 5%–10% of adult acute leukemia and 70% of infant acute leukemia. Current treatment options are limited, mostly involving chemotherapy drugs, with a poor prognosis and a high relapse rate.

[0003] Menin is a nucleus-based protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. It is a key cofactor of the oncogenic MLL-r fusion protein and exhibits a high affinity for MLL-r. Upon binding to MLL-r, Menin recruits chromatin-modifying enzymes such as the Dot1L or pTEFb complex, leading to enhanced transcription of genes including HOXA and MEIS1. Abnormal expression of these genes inhibits hematopoietic cell differentiation and promotes their proliferation. In vitro and in vivo experiments have shown that Menin inhibitors disrupt the interaction between Menin and MLL-r and specifically induce growth inhibition and apoptosis in leukemia cells carrying MLL-r mutations (Cancer Cell 36, 660–673). Studies have also found that Menin inhibitors are effective against leukemia with NPM1 gene mutations, which account for approximately 20-30% of acute myeloid leukemia patients (Science 367, 586–590).

[0004] Several Menin inhibitors are currently undergoing phase 1 / 2 clinical trials for patients with relapsed / refractory acute leukemia harboring MLL-r or NPM1 mutations, such as Syndax's SNDX-5613, Kura Oncology's KO-539, and Daichi Sankyo Group's DS-1594b. In a clinical trial called AUGMENT-101, 53% of the 60 evaluable patients responded to the drug; however, after the second treatment cycle, some patients developed resistance to SNDX-5613. The study found that these resistant patients had MEN1 gene mutations, leading to amino acid changes in Menin proteins M3271, M327V, G331R, G331D, T349M, and S160C. These amino acid point mutations located within the Menin drug-binding pocket interfere with the binding of drug molecules to target proteins, thereby reducing drug affinity. Importantly, the affinity of these mutant Menin proteins for the KMT2A peptide is not significantly affected by structural changes. Studies have shown that proteins with M327I and T349M point mutations are significantly less sensitive to reported inhibitors, thus gaining a significant selective advantage (Nature 615, 913–919). Therefore, developing inhibitors that can bind to both wild-type and mutant Menin proteins, especially M327I and T349M point mutations, is particularly important and will bring hope of cure to these drug-resistant patients. In addition, researchers have found that some current Menin inhibitors also have CYP inhibition problems, especially CYP3A4 inhibition and hERG inhibition, leading to potential risks such as affecting drug combination and cardiotoxicity. How to solve these problems simultaneously will also become one of the key focuses of Menin inhibitor research.

[0005] Furthermore, excessive Menin expression can inhibit β-cell proliferation, leading to relative insulin insufficiency. A Menin-MLL inhibitor has been shown to enhance β-cell proliferation, thus offering potential applications in the field of diabetes. Currently, one compound, BMF-219, is undergoing phase 2 clinical trials for type 2 diabetes.

[0006] In conclusion, Menin-MLL interaction inhibitors have promising applications as drugs, and there is a strong clinical need for their development. Summary of the Invention

[0007] This invention provides a compound of Formula I, a pharmaceutically acceptable salt, hydrate, isomer (e.g., stereoisomer or tautomer), prodrug, or mixture thereof:

[0008]

[0009] In Formula I, ------ represents possible chemical bonds (i.e., (Represents a single or double bond).

[0010] In some implementation schemes, It represents a double bond.

[0011] U, Y1, Y2, Y3, and Y4 are each independently selected from CR3 or N, and no more than 3 of Y1, Y2, Y3, and Y4 are N; R3 may be the same or different at different positions, and R3 may be independently selected from H, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt, or -NRsSO2Rt, where Rs and Rt are each independently selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy.

[0012] In some embodiments, the heterocyclic alkyl and heteroaryl groups contain 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S.

[0013] In some implementations, U is N or CH.

[0014] In some implementation schemes, any two of Y1, Y2, Y3, and Y4 are N, and the rest are CR3; or any one of Y1, Y2, Y3, and Y4 is N, and the rest are CR3; or Y1, Y2, Y3, and Y4 are all CR3.

[0015] In some implementations, Y1 and Y2 are N, and Y3 and Y4 are CR3; in some implementations, Y1 and Y3 are N, and Y2 and Y4 are CR3; in some implementations, Y1 and Y4 are N, and Y2 and Y3 are CR3; in some implementations, Y2 and Y3 are N, and Y1 and Y4 are CR3. In some implementations, Y1 is N, and Y2, Y3, and Y4 are CR3; in some implementations, Y2 is N, and Y1, Y3, and Y4 are CR3; in some implementations, Y3 is N, and Y1, Y2, and Y4 are CR3. In some implementations, Y4 is N, and Y1, Y2, and Y3 are CR3.

[0016] R3 at different positions may be the same or different, and R3 may be independently selected from H, halogen, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt or -NRsSO2Rt, wherein Rs and Rt are independently selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, respectively. In some embodiments, R3 at different positions is independently selected from H, F, Cl, Br, I, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, chloromethoxy, fluoromethoxy, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, prop-1-enyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclopropyl, phenyl, -CONHCH3, -CONHCH2CH3, -SO2NHCH3, -SO2NHCH2CH3, -NHSO2CH3, -NCH3SO2CH3 or -NHSO2CH2CH3. In some embodiments, Y1 is CH or N, Y2, Y3, and Y4 are CR3, and R3 is H, F, Cl, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, -CONHCH3, or -SO2NHCH3. In some embodiments, Y1, Y3, and Y4 are CH, Y2 is CR3, and R3 is F, Cl, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, -CONHCH3, -SO2NHCH3, or -NHSO2CH3.

[0017] Ra is R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic alkyl or -ORx, wherein Rx is a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclic alkyl; or R1 and R2 are cyclic together with the nitrogen to which they are attached.

[0018] In some embodiments, R1 and R2 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted 3-4 membered heterocyclic alkyl, or -ORx, where Rx is a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclic alkyl. Specifically, R1 and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc. Methyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl or substituted cyclopropyl, cyclopropoxy, cyclobutyl or substituted cyclobutyl; in some embodiments, R1 is isopropyl and R2 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl.

[0019] In some embodiments, R1 and R2, together with the attached nitrogen, form a 3-10 membered alicyclic ring, which may be selected from monocyclic or polycyclic rings, and the polycyclic ring may be a fused ring, a spirocyclic ring, or a bridged ring. In some embodiments, R1 and R2, together with the attached nitrogen, form a 3-8 membered alicyclic ring. In some embodiments, R1 and R2, together with the attached nitrogen, form a 3-6 membered alicyclic ring. In addition to the existing nitrogen, the alicyclic ring contains 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some specific embodiments, R1 and R2, together with the attached nitrogen, form the following structure:

[0020]

[0021] In some embodiments, the alicyclic ring formed by R1, R2 and the attached nitrogen is substituted at any possible position with one or more groups selected from oxygen, hydroxyl, amino, carboxyl, halogen, cyano, C1-C6 alkyl, C1-C3 alkylamino, C3-C8 cycloalkyl, or 3-8 membered heterocyclic alkyl. In some specific embodiments, the alicyclic ring formed by R1, R2 and the attached nitrogen is optionally substituted with one or more groups selected from oxygen, hydroxyl, amino, carboxyl, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolylalkyl, piperidinyl, or tetrahydro-1H-pyrrolazinyl.

[0022] Alternatively, one or more hydrogen atoms in the aforementioned alicyclic ring formed by R1, R2, or R1 and R2 may be replaced by deuterium atoms.

[0023] Or Ra is X1, X2, X3, and X4 are independently selected from CRd or N, and no more than three of X1, X2, X3, and X4 are N, with the remainder being CRd. The Rd at different positions may be the same or different, and Rd can be independently selected from hydrogen, halogen, cyano, or C1-C6 alkyl. In some embodiments, one of X1, X2, X3, and X4 is N, and the remainder are CRd. Or two of X1, X2, X3, and X4 are N, and the remainder are CRd. Or all of X1, X2, X3, and X4 are CRd.

[0024] In some implementations, X1 is N, and X2, X3, and X4 are CRd; or X2 is N, and X1, X3, and X4 are CRd; or X3 is N, and X1, X2, and X4 are CRd; or X4 is N, and X1, X2, and X3 are CRd. In some implementations, X1 and X3 are N, and X2 and X4 are CRd; or X1 and X4 are N, and X2 and X3 are CRd; or X2 and X4 are N, and X1 and X3 are CRd; or X1 and X2 are N, and X3 and X4 are CRd.

[0025] The Rd at different positions can be independently selected from hydrogen, halogen, cyano, and C1-C3 alkyl. In some embodiments, Rd is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, one of the Rd is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or isopropyl, and the rest are hydrogen. In some embodiments, two of the Rd are independently selected from methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, or iodine, and the rest are hydrogen. In some embodiments, one of the Rd is methyl, and the rest are hydrogen. In some embodiments, one of the Ra is fluorine, and the rest are hydrogen. In some embodiments, Rd at all positions is hydrogen.

[0026] In some implementations, Ra is a structure that is either substituted or unsubstituted by Rd, satisfying the above conditions:

[0027]

[0028] Rc is -(CR4R5) p NR6R7, where p is 1 or 2, and R4, R5, R6, and R7 are independently selected from H or C1-C3 alkyl groups; in some embodiments, R4, R5, R6, and R7 are independently selected from H, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R4 is H, and R5 is selected from H, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, both R4 and R5 are H. In some embodiments, R6 is H, and R7 is selected from H, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, both R6 and R7 are H.

[0029] Or Rc is Cy1 is a 3-14, 3-12, or 3-10 alicyclic ring containing N atoms, with 0-2 ring atoms between the N atom and the ring atom connecting the base (marked with "*").

[0030] Cy1 can be a monocyclic, bridged, spirocyclic, or fused ring; except for N atoms, the framework atoms of Cy1 may contain 0-3 or 0-2 atoms selected from N, O, and S.

[0031] Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclic alkyl.

[0032] In addition to Rb, Cy1 can be independently substituted by one or more R8s at any possible position. R8s can be selected from oxygen, hydroxyl, amino, halogen, cyano, carboxylic acid, ester, amide, sulfonamide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C3 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclic alkyl, 5-8 aryl, 5-8 heteroaryl, or -ORy, wherein Ry is selected from C3-C8 cycloalkyl, 3-8 heterocyclic alkyl, 5-8 aryl, or 5-8 heteroaryl. R8 can be substituted by one or more Rvs at any possible position. Rvs can be selected from hydroxyl, amino, halogen, cyano, amide, sulfonamide, C1-C6 alkyl, or C1-C6 alkoxy. When multiple R8s are present, the R8s at different positions may be the same or different.

[0033] In some implementations, Rc is Furthermore, Rc can be independently replaced by one or more R8s at any possible position, as defined above;

[0034] Where m is 0 or 1; n is 0, 1 or 2;

[0035] T does not exist; or T is CR. 11 R 12 , where R 11 R 12 It can be independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or R 11 and R 12 It forms a ring with the carbon atom it is attached to; in this article, T does not exist, meaning that the two ring atoms attached to T are directly connected by a single bond.

[0036] When L is selected from CH2 or CH2CH2, Z is -Q-(CH2). q -; q is 0, 1, 2, or 3, Q is selected from -NRb, O, or S atoms, Rb is as defined above; or Q does not exist, i.e., Z is -(CH2).q -;

[0037] When L does not exist, that is, Rc is Where Z is Q can be selectively connected to the α-carbon atom end or away from the α-carbon atom end. This represents the option to form a ring, where Q is selected from N, O, or S atoms, or Q is absent, i.e., Z is... R9, R 10 Independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or R9 and R 10 It forms a ring together with the connected carbon atoms;

[0038] Cy does not exist, that is, Rc is Alternatively, Cy may be selected from 3-10 membered alicyclic rings or 3-10 membered heterocyclic rings, or in some embodiments, Cy may be selected from 3-6 membered alicyclic rings or 3-6 membered heterocyclic rings, and Cy may optionally be substituted by one or more groups selected from oxygen, halogen, cyano, carboxyl, ester, amide, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl groups.

[0039] G is selected from O, -OCH2-, substituted or unsubstituted alkylene groups, wherein the substituted alkylene groups are optionally independently substituted by one or two groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl groups; or G is absent, i.e. the two ring atoms attached to G are directly connected by a single bond.

[0040] Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.

[0041] In some implementations, Rc is G, T, Rb, and m are defined as described above.

[0042] In some implementations, Rc is Rb, m, and n are defined as described above.

[0043] In some embodiments, Rc is selected from substituted or unsubstituted 3-8 membered monocyclic rings; in some embodiments, Rc may specifically be selected from N-heterocyclic butyl, pyrrolyl, piperidinyl, azirrocyclic heptyl, azirrocyclic octyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydroimidazolyl, tetrahydropyridinyl, pyrazolyl, piperazinyl, morpholinyl, and thiomorpholinyl; optionally, Rc is substituted with Rb and / or R8 groups, wherein Rb and R8 are as defined above.

[0044] In some implementations, Rc is L is CH2 or CH2CH2, and Z, T, Rb, m, and n are as defined above.

[0045] In some implementations, Rc is Z, T, Rb, m, n are defined as described above.

[0046] In some embodiments, Rc is a substituted or unsubstituted 7-11 quintile spiroring. In some embodiments, Rc is selected from the following structures:

[0047]

[0048] Cy2 is a C3-C6 alicyclic or 3-6 membered alicyclic heterocyclic ring, and Rb is as defined above. In some specific embodiments, Cy2 is selected from the following structures:

[0049]

[0050] In some implementations, Rc is Cy is selected from 3-6 membered alicyclic rings and 3-6 membered heterocyclic rings, and Cy is optionally substituted by one or more groups selected from oxygen, halogen, cyano, carboxylic acid group, ester group, amide group, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, and G, T, Rb, m are as defined above.

[0051] In some embodiments, Rc is a substituted or unsubstituted 7-10 member fused ring. In some embodiments, Rc is selected from the following structures:

[0052]

[0053] Wherein, Cy3 is a C3-C6 alicyclic ring or a 3-6 membered alicyclic-heterocyclic ring, a 5-6 membered aromatic ring or a 5-6 membered heteroaromatic ring, and Rb is as defined above. In some embodiments, Cy3 has the following structure:

[0054]

[0055] In some embodiments, Rc is selected from the following groups:

[0056]

[0057]

[0058] In some embodiments, Rb in the aforementioned Rc group is selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rb may be independently substituted at any possible position by a group selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl. In some embodiments, Rb may be independently substituted at any possible position by a group selected from F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, or 2,2,2-trifluoroethyl. In some embodiments, Rb is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0059] In some embodiments, the aforementioned R8 may be selected from oxygen, hydroxyl, amino, halogen, cyano, carboxylic acid group, ester group, amide group, sulfonamide group, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, C2-C4 alkenyl, C2-C3 alkynyl, C3-C8 cycloalkyl, 3-6 heterocyclic alkyl, 5-6 aryl, 5-6 heteroaryl or -ORy, wherein Ry is selected from C3-C6 cycloalkyl, 3-6 heterocyclic alkyl, 5-6 aryl or 5-6 heteroaryl. In some embodiments, R8 is selected from oxygen, hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methylamino, dimethylamino, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, prop-1-enyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclopropane, oxacyclopropane, oxacyclobutane, furanyl, thiophene, pyrroleyl, phenyl, pyridinyl, pyridin-3-yloxy, formamido, acetamyl, methanesulfonylamino, -CONHCH3, -CH2OH, -CHCH2OH, or -CH2OCH3.

[0060] This invention provides a compound of Formula II, a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof:

[0061]

[0062] In Formula II, ------ represents possible chemical bonds.

[0063] Rm and Rn are each independently selected from H, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rm and Rn are each independently selected from H, halogen, cyano, C1-C3 alkyl, or C1-C3 alkoxy. Optionally, Rm and Rn may be substituted at possible positions with groups selected from halogen, hydroxyl, or amino. In some specific embodiments, Rm is hydrogen, and Rn is selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, amino, methyl, methoxy, fluoromethyl, chloromethyl, or trifluoromethyl.

[0064] U, Y1, Y2, Y3, Y4, Ra, W, and Rc are defined as described above; the range of values ​​for v is also defined as described above.

[0065] This invention provides the following compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] The present invention also provides a pharmaceutical composition comprising any of the compounds described above, a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, and a pharmaceutically acceptable excipient and / or carrier.

[0077] The present invention further provides the use of any of the foregoing compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention, relief or treatment of diseases caused by Menin-MLL protein interactions.

[0078] In this invention, diseases related to the interaction of Menin-MLL proteins include malignant tumors, diabetes, or complications associated with said diseases. Malignant tumors include hematologic malignancies, lymphomas, and solid tumors.

[0079] Hematologic malignancies include leukemia and myeloma, including but not limited to acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute monocytic leukemia, chronic monocytic leukemia, childhood leukemia, acute myeloid leukemia, chronic myeloid leukemia, mixed lineage leukemia, hairy cell leukemia, precursor T-cell lymphocytic leukemia, large granular lymphocytic leukemia, meningeal leukemia, myelodysplastic syndrome, myeloproliferative disorders, myeloproliferative neoplasm, plasmacytoma, and multiple myeloma.

[0080] Lymphomas include, but are not limited to, cutaneous T-cell lymphoma, lymphoid tumor, AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or malignant lymphoma.

[0081] Solid tumors include, but are not limited to, pancreatic cancer, colon cancer, rectal cancer, liver cancer, stomach cancer, glioblastoma, lung cancer, breast cancer, and prostate cancer.

[0082] The related complications include, but are not limited to, leukemic meningitis.

[0083] Experiments have shown that the Menin-MLL protein inhibitor of the present invention has excellent in vitro enzyme inhibitory activity and cell proliferation inhibitory activity. In particular, compared with existing compounds, it has excellent activity in inhibiting the interaction between Menin mutant proteins (especially M327I and T349M point mutant proteins) and MLL proteins, and thus has good prospects for resisting drug resistance. Detailed Implementation

[0084] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0085] Definitions and General Descriptions

[0086] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings. A particular term shall not be considered ambiguous or unclear unless specifically defined, but shall be understood in accordance with its conventional meaning in the art.

[0087] This indicates the connection position of the group with other structures.

[0088] This indicates that the part forms a ring with the connected atoms.

[0089] Indicates the absolute configuration of a chiral carbon atom; When they appear in pairs or opposite pairs on the ring, it indicates that the groups attached to the chiral carbon atom are on the same side or opposite sides of the ring, respectively. For example... This indicates that R30 and R40 are on the same side of the ring. This indicates that R30 and R40 are on opposite sides of the ring. "(±)" indicates a racemic mixture.

[0090] Unless otherwise specified, "substitution" means that a hydrogen atom in a molecule is replaced by another different atom or group.

[0091] "Optional" or "optionally" means that the event or situation described below may, but is not necessarily, occur, and the description includes the possibility that the event or situation may or may not occur. For example, "optionally substituted" includes both substitution and non-substitution, and "optionally contains an element" means that the element may or may not be contained.

[0092] The term “independently” means that when a plurality of substituents are selected from many possible groups, the groups corresponding to these substituents may be the same or different.

[0093] "Alkyl" refers to a saturated hydrocarbon group consisting only of carbon and hydrogen atoms, with single bonds connecting carbon atoms and hydrogen atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0094] "Alkylene" refers to a group formed by removing two hydrogen atoms from an alkane molecule, including straight-chain alkylene and branched alkylene. For example, C1-C6 alkylene refers to straight-chain or branched alkylene composed of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or any range of two of the aforementioned values). Typical alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH[CH(CH3)2]-, -CH2CH2-, and -CH(CH3)CH2-.

[0095] "Heteroatoms" refer to non-carbon atoms in the carbon chain or framework. Typical heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S).

[0096] "Member" refers to the number of skeleton atoms that make up the ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, tetrahydropyrrole, imidazole, thiazole, furan, tetrahydrofuran, and thiophene; typical 6-membered rings include, for example, cyclohexyl, piperidine, piperazine, pyridine, pyran, pyrazine, thiamphenicol, pyridazine, pyrimidine, and benzene.

[0097] "Alicyclic" refers to non-aromatic cyclic hydrocarbons whose skeleton atoms are all carbon atoms, including saturated or unsaturated monocyclic, bicyclic, or polycyclic systems, such as fused 2, 3, or 4 rings, bridged rings, or spirocyclic rings. Specifically, it includes cyclic alkanes or alkenes, with the corresponding groups being alicyclic groups or cycloalkyl groups, examples including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, and cyclohexenyl. The definition of "cycloalkyl" also includes aromatic rings with one or more fused to a cycloalkyl ring, such as benzo[a] or pyrido[b] derivative groups of cyclopentane, cyclopentene, cyclohexane, etc., with a specific example being tetrahydronaphthalene.

[0098] "Alicyclic heterocycles" refer to non-aromatic cyclic hydrocarbons whose skeletal atoms contain one or more heteroatoms, including saturated or unsaturated monocyclic, bicyclic, or polycyclic systems, such as fused 2, 3, 4-rings, bridged rings, or spirocyclic rings. The heteroatoms are selected from nitrogen, oxygen, and sulfur, while the remaining ring atoms are carbon. The corresponding group is a heterocyclic alkyl group, including but not limited to: aziridine, oxadiazine, pyrrolinyl, pyrrolylyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, tetrahydropyridinyl, 3-oxa-6-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, etc. The definition of “heterocyclic alkyl” also includes one or more aromatic rings fused to the aforementioned cycloalkyl ring or heterocyclic alkyl ring, wherein the aromatic ring may or may not contain the aforementioned heteroatoms, specific examples of which include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl or benzoγ-pyranone.

[0099] "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group (e.g., having 2, 3, or 4 fused rings). Typical aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, etc.

[0100] "Heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle (e.g., having 2, 3, or 4 fused rings) having one or more heteroatom aromatic rings selected from N, S, and O. Typical heteroaryl groups include, but are not limited to, pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, benzothiopheneyl, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiopheneyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, etc.

[0101] "Alkenyl" refers to an unsaturated hydrocarbon group having one or more -C=C- (carbon-carbon double bonds). Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, etc.

[0102] "Alynyl" refers to an unsaturated hydrocarbon group having one or more -C≡CH (carbon-carbon triple bonds). Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, pentynyl-4-alkynyl, and pentynyl-1,4-diynyl.

[0103] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0104] “Cyanogen” refers to CN.

[0105] "Halogenated alkyl" means that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group has the meaning described in this invention. Halogenated alkyl includes, but is not limited to, monohalogenated alkyl, dihalogenated alkyl, trihalogenated alkyl, perhalogenated alkyl, etc., such as chloromethyl, dichloromethyl, difluoromethyl, dibromomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc.

[0106] "Alkoxy" refers to -O-alkyl, where alkyl has the meaning as described in this invention.

[0107] "Haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogens, including but not limited to chloromethoxy, fluoromethoxy, difluoromethoxy, etc.

[0108] The word "amino" alone or in combination with other terms refers to the -NH2 group.

[0109] "Aminoalkyl" indicates that an alkyl group is replaced by one or more amino groups, wherein the alkyl group has the meaning described in this invention. For example, C1-C6 aminoalkyl means a C1-C6 alkyl group replaced by one or more amino groups. Aminoalkyl includes, but is not limited to, aminomethyl and 2-aminoethyl.

[0110] "alkylamino" represents a -NH (alkyl) group or a di-N (alkyl) group, wherein the alkyl group has 1-6 carbon atoms. In some embodiments, the alkyl group has 1-3 carbon atoms. In some specific embodiments, the alkylamino group may be methylamino or ethylamino. The dialkylamino group is dimethylamino or diethylamino.

[0111] "Hydroxy" refers to -OH.

[0112] "Oxygen substitution" means =O.

[0113] The "carboxylic acid group" refers to -(CH2)rCOOH, where r is selected from 0 to 5. In this paper, r is preferably 0 to 2.

[0114] "Ester group" refers to -COOR, where R is a lower alkyl group. In this structure, R is preferably methyl, ethyl, n-propyl, or isopropyl.

[0115] "Amide group" refers to -CONRR′, where R and R′ are independently selected from H or lower alkyl groups. In this structure, R and R′ are preferably independently selected from H, methyl, or ethyl groups.

[0116] "Sulfanamide group" refers to -NRSO2R′, where R is H or a lower alkyl group, and R′ is a lower alkyl group. In this structure, R is preferably H or methyl, and R′ is preferably methyl or methyl.

[0117] The compounds of the present invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include atoms having the same number of atoms but different mass numbers. The isotopes of the component atoms of the compounds of the present invention can exist in natural or non-natural abundance. Examples of hydrogen isotopes include deuterium and tritium. In some embodiments, the compounds of the present invention are deuterated, i.e., at least one deuterium atom replaces a hydrogen atom. In some specific embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms in the compounds of the present invention are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art.

[0118] In this document, unless otherwise stated, the term "Ca-Cb" as used refers to a portion having ab carbon atoms (b is greater than a, and both are integers). For example, C 1- C3 indicates that the modified part has 1 to 3 carbon atoms, such as 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0119] "pq-membered heterocyclic hydrocarbon group" refers to the portion modified by this term having pq carbon atoms (q is greater than p, and both are integers) and the number of heteroatoms involved in cyclization. For example, a 3-6 membered heterocyclic hydrocarbon group indicates that its modified cyclic structure has 3, 4, 5, or 6 atoms, including carbon atoms and at least one heteroatom.

[0120] "yz-membered (hetero)aryl" refers to the total number of carbon atoms (z is greater than y, and both are integers) and heteroatoms involved in ring formation in the modified part. For example, 5-7-membered aryl indicates that the modified aryl structure has 5, 6, or 7 carbon atoms; for example, 5-7-membered heteroaryl indicates that the modified heteroaryl structure has 5, 6, or 7 atoms, including carbon atoms and at least one heteroatom.

[0121] "Optional" means that the events or circumstances described below can be freely chosen or not chosen.

[0122] "Hydrate" refers to an aggregate of one or more water molecules contained in the compounds of this invention, including hemihydrates, monohydrates, dihydrates, trihydrates, etc.

[0123] "Isomer" refers to the fact that when the compounds of the present invention contain one or more asymmetric centers, they can exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The compounds of the present invention may have asymmetric centers, thereby resulting in two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compounds of the present invention contain an olefin double bond, the scope of the present invention includes cis and trans isomers unless otherwise specified. The compounds of the present invention can exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, a ketone and its enol form are keto-enol tautomers. All tautomers and mixtures thereof are within the scope of the present invention. Enantiomers of all compounds. Diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are all within the scope of the present invention.

[0124] "Prodrug" refers to a derivative compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derivative compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise stated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, for example, T. Higuchi, V. Stella, Prodrugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, the present invention also covers compounds of the present invention containing a protecting group. In any process of preparing the compounds of the present invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene, P.G. M. W. Uts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protective bases can be removed at appropriate subsequent stages using methods known in the art.

[0125] "Pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0126] "Pharmaceutical acceptable" means a substance, such as a carrier, diluent, or excipient, that does not affect the biological activity or properties of the compounds of this invention and is relatively non-toxic, meaning that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition. For example, "excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / coloring agents, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or animal use.

[0127] "Pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0128] The present invention also provides a method for synthesizing the above-mentioned compounds. The method of synthesis of the present invention mainly adopts the preparation methods reported in chemical literature or uses commercially available chemical reagents as starting materials for related synthesis.

[0129] Abbreviation Explanation

[0130] PhLi represents lithium phenylene.

[0131] s-BuLi represents sec-butyllithium

[0132] TMEDA represents N,N,N',N'-tetramethylethylenediamine.

[0133] CbzCl represents benzyl chloroformate.

[0134] MsCl represents methylsulfonyl chloride.

[0135] TEA represents triethylamine.

[0136] DMAP represents 4-dimethylaminopyridine

[0137] DCM represents dichloromethane.

[0138] THF represents tetrahydrofuran.

[0139] ACN indicates acetonitrile.

[0140] DMF stands for N,N-dimethylformamide

[0141] AcOH represents glacial acetic acid.

[0142] TsOH indicates p-toluenesulfonic acid

[0143] EtOH represents ethanol.

[0144] TFA represents trifluoroacetic acid.

[0145] DIEA represents ethyl diisopropylamine.

[0146] NaBH4 represents sodium borohydride.

[0147] NaBH3CN represents sodium cyanoborohydride.

[0148] Cs2CO3 represents cesium carbonate.

[0149] Na2CO3 represents sodium carbonate.

[0150] Pd(OAc)2 represents palladium acetate.

[0151] Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0152] DAST represents diethylaminosulfuric acid.

[0153] Dppb represents 1,4-bis(diphenylphosphine)butane.

[0154] LiAlH4 represents lithium aluminum hydride.

[0155] Tf2O represents trifluoromethanesulfonic anhydride.

[0156] Zn(CN)2 represents zinc cyanide.

[0157] PPh3 represents triphenylphosphine.

[0158] DMAc stands for N,N-dimethylacetamide

[0159] PtO2 represents platinum dioxide.

[0160] EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole.

[0161] Preparation of intermediates Example 1: Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester

[0162]

[0163] Step 1: Preparation of tert-butyl 3-(1-azabicyclo[1.1.0]but-3-yl)-3-hydroxyazacyclobutane-1-carboxylic acid

[0164]

[0165] 2,3-Dibromopropane-1-amine hydrobromide (4.8 g, 16.12 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and the reaction system was cooled to -65 °C. Then, a solution of phenyllithium (2N, 48.35 mmol) in n-butyl ether was slowly added dropwise while maintaining the temperature below -60 °C. After the addition was complete, the reaction system was stirred at -65 °C for 2 hours. The cryogenic bath was then removed, and the temperature was rapidly raised to room temperature and stirred for 10 minutes. The reaction system was then cooled to -65 °C again, and a mixed solution of N,N,N',N'-tetramethylethylenediamine (2.25 g, 19.34 mmol) and sec-butyllithium (1.3N, 19.34 mmol) in cyclohexane and n-hexane was added dropwise while maintaining the temperature below -60 °C. After the addition of the reactants was complete, the reaction was stirred at -65°C for 1 hour. Then, a tetrahydrofuran solution of 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester (3.59 g, 20.95 mmol) was slowly added dropwise. After the addition of the reactants was complete, the reaction system was stirred at -65°C for 1 hour. LCMS analysis showed that the reactants reacted completely. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and then used directly in the next step of the reaction.

[0166] Step 2: Preparation of 1-benzyl 1'-(tert-butyl)3'-hydroxy-3-iodo-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid ester

[0167]

[0168] 3-(1-azabicyclo[1.1.0]but-3-yl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (2.41 g, 10.65 mmol) and sodium iodide (3.19 g, 21.30 mmol) were dissolved in acetonitrile (30 mL). The reaction system was cooled to 0 °C, and then benzyl chloroformate (2.18 g, 12.78 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at 0 °C for 30 minutes. After the reaction was complete, the sample was purified by column chromatography to give 4.58 g of the title compound.

[0169] MS(ESI)m / z(M+H-100) + =389.1

[0170] Step 3: Preparation of 1-benzyl 1'-(tert-butyl)3-iodo-3'-((methanesulfonyl)oxy)-[3,3'-bis(azetane)-1,1'-dicarboxylic acid ester

[0171]

[0172] 1-Benzyl 1'-(tert-butyl)3'-hydroxy-3-iodo-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid ester (2.12 g, 4.34 mmol) was dissolved in dichloromethane (50 mL). After cooling the reaction system to 0 °C, triethylamine (878 mg, 8.68 mmol) and 4-dimethylaminopyridine (1.06 g, 8.68 mmol) were added; subsequently, methanesulfonyl chloride (995 mg, 8.68 mmol) was slowly added dropwise. After the addition was complete, the reaction system was stirred at room temperature for 30 minutes. After the reaction was complete, the sample was purified by column chromatography to obtain 1.82 g of the title compound.

[0173] MS(ESI)m / z(M+H-100) + =467.1.

[0174] Step 4: Preparation of 1-benzyl 1'-(tert-butyl)2H,2'H-[3,3'-diazamethylene]-1,1'(4H,4'H)-dicarboxylic acid ester

[0175]

[0176] 1-Benzyl 1'-(tert-butyl)3-iodo-3'-((methanesulfonyl)oxy)-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid ester (1.8 g, 3.18 mmol) was dissolved in acetic acid (20 mL). Zinc powder (1.04 g, 15.89 mmol) was then added. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the mixture was purified to obtain 980 mg of the title compound.

[0177] MS(ESI)m / z(M+H-100) + =245.2.

[0178] 1 H NMR (400MHz, Chloroform-d) δ7.35 (d, J = 3.8Hz, 5H), 5.11 (s, 2H), 4.49 (m, 4H), 4.43–4.38 (m, 4H), 1.44 (s, 9H).

[0179] Step 5: Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester

[0180]

[0181] 1-Benzyl 1'-(tert-butyl)2H,2'H-[3,3'-diazamethylene]-1,1'(4H,4'H)-dicarboxylic acid ester (980 mg, 2.80 mmol) was dissolved in ethanol (32 mL), and then p-toluenesulfonic acid (1.6 g, 9.29 mmol) was added. The reaction mixture was stirred at 50 °C for 6 hours. After the reaction was complete, the product was purified by column chromatography to give 1.16 g of the title compound, p-toluenesulfonate.

[0182] MS(ESI)m / z(M+H) + =245.1.

[0183] Preparation Example 2: Preparation of 2-((5-(1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0184]

[0185] Step 1: Preparation of 1'-(3,6-dichloro-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester

[0186]

[0187] Under ice-water bath conditions, triethylamine (13.72 g, 135.57 mmol) and benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester p-toluenesulfonate (14.57 g, 59.65 mmol) were added to a solution of trichloro-1,2,4-triazine (10 g, 54.23 mmol) in dichloromethane (200 mL). The reaction system was reacted at this temperature for 1 hour. The reaction was confirmed to be complete by LC-MS. The solvent was evaporated, and the crude product was subjected to silica gel column chromatography to give 15.14 g of the title compound.

[0188] MS(ESI)m / z(M+H) + =392.2.

[0189] Step 2: Preparation of 1'-(6-chloro-3-hydrazino-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester

[0190]

[0191] At room temperature, hydrazine hydrate (8.17 g, 163.2 mmol) was added to an ethanol (200 mL) solution of 1'-(3,6-dichloro-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (8 g, 20.40 mmol). The mixture was stirred and heated to 70 °C for 4 hours. After the reaction was complete, the reaction system was cooled to room temperature. The mixture was filtered, and the filter cake was washed with water and ethanol. 6.51 g of the title compound was dried.

[0192] MS(ESI)m / z(M+H) + =388.1.

[0193] Step 3: Preparation of 1'-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester

[0194]

[0195] At room temperature, N-ethyl-5-fluoro-2-hydroxy-N-(prop-2-yl)benzyl ester of 1'-(6-chloro-3-hydrazino-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid (6.511 g, 16.79 mmol) in N,N-dimethylformamide (40 mL) was added, along with cesium carbonate (16.41 g, 50.37 mmol). After the addition was complete, the reaction mixture was heated to 100 °C and reacted for 6 hours. After the reaction was completed as monitored by LCMS, the target fraction was purified by reversed-phase column chromatography and lyophilized to obtain 4.1 g of the title compound.

[0196] MS(ESI)m / z(M+H) + =547.2.

[0197] Step 4: Preparation of 2-((5-(1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0198]

[0199] At room temperature, 15 mL of trifluoroacetic acid was added to 4.1 g (7.50 mmol) of benzyl 1'-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid, and the mixture was then heated to 60 °C and reacted for 3 h. After the reaction was monitored by LCMS until complete, the solvent was evaporated, and the crude product was purified by column chromatography to give 2.41 g of the title compound.

[0200] MS(ESI)m / z(M+H) + =413.2.

[0201] Preparation Example 3: Preparation of 2-((5-(1',4'-dihydro-2H,2'H-[3,3'-bisazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0202]

[0203] Using commercially available reagents as raw materials, Preparation Example 3 was obtained by referring to the synthetic route of Preparation Example 2.

[0204] MS(ESI)m / z(M+H) + =427.2.

[0205] Preparation Example 4: Preparation of 3-bromo-5-fluoropyridine-2-amine

[0206]

[0207] 10.0 g (89.29 mmol) of 5-fluoropyridine-2-amine was dissolved in glacial acetic acid (50 mL). Sodium acetate (11.0 g, 133.94 mmol) and liquid bromine (21.4 g, 133.94 mmol) were added sequentially at 0 °C. After the addition was complete, the mixture was allowed to return to room temperature for 4 hours. LC-MS analysis showed that the reactants had reacted completely. The system was then neutralized with 6N sodium hydroxide solution, extracted three times with ethyl acetate, and the organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 13 g of the title compound.

[0208] MS(ESI)m / z(M+H) + =191.1.

[0209] Preparation Example 5: Preparation of 3-bromo-2-cyclopropyl-5-fluoropyridine

[0210]

[0211] Step 1: Preparation of 2-cyclopropyl-5-fluoropyridine-3-amine

[0212]

[0213] At room temperature, 2-bromo-5-fluoropyridine-3-amine (5.0 g, 26.2 mmol), cyclopropylboronic acid (2.2 g, 130.9 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1.9 g, 2.6 mmol), potassium carbonate (1.1 g, 78.5 mmol), and 1,4-dioxane (20 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 120 °C and reacted for 1 hour. After the reaction was complete as monitored by LCMS, the mixture was filtered, concentrated, and purified by column chromatography to obtain 3.7 g of the product 2-cyclopropyl-5-fluoropyridine-3-amine.

[0214] MS(ESI)m / z(M+H) + =153.1.

[0215] Step 2: Preparation of 3-bromo-2-cyclopropyl-5-fluoropyridine

[0216]

[0217] Under ice-water bath conditions, 2-cyclopropyl-5-fluoropyridin-3-amine (2.5 g, 16.4 mmol) and 20 mL of 48% hydrobromic acid were added to a reaction flask. Sodium nitrite (1.1 g, 16.4 mmol) was slowly added. After the addition was complete, the mixture was stirred for 1 hour. Cuprous bromide (2.4 g, 16.4 mmol) and 10 mL of 48% hydrobromic acid were then mixed thoroughly and added dropwise to the system. The reaction system was gradually brought to room temperature and the reaction was continued for 2 hours. The reaction was monitored by LCMS to ensure completeness. The pH was adjusted to weakly alkaline by adding sodium hydroxide solution. The mixture was extracted with dichloromethane, rotary evaporated, and the crude product was purified by column chromatography to obtain 259 mg of 3-bromo-2-cyclopropyl-5-fluoropyridinium.

[0218] MS(ESI)m / z(M+H) + =216.1.

[0219] Preparation Example 6: 2-Bromo-3-cyclopropyl-5-fluoropyridine

[0220]

[0221] Using commercially available reagents as raw materials, Preparation Example 6 was obtained by referring to the synthetic route of Preparation Example 5.

[0222] Preparation Example 7: Preparation of 3-chloro-4-cyclopropyl-6-methylpyridazine

[0223]

[0224] Step 1: Preparation of 4-cyclopropyl-6-methylpyridazine-3-ol

[0225]

[0226] At room temperature, 2.5 g (13.23 mmol) of 4-bromo-6-methylpyridazin-3-ol, 3.41 g (39.69 mmol) of cyclopropylboronic acid, 0.15 g (0.66 mmol) of palladium acetate, 0.37 g (1.32 mmol) of tricyclohexylphosphine, 5.49 g (39.69 mmol) of potassium carbonate, 50 mL of 1,4-dioxane, and 10 mL of water were added to a 100 mL single-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and reacted overnight. The reaction was confirmed to be complete by LC-MS. After cooling to room temperature, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, dissolved in acetonitrile, subjected to reversed-phase column chromatography, and freeze-dried to give 0.897 g of the title compound.

[0227] MS(ESI)m / z(M+H) + =151.2.

[0228] Step 2: Preparation of 3-chloro-4-cyclopropyl-6-methylpyridazine

[0229]

[0230] At room temperature, 780 mg (5.19 mmol) of 4-cyclopropyl-6-methylpyridazin-3-ol was added to phosphorus oxychloride (42 g, 273.92 mmol), and the mixture was heated to 90 °C and reacted for 3 hours. The reaction was confirmed to be complete by LC-MS. After concentration under reduced pressure, the mixture was dissolved in a small amount of dichloromethane, and then silica gel column chromatography was performed to give 0.41 g of the title compound.

[0231] MS(ESI)m / z(M+H) + =169.1.

[0232] Preparation Example 8: Preparation of 3-chloro-4-cyclopropylpyridazine

[0233]

[0234] Step 1: Preparation of 4,5-dibromo-2-(oxacyclohexane-2-yl)-2,3-dihydropyridazin-3-one

[0235]

[0236] At room temperature, p-toluenesulfonic acid (680 g, 3.9 mmol) was added to 4,5-dibromo-2,3-dihydropyridazin-3-one (10.0 g, 39.4 mmol), 3,4-dihydro-2H-pyran (13.3 g, 157.6 mmol), and tetrahydrofuran (30 mL), and the mixture was heated to 70 °C and reacted overnight. LCMS monitoring showed that the reaction ceased. The system was cooled to room temperature, and water and ethyl acetate were added for extraction and phase separation. The organic phase was collected, evaporated to dryness, and purified by column chromatography to give 7.2 g of the title compound.

[0237] MS(ESI)m / z(M+H) + =339.1.

[0238] Step 2: Preparation of 4-bromo-2-(oxacyclohexane-2-yl)-2,3-dihydropyridazin-3-one

[0239]

[0240] Under ice bath conditions, 7.0 g (20.7 mmol) of 4,5-dibromo-2-(oxacyclohexan-2-yl)-2,3-dihydropyridazin-3-one and 30 mL of ethylene glycol dimethyl ether were added to a reaction flask and stirred until homogeneous. Sodium borohydride (1.6 g, 41.4 mmol) was slowly added. After the addition was complete, the reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by LC-MS to ensure complete reaction. The reaction was quenched with ammonium chloride solution under ice bath conditions, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by column chromatography to give 1.2 g of the title compound.

[0241] MS(ESI)m / z(M+H) + =259.2.

[0242] Step 3: Preparation of 4-cyclopropyl-2-(oxacyclohexane-2-yl)-2,3-dihydropyridazin-3-one

[0243]

[0244] At room temperature, 4-bromo-2-(oxacyclohexane-2-yl)-2,3-dihydropyridazin-3-one (1.0 g, 3.9 mmol), cyclopropylboronic acid (1.7 g, 19.3 mmol), tetrakis(triphenylphosphine)palladium (450 mg, 0.4 mmol), sodium carbonate (1.6 g, 15.4 mmol), 1,4-dioxane (30 mL), and water (1.5 mL) were added all at once to a reaction flask. The mixture was purged with nitrogen, and the temperature was slowly increased to 90 °C. The reaction was carried out overnight at this temperature, and the reaction was monitored by LC-MS to ensure complete reaction. After cooling, water and ethyl acetate were added, the phases were extracted and separated, the organic phase was collected, evaporated to dryness, and purified by column chromatography to give 830 mg of the title compound.

[0245] MS(ESI)m / z(M+H) +=221.2.

[0246] Step 4: Preparation of 4-cyclopropyl-2,3-dihydropyridazin-3-one

[0247]

[0248] At room temperature, 830 mg (3.8 mmol) of 4-cyclopropyl-2-(oxacyclohexane-2-yl)-2,3-dihydropyridazin-3-one was added to methanol (10 mL) and hydrochloric acid (3 mL), and the mixture was heated to 50 °C for 3 hours. The reaction was monitored by LCMS until complete, and the solution was evaporated to dryness to obtain 510 mg of crude compound, which was used directly in the next step.

[0249] MS(ESI)m / z(M+H) + =137.2.

[0250] Step 5: Preparation of 3-chloro-4-cyclopropylpyridazine

[0251]

[0252] Under ice bath conditions, 4-cyclopropyl-2,3-dihydropyridazin-3-one (510 mg, 3.8 mmol) and acetonitrile (20 mL) were added to a reaction flask and stirred until homogeneous. Phosphorus oxychloride (6.0 g, 38.1 mmol) was slowly added. After the addition was complete, the temperature was slowly raised to 80 °C. The reaction was carried out at this temperature for 2 hours, and the reaction was monitored by LC-MS to ensure complete reaction. The solvent was removed by rotary evaporation, and saturated sodium bicarbonate solution and ethyl acetate were added under ice bath conditions. The mixture was extracted, the phases were separated, the organic phase was collected, evaporated to dryness, and purified by column chromatography to give 601 mg of the title compound.

[0253] MS(ESI)m / z(M+H) + =155.2.

[0254] Preparation Example 9: Preparation of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol

[0255]

[0256] At room temperature, (5-fluoro-2-hydroxyphenyl)boronic acid (1 g, 6.41 mmol), 5-bromo-4-cyclopropylpyrimidine (1.28 g, 6.41 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.1 g, 0.14 mmol), sodium carbonate (2.38 g, 19.23 mmol), 1,4-dioxane (60 mL), and water (15 mL) were added to a 150 mL single-necked flask. After purging with nitrogen, the reaction system was heated to 100 °C and reacted for 5 hours. The reaction was confirmed to be complete by LC-MS. After concentration under reduced pressure, the sample was stirred with silica gel and purified by column chromatography to obtain 1.35 g of the title compound.

[0257] MS(ESI)m / z(M+H) + =231.2.

[0258] Referring to the synthesis method of Preparation Example 9, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in the table.

[0259] Table 1 Information on intermediate compounds obtained from the preparation examples.

[0260]

[0261] Preparation Example 15: Preparation of 1-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene hydrocarbon

[0262]

[0263] Step 1: Preparation of benzyl 1'-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester

[0264]

[0265] At room temperature, 2-(4-cyclopropylpyrimidin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (0.726 g, 1.87 mmol) was added to a solution of 1'-(6-chloro-3-hydrazino-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (15 mL) in N,N-dimethylformamide (0.43 g, 1.87 mmol) and cesium carbonate (1.37 g, 4.21 mmol). The mixture was then heated to 100 °C and reacted for 3 hours. LC-MS showed that the reaction was complete. After quenching with water, the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used directly in subsequent reactions.

[0266] MS(ESI)m / z(M+H) + =552.2.

[0267] Step 2: Preparation of 1-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene hydrocarbon

[0268]

[0269] At room temperature, trifluoroacetic acid (20 mL) was added to the benzyl 1'-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester obtained in the previous step. The reaction was then heated to 60 °C and reacted for 1 hour. The reaction was confirmed to be complete by LCMS, concentrated under reduced pressure, purified by alkaline column chromatography, and lyophilized to give 234 mg of the title compound.

[0270] MS(ESI)m / z(M+H) + =418.2.

[0271] Referring to the synthesis method of Preparation Example 15, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in the table.

[0272] Table 2 Information on intermediate compounds obtained from the preparation examples.

[0273]

[0274]

[0275] Preparation Example 21: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-methoxybenzamide

[0276]

[0277] Step 1: Preparation of 2-(benzyloxy)-5-fluoro-N-hydroxy-N-isopropylbenzamide

[0278]

[0279] 1.4 g (5.69 mmol) of 2-(benzyloxy)-5-fluorobenzoic acid was dissolved in acetonitrile (20 mL), cooled to 0 °C, and 1.4 g (11.38 mmol) of oxaloyl chloride was added. After the reaction was allowed to proceed at room temperature for 2 hours, the mixture was concentrated to obtain a crude white solid. 20 mL of dichloromethane was added to the crude solid, followed by the sequential addition of triethylamine (1.7 g, 17.07 mmol) and N-isopropylhydroxylamine hydrochloride (637 mg, 5.69 mmol). After the addition was complete, the mixture was reacted overnight at room temperature. LC-MS showed complete consumption of the starting material. 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to obtain 900 mg of the title compound.

[0280] MS(ESI)m / z(M+H)+ =304.1.

[0281] Step 2: Preparation of 2-(benzyloxy)-5-fluoro-N-isopropyl-N-methoxybenzamide

[0282]

[0283] 2-(benzyloxy)-5-fluoro-N-hydroxy-N-isopropylbenzamide (900.0 mg, 2.97 mmol) was weighed and dissolved in acetonitrile (10 mL). Potassium carbonate (410.0 mg, 2.97 mmol) and methyl iodoform (464.0 mg, 3.27 mmol) were added sequentially at room temperature. After the addition was complete, the mixture was reacted overnight at room temperature. LC-MS showed complete reaction of the starting material. Water (100 mL) was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (V:V)) to give 450 mg of the title compound.

[0284] MS(ESI)m / z(M+H) + =318.1.

[0285] Step 3: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-methoxybenzamide

[0286]

[0287] 450 mg (1.42 mmol) of 2-(benzyloxy)-5-fluoro-N-isopropyl-N-methoxybenzamide was dissolved in 10 mL of methanol. Palladium on carbon (45.0 mg, 10% (w / w)) was slowly added in portions at room temperature. After the addition was complete, the system was reacted at room temperature for 5 hours. LC-MS showed that the starting material was completely consumed. The system was filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 280 mg of the title compound.

[0288] MS(ESI)m / z(M+H) + =228.1.

[0289] Preparation Example 22: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-(trifluoromethyl)benzamide

[0290]

[0291] Step 1: Preparation of isopropylaminodithioethyl ester

[0292]

[0293] Isopropylamine (4.4 g, 75.0 mmol) and dichloromethane (10 mL) were added to a reaction flask under an ice-water bath and stirred until homogeneous. Iodoethane (5.9 g, 37.5 mmol) and carbon disulfide (5.7 g, 75.0 mmol) were then added sequentially. After the addition was complete, the mixture was gradually brought to room temperature and stirred overnight. The reaction was monitored by LCMS until complete. The solution was evaporated to dryness and purified by column chromatography to obtain 5.8 g of the title compound.

[0294] MS(ESI)m / z(M+H) + =164.1.

[0295] Step 2: Preparation of ethyl (5-fluoro-2-methoxybenzoyl)(isopropyl)aminodithioate

[0296]

[0297] At room temperature, isopropylaminodithioethyl ester (2.6 g, 15.9 mmol), 5-fluoro-2-methoxybenzoic acid (3.0 g, 17.5 mmol), 1,3-dicyclohexylcarbodiimide (5.9 g, 28.7 mmol), 4-dimethylaminopyridine (190 mg, 1.6 mmol), and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. The mixture was stirred at room temperature for half an hour, then heated to reflux and reacted overnight. LC-MS monitoring showed that a small amount of the starting material remained. The solvent was removed by rotary evaporation, and the product was purified by column chromatography to give 4.0 g of the title compound.

[0298] MS(ESI)m / z(M+H) + =316.2.

[0299] Step 3: Preparation of 5-fluoro-N-isopropyl-2-methoxy-N-(trifluoromethyl)benzamide

[0300]

[0301] At -78°C, bromosuccinimide (9.0 g, 50.7 mmol) and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. The mixture was purged with nitrogen, and a dichloromethane solution of (5-fluoro-2-methoxybenzoyl)(isopropyl)aminodithioate ethyl ester (4.0 g, 12.7 mmol) was slowly added. A dichloromethane solution of pyridine hydrofluoric acid (9.8 g, 63.4 mmol) was then slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and reacted for one hour. The reaction was monitored by LC-MS until complete. The reaction was quenched with sodium sulfite solution, and the phases were separated by extraction. The organic solution was collected, evaporated to dryness, and purified by column chromatography to give 871 mg of the title compound.

[0302] MS(ESI)m / z(M+H) + =280.2.

[0303] Step 4: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-(trifluoromethyl)benzamide

[0304]

[0305] Under ice bath conditions, 5-fluoro-N-isopropyl-2-methoxy-N-(trifluoromethyl)benzamide (871 mg, 3.1 mmol) and dichloromethane (20 mL) were added to a reaction flask. The flask was purged with nitrogen, and 1 M boron tribromide (1.5 g, 6.2 mmol) was slowly added. After the addition was complete, the flask was transferred to room temperature and the reaction was allowed to continue for half an hour. The reaction was monitored by LC-MS until complete. The reaction was quenched with methanol under ice bath conditions, evaporated to dryness, and purified by column chromatography to give 791 mg of the title compound.

[0306] MS(ESI)m / z(M+H) + =266.2.

[0307] Preparation Example 23: Preparation of N-(ethyl-d5)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0308]

[0309] Step 1: Preparation of 5-fluoro-N-isopropyl-2-methoxybenzamide

[0310]

[0311] Under ice bath conditions, 5-fluoro-2-methoxybenzoic acid (8.3 g, 48.8 mmol) and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. An N,N-dimethylformamide catalyst was used, and a dichloromethane solution of oxaloyl chloride (12.4 g, 97.6 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for one hour, and the solvent was removed by rotary evaporation. Fresh dichloromethane was added, followed by a dichloromethane solution of isopropylamine (3.5 g, 58.5 mmol) and triethylamine (9.9 g, 97.6 mmol). After the addition was complete, the reaction was continued at room temperature for another half hour, and the reaction was monitored by LC-MS to ensure completeness. The reaction was quenched with saturated sodium bicarbonate solution, and the organic phase was collected by phase separation, dried, and the solvent was evaporated to obtain 10.3 g of crude product, which was directly used in the next reaction step.

[0312] MS(ESI)m / z(M+H) + =212.1.

[0313] Step 2: Preparation of N-(ethyl-d5)-5-fluoro-N-isopropyl-2-methoxybenzamide

[0314]

[0315] Under ice bath conditions, 5-fluoro-N-isopropyl-2-methoxybenzamide (600 mg, 2.8 mmol) and N,N-dimethylformamide (10 mL) were added to a reaction flask and stirred until homogeneous. Sodium hydride (136.3 mg, 5.7 mmol) was slowly added, and the mixture was stirred for another 10 minutes at room temperature. 1-Iodoethane-1,1,2,2,2-d5 (548.7 mg, 3.4 mmol) was then added to the system, and the reaction was continued at room temperature for another half hour after the addition was complete. The reaction was monitored by LC-MS until complete. The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by column chromatography to give 690 mg of the title compound.

[0316] MS(ESI)m / z(M+H) + =245.2.

[0317] Step 3: Preparation of N-(ethyl-d5)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0318]

[0319] Under ice bath conditions, N-(ethyl-d5)-5-fluoro-N-isopropyl-2-methoxybenzamide (690 mg, 2.8 mmol) and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. The mixture was then purged with nitrogen, and boron tribromide (1.4 g, 5.6 mmol) was slowly added. After the addition was complete, the mixture was transferred to room temperature for further reaction. After 2 hours, the reaction was monitored by LC-MS to ensure complete reaction, and the reaction was quenched with methanol. The solution was evaporated to dryness, and saturated sodium chloride solution and ethyl acetate were added. The mixture was extracted and the phases separated. The organic phase was collected, evaporated to dryness, and purified by column chromatography to give 604 mg of the title compound.

[0320] MS(ESI)m / z(M+H) + =231.2.

[0321] Preparation Example 24: Preparation of (3-oxa-8-azabicyclo[3.2.1]octane-8-yl)(2-((5-(1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl) methyl ketone

[0322]

[0323] Step 1: Preparation of (3-oxa-8-azabicyclo[3.2.1]octane-8-yl)(5-fluoro-2-hydroxyphenyl) methyl ketone

[0324]

[0325] 1.56 g (10.0 mmol) of 5-fluoro-2-hydroxybenzoic acid was dissolved in 100 mL of dichloromethane. Oxaloyl chloride (2.12 mL, 25 mmol) was added dropwise under ice bath conditions, followed by 0.1 mL of N,N-dimethylformamide. The mixture was stirred at 45 °C for 3 hours. LC-MS showed the reaction was complete, and the system was concentrated. The crude product was added to 50 mL of dichloromethane, followed by a solution of triethylamine (5.06 g, 50 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane (2.26 g, 20 mmol). The mixture was reacted at room temperature for 1 hour. LC-MS showed the reaction was complete. The system was concentrated to dryness and purified by silica gel column chromatography to give 2 g of the title compound.

[0326] MS(ESI)m / z(M+H) + =252.1.

[0327] Step 2: Preparation of 1'-(6-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester

[0328]

[0329] 1'-(6-chloro-3-hydrazino-1,2,4-triazin-5-yl)-1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (3.1 g, 7.99 mmol) and (3-oxa-8-azabicyclo[3.2.1]octane-8-yl)(5-fluoro-2-hydroxyphenyl) methyl ketone (2.01 g, 7.99 mmol) were dissolved in N,N-dimethylformamide (100 mL), and cesium carbonate (5.21 g, 15.98 mmol) was added. The mixture was reacted at 100 °C for 3 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, the filtrate was concentrated, and purified by reverse-phase chromatography to obtain 1.2 g of the title compound.

[0330] MS(ESI)m / z(M+H) + =573.2.

[0331] Step 3: Preparation of (3-oxa-8-azabicyclo[3.2.1]octane-8-yl)(2-((5-(1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl) methyl ketone

[0332]

[0333] 1.2 g (2.1 mmol) of 1'-(6-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester was dissolved in trifluoroacetic acid (30 mL) and reacted at 70 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the system was concentrated to obtain a crude product, which was purified by reverse phase after adjusting the alkali with sodium bicarbonate and lyophilized to obtain 0.9 g of the title compound.

[0334] MS(ESI)m / z(M+H) + =439.1.

[0335] Using commercially available reagents as raw materials, the following preparation examples were obtained according to the synthetic routes of Preparation Examples 23-24.

[0336] Table 3 Intermediate Compounds

[0337]

[0338]

[0339]

[0340] Preparation Example 34: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)pyrrolidine-1-carboxylate

[0341]

[0342] Step 1: Preparation of tert-butyl (4-(5-bromo-2-fluorophenyl)-4-oxobutyl)carbamate

[0343]

[0344] 4-Bromo-1-fluoro-2-iodobenzene (3 g, 9.97 mmol) and tetrahydrofuran (25 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, isopropyl magnesium bromide (10 mL, 9.97 mmol) was added at 0 °C, and the mixture was reacted at room temperature for 1 hour. Subsequently, tert-butyl 2-oxopyrrolidine-1-carboxylic acid (1.85 g, 9.97 mmol) was added, and the mixture was stirred thoroughly and reacted overnight at room temperature. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.8 g of a yellow liquid product.

[0345] MS(ESI)m / z(M-100+H) + =260.9.

[0346] Step 2: Preparation of 5-(5-bromo-2-fluorophenyl)-3,4-dihydro-2H-pyrrole

[0347]

[0348] (4-(5-bromo-2-fluorophenyl)-4-oxobutyl)carbamate tert-butyl ester (1.8 g, 5.00 mmol), dichloromethane (20 mL), and then trifluoroacetic acid (5 mL) were added sequentially to a reaction flask. After stirring until homogeneous, the reaction system was reacted at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 1.2 g of a yellow liquid product.

[0349] MS(ESI)m / z(M+H) + =242.9.

[0350] Step 3: Preparation of 2-(5-bromo-2-fluorophenyl)pyrrolidine

[0351]

[0352] 5-(5-bromo-2-fluorophenyl)-3,4-dihydro-2H-pyrrole (1.2 g, 4.96 mmol), methanol (10 mL), and sodium borohydride (380 mg, 9.92 mmol) were added sequentially to a reaction flask at 0 °C. After stirring thoroughly, the reaction system was reacted at 0 °C for 1 hour. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 1.2 g of a colorless liquid product.

[0353] MS(ESI)m / z(M+H) + =244.1.

[0354] Step 4: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)pyrrolidine-1-carboxylate

[0355]

[0356] 2-(5-bromo-2-fluorophenyl)pyrrolidine (1.2 g, 4.9 mmol), 4-dimethylaminopyridine (0.12 g, 0.98 mmol), and dichloromethane (15 mL) were added sequentially to a reaction flask, followed by di-tert-butyl dicarbonate (2.14 g, 9.8 mmol). After stirring thoroughly, the reaction was allowed to proceed at room temperature for 3 hours. Once the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.0 g of the title compound.

[0357] MS(ESI)m / z(M-56+H) + =288.2.

[0358] Preparation Example 35: Preparation of tert-butyl 2-oxo-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid

[0359]

[0360] Step 1: Preparation of 4-(2,2,2-trifluoroethyl)piperazin-2-one

[0361]

[0362] Piperazin-2-one (2 g, 19.98 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (5.56 g, 23.98 mmol), and cesium carbonate (9.76 g, 29.97 mmol) were added sequentially to a reaction flask, followed by acetonitrile (20 mL). After stirring thoroughly, the reaction was carried out overnight at 80 °C. Once complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.5 g of the title compound.

[0363] MS(ESI)m / z(M+H) + =183.0.

[0364] Step 2: Preparation of tert-butyl 2-oxo-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid

[0365]

[0366] 4-(2,2,2-trifluoroethyl)piperazin-2-one (1.5 g, 8.24 mmol), 4-dimethylaminopyridine (0.20 g, 1.65 mmol), and dichloromethane (15 mL) were added sequentially to a reaction flask, followed by di-tert-butyl dicarbonate (3.60 g, 16.48 mmol). After stirring thoroughly, the reaction was allowed to proceed at room temperature for 3 hours. Once the reaction was complete, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.3 g of the title compound.

[0367] MS(ESI)m / z(M-56+H) + =226.9.

[0368] Preparation Example 36: Preparation of tert-butyl 4-(oxetane-3-yl)-2-oxoperpiperazine-1-carboxylic acid

[0369]

[0370] Step 1: Preparation of 4-(oxetane-3-yl)piperazin-2-one

[0371]

[0372] Piperazin-2-one (2 g, 19.98 mmol), oxetane-3-one (1.73 g, 23.98 mmol), and methanol (10 mL) were added sequentially to a reaction flask, followed by acetic acid (1.20 g, 19.98 mmol). After stirring thoroughly, the reaction was allowed to proceed at room temperature for 2 hours. Then, sodium cyanoborohydride (3.77 g, 59.94 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.5 g of the title compound.

[0373] MS(ESI)m / z(M+H) + =157.0.

[0374] Step 2: Preparation of 4-(oxetane-3-yl)-2-oxoperpiperazine-1-carboxylic acid tert-butyl ester

[0375]

[0376] 4-(oxecyclobutan-3-yl)piperazin-2-one (1.25 g, 8.00 mmol), 4-dimethylaminopyridine (0.20 g, 1.6 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask, followed by di-tert-butyl dicarbonate (3.49 g, 16 mmol). After stirring thoroughly, the reaction was carried out at room temperature for 3 hours. Once complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 1.0 g of the title compound.

[0377] MS(ESI)m / z(M-56+H) + =201.0.

[0378] Preparation Example 37: Preparation of tert-butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylic acid

[0379]

[0380] Step 1: Preparation of tert-butyl 6-azaspiro[2.5]octane-6-carboxylic acid

[0381]

[0382] 3.5 g (31.53 mmol) of 6-azaspiro[2.5]octane was dissolved in 40 mL of dichloromethane. Triethylamine (6.4 g, 63.06 mmol) and di-tert-butyl dicarbonate (6.9 g, 31.53 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 3 hours. Once the reaction was complete as indicated by TLC, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 3.5 g of the title compound.

[0383] MS(ESI)m / z(M+H) + =212.1.

[0384] Step 2: Preparation of tert-butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylic acid

[0385]

[0386] 3.5 g (16.59 mmol) of 6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (40 mL). Ruthenium oxide (66.2 mg, 0.50 mmol), sodium periodate (13.4 g, 63.04 mmol), and water solution (120 mL) were added sequentially at room temperature. After the addition was complete, the system was allowed to react overnight at this temperature. After LCMS showed complete reaction, 500 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 3.3 g of the title compound.

[0387] MS(ESI)m / z(M+H) + =226.1.

[0388] Referring to the synthesis method of Preparation Example 37, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in Table 4.

[0389] Table 4 Information on intermediate compounds obtained from the preparation examples.

[0390]

[0391]

[0392] Preparation Example 44: Preparation of tert-butyl 4-(difluoromethyl)-2-oxopiperidin-1-carboxylic acid

[0393]

[0394] Step 1: Preparation of tert-butyl 4-(difluoromethyl)piperidine-1-carboxylic acid

[0395]

[0396] Diethylaminosulfur trifluoride (DAST) (1.6 g, 10.32 mmol) was dissolved in dichloromethane (30 mL), and 4-formylpiperidin-1-carboxylic acid tert-butyl ester (2.0 g, 9.38 mmol) was slowly added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 1.3 g of the title compound.

[0397] MS(ESI)m / z(M+H) + =236.2.

[0398] Step 2: Preparation of tert-butyl 4-(difluoromethyl)-2-oxoperidin-1-carboxylic acid

[0399]

[0400] 1.3 g (5.53 mmol) of 4-(difluoromethyl)piperidin-1-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (20 mL). A solution of ruthenium oxide (25.0 mg, 0.17 mmol) and sodium periodate (4.5 g, 21.01 mmol) in water (40 mL) was added at room temperature. The reaction was allowed to proceed for 3 hours at room temperature. After TLC showed complete reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (to pure ethyl acetate) to give 1.1 g of the title compound.

[0401] MS(ESI)m / z(M+H) + =250.2.

[0402] Preparation Example 45: Preparation of tert-butyl 5-oxo-7-oxa-4-azaspiro[2.5]octane-4-carboxylic acid

[0403]

[0404] Step 1: Preparation of 2-chloro-N-(1-(hydroxymethyl)cyclopropyl)acetamide

[0405]

[0406] 1-Aminocyclopropanemethanol hydrochloride (2.2 g, 17.89 mmol) and triethylamine (3.9 g, 38.96 mmol) were dissolved in dichloromethane (30 mL). 2-Chloroacetyl chloride (2.0 g, 17.71 mmol) was slowly added at 0 °C, and the reaction was allowed to proceed at room temperature for 3 hours after the addition was complete. After TLC showed complete reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain 2.2 g of crude product, which was used directly in the next reaction step.

[0407] MS(ESI)m / z(M+H) + =164.2.

[0408] Step 2: Preparation of 7-oxa-4-azaspiro[2.5]octane-5-one

[0409]

[0410] 2-Chloro-N-(1-(hydroxymethyl)cyclopropyl)acetamide (2.2 g, 13.45 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium hydride (0.3 g, 13.45 mmol) was added in portions under an ice-water bath. After the addition was complete, the mixture was gradually brought to room temperature and reacted for 1 hour. After the reaction was confirmed to be complete by TLC, a saturated aqueous solution of ammonium chloride was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain 1.1 g of crude product, which was used directly in the next reaction step.

[0411] MS(ESI)m / z(M+H) + =128.2.

[0412] Step 3: Preparation of tert-butyl 5-oxo-7-oxa-4-azaspiro[2.5]octane-4-carboxylic acid

[0413]

[0414] 7-oxa-4-azaspiro[2.5]octane-5-one (1.0 g, 7.87 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (280.0 mg, 11.80 mmol) was added at room temperature. After stirring for half an hour, di-tert-butyl dicarbonate (2.0 g, 9.44 mmol) was added, and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was confirmed to be complete by TLC, a saturated aqueous solution of ammonium chloride was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 1.1 g of the title compound.

[0415] MS(ESI)m / z(M+H) + =228.2.

[0416] Referring to the synthesis method of Preparation Example 34, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in the table.

[0417] Table 5 Information on intermediate compounds obtained from the preparation examples.

[0418]

[0419]

[0420] Preparation Example 58: Preparation of tert-butyl 3-(5-bromo-2-fluorophenyl)-3-fluoropyrrolidine-1-carboxylic acid

[0421]

[0422] Step 1: Preparation of tert-butyl 3-(5-bromo-2-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylic acid

[0423]

[0424] At -40°C, 4-bromo-1-fluoro-2-iodobenzene (1 g, 3.32 mmol), tetrahydrofuran (10 mL), and isopropyl magnesium chloride-lithium chloride solution (0.48 g, 3.32 mmol) were added sequentially to a reverse-drying reaction flask. The reaction was carried out at this temperature for 2 hours. Subsequently, tert-butyl 3-oxopyrrolidine-1-carboxylic acid (0.61 g, 3.32 mmol) was added, and the mixture was stirred thoroughly and reacted for another 30 minutes. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 0.42 g of the title compound.

[0425] MS(ESI)m / z(M+Na) + =383.1.

[0426] Step 2: Preparation of tert-butyl 3-(5-bromo-2-fluorophenyl)-3-fluoropyrrolidine-1-carboxylic acid

[0427]

[0428] 3-(5-bromo-2-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (385 mg, 1.07 mmol) and dichloromethane (10 mL) were added sequentially to a reaction flask, followed by diethylaminosulfur trifluoride (0.21 g, 1.28 mmol) at 0 °C. After stirring thoroughly, the reaction was allowed to proceed at room temperature for 2 hours. Once the reaction was complete, water was added to quench the reaction. The product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 275 mg of a colorless liquid product.

[0429] MS(ESI)m / z(M-56+H) + =306.8.

[0430] Preparation Example 59: Preparation of tert-butyl 3-(3-bromophenyl)-3-fluoropyrrolidine-1-carboxylate

[0431]

[0432] Using commercially available reagents as raw materials, and following the synthetic route described above, Preparation Example 59 was obtained by referring to the synthetic method of Preparation Example 58.

[0433] MS(ESI)m / z(M+Na) + =366.8.

[0434] Preparation Example 60: Preparation of 2-(5-bromo-2-fluorophenyl)-4-methylmorpholine

[0435]

[0436] Step 1: Preparation of 2-bromo-1-(5-bromo-2-fluorophenyl)ethyl-1-one

[0437]

[0438] 1-(5-bromo-2-fluorophenyl)ethyl-1-one (2.0 g, 9.21 mmol) was dissolved in tetrahydrofuran (40 mL), and phenyltrimethylammonium tribromide (3.4 g, 9.21 mmol) was added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 (V:V)) to give 2.6 g of the title compound.

[0439] MS(ESI)m / z(M+H) + =294.9.

[0440] Step 2: Preparation of 2-(5-bromo-2-fluorophenyl)-4-methylmorpholin-2-ol

[0441]

[0442] 2-(methylamino)ethane-1-ol (253.8 mg, 3.38 mmol) was dissolved in acetonitrile (20 mL), and 2-bromo-1-(5-bromo-2-fluorophenyl)ethane-1-one (1.0 g, 3.38 mmol) was slowly added at room temperature. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 12 hours. After the reaction was confirmed to be complete by TLC, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (dichloromethane / methanol = 10 / 1 (V:V)) to give 600.0 mg of the title compound.

[0443] MS(ESI)m / z(M+H) + =290.1.

[0444] Step 3: Preparation of 2-(5-bromo-2-fluorophenyl)-4-methylmorpholine

[0445]

[0446] 2-(5-bromo-2-fluorophenyl)-4-methylmorpholin-2-ol (600.0 mg, 2.07 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (6 mL). Triethylsilane (1444.2 mg, 12.42 mmol) was added at room temperature, and the reaction was allowed to proceed for 12 hours at room temperature. After the reaction was complete as indicated by TLC, the solvent was concentrated, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (dichloromethane / methanol = 10 / 1 (V:V)) to give 200.0 mg of the title compound.

[0447] MS(ESI)m / z(M+H) + =274.1.

[0448] Preparation Example 61: Preparation of tert-butyl 2-(2-fluoro-5-formylphenyl)pyrrolidine-1-carboxylic acid

[0449]

[0450] Palladium acetate (0.020 g, 0.087 mmol), 1,4-bis(diphenylphosphine)butane (0.056 g, 0.13 mmol), sodium carbonate (0.23 g, 2.17 mmol), tert-butyl 2-(5-bromo-2-fluorophenyl)pyrrolidine-1-carboxylic acid (500 mg, 1.45 mmol), and 1,1,3-trioxo-2,3-dihydro-1,6,2-benzothiazol-2-carboxaldehyde (0.46 g, 2.17 mmol) were added sequentially to the reaction flask. After purging with nitrogen three times, N,N-dimethylformamide (6 mL) and triethylsilane (0.22 g, 1.89 mmol) were added. The mixture was stirred thoroughly and reacted at 80 °C for 8 hours. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give 400 mg of the title compound.

[0451] MS(ESI)m / z(M-56+H) + =238.0.

[0452] Referring to the synthesis method of Preparation Example 61, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in Table 6.

[0453] Table 6 Intermediate Compounds

[0454]

[0455]

[0456]

[0457] Preparation Example 77: Preparation of tert-butyl 3-(2-fluoro-5-formylphenyl)piperidine-1-carboxylic acid

[0458]

[0459] Step 1: Preparation of 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide

[0460]

[0461] 3-Bromo-4-fluorobenzoic acid (3.0 g, 13.7 mmol), dimethylhydroxylamine hydrochloride (1.5 g, 15.07 mmol), and 1-hydroxybenzotriazole (2.2 g, 16.44 mmol) were dissolved in N,N-dimethylformamide (50 mL). N,N-diisopropylethylamine (8.8 g, 68.50 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.2 g, 16.44 mmol) were added at room temperature, and the mixture was reacted at room temperature for 2 hours. After TLC showed complete reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 3.3 g of the title compound.

[0462] MS(ESI)m / z(M+H) + =262.0.

[0463] Step 2: Preparation of tert-butyl 5-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid

[0464]

[0465] 3-Bromo-4-fluoro-N-methoxy-N-methylbenzamide (300.0 mg, 1.14 mmol), 5-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (387.7 mg, 1.25 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (83.4 mg, 0.11 mmol), and potassium carbonate (315.1 mg, 1 mmol) were added. The title compound (2.28 mg, mmol) was dissolved in 1,4-dioxane (10 mL) and water (1.5 mL). After purging with nitrogen gas, the reaction system was heated to 90 °C and reacted for 5 hours. After TLC showed that the reaction was complete, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (V:V)) to give 400.0 mg of the title compound.

[0466] MS(ESI)m / z(M+H) + =365.2.

[0467] Step 3: Preparation of tert-butyl 3-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)piperidine-1-carboxylic acid

[0468]

[0469] 400.0 mg (1.10 mmol) of 5-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester was dissolved in methanol (15 mL). Palladium / carbon (200.0 mg (1.88 mmol) was added at room temperature. After the addition was complete, hydrogen gas was purged, and the reaction was carried out at room temperature for 12 hours. After the reaction was confirmed to be complete by TLC, solid impurities were removed by filtration, the solution was concentrated to obtain the crude product, and column chromatography was used to purify 330.0 mg of the title compound.

[0470] MS(ESI)m / z(M+H) + =367.2.

[0471] Step 4: Preparation of tert-butyl 3-(2-fluoro-5-formylphenyl)piperidine-1-carboxylic acid

[0472]

[0473] 3-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (330.0 mg, 0.90 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (41.3 mg, 1.09 mmol) was added at room temperature. After the addition was complete, the reaction was carried out at room temperature for 2 hours. After TLC showed that the reaction was complete, 41 μL of water was added to quench the reaction, followed by 41 μL of 15% sodium hydroxide aqueous solution, and finally 123 μL of aqueous solution was added. The mixture was stirred for 15 minutes and then dried over anhydrous sodium sulfate. The solid was removed by filtration, and the solvent was concentrated to obtain the crude product. The crude product was purified by column chromatography to give 220.0 mg of the title compound.

[0474] MS(ESI)m / z(M+H) + =308.2.

[0475] Referring to the synthesis methods of Preparation Examples 34, 61, and 77, the following intermediate compounds can be prepared using commercial reagents or intermediates prepared in this invention as raw materials; Preparation Example 79 yielded intermediates 81 and 82 by chiral column separation, as shown in Table 7.

[0476] Table 7 Intermediate Compounds

[0477]

[0478]

[0479] Preparation Example 86: Preparation of tert-butyl 3-(2-cyano-5-formylphenyl)pyrrolidine-1-carboxylic acid

[0480]

[0481] Step 1: Preparation of 3-bromo-4-hydroxy-N-methoxy-N-methylbenzamide

[0482]

[0483] 3-Bromo-4-hydroxybenzoic acid (2.0 g, 9.22 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.9 g, 9.22 mmol) were dissolved in pyridine (20 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g, 13.83 mmol) was added at room temperature, and the mixture was reacted at room temperature for 2 hours. After TLC showed complete reaction, the solvent was concentrated, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 1.1 g of the title compound.

[0484] MS(ESI)m / z(M+H) + =260.1.

[0485] Step 2: Preparation of tert-butyl 3-(2-hydroxy-5-(methoxy(methyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid

[0486]

[0487] 3-Bromo-4-hydroxy-N-methoxy-N-methylbenzamide (1.0 g, 3.84 mmol), 3-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (1.1 g, 3.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.3 g, 0.38 mmol), and potassium carbonate (1.1 g, 7.68 mmol) were weighed into a reaction tube. Nitrogen gas was introduced, followed by the addition of 1,4-dioxane (20 mL) and water (3 mL), and then nitrogen gas was introduced again. The system was heated to 90 °C and reacted for 5 hours. After TLC showed complete reaction, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (V:V)) to give 1.1 g of the title compound.

[0488] MS(ESI)m / z(M+H) + =349.2.

[0489] Step 3: Preparation of tert-butyl 3-(2-hydroxy-5-(methoxy(methyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid

[0490]

[0491] 1.0 g (2.87 mmol) of 3-(2-hydroxy-5-(methoxy(methyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester was dissolved in methanol (20 mL). Palladium / carbon (0.2 g, 1.88 mmol) was added at room temperature, and hydrogen was substituted. The reaction proceeded at room temperature for 12 hours. After TLC showed complete reaction, solid impurities were removed by filtration, and the mixture was dried over anhydrous sodium sulfate. The solvent was concentrated, and the solution was purified by column chromatography to give 920.0 mg of the title compound.

[0492] MS(ESI)m / z(M+H) + =351.2.

[0493] Step 4: Preparation of tert-butyl 3-(5-(methoxy(methyl)carbamoyl)-2-(trifluoromethanesulfonyloxy)phenyl)pyrrolidine-1-carboxylic acid

[0494] 3-(2-hydroxy-5-(methoxy(methyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (115.3 mg, 1.14 mmol) was added at room temperature, followed by the slow addition of trifluoromethanesulfonic anhydride (241.2 mg, 0.85 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 8 hours. After TLC showed that the reaction was complete, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 (V:V)) to give 180.0 mg of the title compound.

[0495] MS(ESI)m / z(M+H) + =483.2.

[0496] Step 5: Preparation of tert-butyl 3-(2-cyano-5-(methoxy(methyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid

[0497]

[0498] 3-(5-(methoxy(methyl)carbamoyl)-2-(trifluoromethanesulfonyloxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (150.0 mg, 0.31 mmol), zinc cyanide (182.0 mg, 1.55 mmol), palladium acetate (6.9 mg, 0.031 mmol), and triphenylphosphine (16.2 mg, 0.062 mmol) were weighed into a dry reaction tube. Nitrogen gas was introduced, followed by the addition of N,N-dimethylacetamide (5 mL), and nitrogen gas was introduced again. The system was heated to 140 °C and reacted for 8 hours. After TLC showed complete reaction, saturated brine was added, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 (V:V)) to give 100.0 mg of the title compound.

[0499] MS(ESI)m / z(M+H) + =360.2.

[0500] Step 6: Preparation of tert-butyl 3-(2-cyano-5-formylphenyl)pyrrolidine-1-carboxylic acid

[0501]

[0502] 100.0 mg (0.28 mmol) of 3-(2-cyano-5-(methoxy(methyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (15.9 mg (0.42 mmol)) was added at 0 °C. After the addition was complete, the reaction was continued at this temperature for 2 hours. After TLC showed that the reaction was complete, water (16 μL), 15% sodium hydroxide (16 μL), and water (48 μL) were added sequentially to the system. After the addition was complete, the mixture was stirred for 15 minutes, and then anhydrous sodium sulfate was added for drying. The solid was removed by filtration, and the solvent was concentrated to obtain 50.0 mg of the product.

[0503] MS(ESI)m / z(M+H) + =301.2.

[0504] Preparation Example 87: Preparation of N-((6-bromopyridin-2-yl)methyl)methanesulfonamide

[0505]

[0506] Step 1: Preparation of 2-((6-bromopyridin-2-yl)methyl)isoindoline-1,3-dione

[0507]

[0508] Under nitrogen protection, triphenylphosphine (4.28 g, 16.32 mmol), isoindolin-1,3-dione (2.40 g, 16.32 mmol), and diethyl azodicarbonate (2.84 g, 16.32 mmol) were added to a 100 mL solution of (6-bromopyridin-2-yl)methanol in an ice-water bath. The reaction was allowed to proceed naturally at elevated temperature for 1 hour. LC-MS showed a good reaction. After concentration under reduced pressure, the sample was stirred with silica gel and purified by column chromatography to obtain 7.0 g of crude product with a purity of 45%, which was directly used in the next reaction.

[0509] MS(ESI)m / z(M+H) + =317.1.

[0510] Step 2: Preparation of (6-bromopyridin-2-yl)methylamine

[0511]

[0512] A solution of 2-((6-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (6.95 g, 9.86 mmol) and hydrazine hydrate (0.99 g, 19.72 mmol) in ethanol (100 mL) was heated to reflux for 1 hour. The reaction was confirmed to be complete by LCMS, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography to give 1.933 g of the title compound.

[0513] MS(ESI)m / z(M+H) + =187.0.

[0514] Step 3: Preparation of N-((6-bromopyridin-2-yl)methyl)methanesulfonamide

[0515]

[0516] Under nitrogen protection, in an ice-water bath, triethylamine (1.77 g, 17.46 mmol) and methanesulfonyl chloride (1.10 g, 9.60 mmol) were added to a solution of (6-bromopyridin-2-yl)methylamine (1.633 g, 8.73 mmol) in dichloromethane (50 mL). The reaction was allowed to proceed naturally at elevated temperature for 10 minutes, and LC-MS showed that the reaction was complete. After concentration under reduced pressure, stirring with silica gel, and purification by column chromatography, 2.342 g of the title compound was obtained.

[0517] MS(ESI)m / z(M+H) + =265.1.

[0518] Preparation Example 88: Preparation of tert-butyl cis-2-(2-fluoro-5-formylphenyl)-4-methylpiperidine-1-carboxylic acid

[0519]

[0520] Step 1: Preparation of 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide

[0521]

[0522] Under ice-water bath conditions, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.50 g, 54.79 mmol) was added to a pyridine (40 mL) solution of 3-bromo-4-fluorobenzoic acid (10 g, 45.66 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.34 g, 54.79 mmol). The reaction was allowed to proceed at room temperature for 30 minutes, and LC-MS showed complete reaction. The solution was concentrated under reduced pressure, mixed with silica gel, purified by column chromatography, and concentrated again under reduced pressure to obtain 11.9 g of the title compound.

[0523] MS(ESI)m / z(M+H) + =262.0.

[0524] Step 2: Preparation of 4-fluoro-N-methoxy-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzamide

[0525] 3-Bromo-4-fluoro-N-methoxy-N-methylbenzamide (3 g, 11.45 mmol), pinacol diborate (4.36 g, 17.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.28 g, 0.38 mmol), potassium acetate (2.25 g, 22.9 mmol), and 1,4-dioxane (40 mL) were added to a 100 mL single-necked flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted overnight. The reaction was confirmed to be complete by LC-MS. The diatomaceous earth filtration was used directly for subsequent reactions.

[0526] MS(ESI)m / z(M+H) + =310.1.

[0527] Step 3: Preparation of 4-fluoro-N-methoxy-N-methyl-3-(4-methylpyridin-2-yl)benzamide

[0528]

[0529] 4-Fluoro-N-methoxy-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzamide (1.18 g, 3.82 mmol), 2-bromo-4-methylpyridine (0.79 g, 4.58 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.098 g, 0.13 mmol), sodium carbonate (0.81 g, 7.64 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added to a 100 mL single-necked flask. After nitrogen purging, the mixture was heated to 100 °C and reacted for 3 hours. The reaction was confirmed to be complete by LC-MS. The mixture was directly stirred with silica gel and purified by column chromatography to obtain 1.645 g of the title compound.

[0530] MS(ESI)m / z(M+H) + =275.1.

[0531] Step 4: Preparation of 4-fluoro-N-methoxy-N-methyl-3-((cis-4-methylpiperidin-2-yl)benzamide

[0532]

[0533] To a methanol (30 mL) solution of 4-fluoro-N-methoxy-N-methyl-3-(4-methylpyridin-2-yl)benzamide (1.445 g, 2.63 mmol, 50%), concentrated hydrochloric acid (2 mL), palladium on carbon (200 mg), and platinum dioxide (0.60 g, 2.63 mmol) were added. After purging with hydrogen, the reaction was allowed to proceed overnight at room temperature. LC-MS showed that the reaction was complete. The solution was adjusted to alkaline with sodium bicarbonate, filtered through diatomaceous earth, concentrated, mixed with silica gel, and purified by column chromatography to give 0.669 g of the title compound.

[0534] MS(ESI)m / z(M+H) + =281.1.

[0535] Step 5: Preparation of cis-2-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester

[0536]

[0537] At room temperature, tert-butoxycarbonyl anhydride (0.78 g, 3.58 mmol) and triethylamine (0.48 g, 4.78 mmol) were added to a methanol (30 mL) solution of 4-fluoro-N-methoxy-N-methyl-3-(cis-4-methylpiperidin-2-yl)benzamide (0.669 g, 2.39 mmol). The reaction was allowed to proceed for 1 hour at room temperature, and the reaction was confirmed to be complete by LC-MS. After concentration under reduced pressure and mixing with silica gel, the sample was purified by column chromatography to give 0.215 g of the title compound.

[0538] MS(ESI)m / z(M+H) + =381.2.

[0539] Step 6: Preparation of cis-2-(2-fluoro-5-formylphenyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester

[0540]

[0541] Under nitrogen protection, lithium aluminum hydride (0.030 g, 0.80 mmol) was added to a 20 mL solution of cis-2-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)-4-methylpiperidin-1-carboxylic acid tert-butyl ester (0.2 g, 0.53 mmol) in tetrahydrofuran under an ice-water bath. The reaction was carried out for 30 minutes in an ice-water bath, and the reaction was confirmed to be complete by LC-MS. The reaction was quenched by adding ammonium chloride aqueous solution, and the compound was purified by direct silica gel column chromatography to give 0.12 g of the title compound.

[0542] MS(ESI)m / z(M+H) + =322.2.

[0543] Referring to the synthesis method of Preparation Example 88, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in Table 8.

[0544] Table 8 Intermediate Compounds

[0545]

[0546]

[0547]

[0548] Preparation Example 105: Preparation of tert-butyl (2-fluoro-5-formylbenzyl) carbamate

[0549]

[0550] Step 1: Preparation of tert-butyl N-[(5-bromo-2-fluorophenyl)methyl]carbamate

[0551]

[0552] At room temperature, 5-bromo-2-fluorobenzylamine hydrochloride (500.0 mg, 2.1 mmol) was dissolved in methanol (10 mL), followed by the addition of triethylamine (0.6 g, 6.2 mmol) and di-tert-butyl dicarbonate (0.5 g, 2.5 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour, and the reaction was monitored by LC-MS to indicate completion. The reaction solution was concentrated to dryness and purified by column chromatography to give 600.0 mg of the title compound.

[0553] MS(ESI)m / z(M+H) + =304.3.

[0554] Step 2: Preparation of tert-butyl (2-fluoro-5-formylbenzyl) carbamate

[0555]

[0556] The starting materials, tert-butyl N-[(5-bromo-2-fluorophenyl)methyl]carbamate (200.0 mg, 0.7 mmol) and N-formylsaccharin (0.2 g, 1.0 mmol), were dissolved in N,N-dimethylformamide (10 mL). Then, sodium carbonate (0.1 g, 1.0 mmol), palladium acetate (8.9 mg, 0.04 mmol), and 1,4-bis(diphenylphosphine)butane (34.0 mg, 0.08 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at room temperature for 10 min. Triethylsilane (0.1 g, 0.9 mmol) was then added. After the addition was complete, the mixture was heated to 80 °C under nitrogen protection and reacted for 12 h. The reaction was monitored by LC-MS to ensure complete reaction. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, concentrated, and purified by column chromatography to give 45.0 mg of the title compound.

[0557] MS(ESI)m / z(M+H) + =254.2.

[0558] Preparation Example 106: Preparation of N-(1-(3-fluoro-6-formylpyridin-2-yl)ethyl)carbamate tert-butyl ester

[0559]

[0560] Step 1: Preparation of N-[(1E)-(6-bromo-3-fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide

[0561]

[0562] 6-Bromo-3-fluoropyridine-2-carboxaldehyde (1 g, 4.9 mmol) and tert-butylsulfinamide (0.71 g, 5.88 mmol) were weighed and dissolved in dichloromethane (20 mL). Magnesium sulfate (1.18 g, 9.8 mmol) was added at room temperature, and the mixture was stirred at room temperature for 12 hours. After the reaction was confirmed to be complete by LC-MS, the system was filtered, concentrated, and purified by silica gel column chromatography to give 0.918 g of the title compound.

[0563] MS(ESI)m / z(M+H) + =307.1.

[0564] Step 2: Preparation of N-(1-(6-bromo-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

[0565]

[0566] N-[(1E)-(6-bromo-3-fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (918 mg, 2.99 mmol) was weighed and dissolved in tetrahydrofuran (30 mL). 3M magnesium chloride solution (1.2 mL, 3.6 mmol) was added under dry ice bath, and the mixture was slowly heated to room temperature and stirred for 2 hours. After LC-MS showed complete reaction, the system was quenched with ammonium chloride solution, extracted three times with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to give 0.917 g of the title compound.

[0567] MS(ESI)m / z(M+H) + =323.1.

[0568] Step 3: Preparation of 1-(6-bromo-3-fluoropyridin-2-yl)ethylamine

[0569]

[0570] 917 mg (2.84 mmol) of N-(1-(6-bromo-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was dissolved in 5 mL of dichloromethane. 5 mL of 4 M 1,4-dioxane hydrochloride solution was added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. After LC-MS showed complete reaction, the system was concentrated and purified by silica gel column chromatography to give 0.621 g of the title compound.

[0571] MS(ESI)m / z(M+H) + =219.1.

[0572] Step 4: Preparation of N-(1-(6-bromo-3-fluoropyridin-2-yl)ethyl)carbamate tert-butyl ester

[0573]

[0574] 0.621 g (2.83 mmol) of 1-(6-bromo-3-fluoropyridin-2-yl)ethylamine was dissolved in 20 mL of dichloromethane. Triethylamine (0.78 mL, 5.66 mmol) was added, and di-tert-butyl dicarbonate (1.24 g, 5.66 mmol) was added dropwise under ice bath conditions. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was confirmed to be complete by TLC, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was concentrated, purified by silica gel column chromatography, and concentrated to give 0.76 g of the title compound.

[0575] MS(ESI)m / z(M+H) + =319.1.

[0576] Step 5: Preparation of N-(1-(3-fluoro-6-formylpyridin-2-yl)ethyl)carbamate tert-butyl ester

[0577]

[0578] Weigh out 0.4 g (1.25 mmol) of N-(1-(6-bromo-3-fluoropyridin-2-yl)ethyl)carbamate tert-butyl ester and 0.4 g (1.88 mmol) of N-formylsaccharin and dissolve them in 10 mL of N,N-dimethylformamide. Add palladium acetate (0.017 g, 0.075 mmol), 1,4-bis(diphenylphosphine)butane (0.048 g, 0.09 mmol), triethylsilane (0.19 g, 1.63 mmol), and sodium carbonate (0.20 g, 1.88 mmol). React at 80 °C for 12 hours. LC-MS showed that the reaction was complete. Add water to the system, extract three times with ethyl acetate, dry and concentrate the organic phase, and purify by silica gel column chromatography to obtain 0.07 g of the title compound.

[0579] MS(ESI)m / z(M+H) + =269.1.

[0580] Preparation Example 107: Preparation of (S)-2-(5-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridine

[0581]

[0582] Step 1: Preparation of (R)-N-[(1E)-(5-bromo-2-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide

[0583]

[0584] At room temperature, 10 g (49.3 mmol) of 5-bromo-2-fluorobenzaldehyde, 7.2 g (59.1 mmol) of (R)-(+)-tert-butylsulfinamide, 23.7 g (197.0 mmol) of magnesium sulfate, and 30 mL of dichloromethane were added to a reaction flask and stirred until homogeneous. The reaction was allowed to proceed overnight at room temperature. The reaction was stopped when most of the starting material was converted, as monitored by LC-MS. The filtrate was collected by filtration, the reaction mixture was evaporated to dryness, and purified by column chromatography to give 5.5 g of the title compound.

[0585] MS(ESI)m / z(M+H) + =306.0.

[0586] Step 2: Preparation of (R)-N-((S)-1-(5-bromo-2-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0587]

[0588] At room temperature, (R)-N-[(1E)-(5-bromo-2-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide (2 g, 6.5 mmol) and dichloromethane (20 mL) were added to a reaction flask, and the mixture was purged with nitrogen. The mixture was cooled to -40 °C, and allyl magnesium bromide (3.8 g, 26.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes, and the reaction was monitored for completeness by LC-MS. The reaction was quenched with ammonium chloride solution, cooled to room temperature, extracted, and the organic phase was collected, evaporated to dryness, and purified by column chromatography to give 2.2 g of the title compound.

[0589] MS(ESI)m / z(M+H) + =348.1.

[0590] Step 3: Preparation of (R)-N-allyl-N-((S)-1-(5-bromo-2-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0591]

[0592] At room temperature, (R)-N-((S)-1-(5-bromo-2-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 5.7 mmol), sodium hydride (210 mg, 8.6 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask and stirred until homogeneous. 3-bromoprop-1-ene (1.0 g, 8.6 mmol) was added, and the reaction was carried out at room temperature for half an hour. The reaction was monitored by LCMS until complete. The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by column chromatography to obtain 2.0 g of the title compound.

[0593] MS(ESI)m / z(M+H) + =388.1.

[0594] Step 4: Preparation of (S)-2-(5-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridine

[0595]

[0596] At room temperature, (R)-N-allyl-N-((S)-1-(5-bromo-2-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 5.1 mmol), Grubbs II (220 mg, 0.3 mmol), and dichloromethane (20 mL) were added to a reaction flask, the mixture was purged with nitrogen, and the reaction mixture was heated to 40 °C and reacted for one hour. The reaction was monitored by LCMS until complete, and the solution was evaporated to dryness and purified by column chromatography to give 1.5 g of the title compound.

[0597] MS(ESI)m / z(M+H) + =360.1.

[0598] Preparation Example 108: Preparation of 3-((S)-1-((R)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridin-2-yl)-4-fluorobenzaldehyde

[0599]

[0600] At room temperature, (S)-2-(5-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridine (200 mg, 0.6 mmol), N-formylsaccharin (177.4 mg, 0.8 mmol), 1,4-bis(diphenylphosphino)butane (14.3 mg, 0.03 mmol), sodium carbonate (89.0 mg, 0.8 mmol), palladium acetate (11.3 mg, 0.05 mmol), and N,N-dimethylformamide (10 mL) were added to a sealed tube. The tube was purged with nitrogen, and triethylsilane (84.7 mg, 0.7 mmol) was added. The mixture was stirred at room temperature for ten minutes, then slowly heated to 80 °C and reacted overnight. The reaction was monitored by LC-MS to ensure complete reaction. After cooling to room temperature, the organic phase was extracted and separated. The organic phase was collected, evaporated to dryness, and purified by column chromatography to give 143 mg of the title compound.

[0601] MS(ESI)m / z(M+H) + =310.1.

[0602] Preparation Example 109: Preparation of tert-butyl (5R)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid

[0603]

[0604] Step 1: Preparation of (R)-3-((tert-butyldiphenylsilyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0605]

[0606] (R)-1-Boc-3-hydroxypiperidine (5.0 g, 24.88 mmol) was dissolved in N,N-dimethylformamide (50 mL). Imidazole (2.6 g, 29.86 mmol) and tert-butyldiphenylchlorosilane (6.8 g, 24.88 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 3 hours. After TLC showed complete reaction, 300 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 10 g of the title compound.

[0607] MS(ESI)m / z(M+H) + =440.1.

[0608] Step 2: Preparation of (R)-5-((tert-butyldiphenylsilyl)oxy)-2-oxopiperidin-1-carboxylic acid tert-butyl ester

[0609]

[0610] (R)-3-((tert-butyldiphenylsilyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (10.0 g, 22.78 mmol) was dissolved in ethyl acetate (50 mL). Ruthenium oxide (90.0 mg, 0.68 mmol) and sodium periodate (18.4 g, 85.56 mmol) were added sequentially to a 150 mL water solution at room temperature. The reaction was allowed to proceed overnight at this temperature. After LC-MS showed complete reaction, 500 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 6.8 g of the title compound.

[0611] MS(ESI)m / z(M+H) + =454.1.

[0612] Step 3: Preparation of (R)-(5-(5-bromo-2-fluorophenyl)-2-((tert-butyldiphenylsilyl)oxy)-5-oxopentyl)carbamate tert-butyl ester

[0613]

[0614] 4.5 g (15.00 mmol) of 2-iodo-4-bromofluorobenzene was dissolved in 40 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 15.00 mmol (1 M tetrahydrofuran solution, 15.00 mL) of isopropyl magnesium bromide was added. After the addition was complete, the mixture was reacted at this temperature for 2 hours. Then, a 20 mL solution of (R)-5-((tert-butyldiphenylsilyl)oxy)-2-oxopiperidin-1-carboxylic acid tert-butyl ester (6.8 g (15.00 mmol)) in tetrahydrofuran was slowly added. LC-MS showed that the starting material was completely consumed. 100 mL of water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 3.5 g of the title compound.

[0615] MS(ESI)m / z(M+H) + =628.1.

[0616] Step 4: Preparation of (R)-6-(5-bromo-2-fluorophenyl)-3-((tert-butyldiphenylsilyl)oxy)-2,3,4,5-tetrahydropyridine

[0617]

[0618] (R)-(5-(5-bromo-2-fluorophenyl)-2-((tert-butyldiphenylsilyl)oxy)-5-oxopentyl)carbamate tert-butyl ester (3.5 mg, 5.58 mmol) was weighed and dissolved in dichloromethane (20 mL). Trifluoroacetic acid (5 mL) was added at room temperature, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was confirmed to be complete by LCMS, the system was concentrated, water (100 mL) was added, the pH was adjusted to alkaline, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 2.8 g of the title compound.

[0619] MS(ESI)m / z(M+H) + =510.1.

[0620] Step 5: Preparation of (5R)-2-(5-bromo-2-fluorophenyl)-5-((tert-butyldiphenylsilyl)oxy)piperidine

[0621]

[0622] (R)-6-(5-bromo-2-fluorophenyl)-3-((tert-butyldiphenylsilyl)oxy)-2,3,4,5-tetrahydropyridine (2.8 g, 5.50 mmol) was weighed and dissolved in methanol (50 mL). Sodium cyanoborohydride (346.0 mg, 5.50 mmol) and trifluoroacetic acid (125.0 mg, 1.1 mmol) were added sequentially at room temperature. After the additions were complete, the mixture was reacted at room temperature for 1 hour. LC-MS showed complete consumption of the starting material. Water (100 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 2.5 g of the title compound.

[0623] MS(ESI)m / z(M+H) + =512.1.

[0624] Step 6: Preparation of (3R)-6-(5-bromo-2-fluorophenyl)piperidin-3-ol

[0625]

[0626] (5R)-2-(5-bromo-2-fluorophenyl)-5-((tert-butyldiphenylsilyl)oxy)piperidine (2.5 g, 4.89 mmol) was weighed and dissolved in tetrahydrofuran (20 mL). Tetrabutylammonium fluoride (5.9 mL, 1 M tetrahydrofuran solution, 5.87 mmol) was added sequentially at room temperature. After the addition was complete, the system was reacted overnight at 60 °C. LC-MS showed complete consumption of the starting material. Water (100 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 700 mg of the title compound.

[0627] MS(ESI)m / z(M+H) + =274.1.

[0628] Step 7: Preparation of tert-butyl (5R)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylate

[0629]

[0630] (3R)-6-(5-bromo-2-fluorophenyl)piperidin-3-ol (700.0 mg, 2.56 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (517.0 mg, 5.12 mmol) and di-tert-butyl dicarbonate (558.0 mg, 2.56 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 3 hours. After LC-MS showed complete reaction, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 800 mg of the title compound.

[0631] MS(ESI)m / z(M+H) + =374.1.

[0632] Preparation Example 110: Preparation of (5S)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0633]

[0634] Step 1: Preparation of tert-butyl (5S)-2-(5-bromo-2-fluorophenyl)-5-((4-nitrobenzoyl)oxy)piperidine-1-carboxylic acid

[0635]

[0636] (5R)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidin-1-carboxylic acid tert-butyl ester (150.0 mg, 0.40 mmol) was dissolved in tetrahydrofuran (5 mL). Under ice bath conditions, p-nitrobenzoic acid (100.0 mg, 0.60 mmol), triphenylphosphine (210.0 mg, 0.80 mmol), and diethyl azodicarbonate (104.0 mg, 0.60 mmol) were added sequentially. After the addition was complete, the mixture was allowed to return to room temperature for 3 hours. After LC-MS showed complete reaction, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 150 mg of the title compound.

[0637] MS(ESI)m / z(M+H) + =523.1.

[0638] Step 2: Preparation of (5S)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0639]

[0640] (5S)-2-(5-bromo-2-fluorophenyl)-5-((4-nitrobenzyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (150.0 mg, 0.29 mmol) was weighed and dissolved in methanol (5 mL). Potassium carbonate (160.0 mg, 1.16 mmol) was added at room temperature, and the mixture was allowed to return to room temperature for 3 hours after the addition was complete. After LCMS showed that the reaction was complete, 50 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 100 mg of the title compound.

[0641] MS(ESI)m / z(M+H) + =374.1.

[0642] Preparation Examples 111-112: Preparation of (5S)-2-(2-fluoro-5-formylphenyl)-5-methoxypiperidine-1-carboxylic acid tert-butyl ester

[0643]

[0644] Step 1: Preparation of tert-butyl (5S)-2-(5-bromo-2-fluorophenyl)-5-methoxypiperidine-1-carboxylic acid

[0645]

[0646] (5S)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100.0 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (5 mL). Sodium hydroxide (108.0 mg, 2.70 mmol) and methyl iodide (383.0 mg, 2.70 mmol) were added sequentially at room temperature. After the addition was complete, the mixture was allowed to return to room temperature and reacted overnight. LC-MS analysis showed complete reaction of the starting material. 50 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 80 mg of the title compound.

[0647] MS(ESI)m / z(M+H) + =388.1.

[0648] Step 2: Preparation of (2S,5S)-2-(2-fluoro-5-formylphenyl)-5-methoxypiperidine-1-carboxylic acid tert-butyl ester and (2R,5S)-2-(2-fluoro-5-formylphenyl)-5-methoxypiperidine-1-carboxylic acid tert-butyl ester

[0649]

[0650] Weigh out tert-butyl (5S)-2-(5-bromo-2-fluorophenyl)-5-methoxypiperidine-1-carboxylate (80.0 mg, 0.24 mmol), n-formylsaccharin (76.0 mg, 0.36 mmol), triethylsilane (36.0 mg, 0.31 mmol), palladium acetate (8.0 mg, 0.04 mmol), 1,4-bis(diphenylphosphine)butane (30.0 mg, 0.07 mmol), and sodium carbonate (38.0 mg, 0.36 mmol), dissolve them in N,N-dimethylformamide (5 mL), purge three times with nitrogen, and then react the mixture at 80 °C for 4 hours. After LCMS showed that the reaction was complete, add 100 mL of water to the system, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 20 mg of (2S,5S)-2-(2-fluoro-5-formylphenyl)-5-methoxypiperidine-1-carboxylic acid tert-butyl ester (yellow oil) and 25 mg of (2R,5S)-2-(2-fluoro-5-formylphenyl)-5-methoxypiperidine-1-carboxylic acid tert-butyl ester (yellow oil).

[0651] MS(ESI)m / z(M+H) + =338.1.

[0652] Preparation Example 113: Preparation of tert-butyl (2R,5S)-5-fluoro-2-(2-fluoro-5-formylphenyl)piperidine-1-carboxylate

[0653]

[0654] Step 1: Preparation of tert-butyl (5S)-2-(5-bromo-2-fluorophenyl)-5-fluoropiperidine-1-carboxylic acid

[0655]

[0656] (5R)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester (150.0 mg, 0.40 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (129.0 mg, 0.80 mmol) was added. The mixture was then reacted at room temperature for 2 hours. After LCMS showed that the reaction was complete, 50 mL of water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 60 mg of the title compound.

[0657] MS(ESI)m / z(M+H) + =376.1.

[0658] Step 2: Preparation of tert-butyl (2R,5S)-5-fluoro-2-(2-fluoro-5-formylphenyl)piperidine-1-carboxylate

[0659]

[0660] Weigh out tert-butyl (5S)-2-(5-bromo-2-fluorophenyl)-5-fluoropiperidin-1-carboxylate (60.0 mg, 0.16 mmol), n-formylsaccharin (51.0 mg, 0.24 mmol), triethylsilane (24.0 mg, 0.21 mmol), palladium acetate (7.0 mg, 0.03 mmol), 1,4-bis(diphenylphosphine)butane (20.0 mg, 0.05 mmol), and sodium carbonate (25.0 mg, 0.24 mmol), dissolve them in N,N-dimethylformamide (5 mL), purge three times with nitrogen, and then react the mixture at 80 °C for 4 hours. After LCMS showed that the reaction was complete, add 100 mL of water to the system, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 40 mg of the title compound.

[0661] MS(ESI)m / z(M+H) + =326.1.

[0662] Referring to the synthesis methods of Preparation Examples 109-113, using commercial reagents or intermediates prepared in this invention as raw materials, the following intermediate compounds can be prepared, as shown in the table.

[0663] Table 9 Information on intermediate compounds obtained from the preparation examples.

[0664]

[0665] Preparation Example 117: Preparation of tert-butyl (5R)-2-(2-fluoro-5-formylphenyl)-5-(pyridin-3-yloxy)piperidine-1-carboxylate

[0666]

[0667] Step 1: Preparation of tert-butyl (5R)-2-(5-bromo-2-fluorophenyl)-5-(pyridin-3-yloxy)piperidine-1-carboxylic acid

[0668]

[0669] (5R)-2-(5-bromo-2-fluorophenyl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.54 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of potassium tert-butoxide (121.0 mg, 1.08 mmol) and 3-fluoropyridine (105.0 mg, 1.08 mmol). The mixture was then reacted at 80 °C for 8 hours. After LCMS showed complete reaction, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 90 mg of a yellow oil.

[0670] MS(ESI)m / z(M+H) + =451.1.

[0671] Step 2: Preparation of tert-butyl (5R)-2-(2-fluoro-5-formylphenyl)-5-(pyridin-3-yloxy)piperidine-1-carboxylate

[0672]

[0673] Weigh out (5R)-2-(5-bromo-2-fluorophenyl)-5-(pyridin-3-yloxy)piperidine-1-carboxylic acid tert-butyl ester (90.0 mg, 0.20 mmol), n-formylsaccharin (63.0 mg, 0.30 mmol), triethylsilane (30.0 mg, 0.26 mmol), palladium acetate (7.0 mg, 0.03 mmol), 1,4-bis(diphenylphosphine)butane (25.0 mg, 0.06 mmol), and sodium carbonate (32.0 mg, 0.30 mmol), dissolve them in N,N-dimethylformamide (5 mL), purge three times with nitrogen, and then react the mixture at 80 °C for 4 hours. After LCMS showed that the reaction was complete, add 100 mL of water to the system, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 50 mg of the title compound.

[0674] MS(ESI)m / z(M+H) + =401.1.

[0675] Preparation Example 118: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)azapyrrolidone-1-carboxylic acid

[0676]

[0677] Referring to the synthesis method in step 2 of Preparation Examples 34 and 35, using commercial reagents as raw materials, step 4 can be added to prepare intermediate compound 118.

[0678] Step 4: Add 220 mg (0.76 mmol) of 6-amino-1-(5-bromo-2-fluorophenyl)hex-1-one and 0.061 g (1.52 mmol) of sodium hydroxide to the reaction flask, followed by 10 mL of methanol. After stirring thoroughly, allow the reaction to proceed at room temperature for 2 hours. Once the reaction is complete, quench the reaction with water, extract three times with ethyl acetate, dry to anhydrous sodium sulfate, filter under reduced pressure, and concentrate the organic phase. The crude product can be used directly in the next reaction at 0.2 g without further purification.

[0679] MS(ESI)m / z(M+H) + =272.0.

[0680] Preparation Example 119: Preparation of tert-butyl 2-(2-fluoro-5-formylphenyl)azacyclohexane-1-carboxylic acid

[0681]

[0682] 2-(5-bromo-2-fluorophenyl)azapyro-1-carboxylic acid tert-butyl ester (200 mg, 0.54 mmol), palladium acetate (0.0073 g, 0.032 mmol), 1,4-bis(diphenylphosphine)butane (0.021 g, 0.049 mmol), sodium carbonate (0.086 g, 0.81 mmol), and 1,1,3-trioxo-2,3-dihydro-1,6,2-benzothiazol-2-carboxaldehyde (0.17 g, 0.81 mmol) were added sequentially to the reaction flask. After purging with nitrogen three times, N,N-dimethylformamide (2.5 mL) and triethylsilane (0.082 g, 0.70 mmol) were added. The mixture was stirred until homogeneous and reacted at 80 °C for 8 hours. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 100 mg of the title compound.

[0683] MS(ESI)m / z(M-56+H) + =266.0.

[0684] Preparation Example 120: Preparation of tert-butyl 2-(2-((tert-butoxycarbonyl)oxy)-5-formylphenyl)piperidine-1-carboxylate

[0685]

[0686] Step 1: Preparation of 4-(benzyloxy)-3-bromo-N-methoxy-N-methylbenzamide

[0687]

[0688] 3-Bromo-4-hydroxy-N-methoxy-N-methylbenzamide (1 g, 3.86 mmol), potassium carbonate (1.04 g, 7.72 mmol), and acetonitrile (20 mL) were added sequentially to a reaction flask, followed by benzyl bromide (0.99 g, 5.80 mmol). After stirring thoroughly, the reaction was carried out at 80°C for 5 hours. Once complete, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound (1.0 g, 75%).

[0689] MS(ESI)m / z(M+H) + =350.0.

[0690] Steps 2 to 5 are performed according to the method of Preparation Example 88 to obtain tert-butyl 2-(2-((tert-butoxycarbonyl)oxy)-5-formylphenyl)piperidine-1-carboxylate.

[0691] MS(ESI)m / z(M-200+H) + =206.0.

[0692] Preparation Example 121: Preparation of 2-bromo-6-(((tert-butyldiphenylsilyl)oxy)methyl)pyridine

[0693]

[0694] Step 1: Preparation of (6-bromopyridin-2-yl)methanol

[0695]

[0696] Under nitrogen protection, sodium borohydride (0.41 g, 10.75 mmol) was added to a tetrahydrofuran (30 mL) solution of 6-bromopyridine-2-carboxaldehyde (2 g, 10.75 mmol) in an ice-water bath. The reaction was carried out for 30 minutes, and LC-MS showed that the reaction was complete. The reaction was quenched by adding a small amount of ammonium chloride aqueous solution. After drying with anhydrous sodium sulfate, filtration through diatomaceous earth, and concentration under reduced pressure, 2.036 g of the title compound was obtained and used directly in the next reaction.

[0697] MS(ESI)m / z(M+H) + =188.0.

[0698] Step 2: Preparation of 2-bromo-6-(((tert-butyldiphenylsilyl)oxy)methyl)pyridine

[0699]

[0700] Under nitrogen protection, 1-methyl-1H-imidazole (2.62 g, 31.92 mmol) and tert-butyldiphenylchlorosilane (3.22 g, 11.70 mmol) were added to a solution of (6-bromopyridin-2-yl)methanol (2 g, 10.64 mmol) in N,N-dimethylformamide (10 mL) in an ice-water bath. The ice-water bath was removed, and the reaction was allowed to proceed at room temperature for 1 hour. LC-MS showed complete reaction. The mixture was separated into layers by adding water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by normal-phase column chromatography to give 4.574 g of the title compound.

[0701] MS(ESI)m / z(M+H) + =426.1.

[0702] Preparation Example 122: Preparation of 3-((cis)-6-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-2-yl)-4-fluorobenzaldehyde

[0703]

[0704] Compound 122 of the preparation example can be prepared by referring to the synthesis method of Preparation Example 88 and using commercial reagents or intermediates prepared in this invention as raw materials.

[0705] MS(ESI)m / z(M+H) + =476.1.

[0706] Preparation Example 123: Preparation of 4-fluoro-3-((cis)-6-(hydroxymethyl)piperidin-2-yl)benzaldehyde

[0707]

[0708] At room temperature, tetrabutylammonium fluoride (0.47 g, 1.80 mmol) was added to a tetrahydrofuran (10 mL) solution of 3-((cis)-6-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-2-yl)-4-fluorobenzaldehyde (0.17 g, 0.36 mmol) and added. The reaction was allowed to proceed for 2 hours. LC-MS showed that the reaction was complete. After concentration under reduced pressure, the solution was purified by reverse-phase column chromatography to give 60 mg of the title compound.

[0709] MS(ESI)m / z(M+H) + =238.1.

[0710] Preparation Example 124: Preparation of 4-chloro-3-((cis)-6-(hydroxymethyl)piperidin-2-yl)benzaldehyde

[0711]

[0712] Compound 124 of the preparation example can be prepared by referring to the synthesis method of preparation example 123, using commercial reagents or intermediates prepared in this invention as raw materials.

[0713] MS(ESI)m / z(M+H) + =254.0.

[0714] Preparation Example 125: Preparation of tert-butyl 3-(2-fluoro-5-formylphenyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

[0715]

[0716] Step 1: Preparation of 3-(5-bromo-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane

[0717]

[0718] 4-Bromo-1-fluoro-2-iodobenzene (1.2 g, 3.99 mmol) was dissolved in tetrahydrofuran (10 mL), and isopropyl magnesium bromide (587.7 mg, 3.99 mmol) was added under ice bath conditions, and the reaction was carried out under ice bath conditions for 2 hours. 2-azabicyclo[2.2.1]heptane (232.6 mg, 2.39 mmol) was dissolved in diethyl ether (5 mL), and n-butyllithium (171.2 mg, 2.67 mmol) was added at -78 °C and stirred for 10 minutes. 2,2,2-trifluoroacetophenone (555.7 mg, 3.19 mmol) was added, and the reaction was continued for 1 hour. Then, the freshly prepared (5-bromo-2-fluorophenyl) magnesium bromide was added, followed by the rapid addition of boron trifluoride diethyl ether (509.6 mg, 3.59 mmol). After the addition was complete, the reaction was slowly brought back to room temperature and allowed to proceed for 12 hours. After TLC showed that the reaction was complete, methanol (2 mL) was added to the reaction system to quench the reaction. Saturated brine was then added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was then purified by column chromatography (dichloromethane / ethyl acetate = 1 / 2 (V:V)) to give 100.0 mg of the title compound.

[0719] MS(ESI)m / z(M+H) + =270.0.

[0720] Step 2: Preparation of tert-butyl 3-(5-bromo-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

[0721]

[0722] 3-(5-bromo-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane (100.0 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (121.1 mg, 0.55 mmol) and triethylamine (74.8 mg, 0.74 mmol) were added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 12 hours. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 (V:V)) to give 125.0 mg of the title compound.

[0723] MS(ESI)m / z(M+H) + =370.0.

[0724] Step 3: Preparation of tert-butyl 3-(2-fluoro-5-formylphenyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

[0725]

[0726] 3-(5-bromo-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (80.0 mg, 0.11 mmol), N-formylsaccharin (34.8 mg, 0.17 mmol), palladium acetate (2.5 mg, 0.011 mmol), 1,4-bis(diphenylphosphine)butane (9.5 mg, 0.022 mmol), and sodium carbonate (17.5 mg, 0.17 mmol) were weighed into a test tube, purged with nitrogen, and N,N-dimethylformamide (3 mL) and triethylsilane (17.0 mg, 0.14 mmol) were added. Nitrogen was then purged again, and the system was heated to 75 °C and reacted for 8 hours. After TLC showed complete reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 10.0 mg of the title compound.

[0727] MS(ESI)m / z(M+H) + =320.2.

[0728] Preparation Example 126: Preparation of tert-butyl 2-(2-fluoro-5-formylphenyl)azacyclooctane-1-carboxylic acid

[0729]

[0730] Compound 126 of the preparation example can be prepared by referring to the synthesis method of Preparation Example 125, using commercial reagents or intermediates prepared in this invention as raw materials.

[0731] MS(ESI)m / z(M+H) + =336.2.

[0732] Preparation Example 127: Preparation of tert-butyl 2-(5-formyl-2-(methylsulfonamido)phenyl)piperidine-1-carboxylate

[0733]

[0734] By referring to the synthesis method of Preparation Example 88, using commercial reagents or intermediates prepared in this invention as raw materials, and adding step 4, Preparation Example Compound 127 can be prepared.

[0735] Step 4: Preparation of N-methoxy-N-methyl-4-(methanesulfonamido)-3-(pyridin-2-yl)benzamide

[0736]

[0737] Under nitrogen protection, methanesulfonyl chloride (0.13 g, 1.14 mmol) was added to a pyridine (10 mL) solution of 4-amino-N-methoxy-N-methyl-3-(pyridin-2-yl)benzamide (0.268 g, 1.04 mmol). The reaction was allowed to proceed naturally at elevated temperature for 4 hours. LC-MS detected a clear target product and disubstituted byproducts. The product was concentrated under reduced pressure and purified by reversed-phase column chromatography to give 188 mg of the title compound.

[0738] MS(ESI)m / z(M+H) + =336.2.

[0739] Preparation Example 128: Preparation of (R)-2-(2-chloro-5-formylphenyl)piperidine-1-carboxylic acid tert-butyl ester

[0740]

[0741] Step 1: Preparation of (S,E)-N-(5-bromo-2-chlorobenzyl)-2-methylpropane-2-sulfinamide

[0742]

[0743] 5-Bromo-2-chlorobenzaldehyde (5.0 g, 22.93 mmol) was dissolved in tetrahydrofuran (50 mL), and tetraethyl titanate (15.7 g, 68.81 mmol) was added at room temperature. The reaction was carried out at 75 °C for 3 hours. After the reaction of the starting material was complete as shown by LCMS, 300 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 6.5 g of the title compound.

[0744] MS(ESI)m / z(M+H) + =322.1.

[0745] Step 2: Preparation of (S)-N-((R)-1-(5-bromo-2-chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0746]

[0747] (S,E)-N-(5-bromo-2-chlorobenzyl)-2-methylpropane-2-sulfinamide (6.5 g, 20.25 mmol) was dissolved in dichloromethane (100 mL), purged three times with nitrogen, and cooled to -40 °C. Allyl magnesium bromide (40.5 mL, 1 mmol / L in THF, 40.50 mmol) was slowly added, and the mixture was allowed to react at this temperature for 1 hour. After LCMS showed complete reaction of the starting material, 500 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give the title compound 5.5.

[0748] MS(ESI)m / z(M+H) + =364.1.

[0749] Step 3: Preparation of (S)-N-allyl-N-((R)-1-(5-bromo-2-chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0750]

[0751] (S)-N-((R)-1-(5-bromo-2-chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5.5 g, 15.15 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0 °C, and sodium hydrogen (909.0 mg, 60% W, 22.73 mmol) was added. After reacting at this temperature for 1 hour, allyl bromide (2.8 g, 22.73 mmol) was added. After the addition was complete, the system was reacted at room temperature for 2 hours. LC-MS showed that the starting material was completely consumed. Water (500 mL) was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (V:V)) to give 4.8 g of the title compound.

[0752] MS(ESI)m / z(M+H) + =404.1.

[0753] Step 4: Preparation of (R)-2-(5-bromo-2-chlorophenyl)-1-((S)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridine

[0754]

[0755] (S)-N-allyl-N-((R)-1-(5-bromo-2-chlorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (4.8 g, 11.91 mmol) was dissolved in dichloromethane (20 mL). The reaction was carried out at room temperature with Grubbs' second-generation catalyst (506.0 mg, 0.60 mmol), followed by nitrogen purging three times and reaction at 50 °C for 4 hours. After LC-MS showed complete reaction of the starting material, water (100 mL) was added, and the mixture was extracted three times with dichloromethane. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1 (V:V)) to give 4.0 g of the title compound.

[0756] MS(ESI)m / z(M+H) + =376.2.

[0757] Step 5: Preparation of (R)-2-(5-bromo-2-chlorophenyl)-1,2,3,6-tetrahydropyridine

[0758]

[0759] (R)-2-(5-bromo-2-chlorophenyl)-1-((S)-tert-butylsulfinyl)-1,2,3,6-tetrahydropyridine (4.0 g, 10.67 mmol) was weighed and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was allowed to react at room temperature for 1 hour. LC-MS showed that the starting material was completely consumed. The mixture was filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 2.5 g of the title compound.

[0760] MS(ESI)m / z(M+H) + =272.1.

[0761] Step 6: Preparation of (R)-2-(5-bromo-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0762]

[0763] (R)-2-(5-bromo-2-chlorophenyl)-1,2,3,6-tetrahydropyridine (2.5 g, 9.23 mmol) was dissolved in dichloromethane (40 mL). Triethylamine (2.8 g, 27.68 mmol) and di-tert-butyl dicarbonate (2.0 g, 9.23 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted overnight. After LC-MS showed complete reaction, 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 3.0 g of the title compound.

[0764] MS(ESI)m / z(M+H) + =372.1.

[0765] Step 7: Preparation of (R)-2-(5-bromo-2-chlorophenyl)piperidine-1-carboxylic acid tert-butyl ester

[0766]

[0767] (R)-2-(5-bromo-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.0 g, 8.09 mmol) was dissolved in ethyl acetate (30 mL). Platinum dioxide (600.0 mg, 20% (w / w)) was slowly added in portions at room temperature, with hydrogen purging three times. After the addition was complete, the system was reacted at room temperature for 6 hours. LC-MS showed that the starting material was completely consumed. The system was filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 2.5 g of the title compound.

[0768] MS(ESI)m / z(M+H) + =374.2.

[0769] Step 8: Preparation of (R)-2-(2-chloro-5-formylphenyl)piperidine-1-carboxylic acid tert-butyl ester

[0770]

[0771] Weigh out (R)-2-(5-bromo-2-chlorophenyl)piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 6.70 mmol), n-formylsaccharin (2.1 g, 10.05 mmol), triethylsilane (1.0 g, 8.71 mmol), palladium acetate (226 mg, 1.01 mmol), 1,4-bis(diphenylphosphine)butane (840 mg, 2.01 mmol), and sodium carbonate (1.1 g, 10.05 mmol), and dissolve them in N,N-dimethylformamide (15 mL). Purge the mixture three times with nitrogen, and then react the mixture at 80 °C overnight. After LC-MS confirms complete reaction, add 100 mL of water, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (V:V)) to give 1.3 g of the title compound, with an er value of 88:12. Further chiral column resolution yielded the title compound in a single configuration.

[0772] MS(ESI)m / z(M+H) + =324.2.

[0773] Preparation Example 129: Preparation of (R)-2-(2-fluoro-5-formylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0774]

[0775] By referring to the synthesis method of Preparation Example 128, Preparation Example 129 can be prepared using commercial reagents or intermediates prepared in this invention as raw materials.

[0776] MS(ESI)m / z(M+H) + =306.2.

[0777] Preparation Example 130: Preparation of tert-butyl 2-(5-acetyl-2-fluorophenyl)piperidine-1-carboxylic acid

[0778]

[0779] 200 mg (0.55 mmol) of 2-(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (5 mL). Methyl magnesium bromide (1.1 mL, 1 M in THF, 1.10 mmol) was added at 0 °C, and the mixture was allowed to return to room temperature for 2 hours. After LC-MS analysis showed complete reaction of the starting material, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 150 mg of the title compound.

[0780] MS(ESI)m / z(M+H) + =322.2.

[0781] Example 1: Preparation of N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidin-2-yl)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0782]

[0783] Step 1: Preparation of tert-butyl 2-(5-((1'-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)methyl)-2-fluorophenyl)pyrrolidine-1-carboxylic acid

[0784]

[0785] 2-((5-(1',4'-dihydro2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (30 mg, 0.073 mmol), 2-(2-fluoro-5-formylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21.41 mg, 0.073 mmol), and methanol (1 mL) were added sequentially to the reaction flask. Acetic acid (0.0044 g, 0.073 mmol) was then added. After stirring, the reaction was carried out at room temperature for 2 hours. Sodium cyanoborohydride (0.014 g, 0.22 mmol) was then added, and the reaction was carried out at room temperature overnight. After the reaction was completed, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 50 mg of the title compound.

[0786] MS(ESI)m / z(M+H) + =690.3.

[0787] Step 2: Preparation of N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidone-2-yl)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0788]

[0789] 2-(5-((1'-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)methyl)-2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.072 mmol), trifluoroacetic acid (1 mL), and dichloromethane (1 mL) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by HPLC to obtain 24 mg of the title compound.

[0790] 1 H NMR(400MHz, Methanol-d4)δ8.42(s,1H),7.44–7.37(m,2H),7.32–7.20(m,2H),7.20(dd,J=8.0, 3.0Hz,1H),7.05(dd,J=10.5,8.4Hz,1H),5.13(s,2H),4.72(s,2H),4.44–4.31(m,1H),3.92(s,4H ),3.80(p,J=6.7Hz,1H),3.75(s,2H),3.55–3.42(m,1H),3.25–3.14(m,2H),3.06–2.95(m,1H),2 .32–2.21(m,1H),2.06–1.87(m,2H),1.85–1.71(m,1H),1.23–1.01(m,7H),0.79(d,J=6.6Hz,2H).

[0791] MS(ESI)m / z(M+H) + =590.2.

[0792] Example 2: Preparation of N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(1-methylpyrrolidin-2-yl)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0793]

[0794] N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidine-2-yl)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (30 mg, 0.051 mmol), paraformaldehyde (0.0031 g, 0.10 mmol), sodium methoxide (5.5 mg, 0.10 mmol), sodium cyanoborohydride (9.6 mg, 0.15 mmol), and methanol (1 mL) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by HPLC to give 18.2 mg of the title compound.

[0795] 1 H NMR(400MHz, Methanol-d4)δ8.42(s,1H),7.48–7.36(m,2H),7.32–7.15(m,3H),7.03(dd,J=10 .2,8.4Hz,1H),5.13(s,2H),4.73(s,2H),3.92(s,4H),3.80(p,J=6.6Hz,1H),3.75(d,J=2.3Hz ,2H),3.57–3.42(m,2H),3.26–3.17(m,1H),2.35(q,J=9.1Hz,1H),2.32–2.21(m,1H),2.20(s, 3H), 2.03–1.84 (m, 2H), 1.77 (q, J=16.3, 13.6Hz, 1H), 1.26–1.01 (m, 7H), 0.79 (d, J=6.6Hz, 2H).

[0796] MS(ESI)m / z(M+H) + =604.1.

[0797] Using the intermediate compounds prepared in the preparation examples as raw materials, the following Examples 3-141 were prepared according to the synthesis methods of Examples 1 and 2. In the preparation of Examples 10 and 22, acetone was used instead of paraformaldehyde; in the preparation of Example 11, (1-methoxycyclopropoxy)trimethylsilane was used instead of paraformaldehyde; Examples 99 and 100 were obtained by simple hydrogenation of Examples 7 and 32, respectively; except for the compounds synthesized using a single chiral raw material or the intermediates prepared in this invention as described above, the single chiral compounds were all obtained by chiral resolution, and the specific information is shown in Table 10.

[0798] Table 10 Compound Information from Examples

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835] The analytical data described above, including NMR and LC-MS data, are shown in Table 11.

[0836] Table 11 NMR and LC-MS data of compounds in Examples 3-141

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855] Experimental Example 1: Menin-MLL Protein Interaction Inhibition Activity Assay

[0856] (1) Inhibitory activity test of the interaction between Menin and MLL protein

[0857] The IC50 of the test compound inhibiting Menin-MLL protein interaction was detected using the Fluorescence Polarization method. 50 value.

[0858] The specific steps are as follows: The compound stock solution (10 mM, prepared in DMSO) was serially diluted three-fold with DMSO to ten concentrations: 10000.00, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0.51 nM. Using an ECHO665 Series Acoustic Liquid Handler (BECKMAN Inc.), 50 nL of each concentration of the test compound (10 concentration gradients) and a DMSO solution without the compound (negative control well) were transferred to a 384-well plate and centrifuged at 1000 rpm. Using an I.DOT (DISPENDIX Inc.) syringe, 5 μL of Menin (ICE Inc., Cat No. E2208F-H15H) was added to each well and incubated at 25°C for 10 minutes. Using I.DOT, 5 μL of FITC-MLL4-43 (Genscrip Inc.) was added to each well, centrifuged at 1000 rpm, and incubated for 60 minutes. FP signal was measured using a Pherastar FSX multi-plate reader (BMGLabtech Inc.), and the data were processed.

[0859] The IC50 of each compound was fitted using a nonlinear regression equation: Inhibition% = (Signal from negative control wells - Signal from compound wells) / (Signal from negative control wells - Background signal) * 100% (Background signal is the signal value detected in wells containing only 10 μM SNDX-5613). The logarithmic value of the compound concentration was used as the X-axis, and the percentage inhibition rate (Inhibition%) as the Y-axis. A dose-response curve was fitted to derive the IC50 of each compound in inhibiting Menin-MLL protein interaction. 50 Values. The experimental results are shown in Table 8.

[0860] Note: SNDX-5613 refers to N-ethyl-2-((4-(7-((trans-4-(ethylsulfonylamino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide, purchased from Shanghai Loulan Biotechnology Co., Ltd., with the following structural formula:

[0861]

[0862] (2) Inhibition activity test of interaction between mutant Menin-M327I and Menin-T349M and MLL protein

[0863] The IC50 of the test compounds inhibiting the interaction between Menin-M327I, Menin-T349M and MLL protein was detected using fluorescence polarization. 50 value.

[0864] The specific steps are as follows: The compound stock solution (10 mM, prepared in DMSO) was serially diluted three-fold with DMSO to ten concentrations: 10000.00, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0.51 nM. Using an ECHO665 Series Acoustic Liquid Handler (BECKMAN Inc.), 50 nL of each concentration of the test compound (10 concentration gradients) and a DMSO solution without the compound (negative control well) were transferred to a 384-well plate and centrifuged at 1000 rpm for later use. Using I.DOT (DISPENDIX Inc.), 5 μL of Menin-M327I (ICE Inc. Cat No. A130412011) and Menin-T349M (ICE Inc. Cat No. A130413011) were added to each well, and incubated at 25°C for 10 minutes. Using I.DOT, 5 μL of FITC-MLL4-43 (Genscrip Inc.) was added to each well, centrifuged at 1000 rpm, and incubated for 60 minutes. FP signals were measured using a Pherastar FSX multi-plate reader (BMG Labtech Inc.), and the data were processed.

[0865] Fitting compound IC with a nonlinear regression equation 50 Inhibition% = (Negative control well signal - Compound well signal) / (Negative control well signal - Background signal) * 100% (Background signal is the signal value detected in wells containing only 100 μM SNDX-5613). Using the log value of compound concentration as the X-axis and the percentage inhibition rate (Inhibition%) as the Y-axis, a dose-response curve was fitted to obtain the IC50 of each compound inhibiting the interaction between Menin-M327I, Menin-T349M, and MLL protein. 50 Values. The experimental results are shown in Table 11.

[0866] Experiment Example 2: Cell Proliferation Inhibition Experiment

[0867] (1) Cell plating:

[0868] Remove the cells from the incubator and place them on the worktable. Gently pipette them together and count them using CounterStar.

[0869] Dilute the cells to the required density using fresh complete culture medium. MV-4-11 cells (source: Nanjing Kebai, catalog number: CBP60522) were cultured in RPMI 1640 (containing HEPES) (BOSTER, catalog number: PYG0122) + 10% FBS (GIBCO, catalog number: 10099-141C) + 1% P / S (HyClone, catalog number: SV30010) at a density of 1×10^4 cells / well, 100 μL / well.

[0870] MV-4-11MEN1 M327I / M327I Cells (based on MV-4-11 cells with catalog number CBP60522, the MEN1 gene was edited using CRISPR technology to mutate amino acid methionine (number 327) of the protein product it encodes to isoleucine I, RPMI1640 + 10% FBS + 1% P / S) were plated at a density of 1 × 10^4 cells / well, 100 μL / well.

[0871] MV-4-11MEN1 T349M / T349M Cells (based on MV-4-11 cells with catalog number CBP60522, the MEN1 gene was edited using CRISPR technology to mutate the 349th amino acid threonine T of the protein product it encodes to methionine M, RPMI1640+15%FBS+1%P / S) were plated at a density of 1×10^4 cells / well, 100μL / well.

[0872] Use a power pipette to aspirate 100 μL of each of the above cell suspensions into a 96-well plate.

[0873] (2) Preparation of compounds:

[0874] The mother liquor of the compound was diluted from 10 mM to 4000, 1200, 400, 120, 40, 12, 4, 1.2 and 0 μM with DMSO, with 0 μM serving as the control well.

[0875] After thorough mixing, 1.3 μL was taken out with an electric pipette and added to 258.7 μL of culture medium. At this point, it was diluted 100 times, and the DMSO content was 0.5%.

[0876] After thoroughly mixing using a multi-channel pipette, remove the cells that have been plated above. Set up two replicates for each compound concentration. Add 100 μL of the compound diluted in step 2 to each replicate well. The final compound concentrations are: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0 μM. At this point, there is a total of 200 μL of culture medium in each well of the cell culture plate, with a DMSO content of 0.25%. The well containing only 0.25% DMSO (compound concentration of 0) is the control well.

[0877] The cells were returned to a 37°C, 5% CO2 incubator for further culture, and then tested after 3 days of treatment with the added compound.

[0878] (3) CTG detection:

[0879] After the culture time is up, remove the cells and aspirate some of the culture medium, leaving 50 μL of culture medium in each well. Add 50 μL of CTG reagent (cellcounting-Lite 2.0, Vazyme, DD1101-02) per well using a multipipe.

[0880] Incubate in a shaker at room temperature for 15 minutes, then allow to stand at room temperature for 15 minutes to equilibrate.

[0881] Detection was performed using a multi-functional microplate reader.

[0882] (4) Data Analysis:

[0883] Calculate cell viability%, Cell viability% = As / Ac × 100%. As: Test wells (containing cell culture medium, CTG, and test compound), Ac: Control wells (containing cell culture medium, CTG, and no test compound).

[0884] Using the logarithm of compound concentration as the X-axis and cell viability (%) as the Y-axis, a dose-response curve was fitted to derive the IC50 of each compound's inhibitory activity on cell proliferation. 50 Values. Specific results are shown in Table 11.

[0885] Table 11 Activity data of the compounds of the present invention

[0886]

[0887]

[0888]

[0889]

[0890] Note: In Table 11, "-" indicates that the compound was not detected. "Compound number" indicates the compound in the corresponding example. Compounds 1-34 are compounds from Chinese patent application publication number CN118930525A, with the following structure:

[0891]

[0892] The results in Table 11 show that the compounds of this invention exhibit excellent activity in inhibiting the interaction between Menin and MLL proteins, and also excellent activity in inhibiting the interaction between Menin mutant proteins (Menin-M327I, Menin-T349M) and MLL proteins. Furthermore, the compounds of this invention can also effectively inhibit MV-4-11 and its mutant cells MV-4-11MEN1. M327I / M327I MV-4-11MEN1 T349M / T349M Cell proliferation. Therefore, the compounds of this invention have good prospects for clinical development. In particular, compared with existing compounds, the present invention has excellent activity in inhibiting the interaction between Menin-M327I and Menin-T349M mutant proteins and MLL protein, thus showing good potential for resistance to drug resistance.

Claims

1. A compound represented by Formula I or Formula II, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof: In Formula I or Formula II, ----- represents a possible chemical bond, i.e. Represents a single bond or a double bond; U, Y1, Y2, Y3, and Y4 are each independently selected from CR3 or N, and no more than 3 of Y1, Y2, Y3, and Y4 are N; R3 may be the same or different at different positions, and R3 may be independently selected from H, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt, or -NRsSO2Rt, where Rs and Rt are each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Ra is R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic alkyl or -ORx, wherein Rx is a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclic alkyl; or R1 and R2 are cyclic together with the nitrogen to which they are attached. Or Ra is X1, X2, X3, and X4 are independently selected from CRd or N, and no more than 3 of X1, X2, X3, and X4 are N, while the rest are CRd; Rd at different positions may be the same or different, and Rd may be independently selected from hydrogen, halogen, cyano, or C1-C6 alkyl. Rc is -(CR4R5)pNR6R7, where p is 1 or 2, and R4, R5, R6, and R7 are independently selected from H or C1-C3 alkyl groups; Or Rc is in, Cy1 is a 3-14 member, 3-12 member, or 3-10 member alicyclic ring containing the N atom shown in the figure. The N atom shown in the figure is separated from the ring atom connected to the base end (marked with "*" by 0-2 ring atoms). Cy1 is a monocyclic ring, bridged ring, spirocyclic ring, or fused ring. In addition to the N atom shown in the diagram, the skeleton atoms of Cy1 may contain 0-3 or 0-2 atoms selected from N, O, and S; Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; Besides Rb, Cy1 can be independently substituted by one or more R8s at any possible position. R8s can be selected from oxygen, hydroxyl, amino, halogen, cyano, carboxylic acid, ester, amide, sulfonamide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C3 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 heterocyclic alkyl, 5-8 aryl, 5-8 heteroaryl, or -ORy, wherein Ry is selected from C3-C8 cycloalkyl, 3-8 heterocyclic alkyl, 5-8 aryl, or 5-8 heteroaryl. R8 can be substituted by one or more Rvs at any possible position. Rvs can be selected from hydroxyl, amino, halogen, cyano, amide, sulfonamide, C1-C6 alkyl, or C1-C6 alkoxy. When multiple R8s are present, the R8s at different positions may be the same or different. Rm and Rn are independently selected from H, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

2. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, It is a double bond; U is N or CH; or U is N.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, Any two of Y1, Y2, Y3, and Y4 are N, and the rest are CR3; or Y1 and Y2 are N, Y3 and Y4 are CR3; or Y1 and Y3 are N, Y2 and Y4 are CR3; or Y1 and Y4 are N, Y2 and Y3 are CR3; or Y2 and Y3 are N, Y1 and Y4 are CR3; or Any one of Y1, Y2, Y3, and Y4 is N, and the rest are CR3; or Y1 is N, and Y2, Y3, and Y4 are CR3; or Y2 is N, and Y1, Y3, and Y4 are CR3; or Y3 is N, and Y1, Y2, and Y4 are CR3; or Y4 is N, and Y1, Y2, and Y3 are CR3; or Y1, Y2, Y3, and Y4 are all CR3.

4. The compound according to claim 3, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, R3 at different positions may be the same or different, and R3 may be independently selected from H, halogen, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt or -NRsSO2Rt, wherein Rs and Rt are independently selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, respectively; or R3 at different positions is independently selected from H, F, Cl, Br, I, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, chloromethoxy, fluoromethoxy, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, prop-1-enyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclopropyl, phenyl, -CONHCH3, -CONHCH2CH3, -SO2NHCH3, -SO2NHCH2CH3, -NHSO2CH3, -NCH3SO2CH3 or -NHSO2CH2CH3.

5. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, Ra is Wherein R1 and R2 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted 3-4 membered heterocyclic alkyl or -ORx, and Rx is a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclic alkyl; or R1 and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl or substituted cyclopropyl, cyclopropoxy, cyclobutyl or substituted cyclobutyl; or R1 is isopropyl and R2 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl.

6. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, Ra is R1 and R2, together with the nitrogen atom they are attached to, form a 3-10 membered alicyclic ring. This alicyclic ring can be selected from monocyclic or polycyclic rings; the polycyclic ring can be a fused ring, a spirocyclic ring, or a bridged ring. In addition to the nitrogen atom, the alicyclic ring contains 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur. R1 and R2 together with the nitrogen they are attached to form 3-8 membered alicyclic rings; or R1 and R2 together with the nitrogen they are attached to form 3-6 membered alicyclic rings; or R1, R2, together with the attached nitrogen, form the following structure: The alicyclic heterocycles formed by R1, R2 and the attached nitrogen are substituted at any possible position by one or more groups selected from oxygen, hydroxyl, amino, carboxyl, halogen, cyano, C1-C6 alkyl, C1-C3 alkylamino, C3-C8 cycloalkyl or 3-8 membered heterocyclic alkyl.

7. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof according to any one of claims 1-6, characterized in that, One or more hydrogen atoms in the ring formed by R1, R2, or R1 and R2 are replaced by deuterium atoms.

8. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, Ra is X1, X2, X3, and X4 are independently selected from CRd or N, and no more than three of X1, X2, X3, and X4 are N, with the remainder being CRd; Rd at different positions may be the same or different, and Rd may be independently selected from hydrogen, halogen, cyano, or C1-C6 alkyl; or Rd at different positions can be independently selected from H, halogen, cyano, C1-C3 alkyl; or Rd can be independently selected from H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl.

9. The compound according to claim 8, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that, One of X1, X2, X3, and X4 is N, and the rest are CRd; or X1 is N, and X2, X3, and X4 are CRd; or X2 is N, and X1, X3, and X4 are CRd; or X3 is N, and X1, X2, and X4 are CRd; or X4 is N, and X1, X2, and X3 are CRd; or Two of X1, X2, X3, and X4 are N, and the rest are CRa; or X1 and X3 are N, and X2 and X4 are CRd; or X1 and X4 are N, and X2 and X3 are CRd; or X2 and X4 are N, and X1 and X3 are CRd; or X1 and X2 are N, and X3 and X4 are CRd; or X1, X2, X3, and X4 are all CRd; or Ra is the following structure, either substituted or unsubstituted by Rd, that satisfies the above conditions:

10. The pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof of the compound according to claim 1, characterized in that, Rc is Where m is 0 or 1; n is 0, 1 or 2; T is absent; or T is CR11R12, wherein R11 and R12 may be independently selected from H, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; or R11 and R12 are cyclic together with the carbon to which they are attached; When L is selected from CH2 or CH2CH2, Z is -Q-(CH2)q-; q is 0, 1, 2 or 3, and Q is selected from -NRb, O or S atoms; or Q does not exist, that is, Z is -(CH2)q-; When L does not exist, that is, Rc is Z is Q can be selectively connected to the α-carbon atom end or away from the α-carbon atom end. This represents the option to form a ring, where Q is selected from N, O, or S atoms, or Q is absent, i.e., Z is... R9 and R10 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or R9 and R10 are cyclic with the connected carbon. Cy does not exist, that is, Rc is Alternatively, Cy may be selected from 3-10 membered alicyclic rings or 3-10 membered heterocyclic rings; or Cy may be selected from 3-6 membered alicyclic rings or 3-6 membered heterocyclic rings; and Cy may optionally be substituted by one or more groups selected from oxygen, halogen, cyano, carboxylic acid group, ester group, amide group, amino group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group or C1-C6 haloalkyl group; G is selected from O, -OCH2-, substituted or unsubstituted alkylene groups, wherein the substituted alkylene groups are optionally independently substituted by one or two groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl groups; or G is absent; Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.

11. The pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof of the compound according to claim 10, characterized in that, Rc is Or Rc is or Rc is selected from substituted or unsubstituted 3-8 member monocyclic rings; or Rc is selected from N-heterocyclic butyl, pyrrolyl, piperidinyl, azirrocyclic heptyl, azirrocyclic octyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydroimidazolyl, tetrahydropyridinyl, pyrazolyl, piperazine, morpholinyl, and thiomorpholinyl.

12. The pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof of the compound according to any one of claims 1-11, characterized in that, Rc is selected from the following structures:

13. The pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof of the compound according to claim 12, characterized in that, Rb is selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; Rb can be independently substituted at any possible position by a group selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl; or Rb is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

14. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof according to any one of claims 1-13, characterized in that, Rm and Rn are independently selected from H, halogen, cyano, C1-C3 alkyl, and C1-C3 alkoxy, respectively; Rm and Rn may be substituted at possible positions by groups selected from halogen, hydroxyl, and amino; or Rm is hydrogen and Rn is selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, amino, methyl, methoxy, fluoromethyl, chloromethyl, or trifluoromethyl.

15. A compound, a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, selected from:

16. A pharmaceutical composition, characterized in that, Includes the compound of any one of claims 1-15, its pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, pharmaceutically acceptable excipients and / or carriers.

17. Use of the compound of any one of claims 1-15, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, or the pharmaceutical composition of claim 16, in the preparation of a medicament for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions.

18. The use according to claim 17, characterized in that, Diseases associated with the Menin-MLL protein interaction include malignancies, diabetes, or complications related to these diseases; among which malignancies include hematologic malignancies, lymphomas, and solid tumors.

19. The use according to claim 18, characterized in that, Hematologic malignancies include leukemia and myeloma, including but not limited to acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute monocytic leukemia, chronic monocytic leukemia, childhood leukemia, acute myeloid leukemia, chronic myeloid leukemia, mixed lineage leukemia, hairy cell leukemia, precursor T-cell lymphocytic leukemia, large granular lymphocytic leukemia, meningeal leukemia, myelodysplastic syndrome, myeloproliferative disorders, myeloproliferative neoplasm, plasmacytoma, and multiple myeloma; Lymphomas include, but are not limited to, cutaneous T-cell lymphoma, lymphoid tumors, AIDS-related lymphomas, Hodgkin lymphomas, non-Hodgkin lymphomas, or malignant lymphomas. Solid tumors include, but are not limited to, pancreatic cancer, colon cancer, rectal cancer, liver cancer, stomach cancer, glioblastoma, lung cancer, breast cancer, and prostate cancer; The related complications include, but are not limited to, leukemic meningitis.

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