Biazacycloalkane menin-MLL protein inhibitors, pharmaceutical composition thereof and use thereof

Abstract

Provided are biazacycloalkane compounds represented by formula I and formula II, pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug for preventing, alleviating or treating related diseases caused by Menin-MLL protein interaction.

Description

Azacycloalkane Menin-MLL protein inhibitors, their pharmaceutical compositions and uses Technical Field

[0001] This disclosure relates to diazacycloalkane 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 occur in 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 (Nature 615, 913-919). 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 disclosure provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, an isomer (e.g., a stereoisomer or a tautomer), a prodrug thereof, or a mixture thereof:

[0008] In formula I, Represents the possible chemical bonds (i.e., (Represents a single or double bond).

[0009] In some implementation schemes, It represents a double bond.

[0010] 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, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-14 membered aryl, and 5-14 membered heteroaryl.

[0011] In some implementations, U is N or CH.

[0012] 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.

[0013] 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.

[0014] The R3 at different positions may be the same or different, and R3 may be independently selected from H, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 ynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, the R3 at different positions is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, prop-1-ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, or phenyl. In some embodiments, Y1 is CR3 or N, Y2, Y3, and Y4 are CR3, and R3 is H, F, Cl, or cyano. In some embodiments, the heterocyclic alkyl and heteroaryl groups contain 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S. In some embodiments, Y1, Y3, and Y4 are CH, Y2 is CR3, and R3 is as defined herein (e.g., R3 may be independently selected from H, halogen, cyano, or C1-C3 alkyl).

[0015] In some embodiments, Y1, Y2, Y3, and Y4 are all CR3, and R3 is each independently H, F, Cl, Br, or cyano. In some embodiments, Y1, Y3, and Y4 are all CR3, and R3 is each independently H, F, Cl, or cyano. In some embodiments, Y1, Y3, and Y4 are CH, Y2 is CR3, and R3 is H, F, Cl, or cyano.

[0016] W is selected from O, NRe, or CRfRg; Re is selected from H, C1-C6 alkyl; Rf and Rg are independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl.

[0017] In some embodiments, W is O. In some embodiments, W is NRe, and Re is H or a C1-C3 alkyl group; in some embodiments, Re is H, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, W is CRfRg, where Rf and Rg are independently selected from H, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, Rf and Rg are independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, and piperidinyl. In some embodiments, W is O or NRe, and Re is H or a C1-C3 alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl).

[0018] v is selected when n is 0, 1, or 2. In some implementations, v is 0 or 1. In some implementations, when W is 0, v is 0 or 1; when W is NRe, v is 0.

[0019] Ra is R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 alkoxy groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted 3-6 membered heterocyclic alkyl groups; or R1 and R2 are cyclic with the attached nitrogen; in some embodiments, the C1-C6 alkyl, C3-C6 alkoxy, C3-C6 cycloalkyl, or 3-6 membered heterocyclic alkyl groups may be substituted with one or more of the following groups: deuterium, halogen (e.g., F, Cl, Br, or I), CN, OH; in some embodiments, R1 and R2 are independently selected from C1-C4 alkyl groups, C1-C3 alkoxy groups, C1-C3 deuterated alkyl groups, C1-C3 haloalkyl groups, or substituted or unsubstituted groups. The substituted 3-6 membered heterocyclic alkyl group; specifically, R1 and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, chloromethyl, deuterated methyl, deuterated ethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopentyl; in some specific embodiments, R1 is isopropyl and R2 is methyl, ethyl, n-propyl, isopropyl, methoxy, deuterated methyl, deuterated ethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, or 3,3-difluorocyclobutyl.

[0020] In some embodiments, R1 and R2, together with the attached nitrogen, form a 3-10 membered alicyclic ring (e.g., a heterocyclic alkyl group), 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. The alicyclic ring contains, in addition to the nitrogen, 0-3 (e.g., 0-2) heteroatoms selected from nitrogen, oxygen, and sulfur. In some specific embodiments, R1 and R2, together with the attached nitrogen, form the following structure:

[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 groups. 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. In some specific embodiments, R1 and R2 together with the attached nitrogen form groups that can be substituted with C1-C3 alkyl groups, such as:

[0022] Optionally, one or more hydrogen atoms in the aforementioned R1, R2 or the aliphatic heterocycle formed by R1, R2 and the nitrogen to which they are attached 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 Rds is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or isopropyl, and the rest are hydrogen. In some embodiments, two of the Rds 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 Rds is methyl, and the rest are hydrogen. In some embodiments, one of the Ras is fluorine, and the rest are hydrogen. In some embodiments, Rd at all positions is hydrogen. In some embodiments, X1 and X3 are N, X2 and X4 are CH, and Rd is hydrogen. In some embodiments, Ra is unsubstituted (i.e., Rd is hydrogen) or substituted by Rd ​​as one of the above-mentioned groups other than hydrogen, as follows:

[0026] In some implementations, Ra is Wherein, R1 and R2 are independently substituted or unsubstituted C1-C6 alkyl groups (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl, butyl, or pentyl), substituted or unsubstituted C3-C6 cycloalkyl groups (e.g., C3-C5 cycloalkyl or C3-C4 cycloalkyl), or 4-9 member (e.g., 5-8 member) heterocyclic alkyl groups that, together with the attached nitrogen, form a monocyclic, fused, spirocyclic, or bridged ring. The alkyl or cycloalkyl group may be oxidized by deuterium, halogen (e.g., F, ...). The heterocyclic alkyl group is substituted with one or more groups selected from Cl, Br, or I), CN, and OH. In addition to the nitrogen atom, the heterocyclic alkyl group contains 0-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, or S. The heterocyclic alkyl group may be substituted with one or more groups selected from C1-C3 alkyl groups, halogens (e.g., F, Cl, Br, or I), amino groups, hydroxyl groups, and cyano groups. Two of X1, X2, X3, and X4 are N, and the other two are CRd, where Rd may be independently selected from hydrogen, halogens, cyano groups, and C1-C3 alkyl groups. In some embodiments, Ra is... R1 and R2 are independently unsubstituted C1-C5 alkyl, deuterated C1-C5 alkyl, halogenated C1-C5 alkyl, unsubstituted C3-C5 cycloalkyl, halogenated C3-C5 cycloalkyl (e.g., C3-C4 cycloalkyl), or a monocyclic 5-7 (e.g., 5-6) heterocyclic alkyl or a bridged 6-9 (e.g., 7-8) heterocyclic alkyl formed together with the attached nitrogen atom, wherein the heterocyclic alkyl contains 0-3 (e.g., 0, 1, or 2) heteroatoms selected from N, O, or S (e.g., 1 or 2 heteroatoms selected from O or S) in addition to the nitrogen atom, and the heterocyclic alkyl can be substituted with C1-C3 alkyl; X1 and X3 are N, X2 and X4 are CRd, and Rd can be independently selected from hydrogen, halogen, cyano, or C1-C3 alkyl. In some embodiments, Ra is... R1 and R2 are independently unsubstituted C1-C5 alkyl, deuterated C1-C5 alkyl, halosubstituted C1-C5 alkyl, unsubstituted C3-C5 cycloalkyl, halosubstituted C3-C5 cycloalkyl (e.g., C3-C4 cycloalkyl), or R1 and R2 together with the attached nitrogen to form a monocyclic 5-6-membered heterocyclic alkyl or a bridged 7-8-membered heterocyclic alkyl, wherein the heterocyclic alkyl contains one or two heteroatoms selected from O or S in addition to the nitrogen atom, and the heterocyclic alkyl can be substituted by a C1-C3 alkyl (e.g., R1 and R2 together with the attached nitrogen to form a group that can be substituted by a C1-C3 alkyl). X1 and X3 are N, and X2 and X4 are CH.

[0027] In some implementations, Ra is

[0028] Rc is -(C(R4R5)) 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, R4 and R5 are each independently methyl, ethyl, n-propyl, or isopropyl. 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. In some embodiments, Rc is -C(R4R5)NH2, wherein R4 and R5 are each independently H or C1-C3 alkyl groups.

[0029] Or Rc is Wherein, Cy1 is a 3-14 member, or 3-12 member, or 3-10 member alicyclic heterocycle (e.g., heterocyclic alkyl) containing the N atom shown in the figure. The N atom shown in the figure is separated from the ring atom at the connecting base (marked with "*") by 0-2 ring atoms, such as 0, 1 or 2 ring atoms.

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

[0031] Rb is absent, or Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl (e.g., containing 1-3 or 1-2 atoms selected from N, O, and S); in some embodiments, Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl; in some embodiments, Rb is selected from H, C1-C3 alkyl, or C1-C3 alkoxy. In some embodiments, Rb is substituted by one or more substituents.

[0032] Besides Rb, Cy1 can be independently substituted at any possible position by one or more R8s, which may be selected from oxygen, hydroxyl, amino, halogen, cyano, 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, or 5-8 heteroaryl; when multiple R8s are present, the R8s at different positions may be the same or different. In some embodiments, the heterocyclic alkyl or heteroaryl group contains 1-3 or 1-2 atoms selected from N, O, and S.

[0033] In some implementations, Rc is Wherein, Cy1 is a 4-10 member (e.g., 4-9 or 4-8 member) heterocyclic alkyl group containing a monocyclic, fused, spirocyclic, or bridged ring with a nitrogen atom as shown in the figure. The heterocyclic alkyl group contains 0-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, or S in addition to the nitrogen atom. The heterocyclic alkyl group may be substituted by one or more groups selected from C1-C3 alkyl, halogen (e.g., F, Cl, Br, or I), amino, hydroxyl, and cyano. Rb is absent or is H or C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), and Rb may be independently substituted by one or more groups selected from deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl.

[0034] In some implementations, Rc is Wherein, Cy1 is a monocyclic 4-8 member (e.g., 4-7 or 4-6 member) heterocyclic alkyl group containing the N atom shown in the figure, or a bridged 6-10 member (e.g., 6-9 or 6-8 member) heterocyclic alkyl group, wherein the heterocyclic alkyl group may be substituted by one or more groups selected from C1-C3 alkyl groups, halogens (e.g., F, Cl, Br, or I), Rb is absent or is H or C1-C5 alkyl group (e.g., C1-C4 alkyl group or C1-C3 alkyl group), and Rb may be independently substituted by one or more groups selected from deuterium, halogens, hydroxyl groups or C1-C3 alkoxy groups (e.g., methoxy, ethoxy or propoxy groups).

[0035] In some implementations, Rc is Wherein, Cy1 is a 4-8 member (e.g., 4-7 or 4-6 member) heterocyclic alkyl group containing a N atom as shown in the figure, the heterocyclic alkyl group may be substituted by one or more groups selected from C1-C3 alkyl, halogen (e.g., F, Cl, Br, or I), Rb is H or C1-C5 alkyl (e.g., C1-C4 alkyl or C1-C3 alkyl), and Rb may be independently substituted by one or more groups selected from deuterium, halogen, hydroxyl or C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy);

[0036] Alternatively, Cy1 is a 6-10 member (e.g., 6-9 or 6-8 member) heterocyclic alkyl group containing a bridged ring with N atoms as shown in the diagram, and Rb is absent.

[0037] In some implementations, Rc is Furthermore, Rc can optionally be replaced independently by one or more R8s at any possible position, wherein R8 is as defined above;

[0038] Where m is 0 or 1; n is 0, 1 or 2;

[0039] 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 connected to T in the diagram are directly connected by a single bond.

[0040] When L is selected from CH2 or CH2CH2, Z is -Q-(CH2). q -; q is 0, 1, 2, or 3, Q is selected from N, O, or S atoms, or Q does not exist, i.e., Z is -(CH2). q -;

[0041] When L does not exist, that is, Rc is Where Z is Q can be optionally connected to the α-carbon atom end or away from the α-carbon atom end. This represents optional ring formation, 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;

[0042] Cy does not exist, that is, Rc is Alternatively, Cy may be selected from 3-10 membered alicyclic rings, 3-10 membered heterocyclic rings (e.g., heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S), or in some embodiments, Cy may be selected from 3-6 membered alicyclic rings, 3-6 membered heterocyclic rings, and Cy may optionally be substituted by one or more groups selected from halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl groups.

[0043] G is selected from O, -OCH2, substituted or unsubstituted alkylene (e.g., C1-C6 alkylene), wherein the substituted alkylene is optionally independently substituted by one or two groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; or G is absent, i.e. the two ring atoms connected to G in the figure are directly connected by a single bond.

[0044] Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl (e.g., containing 1-3 or 1-2 atoms selected from N, O, S).

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

[0046] In some implementations, Rc is Rb, m, and n are defined as described above.

[0047] In some embodiments, Rc is selected from substituted or unsubstituted 3- to 8-membered monocyclic rings. In some embodiments, Rc may specifically be selected from N-heterocyclic butyl, pyrrolidinyl, piperidinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydroimidazolyl, pyrazolyl, piperazinyl, morpholinyl, and thiomorpholinyl; optionally, Rc is substituted with Rb and / or R8 groups, wherein Rb and R8 are as defined above.

[0048] In some implementations, Rc is L is CH2 or CH2CH2, and Z, T, Rb, m, and n are as defined above.

[0049] In some implementations, Rc is Z, T, Rb, m, n are defined as described above.

[0050] In some embodiments, Rc is a substituted or unsubstituted 7-11 quintile spiroring. In some embodiments, Rc is selected from the following structures:

[0051] 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:

[0052] In some implementations, Rc is Cy is selected from 3-6 membered alicyclic or 3-6 membered heterocyclic alicyclic compounds, and Cy is optionally substituted by one or more groups selected from halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl groups, and G, T, Rb, and m are as defined above. In some embodiments, Rc is a substituted or unsubstituted 7-10 membered fused ring. In some embodiments, Rc is selected from the following structures:

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

[0055] In some implementations, Rc is selected from the following structures:

[0056] In some implementations, Rc is selected from the following structures:

[0057] In some embodiments, Rb is H or C1-C5 alkyl (e.g., C1-C4 alkyl or C1-C3 alkyl), and Rb may be independently substituted by one or more groups selected from deuterium, halogen, hydroxyl or C1-C3 alkoxy (e.g. methoxy, ethoxy or propoxy).

[0058] In some embodiments, Rb is absent from the aforementioned Rc group. 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. Rb may also be independently substituted at any possible position by one or more groups selected from deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl. In some embodiments, Rb may also be independently substituted at any possible position by groups selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl. In some embodiments, the above-mentioned group is independently substituted at any possible position by groups selected from deuterium, F, Cl, cyano, hydroxyl, 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, deuterated methyl, deuterated ethyl, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, -CH2CH2OCH3, 2,3-dihydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Rb is H, C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), -CD3, 2-hydroxyethyl, 2-fluoroethyl, -CH2CH2OCH3, or 2,3-dihydroxypropyl.

[0059] In some embodiments, the aforementioned R8 may be selected from oxygen, hydroxyl, amino, halogen, cyano, 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 or 5-6 heteroaryl. In some embodiments, R8 is selected from oxygen, hydroxyl, amino, F, Cl, Br, I, cyano, 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, azacyclopropyl, furanyl, thiophene, pyrroleyl, phenyl, or pyridyl. In some embodiments, the aforementioned R8 may be F, Cl, Br, I, or a C1-C3 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl).

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

[0061] In formula II, Represents possible chemical bonds;

[0062] Rx and Ry 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, Rx and Ry are each independently selected from H, halogen, cyano, C1-C3 alkyl, or C1-C3 alkoxy. Optionally, Rx and Ry may be substituted at possible positions with groups selected from halogen, hydroxyl, or amino; in some specific embodiments, Rx is hydrogen, and Ry is selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, amino, methyl, methoxy, fluoromethyl, chloromethyl, or trifluoromethyl.

[0063] 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.

[0064] In some embodiments, the compounds represented by Formula I or Formula II described herein are selected from the compounds represented by Formula III or Formula IV:

[0065] in,

[0066] Y1 is either CR3 or N;

[0067] R3 can be independently selected from H, halogen, cyano or C1-C3 alkyl;

[0068] W is O or NRe, and Re is H or C1-C3 alkyl (e.g., methyl, ethyl, n-propyl or isopropyl);

[0069] v is 0 or 1;

[0070] Rc is -(C(R4R5)) p NR6R7, where p is 1 or 2, R4 and R5 are each independently methyl, ethyl, n-propyl or isopropyl, and R6 and R7 are H;

[0071] Or Rc is Wherein, Cy1 is a monocyclic 4-8 member (e.g., 4-7 or 4-6 member) heterocyclic alkyl group containing the N atom shown in the figure, or a bridged 6-10 member (e.g., 6-9 or 6-8 member) heterocyclic alkyl group, wherein the heterocyclic alkyl group may be substituted by one or more groups selected from C1-C3 alkyl groups, halogens (e.g., F, Cl, Br, or I), Rb is absent or is H or C1-C5 alkyl group (e.g., C1-C4 alkyl group or C1-C3 alkyl group), and Rb may be independently substituted by one or more groups selected from deuterium, halogens, hydroxyl groups or C1-C3 alkoxy groups (e.g., methoxy, ethoxy or propoxy groups);

[0072] Ra is R1 and R2 are independently unsubstituted C1-C5 alkyl, deuterated C1-C5 alkyl, halogenated C1-C5 alkyl, unsubstituted C3-C5 cycloalkyl, halogenated C3-C5 cycloalkyl (e.g., C3-C4 cycloalkyl), or R1 and R2 together with the attached nitrogen to form a monocyclic 5-7 member (e.g., 5-6 member) heterocyclic alkyl or a bridged 6-9 member (e.g., 7-8 member) heterocyclic alkyl, wherein the heterocyclic alkyl contains, in addition to the nitrogen atom, 1-3 (e.g., 1 or 2) heteroatoms selected from N, O, or S (e.g., 1 or 2 heteroatoms selected from O or S), and the heterocyclic alkyl can be substituted with C1-C3 alkyl; X1 and X3 are N, X2 and X4 are CRd, and Rd can be independently selected from hydrogen, halogen, cyano, or C1-C3 alkyl;

[0073] Rx is H or a C1-C6 alkyl group;

[0074] Preferably,

[0075] Y1 is either CR3 or N;

[0076] R3 is H, F, Cl, Br, or cyano;

[0077] When W is O, v is 0 or 1; when W is NRe, v is 0, and Re is H or C1-C3 alkyl (e.g., methyl, ethyl, n-propyl or isopropyl);

[0078] Rc is -C(R4R5)NH2, where R4 and R5 are each independently H or C1-C3 alkyl;

[0079] Alternatively, Rc may be selected from the following structures:

[0080] Rb is H or C1-C5 alkyl (e.g., C1-C4 alkyl or C1-C3 alkyl), and Rb may be independently substituted by one or more groups selected from deuterium, halogen, hydroxyl or C1-C3 alkoxy (e.g. methoxy, ethoxy or propoxy);

[0081] Ra is R1 and R2 are independently unsubstituted C1-C5 alkyl, deuterated C1-C5 alkyl, halosubstituted C1-C5 alkyl, unsubstituted C3-C5 cycloalkyl, halosubstituted C3-C5 cycloalkyl (e.g., C3-C4 cycloalkyl), or R1 and R2 together with the attached nitrogen to form a monocyclic 5-6-membered heterocyclic alkyl or a bridged 7-8-membered heterocyclic alkyl, wherein the heterocyclic alkyl contains one or two heteroatoms selected from O or S in addition to the nitrogen atom, and the heterocyclic alkyl can be substituted by a C1-C3 alkyl (e.g., R1 and R2 together with the attached nitrogen to form a group that can be substituted by a C1-C3 alkyl). X1 and X3 are N, X2 and X4 are CH; preferably, Ra is

[0082] Rx is H or C1-C5 alkyl (e.g., C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl).

[0083] This disclosure provides the following compounds, their pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof:

[0084] This disclosure further 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.

[0085] This disclosure also provides the use of any of the foregoing compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof, or the foregoing pharmaceutical compositions in the preparation of medicaments for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions. Alternatively, this disclosure provides any of the foregoing compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof, or the foregoing pharmaceutical compositions, for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions. Alternatively, this disclosure provides a method for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions in a subject in need, comprising administering to the subject a therapeutically effective amount of any of the foregoing compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof, or the foregoing pharmaceutical compositions. Alternatively, this disclosure provides the use of any of the foregoing compounds, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof, or the foregoing pharmaceutical compositions, for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions.

[0086] The therapeutically effective dose can be determined by a clinician based on the patient's age, weight, sex, general health status, family history, disease severity, route of administration, etc. The compounds disclosed herein, their pharmaceutically acceptable salts, hydrates, isomers, prodrugs, mixtures thereof, or pharmaceutical compositions may be administered via any conventional route known in the art, including but not limited to oral, parenteral, intramuscular, subcutaneous, and intraperitoneal administration.

[0087] In this disclosure, diseases associated with Menin-MLL protein interactions include malignant tumors, diabetes, or complications related to said diseases. Malignant tumors include hematologic malignancies, lymphomas, and solid tumors.

[0088] Hematologic malignancies include leukemia and myeloma, preferably including, but not limited to, acute lymphoblastic leukemia, chronic lymphoblastic 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 lymphoblastic leukemia, large granular lymphoblastic leukemia, meningeal leukemia, myelodysplastic syndrome, myeloproliferative disorders, myeloproliferative neoplasm formation, plasmacytoma, and multiple myeloma.

[0089] Lymphomas include, but are not limited to, cutaneous T-cell lymphoma, lymphoid tumor, AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or malignant lymphoma.

[0090] 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.

[0091] The related complications include, but are not limited to, leukemic meningitis.

[0092] Experiments have demonstrated that the Menin-MLL protein inhibitor disclosed herein possesses excellent in vitro enzyme inhibitory activity and cell proliferation inhibitory activity. In particular, compared with existing compounds, it exhibits superior activity in inhibiting the interaction between Menin mutant proteins (especially M327I and T349M point mutant proteins) and MLL proteins, thus showing promising potential for resistance to drug resistance. Detailed Implementation

[0093] The technical solutions in the embodiments of this disclosure will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of this disclosure, and not all of them. Based on the embodiments in this disclosure, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this disclosure.

[0094] Definitions and General Descriptions

[0095] 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.

[0096] This indicates the connection position of the group with other structures.

[0097] This indicates that the part forms a ring with the connected atoms.

[0098] 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... R represents 30 R 40 On the same side of the ring, R represents 30 R 40 On both sides of the ring.

[0099] “(±)” indicates a racemic mixture.

[0100] Unless otherwise specified, "substitution" means that a hydrogen atom in a molecule is replaced by another different atom or group.

[0101] "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.

[0102] The term "independently" means that when one or more substituents are selected from many possible groups, the groups corresponding to these substituents may be the same or different each time they appear.

[0103] "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. For example, C1-C6 alkyl groups represent saturated hydrocarbon groups containing 1-6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, or any range of two of the aforementioned values). 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.

[0104] "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-.

[0105] "Cycloalkyl" refers to an aliphatic cyclic group with a saturated carbon atom as its backbone. It can be monocyclic, spirocyclic, fused, or bridged. For example, a 3- to 10-membered cycloalkyl group refers to a cyclic group composed of 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values) saturated carbon atoms. Common cycloalkyl groups include, but are not limited to, those listed below. wait.

[0106] "Heteroatoms" refer to non-carbon atoms in the skeleton atoms of a carbon chain or ring. Typical heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S).

[0107] "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.

[0108] "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. For example, 3- to 10-membered alicyclic hydrocarbons refer to aliphatic cyclic groups composed of 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values) skeletal carbon atoms. Specifically, this includes cyclic alkanes or alkenes, with the corresponding groups being cycloalkyl or cycloalkenyl groups. Examples include, but are 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.

[0109] "Alicyclic heterocycles" refer to non-aromatic cyclic hydrocarbons whose skeletal atoms contain one or more (e.g., 1-4, 1-3, or 1-2) heteroatoms. These include saturated or unsaturated monocyclic, bicyclic, or polycyclic systems, such as fused 2, 3, or 4-rings, bridged rings, or spirocyclic rings. For example, 3- to 10-membered alicyclic heterocycles refer to non-aromatic aliphatic cyclic groups containing one or more heteroatoms and consisting of 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values) skeletal atoms. The heteroatoms are selected from nitrogen, oxygen, and sulfur, while the remaining ring atoms are carbon. The corresponding groups for saturated alicyclic heterocycles are heterocyclic alkyl groups, including but not limited to: azirrobutyl, oxadiol, pyrrolinyl, pyrrolylyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 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.

[0110] "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group (e.g., having 2, 3, or 4 fused rings). For example, a 5- to 14-membered aryl group refers to an aromatic hydrocarbon group composed of 5 to 14 skeletal carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or any range of two of the aforementioned values). Typical aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and phenanthrene.

[0111] "Heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle (e.g., having 2, 3, or 4 fused rings), an aromatic ring having one or more (e.g., 1-4, 1-3, or 1-2) heteroatoms selected from N, S, and O. For example, a 5- to 14-membered heteroaryl refers to an aromatic cyclic group containing one or more of the aforementioned heteroatoms, consisting of 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or any range of two of the aforementioned values) skeletal atoms. Typical heteroaryl groups include, but are not limited to, pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophene, benzofuranyl, benzothiophene, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophene, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxoxazolyl, etc.

[0112] "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.

[0113] "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.

[0114] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0115] “Cyanogen” refers to CN.

[0116] "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 disclosure. 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.

[0117] "Deuterated alkyl" means that an alkyl group is replaced by one or more deuterium atoms, wherein the alkyl group has the meaning described in this disclosure. Deuterated alkyl includes, but is not limited to, deuterated methyl (e.g., -CD3) and deuterated ethyl.

[0118] "Alkoxy" refers to -O-alkyl, where alkyl has the meaning described in this disclosure. For example, C1-C6 alkoxy refers to a straight-chain or branched alkoxy consisting 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 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, p-pentoxy, and n-hexoxy. "Amino" used alone or in combination with other terms refers to the -NH2 group.

[0119] "Aminoalkyl" means that an alkyl group is substituted with one or more amino groups, wherein the alkyl group has the meaning described in this disclosure. For example, C1-C6 aminoalkyl means a C1-C6 alkyl group substituted with one or more amino groups. Aminoalkyl includes, but is not limited to, aminomethyl and 2-aminoethyl.

[0120] "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.

[0121] "Hydroxy" refers to -OH.

[0122] "Oxygen substitution" means =O.

[0123] The disclosed compounds 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 disclosed compounds can exist in natural or non-natural abundance. Examples of hydrogen isotopes include deuterium and tritium. In some embodiments, the disclosed compounds 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 disclosed compounds are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art.

[0124] 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.

[0125] "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.

[0126] "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.

[0127] "Optional" means that the events or circumstances described below are free to be chosen or not chosen, including whether the events or circumstances described below exist or not.

[0128] "Hydrate" refers to an aggregate of compounds disclosed herein containing one or more water molecules, including hemihydrates, monohydrates, dihydrates, trihydrates, etc.

[0129] "Isomer" refers to the fact that, when the compounds of this disclosure contain one or more asymmetric centers, they can exist as racemic mixtures and racemic mixtures, as well as as single enantiomers, mixtures of diastereomers, and single diastereomers. The compounds of this disclosure may have asymmetric centers, resulting in two optical isomers. The scope of this disclosure includes all possible optical isomers and mixtures thereof. If the compounds of this disclosure contain an alkene double bond, the scope of this disclosure includes cis and trans isomers unless otherwise specified. The compounds of this disclosure may 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 this disclosure. All enantiomers, diastereomers, racemates, meso-racemates, cis-trans isomers, stereoisomers, tautomers, geometric isomers, epimers, and mixtures thereof are within the scope of this disclosure.

[0130] "Prodrug" refers to a derivative compound that, upon administration to an individual, can directly or indirectly provide the compounds of this disclosure. Particularly preferred derivative compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of this disclosure (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 this disclosure are within the scope of this disclosure, and various prodrug forms are known in the art, see, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, this disclosure also covers compounds of this disclosure containing a protecting group. In any process of preparing the compounds of this disclosure, 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 this disclosure. This can be achieved using conventional protecting groups, such as those described in TWGreene, PGMWuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0131] "Pharmaceutical composition" refers to a formulation of the disclosed compound with a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable excipients / carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0132] "Pharmaceutical acceptable" means a substance, such as a carrier, diluent, or excipient, that does not affect the biological activity or properties of the disclosed compound and is relatively non-toxic, meaning that the substance can be administered to an individual without causing an adverse biological reaction or interacting with any component contained in the composition in an undesirable manner. For example, "excipients" include, but are not limited to, any adjuvants, carriers, 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 governmental regulatory authorities to be acceptable for human or animal use.

[0133] "Pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0134] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0135] Unless otherwise stated, all figures used herein to represent amounts of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0136] Unless the context clearly indicates otherwise, singular terms in this document cover the plural referents, and vice versa.

[0137] The term “subject” is used interchangeably with “patient” and “individual” and refers to a human or a non-human animal (e.g., a mammal, such as a non-human primate, rodent, etc.), such as a mouse, rat, cat, dog, pig, sheep, cow, goat, horse, rabbit, and monkey.

[0138] This disclosure also provides methods for synthesizing the above-mentioned compounds. The methods for synthesizing the compounds disclosed herein are mainly based on preparation methods reported in chemical literature or using commercially available chemical reagents as starting materials.

[0139] Abbreviations: PhLi represents phenyl lithium; s-BuLi represents sec-butyl lithium; TMEDA represents N,N,N',N'-tetramethylethylenediamine; CbzCl represents benzyl chloroformate; MsCl represents methanesulfonyl chloride; TEA represents triethylamine; DMAP represents 4-dimethylaminopyridine; DCM represents dichloromethane; THF represents tetrahydrofuran; ACN represents acetonitrile; DMF represents N,N-dimethylformamide; AcOH represents glacial acetic acid; TsOH represents p-toluenesulfonic acid; EtOH represents ethanol; DMSO represents dimethyl sulfoxide; TFA represents trifluoroacetic acid; DIEA NaBH4 represents ethyl diisopropylamine; NaBH3CN represents sodium borohydride; Cs2CO3 represents cesium carbonate; Na2CO3 represents sodium carbonate; Pd(OAc)2 represents palladium acetate; Dppb represents 1,4-bis(diphenylphosphine)butane; X-Phos represents 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; X-PhosG2 represents chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) MnO2 represents manganese dioxide; Pd2(dba)3 represents tris(dibenzylindeneacetone)palladium dichloride; LiAlH4 represents lithium aluminum hydride; SOCl2 represents sulfoxide; RuCl3 represents ruthenium trichloride; NaIO4 represents sodium periodate; CMBP represents cyanomethylene tri-n-butylphosphine; DEAD represents diethyl azodicarboxylate; PPh3 represents triphenylphosphine; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole; DCC represents N,N'-dicyclohexylcarbodiimide; CS2 represents carbon disulfide; BBr3 represents boron tribromide; NBS represents N-bromosuccinimide; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride(II). TFAA represents trifluoroacetic anhydride; PtO2 represents platinum dioxide; mCPBA represents m-chloroperoxybenzoic acid; DIAD represents diisopropyl azodicarbonate; NaBH(OAc)3 represents sodium triacetoxyborohydride.

[0140] Preparation Example 1: Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester

[0141] Step 1: Preparation of tert-butyl 3-(1-azabicyclo[1.1.0]but-3-yl)-3-hydroxyazacyclobutane-1-carboxylic acid

[0142] 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 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, and concentrated to obtain the title compound, which was directly used in the next step of the reaction.

[0143] Step 2: Preparation of 1-benzyl 1'-(tert-butyl)3'-hydroxy-3-iodo-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid

[0144] 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 silica gel column chromatography to give 4.58 g of the title compound. MS (ESI) m / z (M+H-100) + =389.1

[0145] Step 3: Preparation of 1-benzyl 1'-(tert-butyl)3-iodo-3'-((methanesulfonyl)oxy)-[3,3'-bis(azetane)-1,1'-dicarboxylic acid

[0146] 1-Benzyl-1'-(tert-butyl)3'-hydroxy-3-iodo-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid (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 silica gel column chromatography to give 1.82 g of the title compound. MS (ESI) m / z (M+H-100) + =467.1.

[0147] Step 4: Preparation of 1-benzyl 1'-(tert-butyl)2H,2'H-[3,3'-diazamethylene]-1,1'(4H,4'H)-dicarboxylic acid

[0148] 1-Benzyl-1'-(tert-butyl)3-iodo-3'-((methanesulfonyl)oxy)-[3,3'-diazacyclobutane]-1,1'-dicarboxylic acid (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 solution was purified by silica gel column chromatography to obtain 980 mg of the title compound. MS (ESI) m / z (M+H-100) + =245.2. 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).

[0149] Step 5: Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid ester

[0150] 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 sample was purified by silica gel column chromatography to give 1.16 g of the title compound, p-toluenesulfonate. MS (ESI) m / z (M+H) + =245.1.

[0151] 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

[0152] 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

[0153] 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 purified by silica gel column chromatography to give 15.14 g of the title compound. MS (ESI) m / z (M+H) + =392.2.

[0154] 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

[0155] 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 and dried to give 6.51 g of the title compound.

[0156] MS(ESI)m / z(M+H) + =388.1.

[0157] 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

[0158] 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, 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. MS (ESI) m / z (M+H) + =547.2. 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

[0159] 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 silica gel column chromatography to give 2.41 g of the title compound. MS (ESI) m / z (M+H) + =413.2.

[0160] Preparation Example 3: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-methoxybenzamide

[0161] Step 1: Preparation of 2-(benzyloxy)-5-fluoro-N-hydroxy-N-isopropylbenzamide

[0162] 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 addition was complete, the mixture was allowed to react at room temperature for 2 hours, and then concentrated to obtain a crude product. 20 mL of dichloromethane was added to the crude product, followed by triethylamine (1.7 g, 17.07 mmol) and N-isopropylhydroxylamine hydrochloride (637 mg, 5.69 mmol) in sequence. After the addition was complete, the mixture was allowed to react at room temperature overnight. LC-MS showed that the starting material was completely consumed. 100 mL of water was added to the reaction 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 silica gel column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to obtain 900 mg of the title compound.

[0163] MS(ESI)m / z(M+H) + =304.1.

[0164] Step 2: Preparation of 2-(benzyloxy)-5-fluoro-N-isopropyl-N-methoxybenzamide

[0165] 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 reaction 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 silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 (V:V)) to give 450 mg of the title compound.

[0166] MS(ESI)m / z(M+H) + =318.1.

[0167] Step 3: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-methoxybenzamide

[0168] 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 silica gel column chromatography (dichloromethane / methanol = 20 / 1 (V:V)) to give 280 mg of the title compound.

[0169] MS(ESI)m / z(M+H) + =228.1.

[0170] Preparation Example 4: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-(trifluoromethyl)benzamide

[0171] Step 1: Preparation of isopropylaminodithioethyl ester

[0172] At room temperature, isopropylamine (4.4 g, 75.0 mmol) and dichloromethane (10 mL) were added to a reaction flask and stirred until homogeneous. Iodoethane (5.9 g, 37.5 mmol) and carbon disulfide (5.7 g, 75.0 mmol) were then added sequentially, and the mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until complete. The solution was evaporated to dryness and purified by silica gel column chromatography to give 5.8 g of the title compound. MS (ESI) m / z (M+H) + =164.1.

[0173] Step 2: Preparation of ethyl (5-fluoro-2-methoxybenzoyl)(isopropyl)aminodithioate

[0174] At room temperature, isopropyl aminodithioethyl 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 sample was purified by silica gel column chromatography to give 4.0 g of the title compound. MS (ESI) m / z (M+H) + =316.2.

[0175] Step 3: Preparation of 5-fluoro-N-isopropyl-2-methoxy-N-(trifluoromethyl)benzamide

[0176] 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 LCMS 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 silica gel column chromatography to give 871 mg of the title compound.

[0177] MS(ESI)m / z(M+H) + =280.2.

[0178] Step 4: Preparation of 5-fluoro-2-hydroxy-N-isopropyl-N-(trifluoromethyl)benzamide

[0179] 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 silica gel column chromatography to obtain 791 mg of the title compound.

[0180] MS(ESI)m / z(M+H) + =266.2.

[0181] Preparation Example 5: Preparation of N-(ethyl-d5)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0182] Step 1: Preparation of 5-fluoro-N-isopropyl-2-methoxybenzamide

[0183] 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 thoroughly. 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 the crude title compound, which was directly used in the next reaction. MS (ESI) m / z (M+H) + =212.1.

[0184] Step 2: Preparation of N-(ethyl-d5)-5-fluoro-N-isopropyl-2-methoxybenzamide

[0185] 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. Then, 1-iodoethane-1,1,2,2,2-d5 (548.7 mg, 3.4 mmol) was added, and the reaction was continued at room temperature for another 30 minutes 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 silica gel column chromatography to give 690 mg of the title compound. MS (ESI) m / z (M+H) + =245.2.

[0186] Step 3: Preparation of N-(ethyl-d5)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0187] 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 reaction. After 2 hours, the reaction was monitored by LC-MS to ensure complete reaction, and then 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 silica gel column chromatography to give 604 mg of the title compound. MS (ESI) m / z (M+H) + =231.2.

[0188] Preparation Example 6: 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

[0189] Step 1: Preparation of (3-oxa-8-azabicyclo[3.2.1]octane-8-yl)(5-fluoro-2-hydroxyphenyl) methyl ketone

[0190] 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.

[0191] MS(ESI)m / z(M+H) + =252.1.

[0192] 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

[0193] 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 reversed-phase column chromatography to obtain 1.2 g of the title compound. MS (ESI) m / z (M+H) + =573.2.

[0194] 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

[0195] 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 complete as shown by LC-MS, the system was concentrated to obtain a crude product. The pH was adjusted to alkaline with sodium bicarbonate, and the product was purified by reverse-phase column chromatography and lyophilized to obtain 0.9 g of the title compound. MS (ESI) m / z (M+H) + =439.1.

[0196] Using commercial reagents or compounds prepared in the preparation examples as raw materials, the following preparation example compounds were obtained by referring to the aforementioned preparation example methods.

[0197] Table 1 Intermediate Compounds

[0198] Preparation Example 14: Preparation of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol

[0199] 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 silica gel column chromatography to obtain 1.35 g of the title compound. MS (ESI) m / z (M+H) + =231.2.

[0200] 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

[0201] 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

[0202] 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 reaction was 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.

[0203] MS(ESI)m / z(M+H) + =552.2.

[0204] 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

[0205] 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 for 1 hour. The reaction was confirmed to be complete by LC-MS. After concentration under reduced pressure, the mixture was purified by alkaline silica gel column chromatography and freeze-dried to give 234 mg of the title compound. MS (ESI) m / z (M+H) + =418.2.

[0206] Preparation Example 16: Preparation of 4-fluoro-3-((1-methylpyrrolidone-3-yl)oxy)benzaldehyde

[0207] 4-Fluoro-3-hydroxybenzaldehyde (250.0 mg, 1.78 mmol) and 1-methylpyrrolidone-3-ol (180.0 mg, 1.78 mmol) were dissolved in tetrahydrofuran (5 mL). Triphenylphosphine (161.3 mg, 0.61 mmol) was added at room temperature, followed by the slow dropwise addition of diethyl azodicarbonate (85.6 mg, 0.49 mmol). 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 then purified by preparative HPLC to give 150.0 mg of the title compound.

[0208] MS(ESI)m / z(M+H) + =224.2.

[0209] Referring to the synthetic method of Preparation Example 16, using commercial reagents and / or intermediates prepared according to the methods described herein as raw materials, the following intermediate compounds can be prepared, as shown in Table 2.

[0210] Table 2 Intermediate Compounds

[0211] Preparation Example 26: Preparation of tert-butyl 3-(2-fluoro-5-formylphenoxy)azacyclobutane-1-carboxylate

[0212] At room temperature, 150 mg (1.1 mmol) of 4-fluoro-3-hydroxybenzaldehyde, 221.8 mg (1.6 mmol) of potassium carbonate, and 10 mL of N,N-dimethylformamide were added to a reaction flask. After stirring for 10 minutes, 363.5 mg (1.3 mmol) of tert-butyl 3-iodoazacyclobutane-1-carboxylate was added, and the mixture was reacted at 80 °C for 4 hours. After the reaction was monitored by LCMS until complete, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 300 mg of the title compound. MS (ESI) m / z (M+H) + =296.2.

[0213] Preparation Example 27: Preparation of N-(1-(2-fluoro-5-formylphenoxy)-2-methylpropyl-2-yl)carbamate tert-butyl

[0214] Step 1: Preparation of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid 2-oxide

[0215] Thionyl chloride (1.76 g, 14.78 mmol) and acetonitrile (10 mL) were added sequentially to a reaction flask. N-(1-hydroxy-2-methylprop-2-yl)carbamate tert-butyl ester (1.0 g, 5.28 mmol) was added at -40 °C. After thorough stirring, pyridine (2.0 g, 25.34 mmol) was added. The reaction system was reacted at room temperature for 2 hours. After 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 0.8 g of the title compound. MS (ESI) m / z (M-56+H) + =179.9.

[0216] Step 2: Preparation of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid 2,2-dioxide

[0217] 4,4-Dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid 2-oxide tert-butyl ester (800 mg, 3.40 mmol) and ruthenium trichloride hydrate (0.077 g, 0.34 mmol) were added sequentially to a reaction flask. After purging with nitrogen three times, acetonitrile (10 mL) was added, followed by a solution of sodium periodate (5 g, 23.38 mmol) in water (10 mL) at 0 °C. The reaction was carried out 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 give 600 mg of the title compound. MS (ESI) m / z (M-56+H) + =196.1.

[0218] Step 3: Preparation of N-(1-(2-fluoro-5-formylphenoxy)-2-methylpropyl-2-yl)tert-butyl carbamate

[0219] 4-Fluoro-3-hydroxybenzaldehyde (200 mg, 1.43 mmol), 4,4-dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid 2,2-dioxide tert-butyl ester (0.54 g, 2.15 mmol), and potassium carbonate (0.40 g, 2.86 mmol) were added sequentially to a reaction flask, followed by N,N-dimethylformamide (5 mL). After stirring thoroughly, the reaction mixture was reacted overnight at 70 °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 400 mg of the title compound. MS (ESI) m / z (M-56+H) + =256.2.

[0220] Preparation Example 28: Preparation of tert-butyl cis-3-(2-fluoro-5-formylphenoxy)-4-methylpiperidine-1-carboxylate

[0221] Step 1: Preparation of trans-4-methyl-3-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0222] At 0 °C, tert-butyl trans-3-hydroxy-4-methylhexahydropyridine-1-carboxylate (250.0 mg, 2.2 mmol) and triethylamine (0.4 g, 4.3 mmol) were dissolved in dichloromethane (10 mL). Methylsulfonyl chloride (250.0 mg, 2.2 mmol) was slowly added dropwise to the system while maintaining the temperature at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 2 hours. The reaction was monitored by LC-MS until complete. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and evaporated to dryness to give 400.0 mg of the title compound. MS (ESI) m / z (M+H) + =294.2.

[0223] Step 2: Preparation of tert-butyl cis-3-(2-fluoro-5-formylphenoxy)-4-methylpiperidine-1-carboxylate

[0224] The starting materials trans-4-methyl-3-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (300.0 mg, 1.0 mmol) and 4-fluoro-3-hydroxybenzaldehyde (140.0 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of cesium carbonate (660.0 mg, 2.0 mmol). After the addition was complete, the mixture was heated to 80 °C under nitrogen protection and reacted for 12 hours. After the reaction was monitored by LCMS until complete, the mixture was cooled to room temperature, water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, concentrated, and purified by silica gel column chromatography to give 200 mg of the title compound. MS (ESI) m / z (M+H) + =338.2.

[0225] Preparation Example 29: Preparation of (3R)-3-(5-bromo-2,4-difluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0226] At room temperature, 5-bromo-2,4-difluorophenol (500 mg, 2.4 mmol) and toluene (20 mL) were added to a reaction flask and stirred until homogeneous. Cyanomethylenetri-n-butylphosphine (865.2 mg, 3.6 mmol) was then added, and the mixture was heated to 120 °C and reacted for 3 hours. The reaction was monitored by LC-MS to ensure complete reaction, yielding the title compound. MS (ESI) m / z (M+H) + =392.3.

[0227] Preparation Example 30: Preparation of (R)-2,4-difluoro-5-((1-methylpiperidin-3-yl)oxy)benzaldehyde

[0228] Step 1: Preparation of (3R)-3-(5-bromo-2,4-difluorophenoxy)piperidine

[0229] At room temperature, 545 mg (1.4 mmol) of (3R)-3-(5-bromo-2,4-difluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 20 mL of dichloromethane and 6 mL of trifluoroacetic acid. The mixture was heated to 40 °C and reacted for half an hour. The reaction was monitored by LC-MS until complete. The solvent was removed by rotary evaporation, and a small amount of methanol was added. The pH was adjusted to weakly alkaline with sodium bicarbonate solution, and the solvent was removed by rotary evaporation again to obtain 405 mg of the title compound, which was directly used in the next reaction. MS (ESI) m / z (M+H) + =292.1.

[0230] Step 2: Preparation of (3R)-3-(5-bromo-2,4-difluorophenoxy)-1-methylpiperidine

[0231] At room temperature, (3R)-3-(5-bromo-2,4-difluorophenoxy)piperidine (405 mg, 1.4 mmol), paraformaldehyde (83.5 mg, 2.8 mmol), sodium methoxide (135.2 mg, 2.5 mmol), and methanol (20 mL) were added to a reaction flask and stirred for 30 minutes. Then, sodium cyanoborohydride (174.7 mg, 2.8 mmol) was added, and the reaction was continued at room temperature for another 20 minutes. The reaction was monitored by LCMS until complete. The mixture was quenched with water, evaporated to dryness, and purified by silica gel column chromatography to give 424 mg of the title compound. MS (ESI) m / z (M+H) + =306.2.

[0232] Step 3: Preparation of (R)-(2,4-difluoro-5-((1-methylpiperidin-3-yl)oxy)phenyl)methanol

[0233] At room temperature, (3R)-3-(5-bromo-2,4-difluorophenoxy)-1-methylpiperidine (205 mg, 0.7 mmol), tributyltin methanol (322.7 mg, 1.0 mmol), chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (52.8 mg, 0.07 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask, purged with nitrogen, stirred until homogeneous, and slowly heated to 90 °C for 3 hours. The reaction was monitored by LCMS until complete. The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, evaporated to dryness, and purified by silica gel column chromatography to give 165 mg of the title compound.

[0234] MS(ESI)m / z(M+H) + =258.2.

[0235] Step 4: Preparation of (R)-2,4-difluoro-5-((1-methylpiperidin-3-yl)oxy)benzaldehyde

[0236] At room temperature, (R)-(2,4-difluoro-5-((1-methylpiperidin-3-yl)oxy)phenyl)methanol (165 mg, 0.6 mmol) and dichloromethane (15 mL) were added to a reaction flask, followed by manganese dioxide (166.9 mg, 1.9 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until complete. The mixture was filtered and evaporated to dryness to give 85 mg of the title compound. MS (ESI) m / z (M+H) + =256.2.

[0237] Preparation Examples 31 and 32: Preparation of (R)-3-(2-chloro-5-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (31) and (R)-3-(3-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (32)

[0238] Step 1: Preparation of (R)-3-(5-bromo-2-chlorophenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0239] At room temperature, 5-bromo-2-chlorophenol (1.0 g, 4.8 mmol) and (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (1.0 g, 4.9 mmol) were dissolved in toluene (15 mL), followed by the dropwise addition of cyanomethylenetri-n-butylphosphine (1.5 g, 1.7 mmol). After the addition was complete, the mixture was heated to 80 °C and reacted for 12 hours. The reaction was monitored by LC-MS to ensure completeness. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and evaporated to dryness. The purified solution was then purified by silica gel column chromatography to give 1.0 g of the title compound. MS (ESI) m / z (M+H)+ =390.1.

[0240] Step 2: Preparation of (R)-3-(2-chloro-5-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (31) and (R)-3-(3-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (32)

[0241] The starting materials (R)-3-(5-bromo-2-chlorophenoxy)piperidine-1-carboxylic acid tert-butyl ester (300.0 mg, 0.7 mmol) and N-formylsaccharin (240.0 mg, 1.2 mmol) were dissolved in DMF (10 mL). Then, sodium carbonate (120.0 mg, 1.2 mmol), palladium acetate catalyst (10.0 mg, 0.05 mmol), and 1,4-bis(diphenylphosphine)butane (39.0 mg, 0.1 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 (120.0 mg, 1.0 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 system, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, concentrated, and purified by silica gel column chromatography to obtain 150.0 mg and 100 mg of the title compounds 31 and 32, respectively. Preparation Example 31: MS (ESI) m / z (M+H) + =340.1. Preparation Example 32: MS(ESI) m / z(M+H) + =306.2.

[0242] Preparation Example 33: Preparation of (R)-3-((3-fluoro-6-formylpyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0243] Step 1: Preparation of (R)-3-((6-bromo-3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0244] 6-Bromo-2-chloro-3-fluoropyridine (600 mg, 2.87 mmol) and (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (577 mg, 2.87 mmol) were weighed and dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (466 mg, 1.44 mmol) was added at room temperature. After the addition was complete, the reaction system was reacted at 100 °C for 8 hours. After the reaction was complete as shown by LC-MS, 100 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 silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 240 mg of the title compound. MS (ESI) m / z (M+H)+ =375.1.

[0245] Step 2: Preparation of (R)-3-((3-fluoro-6-formylpyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0246] Weigh out (R)-3-((6-bromo-3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.40 mmol), N-formylsaccharin (127 mg, 0.60 mmol), triethylsilane (60 mg, 0.52 mmol), palladium acetate (14 mg, 0.06 mmol), 1,4-bis(diphenylphosphine)butane (51 mg, 0.12 mmol), and sodium carbonate (64 mg, 0.60 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 the reaction is complete as indicated by LCMS, add 100 mL of water to the mixture, 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. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to give 30 mg of the title compound. MS(ESI)m / z(M+H) + =325.1.

[0247] Preparation Example 34: Preparation of (3R)-3-[(3-fluoro-6-formylpyridin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0248] Step 1: Preparation of 6-chloro-5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide

[0249] At room temperature, pyridine (20 mL), 6-chloro-5-fluoropyridine-2-carboxylic acid (1.0 g, 5.7 mmol), methoxy(methyl)amine hydrochloride (670 mg, 6.8 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol) were added to a reaction flask. The reaction was carried out at 50 °C for one hour. The reaction was monitored by LC-MS until complete. The solution was evaporated to dryness and purified by silica gel column chromatography to give 1.1 g of the title compound. MS (ESI) m / z (M+H) + =219.2.

[0250] Step 2: Preparation of (3R)-3-[(3-fluoro-6-(methoxy(methyl)carbamoyl)pyridin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0251] At room temperature, 6-chloro-5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide (976 mg, 4.5 mmol), (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 6.7 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (106.3 mg, 0.2 mmol), tris(dibenzylacetone)dipalladium (122.5 mg, 0.1 mmol), cesium carbonate (2.9 g, 8.9 mmol), and 1,4-dioxane (8 mL) were added to a reaction flask, purged with nitrogen, and slowly heated to 100 °C overnight. The reaction was stopped by LC-MS monitoring. After cooling to room temperature, the solution was evaporated to dryness and purified by silica gel column chromatography to give 120 mg of the title compound. MS (ESI) m / z (M+H) + =383.2.

[0252] Step 3: Preparation of (3R)-3-[(3-fluoro-6-formylpyridin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0253] At room temperature, (3R)-3-[(3-fluoro-6-(methoxy(methyl)carbamoyl)pyridin-2-yl)amino]piperidin-1-carboxylic acid tert-butyl ester (120 mg, 0.3 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask and stirred until homogeneous. Lithium aluminum hydride (11.8 mg, 0.3 mmol) was slowly added, and the reaction was continued for half an hour. The reaction was monitored by LC-MS until complete. A dilute sodium hydroxide solution was added, the mixture was filtered, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 41 mg of the title compound. MS (ESI) m / z (M+H) + =324.3.

[0254] Preparation Example 35: Preparation of (R)-3-(2-cyano-5-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0255] Step 1: Preparation of (R)-3-(5-bromo-2-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0256] 4-Bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) and (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.52 g, 7.57 mmol) were weighed and dissolved in tetrahydrofuran (20 mL). Triphenylphosphine (1.99 g, 7.57 mmol) was added under ice bath conditions, followed by the dropwise addition of diethyl azodicarbonate (1.32 g, 7.57 mmol). The mixture was then purged with nitrogen and stirred at room temperature for 1 hour. After LC-MS analysis showed that the reaction was complete, the system was concentrated and purified by silica gel column chromatography to give 946 mg of the title compound.

[0257] MS(ESI)m / z(M+H) + =381.1.

[0258] Step 2: Preparation of (R)-3-(2-cyano-5-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0259] (R)-3-(5-bromo-2-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1 mmol) and N-formylsaccharin (0.32 g, 0.99 mmol) were dissolved in N,N-dimethylformamide (10 mL). Palladium acetate (0.013 g, 0.06 mmol), 1,4-bis(diphenylphosphine)butane (0.039 g, 0.09 mmol), triethylsilane (0.15 g, 1.3 mmol), and sodium carbonate (0.16 g, 1.5 mmol) were added, and the mixture was reacted at 80 °C for 12 hours. LC-MS showed the reaction was complete. The mixture was then extracted three times with ethyl acetate, the organic phase was dried and concentrated, and purified by silica gel column chromatography to obtain 0.124 g of the title compound.

[0260] MS(ESI)m / z(M+H) + =331.1.

[0261] Preparation Example 36: Preparation of (3R)-3-[(2-fluoro-5-formylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0262] Step 1: Preparation of (3R)-3-[(2-fluoro-5-(methoxycarbonyl)phenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0263] At room temperature, methyl 3-bromo-4-fluorobenzoate (300 mg, 1.3 mmol), (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (387.5 mg, 1.9 mmol), tris(dibenzylacetone)palladium (59 mg, 0.07 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (61 mg, 0.1 mmol), cesium carbonate (840.6 mg, 2.6 mmol), and 1,4-dioxane (15 mL) were added to a reaction flask, purged with nitrogen, and slowly heated to 100 °C. The reaction was allowed to proceed overnight. The reaction was monitored by LCMS until complete. After cooling to room temperature, the solution was evaporated to dryness and purified by silica gel column chromatography to obtain 330 mg of the title compound.

[0264] MS(ESI)m / z(M+H) + =382.2.

[0265] Step 2: Preparation of (3R)-3-[(2-fluoro-5-formylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0266] Under ice bath conditions, (3R)-3-[(2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (330 mg, 0.9 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask and stirred until homogeneous. Lithium aluminum hydride (33.0 mg, 0.9 mmol) was slowly added, and the reaction was continued under ice bath conditions for another 30 minutes. The reaction was monitored by LC-MS until complete. Sodium hydroxide solution was added, the mixture was filtered, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 125 mg of the title compound. MS (ESI) m / z (M+H) + =323.2.

[0267] Preparation Example 37: Preparation of (3R)-3-[(2-cyano-5-formylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0268] Step 1: Preparation of (3R)-3-[(5-bromo-2-cyanophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0269] At room temperature, 6.0 g (30.0 mmol) of 4-bromo-2-fluorobenzonitrile, 6.6 g (33 mmol) of (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester, 3.9 g (30 mmol) of diisopropylethylamine, and 5 mL of dimethyl sulfoxide were added to a sealed tube, purged with nitrogen, and reacted at 150 °C for 1 hour. The reaction was monitored by LC-MS until complete. After cooling, water was added, and the mixture was extracted with ethyl acetate and washed once more with water. The organic phase was evaporated to dryness and purified by silica gel column chromatography to give 8.1 g of the title compound. MS (ESI) m / z (M+H) + =380.1.

[0270] Step 2: Preparation of (3R)-3-[(2-cyano-5-formylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0271] At room temperature, (3R)-3-[(5-bromo-2-cyanophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (223 mg, 0.6 mmol), N-formamide saccharin (186.9 mg, 0.9 mmol), 1,4-bis(diphenylphosphino)butane (15.1 mg, 0.04 mmol), anhydrous sodium carbonate (93.8 mg, 0.9 mmol), palladium acetate (11.9 mg, 0.05 mmol), and N,N-dimethylformamide (10 mL) were added to a sealed tube. The tube was purged with nitrogen, and triethylsilane (89.2 mg, 0.8 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 silica gel column chromatography to give 120 mg of the title compound. MS (ESI) m / z (M+H) + =330.2.

[0272] Preparation Example 38: Preparation of (cis)-5-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester

[0273] Step 1: Preparation of 2,2,2-trifluoro-N-(6-methylpyridin-3-yl)acetamide

[0274] Under ice bath conditions, 6-methylpyridin-3-amine (5.0 g, 46.2 mmol), triethylamine (9.4 g, 92.5 mmol), and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. Trifluoroacetic anhydride (11.7 g, 55.5 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the mixture was gradually brought to room temperature and the reaction was continued for 20 minutes. The reaction was monitored by LCMS until complete. Saturated sodium bicarbonate solution was added, and the mixture was extracted and the phases separated. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 6.6 g of the title compound.

[0275] MS(ESI)m / z(M+H) + =205.1.

[0276] Step 2: Preparation of 2,2,2-trifluoro-N-((cis)-6-methylpiperidin-3-yl)acetamide hydrochloride

[0277] At room temperature, 6.6 g (32.1 mmol) of 2,2,2-trifluoro-N-(6-methylpyridin-3-yl)acetamide and 30 mL of methanol were added to a reaction flask and stirred until homogeneous. Then, 10.7 g (293.9 mmol) of 12 M hydrochloric acid, 360 mg (1.6 mmol) of platinum dioxide, and 170 mg (1.6 mmol) of palladium on carbon were added sequentially to displace hydrogen gas. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS until complete. The solid was removed by filtration, and the solvent was removed by rotary evaporation to obtain 7.9 g of the crude title compound, which was used directly in the next reaction. MS (ESI) m / z (M+H) + =211.2.

[0278] Step 3: Preparation of tert-butyl (cis)-2-methyl-5-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[0279] At room temperature, 2,2,2-trifluoro-N-((cis)-6-methylpiperidin-3-yl)acetamide hydrochloride (7.9 g, 32.1 mmol), triethylamine (8.1 g, 80.1 mmol), and methanol (20 mL) were added to a reaction flask and stirred until homogeneous. Boc anhydride (10.5 g, 48.1 mmol) was added dropwise. After the addition was complete, the reaction was continued at room temperature for another 30 minutes. The reaction was monitored by LC-MS until complete. The solution was evaporated to dryness, and saturated sodium bicarbonate solution and ethyl acetate were added. The phases were extracted and separated. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 6.3 g of the title compound. MS (ESI) m / z (M+H) + =311.0.

[0280] Step 4: Preparation of tert-butyl (cis)-5-amino-2-methylpiperidine-1-carboxylate

[0281] At room temperature, tert-butyl (cis)-2-methyl-5-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (6.3 g, 20.2 mmol) and lithium hydroxide (730 mg, 30.4 mmol) were added to a reaction flask, followed by water (20 mL) and tetrahydrofuran (20 mL). The reaction system was heated to 50 °C and reacted for 4 hours. The reaction was monitored by LCMS until complete. The mixture was extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 1.9 g of the title compound.

[0282] MS(ESI)m / z(M+H) + =215.0.

[0283] Preparation Example 39: Preparation of tert-butyl 3-amino-4-methylpiperidine-1-carboxylate

[0284] Using commercially available reagents as raw materials, and following the synthetic route shown in the diagram and referring to the synthetic steps of Preparation Example 38, Preparation Example 39 was obtained. MS (ESI) m / z (M+H) + =215.0.

[0285] Preparation Example 40: Preparation of (trans)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid benzyl ester

[0286] Step 1: Preparation of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester

[0287] Under ice bath conditions, 1,2,3,6-tetrahydropyridine-1-carboxylic acid benzyl ester (15.0 g, 69.0 mmol) and dichloromethane (30 mL) were added to a reaction flask and stirred until homogeneous. The mixture was then purged with nitrogen. m-chloroperoxybenzoic acid (11.9 g, 69.0 mmol) was added in portions, and the mixture was stirred for ten minutes. The mixture was then slowly warmed to room temperature and reacted overnight at room temperature. LC-MS monitoring showed that most of the starting material was converted. After quenching the reaction with sodium thiosulfate solution, the mixture was extracted, the organic phase was collected, and the solution was evaporated to dryness to obtain the crude title compound, which was directly used in the next reaction step. MS (ESI) m / z (M+H) + =234.1.

[0288] Step 2: Preparation of (trans)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid benzyl ester

[0289] At room temperature, (cis)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (11.0 g, 47.2 mmol) and triethylamine trifluoride (7.6 g, 47.2 mmol) were added to a reaction flask and stirred until homogeneous. The mixture was then heated to 100 °C and reacted for 8 hours. The reaction was monitored by LC-MS until complete. After cooling to room temperature, the mixture was quenched with a 20% boron trifluoride diethyl ether solution in dichloromethane. The mixture was washed with saturated sodium bicarbonate solution, extracted, and the organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 11.1 g of the title compound. MS (ESI) m / z (M+H) + =254.3.

[0290] Preparation Example 41: Preparation of (cis)-4-fluoro-3-hydroxypiperidine-1-carboxylic acid benzyl ester

[0291] Step 1: Preparation of (cis)-4-fluoro-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylic acid benzyl ester

[0292] At room temperature, (trans)-4-fluoro-3-hydroxypiperidin-1-carboxylic acid benzyl ester (6.2 g, 24.5 mmol), p-nitrobenzoic acid (5.2 g, 31.1 mmol), triphenylphosphine (11.1 g, 42.4 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask, purged with nitrogen, and diethyl azodicarbonate (7.4 g, 42.4 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by LCMS until complete, and the solution was evaporated to dryness and purified by silica gel column chromatography to give 3.6 g of the title compound. MS (ESI) m / z (M+H) + =403.1.

[0293] Step 2: Preparation of (cis)-4-fluoro-3-hydroxypiperidine-1-carboxylic acid benzyl ester

[0294] At room temperature, (cis)-4-fluoro-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylic acid benzyl ester (3.6 g, 8.9 mmol) and methanol (20 mL) were added to a reaction flask and stirred until homogeneous. Potassium carbonate (2.7 g, 19.4 mmol) was then added, and the mixture was stirred for another two hours at room temperature. The reaction was monitored by LCMS until complete. The mixture was filtered, rotary evaporated, and purified by silica gel column chromatography to give 2.1 g of the title compound. MS (ESI) m / z (M+H) + =254.1.

[0295] Preparation Example 42: Preparation of (trans)-3-amino-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0296] Step 1: Preparation of (trans)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0297] Under ice bath conditions, tert-butyl (cis)-4-fluoro-3-hydroxypiperidin-1-carboxylic acid (3.5 g, 13.8 mmol), 2,3-dihydro1H-isoindole-1,3-dione (3.5 g, 23.9 mmol), triphenylphosphine (6.3 g, 23.9 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask. The mixture was purged with nitrogen, and diethyl azodicarbonate (4.2 g, 23.9 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was gradually heated to 40 °C and reacted at this temperature for 1 hour. The reaction was monitored by LCMS until complete. The solution was evaporated to dryness and purified by silica gel column chromatography to give 3.8 g of the title compound. MS (ESI) m / z (M+H) + =383.1.

[0298] Step 2: Preparation of (trans)-3-amino-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0299] At room temperature, (trans)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (3.8 g, 9.9 mmol) and ethanol (20 mL) were added to a reaction flask and stirred until homogeneous. Hydrazine hydrate (2.2 g, 43.3 mmol) was added, and the reaction was carried out at room temperature for two hours. The reaction was monitored by LCMS until complete. The solvent was removed by rotary evaporation, and the sample was purified by silica gel column chromatography to give 1.7 g of the title compound. MS (ESI) m / z (M+H) + =253.2.

[0300] Preparation Example 43: Preparation of (cis)-3-amino-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0301] Using commercially available reagents and intermediates prepared according to the methods described herein, Preparation Example 43 was obtained following the synthetic route of Preparation Example 42. MS (ESI) m / z (M+H) + =253.2.

[0302] Preparation Example 44: Preparation of (trans)-3-((2-cyano-5-formylphenyl)amino)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0303] Step 1: Preparation of (trans)-3-((5-bromo-2-cyanophenyl)amino)-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0304] At room temperature, 4-bromo-2-fluorobenzonitrile (484 mg, 2.4 mmol), (trans)-3-amino-4-fluoropiperidine-1-carboxylic acid benzyl ester (610.5 mg, 2.4 mmol), diisopropylethylamine (625.5 mg, 4.8 mmol), and dimethyl sulfoxide (10 mL) were added to a sealed tube, purged with nitrogen, and reacted in a microwave-assisted reaction at 150 °C for 1 hour. The reaction was monitored by LC-MS until complete. After cooling, water was added, and the mixture was extracted with ethyl acetate and washed once more with water. The organic phase was evaporated to dryness and purified by silica gel column chromatography to give 360 ​​mg of the title compound. MS (ESI) m / z (M+H) + =432.1.

[0305] Step 2: Preparation of (trans)-3-((5-bromo-2-cyanophenyl)amino)-4-fluoropiperidine-1-carboxylic acid benzyl ester

[0306] At room temperature, (trans)-3-((5-bromo-2-cyanophenyl)amino)-4-fluoropiperidine-1-carboxylic acid benzyl ester (360 mg, 0.8 mmol) was added to a reaction flask, followed by slow addition of trifluoroacetic acid (10 mL). The mixture was stirred at 70 °C for 3 hours. The reaction was monitored by LCMS until complete. The sample was purified by rotary evaporation and silica gel column chromatography to give 227 mg of the title compound. MS (ESI) m / z (M+H) + =298.1.

[0307] Step 3: Preparation of (trans)-3-((5-bromo-2-cyanophenyl)amino)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0308] At room temperature, 4-bromo-2-(((trans)-4-fluoropiperidin-3-yl)amino)benzyl nitrile trifluoroacetate (261 mg, 0.6 mmol), triethylamine (159.4 mg, 1.6 mmol), and methanol (20 mL) were added to a reaction flask and stirred until homogeneous. Di-tert-butyl dicarbonate (206.3 mg, 1.0 mmol) was added dropwise. After the addition was complete, the reaction was continued at room temperature for half an hour. The reaction was monitored by LC-MS until complete. The solution was evaporated to dryness, and saturated sodium bicarbonate 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 silica gel column chromatography to give 182 mg of the title compound. MS (ESI) m / z (M+H) + =398.2.

[0309] Step 4: Preparation of (trans)-3-((2-cyano-5-formylphenyl)amino)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0310] At room temperature, (trans)-3-((5-bromo-2-cyanophenyl)amino)-4-fluoropiperidin-1-carboxylic acid tert-butyl ester (182 mg, 0.5 mmol), formamide saccharin (145.7 mg, 0.7 mmol), 1,4-bis(diphenylphosphino)butane (11.8 mg, 0.03 mmol), sodium carbonate (73.1 mg, 0.7 mmol), palladium acetate (9.3 mg, 0.04 mmol), and N,N-dimethylformamide (10 mL) were added to a sealed tube. The tube was purged with nitrogen, and triethylsilane (69.5 mg, 0.6 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 until complete. After cooling to room temperature, the phases were extracted and separated. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 38 mg of the title compound. MS (ESI) m / z (M+H) + =348.2.

[0311] Preparation Example 45: Preparation of tert-butyl (cis)-4-fluoro-3-((2-fluoro-5-formylphenyl)amino)piperidine-1-carboxylate

[0312] Step 1: Preparation of (cis)-4-fluoro-3-((2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino)piperidine-1-carboxylic acid benzyl ester

[0313] At room temperature, 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide (500 mg, 1.9 mmol), (cis)-3-amino-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (481.9 mg, 1.9 mmol), tris(dibenzylacetone)palladium (87.5 mg, 0.1 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (91.1 mg, 0.2 mmol), cesium carbonate (1.2 g, 3.8 mmol), and 1,4-dioxane (15 mL) were added to a reaction flask, purged with nitrogen, and slowly heated to 100 °C. The reaction was allowed to proceed overnight. The reaction was monitored by LCMS until complete. The mixture was filtered, rotary evaporated, and purified by silica gel column chromatography to give 457 mg of the title compound.

[0314] MS(ESI)m / z(M+H) + =434.2.

[0315] Step 2: Preparation of 4-fluoro-3-(((cis)-4-fluoropiperidin-3-yl)amino)-N-methoxy-N-methylbenzamide trifluoroacetate

[0316] At room temperature, (cis)-4-fluoro-3-((2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino)piperidine-1-carboxylic acid benzyl ester (457 mg, 1.1 mmol) was added to a reaction flask, followed by slow addition of trifluoroacetic acid (10 mL). The mixture was stirred at 70 °C for 3 hours. The reaction was monitored by LCMS until complete. Rotary evaporation yielded 435 mg of the title compound, which was used directly in the next reaction. MS (ESI) m / z (M+H) + =300.2.

[0317] Step 3: Preparation of tert-butyl (cis)-4-fluoro-3-((2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino)piperidine-1-carboxylic acid

[0318] At room temperature, 4-fluoro-3-(((cis)-4-fluoropiperidin-3-yl)amino)-N-methoxy-N-methylbenzamide trifluoroacetate (435 mg, 1.1 mmol), triethylamine (265.6 mg, 2.6 mmol), and methanol (20 mL) were added to a reaction flask and stirred until homogeneous. Boc anhydride (343.7 mg, 1.6 mmol) was added dropwise. After the addition was complete, the reaction was continued at room temperature for another 30 minutes. The reaction was monitored by LC-MS until complete. The solution was evaporated to dryness, and saturated sodium bicarbonate solution and ethyl acetate were added. The phases were extracted and separated. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 329 mg of the title compound. MS (ESI) m / z (M+H) + =400.1. Step 4: Preparation of (cis)-4-fluoro-3-((2-fluoro-5-formylphenyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0319] Under ice bath conditions, (cis)-4-fluoro-3-((2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (329 mg, 0.8 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask and stirred until homogeneous. Lithium aluminum hydride (46.7 mg, 1.2 mmol) was slowly added. After the addition was complete, the reaction system was gradually brought to room temperature, and the reaction was continued for half an hour. The reaction was monitored by LC-MS to ensure completeness. A dilute sodium hydroxide solution was added, the mixture was filtered, extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 231 mg of the title compound. MS (ESI) m / z (M+H) + =341.2.

[0320] Using commercially available reagents as raw materials, the following compound was obtained by following the synthetic route described in the previous preparation examples.

[0321] Table 3 Intermediate Compounds

[0322] Preparation Example 54: Preparation of (R)-4-formyl-2-((1-(methyl-d3)piperidin-3-yl)amino)benzonitrile

[0323] Step 1: Preparation of (R)-4-bromo-2-(piperidin-3-ylamino)benzonitrile

[0324] At room temperature, 522 mg (1.4 mmol) of (R)-3-((5-bromo-2-cyanophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by dichloromethane (20 mL) and trifluoroacetic acid (6 mL). The mixture was heated to 40 °C and reacted for half an hour. The reaction was monitored by LCMS until complete. The solvent was removed by rotary evaporation, and a small amount of methanol was added. The pH was adjusted to weakly alkaline with sodium bicarbonate solution, and the solvent was removed by rotary evaporation again to obtain 384 mg of the crude title compound, which was used directly in the next reaction step.

[0325] MS(ESI)m / z(M+H) + =280.1.

[0326] Step 2: Preparation of (R)-4-bromo-2-((1-(methyl-d3)piperidin-3-yl)amino)benzonitrile

[0327] At room temperature, (R)-4-bromo-2-(piperidin-3-ylamino)benzonitrile (384 mg, 1.4 mmol), potassium carbonate (378.7 mg, 2.7 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask and stirred until homogeneous. Deuterated iodomethane (297.9 mg, 2.1 mmol) was slowly added, and the reaction was continued at room temperature for another 30 minutes. The reaction was stopped by LCMS monitoring. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and purified by silica gel column chromatography to give 92 mg of the title compound. MS (ESI) m / z (M+H) + =279.2.

[0328] Step 3: Preparation of (R)-4-formyl-2-((1-(methyl-d3)piperidin-3-yl)amino)benzonitrile

[0329] At room temperature, (R)-4-bromo-2-((1-(methyl-d3)piperidin-3-yl)amino)benzonitrile (92 mg, 0.5 mmol), formamide saccharin (145.7 mg, 0.7 mmol), 1,4-bis(diphenylphosphino)butane (11.8 mg, 0.03 mmol), sodium carbonate (73.1 mg, 0.7 mmol), palladium acetate (9.3 mg, 0.04 mmol), and N,N-dimethylformamide (10 mL) were added to a sealed tube. The tube was purged with nitrogen, and triethylsilane (69.5 mg, 0.6 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 phases were extracted and separated. The organic phase was collected, evaporated to dryness, and purified by silica gel column chromatography to give 38 mg of the title compound. MS (ESI) m / z (M+H) + =247.1.

[0330] Preparation Example 55: Preparation of (R)-3-((2-cyano-5-formylphenyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0331] Step 1: Preparation of (R)-3-((5-bromo-2-cyanophenyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0332] At room temperature, (R)-3-((5-bromo-2-cyanophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (394 mg, 1.0 mmol), sodium hydride (63 mg, 1.6 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask and stirred until homogeneous. Iodomethane (177 mg, 1.3 mmol) was slowly added, and the reaction was continued at room temperature for another 30 minutes. The reaction was monitored by LCMS until complete. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and purified by silica gel column chromatography to give 393 mg of the title compound. MS (ESI) m / z (M+H) + =394.2.

[0333] Step 2: Preparation of (R)-3-((2-cyano-5-formylphenyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0334] At room temperature, (R)-3-((5-bromo-2-cyanophenyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (393 mg, 1.0 mmol), formamide saccharin (316.8 mg, 1.5 mmol), 1,4-bis(diphenylphosphino)butane (25.6 mg, 0.06 mmol), sodium carbonate (159.0 mg, 1.5 mmol), palladium acetate (20.2 mg, 0.09 mmol), and N,N-dimethylformamide (10 mL) were added to a sealed tube. The tube was purged with nitrogen, and triethylsilane (151.2 mg, 1.3 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 silica gel column chromatography to give 136 mg of the title compound. MS (ESI) m / z (M+H) + =344.1.

[0335] Preparation Example 56: Preparation of (R)-3-((5-acetyl-2-fluorophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0336] (R)-3-((2-fluoro-5-(methoxy(methyl)carbamoyl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (450.0 mg, 1.18 mmol) was dissolved in tetrahydrofuran (10 mL), and methyl magnesium bromide (3.54 mL, 3.54 mmol) was added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 1 hour. After TLC showed complete reaction, 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 silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 (V:V)) to give 290.0 mg of the title compound. MS (ESI) m / z (M+H) + =337.2.

[0337] Example 1: Preparation of N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-((1-methylpyrrolidin-3-yl)oxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0338] 2-((5-(1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (30.0 mg, 0.073 mmol) and 4-fluoro-3-((1-methylpyrrolidone-3-yl)oxy)benzaldehyde (16.3 mg, 0.073 mmol) were dissolved in methanol (3 mL). Sodium cyanoborohydride (9.1 mg, 0.15 mmol) was added at room temperature, and the reaction was allowed to proceed for 3 hours at room temperature. 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 then purified by HPLC to give 8.1 mg of the title compound. 1H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 7.50–7.40 (m, 1H), 7.41–7.29 (m, 2H), 7.12 (dd, J = 11.5, 8.2Hz, 1H), 6. 97(dd,J=8.4,1.9Hz,1H),6.86–6.78(m,1H),5.00(s,2H),4.90(dp,J=8.7,2.7Hz,1H),4.63(s,2H),3.77(s, 4H),3.63(d,J=5.7Hz,3H),3.04(dd,J=33.6,5.4Hz,1H),2.76(dd,J=10.5,6.0Hz,1H),2.73–2.59(m,2H),2 .55–2.50(m,1H),2.39–2.27(m,2H),2.26(s,3H),11.84–1.72(m,2H),1.14–0.90(m,7H),0.75–0.67(m,2H). MS(ESI)m / z(M+H) + =620.2.

[0339] Example 2: Preparation of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidine-3-yloxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0340] Step 1: Preparation of (R)-3-(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-fluorophenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0341] (R)-3-(2-fluoro-5-carboxyphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (22.64 mg, 0.073 mmol) and 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 (25 mg, 0.061 mmol) were dissolved in methanol (5 mL). One drop of acetic acid was added, and the mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (7.67 mg, 0.12 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed by LC-MS, the system was quenched with water, and purified by reversed-phase preparative chromatography to obtain 20 mg of the title compound.

[0342] MS(ESI)m / z(M+H) + =706.3.

[0343] Step 2: Preparation of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidine-3-yloxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0344] 20 mg (0.028 mmol) of (R)-3-(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-fluorophenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise under ice bath conditions. The reaction was allowed to proceed at room temperature for 1 hour. After LC-MS showed that the reaction was complete, the system was concentrated and purified by reverse-phase preparative chromatography to give 4.73 mg of the title compound. 1 H NMR(400MHz,Methanol-d4)δ8.44(s,1H),7.45–7.36(m,1H),7.33–7.24(m,1H),7.2 3–7.12(m,3H),7.07–6.99(m,1H),5.28–5.07(m,3H),4.75(s,2H),4.23–4.06(m,4H ),3.91(s,2H),3.80(p,J=6.6Hz,1H),3.62(dt,J=13.1,1.3Hz,1H),3.56–3.46(m,4 H),3.28–3.19(m,1H),2.42–2.23(m,2H),1.25–0.99(m,7H),0.78(d,J=6.6Hz,2H). MS(ESI)m / z(M+H) + =606.0.

[0345] Example 3: Preparation of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-((1-methylpyrrolidin-3-yl)oxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0346] (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(pyrrolidine-3-yloxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (12.87 mg, 0.021 mmol) and paraformaldehyde (1.26 mg, 0.042 mmol) were dissolved in methanol (5 mL). Sodium methoxide (2.04 mg, 0.036 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.64 mg, 0.042 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 12 hours. The reaction was completed by LC-MS. The system was quenched with water, and purified by reversed-phase preparative chromatography to give 4.12 mg of the title compound. 1 H NMR(400MHz,Methanol-d4)δ8.42(s,1H),7.45–7.36(m,1H),7.31–7.17(m,2H),7.09–6.95(m ,2H),6.91–6.82(m,1H),5.13(s,2H),4.95(dt,J=7.2,3.6Hz,1H),4.73(s,2H),3.92(s,4H),3 .86–3.76(m,1H),3.72(s,2H),3.55–3.41(m,1H),3.27–3.04(m,1H),2.96–2.79(m,3H),2.61 –2.50(m,1H),2.45–2.30(m,4H),2.08–1.95(m,1H),1.25–0.99(m,7H),0.79(d,J=6.6Hz,2H). MS(ESI)m / z(M+H) + =620.2.

[0347] Using the intermediate compound and / or commercial reagents obtained in the preparation examples as raw materials, Examples 4-25 were prepared according to the synthesis methods described in the preceding examples. Examples 24 and 25 were obtained by chiral resolution of Example 16, and specific information is shown in Table 4.

[0348] Table 4 Compound Information for Examples

[0349] The analytical data described in the above embodiments, including NMR and LC-MS data, are shown in Table 5.

[0350] Table 5. NMR and LC-MS data of compounds in Examples 4-27

[0351] Example 28: Preparation of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-((1-(2-methoxyethyl)piperidin-3-yl)oxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0352] (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(piperidin-3-yloxy)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (20 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (4 mL). Cesium carbonate (20 mg, 0.06 mmol) and 2-bromoethyl methyl ether (9 mg, 0.06 mmol) were added sequentially at room temperature. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. LC-MS showed complete consumption of the starting material. The solvent was removed by rotary evaporation. The crude product was purified by Pre-HPLC to give 7 mg of the title compound.

[0353] 1 H NMR(400MHz, Methanol-d4)δ8.42(s,1H),7.45–7.36(m,1H),7.31–7.17(m,2H),7.13–7.01(m,2H),6.94–6.85 (m,1H),5.13(s,2H),4.72(s,2H),4.45–4.28(m,1H),3.91(s,4H),3.80(p,J=6.6Hz,1H),3.71(s,2H),3.59–3. 41(m,3H),3.32(s,3H),3.29–3.03(m,2H),2.87–2.72(m,1H),2.63(t,J=5.6Hz,2H),2.38–2.15(m,2H),2.12–1 .99(m,1H),1.90–1.75(m,1H),1.71–1.55(m,1H),1.54–1.39(m,1H),1.24–1.00(m,7H),0.79(d,J=6.6Hz,2H). MS(ESI)m / z(M+H) + =678.2.

[0354] Example 29: Preparation of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0355] At room temperature, (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(piperidin-3-ylamino)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (30 mg, 0.05 mmol), tert-butyldimethylsiloxane acetaldehyde (11 mg, 0.06 mmol), and methanol (10 mL) were added to a reaction flask. Acetic acid was used as a catalyst, and the mixture was stirred for ten minutes. Then, sodium triacetoxyborohydride (20.4 mg, 0.1 mmol) was added, and the reaction was continued at room temperature for another half hour. The reaction was monitored by LCMS until complete. The reaction was quenched with saturated ammonium chloride solution, the solvent was removed by rotary evaporation, and the mixture was filtered. HPLC was used to prepare 13 mg of the title compound. 1 H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.45–7.36(m,1H),7.32–7.20(m,1H),7.19(dd,J=8.0,3.0Hz,1H),6.89(dd,J=11.7,8.1Hz, 1H),6.76(dd,J=8.3,2.0Hz,1H),6.58–6.48(m,1H),5.24–5.01(m,2H),4.80–4.65(m,2H),3.98–3.87(m,4H),3.86–3.73(m,1H),3.72 –3.63(m,4H),3.61–3.49(m,2H),3.27–3.16(m,1H),3.00(d,J=11.0Hz,1H),2.81–2.67(m,1H),2.63–2.48(m,2H),2.37–2.23(m,1H), 2.21–2.04(m,1H),1.99–1.82(m,1H),1.84–1.72(m,1H),1.73–1.57(m,1H),1.50–1.35(m,1H),1.25–1.01(m,7H),0.84–0.72(m,2H). MS(ESI)m / z(M+H) + =662.9.

[0356] Example 30: Synthesis of (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-((1-(2-fluoroethyl)piperidin-3-yl)amino)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0357] At room temperature, (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(piperidin-3-ylamino)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (30 mg, 0.05 mmol), potassium carbonate (13.3 mg, 0.1 mmol), and N,N-dimethylformamide (5 mL) were added to a reaction flask and stirred until homogeneous. 2-fluoroethyl-4-methylbenzene-1-sulfonate (15.7 mg, 0.07 mmol) was slowly added, and the mixture was slowly heated to 45 °C and reacted overnight. The reaction was monitored by LCMS until complete. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, and the solvent was removed by rotary evaporation. The crude product was further processed by HPLC to obtain 6 mg of the title compound.

[0358] 1 H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.45–7.35(m,1H),7.32–7.21(m,1H),7.19(dd,J=8.0,3.0Hz,1H),6.89(dd,J=11.7,8.2Hz,1H),6 .76(dd,J=8.3,2.1Hz,1H),6.63–6.49(m,1H),5.13(s,2H),4.72(s,2H),4.57(dt,J=47.8,4.8Hz,2H),3.92(s,4H),3.80(p,J=6.6Hz,1H),3 .68(s,2H),3.63–3.41(m,2H),3.28–3.19(m,1H),3.03(d,J=11.1Hz,1H),2.76(t,J=4.8Hz,2H),2.69(t,J=4.8Hz,1H),2.30(t,J=10.4Hz,1 H),2.16(t,J=9.9Hz,1H),1.97–1.84(m,1H),1.83–1.72(m,1H),1.73– 1.60(m,1H),1.48–1.34(m,1H),1.23–1.01(m,7H),0.84–0.69(m,2H). MS(ESI)m / z(M+H) +=664.9.

[0359] Example 31: Preparation of 2-((5-(1'-(3-((((R)-1-((R)-2,3-dihydroxypropyl)piperidin-3-yl)amino)-4-fluorobenzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0360] Step 1: Preparation of 2-((5-(1'-(3-(((R)-1-(((R)-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)piperidin-3-yl)amino)-4-fluorobenzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0361] At room temperature, (R)-N-ethyl-5-fluoro-2-((5-(1'-(4-fluoro-3-(piperidin-3-ylamino)benzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (30 mg, 0.05 mmol), (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (10 mg, 0.07 mmol), and methanol (10 mL) were added to a reaction flask. Acetic acid was used as a catalyst, and the mixture was stirred for ten minutes. Then, sodium triacetoxyborohydride (20.4 mg, 0.1 mmol) was added, and the reaction was continued at room temperature for another half hour. The reaction was monitored by LCMS until complete. The reaction was quenched with saturated ammonium chloride solution, the solvent was removed by rotary evaporation, and the mixture was filtered and purified by silica gel column chromatography to obtain 30 mg of the title compound. MS(ESI)m / z(M+H) + =733.2.

[0362] Step 2: Preparation of 2-((5-(1'-(3-((((R)-1-((R)-2,3-dihydroxypropyl)piperidin-3-yl)amino)-4-fluorobenzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0363] At room temperature, 2-((5-(1'-(3-((((R)-1-(((R)-2,2-dimethyl-1,3-dioxane-4-yl)methyl)piperidin-3-yl)amino)-4-fluorobenzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (30 mg, 0.04 mmol) was added to a reaction flask, followed by dichloromethane (20 mL), one drop of water, and trifluoroacetic acid (6 mL). The mixture was heated to 40 °C and reacted for half an hour. The reaction was monitored by LCMS until complete. The solvent was removed by rotary evaporation, a small amount of methanol was added, and the pH was adjusted to weakly alkaline with sodium bicarbonate solution. The solvent was removed by rotary evaporation, and the crude product was further prepared by HPLC to obtain 15 mg of the title compound. 1 H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.45–7.36(m,1H),7.32–7.22(m,1H),7.19(dd,J=8.0,3.0Hz,1H),6.89(dd,J=11 .7,8.2Hz,1H),6.77(dd,J=8.5,2.0Hz,1H),6.58–6.44(m,1H),5.13(s,2H),4.73(s,2H),3.92(s,4H),3.87–3.73(m,2H),3 .67(s,2H),3.63–3.43(m,4H),3.29–3.19(m,1H),2.99(d,J=11.0Hz,1H),2.81–2.62(m,1H),2.54–2.27(m,3H),2.22–2.02 (m,1H),1.93–1.82(m,1H),1.83–1.72(m,1H),1.71–1.57(m,1H),1.50–1.36(m,1H),1.28–1.00(m,7H),0.82–0.72(m,2H). MS(ESI)m / z(M+H) + =693.9.

[0364] Example 32: Preparation of 2-((5-(1'-(3-(((R)-1-((S)-2,3-dihydroxypropyl)piperidin-3-yl)amino)-4-fluorobenzyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0365] Using commercially available reagents as raw materials, Example 32 was obtained by referring to the synthesis route of Example 31. 1H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.46–7.36(m,1H),7.31–7.22(m,1H),7.19(dd,J=8.0,3.0Hz,1H),6.89(dd,J=11 .7,8.2Hz,1H),6.77(dd,J=8.4,2.1Hz,1H),6.59–6.47(m,1H),5.13(s,2H),4.73(s,2H),3.91(s,4H),3.85–3.75(m,2H),3 .67(s,2H),3.62–3.40(m,4H),3.28–3.19(m,1H),2.99(d,J=10.9Hz,1H),2.78–2.64(m,1H),2.55–2.37(m,2H),2.37–2.11 (m,2H),1.93–1.83(m,1H),1.82–1.71(m,1H),1.71–1.56(m,1H),1.50–1.36(m,1H),1.23–1.00(m,7H),0.83–0.75(m,2H). MS(ESI)m / z(M+H) + =692.9.

[0366] Using the intermediate compound and / or commercial reagents prepared in the preparation examples as raw materials, the following Examples 33-65 were prepared according to the synthesis method of the foregoing examples; Example 65 was prepared by adding a catalytic amount of acetic acid to the reaction system and simultaneously heating to 60°C, in accordance with the synthesis method of Example 1. The racemic mixture was chirally resolved to obtain the corresponding chiral compound, and the specific information is shown in Table 6.

[0367] Table 6 Compound Information for Examples

[0368] The analytical data described above, including NMR and LC-MS data, are shown in Table 7.

[0369] Table 7. NMR and LC-MS data of compounds in Examples 33–65

[0370] Experimental Example 1: Menin-MLL Protein Interaction Inhibition Activity Assay

[0371] (1) Inhibitory activity test of the interaction between Menin and MLL protein

[0372] The IC50 of the test compound inhibiting Menin-MLL protein interaction was detected using the Fluorescence Polarization method. 50 value.

[0373] 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 ECHO 665 Series Acoustic Liquid Handler (BECKMAN Inc.), 50 nL of each of the diluted test compound solutions (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 (BMG Labtech Inc.), and the data were processed.

[0374] 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 the assay 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.

[0375] 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:

[0376] (2) Inhibition activity test of interaction between mutant Menin-M327I and Menin-T349M and MLL protein

[0377] The IC50 of the test compounds inhibiting the interaction between Menin-M327I, Menin-T349M and MLL protein was detected using fluorescence polarization. 50 value.

[0378] 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 ECHO 665 Series Acoustic Liquid Handler (BECKMAN Inc.), 50 nL of each of the diluted test compound solutions (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.

[0379] 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 the assay well containing only 100 μM SNDX-5613). Using the log value of the 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 8.

[0380] Experiment Example 2: Cell Proliferation Inhibition Experiment

[0381] (1) Cell plating:

[0382] Remove the following cells from the incubator and place them on the work surface. Gently pipette to mix, and count using CounterStar. Dilute the following cells to the desired density using fresh complete culture medium:

[0383] MV-4-11 cells (sourced from 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 1×10⁻⁶ cells / cm². 4 Cells / well, 100 μL / well.

[0384] MV-4-11MEN1M327I / M327I cells (based on MV-4-11 cells with catalog number CBP60522, the MEN1 gene was edited using CRISPR technology to change the 327th amino acid methionine of its encoded protein product to isoleucine I, RPMI1640 + 10% FBS + 1% P / S) were plated at a density of 1×10⁻⁶. 4 Cells / well, 100 μL / well.

[0385] MV-4-11MEN1T349M / T349M cells (based on MV-4-11 cells with catalog number CBP60522, the MEN1 gene was edited using CRISPR technology to change the 349th amino acid threonine T of its encoded protein product to methionine M, RPMI1640+15%FBS+1%P / S) were plated at a density of 1×10⁻⁶ cells / cm². 4 Cells / well, 100 μL / well.

[0386] Use a power pipette to aspirate 100 μL of each of the above cell suspensions into a 96-well plate.

[0387] (2) Preparation of compounds:

[0388] The mother liquor of the compound was diluted with DMSO from 10 mM to 4000, 1200, 400, 120, 40, 12, 4, 1.2 and 0 μM to obtain compound solutions of different concentrations, with 0 μM serving as the control well.

[0389] After thorough mixing, 1.3 μL of each diluted solution was taken out with an electric pipette and added to 258.7 μL of culture medium. At this point, the solution was diluted 100 times and the DMSO content was 0.5%.

[0390] After thoroughly mixing using a multi-channel pipette, take out the 96-well plate containing cells. Set up two replicates for each compound concentration. Add 100 μL of the diluted compound solution to each replicate well. The final concentrations of the compound in each well 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. The DMSO content in the wells containing the compound is 0.25%, while the control wells contain only 0.25% DMSO (compound concentration is 0).

[0391] 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.

[0392] (3) CTG detection:

[0393] 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.

[0394] Incubate in a shaker at room temperature for 15 minutes, then allow to stand at room temperature for 15 minutes to equilibrate.

[0395] Detection was performed using a multi-functional microplate reader.

[0396] (4) Data Analysis:

[0397] 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).

[0398] Using the logarithm of compound concentration as the X-axis and cell viability percentage 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 8.

[0399] Table 8. Activity data of the compounds disclosed herein Note: In Table 8, "-" indicates that the compound was not detected. "Compound number" indicates the compound in the corresponding example. "Compound 1-34" are compounds from Chinese patent application publication number CN118930525A, and their specific structures are as follows:

[0400] The results in Table 8 show that the disclosed compounds exhibit excellent activity in inhibiting the interaction between Menin and MLL proteins, as well as excellent activity in inhibiting the interaction between Menin mutant proteins (Menin-M327I, Menin-T349M) and MLL proteins. Furthermore, the disclosed compounds also effectively inhibit the cell proliferation of MV-4-11 and its mutant cells MV-4-11MEN1M327I / M327I and MV-4-11MEN1T349M / T349M. Therefore, the disclosed compounds have good prospects for clinical development. In particular, compared with existing compounds, the disclosed compounds exhibit excellent activity in inhibiting the interaction between Menin-M327I and Menin-T349M mutant proteins and MLL proteins, thus showing good potential for overcoming drug resistance.

[0401] For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0402] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, and all such modified solutions fall within the protection scope of this application.

Claims

1. A compound represented by chemical formula I, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof: In formula I, Represents possible chemical bonds; 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, 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, and 5-14 membered heteroaryl. W is selected from O, NRe, or CRfRg; Re is selected from H, C1-C6 alkyl; Rf and Rg are independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl. v is selected from 0, 1, or 2; or v is 0 or 1; Ra is R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 alkoxy, 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 -(C(R4R5)) p NR6R7, 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, 3-12, or 3-10 member alicyclic ring containing N atoms as shown in the diagram. There are 0-2 ring atoms between the N atoms and the ring atoms connecting the base (marked with "*"). Cy1 can be a monocyclic, bridged, spirocyclic, or fused ring. In addition to the N atoms 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; In addition to Rb, Cy1 can be independently substituted by one or more R8s at any possible position. The R8s can be selected from oxygen, hydroxyl, amino, halogen, cyano, 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, or 5-8 heteroaryl. When multiple R8s are present, the R8s at different positions may be the same or different.

2. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, Rb is absent, or Rb is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, and Rb may be independently substituted at any possible position by one or more groups selected from deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, U is N or CH; or U is N.

4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, 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 all of Y1, Y2, Y3, and Y4 are CR3. Preferably, Y1 and Y2 are N, and Y3 and Y4 are CR3; or Y1 and Y3 are N, and Y2 and Y4 are CR3; or Y1 and Y4 are N, and Y2 and Y3 are CR3; or Y2 and Y3 are N, and Y1 and Y4 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.

5. The compound according to any one of claims 1-4, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, R3 at different positions may be the same or different, and R3 may be independently selected from H, halogen, cyano, 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, or 5-10 membered heteroaryl; or R3 at different positions is independently selected from H, F, Cl, Br, I, cyano, 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, aziridine, or phenyl; or Y1 is CR3 or N, Y2, Y3, and Y4 are CR3, and R3 is H, F, Cl, or cyano; or, Y1, Y2, Y3, and Y4 are all CR3, and R3 is independently H, F, Cl, Br, or cyano.

6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, W is O; or W is NRe, where Re is H or C1-C3 alkyl; or W is CRfRg, where Rf and Rg are independently selected from H, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl. Preferably, Re is H, methyl, ethyl, n-propyl, or isopropyl; Rf and Rg are independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, and piperidinyl.

7. The compound according to any one of claims 1-6, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, Ra is Wherein R1 and R2 are independently selected from substituted or unsubstituted C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or 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, deuterated methyl, deuterated ethyl, fluoromethyl, chloromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopentyl; or R1 is isopropyl and R2 is methyl, ethyl, n-propyl, isopropyl, methoxy, deuterated methyl, deuterated ethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, or 3,3-difluorocyclobutyl; or R1 and R2 together with the nitrogen they are attached to form a 3-10 membered alicyclic ring, wherein the alicyclic ring 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 addition to the nitrogen present, the alicyclic ring also contains 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably, R1 and R2 together with the nitrogen they are attached to form a 3-8 membered alicyclic ring; Preferably, R1 and R2 together with the attached nitrogen form a 3-6 membered alicyclic ring; or R1 and R2 together with the attached nitrogen form the following structure: Preferably, the alicyclic rings formed by R1, R2 and the attached nitrogen are 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 groups; 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. Preferably, one of X1, X2, X3, and X4 is N, and the rest are CRd; or two of X1, X2, X3, and X4 are N, and the rest are CRa; or all of X1, X2, X3, and X4 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 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. Preferably, Rd at different positions can be independently selected from H, halogen, cyano, C1-C3 alkyl; or Rd is independently selected from H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or isopropyl; or One of the Rds is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or isopropyl, and the rest are H; or two of the Rds are independently selected from methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, or iodine, and the rest are H; or one of the Rds is methyl, and the rest are H; or one of the Ras is fluorine, and the rest are H; or Rds at all positions are H.

8. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, Rc is -((CR4R5)) p NR6R7, where p is 1, and R4, R5, R6, and R7 are independently selected from H, methyl, ethyl, n-propyl, or isopropyl. Preferably, R4 is H, and R5 is selected from H, methyl, ethyl, n-propyl, or isopropyl; or both R4 and R5 are H; and / or R6 is H, and R7 is selected from H, methyl, ethyl, n-propyl, or isopropyl; or both R6 and R7 are H; or Rc is Wherein, Cy1 is a 4-10 membered heterocyclic alkyl group containing a monocyclic, fused, spirocyclic, or bridged ring with a nitrogen atom as shown in the diagram. The heterocyclic alkyl group, in addition to the nitrogen atom shown in the diagram, contains 0-3 heteroatoms selected from N, O, or S. R8 is independently selected from C1-C3 alkyl, halogen, amino, hydroxyl, and cyano groups. Rb is absent or is H or a C1-C6 alkyl group, and Rb can be independently substituted by one or more groups selected from deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl groups; or Rc is Or Rc is Where m is 0 or 1; n is 0, 1 or 2; 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 atoms it is attached to; 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, or Q is not present; Rb is absent, or is H or C1-C6 alkyl, and Rb may be independently substituted by one or more groups selected from deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.

9. The compound according to any one of claims 1-8, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, Rc is selected from the following structures, either substituted or unsubstituted by R8: or Rc is selected from the following structures: or Rc is selected from the structure shown below:

10. The compound according to any one of claims 1-9, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, Rb is selected from H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or Rb can be independently substituted at any possible position by a group selected from deuterium, halogen, cyano, hydroxyl, 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, deuterated methyl, deuterated ethyl, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, -CH2CH2OCH3, 2,3-dihydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

11. Compounds represented by chemical formula II, their pharmaceutically acceptable salts, hydrates, isomers, prodrugs, or mixtures thereof: In formula II, Represents possible chemical bonds; Rx and Ry are independently selected from H, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; U, Y1, Y2, Y3, Y4, Ra, W, Rc, v are defined as described in any one of claims 1-10; Preferably, Rx and Ry are independently selected from H, halogen, cyano, C1-C3 alkyl, and C1-C3 alkoxy; or Rx and Ry are substituted at possible positions with groups selected from halogen, hydroxyl, and amino groups; or Rx is hydrogen, and Ry is selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, amino, methyl, methoxy, fluoromethyl, chloromethyl, or trifluoromethyl.

12. The compound according to claim 1 or 11, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, The compound is a compound represented by formula III or formula IV: in, Y1 is either CR3 or N; R3 is independently selected from H, halogen, cyano or C1-C3 alkyl; W is O or NRe, and Re is H or C1-C3 alkyl; v is 0 or 1; Rc is -(C(R4R5)) p NR6R7, where p is 1 or 2, R4 and R5 are each independently methyl, ethyl, n-propyl or isopropyl, and R6 and R7 are H; Or Rc is Wherein, Cy1 is a monocyclic 4-8-membered heterocyclic alkyl group containing the N atom shown in the figure, or a bridged 6-10-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group may be substituted by one or more groups selected from C1-C3 alkyl or halogen, Rb is absent or is H or C1-C5 alkyl, and Rb may be independently substituted by one or more groups selected from deuterium, halogen, hydroxyl or C1-C3 alkoxy; Ra is R1 and R2 are independently unsubstituted C1-C5 alkyl, deuterated C1-C5 alkyl, halogenated C1-C5 alkyl, unsubstituted C3-C5 cycloalkyl, halogenated C3-C5 cycloalkyl, and R1 and R2 together with the attached nitrogen to form a monocyclic 5-7-membered heterocyclic alkyl or a bridged 6-9-membered heterocyclic alkyl, wherein the heterocyclic alkyl contains 1-3 heteroatoms selected from N, O or S in addition to the nitrogen atom, and the heterocyclic alkyl can be substituted by C1-C3 alkyl; X1 and X3 are N, X2 and X4 are CRd, and Rd can be independently selected from hydrogen, halogen, cyano, and C1-C3 alkyl; Rx is H or C1-C6 alkyl.

13. A compound, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, wherein, The compound is selected from:

14. A pharmaceutical composition, wherein, Includes the compound of any one of claims 1-13, its pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, pharmaceutically acceptable excipients and / or carriers.

15. The compound of any one of claims 1-13, a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, or the pharmaceutical composition of claim 14, for the prevention, relief, or treatment of diseases related to Menin-MLL protein interactions; Preferably, the diseases associated with Menin-MLL protein interactions include malignant tumors, diabetes, or complications related to said diseases; wherein malignant tumors include hematologic malignancies, lymphomas, and solid tumors. More preferably, the hematologic malignancies include leukemia and myeloma, and more preferably include acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute monocytic leukemia, chronic monocytic leukemia, childhood leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, mixed lineage leukemia, hairy cell leukemia, precursor T-cell lymphoblastic leukemia, large granular lymphoblastic leukemia, meningeal leukemia, myelodysplastic syndrome, myeloproliferative disorders, myeloproliferative neoplasm formation, plasmacytoma, and multiple myeloma; The lymphomas include cutaneous T-cell lymphoma, lymphoid tumor, AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or malignant lymphoma; The solid tumors include pancreatic cancer, colon cancer, rectal cancer, liver cancer, stomach cancer, glioblastoma, lung cancer, breast cancer, and prostate cancer; or Related complications associated with the disease include leukemic meningitis.

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