Menin inhibitors and uses thereof

Abstract

The present invention provides a class of compounds represented by Formula I, which have Menin-MLL protein-protein interaction inhibitory activity and cell proliferation inhibition activity. The present invention also provides their use in treating cancer and other diseases mediated by Menin-MLL interactions.

Description

Technical Field

[0001] The present invention relates to a class of compounds having Menin-MLL protein-protein interaction inhibitory activity and cell proliferation inhibitory activity, and their use in treating cancer and other diseases mediated by Menin-MLL interaction. Background Art

[0002] Mixed lineage leukemia (MLL) proteins are histone methyltransferases mutated in clinically and biologically distinct subtypes of acute leukemia. The MLL gene family, comprising five members (MLL1-5), is closely associated with the development, progression, and metastasis of various tumors. The multiple endocrine oncoprotein (Menin) is encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, which functions as a tumor suppressor in endocrine organs. Menin interacts with numerous proteins, forming a complex network of interactions. Studies have shown that direct interaction between Menin and MLL1 and MLL2 is essential for the complex's enzymatic activity in histone methylation (H3K4), regulation of target gene transcription, and its corresponding functions. Menin interacts with the amide terminus of MLL1 and acts as an oncogenic cofactor that increases transcription of genes such as HOX and MEIS1. The interaction between Menin and MLL fusion proteins is essential for the aberrant activation of a range of gene clusters and the onset of leukemia caused by MLL fusion proteins. Furthermore, Menin, a nuclear protein expressed broadly across tissues, participates in the formation of multiple important transcriptional regulatory complexes and exhibits numerous important biological functions in the body. In addition to participating in the formation of the MLL1 and MLL2 epigenetic regulatory complexes, Menin has been reported to interact with multiple transcription factors, including JunD, NFKB, and SMAD3, to regulate the transcriptional activation or repression of target genes.

[0003] Targeting the Menin-MLL interaction with small molecules is an attractive strategy for developing new therapies for MLL-related leukemias. Furthermore, inhibiting the interaction of Menin with wild-type MLL1 and MLL2 may have potential therapeutic effects on many solid cancers, such as liver, brain, colon, and breast cancer.

[0004] Therefore, inhibitors of Menin-MLL1 protein-protein interaction can be considered as potential tumor therapeutic compounds with broad application prospects. They selectively target this interaction interface and are conducive to the development of new drugs related to it. Summary of the Invention

[0005] The present invention provides a compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] Ring L is selected from wherein n1, n2, n3, and n4 are independently selected from 1 or 2;

[0009] Y 1 、Y 2 are independently selected from CH or N;

[0010] m is selected from 1, 2 or 3;

[0011] W is selected from hydrogen, halogen, cyano, nitro, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR W1 or -C 0～4 Alkylene-NR W1 R W2 ;

[0012] R W1 、R W2 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, 3- to 10-membered carbocyclic group, or 4- to 10-membered heterocyclic alkyl group;

[0013] X is selected from CR a R b NR a , O or S;

[0014] R a 、R b are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 Alkyl, deuterium-substituted -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR A1 、-C 0～4 Alkylene-NR A1 R A2 、-C 0～4 Alkylene-NRA1 C(O)R A2 、-C 0～4 Alkylene-C(O)NR A1 R A2 、-C 0～4 Alkylene-C(O)R A1 、-C 0～4 Alkylene-S(O)2NR A1 R A2 、-C 0～4 Alkylene-NR A1 S(O)2R A2 、-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R B1 replace;

[0015] or R a 、R b Together with the atoms it is connected to, it forms 3-10 membered carbocyclic group or 4-10 membered heterocyclic alkyl group; wherein the carbocyclic group and heterocyclic alkyl group may be further optionally replaced by one, two, three or four independent R B1 replace;

[0016] R A1 、R A2 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～4 Alkylene-C(O)R B1 、-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R B1 replace;

[0017] Each R B1 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, -C 1～6 Alkyl, -C2～6 Alkenyl, -C 2～6 Alkynyl or -C 0～4 Alkylene-OR C1 ;

[0018] R C1 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl;

[0019] R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR D1 、-C 0～4 Alkylene-NR D1 R D2 、-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R D3 replace;

[0020] or R attached to the same atom 1 With R 1′ 、R 2 With R 2′ 、R 3 With R 3′ 、R 4 With R 4′ are independently connected to form 3 to 10-membered carbocyclic groups, 4 to 10-membered heterocyclic alkyl groups, The carbocyclic group and heterocyclic alkyl group may be further optionally replaced by one, two, three or four independent R D3 replace;

[0021] or R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent pairs in R 1 、R 2 、R 3 、R 4 、R 5 Any three of them are connected to each other and together with the ring where the atoms they are connected to form a 7-12 membered bridged cycloalkyl or a 7-12 membered bridged heterocycloalkyl; wherein the bridged cycloalkyl or bridged heterocycloalkyl may be further optionally replaced by one, two, three or four independent R D3 replace;

[0022] R D1 、R D2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R D4 replace;

[0023] Each R D4 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl;

[0024] Each R D3 are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C2～6 Alkynyl, -C 0～4 Alkylene-OR d1 、-C 0～4 Alkylene-OC(O)R d1 、-C 0～4 Alkylene-SR d1 、-C 0～4 Alkylene-S(O)2R d1 、-C 0～4 Alkylene-S(O)R d1 、-C 0～4 Alkylene-S(O)2NR d1 R d2 、-C 0～4 Alkylene-S(O)NR d1 R d2 、-C 0～4 Alkylene-S(O)(NH)R d1 、-C 0～4 Alkylene-S(O)(NH)NR d1 R d2 、-C 0～4 Alkylene-C(O)R d1 、-C 0～4 Alkylene-C(O)OR d1 、-C 0～4 Alkylene-C(O)NR d1 R d2 、-C 0～4 Alkylene-NR d1 R d2 、-C 0～4 Alkylene-NR d1 C(O)R d2 、-C 0～4 Alkylene-NR d1 S(O)2R d2 、-C 0～4 Alkylene-NR d1 S(O)R d2 、-C 0～4 Alkylene-P(O)R d1 R d2 、-C 0～4 Alkylene-P(O)(OR d1 )R d2 、-C 0～4 Alkylene-P(O)(OR d1 )(OR d2 ),-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4Alkylene-(6-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered aromatic heterocycle);

[0025] R d1 、R d2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl;

[0026] R 6 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～4 Alkylene-C(O)R E1 、-C 0～4 Alkylene-C(O)OR E1 、-C 0～4 Alkylene-C(O)NR E1 R E2 、-C 0～4 Alkylene-NR E1 C(O)R E2 、-C 0～4 Alkylene-NR E1 S(O)2R E2 、-C 0～4 Alkylene-NR E1 S(O)R E2 、-C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring), -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-S(O)R E1 、-C 0～4 Alkylene-S(O)2R E1 、-C 0～4 Alkylene-S(O)2NR E1 R E2 、-C 0～4 Alkylene-S(O)(NH)R E1 、-C 0～4 Alkylene-S(O)(NH)NR E1 R E2 、-C 0～4 Alkylene-OR E1、-C 0～4 Alkylene-OC(O)R E1 、-C 0～4 Alkylene-SR E1 、-C 0～4 Alkylene-P(O)R E1 R E2 、-C 0～4 Alkylene-P(O)(OR E1 )R E2 or -C 0～4 Alkylene-P(O)(OR E1 )(OR E2 ) wherein alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, aryl, heteroaryl may be further optionally replaced by one, two, three or four independent R E5 replace;

[0027] R E1 、R E2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-OR E3 、-C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring), -C 0～4 Alkylene-S(O)R E3 、-C 0～4 Alkylene-S(O)2R E3 、-C 0～4 Alkylene--S(O)2NR E3 R E4 、-C 0～4 Alkylene-S(O)(NH)R E3 、-C 0～4 Alkylene-S(O)(NH)NR E3 R E4 、-C 0～4 Alkylene-OC(O)R E3 or -C 0～4 Alkylene-SR E3 wherein alkyl, alkylene, carbocyclyl, heterocycloalkyl, aryl, heteroaryl may be further optionally replaced by one, two, three or four independent R E5 replace;

[0028] or R E1 、R E2Connected to form 4 to 10 membered heterocycloalkyl, 4 to 10 membered bridged heterocycloalkyl; wherein the heterocycloalkyl and bridged heterocycloalkyl can be further optionally replaced by one, two, three or four independent R E5 replace;

[0029] R E3 、R E4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; or R E3 、R E4 The nitrogen atom connected thereto forms a 4-10 membered heterocycloalkyl group or a 4-10 membered bridged heterocycloalkyl group; wherein the heterocycloalkyl group and the bridged heterocycloalkyl group may be further optionally replaced by one, two, three or four independent R E5 replace;

[0030] or R E3 、R E4 Connected to each other, together to form a 4-10 membered heterocycloalkyl, a 4-10 membered bridged heterocycloalkyl; wherein the heterocycloalkyl, bridged heterocycloalkyl can be further optionally replaced by one, two, three or four independent R E5 replace;

[0031] Each R E5 independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -O(C 1～6 Alkyl), -NH2, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring) or -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein the carbocyclic group, heterocyclic alkyl group, aryl group, heteroaryl group may be further optionally replaced by one, two, three or four independent R E6 replace;

[0032] R E6 independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl.

[0033] In some embodiments of the present invention, when R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ are all selected from hydrogen, and X is O, Y 1 When it is CH, m is not 1.

[0034] In some embodiments of the present invention, preferably, n1 and n2 are 1, n3 and n4 are 2; or, n1 and n2 are 2, n3 and n4 are 1. Preferably, Y 1 N, Y 2 N; or Y 1 CH, Y 2 is N. Preferably, m is 1 or 2; more preferably, m is 1.

[0035] In some embodiments of the present invention, preferably, W is selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, methoxymethyl, amino, methylamino, dimethylamino.

[0036] In some embodiments of the present invention, preferably, X is selected from CR a R b NR a or O; more preferably, X is selected from CR a R b or NR a .

[0037] In some embodiments of the present invention, X is selected from CR a R b When, preferably, R a 、R b are independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C0 alkylene-OR A1 、-C1 alkylene-OR A1 、-C2 alkylene-OR A1 、-C3 alkylene-OR A1 ; R A1Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0038] In some embodiments of the present invention, X is selected from CR a R b When, preferably, R a is hydrogen, R b Selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C0 alkylene-OR A1 、-C1 alkylene-OR A1 、-C2 alkylene-OR A1 、-C3 alkylene-OR A1 ; R A1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0039] In some embodiments of the present invention, X is selected from CR a R b When, preferably, R a 、R b are the same and are selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C0 alkylene-OR A1 、-C1 alkylene-OR A1 、-C2 alkylene-OR A1 、-C3 alkylene-OR A1 ; R A1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0040] In some embodiments of the present invention, X is selected from CR a R b When, preferably, R a 、R b Together with the atoms it is connected to, it forms 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; each R B1 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0041] In some embodiments of the present invention, X is selected from NR a When, preferably, R a Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C1 alkylene-OR A1 、-C2 alkylene-OR A1 、-C3 alkylene-OR A1; R A1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0042] In some embodiments of the present invention, preferably, R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ Each of the following groups is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl and trifluoromethyl.

[0043] In some embodiments of the present invention, preferably, R 1′ 、R 2′ 、R 3′ 、R 4′ R is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl; 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent atoms in the group are connected to each other and together with the ring where the atoms they are connected to form a 7-membered bridged cycloalkyl, an 8-membered bridged cycloalkyl, or a 9-membered bridged cycloalkyl; wherein R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent groups connected to each other are selected from -CH2-, -CH2CH2-, -CH2CH2CH 2- More preferably, R 2 and R 4 are connected to each other, or R 2 and R 3 are connected to each other, or R 1 and R 4 are connected to each other.

[0044] In some embodiments of the present invention, preferably, R 6 Selected from -C(O)NR E1 R E2 ; R E1 、R E2They are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -C4 alkyl, -C5 alkyl, -C6 alkyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -C1 alkylene-(3-membered carbocyclyl), -C1 alkylene-(4-membered carbocyclyl), -C1 alkylene-(5-membered carbocyclyl), -C1 alkylene-(6-membered carbocyclyl).

[0045] In some embodiments of the present invention, preferably, R 6 is selected from 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, -C1 alkylene-(5-membered heteroaromatic ring), -C1 alkylene-(6-membered heteroaromatic ring); wherein the heteroaromatic group may be further optionally replaced by one, two, three or four independent R E5 Replace; each R E5 Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, and 6-membered carbocyclyl.

[0046] Furthermore,

[0047] X is selected from CR a R b or NR a ;

[0048] R a 、R b are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 Alkyl, deuterium-substituted -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～2 Alkylene-OR A1 、-C 0～2 Alkylene-NR A1 R A2 、-C 0～2 Alkylene-NR A1 C(O)R A2 、-C 0～4 Alkylene-C(O)NR A1 R A2 、-C 0～4 Alkylene-C(O)R A1 、-C 0～4 Alkylene-S(O)2NR A1 R A2 、-C 0～4 Alkylene-NR A1 S(O)2R A2 、-C0～2 Alkylene-(3-10 membered carbocyclic group), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring) or -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R B1 replace;

[0049] or R a 、R b Together with the atoms it is connected to, it forms 3-6 membered carbocyclic group, 4-6 membered heterocyclic alkyl group; wherein, the carbocyclic group and heterocyclic alkyl group may be further optionally replaced by one, two, three or four independent R B1 replace;

[0050] R A1 、R A2 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 1～2 Alkylene-C(O)R B1 、-C 1～2 Alkylene-(3-10 membered carbocyclic group), -C 1～2 Alkylene-(4-10 membered heterocycloalkyl), -C 1～2 Alkylene-(6-10 membered aromatic ring) or -C 1～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R B1 replace;

[0051] Y 1 、Y 2 are independently selected from CH or N;

[0052] m is selected from 1 or 2;

[0053] W is selected from hydrogen, methyl, trifluoromethyl, methoxy, and methylamino.

[0054] Furthermore,

[0055] X is selected from NR a ;

[0056] R a Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,

[0057] Furthermore,

[0058] X is selected from CR a R b ;

[0059] R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0060] Or, R a 、R b Together with the atoms it is connected to, it forms

[0061] In some embodiments of the present invention, R a is hydrogen, R b Selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0062] In some embodiments of the present invention, R a 、R b The same, and selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0063] In some embodiments of the present invention, further,

[0064] The ring L is selected from

[0065] In some embodiments of the present invention, further,

[0066] The ring L is selected from The one marked with * is connected to the aromatic ring, and the other is connected to the methylene group.

[0067] In some embodiments of the present invention, further,

[0068] R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 Alkyl, -C2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Preferably, R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ All are hydrogen.

[0069] In some embodiments of the present invention, further,

[0070] R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR D1 or -C 0～4 Alkylene-NR D1 R D2 ;

[0071] R D1 、R D2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl or -C 2～6 Alkynyl;

[0072] R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent atoms in the group are connected to each other and together with the ring where the atoms they are connected to form a 7-12 membered bridged cycloalkyl group or a 7-12 membered bridged heterocycloalkyl group;

[0073] Among them, R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent groups connected to each other are selected from -O-, -(CRD3 R D3 ) q -、-(CR D3 R D3 ) n -O-(CR D3 R D3 ) n -、-(CR D3 R D3 ) n -S-(CR D3 R D3 ) n -、-(CR D3 R D3 ) n -N(R D3 )-(CR D3 R D3 ) n -、-O-(CR D3 R D3 ) n -O-、-O-(CR D3 R D3 ) n -S-、-O-(CR D3 R D3 ) n -N(R D3 )-、-S-(CR D3 R D3 ) n -O-、-S-(CR D3 R D3 ) n -S-、-S-(CR D3 R D3 ) n -N(R D3 )-、-N(R D3 )-(CR D3 R D3 ) n -N(R D3 )-、-N(R D3 )-(CR D3 R D3 ) n -O- or -N(R D3 )-(CR D3 R D3 ) n -S-;

[0074] Each n is independently selected from 0, 1, 2 or 3;

[0075] Each q is independently selected from 1, 2 or 3;

[0076] Each R D3 are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl; or two R D3 Together

[0077] More specifically,

[0078] R 1 、R 2 、R 3 、R 4 、R 5 The two atoms are connected to each other and together form a ring with the atoms they are connected to.

[0079] Among them, R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen, -C 1-6 alkyl.

[0080] In some embodiments of the present invention, further,

[0081] R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR D1 or -C 0～4 Alkylene-NR D1 R D2 ;

[0082] R D1 、R D2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl or -C 2～6 Alkynyl;

[0083] R 1 、R 2 、R 3 、R 4 、R 5 Any three of them are connected to each other and together with the ring where the atoms they are connected to form a 7-12 membered bridged cycloalkyl or a 7-12 membered bridged heterocycloalkyl;

[0084] Among them, R 1 、R 2 、R 3 、R 4 、R 5 Any two of them are connected to each other and are selected from -O-, -(CR D3 R D3 ) q -、-(CR D3 R D3 ) n -O-(CR D3 R D3 ) n -、-(CR D3 R D3 ) n -S-(CR D3 R D3 ) n -、-(CR D3 R D3 ) n -N(R D3 )-(CR D3 R D3 ) n -、-O-(CR D3 R D3 ) n -O-、-O-(CR D3 R D3 ) n -S-、-O-(CR D3 R D3 ) n -N(R D3 )-、-S-(CR D3 R D3 ) n -O-、-S-(CR D3 R D3 ) n -S-、-S-(CR D3 R D3 ) n -N(R D3 )-、-N(R D3 )-(CR D3 R D3 ) n -N(RD3 )-、-N(R D3 )-(CR D3 R D3 ) n -O- or -N(R D3 )-(CR D3 R D3 ) n -S-; the third party is connected to the carbon atom or nitrogen atom on the connecting chain formed by the first two.

[0085] Each n is independently selected from 0, 1, 2 or 3;

[0086] Each q is independently selected from 1, 2 or 3;

[0087] Each R D3 are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl; or two R D3 Together

[0088] More specifically,

[0089] R 1 、R 4 、R 5 The three are connected to each other and together with the ring where the atoms they are connected to form

[0090] In some embodiments of the present invention, further,

[0091] R 6 Selected from -C(O)NR E1 R E2 、-NR E1 C(O)R E2 、-NR E1 S(O)2R E2 、-NR E1 S(O)R E2 , -5- to 10-membered aromatic ring, -5- to 10-membered heteroaromatic ring, -3- to 10-membered carbocyclic group, -4- to 10-membered heterocycloalkyl group, -S(O)R E1 、-S(O)2R E1 、-S(O)2NR E1 R E2 、-S(O)(NH)R E1 、-S(O)(NH)NRE1 R E2 、-OR E1 、-OC(O)R E1 or -SR E1 wherein alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, aryl, heteroaryl may be further optionally replaced by one, two, three or four independent R E5 replace.

[0092] Preferably, R 6 Selected from -C(O)NR E1 R E2 、-NR E1 C(O)R E2 、-NR E1 S(O)2R E2 、-NR E1 S(O)R E2 , 6-membered aromatic ring, -5-membered heteroaromatic ring, -6-membered heteroaromatic ring, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -4-membered heterocycloalkyl, -5-membered heterocycloalkyl, -6-membered heterocycloalkyl, -S(O)R E1 、-S(O)2R E1 、-S(O)2NR E1 R E2 、-S(O)(NH)R E1 、-S(O)(NH)NR E1 R E2 、-OR E1 、-OC(O)R E1 or -SR E1 wherein the carbocyclyl, heterocyclylalkyl, aryl, heteroaryl may be further optionally replaced by one, two, three or four independent R E5 replace;

[0093] Preferably, R E1 、R E2 Each of the following groups is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C4 alkyl, -C5 alkyl, -C6 alkyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -C1 alkylene-(3-membered carbocyclyl), -C1 alkylene-(4-membered carbocyclyl), -C1 alkylene-(5-membered carbocyclyl), and -C1 alkylene-(6-membered carbocyclyl).

[0094] More specifically, R 6 Selected from:

[0095]

[0096] In some embodiments of the present invention, the general formula shown in Formula I can be as follows:

[0097]

[0098]

[0099] Wherein, the substituents are defined as above.

[0100] In some embodiments of the present invention, the general formula shown in Formula I can be as follows:

[0101]

[0102] Wherein, the substituents are defined as above.

[0103] In some embodiments of the present invention, further, the general formula shown in Formula I can be as follows:

[0104]

[0105]

[0106] Wherein, the substituents are defined as above.

[0107] In some embodiments of the present invention, the compound is represented by Formula II:

[0108]

[0109] Among them, Y 1 、Y 2 , W, X, R 6 ,m,R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ The definitions are as above.

[0110] In some embodiments of the present invention, the compound is represented by Formula IIa or Formula IIb:

[0111]

[0112] Among them, Y 1 、Y 2 , W, X, R 6 The definitions are as above.

[0113] In some embodiments of the present invention, the compound is represented by Formula IIIa or Formula IIIb:

[0114]

[0115] in,

[0116] Y 1 、Y 2 are independently selected from CH or N; preferably, Y 1 N, Y 2 N; or, Y 1 CH, Y 2 is N;

[0117] R a Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,

[0118] R 6 Selected from

[0119]

[0120] In some embodiments of the present invention, the compound is represented by Formula IVa or Formula IVb:

[0121]

[0122] in,

[0123] Y 1 、Y 2 are independently selected from CH or N; preferably, Y 1 N, Y 2 N; or, Y 1 CH, Y 2 is N;

[0124] R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0125] or

[0126] Or, R a 、R b Together with the atoms it is connected to, it forms

[0127] Preferably, Ra is hydrogen, R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0128] Or, R a 、R b The same, and selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0129] R 6 Selected from

[0130]

[0131] In some embodiments of the present invention, the compound is represented by Formula Va:

[0132]

[0133] in,

[0134] Y 1 、Y 2 are independently selected from CH or N; preferably, Y 1 N, Y 2 N; or, Y 1 CH, Y 2 is N;

[0135] R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl,

[0136] Or, R a 、R b Together with the atoms it is connected to, it forms

[0137] R 6 Selected from

[0138] In some specific embodiments of the present invention, the compound is specifically:

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158] In other specific embodiments of the present invention, the compound is specifically:

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] The present invention also provides the use of the above-mentioned compound, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt in the preparation of a drug for treating a disease associated with abnormal Menin activity.

[0167] The present invention also provides the use of the above-mentioned compound, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt in the preparation of a drug for treating cancer.

[0168] The present invention also provides a pharmaceutical composition comprising a preparation prepared from any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0169] The pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0170] The compound of the present invention has excellent Menin-MLL protein-protein interaction inhibitory activity and cell proliferation inhibitory activity, and has excellent performance in safety, bioavailability and animal efficacy.

[0171] Diseases associated with Menin-MLL interaction or Menin-MLL fusion protein interaction as defined herein include one or more of cancer or malignant tumors, diabetes, and other Menin-related diseases. "Cancer" or "malignant tumor" refers to any of a variety of diseases characterized by uncontrolled abnormal cell proliferation, the ability of affected cells to spread locally or to other parts of the body via the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cell" refers to a cell that is undergoing an early, intermediate, or late stage of multi-step tumor progression. The "cancer" or "malignant tumor" is leukemia, lymphoma, sarcoma, lung cancer, esophageal cancer, gastric cancer, liver cancer, brain tumor, myeloma, pancreatic cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, multiple myeloma, brain tumor, or multiple endocrine carcinoma.

[0172] In particular embodiments, the compounds of the invention are used to treat leukemias associated with MLL rearrangement, acute lymphocytic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoid leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute myeloblastic leukemia associated with MLL rearrangement, where "MLL rearrangement" as used herein means rearrangement of the MLL gene. In certain embodiments, diseases or conditions treatable with the compounds of the invention include insulin resistance, prediabetes, diabetes (such as type II diabetes or type I diabetes), and risk of diabetes, and hyperglycemia.

[0173] Combination Therapies: The present invention also relates to combination therapies for treating the diseases or disorders described herein. In certain embodiments, combination therapies comprise administering at least one compound of the present invention in combination with one or more other pharmaceutically active agents for treating cancer or other diseases mediated by Menin / MLL. The pharmaceutically active agents can be combined with the compounds of the present invention in a single dosage form, or the therapeutic agents can be administered simultaneously or sequentially as separate dosage forms. The compounds of the present invention can also be used in combination with immunotherapies, including but not limited to cell-based therapies, antibody therapies, and cytokine therapies, for treating the diseases or disorders disclosed herein.

[0174] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0175] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0176] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons in the atoms in the molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0177] “May be further optionally substituted”, “may be further substituted”, and “may be optionally substituted” all mean that “substitution” may but does not have to occur, and the description includes situations where it occurs or does not occur.

[0178] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0179] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as -O(C 1～6 alkyl).

[0180] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0181] The -C0-4 alkylene group of the present invention can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-), a C3 alkylene group, or a C4 alkylene group. A C0 alkylene group refers to a group that is absent and connected by a chemical bond. A-C0 alkylene-B refers to AB, where the A group and the B group are directly connected by a chemical bond. For example, -C0 alkylene-(3-membered cycloalkyl) refers to a cyclopropyl group.

[0182] The unsaturated group mentioned in the present invention refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, etc.

[0183] "Alkenyl" refers to a straight or branched chain hydrocarbon group having at least one site of vinyl unsaturation (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0184] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon radicals having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0185] " carbocyclyl " described in the present invention refers to the saturated or non-aromatic partially saturated cyclic group with multiple carbon atoms and no ring heteroatoms with single ring or multiple rings (fused, bridged, spiro).Term " carbocyclyl " includes cycloalkenyl groups, such as cyclohexenyl.The example of monocarbocyclyl group includes for example cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.The carbocyclyl group example of condensed carbocyclyl system comprises dicyclohexyl, dicyclopentyl, dicyclooctyl etc., and exemplifies and names two kinds of this type of bicyclic alkyl polycyclic structures below: Biscyclohexyl and Examples of carbocyclyl groups of the bridged carbocyclyl system include Adamantyl, etc. Examples of the carbocyclyl group of the spirocarbocyclyl system include The term "carbocyclyl" also includes partially saturated cyclic groups formed by condensing an aromatic ring with a non-aromatic ring, wherein the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0186] The "bridged ring" and "bridged cycloalkyl" mentioned in the present invention refer to a saturated or non-aromatic partially saturated cyclic group formed by bridging multiple rings with multiple carbon atoms and no ring heteroatoms. Examples of this term include but are not limited to Adamantyl, etc.

[0187] As used herein, "heterocycloalkyl" refers to a saturated or non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, or spiro) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, or the like. It generally refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system with multiple ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyl groups in monoheterocycloalkyl systems include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, and the like. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems include etc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system include Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl. The term "heterocycloalkyl" also includes partially saturated cyclic groups formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, wherein the attachment point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. Examples include

[0188] The "bridged heterocycle" and "bridged heterocycloalkyl" mentioned in the present invention refer to a saturated ring or a non-aromatic partially saturated ring formed by bridging multiple rings containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of this term include but are not limited to wait.

[0189] As used herein, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0190] As used herein, "aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; the heteroatom being a nitrogen atom, an oxygen atom, a sulfur atom, or the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heterocyclic aryl groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0191] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0192] The "halogen-substituted alkyl" mentioned in the present invention refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen; for example, a halogen-substituted C 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0193] The "deuterium-substituted alkyl" mentioned in the present invention refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium; for example, a deuterium-substituted C 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which one or more deuterium atoms replace a hydrogen atom; examples include monodeuteriomethyl, dideuteriomethyl, and trideuteriomethyl.

[0194] The "-OR", "-NRR" and the like described in the present invention refer to that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0195] In the present invention, the oxygen atom in "-C(O)R", "-S(O)2R", etc. is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond. For example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0196] The "oxo" mentioned in the present invention refers to =O, that is, an oxygen atom replaces two hydrogen atoms or lone pairs of electrons through a double bond.

[0197] “___” in the description of the group of the present invention It is used to describe the position of the substitution group. For example refers to the tetrahydropyrrole ring passing through The position forms a spiral ring with other rings in the structure.

[0198] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0199] "Stereoisomers" of the present invention refer to compounds composed of the same atoms, bonded by the same chemical bonds, but with different three-dimensional structures. The stereoisomers of the present invention cover each single stereoisomer and its compounds, including but not limited to enantiomers and diastereomers. The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, such as crystallization and chiral chromatography.

[0200] When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the compounds of the present invention include cis- and trans-isomers of the E- and Z-types. All tautomeric forms of the compounds of the present invention are also included within the scope of the present invention.

[0201] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0202] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0203] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0204] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made. BRIEF DESCRIPTION OF THE DRAWINGS

[0205] Figure 1 : X-ray single crystal diffraction pattern of intermediate A1-a;

[0206] Figure 2 : X-ray single crystal diffraction pattern of intermediate A1-b;

[0207] Figure 3 : X-ray single crystal diffraction pattern of intermediate 7-5a1;

[0208] Figure 4 : X-ray single crystal diffraction pattern of intermediate 7-5a2;

[0209] Figure 5 : X-ray single crystal diffraction results of Example 19. DETAILED DESCRIPTION

[0210] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0211] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0212] The reagent abbreviations described in the examples are as follows: UHP: urea peroxide; DBU: 1,8-diazabicycloundec-7-ene; TCCA: trichloroisocyanuric acid; KOAc: potassium acetate; Na2HPO4: disodium hydrogen phosphate; TFAA: trifluoroacetic anhydride; DIPEA: N,N-diisopropylethylamine; n-BuLi: n-butyllithium; NH2OH·HCl: hydroxylamine hydrochloride; NiCl2·6H2O: nickel chloride hexahydrate; NaBH4: sodium borohydride; NaBH3CN: sodium cyanoborohydride; NFSI: N-fluorobisbenzenesulfonamide; TEA: triethylamine; Py SO3: sulfur trioxide pyridine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMF: N,N-dimethylformamide; DCM: dichloromethane; DCE: 1,2-dichloroethane; TFA: trifluoroacetic acid; MeCN: acetonitrile; EtOH: ethanol; MeOH: methanol; NMP: N-methylpyrrolidone.

[0213] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0214] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a (Bruker AvanceIII 400MHz and Bruker Avance NEO600MHz) nuclear magnetic spectrometer, with the solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard being tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu LC-MS2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) was performed using a Gilson GX-281 reverse phase preparative chromatograph. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as a carrier. Supercritical fluid chromatography (SFC) analysis and preparative analysis are performed using a SHIMADZU SFC-30A instrument.

[0215] Synthesis of intermediates 1-3

[0216]

[0217] Step 1: Synthesis of 1-2

[0218] To a solution of 5-fluoro-2-methoxybenzoic acid (45 g, 264.49 mmol) and ethylisopropylamine (23.21 g, 317.39 mmol) in DCM (880 mL) at 0°C were added HATU (120.61 g, 317.39 mmol) and DIPEA (102.55 g, 793.48 mmol, 138.21 mL). The reaction mixture was slowly warmed to room temperature and stirred for 17 hours. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined. The crude product obtained by concentration was purified by silica gel column chromatography to afford Intermediate 1-2 (60 g, 250.75 mmol, 94.8% yield). MS m / z = 240 [M+H] + .

[0219] Step 2: Synthesis of 1-3

[0220] To a solution of 1-2 (63 g, 263.28 mmol) in DCM (200.00 mL) was added dropwise BBr (131.64 g, 526.57 mmol) at -70°C. The reaction mixture was slowly warmed to room temperature and stirred for 17 hours. After completion, the mixture was cooled to -70°C and quenched with MeOH. Extraction was performed with EA. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product 1-3 (49 g, 217.53 mmol, 82.6% yield) was used directly in the next step without further purification. MS m / z = 226 [M+H] + .

[0221] Synthesis of intermediates 1-5

[0222]

[0223] Referring to the synthetic route of intermediate 1-3, diisopropylamine was used instead of ethylisopropylamine to obtain intermediate 1-5. MSm / z=240[M+H] + .

[0224] Synthesis of intermediates 1-7

[0225]

[0226] Referring to the synthetic route of intermediate 1-3, dicyclopropylamine was used instead of ethylisopropylamine to obtain intermediate 1-7. MS m / z = 236 [M+H] + .

[0227] Synthesis of intermediate 1-11

[0228]

[0229] Step 1: Synthesis of 1-9

[0230] At room temperature, 1-8 (3 g, 52.54 mmol) was dissolved in anhydrous methanol (40 mL), followed by the addition of 4N HCl / MeOH (46 mL), acetone (7.63 g, 131.37 mmol), and NaBH3CN (4.97 g, 78.81 mmol). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated directly, and the crude product was dissolved in 10% aqueous NaOH and extracted three times with MTBE. The organic phases were combined, acidified with HCl / MeOH, and concentrated to yield the crude product (6.5 g, 47.92 mmol, 91.2% yield), which was used directly in the next reaction. MS m / z = 100 [M+H] + .

[0231] Step 2~Step 3: Synthesis of 1-11

[0232] Referring to the synthetic route of intermediate 1-3, 1-9 was used instead of ethylisopropylamine to obtain the target intermediate 1-11. MSm / z=238[M+H] + .

[0233] Synthesis of intermediate 1-15

[0234]

[0235] Step 1: Synthesis of 1-13

[0236] At room temperature, 1-12 (3.56 g, 50.06 mmol) was dissolved in anhydrous methanol (40 mL), followed by the addition of acetone (7.27 g, 125.14 mmol) and NaBH3CN (4.73 g, 75.08 mmol), and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated directly, and the crude product was dissolved in 10% aqueous NaOH and extracted three times with MTBE. The organic phases were combined, acidified with HCl / MeOH, and concentrated to yield the crude product (6.5 g, 43.43 mmol, 86.7% yield), which was used directly in the next reaction. MS m / z = 114 [M+H] + .

[0237] Step 2~Step 3: Synthesis of 1-15

[0238] Referring to the synthetic route of intermediate 1-3, 1-13 was substituted for ethylisopropylamine to obtain the target intermediate 1-15. MS m / z = 252 [M+H] + .

[0239] Synthesis of intermediate 1-17

[0240]

[0241] Referring to the synthetic route of intermediate 1-3, ethylisopropylamine was replaced with isopropylmethylamine to obtain intermediate 1-17. MS m / z = 212 [M+H] + .

[0242] Synthesis of intermediate 1-22

[0243]

[0244] Step 1: Synthesis of 1-18

[0245] Under ice, 1-8 (3.0 g, 52.54 mmol) was dissolved in DCM (50 mL). (Boc)2O (12.04 g, 55.17 mmol) and triethylamine (6.37 g, 63.05 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. After completion, the reaction was diluted with water and extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product 1-18 was used directly in the next reaction without further purification. MS m / z = 158 [M+H] + .

[0246] Step 2: Synthesis of 1-19

[0247] 1-18 (8.33 g, 52.99 mmol) was dissolved in anhydrous DMF at 0°C. NaH (1.34 g, 55.64 mmol) was added under nitrogen and allowed to react at 0°C for 30 min. Ethyl iodide (9.9 g, 58.29 mmol) was slowly added dropwise. After completion of the addition, the mixture was warmed to room temperature and stirred. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to yield 1-19 (5.6 g, 30.23 mmol, 57% yield). MS m / z = 186 [M+H] + .

[0248] Step 3: Synthesis of 1-20

[0249] Dissolve 1-19 (5.6 g, 30.23 mmol) in MTBE, slowly add HCl / EA dropwise, stir at room temperature until solid no longer precipitates, filter, and rinse the filter cake with a small amount of EA to obtain intermediate 1-20 (2.74 g, 22.53 mmol, yield 74.52%). MS m / z = 86 [M+H] + .

[0250] Step 4~Step 5: Synthesis of 1-22

[0251] Referring to the synthetic route of intermediate 1-3, 1-20 was substituted for ethylisopropylamine to obtain the target intermediate 1-22. MS m / z = 224 [M+H] + .

[0252] Synthesis of intermediate 1-25

[0253]

[0254] 1-23 (680 mg, 3.56 mmol) was dissolved in a mixture of dioxane (15 mL) and water (3 mL). 1-24 (1.01 g, 4.27 mmol), Na2CO3 (754.77 mg, 7.12 mmol), and Pd(dppf)Cl2 (130.13 mg, 0.178 mmol) were added sequentially, and the mixture was stirred at 90°C overnight. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to yield 1-25 (700 mg, 3.18 mmol, 89% yield). MS m / z = 221 [M+H] + .

[0255]

[0256] Referring to the synthesis method of 1-25, 1-26 was used instead of 1-24 to give 1-27 (232 mg, 1.0 mmol, yield 80%). MS m / z = 233 [M+H] + .

[0257] Synthesis of intermediates M1-M8

[0258]

[0259] Step 1: Synthesis of 2-2

[0260] At 0°C, 2-1 (4.9 g, 26.57 mmol) and TEA (5.38 g, 53.14 mmol) were dissolved in DCM. A solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (4.81 g, 21.26 mmol) in DCM was slowly added dropwise. The mixture was stirred at this temperature for 2 h. After completion of the reaction, the mixture was diluted with water and extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 5:1 to 1:1, v / v) to afford 2-2 (6.5 g, 17.37 mmol, yield 65.37%). MS m / z = 374 [M+H] + .

[0261] Step 2: Synthesis of 2-3

[0262] At 0°C, 2-2 (1.0 g, 2.67 mmol) and DBU (488.13 mg, 3.21 mmol) were dissolved in THF. 1-3 (601 mg, 2.67 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 10:1 to 5:1, v / v) to afford 2-3 (1.04 g, 1.84 mmol, 68.9% yield). MS m / z = 563 [M+H] + .

[0263] Step 3: Synthesis of 2-4

[0264] At room temperature, 2-3 (1.04 g, 1.84 mmol) was dissolved in anhydrous methanol, and Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added. The hydrogen atmosphere was replaced and the reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the reaction was filtered, the filtrate was concentrated, and purified on a silica gel column (PE / EA = 5:1 to 1:1, v / v) to afford 2-4 (625 mg, 1.18 mmol, yield 64.13%). MS m / z = 529 [M+H] + .

[0265] Step 4: Synthesis of M1

[0266] 2-4 (40 g, 75.67 mmol) was dissolved in DCM (70 mL) at 0°C. TFA (30 mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was concentrated and adjusted to a weakly alkaline state by adding aqueous NaHCO₃. The crude product M1 was extracted and concentrated with DCM and used directly in the next reaction. MS m / z = 429 [M+H] + .

[0267] Synthesis of intermediate M2

[0268]

[0269] Step 1: Synthesis of 2-5

[0270] At 0°C, M1 intermediate 2-2 (1.0 g, 2.67 mmol) and DBU (488.13 mg, 3.21 mmol) were dissolved in THF. 1-5 (601 mg, 2.67 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 10:1 to 5:1, v / v) to afford 2-5 (1.0 g, 1.73 mmol, 64.9% yield). MS m / z = 577 [M+H] + .

[0271] Step 2: Synthesis of 2-6

[0272] At room temperature, 2-5 (1.0 g, 1.73 mmol) was dissolved in anhydrous methanol, and Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added. The hydrogen atmosphere was replaced and the reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the reaction was filtered, the filtrate was concentrated, and purified on a silica gel column (PE / EA = 5:1 to 1:1, v / v) to give 2-6 (720 mg, 1.33 mmol, yield 76.79%). MS m / z = 543 [M+H] + .

[0273] Step 3: Synthesis of M2

[0274] 2-6 (4.0 g, 7.38 mmol) was dissolved in DCM (7 mL) at 0°C. TFA (3 mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was concentrated and adjusted to a weakly alkaline state by adding aqueous NaHCO₃. The crude product M2 was extracted and concentrated with DCM and used directly in the next reaction. MS m / z = 443 [M+H] + .

[0275] Referring to the synthesis method of intermediate M1, 1-7, 1-11, 1-15, 1-17, 1-22, and 1-27 were used to replace 1-3, and the corresponding intermediates M3-M8 were obtained.

[0276]

[0277] Synthesis of intermediates N1-N6

[0278]

[0279]

[0280] Step 1: Synthesis of 3-1

[0281] At room temperature, 1-3 (10 g, 44.39 mmol) and 5-bromopyrimidine (21.17 g, 133.18 mmol) were dissolved in DMF, cesium carbonate (43.39 g, 133.18 mmol) was added, and the mixture was heated to 130°C and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 4:1, v / v) to afford 3-1 (11 g, 36.26 mmol, yield 81.68%). MS m / z = 304 [M+H] + .

[0282] Step 2: Synthesis of 3-2

[0283] 3-1 (8.0 g, 26.37 mmol) was dissolved in DCM, and m-CPBA (13.61 g, 79.12 mmol) was slowly added at 0°C. The mixture was allowed to warm to room temperature and stirred for 24 h. After completion, the reaction was cooled to 0°C and quenched with saturated aqueous sodium thiosulfate. The mixture was then extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column to yield 3-2 (5.6 g, 17.54 mmol, 66.51% yield). MS m / z = 320 [M+H] + .

[0284] Step 3: Synthesis of 3-3

[0285] Dissolve triethylamine (3.55 g, 35.07 mmol) in DCM and slowly add POCl3 (4.03 g, 26.31 mmol) dropwise at 0°C. Then, add a DCM solution of 3-2 (5.6 g, 17.54 mmol) dropwise to the reaction mixture. After the addition is complete, warm to room temperature and stir overnight. After completion of the reaction, slowly pour the reaction mixture into ice water, stir for half an hour, and extract three times with DCM. The organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product is purified on a silica gel column to yield 3-3 (1.7 g, 5.03 mmol, 28.67% yield). MS m / z = 338 [M+H] + .

[0286] Step 4: Synthesis of 3-4

[0287] 3-3 (1.0 g, 2.96 mmol) was dissolved in isopropanol, and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (871 mg, 3.85 mmol) and DIPEA (1.15 g, 8.88 mmol) were added at room temperature. The mixture was heated to 80°C and stirred for 2 h. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 2:1, v / v) to afford 3-4 (1.54 g, 2.92 mmol, 98.6% yield). MS m / z = 528 [M+H] + .

[0288] Step 5: Synthesis of N1

[0289] 3-4 (1.54 g, 2.92 mmol) was dissolved in DCM (20 mL) at 0°C. TFA (10 mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was concentrated and adjusted to a weakly alkaline state by adding aqueous NaHCO₃. The crude product was extracted and concentrated with DCM and used directly in the next reaction. MS m / z = 428 [M+H] + .

[0290] Referring to the synthesis method of intermediate N1, 1-3 was replaced by 1-5, 1-7, 1-11, 1-15, and 1-25, respectively, to obtain the corresponding intermediates N2-N6.

[0291]

[0292] Synthesis of intermediates A1-a and A1-b

[0293]

[0294] Step 1: Synthesis of 4-2

[0295] To a solution of ethyl p-cyclohexanonecarboxylate (6.8 g, 40 mmol) in EtOH (80 mL) at room temperature were added hydroxylamine hydrochloride (3.34 g, 48.06 mmol) and KOAc (4.72 g, 48.08 mmol). The reaction mixture was heated to 80°C and stirred for 4 h. After completion of the reaction, the organic phase was removed by rotary evaporation to obtain the crude product, which was diluted with water and extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified on a silica gel column (PE / EA = 5:1, v / v) to afford 4-2 (4.08 g, 22.02 mmol, 55.05% yield). MS m / z = 186 [M+H] + .

[0296] Step 2: Synthesis of 4-3

[0297] 4-2 (372 mg, 2.01 mmol) and sodium bicarbonate (4.22 g, 50.21 mmol) were dissolved in ethyl acetate (60 mL) and water (60 mL), respectively. TCCA (2.33 g, 10.04 mmol) was added portionwise while the two phases were mixed and stirred. The organic phase turned blue. After stirring at room temperature for 9 h, the organic phase turned from blue to colorless. After completion of the reaction, the reaction mixture was placed in a separatory funnel and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 10:1, v / v) to obtain 4-3 (320 mg, 1.36 mmol, yield 67.66%). MS m / z = 236 [M+H] + .

[0298] Step 3: Synthesis of 4-4

[0299] NaBH4 (4.05 g, 106.93 mmol) was added portionwise to a solution of 4-3 (18 g, 76.38 mmol) and Pd / C (1.27 g, 10.49 mmol) in EtOH (200 mL) at -20°C. The reaction was complete upon completion of the addition. After completion, the reaction was filtered through Celite, the filtrate concentrated, dissolved in EA, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and dried. The concentrated crude product was purified on a silica gel column (PE / EA = 10:1, v / v) to afford 4-4 (8.4 g, 41.75 mmol, 54.67% yield). MS m / z = 202 [M+H] + .

[0300] Step 4: Synthesis of 4-5a and 4-5b

[0301] DBU (1.97 g, 12.94 mmol) was added dropwise to a solution of 4-4 (2.17 g, 10.78 mmol) in MeCN (30 mL) at 0°C, and methyl acrylate (1.11 g, 12.94 mmol) was added dropwise thereto, followed by reaction at 0°C for 1 h. After completion of the reaction, water was added, and the mixture was extracted with EA, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and dried. The mixture was purified by silica gel column chromatography (PE / EA = 40 / 1 → 10 / 1) to give the product 4-5a (1.035 g, 3.6 mmol, 33.39% yield, PE / EA = 30 / 1, MS m / z = 288 [M+H] + ) and 4-5b (1.424 g, 4.96 mmol, yield 46%, PE / EA = 10 / 1, MS m / z = 288 [M+H] + ). TLC developing solvent PE / EA=5 / 1:4-5a, R f =0.5;4-5b,Rf =0.3.

[0302] Step 5: Synthesis of 4-6a and 4-6b

[0303] To a solution of 4-5a (330 mg, 1.15 mmol) and NiCl2·6H2O (272.88 mg, 1.15 mmol) in MeOH (3 mL) was added portionwise with NaBH4 (217.26 mg, 5.74 mmol) at -10°C for 2 h. A solution of K2CO3 (634.94 mg, 4.59 mmol) in water (1 mL) was then added dropwise, followed by 2 h at 0°C. After completion, the reaction was filtered over Celite, and the filtrate was adjusted to neutral or acidic with 1N HCl. The filtrate was concentrated and extracted with EA. The combined organic layers were washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, and purified by silica gel column chromatography (DCM / MeOH = 40:1) to afford product 4-6a (197 mg, 0.874 mmol, 76% yield). MS m / z = 226 [M+H] + (The synthesis method of 4-6b is the same as above)

[0304] Step 6: Synthesis of 4-7a

[0305] To a solution of 4-6a (598 mg, 2.65 mmol) in THF (10 mL) was added LiAlH₄ (120.88 mg, 3.19 mmol) under ice, and the reaction was stirred at zero degrees Celsius for 1 hour. The mixture was quenched with water (100 μL), followed by the addition of aq. NaOH (15% wt, 100 μL) and H₂O (300 μL), and stirred at room temperature for 10 minutes. The filtrate was filtered and concentrated to afford crude 4-7a (457 mg, 2.49 mmol, 93.95% yield), which was used directly in the next step without further purification. MS m / z = 184 [M+H] + (The synthesis method of 4-7b is the same as above)

[0306] Step 7: Synthesis of A1-a

[0307] To a solution of 4-7a (457 mg, 2.49 mmol) in DCM (12 mL) / DMSO (4 mL) was added DIPEA (1.29 g, 9.98 mmol, 1.74 mL), followed by the dropwise addition of a suspension of Py·SO3 (1.57 g, 9.98 mmol) in DMSO (4 mL). The reaction was stirred at room temperature for 10 min, then cooled to 0°C and added with DCM (10 mL) / 1N aq HCl (10 mL). The separated aqueous phase was extracted with EA, and the combined organic phases were washed sequentially with 1N HCl and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column to afford A1-a (279 mg, 1.54 mmol, 61.73% yield). 1 H NMR(400MHz,Chloroform-d)δ9.68(s,1H),7.11(s,1H),2.40(t,J=8.1Hz,2H), 2.35–2.24(m,1H),2.00–1.87(m,2H),1.78–1.70(m,2H),1.68–1.53(m,4H).MS m / z=184[M+H] + (The synthesis method of A1-b is the same as above)

[0308] Synthesis of intermediates B1-a and B1-b

[0309]

[0310] Step 1: Synthesis of 4-9

[0311] To a solution of diisopropylamine (2.78 g, 27.46 mmol) in diethyl ether (20 mL) was added dropwise n-BuLi (11 mL, 27.5 mmol, 2.5 M in hexane) at -78°C. The mixture was gradually warmed to -11°C, and a solution of 2-cyclohexen-1-one (2.4 g, 24.97 mmol) in diethyl ether (20 mL) was added dropwise, maintaining the reaction temperature between -11°C and -3°C. The reaction mixture was stirred for 25 minutes, followed by the dropwise addition of a solution of methyl acrylate (2.15 g, 24.97 mmol) in THF (20 mL). The mixture was stirred at -10°C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride (200 mL) solution and stirred for 15 min. The mixed solution was extracted with EA, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was separated and purified on a silica gel column (PE / EA = 5:1, v / v) to obtain 4-9 (2.1 g, 11.52 mmol, yield 46.16%).

[0312] Step 2: Synthesis of 4-10

[0313] To a solution of 4-9 (4.83 g, 26.5 mmol) in EtOH (25 mL) at room temperature were added hydroxylamine hydrochloride (2.21 g, 31.8 mmol) and NaOAc (2.61 g, 31.8 mmol). The reaction mixture was heated to 80°C and stirred for 4 h. After completion of the reaction, the organic phase was removed by rotary evaporation to obtain the crude product, which was diluted with water and extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to afford 4-10 (4.45 g, 22.47 mmol, 84.7% yield). MS m / z = 198 [M+H] + .

[0314] Step 3: Synthesis of 4-11

[0315] To a turbid solution of 4-10 (4.45 g, 22.56 mmol) and NaHCO₃ (37.6 g, 564 mmol) in EA (500 mL) / H₂O (500 mL) was added trichloroisocyanuric acid (26.2 g, 112.81 mmol) dropwise in portions. After stirring at room temperature for 20 min, the reaction solution turned blue and continued stirring for 9 h until the organic phase became a colorless solution. After completion of the reaction, the mixture was extracted with EA. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified on a silica gel column to afford 4-11 (4.48 g, 18.13 mmol, 80.36% yield).

[0316] Step 4: Synthesis of 4-12

[0317] To a solution of 4-11 (4.4 g, 17.8 mmol) and Pd / C (300 mg) in EtOH (80 mL) was added portionwise NaBH4 (950 mg, 24.92 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the Pd / C was filtered off, and the filtrate was concentrated and purified on a silica gel column to afford 4-12 (3.04 g, 14.27 mmol, 80% yield).

[0318] Step 5: Synthesis of 4-13a and 4-13b

[0319] To a solution of 4-12 (3.04 g, 14.26 mmol) in MeCN (30 mL) was added DBU (2.56 mL, 17.11 mmol) at zero degrees Celsius, followed by dropwise addition of methyl acrylate (1.54 mL, 17.11 mmol). The reaction mixture was stirred at zero degrees Celsius for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated. The crude product was separated and purified on a silica gel column (PE / EA = 10:1, v / v) to give 4-13a (1.66 g, 5.55 mmol, yield 38.92%) and 4-13b (1.55 g, 5.18 mmol, yield 36.32%), respectively. (TLC developing solvent PE / EA = 5 / 1: 4-13a, R f =0.40;4-13b, R f =0.35).

[0320] By following the method of steps 5 to 7 in the synthetic route of A1-a, intermediates B1-a and B1-b were obtained. B1-a and B1-b were used directly in the next step without further separation. MS m / z = 208 [M+H] + .

[0321] Synthesis of intermediates 5-4a and 5-4b

[0322]

[0323] Step 1: Synthesis of 5-2

[0324] Place 5-1 (hydrochloride salt, 193 g, 1.0 mol) in a 5 L beaker, add 400 mL of a mixed solvent (DCM / IPA = 3 / 1), and slowly add an aqueous solution of potassium carbonate (110 g, 0.8 mol) under an ice bath, controlling the temperature below 20°C. Repeat extraction with the mixed solvent 3-4 times, combine the organic phases, and concentrate to obtain a crude product, which is directly used for the next reaction.

[0325] The crude product was dissolved in DCE (2.5 L), cooled to 10°C, and m-CPBA (688 g, 4 mol) was added portionwise, maintaining the temperature below 35°C. After addition, the temperature was raised to reflux and stirred for 3 h. After completion of the reaction, the temperature was lowered to below 10°C, stirred for 20 min, filtered, and the reaction flask rinsed with the filtrate. The filter cake was rinsed with an appropriate amount of DCE and then drained. The filtrate was carefully quenched with aqueous Na2SO3 solution and tested with potassium iodide starch paper. The filtrate was extracted three times with DCM, concentrated, and purified by silica gel column chromatography (PE / EA = 80 / 1 → 30 / 1) to afford product 5-2 (138 g, 0.737 mol, 73.7% yield). MS m / z = 188 [M+H] + .

[0326] Step 2: Synthesis of 5-3a and 5-3b

[0327] Referring to the synthesis method of 4-5a and 4-5b, the target intermediate 5-3a (PE / EA=30 / 1, MS m / z=274[M+H] + ) and 5-3b (PE / EA=20 / 1, MS m / z=274[M+H] + ). TLC developing solvent PE / EA=5 / 1:5-3a, R f =0.3;5-3b,R f =0.2.

[0328] Step 3: Synthesis of 5-4a and 5-4b

[0329] Referring to the synthesis method of 4-6a, 5-3a and 5-3b were used as raw materials to obtain 5-4a (MS m / z=212[M+H] + ) and 5-4b (MS m / z=212[M+H] + ).

[0330] Synthesis of intermediate C1

[0331]

[0332]

[0333] 5-4a (25 g, 118.34 mmol), (Boc)2O (103.31 g, 473.36 mmol), and DMAP (5.78 g, 47.34 mmol) were dissolved in acetonitrile (250 mL) and reacted at 60°C overnight under nitrogen. After completion, the reaction was concentrated directly, and the crude product was purified on a silica gel column (PE / EA = 5:1-3:1, v / v) to afford 6-1a (34.28 g, 110.09 mmol, 93.02% yield). MS m / z = 312 [M+H] + .

[0334] Step 2: Synthesis of 6-2a

[0335] 6-1a (100 mg, 0.307 mmol) was dissolved in THF (20 mL), cooled to -78°C, and LiHMDS (0.614 mmol, 2.0 eq) was added dropwise under nitrogen. The mixture was stirred at this temperature for 1 h. A THF solution of MOMBr (96 mg, 0.768 mmol) was then slowly added dropwise. After addition, the mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to yield 6-2a (99 mg, 0.239 mmol, yield 77.85%). MS m / z = 400 [M+H] + .

[0336] Step 3: Synthesis of 6-3a

[0337] Dissolve 6-2a (244 mg, 0.59 mmol) in anhydrous DCM (7 mL) and add TFA (3 mL) dropwise. Stir at room temperature for 1 h. After the reaction is complete, concentrate the resulting crude product (114 mg, 0.363 mmol) and proceed directly to the next step. MS m / z = 300 [M+H] + .

[0338] Step 4: Synthesis of 6-4a

[0339] Dissolve 6-3a (114 mg, 0.363 mmol) in THF (10 mL) and add LiAlH4 (16.57 mg, 0.436 mmol) at 0°C. Stir at this temperature for 1 h. After the reaction is complete, add sodium sulfate decahydrate portionwise in an ice bath until no bubbles form. Filter and concentrate the filtrate to obtain the crude product, which is directly carried to the next step. MS m / z = 272 [M+H] + .

[0340] Step 5: Synthesis of C1

[0341] 6-4a (100 mg, 0.368 mmol) was dissolved in a mixed solvent of DCM / DMSO (6 mL / 2 mL) and cooled to 0°C. DIPEA (190.51 mg, 1.47 mmol) and pyridine sulfur trioxide (234.62 mg, 1.47 mmol) in DMSO (2 mL) were added dropwise. The mixture was warmed to room temperature and stirred for 30 min. After completion, the reaction was transferred to an ice bath and quenched with 1N HCl. The mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to yield C1 (75 mg, 0.278 mmol, 75.54% yield). MS m / z = 270 [M+H] + .

[0342] Synthesis of intermediate C2

[0343]

[0344] Step 1: Synthesis of 6-5a

[0345] Dissolve 6-1a (2.8 g, 8.7 mmol) in THF, cool to -78°C, and add LiHMDS (15.96 ml, 2.4 eq) dropwise under nitrogen. Stir at this temperature for 1 hour. Then, slowly add a solution of iodomethane (2.93 g, 20.65 mmol) in THF dropwise. After addition, warm to room temperature and stir for 2 hours. After completion, the reaction is quenched with saturated ammonium chloride and extracted three times with DCM. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product is purified on a silica gel column (PE / EA = 5:1, v / v) to afford 6-5a (2.4 g, 6.85 mmol, 78.73% yield). 1 H NMR(400MHz,Chloroform-d)δ9.67(s,1H),6.51(s,1H),2.32-2.22(m,1H),2.00 –1.90(m,2H),1.85(s,2H),1.79–1.66(m,2H),1.63–1.50(m,4H),1.23(s,6H).MS m / z=340[M+H] + .

[0346] Step 2-Step 4: Synthesis of C2

[0347] Refer to the synthesis method of C1 to obtain intermediate C2. MS m / z = 210 [M+H] + .

[0348] Synthesis of intermediate C3

[0349]

[0350] Step 1: Synthesis of 6-8a

[0351] 4-4 (100 mg, 0.496 mmol) was dissolved in acetonitrile, and DBU (150 mg, 0.596 mmol) and methyl 2-(bromomethyl)acrylate (106 mg, 0.596 mmol) were added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 2 h. After completion, the reaction was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 5:1, v / v) to afford 6-8a (52 mg, 0.173 mmol, 34.8% yield, containing two isomers). MS m / z = 300 [M+H] + .

[0352] Step 2: Synthesis of 6-9a

[0353] Dissolve trimethylsulfoxide iodide (19.12 g, 86.86 mmol) in DMSO. Add NaH (2.08 g, 86.86 mmol) at 0°C, slowly warm to room temperature, and stir for 1 h. Add 6-8a (20 g, 66.82 mmol) and allow to react at room temperature for 17 h. After completion, quench the reaction with saturated ammonium chloride and extract three times with EA. The combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product is purified on a silica gel column (PE / EA = 4:1, v / v) to afford 6-9a (8.5 g, 27.13 mmol, 40.6% yield, containing two isomers). MS m / z = 314 [M+H] + .

[0354] Step 3-Step 5: Synthesis of C3

[0355] Referring to the synthetic method of C1, intermediate C3 (containing two isomers) was obtained. MS m / z=208[M+H] + .

[0356] Synthesis of intermediate C4

[0357]

[0358] Referring to the synthesis method of C1, deuterated iodomethane was used instead of iodomethane to obtain intermediate C4. MS m / z = 216 [M+H] + .

[0359] Synthesis of intermediate C5

[0360]

[0361] Step 1: Synthesis of 6-15a

[0362] 10-1a (1.7 g, 6.0 mmol) was dissolved in DCM (40 mL), and TEA (2.43 g, 24 mmol), TsCl (465.45 mg, 6.6 mmol), and DMAP (73.29 mg, 0.60 mmol) were added sequentially. The mixture was stirred at 0°C for 2 h under nitrogen. After completion, the reaction was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 3:1, v / v) to afford 6-15a (2.1 g, 4.8 mmol, 80% yield). MS m / z = 438 [M+H] + .

[0363] Step 2: Synthesis of C5

[0364] 6-15a (200 mg, 0.45 mmol) was dissolved in anhydrous THF (3 mL) and cooled to -78°C. LiHMDS (1 mL, 1.28 mmol) was slowly added dropwise under nitrogen. The mixture was stirred at this temperature for 1 h. Subsequently, a solution of NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) was slowly added dropwise, followed by stirring at room temperature for 4 h. The mixture was cooled to -78°C again, and LiHMDS (1 mL, 1.28 mmol) was slowly added dropwise, stirred for 1 h. Subsequently, a solution of NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) was slowly added dropwise, followed by stirring at room temperature for 16 h. After completion, the reaction was quenched with saturated ammonium chloride and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to yield C5 (90 mg, 0.19 mmol, 42.2% yield). MS m / z = 474 [M+H] + .

[0365] Synthesis of intermediate C6

[0366]

[0367] Step 1: Synthesis of 6-16a

[0368] 6-15a (500 mg, 1.14 mmol) was dissolved in anhydrous THF (10 mL), cooled to -30°C, and LDA (183.61 mg, 1.71 mmol) and methyl methylthiosulfonate (216.3 mg, 1.17 mmol) were slowly added dropwise under nitrogen. The mixture was stirred at room temperature for 20 h. After completion, the reaction was quenched with saturated ammonium chloride solution and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 5:1, v / v) to afford 6-16a (303 mg, 0.57 mmol, 50% yield). MS m / z = 530 [M+H] + .

[0369] Step 2: Synthesis of 6-17a

[0370] 6-16a (303 mg, 0.57 mmol) was dissolved in a mixture of acetonitrile and water (5 mL:0.5 mL), cooled to 0°C, and under nitrogen, PIFA (757.93 mg, 1.76 mmol) was added. The mixture was then stirred at this temperature for 3 h. After completion, the reaction was quenched with saturated sodium bicarbonate solution and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (DCM / MeOH = 100:1, v / v) to afford 6-17a (170 mg, 0.37 mmol, 64.91% yield). MS m / z = 452 [M+H] + .

[0371] Step 3: Synthesis of C6

[0372] 6-17a (170 mg, 0.376 mmol) was dissolved in DCM (2 mL) at 0°C and TFA (1 mL) was slowly added dropwise. The mixture was warmed to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was concentrated and the crude product was used directly in the next reaction without further purification. MS m / z = 352 [M+H] + .

[0373] Synthesis of intermediate C7

[0374]

[0375] Step 1: Synthesis of 6-18a

[0376] 4-6a (12.5 g, 55.5 mmol), (Boc)2O (51.6 g, 237 mmol), and DMAP (2.89 g, 23.7 mmol) were dissolved in acetonitrile (250 mL) and reacted at 60°C overnight under nitrogen. After completion, the reaction was concentrated directly, and the crude product was purified on a silica gel column (PE / EA = 5:1-3:1, v / v) to afford 6-18a (17 g, 52 mmol, 93.69% yield). MS m / z = 326 [M+H] + .

[0377] Step 2: Synthesis of 6-19a

[0378] 6-18a (500 mg, 1.54 mmol) was dissolved in THF (15 mL), cooled to -78°C, and LiHMDS (3 ml, 3.84 mmol) was added dropwise under nitrogen. The mixture was stirred at this temperature for 1 h. A solution of 2-iodoethyl ether (751 mg, 2.3 mmol) in THF (15 mL) was then slowly added dropwise. After addition, the mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to yield 6-19a (62 mg, 0.156 mmol, 10.12% yield). MS m / z = 396 [M+H] + .

[0379] Step 3 to Step 5: Synthesis of C7

[0380] Referring to the synthesis method of C1, intermediate C7 (45 mg, 0.179 mmol) was obtained by the same experimental operation. MS m / z = 252 [M+H] + .

[0381] Synthesis of intermediates D1-a1 and D1-a2

[0382]

[0383]

[0384] Step 1: Synthesis of 7-1a

[0385] Dissolve 6-1a (34.28 g, 110.09 mmol) in THF, cool to -78°C, and add LiHMDS (93 ml, 1.1 eq) dropwise under nitrogen. Stir at this temperature for 1 h. Then, slowly add a THF solution of MOMBr (17.89 g, 143.12 mmol) dropwise. After addition, warm to room temperature and stir for 2 h. After completion, quench the reaction with saturated ammonium chloride and extract three times with DCM. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product is purified by MPLC to yield 7-1a (25.6 g, 72.03 mmol, 65.43% yield). MS m / z = 356 [M+H] + .

[0386] Step 2: Synthesis of 7-2a

[0387] Dissolve 7-1a (25.6 g, 72.03 mmol) in anhydrous DCM (250 mL) and add TFA (40 mL) dropwise. Stir at room temperature for 1 h. After the reaction is complete, concentrate the crude product and proceed directly to the next step. MS m / z = 256 [M+H] + .

[0388] Step 3: Synthesis of 7-3a

[0389] Dissolve 7-2a (18.34 g, 71.83 mmol) in THF (400 mL) and add LiAlH4 (3.27 g, 86.20 mmol) at 0°C. Stir at this temperature for 1 h. After the reaction is complete, add sodium sulfate decahydrate portionwise in an ice bath until no bubbles form. Filter and concentrate the filtrate to obtain the crude product, which is then directly processed into the next step. MS m / z = 228 [M+H] + .

[0390] Step 4: Synthesis of 7-4a

[0391] 7-3a (16.16 g, 71.10 mmol) was dissolved in anhydrous DMF (160 mL), and imidazole (7.26 g, 106.64 mmol) and TBDPS-Cl (29.31 g, 106.64 mmol) were added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford 7-4a (33 g, 70.86 mmol, yield 99.7%). MS m / z = 466 [M+H] + Step 5: Synthesis of 7-4a1 and 7-4a2

[0392] 7-4a was separated by SFC to obtain isomers 7-4a1 (SFC peak retention time: 2.986 min) and 7-4a2 (SFC peak retention time: 4.269 min).

[0393] (SFC method for intermediates 7-4a1 and 7-4a2: Chiral column model: CHIRALPAK AS; specifications: 3 μm, 150 mm*3 mm; mobile phase: A-CO2, mobile phase B-ethanol, A / B=70 / 30; flow rate: 1 mL / min; column temperature: 40°C) Step 6: Synthesis of 7-5a1 and 7-5a2

[0394] 7-4a1 (654 mg, 1.40 mmol) was dissolved in THF (10 mL), TBAF (1.47 g, 5.62 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford 7-5a1 (300 mg, 1.32 mmol, 94.28% yield). MS m / z = 228 [M+H] + (The synthesis method of 7-5a2 is the same as above)

[0395] Step 7: Synthesis of D1-a1 and D1-a2

[0396] Dissolve 7-5a1 (300 mg, 1.32 mmol) in a mixture of DCM / DMSO (24 mL / 4 mL) and cool to 0°C. DIPEA (682.31 mg, 5.28 mmol) and pyridine sulfur trioxide (840.27 mg, 5.28 mmol) in DMSO (2 mL) were added dropwise, followed by warming to room temperature and stirring for 30 min. After completion, the reaction was transferred to an ice bath and quenched with 1N HCl. The mixture was diluted with water and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to afford D1-a1 (130 mg, 1.02 mmol, 77.27% yield) in a single configuration. 1 H NMR(400MHz,Chloroform-d)δ9.67(s,1H),7.01(s,1H),3.59(d,J=5.0Hz,2H),3.36(s,3H),2.76(tt,J=9.5,4.9Hz ,1H),2.33–2.21(m,1H),2.16(dd,J=13.0,9.5Hz,1H),2.00–1.90(m,2H),1.85–1.69(m,3H),1.67–1.48(m,4H).MS m / z=226[M+H] + .

[0397] (The synthesis method of another single configuration D1-a2 is the same as above)

[0398] Synthesis of intermediates D2-a1 and D2-a2

[0399]

[0400]

[0401] Referring to the synthesis methods of D1-a1 and D1-a2, iodomethane was used instead of MOMBr to obtain the intermediate D2-a1 (MS m / z = 196 [M+H] + ) and D2-a2 (MS m / z=196[M+H] + ).

[0402] (SFC method for intermediates 8-4a1 and 8-4a2: chiral column model: CHIRAL ART Cellulose-SC; specification: 3um, 150mm*3mm; mobile phase: A-CO2, mobile phase B-isopropanol, A / B=70 / 30; flow rate: 1mL / min; column temperature: 40℃; SFC peak times of 8-4a1 and 8-4a2 are: 3.809min and 4.479min, respectively).

[0403] Synthesis of intermediates D3-a1 and D3-a2

[0404]

[0405] Referring to the synthesis methods of D1-a1 and D1-a2, deuterated iodomethane was used instead of MOMBr to obtain the intermediate D3-a1 (MS m / z = 199 [M+H] + ) and D3-a2 (MS m / z=199[M+H] + ).

[0406] (SFC method for intermediates 9-4a1 and 9-4a2: Chiral ART Cellulose-SC column; specifications: 3 μm, 150 mm x 3 mm; mobile phase A: CO2, mobile phase B: isopropanol, A / B = 65 / 35; flow rate: 1 mL / min; column temperature: 40°C; SFC peak elution times for 9-4a1 and 9-4a2: 2.936 min and 3.386 min, respectively)

[0407] Synthesis of intermediates D4-a and D5-a

[0408]

[0409] Step 1: Synthesis of 10-1a

[0410] 4-7a (1.83 g, 10 mmol), (Boc)2O (8.72 g, 40 mmol), and DMAP (0.48 mg, 4 mmol) were dissolved in acetonitrile (20 mL) and reacted at 60°C overnight under nitrogen. After completion, the reaction was concentrated directly, and the crude product was purified on a silica gel column (PE / EA = 5:1-3:1, v / v) to afford 10-1a (2.9 g, 9.3 mmol, 93% yield). MS m / z = 284 [M+H] + .

[0411] Step 2: Synthesis of 10-2a

[0412] 10-1a (2.9 g, 9.3 mmol) was dissolved in anhydrous DMF (10 mL), and imidazole (0.95 g, 13.88 mmol) and TBDPS-Cl (3.81 g, 13.88 mmol) were added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford 10-2a (4.83 g, 9.26 mmol, yield 99.57%). MS m / z = 522 [M+H] + .

[0413] Step 3: Synthesis of 10-3a

[0414] 10-2a (916 mg, 1.76 mmol) was dissolved in anhydrous THF (10 mL). LiHMDS (1.93 mmol, 1.1 eq) was slowly added dropwise at -70°C, and the mixture was stirred at this temperature for 1 h. Acetone (112.16 mg, 1.93 mmol) and boron trifluoride etherate (274.22 mg, 1.93 mmol) were then added dropwise at -70°C, and the mixture was allowed to warm to room temperature and stirred for 2.5 h. After completion, the reaction was quenched with saturated ammonium chloride and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to yield 10-3a (883 mg, 1.52 mmol, 86.36% yield). MS m / z = 580 [M+H] + .

[0415] Step 4: Synthesis of 10-4a

[0416] 10-3a (883 mg, 1.52 mmol) was dissolved in THF (10 mL), TBAF (1.59 g, 6.08 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford 10-4a (488 mg, 1.43 mmol, yield 94.08%). MS m / z = 342 [M+H] + .

[0417] Step 4: Synthesis of D4-a

[0418] 10-4a (488 mg, 1.43 mmol) was dissolved in a mixed solvent of DCM / DMSO (24 mL / 4 mL) and cooled to 0°C. DIPEA (784.65 mg, 6.07 mmol) and pyridine sulfur trioxide (966.31 mg, 6.07 mmol) in DMSO (2 mL) were added dropwise, followed by warming to room temperature and stirring for 30 min. After completion, the reaction was transferred to an ice bath and quenched with 1N HCl, diluted with water, and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to yield D4-a (397.88 mg, 1.17 mmol, 81.8% yield, containing two isomers, used directly in the next step without resolution). MS m / z = 340 [M+H] + .

[0419] Step 5: Synthesis of 10-5a

[0420] 10-3a (499 mg, 0.86 mmol) was dissolved in DCM (8 mL). TEA (870.82 mg, 8.61 mmol) and MsCl (98.58 mg, 0.86 mmol) were added dropwise at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 days. After completion, the reaction was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to afford 10-5a (263 mg, 0.47 mmol, 54.7% yield). MS m / z = 562 [M+H] + .

[0421] Step 6-Step 7: Synthesis of D5-a

[0422] Referring to the synthesis method of D4-a, intermediate D5-a was obtained by deprotection of TBDPS and oxidation. MS m / z = 322 [M+H] + .

[0423] Synthesis of intermediates E2-a and E2-b

[0424]

[0425] Step 1: Synthesis of 12-1a

[0426] 4-1 (1.65 g, 8.20 mmol) was dissolved in acetonitrile (7.37 mL), and TEA (912.74 mg, 9.02 mmol) and formaldehyde solution (492.43 mg, 16.2 mmol) were added dropwise at 0°C. The reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, it was directly concentrated. The crude product was purified by silica gel column (PE / EA=4:1, v / v) to give stereoisomer 12-1a (764 mg, 3.3 mmol, PE / EA=4 / 1, MS m / z=232 [M+H] + ) and another stereoisomer 12-1b (1.09 g, 4.7 mmol, yield 57.3%, PE / EA = 2 / 1, MS m / z = 232 [M+H] + ). TLC developing solvent PE / EA=1 / 1:12-1a, R f =0.3;12-1b,R f =0.2.

[0427] Step 2: Synthesis of 12-2a

[0428] 12-1a (746 mg, 3.63 mmol) was dissolved in isopropanol (20 mL) and Raney Ni (70 mg, 3.23 mmol) was added to displace the hydrogen atmosphere. The mixture was heated to 70°C and stirred overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to obtain the crude product (640 mg, 3.18 mmol, 87.6% yield), which was directly used in the next step without purification. MS m / z = 202 [M+H] + .

[0429] Step 3: Synthesis of 12-3a

[0430] 12-2a (640 mg, 3.18 mmol) was dissolved in THF (25 mL), and TEA (386.13 mg, 3.82) was added dropwise. After cooling to -10°C, a THF solution of triphosgene (350 mg, 1.18) was slowly added dropwise. The reaction mixture was stirred at this temperature for 30 minutes, then moved to room temperature and stirred for 2 hours. After completion of the reaction, saturated sodium bicarbonate and ethyl acetate were added, and the organic phases were extracted three times. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford 12-3a (380 mg, 1.67 mmol, 52.5% yield). MS m / z = 228 [M+H] + .

[0431] Step 4: Synthesis of 12-4a

[0432] 12-3a (380 mg, 1.67 mmol) was dissolved in THF (10 mL). LiAlH4 (76.15 mg, 2.01 mmol) was added at 0°C and stirred at this temperature for 1 h. After the reaction was complete, sodium sulfate decahydrate was added portionwise under an ice bath until no bubbles formed. The mixture was filtered and the filtrate was concentrated to obtain the crude product (304 mg, 1.64 mmol, 98.2% yield), which was directly carried to the next step. MS m / z = 186 [M+H] + .

[0433] Step 5: Synthesis of E2-a

[0434] 12-4a (304 mg, 1.64 mmol) was dissolved in a mixture of DCM / DMSO (12 mL / 2 mL) and cooled to 0°C. DIPEA (848.48 mg, 6.57 mmol) and a solution of pyridine sulfur trioxide (1.04 g, 6.57 mmol) in DMSO (2 mL) were added dropwise. The mixture was warmed to room temperature and stirred for 30 min. After completion, the reaction was transferred to an ice bath and quenched with 1N HCl. The mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to afford E2-a (single configuration, 167 mg, 0.91 mmol, 55.5% yield). 1 HNMR(400MHz,Chloroform-d)δ9.67(s,1H),6.42(s,1H),4.11(s,2H),2.40–2.30(m,1H),2.03–1.94(m,2H),1.87–1.79(m,2H),1.73–1.56(m,4H).MS m / z=184[M+H] + .

[0435] Referring to the synthesis method of E2-a, another single-configuration intermediate E2-b can be obtained by the same experimental operation. MS m / z=184[M+H] + .

[0436] Synthesis of intermediates E3-a and E3-b

[0437]

[0438]

[0439] Referring to the synthesis method of E2-a, the intermediate E3-a (PE / EA=5 / 1, MSm / z=210[M+H] + , used directly in the next step without separation) and E3-b (obtained by PE / EA=3 / 1, MS m / z=210[M+H] +, used directly in the next step without separation). TLC developing solvent PE / EA=5 / 1: E3-a, R f =0.4; E3-b, R f =0.3.

[0440] Synthesis of intermediates E4-a and E4-b

[0441]

[0442] Step 1: Synthesis of 14-2a

[0443] 14-1a (refer to the synthesis of 12-2a, obtained from starting material 5-2, 720 mg, 3.85 mmol, isomer separation favors the less polar isomer), (Boc)2O (1.01 g, 4.61 mmol), and TEA (778 mg, 7.67 mmol) were dissolved in acetonitrile (20 mL) and reacted overnight at 60°C under nitrogen. After completion, the reaction was concentrated directly, and the crude product was purified on a silica gel column (PE / EA = 5:1-3:1, v / v) to afford 14-2a (650 mg, 2.26 mmol, 58.7% yield). MS m / z = 288 [M+H] + .

[0444] Step 2: Synthesis of 14-3a

[0445] 14-2a (650 mg, 2.26 mmol) was dissolved in DCM (15 mL) and cooled to 0°C. Dess-Martin oxidant (1.92 g, 4.52 mmol) was added portionwise under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2 h. After completion, the reaction was quenched with water, filtered, and the filtrate was extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (PE / EA = 10:1 to 8:1, v / v) to afford 14-3a (537 mg, 1.88 mmol, 83.18% yield). MS m / z = 286 [M+H] + .

[0446] Step 3: Synthesis of 14-4a

[0447] 14-3a (537 mg, 1.88 mmol) and methylamine hydrochloride (190.60 mg, 2.82 mmol) were dissolved in anhydrous methanol (10 mL). TEA was then added to adjust the pH to approximately 8, and the reaction was stirred at room temperature for 0.5 h. Acetic acid was then added to adjust the pH to 5, followed by the addition of sodium cyanoborohydride (237.13 mg, 3.76 mmol), and the mixture was stirred at room temperature for 1.5 h. After completion, the reaction was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (DCM / MeOH = 50:1, v / v) to afford 14-4a (397 mg, 1.32 mmol, 70.21% yield). MS m / z = 301 [M+H] + .

[0448] Step 4: Synthesis of 14-5a

[0449] 14-4a (397 mg, 1.32 mmol) was dissolved in DCM (4 mL) at 0°C. TFA (2 mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was concentrated, and the crude product was used directly in the next reaction without further purification. MS m / z = 201 [M+H] + .

[0450] Step 5: Synthesis of 14-6a

[0451] The crude product from the previous step was dissolved in THF (10 mL), cooled to 0°C, and CDI (285.37 mg, 1.98 mmol) was added under nitrogen. The mixture was then warmed to room temperature and stirred for 1 h. After completion of the reaction, saturated sodium bicarbonate solution was added to quench the reaction. The organic phases were extracted three times with ethyl acetate, combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a silica gel column (DCM / MeOH = 60:1, v / v) to afford 14-6a (190 mg, 0.84 mmol, 63.6% yield). MS m / z = 227 [M+H] + .

[0452] Step 6: Synthesis of 14-7a

[0453] 14-6a (190 mg, 0.84 mmol) was dissolved in THF (5 mL). LiAlH4 (41.43 mg, 1.09 mmol) was added at 0°C and stirred at this temperature for 1 h. After the reaction was complete, sodium sulfate decahydrate was added portionwise under an ice bath until no bubbles formed. The mixture was filtered and the filtrate was concentrated to obtain the crude product (120 mg, 0.6 mmol), which was directly used in the next step. MS m / z = 199 [M+H] + .

[0454] Step 7: Synthesis of E4-a

[0455] 14-7a (120 mg, 0.6 mmol) was dissolved in a mixed solvent of DCM / DMSO (4 mL / 0.5 mL) and cooled to 0°C. DIPEA (312.9 mg, 2.24 mmol) and pyridine sulfur trioxide (385.43 mg, 2.42 mmol) in DMSO (0.5 mL) were added dropwise. The mixture was warmed to room temperature and stirred for 30 min. After completion, the reaction was transferred to an ice bath and quenched with 1N HCl. The mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified on a silica gel column to yield a single isomer, E4-a (35 mg, 0.178 mmol, 29.7% yield). MS m / z = 197 [M+H] + .

[0456] Similarly, referring to the synthesis method of E4-a, another single-configuration intermediate E4-b can be obtained through the same experimental operation. MS m / z = 197 [M+H] + .

[0457] Synthesis of Example 1

[0458]

[0459] To a solution of A1-a (95 mg, 524.19 μmol) in MeOH (10 mL) was added N1 (268.92 mg, 629.03 μmol). The mixture was stirred at room temperature for 1 h. AcOH was added to adjust the pH to 4-5, followed by the addition of NaBH3CN (49.54 mg, 786.29 μmol). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was isolated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 1 (133.16 mg, 220.16 μmol, 42.00% yield, 98% purity) as a white solid. MS m / z = 593 [M+H] + . NMR spectrum 1H NMR(600MHz, Methanol-d4)δ8.23(d,J=9.6Hz,1H),7.72(d,J=24.6Hz,1H),7.23–7.14(m,2H),6.99(dd,J=9.0,4.2Hz,1H) ,4.04–3.88(m,4H),3.52(dd,J=13.7,7.0Hz,1H),3.36(dd,J=13.7,7.0Hz,1H),3.26(q,J=7.1Hz,1H),2.35(dd,J=8.6,7.5 Hz, 5H), 2.16 (d, J = 6.8 Hz, 2H), 1.96 (t, J = 8.1 Hz, 2H), 1.84–1.76 (m, 6H), 1.70 (d, J = 12.9 Hz, 2H), 1.54 (td, J = 13.3, 3.9 Hz, 3H), 1.31 (d, J = 6.5 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.7 Hz, 2H), 1.15 (d, J = 6.7 Hz, 2H), 1.13–1.05 (m, 3H). Synthesis of Example 5

[0460]

[0461] To a solution of A1-a (1.62 g, 8.94 mmol) in DCM (30 mL) was added N₂ (3.95 g, 8.94 mmol). The mixture was stirred at room temperature for 1 h. AcOH was added to adjust the pH to 4-5, followed by the addition of NaBH(OAc)₃ (5.68 g, 26.82 mmol). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was isolated and purified by Pre-HPLC (10 mM aqueous NH₄HCO₃ / acetonitrile) to obtain Example 5 (2.14 g, 3.53 mmol, 39.46% yield, 98% purity) as a white solid. MS m / z = 607 [M+H] + . NMR spectrum 1H NMR (600MHz, CDCl3) δ8.38(s,1H),7.77(s,1H),7.00(d,J=7.6Hz,2H),6.87–6.70(m,1H),5.78(s,1H),3.97( s,2H),3.88(d,J=9.2Hz,2H),3.84–3.76(m,1H),3.56–3.45(m,1H),2.39(t,J=8.1Hz,3H),2.28(d,J=15.3Hz, 3H),2.11(d,J=6.7Hz,2H),1.94(t,J=8.1Hz,2H),1.83(s,1H),1.76(s,9H),1.56(s,3H),1.50(d,J=6.8Hz,3 H),1.45(td,J=12.8,3.2Hz,3H),1.15(d,J=6.6Hz,3H),1.11(d,J=6.7Hz,3H),1.04(dd,J=24.3,11.4Hz,2H).

[0462] Synthesis of Example 7

[0463]

[0464] To a solution of A1-a (16.92 mg, 93.35 μmol) in MeOH (5 mL) was added M1 (40 mg, 93.35 μmol). The mixture was stirred at room temperature for 1 h. AcOH was added to adjust the pH to 4-5, followed by the addition of NaBH3CN (8.82 mg, 140.02 μmol). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was isolated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 7 (40.42 mg, 66.55 μmol, 71% yield, 97% purity) as a white solid. MS m / z = 594 [M+H] + . NMR spectrum 1H NMR (600MHz, Methanol-d4) δ8.38(d,J=1.8Hz,1H),7.44–7.38(m,1H),7.27(tt,J=8.5,4.2Hz,1H),7.21(ddd,J=14.9,8 .0,3.1Hz,1H),4.36(d,J=24.3Hz,2H),3.98–3.86(m,2H),3.81(p,J=6.6Hz,1H),3.53–3.46(m,1H),3.26–3.20(m,1H),2 .36(t,J=8.1Hz,5H),2.18(d,J=6.8Hz,2H),1.97(t,J=8.1Hz,2H),1.87(d,J=5.2Hz,4H),1.83–1.76(m,2H),1.75–1.68( m,2H),1.54(td,J=13.3,3.8Hz,3H),1.21(d,J=6.8Hz,2H),1.15(d,J=7.0Hz,5H),1.12–1.04(m,3H),0.86–0.75(m,2H).

[0465] Synthesis of Example 19

[0466]

[0467] To a solution of C1 (15 mg, 55.59 μmol) in MeOH (3 mL) was added M1 (26.2 mg, 61.26 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (38.3 mg, 610.1 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 20 (200 mg, 287.4 μmol, 70.66% yield, 98% purity) as a white solid. MS m / z = 696 [M+H] + . NMR spectrum

[0468] Synthesis of Example 20

[0469]

[0470] To a solution of C1 (98.6 mg, 366.1 μmol) in MeOH (5 mL) was added M2 (180 mg, 406.8 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (38.3 mg, 610.1 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 20 (200 mg, 287.4 μmol, 70.66% yield, 98% purity) as a white solid. MS m / z = 696 [M+H] + . NMR spectrum 1 H NMR (400MHz, Chloroform-d) δ8.46 (s, 1H), 7.26–7.23 (m, 1H), 7.10 (ddd, J=9.1, 7.9, 3.0Hz, 1H), 6.96 (dd, J=7 .8,3.0Hz,1H),5.75(s,1H),4.47(d,J=10.3Hz,1H),4.28(d,J=10.3Hz,1H),3.94–3.83(m,2H),3.79(p,J=6.6H z,1H),3.46(d,J=8.9Hz,2H),3.43–3.36(m,1H),3.33(s,7H),3.30(s,1H),2.32(s,3H),2.13–2.02(m,4H),1. 90–1.64(m,9H),1.50(d,J=6.8Hz,3H),1.37(dd,J=12.9,8.7Hz,6H),1.16–0.95(m,5H),0.72(d,J=6.6Hz,3H).

[0471] Synthesis of Example 23

[0472]

[0473] To a solution of C2 (21.9 mg, 104.6 μmol) in MeOH (5 mL) was added N4 (46 mg, 104.6 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (9.85 mg, 156.9 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 23 (29 mg, 45.83 μmol, 43% yield, 98% purity) as a white solid. MS m / z = 633 [M+H] + . NMR spectrum 1HNMR(600MHz, CDCl3)δ8.38(s,1H),7.80(s,1H),7.00(s,2H),6.73(d,J=5.1Hz,1H),5.43(s,1H),4.53(s,1H),3.86(s,4H),2.56(s,1H),2.25( s,3H),2.07(d,J=4.8Hz,2H),1.86(s,2H),1.73(s,11H),1.43(s,3H),1 .35(d,J=6.4Hz,6H),1.21(s,7H),1.01(d,J=11.6Hz,2H),0.56(s,4H).

[0474] Synthesis of Example 26

[0475]

[0476] To a solution of C2 (21 mg, 100.34 μmol) in MeOH (3 mL) was added M1 (43 mg, 100.34 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (9.46 mg, 150.51 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to obtain Example 26 (12.63 mg, 20.29 μmol, 20.22% yield, 99% purity) as a white solid. MS m / z = 622 [M+H] + . NMR spectrum 1 H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.45–7.36 (m, 1H), 7.33–7.16 (m, 2H), 4.51–4.14 (m, 2H), 4.02–3.70 (m, 3H), 3.61–3.39 (m, 1H), 3.28–3.18 (m, 1H), 2.59–2.28 (m, 4H), 2.17 (d, J = 6.8 Hz, 2H), 1.93–1.83 (m, 6H), 1.83–1.75 (m, 2H), 1.71–1.63 (m, 2H), 1.63–1.44 (m, 3H), 1.25–1.01 (m, 15H), 0.88–0.76 (m, 2H). Synthesis of Example 38-2

[0477]

[0478] To a solution of D1-a2 (33.79 mg, 150 μmol) in MeOH (2 mL) was added M2 (66.38 mg, 150 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (14.14 mg, 225 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile) to obtain Example 38-2 (42.76 mg, 63.63 μmol, 42.42% yield, 97% purity) as a white solid. MS m / z = 652 [M+H] + . NMR spectrum 1 H NMR(400MHz, Methanol-d4)δ8.38(s,1H),7.39(dd,J=9.1,4.5Hz,1H),7.25(ddd,J=9.1 ,8.1,3.0Hz,1H),7.16(dd,J=8.0,3.0Hz,1H),4.48–4.31(m,2H),3.92(q,J=10.5Hz,2H) ,3.75(p,J=6.6Hz,1H),3.63–3.47(m,3H),3.329(s,3H),2.78–2.69(m,1H),2.58–2.11 (m,7H),1.92–1.64(m,9H),1.63–1.35(m,9H),1.21–1.00(m,5H),0.75(d,J=6.6Hz,3H).

[0479] Synthesis of Example 41-1

[0480]

[0481] To a solution of D2-a1 (19.59 mg, 100.34 μmol) in MeOH (3 mL) was added M2 (44.40 mg, 100.34 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (9.46 mg, 150.51 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile) to obtain Example 41-1 (25.06 mg, 40.26 μmol, 40.13% yield, 99% purity) as a white solid. MS m / z = 622 [M+H] + . NMR spectrum 1H NMR (400MHz, Methanol-d4) δ8.38(s,1H),7.39(dd,J=9.0,4.5Hz,1H),7.25(ddd,J=9.0,8.0 ,3.0Hz,1H),7.16(dd,J=8.0,3.0Hz,1H),4.49–4.29(m,2H),3.92(q,J=10.5Hz,2H),3.75(he pt,J=6.6Hz,1H),3.54(hept,J=6.9Hz,1H),2.65–2.22(m,6H),2.17(d,J=6.9Hz,2H),1.91– 1.69(m,7H),1.71–1.58(m,2H),1.58–1.31(m,9H),1.24–0.99(m,8H),0.75(d,J=6.6Hz,3H).

[0482] Synthesis of Example 41-2

[0483]

[0484] To a solution of D2-a2 (19.59 mg, 100.34 μmol) in MeOH (3 mL) was added M2 (44.40 mg, 100.34 μmol). The mixture was stirred at room temperature for 1 h. AcOH was then added to adjust the pH to 4-5. NaBH3CN (9.46 mg, 150.51 μmol) was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile) to obtain Example 41-2 (20.57 mg, 33.05 μmol, 32.94% yield, 99% purity) as a white solid. MS m / z = 622 [M+H] + . NMR spectrum 1H NMR(400MHz, Methanol-d4)δ8.38(s,1H),7.39(dd,J=9.0,4.5Hz,1H),7.25(ddd,J=9.0,8.0,3 .0Hz,1H),7.16(dd,J=8.0,3.0Hz,1H),4.49–4.29(m,2H),3.92(q,J=10.5Hz,2H),3.75(hept,J =6.6Hz,1H),3.54(hept,J=6.9Hz,1H),2.65–2.22(m,2H),2.17(d,J=6.9Hz,2H),1.91–1.69(m, 7H),1.63(dd,J=11.9,3.4Hz,2H),1.58–1.31(m,9H),1.24–0.99(m,8H),0.75(d,J=6.6Hz,3H).

[0485] Referring to the synthesis method of Example 1, the following example molecules were obtained by reacting raw material 1 and raw material 2:

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] Synthesis of Example 54

[0504]

[0505] C6 (132 mg, 0.284 mmol, TF) was dissolved in NMP (3 mL), and KI (94.79 mg, 0.571 mmol) was added. The mixture was stirred at room temperature for 0.5 h, followed by the addition of M1 (177 mg, 0.38 mmol, Cl) and KCO (525 mg, 3.81 mmol). After nitrogen was replaced, the temperature was raised to 70°C and stirred overnight. After completion, the reaction was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by pre-HPLC (10 mM aqueous NHHCO / acetonitrile) to afford Example 54 (1.55 mg, 0.002 mmol, 5.9%). 1H NMR(400MHz,Chloroform-d)δ8.40(d,J=1.5Hz,1H),7.21(d,J=4.5Hz,0H),7.18(s,0H),7.06(ddd,J=7.9,6.4,3.1 Hz,1H),6.95(ddd,J=13.5,7.9,3.0Hz,1H),5.91(d,J=1.9Hz,1H),5.84(s,1H),4.46–4.21(m,2H),3.92–3.74(m,3 H),3.48(d,J=6.1Hz,3H),3.09(d,J=54.9Hz,5H),1.89–1.82(m,4H),1.77(d,J=14.0Hz,2H),1.62(dd,J=12.8,3.6 Hz,2H),1.58–1.55(m,2H),1.50(d,J=18.5Hz,2H),1.26–1.13(m,3H),1.11–0.94(m,7H),0.70(d,J=6.6Hz,2H).MS m / z=608[M+H] + .

[0506] Synthesis of Example 56

[0507]

[0508] C5 (45 mg, 95.3 μmol) was dissolved in NMP (1 mL), and KI (19.39 mg, 116.8 μmol) was added. The mixture was stirred at room temperature for 0.5 h, followed by the addition of M2 (44 mg, 77.87 μmol) and K2CO3 (59.51 mg, 431.22 μmol). After nitrogen was replaced, the temperature was raised to 70°C and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile system) to afford Intermediate-1 (15 mg, 20.55 μmol, yield 26.39%).

[0509] Intermediate-1 (15 mg, 20.55 μmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated and the resulting crude product was purified by pre-HPLC to afford Example 56 (1.16 mg, 1.84 μmol, 8.9% yield). MS m / z = 630 [M+H] + .

[0510] The synthetic method of reference example 56 was used to obtain the following example molecules:

[0511]

[0512]

[0513] Synthesis of Example 62

[0514]

[0515] Example 5 (230 mg, 0.38 mmol), (Boc)2O (124 mg, 0.57 mmol), DMAP (9 mg, 0.076 mmol), and TEA (78 mg, 0.76 mmol) were dissolved in DCM (3 mL) and reacted at 60°C overnight under nitrogen. After completion, the reaction was concentrated directly, and the crude product was purified on a silica gel column (PE / EA = 5:1-3:1, v / v) to afford Intermediate-2 (190 mg, 0.236 mmol, 62.1% yield). MS m / z = 707 [M+H] + .

[0516] Intermediate-2 (95 mg, 134.39 μmol) was dissolved in THF (2 mL), cooled to -78°C, and LiHMDS (0.2 mL, 268.78 μmol) was slowly added dropwise. The mixture was then stirred at this temperature for 1 h. Ethyl trifluoroacetate (81.86 mg, 416.62 μmol) was then added, and the mixture was allowed to warm to room temperature and stirred overnight. After completion, the reaction was moved to an ice bath, quenched with saturated aqueous ammonium chloride, and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield crude Intermediate-3. MS m / z = 803 [M+H] + .

[0517] Intermediate-3 (60 mg, 74.73 μmol) and paraformaldehyde (78.53 mg, 2.62 mmol) were dissolved in toluene (2 mL). Potassium carbonate (32.02 mg, 231.66 μmol) and 18-crown ether-6 (5.93 mg, 22.42 μmol) were then added. The mixture was heated to 110°C and stirred overnight. After completion, the reaction was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (PE / EA = 1:1, v / v) to afford Intermediate-4 (20 mg, 27.82 μmol, yield 37.23%). MS m / z = 719 [M+H] + .

[0518] Intermediate-4 (4 mg, 5.48 μmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated and the resulting crude product was purified by pre-HPLC to afford Example 62 (1.16 mg, 1.84 μmol, 33.58% yield). MS m / z = 619 [M+H] + .

[0519] Synthesis of Example 63

[0520]

[0521] Example 20 (70 mg, 100 μmol) was dissolved in anhydrous DCM (1 mL), cooled to -70°C, and BBr3 solution (0.6 mL, 600 μmol) was slowly added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the mixture was concentrated, and the crude product was purified by pre-HPLC (10 mM aqueous NH4HCO3 / acetonitrile) to afford Example 63 (10 mg, 14.9 μmol, 14.9% yield). MS m / z = 668 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.45 (s, 1H), 7.24 (d, J = 4.5Hz, 1H), 7.10 (ddd, J = 9.0, 7.8, 3. 0Hz,1H),6.95(dd,J=7.8,3.0Hz,1H),5.75(s,1H),4.47(d,J=10.4Hz,1H),4.28(d,J=10.3H z,1H),3.87(s,2H),3.81–3.68(m,5H),3.39(p,J=6.7Hz,1H),2.33(s,3H),2.10(d,J=5.6Hz ,2H),1.85–1.74(m,11H),1.57–1.31(m,10H),1.08(d,J=6.5Hz,4H),0.71(d,J=6.4Hz,3H).

[0522] Synthesis of Example 64 and Example 65

[0523] Referring to the synthesis method of Example 1, the following example molecules were obtained by reacting raw material 1 and raw material 2:

[0524]

[0525]

[0526] The SFC chiral separation peak retention times and conditions of some of the example compounds in the above table are shown in the table below.

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] In order to illustrate the absolute configuration of the compound of the present invention, intermediate A1-a ( Figure 1 )、A1-b( Figure 2 )、7-5a1( Figure 3 )、7-5a2( Figure 4 ) and Example 19 ( Figure 5 ) crystal. The instrument parameters are as follows: detection instrument: Bruker D8 Venture; instrument model: D8 Venture; light source: gallium target; X-ray: The technical effects of the present invention are described below through test examples:

[0534] Experimental Example 1: Menin-MLL interaction inhibitory activity test

[0535] The experiment quantitatively detected the inhibition of the Menin / MLL-4-43 peptide interaction by small molecule inhibitors through fluorescence polarization competition experiment. The experiment was carried out in a 384-well plate (Corning, Cat#3575), and the reaction buffer used was composed of 50mM Tris, pH 7.5, 50mM NaCl, and 1mM DTT. The 40μL reaction system included 10μL 8nM Menin recombinant protein and 10μL of different concentrations of the test compound. The compound was pre-incubated with Menin protein for 15 minutes, and then 20μL 10nM FITC-MLL4-43-peptide was added. After incubation on a shaker at 25 degrees for 60 minutes, the fluorescence polarization signal (FP 485 520 520) was read using BMG HERAStar. The experimental data were analyzed and processed by GraphPad Prism 6 software to obtain IC 50 The reference compound 1 was prepared according to the method of Example 64 in WO2017214367.

[0536] Table 1. Menin-MLL interaction inhibitory activity test

[0537]

[0538]

[0539]

[0540] Experimental Example 2: Testing the Cell Proliferation Inhibition Ability of Menin-MLL Interaction Inhibitors

[0541] The cell viability analysis method was used to evaluate the inhibitory effect of the compounds of the invention on the proliferation of tumor cell lines (such as cell lines MV4-11, MOLM-13, THP-1, NOMO-1 containing MLL fusion protein, control cell lines HL-60, K562, MOLM-16 not containing MLL fusion protein, and cell line OCI-AML3 containing NPM1 mutation). Cells were seeded in a 96-well plate at a certain concentration (e.g., 5000-20000 cells / well), and then an equal volume of culture medium containing 2 times the final concentration of the test compound (final concentration range of 1nM to 10μM) was added. The plate was placed in an incubator and cultured for 72-168h at 37°C and 5% CO2. Before the test, an equal volume of Luminescent reagent was incubated at room temperature for 10 minutes and then detected using a microplate reader (BMGLABTECH). The data were analyzed using GraphPad Prism software and the IC 50 The control compound 1 was prepared according to the method of Example 64 in WO2017214367.

[0542] Table 2. Test of the ability of Menin-MLL interaction inhibitors to inhibit cell proliferation

[0543]

[0544]

[0545]

[0546] Test Example 3: Liver microsome stability test of the compound

[0547] Experimental purpose: To determine the stability of some of the compounds of the present invention in mouse, dog and human liver microsomes by LC-MS / MS.

[0548] Test materials: The test drug is a homemade example compound of the present invention; the positive reference compound SNDX-5613 was prepared by the method of Example 253 in reference patent WO2017214367; the control compound 1 was prepared by the method of Example 64 in reference WO2017214367; liver microsomes were purchased from Corning.

[0549] Test method:

[0550] Each incubation system was in a total volume of approximately 45 μL, containing 100 mM phosphate buffered saline (PBS, pH 7.4) containing a final concentration of 0.5 mg / mL liver microsomal protein, 1.00 μM compound, and 2.00 mM NADPH. The organic phase content was <1%. Incubation was performed at 37°C, and the reaction was terminated by the addition of 135 μL of ice-cold acetonitrile after 0, 5, 15, 30, and 60 minutes. A positive control was incubated at 37°C with 1.00 μM ketanserin, 0.5 mg / mL liver microsomal protein, and 2.00 mM NADPH, for 0, 5, 15, 30, and 60 minutes, followed by the addition of 135 μL of ice-cold acetonitrile. The 96-well plate was shaken at 600 rpm for 10 minutes and then centrifuged at 4700 rpm for 15 minutes at 4°C. 80 μL of supernatant was mixed with 320 μL of pure water. The remaining amount of the compound was detected by LC-MS / MS. The in vitro half-extinction period (T1 / 2) and intrinsic clearance (CLint) were calculated according to the following formula:

[0551] T 1 / 2 =0.693 / k;

[0552] Intrinsic clearance (Clint) = (0.693 / T 1 / 2 )×(1 / liver microsome concentration)×conversion coefficient. k is the linear regression slope of ln residual compound percentage-incubation time. The conversion coefficient is as follows:

[0553]

[0554] The specific test results are shown in Table 3.

[0555] Table 3. Stability of test compounds in mouse, human and dog liver microsomes

[0556]

[0557] Compared with the positive compound SNDX-5613, some of the compounds of the present invention have better metabolic stability in liver microsomes, especially have a significant advantage in stability in human liver microsomes.

[0558] Test Example 4: In vivo pharmacokinetic study

[0559] Purpose of the experiment: To determine the pharmacokinetic properties of some of the compounds of the present invention in mice, rats and dogs after single intravenous injection (iv) and oral gavage (ig) by LC-MS / MS.

[0560] Methods: An appropriate amount of compound was weighed and prepared into a clear solution of the desired concentration using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution based on the molar mass of the compound. After overnight fasting, SPF male ICR mice, SPF male SD rats, and male beagle dogs were administered the test compound solution by intravenous injection or oral gavage at the appropriate dose. Anticoagulated whole blood was collected from the animals at 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration, and plasma was separated. Plasma samples were analyzed at various time points using LC-MS / MS, and plasma concentrations were determined using a standard curve calibration method. Pharmacokinetic parameters including terminal elimination half-life (t½), peak plasma concentration (Cmax), area under the concentration-time curve (AUC), clearance (CL), and bioavailability (F%) were calculated using a non-compartmental model in Phoenix WinNonlin 5.2. These parameters were directly derived from serum concentrations. Blood drug concentrations and pharmacokinetic parameters were expressed as mean ± standard deviation (X ± SD). The specific experimental plans for each genus are as follows.

[0561] Mouse pharmacokinetic test

[0562] Experimental animals: SPF male ICR mice, weighing 25-30 g, 12 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0563] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 2 hours after administration.

[0564] Preparation of test compound solution: For oral administration, the test compound concentration is 1 mg / mL. Weigh an appropriate amount of compound and prepare it into a 1 mg / mL transparent clear solution using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. For intravenous injection, the test compound concentration is 0.2 mg / mL. Take a 1 mg / mL transparent clear solution and dilute it to a concentration of 0.2 mg / mL with 0.9% sodium chloride injection. The volume of 1M HCl solution added is calculated as follows: 1M HCl solution added volume (mL) = compound weighed amount (mg) / molecular weight × 1.5 × 1000. The amount added during preparation must not exceed the calculated value.

[0565] The test substance was administered as follows: intravenous injection: 1 mg / kg, 5 mL / kg, 6 animals; oral gavage: 10 mg / kg, 10 mL / kg, 6 animals.

[0566] Sample Collection: Blood (40-50 μl) was collected via orbital venous puncture at 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration into anticoagulant tubes pre-coated with EDTA-K2. Within 1 hour, the blood samples were centrifuged at 10,000 rpm for 20 minutes (stored on wet ice before and after centrifugation). The supernatant, i.e., plasma, was collected and frozen at -20°C or below for LC-MS / MS analysis. Full PK analysis was performed in male ICR mice (two mice per group, four blood collection time points per group, cross-sectional analysis).

[0567] Table 4. Pharmacokinetic parameters of the compounds in mice a

[0568]

[0569]

[0570] Remark: a The intravenous dose is 1 mg / kg

[0571] Compared with the positive compound SNDX-5613, some of the compounds of the present invention have more excellent pharmacokinetic properties, especially in terms of exposure and oral bioavailability.

[0572] Rat pharmacokinetic test

[0573] Experimental animals: SPF male SD rats, weighing 180-220 g, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0574] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not deprived of water for 12 to 14 hours before administration and were fed 2 hours after administration.

[0575] Preparation of test compound solution: For oral gavage, the test compound concentration is 1 mg / mL. Weigh an appropriate amount of compound and prepare it into a 1 mg / mL transparent clear solution using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. For intravenous injection, the test compound concentration is 0.5 mg / mL. Take a 1 mg / mL transparent clear solution and dilute it to a concentration of 0.5 mg / mL with 0.9% sodium chloride injection. The volume of 1M HCl solution added is calculated as follows: 1M HCl solution added volume (mL) = compound weighed amount (mg) / molecular weight × 1.5 × 1000. The amount added during preparation must not exceed the calculated value.

[0576] The test substance was administered as follows: intravenous injection: 1 mg / kg, 2 mL / kg, 3 animals; oral gavage: 10 mg / kg, 10 mL / kg, 3 animals.

[0577] Sample Collection: Blood (40-50 μl) was collected via orbital venous puncture at 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration into anticoagulant tubes pre-sprayed with EDTA-K2. Within 1 hour, the blood samples were centrifuged at 10,000 rpm for 20 minutes (stored on wet ice before and after centrifugation). The supernatant, i.e., plasma, was collected and frozen at -20°C or below for LC-MS / MS analysis. Full PK analysis of male Sprague-Dawley rats (1 rat per group, 8 blood collection time points per rat).

[0578] Some of the compounds of the present invention have excellent pharmacokinetic properties in rats, especially in terms of exposure and oral bioavailability.

[0579] Beagle dog pharmacokinetic testing

[0580] Test animals: Male beagle dogs, weighing 8-10 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0581] Experimental design: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not deprived of water for 12 to 14 hours before administration and were fed 4 hours after administration.

[0582] Preparation of test compound solution: For oral gavage, the test compound concentration is 5 mg / mL. Weigh an appropriate amount of compound and prepare it into a 1 mg / mL transparent clear solution using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. For intravenous injection, the test compound concentration is 1 mg / mL. Take 5 mg / mL of the transparent clear solution and dilute it to a concentration of 1 mg / mL with 0.9% sodium chloride injection. The volume of 1M HCl solution added is calculated as follows: Volume of 1M HCl solution added (mL) = amount of compound weighed (mg) / molecular weight × 1.5 × 1000. The amount added during preparation must not exceed the calculated value.

[0583] The test substance was administered as follows: intravenous injection: 1 mg / kg, 1 mL / kg, 3 mice; oral gavage: 5 mg / kg, 5 mL / kg, 3 mice.

[0584] Sample collection: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, blood (500ul) was collected by venous puncture into anticoagulant tubes pre-sprayed with EDTA-K2. The blood samples were centrifuged within 1 hour (3000g, 4°C, 5 min) and the upper layer, i.e. plasma, was collected and frozen at -20°C or below for LC-MS / MS analysis.

[0585] Some of the compounds of the present invention have excellent oral bioavailability in beagle dogs.

[0586] Test 5: CYP450 enzyme inhibition test

[0587] This test uses human CYP enzyme recombinant protein to be co-incubated with different concentrations of test compounds (1 and 10 μM) and corresponding probe drugs, and then measures the changes in CYP enzyme activity to evaluate the inhibitory ability of the test compounds on each CYP subtype.

[0588] The test results show that some of the compounds of the present invention have basically no inhibitory effect on CYP3A4, CYP2C9, CYP2C8, CYP2C19, CYP2D6, and CYP1A2 at a concentration of 10 μM, and the IC50 is greater than 10 μM.

[0589] Experiment 6: hERG potassium channel effect test

[0590] hERG inhibition tests were performed on some of the compounds of the present invention using the manual electrophysiological patch clamp method. The cell line was derived from HEK293 cells overexpressing hERG potassium channels. The specific experimental protocol was developed by PharmaCoreLabs with reference to literature published in peer-reviewed journals and was performed by PharmaCoreLabs according to its standard experimental operating procedures. The maximum test concentration was 30 μM. The results are shown in Table 5.

[0591] Table 5. Effects of compounds on hERG potassium channels

[0592] serial number <![CDATA[hERG IC 50 (μM)]]> Average inhibition rate of hERG current at the highest compound tested concentration (%) Example-5 >30 <![CDATA[33.09% @30μM ]]> Example-19 >30 <![CDATA[12.81% @30μM ]]> Example-20 >30 <![CDATA[13.22% @30μM ]]> Example 37-1 >30 <![CDATA[13.18% @30μM ]]> Example 38-1 >30 <![CDATA[10.33% @30μM ]]> Example 41-1 >30 <![CDATA[13.18% @30μM ]]>

[0593] The results showed that some of the compounds of the present invention had almost no significant blocking effect on hERG potassium ion channels within the tested concentration range, and were significantly better than the positive reference compound SNDX-5613 reported IC 50 Value 5~15μM.

[0594] Experimental Example 10: Antitumor efficacy study of the example compounds on BALB / c nude mouse models with MV-4-11 cell subcutaneous transplantation tumors

[0595] Eight-week-old female BALB / c nude mice were purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd.; MV-4-11 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. and cultured in IMDM supplemented with 10% FBS at 37°C and 5% CO2. MV-4-11 cells were cultured in vitro (suspension cells). Cells in the logarithmic growth phase were harvested and gently rinsed twice with PBS. The cell pellet was gently pipetted and resuspended in PBS to prepare a single-cell suspension. After counting, the cells were adjusted to a final concentration of 1×10 7 Cells / 100 μL were added to completely liquefied Matrigel and mixed at a ratio of 1:1. 1×10 7 cells / mouse, the inoculation volume was 100 μL / mouse. Tumor growth was observed regularly. On the 8th day after inoculation, the tumor grew to an average of 131 mm 3 The mice were randomly divided into groups (n=8) according to the tumor size and weight, and were gavaged with 15 mg / kg and 30 mg / kg of the example compound twice a day for 32 consecutive days. The clear solution of the example compound was vortex-mixed with an appropriate amount of 0.9% sodium chloride injection and then dissolved with 1.5 equivalents of 1N HCl based on the molar number of the compound. During the experiment, animal activity was observed once a day, each animal was weighed once before administration, and the long and short diameters of the tumor were measured with a vernier caliper twice a week. After 32 days of administration, the tumor volume was measured to evaluate the anti-tumor efficacy of the example compound. At the end of the experiment, all surviving experimental animals were killed. The formula for calculating the tumor volume is: V=0.5(a×b2 ), a and b represent the long diameter and short diameter of the tumor, respectively.

[0596] The results showed that some of the compounds of the embodiments of this patent showed good in vivo efficacy at doses of 15 mg / kg and 30 mg / kg.

[0597] In summary, the compounds provided by the present invention have excellent Menin-MLL protein-protein interaction inhibitory activity and cell proliferation inhibitory activity, and have more significant advantages in safety and bioavailability. They may become new clinical drugs for the treatment of cancer or other diseases mediated by Menin-MLL interactions.

Claims

1. A compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ring L is selected from wherein n1, n2, n3, and n4 are independently selected from 1 or 2; Y 1 are independently selected from CH or N; Y 2 Selected from N; m is selected from 1; W is selected from hydrogen; X is selected from CR a R b NR a or O; R a 、R b are independently selected from hydrogen, halogen, -C 1-6 Alkyl, deuterium-substituted -C 1-6 Alkyl, -C 0～4 Alkylene-OR A1 wherein the alkyl group may be further optionally replaced by one, two, three or four independent R B1 replace; or R a 、R b Together with the atoms it is connected to, it forms 3- to 10-membered carbocyclic group or 4- to 10-membered heterocyclic alkyl group; R A1 Selected from hydrogen, -C 1-6 alkyl; Each R B1 are independently selected from hydrogen, -C 1～6 Alkyl or -C 0～4 Alkylene-OR C1 ; R C1 independently selected from hydrogen, -C 1～6 alkyl; R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ are independently selected from hydrogen; or R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent atoms in the group, together with the ring where the atoms they are connected to form a 7-12 membered bridged cycloalkyl group; R 6 Selected from -C 0～4 Alkylene-C(O)NR E1 R E2 、-C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein the heteroaromatic ring may be further optionally replaced by one, two, three or four independent R E5 replace; R E1 、R E2 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group); Each R E5 independently selected from hydrogen, -C 1～6 alkyl.

2. The compound according to claim 1, characterized in that: X is selected from NR a ; R a Selected from hydrogen, methyl, ethyl, isopropyl.

3. The compound according to claim 1, characterized in that: X is selected from CR a R b ; R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl, Or, R a 、R b Together with the atoms it is connected to, it forms 4. The compound according to claim 1, characterized in that: The ring L is selected from 5. The compound according to claim 1, characterized in that: R 1 、R 2 、R 3 、R 4 、R 5 The two atoms are connected to each other and together form a ring with the atoms they are connected to. Among them, R 1′ 、R 2′ 、R 3′ 、R 4′ are each independently selected from hydrogen.

6. The compound according to claim 1, characterized in that: R 6 Selected from:

7. The compound according to claim 1, characterized in that: The compound is shown in Formula II: Among them, Y 1 、Y 2 , W, X, R 6 ,m,R 1 、R 2 、R 3 、R 4 、R 5 、R 1′ 、R 2′ 、R 3′ 、R 4′ Definition as in claim 1.

8. The compound according to claim 1, characterized in that: The compound is shown in Formula IIa or Formula IIb: Among them, Y 1 、Y 2 , W, X, R 6 Definition as in claim 1.

9. The compound according to claim 8, characterized in that: The compound is shown in Formula IIIa or Formula IIIb: in, Y 1 are independently selected from CH or N; Y 2 Selected from N; R a is selected from hydrogen, methyl, ethyl, isopropyl; R 6 Selected from:

10. The compound according to claim 8, characterized in that: The compound is shown in Formula IVa or Formula IVb: in, Y 1 are independently selected from CH or N; Y 2 Selected from N; R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl, Or, R a 、R b Together with the atoms it is connected to, it forms R 6 Selected from 11. The compound according to claim 10, characterized in that: The compound is shown in formula Va: in, Y 1 are independently selected from CH or N; Y 2 Selected from N; R a 、R b are independently selected from hydrogen, fluorine, methyl, Ethyl, isopropyl, Or, R a 、R b Together with the atoms it is connected to, it forms R 6 Selected from 12. Compound, specifically:

13. Compound, specifically:

14. Use of the compound according to any one of claims 1 to 13, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with the interaction of Menin-MLL fusion protein.

15. Use of the compound of claim 14, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with the interaction of Menin-MLL fusion protein, characterized in that: The disease is cancer.

16. A pharmaceutical composition comprising a preparation prepared from the compound according to any one of claims 1 to 13, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 16, further comprising a pharmaceutically acceptable carrier, excipient, or vehicle.

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