Menin inhibitors and their uses

Abstract

The present invention relates to a compound of formula I: The present invention further provides compounds of the formula: JPEG2025501287000236.jpg5861 for use in the treatment of cancer and other diseases mediated by the interaction of Menin and MLL.

Description

[Technical field]

[0001] The present invention relates to compounds having inhibitory activity on the interaction of Menin and MLL proteins and cell proliferation inhibitory activity, and their use in the treatment of cancer and other diseases mediated by the interaction of Menin and MLL. [Background technology]

[0002] Mixed lineage leukemia (MLL) proteins are histone methyltransferases mutated in clinically and biologically unique subtypes of acute leukemia. The MLL gene family includes five members, MLL1-5, and is closely associated with the development, progression, and metastasis of multiple tumors. Menin protein is encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, which acts as a tumor suppressor gene in endocrine organs. Menin protein interacts with multiple proteins to form a complex interaction network. Studies have revealed that direct interaction of menin with MLL1 and MLL2 proteins is essential for the enzymatic activity of the complex to modify histone methylation (H3K4), regulate the transcription of target genes, and the corresponding functions. Menin interacts with the amide terminus of MLL1 and acts as an oncogenic cofactor that increases the transcription of gene clusters such as HOX and MEIS1. The interaction between Menin and MLL fusion proteins is essential for the abnormal activation of a series of gene clusters by MLL fusion proteins and the pathogenesis of leukemia. Furthermore, as a nuclear protein widely expressed in tissues, Menin is involved in the formation of several important transcription control complexes, and is expressed in several important biological functions in the body. In addition to being involved in the formation of the epigenetic control complex of MLL1 and MLL2, it has been reported that Menin interacts with several transcription factors, including JunD, NFKB, and SMAD3, and controls the transcription activation or repression of target genes.

[0003] Targeting the Menin-MLL interaction with small molecules is an attractive strategy for developing new therapeutic approaches for MLL leukemia. At the same time, 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 cancers.

[0004] Therefore, Menin protein-MLL1 protein interaction inhibitors (inhibitors of the interaction between Menin protein and MLL1 protein) are considered to be potential tumor treatment compounds and have a wide range of potential applications. Selective targeting of the action interface is advantageous for the development of related new drugs. Summary of the Invention

[0005] The present invention provides a compound represented by Formula I, a deuterated compound thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, Ring L is [ka] (wherein n1, n2, n3, and n4 are each independently 1 or 2); Y 1 , Y 2 are each independently CH or N; m is 1, 2, or 3; W is hydrogen, halogen, cyano group, nitro group, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR W1 , and -C 0~4Alkylene group -NR W1 R W2 Selected from the group consisting of; R W1 , R W2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 selected from the group consisting of an alkynyl group, a 3- to 10-membered carbocyclic group, and a 4- to 10-membered heterocycloalkyl group; X is CR a R b , N.R. a , O, and S; R a , R b are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C 1~6 Alkyl groups, deuterium-substituted -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR A1 , -C 0~4 Alkylene group -NR A1 R A2 , -C 0~4 Alkylene group -NR A1 C(O)R A2 , -C 0~4 Alkylene group -C(O)NR A1 R A2 , -C 0~4 Alkylene group -C(O)R A1 , -C 0~4 Alkylene group -S(O)NR A1 R A2 , -C 0~4 Alkylene group -NR A1 S(O)2R A2 , -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4Alkylene group -(6-10 membered aromatic ring), and -C 0~4 alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R B1 (which may be replaced by Or R a , R b together with the atoms connected to it. [ka] , forming a 3- to 10-membered carbocyclic group, or a 4- to 10-membered heterocycloalkyl group, wherein the carbocyclic group, the heterocycloalkyl group, further optionally includes one, two, three, or four independent R B1 may be substituted);

[0006] R A1 , R A2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 0~4 Alkylene group -C(O)R B1 , -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 membered aromatic ring), and -C 0~4 alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R B1 may be substituted); Each R B1 are each independently hydrogen, deuterium, halogen, cyano group, nitro group, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6Alkynyl groups, and -C 0~4 Alkylene group -OR C1 Selected from the group consisting of; R C1 are independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups; R 1 , R 2 , R 3 , R 4 , R 5 , R 1’ , R 2’ , R 3’ , R 4’ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR D1 , -C 0~4 Alkylene group -NR D1 R D2 , -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 membered aromatic ring) and -C 0~4 alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R D3 (which may be replaced by Or R connected to the same atom 1and R 1' , R 2 and R 2' , R 3 and R 3' , R 4 and R 4' each independently represents a 3- to 10-membered carbocyclic group, a 4- to 10-membered heterocycloalkyl group, [ka] wherein the carbocyclic, heterocycloalkyl group further optionally comprises one, two, three, or four independent R D3 (which may be replaced by Or R 1 , R 2 , R 3 , R 4 , R 5 Any non-adjacent both of, or R 1 , R 2 , R 3 , R 4 , R 5 any three of the atoms connected together form, together with the ring in which they are located, a 7- to 12-membered bridged cycloalkyl group or a 7- to 12-membered bridged heterocycloalkyl group, wherein the bridged cycloalkyl group or bridged heterocycloalkyl group may further optionally include one, two, three, or four independent R D3 may be substituted); R D1 , R D2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 membered aromatic ring), and -C 0~4alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R D4 may be substituted);

[0007] Each R D4 are independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups; Each R D3 are each independently hydrogen, halogen, cyano group, nitro group, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR d1 , -C 0~4 Alkylene group -OC(O)R d1 , -C 0~4 Alkylene group -SR d1 , -C 0~4 Alkylene group -S(O)R d1 , -C 0~4 Alkylene group -S(O)R d1 , -C 0~4 Alkylene group -S(O)NR d1 R d2 , -C 0~4 Alkylene group -S(O)NR d1 R d2 , -C 0~4 Alkylene group -S(O)(NH)R d1 , -C 0~4 Alkylene group -S(O)(NH)NRd1 R d2 , -C 0~4 Alkylene group -C(O)R d1 , -C 0~4 Alkylene group -C(O)OR d1 , -C 0~4 Alkylene group -C(O)NR d1 R d2 , -C 0~4 Alkylene group -NR d1 R d2 , -C 0~4 Alkylene group -NR d1 C(O)R d2 , -C 0~4 Alkylene group -NR d1 S(O)2R d2 , -C 0~4 Alkylene group -NR d1 S(O)R d2 , -C 0~4 Alkylene group -P(O)R d1 R d2 , -C 0~4 Alkylene group -P(O)(OR d1 )R d2 , -C 0~4 Alkylene group -P(O)(OR d1 )(OR d2 ), -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 membered aromatic ring), and -C 0~4 alkylene group-(5-10 membered aromatic heterocycle); R d1 , R d2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups;

[0008] R 6is hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 0~4 Alkylene group -C(O)R E1 , -C 0~4 Alkylene group -C(O)OR E1 , -C 0~4 Alkylene group -C(O)NR E1 R E2 , -C 0~4 Alkylene group -NR E1 C(O)R E2 , -C 0~4 Alkylene group -NR E1 S(O)2R E2 , -C 0~4 Alkylene group -NR E1 S(O)R E2 , -C 0~4 Alkylene group -(5-10 membered aromatic ring), -C 0~4 Alkylene group -(5-10 membered heteroaromatic ring), -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -S(O)R E1 , -C 0~4 Alkylene group -S(O)R E1 , -C 0~4 Alkylene group -S(O)NR E1 R E2 , -C 0~4 Alkylene group -S(O)(NH)R E1 , -C 0~4 Alkylene group -S(O)(NH)NR E1 R E2 , -C 0~4 Alkylene group -OR E1 , -C 0~4 Alkylene group -OC(O)R E1 , -C 0~4 Alkylene group -SR E1 , -C 0~4 Alkylene group -P(O)R E1 R E2 , -C 0~4 Alkylene group -P(O)(OR E1 )R E2, and -C 0~4 Alkylene group -P(O)(OR E1 )(OR E2 wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups may further optionally be selected from the group consisting of one, two, three, or four independent R E5 may be substituted); R E1 , R E2 are each independently hydrogen, -C 1~6 Alkyl group, -C 0~4 Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -OR E3 , -C 0~4 Alkylene group -(5-10 membered aromatic ring), -C 0~4 Alkylene group -(5-10 membered heteroaromatic ring), -C 0~4 Alkylene group -S(O)R E3 , -C 0~4 Alkylene group -S(O)R E3 , -C 0~4 Alkylene group --S(O)NR E3 R E4 , -C 0~4 Alkylene group -S(O)(NH)R E3 , -C 0~4 Alkylene group -S(O)(NH)NR E3 R E4 , -C 0~4 Alkylene group -OC(O)R E3 , and -C 0~4 Alkylene group -SR E3 wherein the alkyl, alkylene, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups are further optionally selected from the group consisting of one, two, three, or four independent R E5 may be substituted); Or, R E1 , R E2are linked together to form a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group or the bridged heterocycloalkyl group may further optionally include one, two, three, or four independent R E5 may be substituted); R E3 , R E4 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups; Or R E3 , R E4 together with the nitrogen atom to which it is attached form a 4-10 membered heterocycloalkyl group or a 4-10 membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group, bridged heterocycloalkyl group, optionally further comprise one, two, three, or four independent R E5 (which may be replaced by Or R E3 , R E4 are linked together to form a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group or the bridged heterocycloalkyl group may further optionally include one, two, three, or four independent R E5 may be substituted); Each R E5 are independently hydrogen, halogen, cyano, nitro, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -O(C 1~6 alkyl group), -NH2, -C 0~4Alkylene group -(3-10 membered carbocyclic group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(5-10 membered aromatic ring), and -C 0~4 alkylene-(5-10 membered heteroaromatic ring), wherein the carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups may further optionally have one, two, three, or four independent R E6 may be substituted); R E6 are independently hydrogen, halogen, cyano group, nitro group, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups.

[0009] In some embodiments of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 1’ , R 2’ , R 3’ , R 4’ are all hydrogen, X is O, and Y 1 If CH is In this case, m is not 1.

[0010] In some embodiments of the present invention, preferably, n1 and n2 are 1 and n3 and n4 are 2, or n1 and n2 are 2 and n3 and n4 are 1. Preferably, Y 1 is N and Y 2 is N or Y 1 is CH and Y 2 is N. Preferably, m is 1 or 2, more preferably, m is 1.

[0011] In some embodiments of the present invention, W is preferably selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, methoxymethyl, amino, methylamino, and dimethylamino.

[0012] In some embodiments of the present invention, X is preferably CR a R b , N.R. a or O, more preferably, X is CR a R b or NR a It is.

[0013] In some embodiments of the invention, X is CR a R b When a , R b each independently represents hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monodeuteromethyl, dideuteromethyl, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CO alkylene group, -OR A1 , -C1 alkylene group -OR A1 , -C2 alkylene group -OR A1 and -C3 alkylene group -OR A1 Selected from the group consisting of: R A1 is selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0014] In some embodiments of the invention, X is CR a R b When a is hydrogen, and R bis hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CO alkylene group -OR A1 , -C1 alkylene group -OR A1 , -C2 alkylene group -OR A1 and -C3 alkylene group -OR A1 Selected from the group consisting of: R A1 is selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0015] In some embodiments of the invention, X is CR a R b When a , R b are the same and are selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, monodeuteromethyl, dideuteromethyl, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CO alkylene group, -OR A1 , -C1 alkylene group -OR A1 , -C2 alkylene group -OR A1 , -C3 alkylene group -OR A1 Selected from the group consisting of: R A1 is selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0016] In some embodiments of the invention, X is CR a R b In the case where R is a , R b together with the atoms connected to it. [ka] , a 3-membered carbocyclic group, a 4-membered carbocyclic group, a 5-membered carbocyclic group, a 6-membered carbocyclic group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group; B1 are each independently selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0017] In some embodiments of the invention, X is NR a When selected from, preferably, R a is hydrogen, methyl, ethyl, n-propyl, isopropyl, mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C1 alkylene group -OR A1 , -C2 alkylene group -OR A1 and -C3 alkylene group -OR A1 Selected from the group consisting of: R A1 is selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0018] 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’ are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteromethyl, dideuteromethyl, trideuteromethyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0019] In some embodiments of the present invention, preferably, R 1’ , R 2’ , R 3’ , R 4’are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteromethyl, dideuteromethyl, trideuteromethyl, monofluoromethyl, difluoromethyl and trifluoromethyl; R 1 , R 2 , R 3 , R 4 , R 5 any two non-adjacent atoms of are joined together to form a 7-membered bridged cycloalkyl group, an 8-membered bridged cycloalkyl group, or a 9-membered bridged cycloalkyl group together with the rings in which the joined atoms are located; 1 , R 2 , R 3 , R 4 , R 5 Any two of these that are not adjacent to each other are -CH2-, -CH2CH2-, and -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.

[0020] In some embodiments of the present invention, preferably, R 6 is -C(O)NR E1 R E2 Here, R E1 , R E2 are each independently selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a -C4 alkyl group, a -C5 alkyl group, a -C6 alkyl group, a 3-membered carbocyclic group, a 4-membered carbocyclic group, a 5-membered carbocyclic group, a 6-membered carbocyclic group, a -C1 alkylene group-(3-membered carbocyclic group), a -C1 alkylene group-(4-membered carbocyclic group), a -C1 alkylene group-(5-membered carbocyclic group), and a -C1 alkylene group-(6-membered carbocyclic group).

[0021] In some embodiments of the present invention, preferably, R 6is selected from the group consisting of a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, -C1 alkylene group-(5-membered heteroaromatic ring), and -C1 alkylene group-(6-membered heteroaromatic ring), wherein the heteroaryl group is further optionally selected from the group consisting of one, two, three, or four independent R E5 each R E5 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, 3-membered carbocyclic group, 4-membered carbocyclic group, 5-membered carbocyclic group, and 6-membered carbocyclic group.

[0022] Furthermore, X is CR a R b or NR a and; R a , R b are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C 1~6 Alkyl groups, deuterium-substituted -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~2 Alkylene group -OR A1 , -C 0~2 Alkylene group -NR A1 R A2 , -C 0~2 Alkylene group -NR A1 C(O)R A2 , -C 0~4 Alkylene group -C(O)NR A1 R A2 , -C 0~4 Alkylene group -C(O)R A1 , -C 0~4 Alkylene group -S(O)NR A1 R A2 , -C 0~4 Alkylene group -NR A1 S(O)2R A2 , -C 0~2Alkylene group -(3-10 membered carbocyclic group), -C 0~2 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(6-10 membered aromatic ring), and -C 0~2 alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R B1 (which may be replaced by Or R a , R b together with the atoms connected to it. [ka] , a 3- to 6-membered carbocyclic group, or a 4- to 6-membered heterocycloalkyl group, wherein the carbocyclic group, the heterocycloalkyl group, further optionally includes one, two, three, or four independent R B1 may be substituted); R A1 , R A2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~2 Alkylene group -C(O)R B1 , -C 1~2 Alkylene group -(3-10 membered carbocyclic group), -C 1~2 Alkylene group -(4-10 membered heterocycloalkyl group), -C 1~2 Alkylene group -(6-10 membered aromatic ring), and -C 1~2 alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R B1 may be substituted); Y 1 , Y 2 are each independently CH or N; m is 1 or 2; W is selected from hydrogen, a methyl group, a trifluoromethyl group, a methoxy group, and a methylamine group.

[0023] Furthermore, X is NR a It is. Here, R a is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, [ka] is selected from the group consisting of:

[0024] Furthermore, X is CR a R b It is. Here, R a , R b each independently represents a hydrogen atom, a fluorine atom, a methyl group, [ka] , ethyl group, isopropyl group, [ka] or selected from the group consisting of Or, R a , R b together with the atoms connected to it. [ka] It is formed.

[0025] In some embodiments of the present invention, R a is hydrogen, and R b is hydrogen, fluorine, methyl group, [ka] , ethyl group, isopropyl group, [ka] is selected from the group consisting of:

[0026] In some embodiments of the present invention, R a , R b are the same and are hydrogen, fluorine, a methyl group, [ka] , ethyl group, isopropyl group, [ka] is selected from the group consisting of:

[0027] In some embodiments of the present invention, further comprising: The ring L is [ka] is selected from the group consisting of:

[0028] In some embodiments of the present invention, The ring L is [ka] Here, the symbol * indicates that one end is connected to an aromatic ring and the other end is connected to a methylene group.

[0029] In some embodiments of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 1’ , R 2’ , R 3’ , R 4’ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6Alkenyl and halogen-substituted -C 2~6 alkynyl groups. Preferably, R 1 , R 2 , R 3 , R 4 , R 5 , R 1' , R 2' , R 3' , R 4' are both hydrogen.

[0030] In some embodiments of the present invention, further comprising: R 1’ , R 2’ , R 3’ , R 4’ are each independently hydrogen, halogen, cyano group, nitro group, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR D1 , and -C 0~4 Alkylene group -NR D1 R D2 Selected from the group consisting of; R D1 , R D2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl groups, and -C 2~6 alkynyl groups; R 1 , R 2 , R 3 , R 4 , R 5 any two of which are not adjacent may be joined together to form, together with the ring in which the joined atoms are located, a 7- to 12-membered bridged cycloalkyl group, a 7- to 12-membered bridged heterocycloalkyl group; Here, R 1 , R 2 , R 3, R 4 , R 5 Any non-adjacent pair of -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(R D3 )-, -N(R D3 )-(CR D3 R D3 ) n -O- and -N(R D3 )-(CR D3 R D3 ) n -S-; each n is independently 0, 1, 2, or 3; each q is independently 1, 2, or 3; Each R D3 are each independently hydrogen, halogen, cyano group, nitro group, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl and halogen-substituted -C 2~6 alkynyl groups, or two R D3 together [ka] It is formed.

[0031] More specifically, R 1 , R 2 , R 3 , R 4 , R 5 Two of the atoms are connected to each other, together with the ring in which they are located. [ka] Here, R 1’ , R 2’ , R 3’ , R 4’ are each independently hydrogen or -C 1~6 It is an alkyl group.

[0032] In some embodiments of the present invention, further comprising: R 1’ , R 2’ , R 3’ , R 4’ are each independently hydrogen, halogen, cyano group, nitro group, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR D1 , and -C 0~4 Alkylene group -NR D1 R D2 Selected from the group consisting of R D1 , R D2 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl groups, and -C 2~6 alkynyl groups, R 1 , R 2 , R 3 , R 4 , R 5 any three of the following may be joined together to form, together with the ring in which the joined atoms are located, a 7- to 12-membered bridged cycloalkyl group or a 7- to 12-membered bridged heterocycloalkyl group; Here, R 1 , R 2 , R 3 , R 4 , R 5 Any two of the groups are -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 RD3 ) 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- and -N(R D3 )-(CR D3 R D3 ) n -S-, and a third group is connected to a carbon or nitrogen atom in the linkage formed by the two groups; each n is independently 0, 1, 2, or 3; each q is independently 1, 2, or 3; Each R D3 are each independently hydrogen, halogen, cyano group, nitro group, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 -C substituted with alkenyl or halogen 2~6 or two R D3 Together [ka] It is formed.

[0033] More specifically, R 1 , R 4 , R 5 are connected to each other and together with the ring in which the connected atoms are located [ka] It is formed.

[0034] In some embodiments of the present invention, further comprising: R 6 is -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)NR E1 R E2 , -S(O)(NH)R E1 , -S(O)(NH)NR E1 R E2 , -OR E1 , -OC(O)R E1 , and -SR E1 wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups may further optionally be selected from the group consisting of one, two, three, or four independent R E5 It may be substituted.

[0035] Preferably, R 6 is -C(O)NR E1 R E2 , -NR E1 C(O)R E2 , -NR E1 S(O)2R E2 , -NR E1 S(O)R E2, a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-membered carbocyclic group, a 4-membered carbocyclic group, a 5-membered carbocyclic group, a 6-membered carbocyclic group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, -S(O)R E1 , -S(O)2R E1 , -S(O)NR E1 R E2 , -S(O)(NH)R E1 , -S(O)(NH)NR E1 R E2 , -OR E1 , -OC(O)R E1 , and -SR E1 wherein the carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups are further optionally selected from the group consisting of one, two, three, or four independent R E5 may be substituted.

[0036] Preferably, R E1 , R E2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, monodeuteromethyl, dideuteromethyl, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -C4 alkyl, -C5 alkyl, -C6 alkyl, 3-membered carbocyclic group, 4-membered carbocyclic group, 5-membered carbocyclic group, 6-membered carbocyclic group, -C1 alkylene group-(3-membered carbocyclic group), -C1 alkylene group-(4-membered carbocyclic group), -C1 alkylene group-(5-membered carbocyclic group), and -C1 alkylene group-(6-membered carbocyclic group).

[0037] More specifically, R 6 teeth, [ka] is selected from the group consisting of:

[0038] In some embodiments of the present invention, the general formula represented by Formula I is as follows: [ka] wherein said substituents are defined as above.

[0039] In some embodiments of the present invention, the general formula represented by Formula I is as follows: [ka] wherein said substituents are defined as above.

[0040] In some embodiments of the present invention, the general formula represented by Formula I is further as follows: [ka] wherein said substituents are defined as above.

[0041] In some embodiments according to the invention, the compound is as shown in Formula II: [ka] Formula II In the formula, 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’ is defined as above.

[0042] In some embodiments according to the invention, the compound has Formula IIa or Formula IIb. [ka] In the formula, Y 1 , Y 2 , W, X, R 6 is defined as above.

[0043] In some embodiments according to the invention, the compound has Formula IIIa or Formula IIIb. [ka] During the ceremony, Y 1 , Y 2 are each independently CH or N; Preferably, Y 1 is N and Y 2 is N or Y 1 is CH and Y 2 is N; R a is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, [ka] Selected from the group consisting of; R 6 teeth, [ka] is selected from the group consisting of:

[0044] In some embodiments according to the invention, the compound has Formula IVa or Formula IVb. [ka] During the ceremony, Y 1 , Y 2 are each independently CH or N; Preferably, Y 1 is N and Y 2 is N or Y 1 is CH and Y 2 is N, R a , R b each independently represents a hydrogen atom, a fluorine atom, a methyl group, [ka] , ethyl group, isopropyl group, [ka] or selected from the group consisting of Or, R a , R b together with the atoms connected to it. [ka] It forms; Preferably, R a is hydrogen, and R b each independently represents a hydrogen atom, a fluorine atom, a methyl group, [ka] , ethyl group, isopropyl group, [ka] or R a , R b are the same and are hydrogen, fluorine, a methyl group, [ka] , ethyl group, isopropyl group, [ka] Selected from the group consisting of R 6 teeth, [ka] is selected from the group consisting of:

[0045] In some embodiments according to the invention, the compound has Formula Va: [ka] During the ceremony, Y 1 , Y 2are each independently CH or N; Preferably, Y 1 is N and Y 2 is N or Y 1 is CH and Y 2 is N, R a , R b each independently represents a hydrogen atom, a fluorine atom, a methyl group, [ka] , ethyl group, isopropyl group, [ka] or selected from the group consisting of Or, R a , R b together with the atoms connected to it. [ka] It forms; R 6 teeth, [ka] is selected from the group consisting of:

[0046] In some specific embodiments of the present invention, the compound is specifically [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is.

[0047] In some other specific embodiments of the invention, the compound is specifically [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is.

[0048] The present invention further provides use of the above compound, a deuterated compound thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease associated with abnormalities in Menin activity.

[0049] The present invention further provides the use of the above compound, its deuterated compound, its stereoisomer, or its pharma- ceutically acceptable salt in the manufacture of a medicament for the treatment of cancer.

[0050] The present invention further provides a pharmaceutical composition comprising a formulation made with any one of the above compounds, deuterated compounds thereof, stereoisomers thereof, or pharma- ceutically acceptable salts thereof.

[0051] The pharmaceutical composition further comprises a pharma- ceutically acceptable carrier, excipient, or vehicle.

[0052] The compounds of the present invention have excellent inhibitory activity against the interaction between Menin protein and MLL protein and cell proliferation inhibitory activity, and also have excellent properties in terms of safety, bioavailability, and efficacy in animals.

[0053] The diseases associated with Menin-MLL interaction or Menin-MLL fusion protein interaction as defined in the present invention include one or more of cancer or malignant tumor, diabetes, and other Menin-related diseases. "Cancer" or "malignant tumor" refers to any one of a number of diseases characterized by abnormal uncontrolled cell proliferation, an entity in which affected cells have the ability to spread locally or via the bloodstream and lymphatic system to other sites (i.e., metastasis) and any one of a number of characteristic structural and / or molecular features. "Cancer cell" refers to a cell at an early, intermediate, or late stage that has undergone multi-stage carcinogenesis. The aforementioned "cancer" or "malignant tumor" is leukemia, lymphoma, sarcoma, lung cancer, esophageal cancer, gastric cancer, liver cancer, brain cancer, myeloma, pancreatic cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, multiple myeloma, brain tumor, or multiple endocrine neoplasia.

[0054] In particular embodiments, the compounds of the invention are used to treat leukemia associated with MLL rearrangements, acute lymphocytic leukemia associated with MLL rearrangements, acute lymphoblastic leukemia associated with MLL rearrangements, lymphoblastic lymphoma associated with MLL rearrangements, acute myeloid leukemia associated with MLL rearrangements, or acute myeloid leukemia with maturation associated with MLL rearrangements, where "MLL rearrangements" as used herein means rearrangements of the MLL gene. In certain embodiments, diseases or conditions treatable by the compounds of the invention include insulin resistance, prediabetes, diabetes (e.g., type II diabetes or type I diabetes), and risk of diabetes, and hyperglycemia.

[0055] With regard to combination therapy, the present invention further relates to combination therapy for treating the diseases or disorders described in the present invention. In one embodiment, the combination therapy involves administering one or more other pharmacoactive agents in combination with at least one of the compounds of the present invention to treat cancer or other diseases mediated by Menin / MLL. The pharmacoactive 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 immunotherapy, including but not limited to cell-based immunotherapy, antibody therapy, and cytokine therapy, to treat the diseases or disorders disclosed herein.

[0056] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Literature Abstracts Service, Inc., Columbus, Ohio) naming systems.

[0057] Regarding the definitions of the terms used in the present invention, unless otherwise specified, the initial definition provided for a group or term in this specification applies to the group or term throughout the specification, but for terms that are not specifically defined in this specification, a meaning that can be understood by a person skilled in the art based on the disclosure and context should be given.

[0058] "Substituted" means that a hydrogen atom in a molecule is replaced with another different atom or group, or that a lone pair electron of an atom in a molecule is replaced with another atom or group, for example, a lone pair electron on an S atom is replaced with an O atom. [ka] may be formed.

[0059] "May be further optionally substituted", "may be further substituted", "may be optionally substituted" all mean that "substitution" may occur but does not necessarily occur, and the description includes whether it occurs or not.

[0060] The minimum and maximum carbon atom content in the hydrocarbon group are represented by prefixes, e.g., C a~b Alkyl groups (prefixed with C a~b ) means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1~6 An alkyl group is an alkyl group containing 1 to 6 carbon atoms.

[0061] An "alkyl group" is a saturated hydrocarbon chain having a specified number of member atoms. An alkyl group may be straight or branched. Representative branched alkyl groups have one, two or three branches. An alkyl group may be optionally substituted one or more times with 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. An alkyl group may be, for example, -O(C 1~6 It may also be part of another group such as an alkyl group.

[0062] An "alkylene group" is a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. a ~ b An alkylene group is an alkylene group having a to b carbon atoms. Alkylene groups are branched and straight chain hydrocarbon groups. For example, the term "propylene group" means: [ka] Similarly, the term "dimethylbutylene group" includes, for example, [ka] One of the following is listed.

[0063] The -C0-4 alkylene group according to the present invention may be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-, etc.), a C3 alkylene group, or a C4 alkylene group, and the C0 alkylene group means that the group does not exist and is bonded as a chemical bond, and the A-C0 alkylene group-B means AB, that is, the A group and the B group are connected by a chemical bond. For example, the -C0 alkylene group-(3-membered cycloalkyl group) means a cyclopropyl group.

[0064] The term "unsaturated" as used herein means that a group or molecule contains a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-nitrogen triple bond, or the like.

[0065] An "alkenyl group" is a straight or branched chain hydrocarbon group containing at least one site of vinyl unsaturation (>C=C<). For example, C a-b The alkenyl group is intended to mean an alkenyl group having a to b carbon atoms, including, for example, a vinyl group, a propenyl group, an isopropenyl group, a 1,3-butadienyl group, and the like.

[0066] An "alkynyl group" refers to a straight chain or branched chain hydrocarbon group containing at least one triple bond. The term "alkynyl group" is further intended to include hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl groups are intended to include ethynyl, propynyl groups, and the like.

[0067] The term "carbocyclic group" as used herein refers to a saturated cyclic group or a non-aromatic partially saturated cyclic group having a single ring or multiple rings (fused, bridged, spiro-bonded) with multiple carbon atoms but no ring-constituting heteroatoms. The term "carbocyclic group" includes cycloalkenyl groups, such as cyclohexenyl groups. Examples of single carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl groups. Examples of carbocyclic groups of the fused carbocyclic group system include dicyclohexyl, dicyclopentyl, and dicyclooctyl groups. Hereinafter, the polycyclic structure such as the above dicycloalkyl group will be named as dicyclohexyl group. [ka] and is named dicyclohexyl group. [ka] Examples of carbocyclic groups in bridged ring systems include: [ka] , adamantyl, etc. Illustrative examples of spirocyclic carbocyclic groups include: [ka] The term "carbocyclic group" may also include partially saturated cyclic groups formed by the fusion of an aromatic ring with a non-aromatic ring, where the attachment point may be at a non-aromatic or aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalen-5-yl and 5,6,7,8-tetrahydronaphthalen-5-yl.

[0068] The term "bridged ring" or "bridged cycloalkyl group" as used herein refers to a saturated or non-aromatic partially saturated cyclic group that is bridged to form rings having multiple carbon atoms but no ring-constituting heteroatoms. Illustrative examples of this term are: [ka] These include, but are not limited to, adamantyl groups and the like.

[0069] The term "heterocycloalkyl group" as used herein refers to a saturated or partially saturated non-aromatic ring having one or more rings (fused, bridged, spiro-linked) containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. In general, a "heterocycloalkyl group" refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system having multiple ring atoms, containing one, two or three ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Illustrative examples of heterocycloalkyl groups of monocyclic heterocycloalkyl systems include oxetanyl, azetidinyl, pyrrolidine, 2-oxo-pyrrolidin-3-yl, tetrahydrofuran, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxoazepanyl. Illustrative examples of heterocycloalkyl groups in the fused heterocycloalkyl system include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxo-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Illustrative examples of heterocycloalkyl groups in the bridged heterocycloalkyl system include: [ka] Illustrative examples of heterocycloalkyl groups in the spirocyclic heterocycloalkyl series include: [ka] Examples of partially saturated heterocycloalkyl groups include dihydrofuran, imidazoline, tetrahydropyridinyl, or dihydropyranyl groups. The term "heterocycloalkyl group" may further include partially saturated cyclic groups formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, the connection of which may be at a non-aromatic carbon atom, an aromatic carbon atom, or a heteroatom, examples of which include: [ka] Examples include:

[0070] The term "bridged heterocycle" or "bridged heterocycloalkyl group" as used herein means a saturated ring or a partially saturated non-aromatic ring formed by bridging multiple rings containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of this term include: [ka] These include, but are not limited to:

[0071] The term "aromatic ring" according to the present invention means an aromatic hydrocarbon group having multiple carbon atoms. The aryl group is usually a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Furthermore, the term "aryl group" as used herein means an aromatic substituent which may be a single aromatic ring or multiple condensed aromatic rings. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl groups.

[0072] The "aromatic heterocycle" described in the present invention means an aromatic unsaturated ring containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. In general, it is an aromatic monocyclic or bicyclic hydrocarbon containing one or more ring atoms selected from the heteroatoms of O, N, and S. The heterocyclic aryl group preferably has 1 to 3 heteroatoms, and examples thereof include a pyridinyl group, an indolyl group, a quinoxalinyl group, a quinolyl group, an isoquinolyl group, a benzothienyl group, a benzofuranyl group, a benzothienyl group, a benzopyranyl group, a benzothiopyranyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, an imidazolyl group, a thienyl group, an oxadiazolyl group, a benzimidazolyl group, a benzothiazolyl group, and a benzoxazolyl group.

[0073] "Halogen" according to the present invention refers to fluorine, chlorine, bromine or iodine. The "halogen-substituted alkyl group" according to the present invention is an alkyl group in which one or more hydrogen atoms are substituted with halogen, for example, C 1~4 The alkyl group is an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms, and further includes, for example, a monofluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.

[0074] The term "deuterium-substituted alkyl group" as used herein means an alkyl group in which one or more hydrogen atoms have been replaced with deuterium. For example, C 1~4 The alkyl group is an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is replaced with one or more deuterium atoms, and further includes, for example, a monodeuteromethyl group, a dideuteromethyl group, and a trideuteromethyl group.

[0075] In the present invention, "-OR", "-NRR" and the like mean that the R group is connected to an oxygen atom or a nitrogen atom via a single bond.

[0076] In the present invention, the oxygen atom in "-C(O)R", "-S(O)R" and the like is connected to a carbon atom or a sulfur atom by a double bond, and the R group is connected to an oxygen atom or a sulfur atom by a single bond. For example, "-S(O)(NH)R" means that an oxygen atom and a nitrogen atom are connected to a sulfur atom by a double bond, and an R group is connected to a sulfur atom by a single bond.

[0077] According to the present invention, "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms or a lone pair electrons via a double bond.

[0078] In the description of groups according to the present invention, [ka] is used to describe the site of substitution on a group. For example, [ka] The tetrahydropyrrole ring is [ka] This means that the ring forms a spiro ring together with other rings in the structure through the position.

[0079] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms have been replaced with deuterium atoms. Here, the ratio of deuterium atoms means that it is greater than the abundance ratio of deuterium in nature.

[0080] A "stereoisomer" of the present invention is a compound that consists of the same atoms and is bonded by the same chemical bonds, but has a different three-dimensional structure. The stereoisomers of the present invention include each single stereoisomer and the compound, including, but not limited to, enantiomers and diastereomers. The compounds of the present invention or their pharma- ceutically acceptable salts may contain one or more chiral carbon atoms, which may give rise to enantiomers, diastereomers and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. In preparing the compounds of the present invention, racemates, diastereomers or enantiomers may be selected as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or may be resolved by conventional means such as crystallization and chiral chromatography.

[0081] When the compound of the present invention contains an ethylenic double bond, unless otherwise specified, the compound of the present invention includes cis-trans isomers of E and Z isomers. All tautomers of the compound of the present invention are also included within the scope of the present invention.

[0082] The term "pharmaceutical acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form, and is physiologically compatible with the recipient.

[0083] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed with the above compounds or their stereoisomers, inorganic and / or organic acids and bases, including zwitterionic salts (inner salts) and further including quaternary ammonium salts such as alkylammonium salts. These salts are obtained directly from the final isolation and purification of the compounds. The above compounds or their stereoisomers are obtained by mixing with a certain number of acids or bases in appropriate amounts (e.g., equal equivalents). These salts are obtained by collecting precipitates formed in the solution by means of filtration, by recovering after evaporation of the solvent, or by reacting in an aqueous medium and then lyophilizing.

[0084] In some embodiments, one or more compounds of the present invention can be used in combination with each other. The compounds of the present invention can also be used in combination with any other active agent to prepare pharmaceuticals or pharmaceutical compositions for regulating cell function or treating disease. When the compounds used are a series, they can be administered to a subject simultaneously, separately or sequentially.

[0085] In addition, based on the contents described in the present invention, it will be apparent that many other modifications, substitutions or changes can be made in accordance with common technical knowledge and conventional means in the art, without departing from the basic technical idea of ​​the present invention. [Brief description of the drawings]

[0086] [Figure 1] FIG. 1 shows a structural analysis diagram of intermediate A1-a by single crystal X-ray diffraction method. [Diagram 2] FIG. 2 shows a structural analysis diagram of intermediate A1-b by single crystal X-ray diffraction method. [Diagram 3] FIG. 3 shows a structural analysis diagram of intermediate 7-5a1 by single crystal X-ray diffraction method. [Figure 4] FIG. 4 shows the structure analysis diagram of intermediate 7-5a2 by single crystal X-ray diffraction method. [Diagram 5] FIG. 5 shows a structural analysis diagram of Example 19 by the single crystal X-ray diffraction method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] The technical solutions of the present invention will be described in more detail below through specific embodiments as examples. However, it should not be understood that the scope of protection of the subject matter of the present invention is limited to the following examples. Any technology realized based on the content of the present invention belongs to the scope of the present invention.

[0088] The known starting materials according to the present invention can be synthesized by conventional methods in the art or can be purchased from companies such as Ananji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0089] The abbreviations of the reagents in the examples are: UHP: urea peroxide; DBU: 1,8-diazabicycloundecane-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-fluorobis(phenylsulfonyl)amine; TEA: triethylamine; Py SO3: sulfur trioxide-pyridine; HATU: 2-(7-azabenzotriazol-1-yl)-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.

[0090] In the examples, unless otherwise specified, the reaction was carried out under a nitrogen atmosphere. In the examples, unless otherwise specified, the solution refers to an aqueous solution. In the examples, unless otherwise specified, the reaction temperature is room temperature. Room temperature between 20°C and 30°C is the optimal reaction temperature. In the examples, unless otherwise specified, M indicates moles / 1L.

[0091] The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR chemical shifts (δ) were 10 -6 The values ​​were given in ppm. NMR measurements were performed using (BrukeRAvanceIII 400MHz and BrukeRAvance NEO 600MHz) nuclear magnetic resonance instruments, with deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS measurements were performed using a Shimadzu liquid chromatograph mass spectrometer (Shimadzu LC-MS 2020(ESI)). HPLC measurements were performed using a Shimadzu ultra-high performance liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure liquid chromatography) was performed using a Gilson GX-281 reversed phase preparative liquid chromatograph. Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates were used as thin-layer chromatography plates, and thin-layer chromatography with a size of 0.4 mm to 0.5 mm was used to separate and purify the products. For column chromatography, Yantai Yellow Sea silica gel with a mesh size of 200 to 300 was generally used as the carrier. The equipment used for the analysis and preparation of supercritical fluid chromatography (SFC) was a SHIMADZU SFC-30A.

[0092] Synthesis of intermediates 1-3 [ka] Step 1: Synthesis of 1-2 At 0°C, HATU (120.61g, 317.39mmol) and DIPEA (102.55g, 793.48mmol, 138.21mL) were added to a solution of 5-fluoro-2-methoxybenzoic acid (45g, 264.49mmol) and ethylisopropylamine (23.21g, 317.39mmol) in DCM (880mL). The reaction mixture was gradually warmed to room temperature and reacted for 17h with stirring. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted three times with EA, and the organic phases were combined. The concentrated crude product was separated and purified using a silica gel column to obtain intermediate 1-2 (60g, 250.75mmol, 94.8% yield). MS m / z=240[M+H] + .

[0093] Step 2: Synthesis of 1-3 Under the condition of -70 ° C, BBr3 (131.64 g, 526.57 mmol) was added dropwise to a solution of 1-2 (63 g, 263.28 mmol) in DCM (200.00 mL), and after the dropwise addition, the reaction mixture was gradually warmed to room temperature and reacted for 17 h with stirring. After the reaction was completed, the mixture was cooled to -70 ° C, quenched with MeOH, extracted with EA, the organic phase was combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the crude product 1-3 (49 g, 217.53 mmol, yield 82.6%) after concentration was used in the next reaction without further purification. MS m / z = 226 [M + H] + .

[0094] Synthesis of intermediates 1-5 [ka] By referring to the synthetic route of intermediate 1-3, diisopropylamine was used instead of ethylisopropylamine, and the reaction gave intermediate 1-5. MS m / z=240[M+H] + .

[0095] Synthesis of intermediates 1-7 [ka] By referring to the synthetic route of intermediate 1-3, dicyclopropylamine was used instead of ethylisopropylamine, and the reaction gave intermediate 1-7. MS m / z=236[M+H] + .

[0096] Synthesis of intermediates 1-11 [ka] Step 1: Synthesis of 1-9 At room temperature, 1-8 (3 g, 52.54 mmol) was dissolved in anhydrous methanol (40 mL), then 4N HCl / MeOH (46 mL), acetone (7.63 g, 131.37 mmol), and NaBH3CN (4.97 g, 78.81 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, and the crude product after concentration was dissolved in 10% aqueous NaOH solution, extracted three times with MTBE, and the organic phases were combined, oxidized by adding HCl / MeOH, and then concentrated to obtain the crude product (6.5 g, 47.92 mmol, yield 91.2%), which was used as it was in the next reaction. MS m / z=100[M+H] + .

[0097] Step 2-Step 3: Synthesis of 1-11 By following the synthesis route of intermediate 1-3, 1-9 was used instead of ethylisopropylamine, and the reaction gave the desired intermediate 1-11. MS m / z=238[M+H] + .

[0098] Synthesis of intermediates 1-15 [ka]

[0099] Step 1: Synthesis of 1-13 At room temperature, 1-12 (3.56 g, 50.06 mmol) was dissolved in anhydrous methanol (40 mL), then acetone (7.27 g, 125.14 mmol) and NaBH3CN (4.73 g, 75.08 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, and the crude product after concentration was dissolved in 10% aqueous NaOH solution, extracted three times with MTBE, and the organic phases were combined, oxidized by adding HCl / MeOH, and then concentrated to obtain the crude product (6.5 g, 43.43 mmol, yield 86.7%), which was used as it was in the next reaction. MS m / z=114[M+H] + .

[0100] Step 2-Step 3: Synthesis of 1-15 By referring to the synthetic route of intermediate 1-3, 1-13 was used instead of ethylisopropylamine, and the reaction gave the desired intermediate 1-15. MS m / z=252[M+H] + .

[0101] Synthesis of intermediate 1-17 [ka] By referring to the synthetic route of intermediate 1-3, isopropylmethylamine was used instead of ethylisopropylamine, and the reaction gave intermediate 1-17. MS m / z=212[M+H] + .

[0102] Synthesis of intermediate 1-22 [ka]

[0103] Step 1: Synthesis of 1-18 1-8 (3.0 g, 52.54 mmol) was dissolved in DCM (50 mL) under ice bath, (Boc)2O (12.04 g, 55.17 mmol) and triethylamine (6.37 g, 63.05 mmol) were added, and the mixture was gradually warmed to room temperature and stirred overnight to react. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product 1-18 after concentration was used in the next reaction without further purification. MS m / z=158[M+H] + .

[0104] Step 2: Synthesis of 1-19 At 0°C, 1-18 (8.33g, 52.99mmol) was dissolved in anhydrous DMF, and NaH (1.34g, 55.64mmol) was added under nitrogen protection, and the mixture was reacted at 0°C for 30min. Ethyl iodide (9.9g, 58.29mmol) was slowly added dropwise, and after the addition was completed, the mixture was warmed to room temperature and stirred. The reaction was monitored by LCMS, and after the reaction was completed, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column to obtain 1-19 (5.6g, 30.23mmol, yield 57%). MS m / z=186[M+H] + .

[0105] Step 3: Synthesis of 1-20 1-19 (5.6 g, 30.23 mmol) was dissolved in MTBE, HCl / EA was slowly added dropwise, and the mixture was stirred at room temperature until no solid precipitated, and the mixture was suction filtered. The cake was washed with a small amount of EA to obtain intermediate 1-20 (2.74 g, 22.53 mmol, 74.52% yield). MS m / z=86 [M+H] + .

[0106] Step 4-Step 5: Synthesis of 1-22 Using the synthesis route of intermediate 1-3 as a reference, 1-20 was used instead of ethylisopropylamine, and the reaction gave the desired intermediate 1-22. MS m / z=224[M+H] + .

[0107] Synthesis of intermediate 1-25 [ka] 1-23 (680 mg, 3.56 mmol) was dissolved in a mixed solvent of dioxane (Dioxane, 15 mL) and water (3 mL), and 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 in that order, and the mixture was stirred at 90 ° C overnight. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column to obtain 1-25 (700 mg, 3.18 mmol, 89% yield). MS m / z = 221 [M + H] + .

[0108] [ka] Following the synthesis method of 1-25, 1-26 was used instead of 1-24, and the reaction gave 1-27 (232 mg, 1.0 mmol, 80% yield). MS m / z=233[M+H] + .

[0109] Synthesis of intermediates M1-M8 [ka]

[0110] Step 1: Synthesis of 2-2 At 0°C, 2-1 (4.9 g, 26.57 mmol) and TEA (5.38 g, 53.14 mmol) were dissolved in DCM, and a DCM solution of tetr-butyl 2,7-azaspiro[3.5]nonane-7-carboxylate (4.81 g, 21.26 mmol) was slowly added dropwise, and the mixture was stirred at the same temperature for 2 h. After the reaction was completed, the mixture was diluted with water and extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified on a silica gel column (PE / EA=5:1 to 1:1, v / v) to obtain 2-2 (6.5 g, 17.37 mmol, yield 65.37%). MS m / z=374[M+H] + .

[0111] Step 2: Synthesis of 2-3 At 0°C, 2-2 (1.0g, 2.67mmol) and DBU (488.13mg, 3.21mmol) were dissolved in THF, 1-3 (601mg, 2.67mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the mixture was diluted with water and extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified on a silica gel column (PE / EA=10:1-5:1, v / v) to obtain 2-3 (1.04g, 1.84mmol, yield 68.9%). MS m / z=563[M+H] + .

[0112] Step 3: Synthesis of 2-4 At room temperature, 2-3 (1.04 g, 1.84 mmol) was dissolved in anhydrous methanol, Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added, and hydrogen gas was replaced, followed by reaction at room temperature for 2 h. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and purified using a silica gel column (PE / EA = 5:1 to 1:1, v / v) to obtain 2-4 (625 mg, 1.18 mmol, yield 64.13%). MS m / z = 529 [M + H] + .

[0113] Step 4: Synthesis of M1 At 0°C, 2-4 (40g, 75.67mmol) was dissolved in DCM (70mL), TFA (30mL) was slowly added, and the mixture was warmed to room temperature and stirred for 0.5h. After the reaction was completed, the mixture was concentrated, and an aqueous NaHCO3 solution was added to adjust the pH to a weak alkali. The crude product M1 was extracted with DCM and concentrated, and used directly in the next reaction. MS m / z=429[M+H] + .

[0114] Synthesis of intermediate M2 [ka]

[0115] Step 1: Synthesis of 2-5 At 0°C, M1 intermediate 2-2 (1.0g, 2.67mmol) and DBU (488.13mg, 3.21mmol) were dissolved in THF, 1-5 (601mg, 2.67mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified on a silica gel column (PE / EA=10:1-5:1, v / v) to obtain 2-5 (1.0g, 1.73mmol, 64.9% yield). MS m / z=577[M+H] + .

[0116] Step 2: Synthesis of 2-6 At room temperature, 2-5 (1.0 g, 1.73 mmol) was dissolved in anhydrous methanol, Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added, and the mixture was reacted at room temperature for 2 h after replacing with hydrogen gas. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and purified by a silica gel column (PE / EA = 5:1 to 1:1, v / v) to obtain 2-6 (720 mg, 1.33 mmol, yield 76.79%). MS m / z = 543 [M + H] + .

[0117] Step 3: Synthesis of M2 At 0°C, 2-6 (4.0g, 7.38mmol) was dissolved in DCM (7mL), TFA (3mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5h. After the reaction was completed, the mixture was concentrated, and an aqueous NaHCO3 solution was added to adjust the pH to a weak alkali. The crude product M2 was extracted with DCM and concentrated, and used directly in the next reaction. MS m / z=443[M+H] + .

[0118] By referring to the synthesis method of intermediate M1, 1-7, 1-11, 1-15, 1-17, 1-22, and 1-27 were used instead of 1-3, and the reaction was carried out to obtain the corresponding intermediates M3 to M8. [ka]

[0119] Synthesis of intermediates N1-N6 [ka]

[0120] Step 1: Synthesis of 3-1 1-3 (10 g, 44.39 mmol) and 5-bromopyrimidine (21.17 g, 133.18 mmol) were dissolved in DMF at room temperature, cesium carbonate (43.39 g, 133.18 mmol) was added, and the mixture was heated to 130 °C and stirred overnight. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified on a silica gel column (PE / EA = 4:1, v / v) to obtain 3-1 (11 g, 36.26 mmol, yield 81.68%). MS m / z = 304 [M + H] + .

[0121] Step 2: Synthesis of 3-2 3-1 (8.0 g, 26.37 mmol) was dissolved in DCM, m-CPBA (13.61 g, 79.12 mmol) was slowly added dropwise at 0°C, and the mixture was warmed to room temperature and stirred for 24 h. After the reaction was completed, the temperature was lowered to 0°C, and the mixture was quenched by adding a saturated aqueous solution of sodium thiosulfate, and then extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified through a silica gel column to obtain 3-2 (5.6 g, 17.54 mmol, yield 66.51%). MS m / z=320[M+H] + .

[0122] Step 3: Synthesis of 3-3 Triethylamine (3.55g, 35.07mmol) was dissolved in DCM, and POCl3 (4.03g, 26.31mmol) was slowly added dropwise at 0°C. Then, a DCM solution of 3-2 (5.6g, 17.54mmol) was added dropwise to the reaction solution. After the addition was completed, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction solution was slowly poured into ice water, stirred for 30 minutes, and then extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified through a silica gel column to obtain 3-3 (1.7g, 5.03mmol, yield 28.67%). MS m / z=338[M+H] + .

[0123] Step 4: Synthesis of 3 and 4 3-3 (1.0 g, 2.96 mmol) was dissolved in isopropanol, and 2,7-azaspiro[3.5]nonane-7-carboxylate tetr-butyl (871 mg, 3.85 mmol) and DIPEA (1.15 g, 8.88 mmol) were added at room temperature, and the mixture was heated to 80°C and stirred for 2 h. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified on a silica gel column (PE / EA=2:1, v / v) to obtain 3-4 (1.54 g, 2.92 mmol, yield 98.6%). MS m / z=528[M+H] + .

[0124] Step 5: Synthesis of N1 At 0°C, 3-4 (1.54g, 2.92mmol) was dissolved in DCM (20mL), TFA (10mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5h. After the reaction was completed, the mixture was concentrated, and an aqueous NaHCO3 solution was added to adjust the pH to a weak alkali. The crude product was extracted with DCM and concentrated, and used as it was in the next reaction. MS m / z=428[M+H] + .

[0125] By referring to the synthesis method of intermediate N1, 1-5, 1-7, 1-11, 1-15, and 1-25 were used instead of 1-3 to obtain the corresponding intermediates N2 to N6. [ka]

[0126] Synthesis of intermediates A1-a and A1-b [ka]

[0127] Step 1: Synthesis of 4-2 Hydroxylamine hydrochloride (3.34 g, 48.06 mmol) and KOAc (4.72 g, 48.08 mmol) were added to a solution of ethyl 4-cyclohexanonecarboxylate (6.8 g, 40 mmol) in EtOH (80 mL) at room temperature, and the reaction mixture was heated to 80 °C and stirred for 4 h. After the reaction was completed, the organic phase was removed using a rotary evaporator to obtain a crude product, which was diluted with water and extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (PE / EA = 5:1, v / v) to obtain 4-2 (4.08 g, 22.02 mmol, yield 55.05%). MS m / z = 186 [M + H] + .

[0128] Step 2: Synthesis of 4-3 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 in batches while mixing and stirring the two phases, and the organic phase turned blue. After stirring at room temperature for 9 h, the organic phase changed from blue to colorless. After the reaction was completed, the reaction solution was placed in a separatory funnel and extracted three times with EA. The combined organic phase was washed with saturated saline and dried over anhydrous sodium sulfate. The crude product after concentration 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] + .

[0129] Step 3: Synthesis of 4-4 NaBH4 (4.05 g, 106.93 mmol) was added batchwise 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, and the reaction was completed when the addition was complete. After the reaction was completed, it was filtered through diatomaceous earth, the filtrate was concentrated, dissolved with EA, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, rotary evaporated to dryness, and the concentrated crude product was purified on a silica gel column (PE / EA = 10:1, v / v) to give 4-4 (8.4 g, 41.75 mmol, 54.67% yield). MS m / z = 202 [M+H] + .

[0130] Step 4: Synthesis of 4-5a and 4-5b At 0°C, 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), and then methyl acrylate (1.11 g, 12.94 mmol) was added dropwise thereto, and the mixture was reacted at 0°C for 1 h. After the reaction was completed, water was added, EA was added for extraction, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness by rotary evaporation, and separated and purified by silica gel column chromatography (PE / EA=40 / 1→10 / 1) to give product 4-5a (1.035 g, 3.6 mmol, yield 33.39%, 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] + ) was obtained. TLC developer PE / EA=5 / 1:4-5a, R f =0.5;4-5b, R f =0.3.

[0131] Step 5: Synthesis of 4-6a and 4-6b At -10℃, 4-5a (330mg, 1.15mmol) and NiCl2·6H2O (272.88mg, 1.15mmol) in MeOH (3mL) were added with NaBH4 (217.26mg, 5.74mmol) in batches, and the mixture was reacted at -10℃ for 2h. In addition, an aqueous solution (1mL) of K2CO3 (634.94mg, 4.59mmol) was added dropwise thereto, and the mixture was reacted at 0℃ for 2h. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was adjusted to neutral or acidic with 1N HCl, concentrated, and extracted with EA. The organic layers were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporate to dryness by rotary evaporation, and separated and purified by silica gel column chromatography (DCM / MeOH=40:1) to obtain product 4-6a (197mg, 0.874mmol, 76% yield). MS m / z=226[M+H] + (The synthesis method of 4-6b is the same as above.)

[0132] Step 6: Synthesis of 4-7a LiAlH4 (120.88 mg, 3.19 mmol) was added to a solution of 4-6a (598 mg, 2.65 mmol) in THF (10 mL) under ice bath, and the reaction was stirred at 0 °C for 1 h. (100 μL) was added to quench the reaction, and then aq.NaOH (15% wt, 100 μL) and H2O (300 μL) were added, and the mixture was stirred at room temperature for 10 min. The filtrate was filtered, and after concentration, the crude product 4-7a (457 mg, 2.49 mmol, 93.95% yield) was obtained, which was used in the next reaction without further purification. MS m / z=184 [M+H] + (The synthesis method of 4-7b is the same as above.)

[0133] Step 7: Synthesis of A1-a DIPEA (1.29 g, 9.98 mmol, 1.74 mL) was added to a solution of 4-7a (457 mg, 2.49 mmol) in DCM (12 mL) / DMSO (4 mL), followed by dropwise addition of a suspension of Py·SO3 (1.57 g, 9.98 mmol) in DMSO (4 mL). The mixture was stirred at room temperature for 10 min, cooled to 0°C, and DCM (10 mL) / 1N aqHCl (10 mL) was added. The separated aqueous phase was extracted with EA, and the combined organic phase was washed with 1N HCl and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column to give A1-a (279 mg, 1.54 mmol, 61.73% yield). 1 H NMR (400 MHz, chloroform-d) δ 9.68(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.)

[0134] Synthesis of intermediates B1-a and B1-b [ka]

[0135] Step 1: Synthesis of 4-9 At -78°C, n-BuLi (11mL, 27.5mmol, 2.5M hexane solution) was added dropwise to a solution of diisopropylamine (2.78g, 27.46mmol) in diethyl ether (20mL). The mixture was gradually heated to -11°C, and a solution of 2-cyclohexen-1-one (2.4g, 24.97mmol) in diethyl ether (20mL) was added dropwise to the mixture, and the internal temperature of the reaction solution was maintained between -11°C and -3°C during the addition process. The reaction solution was stirred for 25min, and then a solution of methyl acrylate (2.15g, 24.97mmol) in THF (20mL) was added drop by drop. After the addition, the mixture was stirred at -10°C for 1h to react. After completion of the reaction, the reaction solution was poured into a saturated ammonium chloride (200 mL) solution and stirred for 15 min. EA was added to the mixture for extraction. The combined organic phase was dried over anhydrous sodium sulfate, and the concentrated crude product 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%).

[0136] Step 2: Synthesis of 4-10 Hydroxylamine hydrochloride (2.21 g, 31.8 mmol) and NaOAc (2.61 g, 31.8 mmol) were added to a solution of 4-9 (4.83 g, 26.5 mmol) in EtOH (25 mL) at room temperature, and the reaction mixture was heated to 80°C and stirred for 4 h. After the reaction was completed, the organic phase was removed using a rotary evaporator to obtain a crude product, which was diluted with water and extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel column to obtain 4-10 (4.45 g, 22.47 mmol, yield 84.7%). MS m / z=198[M+H] + .

[0137] Step 3: Synthesis of 4-11 4-10 (4.45 g, 22.56 mmol) and NaHCO 3(Trichloroisocyanuric acid (26.2 g, 112.81 mmol) was added dropwise in batches to a suspension of 4-13 (37.6 g, 564 mmol) in EA (500 mL) / HO (500 mL), and the mixture was stirred at room temperature for 20 min to react, after which the reaction mixture turned blue and the organic phase was stirred for 9 h until the organic phase became a colorless solution. After the reaction was completed, the mixture was extracted with EA, and the combined organic phase was washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified using a silica gel column to obtain 4-11 (4.48 g, 18.13 mmol, 80.36% yield).

[0138] Step 4: Synthesis of 4-12 At 0℃, NaBH4 (950 mg, 24.92 mmol) was added in batches to a solution of 4-11 (4.4 g, 17.8 mmol) and Pd / C (300 mg) in EtOH (80 mL), and the mixture was stirred at room temperature for 1 h to react. After the reaction was completed, the Pd / C was removed by filtration, and the filtrate was concentrated and then separated and purified using a silica gel column to obtain 4-12 (3.04 g, 14.27 mmol, yield 80%).

[0139] Step 5: Synthesis of 4-13a and 4-13b At 0°C, DBU (2.56mL, 17.11mmol) was added to a solution of 4-12 (3.04g, 14.26mmol) in MeCN (30mL), and then methyl acrylate (1.54mL, 17.11mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 1h. After the reaction was completed, the reaction was quenched by adding water, extracted with EA, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by a silica gel column (PE / EA=10:1, v / v) to give 4-13a (1.66g, 5.55mmol, yield 38.92%) and 4-13b (1.55g, 5.18mmol, yield 36.32%), respectively (TLC eluent PE / EA=5 / 1:4-13a, R f= 0.40;4-13b, R f= 0.35).

[0140] Intermediate B1-a and B1-b were obtained by referring to the method of steps 5 to 7 in the synthetic route of A1-a. Here, B1-a and B1-b were directly used in the next step without separation. MS m / z=208[M+H] + .

[0141] Synthesis of intermediates 5-4a and 5-4b [ka] Step 1: Synthesis of 5-2 5-1 (hydrochloride, 193 g, 1.0 mol) was placed in a 5 L beaker, 400 mL of mixed solvent (DCM / IPA=3 / 1) was added, and an aqueous solution of potassium carbonate (110 g, 0.8 mol) was slowly added under an ice bath to control the temperature below 20 ° C. Extraction was repeated 3-4 times with the mixed solvent, and the organic phase was combined and concentrated to obtain the crude product, which was used as it was in the next reaction.

[0142] The crude product was dissolved in DCE (2.5 L), cooled to 10°C, and m-CPBA (688 g, 4 mol) was added in batches, and the temperature was controlled to be less than 35°C. After addition, the temperature was raised to reflux and stirred for 3 h. After the reaction was completed, the temperature was lowered to below 10°C, stirred for 20 min, filtered, rinsed the reaction bottle with the filtrate, rinsed the cake with an appropriate amount of DCE, and sucked to dryness. The filtrate was carefully quenched with Na2SO3 aqueous solution and detected with potassium iodide starch test paper. The filtrate was extracted three times with DCM, concentrated, and separated and purified by silica gel column chromatography (PE / EA=80 / 1→30 / 1) to obtain product 5-2 (138 g, 0.737 mol, yield 73.7%). MS m / z=188[M+H] + .

[0143] Step 2: Synthesis of 5-3a and 5-3b By referring to the synthesis methods of 4-5a and 4-5b, the desired intermediate 5-3a (PE / EA=30 / 1, MS m / z=274[M+H]) was purified and separated using a silica gel column. + ) and 5-3b (PE / EA=20 / 1, MS m / z=274[M+H] +) was obtained. TLC developer: PE / EA=5 / 1:5-3a, R f =0.3;5-3b, R f =0.2.

[0144] Step 3: Synthesis of 5-4a and 5-4b By 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] + ) was obtained.

[0145] Synthesis of intermediate C1 [ka] Step 1: Synthesis of 6-1a 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 overnight at 60°C under nitrogen protection. After the reaction was completed, the mixture was concentrated and the crude product was purified using a silica gel column (PE / EA=5:1-3:1, v / v) to obtain 6-1a (34.28 g, 110.09 mmol, yield 93.02%). MS m / z=312 [M+H] + .

[0146] Step 2: Synthesis of 6-2a 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 protection, and stirred at the same temperature for 1 h. Then, a THF solution of MOMBr (96 mg, 0.768 mmol) was slowly added dropwise, and after addition, the temperature was raised to room temperature and stirred for 2 h. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride and extracted three times with DCM. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by MPLC to obtain 6-2a (99 mg, 0.239 mmol, yield 77.85%). MS m / z = 400 [M + H] +.

[0147] Step 3: Synthesis of 6-3a 6-2a (244 mg, 0.59 mmol) was dissolved in anhydrous DCM (7 mL), TFA (3 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the concentrated crude product (114 mg, 0.363 mmol) was used as it was in the next reaction. MS m / z=300 [M+H] + .

[0148] Step 4: Synthesis of 6-4a 6-3a (114 mg, 0.363 mmol) was dissolved in THF (10 mL), LiAlH4 (16.57 mg, 0.436 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 1 h. After the reaction was completed, sodium sulfate decahydrate was added in batches in an ice bath until no bubbles were generated in the system, and the mixture was filtered and the filtrate was concentrated to obtain a crude product, which was used as it was in the next reaction. MS m / z=272[M+H] + .

[0149] Step 5: Synthesis of C1 6-4a (100 mg, 0.368 mmol) was dissolved in a mixed solvent of DCM / DMSO=6 mL / 2 mL, cooled to 0°C, and a solution of DIPEA (190.51 mg, 1.47 mmol) and sulfur trioxide pyridine complex (234.62 mg, 1.47 mmol) in DMSO (2 mL) was added dropwise in sequence, and the mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the mixture was transferred to an ice bath, quenched by adding 1N HCl, diluted with water, and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column to obtain C1 (75 mg, 0.278 mmol, yield 75.54%). MS m / z=270[M+H] + .

[0150] Synthesis of intermediate C2 [ka] Step 1: Synthesis of 6-5a 6-1a (2.8g, 8.7mmol) was dissolved in THF, cooled to -78℃, and LiHMDS (15.96mL, 2.4eq) was added dropwise under nitrogen protection, and stirred at the same temperature for 1h. Then, a THF solution of iodomethane (2.93g, 20.65mmol) was slowly added dropwise, and after addition, the mixture was warmed to room temperature and stirred for 2h. After completion of the reaction, the mixture was quenched by adding saturated ammonium chloride, and extracted three times with DCM. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by a silica gel column (PE / EA=5:1, v / v) to obtain 6-5a (2.4g, 6.85mmol, yield 78.73%). 1 H NMR (400 MHz, chloroform-d) δ 9.67(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] + .

[0151] Step 2-Step 4: Synthesis of C2 Intermediate C2 was obtained by referring to the synthesis method of C1. MS m / z=210[M+H] + .

[0152] Synthesis of intermediate C3 [ka]

[0153] Step 1: Synthesis of 6-8a 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. The mixture was then warmed to room temperature and stirred for 2 h. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by a silica gel column (PE / EA=5:1, v / v) to obtain 6-8a (52 mg, 0.173 mmol, yield 34.8%, contains two isomers). MS m / z=300[M+H] + .

[0154] Step 2: Synthesis of 6-9a Trimethyl iodide sulfoxide (19.12 g, 86.86 mmol) was dissolved in DMSO, and NaH (2.08 g, 86.86 mmol) was added at 0°C. The mixture was gradually warmed to room temperature and stirred for 1 h. 6-8a (20 g, 66.82 mmol) was added and reacted at room temperature for 17 h. After the reaction was completed, the mixture was quenched by adding saturated ammonium chloride and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA=4:1, v / v) to obtain 6-9a (8.5 g, 27.13 mmol, yield 40.6%, contains two isomers). MS m / z=314[M+H] + .

[0155] Step 3-Step 5: Synthesis of C3 By referring to the synthesis method of C1, intermediate C3 (including two isomers) was obtained. MS m / z=208[M+H] + .

[0156] Synthesis of intermediate C4 [ka] By referring to the synthesis method of C1, deuterated iodomethane was used instead of iodomethane to obtain intermediate C4. MS m / z=216[M+H] + .

[0157] Synthesis of intermediate C5 [ka]

[0158] Step 1: Synthesis of 6-15a 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 in sequence. The mixture was stirred for 2 h at 0°C under nitrogen protection. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA=3:1, v / v) to obtain 6-15a (2.1 g, 4.8 mmol, 80% yield). MS m / z=438[M+H] + .

[0159] Step 2: Synthesis of C5 6-15a (200 mg, 0.45 mmol) was dissolved in anhydrous THF (3 mL), cooled to -78 ° C, LiHMDS (1 mL, 1.28 mmol) was slowly added dropwise under nitrogen protection, and the mixture was stirred at the same temperature for 1 h. Then, a solution of NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 4 h. The temperature was again cooled to -78 ° C, and the mixture was stirred for 1 h while slowly adding LiHMDS (1 mL, 1.28 mmol), and then a solution of NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was quenched by adding saturated ammonium chloride and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by MPLC to give C5 (90 mg, 0.19 mmol, 42.2% yield). MS m / z=474 [M+H] + .

[0160] Synthesis of intermediate C6 [ka] Step 1: Synthesis of 6-16a 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 methanethiosulfonate (216.3 mg, 1.17 mmol) were added dropwise in sequence under nitrogen protection, and the mixture was stirred at room temperature for 20 h. After the reaction was completed, the mixture was quenched by adding saturated ammonium chloride solution and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA=5:1, v / v) to obtain 6-16a (303 mg, 0.57 mmol, 50% yield). MS m / z=530[M+H] + .

[0161] Step 2: Synthesis of 6-17a 6-16a (303 mg, 0.57 mmol) was dissolved in a mixed solvent of acetonitrile and water (5 mL:0.5 mL), cooled to 0°C, and PIFA (757.93 mg, 1.76 mmol) was added under nitrogen protection, followed by stirring at the same temperature for 3 h. After completion of the reaction, the reaction was quenched by adding saturated sodium bicarbonate solution and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (DCM / MeOH=100:1, v / v) to obtain 6-17a (170 mg, 0.37 mmol, yield 64.91%). MS m / z=452[M+H] + .

[0162] Step 3: Synthesis of C6 At 0°C, 6-17a (170 mg, 0.376 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was slowly added dropwise. The mixture was then warmed to room temperature and stirred for 0.5 h. After the reaction was completed, the crude product obtained by concentration was used in the next reaction without further purification. MS m / z=352[M+H] + .

[0163] Synthesis of intermediate C7 [ka] Step 1: Synthesis of 6-18a 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 overnight at 60° C. under nitrogen protection. After the reaction was completed, the mixture was concentrated and the crude product was purified by silica gel column (PE / EA=5:1-3:1, v / v) to obtain 6-18a (17 g, 52 mmol, yield 93.69%). MS m / z=326[M+H] + .

[0164] Step 2: Synthesis of 6-19a 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 protection, and stirred at the same temperature for 1 h. Then, a solution of 2-iodoethyl ether (751 mg, 2.3 mmol) in THF (15 mL) was slowly added dropwise, and after addition, the mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the mixture was quenched by adding saturated ammonium chloride and extracted three times with DCM. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by MPLC to obtain 6-19a (62 mg, 0.156 mmol, 10.12% yield). MS m / z = 396 [M + H] + .

[0165] Step 3 to Step 5: Synthesis of C7 By following the same procedure as in C1, intermediate C7 (45 mg, 0.179 mmol) was obtained. MS m / z=252[M+H] + .

[0166] Synthesis of intermediates D1-a1 and D1-a2 [ka]

[0167] Step 1: Synthesis of 7-1a 6-1a (34.28g, 110.09mmol) was dissolved in THF, cooled to -78℃, and LiHMDS (93mL, 1.1eq) was added dropwise under nitrogen protection, and stirred at the same temperature for 1h. Then, a THF solution of MOMBr (17.89g, 143.12mmol) was slowly added dropwise, and after addition, the mixture was warmed to room temperature and stirred for 2h. After the reaction was completed, the mixture was quenched by adding saturated ammonium chloride, and extracted three times with DCM. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by MPLC to obtain 7-1a (25.6g, 72.03mmol, yield 65.43%). MS m / z=356[M+H] + .

[0168] Step 2: Synthesis of 7-2a 7-1a (25.6 g, 72.03 mmol) was dissolved in anhydrous DCM (250 mL), TFA (40 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the concentrated crude product was used as it was in the next reaction. MS m / z=256[M+H] + .

[0169] Step 3: Synthesis of 7-3a 7-2a (18.34 g, 71.83 mmol) was dissolved in THF (400 mL), LiAlH4 (3.27 g, 86.20 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 1 h. After the reaction was completed, sodium sulfate decahydrate was added in batches in an ice bath until no bubbles were generated in the system, and the mixture was filtered and the filtrate was concentrated to obtain a crude product, which was used as it was in the next reaction. MS m / z=228[M+H] + .

[0170] Step 4: Synthesis of 7-4a 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, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with EA three times. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA=1:1, v / v) to give 7-4a (33 g, 70.86 mmol, 99.7% yield). MS m / z=466 [M+H] + .

[0171] Step 5: Synthesis of 7-4a1 and 7-4a2 7-4a was resolved by SFC to give isomers 7-4a1 (SFC peak retention time: 2.986 min) and 7-4a2 (SFC peak retention time: 4.269 min).

[0172] (SFC method for intermediates 7-4a1 and 7-4a2: Chiral column model number: CHIRALPAK AS; specification: 3um, 150mm x 3mm; mobile phase: A-CO2, mobile phase B-ethanol, A / B=70 / 30: flow rate: 1mL / min; column temperature: 40°C).

[0173] Step 6: Synthesis of 7-5a1 and 7-5a2 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 the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with EA three times. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by a silica gel column (PE / EA=1:1, v / v) to obtain 7-5a1 (300 mg, 1.32 mmol, yield 94.28%). MS m / z=228[M+H] + (The synthesis method of 7-5a2 is the same as above.)

[0174] Step 7: Synthesis of D1-a1 and D1-a2 7-5a1 (300 mg, 1.32 mmol) was dissolved in a mixed solvent of DCM / DMSO=24 mL / 4 mL, cooled to 0°C, and successively added dropwise a solution of DIPEA (682.31 mg, 5.28 mmol) and sulfur trioxide pyridine complex (840.27 mg, 5.28 mmol) in DMSO (2 mL). The mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the mixture was transferred to an ice bath, quenched with 1 N hCl, diluted with water, and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified through a silica gel column to obtain D1-a1 (130 mg, 1.02 mmol, 77.27% yield) of single configuration. 1 H NMR (400 MHz, chloroform-d)δ 9.67(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] + (The synthesis method of another single configuration D1-a2 is similar to that described above.)

[0175] Synthesis of intermediates D2-a1 and D2-a2 [ka]

[0176] By referring to the synthesis method of D1-a1 and D1-a2, iodomethane was used instead of MOMBr to obtain intermediate D2-a1 (MS m / z = 196 [M + H] + ) and D2-a2(MS m / z=196[M+H] + ) were obtained. (SFC method for intermediates 8-4a1 and 8-4a2: Chiral column model number: CHIRAL ART CellμLose-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 retention times of 8-4a1 and 8-4a2 are 3.809min and 4.479min, respectively.).

[0177] Synthesis of intermediates D3-a1 and D3-a2 [ka]

[0178] By referring to the synthesis method of D1-a1 and D1-a2, deuterated iodomethane was used instead of MOMBr to obtain intermediate D3-a1 (MS m / z = 199 [M + H] + ) and D3-a2 (MS m / z = 199 [M + H] + ) were obtained, respectively. (SFC method for intermediates 9-4a1 and 9-4a2: Chiral column model number: CHIRAL ART CellμLose-SC; specification: 3um, 150mm×3mm; mobile phase A-CO2, mobile phase B-isopropanol, A / B=65 / 35: flow rate: 1mL / min; column temperature: 40℃; SFC retention times of 9-4a1 and 9-4a2 are 2.936min and 3.386min, respectively.)

[0179] Synthesis of intermediates D4-a and D5-a [ka]

[0180] Step 1: Synthesis of 10-1a 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 overnight at 60° C. under nitrogen protection. After the reaction was completed, the mixture was concentrated and the crude product was purified by a silica gel column (PE / EA=5:1-3:1, v / v) to obtain 10-1a (2.9 g, 9.3 mmol, yield 93%). MS m / z=284[M+H] + .

[0181] Step 2: Synthesis of 10-2a 10-1a (2.9 g, 9.3 mmol) was dissolved in anhydrous DMF (10 mL), imidazole (0.95 g, 13.88 mmol) and TBDPS-Cl (3.81 g, 13.88 mmol) were added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with EA three times. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA=1:1, v / v) to obtain 10-2a (4.83 g, 9.26 mmol, yield 99.57%). MS m / z=522 [M+H] + .

[0182] Step 3: Synthesis of 10-3a 10-2a (916 mg, 1.76 mmol) was dissolved in anhydrous THF (10 mL), and LiHMDS (1.93 mmol, 1.1 eq) was slowly added dropwise at -70°C, and the mixture was stirred at the same temperature for 1 h. Then, acetone (112.16 mg, 1.93 mmol) and boron trifluoride ethyl ether (274.22 mg, 1.93 mmol) were added dropwise at -70°C, and the mixture was warmed to room temperature and stirred for 2.5 h. After the reaction was completed, the mixture was quenched by adding saturated ammonium chloride and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by MPLC to obtain 10-3a (883 mg, 1.52 mmol, yield 86.36%). MS m / z=580[M+H] + .

[0183] Step 4: Synthesis of 10-4a 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 the reaction was completed, water was added to dilute the mixture, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by a silica gel column (PE / EA=1:1, v / v) to obtain 10-4a (488 mg, 1.43 mmol, yield 94.08%). MS m / z=342 [M+H] + .

[0184] Step 4: Synthesis of D4-a 10-4a (488 mg, 1.43 mmol) was dissolved in a mixed solvent of DCM / DMSO=24 mL / 4 mL, cooled to 0°C, and a solution of DIPEA (784.65 mg, 6.07 mmol) and sulfur trioxide pyridine complex (966.31 mg, 6.07 mmol) in DMSO (2 mL) was added dropwise in sequence, and the mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the mixture was transferred to an ice bath, quenched by adding 1N HCl, diluted with water, and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column to obtain D4-a (397.88 mg, 1.17 mmol, yield 81.8%, contains two isomers, but is used in the next step without separation). MS m / z=340[M+H] + .

[0185] Step 5: Synthesis of 10-5a 10-3a (499 mg, 0.86 mmol) was dissolved in DCM (8 mL), and 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 warmed to room temperature and stirred for 2 days. After the reaction was completed, water was added to dilute the mixture and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified through a silica gel column to obtain 10-5a (263 mg, 0.47 mmol, yield 54.7%). MS m / z=562[M+H] + .

[0186] Step 6-Step 7: Synthesis of D5-a By referring to the synthesis method of D4-a, intermediate D5-a was obtained by TBDPS deprotection and oxidation. MS m / z=322[M+H] + .

[0187] Synthesis of intermediates E2-a and E2-b [ka]

[0188] Step 1: Synthesis of 12-1a 4-1 (1.65 g, 8.20 mmol) was dissolved in acetonitrile (7.37 mL), and TEA (912.74 mg, 9.02 mmol) and aqueous formaldehyde solution (492.43 mg, 16.2 mmol) were added dropwise in sequence at 0°C. The reaction solution was warmed to room temperature and stirred overnight. After completion of the reaction, the crude product obtained by concentration was purified using a 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] + ) was obtained. TLC developer PE / EA=1 / 1; 12-1a, R f =0.3;12-1b, R f =0.2.

[0189] Step 2: Synthesis of 12-2a 12-1a (746 mg, 3.63 mmol) was dissolved in isopropanol (20 mL), Raney nickel (70 mg, 3.23 mmol) was added, hydrogen gas was replaced, the temperature was raised to 70 ° C, and the mixture was stirred overnight. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain a crude product (640 mg, 3.18 mmol, yield 87.6%), which was used in the next reaction without purification. MS m / z = 202 [M + H] + .

[0190] Step 3: Synthesis of 12-3a 12-2a (640 mg, 3.18 mmol) was dissolved in THF (25 mL), TEA (386.13 mg, 3.82) was added dropwise, and the mixture was cooled to -10°C, followed by slowly adding a THF solution of triphosgene (350 mg, 1.18). The reaction mixture was stirred at the same temperature for 30 min, then transferred to room temperature and stirred for 2 h. After the reaction was completed, saturated sodium bicarbonate and ethyl acetate were added, and the organic phases were combined after extraction three times, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by a silica gel column (PE / EA=1:1, v / v) to obtain 12-3a (380 mg, 1.67 mmol, yield 52.5%). MS m / z=228[M+H] + .

[0191] Step 4: Synthesis of 12-4a 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 the mixture was stirred at the same temperature for 1 h. After the reaction was completed, sodium sulfate decahydrate was added in batches in an ice bath until no bubbles were generated in the system, filtered, and the filtrate was concentrated to obtain a crude product (304 mg, 1.64 mmol, 98.2% yield), which was used as it was for the next reaction. MS m / z=186[M+H] + .

[0192] Step 5: Synthesis of E2-a 12-4a (304 mg, 1.64 mmol) was dissolved in a mixed solvent of DCM / DMSO=12 mL / 2 mL, cooled to 0°C, and a solution of DIPEA (848.48 mg, 6.57 mmol) and sulfur trioxide pyridine complex (1.04 g, 6.57 mmol) in DMSO (2 mL) was added dropwise in sequence, and the mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the mixture was transferred to an ice bath, quenched by adding 1N HCl, diluted with water, and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column to obtain E2-a (single configuration, 167 mg, 0.91 mmol, yield 55.5%). 1H NMR (400 MHz, chloroform-d) δ 9.67(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] + .

[0193] Using the synthesis method of E2-a as a reference, a similar experimental procedure was carried out to obtain another single configuration intermediate E2-b. MS m / z=184[M+H] + .

[0194] Synthesis of intermediates E3-a and E3-b [ka]

[0195] By referring to the synthesis method of E2-a, the intermediate E3-a (PE / EA=5 / 1, MS m / z=210[M+H] + , used in the next step without resolution.) and E3-b (PE / EA=3 / 1, MS m / z=210 [M+H] + , which was used in the next step without separation.) was obtained. TLC developer PE / EA=5 / 1; E3-a, R f = 0.4; E3-b, R f =0.3.

[0196] Synthesis of intermediates E4-a and E4-b [ka]

[0197] Step 1: Synthesis of 14-2a 14-1a (14-1a was obtained by referring to the synthesis of 12-2a, using 5-2 as the raw material, and 720 mg, 3.85 mmol was obtained as the isomer with the lower polarity when the isomers were separated), (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 protection. After the reaction was completed, the mixture was concentrated and the crude product was purified by a silica gel column (PE / EA = 5:1-3:1, v / v) to obtain 14-2a (650 mg, 2.26 mmol, yield 58.7%). MS m / z = 288 [M + H] + .

[0198] Step 2: Synthesis of 14-3a 14-2a (650 mg, 2.26 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and Dess-Martin periodinane (1.92 g, 4.52 mmol) was added by patch under nitrogen protection. The mixture was warmed to room temperature and stirred for 2 h. After the reaction was completed, it was quenched by adding water, filtered, and the filtrate was extracted three times with DCM. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (PE / EA = 10:1 to 8:1, v / v) to give 14-3a (537 mg, 1.88 mmol, 83.18% yield). MS m / z = 286 [M + H] + .

[0199] Step 3: Synthesis of 14-4a 14-3a (537 mg, 1.88 mmol) and methylamine hydrochloride (190.60 mg, 2.82 mmol) were dissolved in anhydrous methanol (10 mL), and then TEA was added to adjust the pH to about 8, and the reaction was stirred at room temperature for 0.5 h. Next, acetic acid was added to adjust the pH to 5, and sodium cyanoborohydride (237.13 mg, 3.76 mmol) was added and stirred at room temperature for 1.5 h. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and then the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (DCM / MeOH=50:1, v / v) to obtain 14-4a (397 mg, 1.32 mmol, yield 70.21%). MS m / z=301[M+H] + .

[0200] Step 4: Synthesis of 14-5a At 0°C, 14-4a (397 mg, 1.32 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 h. After the reaction was completed, the crude product obtained by concentration was used in the next reaction without further purification. MS m / z=201[M+H] + .

[0201] Step 5: Synthesis of 14-6a The crude product obtained in step 4 was dissolved in THF (10 mL), cooled to 0°C, and CDI (285.37 mg, 1.98 mmol) was added under nitrogen protection, then warmed to room temperature and stirred for 1 h. After the reaction was completed, the mixture was quenched by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by silica gel column (DCM / MeOH=60:1, v / v) to obtain 14-6a (190 mg, 0.84 mmol, yield 63.6%). MS m / z=227[M+H] + .

[0202] Step 6: Synthesis of 14-7a 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 the mixture was stirred at the same temperature for 1 h. After the reaction was completed, sodium sulfate decahydrate was added in batches in an ice bath until no bubbles were generated in the system, and the mixture was filtered and the filtrate was concentrated to obtain a crude product (120 mg, 0.6 mmol), which was used as it was for the next reaction. MS m / z=199[M+H] + .

[0203] Step 7: Synthesis of E4-a 14-7a (120 mg, 0.6 mmol) was dissolved in a mixed solvent of DCM / DMSO=4 mL / 0.5 mL, cooled to 0°C, and a solution of DIPEA (312.9 mg, 2.24 mmol) and sulfur trioxide pyridine complex (385.43 mg, 2.42 mmol) in DMSO (0.5 mL) was added dropwise in sequence, and the mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the mixture was transferred to an ice bath, quenched by adding 1N HCl, diluted with water, and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified through a silica gel column to obtain E4-a (35 mg, 0.178 mmol, 29.7% yield), which is one of the single isomers. MS m / z=197[M+H] + .

[0204] Similarly, by referring to the synthesis method of E4-a, another single configuration intermediate E4-b was obtained by the same experimental procedure. MS m / z=197[M+H] + .

[0205] Synthesis of Example 1 [ka] A1-a (95 mg, 524.19 μmol) was added to a MeOH (10 mL) solution of 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, and then NaBH3CN (49.54 mg, 786.29 μmol) was added, and the mixture was stirred at room temperature for 16 h to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 1 (133.16 mg, 220.16 μmol, yield 42.00%, purity 98%) as a white solid. MS m / z=593[M+H] + Nuclear magnetic resonance spectroscopy 1 H NMR (600 MHz, methanol-d4)δ 8.23(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, 7.5hz, 5H), 2 .16(d, J=6.8hz, 2H), 1.96(t, J=8.1hz, 2H), 1.84-1.76(m, 6H), 1.70(d, J=12.9hz, 2H), 1.54(td, J=13.3, 3.9hz, 3 H), 1.31(d, J=6.5hz, 2H), 1.23(t, J=7.0hz, 3H), 1.18(d, J=6.7hz, 2H), 1.15(d, J=6.7hz, 2H), 1.13-1.05(m, 3H).

[0206] Synthesis of Example 5 [ka] N2 (3.95 g, 8.94 mmol) was added to a solution of A1-a (1.62 g, 8.94 mmol) in DCM (30 mL), the mixture was stirred at room temperature for 1 h, AcOH was added to adjust the pH to 4-5, and then NaBH(OAc)3 (5.68 g, 26.82 mmol) was added, and the mixture was stirred at room temperature for 16 h to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 5 (2.14 g, 3.53 mmol, yield 39.46%, purity 98%) as a white solid. MS m / z=607[M+H] + Nuclear magnetic resonance spectroscopy 1 H NMR (600 MHz, CDCl3)δ 8.38(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, 3H), 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).

[0207] Synthesis of Example 7 [ka] M1 (40 mg, 93.35 μmol) was added to a solution of A1-a (16.92 mg, 93.35 μmol) in MeOH (5 mL), the mixture was stirred at room temperature for 1 h, AcOH was added to adjust the pH to 4-5, and then NaBH3CN (8.82 mg, 140.02 μmol) was added, and the mixture was stirred at room temperature for 16 h to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 7 (40.42 mg, 66.55 μmol, yield 71%, purity 97%) as a white solid. MS m / z=594[M+H] + Nuclear magnetic resonance spectroscopy 1 H NMR (600 MHz, methanol-d4)δ 8.38(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=8.1h) z, 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).

[0208] Synthesis of Example 19 [ka] M1 (26.2 mg, 61.26 μmol) was added to a solution of C1 (15 mg, 55.59 μmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 20 (200 mg, 287.4 μmol, yield 70.66%, purity 98%) as a white solid. MS m / z=696[M+H] + Nuclear magnetic resonance spectroscopy

[0209] Synthesis of Example 20 [ka] M2 (180 mg, 406.8 μmol) was added to a solution of C1 (98.6 mg, 366.1 μmol) in MeOH (5 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 20 (200 mg, 287.4 μmol, yield 70.66%, purity 98%) as a white solid. MS m / z=696[M+H] + Nuclear magnetic resonance spectroscopy 1H NMR (400 MHz, chloroform-d)δ 8.46(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=6.6hz, 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), 1.90-1.6 4(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).

[0210] Synthesis of Example 23 [ka] N4 (46 mg, 104.6 μmol) was added to a solution of C2 (21.9 mg, 104.6 μmol) in MeOH (5 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 23 (29 mg, 45.83 μmol, yield 43%, purity 98%) as a white solid. MS m / z=633[M+H] + Nuclear magnetic resonance spectroscopy 1H NMR (600 MHz, CDCl3)δ 8.38(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), 2.0 7(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).

[0211] Synthesis of Example 26 [ka] M1 (43 mg, 100.34 μmol) was added to a solution of C2 (21 mg, 100.34 μmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 26 (12.63 mg, 20.29 μmol, yield 20.22%, purity 99%) as a white solid. MS m / z=622 [M+H] + Nuclear magnetic resonance spectroscopy 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=6.8hz, 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).

[0212] Synthesis of Example 38-2 [ka] M2 (66.38 mg, 150 μmol) was added to a solution of D1-a2 (33.79 mg, 150 μmol) in MeOH (2 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 38-2 (42.76 mg, 63.63 μmol, yield 42.42%, purity 97%) as a white solid. MS m / z=652[M+H] + Nuclear magnetic resonance spectroscopy 1 H NMR (400 MHz, methanol-d4)δ 8.38(s, 1H), 7.39(dd, J=9.1, 4.5hz, 1H), 7.25(ddd, J=9.1, 8.1, 3.0hz, 1H), 7.1 6(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).

[0213] Synthesis of Example 41-1 [ka] M2 (44.40 mg, 100.34 μmol) was added to a solution of D2-a1 (19.59 mg, 100.34 μmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 41-1 (25.06 mg, 40.26 μmol, yield 40.13%, purity 99%) as a white solid. MS m / z=622[M+H] + Nuclear magnetic resonance spectroscopy 1 H 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(hep t, 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).

[0214] Synthesis of Example 41-2 [ka] M2 (44.40 mg, 100.34 μmol) was added to a solution of D2-a2 (19.59 mg, 100.34 μmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 1 h. Then, AcOH was 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 to react. After the reaction was completed, the mixture was separated and purified by Pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 41-2 (20.57 mg, 33.05 μmol, yield 32.94%, purity 99%) as a white solid. MS m / z=622[M+H] + Nuclear magnetic resonance spectroscopy 1 H 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, 3.0h z, 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, 7 H), 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).

[0215] Referring to the synthesis method of Example 1, the molecules in the following examples are obtained by reacting Material 1 with Material 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

[0216] Synthesis of Example 54 [ka] C6 (132 mg, 0.284 mmol, TF) was dissolved in NMP (3 mL), KI (94.79 mg, 0.571 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Then, M1 (177 mg, 0.38 mmol, Cl) and K2CO3 (525 mg, 3.81 mmol) were added, and the mixture was purged with nitrogen, and then heated to 70 ° C. and stirred overnight. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain the compound of Example 54 (1.55 mg, 0.002 mmol, 5.9%). 1 H NMR (400 MHz, chloroform-d)δ 8.40(d, J=1.5hz, 1H), 7.21(d, J=4.5hz, 0H), 7.18(s, 0H), 7.06(ddd, J=7.9, 6.4, 3.1hz, 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, 3H), 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, 3.6hz, 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] + .

[0217] Synthesis of Example 56 [ka] C5 (45 mg, 95.3 μmol) was dissolved in NMP (1 mL), KI (19.39 mg, 116.8 μmol) was added, and the mixture was stirred at room temperature for 0.5 h. Then, M2 (44 mg, 77.87 μmol) and K2CO3 (59.51 mg, 431.22 μmol) were added, and the mixture was purged with nitrogen, and then heated to 70 ° C. and stirred overnight. After the reaction was completed, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product after concentration was purified by pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain intermediate-1 (15 mg, 20.55 μmol, yield 26.39%).

[0218] Intermediate-1 (15 mg, 20.55 μmol) was dissolved in DCM (0.5 mL), TFA (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the crude product obtained by concentration was purified by pre-HPLC to obtain Example 56 (1.16 mg, 1.84 μmol, yield 8.9%). MS m / z=630 [M+H] + .

[0219] The molecules in the following examples were obtained by referring to the synthesis method in Example 56. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0220] Synthesis of Example 62 [ka] The compound of 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 overnight at 60° C. under nitrogen protection. After the reaction was completed, the mixture was concentrated and the crude product was purified by a silica gel column (PE / EA=5:1-3:1, v / v) to obtain intermediate-2 (190 mg, 0.236 mmol, yield 62.1%). MS m / z=707[M+H] + .

[0221] Intermediate-2 (95 mg, 134.39 μmol) was dissolved in THF (2 mL), cooled to -78°C, LiHMDS (0.2 mL, 268.78 μmol) was slowly added dropwise, and then stirred at the same temperature for 1 h. Ethyl trifluoroacetate (81.86 mg, 416.62 μmol) was then added, and the mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the mixture was transferred to an ice bath, quenched by adding a saturated aqueous ammonium chloride solution, and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product Intermediate-3. MS m / z=803[M+H] + .

[0222] Intermediate-3 (60 mg, 74.73 μmol) and polyformaldehyde (78.53 mg, 2.62 mmol) were dissolved in toluene (2 mL), and then potassium carbonate (32.02 mg, 231.66 μmol) and 18-crown-6-ether (5.93 mg, 22.42 μmol) were added, and the mixture was heated to 110° C. and stirred overnight. After the reaction was completed, water was added to dilute the mixture and extracted three times with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a silica gel column (PE / EA=1:1, v / v) to obtain intermediate-4 (20 mg, 27.82 μmol, yield 37.23%). MS m / z=719[M+H] + .

[0223] Intermediate-4 (4 mg, 5.48 μmol) was dissolved in DCM (0.5 mL), TFA (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated, and the obtained crude product was purified by pre-HPLC to obtain Example 62 (1.16 mg, 1.84 μmol, yield 33.58%). MS m / z=619 [M+H] + .

[0224] Synthesis of Example 63 [ka] 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. After addition, the mixture was allowed to naturally warm to room temperature and stirred overnight. After the reaction was completed, the mixture was concentrated and the resulting crude product was purified by pre-HPLC (10 mM NH4HCO3 aqueous solution / acetonitrile system) to obtain Example 63 (10 mg, 14.9 μmol, yield 14.9%). MS m / z=668[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.45 (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 = 10.3hz, 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).

[0225] Synthesis of Example 64 and Example 65 With reference to the synthesis method of Example 1, the following example molecule was obtained by reacting raw material 1 with raw material 2. [Table 3]

[0226] The peak retention times and conditions during SFC chiral separation of some of the example compounds in the above table are shown in the table below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0227] In order to explain the absolute configuration of the compounds of the present invention, crystals of intermediates A1-a (Figure 1), A1-b (Figure 2), 7-5a1 (Figure 3), 7-5a2 (Figure 4) and Example 19 (Figure 5) were obtained by culturing. The instrument parameters are: detector: Bruke RD8 Venture; instrument model: D8 Venture; light source: gallium target; X-ray: Ga (λ=1.34 Å). The technical effects of the present invention are described below by test examples.

[0228] Test Example 1. Measurement of inhibitory activity against menin-MLL interaction The experiment quantitatively measured the inhibition of small molecule inhibitors on Menin / MLL-4-43 peptide interaction by fluorescence polarization competition experiments. The experiment was performed in a 384-well plate (Corning, Cat# 3575), and the reaction buffer used was 50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT. The 40 μL reaction system contained 10 μL of 8 nM Menin recombinant protein and 10 μL of test compounds at different concentrations. After pre-incubating the compounds with Menin protein for 15 min, 20 μL of 10 nM FITC-MLL4-43 peptide was added and incubated on a shaker at 25 °C for 60 min, and the fluorescence polarization signal (FP 485 520 520) was detected by reading it using a BMG PHERAStar. The experimental data was analyzed and processed using GraphPad Prism 6 software to obtain IC 50 The control compound 1 was prepared according to the method of Example 64 in WO2017214367.

[0229] [Table 5]

[0230] Test Example 2: Measurement of the inhibitory effect of menin-MLL interaction inhibitors on cell proliferation The inhibitory ability of the compounds of the present invention on the proliferation of tumor cell lines (e.g., 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, cell line OCI-AML3 containing NPM1 mutation) was evaluated using a cell viability analysis method. The cells were seeded in a 96-well plate at a certain concentration (e.g., 5,000 to 20,000 cells / well), and the same volume of medium containing twice the final concentration of the test compound (final concentration range was 1 nM to 10 μM) was added, placed in an incubator, and cultured for 72 to 168 h under conditions of 37 °C and 5% CO2. Before measurement, the same volume of CellTiter-Glo (registered trademark) Luminescent reagent was added, incubated at room temperature for 10 minutes, and then measured using a microplate reader (BMG LABTECH). The data was analyzed using GraphPad Prism software, and IC 50 The regression curve of the value and the compound was obtained. Control compound 1 was prepared according to the method of Example 64 in WO2017214367. [Table 6-1] [Table 6-2]

[0231] Test Example 3. Test of compound stability in liver microsomes Test purpose: The stability of some example compounds of the present invention in mouse, dog and human liver microsomes was measured by LC-MS / MS method.

[0232] Test materials: The test drugs were the controlled example compounds of the present invention. The positive reference compound SNDX-5613 was prepared with reference to the method of Example 253 in WO2017214367. The control compound 1 was prepared with reference to the method of Example 64 in WO2017214367. Liver microsomes were purchased from Corning.

[0233] Test Method: Each incubation system had a total volume of approximately 45 μL, a medium of 100 mM phosphate buffer (PBS, pH 7.4), and contained a final concentration of 0.5 mg / mL liver microsomal protein, 1.00 μM compound, and 2.00 mM NADPH, with an organic phase content of less than 1%, and was incubated for 37 h at 4°C. o The mixture was incubated at 37 °C in an incubator, and the reaction was stopped after 0, 5, 15, 30, and 60 minutes, respectively, by adding 135 μL of ice-cold acetonitrile. In the positive control group, 1.00 μM ketanserin was used together with 0.5 mg / mL liver microsomes and 2.00 mM NADPH at 37 °C. o After incubation in an incubator at 4°C for 0, 5, 15, 30, and 60 minutes, the reaction was stopped by adding 135 μL of ice-cold acetonitrile. The 96-well plate was shaken at 600 rpm for 10 minutes, and then o C, and centrifuged at 4700 rpm for 15 minutes. 80 μL of the supernatant was mixed with 320 μL of pure water, and the remaining amount of the compound was detected by LC-MS / MS. The in vitro half-life (T1 / 2) and intrinsic clearance (CLint) were calculated according to the following formula. T 1 / 2 =0.693 / k Intrinsic clearance (Clint) = (0.693 / T 1 / 2 ) × (1 / concentration of liver microsomes) × conversion factor. k is the slope of the regression line of the percentage of remaining amount of ln compound vs. incubation time. The conversion factors are shown in the table below.

[0234] [Table 7]

[0235] Specific measurement results are shown in Table 3. [Table 8]

[0236] Some of the example compounds according to the present invention have superior metabolic stability to liver microsomes compared to the positive compound SNDX-5613, and in particular have a remarkable superiority in metabolic stability to human liver microsomes.

[0237] Test Example 4. In vivo pharmacokinetic study Test objective: The pharmacokinetic properties of some example compounds of the present invention in mice, rats and dogs after a single intravenous injection (iv) and intragastric administration (ig) were measured using LC-MS / MS.

[0238] Research method: Weigh out an appropriate amount of compound, and prepare a clear solution of a certain concentration using 0.9% sodium chloride injection and 1M HCl aqueous solution based on 1.5 equivalent moles of compound. After overnight fasting, SPF male ICR mice, SPF male SD rats, and male beagle dogs were administered the corresponding doses of the test compound solution by intravenous injection and intragastric administration. Anticoagulated whole blood was collected from the test animals at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration, and plasma was separated. LC-MS / MS was used to detect plasma samples at each time point, and the plasma concentration of the compound was measured by the calibration curve correction method. The terminal phase elimination half-life (t1 / 2), maximum blood concentration (Cmax), area under the blood concentration curve (AUC), and clearance (CL) were calculated as pharmacokinetic parameters using the Phoenix WinNonlin 5.2 non-compartment model, and bioavailability (F%) was calculated from the results of serum drug concentration. The blood drug concentration and pharmacokinetic parameters were expressed as mean ± standard deviation (X ± SD). The specific test plans for each type are as follows:

[0239] Pharmacokinetic studies in mice Test animals: SPF male ICR mice, weighing 25-30g, 12 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd. Test design: On the day of the test, ICR mice were randomly divided into groups according to body weight, fasted for 12-14 hours before administration, and fed 2 hours after administration.

[0240] Preparation of the solution of the test compound: A suitable amount of the compound was weighed out so that the concentration of the test compound for intragastric administration was 1 mg / mL, and a clear and transparent solution of 1 mg / mL was prepared using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. A 1 mg / mL clear and transparent solution was taken and diluted to a concentration of 0.2 mg / mL with 0.9% sodium chloride injection so that the concentration of the test compound for intravenous injection was 0.2 mg / mL. Here, the volume of the 1M HCl solution added was calculated by the formula: Volume of 1M HCl solution added (mL) = Compound weighed (mg) / Molecular weight x 1.5 x 1000. The amount added during preparation must not exceed the calculated value.

[0241] Administration of the test substance: intravenous injection: dose 1 mg / kg, dose volume 5 mL / kg, 6 animals; intragastric administration: dose 10 mg / kg, dose volume 10 mL / kg, 6 animals. Sample collection: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, blood (40-50μL) was collected from the orbital venous plexus by puncture into an anticoagulant tube pre-sprayed with EDTA-K2, and the blood sample was centrifuged at 10,000rpm for 20 minutes within 1 hour (stored on wet ice before and after centrifugation) to collect the upper layer, plasma, which was frozen and stored in a refrigerator below -20℃, and prepared for LC-MS / MS analysis. Full PK of male ICR mice (2 mice per group, 4 blood collection time points per mouse, cross-sectionally performed).

[0242] [Table 9]

[0243] Some of the example compounds of the present invention have superior pharmacokinetic properties to the positive compound SNDX-5613, and are significantly superior in terms of exposure and oral bioavailability.

[0244] Pharmacokinetic study in rats Test animals: SPF male SD rats, weighing 180-220g, 6 rats / compound, purchased from Chengdu Dashuo Experimental Supplies Co., Ltd. Test design: On the day of the test, SD rats were randomly divided into groups according to body weight, fasted for 12-14 hours one day before administration, and fed 2 hours after administration.

[0245] Preparation of test compound solution: An appropriate amount of the compound was weighed out so that the concentration of the test compound for intragastric administration was 1 mg / mL, and a clear and transparent solution of 1 mg / mL was prepared using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. A clear and transparent solution of 1 mg / mL was taken and diluted to a concentration of 0.5 mg / mL with 0.9% sodium chloride injection so that the concentration of the test compound for intravenous injection was 0.5 mg / mL. Here, the volume of the 1M HCl solution added was calculated by the formula: 1MhCl solution added volume (mL) = compound weighed amount (mg) / molecular weight x 1.5 x 1000. The amount added during preparation must not exceed the calculated value.

[0246] Administration of the test substance: intravenous injection: dose 1 mg / kg, dose volume 2 mL / kg, 3 animals; intragastric administration: dose 10 mg / kg, dose volume 10 mL / kg, 3 animals. Sample collection: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, blood was collected (40-50μl) from the orbital venous plexus by puncture into an anticoagulant tube pre-sprayed with EDTA-K2, and the blood sample was centrifuged at 10,000rpm for 20 minutes within 1 hour (stored on wet ice before and after centrifugation) to collect the upper layer, plasma, which was frozen and stored in a refrigerator below -20℃, and prepared for LC-MS / MS analysis. Full PK in male SD rats (one animal per group, eight blood collection times per animal).

[0247] Some of the example compounds of the present invention have excellent pharmacokinetic properties in rats, and are significantly superior, particularly in terms of exposure and oral bioavailability.

[0248] Pharmacokinetic study in beagle dogs Test animals: male beagle dogs, weight 8~10Kg, 6 / compound. Beijing Marshall Biotechnology Co., Ltd. Study design: On the day of the study, beagle dogs were randomly divided into groups according to body weight, fasted for 12-14 hours before administration (no food or water), and fed 4 hours after administration.

[0249] Preparation of test compound solution: An appropriate amount of the compound was weighed out so that the concentration of the test compound for intragastric administration was 5 mg / mL, and a clear, transparent solution of 1 mg / mL was prepared using 0.9% sodium chloride injection and 1.5 equivalents of 1M HCl aqueous solution. A clear, transparent solution of 5 mg / mL was taken and diluted to a concentration of 1 mg / mL with 0.9% sodium chloride injection so that the concentration of the test compound for intravenous injection was 1 mg / mL. Here, the volume of the 1M HCl solution added was calculated by the formula: Volume of 1M HCl solution added (mL) = Compound weighed (mg) / Molecular weight x 1.5 x 1000. The amount added during preparation must not exceed the calculated value.

[0250] Administration of the test substance: intravenous injection, dose 1 mg / kg, administration volume 1 mL / kg, 3 animals; intragastric administration, dose 5 mg / kg, administration volume 5 mL / kg, 3 animals. Sample collection: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, blood (500 μL) was collected by vein puncture into anticoagulant tubes pre-sprayed with EDTA-K2, and the blood samples were centrifuged (3000 g, 4°C, 5 minutes) within 1 hour to collect the supernatant, i.e., plasma, which was frozen and stored in a refrigerator below -20°C and prepared for LC-MS / MS analysis.

[0251] Some example compounds of the present invention showed excellent oral bioavailability in beagle dogs.

[0252] Test 5. CYP450 enzyme inhibition test In this study, human CYP recombinant proteins were used and incubated with different concentrations of the test compounds (1 and 10 μM) and their corresponding probe drugs, and the changes in CYP enzyme activity were then measured to evaluate the inhibitory ability of the test compounds on various CYP subfamilies.

[0253] As the test results show, some of the example compounds of the present invention had almost no inhibitory effect on CYP3A4, CYP2C9, CYP2C8, CYP2C19, CYP2D6, and CYP1A2 at a concentration of 10 μM, and all of the IC50s were greater than 10 μM.

[0254] Test 6. hERG potassium ion channel action test Some of the compounds in the examples of the present invention were tested for hERG inhibition by electrophysiological manual patch clamp method. The cell line was derived from HEK293 cells overexpressing hERG potassium ion channel. The specific experimental design was prepared by PharmaCore Labs with reference to the literature published in the Journal of the Association of Peer Studies, and PharmaCore Labs carried out the experiment according to its standard experimental protocol, with the highest test concentration being 30μM. The results are shown in Table 5.

[0255] [Table 10]

[0256] As the results show, some of the example compounds of the present invention have little obvious blocking effect on the hERG potassium ion channel within the test concentration range, and the IC reported for the positive reference compound SNDX-5613 was higher than that of the control compound SNDX-5613. 50 This is significantly better than the values ​​of 5 to 15 μM.

[0257] Test Example 10. Study on the antitumor efficacy of the example compounds using MV-4-11 cell subcutaneously transplanted tumor BALB / c nude mouse model Eight-week-old female BALB / c nude mice were purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd., and MV-4-11 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. The medium used was IMDM containing 10% FBS serum, and the culture was performed under conditions of 37°C and 5% CO2. MV-4-11 cells were cultured in vitro (suspension cells), and cells in the logarithmic growth phase were collected and gently rinsed twice with PBS, and the cells were resuspended by gently blowing the cell pellet in PBS to prepare a single-cell suspension. After counting, the final cell concentration was 1 × 107 The cells were adjusted to 100 μL, and the fully liquefied Matrigel basement membrane matrix was added at a ratio of 1:1 and mixed well. 7 The cells were inoculated at 100 μL per animal. The tumor growth was periodically observed, and the tumor size was 131 mm on average on the 8th day after inoculation. 3 When the tumors grew to 100 mm, they were randomly divided into groups (n=8) based on tumor size and mouse body weight, and administered with 15 mg / kg and 30 mg / kg of the example compounds, respectively, intragastrically twice a day for 32 days. A clear solution of the example compound was obtained by mixing well with an appropriate amount of 0.9% sodium chloride injection by swirling, and then adding 1N HCl hydrochloric acid based on 1.5 mole equivalents of the compound to dissolve. During the experimental period, the animal activity was observed once a day, and the body weight of each animal was weighed once before administration, and the long and short diameters of the tumor were measured with a needle. After 32 days of administration, the tumor volume was measured to evaluate the antitumor efficacy of the example compound. At the end of the experiment, all surviving experimental animals were killed. The tumor volume was calculated using the formula: V=0.5(a×b 2 ) where a and b represent the long and short diameters of the tumor, respectively.

[0258] As a result, some of the example compounds of the present application showed good internal pharmacological effects at doses of 15 mg / kg and 30 mg / kg.

[0259] In conclusion, the compounds provided by the present invention have excellent inhibitory activity against Menin protein-MLL protein interaction and cell proliferation inhibitory activity, and further have significant advantages in terms of safety and bioavailability, and therefore may become new drugs for clinically treating cancer or other diseases mediated by Menin-MLL interaction.

Claims

1. The compound of formula I shown below: 【Chemistry 1】 [In the formula, Ring L is 【Chemistry 2】 (wherein n1, n2, n3, and n4 are each independently 1 or 2); Y １ , Y ２ are each independently CH or N; m is 1, 2, or 3; W is hydrogen, halogen, cyano group, nitro group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR Ｗ１ , and -C ０～４ Alkylene group -NR Ｗ１ R Ｗ２ Selected from the group consisting of: R Ｗ１ , R Ｗ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ selected from the group consisting of alkynyl groups, 3- to 10-membered carbocyclic groups, and 4- to 10-membered heterocycloalkyl groups; X is CR ａ R ｂ , N.R. ａ , O, and S; R ａ , R ｂ each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C １～６ Alkyl groups, deuterium-substituted -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR Ａ１ , -C ０～４ Alkylene group -NR Ａ１ R Ａ２ , -C ０～４ Alkylene group -NR Ａ１ C(O)R Ａ２ , -C ０～４ Alkylene group -C(O)NR Ａ１ R Ａ２ , -C ０～４ Alkylene group -C(O)R Ａ１ , -C ０～４ Alkylene group -S(O) ２ N.R. Ａ１ R Ａ２ , -C ０～４ Alkylene group -NR Ａ１ S (O) ２ R Ａ２ , -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene-(5-10 membered aromatic heterocycle), wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R Ｂ１ may be substituted with Or, R ａ , R ｂ together with the atoms connected to it. 【Chemistry 3】 , 3-10 membered carbocyclic group, or 4-10 membered heterocycloalkyl group, wherein the carbocyclic group, heterocycloalkyl group, optionally further comprises one, two, three, or four independent R Ｂ１ (which may be replaced by); R Ａ１ , R Ａ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C ０～４ Alkylene group -C(O)R Ｂ１ , -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R Ｂ１ (which may be replaced by); Each R Ｂ１ are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl groups, and -C ０～４ Alkylene group -OR Ｃ１ Selected from the group consisting of: R Ｃ１ are independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups; R １ , R ２ , R ３ , R ４ , R ５ , R １’ , R ２’ , R ３’ , R ４’ each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR Ｄ１ , -C ０～４ Alkylene group -NR Ｄ１ R Ｄ２ , -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl, alkenyl, alkynyl, alkylene group, carbocyclic, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R Ｄ３ may be substituted with Alternatively, R １ and R １’ , R ２ and R ２’ , R ３ and R ３’ , R ４ and R ４’ each independently represents a 3- to 10-membered carbocyclic group or a 4- to 10-membered heterocycloalkyl group connected together; 【Chemistry 4】 wherein the carbocyclic, heterocycloalkyl group further optionally comprises one, two, three, or four independent R Ｄ３ may be substituted with Or, R １ , R ２ , R ３ , R ４ , R ５ or R １ , R ２ , R ３ , R ４ , R ５ any three of the following may be joined together to form, together with the ring in which the joined atoms are located, a 7- to 12-membered bridged cycloalkyl group or a 7- to 12-membered bridged heterocycloalkyl group, wherein the bridged cycloalkyl group or bridged heterocycloalkyl group may further optionally be one, two, three, or four independent R Ｄ３ (which may be replaced by); R Ｄ１ , R Ｄ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R Ｄ４ (which may be replaced by); Each R Ｄ４ are independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups; Each R Ｄ３ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR ｄ１ , -C ０～４ Alkylene group -OC(O)R ｄ１ , -C ０～４ Alkylene group -SR ｄ１ , -C ０～４ Alkylene group -S(O) ２ R ｄ１ , -C ０～４ Alkylene group -S(O)R ｄ１ , -C ０～４ Alkylene group -S(O) ２ N.R. ｄ１ R ｄ２ , -C ０～４ Alkylene group -S(O)NR ｄ１ R ｄ２ , -C ０～４ Alkylene group -S(O)(NH)R ｄ１ , -C ０～４ Alkylene group -S(O)(NH)NR ｄ１ R ｄ２ , -C ０～４ Alkylene group -C(O)R ｄ１ , -C ０～４ Alkylene group -C(O)OR ｄ１ , -C ０～４ Alkylene group -C(O)NR ｄ１ R ｄ２ , -C ０～４ Alkylene group -NR ｄ１ R ｄ２ , -C ０～４ Alkylene group -NR ｄ１ C(O)R ｄ２ , -C ０～４ Alkylene group -NR ｄ１ S (O) ２ R ｄ２ , -C ０～４ Alkylene group -NR ｄ１ S(O)R ｄ２ , -C ０～４ Alkylene group -P(O)R ｄ１ R ｄ２ , -C ０～４ Alkylene group -P(O)(OR ｄ１ ) R ｄ２ , -C ０～４ Alkylene group -P(O)(OR ｄ１ ) (OR ｄ２ ), -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene group-(5-10 membered aromatic heterocycle); R ｄ１ , R ｄ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups; R ６ is hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C ０～４ Alkylene group -C(O)R Ｅ１ , -C ０～４ Alkylene group -C(O)OR Ｅ１ , -C ０～４ Alkylene group -C(O)NR Ｅ１ R Ｅ２ , -C ０～４ Alkylene group -NR Ｅ１ C(O)R Ｅ２ , -C ０～４ Alkylene group -NR Ｅ１ S (O) ２ R Ｅ２ , -C ０～４ Alkylene group -NR Ｅ１ S(O)R Ｅ２ , -C ０～４ Alkylene group -(5- to 10-membered aromatic ring), -C ０～４ Alkylene group -(5- to 10-membered heteroaromatic ring), -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -S(O)R Ｅ１ , -C ０～４ Alkylene group -S(O) ２ R Ｅ１ , -C ０～４ Alkylene group -S(O) ２ N.R. Ｅ１ R Ｅ２ , -C ０～４ Alkylene group -S(O)(NH)R Ｅ１ , -C ０～４ Alkylene group -S(O)(NH)NR Ｅ１ R Ｅ２ , -C ０～４ Alkylene group -OR Ｅ１ , -C ０～４ Alkylene group -OC(O)R Ｅ１ , -C ０～４ Alkylene group -SR Ｅ１ , -C ０～４ Alkylene group -P(O)R Ｅ１ R Ｅ２ , -C ０～４ Alkylene group -P(O)(OR Ｅ１ ) R Ｅ２ , and -C ０～４ Alkylene group -P(O)(OR Ｅ１ ) (OR Ｅ２ wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups may further optionally be selected from the group consisting of one, two, three, or four independent R Ｅ５ (which may be replaced by); R Ｅ１ , R Ｅ２ are each independently hydrogen, -C １～６ Alkyl group, -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -OR Ｅ３ , -C ０～４ Alkylene group -(5- to 10-membered aromatic ring), -C ０～４ Alkylene group -(5- to 10-membered heteroaromatic ring), -C ０～４ Alkylene group -S(O)R Ｅ３ , -C ０～４ Alkylene group -S(O) ２ R Ｅ３ , -C ０～４ Alkylene group -S(O) ２ N.R. Ｅ３ R Ｅ４ , -C ０～４ Alkylene group -S(O)(NH)R Ｅ３ , -C ０～４ Alkylene group -S(O)(NH)NR Ｅ３ R Ｅ４ , -C ０～４ Alkylene group -OC(O)R Ｅ３ , and -C ０～４ Alkylene group -SR Ｅ３ wherein the alkyl, alkylene, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups are further optionally selected from the group consisting of one, two, three, or four independent R Ｅ５ may be substituted with Or, R Ｅ１ , R Ｅ２ are linked together to form a 4- to 10-membered heterocycloalkyl group, a 4- to 10-membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group, the bridged heterocycloalkyl group, optionally further comprises one, two, three, or four independent R Ｅ５ (which may be replaced by); R Ｅ３ , R Ｅ４ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups; Or, R Ｅ３ , R Ｅ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group, bridged heterocycloalkyl group, optionally further comprises one, two, three, or four independent R Ｅ５ may be substituted with Or, R Ｅ３ , R Ｅ４ are joined together to form a 4- to 10-membered heterocycloalkyl group, a 4- to 10-membered bridged heterocycloalkyl group, wherein the heterocycloalkyl group, the bridged heterocycloalkyl group, optionally further comprises one, two, three, or four independent R Ｅ５ (which may be replaced by); Each R Ｅ５ are independently hydrogen, halogen, cyano group, nitro group, oxo, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, —O(C １～６ alkyl group), -NH ２ , -C ０～４ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～４ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～４ Alkylene group -(5- to 10-membered aromatic ring), and -C ０～４ alkylene-(5-10 membered heteroaromatic ring), wherein the carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups may further optionally be selected from the group consisting of one, two, three, or four independent R Ｅ６ (which may be replaced by); R Ｅ６ are independently hydrogen, halogen, a cyano group, a nitro group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups] A compound represented by the formula:

2. X is CR ａ R ｂ Or NR ａ and R ａ , R ｂ each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C １～６ Alkyl groups, deuterium-substituted -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～２ Alkylene group -OR Ａ１ , -C ０～２ Alkylene group -NR Ａ１ R Ａ２ , -C ０～２ Alkylene group -NR Ａ１ C(O)R Ａ２ , -C ０～４ Alkylene group -C(O)NR Ａ１ R Ａ２ , -C ０～４ Alkylene group -C(O)R Ａ１ , -C ０～４ Alkylene group -S(O) ２ N.R. Ａ１ R Ａ２ , -C ０～４ Alkylene group -NR Ａ１ S (O) ２ R Ａ２ , -C ０～２ Alkylene group -(3- to 10-membered carbocyclic group), -C ０～２ Alkylene group -(4-10 membered heterocycloalkyl group), -C ０～２ Alkylene group -(6- to 10-membered aromatic ring), and -C ０～２ alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl, alkenyl, alkynyl, alkylene group, carbocyclic, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be selected from the group consisting of one, two, three, or four independent R Ｂ１ may be substituted with Or, R ａ , R ｂ together with the atoms connected to it. 【Chemistry 5】 , 3- to 6-membered carbocyclic group, 4- to 6-membered heterocycloalkyl group, wherein the carbocyclic group, the heterocycloalkyl group, further optionally have one, two, three, or four independent R Ｂ１ (which may be replaced by); R Ａ１ , R Ａ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～２ Alkylene group -C(O)R Ｂ１ , -C １～２ Alkylene group -(3- to 10-membered carbocyclic group), -C １～２ Alkylene group -(4-10 membered heterocycloalkyl group), -C １～２ Alkylene group -(6- to 10-membered aromatic ring), and -C １～２ alkylene group-(5-10 membered aromatic heterocycle), wherein the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, and aromatic heterocycle may further optionally have one, two, three, or four independent R Ｂ１ (which may be replaced by); Y １ , Y ２ are each independently CH or N; m is 1 or 2; 2. The compound according to claim 1, wherein W is selected from the group consisting of hydrogen, a methyl group, a trifluoromethyl group, a methoxy group, and a methylamine group.

3. X is NR ａ and R ａ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, 【Chemistry 6】 3. The compound according to claim 2, which is selected from the group consisting of:

4. X is CR ａ R ｂ Selected from R ａ , R ｂ each independently represents a hydrogen atom, a fluorine atom, a methyl group, 【Chemistry 7】 , ethyl group, isopropyl group, 【Chemistry 8】 or selected from the group consisting of Or, R ａ , R ｂ together with the atoms connected to it. 【Chemistry 9】 3. The compound according to claim 2, characterized in that it forms:

5. The ring L is 【Chemistry 10】 The compound according to any one of claims 1 to 4, characterized in that it is selected from the group consisting of:

6. R １ , R ２ , R ３ , R ４ , R ５ , R １’ , R ２’ , R ３’ , R ４’ each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ The compound according to any one of claims 2 to 5, characterized in that it is selected from the group consisting of alkynyl groups.

7. R １’ , R ２’ , R ３’ , R ４’ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR Ｄ１ , and -C ０～４ Alkylene group -NR Ｄ１ R Ｄ２ Selected from the group consisting of: R Ｄ１ , R Ｄ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl groups, and -C ２～６ alkynyl groups; R １ , R ２ , R ３ , R ４ , R ５ any two of which are not adjacent are joined together to form a 7- to 12-membered bridged cycloalkyl group, a 7- to 12-membered bridged heterocycloalkyl group together with the rings in which the joined atoms are located; Here, R １ , R ２ , R ３ , R ４ , R ５ Any two of the non-adjacent groups are -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(R Ｄ３ ) -, -N(R Ｄ３ )-(CR Ｄ３ R Ｄ３ ) ｎ -O- and -N(R Ｄ３ )-(CR Ｄ３ R Ｄ３ ) ｎ are linked together to form a radical selected from the group consisting of: -S-; Each n is independently 0, 1, 2, or 3; each q is independently 1, 2, or 3; Each R Ｄ３ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups, or two R Ｄ３ together 【Chemistry 11】 The compound according to any one of claims 2 to 5, characterized in that it forms

8. R １ , R ２ , R ３ , R ４ , R ５ Two of the atoms are connected to each other together with the ring in which they are located. 【Chemistry 12】 It is formed, Here, R １’ , R ２’ , R ３’ , R ４’ are each independently hydrogen or -C １～６ The compound according to claim 7, characterized in that it is an alkyl group.

9. R １’ , R ２’ , R ３’ , R ４’ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -C ０～４ Alkylene group -OR Ｄ１ , and -C ０～４ Alkylene group -NR Ｄ１ R Ｄ２ Selected from the group consisting of: R Ｄ１ , R Ｄ２ are each independently hydrogen, -C １～６ Alkyl group, -C ２～６ Alkenyl groups, and -C ２～６ alkynyl groups; R １ , R ２ , R ３ , R ４ , R ５ any three of are joined together to form, together with the rings in which the joined atoms are located, a 7- to 12-membered bridged cycloalkyl group, a 7- to 12-membered bridged heterocycloalkyl group; Here, R １ , R ２ , R ３ , R ４ , R ５ Any two of the groups are -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(R Ｄ３ ) -, -N(R Ｄ３ )-(CR Ｄ３ R Ｄ３ ) ｎ -O- and -N(R Ｄ３ )-(CR Ｄ３ R Ｄ３ ) ｎ -S-, and a third group is attached to a carbon or nitrogen atom in the chain formed by the two groups; each n is independently 0, 1, 2, or 3; each q is independently 1, 2, or 3; Each R Ｄ３ are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ Alkyl group, halogen-substituted -C ２～６ Alkenyl groups and halogen-substituted -C ２～６ alkynyl groups, or two R Ｄ３ together 【Chemistry 13】 The compound according to claims 2 to 5, characterized in that it forms

10. R １ , R ４ , R ５ are connected to each other and together with the ring in which the connected atoms are located 【Chemistry 14】 10. The compound according to claim 9, characterized in that it forms:

11. R ６ is -C(O)NR Ｅ１ R Ｅ２ , -NR Ｅ１ C(O)R Ｅ２ , -NR Ｅ１ S (O) ２ R 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) ２ R Ｅ１ , -S(O) ２ N.R. Ｅ１ R Ｅ２ , -S(O)(NH)R Ｅ１ , -S(O)(NH)NR Ｅ１ R Ｅ２ , -OR Ｅ１ , -OC(O)R Ｅ１ , and -SR Ｅ１ wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocycloalkyl, aryl, and heteroaryl groups are further optionally selected from the group consisting of one, two, three, or four independent R Ｅ５ The compound according to claims 1 to 10, characterized in that it is optionally substituted with

12. R ６ teeth, 【Chemistry 15】 The compound according to claim 11, characterized in that it is selected from the group consisting of:

13. The compound represented by the following formula II: 【Chemistry 16】 [In the formula, 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’ is defined as set forth in claim 1. The compound according to claim 1, characterized in that it is represented by:

14. Formula IIa or IIb below: 【Chemistry 17】 [In the formula, Y １ , Y ２ , W, X, R ６ is defined as set forth in claim 1. The compound according to claim 1, characterized in that it is represented by:

15. Formula IIIa or IIIb: 【Chemistry 18】 [In the formula, Y １ , Y ２ are each independently CH or N; R ａ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, 【Chemistry 19】 Selected from the group consisting of R ６ teeth, 【Chemistry 20】 selected from the group consisting of The compound according to claim 14, characterized in that it is represented by:

16. Formula IVa or IVb: 【Chemistry 21】 [In the formula, Y １ , Y ２ are each independently CH or N; R ａ , R ｂ each independently represents a hydrogen atom, a fluorine atom, a methyl group, 【Chemical 22】 , ethyl group, isopropyl group, 【Chemistry 23】 or selected from the group consisting of Or, R ａ , R ｂ together with the atoms connected to it. 【Chemistry 24】 It is formed, R ６ teeth, 【Chemistry 25】 selected from the group consisting of The compound according to claim 14, characterized in that it is represented by:

17. The following formula Va: 【Chemistry 26】 [In the formula, Y １ , Y ２ are each independently CH or N; R ａ , R ｂ each independently represents a hydrogen atom, a fluorine atom, a methyl group, 【Chemistry 27】 , ethyl group, isopropyl group, 【Chemistry 28】 or selected from the group consisting of Or, R ａ , R ｂ together with the atoms connected to it. 【Chemical 29】 It is formed, R ６ teeth, 【Chemistry 30】 selected from the group consisting of The compound according to claim 16, characterized in that it is represented by:

18. in particular, 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 The compound according to any one of claims 1 to 17, characterized in that it is

19. in particular, 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemistry 56】 【Chemistry 57】 The compound according to any one of claims 1 to 17, characterized in that it is

20. 20. Use of the compound according to any one of claims 1 to 19, its deuterated compound, its stereoisomer, or a pharma- ceutically acceptable salt thereof in the manufacture of a pharmaceutical for treating a disease associated with abnormality in menin protein (Menin) activity.

21. 20. Use of the compound according to any one of claims 1 to 19, a deuterated compound thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.

22. A pharmaceutical composition comprising a formulation prepared from the compound according to any one of claims 1 to 19, a deuterated compound thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

23. 23. The pharmaceutical composition of claim 22, further comprising a pharma- ceutically acceptable carrier, excipient, or vehicle.

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