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] This invention relates to compounds having inhibitory activity on the interaction between Menin protein and MLL protein and inhibitory activity on cell proliferation, as well as their use in the treatment of cancer and other diseases mediated by the interaction between Menin and MLL. [Background technology]

[0002] Mixed lineage leukemia (MLL) proteins are mutated histone methyltransferases found in clinically and biologically unique subtypes of acute leukemia. The MLL gene family consists of five members, MLL1-5, and is closely associated with the development, progression, worsening, and metastasis of multiple tumors. Multiple endocrine oncoprotein (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, forming a complex interaction network. Studies have revealed that direct interactions between Menin and MLL1 and MLL2 proteins are essential for the enzymatic activity of histone methylation modification (H3K4) by the complex, the regulation of target gene transcription, and corresponding functions. Menin interacts with the amide terminus of MLL1 and acts as a co-oncogenic factor, increasing 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 for the development of leukemia. Furthermore, as a nuclear protein widely expressed in tissues, Menin is involved in the formation of several important transcriptional regulatory complexes and is expressed in vivo as multiple important biological functions. Aside from its involvement in the formation of the MLL1 and MLL2 epigenetic regulatory complexes, Menin proteins have been reported to interact with several transcription factors, including JunD, NFKB, and SMAD3, to control the transcriptional activation or repression of target genes.

[0003] Targeting the interaction of Menin-MLL with small molecules is an attractive strategy for developing new treatments for MLL leukemia. At the same time, inhibiting the interaction between Menin and wild-type MLL1 and MLL2 may have potential therapeutic effects on many solid tumors such as liver cancer, brain cancer, colon cancer, breast cancer, etc.

[0004] Therefore, a Menin protein-MLL1 protein interaction inhibitor (an inhibitor against the interaction between Menin protein and MLL1 protein) is considered a potential tumor therapeutic compound and has future prospects for wide application. Selectively targeting this interaction 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, its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt.

Chemical formula

Chemical formula

[0006] R A1 , R A2 These are, independently, hydrogen and -C. 1~6 Alkyl 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 member heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 member aromatic ring), and -C 0~4 Selected from the group consisting of alkylene groups (5-10 member aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of any one, two, three, or four independent R groups). B1 (May be replaced with); Each R B1 These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6An alkynyl group, and -C 0~4 an alkylene group -OR C1 selected from the group consisting of; R C1 is independently hydrogen, -C 1~6 an alkyl group, -C 2~6 an alkenyl group, -C 2~6 an alkynyl group, -C substituted with halogen 1~6 an alkyl group, -C substituted with halogen 2~6 an alkenyl group, and -C substituted with halogen 2~6 an alkynyl group selected from the group consisting of; R 1 、R 2 、R 3 、R 4 、R 5 、R 1’ 、R 2’ 、R 3’ 、R 4’ [[ID=...]]は、それぞれ独立に、水素、ハロゲン、シアノ基、ニトロ基、-C 1~6 アルキル基、-C 2~6 アルケニル基、-C 2~6 アルキニル基、ハロゲンで置換された-C 1~6 アルキル基、ハロゲンで置換された-C 2~6 アルケニル基、ハロゲンで置換された-C 2~6 アルキニル基、-C 0~4 [[ID=...]]アルキレン基-OR D1 、-C 0~4 アルキレン基-NR D1 R D2 、-C 0~4 アルキレン基-(3~10員の炭素環基)、-C 0~4 アルキレン基-(4~10員のヘテロシクロアルキル基)、-C 0~4 アルキレン基-(6~10員の芳香環)及び-C 0~4 アルキレン基-(5~10員の芳香族複素環)からなる群より選ばれるか(ここで、アルキル基、アルケニル基、アルキニル基、アルキレン基、炭素環基、ヘテロシクロアルキル基、芳香環、芳香族複素環は、さらに、任意に1つ、2つ、3つ、又は4つの独立したR D3 で置換されてもよい)、 或いは同一の原子に連接しているR 1and R 1' , R 2 and R 2' , R 3 and R 3' , R 4 and R 4' Each of these independently forms a 3-10 membered carbon ring group, a 4-10 membered heterocycloalkyl group, and is linked to each other. [ka] Whether it forms (where the carbocyclic group, heterocycloalkyl group, further optionally one, two, three, or four independent R D3 (May be replaced by), Or R 1 , R 2 , R 3 , R 4 , R 5 Any two non-adjacent elements of R 1 , R 2 , R 3 , R 4 , R 5 Any three of these atoms are linked together to form a 7-12 member bridged ring alkyl group or a 7-12 member bridged heterocycloalkyl group (where the bridged cycloalkyl group and bridged heterocycloalkyl group are further optionally linked to one, two, three, or four independent R atoms). D3 (May be replaced with); R D1 , R D2 These are, independently, hydrogen and -C. 1~6 Alkyl 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 member heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 member aromatic ring), and -C 0~4Selected from the group consisting of alkylene groups (5-10 member aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of any one, two, three, or four independent R groups). D4 (May be replaced with);

[0007] Each R D4 These are, independently, hydrogen, -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of alkynyl groups; Each R D3 These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 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)2R d1 , -C 0~4 Alkylene group -S(O)R d1 , -C 0~4 Alkylene group -S(O)2NR 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 member heterocycloalkyl group), -C 0~4 Alkylene group -(6-10 member aromatic ring), and -C 0~4 Selected from the group consisting of an alkylene group and a (5-10 membered aromatic heterocycle); R d1 , R d2 These are, independently, hydrogen and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of alkynyl groups;

[0008] R 6is hydrogen, -C 1~6 Alkyl 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 member aromatic ring), -C 0~4 Alkylene group - (5-10 member heteroaromatic ring), -C 0~4 Alkylene group - (3-10 membered carbocyclic group), -C 0~4 Alkylene group - (4-10 member heterocycloalkyl group), -C 0~4 Alkylene group -S(O)R E1 , -C 0~4 Alkylene group -S(O)2R E1 , -C 0~4 Alkylene group -S(O)2NR 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 Selected from the group consisting of (where alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and optionally one, two, three, or four independent R groups) E5 (May be replaced with); R E1 , R E2 These are, independently, hydrogen and -C. 1~6 Alkyl alkyl group, -C 0~4 Alkylene group - (3-10 membered carbocyclic group), -C 0~4 Alkylene group - (4-10 member heterocycloalkyl group), -C 0~4 Alkylene group-OR E3 , -C 0~4 Alkylene group - (5-10 member aromatic ring), -C 0~4 Alkylene group - (5-10 member heteroaromatic ring), -C 0~4 Alkylene group -S(O)R E3 , -C 0~4 Alkylene group -S(O)2R E3 , -C 0~4 Alkylene group -- S(O)2NR 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 Selected from the group consisting of (where alkyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and optionally one, two, three, or four independent R groups) E5 (May be replaced with); Alternatively, R E1 , R E2These are linked together to form a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group (where the heterocycloalkyl group and bridged heterocycloalkyl group are further optionally connected to one, two, three, or four independent R groups). E5 (May be replaced with); R E3 , R E4 These are, independently, hydrogen and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of alkynyl groups, Or R E3 , R E4 It forms a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group together with the nitrogen atom attached to it (where the heterocycloalkyl group and bridged heterocycloalkyl group are further optionally one, two, three, or four independent R E5 (May be replaced by), Or R E3 , R E4 These are linked together to form a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group (where the heterocycloalkyl group and bridged heterocycloalkyl group are further optionally connected to one, two, three, or four independent R groups). E5 (May be replaced with); Each R E5 These are independently hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -O(C 1~6 Alkyl(alkyl group), -NH2, -C 0~4Alkylene group - (3-10 membered carbocyclic group), -C 0~4 Alkylene group - (4-10 member heterocycloalkyl group), -C 0~4 Alkylene group -(5-10 member aromatic ring), and -C 0~4 Selected from the group consisting of alkylene groups (5-10 membered heteroaromatic rings) (wherein a carbocyclic group, heterocycloalkyl group, aryl group, heteroaryl group may further be any one, two, three, or four independent R groups) E6 (May be replaced with); R E6 These are independently hydrogen, halogen, cyano group, nitro group, and -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of 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’ Both are hydrogen, and X is O, and Y 1 The field is CH 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 it N or Y? 1 CH is 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 group, methyl group, ethyl group, n-propyl group, isopropyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, hydroxy group, methoxy group, ethoxy group, methoxymethyl group, amino group, methylamino group, and dimethylamino group.

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

[0013] In some embodiments of the present invention, X is CR a R b In that case, preferably R a , R b These are, independently, hydrogen, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, -C0 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 The group is selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, and isopropyl group.

[0014] In some embodiments of the present invention, X is CR a R b In that case, preferably R a is hydrogen, R bThis includes hydrogen, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, -C0 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 The group is selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, and isopropyl group.

[0015] In some embodiments of the present invention, X is CR a R b In that case, preferably R a , R b These are identical, and also hydrogen, fluorine, chlorine, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, -C0 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 The group is selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, and isopropyl group.

[0016] In some embodiments of the present invention, X is CR a R b In the case of R, a , R b together with the atom connected to it [ka] , forming a 3-membered carbon ring group, a 4-membered carbon ring group, a 5-membered carbon ring group, a 6-membered carbon ring group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, and a 6-membered heterocycloalkyl group; each R B1 Each of these is independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, and isopropyl group.

[0017] In some embodiments of the present invention, X is NR a If selected from, preferably R a This includes hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, -C1 alkylene group-OR A1 -C2 alkylene group-OR A1 , and -C3 alkylene group-OR A1 Selected from the group consisting of; R A1 The group is selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, and 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’ Each of these is independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, and trifluoromethyl group.

[0019] In some embodiments of the present invention, preferably, R 1’ , R 2’ , R 3’ , R 4’Each is independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, and difluoromethyl group, trifluoromethyl group; R 1 , R 2 , R 3 , R 4 , R 5 Any two non-adjacent atoms of these are linked together to form a 7-membered bridged cycloalkyl group, an 8-membered bridged cycloalkyl group, or a 9-membered bridged cycloalkyl group with the ring on which these linked atoms are located; where R 1 , R 2 , R 3 , R 4 , R 5 Any two non-adjacent channels in our group are -CH2-, -CH2CH2-, and -CH2CH2CH 2- They are connected to each other so that they become selected groups. More preferably, R 2 and R 4 They are connected to each other, or R 2 and R 3 They are connected to each other, or R 1 and R 4 They 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 Each is independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, -C4 alkyl group, -C5 alkyl group, -C6 alkyl group, 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).

[0021] In some embodiments of the present invention, preferably, R 6The group is selected from the group consisting of a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a -C1 alkylene group-(5-membered heteroaromatic ring), and a -C1 alkylene group-(6-membered heteroaromatic ring) (where the heteroaryl group is further optionally one, two, three, or four independent R groups). E5 (may be replaced by) each R E5 These are independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, 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 These are, independently, hydrogen, halogen, cyano group, nitro group, and -C. 1~6 Alkyl, deuterium-substituted -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 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)2NR 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 member heterocycloalkyl group), -C 0~2 Alkylene group -(6-10 member aromatic ring), and -C 0~2 Selected from the group consisting of alkylene groups - (5-10 membered aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of any one, two, three, or four independent R groups). B1 (May be replaced by), Or R a , R b together with the atom connected to it [ka] , forming a 3-6 membered carbon ring group or a 4-6 membered heterocycloalkyl group (wherein the carbon ring group and heterocycloalkyl group, there are optionally one, two, three, or four independent R B1 (May be replaced with); R A1 , R A2 These are, independently, hydrogen and -C. 1~6 Alkyl 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 member heterocycloalkyl group), -C 1~2 Alkylene group -(6-10 member aromatic ring), and -C 1~2 Selected from the group consisting of alkylene groups (5-10 member aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of any one, two, three, or four independent R groups). B1 (May be replaced with); Y 1 , Y 2 Each is independently either CH or N; m is either 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 That is the case. Here, R a These are hydrogen, methyl group, ethyl group, isopropyl group, cyclopropyl group, [ka] It is selected from the group consisting of the following.

[0024] Furthermore, X is CR a R b That is the case. Here, R a , R b These are, independently, hydrogen, fluorine, and a methyl group. [ka] ethyl group, isopropyl group, [ka] Selected from a group consisting of, Alternatively, R a , R b together with the atom connected to it [ka] It forms a structure.

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

[0026] In some embodiments of the present invention, R a , R b They are identical, and also contain hydrogen, fluorine, methyl groups, [ka] ethyl group, isopropyl group, [ka] It is selected from the group consisting of the following.

[0027] In some embodiments of the present invention, The aforementioned ring L is [ka] It is selected from the group consisting of the following.

[0028] In some embodiments of the present invention, moreover, The aforementioned ring L is [ka] Selected from the group consisting of the following. Here, the symbol * indicates that one side is connected to an aromatic ring and the other side 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’ These are, independently, hydrogen, halogen, cyano group, nitro group, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of alkynyl groups. Preferably, R 1 , R 2 , R 3 , R 4 , R 5 , R 1' , R 2' , R 3' , R 4' Both are hydrogen.

[0030] In some embodiments of the present invention, R 1’ , R 2’ , R 3’ , R 4’ These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 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 These are, independently, hydrogen and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, and -C 2~6 Selected from the group consisting of alkynyl groups; R 1 , R 2 , R 3 , R 4 , R 5 Any two non-adjacent atoms of these atoms can link together to form a 7-12 member bridged cycloalkyl group or a 7-12 member bridged heterocycloalkyl group, together with the ring on which the linked atoms are located. Here, R 1 , R 2 , R 3, R 4 , R 5 Any two non-adjacent pairs among them 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 They are interconnected so as to be 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 These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 Alkenyl groups and halogen-substituted -C 2~6 Selected from the group consisting of alkynyl groups, or two R groups D3 together [ka] It forms a structure.

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

[0032] In some embodiments of the present invention, R 1’ , R 2’ , R 3’ , R 4’ These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6-C substituted with alkyl groups or halogens 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 These are, independently, hydrogen and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, and -C 2~6 Selected from the group consisting of alkynyl groups, R 1 , R 2 , R 3 , R 4 , R 5 Any three of these can link together to form a 7-12 member bridged cycloalkyl group or a 7-12 member bridged heterocycloalkyl group, together with the ring on which the linked atoms are located. Here, R 1 , R 2 , R 3 , R 4 , R 5 Any two of these groups are -O- and -(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 The groups are linked together to form a chain selected from the group consisting of -S-, and the third group is linked to a carbon or nitrogen atom in the chain formed with the two groups mentioned above. Each n is independently 0, 1, 2, or 3. Each q is independently 1, 2, or 3. Each R D3 These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 -C substituted with alkyl groups or halogens 2~6 -C substituted with alkenyl groups or halogens 2~6 Either an alkynyl group is formed, or two R groups are formed. D3 together [ka] It forms a structure.

[0033] More specifically, R 1 , R 4 , R 5 These three are connected to each other, together with the ring in which those connected atoms are located. [ka] It forms a structure.

[0034] In some embodiments of the present invention, 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 member aromatic rings, -5 to 10 member heteroaromatic rings, -3 to 10 member carbocyclic groups, -4 to 10 member heterocycloalkyl groups, -S(O)R E1 -S(O)2R E1 -S(O)2NR E1 R E2 -S(O)(NH)R E1 -S(O)(NH)NR E1 R E2 , -OR E1 -OC(O)R E1 , and -SR E1 Selected from the group consisting of: Here, alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups may be further selected from any one, two, three, or four independent groups. E5 It may be replaced.

[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, 6-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, 3-membered carbocyclic group, 4-membered carbocyclic group, 5-membered carbocyclic group, 6-membered carbocyclic group, 4-membered heterocycloalkyl group, 5-membered heterocycloalkyl group, 6-membered heterocycloalkyl group, -S(O)R E1 -S(O)2R E1 -S(O)2NR E1 R E2 -S(O)(NH)R E1 -S(O)(NH)NR E1 R E2 , -OR E1 -OC(O)R E1 , and -SR E1 Selected from the group consisting of: Here, the carbocyclic group, heterocycloalkyl group, aryl group, and heteroaryl group are further optionally one, two, three, or four independent R E5 It may be replaced with.

[0036] Preferably, R E1 , R E2 Each is independently selected from the group consisting of hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, monodeuterium methyl group, dideuterium methyl group, trideuterium methyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, -C4 alkyl group, -C5 alkyl group, -C6 alkyl group, 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] It is selected from the group consisting of the following.

[0038] In some embodiments of the present invention, the general formula represented by formula I is as follows: [ka] Here, the substituent is defined as described above.

[0039] In some embodiments of the present invention, the general formula represented by formula I is as follows: [ka] Here, the substituent is defined as described above.

[0040] In some embodiments of the present invention, the general formula represented by formula I is as follows: [ka] Here, the substituent is defined as described above.

[0041] In some embodiments of the present invention, the compound is represented by 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’ It is defined as described above.

[0042] In some embodiments of the present invention, the compound is represented by formula IIa or formula IIb. [ka] In the formula, Y 1 , Y 2 W, X, R 6 It is defined as described above.

[0043] In some embodiments of the present invention, the compound is represented by formula IIIa or formula IIIb. [ka] During the ceremony, Y 1 , Y 2 Each is independently either CH or N; Preferably, Y 1 is N and Y 2 Is it N, or Y? 1 CH is Y 2 is N; R a These are hydrogen, methyl group, ethyl group, isopropyl group, cyclopropyl group, [ka] Selected from a group consisting of; R 6 teeth, [ka] It is selected from the group consisting of the following.

[0044] In some embodiments of the present invention, the compound is represented by formula IVa or formula IVb. [ka] During the ceremony, Y 1 , Y 2 Each is independently either CH or N; Preferably, Y 1 is N and Y 2 Is it N, or Y? 1 CH is Y 2 is N, R a , R b These are, independently, hydrogen, fluorine, and a methyl group. [ka] ethyl group, isopropyl group, [ka] Selected from a group consisting of, Alternatively, R a , R b together with the atom connected to it [ka] It forms; Preferably, R a is hydrogen, R b These are, independently, hydrogen, fluorine, and a methyl group. [ka] ethyl group, isopropyl group, [ka] Selected from the group consisting of R a , R b They are identical, and also contain hydrogen, fluorine, methyl group, [ka] ethyl group, isopropyl group, [ka] Selected from the group consisting of, R 6 teeth, [ka] It is selected from the group consisting of the following.

[0045] In some embodiments of the present invention, the compound is represented by formula Va. [ka] During the ceremony, Y 1 , Y 2Each is independently either CH or N; Preferably, Y 1 is N and Y 2 Is it N, or Y? 1 CH is Y 2 is N, R a , R b These are, independently, hydrogen, fluorine, and a methyl group. [ka] ethyl group, isopropyl group, [ka] Selected from a group consisting of, Alternatively, R a , R b together with the atom connected to it [ka] It forms; R 6 teeth, [ka] It is selected from the group consisting of the following.

[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] That is the case.

[0047] In some other specific embodiments of the present invention, the compound is specifically: [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0048] The present invention further provides the use of the above-mentioned compounds, their deuterated compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of diseases related to Menin activity abnormalities.

[0049] The present invention further provides the use of the above-mentioned compounds, their deuterated compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in the manufacture of cancer treatment drugs.

[0050] The present invention further provides a pharmaceutical composition comprising a formulation prepared from any one of the above-mentioned compounds, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0051] The aforementioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier, additive, or vehicle.

[0052] The compounds according to the present invention exhibit excellent inhibitory activity on the interaction between Menin protein and MLL protein, as well as cell proliferation inhibitory activity, and also possess excellent performance in terms of safety, bioavailability, and efficacy in animals.

[0053] Diseases related to the menin-MLL interaction or Menin-MLL fusion protein interaction as defined in this invention include one or more of the following: cancer or malignant tumors, diabetes, and other Menin-related diseases. "Cancer" or "malignant tumor" means one of several diseases characterized by uncontrolled abnormal cell proliferation, and means one of several characteristic structural and / or molecular features, including the ability of affected cells to spread locally or to other sites via the bloodstream and lymphatic system (i.e., metastasis) and many characteristic structures and / or molecular features. "Cancer cells" means cells in the early, middle, or late stages of 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 a particular embodiment, the compounds of the present invention are used to treat MLL rearrangement-related leukemia, MLL rearrangement-related acute lymphoblastic leukemia, MLL rearrangement-related acute lymphoblastic leukemia, MLL rearrangement-related lymphoblastic lymphoma, MLL rearrangement-related acute myeloid leukemia, or MLL rearrangement-related matured acute myeloid leukemia, where "MLL rearrangement" as used herein means rearrangement of the MLL gene. In a particular embodiment, diseases or conditions treatable by the compounds of the present invention include insulin resistance, prediabetes, diabetes (e.g., type II or type I diabetes), diabetes risk, and hyperglycemia.

[0055] With regard to combination therapy, the present invention further relates to combination therapies for treating the diseases or disorders described herein. In some embodiments, the combination therapy involves administering one or more other pharmaceutically active agents in combination with at least one of the compounds according to the present invention to treat cancer or other diseases mediated by Menin / MLL. The pharmaceutically active agents may be combined with the compounds of the present invention to form a single dosage form, or the therapeutic agents may be administered simultaneously or sequentially as separate dosage forms. The compounds according to the present invention may also be used in combination with immunotherapies, including cell-based immunotherapy, antibody therapy, and cytokine therapy, to treat the diseases or disorders disclosed herein, but are not limited to these.

[0056] The compounds and derivatives provided in this invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Columbus, OH) naming system.

[0057] With respect to terms used in this invention, unless otherwise specified, the first definition of a base or term provided herein applies to that base or term throughout this specification. However, terms not specifically defined herein should be given a meaning that will be understood by those skilled in the art, based on the disclosure and context.

[0058] "Substitution" means that a hydrogen atom in a molecule is replaced by another different atom or group, or that an orb pair of electrons on an atom in a molecule is replaced by another atom or group. For example, an orb pair of electrons on an S atom is replaced by an O atom. [ka] It may form.

[0059] The phrases "may be further optionally substituted," "may be further optionally substituted," and "may be optionally substituted" all mean that substitution is possible but does not necessarily have to occur, and the explanation includes whether or not it occurs.

[0060] The minimum and maximum carbon atom content in a carbon-hydrogen group is expressed by a prefix, for example, C a~b Alkyl alkyl groups (with the prefix C) a~b This means that ) refers to any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, C 1~6 An alkyl group is an alkyl group that contains 1 to 6 carbon atoms.

[0061] An alkyl group is a saturated hydrocarbon chain having a specified number of constituent atoms. Alkyl groups may be linear or branched. Typical branched alkyl groups have one, two, or three branched chains. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl groups. For example, alkyl groups may be -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 constituent atoms. a ~ b An alkylene group is an alkylene group having a to b carbon atoms. Alkylene groups are branched-chain and straight-chain hydrocarbon groups. For example, the term "propylene group" is... [ka] The following are listed. Similarly, the term "dimethylbutylene group" is, for example, [ka] One of the following will be listed.

[0063] The -C0~4 alkylene group in the present invention may be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-), a C3 alkylene group, or a C4 alkylene group. In the case of a C0 alkylene group, the group shown is absent and is bonded by a chemical bond. In the case of A-C0 alkylene group-B, A and B are meant to be linked by a chemical bond. For example, -C0 alkylene group-(3-membered cycloalkyl group) means a cyclopropyl group.

[0064] The term "unsaturated" as used in this invention refers to a group or molecule containing carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-nitrogen double bonds, carbon-nitrogen triple bonds, and the like.

[0065] An "alkenyl group" is a linear or branched carbon-hydrogen group having at least one vinyl unsaturated moiety (>C=C<). For example, C a-b The term "alkenyl group" refers to alkenyl groups having a to b carbon atoms, such as vinyl groups, propenyl groups, isopropenyl groups, and 1,3-butadienyl groups.

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

[0067] The term "carbocyclic group" as used in this invention refers to a saturated cyclic group or a non-aromatic partially saturated cyclic group having a single ring or multiple rings (condensed, cross-linked, or spiro-bonded) that have multiple carbon atoms but no ring-forming heteroatoms. The term "carbocyclic group" includes, for example, cycloalkenyl groups such as the cyclohexenyl group. Examples of monocarbocyclic groups include, for example, the cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group, cyclooctyl group, cyclopentenyl group, and cyclohexenyl group. Examples of condensed carbocyclic groups include the dicyclohexyl group, dicyclopentyl group, and dicyclooctyl group. Hereinafter, polycyclic structures such as the dicycloalkyl group described above will be named the dicyclohexyl group. [ka] and named the dicyclohexyl group [ka] The following two groups are listed. Examples of carbocyclic groups in a bridging ring system include: [ka] Examples include the adamantyl group. Examples of spirocyclic carbocyclic groups include: [ka] These are some examples. The term "carbocyclic group" may also include partially saturated cyclic groups formed by the condensation of an aromatic ring and a non-aromatic ring, the bonding site of which may be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0068] The terms "bridged ring" and "bridged cycloalkyl group" as used in this invention refer to saturated or non-aromatic partially saturated cyclic groups in which multiple rings having multiple carbon atoms but lacking ring-constituting heteroatoms are formed by bridge crosslinking. Examples of these terms are: [ka] This includes, but is not limited to, adamantyl groups.

[0069] The term "heterocycloalkyl group" as used in this invention refers to a saturated ring or a non-aromatic partially saturated ring having a monocyclic or multiple rings (condensed, cross-linked, or spiro-bonded) that contains at least one heteroatom. Here, a heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Generally, a "heterocycloalkyl group" represents a monocyclic or polycyclic ring system that is monovalently saturated or partially unsaturated and has multiple ring atoms, containing one, two, or three ring-forming heteroatoms selected from N, O, and S, with the remaining ring-forming atoms being carbon. Examples of heterocycloalkyl groups in monocyclic heterocycloalkyl systems include oxetanyl group, azetidinyl group, pyrrolidine group, 2-oxo-pyrrolidine-3-yl, tetrahydrofuran group, tetrahydrothienyl group, pyrazolidinyl group, imidazolidinyl group, thiazolidinyl group, piperidinyl group, tetrahydropyranyl group, tetrahydropyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxo-thiomorpholin-4-yl, azepanyl group, diazepanyl group, homopiperazinyl group, or oxoazepanyl group. Examples of heterocycloalkyl groups in fused ring heterocycloalkyl systems include the 8-aza-bicyclo[3.2.1]octyl group, the quinuclidinyl group, the 8-oxo-3-aza-bicyclo[3.2.1]octyl group, and the 9-aza-bicyclo[3.3.1]nonyl group. Examples of heterocycloalkyl groups in bridged ring heterocycloalkyl systems include, [ka] Examples include: [ka] Examples include the dihydrofuran group, imidazoline group, tetrahydropyridinyl group, or dihydropyranyl group. The term "heterocycloalkyl group" may also include partially saturated cyclic groups formed by the condensation of an aromatic ring containing at least one heteroatom with a non-aromatic ring, and the junction site may be located at a non-aromatic carbon atom, an aromatic carbon atom, or a heteroatom. Examples include, [ka] These are some examples.

[0070] The terms "bridged heterocycle" and "bridged heterocycloalkyl group" as used in this invention refer to saturated rings or non-aromatic partially saturated rings formed by bridge cross-linking of multiple rings containing at least one heteroatom. Here, heteroatoms refer to nitrogen atoms, oxygen atoms, sulfur atoms, etc. Examples of these terms include: [ka] This includes, but is not limited to, these examples.

[0071] In this invention, the term "aromatic ring" means an aromatic hydrocarbon group having multiple carbon atoms. An aryl group is typically a monocyclic, dicyclic, or tricyclic aryl group having multiple carbon atoms. Furthermore, as used herein, the term "aryl group" means an aromatic substituent which may be a single aromatic ring or a fused group of multiple aromatic rings. Non-limiting examples include a phenyl group, a naphthyl group, or a tetrahydronaphthyl group.

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

[0073] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine. The "halogen-substituted alkyl group" described in this invention refers to an alkyl group in which one or more hydrogen atoms are substituted with halogens, for example, halogen-substituted C 1~4 Alkyl groups are alkyl groups containing 1 to 4 carbon atoms in which one or more hydrogen atoms are substituted with halogen atoms. Examples include monofluoromethyl groups, difluoromethyl groups, and trifluoromethyl groups.

[0074] The term "deuterium-substituted alkyl group" as used in this invention means an alkyl group in which one or more hydrogen atoms are substituted with deuterium. For example, deuterium-substituted C 1~4 An alkyl group is an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by deuterium atoms. Examples of alkyl groups include monodeuterium methyl groups, dideuterium methyl groups, and trideuterium methyl groups.

[0075] The terms "-OR" and "-NRR" used in this invention refer to a configuration in which the R group is linked to an oxygen atom or a nitrogen atom by a single bond.

[0076] In the "-C(O)R" and "-S(O)2R" described in this invention, the oxygen atom 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 the oxygen atom and nitrogen atom are connected to the sulfur atom by a double bond, and the R group and the sulfur atom are connected by a single bond.

[0077] In this invention, "oxo" means =O, where an oxygen atom substitutes two hydrogen atoms or an orb pair of electrons through a double bond.

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

[0079] The "deuterated compound" of this invention refers to a compound in which one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms. Here, the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0080] In this invention, "stereoisomers" are compounds that consist of the same atoms and are bonded by the same chemical bonds, but have different three-dimensional structures. The stereoisomers of this invention encompass each single stereoisomer and its compound, and include, but are not limited to, enantiomers and diastereomers. The compounds of this invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms, thereby giving rise to enantiomers, diastereomers and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. This invention intends to include all possible isomers, as well as their racemic and optically pure forms. For the preparation of the compounds of this invention, racemics, diastereomers, or enantiomers may be selected as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or they can be resolved by conventional means such as crystallization and chiral chromatography.

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

[0082] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, additive, and / or a salt formed therefrom is chemically or physically compatible with other components of a pharmaceutical dosage form and physiologically compatible with its receptor.

[0083] The terms “salt” and “pharmaceutically acceptable salt” refer to acidic and / or basic salts formed with the above-mentioned compounds or their stereoisomers, inorganic and / or organic acids and bases, including amphoteric salts (internal salts) and further including quaternary ammonium salts such as alkylammonium salts. These salts are obtained directly from the final separation and purification of the compounds. The above-mentioned compounds or their stereoisomers are obtained by mixing them with a certain number of acids or bases in appropriate amounts (e.g., equal equivalents). These salts are obtained by collecting precipitates formed in solution by filtration, recovering them after evaporation of the solvent, or by freeze-drying after reaction in an aqueous medium.

[0084] In some embodiments, one or more compounds according to 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 reagents to prepare pharmaceuticals or pharmaceutical compositions for controlling cell function or treating diseases. If the compounds used are in a series, they can be administered to a subject simultaneously, separately, or sequentially.

[0085] Furthermore, it will become clear from the contents of this invention that many other modifications, substitutions, or changes can be made in accordance with the general technical knowledge and conventional means of the art, provided that they do not depart from the basic technical concept of this invention. [Brief explanation of the drawing]

[0086] [Figure 1] Figure 1 shows the structural analysis of intermediate A1-a by single-crystal X-ray diffraction. [Figure 2] Figure 2 shows the structural analysis of intermediate A1-b by single-crystal X-ray diffraction. [Figure 3] Figure 3 shows the structural analysis of intermediate 7-5a1 by single-crystal X-ray diffraction. [Figure 4] Figure 4 shows the structural analysis of intermediate 7-5a2 by single-crystal X-ray diffraction. [Figure 5] Figure 5 shows the structural analysis diagram of Example 19 by single-crystal X-ray diffraction. [Modes for carrying out the invention]

[0087] The technical proposal of the present invention will be described in more detail below with reference to 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 falls within the scope of the present invention.

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

[0089] The abbreviations for the reagents used in the examples are: UHP: urea peroxide; DBU: 1,8-diazabicycloundecane-7-ene; TCCA: trichloroisocyanuric acid; KOAc: potassium acetate; Na2HPO4: disodium hydrogen phosphate; TFAA: anhydrous trifluoroacetic acid; DIPEA: N,N-diisopropylethylamine; n-BuLi: n-butyllithium; NH2OH·HCl: hydroxylamine hydrochloride; NiCl2·6H2O: nickel chloride hexahydrate; NaBH4: sodium borohydride; NaBH3CN: sodium borohydride cyanohydride; 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 reactions were carried out under a nitrogen atmosphere. In the examples, unless otherwise specified, "solution" refers to an aqueous solution. In the examples, unless otherwise specified, the reactive temperature is room temperature. Room temperature between 20°C and 30°C is the optimal reaction temperature. In the examples, unless otherwise specified, M represents moles / L.

[0091] The compound structure was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR chemical shift value (δ) was 10. -6 The values ​​were given in units of ppm. For NMR measurements, nuclear magnetic resonance spectrometers (BrukeRAvanceIII 400MHz and BrukeRAvance NEO 600MHz) were used, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. For LC-MS measurements, a Shimadzu LC-MS 2020 (ESI) liquid chromatograph mass spectrometer was used. For HPLC measurements, a Shimadzu LC-20A ultrafast liquid chromatograph was used. For MPLC (medium-pressure liquid chromatography), a Gilson GX-281 reverse-phase preparative liquid chromatography system was used. For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used, and thin-layer chromatography with a specification of 0.4 mm to 0.5 mm was performed for the separation and purification of products. For column chromatography, 200 to 300 mesh silica gel, such as Yantai Huanghai silica gel, was generally used as the support. The instrument used for supercritical fluid chromatography (SFC) analysis and preparation 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 DCM (880mL) solution of 5-fluoro-2-methoxybenzoic acid (45g, 264.49mmol) and ethyl isopropylamine (23.21g, 317.39mmol). The reaction mixture was gradually heated to room temperature and reacted for 17 hours with stirring. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, and the organic phase was combined. The concentrated crude product was separated and purified by silica gel column chromatography to obtain intermediates 1-2 (60g, 250.75mmol, yield 94.8%). MS m / z = 240 [M + H] + .

[0093] Step 2: Synthesis of 1-3 Under conditions 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). The reaction mixture was then gradually warmed to room temperature and stirred for 17 hours. After the reaction was complete, the mixture was cooled to -70°C, quenched with MeOH, extracted with EA, and the organic phase was combined. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 1-3 (49 g, 217.53 mmol, yield 82.6%) was used in the next reaction without further purification. MS m / z = 226 [M + H] + .

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

[0095] Synthesis of intermediates 1-7 [ka] Referring to the synthetic route of intermediates 1-3, dicyclopropylamine was used instead of ethylisopropylamine, and the reaction yielded intermediates 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 hours. After the reaction was complete, the mixture was concentrated, and the concentrated crude product was dissolved in a 10% aqueous NaOH solution. It was extracted three times with MTBE, the organic phase was combined, oxidized with HCl / MeOH, and then concentrated to obtain the crude product (6.5 g, 47.92 mmol, yield 91.2%), which was used directly in the next reaction. MS m / z = 100 [M + H] + .

[0097] Steps 2-3: Synthesis of 1-11 Referring to the synthetic route of intermediates 1-3, intermediates 1-9 were used instead of ethylisopropylamine and reacted to obtain 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 hours. After the reaction was complete, the mixture was concentrated, and the concentrated crude product was dissolved in a 10% aqueous NaOH solution, extracted three times with MTBE, and the organic phase was combined. The mixture was then oxidized with HCl / MeOH and concentrated to obtain the crude product (6.5 g, 43.43 mmol, yield 86.7%), which was used directly in the next reaction. MS m / z = 114 [M + H] + .

[0100] Steps 2-3: Synthesis of 1-15 Referring to the synthetic route of intermediates 1-3, intermediates 1-13 were used instead of ethylisopropylamine and the reaction was carried out to obtain the desired intermediate 1-15. MS m / z = 252 [M + H] + .

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

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

[0103] Step 1: Synthesis of 1-18 Under ice bath conditions, 1-8 (3.0 g, 52.54 mmol) was dissolved in DCM (50 mL), and (Boc)2O (12.04 g, 55.17 mmol) and triethylamine (6.37 g, 63.05 mmol) were added. The mixture was gradually heated to room temperature and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 1-18 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 (8.33 g, 52.99 mmol) was dissolved in anhydrous DMF, and under nitrogen protection, NaH (1.34 g, 55.64 mmol) was added. The reaction was carried out at 0°C for 30 minutes. Ethyl iodide (9.9 g, 58.29 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and the mixture was stirred. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain 1-19 (5.6 g, 30.23 mmol, yield 57%). MS m / z = 186 [M + H] + .

[0105] Step 3: Synthesis of 1-20 Dissolve 1-19 (5.6 g, 30.23 mmol) in MTBE, slowly add HCl / EA dropwise, stir at room temperature until no solid precipitate forms, filter by suction, wash the cake with a small amount of EA to obtain intermediate 1-20 (2.74 g, 22.53 mmol, yield 74.52%). MS m / z = 86 [M + H] + .

[0106] Steps 4-5: Synthesis of 1-22 Referring to the synthetic route of intermediates 1-3, intermediates 1-20 were used instead of ethylisopropylamine and reacted to obtain the desired intermediate 1-22. MS m / z = 224 [M + H] + .

[0107] Synthesis of intermediates 1-25 [ka] 1-23 (680 mg, 3.56 mmol) was dissolved in a mixed solvent of dioxane (15 mL) and water (3 mL). 1-24 (1.01 g, 4.27 mmol), Na2CO3 (754.77 mg, 7.12 mmol), and Pd(dppf)Cl2 (130.13 mg, 0.178 mmol) were added in that order, and the mixture was stirred overnight at 90°C. The reaction was monitored by LC-MS. After the reaction was complete, water was added to dilute the mixture, and it was extracted three times with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain 1-25 (700 mg, 3.18 mmol, yield 89%). MS m / z = 221 [M + H] + .

[0108] [ka] Referring to the synthesis method for 1-25, 1-26 was used instead of 1-24 and reacted to obtain 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. A DCM solution of 2,7-azaspiro[3.5]nonane-7-carboxylate tetr-butyl (4.81 g, 21.26 mmol) was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (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 (1.0 g, 2.67 mmol) and DBU (488.13 mg, 3.21 mmol) were dissolved in THF, 1-3 (601 mg, 2.67 mmol) was added, and the mixture was heated to room temperature and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 10:1~5:1, v / v) to obtain 2-3 (1.04 g, 1.84 mmol, 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, and Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added. After purging with hydrogen gas, the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by 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, 75.67 mmol) was dissolved in DCM (70mL), TFA (30mL) was slowly added, and the temperature was raised to room temperature, with stirring for 0.5 hours. After the reaction was complete, the mixture was concentrated, and an aqueous solution of NaHCO3 was added to adjust the pH to weakly alkaline. The crude product M1, extracted and concentrated using DCM, was 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 (1.0 g, 2.67 mmol) and DBU (488.13 mg, 3.21 mmol) were dissolved in THF, 1-5 (601 mg, 2.67 mmol) was added, and the mixture was heated to room temperature and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 10:1~5:1, v / v) to obtain 2-5 (1.0 g, 1.73 mmol, yield 64.9%). 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, and Pd / C (250 mg, 0.6 mmol) and triethylamine (558 mg, 5.52 mmol) were added. After purging with hydrogen gas, the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by 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 (4.0 g, 7.38 mmol) was dissolved in DCM (7 mL), TFA (3 mL) was slowly added dropwise, and the temperature was raised to room temperature, with stirring for 0.5 hours. After the reaction was complete, the mixture was concentrated, and an aqueous solution of NaHCO3 was added to adjust the pH to weakly alkaline. The crude product M2, extracted and concentrated with DCM, was used directly in the next reaction. MS m / z = 443 [M + H] + .

[0118] Referring to the synthesis method for intermediate M1, we replaced 1-3 with 1-7, 1-11, 1-15, 1-17, 1-22, and 1-27 respectively, and reacted them to obtain the corresponding intermediates M3-M8. [ka]

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

[0120] Step 1: Synthesis of 3-1 At room temperature, 1-3 (10 g, 44.39 mmol) and 5-bromopyrimidine (21.17 g, 133.18 mmol) were dissolved in DMF, cesium carbonate (43.39 g, 133.18 mmol) was added, and the mixture was heated to 130°C and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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, and m-CPBA (13.61 g, 79.12 mmol) was slowly added dropwise at 0°C. The mixture was then heated to room temperature and stirred for 24 hours. After the reaction was complete, the temperature was lowered to 0°C, saturated sodium thiosulfate aqueous solution was added to quench the reaction, and then the mixture was extracted three times with DCM. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography 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 (3.55 g, 35.07 mmol) was dissolved in DCM, and POCl3 (4.03 g, 26.31 mmol) was slowly added dropwise at 0°C. Then, a DCM solution of 3-2 (5.6 g, 17.54 mmol) was added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to room temperature and the mixture was stirred overnight. After the reaction was complete, the reaction mixture was slowly poured into ice water and stirred for 30 minutes. DCM was then added and the mixture was extracted three times. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain 3-3 (1.7 g, 5.03 mmol, yield 28.67%). MS m / z = 338 [M + H] + .

[0123] Step 4: Synthesis of 3-4 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. The mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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 (1.54 g, 2.92 mmol) was dissolved in DCM (20 mL), TFA (10 mL) was slowly added dropwise, and the temperature was raised to room temperature, with stirring for 0.5 hours. After the reaction was complete, the mixture was concentrated, and an aqueous solution of NaHCO3 was added to adjust the pH to weakly alkaline. The crude product, extracted with DCM and concentrated, was used directly in the next reaction. MS m / z = 428 [M + H] + .

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

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

[0127] Step 1: Synthesis of 4-2 At room temperature, 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). The reaction mixture was heated to 80°C and stirred for 4 hours. After the reaction was complete, the organic phase was removed using a rotary evaporator to obtain the crude product. The product was diluted with water, extracted with ethyl acetate, and the combined organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (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. The mixture was stirred at room temperature for 9 hours, after which the organic phase changed from blue to colorless. After the reaction was complete, the reaction solution was placed in a separatory funnel and extracted three times with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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 At -20°C, NaBH4 (4.05 g, 106.93 mmol) was added in batches to a solution of 4-3 (18 g, 76.38 mmol) and Pd / C (1.27 g, 10.49 mmol) in EtOH (200 mL). The reaction was complete once the additions were finished. After the reaction, the solution was filtered through diatomaceous earth, the filtrate was concentrated, dissolved with EA, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated by rotation. The concentrated crude product was purified by silica gel column (PE / EA = 10:1, v / v) to obtain 4-4 (8.4 g, 41.75 mmol, yield 54.67%). 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 4-4 (2.17 g, 10.78 mmol) solution in MeCN (30 mL), and then methyl acrylate (1.11 g, 12.94 mmol) was added dropwise. The reaction was then allowed to proceed at 0°C for 1 hour. After the reaction was complete, water was added, EA was added for extraction, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated dry by rotation. Separation and purification by silica gel column chromatography (PE / EA = 40 / 1 → 10 / 1) yielded 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 (1.424g, 4.96 mmol, yield 46%, PE / EA=10 / 1, MS m / z=288[M+H]) + ) was obtained. TLC developing agent 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°C, 4-5a (330 mg, 1.15 mmol) and NiCl2·6H2O (272.88 mg, 1.15 mmol) in MeOH (3 mL) were batch-added with NaBH4 (217.26 mg, 5.74 mmol), and the mixture was reacted at -10°C for 2 hours. Then, an aqueous solution of K2CO3 (634.94 mg, 4.59 mmol) (1 mL) was added dropwise, and the mixture was reacted at 0°C for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filtrate was adjusted to neutral or acidic with 1N HCl, concentrated, and extracted with EA. The organic layer was combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, rotated and evaporated, and separated and purified by silica gel column chromatography (DCM / MeOH = 40:1) to obtain product 4-6a (197 mg, 0.874 mmol, yield 76%). MS m / z = 226[M+H] + (The synthesis method for 4-6b is the same as described above.)

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

[0133] Step 7: Synthesis of A1-a To a solution of 4-7a (457 mg, 2.49 mmol) in DCM (12 mL) / DMSO (4 mL), DIPEA (1.29 g, 9.98 mmol, 1.74 mL) was added, followed by the addition of a DMSO (4 mL) suspension of Py·SO3 (1.57 g, 9.98 mmol) dropwise. The mixture was stirred at room temperature for 10 minutes to allow the reaction to proceed, then cooled to 0°C. DCM (10 mL) / 1N aqHCl (10 mL) was added, and the separated aqueous phase was extracted with EA. The combined organic phase was washed sequentially with 1N HCl and saturated saline solution, dried over anhydrous sodium sulfate, and the crude product after vacuum concentration was separated and purified by silica gel column to obtain A1-a (279 mg, 1.54 mmol, yield 61.73%). 1 ¹H NMR (400 MHz, chloroform-d) δ 9.68 (s, 1H), 7.11 (s, 1H), 2.40 (t, J=8.1 Hz, 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 for A1-b is the same as described above.)

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

[0135] Step 1: Synthesis of 4-9 At -78°C, n-BuLi (11 mL, 27.5 mmol, 2.5 M hexane solution) was added dropwise to a solution of diisopropylamine (2.78 g, 27.46 mmol) in diethyl ether (20 mL). The mixture was gradually heated to -11°C, and a solution of 2-cyclohexen-1-one (2.4 g, 24.97 mmol) in diethyl ether (20 mL) was added dropwise, maintaining the internal temperature of the reaction mixture between -11°C and -3°C during the addition process. The reaction mixture was stirred for 25 minutes, after which a solution of methyl acrylate (2.15 g, 24.97 mmol) in THF (20 mL) was added dropwise, and after each addition, the mixture was stirred at -10°C for 1 hour to allow the reaction to proceed. After the reaction was complete, the reaction mixture was poured into a saturated ammonium chloride (200 mL) solution and stirred for 15 minutes. EA was added to the mixture for extraction, and the combined organic phase was dried over anhydrous sodium sulfate. The concentrated crude product was separated and purified by 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 At room temperature, hydroxylamine hydrochloride (2.21 g, 31.8 mmol) and NaOAc (2.61 g, 31.8 mmol) were added to a 25 mL solution of 4-9 (4.83 g, 26.5 mmol) in EtOH. The reaction mixture was heated to 80°C and stirred for 4 hours. After the reaction was complete, the organic phase was removed using a rotary evaporator to obtain the crude product. The product was diluted with water, extracted with ethyl acetate, and the combined organic phase was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography 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 (4.45g, 22.56 mmol) and NaHCO3 3(Trichloroisocyanuric acid (26.2 g, 112.81 mmol) was added dropwise in batches to a suspension of 37.6 g, 564 mmol) of EA (500 mL) / H2O (500 mL). The mixture was stirred at room temperature for 20 minutes to allow it to react, and then stirred for 9 hours until the reaction mixture turned blue and the organic phase became a colorless solution. After the reaction was complete, the mixture was extracted with EA, and the combined organic phase was washed with water and saturated brine in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by 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°C, 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 hour to allow the reaction to proceed. After the reaction was complete, the Pd / C was removed by filtration, and the filtrate was concentrated and separated and purified by 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 (2.56 mL, 17.11 mmol) was added to a 30 mL solution of 4-12 (3.04 g, 14.26 mmol) in MeCN, and then methyl acrylate (1.54 mL, 17.11 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, water was added to quench the reaction, EA was added for extraction, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was separated and purified by silica gel column (PE / EA = 10:1, v / v) to obtain 4-13a (1.66 g, 5.55 mmol, yield 38.92%) and 4-13b (1.55 g, 5.18 mmol, yield 36.32%), respectively (TLC developing agent PE / EA = 5 / 1:4-13a, R f= 0.40;4-13b, R f= 0.35).

[0140] Intermediates B1-a and B1-b were obtained by referring to the method of steps 5 to 7 in the synthesis route of A1-a. Here, B1-a and B1-b were used directly in the next step without partitioning. 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 salt, 193g, 1.0mol) was placed in a 5L beaker, 400mL of mixed solvent (DCM / IPA=3 / 1) was added, and an aqueous solution of potassium carbonate (110g, 0.8mol) was slowly added under ice bath conditions, controlling the temperature to below 20°C. Extraction was repeated 3-4 times with the mixed solvent to combine the organic phases, concentrate to obtain the crude product, which was then used directly 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, controlling the temperature to below 35°C. After addition, the temperature was raised to reflux and stirred for 3 hours. After the reaction was complete, the temperature was cooled to below 10°C, stirred for 20 minutes, filtered, the reaction bottle was rinsed with the filtrate, the cake was rinsed with an appropriate amount of DCE, and aspirated before drying. 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 Referencing 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 by silica gel column chromatography. + ) and 5-3b (PE / EA=20 / 1, MS m / z=274[M+H] +) was obtained. TLC developing agent: 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 Referring to the synthesis method of 4-6a, 5-3a and 5-3b were used as raw materials to produce 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 (25g, 118.34 mmol), (Boc)2O (103.31g, 473.36 mmol), and DMAP (5.78g, 47.34 mmol) were dissolved in acetonitrile (250 mL) and reacted overnight at 60°C under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 5:1-3:1, v / v) to obtain 6-1a (34.28g, 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. The mixture was stirred at the same temperature for 1 hour. Then, a THF solution of MOMBr (96 mg, 0.768 mmol) was slowly added dropwise. The mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times by DCM. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 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 hour. After the reaction was complete, the concentrated crude product (114 mg, 0.363 mmol) was used directly 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), and LiAlH4 (16.57 mg, 0.436 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added in batches under an ice bath until no more bubbles were generated in the system. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then used directly 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 DIPEA (190.51 mg, 1.47 mmol) and a DMSO (2 mL) solution of sulfur trioxide pyridine complex (234.62 mg, 1.47 mmol) were sequentially added dropwise. The mixture was then heated to room temperature and stirred for 30 minutes. After the reaction was complete, the mixture was transferred to an ice bath, quenched with 1N HCl, diluted with water, and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography 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 (2.8 g, 8.7 mmol) was dissolved in THF, cooled to -78°C, and LiHMDS (15.96 mL, 2.4 eq) was added dropwise under nitrogen protection. The mixture was stirred at the same temperature for 1 hour. Next, a THF solution of methane iodide (2.93 g, 20.65 mmol) was slowly added dropwise. After addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times by DCM. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 5:1, v / v) to obtain 6-5a (2.4 g, 6.85 mmol, yield 78.73%). 1 ¹H 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] Steps 2-4: 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 heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 5:1, v / v) to obtain 6-8a (52 mg, 0.173 mmol, yield 34.8%, containing 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 heated to room temperature and stirred for 1 hour. 6-8a (20 g, 66.82 mmol) was added, and the reaction was allowed to proceed at room temperature for 17 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (PE / EA = 4:1, v / v) to obtain 6-9a (8.5 g, 27.13 mmol, yield 40.6%, containing two isomers). MS m / z = 314 [M + H] + .

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

[0156] Synthesis of intermediate C4 [ka] Referring to the synthesis method for C1, deuterated methane iodide was used instead of methane iodide 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 (1.7g, 6.0 mmol) was dissolved in DCM (40 mL), and TEA (2.43g, 24 mmol), TsCl (465.45 mg, 6.6 mmol), and DMAP (73.29 mg, 0.60 mmol) were added sequentially. The mixture was stirred for 2 hours at 0°C under nitrogen protection. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 3:1, v / v) to obtain 6-15a (2.1g, 4.8 mmol, yield 80%). MS m / z = 438 [M + H] + .

[0159] Step 2: Synthesis of C5 Dissolve 6-15a (200 mg, 0.45 mmol) in anhydrous THF (3 mL), cool to -78°C, and slowly add LiHMDS (1 mL, 1.28 mmol) dropwise under nitrogen protection. Stir at the same temperature for 1 hour, then slowly add NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) dropwise, and stir at room temperature for 4 hours. Cool again to -78°C, slowly add LiHMDS (1 mL, 1.28 mmol) dropwise while stirring for 1 hour, then slowly add NFSI (248.28 mg, 1.28 mmol) in THF (3 mL) dropwise, and stir at room temperature for 16 hours. After the reaction was complete, quench with saturated ammonium chloride and extract three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to obtain C5 (90 mg, 0.19 mmol, yield 42.2%). 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. The mixture was stirred at room temperature for 20 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the mixture, and it was extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 5:1, v / v) to obtain 6-16a (303 mg, 0.57 mmol, yield 50%). 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 under nitrogen protection, PIFA (757.93 mg, 1.76 mmol) was added. The mixture was then stirred at the same temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (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 heated to room temperature and stirred for 0.5 hours. After the reaction was complete, the concentrated crude product 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 complete, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (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. The mixture was stirred at the same temperature for 1 hour. Next, a solution of 2-iodoethyl ether (751 mg, 2.3 mmol) in THF (15 mL) was slowly added dropwise. The mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times using DCM. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to obtain 6-19a (62 mg, 0.156 mmol, yield 10.12%). MS m / z = 396 [M + H] + .

[0165] Steps 3-5: Synthesis of C7 Intermediate C7 (45 mg, 0.179 mmol) was obtained by similar experimental procedures, referring to the synthesis method of C1. 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 (34.28 g, 110.09 mmol) was dissolved in THF, cooled to -78°C, and LiHMDS (93 mL, 1.1 eq) was added dropwise under nitrogen protection. The mixture was stirred at the same temperature for 1 hour. Next, a THF solution of MOMBr (17.89 g, 143.12 mmol) was slowly added dropwise. After addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times by DCM. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by MPLC to obtain 7-1a (25.6 g, 72.03 mmol, 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 hour. After the reaction was complete, the concentrated crude product was used directly 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), and LiAlH4 (3.27 g, 86.20 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added in batches under an ice bath until no more bubbles were generated in the system. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then used directly 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), 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 hour. After the reaction was complete, water was added to dilute the mixture, and it was extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 1:1, v / v) to obtain 7-4a (33 g, 70.86 mmol, yield 99.7%). MS m / z = 466 [M + H] + .

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

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

[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 overnight at room temperature. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (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 for 7-5a2 is the same as described 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 sequentially added dropwise solutions 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 then heated to room temperature and stirred for 30 minutes. After the reaction was complete, the mixture was transferred to an ice bath, quenched with 1 NhCl, diluted with water, and extracted three times with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain D1-a1 (130 mg, 1.02 mmol, yield 77.27%) with a single stereochemistry. 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 method for synthesizing D1-a2 in a different single stereochemistry is the same as described above.)

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

[0176] Referring to the synthesis methods for D1-a1 and D1-a2, methane iodide was used instead of MOMBr to produce the single-steric intermediate D2-a1 (MS m / z=196[M+H]). + ) and D2-a2(MS m / z=196[M+H] + We obtained each of the following: (SFC method for intermediates 8-4a1 and 8-4a2: Chiral column model number: CHIRAL ART CellμLose-SC; Specifications: 3um, 150mm x 3mm; Mobile phase: A-CO2, Mobile phase B-isopropanol, A / B=70 / 30; Flow rate: 1mL / min; Column temperature: 40℃; SFC retention times for 8-4a1 and 8-4a2 are 3.809min and 4.479min, respectively.)

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

[0178] Referring to the synthesis methods of D1-a1 and D1-a2, deuterated methane iodide was used instead of MOMBr to produce the single-steric intermediate D3-a1 (MS m / z=199[M+H]). + ) and D3-a2(MS m / z=199[M+H] + They obtained the following results. (SFC method for intermediates 9-4a1 and 9-4a2: Chiral column model number: CHIRAL ART CellμLose-SC; Specifications: 3um, 150mm x 3mm; Mobile phase A - CO2, Mobile phase B - Isopropanol, A / B = 65 / 35; Flow rate: 1 mL / min; Column temperature: 40°C; SFC retention times for 9-4a1 and 9-4a2 are 2.936 min and 3.386 min, 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 complete, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 5:1-3:1, v / v) to obtain 10-1a (2.9 g, 9.3 mmol, 93% yield). 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 hour. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 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. The mixture was stirred at the same temperature for 1 hour. Then, acetone (112.16 mg, 1.93 mmol) and ethyl boron trifluoride (274.22 mg, 1.93 mmol) were added dropwise at -70°C, and the mixture was heated to room temperature and stirred for 2.5 hours. After the reaction was complete, saturated ammonium chloride was added to quench the mixture, and it was extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 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 overnight at room temperature. After completion of the reaction, water was added for dilution, and the mixture was extracted 3 times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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 solutions of DIPEA (784.65 mg, 6.07 mmol) and sulfur trioxide pyridine complex (966.31 mg, 6.07 mmol) in DMSO (2 mL) were sequentially added dropwise. After warming to room temperature, the mixture was stirred for 30 min. After completion of the reaction, it was transferred to an ice bath, quenched by adding 1N HCl, diluted with water, and extracted 3 times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column to obtain D4-a (397.88 mg, 1.17 mmol, yield 81.8%, containing two isomers, which was 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. After warming the reaction solution to room temperature, it was stirred for 2 days. After completion of the reaction, water was added for dilution, and the mixture was extracted 3 times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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 Referring to the synthesis method of D4-a, the 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 [Chemical formula]

[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 sequentially added dropwise at 0 °C. After the reaction solution was warmed to room temperature, it was stirred overnight. After the reaction was completed, the concentrated crude product was purified by silica gel column (PE / EA = 4:1, v / v) to obtain stereoisomer 12-1a (764 mg, 3.3 mmol, PE / EA = 4 / 1, MS m / z = 232 [M+H] + ) and another stereoisomer 12-1b (1.09 g, 4.7 mmol, yield 57.3%, PE / EA = 2 / 1, MS m / z = 232 [M+H] + ). TLC developing agent 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), and Raney nickel (70 mg, 3.23 mmol) was added. After replacing with hydrogen gas, the temperature was raised to 70 °C and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was concentrated to obtain a crude product (640 mg, 3.18 mmol, yield 87.6%) and 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 mmol) was added dropwise, and after cooling to -10°C, a THF solution of triphosgene (350 mg, 1.18 mmol) was slowly added dropwise. The reaction mixture was stirred at the same temperature for 30 min, then transferred to room temperature and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate and ethyl acetate were added, and after extraction three times, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by 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), and LiAlH4 (76.15 mg, 2.01 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added in batches under an ice bath until no more bubbles were generated in the system. The mixture was filtered, and the filtrate was concentrated to obtain the crude product (304 mg, 1.64 mmol, yield 98.2%), which was then used as is 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 DMSO (2 mL) solution of DIPEA (848.48 mg, 6.57 mmol) and sulfur trioxide pyridine complex (1.04 g, 6.57 mmol) was sequentially added dropwise. The mixture was then heated to room temperature and stirred for 30 minutes. After the reaction was complete, the mixture was transferred to an ice bath, quenched with 1N HCl, diluted with water, and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain E2-a (single stereoconfiguration, 167 mg, 0.91 mmol, yield 55.5%). 1¹H 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] Referring to the synthesis method for E2-a, a similar experimental procedure yielded another single-stereoconfiguration intermediate, E2-b. MS m / z = 184 [M + H] + .

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

[0195] Referring to the synthesis method of E2-a, intermediate E3-a (PE / EA=5 / 1, MS m / z=210[M+H]) was obtained by similar experimental procedures. + , used in the next step without splitting. ) and E3-b(PE / EA=3 / 1, MS m / z=210[M+H] + , used in the next step without division. ) obtained. TLC developing agent 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 synthesized by referring to the synthesis of 12-2a, using 5-2 as the starting material, and 720 mg, 3.85 mmol was obtained as the less polar isomer during isomer separation), (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 complete, the mixture was concentrated, and the crude product was purified by 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 des-martin periodinane (1.92 g, 4.52 mmol) was added in a patch under nitrogen protection. The mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, water was added to quench the mixture, and after filtration, the filtrate was extracted three times using DCM. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (PE / EA = 10:1~8:1, v / v) to obtain 14-3a (537 mg, 1.88 mmol, yield 83.18%). 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), then TEA was added to adjust the pH to approximately 8, and the reaction was stirred at room temperature for 0.5 hours. Next, acetic acid was added to adjust the pH to 5, and then sodium borohydride cyanohydride (237.13 mg, 3.76 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, and the organic phase was extracted three times with ethyl acetate. The organic phase was then combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 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 heated to room temperature and stirred for 0.5 hours. After the reaction was complete, the concentrated crude product 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 under nitrogen protection, CDI (285.37 mg, 1.98 mmol) was added. The mixture was then heated to room temperature and stirred for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was then combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (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), and LiAlH4 (41.43 mg, 1.09 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added in batches under an ice bath until no more bubbles were generated in the system. The mixture was filtered, and the filtrate was concentrated to obtain the crude product (120 mg, 0.6 mmol), which was then used as is 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 DMSO (0.5 mL) solution of DIPEA (312.9 mg, 2.24 mmol) and sulfur trioxide pyridine complex (385.43 mg, 2.42 mmol) was sequentially added dropwise. The mixture was then heated to room temperature and stirred for 30 minutes. After the reaction was complete, the mixture was transferred to an ice bath, quenched with 1N HCl, diluted with water, and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography to obtain one of the single isomers, E4-a (35 mg, 0.178 mmol, yield 29.7%). MS m / z = 197 [M + H] + .

[0204] Similarly, referring to the synthesis method of E4-a, another single-stereoconfiguration intermediate, E4-b, was obtained through similar experimental procedures. MS m / z = 197 [M + H] + .

[0205] Synthesis of Example 1 [ka] To a solution of A1-a (95 mg, 524.19 μmol) in MeOH (10 mL), N1 (268.92 mg, 629.03 μmol) was added. The mixture was stirred at room temperature for 1 hour, and AcOH was added to adjust the pH to 4-5. Then, NaBH3CN (49.54 mg, 786.29 μmol) was added, and the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of A1-a (1.62 g, 8.94 mmol) in DCM (30 mL), N2 (3.95 g, 8.94 mmol) was added. The mixture was stirred at room temperature for 1 hour, and AcOH was added to adjust the pH to 4-5. Then, NaBH(OAc)3 (5.68 g, 26.82 mmol) was added, and the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of A1-a (16.92 mg, 93.35 μmol) in MeOH (5 mL), M1 (40 mg, 93.35 μmol) was added. The mixture was stirred at room temperature for 1 hour, and AcOH was added to adjust the pH to 4-5. Then, NaBH3CN (8.82 mg, 140.02 μmol) was added, and the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of C1 (15 mg, 55.59 μmol) in MeOH (3 mL), M1 (26.2 mg, 61.26 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (38.3 mg, 610.1 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum

[0209] Synthesis of Example 20 [ka] To a solution of C1 (98.6 mg, 366.1 μmol) in MeOH (5 mL), M2 (180 mg, 406.8 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (38.3 mg, 610.1 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of C2 (21.9 mg, 104.6 μmol) in MeOH (5 mL), N4 (46 mg, 104.6 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (9.85 mg, 156.9 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of C2 (21 mg, 100.34 μmol) in MeOH (3 mL), M1 (43 mg, 100.34 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (9.46 mg, 150.51 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 1 1H 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] To a solution of D1-a2 (33.79 mg, 150 μmol) in MeOH (2 mL), M2 (66.38 mg, 150 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (14.14 mg, 225 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of D2-a1 (19.59 mg, 100.34 μmol) in MeOH (3 mL), M2 (44.40 mg, 100.34 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (9.46 mg, 150.51 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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] To a solution of D2-a2 (19.59 mg, 100.34 μmol) in MeOH (3 mL), M2 (44.40 mg, 100.34 μmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, AcOH was added to adjust the pH to 4-5, and NaBH3CN (9.46 mg, 150.51 μmol) was added. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, 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 spectrum 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 the reaction of raw material 1 and raw 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 [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32]

[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 hours. Then, M1 (177 mg, 0.38 mmol, Cl) and K2CO3 (525 mg, 3.81 mmol) were added, the mixture was purged with nitrogen, and the temperature was raised to 70°C and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product 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 hours. Then, M2 (44 mg, 77.87 μmol) and K2CO3 (59.51 mg, 431.22 μmol) were added, the mixture was purged with nitrogen, and the temperature was raised to 70°C and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product 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 hour. After the reaction was complete, the crude product was concentrated and 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 of the following examples were obtained by referring to the synthesis method of Example 56. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0220] Synthesis of Example 62 [ka] The compound from 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 complete, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (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, and LiHMDS (0.2 mL, 268.78 μmol) was slowly added dropwise. The mixture was then stirred at the same temperature for 1 hour. Next, ethyl trifluoroethyl acetate (81.86 mg, 416.62 μmol) was added, the mixture was heated to room temperature, and stirred overnight. After the reaction was complete, the mixture was transferred to an ice bath, quenched with saturated ammonium chloride aqueous solution, and extracted three times with EA. The organic phase was combined, washed with saturated brine, 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), 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 complete, the mixture was diluted with water and extracted three times with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after concentration, the crude product was purified by 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 hour. After the reaction was complete, the mixture was concentrated, and the resulting 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 rise naturally to room temperature and stirred overnight. After the reaction was complete, 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 ¹H 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 Examples 64 and 65 Referring to the synthesis method of Example 1, the following example molecules were obtained by the reaction of raw material 1 and raw material 2. [Table 3]

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

[0227] To illustrate 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 cultured. The instrument parameters were: detection instrument: BrukeRD8 Venture; instrument model: D8 Venture; light source: gallium target; X-ray: Ga (λ=1.34 Å). The technical effects of the present invention will be explained below with reference to test examples.

[0228] Test Example 1. Measurement of inhibitory activity on Menin-MLL interaction The experiment quantitatively measured the inhibition of Menin / MLL-4-43 peptide interactions by small molecule inhibitors using a fluorescence polarization competition. The experiment was performed in a 384-well plate (Corning, Cat# 3575), and the reaction buffer used consisted of 50 mM Tris, pH 7.5, 50 mM NaCl, and 1 mM DTT. A 40 μL reaction system contained 10 μL of 8 nM Menin recombinant protein and 10 μL of different concentrations of the test compound. After pre-incubating the compound with the Menin protein for 15 minutes, 20 μL of 10 nM FITC-MLL4-43 peptide was added, and the mixture was incubated in a shaker at 25°C for 60 minutes. The fluorescence polarization signal (FP 485 520 520) was then detected using a BMG PHERAStar. The experimental data was analyzed using GraphPad Prism 6 software for IC50. 50 Values ​​were obtained. Control compound 1 was prepared by referring to the method of Example 64 in WO2017214367.

[0229] [Table 5]

[0230] Test Example 2. Measurement of the inhibitory ability of menin-MLL interaction inhibitors on cell proliferation. The inhibitory effect of the compounds of the present invention on tumor cell lineage (e.g., cell lines containing MLL fusion protein MV4-11, MOLM-13, THP-1, NOMO-1; control cell lines not containing MLL fusion protein HL-60, K562, MOLM-16; and cell line OCI-AML3 containing NPM1 mutation) was evaluated using a cell viability analysis method. Cells were seeded in 96-well plates at a constant concentration (e.g., 5,000 to 20,000 cells / well), and an equal volume of medium containing twice the final concentration of the test compound (with a final concentration range of 1 nM to 10 μM) was added. The plates were placed in an incubator and cultured for 72 to 168 hours under conditions of 37°C and 5% CO2. Before measurement, an equal volume of CellTiter-Glo® Luminescent reagent was added, incubated for 10 minutes at room temperature, and then measured using a microplate reader (BMG LABTECH). Data were analyzed using GraphPad Prism software, and IC 50 Regression curves for the values ​​and compounds were 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. Testing the stability of compounds in liver microsomes. Test Objective: The stability of some example compounds of the present invention in mouse, dog, and human liver microsomes was measured by LC-MS / MS.

[0232] Test materials: The test compounds were self-contained example compounds of the present invention. The positive reference compound SNDX-5613 was prepared referring to the method of Example 253 in WO2017214367. Control compound 1 was prepared referring 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, used 100 mM phosphate buffer (PBS, pH 7.4) as the medium, and contained liver microsomal protein at a final concentration of 0.5 mg / mL, 1.00 μM compound, and 2.00 mM NADPH, with an organic phase content of less than 1%, and 37 o The cells were incubated in a 14C incubator, and after reaction times of 0, 5, 15, 30, and 60 minutes, the reaction was stopped by adding 135 μL of ice-cold acetonitrile. In the positive control group, 1.00 μM ketanserin was used along with 0.5 mg / mL liver microsomes and 2.00 mM NADPH for 37 minutes. o After incubation in an incubator at C for 0, 5, 15, 30, and 60 minutes respectively, 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 4 o The solution was 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 between the percentage of residual ln compound and incubation time. The conversion factors are shown in the table below.

[0234] [Table 7]

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

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

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

[0238] Research Methods: Appropriate amounts of the compound were weighed, and a clear, clarified solution of a constant concentration was prepared using 0.9% sodium chloride injection and a 1M HCl aqueous solution based on 1.5 molar equivalents of the compound. SPF-grade male ICR mice, SPF-grade male SD rats, and male beagle dogs were fasted overnight, and the test compound solution was administered intravenously and intragastricly at the corresponding doses. 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 the plasma was separated. Plasma samples at each time point were detected using LC-MS / MS, and the plasma concentration of the compound was measured using a calibration curve correction method. Using the Phoenix WinNonlin 5.2 non-compartment model, pharmacokinetic parameters such as terminal phase elimination half-life (t1 / 2), peak blood concentration (Cmax), area under the blood concentration curve (AUC), and clearance (CL) were calculated, and bioavailability (F%) was determined from the serum drug concentration results. Blood drug concentrations and pharmacokinetic parameters were measured using the mean ± standard deviation (X ± SD). Specific test proposals for each type are as follows:

[0239] Pharmacokinetic studies in mice Test animals: SPF-grade male ICR mice, body weight 25-30g, 12 mice / compound. Purchased from Chengdu Dashuo Laboratory Animals Co., Ltd. Study design: On the day of the study, ICR mice were randomly divided into groups according to body weight, fasted for 12-14 hours one day prior to administration (no food or water restriction), and fed 2 hours after administration.

[0240] Preparation of the test compound solution: To obtain a concentration of 1 mg / mL for intragastric administration, an appropriate amount of the compound was weighed, and a clear 1 mg / mL solution was prepared using 0.9% sodium chloride injection and 1.5 equivalents of 1 M HCl aqueous solution. To obtain a concentration of 0.2 mg / mL for intravenous injection, a 1 mg / mL clear clarified solution was taken and diluted to a concentration of 0.2 mg / mL with 0.9% sodium chloride injection. The volume of 1 M HCl solution added was calculated using the following formula: Volume of 1 M HCl solution added (mL) = Amount of compound weighed (mg) / Molecular weight × 1.5 × 1000. The amount added during preparation must not exceed this calculated value.

[0241] Administration of the test substance: Intravenous injection: Dosage 1 mg / kg, volume 5 mL / kg, 6 animals; Intragastric administration: Dosage 10 mg / kg, volume 10 mL / kg, 6 animals. Sample collection: Blood (40-50 μL) was collected from the orbital venous plexus by puncture at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration into anticoagulation tubes press-sprayed with EDTA-K2. The blood samples were centrifuged at 10,000 rpm for 20 minutes within 1 hour (stored on moist ice before and after centrifugation) to collect the upper layer of plasma, which was then frozen and stored in a refrigerator at -20°C or below for LC-MS / MS analysis. Full PK was performed on male ICR mice (2 mice per group, 4 blood sampling times per mouse, cross-referencing).

[0242] [Table 9]

[0243] Some of the example compounds of the present invention exhibit superior pharmacokinetic properties compared to the positive compound SNDX-5613, and have a significant advantage, particularly in terms of exposure level and oral bioavailability.

[0244] Pharmacokinetic studies in rats Test animals: SPF-grade male SD rats, 180-220g body weight, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Materials Co., Ltd. Study design: On the day of the study, SD rats were randomly divided into groups based on body weight. They were fasted for 12-14 hours one day prior to administration, but not for dehydrated. They were fed 2 hours after administration.

[0245] Preparation of test compound solution: An appropriate amount of the test compound was weighed to achieve a concentration of 1 mg / mL for intragastric administration, and a clear clarified solution of 1 mg / mL was prepared using 0.9% sodium chloride injection and 1.5 equivalents of 1 M HCl aqueous solution. To achieve a concentration of 0.5 mg / mL for intravenous injection, a 1 mg / mL clear clarified solution was taken and diluted to a concentration of 0.5 mg / mL with 0.9% sodium chloride injection. The volume of 1 M HCl solution added was calculated using the formula: Volume of 1 M HCl solution added (mL) = Amount of compound weighed (mg) / Molecular weight × 1.5 × 1000. The amount added during preparation must not exceed this calculated value.

[0246] Administration of the test substance: Intravenous injection: Dosage 1 mg / kg, volume 2 mL / kg, 3 animals; Intragastric administration: Dosage 10 mg / kg, volume 10 mL / kg, 3 animals. Sample collection: Blood (40-50 μl) was collected from the orbital venous plexus by puncture at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration into an anticoagulant tube press-sprayed with EDTA-K2. The blood sample was centrifuged at 10,000 rpm for 20 minutes within 1 hour (stored on moist ice before and after centrifugation) to collect the upper layer of plasma, which was then frozen and stored in a refrigerator at -20°C or below for LC-MS / MS analysis. Full PK samples were collected from male SD rats (one rat per group, with 8 blood sampling points per rat).

[0247] Some of the example compounds of the present invention have excellent rat pharmacokinetic properties, and exhibit remarkable advantages, particularly in terms of exposure and oral bioavailability.

[0248] Pharmacokinetic studies of 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 based on weight. They were fasted for 12-14 hours one day prior to administration, but not for dehydration. They were fed 4 hours after administration.

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

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

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

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

[0253] As the test results show, some of the example compounds of the present invention showed almost no inhibitory effect on CYP3A4, CYP2C9, CYP2C8, CYP2C19, CYP2D6, and CYP1A2 at a concentration of 10 μM, and their IC50 values ​​were all greater than 10 μM.

[0254] Test 6. Effect on hERG potassium ion channels hERG inhibition tests were performed on some of the example compounds of the present invention using the electrophysiological manual (manual) patch-clamp method. The cell line used was HEK293 cells that overexpressed hERG potassium ion channels. The specific experimental procedure was developed by PharmaCore Labs based on literature published in a peer review journal, and was carried out by PharmaCore Labs according to its standard experimental protocol, with a maximum test concentration of 30 μM. The results are shown in Table 5.

[0255] [Table 10]

[0256] As the results show, some of the example compounds of the present invention showed almost no apparent blocking effect on hERG potassium ion channels within the test concentration range, and the IC reported with the positive reference compound SNDX-5613 50 This is significantly better than values ​​of 5-15 μM.

[0257] Study Example 10: Research on the antitumor efficacy of the example compounds in a BALB / c nude mouse model of MV-4-11 cell subcutaneous transplanted tumors. 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 culture medium used was IMDM containing 10% FBS serum, and cultivation was carried out at 37°C under 5% CO2 conditions. MV-4-11 cells were cultured in vitro (suspension), and cells in the logarithmic growth phase were collected. The cells were lightly rinsed twice with PBS, and the cell pellet was lightly blown with PBS to resuspend the cells and prepare a single-cell suspension. After counting, the final cell concentration was 1 × 10⁶.7 The solution was adjusted to a cell / 100 μL ratio, and a fully liquefied Matrigel basement membrane matrix was added in a 1:1 ratio and thoroughly mixed. 1 × 10⁶ cells were placed under the right armpit. 7 Inoculation was performed with cells per animal and an inoculation volume of 100 μL per animal. Tumor growth was observed regularly, and on the 8th day after inoculation, the tumors averaged 131 mM. 3 When the tumors grew to a certain size, the mice were randomly divided into groups (n=8) based on tumor size and body weight. The example compounds were administered intragastricly at doses of 15 mg / kg and 30 mg / kg, respectively, twice daily for 32 days. A clarified solution of the example compound was obtained by thoroughly mixing it with an appropriate amount of 0.9% sodium chloride injection by swirling, and then dissolving it with 1N HCl hydrochloric acid based on 1.5 equivalent moles of the compound. During the experiment, animal activity was observed once daily. The body weight of each animal was weighed once before administration, and the long and short diameters of the tumors were measured using a nodule. 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. Tumor volume was calculated using the formula: V=0.5(a×b 2 This was determined by the following formula. Here, a and b represent the long and short diameters of the tumor, respectively.

[0258] As a result, some of the example compounds of this application showed good efficacy in the body at doses of 15 mg / kg and 30 mg / kg.

[0259] Based on the above, the compounds provided in this invention exhibit excellent inhibitory activity against Menin protein-MLL protein interactions and cell proliferation inhibitory activity, and also have significant advantages in terms of safety and bioavailability, making them potentially novel drugs for the clinical treatment of cancer or other diseases mediated by Menin-MLL interactions. Furthermore, the present invention includes the following embodiments. [Aspect 1] Equation I below: [ka] [In the formula, Ring L is,

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Claims

1. Equation I below: 【Chemistry 1】 [In the formula, Ring L is, 【Chemistry 2】 (where n1, n2, n3, and n4 are each independently either 1 or 2); Y １ , Y ２ Each is independently either CH or N; m is either 1 or 2; W is selected from the group consisting of hydrogen, methyl group, trifluoromethyl group, methoxy group, and methylamine group; X is CR ａ R ｂ Or NR ａ And; R ａ 、R ｂ is, independently of one another, hydrogen, halogen, cyano group, nitro group, -C １～６ alkyl group, -C １～６ alkyl group substituted with deuterium, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ alkyl group substituted with halogen, -C ２～６ alkenyl group substituted with halogen, -C ２～６ alkynyl group substituted with halogen, -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 NR 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- to 10-membered heterocycloalkyl group), -C ０～２ alkylene group -(6- to 10-membered aromatic ring), and -C ０～２ alkylene group -(5- to 10-membered aromatic heterocyclic ring) selected from the group consisting of, where the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, aromatic heterocyclic ring may be further optionally substituted with one, two, three, or four independent R Ｂ１ (and may be substituted). Or, R ａ , R ｂ together with the atom connected to it 【Transformation 3】 It forms a 3-6 membered carbon ring group and a 4-6 membered heterocycloalkyl group (where the carbon ring group and heterocycloalkyl group may further optionally have one, two, three, or four independent R Ｂ１ (May be replaced with); R Ａ１ , R Ａ２ These are, independently, hydrogen and -C. １～６ Alkyl 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 member heterocycloalkyl group), -C １～２ Alkylene group - (6-10 membered aromatic ring), and -C １～２ Selected from the group consisting of alkylene groups (5-10 membered aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of one, two, three, or four independent R groups). Ｂ１ (May be replaced with); Each R Ｂ１ These are, independently, hydrogen, deuterium, halogen, cyano group, nitro group, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group and -C ０～４ Alkylene group -OR Ｃ１ Selected from the group consisting of; R Ｃ１ These are, independently, hydrogen, -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups; R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R １’ 、R ２’ 、R ３’ 、R ４’ 、R １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ alkyl group substituted with halogen, -C ２～６ alkenyl group substituted with halogen, -C ２～６ alkynyl group substituted with halogen, -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- to 10-membered heterocycloalkyl group), -C ０～４ alkylene group -(6- to 10-membered aromatic ring), and -C ０～４ alkylene group -(5- to 10-membered aromatic heterocycle), and is selected from the group consisting of (where the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring, aromatic heterocycle may be further optionally substituted with one, two, three, or four independent R Ｄ３ ), Alternatively, R linked to the same atom １ and R １’ 、R ２ and R ２’ 、R ３ and R ３’ 、R ４ and R ４’ are each independently linked to each other to form a 3- to 10-membered carbocyclic group 【Chemistry 4】 It forms (where the carbon ring group is further optionally one, two, three, or four independent R Ｄ３ (May be replaced by) Or, R １ , R ２ , R ３ , R ４ , R ５ Any two of the non-adjacent ones, or R １ , R ２ , R ３ , R ４ , R ５ Any three of these atoms are linked together to form a 7- to 12-membered bridged cycloalkyl group with the ring in which the linked atoms are located (where the bridged cycloalkyl group is further optionally linked to one, two, three, or four independent R atoms). Ｄ３ (May be replaced with); R Ｄ１ , R Ｄ２ These are, independently, hydrogen and -C. １～６ Alkyl 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 member heterocycloalkyl group), -C ０～４ Alkylene group - (6-10 membered aromatic ring), and -C ０～４ Selected from the group consisting of alkylene groups (5-10 membered aromatic heterocycles) (where alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aromatic rings, and aromatic heterocycles may further consist of one, two, three, or four independent R groups). Ｄ４ (May be replaced with); Each R Ｄ４ These are, independently, hydrogen, -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups; Each R Ｄ３ These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens 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 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)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 - (3-10 membered carbocyclic group), -C ０～４ Alkylene group - (4-10 member heterocycloalkyl group), -C ０～４ Alkylene group - (6-10 membered aromatic ring), and -C ０～４ Selected from the group consisting of an alkylene group (a 5-10 member aromatic heterocycle); R ｄ１ , R ｄ２ These are, independently, hydrogen and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups; R ６ is hydrogen, -C １～６ Alkyl 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 - (5-10 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 member 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 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 Selected from the group consisting of (where alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and optionally one, two, three, or four independent R groups) Ｅ５ (May be replaced with); R Ｅ１ , R Ｅ２ These are, independently, hydrogen and -C. １～６ Alkyl alkyl group, -C ０～４ Alkylene group - (3-10 membered carbocyclic group), -C ０～４ Alkylene group - (4-10 member 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) ２ R Ｅ３ , -C ０～４ Alkylene group -S(O) ２ 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 Selected from the group consisting of (where alkyl groups, alkylene groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups may further consist of one, two, three, or four independent R groups) Ｅ５ (May be replaced by) Or, R Ｅ１ , R Ｅ２ These are linked together to form a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group (where the heterocycloalkyl group and bridged heterocycloalkyl group are further optionally connected to one, two, three, or four independent R groups). Ｅ５ (May be replaced with); R Ｅ３ , R Ｅ４ These are, independently, hydrogen and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups, Or, R Ｅ３ , R Ｅ４ These, together with the nitrogen atoms linked to them, form a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group (where the heterocycloalkyl group and bridged heterocycloalkyl group may further optionally have one, two, three, or four independent R Ｅ５ (May be replaced by) Or, R Ｅ３ , R Ｅ４ These are linked together to form a 4-10 member heterocycloalkyl group or a 4-10 member bridged heterocycloalkyl group (where the heterocycloalkyl group and bridged heterocycloalkyl group are further optionally connected to one, two, three, or four independent R groups). Ｅ５ (May be replaced with); Each R Ｅ５ These are independently hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl group, halogen-substituted -C ２～６ Alkynyl group, -O(C) １～６ Alkyl(alkyl group), -NH ２ , -C ０～４ Alkylene group - (3-10 membered carbocyclic group), -C ０～４ Alkylene group - (4-10 member heterocycloalkyl group), -C ０～４ Alkylene group - (5-10 membered aromatic ring), and -C ０～４ Selected from the group consisting of alkylene groups (5-10 membered heteroaromatic rings) (wherein a carbocyclic group, heterocycloalkyl group, aryl group, heteroaryl group may further consist of one, two, three, or four independent R groups). Ｅ６ (May be replaced with); R Ｅ６ These are independently hydrogen, halogen, cyano group, nitro group, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups. Compounds represented by , deuterated compounds thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

2. X is NR ａ And, R ａ These are hydrogen, methyl group, ethyl group, isopropyl group, cyclopropyl group, 【Transformation 5】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

3. X is CR ａ R ｂ Selected from, R ａ , R ｂ These are, independently, hydrogen, fluorine, and a methyl group. 【Transformation 6】 ethyl group, isopropyl group, 【Transformation 7】 Selected from a group consisting of, Or, R ａ , R ｂ together with the atom connected to it 【Transformation 8】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by forming a compound.

4. The aforementioned ring L is 【Chemistry 9】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the group consisting of the above.

5. R １ , R ２ , R ３ , R ４ , R ５ , R １’ , R ２’ , R ３’ , R ４’ These are, independently, hydrogen, halogen, cyano group, nitro group, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ A compound according to claim 2, characterized by being selected from the group consisting of alkynyl groups, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. R １’ , R ２’ , R ３’ , R ４’ These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens 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 These are, independently, hydrogen and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group and -C ２～６ Selected from the group consisting of alkynyl groups; R １ , R ２ , R ３ , R ４ , R ５ Any two non-adjacent atoms of these atoms are linked together to form a 7- to 12-membered bridging cycloalkyl group with the ring in which the linked atoms are located; Here, R １ , R ２ , R ３ , R ４ , R ５ Any two non-adjacent points in our group 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 They are connected to each other so that they become a group 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 These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups, or two R groups Ｄ３ together 【Chemistry 10】 A compound according to claim 2, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it forms a compound.

7. R １ , R ２ , R ３ , R ４ , R ５ Two of them are connected to each other, together with the ring in which those connected atoms are located. 【Chemistry 11】 It forms, Here, R １’ , R ２’ , R ３’ , R ４’ These are, independently, hydrogen or -C. １～６ A compound according to claim 6, characterized by being an alkyl group, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. R １’ , R ２’ , R ３’ , R ４’ These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens 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 These are, independently, hydrogen and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group and -C ２～６ Selected from the group consisting of alkynyl groups; R １ , R ２ , R ３ , R ４ , R ５ Any three of these atoms are linked together to form a 7- to 12-membered bridged cycloalkyl group or a 7- to 12-membered bridged heterocycloalkyl group with the ring on which the linked atoms are located; Here, R １ , R ２ , R ３ , R ４ , R ５ Any two of these 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 They are linked together to form a chain selected from the group consisting of -S-, and the third group is linked 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 These are, independently, hydrogen, halogen, cyano group, nitro group, oxo, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, halogen-substituted -C １～６ -C substituted with alkyl groups and halogens ２～６ Alkenyl groups and halogen-substituted -C ２～６ Selected from the group consisting of alkynyl groups, or two R groups Ｄ３ together 【Chemistry 12】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by forming a compound.

9. R １ , R ４ , R ５ These three are connected to each other, together with the ring in which the connected atoms are located. 【Chemistry 13】 The compound according to claim 8, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by forming a compound.

10. 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 rings, -5 to 10 membered heteroaromatic rings, -3 to 10 membered carbocyclic groups, -4 to 10 membered heterocycloalkyl groups, -S(O)R Ｅ１ , -S(O) ２ R Ｅ１ , -S(O) ２ 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 Selected from the group consisting of (where alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and optionally one, two, three, or four independent R groups) Ｅ５ A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it may be substituted with (which).

11. R ６ teeth, 【Chemistry 14】 A compound according to claim 10, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the group consisting of the above.

12. Equation II below: 【Chemistry 15】 [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’ [This is defined as described in claim 1] A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being represented by [the formula shown].

13. The following formula IIa or formula IIb: 【Chemistry 16】 [In the formula, Y １ , Y ２ W, X, R ６ [This is defined as described in claim 1] A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being represented by [the formula shown].

14. The following formula IIIa or formula IIIb: 【Chemistry 17】 [In the formula, Y １ , Y ２ Each is independently CH or N, R ａ These are hydrogen, methyl group, ethyl group, isopropyl group, cyclopropyl group, [Chemistry 18] Selected from the group consisting of, R ６ teeth, 【Chemistry 19】 Selected from the group consisting of: A compound according to claim 13, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being represented by [the formula shown].

15. The following formula IVa or formula IVb: 【Chemistry 20】 [In the formula, Y １ , Y ２ Each is independently CH or N, R ａ , R ｂ These are, independently, hydrogen, fluorine, and a methyl group. 【Chemistry 21】 ethyl group, isopropyl group, 【Chemistry 22】 Selected from a group consisting of, Or, R ａ , R ｂ together with the atom connected to it 【Chemistry 23】 It forms, R ６ teeth, 【Chemistry 24】 Selected from the group consisting of: A compound according to claim 13, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being represented by [the formula shown].

16. The following equation Va: 【Chemistry 25】 [In the formula, Y １ , Y ２ Each is independently CH or N, R ａ , R ｂ These are, independently, hydrogen, fluorine, and a methyl group. 【Chemistry 26】 ethyl group, isopropyl group, 【Chemistry 27】 Selected from a group consisting of, Or, R ａ , R ｂ together with the atom connected to it 【Chemistry 28】 It forms, R ６ teeth, 【Chemistry 29】 Selected from the group consisting of: A compound according to claim 15, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being represented by [the formula shown].

17. in particular, 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is such.

18. in particular, 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 A compound according to claim 1, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is such.

19. A pharmaceutical agent for treating cancer, comprising a compound according to any one of claims 1 to 18, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, a deuterated compound thereof, a stereoisomer thereof, or a preparation prepared with a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 20, further comprising a pharmaceutically acceptable carrier, additive, or vehicle.

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