Menin inhibitors and their uses

Abstract

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

Description

Technical Field

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

[0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase mutated in clinically and biologically distinct subtypes of acute leukemia. The MLL gene family includes five members, MLL1-5, which are closely related to the occurrence, development, deterioration, and metastasis of various tumors. The multiple endocrine neoplasia protein (Menin protein) is encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, and the MEN1 gene functions as a tumor suppressor gene in endocrine organs. The Menin protein interacts with a variety of proteins, forming a complex interaction network. Studies have shown that the direct interaction between Menin and MLL1 and MLL2 proteins is essential for the enzymatic activity of the complex histone methylation modification (H3K4), the transcriptional regulation of target genes, and their corresponding functions. Menin interacts with the amide terminus of MLL1 and acts as an oncogenic cofactor that increases the transcription of gene clusters such as HOX and MEIS1. The interaction between Menin and the MLL fusion protein is essential for the abnormal activation of a series of gene clusters caused by the MLL fusion protein and the onset of leukemia. In addition, as a nuclear protein with broad tissue expression, Menin is involved in the formation of a variety of important transcriptional regulatory complexes and exhibits a variety of important biological functions in the body. In addition to participating in the formation of MLL1 and MLL2 epigenetic regulatory complexes, the Menin protein has been reported to interact with a variety of transcription factors, including JunD, NFKB, and SMAD3, to regulate the transcriptional activation or inhibition of target genes.

[0003] Using small molecules to target the Menin-MLL interaction is an attractive strategy for developing new therapies 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 cancers, such as liver cancer, brain, colon, breast cancer, etc.

[0004] Therefore, the Menin-MLL1 protein-protein interaction inhibitor can be considered a potential anti-tumor compound with broad application prospects. Selectively targeting this interaction interface is beneficial for the development of new drugs related thereto. Summary of the Invention

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

[0006]

[0007] Among them,

[0008] U is selected from N or CR y ;

[0009] R y is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR y1 -C 0～4 alkylene-NR y1 R y2 -C 0～4 alkylene-(3- to 10-membered carbocyclic group), -C 0～4 alkylene-(4- to 10-membered heterocycloalkyl group); where the alkyl, alkylene, carbocyclic group, and heterocycloalkyl group may further optionally be substituted by one, two, three, or four independent R y3 substituents;

[0010] R y1 and R y2 are each independently selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-(3- to 10-membered carbocyclic group), -C 0～4 alkylene-(4- to 10-membered heterocycloalkyl group);

[0011] R y3 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl;

[0012] W is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkynyl, -C 0～4 Alkylene -NR C1 R C2 、-C 0～4 Alkylene -OR C1 ;

[0013] R C1 、R C2 Are each independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkynyl;

[0014] Ring A is selected from 5- to 10-membered carbocyclic rings, 5- to 10-membered heterocyclic rings; wherein, the carbocyclic ring and the heterocyclic ring may be further substituted by one, two, three or four independent R A1 Substituents;

[0015] R A1 Is selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR a1 R a2 、-C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkynyl, -C 0～4 Alkylene -OR a1 、-C 0～4 Alkylene -NR a1 R a2 、-C 0～4 Alkylene -NR a1 COR a2 、-C 0～4 Alkylene -CONR a1 R a2 、-C 0～4 Alkylene -COOR a1 、-C 0～4 Alkylene -COR a1 、-C 0～4 Alkylene -(3- to 10-membered carbocyclic group), -C 0～4 Alkylene -(4- to 10-membered heterocyclic alkyl group), -C 0～4 Alkylene -(6- to 10-membered aromatic ring) or -C 0～4Alkylene-(5- to 10-membered heteroaryl ring); wherein, the alkyl, alkylene, alkenyl, alkynyl, alkylene, carbocyclic group, heterocycloalkyl group, aryl ring, heteroaryl ring may be further optionally substituted by one, two, three or four independent Rs a3 substituted;

[0016] or two Rs attached to the same atom A1 together with the atom to which they are attached form a 3- to 10-membered carbocyclic ring or a 4- to 10-membered heterocyclic ring; wherein, the carbocyclic ring and the heterocyclic ring may be further optionally substituted by one, two, three or four independent Rs a3 substituted;

[0017] R a1 and R a2 are each independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl;

[0018] R a3 is selected from hydrogen, deuterium, halogen, cyano, nitro, =O, =S, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -OC 1-6 alkyl;

[0019] L is selected from -NR B1 -(5- to 10-membered carbocyclic ring)-NR B2 -, -NR B1 -(5- to 10-membered heterocyclic ring)-NR B2 -, -NR B1 -(5- to 12-membered spiro ring)-NR B2 -, -NR B1 -(5- to 12-membered spiroheterocyclic ring)-NR B2 -, -NR B1 -(5- to 12-membered bridged ring)-NR B2 -, -NR B1 -(5- to 12-membered bridged heterocyclic ring)-NR B2 -, -NR B1 -(5- to 10-membered carbocyclic ring)-, -NR B1 -(5- to 10-membered heterocyclic ring)-, -NR B1 -(5- to 12-membered spiro ring)-, -NR B1-(5 to 12-membered spiroheterocyclic ring)-, -NR B1 -(5 to 12-membered bridged ring)-, -NR B1 -(5 to 12-membered bridged heterocyclic ring)-, -(5 to 12-membered carbocyclic ring)-NR B2 -, -(5 to 10-membered heterocyclic ring)-NR B2 -, -(5 to 12-membered spiro ring)-NR B2 -, -(5 to 12-membered spiroheterocyclic ring)-NR B2 -, -(5 to 12-membered bridged heterocyclic ring)-NR B2 -, -(5 to 12-membered carbocyclic ring)-, -(5 to 10-membered heterocyclic ring)-, -(5 to 12-membered spiro ring)-, -(5 to 12-membered spiroheterocyclic ring)-, -(5 to 12-membered bridged heterocyclic ring)-; wherein, the carbocyclic ring, heterocyclic ring, spiro ring, spiroheterocyclic ring, bridged ring, and bridged heterocyclic ring can be further optionally substituted by one, two, three, or four independent R b1 substituents;

[0020] R B1 and R B2 are each independently selected from hydrogen, -C 1-6 alkyl, -C 1～4 alkylene-OR b2 ;

[0021] R b1 is selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR b3 -, -C 0～4 alkylene-NR b3 COR b4 -, -C 0～4 alkylene-CONR b3 R b4 -, -C 0～4 alkylene-(3 to 10-membered carbocyclic group), -C 0～4 alkylene-(4 to 10-membered heteroalkyl group), -C 0～4 alkylene-(6 to 10-membered aromatic ring), -C 0～4 alkylene-(5 to 10-membered heteroaromatic ring);

[0022] R b2 is selected from hydrogen, -C 1-6 alkyl;

[0023] R b3 and Rb4 Each independently selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl or halogen-substituted -C 2～6 alkynyl;

[0024] R 1 、R 2 、R 3 、R 4 、R 5 、R 1 ’, R 2 ’, R 3 ’, R 4 ’ are each independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR D1 、-C 0～4 alkylene-NR D1 R D2 、-C 0～4 alkylene-(3- to 10-membered carbocyclic group), -C 0～4 alkylene-(4- to 10-membered heterocycloalkyl group), -C 0～4 alkylene-(6- to 10-membered aromatic ring) or -C 0～4 alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocycloalkyl group, aromatic ring, heteroaromatic ring may be further optionally substituted by one, two, three or four independent R D3 substituents;

[0025] Or R 1 connected to the same atom and R 1 ’, R 2 connected to the same atom and R 2 ’, R 3 connected to the same atom and R 3 ’, R 4 connected to the same atom and R 4 ’ together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic group, 4- to 10-membered heterocycloalkyl group, wherein the carbocyclic group and heterocycloalkyl group may be further optionally substituted by one, two, three or four independent R D3 substituents;

[0026] or R 1 、R 2 、R 3 、R 4 、R 5 any two non-adjacent ones among, or R 1 、R 2 、R 3 、R 4 、R 5 are connected to each other, and together with the ring where the connecting atom is located, form a 7- to 12-membered bridged cycloalkyl group or a 7- to 12-membered bridged heterocycloalkyl group, wherein the bridged cycloalkyl group and the bridged heterocycloalkyl group may be further optionally substituted by one, two, three or four independent R D3 substituents;

[0027] R D1 、R D2 are each independently selected from hydrogen, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, -C 0～4 alkylene-(3- to 10-membered carbocyclic group), -C 0～4 alkylene-(4- to 10-membered heterocycloalkyl group);

[0028] Each R D3 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR d1 、-C 0～4 alkylene-NR d1 R d2 ;

[0029] R d1 、R d2 are each independently selected from hydrogen, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl or halogen-substituted -C 2～6 alkynyl.

[0030] Furthermore,

[0031] L is selected from -NR B1 -(5-membered carbocyclic ring)-NR B2-, -NR B1 -(6-membered carbocyclic ring)-NR B2 -, -NR B1 -(7-membered carbocyclic ring)-NR B2 -, -NR B1 -(5-membered heterocyclic ring)-, -NR B1 -(6-membered heterocyclic ring)-, -NR B1 -(7-membered heterocyclic ring)-, -(5-membered heterocyclic ring)-NR B2 -, -(6-membered heterocyclic ring)-NR B2 -, -(7-membered heterocyclic ring)-NR B2 -, -(7-membered spiro heterocyclic ring)-NR B2 -, -(8-membered spiro heterocyclic ring)-NR B2 -, -(9-membered spiro heterocyclic ring)-NR B2 -, -(7-membered spiro heterocyclic ring)-, -(8-membered spiro heterocyclic ring)-, -(9-membered spiro heterocyclic ring)-; wherein, the carbocyclic ring, heterocyclic ring, and spiro heterocyclic ring may be further optionally substituted by one, two, three, or four independent R b1 substituents;

[0032] R B1 、R B2 are each independently selected from hydrogen, -C 1-6 alkyl, -C 1～2 alkylene-OR b2 ;

[0033] R b1 is selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～2 alkylene-OR b3 、-C 0～2 alkylene-NR b3 COR b4 、-C 0～2 alkylene-CONR b3 R b4 、-C 0～2 alkylene-(3- to 10-membered carbocyclic group), -C 0～2 alkylene-(4- to 10-membered heteroalkyl group), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5- to 10-membered heteroaromatic ring);

[0034] R b2 is selected from hydrogen, -C1-6 Alkyl;

[0035] R b3 and R b4 are each independently selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl or halogen-substituted -C 2～6 alkynyl;

[0036] W is selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl, -C 0～2 alkylene-NR C1 R C2 、-C 0～2 alkylene-OR C1 ;

[0037] U is selected from N or CR y ;

[0038] R y is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl, -C 0～2 alkylene-OR y1 、-C 0～2 alkylene-NR y1 R y2 ;

[0039] R y1 is selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, 3- to 6-membered cycloalkyl.

[0040] Furthermore,

[0041] L is selected from

[0042]

[0043] Furthermore,

[0044] L is selected from

[0045]

[0046] Among them, one side of the aa label is connected to the methylene group, and the other side is connected to the aromatic ring.

[0047] Furthermore,

[0048] W is selected from hydrogen, methyl, ethyl, trifluoromethyl, -NHCH3, -OCH3;

[0049] R y is selected from hydrogen, halogen, cyano, nitro, methyl, ethyl, trifluoromethyl, -NHCH3, -OCH3.

[0050] In some embodiments of the present invention,

[0051] R 1 、R 2 、R 3 、R 4 、R 5 、R 1 ’、R 2 ’、R 3 ’、R 4 ’ are each independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl. Preferably, R 1 、R 2 、R 3 、R 4 、R 5 、R 1 ’、R 2 ’、R 3 ’、R 4 ’ are all hydrogen.

[0052] In some embodiments of the present invention,

[0053] R 1 ’、R 2 ’、R 3 ’、R 4 ’ are each independently selected from hydrogen, halogen, cyano, nitro, =O, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6Alkynyl, -C 0～4 Alkylene-OR D1 、-C 0～4 Alkylene-NR D1 R D2 ;

[0054] R D1 、R D2 Are each independently selected from hydrogen, -C 1～6 Alkyl;

[0055] R 1 、R 2 、R 3 、R 4 、R 5 Any two non-adjacent ones of them and the ring where their connecting atoms are located together form a 7- to 12-membered bridged cycloalkyl or 7- to 12-membered bridged heterocycloalkyl; wherein the bridged cycloalkyl and bridged heterocycloalkyl may be further optionally substituted by one, two, three or four independent R D3 Substituted;

[0056] Each R D3 Is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkynyl.

[0057] In some embodiments of the present invention, further,

[0058] R 1 、R 2 、R 3 、R 4 、R 5 Together with the ring where their connecting atoms are located form

[0059] Wherein, R 1 ’, R 2 ’, R 3 ’, R 4 ’ are each independently selected from hydrogen, -C 1-6 Alkyl.

[0060] In some embodiments of the present invention,

[0061] R 1 ’、R 2 ’、R 3 ’、R 4' are each independently selected from hydrogen, halogen, cyano, nitro, =O, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR D1 、-C 0～4 alkylene-NR D1 R D2 ;

[0062] R D1 、R D2 are each independently selected from hydrogen, -C 1～6 alkyl;

[0063] R 1 、R 2 、R 3 、R 4 、R 5 Any three of them and the ring to which their connecting atoms belong together form a 7- to 12-membered bridged cycloalkyl or 7- to 12-membered bridged heterocycloalkyl; wherein the bridged cycloalkyl and bridged heterocycloalkyl may further be optionally substituted by one, two, three or four independent R D3 substituents;

[0064] Each R D3 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl.

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

[0066] R 1 、R 4 、R 5 together with the ring to which their connecting atoms belong form

[0067] In some embodiments of the present invention, the general formula shown in Formula I can be as follows:

[0068]

[0069] Wherein, the substituents are defined as described above.

[0070] Further,

[0071] Ring A is selected from 5-membered heterocycles and 6-membered heterocycles; wherein, the heterocycle may be further substituted by one, two, three or four independent R A1 substituents;

[0072] R A1 is selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR a1 R a2 , -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～2 alkylene-OR a1 , -C 0～2 alkylene-NR a1 R a2 , -C 0～2 alkylene-NR a1 COR a2 , -C 0～2 alkylene-CONR a1 R a2 , -C 0～2 alkylene-COOR a1 , -C 0～2 alkylene-COR a1 , -C 0～2 alkylene-(3-6-membered carbocyclic group), -C 0～2 alkylene-(4-6-membered heterocyclic alkyl group); wherein, the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocyclic alkyl group may be further optionally substituted by one, two, three or four independent R a3 substituents;

[0073] Alternatively, two R A1 connected to the same atom and the atom to which they are attached together form cyclopropane, cyclobutane, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle; wherein, the cyclopropane, cyclobutane, heterocycle may be further optionally substituted by one, two, three or four independent R a3 substituents;

[0074] R a1 , R a2 are each independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6Alkynyl group.

[0075] Furthermore,

[0076] Ring A is selected from wherein, the ring selected by Ring A can be further substituted by one, two, three or four independent R A1 substitutions.

[0077] In some embodiments of the present invention, the structure of the compound is shown as Formula IIa:

[0078]

[0079] wherein,

[0080] X is selected from CR E1 R E2 , O or NR E1 ;

[0081] m is selected from 1 or 2;

[0082] R E1 , R E2 are each independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～2 alkylene-OR e1 , -C 0～2 alkylene-NR e1 R e2 , -C 0～2 alkylene-NR e1 COR e2 , -C 0～2 alkylene-CONR e1 R e2 , -C 0～2 alkylene-COOR e1 , -C 0～2 alkylene-COR e1 , -C 0～2 alkylene-(3- to 6-membered carbocyclic group), -C 0～2 alkylene-(4- to 6-membered heterocycloalkyl group); wherein, alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocycloalkyl group can be further optionally substituted by one, two, three or four independent R e3 substitutions;

[0083] Alternatively, R E1 , R E2Together with the atoms to which it is attached, form cyclopropane, cyclobutane, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle; wherein, the cyclopropane, cyclobutane, and heterocycle may further optionally be substituted by one, two, three, or four independent R e3 substituents;

[0084] R e1 and R e2 are each independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, or halogen-substituted -C 2～6 alkynyl;

[0085] R e3 is selected from hydrogen, deuterium, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -OC 1-6 alkyl.

[0086] In some embodiments of the present invention, further,

[0087] X is selected from NR E1 ;

[0088] R E1 is selected from hydrogen, isopropyl, cyclopropyl,

[0089] In some embodiments of the present invention, further,

[0090] X is selected from CR E1 R E2 ;

[0091] R E2 and R E2 are each independently selected from hydrogen, halogen, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy,

[0092]

[0093]

[0094] Alternatively, R E1 and RE2 Together with the atoms to which it is attached, form cyclopropane, cyclobutane,

[0095] In some embodiments of the present invention, R E2 is hydrogen, and R E2 is selected from hydrogen, halogen, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy,

[0096] In some embodiments of the present invention, R E2 , R E2 are the same and are selected from hydrogen, halogen, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy,

[0097] In some embodiments of the present invention, the general formula shown in Formula I can be as follows:

[0098]

[0099]

[0100] wherein the substituents are defined as described above.

[0101] In some embodiments of the present invention, the general formula shown in Formula I can be as follows:

[0102]

[0103] wherein the substituents are defined as described above.

[0104] In some embodiments of the present invention, the compound structure is as shown in Formula IIb:

[0105]

[0106] wherein,

[0107] Y 1 , Y 2 are each independently selected from O;

[0108] n is selected from 1 or 2.

[0109] In some embodiments of the present invention, the compound structure is as shown in Formula IIc:

[0110]

[0111] wherein,

[0112] Y1 and Y 2 are each independently selected from NR F , O;

[0113] n is selected from 1 or 2;

[0114] R F is each independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl, halogen-substituted -C 2～6 alkynyl, -C 0～4 alkylene-OR f1 , -C 0～4 alkylene-NR f1 R f2 , -C 0～4 alkylene-NR f1 COR f2 , -C 0～4 alkylene-CONR f1 R f2 , -C 0～4 alkylene-COOR f1 , -C 0～4 alkylene-COR f1 ;

[0115] R f1 , R f2 are each independently selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen-substituted -C 1～6 alkyl, halogen-substituted -C 2～6 alkenyl or halogen-substituted -C 2～6 alkynyl.

[0116] In some embodiments of the present invention, further,

[0117] R F is each independently selected from hydrogen, -C 1-6 alkyl, -C 0～4 alkylene-OR f1 ;

[0118] R f1 is each independently selected from hydrogen, -C 1-6 alkyl.

[0119] In some specific embodiments of the present invention, the compound is specifically:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] The present invention also provides the use of the above-mentioned compound, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt in the preparation of a medicament for treating diseases associated with abnormal Menin activity.

[0133] The present invention also provides the use of the above-mentioned compound, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt in the preparation of a medicament for treating cancer.

[0134] The present invention also provides a pharmaceutical composition comprising a preparation prepared from any one of the above-mentioned compounds, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt.

[0135] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle.

[0136] The Menin-mediated diseases defined by the present invention include one or more of cancer or malignancy, diabetes, and other Menin-related diseases. "Cancer" or "malignancy" refers to any one of a variety of diseases characterized by uncontrolled abnormal cell proliferation, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any one of many characteristic structures and / or molecular features. "Cancer cells" refer to cells that have undergone the early, middle, or late stages of multi-step tumor progression. The "cancer" or "malignancy" is leukemia, liver cancer, brain cancer, myeloma, pancreatic cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, or multiple endocrine adenocarcinoma.

[0137] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0138] Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to such groups or terms throughout the specification; for terms not specifically defined herein, their meanings should be given based on the disclosure and context, as would be understood by those skilled in the art.

[0139] "Substituted" means that a hydrogen atom in a molecule is replaced by a different atom or group; or a lone pair of electrons of an atom in a molecule is replaced by another atom or group. For example, a lone pair of electrons on an S atom can be replaced by an O atom to form

[0140] "May be further optionally substituted" or "may be further substituted" means that "substitution" can but does not have to occur, and this description includes the cases of occurrence or non-occurrence.

[0141] The minimum and maximum carbon atom contents in a hydrocarbon group are indicated by a prefix. For example, the prefix C a～b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C 1～6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms.

[0142] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two, or three branches. Alkyl groups can be optionally substituted by one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups can also be part of other groups, such as -O(C1～6 alkyl).

[0143] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. C a～b Alkylene refers to an alkylene group having a to b carbon atoms. The alkylene group includes branched and straight-chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structures: Similarly, the term "dimethylbutylene" can be exemplified by any of the following structures:

[0144] The -C0-4 alkylene of the present invention can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-), C3 alkylene or C4 alkylene; C0 alkylene means that the group does not exist here and is connected in the form of a chemical bond. A-C0 alkylene-B means A-B, that is, group A and group B are directly connected by a chemical bond.

[0145] The unsaturation described in the present invention means that the group or molecule contains carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc.

[0146] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having at least 1 vinyl unsaturation site (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0147] "Alkynyl" refers to a straight-chain monovalent hydrocarbon group or a branched-chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is intended to include ethynyl, propynyl, etc.

[0148] The "carbocyclic group" and "carbocycle" described in the present invention refer to a saturated or non-aromatic partially saturated cyclic group having a single ring or multiple rings (fused) with multiple carbon atoms and no ring heteroatoms. The term "carbocyclic group" includes cycloalkenyl groups such as cyclohexenyl. Examples of monocyclic carbocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclic groups of fused carbocyclic systems include dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Two such bicycloalkyl polycyclic structures are exemplified and named below: Dicyclohexyl and Dicyclohexyl. The term "carbocyclic group" also includes the case of a partially saturated cyclic group formed by the fusion of an aromatic ring and a non-aromatic ring, and its connecting site can be located at a non-aromatic carbon atom or an aromatic carbon atom. Examples include 1,2,3,4-tetrahydronaphthalen-5-yl, 5,6,7,8-tetrahydronaphthalen-5-yl.

[0149] As used herein, the "bridged ring" and "bridged cycloalkyl" refer to a saturated or non-aromatic partially saturated cyclic group formed by bridging multiple rings having multiple carbon atoms and no ring heteroatoms. Examples of the bridged ring system include Adamantyl and the like.

[0150] As used herein, the "spiro ring" and "spiro cycloalkyl" refer to a saturated or non-aromatic partially saturated cyclic group formed by spiro-fusing multiple rings having multiple carbon atoms and no ring heteroatoms. Examples of the spiro ring system include And the like.

[0151] As used herein, the "heterocycloalkyl" and "heterocycle" refer to a saturated ring or a non-aromatic partially saturated ring having a single ring or multiple rings (fused) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It generally represents a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system having multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of the heterocycloalkyl group of the monocyclic heterocycloalkyl system are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl and the like. Examples of the heterocycloalkyl group of the fused heterocycloalkyl system include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl and the like. Examples of the partially saturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl and the like. The term "heterocycloalkyl" also includes the case of a partially saturated cyclic group formed by the fusion of an aromatic ring containing at least one heteroatom and a non-aromatic ring, and its connecting site can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. Examples include

[0152] As used herein, the "bridged heterocycle" and "bridged heterocycloalkyl" refer to a saturated or non-aromatic partially saturated cyclic group formed by bridging multiple rings containing at least one heteroatom. Examples of the bridged heterocycloalkyl system include And the like.

[0153] As used herein, the terms "spiroheterocycle" and "spiroheterocycloalkyl" refer to saturated or partially saturated non-aromatic cyclic groups formed by the spiro-connection of multiple rings containing at least one heteroatom. Examples of spiroheterocycloalkyl systems include and the like.

[0154] As used herein, the term "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. An aryl group is usually a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. In addition, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

[0155] As used herein, the term "heteroaromatic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which are heteroatoms selected from O, N, S. Preferably, there are one to three heteroatoms. Heteroaryl groups are represented, for example, by: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuryl, benzothienyl, benzopyranyl, benzothiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

[0156] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0157] As used herein, the term "halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by a halogen; for example, halogen-substituted C 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms; for example, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0158] As used herein, the terms "-OR", "-NRR", etc. refer to an R group connected to an oxygen atom or a nitrogen atom by a single bond.

[0159] As used herein, in "-C(O)R", "-S(O)2R", etc., the oxygen atom is connected to the carbon atom or the sulfur atom by a double bond.

[0160] As used herein, in "-C(O)R", "-S(O)2R", etc., the oxygen atom is connected to the carbon atom or the sulfur atom by a double bond, and the R group is connected to the oxygen atom or the sulfur atom by a single bond; for another example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0161] In the present invention, "=O" refers to an oxygen atom substituting two hydrogen atoms or lone pair electrons through a double bond.

[0162] In the description of the groups of the present invention, "---", " " is used to describe the position of group substitution. For example refers to the pyrrolidine ring forming a spiro ring with other rings in the structure through the position.

[0163] The "deuterated compound" of the present invention refers to a compound in which one or more hydrogen atoms in a molecule or group are substituted by deuterium atoms, and the proportion of deuterium atoms is greater than the natural abundance of deuterium.

[0164] The term "pharmaceutically acceptable" means that a certain carrier, vehicle, diluent, excipient, and / or the formed salt is usually chemically or physically compatible with other components constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0165] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid salts and / or base salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained in the final separation and purification of the compound. They can also be obtained by appropriately (e.g., equimolarly) mixing the above-mentioned compounds or their stereoisomers with a certain amount of acid or base. These salts may form precipitates in solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by lyophilization after reaction in an aqueous medium.

[0166] In certain embodiments, one or more compounds of the present invention can be used in combination with each other. Optionally, the compounds of the present invention can be combined with any other active reagent for preparing a drug or pharmaceutical composition for regulating cell function or treating diseases. If a group of compounds is used, these compounds can be administered to the subject simultaneously, separately, or sequentially.

[0167] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions, or changes can be made.

[0168] The above content of the present invention will be further described in detail below through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0169] Figure 1 It is the X-ray single crystal diffraction pattern of intermediate A1a;

[0170] Figure 2 is the X-ray single crystal diffraction pattern of intermediate A1b;

[0171] Figure 3 is the X-ray single crystal diffraction pattern of intermediate A6-5a1;

[0172] Figure 4 is the X-ray single crystal diffraction pattern of intermediate A6-5a2. Detailed implementation manners

[0173] The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from companies such as Energy Chemical, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, and J&K Scientific.

[0174] The abbreviations of the reagents described in the examples are as follows: UHP: urea peroxide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; KOAc: potassium acetate; Na2HPO4: disodium hydrogen phosphate; TFAA: trifluoroacetic anhydride; DIPEA: N,N-diisopropylethylamine; n-BuLi: n-butyllithium; NH2OH·HCl: hydroxylamine hydrochloride; NiCl2·6H2O: nickel(II) chloride hexahydrate; NaBH4: sodium borohydride; NaBH3CN: sodium cyanoborohydride; TEA: triethylamine; Py·SO3: pyridine sulfur trioxide; 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.

[0175] Unless otherwise specified in the examples, the reactions are carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is mole per liter.

[0176] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in the unit of (ppm). The NMR measurement was performed using (Bruker AvanceIII 400MHz and Bruker Avance NEO600MHz) nuclear magnetic resonance spectrometers. The solvents for measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). The LC-MS measurement was carried out using a Shimadzu liquid chromatography-mass spectrometer (Shimadzu LC-MS2020 (ESI)). The HPLC measurement was performed using a Shimadzu high-performance liquid chromatograph (Shimadzu LC-20A). MPLC (medium-pressure preparative chromatography) used a Gilson GX-281 reverse-phase preparative chromatograph. The isomer analysis and separation were carried out using a SHIMADZU SFC 30A supercritical fluid chromatography SFC instrument. The thin-layer chromatography silica gel plate used was Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification for thin-layer chromatography separation and purification of products was 0.4 mm to 0.5 mm. Column chromatography generally used Yantai Huanghai silica gel with 200 - 300 mesh as the carrier.

[0177] Synthesis of Intermediate A1a

[0178]

[0179] Step 1: Synthesis of A1-1

[0180] At room temperature, hydroxylamine hydrochloride (1.67 g, 24.03 mmol) and KOAc (2.36 g, 24.05 mmol) were added to a solution of ethyl p-cyclohexanonecarboxylate (3.4 g, 19.98 mmol) in EtOH (40 mL). The reaction mixture was heated to 80 °C and stirred for 4 h. After the reaction was completed, the organic phase was removed by rotary evaporation to obtain the crude product, which was diluted with water and extracted with ethyl acetate. The combined organic phases were distilled under reduced pressure to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain A1-1 (2.04 g, 11.01 mmol, yield 55.14%). MS m / z = 186 [M+1] + .

[0181] Step 2: Synthesis of A1-2

[0182] At -10 °C, a solution of TFAA (49.53 g, 235.83 mmol) in MeCN (60 mL) was slowly added dropwise to a suspension of UHP (22.18 g, 235.83 mmol) in MeCN (120 mL). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 h. At 80 °C, the above reaction solution was added dropwise to a solution of A1-1 (14.56 g, 78.61 mmol) and Na2HPO4 (78.12 g, 550.27 mmol) in MeCN (120 mL). After the addition was complete, the reaction mixture was stirred at 80 °C for 30 min. After the reaction was completed, the reaction solution was left overnight. The filtrate was poured into water, extracted with EA, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 10:1, v / v) to obtain A1-2 (2.17 g, 10.78 mmol, yield 13.72%).

[0183] Step 3: Synthesis of A1-3a and A1-3b

[0184] At 0 °C, DBU (1.97 g, 12.94 mmol) was added to a solution of A1-2 (2.17 g, 10.78 mmol) in MeCN (10 mL), and then methyl acrylate (1.11 g, 12.94 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched with water, extracted with EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 10:1, v / v) to obtain two components, A1-3a (1.035 g, 3.61 mmol, yield 33.48%) and A1-3b (1.424 g, 4.95 mmol, yield 45.9%), (TLC eluent PE / EA = 5 / 1: for A1-3a, R f = 0.5; for A1-3b, R f = 0.3).

[0185]

[0186] Step 4: Synthesis of A1-4a

[0187] At -10 °C, NaBH4 (217.26 mg, 5.74 mmol) was added portionwise to a mixture of A1-3a (330 mg, 1.15 mmol) and NiCl2·6H2O (272.88 mg, 1.15 mmol) in MeOH (3 mL). After stirring the reaction mixture at this temperature for 2 h, at 0 °C, the reaction solution was quenched with an aqueous potassium carbonate solution. The reaction mixture was stirred at 0 °C for 3 h and then slowly warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction solution was filtered and concentrated. The crude product was separated and purified by silica gel column (DCM / MeOH = 30:1, v / v) to obtain A1-4a (197 mg, 874.45 μmol, yield 76.13%), MS m / z = 226 [M+1] + 。

[0188] Step 5: Synthesis of A1-5a

[0189] Under an ice bath, LiAlH4 (120.88 mg, 3.19 mmol) was added to a solution of A1-4a (598 mg, 2.65 mmol) in THF (10 mL). The reaction mixture was stirred at 0 °C for 1 h. It was quenched by adding water (100 μL), then aq. NaOH (15% wt, 100 μL) and H2O (300 μL) were added, and the mixture was stirred at room temperature for 10 min. After filtration, the filtrate was obtained, and after concentration, the crude product of A1-5a (457 mg, 2.49 mmol, yield 93.95%) was obtained and used directly in the next step without further purification. MS m / z = 184 [M+1] + 。

[0190] Step 6: Synthesis of A1a

[0191] To a solution of A1-5a (457 mg, 2.49 mmol) in DCM (12 mL) / DMSO (4 mL) was added DIPEA (1.29 g, 9.98 mmol, 1.74 mL), and then a suspension of Py·SO3 (1.57 g, 9.98 mmol) in DMSO (4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 10 min, then cooled to 0 °C, and DCM (10 mL) / 1N aq HCl (10 mL) was added. The separated aqueous phase was extracted with EA. The combined organic phases were washed successively with 1N HCl and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column to obtain A1a (279 mg, 1.54 mmol, yield 61.73%), MS m / z = 182 [M+1] + 。

[0192] Synthesis of Intermediate A1b

[0193]

[0194] Referring to the method of steps 4 to 6 in the synthesis method of intermediate A1a, using component A1-3b to replace A1-3a as the starting material, with the remaining reagents and operations unchanged, intermediate A1b can be obtained. MS m / z = 182 [M+1] + 。

[0195] Synthesis of intermediate A2a

[0196]

[0197] Step 1: Synthesis of A2-1

[0198] At -78 °C, n-BuLi (11 mL, 27.5 mmol, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (2.78 g, 27.46 mmol) in diethyl ether (20 mL). The mixture was gradually warmed to -11 °C, and a solution of 2-cyclohexen-1-one (2.4 g, 24.97 mmol) in diethyl ether (20 mL) was added dropwise to the mixture, and the internal temperature of the reaction solution was maintained between -11 °C and -3 °C during the addition. The reaction solution was stirred for another 25 min and then a solution of methyl acrylate (2.15 g, 24.97 mmol) in THF (20 mL) was added dropwise. After the addition, the mixture was stirred at -10 °C for 1 h. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride (200 mL) solution and stirred for 15 min. The mixture was extracted with EA, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by silica gel column (PE / EA = 5:1, v / v) to obtain A2-1 (2.1 g, 11.52 mmol, yield 46.16%).

[0199] Step 2: Synthesis of A2-2

[0200] At room temperature, hydroxylamine hydrochloride (2.21 g, 31.8 mmol) and NaOAc (2.61 g, 31.8 mmol) were added to a solution of A2-1 (4.83 g, 26.5 mmol) in EtOH (25 mL). The reaction mixture was heated to 80 °C and stirred for 4 h. After the reaction was completed, the organic phase was removed by rotary evaporation to obtain the crude product, which was diluted with water, extracted with ethyl acetate, and the combined organic phases were distilled under reduced pressure to obtain the crude product, which was separated and purified by silica gel column to obtain A2-2 (4.45 g, 22.47 mmol, yield 84.7%). MS m / z = 198 [M+1] + 。

[0201] Step 3: Synthesis of A2-3

[0202] To a turbid solution of A2-2 (4.45 g, 22.56 mmol) and NaHCO3 (37.6 g, 564 mmol) in EA (500 mL) / H2O (500 mL), trichloroisocyanuric acid (26.2 g, 112.81 mmol) was added dropwise in portions. After stirring at room temperature for 20 min, the reaction solution turned blue and was stirred for another 9 h until the organic phase became a colorless solution. After completion of the reaction, the mixture was extracted with EA, and the combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was separated and purified by silica gel column chromatography to give A2-3 (4.48 g, 18.13 mmol, 80.36% yield).

[0203] Step 4: Synthesis of A2-4

[0204] At zero degree, NaBH4 (950 mg, 24.92 mmol) was added in portions to a solution of A2-3 (4.4 g, 17.8 mmol) and Pd / C (300 mg) in EtOH (80 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, Pd / C was filtered off, and the filtrate was concentrated and separated and purified by silica gel column chromatography to give A2-4 (3.04 g, 14.27 mmol, 80% yield).

[0205] Step 5: Synthesis of A2-5a and A2-5b

[0206] At zero degree, DBU (2.56 mL, 17.11 mmol) was added to a solution of A2-4 (3.04 g, 14.26 mmol) in MeCN (30 mL), and then methyl acrylate (1.54 mL, 17.11 mmol) was added dropwise. The reaction mixture was stirred at zero degree for 1 h. After completion of the reaction, the reaction was quenched with water, extracted with EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was separated and purified by silica gel column (PE / EA = 10:1, v / v) to give two components A2-5a (1.66 g, 5.55 mmol, 38.92% yield) and A2-5b (1.55 g, 5.18 mmol, 36.32% yield), (TLC eluent PE / EA = 5 / 1: for A2-5a, R f = 0.4; for A2-5b, R f = 0.35).

[0207] Steps 6 to 8: Synthesis of A2a

[0208]

[0209] Referring to the method of steps 3 to 5 in the synthetic route of intermediate A1a, replace A1-3a with A2-5a in the starting step, and keep the rest of the reagents and operations the same, to obtain intermediate component A2a. MS m / z = 208 [M+1] + 。

[0210] Synthesis of intermediate A2b

[0211]

[0212] Referring to the method of steps 3 to 5 in the synthetic route of intermediate A1a, replace A1-3a with A2-5b in the starting step, and keep the rest of the reagents and operations the same, to obtain intermediate component A2b. MS m / z = 208 [M+1] + 。

[0213] Synthesis of intermediate A3a

[0214]

[0215] Step 1: Synthesis of A3-2

[0216] Place A3-1 (hydrochloride, 193 g, 1.0 mol) in a 5 L beaker, add 400 mL of mixed solvent (DCM / IPA = 3 / 1), and slowly add an aqueous solution of potassium carbonate (110 g, 0.8 mol) under an ice bath, controlling the temperature below 20°C. Extract with the mixed solvent 3 - 4 times repeatedly, combine the organic phases, and concentrate to obtain the crude product for direct use in the next step of the reaction.

[0217] Dissolve the crude product in DCE (2.5 L), cool to 10°C, and add m-CPBA (688 g, 4 mol) in batches, controlling the temperature below 35°C. After addition, raise the temperature to reflux and stir for 3 h. After the reaction is completed, cool to below 10°C, stir for 20 min, filter, rinse the reaction flask with the filtrate, rinse the filter cake with an appropriate amount of DCE, and drain. Quench the filtrate carefully with an aqueous solution of Na2SO3 and detect with a starch potassium iodide test paper. Extract the filtrate with DCM three times, concentrate and purify by silica gel column chromatography (PE / EA = 80 / 1 → 30 / 1) to obtain product A3-2 (138 g, 0.737 mol, yield 73.7%). MS m / z = 188 [M+H] + 。

[0218] Step 2: Synthesis of A3-3a and A3-3b

[0219] Referring to the synthesis methods of A1-3a and A1-3b, the target intermediate A3-3a is obtained by purification and separation through a silica gel column (PE / EA = 30 / 1, MS m / z = 274 [M+H] +) and A3-3b (PE / EA = 20 / 1, MS m / z = 274 [M+H] + ). TLC developing solvent PE / EA = 5 / 1: A3-3a, R f = 0.3; A3-3b, R f = 0.2.

[0220] Step 3: Synthesis of A3-4a and A3-4b

[0221] Referring to the synthesis method of A1-4a, using A3-3a and A3-3b as raw materials respectively, A3-4a (MS m / z = 212 [M+H] + ) and A3-4b (MS m / z = 212 [M+H] + ) were obtained.

[0222] Synthesis of Intermediate A3

[0223]

[0224]

[0225] Step 1: Synthesis of A3-5a

[0226] Dissolve A3-4a (25 g, 118.34 mmol), (Boc)2O (103.31 g, 473.36 mmol) and DMAP (5.78 g, 47.34 mmol) in acetonitrile (250 mL), and react at 60 °C overnight under nitrogen protection. After the reaction is completed, directly concentrate, and the crude product is purified by silica gel column (PE / EA = 5:1 - 3:1, v / v) to obtain A3-5a (34.28 g, 110.09 mmol, yield 93.02%). MS m / z = 312 [M+H] + .

[0227] Step 2: Synthesis of A3-6a

[0228] Dissolve A3-5a (100 mg, 0.307 mmol) in THF (20 mL), cool down to -78 °C, and dropwise add LiHMDS (0.614 mmol, 2.0 eq) under nitrogen protection, and stir at this temperature for 1 h. Subsequently, slowly dropwise add a THF solution of MOMBr (96 mg, 0.768 mmol). After adding, warm up to room temperature and stir for 2 h. After the reaction is completed, quench with saturated ammonium chloride, and extract three times with DCM. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and the concentrated crude product is purified by MPLC to obtain A3-6a (99 mg, 0.239 mmol, yield 77.85%). MS m / z = 400 [M+H] + .

[0229] Step 3: Synthesis of A3-7a

[0230] Dissolve A3-6a (244 mg, 0.59 mmol) in anhydrous DCM (7 mL), add dropwise TFA (3 mL), and stir at room temperature for 1 h. After the reaction is completed, concentrate the obtained crude product (114 mg, 0.363 mmol) and directly proceed to the next step. MS m / z = 300 [M+H] + 。

[0231] Step 4: Synthesis of A3-8a

[0232] Dissolve A3-7a (114 mg, 0.363 mmol) in THF (10 mL), add LiAlH4 (16.57 mg, 0.436 mmol) at 0 °C, and stir at this temperature for 1 h. After the reaction is completed, add sodium sulfate decahydrate portionwise under an ice bath until no bubbles are generated in the system, filter, concentrate the filtrate to obtain the crude product, and directly proceed to the next step. MS m / z = 272 [M+H] + 。

[0233] Step 5: Synthesis of A3

[0234] Dissolve A3-8a (100 mg, 0.368 mmol) in a mixed solvent of DCM / DMSO = 6 mL / 2 mL, cool to 0 °C, and successively add dropwise a DMSO (2 mL) solution of DIPEA (190.51 mg, 1.47 mmol) and pyridine sulfur trioxide (234.62 mg, 1.47 mmol). After warming to room temperature, stir for 30 min. After the reaction is completed, transfer to an ice bath, quench with 1N HCl, dilute with water, and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column chromatography to obtain A3 (75 mg, 0.278 mmol, yield 75.54%). MS m / z = 270 [M+H] + 。

[0235] Synthesis of Intermediate A4

[0236]

[0237] Step 1: Synthesis of A4-6a

[0238] Dissolve A3-5a (2.8 g, 8.7 mmol) in THF, cool the temperature to -78 °C, and dropwise add LiHMDS (15.96 ml, 2.4 eq) under nitrogen protection. Stir at this temperature for 1 h. Subsequently, slowly dropwise add a THF solution of methyl iodide (2.93 g, 20.65 mmol). After addition, warm the temperature to room temperature and stir for 2 h. After the reaction is completed, quench with saturated ammonium chloride and extract three times with DCM. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (PE / EA = 5:1, v / v) to obtain A4-6a (2.4 g, 6.85 mmol, yield 78.73%). 1 H NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H), 6.51 (s, 1H), 2.32 - 2.22 (m, 1H), 2.00–1.90 (m, 2H), 1.85 (s, 2H), 1.79–1.66 (m, 2H), 1.63–1.50 (m, 4H), 1.23 (s, 6H). MS m / z=340 [M+H] + 。

[0239] Steps 2 - 4: Synthesis of A4

[0240] Refer to the synthesis method of A3 to obtain the intermediate A4. MS m / z=210 [M+H] + 。

[0241] Synthesis of intermediate A5

[0242]

[0243] Step 1: Synthesis of A5-1a

[0244] Dissolve A1-4a (12.5 g, 55.5 mmol), (Boc)2O (51.6 g, 237 mmol) and DMAP (2.89 g, 23.7 mmol) in acetonitrile (250 mL), and react at 60 °C overnight under nitrogen protection. After the reaction is completed, directly concentrate, and purify the crude product by silica gel column (PE / EA = 5:1 - 3:1, v / v) to obtain A5-1a (17 g, 52 mmol, yield 93.69%). MS m / z=326 [M+H] + 。

[0245] Step 2: Synthesis of A5-2a

[0246] Dissolve A5-1a (500 mg, 1.54 mmol) in THF (15 mL), cool the temperature to -78 °C, and dropwise add LiHMDS (3 ml, 3.84 mmol) under nitrogen protection. Stir for 1 h at this temperature. Subsequently, slowly dropwise add a solution of 2-iodoethyl ether (751 mg, 2.3 mmol) in THF (15 mL). After addition, warm the temperature to room temperature and stir for 2 h. After the reaction is completed, quench with saturated ammonium chloride and extract three times with DCM. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by MPLC to obtain A5-2a (62 mg, 0.156 mmol, yield 10.12%). MS m / z = 396 [M+H] + 。

[0247] Steps 3 to 5: Synthesis of A5

[0248] Refer to the synthesis method of A3, and obtain the intermediate A5 (45 mg, 0.179 mmol) through the same experimental operations. MS m / z = 252 [M+H] + 。

[0249] Synthesis of intermediates A6-a1 and A6-a2

[0250]

[0251] Step 1: Synthesis of A6-1a

[0252] Dissolve A3-4a (34.28 g, 110.09 mmol) in THF, cool the temperature to -78 °C, and dropwise add LiHMDS (93 ml, 1.1 eq) under nitrogen protection. Stir for 1 h at this temperature. Subsequently, slowly dropwise add a solution of MOMBr (17.89 g, 143.12 mmol) in THF. After addition, warm the temperature to room temperature and stir for 2 h. After the reaction is completed, quench with saturated ammonium chloride and extract three times with DCM. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by MPLC to obtain A6-1a (25.6 g, 72.03 mmol, yield 65.43%). MS m / z = 356 [M+H] + 。

[0253] Step 2: Synthesis of A6-2a

[0254] Dissolve A6-1a (25.6 g, 72.03 mmol) in anhydrous DCM (250 mL), add TFA (40 mL) dropwise, and stir at room temperature for 1 h. After the reaction is completed, directly subject the concentrated crude product to the next reaction. MS m / z = 256 [M+H] + 。

[0255] Step 3: Synthesis of A6-3a

[0256] Dissolve A6-2a (18.34 g, 71.83 mmol) in THF (400 mL), add LiAlH4 (3.27 g, 86.20 mmol) at 0 °C, and stir the mixture at this temperature for 1 h. After the reaction is completed, add sodium sulfate decahydrate portionwise under an ice bath until no bubbles are generated in the system. Filter the mixture, concentrate the filtrate to obtain the crude product, and directly proceed to the next reaction. MS m / z = 228 [M+H] + 。

[0257] Step 4: Synthesis of A6-4a

[0258] Dissolve A6-3a (16.16 g, 71.10 mmol) in anhydrous DMF (160 mL), add imidazole (7.26 g, 106.64 mmol) and TBDPS-Cl (29.31 g, 106.64 mmol), and stir the mixture at room temperature for 1 h. After the reaction is completed, dilute the mixture with water and extract it three times with EA. Combine the organic phases, wash them with saturated brine, dry them over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (PE / EA = 1:1, v / v) to obtain A6-4a (33 g, 70.86 mmol, yield 99.7%). MS m / z = 466 [M+H] + 。Step 5: Synthesis of A6-4a1 and A6-4a2

[0259] A6-4a is resolved by SFC to obtain isomers A6-4a1 (SFC peak retention time: 2.986 min) and A6-4a2 (SFC peak retention time: 4.269 min).

[0260] (SFC method for intermediates A6-4a1 and A6-4a2: Chiral column model: CHIRALPAK AS; Specification: 3 um, 150 mm * 3 mm; Mobile phase: A - CO2, Mobile phase B - ethanol, A / B = 70 / 30; Flow rate: 1 mL / min; Column temperature: 40 °C). Step 6: Synthesis of A6-5a1 and A6-5a2

[0261] Dissolve A6-4a1 (654 mg, 1.40 mmol) in THF (10 mL), add TBAF (1.47 g, 5.62 mmol), and stir the mixture at room temperature overnight. After the reaction is completed, dilute the mixture with water and extract it three times with EA. Combine the organic phases, wash them with saturated brine, dry them over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (PE / EA = 1:1, v / v) to obtain A6-5a1 (300 mg, 1.32 mmol, yield 94.28%). MS m / z = 228 [M+H] + 。(The synthesis method of A6-5a2 is the same as above)

[0262] Step 7: Synthesis of A6-a1 and A6-a2

[0263] Dissolve A6-5a1 (300 mg, 1.32 mmol) in a mixed solvent of DCM / DMSO = 24 mL / 4 mL, cool down to 0 °C, and sequentially add dropwise a DMSO (2 mL) solution of DIPEA (682.31 mg, 5.28 mmol) and pyridine sulfur trioxide (840.27 mg, 5.28 mmol). After warming to room temperature, stir for 30 min. After the reaction is completed, transfer it to an ice bath, quench with 1N HCl, dilute with water, and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column to obtain a single configuration of A6-a1 (130 mg, 1.02 mmol, yield 77.27%). 1 HNMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H), 7.01 (s, 1H), 3.59 (d, J = 5.0 Hz, 2H), 3.36 (s, 3H), 2.76 (tt, J = 9.5, 4.9 Hz, 1H), 2.33–2.21 (m, 1H), 2.16 (dd, J = 13.0, 9.5 Hz, 1H), 2.00–1.90 (m, 2H), 1.85–1.69 (m, 3H), 1.67–1.48 (m, 4H). MS m / z = 226 [M+H] + . (The synthesis method of another single configuration A6-a2 is the same as above)

[0264] Synthesis of intermediates A7-a1 and A7-a2

[0265]

[0266] Referring to the synthesis methods of A6-a1 and A6-a2, using methyl iodide instead of MOMBr, single configuration intermediates A7-a1 (MS m / z = 196 [M+H] + ) and A7-a2 (MS m / z = 196 [M+H] + ) can be obtained respectively.

[0267] (SFC methods for intermediates A7-4a1 and A7-4a2: Chiral column model: CHIRAL ART Cellulose-SC; Specification: 3um, 150mm * 3mm; Mobile phase: A - CO2, Mobile phase B - isopropanol, A / B = 70 / 30: Flow rate: 1 mL / min; Column temperature: 40 °C; SFC elution times of A7-4a1 and A7-4a2 are: 3.809 min and 4.479 min respectively).

[0268] Synthesis of intermediates A8-a and A8-b

[0269]

[0270] Step 1: Synthesis of A8-1a and A8-1b

[0271] Dissolve A3-2 (1.53 g, 8.20 mmol) in acetonitrile (7.37 mL). At 0 °C, successively add TEA (912.74 mg, 9.02 mmol) and aqueous formaldehyde solution (492.43 mg, 16.2 mmol). After the reaction solution is warmed to room temperature, stir overnight. After completion of the reaction, directly concentrate. The obtained crude product is purified by silica gel column (PE / EA = 4:1, v / v) to obtain stereoisomer A8-1a (617 mg, 3.3 mmol, obtained with PE / EA = 4 / 1, MS m / z = 232 [M+H] + ) and another stereoisomer A8-1b (879 mg, 4.7 mmol, yield 57.3%, obtained with PE / EA = 2 / 1, MS m / z = 232 [M+H] + ). TLC eluent PE / EA = 1 / 1: A8-1a, R f = 0.3; A8-1b, R f = 0.2.

[0272] Step 2: Synthesis of A8-2a

[0273] Dissolve A8-1a (720 mg, 3.85 mmol), (Boc)2O (1.01 g, 4.61 mmol) and TEA (778 mg, 7.67 mmol) in acetonitrile (20 mL). React at 60 °C overnight under nitrogen protection. After completion of the reaction, directly concentrate. The crude product is purified by silica gel column (PE / EA = 5:1 - 3:1, v / v) to obtain A8-2a (650 mg, 2.26 mmol, yield 58.7%). MS m / z = 288 [M+H] + .

[0274] Step 3: Synthesis of A8-3a

[0275] Dissolve A8-2a (650 mg, 2.26 mmol) in DCM (15 mL). Cool to 0 °C. Under nitrogen protection, add Dess-Martin oxidant (1.92 g, 4.52 mmol) in batches. After warming to room temperature, stir for 2 h. After completion of the reaction, add water to quench. After filtration, extract the filtrate with DCM three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate. The concentrated crude product is purified by silica gel column (PE / EA = 10:1 - 8:1, v / v) to obtain A8-3a (537 mg, 1.88 mmol, yield 83.18%). MS m / z = 286 [M+H] + .

[0276] Step 4: Synthesis of A8-4a

[0277] Dissolve A8-3a (537 mg, 1.88 mmol) and methylamine hydrochloride (190.60 mg, 2.82 mmol) in anhydrous methanol (10 mL). Subsequently, adjust the pH to about 8 with TEA, and stir the reaction at room temperature for 0.5 h. Then, adjust the pH = 5 with acetic acid and add sodium cyanoborohydride (237.13 mg, 3.76 mmol), and stir at room temperature for 1.5 h. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract three times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (DCM / MeOH = 50:1, v / v) to obtain A8-4a (397 mg, 1.32 mmol, yield 70.21%). MS m / z = 301 [M+H] + 。

[0278] Step 5: Synthesis of A8-5a

[0279] Dissolve A8-4a (397 mg, 1.32 mmol) in DCM (4 mL) at 0 °C, slowly add TFA (2 mL), then raise the temperature to room temperature and stir for 0.5 h. After the reaction is completed, concentrate, and use the obtained crude product directly for the next reaction without further purification. MS m / z = 201 [M+H] + 。

[0280] Step 6: Synthesis of A8-6a

[0281] Dissolve the crude product obtained in the previous step in THF (10 mL), cool to 0 °C, add CDI (285.37 mg, 1.98 mmol) under nitrogen protection, then raise the temperature to room temperature and stir for 1 h. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract three times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (DCM / MeOH = 60:1, v / v) to obtain A8-6a (190 mg, 0.84 mmol, yield 63.6%). MS m / z = 227 [M+H] + 。

[0282] Step 7: Synthesis of A8-7a

[0283] Dissolve A8-6a (190 mg, 0.84 mmol) in THF (5 mL). Add LiAlH4 (41.43 mg, 1.09 mmol) at 0 °C and stir at this temperature for 1 h. After the reaction is completed, add sodium sulfate decahydrate portionwise under an ice bath until no bubbles are generated in the system. Filter and concentrate the filtrate to obtain the crude product (120 mg, 0.6 mmol), which is directly used for the next reaction. MS m / z = 199 [M+H] + 。

[0284] Step 8: Synthesis of A8-a

[0285] Dissolve A8-7a (120 mg, 0.6 mmol) in a mixed solvent of DCM / DMSO = 4 mL / 0.5 mL. Cool the temperature to 0 °C and sequentially add dropwise the DMSO (0.5 mL) solutions of DIPEA (312.9 mg, 2.24 mmol) and pyridine sulfur trioxide (385.43 mg, 2.42 mmol). After warming to room temperature, stir for 30 min. After the reaction is completed, transfer to an ice bath, quench with 1N HCl, dilute with water, and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column chromatography to obtain one of the single isomers A8-a (35 mg, 0.178 mmol, yield 29.7%). MS m / z = 197 [M+H] + 。

[0286] Similarly, referring to the synthesis method of A8-a, another single-configuration intermediate A8-b can be obtained through the same experimental operations. MS m / z = 197 [M+H] + 。

[0287] Synthesis of intermediates A9-a and A9-b

[0288]

[0289] Referring to the method of A8-4a, using ammonium chloride instead of methylamine hydrochloride, intermediate A9-4a is obtained under the same reductive amination conditions, and then intermediate A9-a is synthesized through the same route as the synthesis of A8-a. Similarly, intermediate A9-b is synthesized.

[0290] Synthesis of intermediate A10

[0291]

[0292] Step 1: Synthesis of A10-1

[0293] Dissolve A1-2 (100 mg, 0.496 mmol) in acetonitrile. Add DBU (150 mg, 0.596 mmol) and methyl 2-(bromomethyl)acrylate (106 mg, 0.596 mmol) at 0 °C. After addition, warm to room temperature and stir for 2 h. After completion of the reaction, dilute with water and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the crude product. Purify by silica gel column (PE / EA = 5:1, v / v) to obtain A10-1 (52 mg, 0.173 mmol, yield 34.8%, containing two isomers). MS m / z = 300 [M+H] + 。

[0294] Step 2: Synthesis of A10-2

[0295] Dissolve trimethylsulfoxonium iodide (19.12 g, 86.86 mmol) in DMSO. Add NaH (2.08 g, 86.86 mmol) at 0 °C and slowly warm to room temperature, then stir for 1 h. Add A10-1 (20 g, 66.82 mmol) and react at room temperature for 17 h. After completion of the reaction, quench with saturated ammonium chloride and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the crude product. Purify by silica gel column (PE / EA = 4:1, v / v) to obtain A10-2 (8.5 g, 27.13 mmol, yield 40.6%, containing two isomers). MS m / z = 314 [M+H] + 。

[0296] Steps 3 - 5: Synthesis of A10

[0297] Refer to the synthesis method of A1a to obtain intermediate A10 (containing two isomers). MS m / z = 208 [M+H] + 。

[0298] Synthesis of intermediate A11

[0299]

[0300] Step 1: Synthesis of A11-1

[0301] Dissolve A1-5a (1.83 g, 10 mmol), (Boc)2O (8.72 g, 40 mmol) and DMAP (0.48 mg, 4 mmol) in acetonitrile (20 mL). React under nitrogen protection at 60 °C overnight. After completion of the reaction, concentrate directly. Purify the crude product by silica gel column (PE / EA = 5:1 - 3:1, v / v) to obtain A11-1 (2.9 g, 9.3 mmol, yield 93%). MS m / z = 284 [M+H] + 。

[0302] Step 2: Synthesis of A11-2

[0303] Dissolve A11-1 (2.9 g, 9.3 mmol) in anhydrous DMF (10 mL), add imidazole (0.95 g, 13.88 mmol) and TBDPS-Cl (3.81 g, 13.88 mmol), and stir the mixture at room temperature for 1 h. After the reaction is completed, dilute with water and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (PE / EA = 1:1, v / v) to obtain A11-2 (4.83 g, 9.26 mmol, yield 99.57%). MS m / z = 522 [M+H] + 。

[0304] Step 3: Synthesis of A11-3

[0305] Dissolve A11-2 (916 mg, 1.76 mmol) in anhydrous THF (10 mL), slowly add LiHMDS (1.93 mmol, 1.1 eq) dropwise at -70 °C, and stir the mixture at this temperature for 1 h. Subsequently, add acetone (112.16 mg, 1.93 mmol) and boron trifluoride diethyl etherate (274.22 mg, 1.93 mmol) dropwise at -70 °C, and stir at room temperature for 2.5 h. After the reaction is completed, quench with saturated ammonium chloride and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by MPLC to obtain A11-3 (883 mg, 1.52 mmol, yield 86.36%). MS m / z = 580 [M+H] + 。Steps 4 - 5: Synthesis of A11

[0306] Dissolve A11-3 (883 mg, 1.52 mmol) in THF (10 mL), add TBAF (1.59 g, 6.08 mmol), and stir at room temperature overnight. After the reaction is completed, dilute with water and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify the concentrated crude product by silica gel column (PE / EA = 1:1, v / v) to obtain A11-4 (488 mg, 1.43 mmol, yield 94.08%). MS m / z = 342 [M+H] + 。

[0307] Step 4: Synthesis of A11-5

[0308] Dissolve A11-4 (488 mg, 1.43 mmol) in a mixed solvent of DCM / DMSO = 24 mL / 4 mL. Cool the solution to 0 °C, and successively add dropwise a DMSO (2 mL) solution of DIPEA (784.65 mg, 6.07 mmol) and pyridine sulfur trioxide complex (966.31 mg, 6.07 mmol). After warming to room temperature, stir for 30 min. After completion of the reaction, transfer the reaction mixture to an ice bath, quench with 1 N HCl, dilute with water, and extract three times with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the crude product. The crude product is purified by silica gel column chromatography to obtain A11-5 (397.88 mg, 1.17 mmol, yield 81.8%, containing 2 isomers, directly used for the next step without separation). MS m / z = 340 [M+H] + 。

[0309] Dissolve A11-5 (397.88 mg, 1.17 mmol) in EA (2 mL), and slowly add dropwise a hydrochloric acid ethyl acetate solution (5 mL, 1 M in EA). Stir at room temperature overnight. After completion of the reaction, adjust the pH to alkaline with saturated sodium bicarbonate solution, and then extract three times with EA. Combine and concentrate the organic phases. The crude A11 obtained can be directly used for the next reaction.

[0310] Synthesis of Intermediate C1

[0311]

[0312] Disperse 4,4,4-trifluorobutyraldehyde (2.52 g, 19.98 mmol), cyanoacetamide (1.68 g, 19.98 mmol), TEA (2.43 g, 23.98 mmol, 3.34 mL), and sulfur powder (639.42 mg, 19.98 mmol) in DMF (20 mL). Stir the reaction suspension at room temperature for 23 h. After completion of the reaction, remove the solvent by rotary evaporation to obtain the crude product C1-1 (4.47 g, 19.94 mmol, yield 99.78%), which is directly used for the next reaction without further purification. MS m / z = 225.0 [M+1] + 。

[0313] Add triethyl orthoformate (5.3 mL) to a solution of C1-1 (3.5 g, 15.61 mmol) in AcOH (4 mL). Heat the reaction mixture to 120 °C and stir for 4 h. After completion of the reaction, remove the solvent by rotary evaporation. Pulp the crude product with PE / EA (1 / 1, v / v), and filter to obtain Intermediate C1-2 (1.1 g, 4.70 mmol, yield 30.09%), a brown solid. MS m / z = 235 [M+1] + 。

[0314] DMF (0.02 mL) was added to a solution of C1-2 (1 g, 4.27 mmol) in POCl3 (2.5 mL). The mixture was heated to 100 °C and stirred for 5 h. After completion of the reaction, the mixture was poured into ice water, and the pH was adjusted to 7 with ammonia water. The mixture was extracted with DCM (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain C1 (1 g, 3.96 mmol, 92.70% yield), a yellow oil. MS m / z = 253.0 [M+1] + 。

[0315] Preparation of Intermediate C2

[0316]

[0317] Triphosgene (5.92 g, 19.94 mmol) was added to a solution of C1-1 (4.47 g, 19.94 mmol) in dioxane (20 mL). The reaction mixture was heated to 100 °C and stirred for 4 h. The reaction solution was concentrated to obtain the crude product of C2-1 (4.99 g, 19.94 mmol, 100.00% yield), which was directly used in the next step without further purification. MS m / z = 251.0 [M+1] + 。

[0318] PCl5 (16.65 g, 79.94 mmol) was added to a solution of C2-1 (10 g, 39.97 mmol) in POCl3 (150 mL). The mixture was heated to 100 °C and stirred for 4 h. After completion of the reaction, the reaction solution was slowly poured into ice water, and the pH was adjusted to 7.0 with ammonia water. The reaction mixture was extracted with EA (80 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (EA / PE = 0 - 6%, v / v) to obtain C2 (5.3 g, 18.46 mmol, 46.19% yield), a yellow solid. MS m / z = 287.0 [M+1] + 。

[0319] Preparation of Example 1

[0320]

[0321] Step 1

[0322] To a solution of C1 (590 mg, 2.34 mmol) in isopropanol (20 mL), 4-tert-butoxycarbonyl-1H-azepine (500.46 mg, 2.34 mmol) and DIPEA (905.44 mg, 7.01 mmol, 1.22 mL) were added. The mixture was heated to 50 °C and stirred at this temperature for 4 h. After the reaction was completed, water was added for dilution, and extraction was carried out with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and then separated and purified by silica gel column chromatography (EA / PE = 0 - 50%, v / v) to obtain intermediate 1-1 (880 mg, 2.04 mmol, 87.53% yield) as a yellow solid. MS m / z = 431.0 [M+1] + .

[0323] Step 2

[0324] To a solution of 1-1 (100 mg, 232.30 μmol) in DCM (5 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the crude product of intermediate 1-2 (75 mg, 227.02 μmol, 97.73% yield) as a yellow oil. MS m / z = 331.0 [M+1] + .

[0325] Step 3

[0326] To a solution of intermediate 1-2 (75 mg, 227.02 μmol) in methanol (10 mL), intermediate A1a (41.14 mg, 227.02 μmol) was added. TEA was added to adjust the pH to 9. The mixture was stirred at room temperature for 1 h, then NaCNBH3 (21.40 mg, 340.53 μmol) was added, and then acetic acid was added to adjust the pH to 4 - 5. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the crude product obtained by concentrating the reaction solution was separated and purified by Pre-HPLC to obtain the compound of Example 1 (42.34 mg, 85.43 μmol, 37.63% yield) as a white solid. MS m / z = 496.1 [M+1] + . 1H NMR data 11H NMR (600 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.54 (s, 1H), 4.15 (ddd, J = 14.6, 6.1, 4.0 Hz, 1H), 4.06–3.98 (m, 1H), 3.94–3.84 (m, 3H), 3.80 (ddt, J = 14.1, 9.2, 4.2 Hz, 1H), 2.69 (t, J = 10.0 Hz, 1H), 2.49 (dd, J = 25.8, 6.7 Hz, 2H), 2.35 (t, J = 8.1 Hz, 2H), 2.22 (s, 1H), 2.13–2.05 (m, 1H), 1.94 (t, J = 8.1 Hz, 2H), 1.91–1.86 (m, 1H), 1.76–1.66 (m, 5H), 1.51 (ddt, J = 24.9, 10.7, 2.8 Hz, 3H), 1.39 (ddq, J = 10.4, 6.9, 3.7 Hz, 1H), 1.24–1.16 (m, 1H), 1.09 (dd, J = 13.5, 7.0 Hz, 2H).

[0327] Referring to the synthesis method of Example 1, in Step 1, tert-butyl N-{2-azaspiro[3.4]octan-6-yl}carbamate (i.e., ) was used to replace 4-tert-butoxycarbonyl-1H-azepine; at the same time, in Step 3, the A structure (aldehyde) in the table was used to replace A1a.

[0328] The remaining reagents and operations remained unchanged (for those with SFC resolution, see the notes for details), and the corresponding structure examples in the table could be obtained.

[0329]

[0330]

[0331]

[0332] Referring to the synthesis method of Example 1, in Step 1, was used to replace 4-tert-butoxycarbonyl-1H-azepine; at the same time, in Step 3, the A structure (aldehyde) in the table was used to replace A1a. The remaining reagents and operations remained unchanged (for those with SFC resolution, see the notes for details), and the corresponding structure examples in the table could be obtained.

[0333]

[0334]

[0335]

[0336] Referring to the synthesis method of Example 1, in Step 1, (Refer to Patent US20210269454A1) Replace 4-tert-butoxycarbonyl-1H-azepine; simultaneously replace A1a with structure A (aldehyde) in Table in Step 3. Keep the rest of the reagents and operations unchanged, and the corresponding structure examples in the table can be obtained.

[0337]

[0338]

[0339]

[0340] Preparation of Example 36

[0341]

[0342] Step 1

[0343] Add DIPEA (517.26 mg, 4.00 mmol, 697.12 μL) to a solution of C2 (383 mg, 1.33 mmol) and 2-BOC-2,7-diazaspiro[4.4]nonane (332.11 mg, 1.47 mmol) in THF (5 mL). Heat the reaction mixture to 50 °C and stir for 17 h. After completion of the reaction, dilute with water and extract with EA. The combined organic phases are washed with water, saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained is separated and purified by silica gel column (PE:EA = 4:1, v / v) to obtain intermediate 7-1 (513 mg, 1.08 mmol, 80.62% yield), MS m / z = 477 [M+1] + .

[0344] Step 2

[0345] Add DIPEA (417.04 mg, 3.23 mmol, 562.05 μL) and methylamine (30% methanol solution, 112 mg, 1.08 mmol) to a solution of 7-1 (513 mg, 1.08 mmol) in isopropanol (5 mL). Heat the reaction mixture to 100 °C and stir for 4 h. After completion of the reaction, dilute with water and extract with EA. The combined organic phases are successively washed with water, saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained after concentration is separated and purified by silica gel column (PE:EA = 4:1, v / v) to obtain intermediate 7-2 (373 mg, 791.03 μmol, 73.54% yield), MS m / z = 472 [M+1] + .

[0346] Step 3

[0347] At 0 °C, intermediate 7-2 (100 mg, 212.07 μmol) was dissolved in a mixed solution of TFA / DCM (1 mL / 2 mL), slowly warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction solution was concentrated to obtain crude intermediate 7-3 (70 mg, 188.46 μmol, 88.87% yield), which was directly used in the next step without further purification. MS m / z = 372 [M+1] + 。

[0348] Step 4

[0349] At room temperature, TEA was added dropwise to a solution of intermediate 7-3 (52.06 mg, 287.27 μmol) in MeOH (3 mL) to adjust the pH to 8 - 9, then intermediate A1a (97 mg, 261.16 μmol) was added. The mixture was stirred at room temperature for 30 min, the pH was adjusted to 5 - 6 with acetic acid, then NaCNBH3 (24.62 mg, 391.74 μmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated, the obtained crude product was diluted with water and extracted with DCM / MeOH = 10 / 1. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated. The obtained crude product was separated and purified by Pre-HPLC to obtain Example 36 (70 mg, 0.124 μmol, 47.45% yield), MS m / z = 537 [M+1] + 。Nuclear magnetic resonance hydrogen spectrum data: 1 H NMR (400 MHz, Chloroform-d) δ 7.14 (s, 1H), 5.39 (s, 1H), 4.74 (s, 1H), 3.90–3.70 (m, 3H), 3.63 (d, J = 10.5 Hz, 1H), 3.51 (q, J = 10.2 Hz, 2H), 2.99 (d, J = 5.0 Hz, 3H), 2.70 (s, 1H), 2.57 (s, 2H), 2.47–2.23 (m, 5H), 2.05–1.72 (m, 10H), 1.44 (td, J = 13.0, 4.0 Hz, 3H), 1.07 (q, J = 12.6 Hz, 2H).

[0350] Referring to the synthesis method of Example 36, in Step 1, the B structure (amine) shown in the following table was used to replace 2-BOC-2,7-diazaspiro[4.4]nonane, and in Step 4, the A structure shown in the following table was used to replace intermediate A1a, and the other reagents and operations remained unchanged, and the corresponding structure examples in the table could be obtained.

[0351]

[0352]

[0353]

[0354] Referring to the synthesis method of Example 36, in Step 1, is used to replace 4-tert-butoxycarbonyl-1H-azepine; meanwhile, in Step 3, the A structure (aldehyde) in the table is used to replace A1a. The remaining reagents and operations remain unchanged (for those with SFC resolution, see the notes for details), and the corresponding structure examples in the table can be obtained.

[0355]

[0356]

[0357]

[0358]

[0359] Referring to the synthesis method of Example 36, in Step 1, (refer to Patent US20210269454A1) is used to replace 4-tert-butoxycarbonyl-1H-azepine; meanwhile, in Step 3, the A structure (aldehyde) in the table is used to replace A1a. The remaining reagents and operations remain unchanged, and the corresponding structure examples in the table can be obtained.

[0360]

[0361]

[0362]

[0363] To illustrate the absolute configuration of the compounds of the present invention, single crystals were cultured and X-ray single crystal diffraction patterns of intermediates A1a ( Figure 1 ), A1b ( Figure 2 ), A6-5a1 ( Figure 3 ), and A6-5a2 ( Figure 4 ) were obtained. The instrument parameters are as follows: Detection instrument: Bruker D8 Venture; Instrument model: D8 Venture; Light source: Gallium target; X-ray:

[0364] The effects of the compounds of the present invention are illustrated by the following test examples:

[0365] Test Example 1, Test for Menin-MLL Interaction Inhibitory Activity

[0366] The experiment quantitatively detected the inhibition of the interaction between Menin / MLL-4-43peptide by small molecule inhibitors through a fluorescence polarization competition experiment. The experiment was carried out in a 384-well plate (Corning, Cat#3575), and the reaction buffer used had the following composition: 50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT. The 40 μL reaction system included 10 μL of 8 nM Menin recombinant protein and 10 μL of test compounds at different concentrations. The compounds were pre-incubated with Menin protein for 15 min, and then 20 μL of 10 nM FITC-MLL4-43-peptide was added. After incubation on a shaker at 25 °C for 60 minutes, the fluorescence polarization signal (FP 485 520 520) was detected and read using a BMGPHERAStar. The experimental data was analyzed and processed by GraphPad Prism 6 software to obtain the IC 50 value.

[0367] “+” indicates that the measured IC 50 value is less than or equal to 1 μM and greater than 200 nM;

[0368] “++” indicates that the measured IC50 value is less than or equal to 200 nM.

[0369] Table 1. Inhibition activity test of Menin-MLL interaction

[0370]

[0371]

[0372] The results showed that the compounds of the present invention had good inhibitory activity against the interaction between Menin-MLL proteins.

[0373] Test Example 2. Test for the inhibitory ability of Menin-MLL interaction inhibitors on cell proliferation

[0374] Use the cell viability analysis method to evaluate the inhibitory ability of the inventive compound on the proliferation of tumor cell lines (such as the cell line MV4; 11, MOLM-13, THP-1, NOMO-1 containing the MLL fusion protein, the control cell lines HL-60, K562, MOLM-16 without the MLL fusion protein, and the cell line OCI-AML3 containing the NPM1 mutation). Seed the cells in a 96-well plate at a certain concentration (for example, 5000 - 20000 cells / well), then add an equal volume of medium containing the test compound at twice the final concentration (the final concentration range is 1 nM to 10 μM), place it in an incubator, and continue to culture at 37 °C and 5% CO2 for 72 - 168 h. Before detection, add an equal volume of CellTiter- Luminescent reagent, incubate at room temperature for 10 minutes, and then use a microplate reader (BMGLABTECH) for detection. Analyze the data using GraphPad Prism software and obtain the IC 50 value and the compound fitting curve.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof: Wherein, U is selected from N; W is selected from hydrogen, -C 0～4 alkylene-NR C1 R C2 ; R C1 、R C2 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl; Ring A is selected from 5-membered heterocycles; Among them, the heterocycle can be further substituted by one, two, three or four independent Rs A1 substituted; R A1 selected from hydrogen, =O, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl, -C 0～4 alkylene-OR a1 ; wherein the alkyl and alkylene may further be optionally substituted by one, two, three or four independent R a3 substituents; Or two Rs attached to the same atom A1 together with the atom to which they are attached form a 3-membered carbon ring or a 6-membered heterocyclic ring; wherein the carbon ring and the heterocyclic ring may further optionally be substituted by one, two, three or four independent Rs a3 substituted; R a1 selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl; R a3 selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl; L is selected from -NR B1 -(5-membered carbocyclic ring)-NR B2 -,-(7-membered heterocyclic ring)-NR B2 -,-(8-membered spiroheterocyclic ring)-NR B2 -,-(9-membered spiroheterocyclic ring)-; wherein, the carbocyclic ring, heterocyclic ring, and spiroheterocyclic ring may further be optionally substituted by one, two, three, or four independent R b1 substituents; R B1 、R B2 are each independently selected from hydrogen, -C 1-6 alkyl; R b1 selected from hydrogen, halogen, -C 0～4 alkylene-OR b3 ; R b3 selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl; R 1 、R 2 、R 3 、R 4 、R 5 、R 1 ’、R 2 ’、R 3 ’、R 4 ’ are each independently selected from hydrogen; or R 1 、R 2 、R 3 、R 4 、R 5 Two of them and the ring where the connecting atom is located together form Among them, R 1 ’, R 2 ’, R 3 ’, R 4 ’ are each independently selected from hydrogen.

2. The compound according to claim 1, characterized in that: L is selected from 3. The compound according to claim 1, wherein: W is selected from hydrogen, -NHCH3.

4. The compound according to claim 1, characterized in that: Ring A is selected from wherein the ring from which Ring A is selected may be further substituted by one, two, three or four independent R A1 substituents.

5. The compound according to claim 1, wherein: The structure of the compound is as shown in formula IIa: Wherein, X is selected from CR E1 R E2 or NR E1 ; m is selected from 1; R E1 and R E2 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl, -C 0～2 alkylene-OR e1 ; wherein the alkyl and alkylene may further optionally be substituted by one, two, three or four independent R e3 substituents; Alternatively, R E1 , R E2 together with the atoms to which it is attached form a cyclopropane, 6-membered heterocycle; wherein the cyclopropane, heterocycle may further optionally be substituted by one, two, three or four independent R e3 substituents; R e1 selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl; R e3 selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1～6 alkyl.

6. The compound according to claim 5, characterized in that: X is selected from NR E1 ; R E1 selected from hydrogen, 7. The compound according to claim 5, characterized in that: X is selected from CR E1 R E2 ; R E2 、R E2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, Alternatively, R E1 , R E2 and the atom(s) to which it is attached together form cyclopropane, 8. The specific compound is:

9. Use of the compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating diseases related to abnormal Menin activity.

10. Use of the compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer.

11. A pharmaceutical composition comprising a preparation prepared from the compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, which further comprises a pharmaceutically acceptable carrier, excipient, vehicle.

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