Derivatives comprising an azabicyclic ring moiety

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry, and provides a pharmaceutically acceptable derivative containing an azapine ring moiety or a pharmaceutical composition thereof, and particularly relates to a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and the use thereof in treating diseases.

Description

Technical Field

[0001] This disclosure pertains to the field of pharmaceutical technology and relates to pharmaceutically acceptable derivatives comprising a nitrogen-bridged ring structure moiety, or pharmaceutically acceptable salts thereof, methods of their preparation, pharmaceutical compositions containing the compound, and their use in the treatment of diseases. Background Technology

[0002] Menin protein is derived from the multiple endocrine neoplasia type 1 gene. MEN1 Menin is a widely expressed nuclear protein that primarily regulates tissue-specific gene expression. Menin interacts with DNA through its C-terminal nuclear localization sequence (NLS), including binding to promoters, transcription factors, or enhancers, thereby regulating gene expression and cellular signaling.

[0003] In different tissues, Menin protein can bind to various proteins (such as MLL1 (mixed lineage leukemia protein 1), MYC, and JunD), influencing different downstream functions. For example, the direct interaction between Menin protein and the N-terminal sequence of MLL protein is essential for MLL fusion (MLLr) protein-mediated leukemia. Menin protein binds to the first 10 amino acids of MLL protein, and its binding site is conserved in all MLL fusion proteins. It is a cofactor for MLL protein binding to the HOX gene promoter region and an important oncogenic cofactor for MLLr protein-driven tumorigenesis and development.

[0004] Currently, there are no drugs on the market that target the Menin-MLL protein interaction. The field still needs to develop new compounds with selective inhibitory activity, or better pharmacodynamics, or better pharmacokinetic properties. Summary of the Invention

[0005] This disclosure relates to compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0006] , in, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C1-6 Alkylene-C 6-10 Aryl, -C 1-6 alkylene-5-10 heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 -N(R) c1 )S(O) R d1 -S(O)2R b1 -S(O)2NR c1 R d1 - N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 、or -C(O)NR c1 R d1 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 The alkylene-5-10 heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; R c2 and R d2 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; R 8 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more groups selected from halogen, -CN, -OH or -NH2; Y is selected from O, S, CR x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or C. 1-6 alkyl; W, W 1 W 2 W 3 W 4 and W 5 Each is independently selected from N, C, or CH; Ring A is selected from one or more Rs arbitrarily. a1 The following groups are substituted: C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 heteroarylene; H is selected from bonds, NR z C 3-8 Cycloalkyl or 3-8 heterocycloalkyl, wherein R z Selected from hydrogen or C1-6 alkyl; R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl; R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ -OC(O)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ - S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -CN, -OH or -NH2; R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -OH, -CN or -NH2; R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl substituted; R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -CN, -OH or -NH2; M is selected from -C(O)- or -(CR)- u R v ) q -;R u and R v Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 1, 2, 3, or 4; m and p are each independently selected from 0, 1, 2 or 3; q is selected from 1, 2, or 3; The condition is that when for At that time, R 5 Not for .

[0007] On the other hand, this disclosure relates to compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0008] in, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 alkylene-5-10 heteroaryl, -OR b1 -SR b1 -NR c1 R d1-C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 -N(R) c1 )S(O) R d1 -S(O)2R b1 -S(O)2NR c1 R d1 - N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 、or -C(O)NR c1 R d1 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 The alkylene-5-10 heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; R c2 and R d2 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Y is selected from O, S, CR x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or C. 1-6 alkyl; W, W 1 W 2 W 3 W 4 and W 5 Each is independently selected from N, C, or CH; Ring A is selected from one or more Rs arbitrarily. a1 Replace the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 heteroarylene; R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl; R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’-OC(O)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ - S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; R b’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -CN, -OH or -NH2; R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -OH, -CN or -NH2; R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl substituted; R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -OC 1-6 Alkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -OC 1-6 The alkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; M is selected from -C(O)- or -(CR)- u R v ) q -;R u and R v Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 1, 2, 3, or 4; m and p are each independently selected from 0, 1, 2 or 3; q is selected from 1, 2, or 3; The condition is R 5 Not selected .

[0009] On the other hand, this disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0010] in, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 alkylene-5-10 heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 -N(R) c1 )S(O) R d1 -S(O)2R b1 -S(O)2NR c1 R d1 - N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 、or -C(O)NR c1 R d1 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 The alkylene-5-10 heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; R c2 and R d2 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Y is selected from O, S, CR x R y or NR z , where R x R y Or R zEach is independently selected from hydrogen or C. 1-6 alkyl; W, W 1 W 2 W 3 W 4 and W 5 Each is independently selected from N, C, or CH; Ring A is selected from one or more Rs arbitrarily. a1 Replace the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 heteroarylene; R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl; R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ -OC(O)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ -S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or C 3-6Heterocyclic alkyl groups; R b’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -CN, -OH or -NH2; R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -OH, -CN or -NH2; R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -OC 1-6Alkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -OC 1-6 The alkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; n is selected from 1, 2, 3, or 4; m and p are each independently selected from 0, 1, 2 or 3; The condition is: R 5 Not selected .

[0011] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 alkylene-5-6-membered heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 - N(R) c1 )S(O) R d1 -S(O)2R b1 -S(O)2NR c1 R d1 -N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O) R d1 or -C(O)NR c1 R d1 The C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 The alkylene-5-6-membered heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or -C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; The R b1 R c1 R d1 R c2 and R d2 The definition is as described in this disclosure.

[0012] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 alkylene-5-6-membered heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -S(O)R b1 -S(O)2R b1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 or -C(O)NR c1 R d1 The C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl or -C 1-4 The alkylene-5-6-membered heteroaryl group is optionally surrounded by one or more halogens, OH, -CN, -NH2, C 1-4 Alkyl or -OC 1-4 Alkyl substitution, Or, R 1 and R 2 Combine to form =O or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O or =CR c2 R d2 ; The R b1 R c1 R d1 R c2 and R d2 The definition is as described in this disclosure.

[0013] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 alkylene-5-6-membered heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -OC(O)R b1 -S(O)R b1 -S(O)2R b1 or -OC(O)NR c1 R d1 The C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4alkylene-phenyl or -C 1-4 The alkylene-5-6-membered heteroaryl group is optionally surrounded by one or more halogens, OH, -CN, -NH2, C 1-3 Alkyl or -OC 1-3 Alkyl substitution, Or, R 1 and R 2 Combine to form =O or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O or =CR c2 R d2 ; The R b1 R c1 R d1 R c2 and R d2 The definition is as described in this disclosure.

[0014] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 heterocycloalkyl, -CH2-phenyl, -CH2-5-6 heteroaryl, wherein C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 heterocycloalkyl, -CH2-phenyl, -CH2-5-6 heteroaryl groups are optionally converted by one or more halogens, OH, -CN, -NH2 or C 1-4 Alkyl substitution; Or, R 1 and R 2 Combining to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0015] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, or C. 1-3 alkyl.

[0016] In some implementation schemes, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, or C. 1-3 alkyl; Or, R 1 and R 2 Combining to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0017] In some implementation schemes, R 1 and R 2 Combining to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0018] In some implementation schemes, R 3 and R 4 One of them is hydrogen, and the other is F.

[0019] In some implementation schemes, R 1 and R 2 It is hydrogen; and, R 3 and R 4 One of them is hydrogen, and the other is F, or R. 3 and R 4 The combination forms =O or =CH2. In some implementations, R 1 and R 2 It is hydrogen; and, R 3 and R 4 The combination forms CH2.

[0020] In some implementation schemes, R 3 and R 4 It is hydrogen, and R 1 and R 2 The combination forms =O or =CH2.

[0021] In some implementation schemes, R 1 and R 2 It is hydrogen, and R 3 and R 4 The combination forms =O or =CH2.

[0022] In some specific implementation schemes, R 1 and R 2 It is hydrogen; and R 3 and R 4 One of them is hydrogen, and the other is F.

[0023] In some implementation schemes, R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl groups are optionally bound by one or more halogens, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 Heteroalkyl substitution.

[0024] In some implementation schemes, R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl or C 2-4 alkynyl group, the C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be replaced by one or more halogens, -CN, -OH or -NH2.

[0025] In some implementation schemes, R b1 R c1 and R d1 Each is independently selected from hydrogen or C. 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0026] In some implementation schemes, R b1 R c1 and R d1 Each is independently hydrogen or C 1-3 alkyl.

[0027] In some implementation schemes, R b1 R c1 and R d1 Each is independently a methyl group.

[0028] In some implementation schemes, R c2 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C1-4 Heteroalkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0029] In some implementation schemes, R c2 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl groups.

[0030] In some implementation schemes, R c2 and R d2 Each is independently selected from hydrogen or C. 1-3 alkyl.

[0031] In some implementation schemes, R c2 and R d2 Each is hydrogen independently.

[0032] In some implementation schemes, R 8 Selected from hydrogen or C 1-4 Alkyl group. In some embodiments, R 8 Selected from hydrogen or methyl. In some embodiments, R 8 It is hydrogen.

[0033] In some implementation schemes, Y is selected from O, S, CR x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or C. 1-3 alkyl.

[0034] In some implementation schemes, Y is selected from O, S, CR x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or methyl.

[0035] In some implementations, Y is selected from O, S, CH2, or NH.

[0036] In some implementations, Y is selected from O or S.

[0037] In some implementations, Y is O.

[0038] In some implementations, in structural fragments In the middle, when W, W 1 and / or W 2 With R 7 When connected, then W, W 1 and / or W 2 Let C be the case where W and W' are constants. 1 and / or W 2 Not with R 7 When connected, then W, W 1 and / or W 2 It can be N or CH.

[0039] In some implementations, in structural fragments In the middle, when W 3 W 4 and / or W 5 With R a When connected, then W 3 W 4 and / or W 5 For C, when W 3 W 4 and / or W 5 Not with R a When connected, then W 3 W 4 and / or W 5 It can be N or CH.

[0040] In some implementations, W is selected from N, C, or CH.

[0041] In some implementation schemes, W 1 Selected from N, C, or CH. In some implementations, W 1 Selected from N or CH.

[0042] In some implementation schemes, W 2 Selected from N, C, or CH. In some implementations, W 2 For CH.

[0043] In some implementation schemes, W 3 Selected from N or CH.

[0044] In some implementation schemes, W 4 and W 5 For CH.

[0045] In some implementation schemes, W 3 W 4 and W 5 For CH.

[0046] In some implementation schemes, W1 W 2 W 3 W 4 and W 5 For CH. In some implementations, W is N, and W 1 W 2 W 3 W 4 and W 5 Each is independently selected from C or CH.

[0047] In some implementation schemes, W 1 Let N be a subset of N, and W and W' be subsets of N. 2 W 3 W 4 and W 5 Each is independently selected from C or CH.

[0048] In some implementation schemes, W and W 1 Let N be the number of elements and W be the number of elements. 2 W 3 W 4 and W 5 Each is independently selected from C or CH.

[0049] In some implementation schemes, W and W 3 Each is independently selected from N or CH, and W 1 W 2 W 3 W 4 and W 5 For CH.

[0050] In some implementation schemes, W, W 1 and W 3 Each is independently selected from CH or N, and W 2 W 4 and W 5 For CH.

[0051] In some implementations, W is N, W 1 and W 2 For CH. In some implementations, W and W 1 For N, W 2 For CH or C. In some implementations, W and W 2 For CH, W 1 Let N be the number of elements in the array.

[0052] In some implementations, the W 4 For CH or C, W 3 and W 5 Selected from N, C, or CH.

[0053] In some implementation schemes, when for At that time, R 5 Not for .

[0054] In some implementation schemes, R 5 Not for .

[0055] In some implementation schemes, R a Each is independently selected from halogens, CN, OH, NH2, or C. 1-3 alkyl.

[0056] In some implementation schemes, R a It is fluorine.

[0057] In some implementation schemes, R z It is hydrogen.

[0058] In some implementation schemes, structural units Selected from , or Among them, W and W 1 W 2 R 7 The definitions of p are as described in this disclosure.

[0059] In some implementation schemes, structural units Selected from , or W 3 W 4 W 5 R 5 R 6 R a The definitions of m and m are as described in this disclosure. In some embodiments, structural units... Selected from or W 3 W 4 W 5 R 5 R 6 R a The definitions of m are as described in this disclosure.

[0060] In some implementation schemes, structural units Selected from , , , , or , where R 5 R 6 and Ra The definition is as described in this disclosure.

[0061] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0062] In some implementation schemes, structural units Selected from , , or ,in This indicates that the bond at this position is connected to the H portion or ring A (when H is a bond), and the other side is connected to the Y portion, where R 7 The definition is as described in this disclosure.

[0063] In some implementation schemes, structural units Selected from , , or ,in This indicates that the key at this position is connected to the H part or the ring A (when H is a key), and the other side is connected to the Y part.

[0064] In some implementations, ring A is selected from one or more R... a1 Replace the following groups: C 5-12 Cycloalkylene, 5-12 heterocyclic, C6 arylene or 5-6 heterocyclic.

[0065] In some implementations, ring A is selected from one or more R... a1 Replace the following groups: C 6-10 6-10 membered heterocyclic alkyl groups.

[0066] In some implementations, ring A is selected from one or more R... a1 Replace the following groups: 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic alkyl groups.

[0067] In some implementations, ring A is selected from one or more R... a1 Substituted 7-9 membered heterocyclic alkylene groups, wherein R a1 The definition is as described in this disclosure.

[0068] In some implementations, ring A is selected from one or more R... a1 The substituted 7-9 nucleotide hemispirocycloalkyl group, wherein R a1 The definition is as described in this disclosure. In some embodiments, ring A is selected from rings optionally formed by one or more R... a1 The substituted 9-membered heterospirocycloalkyl group, wherein R a1 The definition is as described in this disclosure. Optionally, ring A contains one, two, or three heteroatoms selected from N, O, or S; or ring A contains two heteroatoms selected from N, O, or S; or ring A contains two N atoms. In some embodiments, ring A is selected from... Where n1, n2, n3, and n4 are each independently selected from 1, 2, or 3, and X is selected from N or CH. In some embodiments, n1, n2, n3, and n4 are each independently selected from 1 or 2.

[0069] In some implementations, ring A is selected from... Where n1, n2, n3, and n4 are independently selected from 1, 2, or 3, and X is selected from N or CH. This indicates the bond and structural fragment at that location. (When H is a bond) it is connected to the other side, and the other side is connected to a group M (in the compound of formula (I) it is represented by the C(O) corresponding to M). In some embodiments, n1 and n2 are selected from 1, n3 and n4 are selected from 2, and X is selected from N.

[0070] In some implementations, ring A is selected from one or more R... a1 Substituted 7-10 nucleotide heterospirocycloalkyl group, wherein R a1 The definition is as described in this disclosure.

[0071] In some implementations, ring A is selected from one or more R... a1 The substituted 7-10-membered heterospirocycloalkyl group, optionally, wherein ring A contains one, two, or three heteroatoms selected from N, O, or S; or, ring A contains one or two heteroatoms selected from N, O, or S; or, ring A contains one or two N atoms; wherein R a1 The definition is as described in this disclosure. In some embodiments, ring A is selected from rings optionally formed by one or more R... a1 Substituted 7-9 member heterospirocycloalkyl (e.g., [3, 3] heterospirocycloalkyl, [3, 5] heterospirocycloalkyl), wherein R a1 Selected from =O or C 1-6 Alkyl group; optionally, ring A contains one or two nitrogen atoms.

[0072] In some implementations, ring A is selected from... The ring A is optionally substituted with one =O or a methyl group, wherein n1, n2, n3 and n4 are each independently selected from 1, 2 or 3 (e.g., n1, n2, n3 and n4 are each independently selected from 1 or 2; or n1 and n2 are 1, and n3 and n4 are 2), and X is each independently selected from N or CH (e.g., one X is N and the other is CH; or both X are N), and the ring A is optionally substituted with one =O or methyl group.

[0073] In some implementations, ring A is selected from one or more R... a1 The following groups are substituted: , , , , , , , or .

[0074] In some implementations, ring A is selected from one or more R... a1 The following groups are substituted: , , , , , , , or In some implementations, R a1 Selected from =O or C 1-6 Alkyl group. In some embodiments, the above structural fragment is optionally substituted with one =O or methyl group.

[0075] In some implementations, ring A is selected from one or more R... a1 The following groups are substituted: , , or ,in This indicates the bond and structural fragment at that location. (When H is absent, i.e., when H is a bond) it is connected to one side, and the other side is connected to M. In some implementations, R a1 Selected from =O or C 1-6 Alkyl group. In some embodiments, the above structural fragment is optionally substituted with one =O or methyl group.

[0076] In some implementations, ring A is selected from... , , , , , , , , , or In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is selected from... , , , , , , or ,in This indicates the bond and structural fragment at that location. Connected to one side, and to the other side with the structural segment. Connected, where W and W 1 W 2 n, R 1 R 2 R 3 and R 4 The definition is as described in this disclosure.

[0077] In some implementations, ring A is selected from... , , , , , , , , , , , or ,in This indicates the bond at that location and the H portion or structural fragment. (When H does not exist, i.e., H is a bond) it is connected, and the other side is connected to the M part, where W, W 1 W 2 n, R 1 R 2 R 3 R 4 M and R 8 The definition is as described in this disclosure.

[0078] In some implementations, ring A is selected from... , , , , or ,in This indicates the bond at that location and the H portion or structural fragment. (When H is the bond) it is connected to the other side, and the other side is connected to the M part.

[0079] In some implementations, ring A is selected from... , , , , , , or ,in This indicates the bond and structural fragment at that location. Connected to one side, and to the other side with the structural segment. Connected, where W and W 1 W 2 n, R 1 R2 R 3 R 4 The definitions of M and M are as described in this disclosure.

[0080] In some implementations, ring A is ,in The meaning is the same as in the previous text.

[0081] In some implementation schemes, R u and R v Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, or C. 1-3 Alkyl group. In some embodiments, R u and R v It is hydrogen.

[0082] In some implementations, M is selected from -CH2- or -C(O)-. In some implementations, M is -C(O)-.

[0083] In some implementations, H stands for bond, i.e., structural unit. It is directly connected to ring A. In some implementations, H is NH.

[0084] In some implementation schemes, R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, or C. 1-6 alkyl.

[0085] In some implementation schemes, R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, or C. 1-3 alkyl.

[0086] In some implementation schemes, R a1 Each is independently selected from O, halogen, or C. 1-3 alkyl.

[0087] In some implementation schemes, R a1 Each is independently selected from =O or C 1-3 alkyl.

[0088] In some specific implementation schemes, R a1 Each is independently selected from =O or methyl.

[0089] In some implementation schemes, R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)Rb’ -N(R) b’ (CO)OR b’ -O(CO)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ - S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein R a’ R b’ R a’’ The definition is as described in this disclosure.

[0090] In some implementation schemes, R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ Or 5-6 heteroaryl groups, of which R a’ R b’ and R a’’ The definition is as described in this disclosure.

[0091] In some implementation schemes, R 5 Selected from halogens, or optionally by one or more R a’’ Substituted groups include: 3-10 membered heterocyclic alkyl C(O)-, C 3-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-6 Alkyl)2、-C(O)N(C 1-6 Alkyl)C 3-10 Cycloalkyl, -C(O)N(C 1-6 Alkyl groups (5-10 membered heterocyclic alkyl groups), -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-10cycloalkyl, -N(C) 1-6 Alkyl)C(O)OC 1-3 Alkyl or 5-10 heteroaryl, wherein R a’’ The definition is as described in this disclosure.

[0092] In some implementation schemes, R 5 Selected from halogens, or optionally by one or more R a’’ Substituted groups include: 4-8 membered heterocyclic alkyl C(O)-, C 8-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-4 Alkyl)C 3-6 Cycloalkyl, -C(O)N(C 1-4 Alkyl groups (4-6 membered heterocyclic alkyl groups), -NHC(O)C 1-4 Alkyl group, -NHC(O)C 3-6 cycloalkyl, -N(C) 1-4 Alkyl)C(O)OC 1-4 Alkyl or 5-6-membered heteroaryl, wherein R a’’ The definition is as described in this disclosure.

[0093] In some implementation schemes, R 5 Selected from halogens, -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)OR b’ -N(R) b’ )C(O)R b’ Or 5-6 quinone heteroaryl, wherein -C(O)NR a’ R b’ -C(O)R b’ -N(R) b’ )C(O)OR b’ -N(R) b’ )C(O)R b’ Alternatively, the 5-6 heteroaryl group may be substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, or C group optionally substituted with one or more halogens or -OH. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl, wherein R a’ and R b’ The definition is as described in this disclosure. In some embodiments, R 5 Selected from F, Cl, Br, 5-7 membered heterocyclic alkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) (4-6 membered heterocyclic alkyl), -NHC(O)C 1-3 Alkyl group, -NHC(O)C 3-5 cycloalkyl, -N(C) 1-3 Alkyl)C(O)OC 1-3 Alkyl or 5-6-membered heteroaryl, wherein the 5-7-membered heterocyclic alkyl group is C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) (4-6 membered heterocyclic alkyl), -NHC(O)C 1-3 Alkyl group, -NHC(O)C 3-5 cycloalkyl or -N(C) 1-3 Alkyl)C(O)OC 1-3 The alkyl or 5-6-membered heteroaryl group is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, or C group optionally substituted with one or more halogens or -OH. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-4 Cycloalkyl or 4-5 membered heterocyclic alkyl.

[0094] In some implementation schemes, R 5 Selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)N(C 1-4 Alkyl)2, -C(O)-pyrroleyl, -C(O)-piperidinyl, -C(O)-morpholinyl, -C(O)-piperazinyl, -C(O)azabicycloheptyl, adamantyl NHC(O)-, -C(O)N(C 1-3 alkyl)cyclopropyl, -C(O)N(C 1-3 alkyl)oxetane butyl, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 Alkyl)C(O)OC 1-3 Alkyl groups, wherein the pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)-morpholinyl, or -C(O)-piperazinyl is optionally surrounded by one or two groups selected from F, Cl, -OH, -CN, methyl, -CF3, -OCH3, cyclopropyl, isopropyl, Or substitution with oxocyclic butyl groups.

[0095] In other implementations, R 5 Selected from F, Cl, Br, -OH, -CN, -NH2, -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ Or 5-6 quinone heteroaryl, the -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)OR b’ -N(R) b’ )C(O)R b’ Alternatively, the 5-6 heteroaryl group may be substituted by one or more of the following groups: halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein R a’ and R b’ The definition is as described in this disclosure.

[0096] In other implementations, R 5 Selected from halogens, 5-7 membered heterocyclic alkyl C(O)-, C 9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) (5-6 membered heterocyclic alkyl), -NHC(O)C 1-3 Alkyl group, -NHC(O)C 3-5 cycloalkyl, -N(C) 1-3 Alkyl)C(O)OC 1-3 Alkyl or 5-6-membered heteroaryl, wherein the 5-7-membered heterocyclic alkyl C(O)-, C 9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) -5-6 membered heterocyclic alkyl, -NHC(O)C 1-3 Alkyl group, -NHC(O)C3-5 cycloalkyl, -N(C) 1-3 Alkyl)C(O)OC 1-3 The alkyl or 5-6-membered heteroaryl group is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C group optionally substituted with one or more halogens. 1-3 Alkyl, -OC 1-3 Alkyl or C 3-4 Cycloalkyl.

[0097] In other implementations, R 5 Selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)-morpholinyl, -C(O)-piperazinyl, -C(O)azabicycloheptyl, -C(O)NH-adamantyl, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-3 alkyl)cyclopropyl, -C(O)N(C 1-3 alkyl)oxetane butyl, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 Alkyl)C(O)OC 1-3 Alkyl groups, including pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)-morpholinyl, -C(O)-piperazinyl, -C(O)azabicycloheptyl, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-3 alkyl)cyclopropyl, -C(O)N(C 1-3 alkyl)oxetane butyl, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl, -C(O)NH-adamantyl or -N(C 1-3 Alkyl)C(O)OC 1-3 The alkyl group is optionally substituted by one or more groups selected from F, Cl, CH3, CF3, -OH, -CN, -OCH3, isopropyl or cyclopropyl.

[0098] In some specific implementation schemes, R 5 Selected from one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ Or 5-10 heteroaryl compounds, of which R a’ and R b’ The definition is as described in this disclosure. In some specific embodiments, R 5 Selected from one or more R a’’The following groups are substituted: -C(O)NR a’ R b’ Or 5-6 heteroaryl groups, of which R a’ and R b’ The definition is as described in this disclosure. In some specific embodiments, R 5 Selected from one or more R a’’ The following groups are substituted: -C(O)N(C 1-6 alkyl) 2 or 5-6 heteroaryl, wherein R a’ and R b’ The definition is as described in this disclosure.

[0099] In some specific implementation schemes, R 5 Selected from one or more R a’’ The following groups are substituted: Or 5-6 member heteroaryl, of which R a’ and R b’ The definition is as described in this disclosure. In some specific embodiments, R 5 Selected from Or optionally by one or more R a’’ Substituted 5-6 aryl groups, of which R a’’ The definition is as described in this disclosure.

[0100] In some specific implementation schemes, R 5 Selected from Or a 5-6 quinone heteroaryl group, wherein the 5-6 quinone heteroaryl group is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C substituted with one or more halogens. 1-6 Alkyl, -OC 1-6 Alkyl or C 3-6 Cycloalkyl.

[0101] In some specific implementation schemes, R 5 for In some specific implementation schemes, R 5 Selected from one or more R a’’ Substituted 5-6 aryl groups, of which R a’’ The definition is as described in this disclosure. In some embodiments, R 5 Selected from one or more R a’’ Substituted 6-membered heteroaryl groups containing N heteroatoms.

[0102] In some implementation schemes, R 5 Selected from Br, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or Or, selected from , , , , , or .

[0103] In some specific implementation schemes, R 5 Selected from one or more R a’’ The following groups may be substituted: pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some specific embodiments, R 5 Selected from one or more R a’’ The following groups are substituted: pyrazolyl, imidazole, thiazolyl, or triazolyl. In some specific embodiments, R 5 Selected from one or more R a’’ The following groups may be substituted: pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0104] In some specific implementation schemes, R 5 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0105] In some specific implementation schemes, R 5 Selected from , , , , , , or In some specific implementation schemes, R 5 Selected from , , , , , , , , , , , , , , , , , , , , , , , or .

[0106] In other implementations, R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -C(O)-(5-6 membered heterocyclic alkyl), -N(C 1-4 Alkyl)(CO)OC 1-4 Alkyl, -C(O)-C 3-6 cycloalkyl, phenyl, or 5-6 heteroaryl, wherein R a’ R b’ and R a’’ The definition is as described in this disclosure.

[0107] In other implementations, R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -C(O)-(5-6 membered heterocyclic alkyl), -N(C 1-3 Alkyl)(CO)OC 1-3 Alkyl or 5-6-membered heteroaryl, wherein R a’ R b’ and R a’’ The definition is as described in this disclosure.

[0108] In other implementations, R 5 Selected from F, Cl, Br, -C(O)(NR) a’ R b’ -C(O)-5-membered heterocyclic alkyl, -N(C 1-2 Alkyl)(CO)OC 1-2 Alkyl or 5-6-membered heteroaryl, wherein the -C(O)-(5-membered heterocyclic alkyl) or 5-6-membered heteroaryl group is optionally surrounded by one or two R groups. a’’ Instead, the R a’ R b’ and R a’’ The definition is as described in this disclosure.

[0109] In other implementations, R 5 Selected from Br, -C(O)(NR) a’ Rb’ ), -C(O)-azacyclopentyl, pyridyl, pyrimidinyl, pyrazolyl or -N(CH2CH3)(CO)OCH3, wherein the -C(O)-azacyclopentyl, pyridyl, pyrimidinyl or pyrazolyl is optionally substituted with one or more isopropyl or cyclopropyl groups, wherein R a’ and R b’ The definition is as described in this disclosure.

[0110] In other implementations, R 5 Selected from Br, , , , , , , or .

[0111] In some implementation schemes, R a’ Selected from hydrogen, methyl, ethyl, C 4-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0112] In some implementation schemes, R a’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0113] In some implementation schemes, R a’ Each is independently selected from hydrogen and C. 1-4 Alkyl or C 3-4 Cycloalkyl.

[0114] In some implementation schemes, R a’ Each is independently selected from hydrogen, methyl, ethyl, isopropyl, Or cyclopropyl.

[0115] In some implementation schemes, R a’ Each is independently selected from hydrogen, methyl, ethyl, Or cyclopropyl.

[0116] In other implementations, R a’ Selected from methyl, ethyl, C 4-5 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0117] In other implementations, R a’ Selected from methyl, ethyl or C 3-5 Cycloalkyl.

[0118] In other implementations, Ra’ Selected from methyl, ethyl or cyclopropyl.

[0119] In some implementation schemes, R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 The cycloalkyl, 4-10 heterocycloalkyl, phenyl or 5-6 heteroaryl groups may be optionally substituted with one or more halogens, -CN, -OH or -NH2.

[0120] In some implementation schemes, R b’ Each of the following groups, independently selected from hydrogen or optionally substituted with one or more halogens: C 1-6 Alkyl, C 3-9 Cycloalkyl or 4-9 membered heterocyclic alkyl.

[0121] In some implementation schemes, R b’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-5 cycloalkyl, C 9-10 Cycloalkyl or 4-7 membered heterocyclic alkyl.

[0122] In some implementation schemes, R b’ Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, adamantyl, oxacyclobutyl, pyrrolidinyl, morpholinyl, piperazine, piperidinyl, or aziridine-bicycloheptyl.

[0123] In some implementation schemes, R b’ Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl , , , , , or .

[0124] In some implementation schemes, R b’ Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl , , , , , , , , , , or .

[0125] In other implementations, R b’ Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 1-4 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl groups may be optionally substituted with one or more halogens, -CN, -OH or -NH2.

[0126] In other implementations, R b’ Selected from C 1-4 Alkyl, 3-5 membered cycloalkyl, or 3-5 membered heterocycloalkyl, wherein C 1-4 Alkyl, 3-5 membered cycloalkyl or 3-5 membered heterocycloalkyl may be optionally substituted with one or more halogens.

[0127] In other implementations, R b’ C 1-3 alkyl.

[0128] In other implementations, R b’ It is isopropyl.

[0129] In some implementation schemes, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl-O-, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -OH, -CN or -NH2.

[0130] In some implementation schemes, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, -NH(C) 1-4 alkyl), -OC 1-4Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, -NH(C) 1-4 alkyl), -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group may optionally be substituted with one or more halogens or -OH.

[0131] In some implementation schemes, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl, wherein C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 The cycloalkyl or 3-5 membered heterocycloalkyl group may be optionally substituted with one, two or three groups selected from the following groups: halogen, -OH, -CN or -NH2.

[0132] In some implementation schemes, R a’’ Each is independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl, cyclopropyl, Or oxoheterobutyl.

[0133] In other implementations, R a’’ Each is independently selected from F, Cl, -OH, -CN, and C. 1-3 Alkyl, -OC 1-3 Alkyl or C 3-4 cycloalkyl, the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms. In other embodiments, R... a’’ Each is independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl, or cyclopropyl.

[0134] In other implementations, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl, the C 1-4 Alkyl, C 3-5 cycloalkyl or C 3-5 Heterocyclic alkyl groups may optionally be substituted with one or more halogens.

[0135] In other implementations, R a’’ Each is independently selected from F, Cl, Br, and C. 1-4 Alkyl, C 3-6cycloalkyl or C 3-6 Heterocyclic alkyl groups.

[0136] In other implementations, R a’’ Each was independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0137] In other implementations, R a’’ Each was independently selected from C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0138] In other implementations, R a’’ Each is independently selected from isopropyl or cyclopropyl.

[0139] In some specific implementation schemes, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 The alkyl group may optionally be substituted with one or more halogens, -OH, -CN, or -NH2.

[0140] In some specific implementation schemes, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-3 Alkyl, C 1-3 Alkyl-O-, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, wherein C 1-4 The alkyl group may optionally be substituted with one or more halogens, -OH, -CN, or -NH2.

[0141] In some implementation schemes, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0142] In some implementation schemes, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl or C1-6 Halogenated alkyl groups.

[0143] In some implementation schemes, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0144] In some implementation schemes, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl groups.

[0145] In some implementation schemes, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-4 Alkyl or C 1-4 Heteroalkyl. In some embodiments, R 6 Selected from hydrogen, halogen or C 1-6 Alkyl group. In some embodiments, R 6 Selected from hydrogen, halogens (e.g., F, Cl, Br, or I) or C 1-3 alkyl.

[0146] In some implementation schemes, R 6 Selected from hydrogen, F, Cl, Br or methyl.

[0147] In some implementation schemes, R 6 Selected from hydrogen, F, or methyl.

[0148] In other implementations, R 6 It is F.

[0149] In some implementation schemes, R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -CN, -OH or -NH2.

[0150] In other implementations, Ra and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl or -OC 1-4 Alkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl or -OC 1-4 The alkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0151] In some implementation schemes, R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0152] In some implementation schemes, R 7 Each is independently selected from halogens, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl.

[0153] In some implementation schemes, R 7 Each was independently selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0154] In some implementation schemes, R 7 Each was independently selected from C 3-4 Cycloalkyl.

[0155] In some implementation schemes, R 7 Each is independently cyclopropyl.

[0156] In other implementations, R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl or -OC 1-4 alkyl.

[0157] In other implementations, R 7 Each is independently selected from halogens, -CN, -OH, -NH2, or C. 1-4 alkyl.

[0158] In other implementations, R 7Each is independently selected from halogen or C 1-3 alkyl.

[0159] In other implementations, R 7 Each is independently selected from F, Cl, or Br.

[0160] In some implementation schemes, R a Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl or -OC 1-4 alkyl.

[0161] In some implementation schemes, R a Each is independently selected from halogens, -CN, -OH, -NH2, or C. 1-4 alkyl.

[0162] In some implementation schemes, R a Each is independently selected from halogen or C 1-3 alkyl.

[0163] In some implementation schemes, R a Each is independently selected from F, Cl, or Br.

[0164] In some implementation schemes, R a Each is independently represented by F.

[0165] In some implementations, m is selected from 0, 1, or 2.

[0166] In some implementations, m is selected from 0 or 1.

[0167] In some implementations, m is selected from 1.

[0168] In some implementations, m is selected from 0.

[0169] In some implementations, n is selected from 1 or 2. In some implementations, n is selected from 2.

[0170] In some implementations, p is selected from 0, 1, or 2.

[0171] In some implementations, p is selected from 0 or 1. In some implementations, p is selected from 1.

[0172] In some implementations, p is selected from 0.

[0173] In some implementations, q is selected from 1.

[0174] In some implementations, structural fragments Selected from , , or .

[0175] In some implementations, structural fragments Selected from or .

[0176] In some embodiments, the heteroalkyl, heteroaryl, heteroarylene, heterocycloalkyl, heterocyclic, heterocyclic, heterocyclic (e.g., heterocyclic monocycloalkyl), or heterospirocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from B, N, O, S, or P, with the remaining ring atoms selected from carbon. In some embodiments, the heteroalkyl, heteroaryl, heteroarylene, heterocycloalkyl, heterocyclic, heterocyclic, heterocyclic, or heterospirocycloalkyl comprises 1, 2, or 3 heteroatoms selected from N, O, or S, with the remaining ring atoms selected from carbon. In some embodiments, the heteroalkyl, heteroaryl, heteroarylene, heterocycloalkyl, heterocyclic, heterocyclic, heterocyclic, or heterospirocycloalkyl comprises 1, 2, or 3 heteroatoms selected from N or O, with the remaining ring atoms selected from carbon. In some embodiments, the heteroalkyl, heteroaryl, heteroarylene, heterocycloalkyl, heterocyclic, heterocyclic, heterocyclic, heterocyclic, or heterospirocyclic comprises one or two heteroatoms selected from N or O, and the remaining ring atoms are selected from carbon.

[0177] In some embodiments, the halogenation is selected from fluorination, chlorination, or bromination. In some embodiments, the halogenation is selected from fluorination or chlorination. In some embodiments, the halogenation is selected from fluorination.

[0178] In some implementations, the C 1-10 Selected from C 1-9 C 1-8 C 1-7 C 1-6 C 1-4 C 1-3 or C 1-2 In some implementations, C 1-6 Selected from C 1-4 C 1-3 or C 1-2 In some implementations, the C 1-4 Selected from C4, C3, C2, or C1. In some embodiments, C... 1-3 Choose from C3, C2, or C1.

[0179] In some implementations, the C 2-10 Selected from C 2-8 C 2-6 C 2-5 C 2-4 C 2-3In some implementations, the C 2-6 Selected from C 2-4 or C 2-3 In some implementations, the C 2-4 Choose from C4, C3, or C2.

[0180] In some implementations, the C 3-6 Selected from C 3-5 C 3-4 C 4-6 C 4-5 or C 5-6 In some implementations, the C 6-10 Selected from C 6-9 C 6-8 C 6-7 C 7-10 C 7-9 C 7-8 C 8-10 C 8-9 or C 9-10 In some implementations, the C 3-10 Selected from C 3-9 C 3-8 C 3-7 C 3-6 C 3-5 C 3-4 C 4-10 C 4-9 C 4-8 C 4-7 C 4-6 C 4-5 C 5-10 C 5-9 C 5-8 C 5-7 C 5-6 C 6-10 C 6-9 C 6-8 C 6-7 C 7-12 C 7-10 C 7-9 C 7-8 C 8-12 C 8-10 C 8-9 C 9-12 or C 9-10 In some implementations, the C 3-15 Selected from C 3-12 Or C 3-10 In some implementations, the C 3-12 Selected from C 3-10 In some implementations, the C 6-12 Selected from C6-10 .

[0181] In some implementations, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some implementations, the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, or 9-10 yuan. In some implementations, the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, and 9-10 yuan. In some implementations, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some implementations, the 3-12 yuan is selected from 3-10 yuan. In some implementations, the 5-12 yuan is selected from 5-10 yuan.

[0182] In some embodiments, the compounds of formula (I), formula (II), or formula (III) of this disclosure, or pharmaceutically acceptable salts thereof, are selected from the following compounds of formula (I'), formula (II'), formula (III'), formula (IA), formula (IIA), formula (IB), formula (IIB), formula (IC), formula (IIC), formula (IID), formula (IA-1), formula (IA-2), formula (IIA-1), formula (IB-1), or formula (IC-1) or pharmaceutically acceptable salts thereof: , Among them, Y, H, n1, n2, n3, n4, W, W 1 W 2 W 3 W 4 W 5 m, p, n, ring A, R 1 R 2 R 3 R 4 R 5R 6 R 7 R 8 R a The definition of M is as described in this disclosure; X t Selected from O or CH(R) c2 ), where R c2 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0183] In some implementation schemes, X t For O. In some implementations, X t Selected from CH(R) c2 In some implementations, X t It is CH2.

[0184] In some implementation schemes, R c2 Selected from hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2.

[0185] In some implementation schemes, R c2 Selected from hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl groups.

[0186] In some implementation schemes, R c2 Selected from hydrogen or C 1-3 alkyl.

[0187] In some implementation schemes, R c2 It is hydrogen.

[0188] In some implementations, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0189] It should be understood that any embodiment of the compounds of this disclosure as described above and any specific Y, ring A, H, W, M, R in the compounds of this disclosure as described above are considered. u R v W 1 W 2 W 3 W 4 W 5 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R a R a’ R b’ R a’’ R a1 R b1 R c1 R d1 R c2 and R d2 Any specific substituent described herein may be independently combined with other embodiments of this disclosure and / or substituents of the compounds to form embodiments of this disclosure not specifically described above. Furthermore, any specific Y, ring A, H, W, M, R mentioned in the specific embodiments and / or claims... u R v W 1 W 2 W 3 W 4 W 5 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R a R a’ R b’ R a’’ R a1 R b1 R c1 R d1 R c2 and R d2 Where a range of substituents is disclosed, it should be understood that one or more substituents may be deleted from that range, and the remaining range of substituents should also be considered as an embodiment of this disclosure. It should be understood that in the case of substituent R... a When it exists (i.e., when m is not 0), it exists in W.3 W 4 、 or W 5 Substitution occurs at the position of substituent R; 7 When it exists (i.e., when p is not 0), it exists in W and W 1 、 or W 2 The position is replaced.

[0190] In some implementations, the following compounds or their pharmaceutically acceptable salts are used: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0191] On the other hand, this disclosure relates to the above-mentioned compounds or their pharmaceutically acceptable salts in crystalline or amorphous forms.

[0192] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds described above or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients.

[0193] In some embodiments, the pharmaceutical composition contains 0.01 mg to 1000 mg (in the free form of the compound) of the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the pharmaceutical composition contains a single dose (based on the compound, its stereoisomers or pharmaceutically acceptable salts thereof) of 0.01 mg to 1000 mg (based on the free form of the compound).

[0195] In some embodiments, the 0.01 mg to 1000 mg is further selected from 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 30 mg to 1000 mg, or 31 mg to 1000 mg.

[0196] In some embodiments, the pharmaceutical composition contains 0.01 to 95% wt or 0.4 to 95% wt (based on the free form of the compound).

[0197] In some embodiments, the 0.01~95%wt is further selected from 0.1~95%wt, 0.4~95%wt, or 1~95%wt.

[0198] In some embodiments, the pharmaceutical composition wherein the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the above-mentioned compound or a pharmaceutically acceptable salt thereof in crystalline or amorphous form.

[0199] In some embodiments, the target of administration of the pharmaceutical composition is selected from mammals, such as humans.

[0200] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions, semi-solid pharmaceutical compositions, liquid pharmaceutical compositions, or gaseous pharmaceutical compositions.

[0201] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions.

[0202] In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions.

[0203] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form.

[0204] In some embodiments, the pharmaceutical composition may be prepared by combining the compounds of this disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0205] In some embodiments, the pharmaceutical composition is typically administered via routes including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous routes.

[0206] In some embodiments, the pharmaceutical composition is selected from tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, or aerosols.

[0207] In some embodiments, the solid pharmaceutical composition is selected from tablets, pills, capsules, powders, or granules.

[0208] In some embodiments, the liquid pharmaceutical composition is selected from suspensions or injections.

[0209] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form.

[0210] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral form.

[0211] In some embodiments, the pharmaceutical composition is selected from injectable pharmaceutical compositions.

[0212] In some embodiments, the pharmaceutical composition is selected from oral solid pharmaceutical compositions.

[0213] In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions for injection.

[0214] In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is selected from oral solid pharmaceutical compositions.

[0215] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may optionally be used in combination with one or more other drugs.

[0216] In some embodiments, the pharmaceutical composition contains a single dose (based on the compound or a pharmaceutically acceptable salt thereof) of 0.01 mg to 1000 mg.

[0217] In some embodiments, the pharmaceutical composition contains the compound or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 95% wt or 0.4 to 95% wt.

[0218] On the other hand, this disclosure provides a method for preventing or treating diseases in mammals, the method comprising administering to a mammal, preferably a human, a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0219] On the other hand, this disclosure provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases.

[0220] On the other hand, this disclosure provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases.

[0221] On the other hand, this disclosure provides the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases.

[0222] In another aspect, this disclosure provides a kit for the prevention or treatment of Menin-related diseases, comprising the compounds disclosed herein or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, and optionally, instructions for use.

[0223] In another aspect, this disclosure provides a kit for the prevention or treatment of Menin-related diseases, comprising the compounds disclosed herein or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, and optionally, instructions for use in combination with one or more other drugs.

[0224] Furthermore, the compound or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, may optionally be used in combination with one or more other drugs.

[0225] Furthermore, this disclosure relates to the use of the aforementioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of Menin-related diseases in combination with one or more other drugs.

[0226] Furthermore, this disclosure relates to the use of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to Menin protein, wherein the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in combination with one or more other medicaments.

[0227] In another aspect, this disclosure relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to Menin protein, wherein the prevention or treatment includes use in combination with one or more other medicaments.

[0228] The compounds disclosed herein, or the compounds described herein, include compounds of general formulas, specific compounds, or compounds of embodiments.

[0229] In some embodiments, the disease is selected from Menin protein-related diseases. In some embodiments, the disease is selected from cancer. Preferably, the cancer is leukemia; in some embodiments, the disease or cancer is selected from non-solid tumors; in some embodiments, the disease is selected from hematological diseases. In some embodiments, the disease is selected from hematologic malignancies. In some embodiments, the disease or cancer is selected from acute leukemia; in some embodiments, the cancer or leukemia is selected from myeloid leukemia. In some embodiments, the cancer or leukemia is selected from acute myeloid leukemia, such as acute monocytic leukemia.

[0230] Technical effect The compounds disclosed herein, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof have one or more of the following beneficial effects: good inhibitory activity against the proliferation of MOLM-13 and / or MV-4-11 cells, while also having activity against the binding of Menin-MLL protein; stable liver microsomal metabolism; good in vivo pharmacokinetic properties (e.g., AUC, Cmax, or T1 / 2); and good in vivo efficacy.

[0231] definition Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0232] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0233] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group being “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0234] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" means one, two, three, four, five, or six; or, "one or more" means one, two, or three.

[0235] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 This means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0236] In this article, "mn" refers to integer elements within a given range. For example, "3-12" means that the group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 elements. Similarly, "5-10" means that the group can have 5, 6, 7, 8, 9, or 10 elements.

[0237] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by two Rs, each R has an independent option.

[0238] When a substituent is cross-bonded between two atoms on a ring, it can bond with any atom on that ring. For example, structural units. or This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0239] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0240] The term "hydroxyl group" refers to the -OH group.

[0241] The term "amino" refers to the -NH2 group.

[0242] The term "nitro" refers to the -NO2 group.

[0243] The term "cyano" refers to the -CN group.

[0244] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0245] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkyl group. For example, the term "C1-6 alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C1-4 alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. Other groups such as "cycloalkylene," "heterocyclic," "spirocyclic," "alkylene," "aryl," or "heteroaryl" are similarly defined, indicating that they are divalent groups. For example, the term "C1-6 alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. 3-12 "Cycloalkylene" refers to cycloalkylene compounds containing 3 to 12 carbon atoms; the term "6-10-membered cycloalkylene" refers to cycloalkylene compounds containing 6 to 10 carbon atoms, including but not limited to... , , , or Examples of heterospirocycloalkyl groups include... , or Examples of heterocyclic alkyl groups include... , or Examples of aryl compounds include, but are not limited to, those of other types. Examples of heteroaryl groups include, but are not limited to, those mentioned above. , or wait.

[0246] The term "alkoxy" refers to -O-alkyl.

[0247] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0248] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0249] The term "bicyclic" or "bicyclic group" refers to a cyclic group containing two rings, which can be fully saturated, partially saturated, or aromatic. The bicyclic group may consist entirely of carbon atoms and may contain one or more heteroatoms selected from, for example, N, O, S, or P. The bicyclic group can be a fused ring, a bridged ring, or a spirocyclic ring.

[0250] The term "cycloalkyl" refers to a fully saturated carbon ring. Unless otherwise indicated, the carbon ring is typically a 5- to 20-membered or 3- to 10-membered ring. Unless otherwise indicated, the cycloalkyl group can be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0251] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups such as: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-. Preferably, the term "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0252] The term "heteroalkyl" refers to a straight-chain or branched alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms, wherein the heteroatom is preferably S, O, and N heteroatoms, and the number is preferably 1, 2, or 3. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatomic group can be located at any internal position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc., including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5, and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0253] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, or a 3- to 10-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring), a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc.

[0254] The term "spirocyclic ring" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 9 to 14 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0255] The term "spirocycloalkyl" refers to a fully saturated polycyclic aromatic hydrocarbon sharing a single carbon atom (called a spiro atom) between its rings. Unless otherwise indicated, the spirocycloalkyl group is 5 to 20 quinary members, preferably 6 to 14 quinary members, and more preferably 9 to 14 quinary members. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of spiro atoms shared between the rings, preferably monospirocycloalkyl and bispirocycloalkyl, and more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include... , , and .

[0256] The term "heterospirocycloalkyl" refers to a fully saturated polycyclic ring in which one or more ring atoms are selected from N, O, and S(O). n P(O) n(where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Unless otherwise indicated, the spiroheteroalkyl group is 5 to 20 quinary, preferably 6 to 14 quinary, and more preferably 6 to 10 quinary. Spiroheterocycles are classified into monospiroheterocycles, bispiroheterocycles, or multispiroheterocycles according to the number of shared spiro atoms between rings, preferably monospiroheterocycles or bispiroheterocycles, more preferably 4-quinary / 4-quinary, 4-quinary / 5-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, or 5-quinary / 6-quinary monospiroheterocycles. Non-limiting examples of spiroheteroalkyl groups include , , , or wait.

[0257] The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbon rings and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5-20 atoms or 5-14 atoms, preferably 6-14 atoms, and more preferably 6-10 atoms. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring, preferably a bicyclic or tricyclic ring, and more preferably a bicyclic ring. When the bridged ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0258] The term "heterocyclic alkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise indicated, the heterocyclic alkyl group typically contains one to three independently selected from N, O, and S(O). n P(O) nA ring of heteroatoms (preferably 1 or 2 heteroatoms) (where n is 0, 1, or 2). Unless otherwise indicated, the heterocyclic alkyl group can be monocyclic, bicyclic, or tricyclic. Unless otherwise indicated, the heterocyclic alkyl group can be monocyclic, spirocyclic, bridged, or fused. Unless otherwise indicated, the heterocyclic alkyl group includes, but is not limited to, 3- to 20-membered rings, 3- to 12-membered rings, 3- to 8-membered rings, or 5- to 8-membered rings. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl. Preferably, monocyclic heterocyclic alkyl groups have 5 or 6 ring atoms.

[0259] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring having a conjugated π-electron system. Unless otherwise indicated, aryl groups may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0260] The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one element selected from N, O, or S(O). n P(O) n The heteroaryl group has at least one aromatic ring, consisting of a ring atom (where n is 0, 1, or 2), with the remaining ring atoms being carbon. Unless otherwise indicated, the heteroaryl group can be monocyclic, bicyclic, or tricyclic. Unless otherwise indicated, the heteroaryl group can have a single 5- to 8-membered ring, or multiple fused rings comprising 6 to 20 or 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0261] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes: (i) Suppress the disease or disease state, that is, curb its development; (ii) To alleviate a disease or disease state, even if the disease or disease state subsides.

[0262] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat the specific disease, condition, or disorder described herein, (ii) to reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) to prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0263] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0264] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0265] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0266] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0267] The word “comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0268] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0269] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, ( R )-and( S - Enantiomers, diastereomers, ( D )-Isomer, ( L (Isomers, racemic mixtures thereof, and other mixtures, such as enantiomers or diastereomer-enriched mixtures, are all within the scope of this disclosure. Additional asymmetric carbon atoms may be present in the alkyl or other substituents. All such isomers and mixtures thereof are included within the scope of this disclosure.)

[0270] Unless otherwise stated, "( D ")" or "(+)" indicates right-handed rotation. L ")" or "(-)" indicates left-handedness, "( DL “)” or “(±)” indicates racemic.

[0271] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a straight solid line key ( ). ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0272] Optically active (electro-active) compounds can be prepared using chiral synthesis, chiral reagents, or other conventional techniques. R )-and( S )-Isomers and D and L Isomers. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, and then the diastereomeric isomer is resolved by conventional methods known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0273] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0274] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0275] In addition, heavier isotopes (such as deuterium) are used. 2 H or D) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases, wherein the deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are substituted by deuterium, for example, methyl (-CH3) completely substituted by deuterium is -CD3.

[0276] The compounds disclosed herein may exist in their tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer may be an imidazole moiety, in which a proton can migrate between two ring nitrogens.

[0277] The compounds disclosed herein are generally present in solid form, which may be crystalline or amorphous. The crystalline compounds of this disclosure can be prepared using methods well known in the art, such as recrystallization. The amorphous compounds of this disclosure can be prepared using methods well known in the art, such as spray drying.

[0278] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients.

[0279] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, and intravenous administration.

[0280] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0281] In all methods of administration of the compounds (I) disclosed herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in single or separate doses.

[0282] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0283] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0284] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure). For example, see Greene's Protective Groups in OrganicSynthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this disclosure are incorporated herein by reference in their entirety.

[0285] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0286] The following abbreviations are used in this disclosure: DCM represents dichloromethane; PE represents petroleum ether; THF represents tetrahydrofuran; EA represents ethyl acetate; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt represents 1-hydroxybenzotriazole; DMF represents N,N-dimethylformamide; TEA represents triethylamine; m-CPBA represents m-chloroperoxybenzoic acid; Pd(dppf)Cl2 represents [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride; DBU represents 1,8-diazabicyclo(5,4,0)-7-undecene; DMAP represents 4-dimethylaminopyridine. Detailed Implementation

[0287] For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. Various changes and modifications to the specific embodiments of this disclosure will be apparent to those skilled in the art without departing from the spirit and scope of this disclosure. All reagents used in this disclosure are commercially available and can be used without further purification.

[0288] The compounds disclosed herein can be obtained using similar preparation methods as described in the examples, including but not limited to adjusting structurally similar raw materials, reagents, or process parameters. The structures of the compounds disclosed herein can be confirmed by MS or HNMR. Results for the compounds disclosed herein can also be obtained using the same efficacy testing methods.

[0289] Example 1: Preparation of Compound 1

[0290] Step 1: Preparation of compound 1-c Compound 1-a (35 mg), compound 1-b (22 mg), EDCI (23 mg), HOBt (17 mg), triethylamine (25 mg), and DMF (2 mL) were added to a reaction flask and stirred overnight at room temperature. After the reaction was confirmed to be complete, ethyl acetate and saturated brine were added, the mixture was stirred, and the layers were separated. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with saturated brine, dried, filtered, and concentrated under reduced pressure to obtain 50 mg of compound 1-c, which was directly added to the next step without purification. ESI-MS: m / z = 679.44 [M+H] + .

[0291] Step 2: Preparation of Compound 1 Compound 1-c (50 mg) was added to a reaction flask containing dichloromethane (6 mL), stirred to dissolve, and then trifluoroacetic acid (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature to check for complete reaction. Water was added, and the pH was adjusted to approximately 8 using TEA. The mixture was separated into liquid and aqueous phases, extracted with DCM, and the organic phases were combined, dried, filtered, and concentrated. The resulting product was purified by preparative liquid chromatography to obtain 23 mg of compound 1. ESI-MS: m / z = 579.28 [M+H] + .

[0292] 1 H-NMR (DMSO- d 6): d H 1.24~1.84 (11H, m), 1.90 (6H, m), 2.28~2.46 (3H,m), 3.13~3.53 (6H, m), 3.74 (1H, m), 3.94~3.84 (4H, m), 4.21~4.16 (1H, m),4.41 (1H, m), 7.06 (1H, m,), 7.23~7.31 (2H, m), 7.67~7.74 (1H, m), 8.26~8.28(1H, m). Example 2: Preparation of Compound 2

[0293] Step 1: Preparation of compound 2-c Following the preparation method of compound 1-c in Example 1, compound 1-b was replaced with compound 2-b to obtain compound 2-c. ESI-MS: m / z = 677.47 [M+H] + .

[0294] Step 2: Preparation of Compound 2 Following the preparation method of compound 1-d in Example 1, compound 1-c was replaced with compound 2-c to obtain compound 2. ESI-MS: m / z = 577.30 [M+H] + .

[0295] 1 H-NMR (CDCl3): d H 1.08~1.90(11H, m) 1.99 (6H, m), 2.38~2.45 (2H, m),2.92 (1H, d, J=17.81 Hz), 3.17~4.10 (12H, m), 4.66 (1H, m), 4.91 (1H, s),5.01 (1H, d, J=11.75 Hz), 6.74 (1H, m), 7.02~6.99 (2H, m), 7.84 (1H, m), 8.41(1H, d, J=5.30 Hz). Example 3: Preparation of Compound 3

[0296] Step 1: Preparation of compound 3-c 3-a (1000 mg), 3-b (832 mg), Cs₂CO₃ (3.42 mg), and DMF (10 mL) were added to a 25 mL reaction flask and stirred at 100 °C for 72 h. After most of the reactants had reacted completely, the reaction solution was filtered, the filter cake was washed with DMF, the filtrates were combined, and purified by silica gel column chromatography (PE:EA = 4:1). The purified solution was concentrated to give 800 mg of compound 3-c. ESI-MS: m / z = 268.84 [M+H] + .

[0297] Step 2: Preparation of compound 3-d 3-c (800 mg) and DCM (10 mL) were added to the reaction flask. m-CPBA (1.54 g) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 24 h until the reaction was complete. NaHSO3 and NaHCO3 solutions were added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed again with NaHCO3 solution, dried, filtered, and concentrated to dryness to obtain 422 mg of compound 3-d. ESI-MS: m / z = 284.90 [M+H] + .

[0298] Step 3: Preparation of compound 3-e POCl3 (341 mg) was added to a 10 mL solution of CHCl3 containing 225 mg of Et3N in an ice bath. The mixture was then added dropwise to a 5 mL solution of CHCl3 containing 422 mg of 3-d in an ice bath. After the addition was complete, the mixture was stirred at 65 °C for 4 h until the reactants were fully reacted. NaHCO3 solution was slowly added to adjust the pH to 7-8. The mixture was separated, and the organic phase was purified by silica gel column chromatography (PE:EA = 4:1) to give 180 mg of compound 3-e. ESI-MS: m / z = 302.93 [M+H] + .

[0299] Step 4: Preparation of compound 3-g 3-e (180 mg), 3-f (134 mg), Na₂CO₃ (126 mg), and acetonitrile (10 mL) were added to a 5 mL reaction flask. The mixture was stirred at room temperature for 12 h until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to dryness to give 100 mg of compound 3 g. ESI-MS: m / z = 493.13 [M+H] + .

[0300] Step 5: Preparation of compound 3-i 3-g (100mg), 3-h (33mg), Pd(dppf)Cl2 (15mg), K2CO3 (56mg), 1,4-dioxane (5mL), and H2O (1mL) were added to the reaction flask. Under N2 protection, the mixture was stirred at 80℃ for 7h until the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic phase was purified by silica gel column chromatography (PE:EA = 2:1) to give 100mg of compound 3-i. ESI-MS: m / z = 532.27 [M+H] + .

[0301] Step Six: Preparation of Compound 3-j 100 mg of 3-i was added to a reaction flask containing 6 mL of DCM and stirred until dissolved. 2 mL of CF3COOH was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. Water was added, and the pH was adjusted to approximately 8 using TEA. The mixture was then separated. The aqueous phase was extracted again with DCM. The organic phases were combined, dried, filtered, and concentrated until no liquid flowed out, yielding 60 mg of compound 3-j. ESI-MS: m / z = 432.25 [M+H] + .

[0302] Step 7: Preparation of compound 3-k Following the preparation method of compound 1-c in Example 1, compound 1-a was replaced with compound 3-j, and compound 1-b was replaced with compound 2-b, yielding compound 3-k. ESI-MS: m / z = 681.41 [M+H] +.

[0303] Step 8: Preparation of Compound 3 Following the preparation method of compound 1-d in Example 1, compound 1-c was replaced with compound 3-k to obtain compound 3. ESI-MS: m / z = 581.42 [M+H] + . 1 H-NMR (CDCl3): δ H 8.45 (1H, dd, J=1.40, 4.70 Hz,),8.28~8.30 (3H, m), 7.68 (1H, s), 7.37 (1H, dd, J=1.50), 7.12~7.15 (2H, m),7.01~7.07 (2H, m), 3.78~3.90 (6H,m), 3.47 (1H, m), 3.23~3.33 (2H, m), 2.97(1H, d, J=18.26 Hz), 2.51 (1H, s), 2.44 (1H, dd, J=1.70, 18.11 Hz), 1.66~2.06(10H, m, ), 1.07 (2H, s), 0.83 (2H, m). Example 4: Preparation of Compound 4

[0304] Step 1: Preparation of compound 4-b Following the preparation method of compound 3-i in Example 3, compound 3-h was replaced with compound 4-a to obtain compound 4-b. ESI-MS: m / z = 523.3 [M+H] + .

[0305] Step 2: Preparation of compound 4-c Referring to the preparation method of compound 3-j in Example 3, compound 3-i was replaced with compound 4-b to obtain compound 4-c.

[0306] Step 3: Preparation of compound 4-d Referring to the preparation method of compound 1-c in Example 1, compound 1-a was replaced with compound 4-c, and compound 1-b was replaced with compound 2-b to obtain compound 4-d.

[0307] Step 4: Preparation of Compound 4 Following the preparation method of compound 1-d in Example 1, compound 1-c was replaced with compound 4-d to obtain compound 4. ESI-MS: m / z = 572.28 [M+H] + .1 H-NMR (DMSO-d6): δ H 7.41~7.47 (3H, m), 6.89 (1H,s), 6.77 (1H, d), 6.49 (1H, dt, J=3.03), 6.42 (1H, dd, J=3.08), 6.32 (1H, dd,J=4.50), 5.48 (1H, d, J=1.70 Hz), 3.72 (1H, s), 3.60 (1H, m,), 3.07~3.11 (4H,m), 2.60~2.94 (4H, m,), 2.03 (1H, d, J=18.16 Hz), 1.90 (1H, s), 1.79 (1H, d,J=17.91 Hz, ), 1.29 (1H, m), 1.04 (2H, t, J=4.88 H), 0.98 (2H, t, J=5.43 Hz), 0.91 (4H,m), 0.58 (6H, d, J=6.60 Hz). Example 5: Preparation of Compound 5

[0308] Step 1: Preparation of compound 5-c Compound 5-a (200 mg), compound 5-b (91 mg), EDCI (368 mg), HOBt (259 mg), triethylamine (258 mg), and DMF (3 mL) were added to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was stirred and separated. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with saturated brine, dried, filtered, and concentrated under reduced pressure to give 121 mg of intermediate 5-c. ESI-MS: m / z = 210.05 [M+H] + .

[0309] Step 2: Preparation of compound 5-e Intermediate 5-c (100 mg), compound 5-d (184 mg), copper iron oxide (58 mg), acetylacetone (1 drop), cesium carbonate (313 mg), and DMF (3 mL) were added to a reaction flask, purged with N2, and heated to 120 °C with stirring for 20 h. The reaction was monitored until complete, and 40 mg of intermediate 5-e was obtained by silica gel column chromatography. ESI-MS: m / z = 512.27 [M+H] + .

[0310] Step 3: Preparation of compound 5-f Intermediate 5-e (40 mg), trifluoroacetic acid (1 mL), and dichloromethane (3 mL) were added to a reaction flask and stirred at room temperature for 1 h. The reaction was monitored until complete. NaHCO3 aqueous solution was added to adjust the pH to neutral, and the mixture was stirred. The liquid was separated, and the organic phase was concentrated under reduced pressure to obtain 40 mg of intermediate 5-f. ESI-MS: m / z = 412.25 [M+H] + .

[0311] Step 4: Preparation of compound 5-g Intermediate 5-f (40 mg), intermediate 2-b (26 mg), EDCI (28 mg), HOBt (20 mg), triethylamine (20 mg), and DMF (3 mL) were added to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated under reduced pressure to obtain 50 mg of intermediate 5-g. ESI-MS: m / z = 661.44 [M+H] + .

[0312] Step 5: Preparation of Compound 5 Intermediate 5-g (40 mg), trifluoroacetic acid (1 mL), and dichloromethane (3 mL) were added to a reaction flask and stirred at room temperature for 1 h. The reaction was monitored until complete, then stirred, separated, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography to obtain 10 mg of compound 5. ESI-MS: m / z = 561.28 [M+H] + .

[0313] 1 H-NMR (CDCl3): δ H 1.21 ~2.05(13H), 2.43 (1H, dd, J=1.58, 18.15Hz),2.50 (1H, s), 2.96 (1H, d, J=18.11 Hz), 3.27~3.38 (4H), 3.48 (1H, m), 3.56(2H, t, J=6.88 Hz), 3.81 (1H, s), 3.89 (1H, m), 3.98~4.02 (4H), 6.79 (1H, dd,J=4.01, 8.86 Hz), 7.03~7.09(2H), 7.84 (1H, s), 8.39 (3H). Examples 6-7 Referring to the preparation method of compound 5 in Example 5, compound 5-b was replaced with the starting material compounds shown in the table below to obtain target compounds 6 and 7.

[0314]

[0315] Example 8: Preparation of Compound 8

[0316] Step 1: Preparation of compound 8-a 3 g (120 mg) of intermediate, 1 mL of trifluoroacetic acid and 3 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. The reaction was monitored until it was complete. NaHCO3 aqueous solution was added to adjust the pH to neutral, and the mixture was stirred. The organic phase was concentrated under reduced pressure to obtain 100 mg of intermediate 8-a.

[0317] Step 2: Preparation of compound 8-b Intermediate 8-a (100 mg), intermediate 2-b (68 mg), EDCI (52 mg), HOBt (73 mg), triethylamine (76 mg), and DMF (8 mL) were added to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was stirred and separated. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with saturated brine, dried, filtered, and concentrated under reduced pressure to obtain 80 mg of intermediate 8-b.

[0318] Step 3: Preparation of Compound 8 Intermediate 8-b (80 mg), trifluoroacetic acid (1 mL), and dichloromethane (3 mL) were added to a reaction flask and stirred at room temperature for 1 h. The reaction was monitored until complete, then stirred, separated, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography to obtain 30 mg of compound 8. ESI-MS: m / z = 542.10 [M+H] + .

[0319] 1 H-NMR (CDCl3) δ H1.59~1.98 (8H, m, J=7.50 Hz), 2.40 (1H, d, J=17.91Hz), 2.44 (1H, s), 2.91 (1H, d, J=17.91 Hz), 3.32 (1H, m), 3.42 (1H, m), 3.48(1H, m), 3.67 (1H, m), 3.85 (1H, m), 4.06 (4H, s), 4.66 (1H, s), 4.91 (1H,s), 5.00 (1H, s), 6.86 (1H, dd, J=4.78, 8.98 Hz), 7.03 (1H, m, J=4.84 Hz),7.40 (1H, dd, J=2.88, 7.53 Hz), 7.69 (1H, s), 8.40 (1H, s). Example 9: Preparation of Compound 9

[0320] Compound 8 (54 mg), 9-a (12 mg), Pd(dppf)Cl2 (7 mg), K2CO3 (27 mg), 1,4-dioxane (5 mL), and H2O (1 mL) were added to the reaction flask. Under N2 protection, the mixture was stirred at 80 °C for 7 h until the reactants were completely reacted. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic phase was purified by silica gel column chromatography to obtain 23 mg of compound 9. ESI-MS: m / z = 542.21 [M+H] + .

[0321] 1 H-NMR (CDCl3)δ H 1.74~2.11 (8H, m), 2.52 (1H, d, J=18.31 Hz), 2.57 (1H,s), 2.97 (1H, d, J=18.41 Hz), 3.34 (2H, m), 3.54 (1H, m), 3.93 (1H, s), 4.02~4.23 (5H, m), 4.77 (1H, s), 5.02 (1H, s), 5.11 (1H, s), 7.20 (1H, dd, J=4.30,8.70 Hz), 7.24~7.32 (2H, m), 7.61 (1H, m), 8.40 (1H, s), 8.97 (2H, s), 9.27(1H, s), 10.84 (1H, m). Examples 10-23 Referring to the preparation method of compound 9 in Example 9, compound 9-a was replaced with the starting material compounds shown in the table below to obtain target compounds 10-23.

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] Example 24: Preparation of compound 24

[0328] Step 1: Preparation of compound 24-b Referring to the preparation method of compound 4-d in Example 4, compound 2-b was replaced with compound 24-a to obtain compound 24-b.

[0329] Step 2: Preparation of Compound 24 Compound 24 was obtained by referring to the preparation method of compound 4 in Example 4. ESI-MS: m / z = 574.28 [M+H] + . 1 H NMR (500MHz CD3CN) δ H 8.41 (1H, s), 7.66 (1H, s), 7.55 (1H, d, J = 1.0), 7.32 (3H, m), 6.28 (1H, d, J = 1.0), 4.99 (1H, s), 4.37 (1H, m), 4.09 (5H,m), 3.61 (5H, m), 2.95 (1H, m), 2.62 (1H, m), 2.54 (1H, dd, J = 19.5, 2.0), 2.12 (1H, m), 1.83 (7H, m), 1.36 (6H, m). Example 25: Preparation of Compound 25

[0330] Step 1: Preparation of compound 25-b Referring to the preparation method of compound 4-b in Example 4, compound 4-a was replaced with compound 25-a to obtain compound 25-b.

[0331] Step 2: Preparation of compound 25-c Compound 25-c was obtained by referring to the preparation method of compound 4-c in Example 4.

[0332] Step 3: Preparation of compound 25-d Referring to the preparation method of compound 4-d in Example 4, compound 2-b was replaced with compound 24-a to obtain compound 25-d.

[0333] Step 4: Preparation of Compound 25 Compound 25 was obtained by referring to the preparation method of compound 4 in Example 4. ESI-MS: m / z = 544.60 [M+H] + .

[0334] 1 H-NMR (CDCl3) δ H 1.22~2.05 (8H, m), 2.31 (1H, m), 2.35 (1H, d, J=1.60Hz), 2.72 (1H, d, J=18.81 Hz), 3.28 (2H, m), 3.50 (1H, m), 3.65 (1H, m), 3.88(4H,m), 4.20 (1H, s), 5.34 (1H, m), 6.93 (1H, dd, J=4.45, 9.00 Hz), 7.15 (1H,m, J=3.23 Hz), 7.20 (1H, dd, J=2.98, 8.28 Hz), 7.73 (1H, s), 8.37 (1H, s) , 8.90 (2H, s), 9.23 (1H, s). Example 26: Preparation of Compound 26

[0335] Step 1: Preparation of compound 26-c Add intermediates 26-a (160 mg), 26-b (100 mg), Cs2CO3 (320 mg), and DMF (5 mL) to the reaction flask, stir at 60 °C for 24 h, and monitor until the reaction of the starting materials is complete. Add water and ethyl acetate to the reaction solution, separate the liquid, and concentrate the organic phase to obtain 180 mg of intermediate 26-c.

[0336] Steps 2 to 5: Preparation of Compound 26 Following the synthetic method described in steps five through eight of Example 3, compound 26 was obtained. ESI-MS: m / z = 582.31 [M+H] + .

[0337] 1 H-NMR (CDCl3) δ H 0.84~0.89 (2H, m), 1.12 (2H, m), 1.22~1.94 (9H, m), 2.09 (1H, m), 2.51~2.57 (2H, m), 2.97 (1H, m), 3.13~3.22 (2H, m), 3.46 (1H,m), 3.65 (1H, m, J=9.89 Hz), 3.93~4.08 (4H, m), 4.76 (1H, m), 5.03 (1H, s), 5.12 (1H, s), 7.54 (1H, m), 7.63 (1H, dd, J=2.90, 7.05 Hz), 7.92 (1H, s),8.18 (1H, d, J=2.85 Hz), 8.54 (1H, s), 8.60 (1H, s), 8.70 (1H, s), 10.95 (1H,s). Example 27: Preparation of Compound 27

[0338] Step 1: Preparation of compound 27-c 27-a (1.2 g), 27-b (1.0 g), triethylamine (0.8 g), and dichloromethane (25 mL) were added to a reaction flask. The mixture was stirred at 0 °C for 24 h until the reactants were completely reacted. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The organic phase was washed with water and concentrated to obtain 1.5 g of intermediate 27-c. ESI-MS: m / z = 374.11 [M+H] + .

[0339] Step 2: Preparation of compound 27-f Referring to the preparation method of intermediate 5-c in Example 5, intermediate 5-b was replaced with compound 27-e to obtain intermediate 27-f.

[0340] Step 3: Preparation of compound 27-g 27-c (200 mg), 27-f (325 mg), DBU (159 mg), and tetrahydrofuran (10 mL) were added to the reaction flask and stirred at room temperature for 72 h. The reaction was continued until the reactants were completely reacted. Water was added to the reaction solution, and EA was added. The mixture was stirred and separated. The aqueous phase was extracted again with EA. The organic phases were combined and purified by silica gel column chromatography to obtain 320 mg of compound 27-g.

[0341] Step 4: Preparation of compound 27-h Add 27-g (320mg), 10% palladium on carbon (100mg), triethylamine (1mL) and methanol (10mL) to the reaction flask, then add 10% palladium on carbon, replace with H2, stir at room temperature for 12h, and monitor until the reactants react completely. Filter the reaction solution and concentrate to dryness to obtain 260mg of compound 27-h.

[0342] Steps 5 to 7: Preparation of compound 27 Following the synthetic method described in steps three through five of Example 5, compound 27 was obtained. ESI-MS: m / z = 578.43 [M+H] + .

[0343] 1 H NMR (500MHz CDCl3) d H 8.50 (1H, s), 8.30 (1H, s), 7.15 (1H, m), 7.03(2H, m), 5.06 (1H, m), 4.96 (1H, brs), 4.81 (1H, brs), 4.42 (3H, m), 3.94(5H, m), 3.34 (6H, m), 2.97 (1H, d, J = 18.1), 2.46 (2H, m), 2.05 (1H, m), 1.90(3H, m), 1.69 (3H, m), 1.14 (6H, m), 0.77 (2H, m). Examples 28-30 Referring to the preparation method of compound 27 in Example 27, compound 27-d was replaced with the starting material compounds shown in the table below to obtain target compounds 28, 29 and 30.

[0344]

[0345] Example 31: Preparation of compound 31

[0346] Step 1: Preparation of compound 31-c Intermediates 31-a (156 mg), 31-b (198 mg), Pd(dppf)Cl2 (73 mg), sodium carbonate (212 mg), 1,4-dioxane (5 mL), and H2O (1 mL) were added to a reaction flask and stirred at 90 °C for 12 h under nitrogen protection. After the reaction was complete, ethyl acetate and water were added to the reaction mixture, and the mixture was stirred and separated. The ethyl acetate phase was purified by silica gel column chromatography and concentrated to give 200 mg of intermediate 31-c. ESI-MS: m / z = 230.06 [M+H] + .

[0347] Steps 2 to 6: Preparation of Compound 31 Following the synthetic method described in steps three through seven of Example 27, compound 31 was obtained. ESI-MS: m / z = 582.37 [M+H] + .

[0348] 1 H NMR (500MHz CDCl3) d H 8.46 (2H, m), 8.21 (1H, s), 7.48 (1H, dd, J =8.6, 4.6), 7.39 (1H, d, J = 7.2), 7.19 (1H, td, J = 8.6, 2.9), 7.09 (2H, m), 5.03(1H, s), 4.93 (1H, s), 4.70 (1H, s), 3.80 (5H, m), 3.39 (4H, m), 2.92 (1H, d, J = 17.6), 2.44 (2H, m), 2.00 (2H, m), 1.70 (7H, m), 0.89 (3H, m), 0.46 (1H,m). Examples 32-34 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compounds 32, 33 and 34.

[0349]

[0350] Example 35: Preparation of compound 35

[0351] Step 1: Preparation of compound 35-b Intermediate 35-a (200 mg), 27-a (304 mg), potassium carbonate (371 mg), and DMF (5 mL) were added to a reaction flask and stirred at 25 °C for 18 h. The reaction was monitored until complete, the reaction solution was filtered, purified by silica gel column chromatography, and concentrated to obtain 300 mg of intermediate 35-b. ESI-MS: m / z = 339.27 [M+H] + .

[0352] Step 2: Preparation of compound 35-c Intermediates 35-b (296 mg), 31-c (200 mg), cesium carbonate (159 mg), and DMF (5 mL) were added to a reaction flask and stirred at 130 °C for 72 h. The reaction mixture was monitored until complete, filtered, purified by silica gel column chromatography, and concentrated to obtain 200 mg of intermediate 35-c. ESI-MS: m / z = 532.29 [M+H] + .

[0353] Steps 3 to 5: Preparation of compound 35 Following the synthetic method described in steps three through five of Example 5, compound 35 was obtained. ESI-MS: m / z = 581.31 [M+H] + . 1 H-NMR (CDCl3): δ H 8.43 (1H, d, J=5.30 Hz), 8.40 (1H, m), 7.43 (1H, dd, J=4.75, 9.00 Hz), 7.37 (1H, dd, J=1.65, 7.60 Hz), 7.16 (1H, dt, J=3.03, 8.43Hz), 7.08 (1H, dd, J=3.03, 8.38 Hz), 7.01 (1H, dd, J=4.88, 7.48 Hz), 6.13(1H, d, J=5.45 Hz), 5.07 (1H, s), 4.97 (1H, s), 4.77 (1H, s), 3.83~3.87 (2H,m), 3.44~3.64 (5H, m), 3.22~3.23 (2H, m), 2.97 (1H, d, J=18.16 Hz), 2.51 (1H,m), 2.45 (1H, m), 2.07 (1H, m), 1.64~1.91 (8H,m), 0.82~0.94 (3H, m), 0.45(1H, m). Example 36 Referring to the preparation method of compound 35 in Example 35, compound 31-c was replaced with the starting compound in the table below to obtain compound 36.

[0354]

[0355] Examples 37-41 Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting material compounds shown in the table below to obtain target compounds 37~41.

[0356]

[0357]

[0358] Example 42: Preparation of compound 42

[0359] Step 1: Preparation of compound 42-a Intermediate 2-b (100 mg), DMAP (304 mg), and dichloromethane (5 mL) were added to a reaction flask and stirred at 25 °C for 10 min. Then, 1-(trifluoroacetyl)-4-(dimethylamino)pyridine trifluoroacetate (100 mg) and pinacol borane (53 mg) were added sequentially, and the mixture was stirred at 25 °C for 10 min. The reaction was quenched with 10 mL of water, extracted with dichloromethane, and the organic phases were combined, dried, filtered, and concentrated to obtain 30 mg of intermediate 42-a.

[0360] Step 2: Preparation of compound 42-b Intermediate 31-f (30 mg), intermediate 42-a (22 mg), and methanol (5 mL) were added to a reaction flask and stirred at 25 °C for 10 min. Then, sodium cyanoborohydride (13 mg) and 1 drop of glacial acetic acid were added sequentially, and the mixture was stirred at 25 °C for 2 hours. The reaction was quenched with 10 mL of water, extracted with dichloromethane, and the organic phases were combined, dried, filtered, and concentrated to obtain 30 mg of intermediate 42-b.

[0361] Step 3: Preparation of compound 42-b Intermediate 42-b (30 mg), trifluoroacetic acid (2 mL), and dichloromethane (5 mL) were added to a reaction flask and stirred at 25 °C for 30 min. The reaction was monitored by TLC until complete. The mixture was concentrated and purified to obtain 10 mg of compound 42. ESI-MS: m / z = 568.30 [M+H] + . 1 H-NMR (CDCl3) d H8.42~8.43 (2H, m), 7.45 (1H, dd, J=4.68, 8.88 Hz), 7.37 (1H, d, J=6.50 Hz), 7.17 (1H, dt, J=2.95, 8.39 Hz), 7.09 (1H, dd, J=3.00, 8.35 Hz), 7.02 (1H, dd, J=4.88, 7.43 Hz), 4.93 (1H, s), 4.82 (1H, s), 3.65~3.72 (3H, m), 3.42~3.47 (3H, m), 2.81 (1H, d, J=17.56 Hz), 2.66 (1H, t,J=11.40 Hz), 2.26~2.48 (7H, m), 1.94~2.01 (4H, m), 1.62~1.75 (5H, m), 0.99(1H, m), 0.93 (1H, m), 0.81 (1H, m), 0.47 (1H, m). Example 43: Preparation of compound 43

[0362] Step 1: Preparation of compound 43-c Referring to the preparation method of compound 5 in Example 5, compounds 5-a and 5-b were replaced with 43-a and 43-b to obtain compound 43-c.

[0363] Steps 2 to 5: Preparation of compound 43 Following the preparation method described in steps two through five of Example 5, compound 43 was obtained. ESI-MS: m / z = 574.36 [M+H] + . Examples 44-46: Preparation of compounds 44-46 Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting material compounds shown in the table below to obtain target compounds 44-46.

[0364]

[0365] Example 47: Preparation of Compound 47

[0366] Following the preparation method of compound 31 in Example 31, compound 31-a was replaced with 4,5-difluoro-2-hydroxyphenylboronic acid to obtain compound 47. ESI-MS: m / z = 600.30 [M+H] + . 1 H-NMR (CDCl3) d H 8.49 (1H, s), 8.45 (1H, m), 7.43 (1H, m) ,7.36 (1H, d,J=7.24 Hz), 7.21 (1H, dd, J=8.75, 9.80 Hz) ,7.06 (1H, m), 5.02 (1H, s), 4.92(1H, s), 4.58 (1H, m), 3.29~3.88 (9H, m), 2.90 (1H, d, J=17.96 Hz), 2.39~2.42(2H, m), 1.64~1.99 (9H, m), 0.47~0.99 (4H, m). Examples 48-49 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compounds 48 and 49.

[0367]

[0368] Examples 50-51 Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting material compounds shown in the table below to obtain target compounds 50-51.

[0369]

[0370] Example 52: Preparation of compound 52

[0371] Compound 31 (50 mg), potassium carbonate (30 mg), 1 drop of iodomethane, and DMF (5 mL) were added to a reaction flask and stirred at 25 °C for 3 hours. The reaction was monitored by TLC until complete. After purification, 18 mg of compound 52 was obtained. ESI-MS: m / z = 596.33 [M+H] + . Example 53: Preparation of compound 53

[0372] Compound 59 (50 mg), 1 M hydrochloric acid (1 mL), and THF (5 mL) were added to a reaction flask and stirred at 25 °C for 12 hours. The reaction was monitored by TLC until complete. Compound 53 was purified and separated to obtain 5 mg of the final product. ESI-MS: m / z = 634.22 [M+H] + . 1 H-NMR (CDCl3) d H 8.57 (1H, s),8.46 (1H, m), 7.54 (1H, t, J=8.08 Hz),7.04~7.38 (5H, m),5.04 (1H, s),4.94 (1H, s), 4.68 (1H, s), 3.72~3.89 (7H, m),3.31~3.45 (4H, m),2.92 (1H, d, J=17.11 Hz), 2.41~2.47 (2H, m), 1.67~2.00(11H, s),1.29(1H, m). Example 54 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compound 54.

[0373]

[0374] Example 55: Preparation of compound 55

[0375] Step 1: Preparation of compound 55-a Compound 27-g (560mg), cyclopropylboronic acid (172mg), Pd(dppf)Cl2 (73mg), K2CO3 (280mg), 1,4-dioxane (10mL) and H2O (2mL) were added to a reaction flask and stirred at 100℃ for 5 hours. The reaction was monitored by TLC until it was complete. After purification, 360mg of compound 55-a was obtained.

[0376] Steps 2 to 4: Preparation of Compound 55 Following the synthetic method described in steps three through five of Example 5, compound 55 was obtained. ESI-MS: m / z = 618.32 [M+H] + .

[0377] 1 H-NMR (CDCl3) d H7.05~7.29 (3H, m), 5.02 (1H, s), 4.92 (1H, s), 4.69(1H, s), 3.92~4.49 (6H, m), 3.70 (1H, m), 3.13~3.52 (5H, m), 2.91 (1H, d, J=17.96 Hz), 2.39~2.46 (2H, m), 1.99 (3H, m), 1.65~1.87 (6H, m), 0.93~1.17(13H, m). Example 56: Preparation of Compound 56

[0378] Following the preparation method of compound 27 in Example 27, compound 27-a was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate to obtain compound 56. ESI-MS: m / z = 550.21 [M+H] + . 1 H-NMR (CDCl3) d H 8.51 (1H, s), 7.24 (1H, m), 7.14 (1H, m), 7.00 (1H,m), 4.85~4.96 (4H, m), 3.86~4.54 (8H, m), 3.44 (2H, m), 3.18 (1H, m), 2.79(1H, d, J=17.01 Hz), 2.35~2.38 (2H, m), 1.60~1.93 (2H, m), 1.05~1.26 (9H, m), 0.79~0.88(2H, m). Example 57: Preparation of Compound 57

[0379] Compound 27 (50 mg), potassium carbonate (30 mg), 1 drop of iodomethane, and DMF (5 mL) were added to a reaction flask and stirred at 25 °C for 3 hours. The reaction was monitored by TLC until complete. After purification, 12 mg of compound 57 was obtained. ESI-MS: m / z = 592.34 [M+H] + . Example 58: Preparation of Compound 58

[0380] Following the preparation method of compound 31 in Example 31, compound 31-a was replaced with 3,5-difluoro-2-hydroxyphenylboronic acid to obtain compound 58. ESI-MS: m / z = 600.26 [M+H] + . 1 H-NMR (CDCl3) d H 8.46~8.48 (2H, m), 7.37 (1H, m), 7.02~7.08 (2H, m), 6.94 (1H, d, J=7.20 Hz), 5.04 (1H, s), 4.95 (1H, s), 4.74 (1H, s), 3.76~3.87(4H, m), 3.32~3.49 (5H, m), 2.94 (1H, d, J=17.71 Hz), 2.47 (1H, s), 2.43 (1H,d, J=18.06 Hz), 1.63~2.01 (9H, m), 1.27 (1H, m), 0.88~0.99 (3H, m). Example 59 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compound 59.

[0381]

[0382] Example 60: Preparation of Compound 60

[0383] Following the preparation method of compound 27 in Example 27, compound 27-a was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and compound 2-b was replaced with 60-e, yielding compound 60. ESI-MS: m / z = 556.30 [M+H] + . 1 H-NMR (CDCl3) d H8.51 (1H, s), 7.26 (1H, dd, J=4.03, 8.63 Hz), 7.15 (1H,m), 7.02 (1H, m), 4.68~4.99 (4H, m), 4.13~4.55 (6H, m), 3.86 (1H, m), 3.73(1H, m), 3.46 (1H, m), 3.20 (1H, m), 2.16~2.33 (3H, m), 1.97 (1H, m), 1.78(1H, m), 1.51 (2H, m), 1.05~1.12 (7H, m), 0.78 (2H, m). Example 61: Preparation of Compound 61

[0384] Step 1: Preparation of compound 61-c Referring to the preparation method of compound 27-c in Example 27, compound 27-a was replaced with 61-a, and compound 27-b was replaced with 61-b to obtain compound 61-c.

[0385] Steps 2 to 4: Preparation of Compound 61 Following the synthetic method described in steps three to five of Example 5, compound 5-e was replaced with 61-c to prepare compound 61. ESI-MS: m / z = 591.33 [M+H] + . 1 H-NMR (CDCl3) d H 8.74 (1H, m), 8.24 (1H, m), 6.96~7.12 (3H, m), 5.06 (1H, s), 4.96 (1H, s), 4.83 (1H, s), 3.19 (1H, m), 3.60~3.88 (7H, m), 3.40 (2H, m), 2.97 (1H, d, J=17.86 Hz), 2.54 (1H, s), 2.45 (1H, d, J=18.21 Hz), 2.03 (4H, m), 1.70 (3H, m), 1.08~1.22 (10H, m). Examples 62-63 Referring to the preparation method of compound 61 in Example 61, compound 61-a was replaced with the raw material compounds shown in the table below to obtain target compounds 62 and 63.

[0386]

[0387] Example 64: Preparation of Compound 64

[0388] Step 1: Preparation of compound 64-b Compound 64-a (1g), trimethyliodosilane (1mL) and acetonitrile (10mL) were added to a reaction flask and stirred at 80°C for 10 hours. The reaction was monitored by TLC until it was complete, and 670mg of compound 64-b was obtained after purification.

[0389] Steps 2 to 6: Preparation of Compound 64 Following the synthetic method described in steps three through seven of Example 27, compound 27-f was replaced with 64-b to obtain compound 64. ESI-MS: m / z = 598.28 [M+H] + . 1 H-NMR (CDCl3) d H 8.47 (1H, s) ,7.36 (1H, m), 7.23 (1H, m), 7.15 (1H,dt, J=2.77, 8.33 Hz), 7.10 (1H, dd, J=2.90, 8.35 Hz), 6.35 (1H, d, J=9.10Hz), 4.98 (1H, s), 4.87 (1H, s), 4.50 (1H, m), 3.79~4.00 (5H, s), 3.32~3.41(4H, m), 2.82 (1H, d, J=17.36 Hz), 2.38~2.40 (2H, m), 1.61~2.01 (9H, m), 0.95(4H, m). Examples 65-66 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compounds 65 and 66.

[0390]

[0391] Example 67: Preparation of Compound 67

[0392] Step 1: Preparation of compound 67-a Referring to the preparation method of compound 27-c in Example 27, compound 27-f was replaced with 31-c, and compound 27-c was replaced with 60-a to obtain compound 67-a.

[0393] Steps 2 to 5: Preparation of Compound 67 Following the synthetic method described in steps four through seven of Example 27, compound 67 was obtained. ESI-MS: m / z = 554.30 [M+H] + . 1 H-NMR (CDCl3) d H 8.47(2H, m), 7.42(2H, m), 7.18(1H, m), 7.10(2H, m),5.10 (1H, m), 4.91(1H, s), 4.69~3.86 (8H, m), 3.57(1H, s), 2.85 (1H, d, J =17.0), 2.40 (2H, m), 1.77 (2H, m), 1.64 (2H, m), 1.27 (2H, m), 0.88 (3H, m), 0.50 (1H, brs). Example 68 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compound 68.

[0394]

[0395] Example 69: Preparation of Compound 69

[0396] Step 1: Preparation of compound 69-b Referring to the preparation method of compound 31-c in Example 31, compound 31-b was replaced with 69-a to obtain compound 69-b.

[0397] Steps 2 to 6: Preparation of Compound 69 Following the synthetic method described in steps three through seven of Example 27, compound 27-c was replaced with 60-a, compound 27-f with 69-b, and compound 2-b with 60-e, yielding compound 69. ESI-MS: m / z = 551.27 [M+H] + . 1H-NMR (CDCl3)δH 8.45(1H, s), 7.53(1H, d, J=2.0), 7.33(1H, dd, J=5.0,9.0), 7.21 (1H, m), 7.06(1H, dd, J=3.0,8.5), 6.18(1H, d, J=2.0), 4.51(4H, s),3.30(2H, t, J=5.5), 3.13(2H, q, J=7.5),2.62(1H, s), 2.42(2H, t, J=6.0), 2.24(6H, s),1.79 (2H, m), 1.29,1.31 (6H, m). Example 70 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compound 70.

[0398]

[0399] Example 71: Preparation of Compound 71

[0400] Following the preparation method of compound 69 in Example 69, compound 60-e was replaced with 2-b to obtain compound 71. ESI-MS: m / z = 545.21 [M+H] + . 1 H-NMR (CDCl3) d H 8.49(1H, s), 8.37(1H, brs),7.55(1H, s), 7.34(1H, brs),7.21(1H, m), 7.07(1H, dd, J =3.0,8.0), 6.16(1H, s), 5.02(1H, s), 4.91(1H, s),4.52(1H, d, J =9.0), 4.29(9H, m), 3.58(1H, s), 2.87(1H, d, J = 18.0), 2.39~2.45(2H, m), 1.98(1H, m), 1.78 (1H, m), 1.66(2H, m), 1.28(6H, m). Example 72: Preparation of Compound 72

[0401] Following the preparation method of compound 67 in Example 67, compound 2-b was replaced with 60-e to obtain compound 72. ESI-MS: m / z = 560.28 [M+H] + . 1 H-NMR (CDCl3) d H 8.47(2H, s), 7.42 (2H, m), 7.18 (1H, m), 7.07~7.12(2H, m), 4.84~4.95(1H, m), 4.26 (10H, m), 3.27(1H, s),2.03~2.14(1H, m), 1.74(3H, m), 1.39 (3H, m), 0.88 (3H, m), 0.50(1H, brs). Example 73: Preparation of Compound 73

[0402] Following the preparation method of compound 69 in Example 69, compound 69-a was replaced with 5-bromo-4-cyclopropylpyrimidine, and compound 60-e was replaced with 2-b, yielding compound 73. ESI-MS: m / z = 555.26 [M+H] + . 1 H-NMR (CDCl3) d H 8.97(1H, s), 8.49 (1H, s), 8.40 (1H, s), 7.36 (1H, m),7.23 (1H, m), 7.47(1H, dd, J =3.0,8.5), 4.94(1H, s), 4.84(1H, s), 4.29 (4H, m),3.97(1H, s), 3.33(1H, s), 2.74(1H, d, J = 18.0), 2.34~2.38 (2H, m), 1.73~1.90(3H, m), 1.59 (4H, m), 1.26 (2H, m), 0.99~1.12 (3H, m), 0.71 (1H, m). Example 74 Referring to the preparation method of Example 31, compound 31-b was replaced with the starting material compounds shown in the table below to obtain target compound 74.

[0403]

[0404] Example 75: Preparation of Compound 75

[0405] Following the preparation method of compound 31 in Example 31, compound 31-b was replaced with 5-bromo-1-isopropyl-1H-pyrazole, and compound 2-b was replaced with 60-e, yielding compound 75. ESI-MS: m / z = 579.30 [M+H] + . 1 H-NMR (CDCl3) d H 8.48 (1H, s), 8.36 (1H, s), 7.54 (1H, s), 7.47 (1H,s), 7.23 (1H, m), 7.07(1H, dd, J =3.0,8.0),6.13(1H, d, J =1.5), 4.87~4.99(1H, m),4.63 (1H, s), 4.26 (1H, m), 3.84 (6H, brs), 3.47 (3H, brs), 2.18(4H, m), 1.76~1.88 (7H, m), 1.30~1.51 (6H, m). Example 76: Preparation of Compound 76

[0406] Following the preparation method of compound 3 in Example 3, compound 3-f was replaced with 7-Boc-2,7-diazaspiro[3.6]decane to obtain compound 76. ESI-MS: m / z = 595.34 [M+H] + . 1 H-NMR (CDCl3) d H 8.45 (1H, dd, J =1.0,4.5), 8.27 (1H, s), 7.66 (1H, s),7.38 (1H, dd, J =1.5,7.5), 7.11 (2H, m), 7.06 (1H, dd, J=4.5,7.5),6.99 (1H, m),4.95 (1H, s), 4.86(1H, s),3.70,3.71(1H, s),3.22~3.88(13H, m), 2.83~2.87(1H,m), 2.35~2.42(2H, m), 1.58~2.02(8H,m), 1.08 (2H, brs), 0.85 (2H, brs). Example 77: Preparation of Compound 77

[0407] Following the preparation method of compound 3 in Example 3, compound 3-h was replaced with (4-cyclopropylpyrimidin-5-yl)boronic acid, and compound 3-f was replaced with 7-Boc-2,7-diazaspiro[3.6]decane to obtain compound 77. ESI-MS: m / z = 596.31 [M+H] + . 1 H-NMR (CDCl3) d H 8.98 (1H, s), 8.40 (1H, s), 8.31 (1H, s), 7.69 (1H,s), 7.15 (2H, m), 6.97 (1H, m), 6.42 (4H, brs), 4.99 (1H, s), 4.90 (1H, s),4.56 (1H, m),3.71~3.90(5H,m), 3.50~3.63(2H,m), 3.24~3.38(2H,m), 2.90 (1H, m),2.47 (1H, s), 2.40 (1H, d, J =18.0), 1.62~2.02(8H,m), 1.22 (2H, t, J =4.0), 0.98(2H, brs). Experimental Example 1: In vitro cell viability assay MOLM-13 or MV-4-11 cells (source: Nanjing Kebai Technology Co., Ltd.) in good growth condition were seeded at 2000-10000 cells per well in 96-well plates (100 μL / well). After overnight culture at 37°C, the compound was serially diluted and added using a pipette, with two replicates per group. A control group was also included. After culturing for 72-120 hours at 37°C, the assay reagent CCK-8 (manufacturer: Dojin Chemical, Japan, 10 μL / well) was added. After culturing for another 3-5 hours at 37°C, the absorbance was measured at 450 nM using a PerkinElmer Envision multi-function plate reader. Four-parameter analysis was performed in GraphPadPrism software to fit the dose-response curve and calculate the IC50. 50 Values. See Table 1 for specific results. Where A represents IC50 < 50 nM.

[0408] Table 1 Cell proliferation inhibition activity

[0409] The results showed that the compounds disclosed herein or pharmaceutical compositions containing the compounds disclosed herein have good inhibitory activity against the proliferation of MV-4-11 cells and / or MOLM-13 cells.

[0410] Experimental Example 2: Detection of the ability of compounds to inhibit Menin-MLL interactions using fluorescence polarization method The binding activity of the compounds to menin protein was determined by fluorescence polarization assay. GST-MENIN (1-615 aa) and FITC-MLL1 were mixed in FP buffer (50 mM Tris-HCl pH 7.5, 50 mM NaCl, 1 mM DTT, 0.01% BSA). 5-43 To dilute, add 10 μL of GST-MENIN (1-615aa) to each well of a black 384-well microtiter plate to a final concentration of 8 nM and FITC-MLL1 to a final concentration of 8 nM. 5-43The mixture was centrifuged at 2500 rpm for 1 min and incubated at room temperature in the dark for 1 h. 5 μL of diluted compound (7 concentration points, 4-fold serial dilution, with blank and negative control wells included) was added, centrifuged at 2500 rpm for 1 min, and incubated at room temperature in the dark for 3 h. After incubation, the FP (480 / 535) values ​​were measured using a PerkinElmer Envision multi-function plate reader. The inhibition rate (%) of each compound concentration was calculated using Equation 1 to determine the compound's ability to inhibit Menin-MLL interaction; Equation 1: Inhibition rate (%) = 1 - (Maximum mP Control - Dose-group mP) / (Maximum mP Control - Minimum mP Control) × 100%. Four-parameter analysis was performed in GraphPad Prism software to fit the dose-response curve and calculate the IC50. 50 Values. See Table 2 for specific results. Where A represents IC50 < 50 nM.

[0411] Table 2 Menin-MLL protein binding inhibitory activity

[0412] The results show that the compound disclosed herein or pharmaceutical compositions containing the compound disclosed herein have good Menin-MLL binding inhibitory activity.

[0413] Experimental Example 3: In vitro stability of liver microsomes Liver microsomal incubation sample preparation: Mixed PBS buffer (pH 7.4), liver microsomal solutions (0.5 mg / mL) from various genera (human, mouse, monkey, dog, and rat), the test compound (final concentration 1 μM), and NADPH + MgCl2 solution were incubated at 37°C and 300 rpm. Samples were taken from the reaction solution at 15 and 60 minutes. The 0-hour sample consisted of mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and the test compound. The sample was precipitated with acetonitrile containing an internal standard to prepare the supernatant, which was then diluted for LC-MS / MS analysis.

[0414] Table 3. In vitro metabolic stability of compounds in mouse liver microsomes

[0415] Table 4. In vitro metabolic stability of compounds in human liver microsomes

[0416] The test results show that the compound disclosed herein or pharmaceutical compositions containing the compound disclosed herein exhibit good properties in in vitro liver microsomal stability tests.

[0417] Experimental Example 4: In vivo pharmacokinetics ICR mice, weighing 18-22 g, were randomly divided into groups of 9 mice each after acclimatization for 3-5 days. The gavage group was given the relevant compound solution by gavage at a dose of 10 mg / kg, while the intravenous injection group was given the relevant compound solution by intravenous injection at a dose of 1 mg / kg.

[0418] Blood was collected via gavage at the following times: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h; blood was collected via intravenous injection at the following times: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h; blood was collected from the orbital rim to prepare plasma samples for testing.

[0419] Take 30 µL of the plasma sample to be tested and the standard curve sample, add acetonitrile solution containing internal standard, and obtain the supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[0420] Pharmacokinetic parameters were fitted using a non-compartmental model.

[0421] The experimental results show that the compound disclosed herein or pharmaceutical compositions containing the compound disclosed herein have good in vivo pharmacokinetic properties (bioavailability, AUC, T). 1 / 2 and C max (e.g., parameters).

[0422] Experimental Example 5: In vivo efficacy study MV-4-11 human acute monocytic leukemia cells were subcutaneously injected into the right axilla of SPF-grade male NOD-SCID mice (source: Lingchang), at a dose of 5 × 10⁻⁶ cells. 6 One tumor per animal (1:1 Matrigel mixture, inoculated). Inoculate when the average tumor volume reaches 250 mm². 3 When moving left or right, group the animals together.

[0423] Day 0 was designated as the day of grouping. From day 0 onwards, the mice were administered the medication via gavage once daily. Tumor volume was measured 2-3 times per week, and mouse weight was recorded. General mouse behavior was observed and recorded daily. At the end of the experiment, the tumors were removed, weighed, and photographed.

[0424] The detection indicators and calculation formulas are as follows: Tumor volume, TV (mm) 3 ) = 1 / 2×(a×b 2 ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0425] Relative to tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, TV t This represents the tumor volume at each measurement.

[0426] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where T RTV For the treatment group, RTV; C RTV The solvent control group is RTV.

[0427] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0)×100%; where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group.

[0428] Body weight change rate, BWC (%) = (Wt) t -Wt0) / Wt0×100%; where Wt0 is the animal's weight on day 0, Wt t The animal's weight at the time of each measurement.

[0429] The experimental results show that the disclosed compound or a pharmaceutical composition containing the disclosed compound can inhibit tumor growth in vivo. On day 21, the tumor volume inhibition rate was greater than 70%, and the tumor weight inhibition rate was greater than 75%.

Claims

1. A pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof, in, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 alkylene-5-10 heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 - N(R) c1 )S(O) R d1 -S(O)2R b1 -S(O)2NR c1 R d1 - N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 、or -C(O)NR c1 R d1 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-C 3-10 cycloalkyl, -C 1-6 Alkylene-3-10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 The alkylene-5-10 heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; R c2 and R d2 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; R 8 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more groups selected from halogen, -CN, -OH or -NH2; Y is selected from O, S, CR x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or C. 1-6 alkyl; W, W 1 W 2 W 3 W 4 and W 5 Each is independently selected from N, C, or CH; Ring A is selected from one or more Rs arbitrarily. a1 The following groups are substituted: C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 heteroarylene; H is selected from bonds, NR z C 3-8 Cycloalkyl or 3-8 heterocycloalkyl, wherein R z Selected from hydrogen or C 1-6 alkyl; R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl; R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ -OC(O)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ -S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -CN, -OH or -NH2; R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl or 5-10 heteroaryl group may be optionally substituted by one or more halogens, -OH, -CN or -NH2; R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl substituted; R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -CN, -OH or -NH2; M is selected from -C(O)- or -(CR)- u R v ) q -;R u and R v Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 1, 2, 3, or 4; m and p are each independently selected from 0, 1, 2 or 3; q is selected from 1, 2, or 3; The condition is: when for At that time, R 5 Not selected ; The pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form; Optionally, the pharmaceutical composition contains 0.01 mg to 1000 mg of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof in a single dose; Optionally, in the pharmaceutical composition, the content of the compound or its pharmaceutically acceptable salt is 0.01-95%wt or 0.4-95%wt; Optionally, the target of administration of the pharmaceutical composition is selected from mammals, such as humans.

2. The pharmaceutical composition of claim 1, wherein the R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 alkylene-5-6-membered heteroaryl, -OR b1 -SR b1 -NR c1 R d1 -C(O)R b1 -OC(O)R b1 -C(O)OR b1 -S(O)R b1 -S(O)NR c1 R d1 - N(R) c1 )S(O)R d1 -S(O)2R b1 -S(O)2NR c1 R d1 -N(R) c1 )S(O)2R d1 -OC(O)NR c1 R d1 -N(R) c1 )C(O)R d1 or -C(O)NR c1 R d1 The C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3-6-membered heterocyclic alkyl, -C 1-4 alkylene-phenyl, -C 1-4 The alkylene-5-6-membered heteroaryl group is optionally surrounded by one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or -C 1-6 Heteroalkyl substitution; Or, R 1 and R 2 Combine to form =O, =S, or =CR c2 R d2 ; and / or, R 3 and R 4 Combine to form =O, =S, or =CR c2 R d2 ; Optional, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 heterocycloalkyl, -CH2-phenyl, -CH2-5-6 heteroaryl, wherein C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 heterocycloalkyl, -CH2-phenyl, -CH2-5-6 heteroaryl groups are optionally converted by one or more halogens, OH, -CN, -NH2 or C 1-4 Alkyl substitution; Or, R 1 and R 2 Combining to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2; Optional, R 1 R 2 R 3 and R 4 Each is independently selected from hydrogen, halogen, -OH, -CN, -NH2, or C. 1-3 alkyl; Or, R 1 and R 2 Combining to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2; Optional, R 3 and R 4 Selected from hydrogen, and R 1 and R 2 Combining to form =O or =CH2; or, R 1 and R 2 Selected from hydrogen, and R 3 and R 4 The combination forms =O or =CH2.

3. The pharmaceutical composition according to claim 1 or 2, wherein the R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally bonded to one or more halogens, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution; Or, R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl groups are optionally bound by one or more halogens, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 Heteroalkyl substitution; Or, R b1 R c1 and R d1 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl or C 2-4 alkynyl group, the C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be substituted by one or more halogens, -CN, -OH or -NH2; Or, R b1 R c1 and R d1 Each is independently selected from hydrogen or C. 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Or, R b1 R c1 and R d1 Each is independently hydrogen or C 1-3 alkyl; Or, R b1 R c1 and R d1 Each is independently a methyl group.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the R c2 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Or, R c2 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl; Or, R c2 and R d2 Each is independently selected from hydrogen or C. 1-3 alkyl; Or, R c2 and R d2 Each is independently selected from hydrogen; Optional, R 8 Selected from hydrogen or C 1-4 Alkyl; or, R 8 Selected from hydrogen or methyl; or, R 8 It is hydrogen.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the Y is selected from O, S, and CR. x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or C. 1-3 alkyl; Alternatively, Y can be selected from O, S, or CR. x R y or NR z , where R x R y Or R z Each is independently selected from hydrogen or methyl; Alternatively, Y can be selected from O, S, CH2, or NH; Alternatively, Y can be selected from O; Optionally, M is selected from -CH2- or -C(O)-; Alternatively, M can be selected from -C(O)-; Optional, R u and R v Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, or C. 1-3 alkyl; Or, R u and R v Selected from hydrogen.

6. The pharmaceutical composition according to any one of claims 1-5, wherein W is selected from N, C, or CH; or, W is selected from N or CH; Optionally, the W 1 Selected from N, C, or CH; or W 1 Selected from N or CH; Optionally, the W 2 Selected from N, C, or CH; or W 2 Selected from CH; optionally, the W 3 Selected from N or CH; Optionally, the W and W 1 For N, W 2 It is CH or C; Optionally, the W 4 For CH or C, W 3 and W 5 Selected from N, C, or CH; Optionally, the W 4 and W 5 Selected from CH; Optionally, the W 1 W 2 W 3 W 4 and W 5 Selected from CH; Alternatively, W is N, and W 1 W 2 W 3 W 4 and W 5 Each is independently selected from C or CH; Or, the W 1 Let N be a subset of N, and W and W' be subsets of N. 2 W 3 W 4 and W 5 Each is independently selected from C or CH; Or, the W and W mentioned above 1 Let N be the number of elements and W be the number of elements. 2 W 3 W 4 and W 5 Each is independently selected from C or CH; Or, the W and W mentioned above 3 Each is independently selected from N or CH, and W 1 W 2 W 3 W 4 and W 5 Selected from CH; Or, the W, W 1 and W 3 Each is independently selected from CH or N, and W 2 W 4 and W 5 Selected from CH.

7. The pharmaceutical composition according to any one of claims 1-6, wherein ring A is selected from rings optionally surrounded by one or more R a1 Replace the following groups: C 5-12 C1-C ... a1 Substituted 7-9-membered heterospirocycloalkyl group; optionally, ring A contains one, two, or three heteroatoms selected from N, O, or S; or, ring A is selected from those optionally divided by one or more R atoms. a1 Substituted 9-membered heterospirocycloalkyl group; Alternatively, ring A is selected from Where n1, n2, n3, and n4 are independently selected from 1, 2, or 3, and X is selected from N or CH; Alternatively, ring A is selected from , , , , , , , , or ,in This indicates the bond and structural fragment at that location. Connected, the bond on the other side is with the structural segment. Connected; or, ring A is ; Optionally, the R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, or C. 1-6 alkyl; Or, R a1 Each is independently selected from halogens, -OH, -CN, -NH2, =O, =S, or C. 1-3 alkyl.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ (CO)OR b’ -O(CO)NR b’ R b’ -C(O)R b’ -S(O)R b’ -S(O)2R b’ -N(R) b’ )S(O)2R b’ - N(R) b’ )S(O)R b’ -S(O)NR b’ R b’ - S(O)2NR b’ R b’ -OC(O)R b’ -C(O)OR b’ C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; Or, R 5 Selected from halogens, -OH, -CN, -NH2, or optionally by one or more R a’’ The following groups are substituted: -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)R b’ -N(R) b’ )C(O)OR b’ Or 5-6 heteroaryl groups; Or, R 5 Selected from halogens, or optionally by one or more R a’’ Substituted groups include: 4-8 membered heterocyclic alkyl C(O)-, C 8-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 1-4 Alkyl)C 3-6 Cycloalkyl, -C(O)N(C 1-4 Alkyl groups (4-6 membered heterocyclic alkyl groups), -NHC(O)C 1-4 Alkyl group, -NHC(O)C 3-6 cycloalkyl, -N(C) 1-4 Alkyl)C(O)OC 1-4 Alkyl or 5-6-membered heteroaryl; Or, R 5 Selected from halogens, -C(O)R b’ -C(O)NR a’ R b’ -N(R) b’ )C(O)OR b’ -N(R) b’ )C(O)R b’ Or 5-6 quinone heteroaryl, wherein -C(O)NR a’ R b’ -C(O)R b’ -N(R) b’ )C(O)OR b’ -N(R) b’ )C(O)R b’ Alternatively, the 5-6 heteroaryl group may be substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, or C group optionally substituted with one or more halogens or -OH. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Or, R 5 Selected from F, Cl, Br, 5-7 membered heterocyclic alkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) (4-6 membered heterocyclic alkyl), -NHC(O)C 1-3 Alkyl group, -NHC(O)C 3-5 cycloalkyl, -N(C) 1-3 Alkyl)C(O)OC 1-3 Alkyl or 5-6-membered heteroaryl, wherein the 5-7-membered heterocyclic alkyl group is C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 Cycloalkyl NHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 Alkyl) (4-6 membered heterocyclic alkyl), -NHC(O)C 1-3 Alkyl group, -NHC(O)C 3-5 cycloalkyl or -N(C) 1-3 Alkyl)C(O)OC 1-3 The alkyl or 5-6-membered heteroaryl group is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, or C group optionally substituted with one or more halogens or -OH. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-4 Cycloalkyl or 4-5 membered heterocyclic alkyl; Or, R 5 Selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)N(C 1-4 Alkyl)2, -C(O)-pyrroleyl, -C(O)-piperidinyl, -C(O)-morpholinyl, -C(O)-piperazinyl, -C(O)azabicycloheptyl, adamantyl NHC(O)-, -C(O)N(C 1-3 alkyl)cyclopropyl, -C(O)N(C 1-3 alkyl)oxetane butyl, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 Alkyl)C(O)OC 1-3 Alkyl groups, wherein the pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)-morpholinyl, or -C(O)-piperazinyl is optionally surrounded by one or two groups selected from F, Cl, -OH, -CN, methyl, -CF3, -OCH3, cyclopropyl, isopropyl, Or substitution of the oxocyclic butyl group; Or, R 5 Selected from Br, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Optionally, the R a’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; Or, R a’ Each is independently selected from hydrogen and C. 1-4 Alkyl or C 3-4 cycloalkyl; Or, R a’ Each is independently selected from hydrogen, methyl, ethyl, isopropyl, Or cyclopropyl; Optionally, the R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 The cycloalkyl, 4-10 heterocycloalkyl, phenyl or 5-6 heteroaryl groups are optionally substituted by one or more halogens, -CN, -OH or -NH2; Or, R b’ Each of the following groups, independently selected from hydrogen or optionally substituted with one or more halogens: C 1-6 Alkyl, C 3-9 Cycloalkyl or 4-9 membered heterocyclic alkyl; Or, R b’ Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl , , , , , or ; Optionally, the R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and -NH(C). 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl-O-, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -OH, -CN or -NH2; Or, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, -NH(C) 1-4 alkyl), -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, -NH(C) 1-4 alkyl), -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group may be optionally substituted with one or more halogens or -OH; Or, R a’’ Each is independently selected from halogens, -OH, -CN, -NH2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl, wherein C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 The cycloalkyl or 3-5 membered heterocycloalkyl group may be optionally substituted with one, two or three groups selected from the following groups: halogen, -OH, -CN or -NH2; Or, R a’’ Each is independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl, cyclopropyl, Or oxoheterobutyl.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Or, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Or, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or, R 6 Selected from hydrogen, halogens, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Heteroalkyl; Or, R 6 Selected from hydrogen, halogen or C 1-6 alkyl; Or, R 6 Selected from hydrogen, F, Cl, Br, or methyl; or, R 6 Selected from hydrogen, F, or methyl.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the R a and R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens, -CN, -OH or -NH2; Optional, R 7 Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; Or, R 7 Each is independently selected from cyclopropyl; Optional, R a Each is independently selected from halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl or -OC 1-4 alkyl; Or, R a Each element is independently selected from halogens, -CN, -OH, -NH2, or C. 1-4 alkyl; Or, R a Each is independently selected from F, Cl, or Br; or, R a Each is independently F; Optionally, m is selected from 0, 1, or 2; or m is selected from 0 or 1. Alternatively, m can be selected from 0; Alternatively, m is selected from 1; Optionally, p is selected from 0, 1, or 2; or, p is selected from 0 or 1. Alternatively, p is selected from 0; Optionally, n can be selected from 1 or 2; or n can be selected from 2. Optionally, q is selected from 1.

11. The pharmaceutical composition according to any one of claims 1-10, wherein H is selected from bonds; optionally, R 8 Selected from hydrogen; R 1 and R 2 It is hydrogen; and, R 3 and R 4 Combining to form =CH2; W and W 1 For N, W 2 It is CH or C.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the composition is selected from compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III'), formula (IA), formula (IIA), formula (IB), formula (IIB), formula (IC), formula (IID), formula (IIC), formula (IA-1), formula (IIA-1), formula (IA-2), formula (IB-1), or formula (IC-1) or a pharmaceutically acceptable salt thereof: ， X t Selected from O or CH(R) c2 ), where R c2 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The heteroalkyl group may optionally be substituted with one or more halogens, -CN, -OH or -NH2; Or, R c2 Selected from hydrogen or C 1-3 Alkyl; or R c2 Selected from hydrogen.

13. Pharmaceutical compositions comprising the following compounds or pharmaceutically acceptable salts thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , or .

14. The pharmaceutical composition according to any one of claims 1-13, further comprising a pharmaceutically acceptable excipient.

15. Use of the pharmaceutical composition according to any one of claims 1-14 in the preparation of a medicament for the prevention or treatment of a disease; optionally, wherein the disease is selected from cancer; optionally, wherein the cancer is selected from leukemia.

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