Azabicyclic derivatives

Abstract

Provided are pharmaceutically acceptable azabicyclic ring derivatives, specifically compounds of formula (III) or a pharmaceutically acceptable salt thereof, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of diseases.

Description

Aza-bridged ring derivatives

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202311466782.3 filed with the State Intellectual Property Office of China on November 6, 2023, Chinese Patent Application No. 202410155014.4 filed with the State Intellectual Property Office of China on February 3, 2024, and Chinese Patent Application No. 202411547399.5 filed with the State Intellectual Property Office of China on October 31, 2024, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to pharmaceutically usable aza-bridged ring derivatives, or pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating diseases. Background Art

[0004] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a ubiquitously expressed nuclear protein that regulates tissue-specific gene expression. Menin interacts with DNA through its C-terminal nuclear localization sequence (NLS), binding to promoters, transcription factors, or enhancers, thereby regulating gene expression and cellular signaling.

[0005] In different tissues, Menin can bind to different proteins (such as MLL1 (mixed lineage leukemia protein 1), MYC, and JunD), leading to different downstream functions. For example, the direct interaction between Menin and the amino-terminal sequence of MLL is necessary for leukemia mediated by MLL fusion (MLLr) proteins. Menin 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 the development of tumors driven by MLLr protein.

[0006] Currently, there are no drugs targeting the Menin-MLL protein interaction target on the market, and there is still a need to develop new compounds with selective inhibitory activity, or better pharmacodynamics, or better pharmacokinetic properties in this field.

[0007] Summary of the Invention

[0008] The present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] R 1 、R 2 、R 3 and R 4 are independently selected from hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 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 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5-10 membered heteroaryl is optionally substituted with one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0011] 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 ;

[0012] R b1 、R c1 and R d1 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0013] R c2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0014] R 8 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more groups selected from halogen, -CN, -OH or -NH2;

[0015] Y is selected from O, S, CR x R y or NR z , where R x 、R y or R zEach independently selected from hydrogen or C 1-6 alkyl;

[0016] W, W 1 、W 2 、W 3 、W 4 and W 5 are independently selected from N, C or CH;

[0017] Ring A is selected from the group consisting of a1 Substituted with the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene;

[0018] H is selected from a bond, NR z 、C 3-8 Cycloalkyl or 3-8 heterocycloalkyl, wherein R z Selected from hydrogen or C 1-6 alkyl;

[0019] R a1 Each independently selected from halogen, -OH, -CN, -NH2, =O, =S, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 heteroalkyl;

[0020] R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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’ 、C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0021] R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl;

[0022] R b’ are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0023] R a” Each independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -OH, -CN or -NH2;

[0024] R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Substituted by cycloalkyl or 3-10 membered heterocycloalkyl;

[0025] R a and R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0026] M is selected from -C(O)- or -(CR u R v ) q -;R u and R v Each independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0027] n is selected from 1, 2, 3 or 4;

[0028] m and p are independently selected from 0, 1, 2 or 3;

[0029] q is selected from 1, 2 or 3;

[0030] The condition is that when for When R 5 Not for

[0031] In another aspect, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0032] in,

[0033] R 1 、R 2 、R 3 and R 4 are independently selected from hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 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 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5-10 membered heteroaryl is optionally substituted with one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0034] 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 ;

[0035] R b1 、R c1 and R d1 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0036] R c2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0037] Y is selected from O, S, CR x R y or NR z , where R x 、R y or Rz are each independently selected from hydrogen or C 1-6 alkyl;

[0038] W, W 1 、W 2 、W 3 、W 4 and W 5 are independently selected from N, C or CH;

[0039] Ring A is selected from the group consisting of a1 Substitute the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene;

[0040] R a1 Each independently selected from halogen, -OH, -CN, -NH2, =O, =S, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 heteroalkyl;

[0041] R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0042] R a’ Selected from hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl;

[0043] R b’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0044] R a” Each independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -OH, -CN or -NH2;

[0045] R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Substituted by cycloalkyl or 3-10 membered heterocycloalkyl;

[0046] R a and R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -OC 1-6 Alkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -OC 1-6 Alkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0047] M is selected from -C(O)- or -(CR u R v ) q -;R u and R v Each independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0048] n is selected from 1, 2, 3 or 4;

[0049] m and p are independently selected from 0, 1, 2 or 3;

[0050] q is selected from 1, 2 or 3;

[0051] The condition is R 5 Not selected

[0052] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0053] in,

[0054] R 1 、R2 、R 3 and R 4 are independently selected from hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 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 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5-10 membered heteroaryl is optionally substituted with one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0055] Or, R 1 and R 2 Combine to form =O, =S or =CR c2 Rd2 and / or, R 3 and R 4 Combine to form =O, =S or =CR c2 R d2 ;

[0056] R b1 、R c1 and R d1 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6- 10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 heteroalkyl substitution;

[0057] R c2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0058] Y is selected from O, S, CR x R y or NR z , where R x 、R y or R z Each independently selected from hydrogen or C 1-6 alkyl;

[0059] W, W 1 、W 2 、W 3 、W 4 and W 5 are independently selected from N, C or CH;

[0060] Ring A is selected from the group consisting of a1Substitute the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene;

[0061] R a1 Each independently selected from halogen, -OH, -CN, -NH2, =O, =S, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 heteroalkyl;

[0062] R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0063] R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl;

[0064] R b’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0065] R a” Each independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -OH, -CN or -NH2;

[0066] R 6 Selected from hydrogen, halogen, -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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0067] R a and R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -OC 1-6 Alkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -OC 1-6Alkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2;

[0068] n is selected from 1, 2, 3 or 4;

[0069] m and p are independently selected from 0, 1, 2 or 3;

[0070] The conditions are: R 5 Not selected

[0071] In some embodiments, R 1 、R 2 、R 3 and R 4 Each independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -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, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -C1-4 Alkylene-phenyl, -C 1- 4-alkylene-5-6 membered heteroaryl is optionally substituted with one or more -OH, -CN, -NH2, halogen, C 1-6 Alkyl or -C 1-6 heteroalkyl substitution;

[0072] 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 ;

[0073] The R b1 、R c1 、R d1 、R c2 and R d2 The definition of is as described in this disclosure.

[0074] In some embodiments, R 1 、R 2 、R 3 and R 4 Each independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -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, -C 1-4Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -C 1-4 Alkylene-phenyl or -C 1-4 Alkylene-5-6 membered heteroaryl is optionally substituted with one or more halogen, OH, -CN, -NH2, C 1-4 Alkyl or -OC 1-4 Alkyl substitution,

[0075] 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 ;

[0076] The R b1 、R c1 、R d1 、R c2 and R d2 The definition of is as described in this disclosure.

[0077] In some embodiments, R 1 、R 2 、R 3 and R 4 are independently selected from hydrogen, halogen, -OH, -CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -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, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4Alkylene-3-6 membered heterocycloalkyl, -C 1-4 Alkylene-phenyl or -C 1-4 Alkylene-5-6 membered heteroaryl is optionally substituted with one or more halogen, OH, -CN, -NH2, C 1-3 Alkyl or -OC 1-3 Alkyl substitution,

[0078] 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 ;

[0079] The R b1 、R c1 、R d1 、R c2 and R d2 The definition of is as described in this disclosure.

[0080] In some embodiments, R 1 、R 2 、R 3 and R 4 Each independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 membered heterocycloalkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 membered heterocycloalkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl are optionally substituted with one or more halogen, OH, -CN, -NH2 or C 1-4 Alkyl substitution;

[0081] Or, R 1 and R 2 Combine to form ═O or ═CH 2 ; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0082] In some embodiments, R 1 、R 2 、R 3 and R 4are each independently selected from hydrogen, halogen, -OH, -CN, -NH2 or C 1-3 alkyl.

[0083] In some embodiments, R 1 、R 2 、R 3 and R 4 are each independently selected from hydrogen, halogen, -OH, -CN, -NH2 or C 1-3 alkyl;

[0084] Or, R 1 and R 2 Combine to form ═O or ═CH 2 ; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0085] In some embodiments, R 1 and R 2 Combine to form ═O or ═CH 2 ; and / or, R 3 and R 4 Combine to form =O or =CH2.

[0086] In some embodiments, R 3 and R 4 Any one of them is hydrogen and the other is F.

[0087] In some embodiments, R 1 and R 2 is hydrogen; and R 3 and R 4 One of them is hydrogen and the other is F, or R 3 and R 4 Combine to form =O or =CH2. In some embodiments, R 1 and R 2 is hydrogen; and R 3 and R 4 The combination forms =CH2.

[0088] In some embodiments, R 3 and R 4 is hydrogen, and R 1 and R 2 Combine to form =O or =CH2.

[0089] In some embodiments, R 1 and R 2 is hydrogen, and R 3 and R 4 Combine to form =O or =CH2.

[0090] In some specific embodiments, R1 and R 2 is hydrogen; and R 3 and R 4 One of them is hydrogen and the other is F.

[0091] In some embodiments, R b1 、R c1 and R d1 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 Heteroalkyl substitution.

[0092] In some embodiments, R b1 、R c1 and R d1 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, the C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl groups are optionally substituted with one or more halogen, -CN, -OH, or -NH2.

[0093] In some embodiments, R b1 、R c1 and R d1 Each independently selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more halogen, -CN, -OH or -NH2.

[0094] In some embodiments, R b1 、R c1 and R d1 are each independently hydrogen or C 1-3 alkyl.

[0095] In some embodiments, R b1 、R c1 and R d1 are each independently methyl.

[0096] In some embodiments, Rc2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH, or -NH2.

[0097] In some embodiments, R c2 and R d2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Heteroalkyl.

[0098] In some embodiments, R c2 and R d2 Each independently selected from hydrogen or C 1-3 alkyl.

[0099] In some embodiments, R c2 and R d2 are each independently hydrogen.

[0100] In some embodiments, R 8 Selected from hydrogen or C 1-4 In some embodiments, R 8 In some embodiments, R 8 For hydrogen.

[0101] In some embodiments, Y is selected from O, S, CR x R y or NR z , where R x 、R y or R z Each independently selected from hydrogen or C 1-3 alkyl.

[0102] In some embodiments, Y is selected from O, S, CR x R y or NR z , where R x 、R y or R z are each independently selected from hydrogen or methyl.

[0103] In some embodiments, Y is selected from O, S, CH2, or NH.

[0104] In some embodiments, Y is selected from O or S.

[0105] In some embodiments, Y is O.

[0106] In some embodiments, in the structural fragment In the case of W, W 1 and / or W 2 With R 7 When connected, W, W 1 and / or W 2 is C, when W, W 1 and / or W 2 Not with R 7 When connected, W, W 1 and / or W 2 is N or CH.

[0107] In some embodiments, in the structural fragment In, when W 3 、W 4 and / or W 5 With R a When connected, W 3 、W 4 and / or W 5 is C, when W 3 、W 4 and / or W 5 Not with R a When connected, W 3 、W 4 and / or W 5 is N or CH.

[0108] In some embodiments, W is selected from N, C, or CH. In some embodiments, W is selected from N or CH.

[0109] In some embodiments, W 1 In some embodiments, W 1 is selected from N or CH.

[0110] In some embodiments, W 2 In some embodiments, W 2 For CH.

[0111] In some embodiments, W 3 is selected from N or CH.

[0112] In some embodiments, W 4 and W 5 For CH.

[0113] In some embodiments, W3 、W 4 and W 5 For CH.

[0114] In some embodiments, W 1 、W 2 、W 3 、W 4 and W 5 In some embodiments, W is N, and W 1 、W 2 、W 3 、W 4 and W 5 are independently selected from C or CH.

[0115] In some embodiments, W 1 is N, and W, W 2 、W 3 、W 4 and W 5 are independently selected from C or CH.

[0116] In some embodiments, W and W 1 is N, and W 2 、W 3 、W 4 and W 5 are independently selected from C or CH.

[0117] In some embodiments, W and W 3 are independently selected from N or CH, and W 1 、W 2 、W 3 、W 4 and W 5 For CH.

[0118] In some embodiments, W, W 1 and W 3 are independently selected from CH or N, and W 2 、W 4 and W 5 For CH.

[0119] In some embodiments, W is N, W 1 and W 2 In some embodiments, W and W 1 N, W 2 is CH or C. In some embodiments, W and W 2 CH, W 1 is N.

[0120] In some embodiments, the W 4CH or C, W 3 and W 5 is selected from N, C or CH.

[0121] In some embodiments, when for When R 5 Not for

[0122] In some embodiments, R 5 Not for

[0123] In some embodiments, R a are independently selected from halogen, CN, OH, NH2 or C 1-3 alkyl.

[0124] In some embodiments, R a For fluorine.

[0125] In some embodiments, R z For hydrogen.

[0126] In some embodiments, the structural unit Selected from Among them, W, W 1 、W 2 、R 7 and p are as defined in this disclosure.

[0127] In some embodiments, the structural unit Selected from Where W 3 、W 4 、W 5 、R 5 、R 6 、R a and m are as defined in this disclosure. In some embodiments, the structural unit Selected from Where W 3 、W 4 、W 5 、R 5 、R 6 、R a and m are as defined in the present disclosure.

[0128] In some embodiments, the structural unit Selected from where R 5 、R 6 and R a The definition of is as described in this disclosure.

[0129] In some embodiments, the structural unit Selected from

[0130] In some embodiments, the structural unit Selected from Where * indicates that the bond at this position is connected to the H part or ring A (when H is a bond), and the other side is connected to the Y part, wherein R 7 The definition of is as described in this disclosure.

[0131] In some embodiments, the structural unit Selected from Wherein * 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.

[0132] In some embodiments, Ring A is selected from the group consisting of a1 Substitute the following groups: C 5-12 5- to 12-membered cycloalkylene, 5- to 12-membered heterocyclylene, C6 arylene or 5- to 6-membered heteroarylene.

[0133] In some embodiments, Ring A is selected from the group consisting of a1 Substitute the following groups: C 6-10 6-10 membered cycloalkylene group, 6-10 membered heterocyclylene group.

[0134] In some embodiments, Ring A is selected from the group consisting of a1 Substitute the following groups: 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocycloalkylene.

[0135] In some embodiments, Ring A is selected from the group consisting of a1 substituted 7-9 membered heterocycloalkylene, wherein R a1 The definition of is as described in this application.

[0136] In some embodiments, Ring A is selected from the group consisting of a1 substituted 7-9 membered heterospirocycloalkylene, wherein R a1 The definition of is as described in the present application. In some embodiments, Ring A is selected from the group consisting of a1 Substituted 9-membered heterospirocycloalkylene, wherein R a1 The definition of is as described in the present application. Optionally, the ring A contains 1, 2 or 3 heteroatoms selected from N, O or S; or, the ring A contains 2 heteroatoms selected from N, O or S; or, the ring A contains 2 N atoms. In some embodiments, the ring A is selected from wherein n1, n2, n3 and n4 are independently selected from 1, 2 or 3, and X is selected from N or CH. In some embodiments, n1, n2, n3 and n4 are independently selected from 1 or 2.

[0137] In some embodiments, Ring A is selected from wherein n1, n2, n3 and n4 are independently selected from 1, 2 or 3, X is selected from N or CH, wherein * represents the bond between the position and the structural fragment In some embodiments, n1 and n2 are selected from 1, n3 and n4 are selected from 2, and X is selected from N.

[0138] In some embodiments, Ring A is selected from the group consisting of a1 substituted 7-10 membered heterospirocycloalkylene, wherein R a1 The definition of is as described in this application.

[0139] In some embodiments, Ring A is selected from the group consisting of a1 substituted 7-10 membered heterospirocycloalkylene, optionally, the ring A contains 1, 2 or 3 heteroatoms selected from N, O or S; or, the ring A contains 1 or 2 heteroatoms selected from N, O or S; or, the ring A contains 1 or 2 N atoms; the R a1 The definition of is as described in the present application. In some embodiments, Ring A is selected from the group consisting of a1 Substituted 7-9 membered heterospirocycloalkylene (eg, [3,3] heterospirocycloalkylene, [3,5] heterospirocycloalkylene), wherein R a1 Selected from =O or C 1-6 Alkyl; optionally, ring A contains 1 or 2 N atoms.

[0140] In some embodiments, Ring A is selected from wherein n1, n2, n3 and n4 are independently selected from 1, 2 or 3 (e.g., n1, n2, n3 and n4 are independently selected from 1 or 2; or n1 and n2 are 1, n3 and n4 are 2), X is independently selected from N or CH (e.g., one X is N and the other is CH; or both X are N), and ring A is optionally substituted with 1 =O or methyl.

[0141] In some embodiments, Ring A is selected from the group consisting of a1 Substituted with the following groups:

[0142] In some embodiments, Ring A is selected from the group consisting of a1 Substituted with the following groups: In some embodiments, R a1 Selected from =O or C 1-6 In some embodiments, the above structural fragment is optionally substituted with one =0 or methyl.

[0143] In some embodiments, Ring A is selected from the group consisting of a1 Substituted with the following groups: Where * indicates the bond and structure fragment at that position (when H is absent, i.e., H is a bond), and the other side is connected to M. In some embodiments, R a1 Selected from =O or C 1-6 In some embodiments, the above structural fragment is optionally substituted with one =0 or methyl.

[0144] In some embodiments, Ring A is selected from In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, Ring A is selected from Where * indicates the bond and structure fragment at that position connected to the other side of the structural fragment Connected, where W, W 1 、W 2 、n、R 1 、R 2 、R 3 and R 4 The definition of is as described in this disclosure.

[0145] In some embodiments, Ring A is selected from Where * indicates the bond between the position and the H part or structural fragment (When H does not exist, that is, H is a bond) connected to the other side and 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 of is as described in this disclosure.

[0146] In some embodiments, Ring A is selected from Where * indicates the bond between the position and the H part or structural fragment (when H is a bond) connected to each other, and the other side is connected to the M part.

[0147] In some embodiments, Ring A is selected from Where * indicates the bond and structure fragment at that position connected to the other side of the structural fragment Connected, where W, W 1 、W 2 、n、R 1 、R 2 、R 3 、R 4 and M are as defined in this disclosure.

[0148] In some embodiments, Ring A is The * means the same as above.

[0149] In some embodiments, R u and R v are each independently selected from hydrogen, halogen, -CN, -OH, -NH2 or C 1-3 In some embodiments, R u and R v For hydrogen.

[0150] In some embodiments, M is selected from -CH2- or -C(O)-. In some embodiments, M is -C(O)-.

[0151] In some embodiments, H is a bond, i.e., a structural unit is directly attached to Ring A. In some embodiments, H is NH.

[0152] In some embodiments, R a1 Each independently selected from halogen, -OH, -CN, -NH2, =O, =S or C 1-6 alkyl.

[0153] In some embodiments, R a1 Each independently selected from halogen, -OH, -CN, -NH2, =O, =S or C 1-3 alkyl.

[0154] In some embodiments, R a1 are independently selected from =O, halogen or C 1-3 alkyl.

[0155] In some embodiments, R a1 Each independently selected from =O or C 1-3 alkyl.

[0156] In some specific embodiments, R a1 Each is independently selected from =0 or methyl.

[0157] In some embodiments, R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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, said R a’ 、R b’ 、R a” The definition of is as described in this disclosure.

[0158] In some embodiments, R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 a 5-6 membered heteroaryl group, wherein R a’ 、R b’ and R a” The definition of is as described in this disclosure.

[0159] In some embodiments, R 5selected from halogen, or optionally substituted by one or more R a” Substituted by the following groups: 3-10 membered heterocycloalkyl C(O)-, C 3-10 CycloalkylNHC(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)(5-10 membered heterocycloalkyl), -NHC(O)C 1-6 Alkyl, -NHC(O)C 3-10 Cycloalkyl, -N(C 1-6 alkyl)C(O)OC 1-3 alkyl or 5-10 membered heteroaryl, said R a” The definition of is as described in this disclosure.

[0160] In some embodiments, R 5 selected from halogen, or optionally substituted by one or more R a” Substituted by the following groups: 4-8 membered heterocycloalkyl C(O)-, C 8-10 CycloalkylNHC(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)(4-6 membered heterocycloalkyl), -NHC(O)C 1-4 Alkyl, -NHC(O)C 3-6 Cycloalkyl, -N(C 1-4 alkyl)C(O)OC 1-4 Alkyl or 5-6 membered heteroaryl, said R a” The definition of is as described in this disclosure.

[0161] In some embodiments, R 5 Selected from halogen, -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 membered heteroaryl, the -C(O)NR a’ R b’ 、-C(O)R b’ 、-N(R b’ )C(O)OR b’ 、-N(R b’ )C(O)R b’or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted with one or more halogen or -OH 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein R a’ and R b’ The definition of is as described in this application. In some embodiments, R 5 Selected from F, Cl, Br, 5-7 membered heterocycloalkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 CycloalkylNHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1- 3-membered alkyl)(4-6-membered heterocycloalkyl), -NHC(O)C 1-3 Alkyl, -NHC(O)C 3-5 Cycloalkyl, -N(C 1-3 alkyl)C(O)OC 1-3 Alkyl or 5-6 membered heteroaryl, the 5-7 membered heterocycloalkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 CycloalkylNHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 alkyl)(4-6 membered heterocycloalkyl), -NHC(O)C 1-3 Alkyl, -NHC(O)C 3-5 Cycloalkyl or -N(C 1-3 alkyl)C(O)OC 1-3 Alkyl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted with one or more halogen or -OH 1-3 Alkyl, -OC 1-3 Alkyl, C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl.

[0162] In some embodiments, R 5 Selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)N(C 1-4 alkyl)2, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)-morpholinyl, -C(O)-piperazinyl, -C(O)azabicycloheptyl, adamantyl NHC(O)-, -C(O)N(C 1-3alkyl)cyclopropyl, -C(O)N(C 1-3 alkyl)oxetane, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 alkyl)C(O)OC 1-3 Alkyl, the pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C (O) -pyrrolidinyl, -C (O) -piperidinyl, -C (O) -morpholinyl or -C (O) -piperazinyl is optionally substituted by 1 or 2 selected from F, Cl, -OH, -CN, methyl, -CF3, -OCH3, cyclopropyl, isopropyl, or substituted with an oxetane group.

[0163] In other embodiments, 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 membered heteroaryl, said -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 membered heteroaryl is optionally 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, said R a’ and R b’ The definition of is as described in this disclosure.

[0164] In other embodiments, R 5 Selected from halogen, 5-7 membered heterocycloalkyl C(O)-, C 9-10 CycloalkylNHC(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 heterocycloalkyl), -NHC(O)C 1-3 Alkyl, -NHC(O)C3-5 Cycloalkyl, -N(C 1-3 alkyl)C(O)OC 1-3 alkyl or 5-6 membered heteroaryl, the 5-7 membered heterocycloalkyl C(O)-, C 9-10 CycloalkylNHC(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 heterocycloalkyl, -NHC(O)C 1-3 Alkyl, -NHC(O)C 3-5 Cycloalkyl, -N(C 1-3 alkyl)C(O)OC 1-3 Alkyl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted with one or more halogen, 1-3 Alkyl, -OC 1-3 Alkyl or C 3-4 Cycloalkyl.

[0165] In other embodiments, R 5 Selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, 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, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 alkyl)C(O)OC 1-3 Alkyl, the 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, -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl, -C(O)NH-adamantyl or -N(C 1-3 alkyl)C(O)OC 1-3The alkyl group is optionally substituted with one or more groups selected from F, Cl, CH3, CF3, -OH, -CN, -OCH3, isopropyl or cyclopropyl.

[0166] In some specific embodiments, R 5 Selected from optionally one or more R a” Substituted with the following groups: -C(O)NR a’ R b’ or a 5-10 membered heteroaryl group, wherein R a’ and R b’ The definition of is as described in this disclosure. In some embodiments, R 5 Selected from optionally one or more R a” Substituted with the following groups: -C(O)NR a’ R b’ or a 5-6 membered heteroaryl group, wherein R a’ and R b’ The definition of is as described in this disclosure. In some embodiments, R 5 Selected from optionally one or more R a” Substituted with the following groups: -C(O)N(C 1-6 alkyl) 2 or 5-6 membered heteroaryl, wherein R a’ and R b’ The definition of is as described in this disclosure.

[0167] In some specific embodiments, R 5 Selected from optionally one or more R a” Substituted with the following groups: or a 5-6 membered heteroaryl group, wherein R a’ and R b’ The definition of is as described in this disclosure. In some embodiments, R 5 Selected from or optionally one or more R a” Substituted 5-6 membered heteroaryl, wherein R a” The definition of is as described in this application.

[0168] In some specific embodiments, R 5 Selected from Or 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted by one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl or C 3-6 Cycloalkyl.

[0169] In some specific embodiments, R 5 for In some specific embodiments, R 5 Selected from optionally one or more R a” Substituted 5-6 membered heteroaryl, wherein R a” The definition of is as described in this application. In some embodiments, R 5 Selected from optionally one or more R a” Substituted 6-membered heteroaryl containing a nitrogen heteroatom.

[0170] In some embodiments, R 5 Selected from Br, Or, choose

[0171] In some specific embodiments, R 5 Selected from optionally one or more R a” substituted with the following groups: pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. In some embodiments, R 5 Selected from optionally one or more R a” substituted with the following groups: pyrazolyl, imidazolyl, thiazolyl or triazolyl. In some embodiments, R 5 Selected from optionally one or more R a” Substituted: pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0172] In some specific embodiments, R 5 Selected from

[0173] In some specific embodiments, R 5 Selected from In some specific embodiments, R 5 Selected from

[0174] In other embodiments, R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -C(O)NR a’ R b’ 、-C(O)-(5-6 membered heterocycloalkyl), -N(C 1-4 Alkyl)(CO)OC 1-4 Alkyl, -C(O)-C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl, said Ra’ 、R b’ and R a” The definition of is as described in this disclosure.

[0175] In other embodiments, R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -C(O)NR a’ R b’ 、-C(O)-(5-6 membered heterocycloalkyl), -N(C 1-3 Alkyl)(CO)OC 1-3 Alkyl or 5-6 membered heteroaryl, said R a’ 、R b’ and R a” The definition of is as described in this disclosure.

[0176] In other embodiments, R 5 Selected from F, Cl, Br, -C(O)(NR a’ R b’ ), -C(O)-5-membered heterocycloalkyl, -N(C 1-2 Alkyl)(CO)OC 1- 2-membered alkyl or 5-6-membered heteroaryl, the -C(O)-(5-membered heterocycloalkyl) or 5-6-membered heteroaryl is optionally substituted by 1 or 2 R a” Substituted, the R a’ 、R b’ and R a” The definition of is as described in this disclosure.

[0177] In other embodiments, R 5 Selected from Br, -C(O)(NR a’ R b’ ), -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 of is as described in this disclosure.

[0178] In other embodiments, R 5 Selected from Br,

[0179] In some embodiments, R a’ Selected from hydrogen, methyl, ethyl, C 4-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0180] In some embodiments, R a’ are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0181] In some embodiments, R a’ are each independently selected from hydrogen, C 1-4 Alkyl or C 3-4 Cycloalkyl.

[0182] In some embodiments, R a’ are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl.

[0183] In some embodiments, R a’ Each independently selected from hydrogen, methyl, ethyl, or cyclopropyl.

[0184] In other embodiments, R a’ Selected from methyl, ethyl, C 4-5 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0185] In other embodiments, R a’ Selected from methyl, ethyl or C 3-5 Cycloalkyl.

[0186] In other embodiments, R a’ is selected from methyl, ethyl or cyclopropyl.

[0187] In some embodiments, R b’ are each independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 3-10 The cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH or -NH2.

[0188] In some embodiments, R b’ are each independently selected from hydrogen, or the following groups optionally substituted by one or more halogens: C 1-6 Alkyl, C 3- 9-membered cycloalkyl or 4-9-membered heterocycloalkyl.

[0189] In some embodiments, R b’ are each independently selected from hydrogen, C 1-4 Alkyl, C 3-5Cycloalkyl, C 9-10 Cycloalkyl or 4-7 membered heterocycloalkyl.

[0190] In some embodiments, R b’ are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, adamantyl, oxetanyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl or azabicycloheptyl.

[0191] In some embodiments, R b’ are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl,

[0192] In some embodiments, R b’ are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl,

[0193] In other embodiments, R b’ Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-4 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH or -NH2.

[0194] In other embodiments, R b’ Selected from C 1-4 Alkyl, 3-5 membered cycloalkyl or 3-5 membered heterocycloalkyl, the C 1-4 The alkyl, 3-5 membered cycloalkyl or 3-5 membered heterocycloalkyl is optionally substituted with one or more halogens.

[0195] In other embodiments, R b’ C 1-3 alkyl.

[0196] In other embodiments, R b’ It is isopropyl.

[0197] In some embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-O-, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -CN or -NH2.

[0198] In some embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, -NH(C 1-4 Alkyl), -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, -NH(C 1-4 Alkyl), -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen or -OH.

[0199] In some embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl, the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 The cycloalkyl or 3-5 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 groups selected from halogen, -OH, -CN or -NH2.

[0200] In some embodiments, R a” Each independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl, cyclopropyl, or oxetanyl.

[0201] In other embodiments, R a” Each independently selected from F, Cl, -OH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl or C 3-4 Cycloalkyl, the C 1-3Alkyl is optionally substituted with 1, 2 or 3 F. In other embodiments, R a” Each is independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl or cyclopropyl.

[0202] In other embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, the C 1-4 Alkyl, C 3-5 Cycloalkyl or C 3-5 Heterocycloalkyl is optionally substituted with one or more halogens.

[0203] In other embodiments, R a” Each independently selected from F, Cl, Br, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl.

[0204] In other embodiments, R a” Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0205] In other embodiments, R a” Each independently selected from C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0206] In other embodiments, R a” Each is independently selected from isopropyl or cyclopropyl.

[0207] In some specific embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 The alkyl group is optionally substituted with one or more halogen, -OH, -CN or -NH2.

[0208] In some specific embodiments, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 3-4Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-4 The alkyl group is optionally substituted with one or more halogen, -OH, -CN or -NH2.

[0209] In some embodiments, R 6 Selected from hydrogen, halogen, -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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH, or -NH2.

[0210] In some embodiments, R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0211] In some embodiments, R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0212] In some embodiments, R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Heteroalkyl.

[0213] In some embodiments, R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl or C 1-4 In some embodiments, R 6 Selected from hydrogen, halogen or C 1-6 In some embodiments, R 6 is selected from hydrogen, halogen (such as F, Cl, Br or I) or C 1-3 alkyl.

[0214] In some embodiments, R 6 is selected from hydrogen, F, Cl, Br or methyl.

[0215] In some embodiments, R 6 is selected from hydrogen, F or methyl.

[0216] In other embodiments, R 6 For F.

[0217] In some embodiments, R a and R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2.

[0218] In other embodiments, R a and R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-4 Alkyl, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-4 The alkyl group is optionally substituted with one or more halogen, -CN, -OH or -NH2.

[0219] In some embodiments, R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1- 4 alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0220] In some embodiments, R 7 are each independently selected from halogen, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl.

[0221] In some embodiments, R 7 Each independently selected from C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0222] In some embodiments, R 7Each independently selected from C 3-4 Cycloalkyl.

[0223] In some embodiments, R 7 are each independently cyclopropyl.

[0224] In other embodiments, R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-4 alkyl.

[0225] In other embodiments, R 7 Each independently selected from halogen, -CN, -OH, -NH2 or C 1-4 alkyl.

[0226] In other embodiments, R 7 are each independently selected from halogen or C 1-3 alkyl.

[0227] In other embodiments, R 7 Each is independently selected from F, Cl or Br.

[0228] In some embodiments, R a Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1- 4 alkyl groups.

[0229] In some embodiments, R a Each independently selected from halogen, -CN, -OH, -NH2 or C 1-4 alkyl.

[0230] In some embodiments, R a are each independently selected from halogen or C 1-3 alkyl.

[0231] In some embodiments, R a Each is independently selected from F, Cl or Br.

[0232] In some embodiments, R a Each is independently F.

[0233] In some embodiments, m is selected from 0, 1 or 2.

[0234] In some embodiments, m is selected from 0 or 1.

[0235] In some embodiments, m is selected from 1.

[0236] In some embodiments, m is selected from 0.

[0237] In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 2.

[0238] In some embodiments, p is selected from 0, 1 or 2.

[0239] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 1.

[0240] In some embodiments, p is selected from 0.

[0241] In some embodiments, q is selected from 1.

[0242] In some embodiments, the structural fragment Selected from

[0243] In some embodiments, the structural fragment Selected from

[0244] In some embodiments, the heteroalkyl, heteroaryl, heteroarylene, heterocycloalkyl, heterocyclyl, heterocyclylene, heterocycloalkylene (e.g., heteromonocycloalkylene), or heterospirocycloalkylene 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, heterocyclyl, heterocyclylene, heterocycloalkylene, or heterospirocycloalkylene 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, heterocyclyl, heterocyclylene, heterocycloalkylene, or heterospirocycloalkylene 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, heterocyclyl, heterocyclylene, heterocycloalkylene, or heterospirocycloalkylene contains 1 or 2 heteroatoms selected from N or O, and the remaining ring atoms are selected from carbon.

[0245] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0246] In some embodiments, the C 1-10 Selected from C 1-9 、C 1-8 、C 1-7 、C1-6 、C 1-4 、C 1-3 , or C 1-2 In some embodiments, C 1- 6 from C 1-4 、C 1-3 , or C 1-2 In some embodiments, the C 1-4 is selected from C4, C3, C2, or C1. In some embodiments, the C 1-3 Selected from C3, C2, or C1.

[0247] In some embodiments, the C 2-10 Selected from C 2-8 、C 2-6 、C 2-5 、C 2-4 、C 2-3 In some embodiments, the C 2-6 Selected from C 2- 4. or C 2-3 In some embodiments, the C 2-4 Selected from C4, C3, or C2.

[0248] In some embodiments, the C 3-6 Selected from C 3-5 、C 3-4 、C 4-6 、C 4-5 , or C 5-6 In some embodiments, 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 embodiments, 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 、C5-6 、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 embodiments, the C 3-15 Selected from C 3-12 or C 3- 10 In some embodiments, the C 3-12 Selected from C 3-10 In some embodiments, the C 6-12 Selected from C 6-10 .

[0249] In some embodiments, 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 embodiments, 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, and 9-10 yuan. In some embodiments, 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, 9-10 yuan. In some embodiments, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.

[0250] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) of the present disclosure, or a pharmaceutically acceptable salt thereof, is 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 a pharmaceutically acceptable salt thereof:

[0251] 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 5 、R 6 、R 7 、R 8 、R a and M is as defined in this disclosure;

[0252] 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH, or -NH2.

[0253] In some embodiments, X t Is O. In some embodiments, X t Selected from CH(R c2 ). In some embodiments, X t For CH2.

[0254] In some embodiments, 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH, or -NH2.

[0255] In some embodiments, R c2 Selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Heteroalkyl.

[0256] In some embodiments, R c2 Selected from hydrogen or C 1-3 alkyl.

[0257] In some embodiments, R c2 For hydrogen.

[0258] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0259] It is understood that any of the embodiments of the compounds of the present disclosure as described above and the descriptions herein with respect to specific Y, Ring A, H, W, M, R, 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 can be independently combined with other embodiments and / or substituents of compounds of the present disclosure to form embodiments of the present disclosure not specifically described above. In addition, any specific substituents described in the specific embodiments and / or claims with respect to any particular Y, Ring A, H, W, M, R 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” 、Ra1 、R b1 、R c1 、R d1 、R c2 and R d2 Where a substituent range is disclosed, it is understood that one or more substituents may be deleted from the range and the remaining substituent range is also considered an embodiment of the present disclosure. a When it exists (i.e. m is not 0), it is in W 3 、W 4 , or W 5 Substitution occurs at the position of the substituent R 7 When it exists (i.e. when p is not 0), it 1 , or W 2 substituted at the position.

[0260] In some embodiments, the following compound or a pharmaceutically acceptable salt thereof:

[0261] In another aspect, the present disclosure provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0262] In another aspect, the present disclosure provides a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0263] In another aspect, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease.

[0264] In another aspect, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in treating a disease.

[0265] In another aspect, the present disclosure provides the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a disease.

[0266] In some embodiments, the disease is selected from a Menin protein-related disease. In some embodiments, the disease is selected from a cancer. Preferably, the cancer is selected from a leukemia; in some embodiments, the cancer or leukemia is selected from a myeloid leukemia (or acute myeloid leukemia).

[0267] Technical Effects

[0268] The compounds disclosed herein have one or more of the following beneficial effects: good MOLM-13 cell and / or MV-4-11 cell proliferation inhibitory activity, and also have the activity of inhibiting Menin-MLL protein binding; stable liver microsomal metabolism; good in vivo pharmacokinetic properties (e.g., AUC, Cmax or T1 / 2); and good in vivo pharmacodynamics.

[0269] definition

[0270] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0271] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0272] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0273] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three.

[0274] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0275] As used herein, m and n are integers within a given range. For example, "3-12 membered" means that the group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 members. For example, "5-10 membered" means that the group may have 5, 6, 7, 8, 9, or 10 members.

[0276] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0277] When a substituent's bond crosses between two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0278] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0279] The term "hydroxy" refers to an -OH group.

[0280] The term "amino" refers to a -NH2 group.

[0281] The term "nitro" refers to a -NO2 group.

[0282] The term "cyano" refers to a -CN group.

[0283] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "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 has the same definition as above.

[0284] 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 "C 1-6 "Alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4"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", "heterocyclylene", "heterospirocycloalkylene", "heterocycloalkylene", "arylene" or "heteroarylene" are similarly defined and indicate that they are divalent groups. For example, the term "C 3-12 The term "cycloalkylene" refers to a cycloalkylene group containing 3 to 12 carbon atoms; the term "6-10 membered cycloalkylene" refers to a cycloalkylene group containing 6 to 10 carbon atoms, including but not limited to etc. Non-limiting examples of heterospirocycloalkylene groups include etc. Non-limiting examples of heterocycloalkylene groups include Examples of arylene groups include, but are not limited to Examples of heteroarylene groups include, but are not limited to wait.

[0285] The term "alkoxy" refers to an -O-alkyl group.

[0286] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0287] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and 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), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0288] The term "bicyclic" or "bicyclyl" refers to a cyclic group containing two rings, which may be fully saturated, partially saturated or aromatic. The bicyclic ring may be composed entirely of carbon atoms and may contain one or more heteroatoms selected from, for example, N, O, S or P. The bicyclic ring may be a fused ring, a bridged ring or a spiro ring.

[0289] The term "cycloalkyl" refers to a fully saturated carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 5-20 or 3-10 membered. Unless otherwise indicated, the cycloalkyl group may 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, and the like.

[0290] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -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 "hetero" denotes a heteroatom or a heteroatom group (ie a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0291] The term "heteroalkyl" is a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbons, more preferably 1 to 10 carbons, even more preferably 1 to 6 carbons, and most preferably 1 to 3 carbons in the chain, wherein the heteroatoms are preferably selected from 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 heteroatom 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, sulfides, etc., including alkoxy, alkylthio, alkylamino; 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.

[0292] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, and a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 3 to 20 rings, 3 to 15 rings, 3 to 12 rings or 3 to 10 rings (such as 3, 4, 5, 6, 7, 8, 9 or 10 rings), 4 to 8 rings, 5 to 8 rings or 5 to 6 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron. The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0293] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0294] The term "spiroalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 9 to 14 yuan. According to the number of spiro atoms shared between rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl, more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0295] The term "heterospirocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n(wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0296] The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5 to 20 members or 5 to 14 members, preferably 6 to 14 members, more preferably 6 to 10 members. Depending on the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic. When the bridged ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0297] The term "heterocycloalkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise indicated, the heterocycloalkyl group is typically a cyclic group containing 1 to 3 atoms independently selected from N, O, S(O), n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms). Unless otherwise indicated, the heterocycloalkyl group may be a monocyclic, bicyclic or tricyclic group. Unless otherwise indicated, the heterocycloalkyl group may be a monocyclic, spirocyclic, bridged or cyclic. Unless otherwise indicated, the heterocycloalkyl 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 heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0298] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. Unless otherwise indicated, an aryl group 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, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0299] The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one ring selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) ring atoms, the remaining ring atoms are C, and have at least one aromatic ring. Unless otherwise indicated, the heteroaryl group can be a monocyclic, bicyclic or tricyclic group. Unless otherwise indicated, the heteroaryl group can have a single 5 to 8-membered ring, or a plurality of fused rings containing 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, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0300] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0301] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0302] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0303] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a specific disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0304] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0305] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0306] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0307] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0308] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0309] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0310] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0311] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0312] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0313] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0314] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present 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 et al.

[0315] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 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 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0316] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H or D)) substitution can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are replaced by deuterium, for example, complete replacement of a methyl group (-CH3) by deuterium yields -CD3.

[0317] The compounds of the present disclosure may exist in their tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer can be an imidazole moiety, in which a proton can migrate between two ring nitrogens.

[0318] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0319] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, and intravenous administration.

[0320] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0321] In all methods of administration of the compounds of (I) disclosed herein, the dosage administered per day is 0.001 to 2000 mg / kg body weight, in single or divided doses.

[0322] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0323] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0324] An important consideration in synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited in the present disclosure are hereby incorporated into the present disclosure in their entirety.

[0325] For the 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 disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0326] This disclosure uses the following abbreviations:

[0327] DCM stands for dichloromethane; PE stands for petroleum ether; THF stands for tetrahydrofuran; EA stands for ethyl acetate; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt stands for 1-hydroxybenzotriazole; DMF stands for N,N-dimethylformamide; TEA stands for triethylamine; m-CPBA stands for m-chloroperbenzoic acid; Pd(dppf)Cl2 stands for [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride; DBU stands for 1,8-diazabicyclo(5,4,0)-7-undecene; and DMAP stands for 4-dimethylaminopyridine. DETAILED DESCRIPTION

[0328] For the sake of clarity, the present disclosure is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0329] The compounds of the present invention can be prepared by similar preparation methods as those described in the examples, including but not limited to adjusting structurally similar raw materials, reagents, or process parameters. The compounds of the present invention can be confirmed by MS or HNMR. The compounds of the present invention can also be tested using the same efficacy test methods to obtain results.

[0330] Example 1: Preparation of Compound 1

[0331] Step 1: Preparation of compound 1-c

[0332] 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 at room temperature overnight. Upon completion of the reaction, ethyl acetate and saturated brine were added, 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 compound 1-c, which was used directly in the next step without purification. ESI-MS: m / z = 679.44 [M+H] + .

[0333] Step 2: Preparation of compound 1

[0334] Compound 1-c (50 mg) was added to a reaction flask containing dichloromethane (6 mL) and stirred to dissolve. Trifluoroacetic acid (2 mL) was slowly added dropwise. After completion of the addition, the mixture was stirred at room temperature. After the reaction was complete, water was added and the pH was adjusted to approximately 8 with TEA. The layers were separated and the aqueous phase was extracted with DCM. The organic phases were combined, dried, filtered, and concentrated. 23 mg of compound 1 was obtained by preparative liquid chromatography. ESI-MS: m / z = 579.28 [M+H] + .

[0335] 1 H-NMR (DMSO-d6):δ 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).

[0336] Example 2: Preparation of Compound 2

[0337] Step 1: Preparation of compound 2-c

[0338] Referring to 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] + .

[0339] Step 2: Preparation of compound 2

[0340] Referring to 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] + .

[0341] 1 H-NMR (CDCl3):δ H 1.08~1.90(11H,m)1.99(6H,m),2.38~2.45(2H,m),2.92(1H,d,J=17.81Hz),3.17~4.10(12H,m),4.66(1H,m) ,4.91(1H,s),5.01(1H,d,J=11.75Hz),6.74(1H,m),7.02~6.99(2H,m),7.84(1H,m),8.41(1H,d,J=5.30Hz).

[0342] Example 3: Preparation of Compound 3

[0343] Step 1: Preparation of compound 3-c

[0344] 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. The reaction mixture was filtered until most of the starting materials were completely reacted. The filter cake was washed with DMF, and the combined filtrates were purified by silica gel column chromatography (PE:EA = 4:1) and concentrated to afford 800 mg of compound 3-c. ESI-MS: m / z = 268.84 [M+H] + .

[0345] Step 2: Preparation of compound 3-d

[0346] 3-c (800 mg) and DCM (10 mL) were added to the reaction flask, followed by m-CPBA (1.54 g) in an ice bath. The reaction mixture was stirred at room temperature for 24 h until the reaction was complete. NaHSO3 solution and NaHCO3 solution were added to the reaction solution, stirred, and the liquids 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]+ .

[0347] Step 3: Preparation of compound 3-e

[0348] POCl (341 mg) was added to a solution of EtN (225 mg) in CHCl (10 mL) under ice-cooling. The mixture was then added dropwise to a solution of 3-d (422 mg) in CHCl (5 mL) under ice-cooling. After addition, the mixture was stirred at 65°C for 4 h until the reaction of the starting material was complete. NaHCO solution was slowly added to adjust the pH to 7-8. The layers were separated, and the organic phase was purified by silica gel column chromatography (PE:EA = 4:1) to obtain 180 mg of compound 3-e. ESI-MS: m / z = 302.93 [M+H] + .

[0349] Step 4: Preparation of compound 3-g

[0350] To a 5 mL reaction vial, 3-e (180 mg), 3-f (134 mg), Na2CO3 (126 mg), and acetonitrile (10 mL) were added and 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 obtain 100 mg of compound 3-g. ESI-MS: m / z = 493.13 [M+H] + .

[0351] Step 5: Preparation of compound 3-i

[0352] 3-g (100 mg), 3-h (33 mg), Pd(dppf)Cl2 (15 mg), K2CO3 (56 mg), 1,4-dioxane (5 mL), and H2O (1 mL) were added to the reaction flask. The mixture was stirred at 80°C for 7 h under N2 protection until the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic phase was purified by silica gel column chromatography (PE:EA = 2:1) to obtain 100 mg of compound 3-i. ESI-MS: m / z = 532.27 [M+H] + .

[0353] Step 6: Preparation of compound 3-j

[0354] 3-i (100 mg) was added to a reaction flask containing DCM (6 mL) and stirred to dissolve. CF3COOH (2 mL) was slowly added dropwise. The reaction was stirred at room temperature until complete. Water was added and the pH was adjusted to approximately 8 with TEA. The layers were separated. The aqueous phase was re-extracted with DCM, and the combined organic phases were dried, filtered, and concentrated until no liquid remained to yield 60 mg of compound 3-j. ESI-MS: m / z = 432.25 [M+H] + .

[0355] Step 7: Preparation of compound 3-k

[0356] Referring to 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 to obtain compound 3-k. ESI-MS: m / z=681.41 [M+H] + .

[0357] Step 8: Preparation of compound 3

[0358] Referring to 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=1.40,4.70Hz,),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=18.26Hz),2.51(1H,s),2.44( 1H,dd,J=1.70,18.11Hz),1.66~2.06(10H,m,),1.07(2H,s),0.83(2H,m).

[0359] Example 4: Preparation of Compound 4

[0360] Step 1: Preparation of compound 4-b

[0361] Referring to 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] + .

[0362] Step 2: Preparation of compound 4-c

[0363] 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.

[0364] Step 3: Preparation of compound 4-d

[0365] 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.

[0366] Step 4: Preparation of compound 4

[0367] Referring to 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=1.70Hz),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=18.16Hz),1.90(1H,s),1.79(1H,d,J=17.91Hz,),1.29(1H,m),1.04(2H ,t,J=4.88H),0.98(2H,t,J=5.43Hz),0.91(4H,m),0.58(6H,d,J=6.60Hz).

[0368] Example 5: Preparation of Compound 5

[0369] Step 1: Preparation of compound 5-c

[0370] 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 at room temperature overnight. After the reaction was complete, ethyl acetate and saturated brine were added, 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 121 mg of intermediate 5-c. ESI-MS: m / z = 210.05 [M+H] + .

[0371] Step 2: Preparation of compound 5-e

[0372] 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. The atmosphere was replaced with nitrogen and the temperature was raised to 120°C with stirring for 20 h. The reaction was detected to be complete and purified by silica gel column chromatography to obtain 40 mg of intermediate 5-e. ESI-MS: m / z = 512.27 [M+H] +.

[0373] Step 3: Preparation of compound 5-f

[0374] 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. After completion of the reaction, aqueous NaHCO3 solution was added to adjust the pH to neutral. The mixture was stirred, 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] + .

[0375] Step 4: Preparation of compound 5-g

[0376] 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 at room temperature overnight. After the reaction was complete, ethyl acetate and saturated brine were added, 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] + .

[0377] Step 5: Preparation of compound 5

[0378] 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 detected to be complete, stirred, separated, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 10 mg of compound 5. ESI-MS: m / z = 561.28 [M+H] + .

[0379] 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=18.11Hz),3.27~3.38(4H),3.48(1H,m),3.56(2H, t,J=6.88Hz),3.81(1H,s),3.89(1H,m),3.98~4.02(4H),6.79(1H,dd,J=4.01,8.86Hz),7.03~7.09(2H),7.84(1H,s),8.39(3H).

[0380] Examples 6-7

[0381] Referring to the preparation method of compound 5 in Example 5, compound 5-b was replaced with the starting compounds shown in the table below to obtain target compounds 6 and 7.

[0382] Example 8: Preparation of Compound 8

[0383] Step 1: Preparation of compound 8-a

[0384] Intermediate 3-g (120 mg), trifluoroacetic acid (1 mL) and dichloromethane (3 mL) were added to a reaction flask and stirred at room temperature for 1 h. After detection until the reaction was complete, NaHCO3 aqueous solution was added to adjust the pH to neutral. The mixture was stirred, separated, and the organic phase was concentrated under reduced pressure to obtain 100 mg of intermediate 8-a.

[0385] Step 2: Preparation of compound 8-b

[0386] 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 at room temperature overnight. After the reaction was complete, ethyl acetate and saturated brine were added, 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 80 mg of intermediate 8-b.

[0387] Step 3: Preparation of compound 8

[0388] 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 detected to be complete, stirred, separated, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 30 mg of compound 8. ESI-MS: m / z = 542.10 [M+H] + .

[0389] 1 H-NMR (CDCl3)δ H1.59~1.98(8H,m,J=7.50Hz),2.40(1H,d,J=17.91Hz),2.44(1H,s),2.91(1H,d, J=17.91Hz),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=4.78,8.98Hz), 7.03(1H,m,J=4.84Hz),7.40(1H,dd,J=2.88,7.53Hz),7.69(1H,s),8.40(1H,s).

[0390] Example 9: Preparation of Compound 9

[0391] 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 and stirred at 80°C for 7 h. After detection, the reaction mixture was decomposed into water and ethyl acetate, and the organic phase was separated and purified by silica gel column chromatography to obtain 23 mg of compound 9. ESI-MS: m / z = 542.21 [M+H] + .

[0392] 1 H-NMR (CDCl3)δ H 1.74~2.11(8H,m),2.52(1H,d,J=18.31Hz),2.57(1H,s),2.97(1H,d,J=18 .41Hz),3.34(2H,m),3.54(1H,m),3.93(1H,s),4.02~4.23(5H,m),4.77(1 H,s),5.02(1H,s),5.11(1H,s),7.20(1H,dd,J=4.30,8.70Hz),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).

[0393] Examples 10 to 23

[0394] Referring to the preparation method of compound 9 in Example 9, compound 9-a was replaced with the starting compounds shown in the table below to obtain target compounds 10 to 23.

[0395] Example 24: Preparation of Compound 24

[0396] Step 1: Preparation of compound 24-b

[0397] 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.

[0398] Step 2: Preparation of compound 24

[0399] 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).

[0400] Example 25: Preparation of Compound 25

[0401] Step 1: Preparation of compound 25-b

[0402] 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.

[0403] Step 2: Preparation of compound 25-c

[0404] Referring to the preparation method of compound 4-c in Example 4, compound 25-c was obtained.

[0405] Step 3: Preparation of compound 25-d

[0406] 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.

[0407] Step 4: Preparation of compound 25

[0408] Compound 25 was obtained by referring to the preparation method of compound 4 in Example 4. ESI-MS: m / z=544.60 [M+H] + .

[0409] 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. 81Hz),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=4.45,9.00Hz),7.15(1H,m,J=3.23Hz),7.20(1H ,dd,J=2.98,8.28Hz),7.73(1H,s),8.37(1H,s),8.90(2H,s),9.23(1H,s).

[0410] Example 26: Preparation of Compound 26

[0411] Step 1: Preparation of compound 26-c

[0412] Intermediate 26-a (160 mg), 26-b (100 mg), Cs2CO3 (320 mg), and DMF (5 mL) were added to the reaction flask and stirred at 60°C for 24 h. After detection, the reaction mixture was completely reacted with water and ethyl acetate. The mixture was separated and the organic phase was concentrated to obtain 180 mg of intermediate 26-c.

[0413] Step 2 to Step 5: Preparation of Compound 26

[0414] The synthetic method of step 5 to step 8 of reference example 3 was used to obtain compound 26. ESI-MS: m / z=582.31[M+H] + .

[0415] 1 H-NMR (CDCl3)δ H0.84~0.89(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=9.89Hz),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=2.90,7.05Hz),7.9 2(1H,s),8.18(1H,d,J=2.85Hz),8.54(1H,s),8.60(1H,s),8.70(1H,s),10.95(1H,s).

[0416] Example 27: Preparation of Compound 27

[0417] Step 1: Preparation of compound 27-c

[0418] 27-a (1.2 g), 27-b (1.0 g), triethylamine (0.8 g), and dichloromethane (25 mL) were added to a reaction flask and stirred at 0°C for 24 h. After checking that the starting materials were completely reacted, water and dichloromethane were added to the reaction solution, and the layers were 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] + .

[0419] Step 2: Preparation of compound 27-f

[0420] 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.

[0421] Step 3: Preparation of compound 27-g

[0422] 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. After detection, the reaction was complete. Water and EA were added to the reaction solution, stirred and separated, and the aqueous phase was re-extracted with EA. The organic phases were combined and purified by silica gel column chromatography to obtain 320 mg of compound 27-g.

[0423] Step 4: Preparation of compound 27-h

[0424] To the reaction flask, 27-g (320 mg), 10% palladium on carbon (100 mg), triethylamine (1 mL) and methanol (10 mL) were added, followed by 10% palladium on carbon, H2 replacement, and stirring at room temperature for 12 h. The reaction was detected until the raw material reaction was complete. The reaction solution was filtered and concentrated to dryness to obtain 260 mg of compound 27-h.

[0425] Steps 5 to 7: Preparation of Compound 27

[0426] The synthetic method of step 3 to step 5 of reference example 5 was used to obtain compound 27. ESI-MS: m / z=578.43 [M+H] + .

[0427] 1 H NMR (500MHz CDCl3)δ 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).

[0428] Examples 28 to 30

[0429] Referring to the preparation method of compound 27 in Example 27, compound 27-d was replaced with the starting compounds shown in the table below to obtain target compounds 28, 29 and 30.

[0430] Example 31: Preparation of Compound 31

[0431] Step 1: Preparation of compound 31-c

[0432] Intermediate 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 under nitrogen for 12 h. After the reaction was complete, ethyl acetate and water were added to the reaction mixture, followed by separation. The ethyl acetate phase was purified by silica gel column chromatography and concentrated to yield 200 mg of Intermediate 31-c. ESI-MS: m / z = 230.06 [M+H] + .

[0433] Step 2 to Step 6: Preparation of Compound 31

[0434] The synthetic method of step 3 to step 7 of reference example 27 was used to obtain compound 31. ESI-MS: m / z=582.37 [M+H] + .

[0435] 1 H NMR (500MHz CDCl3)δ 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(1 H,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).

[0436] Examples 32 to 34

[0437] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compounds shown in the table below to obtain target compounds 32, 33 and 34.

[0438] Example 35: Preparation of Compound 35

[0439] Step 1: Preparation of compound 35-b

[0440] 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 detected to be complete, and 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] + .

[0441] Step 2: Preparation of compound 35-c

[0442] Intermediate 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 was detected to be complete, and the reaction solution was filtered and purified by silica gel column chromatography. The product was concentrated to obtain 200 mg of intermediate 35-c. ESI-MS: m / z = 532.29 [M+H] + Step 3 to Step 5: Preparation of Compound 35

[0443] The synthetic method of step 3 to step 5 of reference example 5 was used to obtain compound 35. ESI-MS: m / z=581.31[M+H] + . 1 H-NMR (CDCl3):δ H 8.43(1H,d,J=5.30Hz),8.40(1H,m),7.43(1H,dd,J=4.75,9.00Hz),7.37(1H,dd,J=1.65,7.60Hz),7.16(1 H,dt,J=3.03,8.43Hz),7.08(1H,dd,J=3.03,8.38Hz),7.01(1H,dd,J=4.88,7.48Hz),6.13(1H,d,J=5.45Hz ),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=18.16Hz),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).

[0444] Example 36

[0445] Referring to the preparation method of compound 35 in Example 35, compound 36 was obtained by replacing compound 31-c with the starting compound in the table below.

[0446] Examples 37 to 41

[0447] Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting compounds shown in the table below to obtain target compounds 37-41.

[0448] Example 42: Preparation of Compound 42

[0449] Step 1: Preparation of compound 42-a

[0450] 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. 1-(Trifluoroacetyl)-4-(dimethylamino)pyridine trifluoroacetate (100 mg) and pinacol borane (53 mg) were then added sequentially and stirred at 25°C for 10 min. 10 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, filtered, and concentrated to afford 30 mg of intermediate 42-a.

[0451] Step 2: Preparation of compound 42-b

[0452] 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. Sodium cyanoborohydride (13 mg) and 1 drop of glacial acetic acid were then added sequentially, and stirred at 25°C for 2 hours. 10 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, filtered, and concentrated to obtain 30 mg of intermediate 42-b.

[0453] Step 3: Preparation of compound 42-b

[0454] 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 detected by TLC until completion. The mixture was concentrated and purified to obtain 10 mg of compound 42. ESI-MS: m / z = 568.30 [M+H] + .

[0455] 1 H-NMR (CDCl3)δ H 8.42~8.43(2H,m),7.45(1H,dd,J=4.68,8.88Hz),7.37(1H,d,J=6.50Hz),7.17(1H,dt,J=2.95,8. 39Hz),7.09(1H,dd,J=3.00,8.35Hz),7.02(1H,dd,J=4.88,7.43Hz),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=17.56Hz),2.66(1H,t,J=11.40Hz),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).

[0456] Example 43: Preparation of Compound 43

[0457] Step 1: Preparation of compound 43-c

[0458] 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.

[0459] Step 2 to Step 5: Preparation of Compound 43

[0460] Referring to the preparation method of step 2 to step 5 in Example 5, compound 43 was obtained. ESI-MS: m / z=574.36 [M+H] + .

[0461] Examples 44-46: Preparation of Compounds 44-46

[0462] Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting compounds shown in the table below to obtain target compounds 44 to 46.

[0463] Example 47: Preparation of Compound 47

[0464] Referring to 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] + .

[0465] 1 H-NMR (CDCl3)δ H 8.49(1H,s),8.45(1H,m),7.43(1H,m),7.36(1H,d,J=7.24Hz),7.21(1H,dd,J=8.75,9.80Hz),7.06(1H,m),5.02(1H,s),4.9 2(1H,s),4.58(1H,m),3.29~3.88(9H,m),2.90(1H,d,J=17.96Hz),2.39~2.42(2H,m),1.64~1.99(9H,m),0.47~0.99(4H,m).

[0466] Examples 48-49

[0467] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compounds shown in the table below to obtain target compounds 48 and 49.

[0468] Examples 50-51

[0469] Referring to the preparation method of compound 27 in Example 27, compound 27-e was replaced with the starting compounds shown in the table below to obtain target compounds 50-51.

[0470] Example 52: Preparation of Compound 52

[0471] 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 detected by TLC until completion. 18 mg of compound 52 was isolated and purified. ESI-MS: m / z = 596.33 [M+H] + .

[0472] Example 53: Preparation of Compound 53

[0473] 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 detected by TLC until completion. 5 mg of compound 53 was isolated and purified. ESI-MS: m / z = 634.22 [M+H] + .

[0474] 1 H-NMR (CDCl3)δ H 8.57(1H,s),8.46(1H,m),7.54(1H,t,J=8.08Hz),7.04~7.38(5H,m),5.04(1H,s),4.94(1H,s),4.68(1H,s),3.7 2~3.89(7H,m),3.31~3.45(4H,m),2.92(1H,d,J=17.11Hz),2.41~2.47(2H,m),1.67~2.00(11H,s),1.29(1H,m).

[0475] Example 54

[0476] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compound shown in the table below to obtain the target compound 54.

[0477] Example 55: Preparation of Compound 55

[0478] Step 1: Preparation of compound 55-a

[0479] Compound 27-g (560 mg), cyclopropylboronic acid (172 mg), Pd(dppf)Cl2 (73 mg), K2CO3 (280 mg), 1,4-dioxane (10 mL) and H2O (2 mL) were added to a reaction flask and stirred at 100°C for 5 hours. The reaction was detected by TLC until completion. After purification, 360 mg of compound 55-a was obtained.

[0480] Step 2 to Step 4: Preparation of Compound 55

[0481] The synthetic method of step 3 to step 5 of reference example 5 was used to obtain compound 55. ESI-MS: m / z=618.32 [M+H] + .

[0482] 1 H-NMR (CDCl3)δ H 7.05~7.29(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=17.96Hz),2.39~2.46(2H,m),1.99(3H,m),1.65~1.87(6H,m),0.93~1.17(13H,m).

[0483] Example 56: Preparation of Compound 56

[0484] Referring to 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] + .

[0485] 1 H-NMR (CDCl3)δ 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=17.01Hz),2.35~2.38(2H,m),1.60~1.93(2H,m),1.05~1.26(9H,m),0.79~0.88(2H,m).

[0486] Example 57: Preparation of Compound 57

[0487] 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 detected by TLC until completion. 12 mg of compound 57 was isolated and purified. ESI-MS: m / z = 592.34 [M+H] + .

[0488] Example 58: Preparation of Compound 58

[0489] Referring to 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] + .

[0490] 1 H-NMR (CDCl3)δ H 8.46~8.48(2H,m),7.37(1H,m),7.02~7.08(2H,m),6.94(1H,d,J=7.20Hz),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=17.71Hz),2.47(1H,s),2.43(1H,d,J=18.06Hz),1.63~2.01(9H,m),1.27(1H,m),0.88~0.99(3H,m).

[0491] Example 59

[0492] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compound shown in the table below to obtain the target compound 59.

[0493] Example 60: Preparation of Compound 60

[0494] Referring to 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 to obtain compound 60. ESI-MS: m / z=556.30 [M+H] + .

[0495] 1 H-NMR (CDCl3)δ H8.51(1H,s),7.26(1H,dd,J=4.03,8.63Hz),7.15(1H,m),7.02(1H,m),4.68~4.99(4H,m),4.13~4.55(6H,m),3.86(1H,m),3.7 3(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).

[0496] Example 61: Preparation of Compound 61

[0497] Step 1: Preparation of compound 61-c

[0498] 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.

[0499] Step 2 to Step 4: Preparation of Compound 61

[0500] Referring to the synthetic method of steps 3 to 5 of Example 5, compound 61 was prepared by replacing compound 5-e with 61-c. ESI-MS: m / z=591.33 [M+H] + . 1 H-NMR (CDCl3)δ 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=17.86Hz),2.54(1H,s),2.45(1H,d,J=18.21Hz),2.03(4H,m),1.70(3H,m),1.08~1.22(10H,m).

[0501] Examples 62-63

[0502] Referring to the preparation method of compound 61 in Example 61, compound 61-a was replaced with the starting compounds shown in the table below to obtain target compounds 62 and 63.

[0503] Example 64: Preparation of Compound 64

[0504] Step 1: Preparation of compound 64-b

[0505] Compound 64-a (1 g), trimethylsilyl iodide (1 mL) and acetonitrile (10 mL) were added to a reaction flask and stirred at 80° C. for 10 hours. The reaction was detected by TLC until completion. After purification, 670 mg of compound 64-b was obtained.

[0506] Step 2 to Step 6: Preparation of Compound 64

[0507] Referring to the synthetic method of steps 3 to 7 of Example 27, compound 27-f was replaced with 64-b to obtain compound 64. ESI-MS: m / z=598.28 [M+H] + .

[0508] 1 H-NMR (CDCl3)δ H 8.47(1H,s),7.36(1H,m),7.23(1H,m),7.15(1H,dt,J=2.77,8.33Hz),7.10(1H,dd,J=2.90,8.35Hz),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=17.36Hz), 2.38~2.40(2H,m), 1.61~2.01(9H,m), 0.95(4H,m).

[0509] Examples 65-66

[0510] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compounds shown in the table below to obtain target compounds 65 and 66.

[0511] Example 67: Preparation of Compound 67

[0512] Step 1: Preparation of compound 67-a

[0513] 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.

[0514] Step 2 to Step 5: Preparation of Compound 67

[0515] The synthetic method of step 4 to step 7 of reference example 27 was used to obtain compound 67. ESI-MS: m / z=554.30 [M+H] + .

[0516] 1 H-NMR (CDCl3)δ 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).

[0517] Example 68

[0518] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compound shown in the table below to obtain the target compound 68.

[0519] Example 69: Preparation of Compound 69

[0520] Step 1: Preparation of compound 69-b

[0521] 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.

[0522] Step 2 to Step 6: Preparation of Compound 69

[0523] Referring to the synthesis method of steps 3 to 7 of Example 27, compound 27-c was replaced with 60-a, compound 27-f was replaced with 69-b, and compound 2-b was replaced with 60-e to obtain compound 69. ESI-MS: m / z=551.27 [M+H] + .

[0524] 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).

[0525] Example 70

[0526] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compound shown in the table below to obtain the target compound 70.

[0527] Example 71: Preparation of Compound 71

[0528] Referring to 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] + .

[0529] 1 H-NMR (CDCl3)δ 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).

[0530] Example 72: Preparation of Compound 72

[0531] Referring to 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] + .

[0532] 1 H-NMR (CDCl3)δ 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).

[0533] Example 73: Preparation of Compound 73

[0534] Referring to 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 to obtain compound 73. ESI-MS: m / z=555.26 [M+H] + .

[0535] 1 H-NMR (CDCl3)δ 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).

[0536] Example 74

[0537] Referring to the preparation method of Example 31, compound 31-b was replaced with the starting compound shown in the table below to obtain the target compound 74.

[0538] Example 75: Preparation of Compound 75

[0539] Referring to 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 to obtain compound 75. ESI-MS: m / z=579.30 [M+H] + .

[0540] 1 H-NMR (CDCl3)δ 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).

[0541] Example 76: Preparation of Compound 76

[0542] Referring to 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] + .

[0543] 1 H-NMR (CDCl3)δ 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).

[0544] Example 77: Preparation of Compound 77

[0545] Referring to 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] + .

[0546] 1 H-NMR (CDCl3)δ H 8.98(1H,s),8.40(1H,s),8.31(1H,s),7.69(1H,s),7.15(2H,m),6.97(1 H,m),6.42(4H,brs),4.99(1H,s),4.90(1H,s),4.56(1H,m),3.71~3.90(5 H,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).

[0547] Test Example 1 In vitro cell activity assay

[0548] MOLM-13 cells or MV-4-11 cells (source: Nanjing Kebai Technology Co., Ltd.) in good growth condition were inoculated into 96-well plates at a density of 2,000-10,000 cells per well (100 μL / well). After overnight culture in a 37°C cell culture incubator, compound gradient dilution and sample addition were performed using a pipette. Two parallel wells were added to each group, and a control group was also set up. After continuing to culture in a 37°C cell culture incubator for 72-120 hours, the detection reagent CCK-8 (manufacturer: Japan Tongren Chemical, 10 μL / well) was added. After continuing to culture at 37°C for 3-5 hours, the absorbance value was detected at 450 nM using a PerkinElmer Envision multi-function plate reader. Four-parameter analysis was performed in GraphPad Prism software to fit the dose-effect curve and calculate the IC 50 The specific results are shown in Table 1. A indicates IC50 < 50 nM.

[0549] Table 1 Cell proliferation inhibitory activity

[0550] The results showed that the compounds disclosed herein have good proliferation inhibitory activity on MV-4-11 cells and / or MOLM-13 cells.

[0551] Experimental Example 2: Fluorescence Polarization Detection of Compounds' Ability to Inhibit Menin-MLL Interaction

[0552] The activity of the compound binding to menin protein was determined by fluorescence polarization assay. GST-MENIN (1-615aa) and FITC-MLL1 were stained with FP buffer (50mM Tris-HCl pH 7.5, 50mM NaCl, 1mM DTT, 0.01% BSA). 5-43 Dilute and add 10 μL of GST-MENIN (1-615aa) at a final concentration of 8 nM and FITC-MLL1 at a final concentration of 8 nM to each well of a black 384-well microtiter plate. 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 control and negative control wells) was added and centrifuged at 2500 rpm for 1 min. The mixture was incubated at room temperature in the dark for 3 h. After incubation, the FP (480 / 535) value was detected using a PerkinElmer Envision multi-function plate reader. The inhibition rate (%) of each compound concentration was calculated using formula 1 to determine the compound's ability to inhibit the Menin-MLL interaction; Formula 1: Inhibition rate (%) = 1-(Maximum mP Control-drug group mP) / (Maximum mP Control-Minimum mP Control) × 100%. Four-parameter analysis was performed in GraphPad Prism software to fit the dose-effect curve and calculate the IC 50 The specific results are shown in Table 2. A indicates IC50 < 50 nM.

[0553] Table 2 Menin-MLL protein binding inhibitory activity

[0554] The results showed that the compounds disclosed herein have good Menin-MLL binding inhibitory activity.

[0555] Test Example 3 In vitro liver microsome stability

[0556] Liver microsome incubation sample preparation: PBS buffer (pH 7.4), liver microsome solutions (0.5 mg / mL) from various species (human, mouse, monkey, dog, and rat), the test compound (final concentration 1 μM), and NADPH + MgCl₂ solution were mixed and incubated at 37°C and 300 rpm. Samples were removed from the reaction solution at 15 and 60 minutes. The 0-hour sample consisted of a mixture of PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), and the test compound. The samples were added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and used for LC-MS / MS analysis.

[0557] Table 3 In vitro metabolic stability of compounds in mouse liver microsomes

[0558] Table 4 In vitro metabolic stability of compounds in human liver microsomes

[0559] The disclosed compounds showed good properties in in vitro liver microsome stability assays.

[0560] Test Example 4: In vivo pharmacokinetics

[0561] ICR mice weighing 18-22 g were randomly divided into 9 groups after acclimation for 3-5 days. The gavage group was given a solution of the relevant compound at a dose of 10 mg / kg by gavage; the intravenous injection group was given a solution of the relevant compound at a dose of 1 mg / kg by intravenous injection.

[0562] The time points for blood collection by gavage are: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, and 24h; the time points for blood collection by intravenous injection are: 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, and 24h; blood is collected from the eye sockets to prepare plasma samples for testing.

[0563] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0564] The non-compartmental model was used to fit the pharmacokinetic parameters.

[0565] The test results show that the compound of the present invention has good in vivo pharmacokinetic properties (bioavailability, AUC, T 1 / 2 and C max and other parameters).

[0566] Experimental Example 5: In vivo efficacy study

[0567] MV-4-11 human acute monocytic leukemia cells were subcutaneously inoculated into the right axilla of SPF male NOD-SCID mice (source: Lingchang) at a rate of 5 × 10 6 (1:1 mixed with Matrigel inoculation). When the average tumor volume reaches 250mm 3 When about 30 seconds, divide the animals into groups.

[0568] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0569] The detection indicators and calculation formulas are as follows:

[0570] 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.

[0571] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0572] Relative tumor growth rate, T / C (%) = TRTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0573] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0574] Body weight change rate, BWC (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of the animal on day 0, Wt t is the animal weight at each measurement.

[0575] The test results show that the compound of the present application can inhibit tumor growth in vivo. On day 21, the tumor volume inhibition rate is greater than 70%, and the tumor weight inhibition rate is greater than 75%.

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 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 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocycloalkyl, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5-10 membered heteroaryl is optionally substituted with 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 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 heteroalkyl substitution; R c2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; R 8 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group is 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 are each independently selected from hydrogen or C 1-6 alkyl; W.W 1 , W 2 , W 3 , W 4 and W 5 are independently selected from N, C or CH; Ring A is selected from optionally substituted with one or more R a1 Substituted with the following groups: C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Arylene or 5-12 membered heteroarylene; H is selected from a bond, NR z , C 3-8 Cycloalkyl or 3-8 heterocycloalkyl, where R z Selected from hydrogen or C 1-6 alkyl; R a1 Each is independently selected from halogen, -OH, -CN, -NH2, =O, =S, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 heteroalkyl; R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 heterocycloalkyl, C 6- 10 Aryl or 5-10 membered heteroaryl; R a’ Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl; R b’ are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or Multiple halogen, -CN, -OH or -NH2 substitutions; R a” Each is independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -OH, -CN or -NH2; R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1- 6-alkyl-O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl substitution; R a and R 7 Each is independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; M is selected from -C(O)- or -(CR u R v ) q -; R u and R v are each independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; n is selected from 1, 2, 3 or 4; m and p are independently selected from 0, 1, 2 or 3; q is selected from 1, 2 or 3; The condition is: when for When R 5 Not selected from 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -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, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3-6 membered heterocycloalkyl, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl is optionally substituted with 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 ; Optionally, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 membered heterocycloalkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -CH2-C 3-6 Cycloalkyl, -CH2-3-6 membered heterocycloalkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl are optionally substituted with one or more halogen, OH, -CN, -NH2 or C 1-4 Alkyl substitution; Or, R 1 and R 2 to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2; Optionally, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, -OH, -CN, -NH2 or C 1-3 alkyl; Or, R 1 and R 2 to form =O or =CH2; and / or, R 3 and R 4 Combine to form =O or =CH2; Optionally, R 3 and R 4 is selected from hydrogen, and R 1 and R 2 Combine to form =O or =CH2; or, R 1 and R 2 is selected from hydrogen, and R 3 and R 4 Combine to form =O or =CH2.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R b1 , R c1 and R d1 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-6 Alkyl or C 1-6 heteroalkyl substitution; Or, R b1 , R c1 and R d1 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more halogen, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 heteroalkyl substitution; Or, R b1 , R c1 and R d1 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, the C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R b1 , R c1 and R d1 are each independently selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R b1 , R c1 and R d1 are independently hydrogen or C 1-3 alkyl; Or, R b1 , R c1 and R d1 are each independently methyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R c2 and R d2 are each independently 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R c2 and R d2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 heteroalkyl; Or, R c2 and R d2 are each independently selected from hydrogen or C 1-3 alkyl; Or, R c2 and R d2 are each independently selected from hydrogen; Optionally, R 8 Selected from hydrogen or C 1-4 Alkyl; or, R 8 is selected from hydrogen or methyl; or, R 8 For hydrogen.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Y is selected from O, S, CR x R y or NR z , where R x , R y or R z are each independently selected from hydrogen or C 1-3 alkyl; Alternatively, Y is selected from O, S, CR x R y or NR z , where R x , R y or R z are each independently selected from hydrogen or methyl; Alternatively, Y is selected from O, S, CH2 or NH; Alternatively, Y is selected from O; Optionally, M is selected from -CH2- or -C(O)-; Alternatively, M is selected from -C(O)-; Optionally, R u and R v are each independently selected from hydrogen, halogen, -CN, -OH, -NH2 or C 1-3 alkyl; Or, R u and R v Selected from hydrogen.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein W is selected from N, C or CH; or, W is selected from N or CH; Optionally, the W 1 is selected from N, C or CH; or W 1 is selected from N or CH; Optionally, the W 2 is selected from N, C or CH; or W 2 is selected from CH; optionally, said W 3 is selected from N or CH; Optionally, the W and W 1 N, W 2 is CH or C; Optionally, the W 4 CH or C, W 3 and W 5 is 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 are independently selected from C or CH; Alternatively, the W 1 is N, and W, W 2 , W 3 , W 4 and W 5 are independently selected from C or CH; Alternatively, the W and W 1 is N, and W 2 , W 3 , W 4 and W 5 are independently selected from C or CH; Alternatively, the W and W 3 are independently selected from N or CH, and W 1 , W 2 , W 3 , W 4 and W 5 Selected from CH; Alternatively, the W, W 1 and W 3 are independently selected from CH or N, and W 2 , W 4 and W 5 Selected from CH.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the ring A is selected from the group consisting of: a1 Substitute the following groups: C 5-12 cycloalkylene, 5-12 membered heterocyclylene, C6 arylene or 5-6 membered heteroarylene; or, Ring A is selected from optionally substituted with one or more R a1 substituted 7-9 membered heterospirocycloalkylene; optionally, the ring A contains 1, 2 or 3 heteroatoms selected from N, O or S; or, the ring A is selected from optionally substituted with one or more R a1 Substituted 9-membered heterospirocycloalkylene; Alternatively, ring A is selected from wherein 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 The * indicates the bond and structure fragment at that position. connected, and the bond on the other side is connected to the structural fragment are connected; or, ring A is Optionally, the R a1 are each independently selected from halogen, -OH, -CN, -NH2, =O, =S or C 1-6 alkyl; Or, R a1 are each independently selected from halogen, -OH, -CN, -NH2, =O, =S or C 1-3 alkyl.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 is selected from halogen, -OH, -CN, -NH2, or optionally substituted by one or more R a” Substituted with the following groups: -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 a 5-6 membered heteroaryl; Or, R 5 is selected from halogen, or optionally substituted by one or more R a” Substituted with the following groups: 4-8 membered heterocycloalkyl C(O)-, C 8-10 CycloalkylNHC(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)(4-6 membered heterocycloalkyl), -NHC(O)C 1- 4-alkyl, -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 halogen, -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 a 5-6 membered heteroaryl group, the -C(O)NR a’ R b’ 、-C(O)R b’ 、-N(R b’ )C(O)OR b’ 、-N(R b’ )C(O)R b’ or 5-6 membered heteroaryl is optionally substituted by one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted by one or more halogen or -OH 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; Or, R 5 Selected from F, Cl, Br, 5-7 membered heterocycloalkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 CycloalkylNHC(O)-, -C(O)N(C 1- 3 alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 alkyl)(4-6 membered heterocycloalkyl), -NHC(O)C 1-3 Alkyl, -NHC(O)C 3-5 Cycloalkyl, -N(C 1-3 Alkyl)C(O)OC 1-3 alkyl or 5-6 membered heteroaryl, the 5-7 membered heterocycloalkyl C(O)-, -C(O)N(C 1-4 Alkyl)2, C 9-10 CycloalkylNHC(O)-, -C(O)N(C 1-3 Alkyl)C 3-5 Cycloalkyl, -C(O)N(C 1-3 alkyl)(4-6 membered heterocycloalkyl), -NHC(O)C 1-3 Alkyl, -NHC(O)C 3-5 Cycloalkyl or -N(C 1-3 Alkyl)C(O)OC 1-3 The alkyl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH2, C optionally substituted with one or more halogen or -OH 1-3 Alkyl, -OC 1-3 Alkyl, C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl; Or, R 5 is selected from Br, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)N(C 1- 4-alkyl)2, -C(O)-pyrrolidinyl, -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 -NHC(O)C 1-3 Alkyl, -NHC(O)-cyclopropyl or -N(C 1-3 Alkyl)C(O)OC 1-3 alkyl, 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 substituted by 1 or 2 selected from F, Cl, -OH, -CN, methyl, -CF3, -OCH3, cyclopropyl, isopropyl, or substituted with an oxetane group; Or, R 5 Selected from Br, Optionally, the R a’ are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, R a’ are each independently selected from hydrogen, C 1-4 Alkyl or C 3-4 Cycloalkyl; Or, R a’ are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl; Optionally, the R b’ are each independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R b’ are each independently selected from hydrogen, or the following groups optionally substituted by one or more halogens: C 1-6 Alkyl, C 3-9 Cycloalkyl or 4-9 membered heterocycloalkyl; Or, R b’ are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, Optionally, the R a” Each is independently selected from halogen, -OH, -CN, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-O-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -CN or -NH2; Or, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, -NH(C 1-4 Alkyl), -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, -NH(C 1-4 Alkyl), -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen or -OH; Or, R a” Each independently selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl, the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from: halogen, -OH, -CN or -NH2; Or, R a” Each is independently selected from F, Cl, -OH, -CN, -OCH3, -CF3, methyl, isopropyl, cyclopropyl, Or oxetanyl.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen, halogen, -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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R 6 Selected from hydrogen, halogen, -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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R 6 Selected from hydrogen, halogen, -OH, -CN, -NH2, C 1-6 Alkyl or C 1-6 Haloalkyl; Or, R 6 Selected from hydrogen, halogen, -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 is selected from hydrogen, F, Cl, Br or methyl; or, R 6 is selected from hydrogen, F or methyl.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R a and R 7 Each is independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Optionally, R 7 Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3- 6-membered cycloalkyl or 3-6-membered heterocycloalkyl; Or, R 7 are each independently selected from cyclopropyl; Optionally, R a Each independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-4 alkyl; Or, R a Each independently selected from halogen, -CN, -OH, -NH2 or C 1-4 alkyl; Or, R a are each independently selected from F, Cl or Br; or, R a Each independently is F; Optionally, m is selected from 0, 1 or 2; or, m is selected from 0 or 1; Alternatively, m is 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 is selected from 1 or 2; or, n is selected from 2; Optionally, q is selected from 1.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein H is selected from a bond; optionally, R 8 is selected from hydrogen; R 1 and R 2 is hydrogen; and R 3 and R 4 Combine to form =CH2; W and W 1 N, W 2 is CH or C.

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, selected from a compound 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 Heteroalkyl is optionally substituted with one or more halogen, -CN, -OH or -NH2; Or, R c2 Selected from hydrogen or C 1-3 Alkyl; or R c2 Selected from hydrogen.

13. The following compound or a pharmaceutically acceptable salt thereof, 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing or treating a disease; optionally, the disease is selected from cancer; optionally, the cancer is selected from leukemia.

Images