Compound comprising fused heteroaromatic ring, pharmaceutical composition thereof, and use thereof

Abstract

Provided is a compound comprising a fused heteroaromatic ring. The present invention specifically relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition comprising the compound, and use thereof in the treatment of a disease (e.g., cancer).

Description

Compounds containing fused heteroaromatic rings, their pharmaceutical compositions and uses

[0001] Cross-reference of related applications

[0002] This disclosure claims the benefits and priority of Chinese Patent Application No. CN202410678252.3, filed with the China National Intellectual Property Administration on May 28, 2024, and Chinese Patent Application No. CN202510639720.0, filed with the China National Intellectual Property Administration on May 16, 2025, the entire contents of which are hereby incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of medicinal chemistry and relates to compounds containing fused heteroaromatic rings or pharmaceutically acceptable salts thereof, methods of their preparation, pharmaceutical compositions containing such compounds, and their use in the treatment of diseases (e.g., cancer). Background Technology

[0004] Akt, also known as protein kinase B (PKB) or Rac, is a serine / threonine kinase of the AGC family, highly homologous to protein kinase A (PKA) and protein kinase C (PKC). Studies have shown that human Akt comprises three subtypes: Akt1, Akt2, and Akt3, each with unique functions and expression profiles. Akt1, Akt2, and Akt3 are key mediators of the PI3K / AKT / mTOR signaling pathway, promoting various physiological processes such as proliferation, migration, anti-apoptotic survival, and protein synthesis.

[0005] AKT1 E17K is a clinically validated oncogenic driver gene that is mutated in approximately 1-2% of all cancers and is enriched in a variety of solid tumors, including breast cancer (approximately 5%), endometrial cancer (approximately 3%), and prostate cancer (approximately 1.5%). While wild-type PI3K or AKT inhibitors have demonstrated clinical efficacy against HR+ / HER2- metastatic breast cancer with PI3K / AKT pathway mutations, adverse events associated with targeting (most commonly hyperglycemia, diarrhea, and rash) hinder the tolerability and long-term efficacy of these drugs. Therefore, AKT1 E17K has become a highly promising anti-tumor target for development. Summary of the Invention

[0006] This disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0007] in,

[0008] X1 X 2 X 3 X 4 and X 5 Each is independently selected from C, N, and CR. a or NR b The condition is X 1 and X 3 Not both N;

[0009] Y 1 and Y 2 Each independently selected from CR c Or N;

[0010] R a R b and R c Each is independently selected from hydrogen, deuterium, -NH2, -COOH, -NO2, -OH, -SH, halogen, -CN, or each is optionally influenced by one or more R. a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3- 12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0011] R a1 Each is independently selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1- 6-alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C) 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0012] R 1 Selected from hydrogen, deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, or each of which is optionally influenced by one or more R. 1a The following groups are substituted: -C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2、-C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C)1-6 alkyl), -SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6- 10 Aryl or 5-12 heteroaryl groups;

[0013] Each R 1a Each is independently selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, Or each of the following groups may be substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1- 6-alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1- 6-alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C) 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0014] R 2 and R 3 Each is independently selected from hydrogen, deuterium, halogen, -OH, -NO2, -NH2, -COOH, -C(O)H, -SH, -CN, or each is optionally influenced by one or more R 2a The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2;

[0015] Or, R 2 and R 3 Together with the carbon atoms attached to them, they form each optionally bounded by one or more R atoms. 3a The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-14 membered heterocyclic alkyl groups;

[0016] Each R 2a or R 3a Each is independently selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl) or -N(C 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3- 12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0017] Ring A is selected from one or more R. A The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0018] Alternatively, ring A can be replaced by the following groups:

[0019] Each R A Each is independently selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1- 6-alkyl, -CONH(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl) or -N(C 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3- 12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0020] L is selected from the bond, -C(R) d )2-、-O-、-S-、-NR d -、-NR d -C(O)-、-NR d -C(O)O-、-NR d-OC(O)-, -C(O)-, -C(O)O-, -S(O)2NR d -、-S(O)-、-S(O)NR d -, -P(O)- or -P(O)O-;

[0021] Each R d Each is independently selected from hydrogen, deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, halogen, -CN, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-12 cycloalkyl;

[0022] R 4 Selected from -CN, or each of which is arbitrarily selected by one or more R 4a The following groups are substituted: -C 2-6 alkenyl, -C 2-6 alkynyl group, -COC 2-6 alkenyl, -S(O)2C 2-6 alkenyl, -COC 2-6 alkynyl group, -S(O)2C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic alkenyl, C 6-10 Aryl or 5-12 heteroaryl groups;

[0023] Each R 4a Each is independently selected from deuterium, -NH2, -NO2, -OH, -CN, -C(O)H, -SH, -COOH, halogens, -OC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C) 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0024] n is selected from 1, 2, or 3;

[0025] Optionally, the R a1 R 1a R 2a R 3a R A R d or R 4a It can be further substituted by one or more substituents.

[0026] In some implementations, optionally, the R a1 R 1a R 2a R 3a R A R d or R 4a It can be further substituted by one or more substituents, said substituents being R', each R' being independently selected from deuterium, -NH2, -NO2, -OH, -SH, -CN, halogens, or -C 1-6 Halogenated alkyl groups.

[0027] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0028] X 1 X 2 X 3 X 4 and X 5 Each is independently selected from C, N, and CR. a or NR b The condition is X 1 and X 3 Not both N;

[0029] Y 1 and Y 2 Each independently selected from CR c Or N;

[0030] R a R b and R c Each is independently selected from hydrogen, -NH2, -COOH, -NO2, -OH, -SH, halogen, -CN, or each is optionally influenced by one or more R. a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0031] R a1 Each is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1- 6-alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C)1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C) 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0032] R 1 Selected from hydrogen, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, or optionally influenced by one or more R 1a The following groups are substituted: -C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C)1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 alkyl), -SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0033] Each R 1a Each is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, Or each of the following groups may be substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C) 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0034] R 2 and R 3 Each is independently selected from hydrogen, halogen, -OH, -NO2, -NH2, -COOH, -C(O)H, -SH, -CN, or each is optionally influenced by one or more R 2a The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2;

[0035] Or, R 2 and R 3 Together with the carbon atoms attached thereto, they form an optional structure with one or more R atoms. 3a The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-14 membered heterocyclic alkyl groups;

[0036] Each R 2a or R 3a Each is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, -C 1- 6-alkyl, -OC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C)1- 6-alkyl)2、-N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl) or -N(C 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3- 12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3- 12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0037] Ring A is selected from one or more R. A The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0038] Alternatively, ring A can be replaced by the following groups:

[0039] Each R A Each is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6alkyl) or -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl) or -N(C 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0040] L is selected from the bond, -C(R) d )2-、-O-、-S-、-NR d -、-NR d -C(O)-、-NR d -C(O)O-、-NR d-OC(O)-, -C(O)-, -C(O)O-, -S(O)2NR d -、-S(O)-、-S(O)NR d -, -P(O)- or -P(O)O-;

[0041] Each R d Each is independently selected from hydrogen, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, halogen, -CN, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-12 cycloalkyl;

[0042] R 4 Selected from -CN, or each of which is arbitrarily selected by one or more R 4a The following groups are substituted: -C 2-6 alkenyl, -C 2-6 alkynyl group, -COC 2-6 alkenyl, -S(O)2C 2-6 alkenyl, -COC 2-6 alkynyl group, -S(O)2C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic alkenyl, C 6-10 Aryl or 5-12 heteroaryl groups;

[0043] Each R 4a Each is independently selected from -NH2, -NO2, -OH, -CN, -C(O)H, -SH, -COOH, halogens, -OC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 alkyl), -N(C) 1-6 Alkyl)CO(C 1-6 alkyl), -SO(C) 1-6 Alkyl), -SON(C) 1-6 Alkyl)2, -N(C 1- 6-alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C) 1-6Alkyl)SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl) or -N(C 3-12 2,-COC (cycloalkyl) 3-12 Cycloalkyl, -C(O)OC 3-12 Cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C) 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3- 12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C) 3-12 cycloalkyl)SO2(C 3- 12 cycloalkyl), C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0044] n is selected from 1, 2, or 3;

[0045] Optionally, the R a1 R 1a R 2a R 3a R A R d or R 4a It can be further substituted by one or more substituents.

[0046] In some implementation schemes, X 1 Let N, X 2 For N or CR a X 3 For CR a .

[0047] In some implementation schemes, X 1 Let C, X 2 For N or CR a X 3 For N or NR b .

[0048] In some implementation schemes, X 1 Let N, X 2 and X 3 For C or CR a .

[0049] In some implementation schemes, X 1 Let N, X 2 and X 3 For CR a .

[0050] In some implementation schemes, X 3 For N or NR b X 1 and X 2 For C or CR a .

[0051] In some implementation schemes, X 3 For NR b X 1 and X 2 For C or CR a .

[0052] In some implementation schemes, X 4 Let C, X 5 Let N, X 1 X 2 and X 3 Each is independently selected from C, N, and CR. a or NR b And X 1 and X 3 They are not both N.

[0053] In some implementation schemes, X 4 Let N, X 5 Let C, X 1 X 2 and X 3 Each is independently selected from C, N, and CR. a or NR b And X 1 and X 3 They are not both N.

[0054] In some implementation schemes, X 4 and X 5 Both are C, X 1 X 2 and X 3 Each is independently selected from C, N, and CR. a or NR b And X 1 and X 3 They are not both N.

[0055] In some implementation schemes, X 1 X 2 and X 4 For C or CR a X 3 and X 5 Let N be the number of elements in the array.

[0056] In some implementation schemes, X 1 X 2 and X 5 For C or CR a X 3 and X 4 Let N be the number of elements in the array.

[0057] In some implementation schemes, X 1 and X 3 At least one of them is N and they are not both N at the same time.

[0058] In some implementation schemes, Y 1 and Y 2 All are N.

[0059] In some implementation schemes, Y 1 and Y 2 At least one of them is N.

[0060] In some implementation schemes, Y 1 For CR c Y 2 Let N be the number of elements in the array.

[0061] In some implementation schemes, Y 1 For N, Y 2 For CR c .

[0062] In some implementation schemes, Y 1 and Y 2 All are CR c .

[0063] In some implementation schemes, Y 1 For N, Y 2 It can be CH or CF.

[0064] In some implementation schemes, Y 1 For N, Y 2 It can be N or CH.

[0065] In some implementation schemes, structural units It is an aromatic ring.

[0066] In some implementation schemes, structural units for

[0067] In some implementation schemes, structural units for

[0068] In some implementation schemes, structural units for

[0069] In some implementation schemes, structural units for

[0070] In some implementation schemes, structural units for

[0071] In some implementation schemes, structural units for

[0072] In some implementation schemes, R a R b and R c Each is independently selected from hydrogen, -OH, halogen, -CN, or each is optionally influenced by one or more R. a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl or 5-12 heteroaryl compounds.

[0073] In some implementation schemes, R a Selected from hydrogen, -OH, halogen, -CN, or each optionally influenced by one or more R a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl or 5-12 heteroaryl compounds.

[0074] In some implementation schemes, R a Selected from hydrogen, -OH, halogen, -CN, or each optionally influenced by one or more R a1 The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, phenyl, or 5-6 heteroaryl groups.

[0075] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: -C 1-6 Alkyl, C 6-10 Aryl or 5-12 heteroaryl groups.

[0076] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: -C 1-4 Alkyl, phenyl, or 5-6 heteroaryl groups.

[0077] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: -C 1-4 Alkyl, phenyl, or containing 1-3 5-6 heteroaryl groups selected from N or O heteroatoms.

[0078] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: -C 1-6 Alkyl or 5-12 heteroaryl groups.

[0079] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: -C 1-4 Alkyl or 5-6 heteroaryl groups.

[0080] In some implementation schemes, R a Selected from one or more R a1 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyridyl, pyrimidinyl, or pyridazinyl.

[0081] In some implementation schemes, R a Selected from one or more R a1 The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, furanyl, pyrrolyl, thiophene, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyridyl, pyrimidinyl, or pyridazinyl.

[0082] In some implementation schemes, R a Selected from one or more R a1 The following groups may be substituted: methyl, phenyl, 1,2,5-oxadiazolyl or pyridyl.

[0083] In some implementation schemes, R a Selected from one or more R a1 The following groups may be substituted: methyl, 1,2,5-oxadiazolyl or pyridyl.

[0084] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: methyl, phenyl, or pyridyl.

[0085] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: methyl, phenyl,

[0086] In some implementation schemes, R a Selected from one or more R a1 The following groups are substituted: methyl, phenyl or

[0087] In some implementation schemes, R a1 Each is independently selected from -NH2, -COOH, -NO2, -OH, -SH, -CN, halogen, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0088] In some implementation schemes, R a1 Each is independently selected from -NH2, -COOH, -NO2, -OH, -SH, -CN, fluorine, chlorine, or bromine.

[0089] In some implementation schemes, R a1 Selected from -NH2.

[0090] In some implementation schemes, R a Selected from methyl, phenyl,

[0091] In some implementation schemes, R a Selected from methyl, phenyl or

[0092] In some implementation schemes, R a Selected from methyl, In some implementation schemes, R a Selected from

[0093] In some implementation schemes, R b Selected from one or more R a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6alkyl) or -N(C) 1-6 Alkyl)2.

[0094] In some implementation schemes, R b Selected from one or more R a1 Replacement -C 1-4 alkyl.

[0095] In some implementation schemes, R b It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0096] In some implementation schemes, R b Selected from methyl.

[0097] In some implementation schemes, R c Selected from hydrogen, -NH2, -NO2, -OH, -SH, halogen, -CN, or -C 1-6 alkyl.

[0098] In some implementation schemes, R c Selected from hydrogen or halogen.

[0099] In some implementation schemes, R c It is selected from hydrogen, fluorine, chlorine or bromine.

[0100] In some implementation schemes, R c Selected from hydrogen or fluorine.

[0101] In some implementation schemes, R c It is hydrogen.

[0102] In some implementation schemes, R 1 Selected from hydrogen, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, or optionally influenced by one or more R 1a The following groups are substituted: -C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(O)OC 1-4 Alkyl, -OC(O)C 1-4 Alkyl group, -CONH(C) 1-4 Alkyl), -CON(C) 1-4 Alkyl)2、-NHCO(C 1- 4-alkyl), -N(C) 1-4 Alkyl)CO(C 1-4 alkyl), -SO(C)1-4 alkyl), -SO2(C 1-4 Alkyl), C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl compounds.

[0103] In some implementation schemes, R 1 Selected from hydrogen, -NH2, -OH, -SH, -CN, halogen, or optionally substituted with one or more R 1a The following groups are substituted: -C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-C(O)OC 1- 6-alkyl, -CONH(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)2、-SO(C 1-6 alkyl), -SO2(C 1-6 Alkyl), C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups.

[0104] In some implementation schemes, R 1 Selected from hydrogen, -NH2, -OH, -SH, -CN, halogen, or optionally substituted with one or more R 1a The following groups are substituted: -C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(O)OC 1- 4-alkyl, -CONH(C) 1-4 Alkyl), -CON(C) 1-4 Alkyl)2、-SO(C 1-4 alkyl), -SO2(C 1-4 Alkyl), C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl compounds.

[0105] In some implementation schemes, R1 Selected from hydrogen, -CN, or optionally by one or more R 1a The following groups are substituted: -C 1-6 Alkyl, -OC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups.

[0106] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl compounds.

[0107] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 5-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0108] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 5-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O.

[0109] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -N(CH2CH3)2, -N(CH2)(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclopentenyl, cyclohexenyl, oxacyclopropyl, azircyclopropyl, oxacyclobutyl, Azacyclobutyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, phenyl, 2(1H)-pyridinoneyl, 5,6-dihydro-2(1H)-pyridinoneyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0110] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups may be substituted: methyl, ethyl, methoxy, -N(CH3)2, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, oxazolidinyl, azirzobutyl, morpholinyl, 3,6-dihydro-2H-pyranyl, phenyl, 2(1H)-pyridoneyl, pyrazolyl, oxazolyl or pyridinyl.

[0111] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups may be substituted: methyl, ethyl, methoxy, -N(CH3)2, cyclobutyl, cyclohexyl, cyclohexenyl, oxacyclobutyl, aziroxybutyl, 3,6-dihydro-2H-pyranyl, phenyl, 2(1H)-pyridone, pyrazolyl, oxazolyl or pyridinyl.

[0112] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally surrounded by one, two, or three Rs. 1a The following groups may be substituted: methyl, ethyl, methoxy, -N(CH3)2, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, oxazolidinyl, azirzobutyl, morpholinyl, 3,6-dihydro-2H-pyranyl, phenyl, 2(1H)-pyridoneyl, pyrazolyl, oxazolyl or pyridinyl.

[0113] In some implementation schemes, R 1 Selected from hydrogen, -CN, or each of which is optionally surrounded by one, two, or three Rs. 1aThe following groups may be substituted: methyl, ethyl, methoxy, -N(CH3)2, cyclobutyl, cyclohexyl, cyclohexenyl, oxacyclobutyl, aziroxybutyl, 3,6-dihydro-2H-pyranyl, phenyl, 2(1H)-pyridone, pyrazolyl, oxazolyl or pyridinyl.

[0114] In some implementation schemes, R 1 Selected from one or more R 1a Replacement C 6-10 Aryl. In some implementations, R 1 It is a phenyl group.

[0115] In some implementation schemes, each R 1a Each is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, Or each of the following groups may be substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-COC 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -OC(O)C 1-4 Alkyl group, -CONH(C) 1-4 Alkyl), -CON(C) 1-4 Alkyl)2、-NHCO(C 1- 4-alkyl), -N(C) 1-4 Alkyl)CO(C 1-4 alkyl), -SO(C) 1-4 Alkyl), -SON(C) 1-4 Alkyl)2, -N(C 1-4 Alkyl)SO(C 1-4 alkyl), -SO2(C 1- 4-alkyl), -N(C) 1-4 Alkyl)SO2(C 1-4 Alkyl), C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -NH(C 3-6 cycloalkyl), -N(C) 3- 6-cycloalkyl)2,-COC 3-6 Cycloalkyl, -C(O)OC 3-6 Cycloalkyl, -OC(O)C 3-6 cycloalkyl, -CONH(C 3-6 cycloalkyl), -CON(C) 3-6 cycloalkyl)2, -NHCO(C3-6 cycloalkyl), -N(C) 3-6 cycloalkyl)CO(C 3-6 cycloalkyl), -SO(C 3-6 cycloalkyl), -SON(C 3-6 cycloalkyl)2, -N(C 3- 6-cycloalkyl)SO(C 3-6 cycloalkyl), -SO2(C 3-6 cycloalkyl), -N(C) 3-6 cycloalkyl)SO2(C 3-6 cycloalkyl), C 3-6 Cycloalkenyl, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl.

[0116] In some implementation schemes, each R 1a Each is independently selected from deuterium, -NH2, -NO2, -OH, -SH, -CN, halogens, Or optionally, the following groups substituted with R': -C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups.

[0117] In some implementation schemes, each R 1a Each is independently selected from deuterium, -NH2, -NO2, -OH, -CN, halogens, Or optionally, the following groups substituted with R': -C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic alkyl.

[0118] In some implementation schemes, each R 1a Each is independently selected from deuterium, -NH2, -NO2, -OH, -CN, halogens, C 3-6 Cycloalkyl, or optionally the following groups substituted with R': -C 1-4 Alkyl, -OC 1-4 Alkyl groups, 3-6 membered heterocyclic alkyl groups.

[0119] In some implementation schemes, each R 1a Each is independently selected from -NH2, -NO2, -OH, -SH, -CN, halogens, Or each of the following groups may be substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C)1-6 Alkyl)2.

[0120] In some implementation schemes, each R 1a Each group is independently selected from -CN, halogen, or each of the following groups that are optionally substituted: -C 1-6 Alkyl, -OC 1-6 alkyl.

[0121] In some implementation schemes, each R 1a Each group is independently selected from -CN, fluorine, chlorine, bromine, or each of the following groups that are optionally substituted: -C 1-4 Alkyl, -OC 1-4 alkyl.

[0122] In some implementation schemes, each R 1a Each is independently selected from deuterium, -CN, fluorine, chlorine, Or, each of the following groups may be optionally substituted with R': methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclobutyl, azircyclobutyl, tetrahydropyrrole, tetrahydrofuranyl, piperidinyl, piperazine, or morpholinyl.

[0123] In some implementations, each R' is independently selected from deuterium, -NH2, -NO2, -OH, -CN, halogen, or...

[0124] In some implementations, each R' is independently selected from deuterium, halogen, or...

[0125] In some implementations, each R' is independently selected from deuterium, fluorine, chlorine, bromine, or...

[0126] In some implementations, each R' is independently selected from deuterium, fluorine, or...

[0127] In some implementation schemes, each R 1a Each is independently selected from -CN, fluorine, chlorine, methyl, trifluoromethyl, methoxy, cyclopropyl, -OCD3,

[0128] In some implementation schemes, each R 1a Each is independently selected from -CN, fluorine, chlorine, methyl or methoxy.

[0129] In some implementation schemes, R 1 Each is independently selected from hydrogen, -CN, ethyl, trifluoromethyl, -N(CH3)2, methoxy,

[0130] In some implementation schemes, R 1 Each is independently selected from hydrogen, -CN, ethyl, trifluoromethyl, -N(CH3)2, methoxy,

[0131] In some implementation schemes, R 1 Each is independently selected from hydrogen, -CN, ethyl, trifluoromethyl, -N(CH3)2, methoxy,

[0132] In some implementation schemes, R 2 and R 3 Each is independently selected from hydrogen, halogen, -OH, -NO2, -NH2, -SH, -CN, or each is optionally influenced by one or more R. 2a The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0133] In some implementation schemes, R 2 and R 3 Each is independently selected from hydrogen or -C. 1-4 alkyl.

[0134] In some implementation schemes, R 2 and R 3 All are selected from hydrogen.

[0135] In some implementation schemes, R 2 and R 3 Together with the carbon atoms attached to them, they form each optionally bounded by one or more R atoms. 3a The following groups are substituted: C 3-6 cycloalkyl, C 3-6 Cycloalkenyl or 3-6 membered heterocyclic alkyl groups.

[0136] In some implementation schemes, R 2 and R 3 Together with the carbon atoms attached thereto, they form an optional structure with one or more R atoms. 3a Replacement C 3-6 Cycloalkyl.

[0137] In some implementation schemes, each R 2a or R 3aEach is independently selected from -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0138] In some implementations, ring A is selected from one or more Rs. A The following groups are substituted: C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkyl or 3-10 membered heterocyclic alkenyl.

[0139] In some implementations, ring A is selected from one or more Rs. A Substituted 3-12 membered heterocyclic alkyl groups.

[0140] In some implementations, ring A is selected from one or more Rs. A Substituted 3-10 membered heterocyclic alkyl groups.

[0141] In some implementations, ring A is selected from one or more Rs. A The substituted compounds contain 1-3 3-10 membered heterocyclic alkyl groups selected from N, O or S heteroatoms.

[0142] In some implementations, ring A is selected from one or more Rs. A The substituted alkyl group contains 1-3 3-10 membered heterocyclic alkyl groups selected from N or O heteroatoms.

[0143] In some implementations, ring A is selected from one or more Rs. A The substituted compounds contain one or two 4-9 membered heterocyclic alkyl groups selected from N heteroatoms.

[0144] In some implementations, ring A is selected from one or more Rs. A Substituted monocyclic, spirocyclic, bridged, or fused heterocyclic alkyl groups of 3-10 members.

[0145] In some implementations, ring A is selected from one or more Rs. A The substituted monocyclic, spirocyclic, bridged, or fused cyclic forms contain 1-3 3-10 membered heterocyclic alkyl groups selected from N, O, or S heteroatoms.

[0146] In some implementations, ring A is selected from one or more Rs. A It is a substituted monocyclic, spirocyclic, bridged, or fused cyclic form containing 1-3 3-10 membered heterocyclic alkyl groups selected from N or O heteroatoms.

[0147] In some implementations, ring A is selected from one or more Rs. A It is a substituted monocyclic, spirocyclic, or fused cyclic form containing one or two 3- to 10-membered heterocyclic alkyl groups selected from N heteroatoms.

[0148] In some implementations, ring A is selected from one or more Rs. A The following groups may be substituted: 3-8 member monocyclic heterocyclic alkyl, 6-10 member spirocyclic heterocyclic alkyl, 6-10 member bridged heterocyclic alkyl or 6-10 member fused heterocyclic alkyl.

[0149] In some implementations, ring A can be replaced by the following groups:

[0150] In some implementations, ring A is selected from one or more Rs. A The following groups are substituted: aziridine, aziridine, piperazinyl, piperidinyl, aziridine-heptyl, 1,4-oxazyridine-heptyl, octahydropyrrolo[3,4-c]pyrrolithyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,6-diazaspiro[3.3]heptyl, 2-aziridine[3.3]heptyl, 2-aziridine[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[3.5]nonyl, 7-aziridine[3.5]nonyl, 2,6 -diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl or 2-azabicyclo[2.2.2]octyl.

[0151] In some implementations, ring A is selected from one or more Rs. A The following groups are substituted:

[0152] In some implementations, ring A is selected from one or more Rs. A The following groups are substituted:

[0153] In some implementations, ring A is selected from... Where * indicates -LR 4 The connected positions.

[0154] In some implementations, ring A is optionally controlled by one or more R... A Substituted piperazine group; in some embodiments, ring A is optionally replaced by one or more R A Replacement In some implementations, ring A is

[0155] In some implementation schemes, each R A Each is independently selected from -NH2, -NO2, -OH, -SH, -CN, halogens, -C 1-6 Alkyl or -OC 1-6 alkyl.

[0156] In some implementation schemes, each R A Each is independently selected from halogens, or -C 1-4 alkyl.

[0157] In some implementations, L is selected from key, -C(R) d )2-、-NR d -、-NR d -C(O)-, -C(O)-, -C(O)O-, -S(O)2NR d -、-S(O)-、-S(O)NR d -、-P(O)- or -P(O)O-.

[0158] In some implementations, L is selected from key, -NR d -、-NR d -C(O)- or -C(O)-.

[0159] In some implementations, L is selected from key, -NR d -、-NR d -C(O)-# or -C(O)-, where # indicates the same as -R. 4 The connected positions.

[0160] In some implementation schemes, each R d Each is independently selected from hydrogen or -C. 1-6 alkyl.

[0161] In some implementation schemes, each R d Each is independently selected from hydrogen or -C. 1-4 alkyl.

[0162] In some implementation schemes, each R dEach is independently selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl.

[0163] In some implementation schemes, each R d Each is independently selected from hydrogen or methyl.

[0164] In some implementations, L is selected from bond, -NH-, -N(CH3)-, -NH-C(O)-#, -N(CH3)-C(O)-#, or -C(O)-, where # indicates a bond with -R. 4 The connected positions.

[0165] In some implementations, L stands for key.

[0166] In some implementation schemes, R 4 Selected from -CN, or each of which is arbitrarily selected by one or more R 4a The following groups are substituted: -COC 2-6 alkenyl, -S(O)2C 2- 6-Alkenyl, -COC 2-6 alkynyl group, -S(O)2C 2-6 alkynyl group, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic alkenyl, C 6-10 Aryl or 5-12 heteroaryl groups.

[0167] In some implementation schemes, R 4 Selected from -CN, or each of which is arbitrarily selected by one or more R 4a The following groups are substituted: -COC 2-4 alkenyl, -S(O)2C 2- 4-Alkenyl, -COC 2-4 alkynyl group, -S(O)2C 2-4 alkynyl group, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

[0168] In some implementation schemes, R 4 Selected from -CN, or each of which is arbitrarily selected by one or more R 4a The following groups are substituted: -COC 2-4 alkenyl, -S(O)2C 2- 4-Alkenyl, -COC 2-4 alkynyl group, -S(O)2C 2-4 alkynyl group, C 3-6 Cycloalkenyl, phenyl, or 5-6 heteroaryl groups.

[0169] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: C 3-12 Cycloalkenyl, C6-10 Aryl or 5-12 heteroaryl groups.

[0170] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: C 3-6 Cycloalkenyl, phenyl, or 5-6 heteroaryl groups.

[0171] In some implementation schemes, R 4 Selected from one or more R 4a Substituted 5-6 heteroaryl groups.

[0172] In some implementation schemes, R 4 Selected from one or more R 4a The substituted compounds contain 1-3 5-6 membered heteroaryl groups selected from N or O heteroatoms.

[0173] In some implementation schemes, R 4 Selected from one or more R 4a The substituted compounds contain 1-3 5-6 membered heteroaryl groups selected from N heteroatoms.

[0174] In some implementation schemes, R 4 Selected from one or more R 4a The substituted form contains one, two, or three six-membered heteroaryl groups selected from N heteroatoms.

[0175] In some implementation schemes, R 4 Selected from one or more R 4a The substituted form contains one or two six-membered heteroaryl groups selected from N heteroatoms.

[0176] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: Phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyridyl, triazinyl, pyrimidinyl, or pyridazinyl.

[0177] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: Phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyridyl, pyrimidinyl, or pyridazinyl.

[0178] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: Phenyl, triazine or pyrimidinyl.

[0179] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: Phenyl or pyrimidinyl.

[0180] In some implementation schemes, R 4 Selected from one or more R 4a The following groups are substituted: phenyl or pyrimidinyl.

[0181] In some implementation schemes, R 4 Selected from one or more R 4a Substituted pyrimidine group.

[0182] In some implementation schemes, each R 4a Each is independently selected from -NO2, -OH, -CN, -C(O)H, -COOH, halogens, or -OC 1-6 alkyl.

[0183] In some implementation schemes, each R 4a Each is independently selected from -NO2, -OH, -CN, -C(O)H, -COOH, fluorine, chlorine, bromine, methoxy or ethoxy.

[0184] In some implementation schemes, each R 4a Each is independently selected from -OH, -CN, -C(O)H or methoxy group.

[0185] In some implementation schemes, R 4a Selected from -CN.

[0186] In some implementation schemes, R 4 Selected from

[0187] In some implementation schemes, R 4 Selected from

[0188] In some implementation schemes, R 4 Selected from

[0189] In some implementations, n is selected from 1 or 2.

[0190] In some embodiments, the heteroaryl, heterocyclic, and heterocyclic alkyl groups comprise 1, 2, 3, 4, or 5 cyclic heteroatoms independently selected from N, O, S, or P, with the remaining cyclic atoms selected from carbon. In some embodiments, the heteroaryl, heterocyclic, and heterocyclic alkyl groups comprise 1, 2, or 3 cyclic heteroatoms independently selected from N, O, or S, with the remaining cyclic atoms selected from carbon. In some embodiments, the heteroaryl, heterocyclic, and heterocyclic alkyl groups comprise 1, 2, or 3 cyclic heteroatoms independently selected from N or O, with the remaining cyclic atoms selected from carbon. In some embodiments, the heteroaryl, heterocyclic, and heterocyclic alkyl groups comprise 1 or 2 cyclic heteroatoms independently selected from N, with the remaining cyclic atoms selected from carbon.

[0191] In some embodiments, the heterocyclic group includes heterocyclic alkyl and heterocyclic alkenyl groups.

[0192] In some implementations, the phrase "by one or more" is each independently selected from "by 1, 2, 3, 4, 5 or 6".

[0193] In some implementations, the phrase "by one or more" is independently selected from "by 1, 2, 3, 4 or 5".

[0194] In some implementations, the phrase "by one or more" is independently selected from "by 1, 2, 3 or 4".

[0195] In some implementations, the phrase "by one or more" is independently selected from "by 1, 2 or 3".

[0196] In some embodiments, the compounds of formula (I) of this disclosure or pharmaceutically acceptable salts thereof are selected from the following compounds of formula (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts thereof:

[0197] Among them, R 1 R a R b R c Rings A, L and R 4 The definition is as described in this disclosure.

[0198] In some implementations, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0199] It should be understood that any embodiment of the compounds of this disclosure as described above and any specific X in the compounds of this disclosure as described above are considered. 1 X 2 X 3 X 4 X 5 Y 1Y 2 Ring A, L, R 1 R 2 R 3 R 4 R a R b R c R d R a1 R 1a R 2a R 3a R 4a R A Any specific substituent described herein may be independently combined with other embodiments of this disclosure and / or substituents of the compound to form embodiments of this disclosure not specifically described above. Furthermore, in the specific embodiments and / or claims, any particular X... 1 X 2 X 3 X 4 X 5 Y 1 Y 2 Ring A, L, R 1 R 2 R 3 R 4 R a R b R c R d R a1 R 1a R 2a R 3a R 4a R A Where the scope of substituents is disclosed, it should be understood that one or more substituents may be removed from that scope, and the remaining scope of substituents should also be considered as an embodiment of this disclosure.

[0200] In some embodiments, the heteroatoms or heteroatomic groups in the heterocyclic alkenyl, heterocyclic alkyl, heterocyclic or heteroaryl groups are selected from N, O, NH, S, S(O), S(O)2, P, P(O) or P(O)2, and the number of heteroatoms is selected from 1, 2, 3, 4 or 5; or, the number of heteroatoms is selected from 1, 2, 3 or 4; or, the number of heteroatoms is selected from 1, 2 or 3; or, the number of heteroatoms is selected from 1, 2 or 3.

[0201] In some embodiments, this disclosure relates to the following compounds or pharmaceutically acceptable salts thereof:

[0202] In some embodiments, this disclosure relates to the following compounds or pharmaceutically acceptable salts thereof:

[0203] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds described above or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this disclosure further comprise pharmaceutically acceptable excipients.

[0204] On the other hand, this disclosure provides a method for treating or preventing a disease in an individual (e.g., a mammal), the method comprising administering to a mammal, preferably a human, a therapeutically or preventively effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0205] On the other hand, this disclosure provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating or preventing diseases.

[0206] On the other hand, this disclosure provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment or prevention of diseases.

[0207] On the other hand, this disclosure provides the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment or prevention of diseases.

[0208] In some implementations, the disease is selected from diseases associated with AKT1 E17K kinase.

[0209] In some embodiments, the disease is selected from those that benefit from the inhibition of AKT1 E17K kinase.

[0210] In some embodiments, the diseases associated with or benefiting from the inhibition of AKT1 E17K kinase are selected from cancer (e.g., hematologic disorders).

[0211] In some embodiments, the disease associated with or benefiting from the inhibition of AKT1 E17K kinase is selected from leukemia.

[0212] The compounds disclosed herein possess good AKT1 E17K kinase inhibitory activity and selectivity, superior cell proliferation inhibitory activity (e.g., good proliferation inhibitory activity against AKT1-E17K / BaF3 cells), good selectivity relative to AN3CA (AKT1 WT) cells, good in vitro liver microsomal metabolic stability, and / or good in vivo efficacy and pharmacokinetic properties.

[0213] definition

[0214] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0215] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0216] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0217] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" means one, two, three, four, five, or six; or, "one or more" means one, two, or three.

[0218] The term "substituent" as used herein includes, but is not limited to, the terms "alkyl," "alkenyl," "alkynyl," "bicycloyl," "tricycloyl," "cycloalkyl," "cycloalkenyl," "heterocyclic," "alkoxy," "cycloalkyl," "heterocyclic," "heteroaryl," "spirocycloalkyl," "spiroheterocyclic," "bridged ring," "heterocyclic alkenyl," "fused ring," etc., as well as corresponding non-limiting or exemplary groups. Some non-limiting examples of the "substituent" include deuterium, tritium, -OH, -SH, halogen, -NH2, nitrate, etc. alkyl, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkathioyl, aryl, aryloxy, arylthio, arylalkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio The group may be substituted with one or more substituents selected from the following: alkyl, heterocyclic, heterocyclic oxy, heterocyclic thio, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic alkylthio, acyl, acyloxy, urethane group, amide group, urea group, epoxy group, and ester group, wherein the substituent is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C (O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heterocyclic aryl, heteroaryl alkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0219] In some embodiments of this document, the "substituent" is selected from hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, diC 1-12 Alkylamino, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C) 1-12 Alkyl)2、-NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0220] In some embodiments of this document, the "substituent" is selected from hydroxyl, mercapto, halogen, amino, nitro, cyano, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylC 1-6 Alkylene, 5-10 heteroaryl, 5-10 heteroaryl C 1-6 Alkylene, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group oxygen, 3-12 membered heterocyclic group C 1-6 Alkylene, C 1-6 Acyl group, C 1-6 Acyloxy group, C 1-6 amide group, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl and oxo, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, carboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl, 6-10 membered aryl, etc.

[0221] In some embodiments herein, the "substituent" is selected from hydroxyl, mercapto, halogen, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylthio, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic and oxo.

[0222] In some embodiments described herein, the "substituent" is selected from deuterium, -NH2, -NO2, -OH, -SH, -CN, halogens, etc. or -C 1- 6-Hydroalkyl groups.

[0223] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 This means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0224] In this article, "mn" refers to integer elements within a given range. For example, "3-14 elements" means that the group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 elements. Similarly, "3-12 elements" means that the group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 elements. Finally, "5-10 elements" means that the group can have 5, 6, 7, 8, 9, or 10 elements.

[0225] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0226] When a substituent is cross-bonded between two atoms on a ring, it can bond with any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0227] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0228] The term "hydroxyl group" refers to the -OH group.

[0229] The term "amino" refers to the -NH2 group.

[0230] The term "nitro" refers to the -NO2 group.

[0231] The term "cyano" refers to the -CN group.

[0232] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0233] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0234] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0235] The term "alkoxy" refers to -O-alkyl.

[0236] The term "cycloalkyl" refers to a fully saturated carbon ring. Unless otherwise indicated, the carbon ring is typically a 3- to 14-membered ring; preferably a 3- to 12-membered ring; more preferably a 3- to 10-membered ring. Unless otherwise indicated, the cycloalkyl group can be a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0237] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, or a 3- to 10-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring), a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring, containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, dihydropyridyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazine, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, octahydropyrrolo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, etc.

[0238] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring (specifically, for example, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0239] The term "heterocyclic alkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise indicated, the heterocyclic alkyl group typically contains one to three independently selected from N, O, and S(O). n P(O) nA ring of heteroatoms (preferably 1 or 2 heteroatoms) (where n is 0, 1, or 2). Unless otherwise indicated, the heterocyclic alkyl group may be a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocyclic alkyl group includes, but is not limited to, 3- to 12-membered rings, 3- to 8-membered rings, or 5- to 8-membered rings. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred. The term "monocyclic heterocyclic alkyl" refers to a heterocyclic alkyl group existing as a single ring.

[0240] The term "heterocyclic alkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, specifically, for example, cycloalkenyl groups in which at most three carbon atoms, at most two carbon atoms, or in one embodiment, one carbon atom is independently replaced by N, O, or S (O), provided that at least one cycloalkenyl carbon-carbon double bond is retained. Heterocyclic alkenyl groups can be cyclic groups existing as monocyclic, bridged, fused, or spirocyclic rings, and can be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, specifically 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyridyl, dihydropyrrole, tetrahydropyridyl, tetrahydroazapyrrolyl, or azaspirooctene.

[0241] The term "monocyclic heterocyclic alkenyl" refers to heterocyclic alkenyl groups that exist as a single ring.

[0242] The term "spirocyclic" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 9 to 14 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0243] The term "spirocycloalkyl" refers to a fully saturated polycyclic aromatic hydrocarbon that shares a single carbon atom (called a spiro atom) between its rings. Unless otherwise indicated, the spirocycloalkyl group is 5 to 20 quinones, preferably 6 to 14 quinones, and more preferably 9 to 14 quinones. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably monospirocycloalkyl and bispirocycloalkyl, and more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups.

[0244] The term "spiroheteroalkyl" refers to a fully saturated polycyclic ring in which one or more ring atoms are selected from N, O, and S(O). n P(O) n (where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Unless otherwise indicated, the spiroheteroalkyl group is 5 to 20 quinary, preferably 6 to 14 quinary, and more preferably 6 to 10 quinary. Spiroheterocycles are classified into monospiroheterocycles, bispiroheterocycles, or multispiroheterocycles according to the number of shared spiro atoms between rings, preferably monospiroheterocycles or bispiroheterocycles, more preferably 4-quinary / 4-quinary, 4-quinary / 5-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, or 5-quinary / 6-quinary monospiroheterocycles. Non-limiting examples of spiroheteroalkyl groups include wait.

[0245] The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbon rings and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5- to 14-membered, preferably 6- to 14-membered, and more preferably 6- to 10-membered. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring, preferably a bicyclic or tricyclic, and more preferably a bicyclic. When the bridged ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Non-limiting examples of bridged heterocyclic alkyl groups include wait.

[0246] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring having a conjugated π-electron system. Unless otherwise indicated, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene, preferably phenyl. In some embodiments, the ring directly connected to the parent structure is a benzene ring; in some preferred embodiments, the aryl group may be a phenyl group fused with a heterocyclic group or cycloalkyl group to form two or more rings (e.g., two, three, four rings, etc.), wherein the ring directly connected to the parent structure is a benzene ring.

[0247] The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one element selected from N, O, or S(O). n P(O) n An aromatic ring consisting of at least one heteroaryl ring, where n is 0, 1, or 2, and the remaining ring atoms are carbon. Unless otherwise indicated, the heteroaryl group can be monocyclic, bicyclic, or tricyclic. Unless otherwise indicated, the heteroaryl group can have a single 5- to 8-membered ring, or multiple fused rings comprising 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoyindoleyl, etc. In some embodiments, the ring directly connected to the parent structure by the heteroaryl group is a heteroaryl ring.

[0248] The "key" in the statement "L is selected from key" refers to a direct-connected key.

[0249] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0250] (i) Suppress the disease or disease state, that is, curb its development;

[0251] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0252] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0253] The term "therapeutic effective amount" means (i) treating the specific disease, condition, or disorder described herein, and (ii) alleviating, improving, or eliminating one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0254] The term "preventive effective amount" means the amount of the disclosed compound used to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "preventive effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0255] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0256] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0257] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0258] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0259] The term "individual" includes both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0260] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0261] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0262] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0263] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0264] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0265] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0266] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. For example, it should be understood that compounds of formula (I), (II), (III), (IV), (V), (VI), (VII) of this disclosure, or compounds in which one or more hydrogen atoms are replaced by deuterium atoms, are still within the scope of compounds of formula (I).

[0267] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0268] In addition, heavier isotopes (such as deuterium) are used. 2 H or D)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases, wherein the deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are substituted by deuterium, for example, methyl (-CH3) completely substituted by deuterium is -CD3.

[0269] The compounds disclosed herein may exist in their tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer may be an imidazole moiety, in which a proton can migrate between two ring nitrogens.

[0270] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients.

[0271] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, and intravenous administration.

[0272] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0273] In all methods of administration of the compound (I) disclosed herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in single or separate doses.

[0274] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0275] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0276] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this disclosure are incorporated herein by reference in their entirety.

[0277] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0278] In some embodiments, the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0279] Preparation route 1:

[0280] Preparation route 2:

[0281] Preparation route 3:

[0282] Preparation route 4:

[0283] Preparation route 5:

[0284] Preparation route 6:

[0285] in,

[0286] Z1 and Z8 are selected from groups such as amino, imino, hydroxyl, halogen, boric acid, borate ester, OTf, ONf, or tin reagent;

[0287] Z4, Z5, and Z6 are selected from groups such as amino, imino, hydroxyl, halogen, OTf, ONf, carboxylic acid, sulfonic acid, acyl chloride, sulfonyl chloride, amide, or sulfonamide.

[0288] Z7 is selected from groups such as amino, imino, hydroxyl, aldehyde, ketone, halogen, OTf or ONf;

[0289] When X 1 Selected from C or CR a In this case, Z2 is selected from groups such as halogen, boric acid, borate ester, OTf, ONf or tin reagent, and Z3 is selected from groups such as halogen, boric acid, borate ester, OTf, ONf or tin reagent.

[0290] When X 1 Selected from N or NR b In this case, Z2 is selected from groups such as hydrogen, and Z3 is selected from groups such as halogen, boric acid, borate ester, OTf, ONf or tin reagent;

[0291] X is selected from halogens;

[0292] X 1 X 2 X 3 X 4 X 5 Y 1 Y 2 Ring A, L, R 1 R 2 R 3 R 4 R a R b The definition is as described in this disclosure.

[0293] The following abbreviations are used in this disclosure:

[0294] Boc represents tert-butyloxycarbonyl; TLC represents thin-layer chromatography; OTf represents trifluoromethanesulfonyl; ONf represents perfluorobutylsulfonic acid; PE represents petroleum ether; EA represents ethyl acetate; DCM represents dichloromethane; MeOH represents methanol; Na2SO4 represents sodium sulfate; NaCl represents sodium chloride. Detailed Implementation

[0295] For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. Various changes and modifications to the specific embodiments of this disclosure will be apparent to those skilled in the art without departing from the spirit and scope of this disclosure. All reagents used in this disclosure are commercially available and can be used without further purification.

[0296] The compounds disclosed herein can be obtained using similar preparation methods as described in the examples, including but not limited to adjusting structurally similar raw materials, reagents, or process parameters. The structures of the compounds disclosed herein can be confirmed by MS or HNMR. Results for the compounds disclosed herein can also be obtained using the same efficacy testing methods.

[0297] Example 1: Preparation of compound I-1

[0298] Method 1:

[0299] Step A: Preparation of compound 1a

[0300] 2-Cryptol-4-chloropyrimidine (1.4 g), piperazine (1.7 g), N,N-diisopropylethylamine (3.2 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was heated and stirred at 100 °C. TLC showed that the reaction proceeded completely. The mixture was concentrated under reduced pressure and then subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 1a (1.5 g).

[0301] Step B: Preparation of compound 1b

[0302] Compound 1a (1.4 g), 4-bromobenzaldehyde (1.5 g), acetic acid (0.1 mL), and methanol (25 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (2.5 g) was slowly added to the above reaction solution under an ice-water bath. After the addition was complete, the reaction solution was transferred to room temperature. TLC showed that the starting material had reacted completely. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate and water, and the organic phase was collected. The phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 1b (1.8 g).

[0303] MS(ESI,[M+H) + )m / z:358.

[0304] Step C: Preparation of compound 1c

[0305] To the reaction flask, add 1b (1.8 g), pinacol diborate (2 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 g), potassium acetate (0.2 g), dioxane (30 mL), and water (2 mL) sequentially. After addition, under nitrogen protection, stir the mixture at 100 °C. Monitor the reaction by TLC until complete. Filter the reaction solution, concentrate it, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 1c (1.7 g).

[0306] MS(ESI,[M+H) + )m / z:406.

[0307] Step D: Preparation of compound 1d

[0308] To a reaction flask, 2.5 g of 4-amino-2-chloro-5-iodopyrimidine, 2.4 g of ditert-butyl dicarbonate, 0.2 g of 4-dimethylaminopyridine, and 40 mL of tetrahydrofuran were added sequentially. After the addition was complete, the mixture was stirred at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was then filtered and concentrated to give compound 1d (3.4 g).

[0309] Step E: Preparation of compound 1e

[0310] Compound 1d (1.4 g), 2-amino-3-propynylpyridine (0.56 g), palladium acetate (0.089 g), potassium acetate (1.960 g), lithium chloride (0.17 g), potassium carbonate (2.76 g), and N,N-dimethylformamide (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was heated and stirred at 120 °C under nitrogen protection. TLC showed that the reactants had reacted completely. The solvent was removed by vacuum distillation, and column chromatography (petroleum ether:ethyl acetate = 4:1) was performed to give compound 1e (0.8 g).

[0311] MS(ESI,[M+H) + )m / z:360.

[0312] Step F: Preparation of compound 1f

[0313] Compound 1e (0.8 g), phenylboronic acid (0.65 g), palladium acetate (0.050 g), potassium carbonate (0.95 g), 1,4-dioxane (20 mL), and water (2 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was heated and stirred at 120 °C under nitrogen protection. TLC showed that the reactants had reacted completely. The solvent was removed by vacuum distillation, and column chromatography (petroleum ether: ethyl acetate = 4:1) was performed to give compound 1f (0.85 g).

[0314] MS(ESI,[M+H) + )m / z:402.

[0315] Step G: Preparation of 1g of compound

[0316] To a reaction flask, compound 1f (0.85 g), dichloromethane (20 mL), and a 4M dioxane solution (5 mL) containing hydrogen chloride were added sequentially. After the addition was complete, the mixture was stirred at room temperature. TLC showed that the reactants had reacted completely. The solvent was removed by vacuum distillation, the pH was adjusted to 9 by saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate and water. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate to give compound 1 g (0.45 g).

[0317] MS(ESI,[M+H) + )m / z:302.

[0318] Step H: Preparation of compound I-1

[0319] To a reaction flask, compound 1 g (0.45 g), compound 1c (0.85 g), N',N'-dimethylethylenediamine (0.04 g), cuprous iodide (0.050 g), tripotassium phosphate (0.12 g), and toluene (15 mL) were added sequentially. After addition, the mixture was placed under nitrogen protection and stirred at 120 °C. TLC showed that the reactants reacted completely. The solvent was removed by vacuum distillation, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate and water, and the organic phase was collected. The phase was washed with saturated brine and dried over anhydrous sodium sulfate to give compound I-1 (0.08 g).

[0320] MS(ESI,[M+H) + )m / z:579.

[0321] Method 2:

[0322] Step A: Preparation of compounds 1-3

[0323] Compound 1-1 (10 g), compound 1-2 (11.66 g), 1,4-dioxane (100 mL), and N,N-isopropylethylamine (12.71 mL) were added sequentially to a 250 mL single-necked flask. The reaction was carried out at 120 °C for 6 h. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate (60 mL × 3), and subjected to column chromatography (developing solvent: PE:EA) to give compound 1-3 (8 g).

[0324] MS(ESI,[M+H) + )m / z:530.2.

[0325] Step B: Preparation of compounds 1-4

[0326] Compounds 1-3 (8 g), potassium acetate (7.41 g), lithium chloride (0.64 g), palladium acetate (0.51 g), N,N-dimethylformamide (20 mL), and trimethylsilylpropyne (3.35 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted in an oil bath at 98 °C for 6 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, the solvent was removed by rotary evaporation, and the solution was subjected to column chromatography (evolving solvent: PE:EA) to obtain the target product compound 1-4 (2.9 g).

[0327] MS(ESI,[M+H) + )m / z:514.4.

[0328] Step C: Preparation of compounds 1-5

[0329] Compound 1-4 (2 g), methanol (10 mL), and dichloromethane (10 mL) were added to a 50 mL single-necked flask. N-iodosuccinimide (1.75 g) and silver tetrafluoride borate (1.14 g) were added at 0-5 °C. The mixture was purged with nitrogen three times and reacted at 25 °C for 5 h. Then, N-iodosuccinimide (1.0 g) and silver tetrafluoride borate (0.6 g) were added, and the reaction was continued for another 12 h. After the reaction was complete, sodium thiosulfate solution was added to quench the reaction. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (20 mL × 3). The filtrate was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the target product compound 1-5 (2.4 g), which was used directly in the next step without further purification.

[0330] MS(ESI,[M+H) + )m / z:568.2.

[0331] Step D: Preparation of compounds 1-6

[0332] Compound 1-5 (2.4 g), 2-amino-3-pinacolboryl ester-pyridine (0.93 g), tetrakis(triphenylphosphine)palladium (0.49 g), potassium carbonate (1.46 g), 1,4-dioxane (50 mL), and water (5.00 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 3 h. After the reaction was complete, column chromatography (developing solvent: DCM:EA) yielded the target product, compound 1-6 (1.3 g).

[0333] MS(ESI,[M+H) + )m / z:534.3

[0334] Step E: Preparation of compounds 1-7

[0335] Compound 1-6 (1.0 g), phenylboronic acid (0.34 g), tetrakis(triphenylphosphine)palladium (0.22 g), potassium carbonate (0.65 g), 1,4-dioxane (25 mL), and water (2.50 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 4 h. After the reaction was complete, column chromatography (developing solvent: DCM:MeOH) yielded compound 1-7 (780 mg).

[0336] MS(ESI,[M+H) + )m / z:576.6.

[0337] Step F: Preparation of compounds 1-8

[0338] Compound 1-7 (780 mg) was dissolved in dioxane (10 mL) in a 100 mL single-necked flask, and HCl / 1,4-dioxane (10 mL, 4 M) solution was added dropwise. The reaction was carried out at 25 °C for 2 h. After the reaction was complete, the solution was directly evaporated to dryness to give the hydrochloride salt of compound 1-8 (860 mg).

[0339] MS(ESI,[M+H) + )m / z:476.5.

[0340] Step G: Preparation of compound I-1

[0341] Compounds 1-8 (95 mg), 1-9 (27.9 mg), N,N-diisopropylethylamine (155 mg), and N-methylpyrrolidone (5 mL) were added sequentially to a 10 mL microwave-safe tube. The reaction was carried out at 130 °C for 1 h. After the reaction was complete, the mixture was extracted with ethyl acetate (5 mL × 3) and subjected to column chromatography (developing solvent: DCM:MeOH) to give the target product compound I-1 (25 mg).

[0342] 1 H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.36-8.35(m,2H),8.26-8.25(m,1H),7.94-7.93(m,1H),7.49-7.43(m,3H),7.37-7.35(m,4H),7 .28-7.26(m,1H),7.10-7.09(m,1H),6.50-6.48(m,1H),5.86(s,2H),3.68-3.66(m,4H),3.56(s,2H),2.53-2.46(m,4H),2.25(s,3H).

[0343] HRMS(ESI,[M+H] + )m / z:579.2729.

[0344] Example 2: Preparation of compound I-2

[0345] Step A: Preparation of compound 2a

[0346] To a reaction flask, 0.59 g of 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-D]pyrimidine, 1 c (1.25 g), 0.25 g of tetra(triphenylphosphine)palladium, 0.78 g of potassium carbonate, 20 mL of 1,4-dioxane, and 2 mL of water were added sequentially. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 0.78 g of compound 2a.

[0347] MS(ESI,[M+H) + )m / z:445.

[0348] Step B: Preparation of compound 2b

[0349] Compound 2a (0.78 g), phenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium (0.22 g), potassium carbonate (0.85 g), 1,4-dioxane (20 mL), and water (2 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 2b (0.81 g).

[0350] MS(ESI,[M+H) + )m / z:487.

[0351] Step C: Preparation of compound 2c

[0352] Compound 2b (0.80 g), 1,2-dichloroethane (20 mL), copper bromide (0.8 g), water (1 mL), and tetrabutylammonium bromide (0.05 g) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 60 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2c (0.60 g).

[0353] MS(ESI,[M+H) + )m / z:565.

[0354] Step D: Preparation of compound I-2

[0355] Compound 2c (0.60 g), 2-aminopyridine-3-boronic acid (0.29 g), tetrakis(triphenylphosphine)palladium (0.12 g), potassium carbonate (0.42 g), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound I-2 (0.4 g).

[0356] MS(ESI,[M+H) + )m / z:579.

[0357] Example 3: Preparation of compound I-3

[0358] Step A: Preparation of compound 3a

[0359] To a reaction flask, 3-amino-6-chloropyridazine (4.6 g), pinacol phenylboronic acid (7.67 g), tetrakis(triphenylphosphine)palladium (8.54 g), potassium carbonate (8.18 g), 1,4-dioxane (200 mL), and water (40 mL) were added sequentially. After the addition was complete, the mixture was heated and stirred at 100 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered and concentrated. The solution was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 3a (4.40 g).

[0360] MS(ESI,[M+H) + )m / z:172.19.

[0361] Step B: Preparation of compound 3b

[0362] Compound 3a (3.30 g), 2-bromo-1-(2-chloropyridin-3-yl)ethyl ketone (2.0 g), isopropanol (40 mL), and N,N-diisopropylethylamine (1.23 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was heated and stirred at 85 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered and concentrated. Compound 3b (2.26 g) was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1).

[0363] MS(ESI,[M+H) + )m / z:306.94.

[0364] Step C: Preparation of compound 3c

[0365] Compound 3b (1.0 g), anhydrous copper sulfate (0.52 g), 28% ammonia (40 mL), and ethanol (20 mL) were added sequentially to the reaction flask. After the addition was complete, the reaction was carried out at 180 °C until it was complete. The reaction solution was concentrated, extracted with ethyl acetate, and the organic phase was separated. After drying, filtration, and concentration, the solution was subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 3c (0.21 g).

[0366] MS(ESI,[M+H) + )m / z:288.01.

[0367] Step D: Preparation of compound 3d

[0368] Compound 3c (0.12 g), N,N-dimethylformamide (10 mL), and N-iodosuccinimide (0.064 g) were added to a reaction flask. After the addition was complete, the reaction was allowed to proceed at room temperature until it was fully reacted. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was separated, dried, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 3d (0.12 g).

[0369] MS(ESI,[M+H) + )m / z:413.95.

[0370] Step E: Preparation of compound I-3

[0371] Compound 3d (0.12 g), compound 1c (0.13 g), tetrakis(triphenylphosphine)palladium (0.049 g), potassium carbonate (0.058 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was heated and stirred at 100 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered and concentrated. The solution was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-3 (0.10 g).

[0372] HRMS(ESI,[M+H] + )m / z:565.2572.

[0373] 1 H NMR (500MHz, CDCl3) δ8.18–8.09(m,1H),8.07–7.85(m,4H),7.69–7.54(m,3H),7.5 3–7.31(m,6H),6.64–6.54(m,1H),6.51(dt,J=8.8,4.3Hz,1H),2.72–2.37(m,10H).

[0374] Example 4: Preparation of compound I-4

[0375] Step A: Preparation of compound 4a

[0376] To a reaction flask, compound 3-bromo-1H-pyrazole-5-amine (3.00 g), N,N-dimethylformamide (20 mL), and 3-dimethylaminopropylphenyl ketone (3.96 g) were added sequentially. After the addition was complete, the mixture was stirred at 150 °C. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution, and after stirring for 5 minutes, ethyl acetate was added to the reaction solution for extraction. The organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 4a (1.50 g).

[0377] MS(ESI,[M+H) + )m / z:276.2.

[0378] Step B: Preparation of compound 4b

[0379] Compound 4a (1.50 g), acetic acid (30 mL), and potassium permanganate (0.16 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution, and the mixture was stirred for 5 minutes. Ethyl acetate was then added to the reaction solution for extraction. The organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 4b (0.42 g).

[0380] MS(ESI,[M+H) + )m / z:274.4.

[0381] Step C: Preparation of compound 4c

[0382] Compound 4b (0.42 g), 2-aminopyridine-3-boronic acid (0.44 g), tetrakis(triphenylphosphine)palladium (0.18 g), potassium carbonate (0.64 g), 1,4-dioxane (18 mL), and water (3 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain compound 4c (0.35 g).

[0383] MS(ESI,[M+H) + )m / z:288.03.

[0384] Step D: Preparation of compound 4d

[0385] Under ice bath conditions, compound 4c (0.35 g), N,N-dimethylformamide (20 mL), and N-succinimide bromide (0.20 g) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. The reaction was monitored by TLC until complete. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted. The organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound 4d (0.28 g).

[0386] MS(ESI,[M+H) + )m / z:365.84.

[0387] Step E: Preparation of compound I-4

[0388] Compound 4d (0.28 g), compound 1c (0.37 g), tetrakis(triphenylphosphine)palladium (0.09 g), potassium carbonate (0.32 g), 1,4-dioxane (12 mL), and water (2 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. The reaction was monitored by TLC until complete. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound I-4 (0.09 g).

[0389] HRMS(ESI,[M+H] + )m / z:565.2605.

[0390] 1 H NMR(500MHz,DMSO-d6)δ9.23(d,J=7.4Hz,1H),8.30–8.23(m,3H),8.03(dd,J=4.9,1.9Hz,1H),7.76(d,J=7.4Hz,1H),7.64–7.53(m,5H),7.37 –7.32(m,3H),7.09(d,J=6.5Hz,1H),6.55(dd,J=7.3,4.9Hz,1H),6.13(s,2H),3.68(s,5H),3.54(s,2H),2.54(s,1H),2.48(d,J=4.8Hz,2H).

[0391] Example 5: Preparation of compound I-5

[0392] Step A: Preparation of compound I-5

[0393] In a 25 mL single-necked flask, compounds 5-1 (31.4 mg), 1-8 (100 mg), N,N-dimethylformamide (4 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg), and N,N-isopropylethylamine (136 mg) were added sequentially under ice bath conditions. The mixture was allowed to warm to room temperature and reacted overnight. After the reaction was complete, the mixture was purified by reverse-phase preparative column chromatography (ammonium bicarbonate + ammonia) and lyophilized to give compound I-5 (8 mg).

[0394] 1 H NMR(500MHz,DMSO-d6)δ10.17(s,1H),9.19(s,1H),8.36-8.35(m,2H),7.93-7.92(m,1H),7.61-7.54(m,1H),7.48-7.45(m,4H),7.44- 7.42(m,4H),7.35-7.33(m,1H),7.27-7.25(m,1H),6.50-6.47(m,1H),5.85(s,2H),3.55-3.48(m,7H),2.40-2.38(m,4H),2.24(s,3H).

[0395] HRMS(ESI,[M+H] + m / z = 624.1868.

[0396] Example 6: Preparation of compound I-6

[0397] Step A: Preparation of compound I-6

[0398] Compound 1-8 (100 mg), methanol (2 mL), compound 6-1 (29.9 mg), and triethylamine (0.147 mL) were added to a 25 mL single-necked flask. The reaction was carried out at 25 °C for 12 h. After the reaction was complete, the mixture was filtered, and the solid was collected to give the target product, compound I-6 (56 mg).

[0399] 1 H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.36-8.35(m,2H),7.94-7.92(m,1H),7.48-7.43(m,3H),7.38-7.33(m,4H),7.27-7 .25(m,1H),6.50-6.48(m,1H),5.85(s,2H),4.29(s,3H),3.78(s,2H),3.56-3.52(m,4H),2.51-2.49(m,4H),2.24(s,3H).

[0400] HRMS(ESI,[M+H] + m / z = 586.3892.

[0401] Example 7: Preparation of compound I-7

[0402] Step A: Preparation of compound 7-2

[0403] Following the method in step A of Example 5, compound 7-1 was reacted with compound 1-2 to prepare compound 7-2.

[0404] MS(ESI,[M+H) + )m / z:544.1.

[0405] Step B: Preparation of compound 7-3

[0406] Following the method in step B of Example 5, compound 7-2 was prepared into compound 7-3 via a cyclization reaction.

[0407] MS(ESI,[M+H) + )m / z:528.2.

[0408] Step C: Preparation of Compound 7-4

[0409] Following the method in step C of Example 5, compound 7-3 was converted to compound 7-4 via an iodination reaction.

[0410] MS(ESI,[M+H) + )m / z:582.1.

[0411] Step D: Preparation of compounds 7-5

[0412] Compound 7-5 was prepared by reacting compound 7-4 with 2-amino-3-pinacol boryl ester-pyridine, following the method in step D of Example 5.

[0413] MS(ESI,[M+H) + )m / z:548.2.

[0414] Step E: Preparation of compounds 7-6

[0415] Following the method in step E of Example 5, compound 7-5 was reacted with phenylboronic acid to prepare compound 7-6.

[0416] MS(ESI,[M+H) + )m / z:590.31.

[0417] Step F: Preparation of compound 7-7

[0418] Following the method in step F of Example 5, compound 7-6 was deprotected to prepare compound 7-7.

[0419] MS(ESI,[M+H) + m / z:490.3

[0420] Step G: Preparation of compound I-7

[0421] Following the method in step G of Example 5, compound 7-7 was reacted with compounds 1-9 to prepare compound I-7.

[0422] 1 H NMR(500MHz, CDCl3)δ9.08(s,1H),8.51–8.41(m,2H),8.21–8.05(m,2H),7.49– 7.38(m,3H),7.31(q,J=8.5Hz,4H),7.23(dd,J=7.4,1.7Hz,1H),6.62(dd,J=7. 4,5.0Hz,1H),6.42(d,J=6.0Hz,1H),4.62(s,2H),3.55(s,2H),2.85(s,1H),2. 39–2.30(m,3H),2.22(t,J=11.3Hz,2H),2.02(s,2H),1.70(s,2H),1.58(s,2H).

[0423] HRMS(ESI,[M+H] + m / z: 593.2886.

[0424] Example 8: Preparation of compound I-8

[0425] Step A: Preparation of compound 8-2

[0426] Referring to the method in step D of Example 5, compound 8-1 was reacted with 4-(4-BOC-piperazinemethyl)phenylboronic acid pinacol ester to prepare compound 8-2.

[0427] MS(ESI,[M+H) + )m / z:518.1.

[0428] Step B: Preparation of compound 8-3

[0429] Following the method in step E of Example 5, compound 8-2 was reacted with phenylboronic acid to prepare compound 8-3.

[0430] MS(ESI,[M+H) + )m / z:560.7.

[0431] Step C: Preparation of compound 8-4

[0432] Following the method in step F of Example 5, compound 8-3 was prepared into compound 8-4 via a deBoc reaction.

[0433] MS(ESI,[M+H) + )m / z:460.7.

[0434] Step D: Preparation of compound I-8

[0435] Following the method in step G of Example 5, compound 8-4 was reacted with compounds 1-9 to prepare compound I-8.

[0436] 1 H NMR (500MHz, DMSO-d6) δ9.26 (s, 1H), 8.58–8.45 (m, 2H), 8.25 (d, J = 6.4Hz, 1H), 7.64–7.43 (m, 10H), 7. 26(d,J=8.2Hz,2H),7.08(d,J=6.5Hz,1H),3.75(s,3H),3.66(s,4H),3.50(s,2H),2.48–2.42(m,4H).

[0437] HRMS(ESI,[M+H] + )m / z:563.2650.

[0438] Example 9: Preparation of compound I-9

[0439] Step A: Preparation of compound 9-2

[0440] Compound 9-1 (10 g), 4-aminobenzyl alcohol (4.93 g), 1,4-dioxane (120 mL), and N,N-isopropylethylamine (9.51 mL) were added sequentially to a 500 mL single-necked flask. The mixture was purged with nitrogen three times, and the temperature was raised to 120 °C for 4 hours. After the reaction was complete, the mixture was purified by column chromatography (developing solvent: PE:EA) to give compound 9-2 (10.57 g).

[0441] MS(ESI,[M+H) + )m / z:361.9.

[0442] Step B: Preparation of compound 9-3

[0443] Compound 9-2 (9.57 g), potassium acetate (12.99 g), lithium chloride (1.122 g), palladium acetate (0.891 g), N,N-dimethylformamide (100 mL), and trimethylsilylacetylene (5.58 mL) were added sequentially to a 500 mL single-necked flask. Nitrogen gas was purged three times, and the reaction was carried out at 100 °C for 6 h. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (developing solvent: PE:EA) to give compound 9-3 (2.96 g).

[0444] MS(ESI,[M+H) + )m / z:346.11.

[0445] Step C: Preparation of Compound 9-4

[0446] Compound 9-3 (2.87 g), methanol (25 mL), and dichloromethane (25 mL) were added to a 250 mL single-necked flask. N-iodosuccinimide (3.73 g) and silver tetrafluoride borate (2.423 g) were then added at 0-5 °C. The mixture was purged with nitrogen three times and reacted at 25 °C for 12 h. After the reaction was complete, the mixture was filtered, and the filtrate was extracted dropwise with an aqueous sodium sulfite solution. The extract was then washed with saturated sodium chloride (8 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 9-4 (2.69 g).

[0447] MS(ESI,[M+H) + )m / z:399.96.

[0448] Step D: Preparation of Compounds 9-5

[0449] Compound 9-4 (2.19 g), 2-amino-3-pinacolboryl ester-pyridine (1.206 g), tetrakis(triphenylphosphine)palladium (0.633 g), potassium carbonate (1.893 g), 1,4-dioxane (50 mL), and water (5.00 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 6 h. After the reaction was complete, the mixture was purified by column chromatography (developing solvent: DCM:MeOH) to give compound 9-5 (1.44 g).

[0450] MS(ESI,[M+H) + )m / z:366.10.

[0451] Step E: Preparation of compounds 9-6

[0452] Compound 9-5 (200 mg), 4-fluorophenylboronic acid (115 mg), tetrakis(triphenylphosphine)palladium (63.2 mg), potassium carbonate (189 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 6 h. After the reaction was complete, the mixture was purified by column chromatography (developing solvent: DCM:MeOH) to give compound 9-6 (235 mg).

[0453] MS(ESI,[M+H) + )m / z:426.17.

[0454] Step F: Preparation of compounds 9-7

[0455] Compound 9-6 (190 mg) was dissolved in dichloromethane (8 mL) in a 50 mL single-necked flask, and thionyl chloride solution (1.34 mL, 1 M) was added dropwise. The reaction was carried out at 25 °C for 2 h. After the reaction was completed, the solution was concentrated to give the hydrochloride compound 9-7 (283 mg).

[0456] MS(ESI,[M+H) + )m / z:444.13.

[0457] Step G: Preparation of compound I-9

[0458] Compound 9-7 (40 mg), compound 9-8 (18.3 mg), N,N-diisopropylethylamine (93 mg), sodium iodide (2 mg), and acetonitrile (8 mL) were added sequentially to a 25 mL single-necked flask. The reaction was carried out at 70 °C for 4 h. The mixture was purified by column chromatography (developing solvent: DCM:MeOH) to obtain compound I-9 (30 mg).

[0459] 1 H NMR(500MHz, CDCl3)δ9.06(s,1H),8.52–8.40(m,2H),8.20–8.05(m,2H),7.48–7.37(m,3H),7.29(m,3H),7.24(m,1H),6.63(m,1H),6.41( d,J=6.0Hz,1H),4.61(s,2H),3.54(s,2H),2.78(s,1H),2.38–2.31(m,3H),2.21(t,J=11.3Hz,2H),2.03(s,2H),1.68(s,2H),1.59(s,2H).

[0460] HRMS(ESI,[M+H] + )m / z:611.2790.

[0461] Example 10: Preparation of compound I-10

[0462] Step A: Preparation of Compound 10-1

[0463] 6-Chlorpyridazine-3-amine (10 g), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (25.7 g), potassium carbonate (21.4 g), and tetraphenylphosphine palladium (4.46 g) were reacted in ethanol (100 mL) and water (20 mL) under nitrogen protection at 120 °C for 16 h with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was added to ethyl acetate (50 mL × 3), washed successively with saturated NaCl aqueous solution (40 mL × 3) and water (50 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by column chromatography to obtain compound 10⁻¹ (9.3 g).

[0464] MS(ESI,[M+H) + )m / z:189.99.

[0465] Step B: Preparation of compound 10-2

[0466] 3-Acetyl-2-chloropyridine (27 g) was added to a hydrobromic acid-acetic acid solution (100 mL), and bromine (30.5 g) was slowly added at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH of the reaction solution was adjusted to neutral with sodium hydroxide solution, and ethyl acetate (100 mL × 3) was added. The mixture was washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by column chromatography to obtain compound 10⁻² (26 g).

[0467] MS(ESI,[M+H) + )m / z:234.01.

[0468] Step C: Preparation of compound 10-3

[0469] Compound 10⁻¹ (2 g), compound 10⁻² (5 g), and triethylamine (1.43 g) were reacted in tetrahydrofuran (50 mL) at 60 °C with stirring for 2 h. After the reaction was complete, the reaction solution was extracted with water (100 mL) and dichloromethane (50 mL × 3), washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by column chromatography to obtain compound 10⁻³ (3.1 g).

[0470] MS(ESI,[M+H) + )m / z:324.90.

[0471] Step D: Preparation of compound 10-4

[0472] Compound 10⁻³ (2 g) and copper sulfate (980 mg) were reacted in ammonia (33 mL) and ethanol (15 mL) at 140 °C for 7 h. After the reaction was complete, the solvent was removed by vacuum distillation of the reaction solution, and the residue was extracted with water and dichloromethane (50 mL × 3). The residue was washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by column chromatography to obtain compound 10⁻⁴ (0.62 g).

[0473] MS(ESI,[M+H) + )m / z:306.04.

[0474] Step E: Preparation of compound 10-5

[0475] Compound 10⁻⁴ (300 mg) was added to N,N-dimethylformamide (2 mL), and N-iodosuccinimide (177 mg) was slowly added. The mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction solution was extracted with water (20 mL) and dichloromethane (50 mL × 3). The solution was washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by column chromatography to obtain compound 10⁻⁵ (210 mg).

[0476] MS(ESI,[M+H) + )m / z:432.24.

[0477] Step F: Preparation of compound 10-6

[0478] Compound 10-5 (200 mg), compound a-1 (232 mg), tetraphenylphosphine palladium (54 mg), potassium carbonate (192 mg), and tetraphenylphosphine palladium (4.46 g) were reacted in 1,4-dioxane (5 mL) and water (1 mL) under nitrogen protection at 105 °C for 2 h with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was added to ethyl acetate (50 mL × 3), washed successively with saturated NaCl aqueous solution (40 mL × 3) and water (50 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated, and separated by column chromatography to obtain compound 10-6 (200 mg).

[0479] Step G: Preparation of compound 10-7

[0480] Compound 10⁻⁶ (100 mg) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL, 4 M) and reacted with stirring at room temperature for 4 h. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the residue was added to water and washed with ethyl acetate (10 mL). The aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to give compound 10⁻⁷ (70 mg).

[0481] Step H: Preparation of compound I-10

[0482] Compound 10-7 (70 mg), N,N-diisopropylethylamine (98 mg), and 4-chloro-2-pyrimidinecarboxynitrile (22 mg) were reacted in N-methylpyrrolidone (2 mL) at 50 °C with stirring for 2 h. After the reaction was complete, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was washed successively with saturated NaCl aqueous solution (20 mL × 3) and water (20 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated, and separated by column chromatography to obtain the crude compound (47 mg). The crude compound was then purified by preparative purification (H2O / MeCN) to obtain compound I-10 (8 mg).

[0483] 1 H NMR(500MHz,DMSO-d6)δ8.32(d,J=9.5Hz,1H),8.13–8.01(m,4H),7.98–7.90(m,2H) ,7.61(s,2H),7.46(s,2H),7.40(t,J=8.8Hz,2H),7.25(dd,J=7.5,1.8Hz,1H),6.68( d,J=5.8Hz,1H),6.62(s,2H),6.45(dd,J=7.5,4.8Hz,1H),3.84(s,1H),3.58(s,1H), 3.36–3.33(m,2H),2.87(s,1H),2.54(s,1H),2.18(s,1H),1.91(s,2H),1.51(s,2H).

[0484] HRMS(ESI,[M+H]+)m / z:597.2630.

[0485] Test Example 1: Activity of Compound on AKT1 E17K Kinase

[0486] Lipid vesicle preparation: Add 25 mg of dioleoylphosphatidylserine sodium (DOPS) to 1 mL of chloroform, and add 24.2 mg of 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC) to 1 mL of chloroform. Mix well and dry with nitrogen gas slowly. A thin phospholipid film will form at the bottom of the flask. To remove the remaining chloroform from the film, place the tube in a vacuum desiccator for at least 4 hours. Resuspend PIP3 in 1 mL of (80% chloroform + 20% methanol), dry with nitrogen gas slowly, and place the tube in a vacuum desiccator for at least 4 hours. Resuspend the DOPC / DOPS membrane in 3 mL of 10 mM HEPES (pH 7.5) at a concentration of 16.4 mg / mL (0.01 M); resuspend the PIP3 in 100 μL of water at a concentration of 1 mg / mL (0.8 M); take 80 μL of DOPC / DOPS and 94 μL of PIP3, mix them, add 1.826 mL of 10 mM HEPES (pH 7.4), mix, and sonicate on ice at 75% power for 30 s until the mixture is clear. (Aliquot and store at -80°C for later use).

[0487] Add 5 μL of AKT1, AKT2, and AKT E17K protein kinase solutions to each well. Use a nanoparticle dispenser to add different compounds dissolved in DMSO to the wells to achieve a final compound concentration of 500 nM - 0.16 nM. Use two replicates and include a control. The above system was incubated for 60 minutes. Then, 5 μL of a mixture was added (1 μL of lipid vesicles (final concentrations of 55 μM DOPC (sigma), 55 μM DOPS (sigma), and 5 μM PIP3 (sigma)), 1 μL of 500 μM ATP (sigma), 1 μL of 10 nM PDK1 (sigma, 1490 nM), 1 μL of 8 nM MAPKAPK2 (thermo, 5854 nM), and 1 μL of 1 μM ULight-crosstide). The mixture was incubated at room temperature for 2 hours. Then, 5 μL of 40 mM EDTA was added, and the reaction was stopped after 5 minutes. Next, 5 μL of 8 nM detection antibody (PerkinElmer) was added, and the mixture was incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multi-mode microplate reader (excitation 320 nm, emission 615 nm / 665 nm). A four-parameter fitting method was used to calculate the IC50. 50 .

[0488] Experimental Example 2: In vitro cell proliferation inhibitory activity

[0489] 2.1 Assay of AKT1-E17K / BaF3 cell proliferation inhibition activity

[0490] Collect healthy AKT1-E17K / BaF3 cells into centrifuge tubes and adjust the cell density to 9 × 10⁻⁶ cells using analysis medium (1640 + 10% FBS). 4 Compounds were seeded at a concentration of 100 μL / well in 96-well plates using a nanoparticle pipette to achieve a final concentration of 1000 nM - 0.06 nM. Two replicates were performed, and a control was also included. After culturing for 72 hours, the assay reagent CCK-8 (Vazyme, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 1.

[0491] 2.2 Assay of AN3CA cell proliferation inhibitory activity

[0492] Collect healthy AN3CA cells into centrifuge tubes and adjust the cell density to 4 × 10⁶ cells using the culture medium (MEM + 10% FBS + 1% non-essential amino acids + 1% sodium pyruvate). 4 The compound was seeded at a concentration of 100 μL / well in 96-well plates and cultured overnight. Then, the compound was added using a nanoparticle pipette to achieve a final concentration of 5000 nM - 2.29 nM, with two replicates. A control was also included. After culturing for 72 hours, the assay reagent CCK-8 (Vazyme, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 1.

[0493] Table 1. In vitro cell proliferation inhibitory activity of the compounds.

[0494] Experimental results show that the disclosed compound has good inhibitory activity against AKT1-E17K / BaF3 cells and exhibits good selective inhibitory effect against AN3CA(AKT1 WT) cells.

[0495] Experimental Example 3: In vitro liver microsomal stability test

[0496] Liver microsomal incubation samples were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution were incubated at 37°C and 150 rpm for 1 h. Samples at 0 h were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. After adding acetonitrile solution containing internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC / MS analysis.

[0497] Experimental results show that the disclosed compound has good liver microsomal stability.

[0498] Experimental Example 4: Pharmacokinetic Study in Mice

[0499] ICR mice, weighing 18–22 g, were acclimatized for 3–5 days and then randomly divided into groups of 9 mice each. The mice were administered the test compound solution by gavage at a dose of 1 mg / kg.

[0500] Blood was collected at 0 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h from the orbital cavity to prepare plasma samples for testing.

[0501] Take 30 μL of the plasma sample to be tested and the standard sample, add acetonitrile solution containing internal standard, and obtain the supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[0502] Experimental results show that the disclosed compound has good in vivo pharmacokinetic properties, such as a high half-life (T0). 1 / 2 (e.g., higher in vivo exposure (AUC), and / or higher bioavailability (F%)).

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from C, N, CR a or NR b , with the proviso that X 1 and X 3 are not simultaneously N; Y 1 and Y 2 are each independently selected from CR c or N; R a R b and R c Each is independently selected from hydrogen, deuterium, -NH2, -COOH, -NO2, -OH, -SH, halogen, -CN, or each is optionally influenced by one or more R. a1 The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3- 12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; R a1 each independently selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COC 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, -CONH(C 1- 6alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SON(C 1-6 alkyl)2, -N(C 1-6 alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C 1-6 alkyl)SO2(C 1-6 alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)2, -COC 3-12 cycloalkyl, -C(O)OC 3-12 cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; R 1 selected from hydrogen, deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, or the following groups each optionally substituted with one or more R 1a substituents: -C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1- 6alkyl)2, -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6- 10 aryl, or 5-12 membered heteroaryl; each R is independently selected from the group consisting of deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, 1a each R is independently selected from the group consisting of deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, or each optionally substituted -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COC 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1- 6alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SON(C 1-6 alkyl)2, -N(C 1-6 alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C 1- 6alkyl)SO2(C 1-6 alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)2, -COC 3-12 cycloalkyl, -C(O)OC 3-12 cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; R 2 and R 3 Each is independently selected from hydrogen, deuterium, halogen, -OH, -NO2, -NH2, -COOH, -C(O)H, -SH, -CN, or each is optionally influenced by one or more R 2a The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Or, R 2 and R 3 Together with the carbon atoms attached to them, they form each optionally bounded by one or more R atoms. 3a The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-14 membered heterocyclic alkyl groups; each R 2a or R 3a each independently is selected from deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COC 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SON(C 1-6 alkyl)2, -N(C 1-6 alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C 1-6 alkyl)SO2(C 1-6 alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), or -N(C 3-12 cycloalkyl)2, -COC 3-12 cycloalkyl, -C(O)OC 3-12 cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)CO(C 3- 12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; Ring A is selected from the group consisting of each optionally substituted with one or more R A substituted C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkenyl; Alternatively, ring A can be replaced by: each R is independently selected from the group consisting of deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, A each R is independently selected from the group consisting of deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, -CN, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COC 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)C 1- alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SON(C 1-6 alkyl)2, -N(C 1-6 alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C 1-6 alkyl)SO2(C 1-6 alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), or -N(C 3-12 cycloalkyl)2, -COC 3-12 cycloalkyl, -C(O)OC 3-12 cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3- 12 cycloalkyl), -N(C 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; L is selected from a bond, -C(R d )2-, -0-, -S-, -NR d -, -NR d -C(O)-, -NR d -C(O)O-, -NR d -OC(O)-, -C(O)-, -C(O)O-, -S(O)2NR d -, -S(O)-, -S(O)NR d -, -P(O)- or -P(O)O-; Each R d Each is independently selected from hydrogen, deuterium, -NH2, -COOH, -C(O)H, -NO2, -OH, -SH, halogen, -CN, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-12 cycloalkyl; R 4 selected from -CN, or the following groups each optionally substituted with one or more R 4a substituted -C 2-6 alkenyl, -C 2-6 alkynyl, -COC 2-6 alkenyl, -S(O)2C 2-6 alkenyl, -COC 2-6 alkynyl, -S(O)2C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocycloalkenyl, C 6-10 aryl or 5-12 membered heteroaryl; each R is independently selected from the group consisting of deuterium, -NH2, -NO2, -OH, -CN, 4a each R is independently selected from the group consisting of deuterium, -NH2, -NO2, -OH, -CN, -C(O)H, -SH, -COOH, halogen, -OC 1- 6alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COC 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -SO(C 1-6 alkyl), -SON(C 1-6 alkyl)2, -N(C 1-6 alkyl)SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), -N(C 1-6 alkyl)SO2(C 1-6 alkyl), C 3-12 cycloalkyl, -OC 3-12 cycloalkyl, -SC 3-12 cycloalkyl, -NH(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)2, -COC 3-12 cycloalkyl, -C(O)OC 3-12 cycloalkyl, -OC(O)C 3-12 cycloalkyl, -CONH(C 3-12 cycloalkyl), -CON(C 3-12 cycloalkyl)2, -NHCO(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)CO(C 3-12 cycloalkyl), -SO(C 3-12 cycloalkyl), -SON(C 3-12 cycloalkyl)2, -N(C 3-12 cycloalkyl)SO(C 3-12 cycloalkyl), -SO2(C 3-12 cycloalkyl), -N(C 3-12 cycloalkyl)SO2(C 3-12 cycloalkyl), C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; n is selected from 1, 2, or 3; Optionally, the R a1 , R 1a , R 2a , R 3a , R A , R d or R 4a may be further substituted by one or more substituents.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, X 1 is N, X 2 and X 3 is CR a ; or X 3 is NR b , X 1 and X 2 is C or CR a ; or X 4 is C, X 5 is N, X 1 , X 2 and X 3 are each independently selected from C, N, CR a or NR b , and X 1 and X 3 are not simultaneously N; or X 4 is N, X 5 is C, X 1 , X 2 and X 3 are each independently selected from C, N, CR a or NR b , and X 1 and X 3 are not simultaneously N; or X 4 and X 5 are each C, X 1 , X 2 and X 3 are each independently selected from C, N, CR a or NR b , and X 1 and X 3 are not simultaneously N; or X 1 and X 3 at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Y 1 and Y 2 are both N; or Y is N; or Y is N, Y is CR 1 is CR c ; or Y is N, Y is CR 2 is CR 1 ; or Y is N, Y is CR 2 is CR c ; or Y is N, Y is CR 1 is CR 2 is N or CH.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein, R a selected from hydrogen, -OH, halogen, -CN, optionally substituted -C a1 alkyl, -OC 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl or 5-12 membered heteroaryl; or R a is selected from the group consisting of -C a1 substituted with one or more R 1-6 alkyl, C 6-10 aryl or 5-12 membered heteroaryl; or R a is selected from the group consisting of -C a1 substituted with one or more R 1-4 alkyl, phenyl or 5-6 membered heteroaryl; or R a is selected from the group consisting of methyl, phenyl, 1,2,5-oxadiazolyl or pyridinyl optionally substituted by one or more R a1 substituents; or R a is selected from the group consisting of methyl, phenyl or pyridyl optionally substituted with one or more R a1 substituents; or R is selected from the group consisting of methyl, phenyl, a selected from the group consisting of methyl, phenyl, or R a is R is optionally -NH2, -COOH, -NO2, -OH, -SH, -CN, halogen, -OC a1 each independently selected from -NH2, -COOH, -NO2, -OH, -SH, -CN, halogen, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; or R a1 is selected from -NH2.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein, R b selected from -C a1 substituted -C 1-4 alkyl; or R b is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl; or R is H, or R b is methyl.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R c selected from hydrogen, -NH2, -NO2, -OH, -SH, halogen, -CN or -C 1-6 alkyl; or R c selected from hydrogen or halogen; or R is hydrogen or C1-4alkyl; and c is hydrogen.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from hydrogen, -NH2, -OH, -SH, -CN, halogen, or the following groups each optionally substituted with one or more R 1a substituents: -C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -C(O)OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1- 6alkyl)2, -SO(C 1-6 alkyl), -SO2(C 1-6 alkyl), C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl; Or, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; or, R 1 Selected from hydrogen, -CN, or each of which is optionally influenced by one or more R 1a The following groups are substituted: -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 5-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O; or R 1 is selected from optionally substituted C 1a is selected from optionally substituted C 6-10 aryl; or R 1 each independently is selected from hydrogen, -CN, ethyl, trifluoromethyl, -N(CH3)2, methoxy, or R is H, or R 1 is phenyl; Optionally, each R 1a each is independently selected from deuterium, -NH2, -NO2, -OH, -CN, halogen, or the following group optionally substituted with R': -C 1-4 alkyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; or each R is independently selected from -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, cyclopropyl, -OCD3, 1a each R is independently selected from -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, cyclopropyl, -OCD3, Optionally, each R' is each independently selected from deuterium, -NH2, -NO2, -OH, -CN, halogen or or each R' is independently selected from deuterium, fluorine or 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 and R 3 are each independently selected from hydrogen or -C 1-4 alkyl; or R 2 and R 3 are each selected from hydrogen; Optional, R 2 and R 3 Together with the carbon atoms attached to them, they form each optionally bounded by one or more R atoms. 3a The following groups are substituted: C 3-6 cycloalkyl, C 3-6 Cycloalkenyl or 3-6 membered heterocyclic alkyl groups.

9. The compound of formula (I) according to any one of claims 1 to 8, wherein Ring A is selected from the group consisting of each optionally substituted with one or more R A substituted C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkyl, or 3-10 membered heterocycloalkenyl; or, ring A is selected from optionally substituted 3-10 membered heterocycloalkyl; A substituted 3-10 membered heterocycloalkyl; or, ring A is selected from optionally substituted 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N or O; A substituted 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N or O; or, ring A is selected from the following groups, each optionally substituted with one or more R A substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R sub Alternatively, ring A can be arbitrarily controlled by one or more R. A Substituted piperazine group; Alternatively, ring A is selected from wherein * indicates the position of attachment to -L-R 4 or, ring A is 10. The compound of formula (I) according to any one of claims 1 to 9, wherein L is selected from the group consisting of a bond, -NR d -, -NR d -C(O)- or -C(O)-; Alternatively, L is selected from a bond, -NR d -, -NR d -C(O)-# or -C(O)-, wherein # indicates the position attached to -R 4 ; Alternatively, L is selected from a bond, -NH-, -N(CH3)-, -NH-C(O)-#, -N(CH3)-C(O)-# or -C(O)-, wherein # indicates the position of attachment to -R 4 the position of attachment; or, L is a bond; Optionally, each R d each is independently selected from hydrogen or -C 1-6 alkyl; or, each R d each is independently selected from hydrogen or methyl.

11. The compound of formula (I) according to any one of claims 1 to 10, wherein R 4 selected from -CN, or the following groups each optionally substituted with one or more R 4a substituted -COC 2-6 alkenyl, -S(O)2C 2-6 alkenyl, -COC 2-6 alkynyl, -S(O)2C 2-6 alkynyl, C 3- 12 cycloalkenyl, 3-14 membered heterocycloalkenyl, C 6-10 aryl or 5-12 membered heteroaryl; or R 4 is selected from the group consisting of optionally substituted C 4a 3-12 Cycloalkenyl, C 6-10 Aryl or 5-12 membered heteroaryl;​ or R 4 is selected from the group consisting of optionally substituted C 4a alkyl, cycloalkyl, cycloalkenyl, phenyl or 5-6 membered heteroaryl; and 3-6 alkyl, cycloalkyl, cycloalkenyl, phenyl or 5-6 membered heteroaryl; and or R 4 is selected from the following groups optionally substituted with one or more R 4a substituents: phenyl, triazinyl, or pyrimidinyl; or R 4 selected from or R 4 is Optionally, each R 4a each is independently selected from -N02, -OH, -CN, -C(O)H, -COOH, halogen or -OC 1-6 alkyl; or each R is independently selected from -OH, -CN, 4a each R is independently selected from -OH, -CN, -C(O)H or methoxy.

12. The compound of Formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, selected from the following compounds of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt thereof: wherein R 1 , R a , R b , R c , ring A, L and R 4 are as defined in any one of claims 1-11.

13. The following compounds or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof.

15. A compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14, for use in the treatment or prevention of a disease selected from a disease that benefits from inhibition of AKT1 E17K kinase; optionally, the disease that benefits from inhibition of AKT1 E17K kinase is selected from a cancer; optionally, the cancer is selected from a leukemia.

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