CN118619921A

CN118619921A - Pyrrolidone structure-containing compounds

Info

Publication number: CN118619921A
Application number: CN202410253557.XA
Authority: CN
Inventors: 刘彦龙; 刘飞; 唐旭静; 顾佳佳; 施伟
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2023-03-07
Filing date: 2024-03-06
Publication date: 2024-09-10

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry, and relates to compounds containing pyrrolidone structures, in particular to compounds of formula I, stereoisomers or pharmaceutically acceptable salts thereof, methods of preparing the same, or pharmaceutical compositions thereof, and use thereof in preparing medicaments for treating or preventing tumor-related diseases.

Description

Pyrrolidone structure-containing compounds

Technical Field

The present disclosure belongs to the field of pharmaceutical chemistry, and provides a pyrrolidone structure-containing compound, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, or a pharmaceutical composition thereof, and an application thereof in preparing a medicament for treating or preventing tumor-related diseases.

Background

Stable repair of DNA Double Strand Breaks (DSBs) is critical to maintaining genomic stability and cell viability. DSBs can be repaired by one of three main pathways: homologous Recombination (HR), non-homologous end joining (NHEJ) and substitution NHEJ (alt-NHEJ). The microhomology-mediated end-linking (MMEJ) is the most well characterized alt-NHEJ mechanism. MMEJ can act simultaneously with the HR and NHEJ pathways.

Unlike normal cells, cancer cell survival is often dependent on the deregulation of the DNA Damage Response (DDR) pathway. Abnormal DDR can also sensitize cancer cells to specific types of DNA damage, so defective DDR can be exploited to develop targeted cancer therapies. It is critical that cancer cells with HR and NHEJ damaged or inactivated become highly dependent on MMEJ-mediated DNA repair.

Therapeutic inactivation of the key protein PolQ in MMEJ, polQ (UniProtKB-O75417 (DPOLQ _human, or Pol theta), will disable the ability of the cells to execute MMEJ and provide a new targeting strategy in a range of established tumor settings, first, polQ has been shown to be critical for the survival of HR defective (HRD) cells and upregulated in HRD tumor cell lines, polQ is largely inhibited in normal tissues, but has been shown to be upregulated in matched cancer samples, thus correlating elevated expression with disease.

Detailed Description

In one aspect, the present disclosure provides a compound of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

Wherein,

Each R ¹ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NR ^xR^y、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, c _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said-OH, -SH, -NR ^xR^y、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl optionally substituted with one or more substituents;

m is selected from 0, 1, 2, 3 or 4;

each R ² is independently selected from halogen, -OH, -CN, -NR ^xR^y、-CH₂-NR^xR^y、-Z-C_6-10 aryl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents;

z is selected from a bond or a C _1-12 alkylene group, one or more CH ₂ in the C _1-12 alkylene group is optionally independently replaced by oxygen or sulfur, or one or more CH in the C _1-12 alkylene group is optionally independently replaced by N;

n is selected from 0, 1, 2, 3 or 4;

R ³ is selected from H, deuterium, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, said C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl optionally substituted with one or more substituents;

Ring a and ring B are each independently selected from C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl;

Each R ⁴ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, c _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, c _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl optionally substituted with one or more substituents;

Each R ^x and R ^y is independently selected from H, C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl, said C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl being optionally substituted with one or more substituents;

p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

q is selected from 1, 2 or 3;

L is selected from the group consisting of a bond, NH, O, S, C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene, said C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene optionally substituted with one or more substituents;

R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl optionally substituted with one or more substituents;

wherein represents that the fragment moiety is attached to ring a or ring B at the position.

In some embodiments, each R ¹ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclyl, The said-OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more substituents.

In some embodiments, each R ¹ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, The said-OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_1-6 alkyl, c _1-6 alkoxy, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl.

In some embodiments, each R ¹ is independently selected from halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, or-NHCOC _1-6 alkyl, the-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONHC _1-6 alkyl, or-NHCOC _1-6 alkyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each of said R ¹ is independently selected from halogen, -CN, -OH, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, -CONH ₂、-CONHC_1-4 alkyl, or-NHCOC _1-4 alkyl, said-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, -CONHC _1-4 alkyl, or-NHCOC _1-4 alkyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each of said R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl, said-NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _1-3 alkoxy, -CONHC _1-3 alkyl, or-NHCOC _1-3 alkyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, or C _1-4 alkoxy, the-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, or C _1-4 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy, the-N (C _1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy, the C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl, halogen substituted C _1-3 alkyl, or C _1-3 alkoxy.

In some embodiments, each R ¹ is independently selected from F, cl, br, -OH, -CN, -NH ₂, a,Methyl, trifluoromethyl, ethyl, isopropyl or methoxy.

In some embodiments, each R ¹ is independently selected from F, cl, br, -OH, -CN, -NH ₂, methyl, or trifluoromethyl.

In some embodiments, each R ¹ is independently selected from C _1-6 alkyl optionally substituted with one or more halogens.

In some embodiments, each R ¹ is independently selected from C _1-4 alkyl optionally substituted with one or more halogens. In some embodiments, each R ¹ is independently selected from C _1-3 alkyl optionally substituted with one or more fluoro.

In some embodiments, each R ¹ is independently selected from methyl or trifluoromethyl.

In some embodiments, m is selected from 0, 1, 2, or 3.

In some embodiments, m is selected from 1, 2, or 3.

In some embodiments, m is selected from 1 or 2.

In some embodiments, each R ² is independently selected from the group consisting of halogen, -OH, -CN, -NR ^xR^y、-CH₂-NR^xR^y、-Z-C_6-10 aryl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl or C _1-12 alkoxy, said-OH, -NR ^xR^y、-CH₂-NR^xR^y、-Z-C_6-10 aryl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl or C _1-12 alkoxy is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-12 cycloalkyl, 3-12 membered heterocyclyl, C _1-12 alkoxy, -NHC _1-12 alkyl, -N (C _1-12 alkyl) ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -COOC _1-12 alkyl or-OCOC _1-12 alkyl.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NR ^xR^y、-CH₂-NR^xR^y、C_1-8 alkyl, or C _1-6 alkoxy, the-OH, -NR ^xR^y、-CH₂-NR^xR^y、C_1-8 alkyl, or C _1-6 alkoxy being optionally substituted with one or more substituents.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy, the-OH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -COOC _1-6 alkyl or-OCOC _1-6 alkyl.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy, the C _1-8 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -COOC _1-6 alkyl or-OCOC _1-6 alkyl.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-5 alkyl, or C _1-4 alkoxy, the C _1-5 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、-CONHC_1-4 alkyl, -NHCOC _1-4 alkyl, -COOC _1-4 alkyl or-OCOC _1-4 alkyl.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NH ₂, or C _1-4 alkyl, the C _1-4 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, -NH ₂, or C _1-3 alkyl, the C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ² is independently selected from halogen, -OH, -CN, or-NH ₂.

In some embodiments, each R ² is selected from-OH.

In some embodiments, Z is selected from a bond or a C _1-6 alkylene, one or more CH ₂ of the C _1-6 alkylene is optionally independently replaced with oxygen or sulfur, or one or more CH of the C _1-6 alkylene is optionally independently replaced with N.

In some embodiments, Z is selected from a bond or a C _1-3 alkylene, 1, 2, or 3 CH ₂ in the C _1-3 alkylene are optionally independently replaced with oxygen or sulfur, or 1, 2, or 3 CH in the C _1-6 alkylene are optionally independently replaced with N.

In some embodiments, Z is selected from a bond, methylene, O, S, or NH.

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

In some embodiments, n is selected from 2.

In other embodiments, a "substituent" of the "substituted with one or more substituents" in the R ³ includes deuterium.

In other embodiments, the R ³ is selected from H, deuterium, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, the C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl being optionally substituted with one or more substituents, the C _1-12 alkyl being optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In other embodiments, the R ³ is selected from H, deuterium, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, the C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl being optionally substituted with one or more substituents, the C _1-12 alkyl, C _3-12 cycloalkyl, or 3-12 membered heterocyclyl being optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In some embodiments, the R ³ is selected from H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-10 membered heterocyclyl, the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-10 membered heterocyclyl being optionally substituted with one or more substituents.

In some embodiments, the R ³ is selected from H, C _1-12 alkyl, C _3-12 cycloalkyl, or 3-12 membered heterocycloalkyl, the C _1-12 alkyl, C _3-12 cycloalkyl, or 3-12 membered heterocycloalkyl being optionally substituted with one or more substituents.

In some embodiments, the R ³ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, the C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl being optionally substituted with one or more substituents.

In some embodiments, the R ³ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, the C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In some embodiments, the R ³ is selected from H, C _1-4 alkyl, C _3-5 cycloalkyl, or 3-5 membered heterocycloalkyl, the C _1-4 alkyl, C _3-5 cycloalkyl, or 3-5 membered heterocycloalkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In some embodiments, the R ³ is selected from H, C _1-3 alkyl or C _3-5 cycloalkyl, the C _1-3 alkyl or C _3-5 cycloalkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In some embodiments, the R ³ is selected from C _1-3 alkyl, the C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂.

In some embodiments, the R ³ is selected from methyl, ethyl, isopropyl, or cyclopropyl, optionally substituted with one or more of the following groups: halogen, protium, deuterium or tritium.

In other embodiments, the R ³ is selected from C _1-3 alkyl optionally substituted with one or more deuterium or halogen (e.g., F, cl, br, or I).

In other embodiments, the R ³ is selected from C _1-2 alkyl optionally substituted with one or more deuterium, F, cl, or Br.

In other embodiments, the R ³ is selected from methyl optionally substituted with one or more deuterium or F.

In other embodiments, the R ³ is selected from-CD ₃、-CF₃、-CHF₂、-CH₂F、-CH₃ or-CH ₂CH₃.

In some embodiments, the R ³ is selected from C _1-3 alkyl optionally substituted with one or more deuterium.

In some embodiments, the R ³ is selected from methyl optionally substituted with one or more deuterium.

In some embodiments, the R ³ is selected from-CD ₃、-CHD₂、-CH₂ D or-CH ₃.

In some embodiments, the R ³ is selected from-CD ₃ or-CH ₃. In some embodiments, the R ³ is selected from-CD ₃.

In some embodiments, the rings a and B are each independently selected from phenyl, naphthyl, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heteroaryl, or 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heterocyclyl.

In some embodiments, the rings A and B are each independently selected from phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl.

In some embodiments, the rings a and B are each independently selected from phenyl, 5-9 membered heteroaryl, or 5-9 membered heterocyclyl.

In some embodiments, the rings a and B are each independently selected from phenyl or 5-10 membered heteroaryl.

In some embodiments, the rings a and B are each independently selected from phenyl, 5 membered heteroaryl, 6 membered heteroaryl, or 9 membered heteroaryl.

In some embodiments, the rings a and B are each independently selected from phenyl, 6 membered heteroaryl, or 9 membered heteroaryl.

In some embodiments, the rings a and B are each independently selected from phenyl or 6 membered heteroaryl.

In some embodiments, the rings a and B are each independently selected from phenyl or pyridinyl.

In some embodiments, the ring a is selected from phenyl. In some embodiments, the ring B is selected from pyridinyl.

In some embodiments, each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, A 6-10 membered aryl, a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more substituents.

In some embodiments, each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, A 6-10 membered aryl, a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl.

In some embodiments, each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl or C _3-6 cycloalkyl, The said-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, or C _3-6 cycloalkyl optionally substituted with one or more of the following groups: halogen, halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-5 cycloalkyl, -CONH ₂、-CONHC_1-4 alkyl or-NHCOC _1-4 alkyl, the-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-5 cycloalkyl, -CONHC _1-4 alkyl or-NHCOC _1-4 alkyl optionally substituted with one or more of the following groups: halogen, halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy, the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-3 alkyl, C _2-4 alkenyl, or C _1-3 alkoxy, the C _1-3 alkyl or C _2-4 alkenyl being optionally substituted with one or more of the following groups: halogen, -CN, -OH or-NH ₂.

In some embodiments, each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-3 alkyl, halo C _1-3 alkyl, C _2-3 alkenyl, or C _1-3 alkoxy.

In some embodiments, each R ⁴ is independently selected from F, cl, br, -OH, -CN, -NH ₂, methyl, ethyl, -CH ₂F、-CHF₂、-CF₃, vinyl, or methoxy.

In some embodiments, each R ⁴ is independently selected from halogen, -OH, -CN, or-NH ₂.

In some embodiments, each R ⁴ is independently selected from halogen.

In some embodiments, each R ⁴ is independently selected from F or Cl.

In some embodiments, each R ^x and R ^y is independently selected from H, C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl, the C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl being optionally substituted with one or more of the following groups: c _1-6 alkyl, C _1-6 alkoxy, halogen, -OH, -CN, -NH ₂、C_3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl.

In some embodiments, each R ^x and R ^y is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, -CO-C _1-6 alkyl, or 3-8 membered heterocyclyl, the C _1-6 alkyl, C _3-8 cycloalkyl, -CO-C _1-6 alkyl, or 3-8 membered heterocyclyl being optionally substituted with one or more of the following groups: c _1-6 alkyl, C _1-6 alkoxy, halogen, -OH, -CN, -NH ₂、C_3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl.

In some embodiments, each R ^x and R ^y is independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, -CO-C _1-3 alkyl, or 3-6 membered heterocyclyl, the C _1-3 alkyl, C _3-6 cycloalkyl, -CO-C _1-3 alkyl, or 3-6 membered heterocyclyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ^x and R ^y is independently selected from H or C _1-3 alkyl, the C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, each R ^x and R ^y is independently selected from H.

In some embodiments, p is selected from 0, 1, 2, 3, or 4.

In some embodiments, p is selected from 0, 1, 2, or 3.

In some embodiments, p is selected from 1,2, or 3.

In other embodiments, p is selected from 4.

In some embodiments, q is selected from 1 or 2.

In some embodiments, q is selected from 1.

In some embodiments, L is selected from the group consisting of a bond, NH, O, S, C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene, the C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, L is selected from the group consisting of a bond, NH, O, S, C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, 3-6 membered heterocycloalkylene, C _6-8 arylene, or 5-8 membered heteroarylene, the C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, 3-6 membered heterocycloalkylene, C _6-8 arylene, or 5-8 membered heteroarylene optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, L is selected from a bond, NH, O, S, C _1-6 alkylene, or C _1-6 heteroalkylene, the C _1-6 alkylene or C _1-6 heteroalkylene being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, L is selected from a bond, C _1-3 alkylene, C _1-3 heteroalkylene, said C _1-3 alkylene or C _0-3 heteroalkylene being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, L is selected from a bond.

In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SONH ₂、-SONHC_1-6 alkyl, -NHSOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-8 cycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-6 membered heterocyclyl, said-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SONH ₂、-SONHC_1-6 alkyl, -NHSOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-8 cycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-6 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl, said-NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, -OH, -NH ₂, or C _1-3 alkyl, said C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂.

In some embodiments, R ⁵ is selected from hydrogen or C _1-6 alkyl.

In some embodiments, R ⁵ is selected from hydrogen or C _1-3 alkyl.

In some embodiments, R ⁵ is selected from hydrogen, methyl, ethyl, propyl, or isopropyl.

In some embodiments, R ⁵ is selected from hydrogen or methyl.

In some embodiments, the fragment portionAttached at position a to ring a.

In some embodiments, the fragment portionAttached at position B.

In some embodiments, the building blockSelected from ethynyl or propynyl.

In some embodiments, the building blockSelected from the group consisting of

In some embodiments, the building blockSelected from the group consisting ofOr is selected from

In some embodiments, the building blockSelected from the group consisting ofOr is selected fromOr is selected from

In some embodiments, the building blockSelected from the group consisting ofOr is selected from Or is selected from

In other embodiments, the building blocksSelected from the group consisting of In some embodiments, the building blockSelected from the group consisting of

The compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, of the present disclosure is selected from the group consisting of a compound of formula II, a stereoisomer or a pharmaceutically acceptable salt thereof,

Wherein ring A, ring B, R ¹、R²、R³、R⁴、R⁵, L, q, m or p are as defined above.

The compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, of the present disclosure is selected from the group consisting of compounds of formula I-A, I-B, II-A or II-B, a stereoisomer or a pharmaceutically acceptable salt thereof,

Wherein ring A, R ¹、R²、R³、R⁴、R⁵, L, q, m, n, or p is as defined above;

X ¹、X²、X³、X⁴ or X ⁵ are each independently selected from CH or N.

In some embodiments, X ¹、X² or X ³ are each independently selected from CH or N, and X ⁴ or X ⁵ are selected from CH.

In some embodiments, X ¹ is selected from CH or N, X ²、X³、X⁴ or X ⁵ is selected from CH.

In some embodiments, X ¹ is selected from N, X ²、X³、X⁴, or X ⁵ is selected from CH.

In some embodiments, the building blockIs defined as before.

In some embodiments, the building blockSelected from the group consisting ofIn some embodiments, the building blockSelected from the group consisting ofIn some embodiments, the building blockSelected from the group consisting ofOr is selected from

In some embodiments, the building blockSelected from the group consisting ofOr is selected fromIn some embodiments, the building blockSelected from the group consisting ofOr is selected from

In still other embodiments, the building blockSelected from the group consisting ofOr is selected from

The compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, as described in the present disclosure, is selected from the group consisting of formula I-1, I-2, I-3, I-4, formula I-1A, formula I-2A, formula I-3A or formula I-4A, a stereoisomer or a pharmaceutically acceptable salt thereof:

Wherein R ¹、R²、R³、R⁴、R⁵, L, q, m, n or p are as defined above.

In some embodiments, m is selected from 2, q is selected from 1 or 2, and n is selected from 0, 1 or 2.

In some embodiments, n is selected from 0,1 or 2 and m is selected from 0,1 or 2.

In some embodiments, m is selected from 2, q is selected from 1, and n is selected from 2.

In some embodiments, n is selected from 2 and m is selected from 2.

In some embodiments, the building blockSelected from the group consisting ofOr is selected fromIn some embodiments, p is selected from 0, 1, 2, or 3. In some embodiments, p is selected from 3.

In some embodiments, q is selected from 1 or 2.

In some embodiments, q is selected from 1 or 2; p is selected from 0,1, 2 or 3.

In some embodiments, p is selected from 0, q is selected from 1, or p is selected from 2, q is selected from 1, or p is selected from 1, q is selected from 1. In other embodiments, the building blocksSelected from the group consisting of

In some embodiments, the building blockSelected from the group consisting of

In some embodiments, the building blockSelected from the group consisting ofIn other embodiments, the building blocksSelected from the group consisting of

In some embodiments, the building blockSelected from the group consisting of

In some embodiments, the present disclosure includes the variables defined above and embodiments thereof, as well as any combination thereof.

In some embodiments, the heteroaryl, heterocyclyl, or heterocycloalkyl of the present disclosure, wherein the heteroatom is selected from NH, N, O, or S; in some embodiments, the number of heteroatoms is selected from 1,2, 3, 4, or 5; in some embodiments, the number of heteroatoms is selected from 1,2, or 3.

In some embodiments, theSelected from the group consisting ofWherein m is selected from 2, r ¹ are each independently selected from C _1-3 alkyl optionally substituted with one or more fluoro; n is selected from 2, R ² is selected from halogen-OH; r ³ is selected from C _1-3 alkyl optionally substituted with one or more deuterium or F; l is selected from a bond; or a structural unitSelected from ethynyl or propynyl.

In another aspect, the present disclosure provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

in another aspect, the present disclosure also provides pharmaceutical compositions comprising the above compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of the present disclosure further comprise a pharmaceutically acceptable excipient.

In another aspect, the present disclosure also provides a method of treating or preventing a disease comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically or prophylactically effective amount of a compound of the present disclosure described above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure also provides the use of the above compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease.

In another aspect, the present disclosure also provides the use of the above compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment or prevention of a disease.

In another aspect, the present disclosure also provides a compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing a disease.

In some embodiments, the disease is selected from a tumor or cancer.

In some embodiments, the disease is selected from the group consisting of Pol Q-related diseases.

In another aspect, the present disclosure also provides a method of treating or preventing PolQ-related various diseases, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically or prophylactically effective amount of a compound of the present disclosure described above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure also provides the use of the above compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing PolQ-related various diseases.

In another aspect, the present disclosure also provides the use of the above compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment or prevention of PolQ-related various diseases.

In another aspect, the present disclosure also provides a compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing PolQ-related various diseases.

In some embodiments, the Pol Q-related disease is selected from a tumor or a cancer.

The compounds of the present disclosure possess good in vitro and in vivo inhibitory activity associated with Pol Q (e.g., pol Q in vitro enzyme inhibitory activity), metabolic stability (e.g., liver microsomal metabolic stability), and good in vivo pharmacokinetic properties.

Definition of the definition

The following terms used in this disclosure have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

When a covalent bond in certain structural units or groups in the present disclosure is not attached to a particular atom, it is meant that the covalent bond may be attached to any atom in the structural unit or group, provided that the valence bond rules are not violated.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂CH₃), monosubstituted (e.g., CH ₂CH₂ F), polysubstituted (e.g., CHFCH ₂F、CH₂CHF₂, etc.), or fully substituted (CF ₂CF₃). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

"Substituents" as used herein include, but are not limited to, the terms "alkyl", "alkoxy", "alkylthio", "cycloalkoxy", "heteroalkyl", "alkenyl", "alkynyl", "cycloalkenyl", "cycloalkyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocyclyl", "aryl", "heteroaryl", "alkylene", and the like, as well as corresponding non-limiting or exemplary groups, where some non-limiting examples of "substituents" include protium, deuterium, tritium, -OH, -SH, halogen, -NH ₂, Nitro, nitroso, -CN, azido, sulfoxide, sulfone, sulfonamide, carboxyl, carboxyaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, Heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, urea, epoxy, ester groups, and the like, optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH ₂, -C (O) NH-alkyl, -C (O) N (alkyl) ₂, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) ₂ -alkyl, -S (O) ₂NH₂、-S(O)₂ NH-alkyl, -S (O) ₂ N (alkyl) ₂, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

Herein, C _m-n is that portion having an integer number of carbon atoms in the given range. For example, "C _1-6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C _1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

In some embodiments herein, the substituents are selected from deuterium, tritium, hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C _1-12 alkyl, halo-C _1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C _2-12 alkenyl, halo-C _2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C _2-12 alkynyl, halo-C _2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C _1-12 heteroalkyl, halo-C _1-12 heteroalkyl, C _1-12 alkoxy, C _1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C _1-12 alkylene, 6-10 membered arylC _1-12 -10 membered arylC _1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C _1-12 alkylene, 3-12 membered heterocyclyl C _1-12 alkoxy, 3-12 membered heterocyclyl C _1-12 alkylthio, C _1-12 acyl, C _1-12 acyloxy, carbamate, C _1-12 amide, urea, epoxy, C _2-12 ester, and oxo, the substituents optionally being substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, Halogen, cyano, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, halogenated C _1-12 alkoxy, C _1-12 alkylamino, di C _1-12 alkylamino, halogenated C _1-12 alkylamino, halogenated di C _1-12 alkylamino, Carboxyl, -C (O) O-C _1-12 alkyl, -OC (O) -C _1-12 alkyl, -C (O) NH ₂、-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, -S (O) ₂NH₂、-S(O)₂NH-C_1-12 alkyl, -S (O) ₂N(C_1-12 alkyl) ₂, 3-12 membered cycloalkyl C _1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl C _1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl C _1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl C _1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl C _1-12 alkylene or 6-10 membered aryloxy.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if one group is substituted with 2R's, then each R has an independent option.

When the number of one linking group is 0, such as- (CH 2) ₀ -, it means that the linking group is a covalent bond.

When one of the variables is selected from a covalent bond, the two groups representing its attachment are directly linked, e.g., when L 'in A-L' -Z represents a covalent bond, it is meant that the structure is actually A-Z.

When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, ring A above represents that the bonds on both sides may be attached to any two different atoms on ring A.

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

The term "alkyl" refers to a hydrocarbon group of the general formula C _nH_2n+1, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group may be straight-chain or branched, and may be, for example, "C _1-12 alkyl" or "C _1-6 alkyl", etc. For example, the term "C _1-12 alkyl" refers to alkyl groups containing 1 to 12 carbon atoms, including C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁ and C ₁₂ alkyl groups, as well as any combination thereof. 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 have the same definition as above. Also for example, the term "C _1-3 alkyl" refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, which may be, for example, "C _2-12 alkenyl" or "C _2-6 alkenyl" or the like. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, and may be, for example, "C _2-12 alkynyl" or "C _2-6 alkynyl" or the like. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.C-CH ₃), 2-propynyl (-CH ₂ -C.ident.CH), 1, 3-butanediynyl (-C.ident.C-C.ident.CH), and the like.

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

The term "alkylthio" refers to-S-alkyl.

The term "cycloalkoxy" refers to-O-cycloalkyl.

The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3-to 10-membered ring, a 4-to 8-membered ring, a 5-to 8-membered ring, or a 5-to 6-membered 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, bicyclo [1.1.1] pent-1-yl, and the like. For example, C _3-4 cycloalkyl includes cyclopropyl and cyclobutyl.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated, has at least one double bond, and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 5-to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "cycloalkynyl" refers to a non-aromatic carbocyclic ring that is not fully saturated, has at least one triple bond, and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 5-to 8-membered ring.

The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, and ring or spiro ring. Unless otherwise indicated, the heterocycle is typically a3 to 10 membered ring (e.g., 3,4, 5, 6, 7, 8, 9 or 10 membered), a4 to 8 membered ring, a 5 to 8 membered ring or a 5 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or a different heteroatom group, and may be "C _1-12 heteroalkyl" or "C _1-6 heteroalkyl" and the like. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH. For example, the term "C _1-6 heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom group may be placed at any position (e.g., an internal or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Typically, where more than one heteroatom group is present, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring (including fused ring), or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10 membered ring, a 3 to 7 membered ring, a4 to 8 membered ring, a 5 to 8 membered ring, or a 5 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and/or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, mercaptoethane, cyclic aziridine, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thioxalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and1, 2,3, 4-tetrahydronaphthalene, and the like.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have a single 5 to 8 membered ring (e.g. 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms (e.g. 6, 7, 8, 9, or 10 ring atoms). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, pyridopyrrolyl, and the like.

The term "alkylene" refers to a divalent group formed by removing one hydrogen at any position of an alkyl group, e.g., the term "C _1-6 alkyl" refers to an alkylene group containing 1to 6 carbon atoms; the term "C _1-4 alkyl" refers to an alkylene group containing 1to 4 carbon atoms, including but not limited to-CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂ -or-CH ₂CH₂CH₂CH₂ -. The terms "heteroalkylene", "cycloalkylene", "heterocycloalkylene", "arylene" and "heteroarylene" are similarly defined and refer to a divalent radical formed by removal of one hydrogen at any position of "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl", respectively.

The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the 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 the present disclosure.

Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysAnd straight dotted line key

Structural unitRepresents a 6-membered aromatic or heteroaromatic ring system, which may be in particular a benzene ring or a pyridine ring.

Unless otherwise indicated, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is attached to two different substituents (of the double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as one substituent to which it is attached), if a wavy line is used between the atom on the double bond and its substituent in the compoundThe term "attached" means the (Z) isomer, (E) isomer or a mixture of both isomers of the compound.

The term "treating" means administering a compound or formulation described in the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;

(ii) The disease or condition is alleviated, even if the disease or condition subsides.

The term "preventing" means that a compound or formulation described in the present disclosure is administered to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or a disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state.

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

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

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

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

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.

The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and ³⁶ Cl, respectively, and the like. For example, it is to be understood that compounds in which one or more hydrogen atoms in the compounds of formula I of the present disclosure are replaced with deuterium atoms are still within the scope of the compounds of formula I of the present disclosure.

Certain isotopically-labeled compounds of the present disclosure (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as ¹⁵O、¹³N、¹¹ C and ¹⁸ F are useful in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below, by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

Furthermore, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means substitution of at least one hydrogen by at least one deuterium, all such forms of compounds being encompassed within the scope of this disclosure.

The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The pharmaceutical compositions of the present disclosure may be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of the compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present disclosure may be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

Therapeutic doses of the compounds of the present disclosure may be based, for example, on the following: the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in the pharmaceutical composition may be variable, depending on a variety of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The compounds of the present disclosure may be provided, for example, by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. Some typical dosages range from about 1 μg/kg to about 1g/kg body weight/day. In certain embodiments, the dosage ranges from about 0.01mg/kg to about 100mg/kg body weight/day. Dosages will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation and its route of administration. The effective dose can be obtained by extrapolation of the dose-response curve derived from in vitro or animal model test systems.

The compounds of the present disclosure may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

The chemical reactions of the embodiments of the present disclosure are accomplished in a suitable solvent that is compatible with the chemical changes of the present disclosure and the reagents and materials required therefor. In order to obtain the compounds of the present disclosure, modifications or choices of synthesis steps or reaction schemes based on the existing embodiments are sometimes required by those skilled in the art.

An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functionalities (such as amino groups in this disclosure), for example, reference may be made to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc.

In some embodiments, compounds of the present disclosure may be prepared by one skilled in the art of organic synthesis with reference to the following routes:

wherein, ring A、X¹、X²、X³、X⁴、X⁵、R¹、R²、R³、R⁴、R⁵、L、q、m、n or p is defined as previously.

The present disclosure employs the following abbreviations:

DME represents ethylene glycol dimethyl ether; KHMDS represents potassium hexamethyldisilazide; pd ₂(dba)₃ represents tris (dibenzylideneacetone) dipalladium; xantphos represents 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene; t ₃ P/DMF represents an N, N-dimethylformamide solution of 1-propylphosphoric acid cyclic anhydride; CD ₃ I represents deuterated iodomethane; DMF stands for N, N-dimethylformamide.

For clarity, the disclosure is further illustrated with examples, but the examples do not limit the scope of the disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

Detailed Description

EXAMPLE 1 Compound 1

1) The preparation method of the compound 1-b comprises the following steps:

1-a (11.8 g) was dispersed in DME (120 mL), triethylamine (11 mL) and isopropyl chloroformate (5.7 mL) were added to the system, stirred at 0deg.C for 3 hours, the reaction was monitored by TLC, the reaction solution was filtered, the filter cake was washed with DME, and the organic phase, namely the DME solution of Compound 1-b, was used directly in the next step.

2) The preparation method of the compound 1-c comprises the following steps:

Sodium borohydride (7.6 g) was dispersed in anhydrous methanol (16 mL) at 0deg.C, added to a DME solution of compound 1-b, and reacted overnight at room temperature after 10 minutes, with TLC monitoring the reaction. 40mL of saturated aqueous ammonium chloride was added to the reaction solution at 0deg.C, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until no liquid was eluted to give compound 1-c (8.2 g) which was used directly in the next step.

3) The preparation method of the compound 1-d comprises the following steps:

1-c (8.1 g) was added to dichloromethane (100 mL), cooled to 0deg.C, dess-Martin reagent (24.6 g) was added, and allowed to react overnight at room temperature, with TLC monitoring of completion. Saturated aqueous sodium hydrogencarbonate (40 mL) was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give compound 1-d (6.4 g).

4) The preparation method of the compound 1-e comprises the following steps:

Compound O, O' -bis (2, 2-trifluoroethyl) phosphomethyl acetate (5.9 g), 18-crown-6 (19.8 g) was added to tetrahydrofuran (30 mL), nitrogen was replaced three times, and the temperature was lowered to-78 ℃. KHMDS (37 mL) was added dropwise to the system, and the mixture was stirred at-78℃for 20 minutes. Compound 1-d (4.2 g) was dissolved in tetrahydrofuran (20 mL), added dropwise to the reaction system, and reacted for 2 hours after the addition, and TLC was monitored for the completion of the reaction. Saturated aqueous ammonium chloride (40 mL) was added to the reaction, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give compound 1-e (3.4 g).

5) The preparation method of the compound 1-f comprises the following steps:

compound 1-e (3.3 g) was added to anhydrous methanol (40 mL), cooled to 0deg.C, acetyl chloride (7.8 g) was added dropwise to the system, the mixture was warmed to room temperature, stirred for 5 hours, and TLC was monitored for completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted, to give Compound 1-f (3.2 g), which was directly taken into the next step.

6) The preparation method of the compound 1-g comprises the following steps:

Compound 1-f (2.7 g) and benzophenone imine (1.8 g) were dispersed in methylene chloride (40 mL) and stirred overnight at room temperature, and TLC was monitored to complete the reaction. Saturated aqueous sodium hydrogencarbonate (40 mL) was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give 1-g (3.4 g) of the compound.

7) The preparation method of the compound 1-h comprises the following steps:

1-g (2.0 g) of the compound was added to tetrahydrofuran (10 mL) and water (10 mL), to which N-methylmorpholine (1.5 g) and K ₂OsO₄·2H₂ O (155 mg) were added, and TLC was monitored for completion of the reaction. Saturated aqueous sodium sulfite solution (40 mL) was added to the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until no liquid was eluted, to give compound 1-h (2.4 g), which was directly added to the next step. ESI-MS: m/z=434.1 [ M+H ] ⁺

8) The preparation method of the compound 1-i comprises the following steps:

Compound 1-h (2.2 g), 2-dimethoxypropane (1.1 g) and pyridine p-toluenesulfonate (314 mg) were dispersed in toluene (20 mL) and stirred at 100deg.C under reflux for 8 hours, and TLC was monitored for completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted, and 20mL of ethyl acetate was added to dilute the reaction solution, and the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give compound 1-i (2.4 g). ESI-MS: m/z=474.1 [ m+h ] ⁺.

9) The preparation method of the compound 1-j comprises the following steps:

Compound 1-i (2.0 g) was added to anhydrous methanol (10 mL), 20% Pd (OH) ₂/C (400 mg) was added thereto, the hydrogen was replaced three times, and stirred overnight at room temperature, and LC-MS was monitored for completion of the reaction. The reaction solution was filtered, and the cake was washed with anhydrous methanol, and the filtrate was concentrated to dryness under reduced pressure to give Compound 1-j (1.0 g). ESI-MS: m/z=278.1 [ M+H ] ⁺

10 Preparation of compound 1-l:

Compound 1-j (139 mg), 2-chloro-6-methyl-4- (trifluoromethyl) pyridine (98 mg), pd ₂(dba)₃ (46 mg), xantphos (58 mg) and cesium carbonate (328 mg) were added to 1, 4-dioxane (5 mL). The nitrogen was replaced three times, the temperature was raised to 110℃and stirred for 3 hours under reflux, and LC-MS monitoring was performed after the reaction was completed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure until no liquid was eluted. Column chromatography (eluent PE: ea=8:1) gave compound 1-l (151 mg). ESI-MS: m/z=437.2 [ M+H ] ⁺.

11 Preparation method of compound 1-m):

Compounds 1-l, 20% Pd (OH) ₂/C (30 mg) and 10% Pd/C (15 mg) were added to anhydrous methanol (2 mL), replaced with hydrogen three times, stirred at 60℃for 10 hours, and LC-MS monitored the reaction. The reaction solution was filtered, and the filter cake was washed with anhydrous methanol, and the filtrate was concentrated to dryness under reduced pressure to give compound 1-m (120 mg). ESI-MS: m/z=347.1 [ M+H ] ⁺.

12 Preparation method of compound 1-n):

Compounds 1 to m (120 mg), sodium periodate (226 mg) and ruthenium trichloride (7 mg) were added to a mixed solution of acetonitrile (2 mL), carbon tetrachloride (2 mL) and water (3 mL), and stirred at room temperature overnight, and LC-MS was monitored for completion of the reaction. To the reaction solution was added water (15 mL), which was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to give 1-n (137 mg). ESI-MS: m/z=361.2 [ M+H ] ⁺.

13 Preparation method of compound 1-p):

Compounds 1-n (50 mg), 3-ethynylaniline (16 mg) and T ₃ P (50% in DMF) (880 mg) were added to pyridine (5.0 mL) and replaced three times with nitrogen. Stirring was carried out at room temperature for 16 hours, and LC-MS was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted. To the concentrate was added saturated aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 1-p (65 mg), and directly feeding into the next step. ESI-MS: m/z=460.1 [ M+H ] ⁺.

14 Preparation method of compound 1-q:

Compounds 1-p (65 mg), cesium carbonate (90 mg) were added to DMF (5.0 mL), CD ₃ I (74 mg) was added, and the mixture was stirred at room temperature for 16 hours, and LC-MS was monitored for completion of the reaction. Water (15 mL) was added to the reaction mixture, and after stirring thoroughly, the mixture was extracted with ethyl acetate, and the organic phases were combined, washed with water and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 1-q (75 mg), and directly feeding into the next step. ESI-MS: m/z=477.2 [ m+h ] ⁺.

15 A process for the preparation of compound 1):

Compound 1-q (75 mg) was added to 4N HCl/1, 4-dioxane (5 mL). Stirring was carried out at room temperature for 16 hours, and LC-MS was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted, and purified by HPLC to give compound 1 (19.9 mg).

ESI-MS:m/z＝437.1[M+H]⁺。

¹H NMR(500MHz,DMSO-d₆)δ8.26(s,1H),7.69(s,1H),7.63–7.50(m,3H),7.41(d,J＝1.5Hz,1H),5.51(d,J＝8.8Hz,1H),5.43(d,J＝5.4Hz,1H),4.91(d,J＝5.6Hz,1H),4.34(s,1H),4.22(t,J＝7.8Hz,1H),4.09–3.96(m,1H),2.58(s,3H).

Example 2: compound 2

1) The preparation method of the compound 2-b comprises the following steps:

Compound 1-n (80 mg), 3-ethynyl-2, 4-difluoroaniline (34 mg) and T ₃ P (50% wtDMF solution) (710 mg) were added to pyridine (5.0 mL) and replaced with nitrogen. Stirring was carried out at room temperature for 3 hours, and LC-MS was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted. To the resulting concentrate was added saturated aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 2-b (110 mg), and directly feeding into the next step. ESI-MS: m/z=496.0 [ m+h ] ⁺.

2) The preparation method of the compound 2-c comprises the following steps:

Compound 2-b (110 mg), cesium carbonate (145 mg) were added to DMF (10.0 mL), CD ₃ I (64 mg) was added, and the mixture was stirred at room temperature for 2 hours, and LC-MS was monitored for completion of the reaction. Water (15 mL) was added to the reaction mixture, and after stirring thoroughly, the mixture was extracted with ethyl acetate, and the organic phases were combined, washed with water and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 2-c (120 mg), and directly feeding into the next step. ESI-MS: m/z=513.1 [ m+h ] ⁺.

3) The preparation method of the compound 2 comprises the following steps:

Compound 2-c (120 mg) was added to 4N HCl/1, 4-dioxane (10 mL). Stirring was carried out at room temperature for 16 hours, and LC-MS was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure until no liquid was eluted, and purified by HPLC to give Compound 2 (3 mg).

ESI-MS:m/z＝473.0[M+H]⁺。

¹H NMR(500MHz,Methanol-d₄)δ8.49–8.32(m,1H),7.81(dtd,J＝75.9,8.8,5.8Hz,1H),7.31–7.09(m,2H),5.09(dd,J＝59.6,5.3Hz,1H),4.56(s,1H),4.29–4.13(m,2H),2.59(d,J＝40.4Hz,3H).

Example 3: compound 3

1) The preparation method of the intermediate 3-a comprises the following steps:

Reference to the preparation of intermediate 2-b in example 2, 3-ethynyl-2, 4-difluoroaniline was replaced with 5-ethynyl-2-fluoroaniline to give intermediate 3-a.

2) The preparation method of the intermediate 3-b comprises the following steps:

With reference to the preparation method of intermediate 2-c in example 2, intermediate 2-b was replaced with intermediate 3-a to give intermediate 3-b.

3) The preparation method of the compound 3 comprises the following steps:

with reference to the preparation of compound 2 in example 2, intermediate 2-c was replaced with intermediate 3-b to give compound 3.

ESI-MS:m/z＝455.15[M+H]⁺。

¹H NMR(500MHz,Methanol-d₄)δ8.37(d,J＝3.8Hz,1H),8.07–7.76(m,1H),7.72–7.58(m,1H),7.48–7.21(m,2H),5.10(dd,J＝97.3,5.3Hz,1H),4.34–4.10(m,2H),3.64(d,J＝11.3Hz,1H),2.78–2.44(m,3H). Example 4: compound 4

1) The preparation method of the compound 4-a comprises the following steps:

compounds 1-n (80 mg), 3-fluoro-5-iodoaniline (53 mg) and EDCI (85 mg) were added to pyridine (5.0 mL), and replaced with nitrogen. Stirring at room temperature for 16 hours, and concentrating the reaction solution under reduced pressure until no liquid flows out after the reaction. To the resulting concentrate was added water (10 mL), extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 4-a (140 mg), and directly feeding into the next step. ESI-MS: m/z=580.00 [ M+H ] ⁺.

2) The preparation method of the compound 4-b comprises the following steps:

Compound 4-a (140 mg) and cesium carbonate (723 mg) were added to DMF (10.0 mL), CD ₃ I (64 mg) was added, and after completion of the reaction, water (10 mL) was added to the reaction mixture, which was stirred well, extracted with ethyl acetate, the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 4-b (150 mg), and directly feeding into the next step. ESI-MS: m/z=597.07 [ M+H ] ⁺.

3) The preparation method of the compound 4-c comprises the following steps:

Compound 4-b (150 mg), pd (PPh ₃)₂Cl₂ (18 mg), cuI (5 mg), triethylamine (51 mg) were added to tetrahydrofuran (5.0 mL), trimethylethynyl silicon (50 mg) was added, nitrogen was substituted, and the mixture was stirred at 50 ℃ for 5 hours, after the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure until no liquid was discharged to obtain 4-c, and then was directly fed to the next step ESI-MS: m/z=567.24 [ m+h ] ⁺.

4) The preparation method of the compound 4-d comprises the following steps:

Compound 4-c was dissolved in tetrahydrofuran (5.0 mL), a 1M tetrahydrofuran solution (1 mL) of tetrabutylammonium fluoride was added, and after completion of the reaction, a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and after sufficient stirring, the mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to obtain 4-d, and directly throwing into the next step. ESI-MS: m/z=495.18 [ m+h ] ⁺. 5) The preparation method of the compound 4 comprises the following steps:

Compound 4-d was added to 4N HCl/1, 4-dioxane (10 mL). After the reaction was completed, the reaction mixture was concentrated under reduced pressure until no liquid was eluted, and then purified by HPLC to give Compound 4 (7 mg).

ESI-MS:m/z＝455.15[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.42(s,1H),7.65(s,1H),7.49(d,J＝9.2Hz,1H),7.36(d,J＝8.8Hz,1H),7.29(s,1H),5.18(d,J＝5.3Hz,1H),4.24(q,J＝6.7Hz,2H),3.80(s,1H),2.64(s,3H).

Example 5: compound 5

1) The preparation method of the intermediate 5-a comprises the following steps:

With reference to the preparation of intermediate 2-b in example 2, the reactant 3-ethynyl-2, 4-difluoroaniline was replaced with 3-ethynyl-4-fluoroaniline to give intermediate 5-a.

2) The preparation method of the intermediate 5-b comprises the following steps:

with reference to the preparation method of intermediate 2-c in example 2, intermediate 2-b was replaced with intermediate 5-a to give intermediate 5-b.

3) The preparation method of the compound 5 comprises the following steps:

Referring to the preparation of compound 2 in example 2, intermediate 2-c was replaced with intermediate 5-b to give compound 5.

ESI-MS:m/z＝455.1[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.40(s,1H),7.82(dd,J＝6.5,2.8Hz,1H),7.71–7.63(m,1H),7.37(t,J＝8.9Hz,1H),7.28(s,1H),5.11(d,J＝5.7Hz,1H),4.24(d,J＝6.2Hz,1H),4.19(t,J＝6.0Hz,1H),3.95(s,1H),2.64(s,3H).

Example 6: compound 6

1) The preparation method of the intermediate 6-a comprises the following steps:

with reference to the preparation of intermediate 3-b in example 3, the starting material deuterated iodomethane was replaced with iodomethane to give intermediate 6-a.

2) The preparation method of the compound 6 comprises the following steps:

referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 6-a to give compound 6.

ESI-MS:m/z＝452.13[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.44–8.33(m,1H),7.92(m,1H),7.63m,1H),7.49–7.20(m,2H),5.09(m,1H),4.35–4.13(m,2H),3.70–3.62(m,1H),3.34(s,3H),2.74–2.46(m,3H).

Example 7: compound 7

1) The preparation method of the intermediate 7-a comprises the following steps:

With reference to the preparation of intermediate 2-c in example 2, the starting material deuterated iodomethane was replaced with iodoethane to afford intermediate 7-a.

2) The preparation method of the compound 7 comprises the following steps:

Referring to the preparation of compound 2 in example 2, intermediate 2-c was replaced with intermediate 7-a to give compound 7.

ESI-MS:m/z＝484.14[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.54–8.43(m,1H),7.81(tt,J＝8.8,3.9Hz,1H),7.14(d,J＝24.4Hz,1H),7.11–7.04(m,1H),5.22(dt,J＝6.8,2.3Hz,1H),4.33–4.21(m,2H),4.19–4.11(m,1H),3.64(d,J＝14.0Hz,1H),3.51–3.28(m,2H),2.66–2.58(m,1H),2.50(s,3H),1.14(q,J＝7.3Hz,3H).

Example 8: compound 8

1) The preparation method of the intermediate 8-a comprises the following steps:

with reference to the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced with 5-ethynyl-2, 4-difluoroaniline to give intermediate 8-a.

2) The preparation method of the intermediate 8-b comprises the following steps:

Referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 8-a to obtain intermediate 8-b.

3) The preparation method of the compound 8 comprises the following steps:

Referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 8-b to give compound 8.

ESI-MS:m/z＝473.1[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.43–8.35(m,1H),7.97(m,1H),7.45–7.20(m,2H),5.10(m,1H),4.33–4.15(m,2H),3.94(d,J＝11.1Hz,1H),2.71–2.50(m,3H).

Example 9: compound 9

1) The preparation method of the intermediate 9-a comprises the following steps:

Reference to the procedure for the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced by 5-ethynyl-2, 3-difluoroaniline to give intermediate 9-a.

2) The preparation method of the intermediate 9-b comprises the following steps:

referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 9-a to obtain intermediate 9-b.

3) The preparation method of the compound 9 comprises the following steps:

Referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 9-b to give compound 9.

ESI-MS:m/z＝473.12[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.48–8.33(m,1H),7.94–7.23(m,3H),5.14(m,1H),4.35–4.12(m,2H),3.76(d,J＝12.4Hz,1H),2.71–2.50(m,3H).

Example 10: compound 10

1) The preparation method of the intermediate 10-a comprises the following steps:

Reference to the procedure for the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced by 5-ethynyl-2, 3, 4-difluoroaniline to give intermediate 10-a.

2) The preparation method of the intermediate 10-b comprises the following steps:

referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 10-a to obtain intermediate 10-b.

3) The preparation method of the compound 10 comprises the following steps:

referring to the preparation method of compound 3 in example 3, intermediate 3-b was replaced with intermediate 10-b to obtain compound 10.

ESI-MS:m/z＝491.17[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.39(d,J＝12.6Hz,1H),7.92–7.65(m,1H),7.35–7.23(m,1H),5.13(m,1H),4.34–4.04(m,3H),2.66–2.53(m,3H).

Example 11: compound 11

1) The preparation method of the compound 11-a comprises the following steps:

with reference to the preparation method of intermediate 4-a in example 4, the reactant 3-fluoro-5-iodoaniline was replaced with 3-iodoaniline to obtain intermediate 11-a.

2) The preparation method of the compound 11-b comprises the following steps:

Referring to the preparation method of intermediate 4-b in example 4, intermediate 4-a was replaced with intermediate 11-a to obtain intermediate 11-b.

3) The preparation method of the compound 11-c comprises the following steps:

Compound 11-b (180 mg), pd (PPh ₃)₂Cl₂ (22 mg), cuI (6 mg) were added to DMF (10.0 mL), 1- (trimethylsilyl) propyne (70 mg) and 1M tetrabutylammonium fluoride in tetrahydrofuran (1.1 mL) were added, nitrogen was replaced, and the mixture was slowly warmed to 53℃and stirred for 3.5 hours, after completion of the reaction, saturated aqueous ammonium chloride (15 mL) was added to the reaction mixture, after sufficient stirring, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid flowed out, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give intermediate 11-c (130 mg). ESI-MS: M/z=491.1 [ M+H ] ⁺.

4) The preparation method of the compound 11 comprises the following steps:

Referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 11-c to give compound 11.

ESI-MS:m/z＝451.1[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.39(s,1H),7.66(s,1H),7.56(d,J＝7.8Hz,1H),7.52–7.44(m,2H),7.28(s,1H),5.10(d,J＝5.5Hz,1H),4.22(d,J＝6.1Hz,1H),4.18(t,J＝5.9Hz,1H),2.64(s,3H),2.04(s,3H).

Example 12: compound 12

1) The preparation method of the intermediate 12-a comprises the following steps:

Reference to the procedure for the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced by 2-ethynyl aniline to give intermediate 12-a.

2) The preparation method of the intermediate 12-b comprises the following steps:

Referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 12-a to obtain intermediate 12-b.

3) The preparation method of the compound 12 comprises the following steps:

referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 12-b to give compound 12.

ESI-MS:m/z＝437.17[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.39(d,J＝35.0Hz,1H),7.86–7.72(m,1H),7.68(ddd,J＝23.4,7.7,1.6Hz,1H),7.52(tdd,J＝7.8,5.5,3.1Hz,1H),7.48–7.42(m,1H),7.12(d,J＝34.1Hz,1H),5.62(d,J＝7.2Hz,1H),4.94(d,J＝4.5Hz,1H),4.43–4.30(m,1H),4.19(dd,J＝34.6,5.9Hz,1H),3.46(s,1H),3.07(s,1H),2.62(s,3H).

Example 13: compound 13

1) The preparation method of the intermediate 13-a comprises the following steps:

Reference to the procedure for the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced by 4-ethynyl aniline to give intermediate 13-a.

2) The preparation method of the intermediate 13-b comprises the following steps:

Referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 13-a to obtain intermediate 13-b.

3) The preparation method of the compound 13 comprises the following steps:

referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 13-b to give compound 13.

ESI-MS:m/z＝437.14[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.48(s,1H),7.73–7.53(m,4H),7.12(s,1H),5.24(d,J＝7.0Hz,1H),4.30(t,J＝6.7Hz,1H),4.21(d,J＝6.4Hz,1H),3.17(s,1H),2.54(s,3H).

Example 14: compound 14

1) The preparation method of the intermediate 14-a comprises the following steps:

Reference to the procedure for the preparation of intermediate 3-a in example 3, the reactant 5-ethynyl-2-fluoroaniline was replaced by 3-chloro-4-ethynyl aniline to give intermediate 14-a.

2) The preparation method of the intermediate 14-b comprises the following steps:

Referring to the preparation method of intermediate 3-b in example 3, intermediate 3-a was replaced with intermediate 14-a to obtain intermediate 14-b.

3) The preparation method of the compound 14 comprises the following steps:

Referring to the preparation of compound 3 in example 3, intermediate 3-b was replaced with intermediate 14-b to give compound 14.

ESI-MS:m/z＝471.06[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.48(s,1H),7.74(d,J＝2.0Hz,1H),7.67(d,J＝8.2Hz,1H),7.55(dd,J＝8.0,2.1Hz,1H),7.13(s,1H),5.21(d,J＝6.9Hz,1H),4.32(t,J＝6.7Hz,1H),4.25(d,J＝6.4Hz,1H),3.47(s,1H),2.57(s,3H).

Example 15: compound 15

1) The preparation method of the compound 15-a comprises the following steps:

With reference to the preparation method of intermediate 4-a in example 4, reactant 3-fluoro-5-iodoaniline was replaced with 4-iodoaniline to obtain intermediate 15-a. 2) The preparation method of the compound 15-b comprises the following steps:

Referring to the preparation method of intermediate 4-b in example 4, intermediate 4-a was replaced with intermediate 15-a to give intermediate 15-b.

3) The preparation method of the compound 15-c comprises the following steps:

referring to the preparation method of intermediate 11-c in example 11, intermediate 11-b was replaced with intermediate 15-b to obtain intermediate 15-c.

4) The preparation method of the compound 15 comprises the following steps:

Referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 15-c to give compound 15.

ESI-MS:m/z＝451.17[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.38(s,1H),7.63–7.45(m,4H),7.27(s,1H),5.10(d,J＝5.5Hz,1H),4.28–4.11(m,2H),2.61(s,3H),2.04(s,3H).

Example 16: compound 16

1) The preparation method of the compound 16-a comprises the following steps:

With reference to the preparation of intermediate 4-a in example 4, reactant 3-fluoro-5-iodoaniline was replaced with 4-bromo-5-chloro-2-fluoroaniline to give intermediate 16-a.

2) The preparation method of the compound 16-b comprises the following steps:

Referring to the preparation method of intermediate 4-b in example 4, intermediate 16-b was obtained by substituting intermediate 4-a with intermediate 16-a.

3) The preparation method of the compound 16-c comprises the following steps:

referring to the preparation method of intermediate 11-c in example 11, intermediate 11-b was replaced with intermediate 16-b to obtain intermediate 16-c.

4) The preparation method of the compound 16 comprises the following steps:

referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 16-c to give compound 16.

ESI-MS:m/z＝503.12[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.55(s,1H),7.80(d,J＝7.2Hz,1H),7.37(d,J＝10.0Hz,1H),7.14(d,J＝7.5Hz,1H),5.54(s,1H),5.44(s,1H),5.05(s,1H),4.69(d,J＝5.1Hz,1H),4.39(d,J＝5.1Hz,1H),2.62(s,3H),2.15(s,3H).

Example 17: compound 17

1) The preparation method of the compound 17-a comprises the following steps:

Compound 17-a-1 (100 mg), 3-bromo-2-fluoroaniline (148 mg) and T ₃ P/DMF (mass ratio=1:1, 1 g) were added to pyridine (5.0 mL), nitrogen substitution. Stirring at room temperature for 16 hours, and concentrating the reaction solution under reduced pressure until no liquid flows out after the reaction. To the resulting concentrate was added water (10 mL), extracted with ethyl acetate, and the organic phases were combined, washed with water and dried over anhydrous sodium sulfate. Concentrated under reduced pressure until no liquid was eluted to give 17-a (240 mg). ESI-MS: m/z=372.97 [ M+H ] ⁺.

2) The preparation method of the compound 17-b comprises the following steps:

Compound 17-a (240 mg), 2-bromo-6-methyl-4- (trifluoromethyl) pyridine (148 mg), cuI (58 mg), DMEDA (16 mg), potassium carbonate (256 mg) were added to 1, 4-dioxane (10.0 mL), nitrogen was replaced, stirring was carried out at 80℃for 4 hours, after completion of the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give 17-b (250 mg). ESI-MS: m/z=531.98 [ M+H ] ⁺.

3) The preparation method of the compound 17-c comprises the following steps:

Compound 17-b (250 mg) and cesium carbonate (1.5 g) were added to DMF (15.0 mL), CD ₃ I (681 mg) was added, and after completion of the reaction, water (15 mL) was added to the reaction mixture, which was stirred well, extracted with ethyl acetate, and the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to give 17-c (230 mg). ESI-MS: m/z=549.02 [ M+H ] ⁺.

4) The preparation method of the compound 17-d comprises the following steps:

Compound 17-c (230 mg), pd (PPh ₃)₄ (48 mg), cuI (8 mg), N-diisopropylethylamine (160 mg) were added to toluene (5.0 mL), triisopropylsilylacethylene (160 mg) was added, nitrogen substitution was performed, and the mixture was slowly stirred at 110 ℃ for 10 hours, after completion of the reaction, filtration was performed, the filtrate was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give 17-d (55 mg). ESI-MS: m/z=651.50 [ m+h ] ⁺.

5) The preparation method of the compound 17-e comprises the following steps:

Compound 17-d (55 mg) was added to 4N HCl/1, 4-dioxane (10 mL). After the reaction was completed, the reaction mixture was concentrated under reduced pressure until no liquid was eluted, and a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the concentrate, followed by extraction with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrated under reduced pressure until no liquid was eluted to give 17-e (41 mg). ESI-MS: m/z=611.37 [ m+h ] ⁺.

6) The preparation method of the compound 17 comprises the following steps:

Compound 17-e (41 mg) was added to tetrahydrofuran (1.0 mL), a 1M tetrahydrofuran solution (1 mL) of tetrabutylammonium fluoride was added, and after completion of the reaction, a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and after sufficient stirring, the mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out, and purifying the concentrate by HPLC to obtain compound 17 (4.7 mg).

ESI-MS:m/z＝455.15[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.47(d,J＝8.1Hz,1H),7.84(m,1H),7.59(ddd,J＝8.0,6.2,1.8Hz,1H),7.28(d,J＝2.9Hz,1H),7.10(s,1H),5.45–5.28(m,1H),4.64(s,1H),4.34(s,1H),4.24(d,J＝6.9Hz,1H),2.48(s,3H).

Example 18: compound 18

1) The preparation method of the compound 18-a comprises the following steps:

Compound 17-a-1 (120 mg), 3-ethynyl-2, 4, 6-trifluoroaniline (102 mg) and T ₃ P/DMF (1.9 g) were added to pyridine (10.0 mL) and replaced with nitrogen. Stirring at room temperature for 16 hours, and concentrating the reaction solution under reduced pressure until no liquid flows out after the reaction. To the resulting concentrate was added water (10 mL), extracted with ethyl acetate, and the organic phases were combined, washed with water and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out to give 18-a (210 mg).

2) The preparation method of the compound 18-b comprises the following steps:

Compound 18-a (210 mg), 2-bromo-6-methyl-4- (trifluoromethyl) pyridine (143 mg), cuI (23 mg), DMEDA (11 mg), potassium carbonate (165 mg) were added to 1, 4-dioxane (10.0 mL), replaced with nitrogen, stirred at 60℃for 16 hours, after completion of the reaction, filtered, and the filtrate was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) and HPLC to give 18-b (12 mg). ESI-MS: m/z=514.17 [ m+h ] ⁺.

3) The preparation method of the compound 18-c comprises the following steps:

compound 18-b (12 mg) and cesium carbonate (38 mg) were added to DMF (2.0 mL), CD ₃ I (17 mg) was added, and after completion of the reaction, water (10 mL) was added to the reaction mixture, which was sufficiently stirred, extracted with ethyl acetate, and the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure until no liquid was eluted to give 18-c (15 mg). ESI-MS: m/z=531.21 [ M+H ] ⁺.

4) The preparation method of the compound 18 comprises the following steps:

Compound 18-c (15 mg) was added to 4N HCl/1, 4-dioxane (10 mL). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by HPLC to give Compound 18 (5.0 mg).

ESI-MS:m/z＝491.22[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.44–8.26(m,1H),7.37–7.00(m,2H),5.06(dd,J＝7.4,4.8Hz,1H),4.49–4.07(m,3H),2.55(dd,J＝13.2,4.2Hz,3H).

Example 19: compound 19

1) The preparation method of the compound 19-a comprises the following steps:

With reference to the preparation method of intermediate 4-a in example 4, the reactant 3-fluoro-5-iodoaniline was replaced with 3-chloro-5-iodoaniline to obtain intermediate 19-a.

2) The preparation method of the compound 19-b comprises the following steps:

Referring to the preparation method of intermediate 4-b in example 4, intermediate 4-a was replaced with intermediate 19-a to obtain intermediate 19-b.

3) The preparation method of the compound 19-c comprises the following steps:

With reference to the preparation method of intermediate 4-c in example 4, intermediate 4-b was replaced with intermediate 19-b to obtain intermediate 19-c.

4) The preparation method of the compound 19-d comprises the following steps:

with reference to the preparation method of intermediate 4-d in example 4, intermediate 4-c was replaced with intermediate 19-c to obtain intermediate 19-d.

5) The preparation method of the compound 19 comprises the following steps:

Referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 19-d to give compound 19.

ESI-MS:m/z＝471.21[M+H]⁺。

Example 20: compound 20

1) The preparation method of the compound 20-a comprises the following steps:

With reference to the preparation of intermediate 17-a in example 17, the reactant 3-bromo-2-fluoroaniline was replaced with 3-bromo-2-chloroaniline to give intermediate 20-a.

2) The preparation method of the compound 20-b comprises the following steps:

referring to the preparation method of intermediate 17-b in example 17, intermediate 17-a was replaced with intermediate 20-a to give intermediate 20-b.

3) The preparation method of the compound 20-c comprises the following steps:

Referring to the preparation method of intermediate 17-c in example 17, intermediate 17-b was replaced with intermediate 20-b to obtain intermediate 20-c.

4) The preparation method of the compound 20-d comprises the following steps:

referring to the preparation method of intermediate 17-d in example 17, intermediate 17-c was replaced with intermediate 20-c to give intermediate 20-d.

5) The preparation method of the compound 20-e comprises the following steps:

Referring to the preparation method of intermediate 17-e in example 17, intermediate 17-d was replaced with intermediate 20-d to obtain intermediate 20-e.

6) The preparation method of the compound 20 comprises the following steps:

referring to the preparation of compound 17 in example 17, intermediate 17-e was replaced with intermediate 20-e to give compound 20.

ESI-MS:m/z＝471.17[M+H]⁺。

Example 21: compound 21

1) The preparation method of the compound 21-a comprises the following steps:

With reference to the preparation of intermediate 17-a in example 17, the reactant 3-bromo-2-fluoroaniline was replaced with 2-chloro-5-iodoaniline to give intermediate 21-a.

2) The preparation method of the compound 21-b comprises the following steps:

Referring to the preparation method of intermediate 17-b in example 17, intermediate 17-a was replaced with intermediate 21-a to give intermediate 21-b.

3) The preparation method of the compound 21-c comprises the following steps:

referring to the preparation method of intermediate 17-c in example 17, intermediate 17-b was replaced with intermediate 21-b to obtain intermediate 21-c.

4) The preparation method of the compound 21-d comprises the following steps:

referring to the preparation method of intermediate 4-c in example 4, intermediate 4-b was replaced with intermediate 21-c to give intermediate 21-d.

5) The preparation method of the compound 21-e comprises the following steps:

referring to the preparation method of intermediate 4-d in example 4, intermediate 4-c was replaced with intermediate 21-d to give intermediate 21-e.

6) The preparation method of the compound 21 comprises the following steps:

Referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 21-e to give compound 21.

ESI-MS:m/z＝471.20[M+H]⁺。

¹H NMR(500MHz,CDCl₃)δ8.38(d,J＝39.8Hz,1H),8.20–7.84(m,1H),7.65–7.47(m,2H),7.14(dd,J＝29.5,1.3Hz,1H),5.16(dd,J＝140.9,5.4Hz,1H),4.62(d,J＝46.3Hz,1H),4.39–4.10(m,2H),3.44(d,J＝40.6Hz,1H),3.23(d,J＝16.3Hz,1H),2.58(d,J＝115.6Hz,3H).

Example 22: compound 22

1) The preparation method of the compound 22-a comprises the following steps:

With reference to the preparation of intermediate 17-a in example 17, the reactant 3-bromo-2-fluoroaniline was replaced with 5-bromo-2-chloro-4-fluoroaniline to afford intermediate 22-a.

2) The preparation method of the compound 22-b comprises the following steps:

Referring to the preparation of intermediate 17-b in example 17, intermediate 17-a was replaced with intermediate 22-a to give intermediate 22-b.

3) The preparation method of the compound 22-c comprises the following steps:

Compound 22-b (80 mg), pd (PPh ₃)₄ (33 mg), triethylamine (71 mg) were added to tetrahydrofuran (5.0 mL), tributyltin acetylene (89 mg) was added, nitrogen was substituted, and the mixture was slowly heated to 75 ℃ and stirred for 9 hours, after the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give 22-c (54 mg). ESI-MS: m/z=512.18 [ m+h ] ⁺.4) preparation method of compound 22-d:

Referring to the preparation of intermediate 17-c in example 17, intermediate 17-b was replaced with intermediate 22-c to give intermediate 22-d.

5) The preparation method of the compound 22 comprises the following steps:

referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 22-d to give compound 22.

ESI-MS:m/z＝489.16[M+H]⁺。

¹H NMR(500MHz,MeOD)δ8.34(d,J＝34.1Hz,1H),8.00(dd,J＝132.4,7.0Hz,1H),7.61(dd,J＝8.8,5.7Hz,1H),7.27(d,J＝32.2Hz,1H),5.03(dd,J＝55.2,4.6Hz,1H),4.48–4.01(m,3H),2.69–2.52(m,3H). Example 23: compound 23

1) The preparation method of the compound 23-a comprises the following steps:

with reference to the preparation of intermediate 17-a in example 17, reactant 3-bromo-2-fluoroaniline was replaced with 5-bromo-4-chloro-2-fluoroaniline to afford intermediate 23-a.

2) The preparation method of the compound 23-b comprises the following steps:

Referring to the preparation method of intermediate 17-b in example 17, intermediate 17-a was replaced with intermediate 23-a to give intermediate 23-b.

3) The preparation method of the compound 23-c comprises the following steps:

referring to the preparation method of intermediate 22-c in example 22, intermediate 22-b was replaced with intermediate 23-b to obtain intermediate 23-c.

4) The preparation method of the compound 23-d comprises the following steps:

Referring to the preparation method of intermediate 17-c in example 17, intermediate 17-b was replaced with intermediate 23-c to give intermediate 23-d.

5) The preparation method of the compound 23 comprises the following steps:

Referring to the preparation of compound 4 in example 4, intermediate 4-d was replaced with intermediate 23-d to give compound 23.

ESI-MS:m/z＝489.0[M+H]⁺。

Example 24: compound 24

1) The preparation method of the intermediate 24-a comprises the following steps:

Compound 3-a (10 mg) and sodium t-butoxide (4 mg) were added to diethylene glycol dimethyl ether (2.0 mL), nitrogen was replaced, the temperature was lowered to-10℃and difluoromethyl methyltrimethylsilane (8.5 mg) was slowly added thereto, followed by stirring at-10℃for 1 hour. After the completion of the reaction, the reaction mixture was added to a saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure until no liquid flows out, and purifying the concentrate by column chromatography (eluent: petroleum ether/ethyl acetate) to obtain 24-a. ESI-MS: m/z=528.11 [ M+H ] ⁺.

2) The preparation method of the compound 24 comprises the following steps:

Referring to the preparation of compound 2 in example 2, intermediate 2-c was replaced with intermediate 24-a to give compound 24.

ESI-MS:m/z＝488.05[M+H]⁺。

Example 25: compound 25

1) The preparation method of the compound 25-a comprises the following steps:

17-a-1 (1 g), benzyl bromide (935 mg), triethylamine (1 g) and acetone (30 mL) were added to the flask, and reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, 20mL of water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate under reduced pressure, it was purified by column chromatography to give 25-a (760 mg). ESI-MS: m/z=292.2 [ m+h ] ⁺.

2) The preparation method of the compound 25-b comprises the following steps:

To 1, 4-dioxane (2 mL) was added compound 25-a (100 mg), 2-bromo-4, 6-bis (trifluoromethyl) pyridine (85 mg), pd ₂(dba)₃ (31 mg), xantphos (39 mg), and cesium carbonate (223 mg). Nitrogen substitution, heating to 90 deg.c and stirring for 3 hr. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give 25-b (50 mg). ESI-MS: m/z=505.1 [ m+h ] ⁺.

3) The preparation method of the compound 25-c comprises the following steps:

Compound 25-b (50 mg) and 10% Pd/C (10 mg) were added to methanol (2 mL). The mixture was replaced with hydrogen and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure until no liquid was eluted, to give 25-c (40 mg). ESI-MS: m/z=415.1

[M+H]⁺。

4) The preparation method of the compound 25-d comprises the following steps:

compound 25-c (40 mg), 5-ethynyl-2-fluoroaniline (14 mg) and EDCI (38 mg) were added to pyridine (1 mL). Stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure until no liquid was discharged. To the resulting concentrate was added saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no liquid was eluted to give 25-d (53 mg). ESI-MS: m/z=532.1 [ M+H ] ⁺.

5) The preparation method of the compound 25-e comprises the following steps:

Compound 25-d (53 mg), cesium carbonate (64 mg) and CD ₃ I (30 mg) were added to DMF (2 mL) and stirred at room temperature for 3 hours. After the completion of the reaction, water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure until no liquid was present, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate) to give 25-e (13 mg). ESI-MS: m/z=549.1 [ M+H ] ⁺.

6) The preparation method of the compound 25 comprises the following steps:

Compound 25-e (13 mg) was added to 4N HCl/1, 4-dioxane (2 mL) and stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure until no liquid was eluted, and the concentrate was purified by HPLC to give Compound 25 (2 mg).

ESI-MS:m/z＝509.1[M+H]⁺。

Experimental example 1 measurement of PolQ protein inhibitory Activity

POLQ protein solution (concentration 4 nM) was added to the assay wells at 6. Mu.L per well, and different compounds dissolved in DMSO were added to the assay wells using a nanoliter applicator to give final compound concentrations of 2000 nM-0.48nM, 2 multiplex wells, with controls. After mixing 100nM PolQ substrate and 40. Mu.M dNTP, 6. Mu.L per well was added to the detection well and the above system incubated for 60 minutes with stop buffer at 1:80 dilution of PicoGreen dye (manufacturer: thermo) added to the detection wells at 8. Mu.L per well; reacting for 90min at room temperature; PERKINELMER ENVISION multifunctional enzyme labeling instrument is used for detection (excitation 485nm and emission 520 nm), and four-parameter fitting is adopted to calculate IC ₅₀.

The experimental results are shown in Table 1. Wherein A represents an active IC ₅₀ < 0.5. Mu.M.

TABLE 1

The test results show that the compound has POLQ protein inhibition activity.

Test example 2: in vitro liver microstation stability evaluation

Liver microsome temperature incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg/ml), test compound and NADPH+MgCl2 solution, and incubating at 37℃and 300rpm for 1 hour. Samples were prepared as mixed PBS buffer (pH 7.4), liver microsome solution (0.5 mg/ml), test compound. The sample is added into acetonitrile solution containing internal standard, protein precipitation is carried out to prepare supernatant, and the supernatant is used for LC/MS/MS determination after dilution. The results are shown in Table 2.

Table 2 liver microposition stability data (residual amount, t=60 min)

Numbering of compounds	Human liver microsome	Numbering of compounds	Human liver microsome	Numbering of compounds	Human liver microsome
						Example 1	＞65％	Example 2	＞65％	Example 3	＞65％

The test result shows that the compound of the application has stable metabolism of liver microsomes.

Test example 3: in vivo pharmacokinetics

ICR mice weighing 18-22 g, after 3-5 days of adaptation, were randomly grouped, 9 animals per group, and were infused with 1mg/kg and 10mg/kg of the compound solution of the examples.

Blood sampling time points 0, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1,2, 4, 6, 8, 10 and 24h are used for preparing plasma samples to be tested by taking blood from the eyesockets.

The blood sampling time of the stomach is 0, 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10 and 24 hours, and the blood is taken from the orbit to prepare the plasma sample to be measured.

And sucking 30 mu L of plasma sample to be detected and standard yeast sample, adding acetonitrile solution containing an internal standard, precipitating the protein to obtain supernatant, and diluting for LC/MS/MS determination. Non-compartmental model fitting was used.

The test results show that the test compounds of the application have good in vivo metabolism kinetics, such as the results of the gastric lavage experiment of compound 3 of example 3: AUC (0- ≡) > 20000, cmax > 3500, absolute bioavailability F > 300%.

Claims

1. A compound of formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof,

Wherein,

m is selected from 0, 1, 2, 3 or 4;

n is selected from 0, 1, 2, 3 or 4;

p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

q is selected from 1, 2 or 3;

2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each R ¹ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclyl, The said-OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more substituents;

Or each R ¹ is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, The said-OH, -SH, -NR ^xR^y、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Or each of said R ¹ is independently selected from halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, or-NHCOC _1-6 alkyl, said-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONHC _1-6 alkyl, or-NHCOC _1-6 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

or each of said R ¹ is independently selected from halogen, -CN, -OH, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, -C _1-4 alkoxy, -CONH ₂、-CONHC_1-4 alkyl, or-NHCOC _1-4 alkyl, said-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, -CONHC _1-4 alkyl, or-NHCOC _1-4 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each of said R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, -C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl, said-NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _1-3 alkoxy, -CONHC _1-3 alkyl, or-NHCOC _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, or C _1-4 alkoxy, the-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, or C _1-4 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy, the-N (C _1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl or C _1-3 alkoxy, said C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ¹ is independently selected from halogen, -OH, -CN, -NH ₂、-N(C_1-3 alkyl) ₂、C_1-3 alkyl, halogen substituted C _1-3 alkyl or C _1-3 alkoxy;

Or each R ¹ is independently selected from F, cl, br, -OH, -CN, -NH ₂, or a combination thereof, Methyl, trifluoromethyl, ethyl, isopropyl or methoxy;

Or each R ¹ is independently selected from F, cl, br, -OH, -CN, -NH ₂, methyl or trifluoromethyl;

or each R ¹ is independently selected from C _1-6 alkyl optionally substituted with one or more halogens;

or each R ¹ is independently selected from C _1-4 alkyl optionally substituted with one or more halogens;

or each R ¹ is independently selected from C _1-3 alkyl optionally substituted with one or more fluoro;

Or each R ¹ is independently selected from methyl or trifluoromethyl;

Optionally, each R ² is independently selected from halogen, -OH, -CN, -NR ^xR^y、-CH₂-NR^xR^y、-Z-C_6-10 aryl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl or C _1-12 alkoxy, said-OH, -NR ^xR^y、-CH₂-NR^xR^y、-Z-C_6-10 aryl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl or C _1-12 alkoxy is optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-12 cycloalkyl, 3-12 membered heterocyclyl, C _1-12 alkoxy, -NHC _1-12 alkyl, -N (C _1-12 alkyl) ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -COOC _1-12 alkyl or-OCOC _1-12 alkyl;

Or each R ² is independently selected from halogen, -OH, -CN, -NR ^xR^y、-CH₂-NR^xR^y、C_1-8 alkyl, or C _1-6 alkoxy, said-OH, -NR ^xR^y、-CH₂-NR^xR^y、C_1-8 alkyl, or C _1-6 alkoxy being optionally substituted with one or more substituents;

Or each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy, the-OH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -COOC _1-6 alkyl or-OCOC _1-6 alkyl;

Or each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-8 alkyl, or C _1-6 alkoxy, the C _1-8 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -COOC _1-6 alkyl or-OCOC _1-6 alkyl;

Or each R ² is independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-5 alkyl, or C _1-4 alkoxy, the C _1-5 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、-CONHC_1-4 alkyl, -NHCOC _1-4 alkyl, -COOC _1-4 alkyl or-OCOC _1-4 alkyl;

Or each R ² is independently selected from halogen, -OH, -CN, -NH ₂, or C _1-4 alkyl, said C _1-4 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

or each R ² is independently selected from halogen, -OH, -CN, -NH ₂, or C _1-3 alkyl, said C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ² is independently selected from halogen, -OH, -CN, or-NH ₂;

or each of said R ² is selected from-OH;

The Z is selected from a bond or a C _1-6 alkylene, one or more CH ₂ in the C _1-6 alkylene is optionally independently replaced by oxygen or sulfur, or one or more CH in the C _1-6 alkylene is optionally independently replaced by N;

Or Z is selected from a bond or a C _1-3 alkylene, 1, 2 or 3 CH ₂ in the C _1-3 alkylene are optionally independently replaced by oxygen or sulfur, or 1, 2 or 3 CH in the C _1-6 alkylene are optionally independently replaced by N;

or Z is selected from a bond, methylene, O, S, or NH.

3. The compound of claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the R ³ is selected from H, deuterium, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, the C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl being optionally substituted with one or more substituents, the C _1-12 alkyl, C _3-12 cycloalkyl, or 3-12 membered heterocyclyl being optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂;

The R ³ is selected from H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-10 membered heterocyclyl, the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-10 membered heterocyclyl optionally substituted with one or more substituents;

or said R ³ is selected from H, C _1-12 alkyl, C _3-12 cycloalkyl or 3-12 membered heterocycloalkyl, said C _1-12 alkyl, C _3-12 cycloalkyl or 3-12 membered heterocycloalkyl optionally being substituted with one or more substituents;

Or said R ³ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally being substituted with one or more substituents;

or said R ³ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally being substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂;

Or said R ³ is selected from H, C _1-4 alkyl, C _3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C _1-4 alkyl, C _3-5 cycloalkyl or 3-5 membered heterocycloalkyl being optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂;

Or the R ³ is selected from H, C _1-3 alkyl or C _3-5 cycloalkyl, the C _1-3 alkyl or C _3-5 cycloalkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂;

Or the R ³ is selected from C _1-3 alkyl, the C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, protium, deuterium, tritium, OH, CN or NH ₂;

or the R ³ is selected from methyl, ethyl, isopropyl, or cyclopropyl, optionally substituted with one or more of the following groups: halogen, protium, deuterium or tritium;

or the R ³ is selected from C _1-3 alkyl optionally substituted with one or more deuterium or halogen (e.g., F, cl, br, or I);

Or the R ³ is selected from C _1-2 alkyl optionally substituted with one or more deuterium, F, cl, or Br;

or R ³ is selected from methyl optionally substituted with one or more deuterium or F;

Or said R ³ is selected from-CD ₃、-CF₃、-CHF₂、-CH₂F、-CH₃ or-CH ₂CH₃;

or the R ³ is selected from C _1-3 alkyl optionally substituted with one or more deuterium;

Or R ³ is selected from methyl optionally substituted with one or more deuterium;

Or said R ³ is selected from-CD ₃、-CHD₂、-CH₂ D or-CH ₃;

Or said R ³ is selected from-CD ₃ or-CH ₃;

Optionally, the rings a and B are each independently selected from phenyl, naphthyl, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heteroaryl, or 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heterocyclyl;

Or the rings A and B are each independently selected from phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or the rings A and B are each independently selected from phenyl, 5-9 membered heteroaryl, or 5-9 membered heterocyclyl;

Or the rings a and B are each independently selected from phenyl or 5-10 membered heteroaryl;

or the rings a, B are each independently selected from phenyl, 5 membered heteroaryl, 6 membered heteroaryl, or 9 membered heteroaryl;

Or the rings a and B are each independently selected from phenyl, 6 membered heteroaryl, or 9 membered heteroaryl;

Or the rings a and B are each independently selected from phenyl or 6 membered heteroaryl;

or the ring a and ring B are each independently selected from phenyl or pyridyl;

Or the ring a is selected from phenyl; or the ring B is selected from pyridinyl;

Optionally, each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, A 6-10 membered aryl, a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more substituents;

Or each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, A 6-10 membered aryl, a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Or each R ⁴ is independently selected from the group consisting of halogen, -OH, -CN, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl or C _3-6 cycloalkyl, The said-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, or C _3-6 cycloalkyl optionally substituted with one or more of the following groups: halogen, halogen, -OH, -CN or-NH ₂;

Or R ⁴ is each independently selected from halogen, -OH, -CN, -NH ₂、-NHC_1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-5 cycloalkyl, -CONH ₂、-CONHC_1-4 alkyl or-NHCOC _1-4 alkyl, the-NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-5 cycloalkyl, -CONHC _1-4 alkyl or-NHCOC _1-4 alkyl optionally substituted with one or more of the following groups: halogen, halogen, -OH, -CN or-NH ₂;

Or each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy, the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

or each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-3 alkyl, C _2-4 alkenyl, or C _1-3 alkoxy, the C _1-3 alkyl or C _2-4 alkenyl being optionally substituted with one or more of the following groups: halogen, -CN, -OH or-NH ₂;

Or each R ⁴ is independently selected from halogen, -OH, -CN, -NH ₂、C_1-3 alkyl, halogenated C _1-3 alkyl, C _2-3 alkenyl or C _1-3 alkoxy;

Or each R ⁴ is independently selected from F, cl, br, -OH, -CN, -NH ₂, methyl, ethyl, -CH ₂F、-CHF₂、-CF₃, vinyl, or methoxy;

Or each R ⁴ is independently selected from halogen, -OH, -CN, or-NH ₂;

or each R ⁴ is independently selected from halogen;

Or each R ⁴ is independently selected from F or Cl.

4. The compound of any one of claims 1-3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each R ^x and R ^y is independently selected from H, C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl, the C _1-12 alkyl, C _3-12 cycloalkyl, -CO-C _1-12 alkyl, or 3-12 membered heterocyclyl optionally substituted with one or more of the following groups: c _1-6 alkyl, C _1-6 alkoxy, halogen, -OH, -CN, -NH ₂、C_3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Or each R ^x and R ^y is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, -CO-C _1-6 alkyl, or 3-8 membered heterocyclyl, said C _1-6 alkyl, C _3-8 cycloalkyl, -CO-C _1-6 alkyl, or 3-8 membered heterocyclyl optionally substituted with one or more of the following groups: c _1-6 alkyl, C _1-6 alkoxy, halogen, -OH, -CN, -NH ₂、C_3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Or each R ^x and R ^y is independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, -CO-C _1-3 alkyl, or 3-6 membered heterocyclyl, said C _1-3 alkyl, C _3-6 cycloalkyl, -CO-C _1-3 alkyl, or 3-6 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ^x and R ^y is independently selected from H or C _1-3 alkyl, said C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or each R ^x and R ^y is independently selected from H;

Optionally, the R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, N, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said-OH, -SH, -NH ₂、-NHC_1-12 alkyl, -N (C _1-12 alkyl) ₂、C_1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -CONH ₂、-CONHC_1-12 alkyl, -NHCOC _1-12 alkyl, -SONH ₂、-SONHC_1-12 alkyl, -NHSOC _1-12 alkyl, -SO ₂NH₂、-SO₂NHC_1-12 alkyl, -NHSO ₂C_1-12 alkyl, C _3-12 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SONH ₂、-SONHC_1-6 alkyl, -NHSOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-8 cycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-6 membered heterocyclyl, said-NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -CONH ₂、-CONHC_1-6 alkyl, -NHCOC _1-6 alkyl, -SONH ₂、-SONHC_1-6 alkyl, -NHSOC _1-6 alkyl, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -NHSO ₂C_1-6 alkyl, C _3-8 cycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-6 membered heterocyclyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or R ⁵ is selected from hydrogen, halogen, -CN, -OH, -SH, -NH ₂、-NHC_1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl, said-NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、C_1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, -CONH ₂、-CONHC_1-3 alkyl, or-NHCOC _1-3 alkyl being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or R ⁵ is selected from hydrogen, halogen, -CN, -OH, -NH ₂, or C _1-3 alkyl, said C _1-3 alkyl optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂; or R ⁵ is selected from hydrogen or C _1-6 alkyl; or R ⁵ is selected from hydrogen or C _1-3 alkyl; or R ⁵ is selected from hydrogen, methyl, ethyl, propyl, or isopropyl; or R ⁵ is selected from hydrogen or methyl.

5. The compound of any one of claims 1-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, NH, O, S, C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene, the C _1-12 alkylene, C _1-12 heteroalkylene, C _3-12 cycloalkylene, 3-12 membered heterocycloalkylene, C _6-10 arylene, or 5-10 membered heteroarylene optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or L is selected from the group consisting of a bond, NH, O, S, C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, 3-6 membered heterocycloalkylene, C _6-8 arylene, or 5-8 membered heteroarylene, said C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, 3-6 membered heterocycloalkylene, C _6-8 arylene, or 5-8 membered heteroarylene optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or L is selected from a bond, NH, O, S, C _1-6 alkylene, or C _1-6 heteroalkylene, said C _1-6 alkylene or C _1-6 heteroalkylene being optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or L is selected from a bond, C _1-3 alkylene, C _1-3 heteroalkylene, said C _1-3 alkylene or C _0-3 heteroalkylene optionally substituted with one or more of the following groups: halogen, -OH, -CN or-NH ₂;

Or L is selected from a bond;

optionally, m is selected from 0, 1, 2 or 3; or m is selected from 1, 2 or 3; or m is selected from 1 or 2;

Optionally, n is selected from 1 or 2; or said n is selected from 2;

Optionally, p is selected from 0, 1, 2, 3 or 4; or p is selected from 0, 1, 2 or 3; or p is selected from 1, 2 or 3; or p is selected from 4; optionally, q is selected from 1 or 2; or q is selected from 1.

6. The compound of any one of claim 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula II, a compound of formula I-A, I-B, II-A, I-B, I-1, I-2, I-3, I-4, a compound of formula I-1A, formula I-2A, formula I-3A or formula I-4A, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

Wherein, X ¹、X²、X³、X⁴ or X ⁵ are each independently selected from CH or N; or X ¹、X² or X ³ are each independently selected from CH or N, X ⁴ or X ⁵ are selected from CH; or X ¹ is selected from CH or N, X ²、X³、X⁴ or X ⁵ is selected from CH; or X ¹ is selected from N, X ²、X³、X⁴ or X ⁵ is selected from CH.

7. The following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

8. a pharmaceutical composition comprising a compound according to any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

9. Use of a compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the prevention or treatment of a disease associated with a tumor.