Heterocyclic compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a heterocyclic compound, and a preparation method therefor and a use thereof. Specifically provided is a heterocyclic compound represented by formula (IG) or a pharmaceutically acceptable salt thereof. The heterocyclic compound or the pharmaceutically acceptable salt thereof provided by the present invention can be used for preparing a drug for preventing and / or treating c-kit-mediated diseases or conditions.

Description

Heterocyclic compounds, processes for their preparation and uses thereof

[0001] This application claims priority to Chinese patent application 2024110262574 with the filing date of 2024 / 07 / 30, Chinese patent application 202411429329X with the filing date of 2024 / 10 / 14, Chinese patent application 2025100888406 with the filing date of 2025 / 01 / 21, Chinese patent application 2025102337770 with the filing date of 2025 / 02 / 28, Chinese patent application 2025105883165 with the filing date of 2025 / 05 / 08, Chinese patent application 2025108806512 with the filing date of 2025 / 06 / 27 and Chinese patent application 2025110218330 with the filing date of 2025 / 07 / 23. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a heterocyclic compound, a preparation method and uses thereof. BACKGROUND

[0003] The KIT ligand is stem cell factor (SCF), which binds to the extracellular domain of KIT to induce receptor dimerization and activate downstream signaling pathways, initiating cell growth and proliferation signal transduction cascades upon SCF binding. SCF ligation of c-kit receptors induces their dimerization, followed by transphosphorylation, resulting in the recruitment and activation of various cytoplasmic substrates. These activated substrates induce various intracellular signaling pathways responsible for cell proliferation and activation. It is well known that these proteins are involved in many cellular mechanisms, and once disrupted, lead to abnormal cell proliferation and migration, and diseases such as inflammation.

[0004] The activity of the c-kit receptor is regulated in normal cells, and the normal functional activity of the c-kit gene product is important for maintaining normal hematopoiesis, melanogenesis, heredity, and the growth and differentiation of mast cells. Inhibition of c-kit kinase activity reduces the growth and differentiation of mast cells, thereby mediating diseases and / or disorders associated with mast cells.

[0005] Currently published patents include WO2015057873A1, WO2016022569A1 and WO2020210293A1, etc. SUMMARY

[0006] The present application provides a compound represented by formula (IG) or a pharmaceutically acceptable salt thereof,

[0007] wherein ring A is a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl;

[0008] T is

[0009] X is O, S or NR 0 ;

[0010] Y is CR 0 or N;

[0011] R 0 is selected from the group consisting of H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0012] R 1 is selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl are optionally substituted with 1 or more R A ;

[0013] R A are the same or different, each independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with 1 or more R g ;

[0014] or, 2 R A together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8cycloalkyl or 3-12 membered heterocyclyl is each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0015] R g are the same or different, each independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of hydroxyl, halogen, oxo, cyano, amino and C 1-6 hydroxyalkyl;

[0016] R 2 is selected from the group consisting of H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0017] each R 3 are the same or different, independently selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0018] each R 4 are the same or different, independently selected from the group consisting of H, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0019] R a and R b are the same or different, each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0020] R 5 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy, said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of -OP(O)(OR k )2, -OS(O)(OR k ) and -OS(O)(OR k )2;

[0021] R k is H or C 1-6 alkyl;

[0022] n is 0, 1, 2, 3 or 4;

[0023] m is 0, 1, 2, 3 or 4;

[0024] p is 1, 2 or 3;

[0025] q is 1, 2 or 3;

[0026] the heteroatoms in said heterocyclyl or heteroaryl are selected from O, N and S, in a number of 1, 2, 3 or 4.

[0027] In some embodiments, certain groups in the compounds or pharmaceutically acceptable salts thereof described herein have the following definitions, and definitions for groups not mentioned are as described in any of the Schemes herein (hereinafter referred to as "in some embodiments").

[0028] In some embodiments,

[0029] R A selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more R g ;

[0030] or, 2 R A together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8 cycloalkyl or 3-12 membered heterocyclyl are each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0031] R g selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more selected from hydroxyl, halogen, oxo, cyano, amino and C 1-6 hydroxyalkyl;

[0032] R 2 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0033] each R 3 is the same or different, independently selected from H, halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0034] In some embodiments, X is O, S, or NH.

[0035] In some embodiments, the compound of Formula (IG) or pharmaceutically acceptable salt thereof, wherein R 1 is the same or different, independently selected from H, halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl, and 5-14 membered heteroaryl, each of which is optionally substituted with one or more R 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl, is optionally substituted with one or more R A ;

[0036] each R 4 is the same or different, independently selected from H, halo, cyano, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, or each of which is optionally substituted with one or more R 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, each independently optionally substituted with one or more R 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; R A , R a , and R b are as defined for Formula (IG).

[0037] In some embodiments, the compound of Formula (IG) or pharmaceutically acceptable salt thereof, wherein the compound of Formula (IG) is a compound of Formula (I),

[0038] R1 H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl optionally substituted with one or more R A ;

[0039] R A halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl optionally substituted with one or more R g ;

[0040] or, 2 R A with the atom to which they are attached form a C 3-8 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8 cycloalkyl or 3-12 membered heterocyclyl are each independently optionally substituted with one or more of halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0041] R g halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl optionally substituted with one or more of hydroxyl, halogen, oxo, cyano, amino and C 1-6 hydroxyalkyl.

[0042] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein,

[0043] Ring A is a 5-membered heteroaryl group;

[0044] R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl and 5-8 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 aryl groups are optionally coated with one or more R groups. A replace;

[0045] R A Selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally surrounded by one or more R groups. g replace;

[0046] Or, 2 Rs A The atoms bonded to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is independently selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 One or more substitutions in cycloalkyl and 3-8 membered heterocyclic groups;

[0047] R g Selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be optionally substituted by one or more groups selected from hydroxyl, halogen, oxo, cyano and amino.

[0048] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof,

[0049] Among them, ring A is Preferred right end and R 4 connect;

[0050] T is

[0051] R 1 Selected from C 1-6 Alkyl, C 2-6 Alkyne group, 5-14 membered heteroaryl group or 3-14 membered heterocyclic group, wherein C 2-6 Alkyne, 3-14 heterocyclic and 5-14 heteroaryl groups are optionally capped by one or more R groups. A replace;

[0052] R A Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally surrounded by one or more R groups. g replace;

[0053] R g Selected from hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may optionally be substituted with one or more selected from hydroxyl groups;

[0054] R 2 Selected from H;

[0055] Each R 3 Same or different, independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Deuterated alkyl groups;

[0056] Each R 4 Same or different, independently selected from C 2-6 alkenyl, C 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl and C 3-8 Each cycloalkyl group may be independently and optionally substituted by one or more substituted groups selected from halogens and hydroxyl groups;

[0057] R 5 is selected from H;

[0058] n is 1 or 2;

[0059] m is 1.

[0060] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions:

[0061] (1) the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl;

[0062] (2) the halo is fluoro, chloro, bromo, or iodo, for example fluoro or chloro;

[0063] (3) the C 3-8 cycloalkyl is C 3-6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example cyclopropyl, cyclobutyl, or cyclohexyl;

[0064] (4) the 3-8 membered heterocyclyl is oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,

[0065] (5) the 5-10 membered heteroaryl, 5-8 membered heteroaryl, or 5 membered heteroaryl is pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0066] In some embodiments, the 3-8 membered heterocyclyl is oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,

[0067] In some embodiments, the 5-10 membered heteroaryl, 5-8 membered heteroaryl, or 5 membered heteroaryl is pyrazolyl (for example ), thiazolyl, oxazolyl, triazolyl (for example ), tetrazolyl,

[0068] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is of Formula (IG) and Formula (I), wherein:

[0069] T is R 1 , R 2 as defined in Formula (IG).

[0070] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein R 2 is halogen, for example, chloro.

[0071] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein R 2 is H.

[0072] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein T is R 1 is as defined for Formula (IG).

[0073] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein T is R 1 is as defined for Formula (IG).

[0074] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein ring A is oxazolyl, triazolyl, or tetrazolyl.

[0075] In some embodiments, is preferably the right end is attached to R 4 .

[0076] In some embodiments, compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein is

[0077] R 4 , R 4A , and R 4B are the same or different, independently selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C

[0078] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein is

[0079] R 4 , R 4A and R 4B are the same or different, independently selected from H, halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C

[0080] In some embodiments, R 4 , R 4A and R 4B are the same or different, independently selected from H, halo, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C

[0081] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein is

[0082] R 4 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with one or more of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl. 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0083] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein 4 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with one or more of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl. 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0084] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein is

[0085] R 4 , R 4A , and R 4B are the same or different, independently selected from H, halogen, cyano, C 1-6 alkyl, and C3-8 cycloalkyl, said C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0086] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0087] R

[0088] R 4 , R 4A and R 4B are the same or different, independently selected from H, halo, cyano, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0089] In some embodiments, the compound of Formula (IG) and Formula (I), or a pharmaceutically acceptable salt thereof, wherein R

[0090] R 4 is selected from H, halo, cyano, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8one or more of the C

[0091] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IG) is a compound of Formula (II) or Formula (III),

[0092] wherein,

[0093] R 4 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0094] R a and R b are the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0095] p is 1, 2 or 3;

[0096] q is 1, 2 or 3;

[0097] R 1 , R 3 and n are as defined in Formula (IG).

[0098] In some embodiments, R 4 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or the C1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0099] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, and 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl is optionally substituted with one or more R A ;

[0100] R A is selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl is optionally substituted with one or more R g ; said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo, cyano, amino, and C 1-6 hydroxyalkyl;

[0101] or, 2 R A together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8 cycloalkyl or 3-12 membered heterocyclyl is each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C

[0102] R g selected from deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, 3-14 membered heterocyclyl, and 5-14 membered heteroaryl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxyl, halogen, oxo, cyano, amino, and C 1-6 hydroxyalkyl.

[0103] In some embodiments, compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, and 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl is optionally substituted with 1 or more R A ;

[0104] R A selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl is optionally substituted with 1 or more R g ;

[0105] or, 2 R A together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8 cycloalkyl or 3-12 membered heterocyclyl is each independently optionally substituted with 1 or more selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 3-8 one or more of the following: halo, hydroxyl, cyano, amino, oxo, C

[0106] R g selected from deuterium, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more of the following: hydroxyl, halo, oxo, cyano, amino, and C 1-6 hydroxyalkyl.

[0107] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered heterocyclyl, and 5-8 membered heteroaryl, said C 1-6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, 3-8 membered heterocyclyl, or 5-8 membered heteroaryl is optionally substituted with 1 or more R A ;

[0108] R A selected from deuterium, halo, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl is optionally substituted with 1 or more R g ;

[0109] or, 2 R A together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more of the following: halo, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-8One or more substitutions in cycloalkyl and 3-8 membered heterocyclic groups;

[0110] R g Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be optionally substituted by one or more groups selected from hydroxyl, halogen, oxo, cyano and amino.

[0111] In some embodiments, the compounds represented by formulas (IG), (I), (II), and (III), or pharmaceutically acceptable salts thereof, wherein R 1 Selected from H, halogens, C 1-6 Alkyl, 3-8 membered heterocyclic and 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, optionally bound by one or more R A replace.

[0112] In some implementations... for R 3 Whether the two are the same or different, each is defined independently as in any embodiment of the present invention.

[0113] In some embodiments, the compounds represented by formulas (IG), (I), (II), and (III), or pharmaceutically acceptable salts thereof, wherein for R 3 R 3A Or R 3B Whether the groups are the same or different, they are each independently selected from halogens, cyano groups, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups (e.g., halogen, cyano or C) 1-6 alkyl).

[0114] In some embodiments, the compounds represented by formulas (IG), (I), (II), and (III), or pharmaceutically acceptable salts thereof, wherein R 1 for

[0115] R A1 R A2 and R A3 Whether the elements are the same or different, they are each independently selected from H, deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl is optionally substituted with one or more R g ;

[0116] R g is selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of hydroxyl, halogen, cyano and C 1-6 hydroxyalkyl;

[0117] or, any one of R A1 and R A2 , R A1 and R A3 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0118] In some embodiments, any one of R A1 and R A2 , R A1 and R A3 form, together with the atom to which they are attached, a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0119] In some embodiments, R A2 and R A3 are the same or different, each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl and C 3-8 cycloalkyl.

[0120] In some embodiments, R A1 is selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more R g ; R g is selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxy, halo, cyano, and C 1-6 hydroxyalkyl.

[0121] In some embodiments, R 1 is R A2 and R A3 are the same or different, each being independently selected from H, C 1-6 alkyl (e.g., methyl), or C 1-6 deuteroalkyl (e.g., CD3).

[0122] In some embodiments, R 1 is R A1 is selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more R g ; R g is selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxy, halo, cyano, and C 1-6 hydroxyalkyl.

[0123] In some embodiments, R 1 is R A1 and R A2 form, with the atom to which they are attached, a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8one or more substituents on the cycloalkyl and 3-8 membered heterocyclyl groups.

[0124] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is H, Cl, Br, methyl,

[0125] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is

[0126] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halogen, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl.

[0127] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl.

[0128] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halogen, cyano, or C 1-6 alkyl.

[0129] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halogen, or C 1-6 alkyl.

[0130] In some embodiments, the compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is chloro or fluoro.

[0131] In some embodiments, a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl; preferably, R 3 is methyl.

[0132] In some embodiments, a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is cyano.

[0133] In some embodiments, R 3 is fluoro, chloro, methyl, deuterated methyl (e.g., CD3), halogenated methyl (e.g., -CHF2), or cyano.

[0134] In some embodiments, a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-8 cycloalkyl are each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0135] R a and R b are the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0136] p is 1 or 2;

[0137] q is 1 or 2.

[0138] In some embodiments, a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R4 H, halogen, cyano, oxo,

[0139] In some embodiments, R 4 C 1-6 alkyl or C 3-8 cycloalkyl (e.g., cyclopropyl or cyclobutyl), said C 1-6 alkyl and C 3- 8cycloalkyl are each independently optionally substituted with one or more selected from the group consisting of halogen and hydroxyl.

[0140] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 4 is

[0141] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 4 is

[0142] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 is H or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of -OP(O)(OH)2, -OS(O)(OH), and -OS(O)(OH)2.

[0143] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 is C 1-3 alkylene-OP(O)(OH)2.

[0144] In some embodiments, the compounds of Formula (IG), Formula (I), Formula (II), and Formula (III), or pharmaceutically acceptable salts thereof, wherein n is 1 or 2; preferably, n is 2.

[0145] In some embodiments, the compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein m is 1 or 2; preferably, m is 1.

[0146] In some embodiments, the compounds of Formula (IG) and Formula (I), or pharmaceutically acceptable salts thereof, wherein R 5 is H.

[0147] In some embodiments, exemplary specific compounds of formulas (IG) and (I) include, but are not limited to, the structures in Table A below:

[0148] Table A

[0149] In some embodiments, exemplary specific compounds of the compounds shown in formula (IG) include, but are not limited to, the structures in Table B below:

[0150] Table B

[0151] Another aspect of this application provides isotope labels for compounds shown in formulas (IG), (I), (II), and (III), or those shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0152] Another aspect of this application provides a method for preparing the compound shown in formula (I), wherein the compound shown in formula (A) undergoes a condensation reaction with the compound shown in formula (B) to obtain the compound shown in formula (I).

[0153] Among them, R 7 For H or C 1-6 alkyl;

[0154] T, R 3 R 4 m and n are as defined in any of the claims in this application.

[0155] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0156] In another aspect, the present application provides the use of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting c-kit.

[0157] In another aspect, the present application provides the use of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease or disorder.

[0158] In another aspect, the present application provides the use of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease or disorder.

[0159] In another aspect, the present application provides a method of inhibiting c-kit, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same.

[0160] In another aspect, the present application provides a method of preventing and / or treating a c-kit-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same.

[0161] In another aspect, the present application provides a method of preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0162] The application also provides a method of preventing and / or treating mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0163] The application also provides a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament.

[0164] The application also provides a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a c-kit inhibitor.

[0165] The application also provides a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a c-kit mediated disease or disorder.

[0166] The application also provides a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a mast cell related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer.

[0167] The application also provides a compound of Formula (IG), Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0168] In some embodiments, the c-kit mediated disease is selected from a mast cell related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer.

[0169] In some embodiments, the c-kit mediated disease is selected from a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0170] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0171] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof. In certain embodiments, the pharmaceutical composition contains 1-99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof.

[0172] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1-99% of one or more pharmaceutically acceptable excipients.

[0173] As pharmaceuticals, the compounds of the present application can be given as pharmaceutical compositions. These compositions can be prepared in a manner well known per se in the pharmaceutical art, and administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the area to be treated. They can be administered topically (e.g., transdermal, transcutaneous, opthalmic, and mucosal including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal, oral or parenteral. Parenteral administration includes subcutaneous, intracutaneous, intramuscular, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration. They can be administered parenterally, e.g., by continuous intravenous infusion.

[0174] In making the compositions of the application, the active ingredient is typically mixed with an excipient, which can take a wide variety of forms depending on the form of preparation desired for unit dosages. Suitable excipients include binders, fillers, absorbents, wetting agents, disintegrating agents, and lubricating agents. The compositions can take the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, solutions, syrups, aerosols (either solid or in liquid vehicles), ointments containing, e.g., up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0175] As used herein, "excipient" refers to an ingredient other than the active ingredient(s) in a pharmaceutical composition, including diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0176] In another aspect, pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have a basic center, base addition salts if the compounds have an acidic center, and internal salts if the compounds contain both an acidic center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0177] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including cis, trans, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, rac mixtures and other mixtures thereof, as falling within the scope of the application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0178] The term "multiple" as used above to indicate the number of substituents or heteroatoms can mean 2, 3, 4, or 5.

[0179] In the chemical structures of the compounds described herein, a bond may represent an unspecified configuration, represents the absolute configuration, i.e., if chiral isomers are present in the chemical structure, a bond may be or both configurations. may be present.

[0180] a bond represents an unspecified configuration, including the cis (E) or trans (Z) configuration.

[0181] In addition, the compounds and intermediates of the present application can exist in different tautomeric forms, and all such forms are embraced within the scope of the present application. "Tautomers" are different energy structures that can interconvert through a low energy barrier. For example, prototropic tautomers (also known as proton shift tautomers) include interconversions through the migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds of the present application are within the scope of the present application. The name of a compound named in a single form does not exclude any tautomers.

[0182] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like. All isotopically-labeled compounds of this application are within the scope of the application. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0183] Unless otherwise stated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are capable of synthesizing compounds in deuterated form by reference to the literature. In making the deuterated forms of the compounds, the commercially available deuterated starting materials can be used, or they can be synthesized using conventional techniques employing deuterated reagents including, but not limited to, deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, and the like.

[0184] A "therapeutically effective amount" of the present application refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by person of skill in the art, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed to the disease, disorder and condition but has not yet experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., retarding the further development of the pathology and / or symptomatology); (3) relieving the disease: for example, relieving a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., reversing the pathology and / or symptomatology). For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the agent to provide the desired effect, without being toxic to the subject. The effective amount will vary depending on the subject's age, general condition and the particular active agent, and appropriate effective amounts can be determined by one of skill in the art using routine trials.

[0185] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, that these compounds, materials, compositions, and / or dosage forms are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0186] "Patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, goats, horses, or primates, most preferably humans.

[0187] Definitions and explanations

[0188] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0189] In the present application means that the corresponding group is attached to the to other fragments, groups in the compounds.

[0190] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing from 1 to 20 carbon atoms, more preferably alkyl groups containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably alkyl groups containing from 1 to 6 carbon atoms (C1-C6alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 3-methyl-hexyl, and the like. The term "alkenyl" refers to unsaturated aliphatic hydrocarbon groups similar to alkyl groups, but containing at least one double bond. Examples of alkenyl groups include straight and branched chains of 2 to 20 carbon atoms (C2-C20alkenyl), preferably 2 to 12 carbon atoms (C2-C12alkenyl), and more preferably 2 to 6 carbon atoms (C2-C6alkenyl), containing at least one double bond. Examples of alkenyl groups include ethylene, propylene, butadiene, and the like. The term "alkynyl" refers to unsaturated aliphatic hydrocarbon groups similar to alkyl groups, but containing at least one triple bond. Examples of alkynyl groups include straight and branched chains of 2 to 20 carbon atoms (C2-C20alkynyl), preferably 2 to 12 carbon atoms (C2-C12alkynyl), and more preferably 2 to 6 carbon atoms (C2-C6alkynyl), containing at least one triple bond. Examples of alkynyl groups include acetylene, propyne, butyne, and the like. 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted.

[0191] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C1-C12alkoxy). More preferred are alkoxyl groups containing 1 to 6 carbon atoms (C1-C6alkoxy). Most preferred are alkoxyl groups containing 1 to 3 carbon atoms (C1-C3alkoxy). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted. 1-12 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C1-C12alkoxy). More preferred are alkoxyl groups containing 1 to 6 carbon atoms (C1-C6alkoxy). Most preferred are alkoxyl groups containing 1 to 3 carbon atoms (C1-C3alkoxy). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted. 1-6 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C1-C12alkoxy). More preferred are alkoxyl groups containing 1 to 6 carbon atoms (C1-C6alkoxy). Most preferred are alkoxyl groups containing 1 to 3 carbon atoms (C1-C3alkoxy). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted.

[0192] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents (preferably protecting monocyclic hydrocarbon substituents), the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like (e.g., cyclopropyl, e.g., cyclobutyl); polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0193] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each single ring is shared by one carbon atom (termed a spiro atom) in the system, which can contain one or more double bonds. Preferred are 6- to 14-membered, more preferred are 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, depending on the number of spiro atoms shared between rings. More preferred are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0194] The term "fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic fused ring alkyl, preferably bi- or tri-cyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bi-cyclic alkyl. Non-limiting examples of fused ring alkyl include:

[0195] The term "bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic bridged ring alkyl, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of bridged ring alkyl include:

[0196] The cycloalkyl ring includes cycloalkyl (including monocyclic, spirocyclic, fused, and bridged) fused to an aryl, heteroaryl, or heterocyclyl ring as described herein, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include etc.; preferably The cycloalkyl can be substituted or unsubstituted.

[0197] The term "heterocyclyl" refers to a saturated or partially unsaturated (partially unsaturated means containing one or more carbon-carbon double bonds, but not having aromaticity) monocyclic or polycyclic ring-containing substituent (preferably a 4-6 membered saturated or partially unsaturated monocyclic heterocycloalkyl, 7-9 membered saturated or partially unsaturated spirocyclic heterocycloalkyl, 6-9 membered saturated or partially unsaturated bridged heterocycloalkyl, 6-9 membered saturated or partially unsaturated fused heterocycloalkyl), containing from 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms (which can be the same or different) selected from nitrogen, oxygen, and sulfur (which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but not including ring portions of -0-0-, -0-S-, or -S-S-), with the remainder of the ring atoms being carbon. Preferably, there are from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which from 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (independently selected from one or more of N, O, and S); more preferably, there are from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which from 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are from 3 to 6 ring atoms, of which from 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which from 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups.

[0198] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each single ring is connected to the others by a common atom (referred to as a spiro atom), of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), with the remainder of the ring atoms being carbon. It can contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bispiroheterocyclyl groups, depending on the number of rings connected by a common spiro atom. More preferably, it is a 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6- membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0199] The term "fused heterocyclyl" refers to a 5- to 20-membered, polycyclic heterocyclic radical in which each ring in the system shares a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). It can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

[0200] The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic radical in which any two rings share two non-adjacent atoms, which can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). It can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0201] The heterocyclyl ring includes heterocyclyl (including monocyclic, spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl) as described herein fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is heterocyclyl, non-limiting examples of which include:

[0202] and the like. The heterocyclyl can be substituted or unsubstituted.

[0203] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares a pair of adjacent carbon atoms with another ring) ring system having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings as described herein fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include: The aryl can be substituted or unsubstituted.

[0204] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 membered or 6 membered, e.g., furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described herein, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include: Heteroaryl can be substituted or unsubstituted.

[0205] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, it can be substituted at any available attachment point with one or more of the same or different substituents, preferably independently optionally selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0206] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl include residues derived from removal of one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heterocyclene", "heteroarylene".

[0207] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0208] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0209] The term "haloalkyl" refers to alkyl substituted with one or more halogens, wherein alkyl is as defined herein.

[0210] The term "deuteroalkyl" refers to alkyl substituted with one or more deuterium, wherein alkyl is as defined herein.

[0211] The term "haloalkoxy" refers to alkoxy substituted with one or more halogens, wherein alkoxy is as defined herein.

[0212] The term "hydroxyalkyl" refers to alkyl substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0213] The term "halogen" refers to F, Cl, Br, or I.

[0214] The term "hydroxy" means -OH.

[0215] The term "amino" means -NH2.

[0216] The term "cyano" means -CN.

[0217] The term "nitro" means -NO2.

[0218] The term "oxo" or "keto" means "=O".

[0219] The term "carbonyl" means C=O.

[0220] The term "carboxyl" means -C(O)OH.

[0221] The term "carboxylate" means -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0222] The term "alkenyl" means a straight or branched chain hydrocarbon group (preferably C2-C6) containing one or more carbon-carbon double bonds, including ethenyl (vinyl), The term "alkynyl" means a straight or branched chain hydrocarbon group (preferably C2-C6) containing one or more carbon-carbon triple bonds, including ethynyl,

[0223] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "an optionally alkyl substituted heterocyclic group" means that an alkyl group can or can not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0224] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced by a corresponding number of substituents. It is self-evident that substituents are only present in chemical positions in which they are possible and can be determined (experimentally or theoretically) by a person skilled in the art without undue effort. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond. It is noted that the way of description "selected from", "are" "are respectively / each independently" "are independently" as employed in the present application is to be interpreted broadly, i.e. when a substituent is plural, each individual described is independent of the other(s), i.e. can be the same or a different specific group. In more detail, the way of description "are independently" can mean that the specific options expressed by the same symbols in different groups are independent of each other; or that the specific options expressed by the same symbols in the same group are independent of each other.

[0225] The above-mentioned preferred conditions can be combined in any manner without departing from the common general knowledge of the skilled person, i.e. to obtain preferred embodiments of the application.

[0226] The reagents and starting materials used in the present application are commercially available. Advantages:

[0227] The present application provides a small molecule compound with a heterocyclic structure, which can be used as a c-kit inhibitor. The compound or pharmaceutical composition has a strong inhibitory effect on the c-kit receptor and excellent pharmacokinetic effects, and can be used for the effective treatment or prevention of c-kit-mediated diseases. DETAILED DESCRIPTION

[0228] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application. The experimental methods not specified in the following examples are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0229] The experimental methods not specified in the following examples are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0230] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is expressed in ppm, using tetramethylsilane as the internal standard. The chemical shifts of the protons (1H) are expressed in ppm, using the signal of the solvent as the internal standard. The chemical shifts of the carbons (13C) are expressed in ppm, using the signal of the solvent as the internal standard. -6ppm) are given. NMR measurements were made on a Bruker Avance III 400 MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0231] Mass spectrometry (MS) was measured by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0232] Chiral HPLC analysis was measured using Shimadzu LC-20AD.

[0233] Thin layer chromatography silica gel plates were used from Cheng Chemical (Shanghai) Co., Ltd. GF254 silica gel plates. The specifications of the silica gel plates used in thin layer chromatography (TLC) were 0.2-0.25 mm, and the specifications of the silica gel plates used in thin layer chromatography separation and purification of products were 0.4-0.5 mm.

[0234] Column chromatography generally used 100-200 mesh silica gel from Cheng Chemical (Shanghai) Co., Ltd. as the carrier.

[0235] High performance liquid chromatography preparation used Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatographs.

[0236] Chiral separation column chromatography used Gilson GX-281 preparative HPLC.

[0237] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere.

[0238] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of about 1 liter.

[0239] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of about 1 liter.

[0240] Unless otherwise specified in the examples, the reaction temperature was room temperature, and the temperature range was 20-30°C.

[0241] The skilled person in the art should understand that the suffixes P1, P2, etc. are used in the names of the compounds to represent chiral compounds, and the suffix P1 represents one of the chiral structures, and the suffix P2 corresponds to the other chiral structure. When the isomer compounds / intermediates are obtained by using a chromatographic column for separation, the separated chiral compounds can be distinguished by the retention time in the chiral chromatographic column, therefore, the chiral compounds separated according to the retention time are also distinguished by the numbered suffixes P1, P2, etc. That is, the suffix P1 represents one of the chiral structures, and the suffix P2 corresponds to one of the chiral structures. If the absolute configuration of the compound is listed in the structural formula, the numbered suffixes P1, P2 (P1 or P2) indicate the two forms of the absolute configuration. The absolute configuration of the compound with the numbered suffixes P1, P2 is the absolute configuration corresponding to the specific retention time.

[0242] Reagent English abbreviation corresponding to reagent name:

[0243] Example 1 (Compound 1)

[0244] Step 1: Synthesis of compound 1c

[0245] Compound 1a (100 mg, 0.36 mmol, synthesis method refer to WO2022136509A1 specification page 183 synthesis of compound intermediate A), compound 1b (0.20 g, 0.72 mmol, synthesis method refer to WO2016000615A1 specification page 224 synthesis of compound Example 53 step 1 and step 2), Cs2CO3 (0.23 g, 0.72 mmol) and Pd(dppf)Cl2 (0.026 g, 0.036 mmol) were added to a mixture of 1,4-dioxane and water (1 mL / 0.2 mL) under nitrogen protection at room temperature. The reaction mixture was stirred at 90°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 ml x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 1c (90 mg). MS m / z (ESI): 349.1 [M+1] + .

[0246] Step 2: Synthesis of compound 1

[0247] A solution of trimethylaluminum in n-hexane (2 M, 0.29 mL, 0.058 mmol) was added dropwise to a solution of compound 1c (10 mg, 0.029 mmol) and compound 1d (8.09 mg, 0.032 mmol, synthesis method refer to WO2024118887A1 specification page 170 synthesis of compound intermediate 73) in toluene (0.5 mL) under ice bath. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction was cooled to room temperature, quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by thin layer chromatography on silica gel plate (ethyl acetate) to give compound 1 (12 mg). MS m / z (ESI): 556.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 4.74 (s, 1H), 4.54 - 4.48 (m, 1H), 3.97 (s, 2H), 2.36 (s, 3H), 1.45 - 1.38 (m, 2H), 1.34 - 1.26 (m, 2H), 1.09 (s, 6H).

[0248] Example 2 (compound 53)

[0249] First step: synthesis of compound 53a

[0250] A solution of trimethylaluminum in n-hexane (0.38 mL, 1 M) was added to a solution of compound 1a (51 mg, 0.19 mmol) and compound 1d (54 mg, 0.19 mmol) in toluene (2 mL). The reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction was concentrated under reduced pressure, the residue was quenched with saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (EA / PE = 0-30%) to give compound 53a (65 mg). MS m / z (ESI): 482.1 [M+1] + .

[0251] Second step: synthesis of compound 53c

[0252] Compound 53b (200 mg, 0.90 mmol) was dissolved in DMF (5 mL) under nitrogen protection, Cs2CO3 (586 mg, 1.80 mmol) and methyl epoxide (162 mg, 2.25 mmol) were added, and the reaction mixture was stirred at 90 °C for 3 h. After the reaction was completed, the reaction liquid was quenched with water (20 mL), extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain compound 53c (460 mg). MS m / z (ESI): 295.4 [M+1] + .

[0253] Step 3: Synthesis of compound 53

[0254] Compound 53a (18 mg, 0.06 mmol) was dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL) under nitrogen protection, Pd(dppf)Cl2 (15 mg, 0.02 mmol), Cs2CO3 (26 mg, 0.08 mmol) and compound 53c (20 mg, 0.04 mmol) were added, and the reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-2%) to obtain crude compound 53 (25 mg). The crude product was purified by high performance liquid preparative chromatography (column: sunfire-C18 19x250 mm, 10 nm; mobile phase: acetonitrile-water (0.1% FA); gradient: 50-55%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 53 (7.59 mg). MS m / z (ESI): 570.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.57 (s, 1H), 8.36-8.25 (m, 2H), 7.89-7.81 (m, 1H), 4.67 (s, 1H), 4.57-4.45 (m, 1H), 3.94 (s, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.45-1.33 (m, 2H), 1.33-1.24 (m, 2H), 1.14 (s, 6H).

[0255] Example 3 (compound 54)

[0256] Step 1: Synthesis of compound 54b

[0257] Compound 54a (400 mg, 3.70 mmol) was dissolved in DMF (10 mL) under nitrogen protection, and Cs2CO3 (2.41 g, 7.40 mmol) and methyl epoxide (667 mg, 9.25 mmol) were added. The reaction mixture was stirred at 90 °C for 3 h. After the reaction was completed, the reaction liquid was quenched with water (30 mL), extracted with EA (15 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-11%) to obtain compound 54b (540 mg). MS m / z (ESI): 181.3 [M+1] + .

[0258] Second step: synthesis of compound 54c

[0259] Compound 54b (440 mg, 2.44 mmol) was dissolved in DCM (10 mL) under nitrogen protection, and dibromohydantoin (349 mg, 1.22 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction liquid was quenched with water (20 mL), extracted with DCM (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain compound 54c (460 mg). MS m / z (ESI): 259.2, 261.2 [M+1, M+3] + .

[0260] Third step: synthesis of compound 54d

[0261] Compound 54c (460 mg, 1.78 mmol) was dissolved in 1,4-dioxane (3 mL) under nitrogen protection, and AcOK (524 mg, 5.34 mmol), Pd(PPh3)2Cl2 (253 mg, 0.36 mmol) and pinacol diboronic acid (904 mg, 3.56 mmol) were added in turn. The reaction mixture was heated to 100 °C and stirred for 12 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EA / PE = 0-9%) to obtain compound 54d (370 mg). MS m / z (ESI): 307.4 [M+1] + .

[0262] Fourth step: synthesis of compound 54

[0263] Compound 54d (19 mg, 0.06 mmol) was dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL) under nitrogen protection, Pd(dppf)Cl2(15 mg, 0.02 mmol), Cs2CO3(26 mg, 0.08 mmol) and compound 53a (20 mg, 0.04 mmol) were added, and the reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-2%) to obtain a crude compound 53 (45 mg). The crude product was purified by high performance liquid preparative chromatography (column: sunfire-C18 19x250 mm, 10 nm; mobile phase: acetonitrile-water (0.1% FA); gradient: 45-55%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 54 (4.53 mg). MS m / z (ESI): 582.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.85 (d, J = 10.0 Hz, 1H), 4.70 (s, 1H), 4.55 - 4.46 (m, 1H), 3.94 (s, 2H), 2.07 - 2.00 (m, 1H), 1.46 - 1.38 (m, 2H), 1.35 - 1.27 (m, 2H), 1.07 (s, 6H), 0.97 - 0.91 (m, 2H), 0.81 - 0.76 (m, 2H).

[0264] Example 4 (Compound 6)

[0265] First Step: Synthesis of compound 6c

[0266] Compound 6a (1 g, 6.21 mmol), compound 6b (0.66 g, 7.45 mmol) and Cs2CO3(4.05 g, 12.42 mmol) were dissolved in DMF (15 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 6c (1.2 g). MS m / z (ESI): 249.0 [M+1] + . 1H NMR (400 MHz, CDC13) δ 7.44 (s, 1H), 4.24 - 4.10 (m, 3H), 3.39 (s, 3H), 3.37 - 3.27 (m, 2H), 2.30 (s, 3H).

[0267] Second Step: Synthesis of compound 6d

[0268] Compound 6c (200 mg, 0.8 mmol), bis-pinacol diboron (304.73 mg, 1.2 mmol), Pd(dppf)Cl2(33 mg, 0.04 mmol) and potassium acetate (235.54 mg, 2.40 mmol) were added to 1,4-Dioxane (10 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-40%) to obtain compound 6d (70 mg). MS m / z (ESI): 297.1 [M+1] + .

[0269] Third Step: Synthesis of compound 6e

[0270] Compound 6d (54 mg, 0.18 mmol), compound 1a (25 mg, 0.091 mmol), potassium carbonate (38 mg, 0.27 mmol) and Pd(dppf)Cl2(7.4 mg, 0.0091 mmol) were added to a DMF (2 mL) solution at room temperature, and the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was added to water (10 mL), extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to obtain compound 6e (20 mg). MS m / z (ESI): 365.0 [M+1] + .

[0271] Fourth Step: Synthesis of compound 6

[0272] Compound 6e (20 mg, 0.055 mmol) and compound Id (17 mg, 0.066 mmol) were added to toluene (1 mL) at room temperature, after addition was completed, nitrogen was replaced for three times, n- hexane solution of trimethylaluminum (0.055 mL, 0.11 mmol, 2M) was added dropwise at 0 °C under nitrogen atmosphere, after dropwise addition was completed, the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, sodium sulfate decahydrate (2 g) was added for quenching, the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to obtain compound 6 (4.3 mg). MS m / z (ESI): 571.8 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 1H), 8.44 (d, J = 17.1 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 5.17 (t, J = 5.0 Hz, 1H), 4.51 (tt, J = 7.5, 3.8 Hz, 1H), 4.18 - 4.07 (m, 1H), 4.02 - 3.92 (m, 2H), 3.30-3.29 (m, 2H), 2.36 (s, 3H), 1.46 - 1.39 (m, 2H), 1.33 - 1.28 (m, 2H).

[0273] Example 5 (compound 62-P1)

[0274] First step: synthesis of compound 62b

[0275] DIPEA (1.14 g, 8.79 mmol) and hydroxylamine hydrochloride (0.49 g, 7.03 mmol) were added to a solution of compound 62a in EtOH (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was added with H2O (150 mL), and a white solid was precipitated, the mixture was filtered, and the filter cake was dried to obtain compound 62b (775 mg). MS m / z (ESI): 203.9 [M+1] + .

[0276] Second step: synthesis of compound 62d

[0277] CDI (1.09 g, 6.72 mmol) was added to a solution of compound 62c (0.64 g, 6.16 mmol) in NMP (10 mL) at 0 °C, the reaction compound was stirred at room temperature for 5 min, then compound 62b (1.14 g, 5.60 mmol) was added, the reaction mixture was stirred at room temperature for 30 min, then heated to 120 °C and stirred for 3 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), washed successively with water (30 mL x 3) and saturated sodium chloride solution (30 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 ~ 3:1) to obtain compound 62d (1.32 g). MS m / z (ESI): 271.9 [M+1] + .

[0278] Step 3: Synthesis of compound 62-P1

[0279] Compound 1c (15 mg, 0.045 mmol) and compound 62d (12.56 mg, 0.050 mmol) were added to toluene (0.5 mL). Under a nitrogen atmosphere, n-hexane solution of trimethylaluminum (0.045 mL, 2M) was slowly added at 0 °C. The reaction mixture was stirred at 100 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding saturated ammonium chloride solution (5 mL), and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 62-P1 (8 mg). MS m / z (ESI): 574.0 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 9.08 (d, J = 7.0 Hz, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.29 (d, J = 9.4 Hz, 1H), 5.12-4.93 (m, 1H), 4.00 (s, 2H), 2.75-2.63 (m, 1H), 2.39 (s, 3H), 1.85-1.76 (m, 1H), 1.63-1.55 (m, 1H), 1.16 (s, 6H).

[0280] Example 6 (compound 55)

[0281] Step 1: Synthesis of compound 55b

[0282] Compound 55a (2 g, 9.19 mmol) was dissolved in tetrahydrofuran (20 mL), and then tribromopyrimidine (4.41 g, 13.79 mmol) was added at room temperature. The reaction mixture was stirred at 25 °C for 12 h. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:0 to 5:1) to obtain compound 55b (2.2 g). MS m / z (ESI): 295.9, 297.9 [M+1, M+3] + .

[0283] Second Step: Synthesis of compound 55d

[0284] Compound 55b (2.93 g, 9.94 mmol) was dissolved in ethanol (50 mL), and then 55c (1.40 g, 9.94 mmol) was added. The reaction mixture was heated to reflux at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 0-10%) to obtain compound 55d (600 mg). MS m / z (ESI): 339.2 [M+H] + .

[0285] Third Step: Synthesis of compound 55e

[0286] Compound 55d (600 mg, 1.78 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (50 mL / 5 mL), and then iron powder (991 mg, 17.75 mmol) and ammonium chloride (4.75 g, 88.76 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80 °C under nitrogen protection for 8 h. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with methanol three times. The combined filtrate was concentrated under reduced pressure, and the residue was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 0-50%) to obtain compound 55e (260 mg). MS m / z (ESI): 309.2 [M+H] + .

[0287] Fourth Step: Synthesis of compound 55

[0288] Compound 55e (16 mg, 0.05 mmol) was dissolved in toluene (1 mL), 1M trimethylaluminum n-hexane solution (0.25 mL, 0.25 mmol) was added to the reaction mixture under nitrogen protection, the reaction mixture was heated at 100°C for 1 hour, after the reaction was completed, a small amount of methanol was added to quench the reaction, methanol and toluene were removed by reduced pressure concentration, the residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain crude compound 55. The crude product was purified by high performance liquid chromatography (chromatography column: Reverse phase chromatography: Spherical C18 20-45um, 100A. Mobile phase: acetonitrile-water (10mM NH4HCO3); Gradient: 0-70%; Column temperature: 25°C; Flow rate: 15 mL / min; Wavelength: 214nm, 254nm; Column pressure: 80bar) to obtain compound 55 (8.66 mg). MS m / z (ESI): 611.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.54 (s, 1H), 8.44 (d, J = 12.2 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.67 (d, J = 10.6 Hz, 1H), 4.69 (s, 1H), 4.03 - 3.97 (m, 2H), 2.53 (s, 1H), 2.36 (s, 3H), 1.27 - 1.04 (m, 10H).

[0289] Example 7 (Compound 57)

[0290] First Step: Synthesis of compound 57b

[0291] Compound 57a (300 mg, 1.40 mmol) was dissolved in DMF (10 mL) under nitrogen protection, Cs2CO3 (912 mg, 2.80 mmol) and methyl epoxide (252 mg, 3.50 mmol) were added, and the reaction mixture was stirred at 90°C for 3 hours. After the reaction was completed, the reaction was quenched with water (30 mL), extracted with EA (15 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-1%) to obtain compound 57b (320 mg). MS m / z (ESI): 287.2, 289.2 [M+1, M+3] + .

[0292] Step 2: Synthesis of compound 57c

[0293] Compound 57b (260 mg, 0.91 mmol) and bis-pinacolborane (231.1 mg, 0.91 mmol) were dissolved in 1,4-dioxane (15 mL), and potassium acetate (265 mg, 2.7 mmol), Pd(PPh3)2Cl2(63.2 mg, 0.09 mmol) were added. The reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated brine (150 mL x 3), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-20%) to give compound 57c (290 mg) as a crude product. MS m / z (ESI): 335.4 [M+1] + .

[0294] Step 3: Synthesis of compound 57

[0295] Compound 57c (82.8 mg, 0.24 mmol), Cs2CO3(60 mg, 0.18 mmol), and Pd(dppf)Cl2(7.3 mg, 0.10 mmol) were added to a mixture of compound 53a (30 mg, 0.06 mmol) in 1,4-dioxane and water (5 mL / 1 mL), and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 0-5%) to give compound 57 (10 mg) as a crude product. The crude product was purified by high performance liquid chromatography (preparative column: UniHybrid 10-120 C18 21.2 x 250 mm; mobile phase: acetonitrile-water (10 mM ammonium bicarbonate); gradient: 45-75%, column temperature: 25 °C; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 57 (1.59 mg). MS m / z (ESI): 610.4 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 6.30 - 6.05 (m, 1H), 4.91 (d, J = 6.7 Hz, 1H), 4.63 - 4.39 (m, 1H), 4.52 - 4.50 (m, 1H), 4.16 (s, 2H), 1.43-1.41 (m, 2H), 1.32 - 1.26 (m, 1H), 1.13 (s, 6H).

[0296] Example 8 (Compound 58)

[0297] First Step: Synthesis of compound 58b

[0298] Under nitrogen atmosphere, n-hexane solution of trimethylaluminum (0.12 mL, 1M) was added dropwise to a solution of compound 58a (20 mg, 0.07 mmol, synthesis method refer to WO202411887A1 page 121, synthesis of intermediate 8, step 1 and step 2) and compound 1a (18 mg, 0.07 mmol) in anhydrous toluene (2 mL), the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous solution of ammonium chloride (40 mL), extracted with DCM (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (EA / PE = 0-20%) to give compound 58b (20 mg). MS m / z (ESI): 532.2 [M+1] + .

[0299] Second Step: Synthesis of compound 58

[0300] Compound 58b (20 mg, 0.04 mmol) and compound lb (15.6 mg, 0.06 mmol) were dissolved in 1,4-dioxane and H2O (4 mL / 1 mL), then Cs2CO3 (36.8 mg, 0.12 mmol) and Pd(PPh3)2Cl2 (2.8 mg, 0.004 mmol) were added successively, and the reaction mixture was stirred at 100 °C for 16 h. After the reaction was completed, the reaction solution was added with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain a crude product (10 mg). The crude product was purified by high performance liquid preparative chromatography (column: Durashell C18(A); 21.2 x 250 mm, 10 nm; mobile phase: acetonitrile-water (10 mM ammonium bicarbonate); gradient: 45-60%; column temperature: 25 °C; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 58 (0.85 mg). MS m / z (ESI): 606.5 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 7.0 Hz, 1H), 8.17-8.07 (m, 1H), 7.97 (s, 1H), 7.83-7.75 (m, 1H), 7.64 (d, J = 32.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.47-5.31 (m, 1H), 4.05 (d, J = 4.0 Hz, 2H), 3.58-3.27 (m, 4H), 2.46 (d, J = 4.0 Hz, 3H), 1.24 (s, 6H).

[0301] Example 9 (Compound 61)

[0302] Trimethylaluminum toluene solution (0.11 mL, 2M) was added to a solution of compound 61a (30 mg, 0.11 mmol, synthesis method refer to WO2013033070 A1 page 96 synthesis of compound 37) and compound 1c (38 mg, 0.11 mmol) in toluene (3 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain compound 61 (4.87 mg). MS m / z (ESI): 568.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.74 (s, 1H), 3.97 (s, 2H), 3.88 (dd, J = 9.4, 7.5 Hz, 1H), 3.29 - 2.98 (m, 4H), 2.36 (s, 3H), 2.35 (s, 3H), 1.10 (s, 6H).

[0303] Example 10 (Compound 63)

[0304] First Step: Synthesis of compound 63b

[0305] N,N'-carbonyldiimidazole (95 mg, 0.59 mmol) was added to a solution of compound 63a (73 mg, 0.54 mmol) in N-methylpyrrolidone (2 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 5 min. Compound 62b (100 mg, 0.49 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 120 °C for 60 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 0-50%) to give compound 63b (20 mg). MS m / z (ESI): 303.9 [M+1] + .

[0306] Second Step: Synthesis of compound 63

[0307] Trimethylaluminum in toluene (0.03 mL, 2M) was added to a solution of compound 1c (11 mg, 0.033 mmol) and compound 63b (10 mg, 0.033 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 4 h. After the reaction was completed, sodium sulfate decahydrate was added to quench the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-7%) to give compound 63 (1.69 mg). MS m / z (ESI): 605.9 [M+1] + .

[0308] Example 11 (Compound 64)

[0309] First Step: Synthesis of compound 64c

[0310] Compound 64b (7.5 g, 69.4 mmol) and cesium carbonate (33.9 g, 104.1 mmol) were added to a solution of compound 64a (5.1 g, 34.7 mmol) in DMF (42 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was quenched by adding water (45 mL) to the reaction mixture, and the mixture was extracted with ethyl acetate (55 mL x 3). The combined organic phase was washed with water (55 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 64c (5.6 g). MS m / z (ESI): 218.9, 220.9 [M+1, M+3] + .

[0311] Second Step: Synthesis of compound 64d

[0312] Bis(pinacolato)diboron (4.2 g, 16.5 mmol), potassium acetate (2.4 g, 24.7 mmol) and XPhos Pd G2 (0.7 g, 0.9 mmol) were added to a solution of compound 64c (2.1 g, 8.2 mmol) in 1,4-Dioxane (15 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was quenched by adding water (25 mL) to the reaction mixture, and the mixture was extracted with ethyl acetate (35 mL x 3). The combined organic phase was washed with water (35 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-10 / 1) to give compound 64d (1.2 g). MS m / z (ESI): 266.9 [M+1] + .

[0313] Third Step: Synthesis of compound 64e

[0314] Compound 64d (0.5 g, 1.5 mmol), potassium carbonate (0.4 g, 2.8 mmol) and Pd(dppf)Cl2 (69 mg, 0.1 mmol) were added to a solution of compound 1a (286.3 mg, 0.94 mmol) in 1,4-Dioxane (8 mL) and water (2 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was quenched by adding water (10 mL) to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with water (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-7 / 1) to give compound 64e (130.6 mg). MS m / z (ESI): 335.0 [M+1] + .

[0315] Fourth Step: Synthesis of compound 64

[0316] Compound 64e (48.3 mg, 0.13 mmol) was added to a solution of compound Id (33 mg, 0.13 mmol) in toluene (5 mL) at room temperature, the reaction solution was cooled to 0 °C, and then a solution of trimethylaluminum in n-hexane (0.065 mL, 2 M) was added dropwise slowly. After the addition was completed, the reaction mixture was stirred at 100 °C for 2 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-5 / 1) to give compound 64 (6.7 mg). MS m / z (ESI): 542.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.26 (d, J = 13.4, 1H), 8.14 (s, 1H), 7.87 (d, J = 7.2, 2H), 4.65 (s, 1H), 4.52 (t, J = 6.1 Hz, 1H), 4.05 (s, 2H), 1.44 - 1.35 (m, 2H), 1.32 - 1.27 (m, 2H), 1.25 - 1.05 (m, 6H).

[0317] Example 13 (compound 66)

[0318] First Step: Synthesis of compound 66b

[0319] Compound 6a (600 mg, 3.73 mmol), compound 66a (430 mg, 3.73 mmol) and Cs2CO3 (2.43 g, 7.46 mmol) were added to DMF (15 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 66b (1 g); MS m / z (ESI): 275.0, 277.0 [M+1, M+3] + .

[0320] Second Step: Synthesis of compound 66c

[0321] Compound 66b (200 mg, 0.73 mmol), bis(pinacolato)diboron (278.06 mg, 1.09 mmol), Pd(dppf)Cl2(30 mg, 0.036 mmol) and potassium acetate (214.93 mg, 2.19 mmol) were added into 1,4-Dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-40%) to give compound 66c (160 mg). MS m / z (ESI): 323.1 [M+1] + .

[0322] Third step: synthesis of compound 66d

[0323] Compound 66c (87 mg, 0.27 mmol), compound 1a (50 mg, 0.18 mmol), potassium carbonate (75 mg, 0.54 mmol) and Pd(dppf)Cl2(15 mg, 0.018 mmol) were added into DMF (2 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to give compound 66d (30 mg). MS m / z (ESI): 391.0 [M+1] + .

[0324] Fourth step: synthesis of compound 66

[0325] Compound 66d (30 mg, 0.077 mmol) and compound 1d (23 mg, 0.092 mmol) were added into toluene (2 mL) at room temperature, and after completion of the addition, the reaction mixture was replaced with nitrogen for three times. Trimethylaluminum n-hexane solution (0.115 mL, 0.23 mmol, 2M) was added dropwise at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched by adding sodium sulfate decahydrate (2 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to give compound 66 (15 mg). MS m / z (ESI): 597.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 12.6 Hz, 1H), 8.28 (dd, J = 7.2, 2.2 Hz, 1H), 8.03 - 7.77 (m, 2H), 4.81 (s, 1H), 4.54 - 4.49 (m, 1H), 4.09 - 4.04 (m, 2H), 3.62 - 3.57 (m, 4H), 2.37 (s, 3H), 1.65 - 1.54 (m, 2H), 1.45 - 1.27 (m, 6H).

[0326] Example 14 (Compound 68)

[0327] First Step: Synthesis of compound 68b

[0328] Compound 68a (100 mg, 1.13 mmol), triethylamine (228.69 mg, 2.26 mmol) and p-toluenesulfonyl chloride (236.98 mg, 1.24 mmol) were added to a solution of DCM (5 mL) under nitrogen atmosphere at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound 68b (203 mg). MS m / z (ESI): 243.0 [M+1] + .

[0329] Second Step: Synthesis of compound 68d

[0330] 2-(Trimethylsilyl)ethoxymethyl chloride (962 mg, 5.77 mmol) and triethylamine (1.46 g, 14.43 mmol) were added to a solution of compound 68c (1 g, 4.81 mmol) in DCM (10 mL) under nitrogen atmosphere at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 68d (1.67 g). MS m / z (ESI): 339.1 [M+1] + .

[0331] Third Step: Synthesis of compound 68e

[0332] Compound 68d (300 mg, 0.85 mmol), compound 1a (467.72 mg, 1.7 mmol), Pd(dppf)Cl2(62.19 mg, 0.085 mmol) and potassium carbonate (234.96 mg, 1.7 mmol) were added into a mixed solution of 1,4-dioxane (5 mL) and water (1 mL) sequentially under nitrogen atmosphere. After sufficient replacement of nitrogen, the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-30%) to obtain compound 68e (364 mg). MS m / z (ESI): 407.0 [M+1] + .

[0333] Fourth step: synthesis of compound 68f

[0334] Compound 68e (200 mg, 0.44 mmol) and compound 1d (111.61 mg, 0.44 mmol) were added into a solution of toluene (5 mL) under ice-bath cooling, and then trimethylaluminum n-hexane solution (2 M, 0.029 mL, 0.88 mmol) was added dropwise. The reaction mixture was stirred at 110 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-10%) to obtain compound 68f (335 mg). MS m / z (ESI): 614.0 [M+1] + .

[0335] Fifth step: synthesis of compound 68g

[0336] Compound 68f (335 mg, 0.55 mmol) was added into a solution of hydrochloric acid-1,4-dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 1 h. After the reaction was completed, the reaction solution was directly filtered to obtain compound 68g (178 mg). MS m / z (ESI): 483.9 [M+1] + .

[0337] Sixth step: synthesis of compound 68

[0338] Compound 68g (20 mg, 0.041 mmol), potassium carbonate (11.33 mg, 0.082 mmol) and compound 68b (19.87 mg, 0.082 mmol) were added into a solution of DMF (5 mL) under nitrogen atmosphere at room temperature, and the reaction mixture was stirred at 70 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to obtain compound 68 (4.47 mg). MS m / z (ESI): 554.0 [M+1]+ .

[0339] Example 15 (Compound 67)

[0340] Compound 67a (13 mg, 0.05 mmol), potassium carbonate (14 mg, 0.10 mmol) were added to a solution of compound 68f (24 mg, 0.05 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to give compound 67 (13 mg). MS m / z (ESI): 572.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 8.48 (d, J = 17.5 Hz, 1H), 8.27 (d, J = 7.1 Hz, 1H), 8.17 (s, 1H), 7.89 - 7.79 (m, 1H), 4.89 - 4.59 (m, 6H), 4.56 - 4.48 (m, 1H), 2.44 - 2.36 (m, 3H), 1.42 (s, 2H), 1.30 (d, J = 5.5 Hz, 2H).

[0341] Example 16 (Compound 69)

[0342] First Step: Synthesis of compound 69b

[0343] Compound 69a (250 mg, 1.52 mmol) was added to a solution of compound 64b (247.54 mg, 2.28 mmol) and Cs2CO3 (1.49 g, 4.56 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-40%) to give compound 69b (350 mg). MS m / z (ESI): 236.9, 238.9 [M+1, M+3] + . 1H NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 3.93 (s, 2H), 2.77 (s, 1H), 1.19 (s, 6H).

[0344] Second Step: Synthesis of compound 69c

[0345] Compound 69b (200 mg, 0.84 mmol), bis-pinacol diboron (319.96 mg, 1.26 mmol), Pd(dppf)Cl2(34 mg, 0.042 mmol), potassium acetate (247.31 mg, 2.52 mmol) were added to a solution of 1,4-Dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-40%) to give compound 69c (100 mg). MS m / z (ESI): 285.1 [M+1] + .

[0346] Third Step: Synthesis of compound 69d

[0347] Compound 1a (20 mg, 0.073 mmol), compound 69d (62.22 mg, 0.22 mmol), potassium carbonate (30.27 mg, 0.22 mmol) and Pd(dppf)Cl2(5.96 mg, 0.0073 mmol) were added to a mixed solution of 1,4-Dioxane (1 mL) and water (0.25 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to give compound 69d (10 mg). MS m / z (ESI): 353.0 [M+1] + .

[0348] Fourth Step: Synthesis of compound 69

[0349] A solution of trimethylaluminum in n-hexane (0.042 mL, 0.084 mmol, 2 M) was added dropwise to a solution of compound 69d (10 mg, 0.028 mmol) and compound 1d (8.52 mg, 0.034 mmol) in toluene (2 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After the reaction was completed, the reaction was cooled to room temperature, quenched by the addition of sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to give compound 69 (4 mg). MS m / z (ESI): 560.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.57 (d, J = 8.3 Hz, 2H), 8.27 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 4.82 (s, 1H), 4.54 - 4.49 (m, 1H), 3.93 (s, 2H), 1.47 - 1.40 (m, 2H), 1.34 - 1.29 (m, 2H), 1.11 (s, 6H).

[0350] Example 17 (compound 70)

[0351] First step: synthesis of compound 70b

[0352] Compound 70a (200 mg, 1.69 mmol), pyridine (0.27 g, 3.38 mmol) and DMAP (21 mg, 0.17 mmol) were added to dichloromethane (2 mL), replaced with nitrogen and cooled to 0 °C, p-toluenesulfonyl chloride (480 mg, 2.54 mmol) was added slowly, and after the addition was completed, it was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to give compound 70b (250 mg). MS m / z (ESI): 290.0 [M+18] + .

[0353] Second step: synthesis of compound 70c

[0354] Compound 53b (50 mg, 0.23 mmol), compound la (63.28 mg, 0.23 mmol), potassium carbonate (63.58 mg, 0.46 mmol) and Pd(dppf)Cl2(16.83 mg, 0.023 mmol) were added into a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL) sequentially. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 70c (45 mg). MS m / z (ESI): 291.0 [M+1] + .

[0355] Third step: synthesis of compound 70d

[0356] Compound 70c (35 mg, 0.12 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (30.01 mg, 0.18 mmol) and potassium carbonate (33.17 mg, 0.24 mmol) were added into DMF (0.5 mL) sequentially. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (5 mL), extracted with methyl tert-butyl ether (5 mL x 2), and the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 0-20%) to obtain compound 70d (29 mg). MS m / z (ESI): 421.1 [M+1] + .

[0357] Fourth step: synthesis of compound 70e

[0358] Compound 70d (24 mg, 0.057 mmol) and compound Id (14.46 mg, 0.057 mmol) were added into toluene (0.5 mL), replaced with nitrogen and cooled to 0 °C, 2M trimethylaluminum n-hexane solution (0.045 mL, 0.090 mmol) was slowly added, after the addition was completed, the temperature was increased to 100 °C and stirred for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding saturated ammonium chloride (5 mL), the mixture was extracted with ethyl acetate (5 mL x 2), the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (ethyl acetate) to obtain compound 70e (10 mg). MS m / z (ESI): 498.0 [M+1] + .

[0359] Fifth step: synthesis of compound 70

[0360] Compound 70e (5 mg, 0.010 mmol) and compound 70b (2.72 mg, 0.010 mmol) were added into DMF (0.2 mL), replaced with nitrogen and cooled to 0 °C, sodium hydride (0.96 mg, 0.040 mmol) was added, after the addition was completed, the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was added to saturated ammonium chloride solution (5 mL) to quench, methyl tert-butyl ether (5 mL x 2) was extracted, the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 70 (5.4 mg). MS m / z (ESI): 598.0 [M+1] + .

[0361] Example 18 (Compound 71)

[0362] First step: synthesis of compound 71b

[0363] TEA (2.35 mL, 16.94 mmol) and p-toluenesulfonyl chloride (1.53 g, 8.0 mmol) were added to a DCM (10 mL) solution of compound 71a at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (100 mL), washed with water (40 mL) and saturated brine (40 mL) in turn, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain compound 71b (469 mg). MS m / z (ESI): 273.0 [M+1] + .

[0364] Second step: synthesis of compound 71

[0365] Compound 71b (12.28 mg, 0.045 mmol) and Cs2CO3 (26.72 mg, 0.082 mmol) were added to a DMF (1 mL) solution of compound 68f (20 mg, 0.041 mmol) at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30 mL), washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL) in turn, and the organic phase was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) to obtain compound 71 (11.56 mg). MS m / z (ESI): 583.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.48 (s, 1H), 18.27 (dd, J = 7.2, 2.3 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 1 5.06 (dd, J = 10.6, 5.3 Hz, 1H), 4.58 (d, J = 6.2 Hz, 1H), 4.51 (dd, J = 7.9, 4.8 Hz, 2H), 4.35 (d, J = 8.7 Hz, 2H), 4.31 (dd, J = 6.1, 2.5 Hz, 2H), 3.48 (dd, J = 7.9, 5.1 Hz, 2H), 2.45 (s, 3H), 1.45 - 1.40 (m, 2H), 1.32 - 1.29 (m, 2H).

[0366] Example 19 (Compound 73)

[0367] First Step: Synthesis of compound 73b

[0368] Azidotrimethylsilane (3.53 g, 30.61 mmol), dibutyltin oxide (7.62 g, 30.61 mmol) were added to a solution of compound 73a (6 g, 30.61 mmol) in toluene (30 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 50%) to give compound 73b (7 g). MS m / z (ESI): 238.9, 240.9 [M+1] + .

[0369] Second Step: Synthesis of compound 73c

[0370] Copper acetate (0.46 g, 2.51 mmol), 1,10-phenanthroline (0.45 g, 2.51 mmol), potassium carbonate (3.47 g, 25.1 mmol), potassium cyclopropyltrifluoroborate (5.57 g, 37.65 mmol) were added to a solution of compound 73b (3 g, 12.55 mmol) in toluene (120 mL) and water (24 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction mixture was filtered, diluted with water (30 mL), extracted with dichloromethane (100 mL x 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 10%) to give compound 73c (1.4 g). MS m / z (ESI): 278.9, 280.9 [M+1, M+3]+ .

[0371] Step 3: Synthesis of compound 73d

[0372] Benzophenone imine (710 mg, 3.94 mmol), cesium carbonate (2.33 g, 7.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium (160 mg, 0.18 mmol) were added to a solution of compound 73c (1 g, 3.58 mmol) in 1,4-dioxane (10 mL) successively at room temperature, and the reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-10%) to give compound 73d (1.3 g). MS m / z (ESI): 380.0 [M+1] + .

[0373] Step 4: Synthesis of compound 73e

[0374] 4N hydrochloric acid 1,4-dioxane (4 mL, 31.6 mmol) was added to a solution of compound 23d (1.2 g, 3.16 mmol) in 1,4-dioxane (12 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 73e (0.5 g, crude). MS m / z (ESI): 216.0 [M+1] + .

[0375] Step 5: Synthesis of compound 73

[0376] Compound 1c (16 mg, 0.046 mmol) was added to a solution of compound 73e (10 mg, 0.046 mmol) in toluene (1 mL) successively at room temperature, cooled to 0 °C, and 2M trimethylaluminum in toluene (0.09 mL, 0.18 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was purified by thin layer chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 73 (3.4 mg). MS m / z (ESI): 517.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 4.73 (s, 1H), 4.50 - 4.43 (m, 1H), 3.97 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.40 (d, J = 3.2 Hz, 2H), 1.34 (d, J = 6.1 Hz, 2H), 1.24 (d, J = 5.7 Hz, 6H).

[0377] Example 20 (Compound 74)

[0378] First Step: Synthesis of compound 74c

[0379] Sodium hydride (0.34 g, 8.42 mmol, purity 60%) was added to a solution of compound 74a (1.5 g, 7.65 mmol) in DMSO (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Then, compound 74b (1.19 g, 8.42 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (100 mL), washed with water (40 mL x 3) and saturated NaCl solution (40 mL) successively, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100:1 to 40:1) to give compound 74c (1.07 g). MS m / z (ESI): 336.9, 338.9 [M+1, M+3] + .

[0380] Second Step: Synthesis of compound 74d

[0381] Iodine (0.90 g, 3.53 mmol), potassium iodide (0.73 g, 4.41 mmol) and potassium carbonate (1.22 g, 8.82 mmol) were added successively to a solution of compound 74c (0.99 g, 2.94 mmol) in DMSO (10 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 6 h. After completion of the reaction, the reaction solution was quenched with saturated Na2S2O3 solution (30 mL), and the aqueous solution was extracted with ethyl acetate (100 mL). The organic phase was washed with water (40 mL x 3) and saturated NaCl solution (40 mL) successively, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 to 4:1) to give compound 74d (84 mg). MS m / z (ESI): 335.0, 336.9 [M+1, M+3] + .

[0382] Step 3: Synthesis of compound 74e

[0383] To a solution of compound 74d (84 mg, 0.25 mmol) in 1,4-Dioxane (1 mL) were added compound benzophenone imine (54.37 mg, 0.30 mmol), XantPhos (28.93 mg, 0.050 mmol), Pd2(dba)3(22.89 mg, 0.025 mmol) and Cs2CO3(162.91 mg, 0.50 mmol) successively at room temperature, and then the reaction was protected by nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and then the organic phase was concentrated under reduced pressure. Compound 74e (61 mg) was obtained by purification on a thin layer chromatography silica gel plate (petroleum ether / ethyl acetate = 3 / 1). MS m / z (ESI): 436.1 [M+1] + .

[0384] Step 4: Synthesis of compound 74f

[0385] To a solution of compound 74e (61 mg, 0.14 mmol) in 1,4-Dioxane (3 mL) was added 4N hydrochloric acid 1,4-Dioxane (0.3 mL, 1.4 mmol) at room temperature, and then the reaction was stirred at room temperature for 2 h. After completion of the reaction, the pH of the reaction mixture was adjusted to about 9 by adding saturated sodium carbonate solution, and then the reaction mixture was extracted with ethyl acetate (30 mL), washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL) successively, and then the organic phase was concentrated under reduced pressure. Compound 74f (34 mg) was obtained by purification on a thin layer chromatography silica gel plate (petroleum ether / ethyl acetate = 1 / 1). MS m / z (ESI): 272.0 [M+1] + .

[0386] Step 5: Synthesis of compound 74

[0387] A solution of trimethylaluminum in n-hexane (2 M, 0.057 mL, 0.11 mmol) was added to a solution of compound 1c (20 mg, 0.057 mmol) and compound 74f (17.01 mg, 0.063 mmol) in toluene (1 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) to give compound 74 (7.59 mg). MS m / z (ESI): 574.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.06 (s, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 - 7.44 (m, 1H), 4.78 (s, 1H), 4.01 (s, 2H), 2.66 - 2.60 (m, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 1.35 - 1.32 (m, 2H), 1.22 - 1.19 (m, 2H), 1.13 (s, 6H).

[0388] Example 21 (Compound 75)

[0389] Compound 68f (20 mg, 0.041 mmol) and triphenylphosphine (12.90 mg, 0.049 mmol) were added to a solution of compound 75a (17.07 mg, 0.16 mmol) in toluene (5 mL) at room temperature, and DIAD (0.01 mL, 0.049 mmol) was added dropwise slowly at 0 °C. The reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to give compound 75 (2.56 mg). MS m / z (ESI): 569.9 [M+1] + .

[0390] Example 22 (Compound 79-P1)

[0391] A solution of trimethylaluminum in n-hexane (2 M, 0.44 mL, 0.88 mmol) was added dropwise to a solution of compound 1c (75 mg, 0.22 mmol) and compound 79a (51.31 mg, 0.22 mmol, synthesis method refer to US2013059846A1 page 65 synthesis of compound 131) in toluene (5 mL) under ice bath. The reaction mixture was stirred at 110 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to give compound 79-P1 (28.19 mg). MS m / z (ESI): 536.0 [M+1] + .

[0392] Example 23 (compound 52)

[0393] First Step: synthesis of compound 52b

[0394] To a solution of compound 52a (1.00 g, 6.02 mmol) in THF (20 mL), sodium borohydride (456 mg, 12.04 mmol) was added and stirred at 0 °C for 2 h. After the reaction was completed, the reaction solution was quenched with water (10 mL) and concentrated under reduced pressure. THF (20 mL) was added and concentrated under reduced pressure again. The above operation was repeated three times to give crude compound 52b (1.10 g), which was used directly for the next step.

[0395] Second Step: synthesis of compound 52c

[0396] To a solution of compound 52b (1.10 g, crude) in DCM (20 mL), imidazole (890 mg, 13.08 mmol), DMAP (79 mg, 0.65 mmol) and TBDPSCl (2.16 g, 7.85 mmol) were added sequentially under nitrogen protection at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was quenched with water (10 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and the residue was purified by column chromatography on silica gel (EA / PE = 0-3%) to give compound 52c (1.80 g). MS m / z (ESI): 429.3 [M+Na] + .

[0397] Third Step: synthesis of compound 52d

[0398] To a mixture of compound 52c (500 mg, 1.23 mmol) in THF (8 mL) and H2O (2 mL) was added lithium hydroxide monohydrate (103 mg, 2.46 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 52d (465 mg, crude).

[0399] Fourth Step: Synthesis of compound 52e

[0400] To a solution of compound 52d (465 mg, 1.23 mmol) in acetonitrile (5 mL) was added CDI (199 mg, 1.23 mmol) under nitrogen protection and stirred at room temperature for 0.5 hours. Compound 62b (167 mg, 0.82 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours and then heated to 100 °C and stirred for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EA / PE = 0-11%) to obtain compound 52e (380 mg). MS m / z (ESI): 546.7 [M+1] + .

[0401] Fifth Step: Synthesis of compound 52f

[0402] Compound 52e (110 mg, 0.208 mmol) was dissolved in toluene (1 mL) under nitrogen protection, compound 1a (50 mg, 0.18 mmol) and 1M trimethylaluminum (0.54 mL) solution in 1,4-dioxane were added, and the reaction mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EA / PE = 0-10%) to obtain compound 52f (120 mg). MS m / z (ESI): 776.8 [M+1] + .

[0403] Sixth Step: Synthesis of compound 52g

[0404] Compound 52f (30 mg, 0.04 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and H2O (0.5 mL) under nitrogen protection, compound 1b (17 mg, 0.06 mmol) was added, Pd(dppf)Cl2(6 mg, 0.008 mmol), Cs2CO3(26 mg, 0.08 mmol), and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-2%) to obtain compound 52g (30 mg). MS m / z (ESI): 848.5 [M+1] + .

[0405] Step 7: Synthesis of compound 52

[0406] Compound 52g (28 mg, 0.03 mmol) was dissolved in THF (0.5 mL), 1M TBAF (0.03 mL) in THF was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction liquid was quenched with water (2 mL), extracted with EA (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: sunfire-C18 19x250 mm, 10 nm; mobile phase: acetonitrile-water (0.1% FA); gradient: 45-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 52 (6.92 mg). MS m / z (ESI): 610.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 12.0 Hz, 1H), 8.33-8.23 (m, 1H), 8.05-7.05 (m, 2H), 6.22-5.90 (m, 2H), 4.71 (d, J = 16.0 Hz, 1H), 4.25 (s, 1H), 4.00 (d, J = 25.6 Hz, 2H), 3.35-3.29 (m, 1H), 3.23-3.14 (m, 1H), 2.48 (s, 1H), 2.36 (s, 2H), 1.11 (d, J = 17.6 Hz, 6H).

[0407] Example 24 (compound 130)

[0408] First step: synthesis of compound 130b

[0409] Compound 130a (300 mg, 2.94 mmol, synthesis method reference patent WO2011095450A1 page 96 step 1 and step 2), methyl epoxide (423.5 mg, 5.87 mmol) and potassium carbonate (803.8 mg, 53.87 mmol) were added to DMF (3 mL), and the reaction mixture was stirred at 100°C under nitrogen for 16 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (methanol / methylene chloride = 0-10%) to obtain compound 130b (240 mg). MS m / z (ESI): 175.0 [M+1] + .

[0410] Step 2: Synthesis of compound 130c

[0411] Compound 130b (240 mg, 1.38 mmol) and NBS (245.1 mg, 1.38 mmol) were added into acetonitrile (2.5 mL), after the addition was completed, the reaction mixture was stirred for 2 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0-15%) to obtain compound 130c (220 mg). MS m / z (ESI): 253.0, 255.0 [M+1, M+3] + .

[0412] Step 3: Synthesis of compound 130d

[0413] Compound 130c (200 mg, 0.79 mmol), pinacol borane (303.3 mg, 2.37 mmol), triethylamine (0.275 mL, 1.98 mmol) and Pd(PPh3)2Cl2 (27.72 mg, 0.04 mmol) were added into 1,4-dioxane (1 mL) in turn, the reaction mixture was replaced with nitrogen and stirred at 100°C for 16 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was purified by reversed phase preparation (Agilent 1290 rapid preparation instrument (C18 reversed phase column, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%) to obtain compound 130d (70 mg). MS m / z (ESI): 301.1 [M+1] + .

[0414] Step 4: Synthesis of compound 130e

[0415] Compound 130d (70 mg, 0.23 mmol), compound 1a (42 mg, 0.15 mmol), Pd(dppf)Cl2 (6.3 mg, 0.008 mmol) and cesium carbonate (99.5 mg, 0.31 mmol) were added into a mixed solution of 1,4-dioxane (1 mL) and water (0.2 mL), the reaction mixture was replaced with nitrogen and stirred at 100°C for 4 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 130e (35 mg). MS m / z (ESI): 369.1 [M+1] + .

[0416] Step 5: Synthesis of compound 130

[0417] Compound 130e (35 mg, 0.09 mmol) and compound 1d (26.50 mg, 0.10 mmol) were added into 1,4-dioxane (1 mL), the reaction mixture was purged with nitrogen and added dropwise with trimethylaluminum in n-hexane (0.142 mL, 2M) at room temperature, after the addition was completed, the reaction mixture was warmed to 100°C and stirred for 2 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was purified by reverse phase preparative purification (Agilent 1290 rapid preparation instrument (C18 reverse phase column, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-90%)) to obtain compound 130 (4.4 mg). MS m / z (ESI): 576.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 4.69 (s, 1H), 4.55-4.52 (m, 1H), 3.95 (s, 2H), 1.45-1.40 (m, 2H), 1.33-1.28 (m, 2H), 1.14 (s, 6H).

[0418] Example 25 (Compound 116-P1)

[0419] First Step: Synthesis of compound 116a

[0420] Compound 53c (1.07 g, 3.63 mmol), cesium carbonate (2.37 g, 7.26 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (82.0 mg, 0.10 mmol) were added into compound 1a (1 g, 3.63 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at room temperature, the reaction mixture was stirred at 100°C for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction liquid was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-80%) to obtain compound 116a (1.1 g). MS m / z (ESI): 363.14 [M+1] + .

[0421] Second Step: Synthesis of compound 116-P1

[0422] Compound 62d (23 mg, 0.083 mmol) was added to a solution of compound 116a (30 mg, 0.083 mmol) in toluene (3 mL) at room temperature, and a solution of trimethylaluminum in n-hexane (0.12 mL, 0.24 mmol, 2 M) was added dropwise to the reaction mixture at 0 °C. After the addition was completed, the reaction mixture was stirred at 100 °C for 4 h. After the reaction was completed, the reaction solution was purified by thin layer chromatography on silica gel plates (dichloromethane / methanol = 20 / 1) to obtain compound 116-P1 (22 mg). MS m / z (ESI): 587.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 7.1 Hz, 1H), 7.87 (d, J = 10.1 Hz, 1H), 5.21-5.38 (m, 1H), 4.68 (s, 1H), 3.95 (s, 2H), 3.16-3.03 (m, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 2.02-1.88 (m, 1H), 1.58-1.63 (m, 1H), 1.14 (s, 6H).

[0423] Example 26 (Compound 83)

[0424] A solution of trimethylaluminum in n-hexane (2 M, 0.06 mL, 0.11 mmol) was added to a solution of compound 116a (20 mg, 0.055 mmol) and compound 74f (16.42 mg, 0.061 mmol) in toluene (1 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (30 mL), and the organic phase was washed successively with water (10 mL) and saturated brine (10 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plates (dichloromethane / methanol = 15 / 1) to obtain compound 83 (17.9 mg). MS m / z (ESI): 588.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 4.68 (s, 1H), 3.95 (s, 2H), 2.69 - 2.65 (m, 1H), 2.39 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 1.33 - 1.27 (m, 2H), 1.19 - 1.16 (m, 2H), 1.14 (s, 6H).

[0425] Example 27 (Compound 82-P1)

[0426] A solution of trimethylaluminum in n-hexane (2 M, 0.6 mL, 1.2 mmol) was added to a solution of compound 116a (20 mg, 0.055 mmol) and compound 79a (13 mg, 0.055 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 1:0 ~ 20:1) to give compound 82-P1 (12.45 mg). MS m / z (ESI): 550.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 5.39 - 5.20 (m, 1H), 4.68 (s, 1H), 3.95 (s, 2H), 3.11 - 2.98 (m, 1H), 2.39 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 2.01 - 1.88 (m, 1H), 1.64 - 1.55 (m, 1H), 1.14 (s, 6H).

[0427] Example 28 (Compound 125)

[0428] First Step: Synthesis of compound 125c

[0429] Potassium carbonate (14.8 g, 107.04 mmol) and compound 125b (4.5 g, 35.68 mmol) were added to a solution of compound 125a (3 g, 35.68 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at 125 °C for 3 h. After completion of the reaction, the reaction solution was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 0 ~ 10 / 4) to give compound 125c (554 mg). MS m / z (ESI): 137.1 [M+1] + .

[0430] Second Step: Synthesis of compound 125d

[0431] Phenylsilane (858.4 mg, 7.93 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedione) manganese (III) (239.9 mg, 0.40 mmol) were added to a solution of compound 125c (540 mg, 3.97 mmol) in a mixture of isopropanol and dichloromethane (10 mL / 2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. After completion of the reaction, it was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10:0 ~ 10:1) to give compound 125d (240 mg). MS m / z (ESI): 155.1 [M+1] + .

[0432] Third Step: Synthesis of compound 125e

[0433] N-Bromosuccinimide (271.3 mg, 1.52 mmol) was added to a solution of compound 125d (235 mg, 1.52 mmol) in acetonitrile (15 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 125e (340 mg). MS m / z (ESI): 232.9, 234.9 [M+1, M+3] + .

[0434] Fourth Step: Synthesis of compound 125f

[0435] To a solution of compound 125e (350 mg, 1.50 mmol) in 1,4-dioxane (10 mL) were added genzanol borane (384.4 mg, 3.00 mmol), triethylamine (0.7 mL, 4.51 mmol), and dichlorobis(triphenylphosphine)palladium (105.4 mg, 0.15 mmol) sequentially at room temperature. The reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 125f (350 mg). MS m / z (ESI): 281.16 [M+1] + .

[0436] Step 5: Synthesis of compound 125g

[0437] To a solution of compound 125f (392.8 mg, 1.43 mmol) and compound 1a (400 mg, 1.43 mmol, synthesis method refer to WO2022136509A1, page 183, synthesis of compound Intermediate A) in water and 1,4-dioxane (2 mL / 8 mL) were added cesium carbonate (930.5 mg, 2.86 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (116.9 mg, 0.14 mmol) sequentially at room temperature. The reaction mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 0 ~ 2 / 1) to give compound 125g (60 mg). MS m / z (ESI): 349.09 [M+1] + .

[0438] Step 6: Synthesis of compound 125

[0439] To a solution of compound 1d (26.21 mg, 0.103 mmol, synthesis method refer to WO2024118887A1, page 170, synthesis of compound intermediate 73) and compound 125g (30 mg, 0.09 mmol) in 1,4-dioxane (3 mL) was added n-hexane solution of trimethylaluminum (2 M) (0.1 mL, 0.17 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 125 (5.5 mg). MS m / z (ESI): 555.8 [M+1] + .

[0440] 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 10.2 Hz, 1H), 7.80 (s, 1H), 5.48 (s, 1H), 4.57 - 4.47 (m, 1H), 4.23 (s, 2H), 4.00 (dd, J = 42.9, 11.8 Hz, 2H), 1.42 (d, J = 3.5 Hz, 2H), 1.32 (d, J = 7.4 Hz, 2H), 1.29 (s, 3H).

[0441] Example 29 (Compound 118)

[0442] First Step: Synthesis of compound 118b

[0443] Compound 118b (480 mg) was obtained by the reaction of compound 118a (500 mg, 2.72 mmol), 4-methoxybenzyl chloride (425 mg, 2.72 mmol) and potassium carbonate (375 mg, 2.72 mmol) in DMF (5 mL) at room temperature for 12 h. MS m / z (ESI): 305.1 [M+1] + .

[0444] Second Step: Synthesis of compound 118c

[0445] Compound 118c (400 mg) was obtained by the reaction of compound 118b (480 mg, 1.58 mmol) and NBS (281 mg, 1.58 mmol) in acetonitrile (5 mL) at room temperature for 3 h. MS m / z (ESI): 282.9 [M+Boc]

[0446] + .

[0447] Third Step: Synthesis of compound 118d

[0448] ​To a solution of compound 118c (350 mg, 0.91 mmol) in 1,4-dioxane (4 mL) were added triethylamine (0.25 mL, 1.83 mmol), dichlorobispalladium (64 mg, 0.09 mmol), and borane-methyl sulfide (351 mg, 2.74 mmol) sequentially at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 118d (200 mg). MS m / z (ESI): 431.2 [M+1] + .

[0449] Fourth Step: Synthesis of compound 118e

[0450] To a solution of compound 118d (150 mg, 0.35 mmol), compound 1a (115 mg, 0.42 mmol), potassium carbonate (96 mg, 0.70 mmol), and Pd(dppf)Cl2(28 mg, 0.04 mmol) in 1,4-dioxane / water (2 mL / 0.4 mL) were added sequentially at room temperature. The reaction mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 118e (80 mg). MS m / z (ESI): 398.9 [M+1] + .

[0451] Fifth Step: Synthesis of compound 118f

[0452] To a solution of compound 118e (70 mg, 0.18 mmol) in hydrochloric acid-dioxane (4 M, 2 mL) was added at room temperature. The reaction mixture was stirred at 25 °C for 3 h. After the reaction was completed, the reaction mixture was directly concentrated to give compound 118f (42 mg). MS m / z (ESI): 278.88 [M+1] + .

[0453] Sixth Step: Synthesis of compound 118h

[0454] Potassium carbonate (124 mg, 0.90 mmol) was added to a solution of compound 118f (50 mg, 0.18 mmol) and compound 118g (104 mg, 0.36 mmol) in DMF (2 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 13 h. After completion of the reaction, the reaction was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give compound 118h (15 mg). MS m / z (ESI): 375.0 [M+1] + .

[0455] Step 7: Synthesis of compound 118

[0456] Trimethylaluminum 2M n-hexane solution (0.04 mL, 0.07 mmol) was added to a solution of compound 1d (9 mg, 0.035 mmol) and compound 118h (13 mg, 0.035 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to give compound 118 (11.17 mg). MS m / z (ESI): 581.8 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 10.1 Hz, 1H), 7.88 (s, 1H), 4.64 - 4.53 (m, 1H), 4.44 (s, 2H), 4.19 (q, J = 12.2 Hz, 2H), 4.00 - 3.87 (m, 2H), 3.76 (d, J = 9.1 Hz, 1H), 3.58 (d, J = 9.1 Hz, 1H), 2.02 - 1.93 (m, 1H), 1.91 - 1.82 (m, 1H), 1.51 - 1.45 (m, 2H), 1.39 - 1.34 (m, 2H).

[0457] Example 30 (compound 129)

[0458] Step 1: Synthesis of compound 129c

[0459] Potassium carbonate (4.5 g, 32.58 mmol) was added to a solution of compound 129a (3 g, 16.29 mmol) and compound 129b (2.4 g, 17.92 mmol) in DMF (30 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine solution (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 129c (3.5 g). MS m / z (ESI): 239.1 [M+1] + .

[0460] Second Step: Synthesis of compound 129d

[0461] Sodium borohydride (1.4 g, 37.78 mmol) was slowly added to a mixture of compound 129c (3 g, 12.59 mmol) and calcium chloride (2.8 g, 12.59 mmol) in ethanol and water (15 mL / 15 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution to quench, and the mixture was filtered and concentrated to give a crude product. The crude product was slurried with a mixture of dichloromethane / methanol (10 / 1) (10 mL) to give compound 129d (2 g). MS m / z (ESI): 183.1 [M+1] + .

[0462] Third Step: Synthesis of compound 129e

[0463] DAST (2.39 g, 14.82 mmol) was added to a solution of compound 129d (1.8 g, 9.88 mmol) in dichloromethane (20 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 3 h. After completion of the reaction, the reaction solution was quenched with water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine solution (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 2 / 1) to give compound 129e (1 g). MS m / z (ESI): 187.1 [M+1] + .

[0464] Fourth Step: Synthesis of compound 129f

[0465] benzenesilane (930 mg, 8.60 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptane acid) manganese (260 mg, 0.43 mmol) were added to a solution of compound 129e (800 mg, 4.30 mmol) in a mixture of isopropanol and dichloromethane (10 ml / 2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 129f (800 mg). MS m / z (ESI): 205.1 [M+1] + .

[0466] Step 5: Synthesis of compound 129g

[0467] NBS (671 mg, 3.77 mmol) was added to a solution of compound 129f (700 mg, 3.43 mmol) in acetonitrile (7 mL) at room temperature. The reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 129g (800 mg). MS m / z (ESI): 283.0, 285.0 [M+1, M+3] + .

[0468] Step 6: Synthesis of compound 129h

[0469] PdCl2(dppf)CH2Cl2(174 mg, 0.25 mmol), pinacolborane (949 mg, 7.5 mmol), and triethylamine (0.7 mL, 5.0 mmol) were added to a solution of compound 129g (700 mg, 2.50 mmol) in 1,4-dioxane (7 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 129h (100 mg). MS m / z (ESI): 331.2 [M+1] + .

[0470] Step 7: Synthesis of compound 129

[0471] To a mixture of compound 129h (30 mg, 0.09 mmol), compound 53a (48 mg, 0.10 mmol), 1,1-bisdiphenylphosphinylferrocenedichloropalladium dichloromethane complex (7 mg, 0.01 mmol) and potassium carbonate (25 mg, 0.18 mmol) in 1,4-dioxane and water (2 mL / 0.4 mL) was added successively at room temperature. The reaction mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to give compound 129 (2.47 mg). MS m / z (ESI): 605.8 [M+1] + .

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 10.1 Hz, 1H), 5.82 (s, 1H), 5.70 (s, 1H), 5.61 (s, 1H), 5.49 (s, 1H), 4.93 (s, 1H), 4.61 - 4.53 (m, 1H), 4.28 (s, 2H), 1.51 - 1.45 (m, 2H), 1.39 - 1.34 (m, 2H), 1.22 (s, 6H).

[0473] Example 31 (compounds 131, 132)

[0474] First step: synthesis of compound 131b, 131c

[0475] To a mixture of compound 131a (1 g, 8.92 mmol), compound 3-bromo-2-methylpropene (1.26 g, 9.36 mmol) and potassium carbonate (2.46 g, 17.84 mmol) in acetonitrile (10 mL) was added successively at room temperature. The mixture was purged with nitrogen and stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), filtered and concentrated to give a mixture of compound 131b and 131c (1.2 g), which was used directly for the next step. MS m / z (ESI): 166.9 [M+1] + .

[0476] Second step: synthesis of compound 131d, 131e

[0477] To a solution of compound 131b and 131c (1.2 g, 7.21 mmol) in dichloromethane (12 mL) was added diethylamine sulfide (2.33 g, 14.44 mmol) dropwise under nitrogen atmosphere. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was concentrated and the residue was purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-30%) to give a mixture of compound 131d and 131e (490 mg). MS m / z (ESI): 168.98 [M+1] + .

[0478] Step 3: Synthesis of compound 131f, 131g

[0479] To a solution of compound 131d and 131e (390 mg, 2.31 mmol) in dichloromethane and isopropanol (0.8 mL / 4 mL) was added manganese tris(2,2,6,6-tetramethyl-3,5-heptanedionate) (140.2 mg, 0.23 mmol) and phenylsilane (501.8 mg, 4.64 mmol) successively under oxygen atmosphere. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was concentrated and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give a mixture of compound 131f and 131g (286 mg). MS m / z (ESI): 187.1 [M+1] + .

[0480] Step 4: Synthesis of compound 131h, 131i

[0481] To a solution of compound 131f and 131g (320 mg, 1.72 mmol) in acetonitrile (3 mL) was added N-bromosuccinimide (305.8 mg, 1.72 mmol) at room temperature. After the addition was completed, the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was concentrated and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give a mixture of compound 131h and 131i (430 mg). MS m / z (ESI): 264.92, 266.92 [M+1, M+3] + .

[0482] Step 5: Synthesis of compound 131j, 131k

[0483] A mixture of compound 131h and 131i (420 mg, 1.58 mmol), pinacolborane (608.2 mg, 4.75 mmol), triethylamine (320 mg, 3.17 mmol) and Pd(dppf)Cl2(111.2 mg, 0.16 mmol) were added to 1,4-dioxane (4.2 mL) at room temperature, replaced with nitrogen and stirred at 100 °C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, concentrated, and the residue was purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-40%) to give a mixture of compound 131j and 131k (100.9 mg). MS m / z (ESI): 313.13 [M+1] + .

[0484] Step 6: Synthesis of compound 131, 132

[0485] A mixture of compound 131j and 131k (80 mg, 0.26 mmol) was dissolved in a mixture of 1,4-dioxane and water (1 mL / 0.2 mL) at room temperature, compound 53a (99.0 mg, 0.21 mmol), potassium carbonate (70.8 mg, 0.51 mmol) and Pd(dppf)Cl2(18.7 mg, 0.026 mmol) were added successively, replaced with nitrogen and heated to 100 °C for stirring for 16 h. After the reaction was completed, the reaction was filtered, concentrated, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to give a crude product, which was purified by high performance liquid chromatography (Agilent 1290 rapid preparation instrument, C18 reversed phase column, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%) to give compound 131 (1 mg) and compound 132 (2.4 mg).

[0486] Compound 131: MS m / z (ESI): 588.1 [M+1] + .

[0487] Compound 132: MS m / z (ESI): 588.1 [M+1] + .

[0488] Example 32 (compound 143)

[0489] Step 1: Synthesis of compound 143b

[0490] Azidotrimethylsilane (3.23 g, 28.03 mmol) and dibutyltin oxide (1.99 g, 5.61 mmol) were added to a solution of compound 143a (6 g, 28.03 mmol) in 1,4-dioxane (30 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was poured into water (100 mL) and the solid was collected by filtration and dried to give compound 143b (5.1 g). MS m / z (ESI): 256.9 [M+1] + .

[0491] Second Step: Synthesis of compound 143c

[0492] Sodium carbonate (4.12 g, 38.90 mmol), copper acetate (0.71 g, 3.89 mmol) and 2,2'-bipyridine (0.71 g, 3.89 mmol) were added to a solution of potassium cyclopropanetriyltrifluoroborate (5.76 g, 38.900 mmol) and compound 143b (5 g, 19.45 mmol) in 1,4-dioxane (50 mL) at room temperature. The reaction mixture was stirred at 65 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 143c (2.3 g). MS m / z (ESI): 296.9, 298.9 [M+1, M+3] + .

[0493] Third Step: Synthesis of compound 143d

[0494] Sodium hydroxide (0.24 g, 6.06 mmol), palladium acetate (0.18 g, 0.81 mmol) and XantPhos (0.7 g, 1.21 mmol) were added to a solution of diphenylmethanamine (0.81 g, 4.44 mmol) and compound 143c (1.2 g, 4.04 mmol) in 1,4-dioxane (25 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 2 / 1) to give compound 143d (1.3 g). MS m / z (ESI): 398.0 [M+1] + .

[0495] Fourth Step: Synthesis of compound 143e

[0496] Hydrochloric acid-1,4-dioxane solution (13 mL, 4 M) was added to a solution of compound 143d (1.3 g, 3.27 mmol) in 1,4-dioxane (13 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 143e (600 mg). MS m / z (ESI): 234.1 [M+1] + .

[0497] Fifth step: synthesis of compound 143

[0498] Trimethylaluminum (2 M in n-hexane) (0.1 mL, 0.17 mmol) was added to a solution of compound 116a (synthesis method, refer to synthesis of compound 116a in Example 25, first step, 29 mg, 0.12 mmol) and compound 143e (30 mg, 0.08 mmol) in 1,4-dioxane (3 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 143 (5.5 mg). MS m / z (ESI): 550.0 [M+1] + .

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 11.3 Hz, 1H), 4.69 (s, 1H), 4.53 - 4.46 (m, 1H), 3.95 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 1.45 - 1.39 (m, 2H), 1.32 - 1.29 (m, 2H), 1.14 (s, 6H).

[0500] Example 33 (compound 141)

[0501] First step: synthesis of compound 141a

[0502] Lithium hydroxide (24.8 mg, 1.04 mmol) was added to a mixture of compound 116a (75 mg, 0.21 mmol) in ethanol and water (2 mL / 1 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 by dropwise addition of 2M aqueous hydrochloric acid solution, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 141a (65 mg). MS m / z (ESI): 335.1 [M+1] + .

[0503] Second Step: Synthesis of compound 141b

[0504] HATU (85.3 mg, 0.22 mmol) and DIEA (58.0 mg, 0.45 mmol) were sequentially added to a solution of compound 141a (50 mg, 0.15 mmol) and ammonium chloride (24.0 mg, 0.45 mmol) in DMF (2 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography on silica gel plates (methanol / dichloromethane = 1 / 20) to give compound 141b (30 mg). MS m / z (ESI): 334.0 [M+1] + .

[0505] Third Step: Synthesis of compound 141c

[0506] Compound 143c (1.0 g, 3.37 mmol) was dissolved in carbon tetrachloride (20 mL) at room temperature, and NBS (1.80 g, 10.1 mmol) and BPO (81.5 mg, 0.34 mmol) were added. After the addition was complete, the reaction solution was heated to 90°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-10%) to give compound 141c (1.2 g). MS m / z (ESI): 454.7, 456.6 [M+3, M+5] + .

[0507] Fourth Step: Synthesis of compound 141d

[0508] Silver tetrafluoroborate (160.5 mg, 0.82 mmol) was added to a solution of compound 141c (1.0 g, 2.20 mmol) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-10%) to give compound 141d (400 mg). MS m / z (ESI): 310.8, 312.9 [M+1, M+3] + .

[0509] Step 5: Synthesis of compound 141e

[0510] DAST (310 mg, 1.93 mmol) was added dropwise to a solution of compound 141d (400 mg, 1.29 mmol) in dichloromethane (10 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-10%) to give compound 141e (300 mg). MS m / z (ESI): 332.9, 334.9 [M+1, M+3] + .

[0511] Step 6: Synthesis of compound 141

[0512] Compound 141b (15 mg, 0.045 mmol), Pd2(dba)3 (8.2 mg, 0.009 mmol), Xantphos (5.2 mg, 0.009 mmol), and Cs2CO3 (44 mg, 0.14 mmol) were sequentially added to a solution of compound 141e (18 mg, 0.054 mmol) in 1,4-dioxane (2 mL) at room temperature. After being replaced with nitrogen three times, the reaction mixture was heated to 100 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to give compound 141 (7 mg). MS m / z (ESI): 585.9 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 8.17 (d, J = 6.5 Hz, 1H), 7.73 (d, J = 10.6 Hz, 1H), 7.20 (t, J = 54.5 Hz, 1H), 4.70 (s, 1H), 4.56 - 4.51 (m, 1H), 3.95 (s, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 1.47 - 1.40 (m, 2H), 1.35 - 1.29 (m, 2H), 1.14 (s, 6H).

[0513] Example 34 (Compound 142)

[0514] First Step: Synthesis of compound 142b

[0515] DAST (5.18 g, 32.14 mmol) was added to a solution of compound 142a (4.5 g, 21.43 mmol) in dichloromethane (45 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 3 h. After completion of the reaction, the reaction solution was quenched with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3), washed with saturated brine solution (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 142b (5 g).

[0516] Second Step: Synthesis of compound 142c

[0517] Azidotrimethylsilane (3.7 g, 32.32 mmol) was added to a solution of compound 142b (5 g, 21.55 mmol) and tin acetate (1.5 g, 4.31 mmol) in 1,4-dioxane (50 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 142c (4 g). MS m / z (ESI): 274.9, 276.9 [M+1, M+3] + .

[0518] Third Step: Synthesis of compound 142d

[0519] Compound 142c (3.5 g, 12.73 mmol) in 1,4-dioxane (70 mL) at room temperature under air atmosphere. The reaction mixture was stirred at 60 °C for 24 h. After completion of the reaction, the reaction mixture was concentrated directly and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 142d (1 g). MS m / z (ESI): 314.9, 316.9 [M+1, M+3] + .

[0520] Fourth Step: Synthesis of compound 142

[0521] Compound 141b (16 mg, 0.048 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (5.5 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium (4.4 mg, 0.005 mmol), cesium carbonate (31 mg, 0.095 mmol) were added to a solution of compound 142d (15 mg, 0.048 mmol) in 1,4-dioxane (1 mL) at room temperature. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give compound 142 (1.24 mg). MS m / z (ESI): 567.9 [M+1] + .

[0522] Example 35 (compound 149, 171)

[0523] First Step: Synthesis of compound 149b

[0524] Compound 149a (1 g, 7.14 mmol) in tetrahydrofuran (20 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was quenched by dropwise addition of methanol (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-20%) to give compound 149b (540 mg). MS m / z (ESI): 101.0 [M+1] + .

[0525] Second Step: Synthesis of compound 149c

[0526] Compound 149b (500 mg, 4.99 mmol) was dissolved in dichlorosulfoxide (5 mL) at room temperature. The reaction mixture was warmed to 80 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was slurried with methyl tert-butyl ether (3 mL), filtered, and dried to obtain compound 149c (605 mg). MS m / z (ESI): 118.9 [M+1] + .

[0527] Third Step: Synthesis of compound 149d

[0528] Compound 149c (500 mg, 4.22 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection in an ice bath, and lithium tetra-deuteride (354.1 mg, 8.44 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, methanol (5 mL) was added dropwise to quench the reaction in an ice bath. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 149d (360 mg, yield 70.2%). MS m / z (ESI): 86.0 [M+1] + .

[0529] Fourth Step: Synthesis of compounds 149e, 149f

[0530] Methyl epoxide propyl (914.8 mg, 12.69 mmol) and potassium carbonate (1169 mg, 8.46 mmol) were sequentially added to compound 149d (360 mg, 4.23 mmol) in N,N-dimethylformamide (4 mL) at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 16 hours. After the reaction was completed, the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a mixture of compounds 149e and 149f (120 mg). MS m / z (ESI): 158.0 [M+1] + .

[0531] Fifth Step: Synthesis of compounds 149g, 149h

[0532] N-bromosuccinimide (916.9 mg, 5.15 mmol) was added to a solution of compound 149e and 149f (810 mg, 5.15 mmol) in acetonitrile (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-30%) to give a mixture of compounds 149g and 149h (610 mg). MS m / z (ESI): 235.9, 237.9 [M+1, M+3] + .

[0533] Step 6: Synthesis of compounds 149i, 149j

[0534] Compound 149g and 149h (300 mg, 1.27 mmol), bis(pinacolato)diboron (322.6 mg, 1.27 mmol), Pd(dppf)Cl2(92.9 mg, 0.13 mmol) and potassium acetate (124.7 mg, 1.27 mmol) were sequentially added to dimethyl sulfoxide (3 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h after being replaced with nitrogen. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-30%) to give a mixture of compounds 149i and 149j (210 mg). MS m / z (ESI): 284.1 [M+1] + .

[0535] Step 7: Synthesis of compounds 149, 171

[0536] To a mixture of compound 149i and 149j (20 mg, 0.071 mmol), compound 53a (34.1 mg, 0.071 mmol), Pd(dppf)Cl2(5.2 mg, 0.007 mmol) and potassium carbonate (19.5 mg, 0.14 mmol) was added to a mixture of 1,4-dioxane and water (0.5 mL / 0.1 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 15%) to give the crude product, which was further purified by preparative high performance liquid chromatography (Instrument: Agilent 1290 rapid preparation instrument; Column: C18 reversed phase column; Mobile phase: acetonitrile-water (0.1% formic acid); Gradient: 20-90%) to give compound 149 (1.23 mg) and 171 (4.06 mg).

[0537] Compound 149: MS m / z (ESI): 558.9 [M+1] + .

[0538] Compound 171: MS m / z (ESI): 558.9 [M+1] + .

[0539] Example 36 (Compound 154)

[0540] First Step: Synthesis of compound 154c

[0541] To a mixture of compound 154a (21.8 g, 118.1 mmol) was added compound 154b (17.6 g, 118.1 mmol) and potassium carbonate (16.3 g, 118.1 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction mixture was quenched with saturated brine (50 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 154c (7.82 g). MS m / z (ESI): 527.0 [2M+23] + .

[0542] Second Step: Synthesis of compound 154d

[0543] Compound 154c (5.1 g, 20.2 mmol) was dissolved in DCM (5 mL) at room temperature, and m-chloroperoxybenzoic acid (4.92 g, 24.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium thiosulfate (50 mL x 2), and the reaction mixture was stirred for another 2 hours. Saturated sodium bicarbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to obtain compound 154d (2.24 g). MS m / z (ESI): 269.1 [M+1] + .

[0544] Step 3: Synthesis of compound 154e

[0545] Compound 154d (2.24 g, 8.3 mmol) was dissolved in DMF (30 mL) at room temperature, and potassium carbonate (3.46 g, 25.0 mmol) was added. The reaction mixture was stirred at 120°C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to obtain compound 154e (962 mg). MS m / z (ESI): 169.1 [M+Boc] + .

[0546] Step 4: Synthesis of compound 154f

[0547] N-Bromosuccinimide (916.2 mg, 5.1 mmol) was added to a solution of compound 154e (962 mg, 5.7 mmol) in acetonitrile (10 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding water (1 mL), and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0-10 / 1) to obtain compound 154f (1.37 g). MS m / z (ESI): 246.9 / 248.9 [M+1, M+3] + .

[0548] Step 5: Synthesis of compound 154g

[0549] Boronic acid pinacol ester (1.69 g, 6.7 mmol), 1,1-bisdiphenylphosphinyl ferrocene palladium dichloride dichloromethane complex (0.4 g, 0.6 mmol) and potassium acetate (1.09 g, 11.1 mmol) were added to a solution of compound 154f (1.37 g, 5.5 mmol) in DMSO (5 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 18 h. After completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 154g (453 mg). MS m / z (ESI): 295.1 [M+1] + .

[0550] Step 5: Synthesis of compound 154

[0551] Compound 53a (49.2 mg, 0.1 mmol), 1,1-bisdiphenylphosphinyl ferrocene palladium dichloride dichloromethane complex (7.5 mg, 0.01 mmol) and potassium carbonate (28.2 mg, 0.2 mmol) were added to a solution of compound 154g (30 mg, 0.1 mmol) in a mixture of 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 18 h. After completion of the reaction, the reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 154 (3.9 mg). MS m / z (ESI): 569.8 [M+1] + .

[0552] 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.26 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.79 (s, 1H), 5.27 (t, J = 6.7 Hz, 2H), 5.03 (s, 1H), 4.53 - 4.46 (m, 2H), 1.44 - 1.42 (m, 2H), 1.31 - 1.29 (m, 2H), 1.27 (s, 3H), 1.12 (s, 3H).

[0553] Example 37 (Compound 158)

[0554] First Step: Synthesis of compound 158a

[0555] Lithium hydroxide (46.5 mg, 1.9 mmol) was added to a mixture of compound 1c (150 mg, 0.4 mmol) in methanol and water (5 mL / 1 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the pH was adjusted to 5 by adding hydrochloric acid (1 N, 20 mL), and the reaction solution was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 158a (178 mg). MS m / z (ESI): 321.9 [M+1] + .

[0556] Second Step: Synthesis of compound 158b

[0557] Ammonium chloride (21.8 mg, 0.4 mmol), HATU (155.3 mg, 0.4 mmol), and DIEA (43.9 mg, 0.3 mmol) were added to a solution of compound 158a (158 mg, 0.3 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 158b (170 mg). MS m / z (ESI): 320.0 [M+1] + .

[0558] Third Step: Synthesis of compound 158

[0559] Compound 158b (11.5 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (6.6 mg, 0.007 mmol), cesium carbonate (23.5 mg, 0.07 mmol), and XantPhos (4.2 mg, 0.007 mmol) were added to a solution of compound 141e (20 mg, 0.04 mmol) in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 100°C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 158 (4.81 mg). MS m / z (ESI): 572.0 [M+1] + .

[0560] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.41 (d, J = 11.4 Hz, 1H), 4.74 (s, 1H), 4.54 - 4.45 (m, 1H), 3.97 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.45 - 1.39 (m, 2H), 1.32 - 1.29 (m, 2H), 1.10 (s, 6H). 6) H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.41 (d, J = 11.4 Hz, 1H), 4.74 (s, 1H), 4.54 - 4.45 (m, 1H), 3.97 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.45 - 1.39 (m, 2H), 1.32 - 1.29 (m, 2H), 1.10 (s, 6H).

[0561] Example 38 (Compound 159)

[0562] First Step: Synthesis of Compound 159

[0563] Trimethylaluminum (2 M in n-hexane) (0.2 mL, 0.33 mmol) was added to a solution of compound 1c (38 mg, 0.11 mmol) and compound 143e (38.2 mg, 0.16 mmol) in toluene (3 mL) at 0 °C under nitrogen protection. The reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 159 (5.9 mg). MS m / z (ESI): 536.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.41 (d, J = 11.4 Hz, 1H), 4.74 (s, 1H), 4.54 - 4.45 (m, 1H), 3.97 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.45 - 1.39 (m, 2H), 1.32 - 1.29 (m, 2H), 1.10 (s, 6H).

[0564] Example 39 (Compound 161)

[0565] First Step: Synthesis of Compound 161

[0566] To a solution of compound 158b (30 mg, 0.094 mmol) in 1,4-dioxane (2 mL) were added successively tris(dibenzylideneacetone)dipalladium (8.6 mg, 0.009 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.9 mg, 0.019 mmol), cesium carbonate (61.2 mg, 0.19 mmol) and compound 142d (32.6 mg, 0.10 mmol) at room temperature. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give compound 161 (3.48 mg). MS m / z (ESI): 553.9 [M+1] + .

[0567] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.11 - 8.07 (m, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 54.9 Hz, 1H), 4.75 (s, 1H), 4.55 - 4.47 (m, 1H), 3.97 (s, 2H), 2.37 (s, 3H), 1.49 - 1.40 (m, 2H), 1.33 - 1.27 (m, 2H), 1.10 (s, 6H).

[0568] Example 40 (compound 162-P1)

[0569] First Step: Synthesis of compound 162b

[0570] To a solution of compound 162a (2 g, 13.3 mmol) in ethanol (20 mL) were added successively hydroxylamine hydrochloride (1.38 g, 20.00 mmol) and DIEA (0.76 mL, 9.86 mmol) at room temperature. The reaction mixture was heated to 80 °C and stirred for 2 h. After completion of the reaction, water (10 mL) was added to the reaction mixture and a white solid precipitated. The solid was filtered and washed with water (4 mL). The solid was dried to give compound 162b (1.5 g). MS m / z (ESI): 183.96 [M+1] + .

[0571] Second Step: Synthesis of compound 162c

[0572] CDI (0.88 g, 0.005 mmol) and compound 62c (0.57 g, 0.005 mmol) were dissolved in NMP (15 mL) at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. Compound 162b (1 g, 0.005 mmol) was added again, and the reaction mixture was warmed to 120 °C and stirred for 30 minutes. After the reaction was completed, the reaction solution was cooled to room temperature, water (5 mL) was added to quench the reaction, extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to obtain compound 162c (300 mg). MS m / z (ESI): 252.0 [M+1] + .

[0573] Third step: synthesis of compound 162-P1

[0574] Trimethylaluminum (0.2 mL, 0.17 mmol, 2M n-hexane solution) was added to a solution of compound 1c (30 mg, 0.086 mmol) and compound 162c (32.5 mg, 0.13 mmol) in toluene (3 mL) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by thin layer silica gel plate chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 162-P1 (36 mg). MS m / z (ESI): 554.0 [M+1] + .

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 11.3 Hz, 1H), 5.37-5.21 (m, 1H), 4.74 (s, 1H), 3.97 (s, 2H), 3.14-3.03 (m, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.02-1.88 (m, 1H), 1.62-1.57 (m, 1H), 1.09 (s, 6H).

[0576] Example 41 (compound 167)

[0577] First step: synthesis of compound 167

[0578] Trimethylaluminum (0.1 mL, 0.22 mmol, 2M in n-hexane) was added to a solution of compound 143e (38.2 mg, 0.16 mmol) and compound 125g (38 mg, 0.11 mmol) in toluene (3 mL) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, the reaction was concentrated under reduced pressure and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 167 (1.59 mg).

[0579] MS m / z (ESI): 535.9 [M+1] + .

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7.79 (s, 1H), 7.40 (d, J = 11.3 Hz, 1H), 5.47 (s, 1H), 4.53 - 4.46 (m, 1H), 4.24 (d, J = 11.0 Hz, 2H), 4.06 - 3.92 (m, 2H), 2.33 (s, 3H), 1.43 - 1.41 (m, 2H), 1.32-1.30 (m, 2H), 1.29 (s, 3H).

[0581] Example 42 (Compound 168-P1)

[0582] First Step: Synthesis of compound 168-P1

[0583] Trimethylaluminum (0.12 mL, 0.24 mmol, 2M in hexane) was added to a solution of compound 162c (30 mg, 0.12 mmol) and compound 116a (43 mg, 0.12 mmol) in toluene (1 mL) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, the reaction was concentrated under reduced pressure and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 168-P1 (27.9 mg). MS m / z (ESI): 568.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 11.3 Hz, 1H), 5.38 - 5.20 (m, 1H), 4.69 (s, 1H), 3.94 (s, 2H), 3.14 - 3.01 (m, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.98 - 1.92 (m, 1H), 1.61 - 1.57 (m, 1H), 1.14 (s, 6H).

[0584] Example 43 (Compound 155)

[0585] First Step: Synthesis of compound 155b

[0586] Compound 155a (6.64 g, 33.8 mmol) was dissolved in tetrahydrofuran and water (40 mL / 10 mL) at room temperature, diethyl acetonediphosphonate (13.0 mL, 67.7 mmol) and potassium carbonate (11.69 g, 84.61 mmol) were added successively, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was added to saturated brine (15 mL), extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 155b (2.8 g). MS m / z (ESI): 137.1.0 [M-100] + .

[0587] Second Step: Synthesis of compound 155c

[0588] Compound 155b (2.35 g, 10.0 mmol) was dissolved in methanol (20 mL) at room temperature, and Pd / C (0.74 g) was added, and the reaction mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 155c (2.2 g). MS m / z (ESI): 183.1 [M-56] + .

[0589] Third Step: Synthesis of compound 155d

[0590] Compound 155c (2.2 g, 9.2 mmol) was added to the reaction mixture at room temperature, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction mixture was added to saturated brine (15 mL), extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 155d (6.5 g). MS m / z (ESI): 153.0 [M-100] + .

[0591] Fourth step: synthesis of compound 155e

[0592] Compound 155d (3.4 g, 8.1 mmol) was dissolved in DMF (30 mL) at room temperature, and potassium carbonate (2.23 g, 16.2 mmol) was added, and then the reaction mixture was stirred at 120°C for 18 hours. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 155e (778 mg). MS m / z (ESI): 153.1 [M+1] + .

[0593] Fifth step: synthesis of compound 155f

[0594] N-bromosuccinimide (396.5 mg, 2.2 mmol) was added to a solution of compound 155e (678 mg, 2.2 mmol) in acetonitrile (5 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding water (1 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 155f (778 mg). MS m / z (ESI): 230.9 / 232.9 [M+1, M+3] + .

[0595] Sixth step: synthesis of compound 155g

[0596] To a solution of compound 155f (200 mg, 0.86 mmol) in dioxane (5 mL) were added bis(pinacolato)diboron (219.7 mg, 0.9 mmol), palladium acetate (19.4 mg, 0.09 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (41.26 mg, 0.09 mmol) and potassium acetate (169.9 mg, 1.7 mmol) sequentially at room temperature. The reaction mixture was stirred at 100 °C for 18 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 155g (132 mg). MS m / z (ESI): 279.0 [M+1] + .

[0597] Seventh step: synthesis of compound 155

[0598] To a solution of compound 53a (97.2 mg, 0.2 mmol), Pd(dppf)Cl2(14.7 mg, 0.02 mmol) and potassium carbonate (55.6 mg, 0.02 mmol) in 1,4-dioxane and water (5 mL / 1 mL) were added compound 155g (56 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 155 (5.23 mg).

[0599] MS m / z (ESI): 553.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.82 (s, 1H), 4.99 (s, 1H), 4.55-4.48 (m, 1H), 3.97 (d, J = 3.0 Hz, 2H), 3.01-2.95 (m, 2H), 1.96-1.88 (m, 1H), 1.86-1.78 (m, 1H), 1.45-1.40 (m, 2H), 1.32 (s, 3H), 1.31-1.27 (m, 2H).

[0600] Example 44 (Compound 156)

[0601] First Step: Synthesis of compound 156b

[0602] Compound la (50 mg, 0.18 mmol), tetra-triphenylphosphonium palladium (21 mg, 0.02 mmol) and potassium carbonate (50 mg, 0.36 mmol) were added to a mixture solution of compound 156a (40.7 mg, 0.18 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 18 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 156b (43 mg). MS m / z (ESI): 293.0 [M+1] + .

[0603] Second Step: Synthesis of compound 156

[0604] Trimethylaluminum (2 M in n-hexane, 0.17 mL, 0.34 mmol) was added dropwise to a solution of compound 156b (33 mg, 0.11 mmol) and compound Id (28.63 mg, 0.11 mmol) in toluene (5 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to give compound 156 (6.66 mg). MS m / z (ESI): 499.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 6.05 (s, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.55-4.49 (m, 1H), 3.87-3.77 (m, 1H), 2.47-2.37 (m, 2H), 2.14-2.04 (m, 1H), 1.89-1.82 (m, 1H), 1.67 - 1.58 (m, 1H), 1.45 - 1.40 (m, 2H), 1.33-1.28 (m, 2H).

[0605] Example 45 (Compound 160)

[0606] First Step: Synthesis of compound 160a

[0607] Cesium carbonate (155.1 mg, 0.48 mmol), Pd(dppf)Cl2(19.5 mg, 0.024 mmol), compound 1a (65.47 mg, 0.238 mmol) were added successively to a mixture of compound 154g (70 mg, 0.238 mmol, synthesis method refer to the synthesis of compound 154g in the fifth step of compound 154 in Reference Example 36) in 1,4-dioxane and water (3 mL / 1 mL) at room temperature. The reaction mixture was stirred at 85 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 160a (21 mg). MS m / z (ESI): 363.0 [M+1] + .

[0608] Second Step: Synthesis of compound 160

[0609] Trimethylaluminum (2M n-hexane solution) (0.06 mL, 0.12 mmol) was added to a solution of compound 143e (20.3 mg, 0.087 mmol, synthesis method refer to the synthesis of compound 143e in the fourth step of compound 143 in Reference Example 32) and compound 160a (21 mg, 0.058 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 160 (2.51 mg). MS m / z (ESI): 549.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.02 (d, J = 7.0 Hz, 1H), 7.78 (s, 1H), 7.40 (d, J = 11.3 Hz, 1H), 5.29-5.25 (m, 2H), 5.02 (s, 1H), 4.52–4.45 (m, 2H), 2.33 (s, 3H), 1.44–1.38 (m, 2H), 1.30-1.29 (m, 2H), 1.27 (s, 3H), 1.12 (s, 3H).

[0610] Example 46 (Compound 163-P1)

[0611] First Step: Synthesis of compound 163-P1

[0612] To a solution of compound 160a (30 mg, 0.083 mmol) in toluene (1 mL) was added compound 162c (22.9 mg, 0.091 mmol) under ice-bath nitrogen atmosphere, then 2M trimethylaluminum in n-hexane (0.17 mL, 0.33 mmol) was added slowly dropwise. After the addition was completed, the reaction mixture was warmed to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 °C and quenched by the slow addition of methanol (2 mL). The mixture was filtered and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, mobile phase: acetonitrile - water (0.1% formic acid); gradient: 20-95%) to give compound 164-P1 (8.7 mg). MS m / z (ESI): 567.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.87 (d, J = 10.1 Hz, 1H), 7.79 (s, 1H), 5.40 - 5.20 (m, 3H), 5.03 (s, 1H), 4.51 - 4.46 (m, 1H), 3.16 - 3.03 (m, 1H), 2.03 - 1.90 (m, 1H), 1.65 - 1.57 (m, 1H), 1.27 (s, 3H), 1.12 (s, 3H).

[0613] Example 47 (Compound 164-P1)

[0614] First Step: Synthesis of compound 164-P1

[0615] To a solution of compound 160a (30 mg, 0.083 mmol) in toluene (1 mL) was added compound 162c (22.9 mg, 0.091 mmol) under ice-bath nitrogen atmosphere, then 2M trimethylaluminum in n-hexane (0.17 mL, 0.33 mmol) was added slowly dropwise. After the addition was completed, the reaction mixture was warmed to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 °C and quenched by the slow addition of methanol (2 mL). The mixture was filtered and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, mobile phase: acetonitrile - water (0.1% formic acid); gradient: 20-95%) to give compound 164-P1 (8.7 mg). MS m / z (ESI): 567.9 [M+1] + .

[0616] 1H NMR (400 MHz, CDC13) δ 8.32 (d, J = 6.7 Hz, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 7.06 (d, J = 10.7 Hz, 1H), 5.17 (t, J = 9.1 Hz, 1H), 5.07-4.92 (m, 1H), 5.02 (m, 1H), 4.45 (dd, J = 8.7, 5.3 Hz, 1H), 2.70-2.64 (m, 1H), 2.45 (s, 1H), 2.33 (s, 3H), 1.81-1.73 (m, 1H), 1.59-1.54 (m, 1H), 1.28 (s, 3H), 1.15 (s, 3H).

[0617] Example 48 (Compound 169-P1)

[0618] First Step: Synthesis of compound 169b

[0619] Compound 169a (0.49 mL, 5.40 mmol) and cesium carbonate (2.93 g, 9.0 mmol) were added to a solution of compound 53b (1 g, 4.5 mmol) in DMF (20 mL) at room temperature, and the reaction mixture was heated to 80 °C and stirred for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (15 mL x 2), and the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 169b (700 mg). MS m / z (ESI): 311.1 [M+1] + .

[0620] Second Step: Synthesis of compound 169c

[0621] Compound 169b (700 mg, 2.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (165 mg, 0.23 mmol) and cesium carbonate (1.47 g, 4.5 mmol) were added to a mixture of compound 1a (620 mg, 2.3 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred for 18 h under a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 169c (211 mg). MS m / z (ESI): 378.9 [M+1] + .

[0622] Third Step: Synthesis of compound 169-P1

[0623] A solution of compound 169c (100 mg, 0.26 mmol) and compound 1d (67 mg, 0.26 mmol) in toluene (5 mL) was added dropwise with a solution of trimethylaluminum in n-hexane (2 M, 0.4 mL, 0.79 mmol) under ice bath. The reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 18 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give a crude product, which was further purified by high performance liquid preparative chromatography (column: Agilent Pursuit XRs C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 169-P1 (57.51 mg). MS m / z (ESI): 585.9 [M+1] C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 169-P1 (57.51 mg). MS m / z (ESI): 585.9 [M+1] + .

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 5.14 (d, J = 5.0 Hz, 1H), 4.55-4.48 (m, 1H), 4.09–4.02 (m, 1H), 4.00–3.93 (m, 2H), 3.32–3.30 (m, 2H), 3.29 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.45–1.40 (m, 2H), 1.33–1.27 (m, 2H).

[0625] Example 49 (compound 178-P1)

[0626] First Step: Synthesis of compound 178-P1

[0627] A solution of compound 169c (100 mg, 0.26 mmol) and compound 143e (61.6 mg, 0.26 mmol) in toluene (5 mL) was added dropwise with a solution of trimethylaluminum in n-hexane (2 M, 0.4 mL, 0.79 mmol) under ice bath. The reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 18 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give a crude product, which was further purified by high performance liquid preparative chromatography (column: Agilent Pursuit XRs C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 178-P1 (32.94 mg). MS m / z (ESI): 565.9 [M+1] + .

[0628] 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 11.3 Hz, 1H), 5.16 (d, J = 4.8 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.11 - 4.03 (m, 1H), 4.01 - 3.93 (m, 2H), 3.35-3.32 (m, 2H), 3.30 (s, 3H), 2.35 (d, J = 6.5 Hz, 6H), 2.25 (s, 3H), 1.45 - 1.38 (m, 2H), 1.32 - 1.26 (m, 2H).

[0629] Example 50 (compound 169-P2)

[0630] First Step: synthesis of compound 169e

[0631] Compound 169d (396.7 mg, 4.50 mmol) and cesium carbonate (1.5 g, 4.50 mmol) were added to a solution of compound 53b (500 mg, 2.25 mmol) in DMF (5 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was directly used for the next step synthesis. MS m / z (ESI): 311.1 [M+1] + .

[0632] Second Step: synthesis of compound 169f

[0633] Palladium(II) chloride [1,1'-bis(diphenylphosphino)ferrocene] complex (158.3 mg, 0.19 mmol), compound 1a (266 mg, 0.97 mmol) and water (1 mL) were added successively into the above reaction solution at room temperature, and the reaction mixture was heated to 80 °C under nitrogen atmosphere and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to obtain compound 169f (160 mg). MS m / z (ESI): 379.0 [M+1] + .

[0634] Step 3: Synthesis of compound 169-P2

[0635] 2M trimethylaluminum n-hexane solution (0.2 mL, 0.42 mmol) was added to a solution of compound 169f (80 mg, 0.21 mmol) and compound 1d (59 mg, 0.23 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was quenched with sodium sulfate decahydrate (1 g), and the resulting mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 169-P2 (11.87 mg).

[0636] MS m / z (ESI): 585.8 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.28 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 5.14 (d, J = 5.0 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.09 - 4.02 (m, 1H), 3.97 (dd, J = 10.1, 6.2 Hz, 2H), 3.31 (s, 2H), 3.29 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 1.45 - 1.39 (m, 2H), 1.33 - 1.27 (m, 2H).

[0637] Example 51 (Compound 178-P2)

[0638] First Step: Synthesis of Compound 178-P2

[0639] A 2 M solution of trimethylaluminum in n-hexane (0.2 mL, 0.42 mmol) was added to a solution of compound 169f (80 mg, 0.21 mmol, synthesis method refer to the synthesis of compound 169f in Example 50 of this application) and compound 143e (54.2 mg, 0.23 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was quenched with sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 178-P2 (13.3 mg). MS m / z (ESI): 565.8 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 11.4 Hz, 1H), 5.21 - 5.12 (m, 1H), 4.55 - 4.46 (m, 1H), 4.11 - 4.03 (m, 1H), 4.02 - 3.92 (m, 2H), 3.34 - 3.31 (m, 2H), 3.30 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.46 - 1.38 (m, 2H), 1.32 - 1.25 (m, 2H).

[0640] Example 52 (Compound 172)

[0641] First Step: Synthesis of Compound 172b

[0642] Palladium on carbon (10% wt, 150 mg, 1.41 mmol), palladium hydroxide on carbon (20% wt, 150 mg, 1.06 mmol) were added to a solution of compound 172a (500 mg, 2.84 mmol) in methanol (20 mL) at room temperature. The reaction mixture was stirred at 60 °C under hydrogen atmosphere (5 atm) for 24 h. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give compound 172b (450 mg, crude), which was used in the next step without further purification. MS m / z (ESI): 181.05 [M+1] + .

[0643] Second Step: Synthesis of compound 172c

[0644] Methyl magnesium bromide in tetrahydrofuran (3.0 M, 2.77 mL, 8.32 mmol) was added to a solution of compound 172b (500 mg, 2.77 mmol) in tetrahydrofuran (5 mL) at 0 °C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to give compound 172c (500 mg). MS m / z (ESI): 181.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 1.6 Hz, 1H), 5.95 (s, 1H), 4.26 - 4.18 (m, 1H), 3.74 (t, J = 12.2 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.64 - 2.53 (m, 1H), 2.07 - 1.98 (m, 1H), 1.97 - 1.86 (m, 1H), 1.46 - 1.34 (m, 1H), 1.16 (s, 3H), 1.14 (s, 3H).

[0645] Third Step: Synthesis of compound 172d

[0646] NBS (444.4 mg, 2.50 mmol) was added to a solution of compound 172c (450 mg, 2.50 mmol) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0:1 ~ 1:10) to give compound 172d (450 mg). MS m / z (ESI): 259.0, 261.0 [M+1, M+3] + .

[0647] Fourth Step: Synthesis of compound 172e

[0648] Borane pinacol (133.3 mg, 1.04 mmol), triethylamine (0.1 mL, 0.7 mmol), and palladium (Pd) chloro(triphenylphosphine) (24.4 mg, 0.04 mmol) were added successively to a solution of compound 172d (90 mg, 0.35 mmol) in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at 110 °C under nitrogen atmosphere for 12 h. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 ~ 2:1) to give compound 172e (70 mg). MS m / z (ESI): 307.1 [M+1] + .

[0649] Fifth Step: Synthesis of compound 172

[0650] Compound 172e (45.7 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium (Pd) dichloride dichloromethane complex (10.2 mg, 0.01 mmol), and potassium carbonate (K2CO3) (34.4 mg, 0.25 mmol) were added successively to a solution of compound 53a (60 mg, 0.12 mmol) in 1,4-dioxane / water (2 mL / 0.4 mL) at room temperature. The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 172 (2.1 mg). MS m / z (ESI): 582.05 [M+1] + .

[0651] 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.82 (s, 1H), 4.55 (s, 1H), 4.54 - 4.48 (m, 1H), 4.28 (dd, J = 12.5, 5.2 Hz, 1H), 3.84 (t, J = 12.1 Hz, 1H), 3.12 (dd, J = 16.8, 3.8 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.17 - 2.11 (m, 1H), 2.02 - 1.94 (m, 1H), 1.56 - 1.47 (m, 1H), 1.45 - 1.38 (m, 2H), 1.33 - 1.27 (m, 2H), 1.19 (s, 3H), 1.16 (s, 3H).

[0652] Example 53 (Compound 173-P1 and 173-P2)

[0653] First Step: Synthesis of Compound 173-P1 and 173-P2

[0654] Under ice-bath, 2M trimethylaluminum in n-hexane (0.06 mL, 0.11 mmol) was added to a solution of compound 143e (13.7 mg, 0.06 mmol) and compound 118h (20 mg, 0.05 mmol, synthesis method refer to synthesis of 118h in example 29, sixth step) in toluene (2 mL) under nitrogen atmosphere, the reaction mixture was stirred at 100 °C for 3 hours. After completion of the reaction, the reaction was quenched with sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), the combined filtrate was concentrated under reduced pressure, the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give racemic product, which was further separated by chiral preparative chromatography (preparative column: Daicel CHIRALCEL IC, 250 mm*30 mm I.D.; flow rate: 25 mL / min column temperature: 35 °C; mobile phase: A: n-hexane B: isopropyl alcohol 30%) to give 173-P1 (6.1 mg) and 173-P2 (5.7 mg).

[0655] Compound 173-P1: MS m / z (ESI): 561.8 [M+1] + SFC retention time: t = 5.562 min.

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7.81 (s, 1H), 7.40 (d, J = 11.3 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.37 (s, 2H), 4.12 (q, J = 12.1 Hz, 2H), 3.91 - 3.81 (m, 2H), 3.69 (d, J = 9.1 Hz, 1H), 3.52 (d, J = 9.1 Hz, 1H), 2.34 (s, 3H), 1.97 - 1.87 (m, 1H), 1.85 - 1.76 (m, 1H), 1.47 - 1.37 (m, 2H), 1.33 - 1.27 (m, 2H).

[0657] Compound 173-P2: MS m / z (ESI): 561.9 [M+1] + SFC retention time: t = 7.444 min.

[0658] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7.81 (s, 1H), 7.40 (d, J = 11.3 Hz, 1H), 4.53 - 4.45 (m, 1H), 4.37 (s, 2H), 4.12 (q, J = 12.1 Hz, 2H), 3.92 - 3.82 (m, 2H), 3.69 (d, J = 9.1 Hz, 1H), 3.52 (d, J = 9.1 Hz, 1H), 2.33 (s, 3H), 1.97 - 1.87 (m, 1H), 1.84 - 1.76 (m, 1H), 1.44 - 1.38 (m, 2H), 1.33 - 1.28 (m, 2H).

[0659] Example 54 (Compound 174)

[0660] First Step: Synthesis of compound 174c

[0661] Triphenylphosphine (23.8 g, 90.841 mmol) and diisopropyl azodicarboxylate (18.4 g, 90.81 mmol) were added to a solution of compound 174a (12 g, 60.54 mmol), compound 174b (5.2 g, 60.54 mmol) in tetrahydrofuran (120 mL) at ice bath. The reaction mixture was stirred at room temperature for 16 hours after the addition was completed. The reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 174c (5.5 g).

[0662] Second Step: Synthesis of compound 174d

[0663] M-chloroperbenzoic acid (3.9 g, 22.72 mmol) was added to a solution of compound 174c (5.5 g, 20.65 mmol) in dichloromethane (55 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was completed, the reaction mixture was quenched by adding saturated sodium carbonate solution (50 mL), and the organic phase was washed with saturated sodium carbonate solution (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue gave compound 174d (6.1 g). MS m / z (ESI): 283.0 [M+1] + .

[0664] Third Step: Synthesis of compound 174e

[0665] Compound 174d (6.1 g, 21.61 mmol) and potassium carbonate (6.0 g, 43.21 mmol) were added into DMF (30 mL) at room temperature, replaced with nitrogen and heated to 130 °C for stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 174e (2.5 g). MS m / z (ESI): 182.97 [M+1] + .

[0666] Fourth Step: Synthesis of compound 174f

[0667] NBS (2.4 g, 13.72 mmol) was added into a solution of compound 174e (2.5 g, 13.72 mmol) in acetonitrile (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0-15%) to obtain compound 174f (2.8 g). MS m / z (ESI): 260.91, 262.91 [M+1, M+3] + .

[0668] Fifth Step: Synthesis of compound 174g

[0669] Pinacolborane (588.1 mg, 4.60 mmol), triethylamine (1 mL, 7 mmol) and Pd(PPh3)2Cl2(161.3 mg, 0.23 mmol) were sequentially added into a solution of compound 174f (600 mg, 2.30 mmol) in 1,4-dioxane (6 mL) at room temperature, and the reaction mixture was heated to 100 °C for stirring under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0-50%) to obtain compound 174g (410 mg). MS m / z (ESI): 309.04 [M+1] + .

[0670] Sixth Step: Synthesis of compound 174h

[0671] Compound 174g (160 mg, 0.52 mmol), compound la (50 mg, 0.18 mmol), potassium carbonate (25.1 mg, 0.18 mmol) and Pd(dppf)Cl2(133.0 mg, 0.18 mmol) were added successively into a mixture of 1,4-dioxane and water (1 mL / 0.2 mL) at room temperature. The reaction mixture was heated to 100 °C under nitrogen atmosphere for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-50%) to give compound 174h (51 mg). MS m / z (ESI): 377.06 [M+1] + .

[0672] Seventh step: synthesis of compound 174

[0673] Compound 174h (25 mg, 0.066 mmol) and compound Id (16.9 mg, 0.066 mmol) in toluene (0.5 mL) was slowly added 2M solution of trimethylaluminum in n-hexane (0.14 mL, 0.28 mmol) under nitrogen atmosphere at ice bath. The reaction mixture was heated to 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 15) to give compound 174 (10.8 mg). MS m / z (ESI): 584.18 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.60 (s, 1H), 8.37 - 8.28 (m, 2H), 7.92 (d, J = 10.1 Hz, 1H), 5.31 - 5.22 (m, 2H), 5.06 (s, 1H), 4.61 - 4.57 (m, 1H), 4.56 - 4.45 (m, 1H), 2.40 (s, 3H), 1.51 - 1.46 (m, 2H), 1.39 - 1.34 (m, 2H), 1.32 (s, 3H), 1.19 (s, 3H).

[0674] Example 55 (compound 175)

[0675] First step: synthesis of compound 175

[0676] A 2 M solution of trimethylaluminum in n-hexane (0.15 mL, 0.30 mmol) was slowly added to a solution of compound 174h (25 mg, 0.066 mmol, synthesis method refer to the synthesis of compound 174h in the sixth step of compound 174 in Example 54 of this application) and compound 1d (17.0 mg, 0.073 mmol) in toluene (0.5 mL) under nitrogen atmosphere with ice bath. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 15) to give compound 175 (10 mg). MS m / z (ESI): 564.2 [M+1] + .

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.46 (d, J = 11.3 Hz, 1H), 5.31 - 5.21 (m, 2H), 5.06 (s, 1H), 4.58 - 4.55 (m, 1H), 4.54 - 4.45 (m, 1H), 2.40 (d, J = 1.5 Hz, 6H), 1.49 - 1.45 (m, 2H), 1.39 - 1.34 (m, 2H), 1.32 (s, 3H), 1.19 (s, 3H).

[0678] Example 56 (Compound 176-P1)

[0679] First Step: Synthesis of compound 176a

[0680] Cesium carbonate (3.5 g, 10.81 mmol), (2S)-2-methyloxirane (65a) (0.63 g, 10.81 mmol) were added to a solution of compound 53b (1.2 g, 5.40 mmol) in DMF (12 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 3 hours. After the reaction was completed, the reaction was directly used for the next step without purification. MS m / z (ESI): 281.1 [M+1] + .

[0681] Second Step: Synthesis of compound 176b

[0682] Potassium carbonate (0.49 g, 3.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (29.2 mg, 0.036 mmol), compound 1a (0.59 g, 2.14 mmol) were added successively to a mixture of compound 176a (1 g, 3.57 mmol) in 1,4-dioxane and water (10 mL / 1 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 0 ~ 10 / 1) to give compound 176b (300 mg). MS m / z (ESI): 349.0 [M+1] + .

[0683] Step 3: Synthesis of compound 176-P1

[0684] Compound 143e (60.9 mg, 0.26 mmol) and compound 176b (70 mg, 0.20 mmol) in toluene (4 mL) was added 2M trimethylaluminum in n-hexane (0.4 mL, 0.80 mmol) under nitrogen atmosphere at ice bath. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 176-P1 (16.8 mg). MS m / z (ESI): 535.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 11.3 Hz, 1H), 4.92 (d, J = 4.8 Hz, 1H), 4.54 - 4.45 (m, 1H), 4.02 - 3.95 (m, 1H), 3.93 (d, J = 5.8 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.41 (d, J = 3.1 Hz, 2H), 1.33 - 1.26 (m, 2H), 1.11 (d, J = 5.9 Hz, 3H).

[0685] Example 57 (compound 176-P2)

[0686] Step 1: Synthesis of compound 176c

[0687] Compound (R)-epoxypropane (262.7 mg, 4.52 mmol) and cesium carbonate (1.5 g, 4.52 mmol) were added to a solution of compound 53b (500 mg, 2.26 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was used for the next step without purification. MS m / z (ESI): 281.1 [M+1] + .

[0688] Second Step: Synthesis of compound 176d

[0689] Palladium [1,1'-bis(diphenylphosphino)ferrocene] dichloride dichloromethane complex (175.3 mg, 0.21 mmol), compound 1a (294.6 mg, 1.07 mmol) and water (1 mL) were added to the reaction mixture of 176c (2.26 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 ~ 0:1) to give compound 176d (160 mg). MS m / z (ESI): 349.0 [M+1] + .

[0690] Third Step: Synthesis of compound 176-P2

[0691] 2M solution of trimethylaluminum in n-hexane (0.3 mL, 0.6 mmol) was added to a solution of compound 143e (58.9 mg, 0.25 mmol) and compound 176d (80 mg, 0.23 mmol) in toluene (2 mL) under nitrogen atmosphere at ice bath. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was quenched with sodium sulfate decahydrate (1 g) and the mixture was filtered. The filter cake was washed with ethyl acetate (5 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 176-P2 (17.7 mg).

[0692] MS m / z (ESI): 535.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.04 (dd, J = 7.0, 2.5 Hz, 1H), 7.41 (d, J = 11.4 Hz, 1H), 4.93 (s, 1H), 4.56 - 4.45 (m, 1H), 4.07 - 3.89 (m, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 1.44 - 1.38 (m, 2H), 1.33 - 1.26 (m, 2H), 1.14 - 1.10 (m, 3H).

[0693] Example 58 (Compound 177)

[0694] First Step: Synthesis of compound 177a

[0695] Compound 172e (46 mg, 0.15 mmol, for the synthesis method, please refer to the synthesis of compound 172e in the fourth step of compound 172 in example 52), potassium carbonate (63.1 mg, 0.46 mmol) and Pd(dppf)Cl2(11.1 mg, 0.015 mmol) were added to a mixture solution of compound 1a (42 mg, 0.15 mmol) in 1,4-dioxane and water (1 mL / 0.2 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0-100%) to give compound 177a (36 mg). MS m / z (ESI): 375.0 [M+1] + .

[0696] Second Step: Synthesis of compound 177

[0697] A 2 M solution of trimethylaluminum in n-hexane (0.10 mL, 0.192 mmol) was added dropwise to a solution of compound 177a (36 mg, 0.096 mmol) and compound 143e (26.9 mg, 0.115 mmol) in toluene (1 mL) under nitrogen atmosphere with ice-bath cooling. The reaction mixture was heated to 100 °C and stirred for 2 h. After completion of the reaction, the reaction was quenched by the addition of sodium sulfate decahydrate (1 g) and the mixture was filtered. The filter cake was washed with ethyl acetate (5 mL) and the combined filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 177 (1.01 mg). MS m / z (ESI): 561.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 11.4 Hz, 1H), 4.56 (s, 1H), 4.54 - 4.46 (m, 1H), 4.28 (dd, J = 12.8, 4.8 Hz, 1H), 3.84 (t, J = 12.2 Hz, 1H), 3.13 (dd, J = 16.8, 3.8 Hz, 1H), 2.85 - 2.81 (m, 1H), 2.34 (s, 3H), 2.15 - 2.13 (m, 1H), 2.01 - 1.98 (m, 1H), 1.47 - 1.46 (m, 1H), 1.45 - 1.39 (m, 2H), 1.32 - 1.30 (m, 2H), 1.29 - 1.18 (m, 6H).

[0698] Example 59 (Compound 179-P1)

[0699] First Step: Synthesis of compound 179a

[0700] Compound (S)-glycidol (0.67 g, 9.01 mmol) and cesium carbonate (2.93 g, 9.01 mmol) were added to a solution of compound 53a (1 g, 4.5 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction was used directly for the next step without any workup. MS m / z (ESI): 297.0 [M+1] + .

[0701] Step 2: Synthesis of compound 179b

[0702] PdCl2[PPh3]2(148.8 mg, 0.18 mmol), Cs2CO3(1.18 g, 3.64 mmol), compound 1a (500 mg, 1.82 mmol) and compound 179a (1.2 g, 4.00 mmol) were added successively into a mixed solvent of N,N-dimethylformamide and water (10 mL / 2 mL) at room temperature. The reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction solution was extracted with ethyl acetate (80 mL), washed successively with water (30 mL x 3) and saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 ~ 30 / 1) to give compound 179b (198 mg).

[0703] MS m / z (ESI): 364.9 [M+1] + .

[0704] Step 3: Synthesis of compound 179-P1

[0705] Trimethylaluminum in n-hexane (2 M, 0.17 mL, 0.34 mmol) was added into a solution of compound 179b (40 mg, 0.11 mmol) and compound 1d (33.4 mg, 0.13 mmol) in toluene (1 mL) under ice bath. The reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution (1 mL), extracted with dichloromethane / methanol = 10 / 1 (30 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (preparative column: Agilent 1290 HPLC C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 179-P1 (10.7 mg). MS m / z (ESI): 571.8 [M+1] + .

[0706] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 4.98 (d, J = 5.4 Hz, 1H), 4.77 (t, J = 5.6 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.11 (dd, J = 13.9, 3.7 Hz, 1H), 3.93 (dd, J = 14.0, 8.0 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.42 - 3.36 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 1.42 (d, J = 3.5 Hz, 2H), 1.33 - 1.28 (m, 2H).

[0707] Example 60 (Compound 179-P2)

[0708] First Step: Synthesis of compound 179c

[0709] (R)-glycidol (670 mg, 9.01 mmol) and cesium carbonate (2.93 g, 4.76 mmol) were added to a solution of compound 53b (1 g, 4.50 mmol) in DMF (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature and directly used for the next reaction. MS m / z (ESI): 297.1 [M+1] + .

[0710] Second Step: Synthesis of compound 179d

[0711] Compound 1a (460 mg, 1.69 mmol), Pd(dppf)Cl2(250 mg, 0.34 mmol) were added to the reaction solution of the previous step at room temperature. The reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 179d (242 mg). MS m / z (ESI): 365.0 [M+1] + .

[0712] Third Step: Synthesis of compound 179-P2

[0713] A 2 M solution of trimethylaluminum in n-hexane (0.25 mL, 0.49 mmol) was added dropwise to a solution of compound 179d (90 mg, 0.25 mmol) and compound 1d (69 mg, 0.27 mmol) in toluene (2 mL) under nitrogen atmosphere with ice-bath cooling. After the addition was completed, the reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched by the addition of sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plates (methanol / dichloromethane = 1 / 20) to give compound 179-P2 (11.8 mg).

[0714] MS m / z (ESI): 571.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 4.98 (d, J = 5.4 Hz, 1H), 4.77 (t, J = 5.6 Hz, 1H), 4.58 - 4.48 (m, 1H), 4.11 (dd, J = 14.0, 3.6 Hz, 1H), 3.96 - 3.91 (m, 1H), 3.82 (s, 1H), 3.43 - 3.36 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 1.47 - 1.40 (m, 2H), 1.33 - 1.28 (m, 2H).

[0715] Example 61 (Compound 180-P1)

[0716] First Step: Synthesis of compound 180-P1

[0717] A solution of trimethylaluminum in n-hexane (2 M, 0.17 mL, 0.34 mmol) was added to a solution of compound 179b (40 mg, 0.11 mmol, synthesis method refer to example 59, synthesis of compound 179-P1 second step 179b) and compound 143e (30.72 mg, 0.13 mmol) in toluene (1 mL) under nitrogen atmosphere with ice bath. The reaction mixture was heated to 100 °C and stirred for 1 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (1 mL), extracted with dichloromethane / methanol = 10 / 1 (30 mL), washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by high performance liquid preparative chromatography (column: Agilent 1290 HPLC C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 180-P1 (9.60 mg). MS m / z (ESI): 551.9 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.41 (d, J = 11.3 Hz, 1H), 5.03 - 4.96 (m, 1H), 4.78 (s, 1H), 4.52 - 4.46 (m, 1H), 4.11 (dd, J = 13.9, 3.6 Hz, 1H), 3.93 (dd, J = 13.9, 8.0 Hz, 1H), 3.83 (s, 1H), 3.38 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.46 - 1.38 (m, 2H), 1.32 - 1.27 (m, 2H).

[0718] Example 62 (compound 180-P2)

[0719] First step: synthesis of compound 180-P2

[0720] A 2 M solution of trimethylaluminum in n-hexane (0.17 mL, 0.33 mmol) was added dropwise to a solution of compound 179d (60 mg, 0.17 mmol, for the synthesis method, please refer to the synthesis of compound 179d in the second step of example 60 herein) and compound 143e (38 mg, 0.17 mmol) in toluene (2 mL) under nitrogen atmosphere with ice-bath cooling. After the addition was completed, the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, sodium sulfate decahydrate (1 g) was added to quench the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / methylene chloride = 1 / 20) to obtain compound 180-P2 (10.17 mg). MS m / z (ESI): 552.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 11.2 Hz, 1H), 4.97 (d, J = 5.4 Hz, 1H), 4.76 (t, J = 5.6 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.11 (dd, J = 14.0, 3.6 Hz, 1H), 3.93 (dd, J = 14.0, 8.0 Hz, 1H), 3.83 (s, 1H), 3.39 - 3.36 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.50 - 1.38 (m, 2H), 1.34 - 1.25 (m, 2H).

[0721] Example 63 (compound 182)

[0722] First step: synthesis of compound 182a

[0723] A 2 M solution of trimethylaluminum in n-hexane (1.1 mL, 2.2 mmol) was added dropwise to a solution of compound 1a (200 mg, 0.73 mmol) and compound 143e (169.6 mg, 0.73 mmol) in toluene (5 mL) under ice-bath cooling. The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-30%) to obtain compound 182a (274 mg). MS m / z (ESI): 461.8, 463.8 [M+1, M+3] + .

[0724] Second step: synthesis of compound 182

[0725] Compound 182a (83.1 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (13.1 mg, 0.018 mmol) and potassium carbonate (49.6 mg, 0.36 mmol) were added to a mixture of compound 155g (50 mg, 0.18 mmol, synthesis method refer to synthesis of intermediate 155g in example 43, sixth step of this application) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature. The reaction mixture was stirred at 100 °C for 18 hours. After completion of the reaction, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 182 (6.14 mg). MS m / z (ESI): 533.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.82 (s, 1H), 7.41 (d, J = 11.3 Hz, 1H), 4.99 (s, 1H), 4.53 - 4.47 (m, 1H), 3.97 (d, J = 2.9 Hz, 2H), 3.02 - 2.94 (m, 2H), 2.34 (s, 3H), 1.95 - 1.90 (m, 1H), 1.85 - 1.77 (m, 1H), 1.44 - 1.39 (m, 2H), 1.32 (s, 3H), 1.31 - 1.26 (m, 2H).

[0726] Example 64 (Compound 183)

[0727] First Step: Synthesis of compound 183b

[0728] Sodium hydride (2.4 g, 99.88 mmol) was added to a solution of compound 183a (10.3 mL, 99.88 mmol) in tetrahydrofuran (100 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction solution was cooled to -20 °C, and n-butyllithium (2.5 M n-hexane solution, 40 mL, 99.88 mmol) was added dropwise. The reaction mixture was stirred at -20 °C for 0.5 h, and a solution of compound 1-bromo-3-methyl-2-butene (14.9 g, 99.88 mmol) in tetrahydrofuran (30 mL) was added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1 h. After the reaction was completed, water (30 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 183b (14 g, crude), which was used directly in the next step. MS m / z (ESI): 169.1 [M+1] + .

[0729] Second step: synthesis of compound 183c

[0730] Tert-butyl hydrazinecarboxylate (11 g, 83.22 mmol) was added to a solution of compound 183b (14 g, 83.22 mmol) in acetic acid (70 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 183c (7.8 g, crude), which was used directly in the next step. MS m / z (ESI): 165.1 [M-Boc] + .

[0731] Third step: synthesis of compound 183d

[0732] M-chloroperbenzoic acid (10.2 g, 59.01 mmol) was added to a solution of compound 183c (7.8 g, 29.50 mmol) in dichloromethane (80 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated sodium sulfite aqueous solution (20 mL x 3), saturated sodium bicarbonate aqueous solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 183d (7.8 g, crude), which was used directly in the next step. MS m / z (ESI): 181.1 [M-Boc] + .

[0733] Fourth Step: Synthesis of compound 183e

[0734] Potassium carbonate (7.7 g, 55.64 mmol) was added to a solution of compound 183d (7.8 g, 27.82 mmol) in DMF (40 mL) at room temperature, and the reaction mixture was stirred at 125 °C for 16 h. After completion of the reaction, the potassium carbonate was removed by filtration, and the filtrate was concentrated to give crude compound 183e (7.8 g, crude), which was used directly in the next step. MS m / z (ESI): 181.1 [M+1] + .

[0735] Fifth Step: Synthesis of compound 183f

[0736] N-Bromosuccinimide (2.5 g, 13.87 mmol) was added to a solution of compound 183e (5 g, 13.87 mmol) in acetonitrile (30 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction solution was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 0 ~ 10 / 1) to give compound 183f (1.3 g). MS m / z (ESI): 258.9, 260.9 [M+1, M+3] + .

[0737] Sixth Step: Synthesis of compound 183g

[0738] Bis(pinacolato)diboron (2 g, 7.72 mmol), potassium acetate (1.13 g, 11.58 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (316 mg, 0.39 mmol) were sequentially added to a solution of compound 183f (1 g, 3.86 mmol) in 1,4-dioxane (20 mL) at room temperature, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. After completion of the reaction, the reaction solution was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 183g (100 mg). MS m / z (ESI): 307.1 [M+1] + .

[0739] Seventh Step: Synthesis of compound 183h

[0740] At room temperature, potassium carbonate (72 mg, 0.52 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (21 mg, 0.026 mmol), and compound 1a (72 mg, 0.26 mmol) were added sequentially to a mixed solution of compound 183 g (80 mg, 0.26 mmol) of 1,4-dioxane and water (4 mL / 1 mL). The reaction mixture was heated to 85 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with water (3 mL), the aqueous phase was extracted with ethyl acetate (5 mL × 3), the combined organic phases were washed with saturated brine (2 mL × 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 0 to 10 / 6) to give compound 183h (10 mg). MS m / z (ESI): 374.9 [M+1] + .

[0741] Step 8: Synthesis of Compound 183

[0742] Under a nitrogen atmosphere and in an ice bath, a 2M trimethylaluminum solution in n-hexane (0.04 mL, 0.08 mmol) was added to a toluene (1 mL) solution of compound 1d (10 mg, 0.04 mmol) and compound 183h (10 mg, 0.027 mmol). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 183 (2.31 mg). MS m / z (ESI): 581.8 [M+1] + .

[0743] Example 65 (Compound 186-P1)

[0744] Step 1: Synthesis of compounds 186a and 186b

[0745] At room temperature, cesium carbonate (3.13 g, 9.61 mmol) was added to a 10 mL DMF solution of compound 68c (1 g, 4.81 mmol) and compound 169d (0.51 g, 5.77 mmol). The reaction mixture was heated to 80 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly added to the next step. MS m / z (ESI): 297.09 [M+1] + .

[0746] Step 2: Synthesis of compounds 186c and 186d

[0747] At room temperature, compound 1a (650.2 mg, 2.36 mmol, synthesis method referred to the synthesis of compound Intermediate A on page 183 of patent WO2022136509A1) was added to a DMF (5 mL) solution of mixture 186a and 186b (700 mg, 2.36 mmol), followed by a mixed solution of 1,4-dioxane (73.2 mg, 0.10 mmol) of Pd(dppf)Cl2 and potassium carbonate (979.9 mg, 7.09 mmol) and water (10 mL / 2 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 186c (30 mg) and compound 186d (50 mg).

[0748] Compound 186c: MS m / z (ESI): 365.0 [M+1] + .

[0749] Compound 186d: MS m / z (ESI): 364.9 [M+1] + .

[0750] Step 3: Synthesis of compound 186-P1

[0751] At room temperature, a hexane solution of trimethylaluminum (2 M, 0.12 mL, 0.24 mmol) was added to a toluene (2 mL) solution of compound 186c (30 mg, 0.082 mmol) and compound 143e (23 mg, 0.099 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-75%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm) to obtain compound 186-P1 (3.59 mg). MS m / z (ESI): 551.9 [M+1] + .

[0752] 1H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.05 (d, J = 6. 8Hz,1H),7.45(s,1H),7.42(d,J=11.4Hz,1H),5.20(d,J=5.4Hz,1H),4.55–4 .45(m,1H),4.28–4.17(m,1H),4.14–4.05(m,1H),4.03–3.92(m,1H),3.32–3 .28(m,5H),2.42(s,3H),2.35(s,3H),1.45–1.37(m,2H),1.33–1.26(m,2H).

[0753] Example 66 (Compound 185-P1)

[0754] At room temperature, a hexane solution of trimethylaluminum (2M, 0.21 mL, 0.42 mmol) was added to a toluene (2 mL) solution of compound 186d (50 mg, 0.14 mmol) and compound 143e (38.4 mg, 0.17 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm) to give compound 185-P1 (4.04 mg). MS m / z(ESI): 551.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.52(s,1H),8.44(d,J=17.2Hz,1H),8.05-7.70(m,2H),7.41(d,J=11.6Hz,1H),5.21–5.15(m,1H),4. 53–4.46(m,1H),4.16–4.08(m,1H),4.04–3.94(m,2H),3.32–3.28(m, 5H),2.36(s,3H),2.34(s,3H),1.45–1.36(m,2H),1.33–1.27(m,2H).

[0755] Example 67 (Compounds 185-P2, 186-P2)

[0756] Step 1: Synthesis of compounds 186e and 186f

[0757] At room temperature, compound 169a (0.52 mL, 5.8 mmol) and Cs₂CO₃ (3.1 g, 9.6 mmol) were added to a DMF (20 mL) solution of compound 68c (1 g, 4.8 mmol). The reaction mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a mixture of 186e and 186f (700 mg). MS m / z (ESI): 297.0 [M+1] + .

[0758] Step 2: Synthesis of compound 186g, 186h

[0759] At room temperature, mixtures 186e and 186f (700 mg, 2.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (173 mg, 0.24 mmol), and cesium carbonate (1.54 g, 4.7 mmol) were added to a mixed solution of compound 1a (650 mg, 2.4 mmol) in 1,4-dioxane and water (5 mL / 1 mL). The reaction mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give a mixture of 186 g and 186 h (181 mg). MS m / z (ESI): 365.0 [M+1] + .

[0760] Step 3: Synthesis of compounds 185-P2 and 186-P2

[0761] Under ice bath conditions, a hexane solution of trimethylaluminum (2 M, 0.37 mL, 0.74 mmol) was added dropwise to a mixture of 186 g and 186 h (90 mg, 0.25 mmol) and a toluene (5 mL) solution of compound 143e (57.6 mg, 0.25 mmol). The reaction mixture was stirred at 100 °C for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane / methanol = 10 / 0-10 / 1) to obtain a crude product, which was then resolved by chiral preparative chromatography (preparative column: DAICEL IJ 4.6mm I.D.*250mmL 5μm; flow rate: 20mL / min; column temperature: room temperature; mobile phase: A:CO2 / MEOH[0.1%NH3 (7M Solution in MeOH)] = 65 / 35) to obtain compounds 185-P2 (12.35mg) and 186-P2 (9.43mg).

[0762] 185-P2:MS m / z(ESI):552.25[M+1] + Supercritical fluid chromatography (SFC): retention time = 7.351 min.

[0763] 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.52(s,1H),8.46(s,1H),8.04(d,J=7.0Hz,1H) ,7.77(s,1H),7.41(d,J=11.5Hz,1H),5.17(d,J=5.4Hz,1H),4.53–4.47(m,1H),4.18– 4.13(m,1H),4.09–4.03(m,1H),4.01–3.95(m,1H),3.36–3.34(m,1H),3.31(d,J=5.5 Hz,1H),3.30(s,3H),2.46(s,3H),2.34(s,3H),1.44–1.40(m,2H),1.32–1.28(m,2H).

[0764] 186-P2:MS m / z(ESI):552.20[M+1] + Supercritical fluid chromatography (SFC): Retention time = 8.891 min.

[0765] 1H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.52(s,1H),8.42(s,1H),8.09–8.01(m,2H),7.41(d,J=11.3Hz,1H),5.19(d,J=5.1Hz,1H),4.53–4.4 7(m,1H),4.17–4.10(m,1H),4.02–3.95(m,2H),3.31(s,2H),3.29(s, 3H),2.36(s,3H),2.34(s,3H),1.45–1.39(m,2H),1.33–1.27(m,2H).

[0766] Example 68 (Compounds 187-P1, 188-P1)

[0767] Step 1: Synthesis of compounds 187a and 187b

[0768] At room temperature, cesium carbonate (1.566 g, 4.81 mmol) and compound (R)-glycidyl (356.0 mg, 4.81 mmol) were added sequentially to a DMF (5 mL) solution of compound 68c (500 mg, 2.40 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was used directly for the next synthesis. MS m / z (ESI): 283.0 [M+1] +

[0769] Step 2: Synthesis of compounds 187c and 187d

[0770] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (174.1 mg, 0.21 mmol), compound 1a (292.5 mg, 1.06 mmol), and water (1 mL) were added sequentially to the reaction solution from the previous step. The reaction mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give mixtures 187c and 187d (200 mg). MS m / z (ESI): 351.0 [M+1] +

[0771] Step 3: Synthesis of compounds 187-P1 and 188-P1

[0772] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.29 mL, 0.57 mmol) was added to a toluene (2 mL) solution of compound 1d (79.6 mg, 0.31 mmol) and mixtures 187c and 187d (100 mg, 0.29 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The reaction solution was quenched with sodium sulfate decahydrate. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini C18; 21.2 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compounds 187-P1 (7.93 mg) and 188-P1 (7.92 mg).

[0773] 1878-P1:MS m / z(ESI):557.95[M+1] + Supercritical fluid chromatography (SFC): retention time = 5.289 min.

[0774] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.56(s,1H),8.47(s,1H),8.28(d,J=7.2Hz ,1H),7.86(d,J=10.1Hz,1H),7.76(s,1H),5.00(d,J=5.4Hz,1H),4.78(t,J=5.6Hz ,1H),4.59–4.43(m,1H),4.20(dd,J=14.1,3.7Hz,1H),4.09–3.97(m,1H),3.87–3 .80(m,1H),3.44–3.35(m,2H),2.47(s,3H),1.47–1.36(m,2H),1.34–1.26(m,2H).

[0775] 187-P1:MS m / z(ESI):557.95[M+1] + Supercritical fluid chromatography (SFC): retention time = 6.464 min.

[0776] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.56(s,1H),8.43(s,1H),8.28(d,J=7.2Hz,1 H),8.07(s,1H),7.86(d,J=10.1Hz,1H),5.02(d,J=5.4Hz,1H),4.77(t,J=5.6Hz,1H ),4.57–4.47(m,1H),4.18–4.16(m,1H),3.98–3.89(m,1H),3.86–3.78(m,1H),3.44 –3.37(m,1H),3.33–3.27(m,1H),2.36(s,3H),1.46–1.40(m,2H),1.34–1.27(m,2H).

[0777] Example 69 (Compounds 187-P2, 188-P2)

[0778] Step 1: Synthesis of compounds 187e and 187f

[0779] At room temperature, cesium carbonate (3.76 g, 11.54 mmol) and (S)-glycidyl (0.85 g, 11.54 mmol) were added to a 12 mL DMF solution of compound 68c (1.2 g, 5.77 mmol). The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, it was used directly in the next step without further treatment. MS m / z (ESI): 283.1 [M+1] + .

[0780] Step 2: Synthesis of compounds 187g and 187h

[0781] At room temperature, potassium carbonate (0.49 g, 3.54 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (0.29 g, 0.35 mmol), and compound 1a (0.59 g, 2.13 mmol) were added sequentially to a mixed solution of 1,4-dioxane and water (10 mL / 1 mL) of mixtures 187e and 187f (1 g, 3.54 mmol). The reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with water (10 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 0 to 10 / 1) to give mixture 187 g, 187 h (300 mg). MS m / z(ESI): 351.0 [M+1] + .

[0782] Step 3: Synthesis of compounds 187-P2 and 188-P2

[0783] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.4 mL, 0.80 mmol) was added to a toluene (4 mL) solution of compound 1d (65.9 mg, 0.26 mmol) and mixtures 187 g and 187 h (70 mg, 0.20 mmol). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to obtain the crude product. Further purification by SFC (Apparatus: SHIMADZU SFC-40P, Column: Chiralpak-IH-10, 30mm ID*250mmL, 10μm, Modifier: CO2 / MeOH[0.1% NH3 (7M Solution in MeOH)]=70 / 30, Total Flow: 80mL / min) yielded compound 188-P2 (11.89mg) and compound 187-P2 (10.37mg).

[0784] 188-P2:MS m / z(ESI):558.0[M+1] + Supercritical fluid chromatography (SFC): retention time = 9.041 min.

[0785] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.56(s,1H),8.43(s,1H),8.27(d,J=7.2Hz,1 H),8.06(s,1H),7.86(d,J=10.1Hz,1H),5.02(d,J=5.4Hz,1H),4.77(t,J=5.6Hz,1H) ,4.55–4.49(m,1H),4.18(dd,J=13.6,3.6Hz,1H),3.95–3.90(m,1H),3.87–3.77(m, 1H), 3.44–3.35 (m, 2H), 2.36 (s, 3H), 1.42 (dd, J = 6.7, 3.3Hz, 2H), 1.34–1.27 (m, 2H).

[0786] 187-P2:MS m / z(ESI):557.95[M+1] + Supercritical fluid chromatography (SFC): retention time = 11.368 min.

[0787] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.56(s,1H),8.47(s,1H),8.28(d,J=7.3Hz ,1H),7.86(d,J=10.1Hz,1H),7.76(s,1H),5.00(d,J=5.4Hz,1H),4.78(t,J=5.6Hz ,1H),4.55–4.49(m,1H),4.19(dd,J=14.1,3.8Hz,1H),4.04–3.99(m,1H),3.85–3 .80(m,1H),3.40–3.36(m,2H),2.46(s,3H),1.44–1.40(m,2H),1.33–1.28(m,2H).

[0788] Example 70 (Compounds 189-P1, 190-P1)

[0789] Step 1: Synthesis of compounds 189-P1 and 190-P1

[0790] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.29 mL, 0.57 mmol) was added to a toluene (2 mL) solution of mixtures 187c and 187d (100 mg, 0.29 mmol, synthesis method referred to step 2 of Example 68 for the synthesis of compounds 187c and 187d) and compound 143e (73.2 mg, 0.31 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated under reduced pressure. The residue was resolved by supercritical fluid chiral chromatography (equipment: SHIMADZU LC-30AD SFC, column: DAICEL IJ 4.6mm I.D.*250mmL 5μm, mobile phase: CO2 / MEOH [0.1% NH3 (7M Solution in MeOH)] = 65 / 35, total flow rate: 20mL / min) to obtain compounds 189-P1 (6.05mg) and 189-P2 (6.04mg).

[0791] 189-P1: Supercritical fluid chromatography (SFC): Retention time = 7.672 min. MS m / z (ESI): 538.00 [M+1] + .

[0792] 1H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.04 (d, J = 7.0Hz, 1H),7.76(s,1H),7.41(d,J=11.3Hz,1H),5.00(d,J=5.4Hz,1H),4.78(t,J=5.6Hz, 1H),4.56–4.45(m,1H),4.26–4.16(m,1H),4.09–3.98(m,1H),3.90–3.76(m,1H),3 .42–3.35(m,2H),2.47(s,3H),2.34(s,3H),1.45–1.37(m,2H),1.34–1.26(m,2H).

[0793] 190-P1: Supercritical fluid chromatography (SFC): Retention time = 10.119 min. MS m / z (ESI): 538.00 [M+1] + .

[0794] 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.52(s,1H),8.42(s,1H),8.06(s,1H),8.04(d,J=7. 0Hz,1H),7.41(d,J=11.4Hz,1H),5.02(d,J=5.4Hz,1H),4.77(t,J=5.6Hz,1H),4.54–4.45 (m,1H),4.18(dd,J=13.6,3.3Hz,1H),3.98–3.89(m,1H),3.87–3.78(m,1H),3.42–3.37(m ,1H),3.33–3.28(m,1H),2.36(s,3H),2.34(s,3H),1.45–1.38(m,2H),1.33–1.26(m,2H).

[0795] Example 71 (Compounds 189-P2, 190-P2)

[0796] Step 1: Synthesis of compounds 189-P2 and 190-P2

[0797] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.4 mL, 0.80 mmol) was added to a toluene (4 mL) solution of compound 143e (60.6 mg, 0.26 mmol) and mixture 187 g, 187 h (70 mg, 0.20 mmol, synthesis method referred to Example 69 for the synthesis of mixture 187 g and 187 h). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was purified by thin-layer chromatography on silica gel plates (dichloromethane / methanol = 20 / 1) to obtain crude product, which was then separated and purified by SFC (Apparatus: SHIMADZU SFC-40P, Column: Waters Torus 2-PIC OBD 19mm ID*250mm Column, 1 / pkg, Modifier: CO2 / MeOH (0.1% FA), Total Flow: 38ml / min) to obtain compound 190-P2 (8.18mg) and compound 189-P2 (3.18mg).

[0798] 190-P2:MS m / z(ESI):538.0[M+1] + Supercritical fluid chromatography (SFC): retention time = 7.404 min.

[0799] 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.52(s,1H),8.42(s,1H),8.06(s,1H),8.04(d, J=7.0Hz,1H),7.41(d,J=11.2Hz,1H),5.02(d,J=5.4Hz,1H),4.77(t,J=5.6Hz,1H),4 .53–4.47(m,1H),4.18(dd,J=13.6,3.6Hz,1H),3.96–3.90(m,1H),3.86–3.79(m,1H) ,3.43–3.37(m,2H),2.36(s,3H),2.34(s,3H),1.44–1.40(m,2H),1.32–1.29(m,2H).

[0800] 189-P2:MS m / z(ESI):538.0[M+1] + Supercritical fluid chromatography (SFC): retention time = 9.557 min.

[0801] 1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.52(s,1H),8.46(s,1H),8.04(d,J=7.0Hz,1H),7 .76(s,1H),7.41(d,J=11.4Hz,1H),5.00(d,J=5.4Hz,1H),4.78(t,J=5.6Hz,1H),4.53– 4.47(m,1H),4.20(dd,J=14.2,3.7Hz,1H),4.02(dd,J=14.0,7.9Hz,1H),3.87–3.79(m, 1H),3.41–3.36(m,2H),2.47(s,3H),2.34(s,3H),1.45–1.39(m,2H),1.33–1.27(m,2H).

[0802] Example 72 (Compound 192)

[0803] Step 1: Synthesis of compound 192a

[0804] Compound 118a (2.0 g, 10.86 mmol) was added to a solution of 1-cyclopropyl-2-bromoethylone (2.3 g, 14.12 mmol) and potassium carbonate (3.0 g, 21.72 mmol) in N,N-dimethylformamide (20 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at 50 °C for 15 hours. After the reaction was complete, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 192a (1.67 g). MS m / z (ESI): 267.1 [M+H] + .

[0805] Step 2: Synthesis of compound 192b

[0806] At 0°C, sodium hydrogen (308.4 mg, 7.71 mmol) was added to a mixed solution of trimethyl sulfoxide (1.7 g, 7.71 mmol) in dimethyl sulfoxide and tetrahydrofuran (10 mL / 10 mL). After the addition was complete, the mixture was stirred at room temperature for 0.5 hours. Then, a tetrahydrofuran solution (10 mL) of compound 192a (1.37 g, 5.14 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for another 15 hours. After the reaction was complete, the reaction mixture was quenched with water (20 mL). The reaction mixture was extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 192b (0.9 g, 40% purity). MS m / z (ESI): 181.1 [M+H] + .

[0807] Step 3: Synthesis of compound 192c

[0808] At room temperature, cesium carbonate (0.65 g, 2 mmol) was added to a solution of compound 192b (900 mg, 2.00 mmol, 40% purity) in N,N-dimethylformamide (10 mL). After the addition was complete, the mixture was stirred at 100 °C for 15 hours. After the reaction was complete, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 192c (200 mg). MS m / z (ESI): 181.1 [M+H] + .

[0809] Step 4: Synthesis of compound 192d

[0810] At 0 °C, N-bromosuccinimide (44.9 mg, 0.25 mmol) was added to a solution of compound 192c (50 mg, 0.28 mmol) in acetonitrile (2 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1–3 / 1) to give compound 192d (50 mg). MS m / z (ESI): 258.9, 260.9 [M+1, M+3] + .

[0811] Step 5: Synthesis of compound 192e

[0812] At room temperature, pinacol borane (790.3 mg, 6.18 mmol), palladium dichloride bis(triphenylphosphine) (216.7 mg, 0.31 mmol), and triethylamine (1.3 mL, 9.26 mmol) were sequentially added to a 1,4-dioxane (10 mL) solution of compound 192d (800 mg, 3.09 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 192e (400 mg). MS m / z (ESI): 307.1 [M+1] + .

[0813] Step 6: Synthesis of compound 192f

[0814] At room temperature, compound 192e (400 mg, 0.65 mmol), Pd(dppf)Cl2 (47.8 mg, 0.065 mmol), and potassium carbonate (270.8 mg, 1.96 mmol) were added to a mixed solution of compound 1a (197.7 mg, 0.72 mmol) in 1,4-dioxane and water (5 mL / 1 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0-50%) to give compound 192f (40 mg). MS m / z (ESI): 375.04 [M+1] + .

[0815] Step 7: Synthesis of Compound 192

[0816] At room temperature, a 2M trimethylaluminum solution in n-hexane (0.08 mL, 0.16 mmol) was added dropwise to a toluene (1 mL) solution of compound 192f (20 mg, 0.053 mmol) and compound 1d (16.3 mg, 0.064 mmol). The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate (1 g), filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15-60%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm) to obtain compound 192 (3.04 mg). MS m / z (ESI): 581.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.52(s,1H),8.39(s,1H),8.28(d,J=7.2Hz,1H) ,7.86(d,J=10.2Hz,1H),7.81(s,1H),5.10(s,1H),4.57–4.49(m,1H),4.39(d,J=11.2H z,1H),4.22(d,J=9.0Hz,1H),4.14(d,J=12.2Hz,1H),3.90(d,J=10.8Hz,1H),1.45–1. 39(m,2H),1.35–1.22(m,2H),0.95–0.85(m,1H),0.55–0.47(m,2H),0.41–0.34(m,2H).

[0817] Example 73 (Compound 146)

[0818] Step 1: Synthesis of Compound 146

[0819] Under ice bath conditions, a 2M solution of trimethylaluminum in n-hexane (0.12 mL, 0.24 mmol) was added dropwise to a 5 mL solution of compound 116a (30 mg, 0.083 mmol) and compound 73e (17.8 mg, 0.083 mmol) in toluene. The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and preparative high-performance liquid chromatography (Agilent Pursuit XRs column). C18 column (5µm, 250*30mm); mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 43mL / min; wavelength: 214nm; column pressure: 80bar) was used to purify compound 146 (3.31mg). MS m / z (ESI): 532.0 [M+1] +1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),8.56(s,1H),8.34(s,1H),8.11(d,J=1.6Hz,1H),7.83(dd,J=7.9,1.7Hz,1H),7.47(d,J=8.0Hz,1H) ,4.69(s,1H),4.50–4.44(m,1H),3.95(s,2H),2.39(s,3H),2.35(s,3H),2.26(s,3H),1.44–1.39(m,2H),1.31–1.25(m,2H),1.15(s,6H).

[0820] Example 74 (Compound 193)

[0821] Step 1: Synthesis of Compound 193

[0822] At room temperature, trimethylaluminum (2M n-hexane solution, 0.08 mL, 0.16 mmol) was added dropwise to a toluene (1 mL) solution of compound 192f (20 mg, 0.053 mmol, synthesis method as described in Example 72, Synthesis of Compound 192f) and compound 143e (15 mg, 0.064 mmol). The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with sodium sulfate decahydrate (1 g), filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-65%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm) to obtain compound 193 (3.04 mg).

[0823] MS m / z(ESI): 562.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.04 (d, J = 7.0Hz, 1H), 7.8 1(s,1H),7.41(d,J=11.4Hz,1H),5.10(s,1H),4.55–4.47(m,1H),4.39(d,J=11.2Hz,1H), 4.22(d,J=9.0Hz,1H),4.14(d,J=12.4Hz,1H),3.90(d,J=11.0Hz,1H),2.34(s,3H),1.44– 1.38(m,2H),1.34–1.27(m,2H),0.96–0.87(m,1H),0.53–0.47(m,2H),0.42–0.33(m,2H).

[0824] Example 75 (Compound 181)

[0825] Step 1: Synthesis of compound 181b

[0826] At 0°C, methanesulfonyl chloride (0.33 mL, 4.30 mmol) was added to a solution of compound 181a (200 mg, 1.72 mmol) and triethylamine (0.7 mL, 5.17 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 181b (468 mg), which was used directly in the next step.

[0827] Step 2: Synthesis of compound 181c

[0828] Compound 181b (388.7 mg, 1.43 mmol) was added to a solution of compound 125a (120 mg, 1.43 mmol) and potassium carbonate (591.7 mg, 4.28 mmol) in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture was stirred at 100 °C for 18 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 181c (80 mg). MS m / z (ESI): 165.2 [M+1] + .

[0829] Step 3: Synthesis of compound 181d

[0830] At room temperature, potassium carbonate (202 mg, 1.46 mmol), potassium ferricyanide (802 mg, 2.44 mmol), and potassium osmium (VI) dihydrate (3.6 mg, 0.01 mmol) were added sequentially to a tert-butanol and water (2 mL / 2 mL) mixture of compound 181c (80 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 181d (90 mg). MS m / z (ESI): 199.2 [M+1] + .

[0831] Step 4: Synthesis of compound 181e

[0832] At room temperature, NBS (80.8 mg, 0.45 mmol) was added to a 2 mL solution of compound 181d (90 mg, 0.45 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was directly concentrated and mixed. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 181e (120 mg). MS m / z (ESI): 277.1, 279.1 [M+1, M+3] + .

[0833] Step 5: Synthesis of compound 181f

[0834] At room temperature, bis(triphenylphosphine) palladium dichloride (203 mg, 0.29 mmol), triethylamine (1.2 mL, 8.66 mmol), and pinacol borane (1.8 g, 14.434 mmol) were added sequentially to a 1,4-dioxane (10 mL) solution of compound 181e (800 mg, 2.89 mmol). The reaction mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give compound 181f (380 mg). MS m / z (ESI): 325.1 [M+1] + .

[0835] Step 6: Synthesis of compound 181g

[0836] At room temperature, compound 1a (322 mg, 1.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (86 mg, 0.12 mmol), and sodium carbonate (373 mg, 3.52 mmol) were added sequentially to a mixed solution of compound 181f (380 mg, 1.17 mmol) in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give compound 181 g (20 mg). MS m / z (ESI): 392.9 [M+1] + .

[0837] Step 7: Synthesis of Compound 181

[0838] Under ice bath conditions, a 2M trimethylaluminum solution in n-hexane (0.05 mL, 0.1 mmol) was added to a toluene (2 mL) solution of compound 181 g (10 mg, 0.025 mmol) and compound 143e (6 mg, 0.025 mmol). The reaction mixture was heated to 100 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agilent 1290 HPLC C18 5 μm, 250*30 mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 181 (0.52 mg). MS m / z (ESI): 579.9 [M+1] + .

[0839] Example 76 (Compound 195)

[0840] Step 1: Synthesis of Compound 195

[0841] Under ice bath conditions, a 2M trimethylaluminum solution in n-hexane (0.05 mL, 0.1 mmol) was added to a solution of compound 181 g (10 mg, 0.025 mmol; the synthesis method of 181 g is as described in Example 75, Synthesis of Compound 181 g) and compound 1d (6 mg, 0.025 mmol) in toluene (2 mL). The reaction mixture was heated to 100 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agilent 1290 HPLC C18 5 μm, 250*30 mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 195 (4.80 mg). MS m / z (ESI): 599.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.52(s,1H),8.37(s,1H),8.27(d,J=7.2Hz,1H),7.85(d,J=10.1Hz,1H),7.81(s,1H),5.40(s,1H),4.89(s,1 H),4.57–4.48(m,1H),4.45–4.38(m,2H),4.31(d,J=12.8Hz,1H),3.93(d ,J=12.2Hz,1H),1.47–1.39(m,2H),1.35–1.28(m,2H),1.26–1.17(m,6H).

[0842] Example 77 (Compound 184)

[0843] Step 1: Synthesis of compound 184b

[0844] At room temperature, triethylamine (3.16 mL, 22.70 mmol) and p-toluenesulfonyl chloride (2.84 g, 11.12 mmol) were added sequentially to a dichloromethane (10 mL) solution of compound 184a (1 g, 11.35 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-33%) to give compound 184b (320 mg).

[0845] Step 2: Synthesis of compound 184c

[0846] At room temperature, DIEA (1.16 g, 9.00 mmol) and SEMCl (1.13 g, 6.75 mmol) were added sequentially to a dichloromethane (10 mL) solution of compound 53b (1 g, 4.50 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 184c (1.5 g). MS m / z (ESI): 353.1 [M+1] + .

[0847] Step 3: Synthesis of compound 184d

[0848] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (300 mg, 0.37 mmol), potassium carbonate (1.02 g, 7.38 mmol), and compound 184c (1.3 g, 3.69 mmol) were added sequentially to a mixed solution of compound 1a (910 mg, 3.32 mmol) in 1,4-dioxane / water (13 mL / 2.5 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 184d (900 mg). MS m / z (ESI): 421.0 [M+1] + .

[0849] Step 4: Synthesis of compound 184e

[0850] At 0 °C under a nitrogen atmosphere, a 2 M trimethylaluminum solution in n-hexane (0.48 mL, 0.95 mmol) was added to a toluene (2 mL) solution of compound 184d (200 mg, 0.48 mmol) and compound 143e (110.9 mg, 0.48 mmol). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 184e (160 mg). MS m / z (ESI): 607.9 [M+1] + .

[0851] Step 5: Synthesis of compound 184f

[0852] Compound 184e (160 mg, 0.26 mmol) was added to a 4 M solution of 1,4-dioxane hydrochloride (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was directly filtered to give compound 184f (120 mg). MS m / z (ESI): 477.9 [M+1] + .

[0853] Step 6: Synthesis of Compound 184

[0854] At room temperature, compound 184b (30.4 mg, 0.13 mmol) and cesium carbonate (81.9 mg, 0.25 mmol) were added sequentially to a 2 mL DMF solution of compound 184f (40 mg, 0.084 mmol). The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10–90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 184 (1.24 mg). MS m / z (ESI): 547.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.53(s,1H),8.33(s,1H),8.04(d,J=7.0Hz,1H),7.40(d,J=11.3Hz,1H),5.58(s,1H),4.55–4.47( m,1H),4.10(s,2H),2.41(s,3H),2.34(s,3H),2.25(s,3H),1.46–1.36(m,2H),1.33–1.26(m,2H),0.80–0.66(m,2H),0.66–0.51(m,2H).

[0855] Example 78 (Compounds 6-P1, 196-P1)

[0856] Step 1: Synthesis of compounds 6-P1,196-P1

[0857] Under ice bath conditions, trimethylaluminum (2M n-hexane solution, 0.37 mL, 0.74 mmol) was added dropwise to a toluene (5 mL) solution of 186 g of the mixture, 186 h of the mixture (90 mg, 0.25 mmol, synthesis method as described in step 2 of Example 67 of this application), and compound 1d of the mixture (57.6 mg, 0.25 mmol). The reaction mixture was stirred at 100 °C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane / methanol = 10 / 0-10 / 1) to obtain crude product, which was then resolved by chiral preparative chromatography (preparative column: Daicel Chiralpak IJ SFC 20mm ID*250mmL, 5μm; flow rate: 48mL / min; column temperature: room temperature; mobile phase: A:CO2 / MEOH[0.1%NH3 (7M Solution in MeOH)] = 60 / 40) to obtain compound 6-P1 (11.53mg) and compound 196-P1 (10.74mg).

[0858] 6-P1: SFC retention time: t = 6.642 min. MS m / z (ESI): 572.30 [M+1] + .

[0859] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.12 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 8.28 (d, J = 7.0Hz, 1H), 7.86 (d, J = 10.1Hz, 1H), 7.77 (s, 1H), 5.18 (d, J = 5.3Hz, 1H), 4.56–4.48 (m, 1H), 4.14–3.98 (m, 3H), 3.39–3.36 (m, 1H), 3.30 (s, 3H), 3.26 (d, J = 4.9Hz, 1H), 2.46 (s, 3H), 1.42 (d, J = 3.4Hz, 2H), 1.34–1.28 (m, 2H). 196-P1: SFC retention time: t = 10.073 min. MS m / z(ESI): 572.30 [M+1] + .

[0860] 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.56(s,1H),8.44(s,1H),8.28(d,J=7.2Hz,1H),8.07(s,1H),7.87(d,J=10.2Hz,1H),5.19(d,J=4. 9Hz,1H),4.54–4.50(m,1H),4.15–4.10(m,1H),4.02–3.94(m,2H),3.31–3.26(m,5H),2.37(s,3H),1.46–1.40(m,2H),1.33–1.27(m,2H).

[0861] Example 79 (Compound 191)

[0862] Step 1: Synthesis of compound 191b

[0863] At room temperature, DMF-DMA (1.33 g, 11.17 mmol) was added dropwise to a toluene (10 mL) solution of compound 191a (1 g, 5.59 mmol). After the addition was complete, the mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain compound 191b (1.3 g). The crude product was used directly in the next step. MS m / z (ESI): 233.9, 235.9 [M+1, M+3] + .

[0864] Step 2: Synthesis of compound 191c

[0865] Compound 191b (1.5 g, 9.66 mmol) was added to a solution of ethyl bromoacetate (2.14 g, 12.81 mmol) in toluene (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, a solid precipitated from the reaction mixture. This solid was directly filtered, and the filter cake was washed with acetonitrile (10 mL). The filter cake was then dried to give compound 191c (600 mg). MS m / z (ESI): 319.9, 321.9 [M, M+2] + .

[0866] Step 3: Synthesis of compound 191d

[0867] At room temperature, DBU (455.0 mg, 2.99 mmol) was added dropwise to a DMF (10 mL) solution of compound 191c (1 g, 4.13 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL × 2), and the combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 191d (300 mg). MS m / z (ESI): 274.9, 276.8 [M+1, M+3] + .

[0868] Step 4: Synthesis of compound 191e

[0869] At room temperature, compound 53c (213.9 mg, 0.73 mmol), cesium carbonate (355.3 mg, 1.09 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (29.8 mg, 0.036 mmol) were added sequentially to a mixed solution of compound 191d (100 mg, 0.36 mmol) in 1,4-dioxane and water (5 mL / 2 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was directly concentrated, and the residue was purified by thin-layer silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 191e (15 mg). MS m / z (ESI): 363.0 [M+1] + .

[0870] Step 5: Synthesis of Compound 191

[0871] At 0 °C and under a nitrogen atmosphere, a hexane solution of trimethylaluminum (2 M, 0.04 mL, 0.08 mmol) was added to a toluene (2 mL) solution of compound 1d (10 mg, 0.028 mmol) and compound 191e (8.4 mg, 0.033 mmol). After the addition was complete, the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and sodium sulfate decahydrate (1 g) was added to quench the reaction. The mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by reversed-phase preparative column chromatography (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-40%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm) to obtain the crude product, which was then purified by thin-layer chromatography on silica gel plates (methanol / dichloromethane = 1 / 20) to obtain compound 191 (3.0 mg). MS m / z (ESI): 569.9 [M+1] + .

[0872] Example 80 (Compound 197)

[0873] Step 1: Synthesis of Compound 197

[0874] At room temperature, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (5.7 mg, 0.009 mmol), cesium carbonate (57.2 mg, 0.18 mmol), and compound 197a (50.9 mg, 0.35 mmol) were added sequentially to a mixed solution of compound 53 (50 mg, 0.088 mmol, synthesized according to the method described in Example 2 for the synthesis of compound 53) in 1,4-dioxane / water (1 mL / 0.2 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 197 (16 mg). MS m / z (ESI): 552.9 [M+1] + .

[0875] 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.53(s,1H),8.34(s,1H),8.04(d,J=7.0Hz,1H),7.40(d,J=11.3Hz,1H),4.69( s,1H),4.53–4.44(m,1H),3.94(s,2H),2.38(s,3H),2.25(s,3H),1.44–1.38(m,2H),1.33–1.26(m,2H),1.15(s,6H).

[0876] Example 81 (Compound 200)

[0877] Step 1: Synthesis of Compound 200b. At room temperature, compound 200a (74.7 mg, 0.68 mmol), cesium carbonate (440.1 mg, 1.35 mmol), and potassium iodide (11.2 mg, 0.068 mmol) were added sequentially to a solution of compound 53b (150 mg, 0.68 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, no further treatment was required, and the process proceeded directly to the next step. MS m / z (ESI): 297.1 [M+1] + .

[0878] Step 2: Synthesis of compound 200c

[0879] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (55.3 mg, 0.068 mmol), cesium carbonate (440.0 mg, 1.35 mmol), compound 1a (222.9 mg, 0.81 mmol, synthesis method referred to page 183 of patent WO2022136509A1, synthesis of compound Intermediate A) were added sequentially to a mixed solvent of compound 200b (200 mg, 0.68 mmol) in N,N-dimethylformamide and water (3 mL / 0.6 mL). The reaction mixture was heated at 100 °C and stirred for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and extracted with ethyl acetate (20 mL). The organic phase was washed successively with water (30 mL × 3) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 200c (38 mg). MS m / z (ESI): 365.0 [M+1] + .

[0880] Step 3: Synthesis of Compound 200

[0881] At 0°C, a hexane solution of trimethylaluminum (2M, 0.082mL, 0.17mmol) was added to a toluene (1mL) solution of compound 200c (20mg, 0.055mmol) and compound 1d (16.7mg, 0.066mmol, for synthesis of compound intermediate 73, see page 170 of patent WO2024118887A1). The reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (1 mL), extracted with dichloromethane / methanol = 10 / 1 (30 mL), and the organic phase was washed successively with water (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Agilent 1290 HPLC C18 5 μm, 250*30 mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25℃; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 200 (1.83 mg). MS m / z (ESI): 571.8 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.57(s,1H),8.35(s,1H),8.28(d,J=7 .2Hz,1H),7.85(d,J=10.1Hz,1H),4.99–4.95(m,1H),4.78–4.73(m,1H),4.56 –4.47(m,1H),4.14–4.07(m,1H),4.01–3.87(m,1H),3.87–3.77(m,1H),3.69– 3.46(m,2H),2.36(s,3H),2.24(s,3H),1.44–1.40(m,2H),1.31–1.28(m,2H).

[0882] Example 82 (Compound 199-P2)

[0883] Step 1: Synthesis of compound 199-P2

[0884] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.17 mL, 0.34 mmol) was added to a toluene (4 mL) solution of compound 1d (21.8 mg, 0.086 mmol, synthesis method referred to page 170 of patent WO2024118887A1, synthesis of compound intermediate 73) and compound 176b (30 mg, 0.086 mmol, synthesis method referred to step 2 of Example 56, synthesis of compound 176b). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was quenched by adding sodium sulfate decahydrate (1 g). The mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), the combined filtrates were concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Agilent Pursuit XRs). C18 5um, 250*30mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 43mL / min; wavelength: 214nm; column pressure: 80bar) purification yielded compound 199-P2 (18mg). MS m / z (ESI): 555.9 [M+1] + .

[0885] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.57(s,1H),8.35(s,1H),8.28(d,J=7.2Hz,1H),7.85(d,J=10.1Hz,1H),4.92(d,J=4.8Hz, 1H), 4.54–4.49 (m, 1H), 4.02–3.87 (m, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.47–1.37 (m, 2H), 1.33–1.28 (m, 2H), 1.11 (d, J = 5.9Hz, 3H).

[0886] Example 83 (Compound 199-P1)

[0887] Step 1: Synthesis of compound 199-P1

[0888] Under an ice bath and nitrogen atmosphere, a 2M trimethylaluminum solution in n-hexane (0.23 mL, 0.46 mmol) was added to a toluene (2 mL) solution of compound 1d (58.2 mg, 0.23 mmol, synthesis method referred to page 170 of patent WO2024118887A1, synthesis of compound intermediate 73) and compound 176d (80 mg, 0.23 mmol, synthesis method referred to step 2 of Example 57, synthesis of compound 176d). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), the combined filtrates were concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-90%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 199-P1 (18.49 mg). MS m / z (ESI): 555.8 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.58(s,1H),8.35(s,1H),8.28(d,J=7.2Hz,1H),7.85(d,J=10.1Hz,1H),4.92(d,J=4.8Hz,1H),4.59 –4.47(m,1H),4.06–3.96(m,1H),3.95–3.81(m,2H),2.36(s,3H),2.25(s,3H),1.48–1.40(m,2H),1.33–1.26(m,2H),1.11(d,J=6.0Hz,3H).

[0889] Example 84 (Compound 198)

[0890] Step 1: Synthesis of Compound 198

[0891] At room temperature, compound 130d (100 mg, 0.22 mmol, synthesis method referred to step 3 of Example 24 for the synthesis of compound 130d), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (17.7 mg, 0.022 mmol) and cesium carbonate (211.4 mg, 0.65 mmol) were added to a mixed solution of 1,4-dioxane and water (5 mL / 1 mL) of compound 182a (71.4 mg, 0.24 mmol, synthesis method referred to step 1 of Example 63 for the synthesis of compound 182a). The reaction mixture was stirred at 100 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 198 (1.72mg). MS m / z (ESI): 555.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.53(s,1H),8.34(s,1H),8.04(d,J=7.1Hz,1H),7.40(d,J=11.3Hz,1H), 4.69(s,1H),4.53–4.45(m,1H),3.94(s,2H),2.34(s,3H),1.44–1.39(m,2H),1.32–1.27(m,2H),1.14(s,6H).

[0892] Example 85 (Compound 201-P1 / P2)

[0893] Step 1: Synthesis of compound 201a

[0894] Compound 53b (3 g, 13.51 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, followed by the addition of 1-cyclopropyl-2-bromoethylone (2.64 g, 16.21 mmol) and cesium carbonate (13.2 g, 40.52 mmol). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL), the cesium carbonate was removed by filtration, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0–15%) to give compound 201a (2.2 g). MS m / z (ESI): 305.1 [M+1] + .

[0895] Step 2: Synthesis of compound 201b

[0896] Compound 201a (2.7 g, 8.88 mmol) was dissolved in methanol (30 mL) at room temperature. After cooling to 0 °C, sodium borohydride (0.67 g, 17.75 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0–15%) to obtain compound 201b (2.54 g). MS m / z (ESI): 307.1 [M+1] + .

[0897] Step 3: Synthesis of compound 201c

[0898] At room temperature, compound 1a (300 mg, 1.090 mmol, synthesis method referred to page 184 of patent WO2022136509A1, synthesis of compound intermediate A) was dissolved in a mixed solvent of 1,4-dioxane and water (10 mL / 2 mL). Compound 201b (400.7 mg, 1.31 mmol), potassium carbonate (452.1 mg, 3.27 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (79.8 mg, 0.11 mmol) were added sequentially. Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0–10%) to give compound 201c (160 mg). MS m / z (ESI): 374.9 [M+1] + .

[0899] Step 4: Synthesis of compounds 201-P1 and 201-P2

[0900] Under ice bath conditions, a 2M trimethylaluminum solution in n-hexane (1.1 mL, 2.14 mmol) was slowly added dropwise to a 1,4-dioxane (5 mL) solution of compound 201c (160 mg, 0.43 mmol) and compound 1d (140.9 mg, 0.56 mmol, synthetic method referred to page 170 of patent WO2024118887A1 for the synthesis of compound intermediate 73). The reaction mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was added dropwise to sodium sulfate decahydrate solid for quenching, diluted with a mixture (dichloromethane / methanol = 10 / 1) (50 mL), filtered and concentrated to obtain compound 201, which was then resolved by SFC (Chiral HPLC; Column ID: IG; Method Filename: MeOH-DCM-DEA-80-20-0.1-20MIN) to obtain compound 201-P1 (27.95 mg) and compound 201-P2 (24.58 mg).

[0901] Compound 201-P1: MS m / z (ESI): 582.20 [M+1] + SFC retention time: 6.304 min;

[0902] 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.57(s,1H),8.34(s,1H),8.28(d,J=7.3Hz,1 H),7.85(d,J=10.1Hz,1H),4.91(d,J=5.2Hz,1H),4.58–4.44(m,1H),4.05(d,J=6.1 Hz,2H),3.29–3.25(m,1H),2.37(s,3H),2.24(s,3H),1.46–1.38(m,2H),1.33–1.28 (m,2H),0.89–0.82(m,1H),0.43–0.34(m,2H),0.32–0.25(m,1H),0.16–0.08(m,1H).

[0903] Compound 201-P2: MS m / z (ESI): 582.20 [M+1] + SFC retention time: 8.673 min;

[0904] 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.57(s,1H),8.34(s,1H),8.28(d,J=7.2Hz,1 H),7.85(d,J=10.1Hz,1H),4.91(d,J=5.2Hz,1H),4.58–4.44(m,1H),4.05(d,J=6.0 Hz,2H),3.29–3.23(m,1H),2.37(s,3H),2.24(s,3H),1.46–1.39(m,2H),1.33–1.27 (m,2H),0.89–0.82(m,1H),0.44–0.35(m,2H),0.31–0.24(m,1H),0.15–0.08(m,1H).

[0905] Example 86 (Compound 202)

[0906] Step 1: Synthesis of Compound 202

[0907] At 0°C, a hexane solution of trimethylaluminum (2M, 0.083mL, 0.17mmol) was added to a toluene (1mL) solution of compound 191e (20mg, 0.055mmol, synthesis method referred to step 4 of Example 79 for the synthesis of compound 191e) and compound 143e (15.5mg, 0.066mmol). The reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (1 mL), extracted with dichloromethane / methanol (30 mL, 10 / 1), and the organic phase was washed successively with water (10 mL) and saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Agilent 1290 HPLC C18 5 μm, 250*30 mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25 °C; flow rate: 43 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 202 (6.71 mg). MS m / z (ESI): 549.9 [M+1] + .

[0908] 1H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.21(s,1H),8.12(s,1H),8.03(d,J=7.0Hz,1H),7.42(d,J=11.4Hz,1H),4.68(s,1H) ,4.53–4.46(m,1H),3.94(s,2H),2.36(s,3H),2.34(s,3H),2.23(s,3H),1.42–1.38(m,2H),1.31–1.27(m,2H),1.13(s,6H).

[0909] Example 87 (Compound 203)

[0910] Step 1: Synthesis of compound 203a

[0911] Compound 184c (100 mg, 0.24 mmol, synthesis method as described in step 2 of Example 77) was dissolved in a mixed solvent of trifluoroacetic acid (1 mL) and dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was neutralized with saturated sodium bicarbonate (50 mL) solution, extracted with ethyl acetate (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 203a (60 mg). MS m / z (ESI): 291.0 [M+1] + .

[0912] Step 2: Synthesis of compound 203c

[0913] At room temperature, compound 203a (60 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of compound 203b (29.8 mg, 0.41 mmol) and cesium carbonate (202 mg, 0.62 mmol). The reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL) and washed with water (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 203c (70 mg). MS m / z (ESI): 363.0 [M+1] + .

[0914] Step 3: Synthesis of Compound 203

[0915] Compound 203c (35 mg, 0.097 mmol) was dissolved in 1,4-dioxane (3 mL), followed by compound 1d (24.5 mg, 0.097 mmol, synthetic method referred to page 170 of patent WO2024118887A1, synthesis of compound intermediate 73). Under nitrogen protection, a 2M trimethylaluminum solution (0.2 mL, 0.39 mmol) in n-hexane was added dropwise in an ice bath. The reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was quenched dropwise in sodium sulfate decahydrate solid, diluted with a mixture (dichloromethane / methanol = 10 / 1) (20 mL), filtered, and the filtrate was concentrated. The residue was purified by preparative high-performance liquid chromatography (HPLC) (equipment: Agilent 1290 HPLC; column: Agilent ZORBAX SB-C18). Compound 203 (5...

Claims

1. A compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein A is a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl; T is X is O, S or NR 0 ; Y is CR 0 or N; R 0 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 1 selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl are optionally substituted with 1 or more R A ; R A the same or different, each independently is selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with 1 or more R g substituents; or, 2 R A with the atom to which it is attached forming C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more of halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R g the same or different, each independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxyl, halogen, oxo, cyano, amino and C 1-6 hydroxyalkyl; R 2 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Each R 3 Whether the groups are the same or different, they are independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Each R 4 Whether the groups are the same or different, they are independently selected from H, halogen, cyano, oxo, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl, 5-10 quinone heteroaryl or The C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a and R b are the same or different, each being independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 5 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy, said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy optionally substituted by one or more substituents selected from -OP(O)(OR k )2, -OS(O)(OR k ) and -OS(O)(OR k )2; R k is H or C 1-6 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3; q is 1, 2 or 3; the heteroatoms in the heterocyclyl or heteroaryl are selected from O, N and S, in a number of 1, 2, 3 or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula (IG), which satisfies one or more of the following conditions: (1) T is (2) R 2 is halogen or H; (3) For Right end with R 4 Connection; (4) R 4 selected from H, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or The C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-8 cycloalkyl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a and R b are the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; p is 1 or 2; q is 1 or 2; (5) For (6) R 3 H, halogen, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; (7) R 5 is H or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents selected from -OP(O)(OH)2, -OS(O)(OH), and -OS(O)(OH)2; (8) R 1 For R A1 , R A2 , and R A3 are the same or different, each being independently selected from H, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 1-6 alkyl being optionally substituted with 1 or more R g ; R g selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxy, halogen, cyano and C 1-6 hydroxyalkyl; or R A1 and R A2 , R A1 and R A3 any one of which groups, together with the atom to which it is attached, form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, each of which C 3-8 cycloalkyl or 3-8 membered heterocyclyl groups is independently optionally substituted with one or more selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

3. The compound of claim 1 having the formula (IG) ###0002### or a pharmaceutically acceptable salt thereof. which satisfies one or more of the following conditions: (1) For R 4 , R 4A , and R 4B are the same or different, and are independently selected from H, halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; (2) R 1 selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, and 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl is optionally substituted with 1 or more R A substituents; R A selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl is optionally substituted with 1 or more R g substituents; or, 2 R A with the atom to which it is attached forming C 3-8 cycloalkyl or 3-12 membered heterocyclyl, C 3-8 cycloalkyl or 3-12 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R g selected from deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxyl, halogen, oxo, cyano, amino, and C 1-6 hydroxyalkyl.

4. The compound of claim 1 of the formula (IG) or a pharmaceutically acceptable salt thereof, wherein The compound represented by the formula (IG) is a compound represented by the formula (II) or the formula (III), R 4 selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or The C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a and R b are the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; p is 1, 2 or 3; q is 1, 2 or 3; R 1 , R 3 and n are as defined in claim 1.

5. The compound of claim 1 having the formula (IG) ###0005### or a pharmaceutically acceptable salt thereof. which is any one of the following schemes: Scheme 1: R A selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with 1 or more R g substituents; or, 2 R A with the atom to which it is attached forming C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R g selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxyl, halogen, oxo, cyano, amino, and C 1-6 hydroxyalkyl; R 2 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Each R 3 Whether the groups are the same or different, they are independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Scheme 2: X is O, S or NH; Scheme Three: R 1 is selected from H, halo, cyano, hydroxy, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl optionally substituted with 1 or more R A substituents; Each R 4 Whether the groups are the same or different, they are independently selected from H, halogen, cyano, oxo, and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl, 5-10 quinone heteroaryl or The C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R A , R a and R b are as defined in claim 1 ; Scheme 4: Compounds of formula (IG) are compounds of formula (I), R 1 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl optionally substituted with 1 or more R A substituents; R A selected from halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with 1 or more R g substituents; or, 2 R A with the atom to which it is attached forming C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 3-8 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R g selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxy, halogen, oxo, cyano, amino and C 1-6 hydroxyalkyl; Scheme 5: A is a 5-membered heteroaryl; R 1 selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl optionally substituted with 1 or more R A substituents; R A selected from halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with 1 or more R g substituents; or, 2 R A with the atom to which it is attached forming C 3-8 cycloalkyl or 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R g selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more selected from hydroxy, halogen, oxo, cyano and amino; Scheme 6: For R 4 selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl is independently optionally substituted with one or more selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

6. The compound of claim 1 or 2 of the formula (IG) or a pharmaceutically acceptable salt thereof, wherein which is any one of the following schemes: (1) R 1 H, Cl, Br, methyl, (2) R 2 is H; (3) R 3 is fluorine, chlorine, methyl, deuterated methyl, halogenated methyl or cyano; (4) R 4 is C 1-6 alkyl or C 3-8 cycloalkyl, each independently optionally substituted with one or more selected from the group consisting of halo and hydroxy; and 1-6 alkyl and C 3-8 cycloalkyl, each independently optionally substituted with one or more selected from the group consisting of halo and hydroxy; and (5) R 5 is H.

7. The compound of claim 1 having the formula (IG) ###0007### or a pharmaceutically acceptable salt thereof. Any one of the following compounds:

8. The compound of claim 1 having the formula (IG) ###0006### or a pharmaceutically acceptable salt thereof. Any one of the following compounds:

9. A pharmaceutical composition, characterized by, which comprises at least one therapeutically effective amount of a compound of formula (IG) as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. Use of a compound of formula (IG) as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, for the manufacture of a medicament for inhibiting c-kit, and / or, for the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease.

11. Use of a compound of formula (IG) as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, for the manufacture of a medicament for preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension or a cancer, for example for preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease or diabetes.

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